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Источник: https://m.cafe.daum.net/panicbird/QzZ4/162?listURI=%2Fpanicbird%2FQzZ4

El periodista Juan Carlos Andara fue encontrado muerto en su casa en Puerto Cortés; más de medio centenar de comunicadores han sido ultimados en Honduras desde 2002 a la fecha y muchos casos no se han esclarecido.

Redacción Central / EL LIBERTADOR

Tegucigalpa.Con al menos 15 puñaladas en su cuerpo, fue encontrado el cadáver del comunicador hondureño, Juan Carlos Andara, la noche del 22 de junio en su casa, en Barrio El Porvenir de Puerto Cortés, al norte de Honduras.

Con este crimen, sólo en 2015 suman seis muertes de comunicadoresy trabajadores de medios de comunicación en Honduras. 

El comunicador laboraba para el Canal Teleport de Puerto Cortés, en su página de Facebook, la radiodifusora informó que “la noche de ayer se hizo el reconocimiento de quien en vida fue Juan Carlos Andara, un compañero de trabajo en esta casa televisora en la cual laboró por mucho años, Canal Teleport se une al dolor de la familia de Juan Carlos Andara que Dios lo tenga en su santa Gloria. Q.D.D.G (sic)”.

Diario Tiempo informó que “de acuerdo al reporte preliminar, el comunicador fue encontrado muerto en su casa sobre su cama, con al menos 15 puñaladas en su cuerpo”, indica esta publicación.

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Con esta, sumarían 56 muertes de comunicadores y trabajadores de medios de comunicación, registradas por C-Libre. Tres sucedieron entre 2003 y 2008 y 53, desde 2009 a la fecha.

Sólo en 2015 ya suman seis muertes de comunicadores y trabajadores de medios: el locutor, Franklin Johan Dubón; el camarógrafo, Cristel Joctan López Bermúdez; el comunicador Artemio Deras; el operador Erick Arriaga y el periodista Carlos Fernández, de acuerdo con el registro de datos del Comité por la Libre Expresión. (Fuente: C-Libre)

Источник: http://www.web.ellibertador.hn/index.php/noticias/nacionales/202-matan-a-punaladas-a-periodista-en-el-norte-de-honduras
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ecancermedicalscience

Pan Pantziarka1,2, Gauthier Bouche1, Vidula Sukhatme3, Lydie Meheus1, Ilse Rooman1,4 and Vikas P Sukhatme3,5

1Anticancer Fund, Brussels, 1853 Strombeek-Bever, Belgium

2The George Pantziarka TP53 Trust, London, UK

3GlobalCures, Inc, Newton MA 02459, USA

4Oncology Research Centre, Vrije Universiteit Brussel, 1090 Brussels, Belgium

5Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA

Correspondence to: Pan Pantziarka. Email: pan.pantziarka@anticancerfund.org

Abstract

Propranolol (PRO) is a well-known and widely used non-selective beta-adrenergic receptor antagonist (beta-blocker), with a range of actions which are of interest in an oncological context. PRO displays effects on cellular proliferation and invasion, on the immune system, on the angiogenic cascade, and on tumour cell sensitivity to existing treatments. Both pre-clinical and clinical evidence of these effects, in multiple cancer types, is assessed and summarised and relevant mechanisms of action outlined. In particular there is evidence that PRO is effective at multiple points in the metastatic cascade, particularly in the context of the post-surgical wound response. Based on this evidence the case is made for further clinical investigation of the anticancer effects of PRO, particularly in combination with other agents. A number of trials are on-going, in different treatment settings for various cancers.

Keywords:Propranolol, beta-blockers, drug repurposing, ReDO project

Copyright: © the authors; licensee ecancermedicalscience. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Published: 12/10/2016; Received: 06/06/2016

Introduction

Propranolol (PRO) is a commonly used non-selective beta-adrenergic receptor antagonist used in the treatment of hypertension, angina, anxiety, cardiac arrhythmia, hyperthyroidism, essential tremor and as a prophylaxis against migraine, variceal bleeding and myocardial infarction. First developed in the 1960s, the drug is now available globally in generic form droid transfer activation key free - Crack Key For U is on the WHO List of Essential Medicines. The drug is available in both standard and extended-release tablet formulations, as an oral solution and also as intravenous injection. Common trade names include Inderal, Angilol, Syprol, Ciplar. A special oral formulation, (Hemangiol in Europe, Hemangeol in the USA), has also been licensed by the EMA and FDA, for the treatment of infantile hemangioma. There is also clinical trial data supporting the off-label use of PRO in a number of conditions, including haemorrhage, sepsis and hypermetabolic syndrome associated with severe burns [1], akathisia associated with Alzheimer’s disease or psychosis [2], and aggression associated with brain injury or disease [3].

In addition to clinical use in these varied indications there is accumulating evidence that propranolol has potent anti-cancer effects, as evidenced by in vitro, in vivo and a range of clinical data.

Current Usage

Dosage

The PRO dose varies by indication. The anti-hypertensive dose is in the range 160 – 320 mg/day, starting at 80 mg and increasing as required to a maintenance dose that is generally 160 mg – 240 mg, in divided doses or as once a day use of extended release tablets. For angina the dose is 120 – 240 mg/day. Migraine prophylaxis is in the range 80 – 240 mg/day [4]. The dose in infantile hemangioma is 1 mg/kg/day for 1 week, then 2 mg/kg/day for 1 week and then 3 mg/kg/day as a maintenance dose for 6 months.

Toxicity

Common side effects include insomnia, fatigue, cold extremities and Raynaud’s syndrome. Less common side effects include nausea, vomiting, diarrhoea. Rarely PRO is associated with heart failure, heart block, hypotension, worsening of symptoms in psoriasis, asthma and psychosis. In general the initiation of PRO may lead to initial, mild adverse effects which resolve during dose titration to a maintenance dose. Sudden termination of treatment is not advised, particularly for patients suffering ischaemic heart disease – in such cases the dose should be tapered rather than stopped abruptly. In general however, PRO has a good toxicology profile and can be used for long-term treatments of many years duration [5].

PRO is contra-indicated in patients suffering from hypotension, asthma, uncontrolled heart failure, severe peripheral artery disease, metabolic acidosis and cardiogenic shock. It is not recommended in pregnancy and during lactation.

Pharmacokinetics

PRO is highly lipophilic and undergoes rapid absorption in the gastrointestinal tract and more than 90% undergoes plasma protein absorption. Excretion is primarily renal, though 1 – 4% of an oral or IV dose of the drug appears in faeces as unchanged drug and metabolites [6]. There is wide distribution to tissues, particularly lungs, liver, kidneys, and heart. Bioavailability after oral dosing is in the range 25 – 35% due to extensive first-pass hepatic clearance, although there is considerable inter-patient variability [7]. Bioavailability can be increased by concomitant food intake, with a mean increase of around 50% reported when taken after a protein-containing meal, however other parameters (time to maximum concentration, half-life etc.) are unchanged [8].

Peak plasma concentrations occur 1.5 – 3 hours following oral dosing, with a plasma half-life of around 4 hours following single dose or around 10 hours for extended release tablets. Mean peak plasma concentration following a single oral dose of 40 mg, in fasting conditions, is 38 ng/ml (0.12 μM) [9]. A single oral dose of 160 mg produced a peak in the range 200 – 245 ng/ml (0.77 – 0.96 μM), while the extended release tablets produced a peak in the range 18 – 50 ng/ml (0.07 – 0.19 μM) [10]. PRO crosses the blood brain barrier [11]. There is some evidence that the effects of PRO are dependent on the plasma concentrations that are achieved, including in the treatment of rare benign tumours in children [12].

Hepatic metabolism of PRO involves multiple pathways in the cytochrome P450 system (CYP2D6, 1A2 and 2C19), and therefore a range of drug interactions are possible [4, 6]. For example, concurrent cimetidine increased the area under the curve (AUC) and doubled peak plasma levels of PRO [13].

Caution is advised when PRO is used with calcium-channel blocking drugs, particularly IV verapamil, in patients with severe cardiomyopathy, congestive heart failure, or recent myocardial infarction due to the negative inotropic and chronotropic action of these drugs [14].

Pre-clinical Evidence in Cancer - In Vitro and In Vivo

Investigation of the possible anticancer properties of PRO began in the late 1970s, primarily with regards to elucidating the roles of catecholamines in carcinogenesis and in identifying beta-adrenergic receptor binding sites in different tissues [15–17].

Leukaemia

One of the first findings that PRO may be of some benefit in cancer treatment was reported by Ramu et al, who, in 1984, published a report that looked at the activity of a range of drugs in reversing in vitro drug resistance in the P388/ADR murine leukaemia cell line [18]. PRO was shown to have moderate effects in restoring sensitivity to doxorubicin in P388/ADR cells, but showed no evidence of additional effects in the parental P388 cell line. Similarly, Tsuruo et al showed that 10 μM of PRO significantly (P < 0.05) enhanced the cytotoxicity of vincristine and doxorubicin in resistant P388/VCR and P388/ADR cell lines respectively [19]. Other investigators have also reported similar effects in reversing resistance in multi-drug resistant human epidermoid KB carcinoma cell lines [20].

Hajighasemia and Mirshafiey investigated the cytotoxicity of Easy Cut Studio License key against Molt-4 and Jurkat human leukaemia and the U937 monocyte cell lines [21]. They showed that the viability of all three cell lines was dose- and time-dependently reduced by PRO above concentrations of 200 μM.

An investigation by Lamkin et al in a murine model of acute lymphoblastic leukaemia (ALL) found that chronic stress enhanced tumour growth and dissemination and that the effect could be inhibited by PRO [22]. PRO has also been shown to inhibit the expression of the tissue remodelling factor matrix metalloproteinase-2 (MMP-2) and the pro-angiogenic vascular endothelial growth factor (VEGF) in human leukaemia cell lines [23].

Breast

Shakhar and Ben-Eliyahu reported on the influence of beta adrenergic agonists and antagonists on natural killer (NK) cell number and activity in F344 rats inoculated with highly metastatic MADB106 syngeneic mammary adenocarcinoma cells [24]. Injection of the beta-adrenergic agonist metaproterenol (MP) led to a transient increase in NK cell numbers which returned to baseline within one hour; however, there was a concomitant decrease in NK activity over the same period. The beta-adrenergic antagonists nadolol and PRO were able to suppress these effects. Furthermore, treatment with MP was associated with a 10-fold increase in the number of injected tumour cells retained in the lungs 1-day post-inoculation, and a corresponding increase in pulmonary metastatic lesions three-weeks post-inoculation. These effects were dose-dependent and reversible by co-treatment with the non-selective beta-blocker nadolol.

Benish et al investigated the effect of inhibiting cyclo-oxygenase-2 (COX-2) and of blocking beta-adrenergic receptors on post-surgical immune function and metastatic tumour growth [25]. F344 rats underwent laparotomy and were injected with syngeneic MADB106 cells. Rats pre-treated with COX-inhibitors (SC560, indomethacin, etodolac, or celecoxib) or vehicle were compared to non-surgically treated controls to assess the impact on tumour cell retention in the lungs (LTR), and it was shown that all surgically treated animals had an elevated rate of LTR compared to non-surgically treated, but that COX-2 inhibition (indomethacin, etodolac, WinDataReflector License key celecoxib, administered one hour prior to surgical incision) significantly attenuated the increase compared to the vehicle treated group. Other experiments combined etodolac and PRO, (both administered one hour prior to incision), and again showed that LTR was reduced by either treatment alone and in combination, and that chronic and acute treatment had similar outcomes. Finally, it was shown that surgery was also associated with reduced NK cell cytotoxicity, which could also be reversed by the combination of etodolac and PRO. Subsequent work by the same group reproduced similar results and additionally showed that combination treatment with the immunostimulant CpG-C increased the effect of the PRO etodolac combination [26].

The effect of sympathetic nervous system signalling was investigating in a murine breast cancer model by Sloan et al [27]. BALB/c mice were subjected to two hours per day of restraint, shown previously to induce catecholamine-mediated stress, or control conditions for five days prior to injection of syngeneic 66cl4 mammary carcinoma cells. Stressed animals showed reduced weight and a 38-fold increase in the rate of metastasis (P = 0.04), both in terms of increased number and size of metastases compared to unstressed controls. Increased stress was not associated with significant changes in primary tumour growth. PRO treatment had no effect on metastatic growth in control animals but completely inhibited the enhanced increase in metastases in stressed animals (P < 0.001). Others have also investigated the role of norepinephrine in the metastatic process and reported a similar anti-metastatic activity of PRO in murine models of breast cancer [28–29].

Having first ascertained that low concentrations of PRO and 5-FU or paclitaxel increased the anti-proliferative and anti-angiogenic effects of these standard chemotherapeutic drugs in a panel of cancer and non-cancer cell lines. Pasquier et al studied the in vivo effects of the combination in NMRI nude mice orthotopically injected with MDA-MB-231 human triple negative breast cancer cells [30]. PRO, at a dose of 10 mg/kg, with paclitaxel increased median survival by 79% compared to paclitaxel alone (P = 0.0005) and PRO with 5-FU increased median survival by 19% (P = 0.0005).

The role of beta-adrenergic signalling in breast cancer metastasis to the bone was investigated by Campbell et al [31]. In vitro experiments showed that beta-adrenergic signalling upregulated RANKL expression in osteoblasts and that this increased MDA-MB-231VU human mammary carcinoma cell migration. An in vivo model, using the same cell line in athymic mice, showed that chronic stress or exogenous beta-adrenergic agonist isoproterenol increased both the number and area of osteolytic lesions compared to controls and that PRO, supplied ad libitum (0.5 g/L) via drinking water, could reverse this increase (P < 0.05).

In HER2-amplified breast cancer, Liu et al investigated the role of catecholamines and PRO on resistance to trastuzumab [32]. After showing a strong association between trastuzumab-resistance and beta2 adrenergic signalling in patient tissue samples, they showed that the catecholamines epinephrine and isoproterenol antagonised the anti-proliferative effect of trastuzumab both in vitro and in vivo. Additionally they showed that PRO could inhibit this antagonist effect, and resensitise resistant cells, both in vitro and in a xenograft model (PRO dosed at 2 mg/kg).

Melanoma

The impact of psychosocial stress on cancer growth in two murine model of cancers was studied by Hasegawa and Saiki [33]. Groups of mice were housed in different conditions to simulate the effects of social crowding on growth of syngeneic tumours (B16 melanoma in C57BL/6 mice and Meth A fibrosarcoma in BALB/c mice). Three housing conditions were used – isolated, grouped and over-crowded – and the effect on tumour growth assessed. B16 melanoma growth rates were increased most in the order over-crowded, isolated and grouped animals. Additionally another over-crowded cohort was administered PRO, at a dose of 30 ppm from days -21 to 21 after tumour implantation. This cohort showed reduced tumour growth dynamics, with the initial growth rate lower than the grouped (non-stressed) cohort and was significantly lower than either of the stressed groups. Organ weight was also assessed and a negative correlation detected between thymic mass and tumour mass (P < 0.05). Repeated experiments compared the effects of over-crowding versus isolation in additional cohorts of melanoma-bearing C57BL/6 mice and in sarcoma-bearing BALB/c mice. Over-crowding was shown to be more strongly associated with increased tumour growth and thymic atrophy than isolation.

Dal Monte et al investigated the role of beta3 adrenergic receptors in melanoma growth and vascularisation [34]. In some of the in vitro experiments PRO was used alongside two selective beta3 adrenergic receptor antagonists, SR59230A and L-748,337. PRO, at a concentration of 10 μM, with and without exogenous norepinephrine, significantly reduced proliferation (P < 0.001) and increased apoptosis (P < 0.01) of B16F10 cells compared to controls. Wrobel and Le Gal also showed that PRO had significant effects on proliferation and apoptosis in vitro on a panel of melanoma cell lines at a high concentration of 100 μM [35]. In vivo experiments using both primary and metastatic human melanoma tumours transplanted into immunodeficient (Nod SCID Gamma) mice showed that PRO at an average dose of 1.7 mg/day, tumour volumes were significantly lower (P < 0.001) than in untreated controls.

Glasner et al investigated the effects of surgical intervention on survival in two syngeneic mouse models, and on the impact of pre-operative PRO and etodolac, a COX-inhibitor, on survival [36]. B16 melanoma-bearing C57BL/6J mice were administered PRO, etodolac, PRO etodolac, or vehicle 30-minutes prior to amputation and/or laparotomy. Treatment with either drug singly showed no statistically significant difference with vehicle in terms of survival for any of the surgical options, whereas combined PRO etodolac significantly improved survival rates (P = 0.0345). In a Lewis Lung carcinoma model mice were pre-treated with IL-12 or vehicle 24-hours prior to amputation, treatment groups were further subdivided and treated with PRO etodolac or vehicle prior to surgery. All treatment groups showed significant increases in survival rates, although there were no differences in effect sizes between IL-12, IL-12 PRO etodolac and PRO etodolac treatments.

Ovarian

Lutgendorf et al noted that ovarian cancer patients with greater levels of social isolation and distress had greater levels of serum VEGF, associated with increased angiogenesis, in contrast to patients with lower levels of social isolation [37]. Subsequent in vitro investigation using the SKOV3 and EG ovarian carcinoma cell lines showed that norepinephrine, epinephrine, isoproterenol (a nonspecific beta-adrenergic agonist), and cortisol enhanced the production of VEGF in both cell lines. Pre-treatment with PRO, at a concentration of 1 μM, abolished this increase in VEGF [38]. Later work showed that in a murine SKOV3 model PRO was able to reduce isoproterenol-induced tumour growth [39].

Subsequent investigation showed that surgical stress, from a wound distant from the implanted tumour, was associated with increased primary tumour growth rate and the multiplicity of metastases in a two murine ovarian cancer models (HeyA8 and SKOV3ip1) but not in beta-adrenergic receptor-negative RMG-II mice [40]. Treatment with PRO via micro-osmotic pump starting seven days prior to surgical intervention inhibited the post-surgical increase in tumour growth rate and reduced the number of metastatic nodules.

Angiosarcoma

In light of the positive clinical experience of PRO in the treatment of infantile hemangioma, most recently confirmed in a large multi-centre randomised controlled trial [41], and evidence of beta-adrenergic receptor expression in a range of vascular tumours [42], a number of investigators have explored the potential benefit of PRO. Stiles et al used in vitro and in vivo Keyword Researcher Pro13.152 Keygen - Free Activators of hemangioendothelioma and angiosarcoma to investigate the impact of beta-blockade with PRO on cell proliferation, migration and apoptosis [43]. Using a panel of canine angiosarcoma, murine angiosarcoma and murine hemangioendothelioma cell lines, it was shown that 25 μM of PRO inhibited proliferation in all lines compared to untreated controls (P < 0.05). At Virtual DJ Pro Crack 2021 + Serial Key Free Download [Latest] higher concentration of 100 μM, PRO induced apoptosis in all cell lines (P < 0.05), and showed synergistic action in cells treated with chemotherapy (cisplatin, busulfan, vincristine, or H2O2) with the exception of the murine hemangioendothelioma cell line. Finally, in a murine model of angiosarcoma PRO treatment at a dose of 20 mg/kg every 2 days led to a significant reduction of tumour growth compared to controls (tumour weight of 357 /-58 mg; N = 17 vs sham 984 /-92 mg; N = 15, P < 0.0001). Despite the reduction in tumour size, tumour sections from both sham and PRO conditions revealed active cell division, suggesting the need to employ combinatorial therapy with PRO.

Pasquier at al showed that immortalised and NRAS-transformed endothelial cells were sensitive to the anti-proliferative effects of PRO [44]. Furthermore, PRO was shown to have antagonistic or additive effects when combined with doxorubicin or paclitaxel, commonly used to treat angiosarcoma, but that the effect was synergistic in combination with vinblastine. In a 3D in vitro model BMST-Ras cells were allowed to form spheroids of ~600 μm in diameter before treatment was initiated. When used alone, 10 μM propranolol and 1 nM vinblastine significantly slowed down the growth of tumour spheroids, resulting in a 19 – 20% decrease in volume after 5 days of treatment as compared to untreated spheroids (P < 0.001). The combination of propranolol and vinblastine completely suppressed the growth of tumour spheroids, leading to a 59% decrease in volume after 5 days as compared to control spheroids (P < 0.001).

Neuroblastoma

Pasquier et al tested a panel of seven beta-adrenergic antagonists, alone and in combination with vincristine, on BE(2)-C and SHEP neuroblastoma cell lines in vitro [45]. Of the seven drugs tested the most potent anti-proliferative and anti-angiogenic agents were carvedilol, nebivolol and PRO. While these three agents did not significantly impact on the anti-cancer effects of a range of chemotherapeutics, they showed significant (P < 0.001) synergy with the vinca alkaloid vincristine. Similar results were obtained with vinblastine and paclitaxel, suggesting the effect was related to microtubule disruption. In vivo results, using a TH-MYCN transgenic mouse model of neuroblastoma, showed that PRO, at a dose of 50 mg/kg i.p., increased the rate of tumour regression induced by vincristine treatment (P < 0.05). Finally, analysis of survival times showed that mice treated with PRO and vincristine had a fourfold increase in median survival compared to treatment with vincristine alone (P < 0.0001). Carvedilol with vincristine seemed the most effective combination and resulted in sustained complete remission in one animal (of ten), which remained tumour-free until study completion (day 60).

A xenograft model of paediatric neuroblastoma, based on the BE(2)-C cell line, was used by Xu et al [46]. Animals with established tumours were treated with different doses of PRO – 2, 5 or 10 mg/kg – for nine days and compared to untreated controls. Animals were sacrificed on day 9 and tumour weights in the 2 mg/kg and 5 mg/kg groups were 36.6% (P < 0.002) and 34.4% (P < 0.005) lower than the control group. Tumour weights in the 10 mg/kg were 18.3% lower than control, a figure not statistically significant. Additional analyses showed that microvessel density (MVD) was lower in the treated groups than in controls (P < 0.01) and VEGF, MMP-2, and MMP-9 protein levels were significantly lower 5 mg/kg and 10 mg/kg groups (P < 0.05).

Wolter et al tested PRO against a panel of 15 neuroblastoma cell lines representing a range of genetic profiles [47]. PRO inhibited cell growth, reducing proliferation and viability, in all lines at IC50 values in the range 114 μM to 218 μM. It was also shown to be synergistic with SN-38, the active metabolite of irinotecan, with significantly reduced viability compared to treatment with either agent alone (P = 0.008 for PRO alone, P = 0.0009 for SN-38 alone). Using SK-N-AS cells in xenograft models, treatment with PRO at 2 mg/kg/day injected subcutaneously produced lower tumour volume at day 14 compared to controls, (P = 0.0246) and was associated with longer median survival (P = 0.0135).

Prostate

Work by Masur et al showed that norepinephrine, at a concentration of 10 μM, increased the migratory activity of PC3 human prostate carcinoma cells in vitro but had no influence on proliferation levels, and that PRO at the same dose significantly inhibited this increase [48]. Furthermore, athymic BALB/c mice injected with PC3 cancer cells were treated with norepinephrine, PRO or a combination, administered via micro-osmotic pumps, and the rate of primary and metastatic tumour growth was assessed. While neither treatment had significant effect on primary tumour growth, norepinephrine was associated with a significant increase (P = 0.014) in metastatic tumour growth compared to controls, and PRO treatment reduced metastatic tumour growth below controls (P = 0.009).

Brohée et al showed that in vitro PRO concentrations of 100 μM potentiated the anti-proliferative effect of rapamycin on human prostate cancer PC3 cells [49].

Pancreatic

Guo et al showed that PRO inhibited MMP-2, MMP-9 and VEGF in pancreatic cancer cell lines [50]. Zhang et al also reported that PRO was able to induce apoptosis in the PC-2 human pancreatic cancer cell line at concentrations of 100 μM [51], and reduce invasiveness in MIA PaCa-2 and BxPC-3 cell lines at the same concentration [52].

Kim-Fuchs et al used Panc-1 human pancreatic cancer cells to establish orthotopic tumours in BALB/c-Foxn1nu nude athymic mice [53]. Mice were subject to restraint or home cell conditions to mimic stress or control respectively. Stress, verified by changes in body weight and tissue catecholamine levels, was associated with an increased rate of pancreatic tumour growth by 11% ± 3 per day compared to control mice (P < 0.01) and increased tumour mass five-fold (7.5 mg ± 5 vs. 41 mg ± 13, P = 0.03). Additionally chronic stress was associated with metastatic spread in 50% of mice, compared to none in the controls. PRO treatment, via osmotic pump delivering 10 mg/kg/day, blocked the effect of stress on primary tumour growth (41 mg ± 13 vs. 21 mg ± 5), although there was no change in the metastatic rate in the time-frame of the experiment.

Partecke et al also investigated the impact OneSafe PC Cleaner Pro 7.3.0.4 Crack license key 2020 - Free Activators chronic stress on pancreatic cancer growth using C57BL/6 mice bearing orthotopic syngeneic 6606PDA tumours [54]. Stress was shown to be associated with immunosuppression and an increase in tumour angiogenesis and cancer cell invasion. Median survival in stressed mice was significantly reduced compared to unstressed control mice (52 days versus 66 days, P < 0.0058). Treatment with PRO, (given orally via drinking water using a concentration of 0.5 g/l of drinking water aiming at 30 – 60 mg/kg mouse/day), reduced tumour growth rates and increased survival compared to untreated controls (59 days versus 52 days in controls, P < 0.0058).

Colorectal

Masur et al investigated the effect of norepinephrine and PRO on the in vitro migratory activity of SW 480 colon carcinoma cells [55]. Where norepinephrine caused a dose dependent increase in the number of migrating cells above basal levels, treatment with PRO at the same concentrations (1 μM, 10 μM and 100 μM) abolished this increase. In contrast treatment with the selective beta1 adrenoreceptor antagonist atenolol did not interfere with the norepinephrine-induced increase in migratory cell numbers. Similarly, Coelho et al explored the impact of a number of beta adrenergic receptor agonists and antagonists on the proliferation of HT-29 colon adenocarcinoma cells [56] and reported the IC50 of PRO as 65.4 μM.

Chin et al also investigated the effect of selective beta2-adrenergic receptor antagonists, including PRO, in a panel of colorectal cancer cells lines [57]. They showed that PRO significantly inhibited the viability of SW620, Colo205, and HT29 cells (IC50 119.5, 86.38, and 69.1 μM, respectively). PRO induced G1-phase arrest and apoptosis in affected cell lines.

Lin et al showed that chronic restraint stress promoted tumour growth in xenograft models of colorectal cancer, and that this effect could be blocked, in vivo, using PRO at a dose of 2 mg/kg [58].

Head and Neck

Yang et al investigated the effects of norepinephrine on nasopharyngeal carcinoma cell lines (HONE-1, HNE-1, and CNE-1) [59]. Treatment of HONE-1 cells with norepinephrine upregulated levels of metalloproteinases (specifically MMP-2 and MMP-9) and VEGF and increased cell invasiveness. Treatment with PRO inhibited this increase in MMP-2, MMP-9 and VEGF. Inhibition by PRO of MMP-9 secretion has also been confirmed in human brain microvascular endothelial cells [60].

Bernabé and colleagues assessed the influence of norepinephrine and cortisol on oral squamous cell carcinoma cell lines (OSCC) [61]. They showed that norepinephrine and cortisol, at physiologically relevant levels, induced IL-6 production in SCC9, SCC15, and SCC25 cells and similar observations were made for isoproterenol in SCC9 and SCC25 cells. These effects were associated with an increase in cell proliferation and PRO, at a concentration of 1 μM, blocked this increase. Wolter et al also showed that PRO reduced the viability of SCC9, SCC17a, SCC25, and FaDu cell lines, and that it synergised with cisplatin and radiotherapy in treating SCC17a cells [62].

Other

Grzanna and co-workers showed, in vivo, that administration of PRO delayed tumour growth of LPC-1 plasmacytoma tumours in female BALB/c mice [63]. Mice were treated with doses of 0.6. 6 and 60 mg/kg/day, administered via osmotic pumps, and compared with untreated mice following subcutaneous injection of LPC-1 cells. All treated mice showed delayed tumour growth compared to untreated controls, in a dose-dependent manner. There was also a dose-dependent decrease in IgG plasma values, confirming the effect seen on tumour size. However, while treatment increased tumour growth latency, there was no difference in growth TC Games3.0.107004 Crack - Free Activators once tumours were established.

The effect of PRO on tumour perfusion was investigated by Bomber et al in a small 1986 study focused on enhancing uptake of Ga-67 to improve imaging of small tumours [64]. PRO was administered, at a dose of 10 mg/kg, 10 minutes prior to administration of radiolabelled gallium citrate. Analysis showed that PRO doubled tumour perfusion and decreased Ga-67 uptake in non-tumour tissues, thereby increasing the relative uptake in the tumour compartment. Subsequently Burton and Gray reported that a combination of norepinephrine and PRO enhanced the relative blood supply to hepatic tumours in rabbits and doubled the embolisation rate of microspheres in the tumour compartment (P < 0.05) compared to either norepinephrine or PRO alone [65].

The effect of PRO was also investigated in two human gastric carcinoma cell lines (SGC-7901 and BGC-823) by Liao and colleagues [66]. In vitro concentrations of 200 μM induced cell cycle arrest and apoptosis in both cell lines. The effect of PRO on the radiosensitivity of the same gastric carcinoma cell lines was also investigated [67]. When pre-treated for 24 hours with PRO at a concentration of 50 μM both cell lines displayed a significant increase in radiosensitivity and apoptosis. PRO was associated with a decreased level of NF-κB and down-regulation of VEGF, COX-2, and EGFR expression.

In non-small cell lung cancer (NSCLC), Al-Wadei and colleagues investigated the effects of chronic exposure to nicotine on cancer cell proliferation [68]. Results showed that nicotine-treated lung adenocarcinoma cells, (NCI-H322, NCI-H441 and NCI-H1299), released norepinephrine and increased proliferation. Cells treated with PRO at a concentration of 1 μM for 10-minutes prior to acute or chronic exposure to nicotine showed significant reductions in the number of viable cells compared to nicotine alone (P < 0.0001). Interestingly, exposure to PRO also reduced viability compared to cells not treated with nicotine. The same authors subsequently extended this line of research and showed a similar nicotine-drive autocrine catecholamine feedback loop in a pancreatic adenocarcinoma model [69].

Kozanoglu et al investigated the in vitro effect of PRO on the U266 human multiple myeloma cell line [70]. They showed a dose and time dependent effect on cell proliferation and apoptosis, with IC50 values of 141, 100, and 75 μM after 24- 48- and 72-h PRO exposure, respectively.

Abdi and colleagues used two doses of PRO, 5 mg/kg and 10 mg/kg, in mice bearing solid Ehrlich carcinoma tumours [71]. While both doses were associated with reductions tumour growth rates and volumes compared to untreated controls, it was only the higher dose group that was associated with improved survival (P < 0.05). Both dosage levels were associated with statistically significant reductions in IL-10, HSP70 and iNOS levels.

Wei et al explored the use of PRO in a panel of human thyroid cancer cell lines [72]. PRO was shown to inhibit growth of 8505C and K1 cell lines, with IC50 values of 200 μM and 280 μM, respectively. Growth inhibition was further analysed in 8505C line was shown to be associated with increased levels of apoptosis. In vivo data from a xenograft mouse model using 8505C cells and treated with PRO at a dose of 10 mg/kg showed reduced tumour volume increase compared to controls, with reduced SUVmax on PET/CT and Ki76 staining of tumour cells.

von Hippel-Lindau (VHL) disease, or von Hippel-Lindau syndrome, is a rare genetic disorder caused by a germ-line mutation in the von Hippel–Lindau tumour suppressor gene. It is characterised by the development of a range of tumour types, including hemangioblastoma of the retina and the central nervous system. Albiñana et al explored the effect of PRO on hemangioblastoma cells from VHL patients and reported a dose-dependent decrease in viability and increase in apoptosis [73]. This effect was enhanced in hypoxic conditions and was associated with a decreased the expression of HIF target genes, including VEGF.

Human Data

The earliest human data to suggest a positive effect of propranolol on cancer came from epidemiological studies comparing cancer incidence in hypertensive and non-hypertensive patients. For example Perron et al reported on the incidence of prostate cancer in Canadian men treated with a range of anti-hypertensive drugs and found that treatment with beta-blockers had a protective effect with an adjusted odds ratio (OR) of 0.86 (95% CI = 0.77– 0.96) [74]. In patients with hepatitis C associated cirrhosis Nkontchou et al reported that PRO use was associated with a decreased risk hepatocellular carcinoma (HCC), with a hazard ratio (HR) = 0.25; (95% CI = 0.09 – 0.65; P < 0.004) [75]. Chang et al published a large cohort study of over 24 238 patients, with a PRO group (> 6 months use, n = 12 119) compared to a non-PRO use group (n = 12 119) over a 12 year period [76]. Overall the risk of cancer was lower in the PRO group (HR = 0.75; 95% CI = 0.67–0.85; P < 0.001), and site specific analysis showed a decreased risk in head and neck cancers (HR = 0.58; 95% CI = 0.35–0.95), oesophagus (HR = 0.35; 95% CI = 0.13 – 0.96), stomach (HR = 0.54; 95% CI = 0.30 – 0.98), colon (HR = 0.68; 95% CI = 0.49 – 0.93), and prostate cancers (HR = 0.52; 95% CI = 0.33 – 0.83).

Zhong et al performed a systematic review and meta-analysis of observational studies of beta-blocker use and cancer mortality [77]. They identified 24 relevant studies that had reported results by May 2015, involving 76 538 patients. Post-diagnosis use of a beta-blocker was associated with a statistically signification reduction in the risk of all-cause mortality (HR = 0.89; 95% CI = 0.81 – 0.98; P = 0.02). When stratified by cancer type the reduction in risk of death was only significant for breast cancer (HR = 0.82; 95% CI = 0.68 – 0.99; P = 0.03). In terms of cancer-specific mortality, beta-blocker use was associated with a reduced risk of cancer-specific mortality (HR = 0.89; 95% CI = 0.79 – 0.99; P = 0.03). However on stratification by cancer type there was no beneficial effect of post-diagnosis use of beta-blockers for breast, colorectal or prostate cancer. For pre-diagnosis use of beta-blockers there was no significant effect on all-cause mortality, but stratification by cancer type showed both a benefit for melanoma (HR = 0.81; 95% CI = 0.67 – 0.97; P = 0.02) and an increased risk for ovarian cancer (HR = 1.17; 95% CI = 1.04 – 1.32; P = 0.01). However, Weberpals et al evaluated a possible immortal time bias in these observational studies and found no clinically meaningful evidence for an association between beta-blocker use and survival when restricting the analysis to studies not prone to immortal time bias. Careful interpretation of observational studies is therefore required when no attempt is made to address immortal time bias [78].

Breast Cancer

Results published by Barron et al in a larger population of breast cancer patients showed protective effects associated with PRO use [79]. Irish women treated with PRO (n = 70) or atenolol (n = 525) in the year prior to breast cancer diagnosis were matched with women not receiving beta-blocker treatment (n = 4738) in the ratio 1:2. PRO use was associated with a lower risk of presenting with a T4 (OR = 0.24, 95% CI = 0.07 – 0.85) or N2/N3/M1 (OR = 0.20; 95%C = microsoft office 2016 free download full version for windows 10 - Crack Key For U – 0.88) diagnosis compared to matched non-users. The cumulative probability of breast cancer-specific mortality was also significantly lower for PRO users compared to matched nonusers (HR = 0.19; 95% CI = 0.06 – 0.60). There was no difference in either outcome between atenolol users and matched non-users.

A systematic review and meta-analysis of beta-blocker use and breast cancer by Childers et al found a non-significant reduction in breast cancer recurrence (HR = 0.67; 95% CI = 0.39 - 1.13), a significant reduction in the risk of breast cancer mortality (HR = 0.50; 95% CI = 0.32 - 0.80) and no impact of all-cause mortality (HR = 1.02; 95% CI = 0.75 - 1.37) [80].

Angiosarcoma

Banavali and colleagues reported on a case of relapsing metastatic angiosarcoma treated with a combination of metronomic oral low-dose chemotherapy (etoposide and cyclophosphamide), celecoxib and PRO (40 mg twice a day) [81]. The patient showed a complete response after two cycles of therapy. After one year of treatment the patient remained on a maintenance treatment of oral cyclophosphamide (50 mg) and PRO (20 mg BID), on alternate days for six additional months after which treatment ceased. The patient relapsed 20 months after initiation of the metronomic treatment and was treated with local palliative radiotherapy and oral thalidomide 100 mg with some response but ultimately died of progressive disease.

Subsequently the same group have reported on a series of seven cases of advanced angiosarcoma treated with a combination of PRO (40 mg BID), weekly vinblastine (i.v. 6 mg/m2 to a maximum of 10 mg) and methotrexate (35 mg/m2 to a maximum 50 mg) for up to 12 months followed by maintenance of PRO (40 mg BID), oral etoposide (50 mg/day) and oral cyclophosphamide (50 mg/day) for 20 consecutive days in cycles of 30 days [44]. The treatment was well tolerated and showed a 100% response rate, including one complete response and three very good partial responses. Median PFS was 11 months (range 5–24) and OS was 16 months (range 10–30).

Chow et al also published a case report in angiosarcoma treated with PRO [82]. The patient presented with a widely disseminated non-metastatic multifocal stage T2 cutaneous angiosarcoma, a diagnosis with a 2-year survival rate of 0%. Treatment with PRO at a dose of 40 mg BID was initiated leading to clinical improvement within a week and a subsequent increase in the dose to 40 mg three times a day. Staining for Ki-67 showed that the PRO monotherapy was associated with a 34% reduction in proliferation rate. Subsequent treatments, administered concurrently with PRO, included 10-weeks of paclitaxel poliglumex (a formulation of paclitaxel designed to increase the therapeutic index of the drug) and radiotherapy. Following cessation of paclitaxel and radiotherapy the patient has continued to take PRO at a dose of 40 mg TID, with clear signs of disease regression and no evidence of metastatic disease.

Other

Bhattacharyya et al reported on the use of the combination of metronomic temozolomide (mTMZ), the COX-2 inhibitor etodolac and PRO in recurrent glioblastoma at ASCO 2014 [83]. A series of 32 patients were randomised to either mTMZ or mTMZ with VT-122 (the combination of PRO 20 mg BID and etodolac 400 mg BID). The median TTP was 5.2 months in the mTMZ arm and 8.8 months in the mTMZ VT-122 arm. Survival at six months was 40% and 63%, and OS at one year was 12% versus 22% respectively. An update in 2015, also reported at ASCO, with 41 patients included, showed a median OS of 9.2 months versus 17.6 months, and a response rate of 35% versus 57% respectively [84].

The same group also reported on a small (n = 37) single centre open-label trial of gemcitabine and nab-paclitxel (GemNab) with and without VT-122 in patients with locally advanced or metastatic pancreatic cancer [85]. Patients in the GemNab VT-122 arm (n = 20) were treated with VT-122 for one week prior to commencement of GemNab, and then continuously with GemNab. PFS was 7.2 and 11.8 months, and OS was 10.5 months versus 15.9 months for the GemNab and GemNab VT-122 arms respectively. Additionally patients in the GemNab VT-122 arm experienced reduced pain and neuropathy and increased weight gain compared to the GemNab patients.

VT-122 was also used in a small (n = 20), multi-centre, randomised controlled trial in combination with sorafenib in HCC [86]. Median OS was 9.6 months versus 17.2 months in the sorafenib and sorafenib VT-122 arms respectively.

There has also been some interest in the role of PRO in addressing cancer-related cachexia, a significant cause of morbidity and mortality in late-stage cancer patients [87]. Hyltander et al explored influences on resting energy expenditure (REE) in weight-losing cancer patients taking PRO (80 mg BID), the non-selective COX inhibitor indomethacin, morphine or placebo [88]. Patients in the PRO group showed a decrease in REE of around 10% compared to base-line after 5 days of treatment (P < 0.02), whereas there were no significant changes in the other treatment groups or controls. A subsequent study by the same group compared PRO (80 mg/day) and atenolol (50 mg/day) in 10 weight-losing solid tumour patients [89]. While both drugs significantly reduced REE (P < 0.05), PRO treatment, accounting for microsoft office word 2007 free download full version - Crack Key For U decline in heart rate, was significantly more pronounced compared with atenolol (P<0.05).

There has also been some interest in the psychological effects of PRO in cancer patients, for example in reducing the level of emotional distress, measured in terms of the number and rate of intrusive thoughts, associated with a cancer diagnosis [90].

Clinical Trials

As of 31st May 2016, a number of clinical trials are investigating the anti-cancer uses of PRO. Only trials which are currently open (recruiting or soon to commence recruitment) or on-going are included.

Feasibility/Phase I

NCT01504126 – A small single arm, open-label (n = 25) trial of PRO, 20 mg BID, with surgery and standard platinum or taxane chemotherapy in ovarian cancer. This is designated as a feasibility study, with a primary end-point of the proportion of patients completing treatment. Treatment commences 48 – 72 hours prior to surgical resection and continues for six cycles of chemotherapy post-surgery.

NCT02013492 – A feasibility study of oral PRO in patients with non-resectable recurrent or metastatic solid tumours. Patients in this open-label study are treated with PRO BID (dose not specified) for four months in the absence of disease progression or unacceptable toxicity. Primary end-points are incidence of toxicity, change in VEGF levels, measurement of impacts on immune response and tumour microenvironment. Secondary outcome measures include one-year PFS and OS.

NCT02897986 (PROVIN) – This planned Phase I dose escalation trial (10, 20 and 30 mg/m² of thrice weekly oral vinorelbine only plus daily PRO 1.5mg/kg/day BID) after completion of the first cycle. Pharmacokinetic analysis of vinorelbine and PRO will be performed. Once the recommended dose of the combination is established four extension cohorts of 9 patients (neuroblastoma, rhabdomyosarcoma, Ewing’s sarcoma, and miscellaneous tumours) will be added. Potential biomarkers (tumour beta-adrenergic receptor expression and beta-tubulin isotypes) will also be evaluated.

NCT02732678 – A dose-finding trial of PRO in combination with metronomic fixed oral cyclophosphamide in patients with locally advanced or metastatic angiosarcoma (PROPAN)

Randomised – no phase listed

NCT00502684 – A randomised, placebo-controlled trial of peri-operative PRO and etodolac in women undergoing breast cancer surgery. Women in the treatment arm will receive 40 mg of PRO and 800 mg of etodolac starting two days prior to surgery and continuing until three days post-surgery. The trial has a number of biochemical primary outcome measures including immune and angiogenesis-related biomarkers (number and cytotoxic activity of NK cells, levels of NK T-cells, lymphocytes, monocytes and granulocytes; levels of cortisol and VEGF). The primary clinical end-point is the five-year recurrence rate.

Phase II

NCT01847001 – A Phase II open-label study in newly diagnosed breast cancer patients undergoing neo-adjuvant chemotherapy. The starting dose of PRO is 20 mg BID, but is up-titrated to 40 mg then 80 mg BID. Primary outcomes are PRO compliance during chemotherapy, changes in angiogenesis (as assessed using Diffuse Optical Tomography) and changes in psychological stress levels. Secondary outcomes include adverse event rates and changes in tumour proliferation (Ki-67 staining).

NCT02596867 – A Phase II open-label ‘window of opportunity’ trial in newly diagnosed breast cancer. PRO, at a dose of 1.5 mg/kg BID, is administered for three weeks prior to surgical resection. The primary outcome is a reduction in the proliferative index (Ki-67), secondary outcomes relate to safety, toxicity and adherence.

NCT01988831 – A Phase II randomised, placebo controlled trial in high-risk primary melanoma. Patients at high risk of disease recurrence will receive PRO at a dose assessed by a cardiologist, to a maximum of 160 mg/day. The primary outcome is five-year PFS. [Recruitment currently suspended due to financial reasons].

NCT01857817 – A Phase II randomised, placebo controlled trial of PRO and etodolac in prostate cancer. The drug combination, at a specific dose of 22 mg PRO and 340 mg etodolac, is designated as VT-122, by the sponsor of the trial, Vicus Therapeutics. The dose used in this trial is 22 mg PRO and 340 mg of etodolac twice a day. Primary outcome is change in PSA at 12 weeks. Secondary outcomes include PSA doubling time, PSA progression and time to symptom progression.

NCT01265576 – A Phase II randomised, placebo-controlled trial of VT-122 with sorafenib in hepatocellular carcinoma (HCC) patients at risk of cachexia. The primary outcome is failure-free survival at 6-months. The clinical benefit rate at 6-months is the secondary outcome. Note that a previous trial of VT-122 in NSCLC-related cachexia has yet to report results (trial completed December 2012).

NCT02641314 – A Phase II randomised trial of metronomic chemotherapy and PRO in children and adolescents with recurrent or progressive high risk neuroblastoma (METRO-NB2012). Treatment consists of eight alternating 28-day-cycles of PRO, celecoxib, oral cyclophosphamide, fortnightly i.v. vinblastine, oral etoposide (PCCVE) and of PRO, celecoxib, oral cyclophosphamide, fortnightly i.v. vinblastine (PCCV) followed by five cycles PCCV resulting in a total of 13 veritas backup exec login - Crack Key For U (364 days of treatment). The daily dose of PRO is 0.5 mg/kg/day, to a maximum of 120 mg/day, in two divided doses. The primary outcome is to demonstrate the non-inferiority of event free survival (EFS) in comparison to a historical control group. Secondary outcomes include the disease control rate at 6 months and overall survival at 12 months.

ACTRN12615000889550 – A Phase II randomised study of perioperative PRO vs placebo on gene expression in newly diagnosed breast cancer. The treatment group will receive 7 days of pre-operative PRO (40 mg BID days 1 – 3, 80 mg BID days 4 - 8) prior to and including the day of surgery and then will be titrated off PRO over two days in the post-operative period. The primary outcome is tumour gene expression for each of 20,000 genes at baseline and at surgical resection.

ACTRN12612000852853 – A Phase II randomised controlled trial of peri-operative PRO and etodolac in colorectal cancer patients undergoing surgical excision of the primary tumour. The primary outcome is a reduction of two-year rate of recurrence and distant metastases.

Phase III

NCT00888797 – This is a sister trial to NCT00502684 and is a Phase III randomised, placebo-controlled trial of peri-operative PRO and etodolac in colorectal cancer patients undergoing resection. Patients in the treatment arm receive etodolac 800 mg BID for the entire intervention period, PRO 20 mg BID for 5 pre-operative days, 80 mg BID on the day of surgery, 40 mg BID for the first postoperative week, 20 mg PO BID for the second postoperative week. The primary clinical end-point is the rate of local and distant recurrence rate at three years. Secondary end points are immune-related.

EudraCT 2014-003671-30 – This open label Phase III trial in patients with VHL syndrome will assess the efficacy of PRO, at a dose of 2 mg/kg, in controlling the growth of papillary and juxta-papillary retinal hemangioblastomas. The primary endpoint is a reduction in the number and size of retinal hemangioblastomas at 12-months.

Mechanisms of Action

PRO is a non-selective beta-adrenergic receptor antagonist, with a similar binding affinity for beta1- and beta2- and a much lower affinity (approximately 100-fold) for the beta3-adrenoreceptor [91]. In this respect PRO has a similar selectivity to some other clinically used beta-blocker drugs, particularly pindolol and carvedilol and there exists some evidence that these particular drugs may also have potential in repurposing [92–93]. There are a number of distinct putative mechanisms of action that have been investigated in relation to the anticancer effects of PRO, many of them associated with the beta2-adrenoreceptor pathway and which may be particularly important in the context of the metastatic process [94].

Proliferation

Investigations of the influence of beta-adrenergic signalling on cellular proliferation extend back more than fifty years. In 1961 Selye, Veilleux and Cantin reported that rats chronically treated with the beta-adrenergic agonist isoproterenol displayed excessive growth of salivary glands, most likely due to an increased mitotic rate [95]. Barka subsequently confirmed that isoproterenol increased the rate of mitosis and triggered DNA synthesis [96]. The converse, a reduction of proliferation due to PRO was also reported in the same era, for example Iwata, Kariya and Fujimoto showed that in a ciliated protozoan beta-adrenergic blockade, with PRO and other agents, was associated with a reduced rate of growth [97]. It has since been shown that PRO is able to inhibit the increase in cancer cell proliferation associated with catecholamines or isoproterenol in a number of cancer cell types [56, 98–100].

In a comparison between PRO and the selective beta adrenergic receptor antagonists atenolol (beta1) and ICI118-551 (beta 2), Işeri and colleagues showed that PRO and ICI118,551 were more potent in reducing the proliferation, migration, and invasion of non-stimulated breast (MCF7), colon (HT-29), and hepatocellular (HepG2) cancer cells than atenolol [101].

In contrast, there have also been contradictory results, for example for breast cancer where Pérez Piñero et al have reported that beta adrenergic agonists isoprenaline and salbutamol reduced breast tumour growth in animal models, and that PRO treatment reversed this inhibition [102] and other authors have reported a decrease in proliferation in breast cancer cell line, for example in the MCF7 cell line [101].

Bernabé et al showed that OSCC proliferation in response to increased beta2 adrenergic signalling was mediated by IL-6 [61]. In addition to showing increased IL-6 production from OSCC cells lines in response to norepinephrine or isoproterenol, neutralising IL-6 using antibodies inhibited the increase in proliferation rate. PRO was also shown to inhibit the increased proliferation rate induced by IL-6. A decrease in circulating IL-6 levels in response to PRO has been reported in a murine melanoma model, concomitant with a lower level of metastatic growth compared to untreated controls [103].

Migration and Invasion

Strell et al have shown that PRO is able to abrogate the norepinephrine-induced increase in migratory activity of a range of breast cancer cell lines [28–29].

Degradation of the extra-cellular matrix is a key factor in tumour progression and the metastatic cascade, with the matrix metalloproteinases (MMPs) playing a central role in the tissue remodelling process [104–105]. Sood et al reported that MMP-2 and MMP-9 were highly expressed during the norepinephrine-induced increase in ovarian cancer invasiveness [39]. Furthermore they showed that PRO treatment could reduce the rate of tumour growth and infiltration in vivo. A similar inhibition of the upregulation of MMP-2 and MMP-9 by PRO has also been reported in nasopharyngeal carcinoma [59], pancreatic cancer [50, 53], gastric adenocarcinoma [66], melanoma [106], prostate cancer [107] and of MMP-9 in medulloblastoma [108] and infantile hemangioma [109–110].

Pon et al described a beta2 adrenergic receptor activated feed-forward loop driving the invasiveness of the highly metastatic MDA-MB-231-HM breast cancer cell line [111]. A range of beta2 adrenergic receptor agonists caused a dose dependent increase in cAMP and Ca2 signalling and a decrease in phosphorylated ERK, which was competitively inhibited by PRO and the selective beta2 adrenergic receptor antagonist ICI-118551. The increased invasion of the MDA-MB-231-HM cell line was shown to be associated with the positive feedback between cAMP and Ca2 but independent of the microsoft visual studio 2017 crack - Crack Key For U on pERK.

Tissue remodelling is one of the key steps in the process of epithelial-mesenchymal transition (EMT) which is important in metastasis [112]. Shan et al showed that the human gastric cancer cell lines BGC-823 and SGC-7901 underwent morphological changes typical of EMT, and showed increased invasiveness, in response to co-culture with norepinephrine via a beta2-adrenergic signalling pathway [113]. Zhang et al showed a similar association between increased catecholamine signalling and initiation of EMT in HT-29 and A549 colorectal cancer cell lines [114]. Additionally they showed that TGF-β1 mediated the norepinephrine induced EMT process and that PRO, at a concentration of 10 μM, inhibited the increase in TGF-β1 and partially decreased the migration and invasiveness of norepinephrine-treated cells.

Related to the degradation of the extra-cellular matrix and the EMT process is the formation of tumour cell invadopodia, which are actin structures formed on the surface of cancer cells believed to be active in the secretion of MMPs [115]. Creed et al have shown that beta2 adrenergic signalling increased the rate of invadopodia formation in human and murine breast cancer cell lines in vitro, and that PRO inhibited this increase [116].

Also important in the metastatic process is cell-cell adhesion, and here too there is evidence that adrenergic signalling is active. Rap1B is a small GTPase that increases cell-cell adhesion. There is SAM Broadcaster Pro 2021.8 Crack With Product Code Free Download to suggest that loss of Rap1B at the plasma membrane decreases cell-cell adhesion and may promote a metastatic phenotype [117–118]. MDA-MB-231 breast cancer cells showed reduced cell-cell adhesion in response to isoproterenol and an increase in cell migration, whereas treatment with PRO reduced the level of migration [119].

The process of metastasis depends also on the creation of a ‘metastatic niche’, in addition to the properties of the primary cancer cells [120–121]. Campbell at al showed that in a mouse model restraint-induced stress or exogenous isoproterenol promoted MDA-231 breast cancer cell colonization of bone via adrenergic signalling effects on the bone marrow stromal compartment [31]. This effect was via upregulation of RANKL, which increased the number of osteolytic lesions in response to catecholamine signalling, and that this effect could be reversed by PRO or the RANKL inhibitor denosumab.

The Keyword Researcher Pro13.152 Keygen - Free Activators of the lymphatic system in metastasis has become increasingly recognised in recent years [122]. Le et al showed that chronic stress induced a remodelling of the tumour lymphatic vasculature, including an increase in lymphatic vessel density and vessel dilation leading to elevated levels of lymphatic draining [123]. These effects were sensitive to beta-adrenergic signalling and could be enhanced by isoproterenol or inhibited by PRO treatment of BALB/c mice injected with MDA-MB-231 breast cancer cells. The stress-induced remodelling was mediated by VEGFC production, which was induced by COX-2/PGE2. PRO has also been explored as a treatment option for congenital lymphangioma [124].

Apoptosis

Zhang et al showed that PRO limited the expansion of the PC-2 pancreatic cancer cell line and that this was due to dvdfab mac crack - Activators Patch increased rate of apoptosis [51]. The pro-apoptotic action of PRO was found to be via blockade of the beta2-adrenergic receptor rather than beta1, as shown by the increased level of apoptosis induced by the selective beta2 antagonist butaxamine and the reduced level due to the beta1 blocker metoprolol. Chin and colleagues also showed that in colorectal cancer cell lines PRO was associated with cell cycle arrest and apoptosis [57].

Liao et al reported that in vitro PRO concentrations of 200 μM induced cell cycle arrest and apoptosis in gastric carcinoma cell lines. Apoptosis was associated with a decrease in levels of NF-κB, VEGF, COX-2, MMP-2 and MMP-9 expression [66].

The pro-apoptotic activity of PRO was also investigated by Wolter and colleagues in their work in head and neck squamous cell carcinoma (HNSCC) cell lines with differing p53 status [62]. PRO treatment was shown to cause apoptosis irrespective of p53 status and was related to down-stream activity of p63 and p73, both p53-family proteins. Following PRO treatment there was evidence of downregulation of the anti-apoptotic ΔNp63a and induction of the pro-apoptotic TAp73b in both SCC9 and SCC17a cell lines. Some of the same authors also investigated the pro-apoptotic effect of PRO on neuroblastoma cell lines and showed that treatment increased expression of p53 and p73 [47].

Angiogenesis

The relationship between adrenergic signalling and angiogenesis was first elucidated in the late 1990s, when it was shown that beta adrenergic signalling by norepinephrine induced increased levels of VEGF expression in brown adipose tissue [125–126].

Lutgendorf and colleagues showed that beta adrenergic agonists increased the expression of VEGF in two ovarian cancer cell lines (EC and SKOV3), and that PRO, at a concentration of 1 μM, blocked this increase [38]. This finding suggested a putative link between behavioural stress and enhanced tumour growth via increased angiogenesis. In vivo work using a murine model of ovarian cancer showed that chronic behavioural stress was associated with increased tumour growth and vascularisation and enhanced expression of VEGF, MMP-2 and MMP-9. In particular beta-adrenergic activation of the cAMP-PKA signalling pathway was identified as a major mechanism by which behavioural stress enhanced tumour angiogenesis [127]. In subsequent work some of the same authors showed that surgical stress induced increased beta-adrenergic signalling in a murine ovarian cancer model and that this was associated with increased rates mobaxterm 12 professional - Activators Patch tumour growth and tumour angiogenesis [40]. Perioperative PRO was shown to inhibit the surgical stress-induced increase in VEGF expression and the consequent increase in angiogenesis and tumour growth.

An anti-angiogenic effect of PRO, via down-regulation of VEGF has also been shown in a range of cancer cell lines including nasopharyngeal carcinoma [59], melanoma [128], pancreatic cancer [50], leukaemia [23], head and neck squamous cell carcinoma [62] and infantile hemangiomas [129–130]. Pasquier et al showed that the combination of beta-blockers, including PRO, with vincristine was associated with increased survival and reduced angiogenesis in a mouse model of neuroblastoma [45].

Other mechanisms may also play a role in the anti-angiogenic effects of PRO. For example, Annabi et al, following initial reports that PRO was effective in infantile hemangiomas [131], investigated PRO activity in human glioblastoma biopsy samples [60]. It was reported that PRO down-regulated endothelial MMP-9 expression and reduced the rate of human brain microvascular endothelial cells tubologenesis, potentially reducing tumour angiogenesis.

Park et al showed that hypoxia-inducible factor 1α (HIF-1α) expression is also upregulated by norepinephrine, via the cAMP/PKA/Akt/p70S6K pathway, in addition to VEGF, and that it plays a key role in the angiogenic process [132]. Silencing of HIF-1α reduced the norepinephrine-induced increase in VEGF expression and capillary tube formation. Furthermore PRO pre-treatment abrogated the effect of adrenergic signalling on HIF-1α, VEGF and angiogenesis. Similar results, using a beta2-adrenergic receptor antagonist (ICI118 551), have been shown in vitro and in vivo in a murine pancreatic cancer model [133].

In addition to VEGF, MMP-2 and MMP-9, Liao et al showed that isoproterenol increased levels of COX-2, in gastric cancer cell lines, while PRO significantly reduced expression (P < 0.05) [66]. The COX-2/prostaglandin E2 (PGE2) pathway is also known to be involved in cancer-associated angiogenesis [134–135]. These effects were partly due to activation of the activation of NF-κB pathway [66]. Ciccarelli and colleagues showed that genetic deletion of b2-adrenergic receptors impaired angiogenesis in a mouse model, and that isoproterenol induced IκBα degradation and enhanced NF-kB transcriptional activity in a time-dependent manner [136].

Treatment Sensitisation

Early in vitro work showed that PRO had the potential to revert the drug resistant phenotype in different cell lines, including doxorubicin-resistant P388 murine leukaemia [18] and human multi-drug resistant (MDR) CEM leukaemia [137] for example. But results were cell line and drug specific, for example PRO seemed to have little impact on the cisplatin sensitivity of NSCLC cell lines [138].

In addition to chemosensitisation there has also been some preclinical work investigating the relationship between PRO and radiation. Liao et al showed that pre-treatment of the human gastric adenocarcinoma (HGC) cell lines BGC-823 and SGC-7901 with PRO, at a concentration of 50 μM for 24 hours, increased the effect of radiotherapy on cell viability in vitro [67]. Similarly, Wolter et al assessed the impact of PRO on HNSCC cell lines and showed that it enhanced the effect of radiation, in addition to displaying evidence of synergy with cisplatin [62]. We may also note the concurrent use of PRO and chemoradiotherapy in one of the case reports of PRO use in angiosarcoma [82].

The mechanism for increased radiosensitivity may be related to the NF-κB/COX-2/PGE2 pathway inhibition that a number of investigators have reported [36, 52, 67]. Evidence exists to suggest that elevated COX-2 expression may confer increased radiation resistance in some cancer cell lines [139–141].

Pasquier et al investigated the synergism of PRO with paclitaxel and 5-FU, both in vitro and in vivo [30]. In vitro analysis of a number of human cancer and non-cancer lines showed a range of synergistic, additive, sub-additive and antagonistic effects on cell proliferation depending on dose, cell line and chemotherapy drug. The synergistic effects were shown to be due to an enhancement of the anti-angiogenic effects of the chemotherapy drugs by low concentrations (10 μM) of PRO. In vivo a murine orthotopic triple negative breast cancer (MDA-MB-231) xenograft model was used with each chemotherapy drug. Four treatment groups of tumour-bearing mice were used, control (saline-treatment), paclitaxel alone (20 mg/kg, 3 days a week for 3 weeks), PRO alone (10 mg/kg, 5 days a week for 5 weeks) or the combination of paclitaxel and PRO. The same protocol was used with 5-FU, and the dose of the drug was 5-FU alone (30 mg/kg, 3 days a week for 5 weeks). The combination treatments produced significantly improved median survival times both for paclitaxel (125 days vs 70 for paclitaxel Keyword Researcher Pro13.152 Keygen - Free Activators, or 47 for control, P = 0.0005) and 5-FU (56 days vs 47 for 5-FU or 44 for control, P = 0.0005). Subsequently the same group published results which showed PRO synergised with vincristine in a murine model of neuroblastoma [45].

There are still other examples of PRO acting to improve cancer cell sensitivity to drug treatment enhancing the effect of rapamycin on human prostate cancer PC3 cells [49], reverting resistance to trastuzumab in HER2 breast cancer [32], inhibiting the stress-related reduction of sunitinib activity in colorectal cancer in an in vivo model [142] and sensitising thyroid cancer cells to the targeted BRAF-V600E inhibitor vemurafenib [72].

Immunological

A number of immune-related mechanisms of action have also been outlined as important in the anti-cancer effects of PRO. These effects are primarily mediated by the effects of sympathetic nervous system (SNS) signalling on different populations of immune cells, the tumour microenvironment and, in some cases, directly on cancer cells. An important aspect of this complex relationship is the link between psychological stress and immune response, a key concern within the field of psychoneuroimmunology and increasingly important in the context of cancer [143]. While there are a number of papers which review the effect of physical and psychological stress on the immune system, for example [144–145], the primary focus in this paper is on direct evidence of the role of PRO, and where relevant, other beta adrenergic receptor antagonists.

Teshima et al showed that in C3H/H and Hotspot shield crack 2018 - Free Activators mice PRO, at a dose of 5 mg/kg, was able to increase the phagocytic activity of macrophages (P < 0.05) and inhibit the reduction of phagocytic activity induced by physical restraint-induced stress (P <0.01) [146].

Shakhar and Ben-Eliyahu showed that the beta-adrenergic agonist metaproterenol induced a dose-dependent transient increase in natural killer (NK) cell numbers within 10 minutes of administration in F344 rats (P < 0.0001) [24]. It should be noted that although it did not reach significance, the time course of NK numbers showed that the initial increase subsided within one hour and before falling below base-line values by three hours and returning to base-line at five hours. Blood NK activity was depressed by metaproterenol (P < 0.03), but this was inhibited by prior administration of PRO (at doses in the range 0.1 – 0.5 mg/kg) or nadolol. Additional experiments showed that nadolol, like PRO a non-selective beta-adrenergic receptor antagonist, reduced the number of lung-retained NK-sensitive MADB106 breast cancer cells and the number of lung metastases.

Subsequently Benish et al showed that surgical intervention (laparotomy) prior to inoculation with MADB106 cells in F344 rats was significantly (P < 0.05) associated with increased the rate of lung tumour cell retention (LTR) [25]. This increase in LTR was attenuated by pre-surgical treatment with COX-2 inhibitors (indomethacin, Traktor Pro Crack, and celecoxib). Pre-surgical PRO, at a dose of 1.5 mg/kg and 4.5 mg/kg, also significantly reduced the LTR rate compared to untreated controls. The combined treatment of etodolac (12.5 mg/kg) and PRO (1.5 mg/kg) was more effective than either single treatment and completely inhibited the effect of surgery. Notably the combined treatment reversed the surgically induced reduction in NK cell numbers and per-cell cytotoxicity. These deleterious impacts on NK cells were later shown to be associated with reduced FasL and CD11a expression post-surgery, and that the combined etodolac PRO treatment counter-acted Keyword Researcher Pro13.152 Keygen - Free Activators effects [36].

Kalinichenko et al investigated the effect of norepinephrine on cytotoxic T lymphocytes (CTL) using a MOPC-315 plasmocytoma model in BALB/c mice [147]. Results showed that norepinephrine inhibited CTL generation via a reduction of TNF-α expression in CD4 and CD8 T cells and F4/80 activated macrophages, a result confirmed by the addition of exogenous TNF-α. Ex vivo use of PRO, at a concentration of 1 μM, completely reversed the effects of norepinephrine on TNF-α and CTL generation. Sloan et al also identified stress-sensitive CD11b F4/80 macrophages as being implicated in the metastatic process in the same mouse model [27].

Wu et al showed that stress induced by social isolation in Balb/c mice injected with colon 26-L5 carcinoma cells increased the rate of liver metastases compared to unstressed controls (P < 0.05) [148]. This was shown to be associated with a reduction in thymus weight, reduction in thymocytes and reduction in cytolytic activity of NK cells. Subsequent research by the same laboratory replicated these findings in additional mouse models and also showed that over-crowding induced similar stress-related thymic atrophy [33]. Additionally it was shown that PRO, at a dose of 30 ppm, slowed the rate of tumour growth of the over-crowded group to below that of the unstressed controls.

Kanemi et al showed that stressed induced by physical restraint in C57BL/6 mice resulted in a significant increase in epinephrine levels (P < 0.001) which returned to base-line values within one hour [149]. Lymphocyte numbers in blood and lungs were depressed (P <0.001) by restraint, but numbers returned to base-line within four hours of cessation of restraint. Lung NK cell numbers were also reduced by restraint-induced stress (P < 0.01), as were all other lymphocyte subsets assessed (CD8CD4B cell and NKT cells). PRO, at a dose of 20 mg/kg, administered prior to restraint was shown to reverse the reduction in NK cell numbers compared to untreated controls but had no effect on other lymphocyte sub-sets in the lungs.

In contrast, Tarr et al showed that repeated social disruption stress (induced by repeatedly introducing aggressive mice into cages of non-aggressive mice), both increased splenic NK cell numbers, NK cytotoxic activity and the expression of activation markers, both immediately and 14 hours after stress [150]. Administration of PRO (10 mg/kg) reduced the ‘priming’ of these NK cells at 14 hours. The authors propose an evolutionary explanation for these findings, suggesting that the priming occurs in order to prepare the host for pathogenic insult during stressful ‘fight or flight’ episodes. However, it has been argued Keyword Researcher Pro13.152 Keygen - Free Activators the complexity of multiple immune compartments, NK cell lineages and complexity of following cell populations in vivo over extended time periods makes interpretation of these results difficult [151].

Catecholamines are also known to impact the immune response via down-regulation of interferon gamma (IFN-γ) production [152]. Khalili et al showed that PRO and a HSP-70-rich tumour lysate vaccine synergised to increase IFN-γ production in a murine model of fibrosarcoma [153]. Treated animals showed lower rates of tumour growth (P < 0.01) and increased level of CTL activity (P < 0.05).

Lymphocytes are also known to secrete catecholamines, with potential downstream impacts on immunity. Huang et al investigated the effect of lymphocyte-derived catecholamines on the differentiation and function of T helper (Th) cells, suggesting that they shifted the Th1/Th2 balance in the direction of greater Th2 polarisation [154–155]. Panina-Bordignon et al had earlier suggested that beta2-adrenergic signalling inhibits production of IL-12, thereby promoting Th2 differentiation and inhibiting the Th1 development associated with anti-tumour immunity [156].

Myeloid derived suppressor cells (MDSC) are implicated in the dysfunctional immune response to cancer and are considered a negative prognostic marker in some cancers [157–158]. Jin et al used BALB/c mice to show that chronic stress induced an immunosuppressive state associated with an accumulation of CD11b Gr1 MDSCs in the bone marrow [159]. In line with previous reports from other groups [160], the data showed that the COX-2/PGE2 axis a central role in this accumulation. In addition there was evidence that stress-related catecholamines were also implicated, and that PRO (10mg/kg) partially reversed the accumulation of MDSCs, both in terms of cell numbers (P < 0.001) and proportion (P = 0.018).

T-regulatory (T-reg) cells are another population of immune cells associated with tumour-associated immune dysfunction. Zhou et al studied the impact of PRO and the COX-2 inhibitor parecoxib on T-reg numbers in breast cancer patients undergoing radical mastectomy [161]. Patients were assigned to control, PRO, parecoxib and PRO parecoxib groups. Patients in the PRO group received 20 mg TID starting from day of surgery until third post-operative day. The parecoxib group received 40 mg per day, IV, from day of surgery to second post-operative day. Patients in the combination group received both treatments at the same dose and schedule. Results showed that surgery was associated with an increase in epinephrine, norepinephrine, PGE2 levels and T-reg numbers. Treatment with PRO or PRO parecoxib attenuated the increase in T-reg numbers though there was no additive or synergistic effect of the parecoxib compared to PRO alone. Ex vivo analysis showed that PRO also reduced the immunosuppressive effect of T-reg cells compared to controls.

Other

In addition to the main mechanisms that have been outlined about, there are also a number of other possible mechanisms of action which have been described in the literature, some of which may be unrelated to the beta-adrenergic receptor antagonist activity of PRO.

Epidermal growth factor receptor (EGFR) signalling plays a central role in many cancer types and is a major drug target [162]. Disrupted endocytic trafficking is implicated in the process by which tumours gain self-sufficiency in growth signals by delays in the inactivation of multiple growth factor receptors, including EGFR [163–164]. It has been proposed by Shaughnessy et al that a strategy for inhibiting EGFR function may be to interfere with the endocytic process directly rather than directly targeting receptor-ligand binding or tyrosine kinase activity [165]. Inhibition of phosphatidic acid phosphohydrolase (PAP) has been shown to cause a reversible trafficking of inactive (empty) EGFR from the cell surface to endosomes, thereby restricting receptor availability to ligands [166]. PRO is a known inhibitor of PAP [167], and has been shown to reduce the cell viability of EGFR-dependent cancer cell lines [165].

Kang et al investigated the impact of PRO on glucose uptake in breast cancer cell lines (4T1, MDA-MB-231 and MCF-7) [168]. In vitro analysis showed that while glucose transporter-1 (GLUT-1) was relatively unaffected in all cell lines by PRO, hexokinase-2 (HK-2) was sensitive to PRO at a concentration of 50 μM. In vivo results using the 4T1 mouse breast cancer line showed that tumours were also sensitive to PRO at a dose of 10 mg/kg, and that this was associated with a reduction in HK-2 expression. PRO may therefore have a metabolic impact on tumour growth.

PGE2 is a key inflammatory molecule with multiple effects in cancer, including effects on immunity, angiogenesis, proliferation and apoptosis [169]. As has already been shown, these diverse effects are also implicated in some of the mechanisms of action of PRO. Nagaraja et al sought to investigate the relationship between beta adrenergic signalling and PGE2 in more detail using primary ovarian cancer cells from patients [170]. Tumour samples from depressed patients showed significantly higher levels of PGE2 and PGF2α, tumour samples from mice bearing Skov3-ip1 ovarian tumours also showed elevated levels of PGE2. Analysis showed that norepinephrine increased the secretion of PGE2 from tumour cells. Furthermore PRO was also shown to inhibit the catecholamine-induced increase in PGE2 in Skov3 and HeyA8 ovarian cancer cells.

Platelets play a complex role in tumour progression and metastasis via the release of pro-angiogenic factors, a role in subverting anti-tumour immunity by ‘cloaking’ tumour cells from NK cells and a role in establishing the metastatic niche [171]. The anticancer effects of aspirin may be related to anti-platelet effects via irreversible inhibition of COX-1 [172–173], and there is also some evidence that other anti-platelet agents, such as low molecular weight heparins and dipyridamole may also have anti-cancer or anti-metastatic activity [174–176]. Beta-adrenergic receptor antagonists are also known to have effects on platelet aggregation and a meta-analysis published in 2014 showed that they decreased platelet aggregation by 13% (95% CI = 8 - 17%, standardised mean difference=-0.54, 95% CI = -0.85 – -0.24, P < 0.0001) [177]. In particular non-selective lipophilic beta-blockers (including PRO) decreased platelet aggregation more than selective non-lipophilic beta-blockers. A small randomised cross-over trial in moderate essential hypertension compared PRO (40mg TID) to atenolol (100 mg/day) confirmed that the number of circulating platelet aggregates decreased significantly with PRO (0.99±0.19) in comparison with both atenolol (1.41±0.70; P = 0.004) and baseline (1.59±0.94; P = 0.002) [178].

Finally, beta-adrenergic signalling is at the intersection between psychological states and physiology. As has been previously mentioned stress arising from social interactions has been shown to have negative effects on proliferation, invasion, metastasis and anticancer immunity. However, it should be noted that not all forms of social stress are necessarily negative – clinical psychology differentiates between positive stress (eustress) and negative stress (distress) with differing physiological correlates [179]. Cao et al showed that a murine model of eustress, related to living in an enriched environment (increased levels of Keyword Researcher Pro13.152 Keygen - Free Activators stimulation, social stimulation and physical exercise), was associated with reduced rate of B16 melanoma growth compared living in a control environment [180]. This reduction in tumour growth rate was associated with down-regulation of hypothalamic brain-derived neurotrophic factor (BDNF) and increased production of leptin in adipocytes via beta-adrenergic signalling. PRO, at a dose of 0.5 g/l in drinking water, inhibited the protective effect of the enriched environment.

Our Take

The evidence outlined above, and summarised in Table 1, suggests that PRO has a number of distinct anti-cancer effects which may be of therapeutic value in different clinical settings. While there is evidence that other drugs in the same class as have anti-cancer effects, for example carvedilol and nebivolol [45], PRO has both the widest range of evidence and extensive clinical use, therefore pragmatic reasons suggest that it be prioritised for further clinical research. Needless to say, the repurposing of other beta-blockers may also carry great potential in the same or other settings/tumours. For PRO the evidence in angiosarcoma, anti-metastatic effects in breast and ovarian cancers and the effect on the rate of distant metastases following surgical intervention are particularly noteworthy. In all future trials, it will be important to assess plasma concentrations of propranolol especially when a direct effect on tumour growth is desirable.

Angiosarcoma

Angiosarcoma is a rare and aggressive soft tissue sarcoma arising in vascular endothelial cells, and is a disease with poor prognosis and reported five-year overall survival rates in the range 30% - 40% [181]. Although no standard treatment exists, the majority of patients are treated with surgical resection, chemotherapy (doxorubicin or paclitaxel most commonly) and radiotherapy [182]. Given the high unmet needs in this disease, the case reports showing some benefit to patients using PRO in combination with other agents are noteworthy [44, 81, 82], along with responses to propranolol observed in other vascular tumours [41, 183–184]. Clinical trials are urgently required to confirm the efficacy of these combinations with PRO.

Anti-metastatic Agent

Metastatic disease remains the primary cause of cancer-related mortality and therefore the search for anti-metastatic agents is of considerable value [185]. As outlined previously, PRO has multiple mechanisms of action which may have some impact on the metastatic process, including reduction in the rate of invasion, down-regulation of angiogenesis and lymphangiogenesis, inhibition of tissue remodelling and down-regulation of COX-2/PGE2 expression. Data from a number of in vivo models has shown that PRO may reduce the rate of metastasis in breast and other cancers via direct effects on beta-adrenergic signalling [27, 36, 48]. The addition of PRO to standard of care for non-metastatic cancers may therefore be a strategy to reduce the rate of metastatic spread.

Table 1. Summary of evidence by cancer type.

Perioperative Intervention

Data from both retrospective analyses of patient outcomes and from animal models suggest that surgical intervention may be associated with distant metastases [186–187]. The ‘wound healing response’ due to the surgical incision initiates a cascade of inflammatory events that lead to suppression of cell-mediated immunity and an increase in pro-angiogenic signalling [188–191]. However, there is now a growing level of interest in targeting some aspects of this post-surgical response so as to reduce the risk of metastatic spread [192–193]. Options for such peri-operative interventions include choice of anaesthesia [194–195], the use of drugs which target the COX-2/PGE2 pathway such as ketorolac [196–198] and diclofenac [199–200], and the H2RA cimetidine [201–202]. As should be clear from the results previously outlined, beta-adrenergic signalling is also implicated in the post-surgical metastatic process and numerous in vivo studies have reported that peri-operative PRO is associated with a reduced rate of metastases [40]. Of note the combination of PRO with a COX-2/PGE2 inhibitor, such as ketorolac or etodolac, has the potential to show synergism in a peri-operative setting and warrants additional investigation. This is particularly the case in those cancers in which post-surgical distant metastases are a frequent occurrence, including breast cancer, osteosarcoma, head and neck cancers, upper GI cancers, NSCLC and ovarian cancer.

Other Cancers

While we have outlined areas where there is a particularly compelling case to be made for further clinical study, there is also sufficient evidence to suggest that there may be some value in assessing the potential benefit of PRO in other cancers. The ubiquity of catecholamine signalling and the apparent expression of adrenergic receptors in multiple tumour types would suggest that the effects of PRO may extend, ultimately, to a much larger number of cancer types than has hitherto been suggested [203–204]. In the meantime there is a good level of evidence for further investigation in pancreatic cancer and neuroblastoma, particularly in combination with other agents, including repurposed drugs such as ketorolac or etodolac.

Psychological Stress

We note that the data for a pro-apoptotic effect of PRO on primary tumour growth comes primarily from in vitro studies which use high concentrations which may not reflect physiologically achievable levels. In many respects this is similar to the case with some NSAIDs, such as diclofenac, where the evidence is that the apoptotic effects are not physiologically achievable, and that therefore the anti-cancer effects are related to aspects of the host environment rather than directly on primary cancer growth [205]. Beta adrenergic signalling is central to the intersection between psychosocial stress and cancer, as evidenced in numerous animal models and epidemiological data. A variety of stress reduction techniques have been clinically investigated, including mindfulness meditation [206], cognitive behavioural stress management [207] and even communal singing [208]. Therefore, while the data for an effect on primary tumour growth may be limited in contrast to the results supporting an anti-metastatic effect, there is reason to believe that beta blockade may be beneficial in terms of psychological effects in addition to physical effects on the host environment.

Next Steps

The current level of clinical trial activity, which is relatively high for a repurposed drug, testifies to the strong level of clinical evidence and it is to be hoped that positive reports from these trials will be forthcoming in the future.

The data are strongest for clinical trials of PRO, in combination with other agents, in the following cancer types:

• Angiosarcoma

• Breast cancer

• Ovarian cancer

• Pancreatic cancer

• Neuroblastoma

The peri-operative use of PRO in combination with ketorolac or etodolac is also of interest in the following cancers:

• Osteosarcoma

• Head and neck cancers

• Oesophageal cancer

• Breast cancer

• Ovarian cancer

• Non-small Cell Lung Cancer

• Pancreatic cancer

Conclusion

There is a significant volume of data from in vitro, animal and human studies to indicate that there are multiple clinically relevant anti-cancer effects associated with PRO. This data has been summarised and presented to make the case that PRO is a very strong candidate for repurposing as an anticancer agent. In particular the potential for synergistic interactions with other drugs has been outlined, including repurposed COX-2/PGE2 inhibitors and a range of chemotherapeutics at both metronomic and standard dosing. The anti-metastatic properties of PRO may be particularly valuable to exploit during surgical intervention, and a number of possible combinations with other agents is discussed in this setting.

Author Contributions

Primary author: Pan Pantziarka. Contributing authors: Ilse Rooman, Vidula Sukhatme, Gauthier Bouche, Lydie Meheus, Vikas P. Sukhatme. All authors read and approved the final manuscript.

Competing Interests

The authors declare that they have no competing interests. All the authors are associated with not for profit organisations that aim to repurpose drugs for oncology treatments. VPS is also a scientific advisory board member of Berg Health and Mitra Biotech and a consultant to Roivant Sciences.

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72. Wei W-J et al (2016) Propranolol sensitizes thyroid cancer cells to cytotoxic effect of vemurafenibOncol Rep36(3) 1576–84 PMID: 27432558

73. Albiñana V et al (2015) Propranolol reduces viability and induces apoptosis in hemangioblastoma cells from von Hippel-Lindau patientsOrphanet J Rare Dis10(1) 118 DOI: 10.1186/s13023-015-0343-5 PMID: 26394686 PMCID: 4579575

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109. Wu S et al (2015) Clinical efficacy of propranolol in the treatment of hemangioma and changes in serum VEGF, bFGF and MMP-9Exp Ther Medicine10(3) 1079–83

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Источник: https://ecancer.org/en/journal/article/680-repurposing-drugs-in-oncology-redo-propranolol-as-an-anti-cancer-agent

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Windows Repair Pro Activation Key

  • VBHGFDE-RTGHBV-BN-HGRE-RTGFCV-BGFD-E
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Keyword Researcher Pro 13.156 Crack + Full Version Download 2021

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CAFE

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19. Zhang H, Xie C, Spencer HJ, Zuo C, Higuchi M, Ranganathan G, Kern PA, Chou MW, Huang Q, Szczesny B, Mitra S, Watson AJ, Margison GP, Fan CY. Obesity and hepatosteatosis in mice with enhanced oxidative DNA damage processing in mitochondria. Am J Pathol. 2011;178(4):1715–1727.[PMC free article] [PubMed] [Google Scholar]

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23. Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ, Roth KA, MacGregor GR, Thompson CB, Korsmeyer SJ. Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science. 2001;292(5517):727–730. [PMC free article] [PubMed] [Google Scholar]

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25. Willis SN, Chen L, Dewson G, Wei A, Naik E, Fletcher JI, Adams JM, Huang DC. Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins. Genes Dev. 2005;19(11):1294–1305.[PMC free article] [PubMed] [Google Scholar]

26. Yin XM, Oltvai ZN, Korsmeyer SJ. BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax. Nature. 1994;369(6478):321–323. [PubMed] [Google Scholar]

27. Cheng EH, Wei MC, Weiler S, Flavell RA, Mak TW, Lindsten T, Korsmeyer SJ. BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol Cell. 2001;8(3):705–711. [PubMed] [Google Scholar]

28. Letai A, Bassik MC, Walensky LD, Sorcinelli MD, Weiler S, Korsmeyer SJ. Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell. 2002;2(3):183–192.[PubMed] [Google Scholar]

29. Certo M, Del Gaizo Moore V, Nishino M, Wei G, Korsmeyer S, Armstrong SA, Letai A. Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell. 2006;9(5):351–365.[PubMed] [Google Scholar]

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32. Gallenne T, Gautier F, Oliver L, Hervouet E, Noel B, Hickman JA, Geneste O, Cartron PF, Vallette FM, Manon S, Juin P. Bax activation by the BH3-only protein Puma promotes cell dependence on antiapoptotic Bcl-2 family members. J Cell Biol. 2009;185(2):279–290. [PMC free article] [PubMed] [Google Scholar]

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Источник: https://m.cafe.daum.net/panicbird/QzZ4/162?listURI=%2Fpanicbird%2FQzZ4

Histone-lysine N-methyltransferase 2A

Feature keyPosition(s)DescriptionActionsGraphical viewLength <p>This subsection of the <a href="http://www.uniprot.org/help/function_section">Function</a> section indicates at which position the protein binds a given metal ion. The nature of the metal is indicated in the 'Description' field.<p><a href='/help/metal' target='_top'>More...</a></p>Metal bindingi1155Zinc 1

<p>Manual validated information which has been generated by the UniProtKB automatic annotation system.</p> <p><a href="/manual/evidences#ECO:0000255">More...</a></p> Manual assertion according to rulesi

<p>Manually validated information inferred from a combination of experimental and computational evidence.</p> <p><a href="/manual/evidences#ECO:0007744">More...</a></p> Manual assertion inferred from combination of experimental and computational evidencei

Manual assertion based on experiment ini

1Metal bindingi1158Zinc 1

Manual assertion according to rulesi

Manual assertion inferred from combination of experimental and computational evidencei

Manual assertion based on experiment ini

1Metal bindingi1161Zinc 1

Manual assertion according to rulesi

Manual assertion inferred from combination of experimental and computational evidencei

Manual assertion based on experiment ini

1Metal bindingi1167Zinc 2

Manual assertion according to rulesi

Manual assertion inferred from combination of experimental and computational evidencei

Manual assertion based on experiment ini

1Metal bindingi1170Zinc 2

Manual assertion according to rulesi

Manual assertion inferred from combination of experimental and computational evidencei

Manual assertion based on experiment ini

1Metal bindingi1173Zinc 2

Manual assertion according to rulesi

Manual assertion inferred from combination of experimental and computational evidencei

Manual assertion based on experiment ini

1Metal bindingi1189Zinc 2

Manual assertion according to rulesi

Manual assertion inferred from combination of experimental and computational evidencei

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1Metal bindingi1194Zinc 1

Manual assertion according to rulesi

Manual assertion inferred from combination of experimental and computational evidencei

Manual assertion based on experiment ini

1 <p>This subsection describes interesting single amino acid sites on the sequence that are not defined in any other subsection. This subsection can be displayed in different sections ('Function', 'PTM / Processing', 'Pathology and Biotech') according to its content.<p><a href='/help/site' target='_top'>More...</a></p>Sitei3765Important for WDR5-recognition and binding

Manual assertion based on experiment ini

1 <p>This subsection of the <a href="http://www.uniprot.org/help/function_section">Function</a> section describes the interaction between a single amino acid and another chemical entity. Priority is given to the annotation of physiological ligands.<p><a href='/help/binding' target='_top'>More...</a></p>Binding sitei3839S-adenosyl-L-methionine

Manual assertion according to rulesi

Manual assertion inferred from combination of experimental and computational evidencei

Manual assertion based on experiment ini

  • "Structural basis for the requirement of additional factors for MLL1 SET domain activity and recognition of epigenetic marks."
    Southall S.M., Wong P.S., Odho Z., Roe S.M., Wilson J.R.
    Mol. Cell 33:181-191(2009) [PubMed] [Europe PMC] [Abstract]

    Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 3785-3969 IN COMPLEX WITH ZINC; S-ADENOSYL-L-HOMOCYSTEINE AND HISTONE H3 PEPTIDE, FUNCTION, CATALYTIC ACTIVITY, DOMAIN SET, INTERACTION WITH ASH2L AND RBBP5, MUTAGENESIS OF TYR-3858; GLN-3867; ASP-3869; ARG-3871; GLU-3872; TYR-3874; LYS-3878 AND TYR-3942.

  • "Structural basis for activity regulation of MLL family methyltransferases."
    Li Y., Han J., Zhang Y., Cao F., Liu Z., Li S., Wu J., Hu C., Wang Y., Shuai J., Chen J., Cao L., Li D., Shi P., Tian C., Zhang J., Dou Y., Li G., Chen Y., Lei M.
    Nature 530:447-452(2016) [PubMed] [Europe PMC] [Abstract]

    Cited for: X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 3813-3969 IN COMPLEX WITH S-ADENOSYL-L-HOMOCYSTEINE AND ZINC, FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, DOMAIN, MUTAGENESIS OF ASN-3861; ARG-3864 AND GLN-3867.

1Binding sitei3841S-adenosyl-L-methionine

Manual assertion according to rulesi

Manual assertion inferred from combination of experimental and computational evidencei

Manual assertion based on experiment ini

  • "Structural basis for the requirement of additional factors for MLL1 SET domain activity and recognition of epigenetic marks."
    Southall S.M., Wong P.S., Odho Z., Roe S.M., Wilson J.R.
    Mol. Cell 33:181-191(2009) [PubMed] [Europe PMC] [Abstract]

    Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 3785-3969 IN COMPLEX WITH ZINC; S-ADENOSYL-L-HOMOCYSTEINE AND HISTONE H3 PEPTIDE, FUNCTION, CATALYTIC ACTIVITY, DOMAIN SET, INTERACTION WITH ASH2L AND RBBP5, MUTAGENESIS OF TYR-3858; GLN-3867; ASP-3869; ARG-3871; GLU-3872; TYR-3874; LYS-3878 AND TYR-3942.

  • "Structural basis for activity regulation of MLL family methyltransferases."
    Li Y., Han J., Zhang Y., Cao F., Liu Z., Li S., Wu J., Hu C., Wang Y., Shuai J., Chen J., Cao L., Li D., Shi P., Tian C., Zhang J., Dou Y., Li G., Chen Y., Lei M.
    Nature 530:447-452(2016) [PubMed] [Europe PMC] [Abstract]

    Cited for: X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 3813-3969 IN COMPLEX WITH S-ADENOSYL-L-HOMOCYSTEINE AND ZINC, FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, DOMAIN, MUTAGENESIS OF ASN-3861; ARG-3864 AND GLN-3867.

1Binding sitei3883S-adenosyl-L-methionine

Manual assertion according to rulesi

Manual assertion inferred from combination of experimental and computational evidencei

Manual assertion based on experiment ini

  • "Structural basis for the requirement of additional factors for MLL1 SET domain activity and recognition of epigenetic marks."
    Southall S.M., Wong P.S., Odho Z., Roe S.M., Wilson J.R.
    Mol. Cell 33:181-191(2009) [PubMed] [Europe PMC] [Abstract]

    Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 3785-3969 IN COMPLEX WITH ZINC; S-ADENOSYL-L-HOMOCYSTEINE AND HISTONE H3 PEPTIDE, FUNCTION, CATALYTIC ACTIVITY, DOMAIN SET, INTERACTION WITH ASH2L AND RBBP5, MUTAGENESIS OF TYR-3858; GLN-3867; ASP-3869; ARG-3871; GLU-3872; TYR-3874; LYS-3878 AND TYR-3942.

  • "Structural basis for activity regulation of MLL family methyltransferases."
    Li Y., Han J., Zhang Y., Cao F., Liu Z., Li S., Wu J., Hu C., Wang Y., Shuai J., Chen J., Cao L., Li D., Shi P., Tian C., Zhang J., Dou Y., Li G., Chen Y., Lei M.
    Nature 530:447-452(2016) [PubMed] [Europe PMC] [Abstract]

    Cited for: X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 3813-3969 IN COMPLEX WITH S-ADENOSYL-L-HOMOCYSTEINE AND ZINC, FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, DOMAIN, MUTAGENESIS OF ASN-3861; ARG-3864 AND GLN-3867.

1Metal bindingi3909Zinc

Manual assertion inferred from combination of experimental and computational evidencei

Manual assertion based on experiment ini

  • "Solution structure of the nonmethyl-CpG-binding CXXC domain of the leukaemia-associated MLL histone methyltransferase."
    Allen M.D., Grummitt C.G., Hilcenko C., Min S.Y., Tonkin L.M., Johnson C.M., Freund S.M., Bycroft M., Warren A.J.
    EMBO J. 25:4503-4512(2006) [PubMed] [Europe PMC] [Abstract]

    Cited for: STRUCTURE BY NMR OF 1146-1214 IN COMPLEX WITH ZINC, DOMAIN CXXC-TYPE ZINC-FINGER, DNA-BINDING, MUTAGENESIS OF ARG-1151; ARG-1153; ARG-1154; CYS-1155; CYS-1158; CYS-1161; GLN-1162; ASP-1166; CYS-1167; CYS-1170; ASN-1172; CYS-1173; ASP-1175; LYS-1176; 1178-LYS--GLY-1181; LYS-1178; PHE-1179; ASN-1183; LYS-1185; LYS-1186; GLN-1187; CYS-1188; CYS-1189; ARG-1192; LYS-1193; CYS-1194; GLN-1195 AND ASN-1196.

  • "Structural basis for the requirement of additional factors for MLL1 SET domain activity and recognition of epigenetic marks."
    Southall S.M., Wong P.S., Odho Z., Roe S.M., Wilson J.R.
    Mol. Cell 33:181-191(2009) [PubMed] [Europe PMC] [Abstract]

    Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 3785-3969 IN COMPLEX WITH ZINC; S-ADENOSYL-L-HOMOCYSTEINE AND HISTONE H3 PEPTIDE, FUNCTION, CATALYTIC ACTIVITY, DOMAIN SET, INTERACTION WITH ASH2L AND RBBP5, MUTAGENESIS OF TYR-3858; GLN-3867; ASP-3869; ARG-3871; GLU-3872; TYR-3874; LYS-3878 AND TYR-3942.

1Metal bindingi3957Zinc

Manual assertion inferred from combination of experimental and computational evidencei

Manual assertion based on experiment ini

  • "Solution structure of the nonmethyl-CpG-binding CXXC domain of the leukaemia-associated MLL histone methyltransferase."
    Allen M.D., Grummitt C.G., Hilcenko C., Min S.Y., Tonkin L.M., Johnson C.M., Freund S.M., Bycroft M., Warren A.J.
    EMBO J. 25:4503-4512(2006) [PubMed] [Europe PMC] [Abstract]

    Cited for: STRUCTURE BY NMR OF 1146-1214 IN COMPLEX WITH ZINC, DOMAIN CXXC-TYPE ZINC-FINGER, DNA-BINDING, MUTAGENESIS OF ARG-1151; ARG-1153; ARG-1154; CYS-1155; CYS-1158; CYS-1161; GLN-1162; ASP-1166; CYS-1167; CYS-1170; ASN-1172; CYS-1173; ASP-1175; LYS-1176; 1178-LYS--GLY-1181; LYS-1178; PHE-1179; ASN-1183; LYS-1185; LYS-1186; GLN-1187; CYS-1188; CYS-1189; ARG-1192; LYS-1193; CYS-1194; GLN-1195 AND ASN-1196.

  • "Structural basis for the requirement of additional factors for MLL1 SET domain activity and recognition of epigenetic marks."
    Southall S.M., Wong P.S., Odho Z., Roe S.M., Wilson J.R.
    Mol. Cell 33:181-191(2009) [PubMed] [Europe PMC] [Abstract]

    Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 3785-3969 IN COMPLEX WITH ZINC; S-ADENOSYL-L-HOMOCYSTEINE AND HISTONE H3 PEPTIDE, FUNCTION, CATALYTIC ACTIVITY, DOMAIN SET, INTERACTION WITH ASH2L AND RBBP5, MUTAGENESIS OF TYR-3858; GLN-3867; ASP-3869; ARG-3871; GLU-3872; TYR-3874; LYS-3878 AND TYR-3942.

1Binding sitei3958S-adenosyl-L-methionine

Manual assertion according to rulesi

Manual assertion inferred from combination of experimental and computational evidencei

Manual assertion based on experiment ini

Источник: https://www.uniprot.org/uniprot/Q03164

You May Also LikeCLion 1.1 Crack + Activation Code Free Download [2021]

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Sweet taste of heavy water

Abstract

Hydrogen to deuterium isotopic substitution has only a minor effect on physical and chemical properties of water and, as such, is not supposed to influence its neutral taste. Here we conclusively demonstrate that humans are, nevertheless, able to distinguish D2O from H2O by taste. Indeed, highly purified heavy water has a distinctly sweeter taste than same-purity normal water and can add to perceived sweetness of sweeteners. In contrast, mice do not prefer D2O over H2O, indicating that they are not likely to perceive heavy water as sweet. HEK 293T cells transfected with the TAS1R2/TAS1R3 heterodimer and chimeric G-proteins are activated by D2O but not by H2O. Lactisole, which is a known sweetness inhibitor acting via the TAS1R3 monomer of the TAS1R2/TAS1R3, suppresses the sweetness of D2O in human sensory tests, as well as the calcium release elicited by D2O in sweet taste receptor-expressing cells. The present multifaceted experimental study, complemented by homology modelling and molecular dynamics simulations, resolves a long-standing controversy about the taste of heavy water, shows that its sweet taste is mediated by the human TAS1R2/TAS1R3 taste receptor, and opens way to future studies of the detailed mechanism of action.

Introduction

Heavy water, D2O, has fascinated researchers since the discovery of deuterium by Urey in 19311,2. The most notable difference in physical properties between D2O and H2O is the roughly 10% higher density of the former liquid, which is mostly a trivial consequence of deuterium being about twice as heavy as hydrogen. A more subtle effect of deuteration is the formation of slightly stronger hydrogen (or deuterium) bonds in D2O as compared to H2O3,4. This results in a small increase of the freezing and boiling points by 3.8 °C and 1.4 °C, respectively, and in a slight increase of 0.44 in pH (or pD) of pure water upon deuteration5. In comparison, a mere dissolution of atmospheric CO2 and subsequent formation of dilute carbonic acid in open containers has a significantly stronger influence on the pH of water, changing it by more than one unit6.

Biological effects are observable for high doses of D2O. While bacteria or yeasts can function in practically pure D2O, albeit with somewhat hindered growth rate7,8,9, for higher organisms damaging effects on cell division and general metabolism occur at around 25% deuteration, with lethal conditions for plants and animals typically occurring at ~40–50% deuteration of the body water2,10,11. Small levels of deuteration are, nevertheless, harmless. This is understandable given the fact that about 1 in every 6400 hydrogens in nature is found in its stable isotope form of deuterium12. Oral doses of several milliliters of D2O are safe for humans13 and are used in the isotopic form D218O for metabolic measurements in clinical praxis (known as “doubly labeled water” technique)14. Probably the best-established effect of D2O is the increase of the circadian oscillation length upon its administration to both animals and plants. This has been attributed to a general slowdown of metabolism upon deuteration, although the exact mechanism of this effect is unknown15,16.

A long-standing unresolved puzzle concerns the taste of heavy water. There is anecdotal evidence from the 1930s that the taste of pure D2O is distinct from the neutral one of pure H2O, being described mostly as “sweet”17. However, Urey and Failla addressed this question in 1935 concluding authoritatively that upon tasting “neither of us could detect the slightest difference between the taste of ordinary distilled water and the taste of pure heavy water”18. This had, with a rare exception19, an inhibitive effect on further human studies, with research concerning effects of D2O focusing primarily on animal or cell models. Experiments in animals indicated that rats developed aversion toward D2O when deuteration of their body water reached harmful levels, but there is conflicting evidence regarding their ability to taste heavy water or use other cues to avoid it20,21.

Within the last two decades, the heterodimer of the taste receptor of the TAS1Rs type of G protein-coupled receptors (GPCRs), denoted as TAS1R2/TAS1R3, was established as the main receptor for sweet taste22. The human TAS1R2/TAS1R3 heterodimer recognizes diverse natural and synthetic sweeteners23. The binding sites of the different types of sweeteners include an orthosteric site (a sugar-binding site in the extracellular Venus flytrap domain of TAS1R2) and several allosteric sites, including sites in the extracellular regions of the TAS1R2 and TAS1R3 subunits and in the transmembrane domain of TAS1R324,25 (Fig. 1). Additional pathways for sweet taste recognition have also been suggested, involving glucose transporters and ATP-gated K+ channel26,27.

Binding sites are represented in yellow. The full receptor heterodimer was prepared with the I-Tasser web server51 based on multiple experimental structures (i.e., 6N51, 5X2M, and 5K5S). The binding site of TAS1R2 is based on coordinates of docked D-glucose to a Venus flytrap (VFT)59 (modeling based on template PDB ID: 5X2M, docking performed with Schrödinger Maestro 2019-1, Glide XP), and the TAS1R3-binding site is based on a lactisole molecule docked to the TAS1R3 TMD model (template PDB IDs: 4OR2 and 4OO9, Schrödinger Maestro 2018-2, Glide SP). The figure was made using ChimeraX (version 0.93)60.

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Interestingly, not all artificial sweeteners are recognized by rodents28. Differences in human and rodent responses to tastants, as well as sweetness inhibitors such as lactisole, have been useful for delineating the molecular recognition of sweet compounds—using human-mouse chimeric receptors, it was shown that the transmembrane domain (TMD) of human TAS1R3 is required for the activating effects of cyclamate29 and for the inhibitory effect of lactisole30.

A combination of TAS1R3 with another member of the TAS1R family, TAS1R1, results in a dimer that mediates umami taste, elicited by molecules such as glutamate or, in case of the rodent umami receptor, other L-amino acids31. Bitter taste is mediated by the taste 2 receptor (TAS2R) gene family32, a branch of Family A GPCRs24. The human genome has 25 TAS2R subtypes and over a thousand of bitter compounds are currently known33, with numerous additional bitter tastants predicted34.

In this study, we systematically address the question of sweet taste of heavy water by a combination of sensory experiments in humans, behavioral experiments in mice, tests on sweet taste receptor-transfected cell lines, and computational modeling including molecular dynamics (MD) simulations. This combined approach consistently leads to the conclusion that the sweet taste of pure D2O is a real effect for human subjects due to activation of the TAS1R2/TAS1R3 sweet taste receptor. While present simulations show, in accord with previous experiments35, that proteins are systematically slightly more rigid and compact in D2O than in H2O, the specific molecular mechanism of the heavy water effect on the TAS1R2/TAS1R3 receptor remains to be established.

Results and discussion

Water purity

We have paid great attention to the purity of the water samples, further degassing and redistilling under vacuum the purest commercially available D2O and H2O. The lack of non-negligible amounts of organic impurities was subsequently confirmed by gas chromatography with mass spectrometry analysis and by experiments with water samples at different levels of purification, see Supplementary Information (SI), Figures S1 and S2. This is extremely important—note in this context that “the vibrational theory of olfaction”, which suggested distinct perception of deuterium isotopes of odorants due to difference in their vibrational spectra36, has been refuted with some of the observed effects turning out to be due to impurities37,38.

Experiments with a human sensory panel

A human sensory panel was employed to study the D2O taste. Triangle tests based on two samples of H2O and one sample of D2O (or vice versa), with random success rate of one-third, were presented to the panelists in a randomized order. Panelists were asked to pick the odd sample out—to smell only, to taste only (with a nose clips), or to taste with open nose. Our results show that humans perceive D2O as being clearly distinguishable from H2O based on its taste: In open nose taste test 22 out of 28 participants identified the odd sample correctly (p = 0.001), and in taste only test 14 out of 26 identified the odd sample correctly (p = 0.03). However, in smell-only triangle test, only 9 out of 25 panelists chose the odd sample correctly (p > 0.05). Data are summarized in Figure S3 in SI.

Next, the perceived sweetness of D2O in increasing proportion to H2O was reported using a 9-point scale, labeled also with verbal descriptions of perceived intensity (1 = no sensation, 3 = slight, 5 = moderate, 7 = very much, 9 = extreme sensation). Sweetness was shown to increase in a D2O-dose-dependent manner, reaching average 3.3 ± 0.4 sweetness (“slight” sweetness) (Fig. 2a). The perceived sweetness of low concentrations of caloric D-glucose (Fig. 2b), sucrose (Fig. 2c), and an artificial sweetener cyclamate (Fig. 2d) was tested when dissolved in H2O or in D2O, in order to check whether the slight sweetness of D2O adds on top of slight sweetness of known sweeteners. As expected39, D-glucose was perceived as less sweet compared to sucrose at the same concentration (Fig. 2b and c). D2O added to the perceived sweetness of all tested concentrations of D-glucose and cyclamate (see Figure S4 in the SI for cyclamate results excluding two outliers). The sweetness of the two lowest concentrations of sucrose was significantly higher when dissolved in D2O compared to H2O.

a Sweetness of D2O mixed at increasing ratios with H2O. Treatments not connected by the same letters are significantly different (p < 0.05 in Tukey Kramer test). bf The effect of D2O (red) compared to H2O (blue) on glucose (b), sucrose (c), cyclamate (d), quinine (e), and MSG (f) taste-specific intensity. Asterisks indicate a significant (p < 0.05) difference between water types using the two-way analysis of variance (ANOVA) with a preplanned comparison t-test. All data are presented as the mean ± the Standard Error of Measurement (SEM); n = 15–30 (4–12 males). The y axis shows the response for individual modalities, while the x axis is labeled with different water samples. Scale for each modality is labeled as 1 = no sensation, 3 = slight, 5 = moderate, 7 = very much, and 9 = extreme sensation.

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We then checked whether the stand-alone and additive effect of D2O is sweetness-specific or general, whereby D2O might elicit other tastes, or add to their intensity. Savory (umami) taste of monosodium glutamate (MSG) and bitter taste of quinine, which are also taste modalities mediated by GPCR receptors expressed in taste cells, were tested in regular and in heavy water. The intensity of savory taste of MSG in D2O did not differ from that in H2O (Fig. 2e), while the perceived bitterness of quinine was in fact slightly reduced in D2O compared to quinine in H2O (Fig. 2f). This is in agreement with the known effect of sweeteners as maskers of bitter taste, that may be due to both local interactions and sensory integration effects40,41,42. Thus, we have ascertained that D2O is sweet and adds to the sweetness of other sweet molecules, but not to the intensity of other GPCR-mediated taste modalities.

Experiments with mice

Next, we addressed the question whether the sweetness of D2O is perceived also by rodents. Lean mice of the C57BL/6J strain were drinking pure H2O, D2O, or a 43 mmol/l H2O sucrose solution for 16 h during a night period. Namely, each of the three groups of mice had a choice from two bottles containing (i) H2O and D2O, (ii) H2O and sucrose solution, or (iii) H2O and H2O (as a control). The food intake was unaffected in all groups (see SI, Figure S5 and Table S1).

The results of the drinking experiments are presented in Fig. 3a–c, with a snapshot of the experimental setup shown in Fig. 3d. In cages where mice were offered both normal water and heavy water (Fig. 3a) consumption of D2O was within statistical error the same as that of H2O. Previous reports have shown that on longer timescales than those reported here mice learned to avoid D2O, as it is poisonous to them in larger quantities10. It is not clear what is the cue that enables the avoidance learning, but it is evident that the early response to D2O is not attractive, suggesting that it is not eliciting sweet taste in mice.

a Volume consumption of D2O is not different from that of H2O (n = 12). b Mice show strong preference to sucrose solution (n = 10). Significance is **p < 0.01, ***p < 0.001. c Volume consumption of the control group drinking H2O only (n = 12). d Snapshot of the automatic drinking monitoring system. Mice were placed in groups of two in individual cages. Data are presented as the mean ± standard error of the mean (SEM). Statistical analysis was performed using two-way ANOVA with a Bonferroni’s multiple comparisons test.

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By contrast, mice exhibit a strong preference for sucrose solution over H2O. Indeed, the consumed volume was significantly increased in line with the predilection of mice for sucrose solutions (Fig. 3b). The amount of H2O consumed by the control group from either of the two bottles, both containing H2O, is depicted in Fig. 3c. Overall, the data shows that in all three experiments mice consumed comparable amounts of H2O and D2O, with significant increase of consumption of the sucrose solution.

Assessing involvement of TAS1R2/TAS1R3 receptor using human sensory panel

The chemical dissimilarity of D2O from sugars and other sweeteners raises the question whether the effect we observed in human subjects is mediated by TAS1R2/TAS1R3, which is the major receptor for sweet taste22. This was first explored by combining water samples with lactisole as an established TAS1R2/TAS1R3 inhibitor30. Using the two-alternative forced-choice (2AFC) method, in which the participant must choose between two samples, 18 out of 25 panelists chose pure D2O as sweeter than D2O + 0.9 mM lactisole solution (p < 0.05, Fig. 4a). In an additional experiment, the sweetness of pure D2O was scored significantly higher than that of D2O + 0.9 mM lactisole solution (p = 0.0003), while the same amount of lactisole had no effect on the perception of sweetness of H2O that served as control (Fig. 4b). These results suggest that D2O elicits sweetness via the TAS1R2/TAS1R3 sweet taste receptor.

a 2AFC test. Pure D2O was chosen to be sweeter (p < 0.05) than the sample with lactisole by 18 participants (n = 25; 11 males). b Effect of 0.9 mM lactisole on sweetness intensity using the 9-point scale. Data are presented as the mean ± SEM. The y axis shows the response for sweetness on a 9-point scale, while the x axis is labeled with different water samples. Statistical analysis was performed using ANOVA with a Tukey Kramer test (n = 27; 9 males); treatments not connected by the same letters are significantly different (p < 0.05). Scale for sweetness is labeled as 1 = no sensation, 3 = slight, 5 = moderate, 7 = very much, and 9 = extreme sensation.

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Cell-based experiments for establishing the role of TAS1R2/TAS1R3

To confirm the involvement of the sweet taste receptor TAS1R2/TAS1R3 in D2O signaling we performed functional calcium mobilization assays using HEK 293 FlpIn T-Rex cells heterologously expressing both required TAS1R subunits as well as the chimeric G protein Gα15Gi343,44. As seen in Fig. 5a, D2O at 1.85 M and 5.84 M concentrations in H2O (3.3% and 10.4%, respectively) elicited robust responses in TAS1R2/TAS1R3 expressing cells. The strong reduction or absence of D2O-elicited fluorescence response in the presence of lactisole confirmed the dependence on TAS1R2/TAS1R3. The inhibitory effect of lactisole on D2O-activation of the human sweet taste receptor was confirmed using an IP1 assay45,46, while lactisole exposure had no effect on cells treated with pure H2O water, as expected (Fig. 5c). As a control, 960 mM D-glucose elicited increase in IP1 levels in TAS1R2/TAS1R3 expressing cell, which was inhibited in the presence of lactisole.

a Dose–response relationship of cells expressing the human sweet taste receptor and treated with different concentrations of D2O (filled red circles, red line). Cells treated with lactisole served as negative controls (open pink circles, pink line). y axis, relative changes in fluorescence upon stimulus application (ΔF/F). x axis, logarithmically scaled molar D2O-concentrations. Asterisks indicate fluorescence changes above baseline significantly different from lactisole-treated controls (p ≤ 0.01). b Raw fluorescence traces of D2O-treated (red-traces, top) and D2O + 0.9 mM lactisole-treated cells (pink-traces, bottom) stimulated with the indicated D2O-concentrations. A scale bar indicating relative fluorescence (relative fluorescence units (RFU) and experimental time (in seconds (s)) is included. c Lactisole inhibitory effect on D2O-activation of the human sweet taste receptor using an IP1 assay. Cells treated with D-glucose served as positive controls. On y axis, relative changes in IP1 accumulation upon stimulus application are shown as % of basal–pure H2O. x axis, different ligands, with and without lactisole. Asterisks indicate IP1 changes that are significantly different from lactisole-treated controls (**p ≤ 0.005 and ****p ≤ 0.0001) using t-test.

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We further used an IP1 assay45,46 on non-transfected HEK 293T cells, where we observed that dose-dependent curves of carbachol—an agonist of the endogenous muscarinic receptor 3 (M3)47—did not show any difference between H2O and D2O-based media (Fig. 6a) and that cell medium that had either 10% or 100% D2O, did not activate basal IP1 accumulation (Fig. 6b). Next, TAS1R2/TAS1R3 receptor along with the chimeric Gα16gust44 subunit44,48 were transiently expressed, and the functionality was illustrated by dose-dependent response to D-glucose (Fig. 6c). Finally, and in agreement with calcium imaging, we found that 10% D2O activated these cells. Activation by 100% D2O was even more pronounced (Fig. 6d).

a Non-transfected HEK 293T cells respond similarly to raising concentrations of carbachol dissolved in D2O (red) as in H2O (blue). b D2O caused no elevation of IP1 levels in non-transfected HEK 293T cells. c HEK 293T cells transiently expressing TAS1R2/TAS1R3 respond positively to D-glucose. d Transfected HEK 293T cells are activated by D2O. Values represent the mean ± SEM of at least three replicates. The horizontal black line represents the basal values of controls. Significant differences in IP1 values from control values are marked with **p ≤ 0.005 and ***p ≤ 0.0005 using Dunnett’s multiple comparisons test.

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Molecular modeling

The cellular response results further support the hypothesis that the sweet taste of D2O is mediated via the TAS1R2/TAS1R3 receptor. Various mechanisms governing this effect can be envisioned. As a potential suspect, we focus on a direct effect on the sweet taste receptor, narrowing on the TAS1R3 TMD (see Fig. 1), as it is already known to be a modulation site with functional differences between humans and rodents23,29,30. Furthermore, water-binding sites were discovered at the TMD of many GPCRs49,50, suggesting a potential target for D2O binding. We modeled the human TAS1R3 TMD using the I-TASSER server51. Positions of H2O molecules were compared among mGluR5 structures (PDB: 4OO9, 5CGC, and 5CGD) and two conserved positions were found. The H2O molecules in these two positions were merged with the TAS1R3 model and minimized (Fig. 7a). The water mapping protocol from OpenEye52 enables mapping of water positions based on the energetics of water, and ~40 water molecules were predicted in the binding site using this protocol (Fig. 7a). Water densities of H2O and D2O in the TMD of the TAS1R2/TAS1R3 receptor were calculated from MD simulations as described below. Overall, all three methods suggest the possibility for at least some internal molecules (trapped in the TMD bundle) in addition to water that surrounds the extracellular and intracellular loops (Fig. 7a).

a Structure of the TMD of the TAS1R2/TAS1R3 receptor with the probability density (volumetric map) of H2O (blue) or D2O (red) molecules within 10 Å from the protein evaluated using the VMD VolMap tool from the MD simulations at an isovalue of 0.1. The conserved water molecules in the X-ray templates are shown in cyan color. Water molecules predicted with the software OpenEye52 are shown in licorice representation. b Time evolution of the radii of gyration in H2O (blue) and D2O (red) from three microsecond-timescale simulations (separated by vertical dashed lines) with total mean values as dashed lines, showing that the protein is more compact in heavy water. c Representative snapshot of the transmembrane part of the human sweet taste receptor color-coded that red/blue represents parts more/less rigid in D2O vs H2O. The embedding lipid membrane is represented in gray. d Difference in root mean square fluctuations in MD trajectories. Negative/positive values mean that structures are more/less rigid in D2O than in H2O. The red line represents the sum over all residues. INT intracellular, EXT extracellular.

Full size image

Next, we carried out microsecond MD simulations of the TMD embedded in a phospatidylcholine (POPC) bilayer in either H2O or D2O (for details including our model of D2O effectively including nuclear quantum effects, see SI, Tables S2–S4). Note that water molecules enter the TMD domain and cluster at positions that partially overlap with the modeled water positions, see Fig. 7a. More precisely, H2O and D2O have mutually slightly shifted densities inside the protein cavity, with H2O overlapping better than D2O with the modeled water positions. Furthermore, MD simulations show clustered water molecules close to the lactisole binding site. These internal positions may have a differential effect between H2O and D2O, though differences between the averaged water densities are not very pronounced. Figure 7b shows the time evolution of the radius of gyration of the TMD domain, while Fig. 7c and d presents the root mean square fluctuations (RMSF) of individual residues of the proteins superimposed on its structure and plotted in a graph together with the mean value of RMSF. A small but significant difference is apparent in the behavior of the protein in H2O vs D2O. Namely, structural fluctuations of most residues (particularly those directly exposed to the aqueous environment) and of the protein as a whole are slightly attenuated in D2O, in which environment the protein is also somewhat more compact than in H2O (Fig. 7b). Additional simulations on other representative systems show that the rigidifying effect of heavy water is apparent also in small soluble proteins (see SI, Figs. S6–S8).

Summary and outlook

Sweet taste never ceases to surprise. Over a decade ago, water was shown to elicit sweet taste by rinsing away inhibitors of sweet taste receptors, both in human sensory experiments and in cell-based studies. This effect was explained in terms of a two-state model, where the receptor shifts to its activated state when released from inhibition by rinsing with water43. Here, we have studied the taste of D2O and H2O per se, not related to washing away of sweet taste inhibitors. Using psychophysics protocols, we show that humans differentiate between D2O and H2O based on taste alone. Importantly, by employing gas chromatography/mass spectrometry analysis we demonstrate that the sweet taste of deuterated water is not due to impurities. Being only isotopically different from H2O, in principle, D2O should be indistinguishable from H2O with regard to taste, namely it should have no taste of its own. Yet, we illustrate that human subjects consistently perceive D2O as being slightly sweet and significantly sweeter than H2O. Furthermore, D2O added to perceived sweetness of low concentrations of other sweeteners. In contrast, it did not elicit umami or bitter taste on its own, nor did it add to the umami taste perception of MSG. D2O did not add to the bitterness of quinine, and reduced the perceived bitterness of 0.1 mM quinine, in agreement with the known effect of bitterness suppression by sweet molecules.

A further important finding is that lactisole, which is an established blocker of the TAS1R2/TAS1R3 sweet taste receptor that acts at the TAS1R3 transmembrane domain30, suppresses both the sweet perception of D2O in sensory tests, as well as the activation of TAS1R/TAS1R3 in calcium imaging and in IP1 cell-based assays. In support of these observations we have demonstrated that HEK 293T cells transfected with TAS1R2/TAS1R3 and Gα16gust44 chimera, but not the non-transfected cells, are activated by D2O, as measured by IP1 accumulation compared to control values. Finally, taste experiments on mice show that these animals do not prefer D2O over H2O.

Our findings point to the human sweet taste receptor TAS1R2/TAS1R3 as being essential for sweetness of D2O. Molecular dynamics simulations show, in agreement with experiment35, that proteins in general are slightly more rigid and compact in D2O than in H2O. At a molecular level, this general behavior may be traced back to the slightly stronger hydrogen bonding in D2O vs H2O, which is due to a nuclear quantum effect, namely difference in zero-point energy3,4. Biologically relevant situations where one may expect strong nuclear quantum effects as implications of H/D substitution directly involve proton or deuteron transfer9. Unless a yet unknown indirect mechanism is involved, this is not the case for the TAS1R2/TAS1R3 sweet taste receptor, thus the nuclear quantum effect is probably weak in the present case. Future studies should be able to elucidate the precise sites and mechanisms of action, as well as the reason why D2O activates TAS1R2/TAS1R3 in particular, resulting in sweet (but not other) taste. To this end, site-directed mutagenesis as well as determination of the precise structure of the TAS1R2/TAS1R3 receptor will be of key importance.

The finding that deuterated water elicits sweet taste via activation of TAS1R/TAS1R2 receptor is of fundamental interest. The difference between hydrogen isotopes is the largest possible isotope effect (doubling of mass in case of deuterium, while tripling in case of tritium), yet deuteration effects on water are generally mild. Nevertheless, water deuteration leads to activation of a GPCR heterodimer to a level that is perceived by humans as sweet taste. While clearly not a practical sweetener, heavy water provides a glimpse into the wide-open chemical space of sweet molecules. Since heavy water may be used in medical procedures, our finding that it can elicit responses of the sweet taste receptor, which is not only located on the tongue but also in other tissues of the human body, represents an important information for clinicians and their patients. Moreover, due to wide application of D2O in chemical structure determination by NMR, chemists will benefit from being aware of the present observations.

Methods

Sensory evaluation experiments

A human sensory panel was used to resolve the gustatory effect in perception of D2O taste. Subjects between the ages 20 and 43 years were recruited. The study included 10 experiments with different groups of participants (15–30 subjects; between 4 and 12 males). The perception was tested by sensory tests as detailed below. Either sterile syringes with solutions (0.3 ml) or identical cups with solutions (7 ml), were presented in randomized order, unless otherwise noted. Participants were required to taste each solution using either ‘tip of the tongue’ or ‘sip and spit’ procedures, rinse their mouth with water after each solution and to wait for 30 s before moving to the next taste sample. All research procedures were ethically approved by the Committee for the Use of Human Subjects in Research in The Robert H. Smith Faculty of Agriculture Food and Environment, the Hebrew University of Jerusalem.

99.9% purity D2O was purchased from Sigma-Aldrich Corp, while 18 MΩ ultrapure grade was used for pure H2O. All water samples were placed under vacuum and treated by ultrasound to remove any dissolved gases. See below for more details on water purification.

D-glucose (CAS Number: 50-99-7), sucrose (CAS Number: 57-50-1), cyclamate (CAS Number: 139-05-9), quinine (CAS Number: 207671-44-1), and MSG (CAS Number: 142-47-2) were purchased from Sigma-Aldrich Corp. All compounds were dissolved in both types of water to a final concentration of 50, 75, and 100 mM for D-glucose and sucrose; 3.5, 4.5, and 5.5 mM for cyclamate; 0.1 and 0.32 mM for quinine; 10, 25, and 50 mM for MSG. Lactisole (CAS Number: 150436-68-3) was purchased from Domino Specialty Ingredients and dissolved to a final concentration of 0.9 mM in D2O water as well as in H2O. The concentration of lactisole was selected based on previous data43,53 and preliminary experiments in our lab, which showed that 0.9 mM decreases the sweetness of 100 mM sucrose. Sweeteners concentrations were selected to be in low intensity of sweetness. All solutions were prepared in the morning of the day of the experiment and were stored in individual plastic syringes (1 ml) for each participant.

The sweetness of heavy water and its effect on other taste compounds was evaluated in several independent experiments: (1) D2O sweetness relative to H2O (Fig. 2a); (2) D2O effect on sweetness of D-glucose (Fig. 2b), sucrose (Fig. 2c), and cyclamate (Fig. 2d); (3) D2O effect on quinine (Fig. 2e) and MSG (Fig. 2f); (4) Lactisole effect on D2O sweetness (Fig. 4b); Intensity of each taste modality—sweetness/bitterness/umami was evaluated on a 9-point scale on Compusense Cloud, ranging from 1 (no sensation) to 9 (extremely strong sensation). In addition, participants had to report any additional tastes they recognized. Statistical tests were conducted using JMP Pro 13 (JMP, Version 13. SAS Institute Inc., Cary, NC, 1989–2019).

Data were first analyzed employing ANOVA with participants as a random effect54. Thereafter, the Tukey Kramer test was used to compare mean sweetness between all samples54. Significance was set at p < 0.05, and preplanned comparison t-tests were used where relevant.

Details concerning the Two-Alternative Forced Choice test55 were as follows: Participants were presented with two blind coded water samples of D2O and D2O + 0.9 mM lactisole. The participants were asked to choose the sweeter solution. For the data analysis, the highest number of responses for one sample was compared to a statistical table55 which states the minimum number of responses required for a significant difference.

Panelists were presented with two identical and one different water samples. All three samples were presented to the subjects at once, and the panelists were instructed to taste or smell the samples from left to right and identify the odd sample. Triangle tests were used to examine the difference in taste, as well as in smell, between H2O and D2O.

Heterologous expression

TAS1R2/TAS1R3 stimulated activation of the G-protein-mediated pathway was measured applying the IP-One HTRF assay (Cisbio) based on the manufacturer’s protocol. In brief, HEK 293T cells (ATCC) were grown to a confluency of ~85–90% and transiently transfected with 6 μg/plate DNA (TAS1R2, TAS1R3, Gα16gust44) by applying LipofectamineTM 2000 (Invitrogen, USA, 30 μl/plate) transfection reagent, according to the manufacturer’s protocol. The next day, cells were suspended with fresh Dulbecco’s modified Eagle’s medium (DMEM), containing 10% fetal bovine serum (FBS), 1% L-glutamine amino acid and 1% penicillin streptomycin (10% DMEM), seeded (0.5 ml cells per well) into 24-well culture plate, and maintained for 8–12 h at 37 °C. Then cells were “starved” overnight by changing the medium to 0.1% DMEM (containing 0.1% FBS), in order to reduce the basal activity of the cells. Cells exposure was performed by addition of 0.5 ml tested compound (pH = 7.4) dissolved in 0.1% DMEM with 50 mM lithium chloride (LiCl) for 5 min directly into the wells. The presence of LiCl in this step is crucial because LiCl leads to IP1 accumulation45. At the end of exposure time, tastant solution was replaced with fresh medium (0.1% DMEM) containing 50 mM LiCl for another 55 min. Later, wells were washed with 100 μl cold phosphate-buffered saline (PBS) + Triton X-100, and kept at −80 °C for a few hours, in order to dissolve the cell membrane. For the IP-One HTRF assay, cell lysate was mixed with the detection reagents (IP1-d2 conjugate and Anti-IP1 cryptate TB conjugate, each dissolved in lysis buffer), and added to each well in a 384-well plate for 60 min incubation at room temperature. Finally, the plate was read using Clariostar plate reader (BMG, Germany) equipped with 620 ± 10 nm and 670 ± 10 nm filters. IP1 levels were measured by calculating the 665 nm/620 nm emission ratio.

All responses are presented as the means ± SEM of IP1 accumulation (%). Dose–response curves were fitted by non-linear regression using the algorithms of PRISM 7 (GraphPad Software, San Diego, CA, USA). Column figures were analyzed using one-way ANOVA with a Dunnett’s54. Each compound was tested in triplicate in three individual experiments in comparison to the reference (carbachol dissolved in H2O or basal levels)45.

In the case of D2O, in order to test its specific effect, we used a powder DMEM medium (CAS Number: D5030, Sigma-Aldrich), dissolved in the needed amount of D2O instead of the liquid one. Other ligands than D2O were purchased from Sigma-Aldrich or Domino Specialty Ingredients as noted above. Unless noted otherwise, ligands were used at final concentrations of 5, 50, 480, 960, 1.8 × 103, and 2.1 × 103 mM for D-glucose; 0.1, 1, and 15 mM for carbachol and D2O at 0–100% proportionately to H2O. Since there was no prior literature on concentrations of lactisole for this assay, the value of 2 mM was chosen based on preliminary experiment with several lactisole concentrations and their effect on IP1 values due to exposure to D-glucose.

For the functional assays with the human sweet taste receptor, we used a cell line (HEK 293 FlpIn T-Rex), which constitutively expresses the sweet taste receptor subunit TAS1R2 as well as the chimeric G protein Gα15gi3, whereas the sweet taste receptor subunit TAS1R3 can be induced by tetracycline43,44. Gαi3 is one of the major species of Gα-subunits capable of coupling to taste receptors, along with Gα-gustducin, GαS, and Gαi256,57 and TAS1R2-TAS1R3-Gαi3 cell system was successfully used in a previous study43. The functional experiments were done as described before44. Briefly, the cells were grown in DMEM supplemented with 10% fetal bovine serum, 100 U Penicillin/ml, 0.1 mg/ml Streptomycin, 2 mM L-glutamine, at 37 °C and 5%-CO2, 100% air humidity. The day before the experiment, cells were seeded to a density of 50–60% onto 96-well plates coated with 10 µg/ml poly-D-lysine and 0.5 µg/ml tetracycline was added. Next, cells were loaded with Fluo-4 AM in the presence of 2.5 mM probenecid for 1 h. After this, cells were washed twice with C1-buffer (130 mM NaCl, 5 mM KCl, 10 mM HEPES, 1 mM sodium pyruvate, and 2 mM CaCl2, pH 7.4) before placing them in a fluorometric imaging plate reader (FLIPRtetra, Molecular Devices) for measurements.

C1-buffer prepared with D2O was mixed with C1-buffer made with H2O to result in the following final D2O-concentrations (a further threefold dilution, which occurs upon application of 50 µL stimulus to 100 µL of C1-buffer in the 96-well plates is already included): 18.47, 5.84, 1.85, 0.584, 0.185, 0.058, 0.018, and 0.000 M. Fluorescence changes were monitored after automated application of stimuli. As specificity control C1-D2O including 0.9 mM lactisole, a selective inhibitor of the human sweet taste receptor58, was applied to identically treated cells. This concentration is the same as used in sensory experiments and close to the 1 mM used in calcium assays in previous work43. Experimental results from five biological replicates performed in quadruplicates were used to establish the dose–response relationship using the software SigmaPlot as before44. As the highest D2O-concentration resulted in fluorescence changes largely resistant to lactisole blocking, the 18.47 M concentration was excluded. Student’s t-test was used to confirm that D2O-induced fluorescence changes above baseline were significantly (p ≤ 0.01) different from lactisole-treated controls.

Animal experiments

All animal experiments followed the ethical guidelines for animal experiments and the Act of the Czech Republic Nr. 246/1992 and were approved by the Committee for Experiments with Laboratory Animals of the Czech Academy of Sciences. Three-month-old male C57BL/6J mice (n = 34) from Charles Rivers Laboratories (Sulzfeld, Germany) were housed at a temperature of 23 °C with a daily cycle of 12 h light and dark (lights on at 6 am). The mice were placed in groups of two in cages with automatic drinking monitoring system (Developmental Workshops of Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic). They were given ad libitum water and a standard rodent chow diet (Ssniff Spezialdiäten GmbH, Soest, Germany). On the day of the experiment, during the dark phase of the cycle, freely fed mice were given weighed food pellets and two 30 ml glass bottles. The two bottles contained pure H2O and pure D2O (n = 12), or H2O and sucrose solution (43 mmol/l sucrose solution in H2O) (n = 10), see Table S1. Mice drinking H2O in both bottles served as a control group (n = 12). Drinking was monitored every 10 min for 16 h (starting from 6 pm) and food intake was determined at the end of the experiment (Figure S5).

All responses are presented as the means ± SEM. Statistical analysis was performed using ANOVA with a Dunnett’s test54 for food intake. Two-way ANOVA with a Bonferroni’s multiple comparisons test was used for analysis of average volume of liquid consumption. Analysis was performed using GraphPad Software, Inc., Prism 8 (GraphPad Software, San Diego, CA, USA). The differences between the control and treated groups were considered significant at p < 0.05.

Modeling and docking

All models were prepared with I-Tasser web server51. The templates that were used by I-Tasser for each of the TAS1R2 and TAS1R3 monomers were: 6N51, 5X2M, and 5K5S. To model the full heterodimer, the monomer models were aligned to a Class-C GPCR Cryo-EM structure (PDB: 6N51) and minimized with Schrödinger Maestro 2019-1. To illustrate the orthosteric binding site of sugars D-glucose was prepared (Schrödinger Maestro 2019-1, LigPrep) and docked with Glide XP, to the TAS1R2 VFT domain model that was based on 5X2M in a protocol that was validated in previous work59. The TAS1R3-binding site is based on a lactisole molecule docked to TAS1R3 TMD model (Schrödinger Maestro 2018-2, Glide SP, template PDB ID: 4OR2 and 4OO9). The figure was made using ChimeraX (version 0.93)60. Water molecules were predicted with a water mapping software (SZMAP 1.5.0.2: OpenEye52) after a successful benchmark over conserved water templates (PDB IDs 5CGC and 5CGD), in which the software was able to identify overall 8 out of 10 crystal water molecules around the ligands of the templates.

Reporting summary

Further information on research design is available in the Nature Research Reporting Summary linked to this article.

Data availability

The data sets generated during the current study are available as Supplementary Data.

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Источник: https://www.nature.com/articles/s42003-021-01964-y
Question of the Week
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Источник: https://www.animationmagazine.net/question_of_the_week.php

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2 Replies to “Keyword Researcher Pro13.152 Keygen - Free Activators”

  1. Idk how ur setup works ive never tried it, but with mine i can only tap strafe the direction im facing

  2. j'ai un iphone 6S mais lorsque j’appuie sur le bouton principal il revient toujours vers l’écran de verrouillage affichant iphone verouiller

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