Inhibition of polo-like kinase 1 (Plk1) enhances the antineoplastic activity of metformin in prostate cancer

The widely used anti-diabetic drug metformin has been shown to exert strong antineoplastic actions in numerous tumor types, including prostate cancer (PCa). In this study, we show that BI2536, a specific Plk1 inhibitor, acted synergistically with metformin in inhibiting PCa cell proliferation. Furthermore, we also provide evidence that Plk1 inhibition makes PCa cells carrying WT p53 much more sensitive to low-dose metformin treatment. Mechanistically, we found that co-treatment with BI2536 and metformin induced p53-dependent apoptosis and further activated the p53/Redd-1 pathway. Moreover, we also show that BI2536 treatment inhibited metformin-induced glycolysis and glutamine anaplerosis, both of which are survival responses of cells against mitochondrial poisons. Finally, we confirmed the cell-based observations using both cultured cell-derived and patient-derived xenograft studies. Collectively, our findings support another promising therapeutic strategy by combining two well tolerated drugs against PCa proliferation and the progression of androgen-dependent PCa to the castration-resistant stage

Immune escape and metastasis mechanisms in melanoma: breaking down the dichotomy

Melanoma is one of the most lethal neoplasms of the skin. Despite the revolutionary introduction of immune checkpoint inhibitors, metastatic spread, and recurrence remain critical problems in resistant cases. Melanoma employs a multitude of mechanisms to subvert the immune system and successfully metastasize to distant organs. Concerningly, recent research also shows that tumor cells can disseminate early during melanoma progression and enter dormant states, eventually leading to metastases at a future time. Immune escape and metastasis have previously been viewed as separate phenomena; however, accumulating evidence is breaking down this dichotomy. Recent research into the progressive mechanisms of melanoma provides evidence that dedifferentiation similar to classical epithelial to mesenchymal transition (EMT), genes involved in neural crest stem cell maintenance, and hypoxia/acidosis, are important factors simultaneously involved in immune escape and metastasis. The likeness between EMT and early dissemination, and differences, also become apparent in these contexts. Detailed knowledge of the mechanisms behind “dual drivers” simultaneously promoting metastatically inclined and immunosuppressive environments can yield novel strategies effective in disabling multiple facets of melanoma progression. Furthermore, understanding progression through these drivers may provide insight towards novel treatments capable of preventing recurrence arising from dormant dissemination or improving immunotherapy outcomes

One Health for Dog-mediated Rabies Elimination in Asia. A Collection of Local Experiences

Although an effective human rabies vaccine has existed since 1885, rabies continues to kill an estimated 59,000 people every year. Sixty per cent of these human deaths occur in Asia. The number of animals, especially dogs, who die of rabies is uncalculated. To work towards the global target of eliminating dog-mediated human rabies deaths, the rabies community is applying the One Health approach by jointly focusing on humans and dogs. Written by a multidisciplinary group of scholars and rabies control programme specialists, this book is a collection of experiences and observations on the challenges and successes along the path to rabies control and prevention in Asia. The book: grounds chapters in solid scientific theory, but retains a direct, practice-focused and inspirational approach;provides numerous examples of lessons learned and experience-based knowledge gained across countries at different levels of rabies elimination;brings together and highlights the practices of a strong, international rabies network that works according to the One Health concept. Covering perspectives from almost a dozen Asian countries and a wide range of sectors and disciplines, such as healthcare facilities, veterinary services, laboratories, public health institutes, wildlife research centres and academia, this book is an invaluable resource for rabies practitioners and scholars, but also those working in the wider fields of disease control and cross-sectoral One Health

Herbal drugs: knowledge, attitude and practice of its concurrent use with allopathic drugs, scientific testing and effectiveness in common diseases among educated class

Background: Craving for a holistic approach for healthcare and concern about side effect of the chemically produced drug is increasing interest in herbal medicine. There is a favourable perception about its effectiveness in complete cure of certain diseases. Its regulation, concurrent use with allopathic medicine and scientific testing has always been of concern.Methods: Cross sectional descriptive study was done using predesigned questionnaire among the educated class. Socio-demographic data, attitude and practice about simultaneous use, effectiveness in common disease, scientific testing and regulation of herbal medicine were asked. Also a rating of different system of medicine i.e allopathy, unani, ayurveda, homeopathy was asked.Results: Total completed participants were 120. Across level of education use of herbal medicine was 55% in the last 1 year, 56.7% have used or intend to use herbal along with allopathic and only 18.9 % tell it to treating physician. 50% consider concurrent use as safe, 43% believe it cures completely, 31.7% consider equally effective than allopathic and 95% have not encountered any side effect or allergic reaction with it. A majority did not know about any scientific testing and clinical study of herbal drugs.Conclusions: Herbal medicines have very positive perception. The regulatory authorities are also patronising it in many countries. They are also being used along with allopathic medicine and many times even without knowledge of treating doctor. The perception about herbal medicine is historical based on personal or clinical experiences, mostly lacking with good grade of strength of evidence. There is need to have Level Ia or Ib evidence for their effectiveness and safety

What Is New for an Old Molecule? Systematic Review and Recommendations on the Use of Resveratrol

BACKGROUND: Resveratrol is a natural compound suggested to have beneficial health effects. However, people are consuming resveratrol for this reason without having the adequate scientific evidence for its effects in humans. Therefore, scientific valid recommendations concerning the human intake of resveratrol based on available published scientific data are necessary. Such recommendations were formulated after the Resveratrol 2010 conference, held in September 2010 in Helsingør, Denmark. METHODOLOGY: Literature search in databases as PUBMED and ISI Web of Science in combination with manual search was used to answer the following five questions: (1)Can resveratrol be recommended in the prevention or treatment of human diseases?; (2)Are there observed side effects caused by the intake of resveratrol in humans?; (3)What is the relevant dose of resveratrol?; (4)What valid data are available regarding an effect in various species of experimental animals?; (5)Which relevant (overall) mechanisms of action of resveratrol have been documented? CONCLUSIONS/SIGNIFICANCE: The overall conclusion is that the published evidence is not sufficiently strong to justify a recommendation for the administration of resveratrol to humans, beyond the dose which can be obtained from dietary sources. On the other hand, animal data are promising in prevention of various cancer types, coronary heart diseases and diabetes which strongly indicate the need for human clinical trials. Finally, we suggest directions for future research in resveratrol regarding its mechanism of action and its safety and toxicology in human subjects

CrossCodeEval: A Diverse and Multilingual Benchmark for Cross-File Code Completion

Code completion models have made significant progress in recent years, yet current popular evaluation datasets, such as HumanEval and MBPP, predominantly focus on code completion tasks within a single file. This over-simplified setting falls short of representing the real-world software development scenario where repositories span multiple files with numerous cross-file dependencies, and accessing and understanding cross-file context is often required to complete the code correctly. To fill in this gap, we propose CrossCodeEval, a diverse and multilingual code completion benchmark that necessitates an in-depth cross-file contextual understanding to complete the code accurately. CrossCodeEval is built on a diverse set of real-world, open-sourced, permissively-licensed repositories in four popular programming languages: Python, Java, TypeScript, and C#. To create examples that strictly require cross-file context for accurate completion, we propose a straightforward yet efficient static-analysis-based approach to pinpoint the use of cross-file context within the current file. Extensive experiments on state-of-the-art code language models like CodeGen and StarCoder demonstrate that CrossCodeEval is extremely challenging when the relevant cross-file context is absent, and we see clear improvements when adding these context into the prompt. However, despite such improvements, the pinnacle of performance remains notably unattained even with the highest-performing model, indicating that CrossCodeEval is also capable of assessing model's capability in leveraging extensive context to make better code completion. Finally, we benchmarked various methods in retrieving cross-file context, and show that CrossCodeEval can also be used to measure the capability of code retrievers.Comment: To appear at NeurIPS 2023 (Datasets and Benchmarks Track

ContraGen: Effective Contrastive Learning For Causal Language Model

Despite exciting progress in large-scale language generation, the expressiveness of its representations is severely limited by the \textit{anisotropy} issue where the hidden representations are distributed into a narrow cone in the vector space. To address this issue, we present ContraGen, a novel contrastive learning framework to improve the representation with better uniformity and discrimination. We assess ContraGen on a wide range of downstream tasks in natural and programming languages. We show that ContraGen can effectively enhance both uniformity and discrimination of the representations and lead to the desired improvement on various language understanding tasks where discriminative representations are crucial for attaining good performance. Specifically, we attain $44\%$ relative improvement on the Semantic Textual Similarity tasks and $34\%$ on Code-to-Code Search tasks. Furthermore, by improving the expressiveness of the representations, ContraGen also boosts the source code generation capability with $9\%$ relative improvement on execution accuracy on the HumanEval benchmark.Comment: 10 page

Epigallocatechin-3-gallate induces mesothelioma cell death via H2O2-dependent T-type Ca2+ channel opening

Malignant mesothelioma (MMe) is a highly aggressive, lethal tumour requiring the development of more effective therapies. The green tea polyphenol epigallocathechin-3-gallate (EGCG) inhibits the growth of many types of cancer cells. We found that EGCG is selectively cytotoxic to MMe cells with respect to normal mesothelial cells. MMe cell viability was inhibited by predominant induction of apoptosis at lower doses and necrosis at higher doses. EGCG elicited H2O2release in cell cultures, and exogenous catalase (CAT) abrogated EGCG-induced cytotoxicity, apoptosis and necrosis. Confocal imaging of fluo 3-loaded, EGCG-exposed MMe cells showed significant [Ca2+]irise, prevented by CAT, dithiothreitol or the T-type Ca2+channel blockers mibefradil and NiCl2. Cell loading with dihydrorhodamine 123 revealed EGCG-induced ROS production, prevented by CAT, mibefradil or the Ca2+chelator BAPTA-AM. Direct exposure of cells to H2O2produced similar effects on Ca2+and ROS, and these effects were prevented by the same inhibitors. Sensitivity of REN cells to EGCG was correlated with higher expression of Cav3.2 T-type Ca2+channels in these cells, compared to normal mesothelium. Also, Cav3.2 siRNA on MMe cells reduced in vitro EGCG cytotoxicity and abated apoptosis and necrosis. Intriguingly, Cav3.2 expression was observed in malignant pleural mesothelioma biopsies from patients, but not in normal pleura. In conclusion, data showed the expression of T-type Ca2+channels in MMe tissue and their role in EGCG selective cytotoxicity to MMe cells, suggesting the possible use of these channels as a novel MMe pharmacological target. \ua9 2012 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd

Evasion of anti-growth signaling: a key step in tumorigenesis and potential target for treatment and prophylaxis by natural compounds

The evasion of anti-growth signaling is an important characteristic of cancer cells. In order to continue to proliferate, cancer cells must somehow uncouple themselves from the many signals that exist to slow down cell growth. Here, we define the anti-growth signaling process, and review several important pathways involved in growth signaling: p53, phosphatase and tensin homolog (PTEN), retinoblastoma protein (Rb), Hippo, growth differentiation factor 15 (GDF15), AT-rich interactive domain 1A (ARID1A), Notch, insulin-like growth factor (IGF), and Krüppel-like factor 5 (KLF5) pathways. Aberrations in these processes in cancer cells involve mutations and thus the suppression of genes that prevent growth, as well as mutation and activation of genes involved in driving cell growth. Using these pathways as examples, we prioritize molecular targets that might be leveraged to promote anti-growth signaling in cancer cells. Interestingly, naturally-occurring phytochemicals found in human diets (either singly or as mixtures) may promote anti-growth signaling, and do so without the potentially adverse effects associated with synthetic chemicals. We review examples of naturally-occurring phytochemicals that may be applied to prevent cancer by antagonizing growth signaling, and propose one phytochemical for each pathway. These are: epigallocatechin-3-gallate (EGCG) for the Rb pathway, luteolin for p53, curcumin for PTEN, porphyrins for Hippo, genistein for GDF15, resveratrol for ARID1A, withaferin A for Notch and diguelin for the IGF1-receptor pathway. The coordination of anti-growth signaling and natural compound studies will provide insight into the future application of these compounds in the clinical setting