Targeting the Epithelial-to-Mesenchymal Transition: The Case for Differentiation-Based Therapy

Although important strides have been made in targeted therapy for certain leukemias and subtypes of breast cancer, the standard of care for most carcinomas still involves chemotherapy, radiotherapy, surgery, or a combination of these. Two processes serve as obstacles to the successful treatment of carcinomas. First, a majority of deaths from these types of cancers occurs as a result of distant metastases and not the primary tumors themselves. Second, subsets of cells that are able to survive conventional therapy drive the aggressive relapse of the tumors, often in forms that are resistant to treatment. A frequently observed feature of malignant carcinomas is the loss of epithelial traits and the gain of certain mesenchymal ones that are programmed by the cell-biological program termed the epithelial-to-mesenchymal transition (EMT). The EMT program can confer (i) an ability to disseminate, (ii) an ability to become stem-like tumor-initiating cells, (iii) an ability to found new tumor colonies at distant anatomical sites, and (iv) an elevated resistance to therapy. These multiple powers of the EMT program explain why it has become an attractive target for therapeutic intervention. Recent work has revealed the variable nature of the EMT, with multiple versions of the program being observed depending on the tissue context and the stage of tumor progression. In this review, we attempt to crystallize emerging concepts in the research on EMTand stemness and discuss the benefits of using a differentiation-based therapeutic strategy for the eradication of stem-like populations that have adopted various versions of the EMT program.National Institutes of Health (U.S.) (grant R01 CA078461)National Institutes of Health (U.S.) (grant (P01 CA080111)Samuel Waxman Cancer Research FoundationMassachusetts Institute of Technology. Ludwig Center for Cancer Researc

Tackling the cancer stem cells — what challenges do they pose?

Since their identification in 1994, cancer stem cells (CSCs) have been objects of intensive study. Their properties and mechanisms of formation have become a major focus of current cancer research, in part because of their enhanced ability to initiate and drive tumour growth and their intrinsic resistance to conventional therapeutics. The discovery that activation of the epithelial-to-mesenchymal transition (EMT) programme in carcinoma cells can give rise to cells with stem-like properties has provided one possible mechanism explaining how CSCs arise and presents a possible avenue for their therapeutic manipulation. Here we address recent developments in CSC research, focusing on carcinomas that are able to undergo EMT. We discuss the signalling pathways that create these cells, cell-intrinsic mechanisms that could be exploited for selective elimination or induction of their differentiation, and the role of the tumour microenvironment in sustaining them. Finally, we propose ways to use our current knowledge of the complex biology of CSCs to design novel therapies to eliminate them.National Institutes of Health (U.S.) (Grant U54-CA163109)United States. Army Research Office (Grant 1210095

Effect of HIV-1 infection on T-Cell-based and skin test detection of tuberculosis infection

RATIONALE: Two forms of the IFN-gamma release assay (IFNGRA) to detect tuberculosis infection are available, but neither has been evaluated in comparable HIV-infected and uninfected persons in a high tuberculosis incidence environment. OBJECTIVE: To compare the ability of the T-SPOT.TB (Oxford Immunotec, Abingdon, UK), QuantiFERON-TB Gold (Cellestis, Melbourne, Australia), and Mantoux tests to identify latent tuberculosis in HIV-infected and uninfected persons. METHODS: A cross-sectional study of 160 healthy adults without active tuberculosis attending a voluntary counseling and testing center for HIV infection in Khayelitsha, a deprived urban South African community with an HIV antenatal seroprevalence of 33% and a tuberculosis incidence of 1,612 per 100,000. MEASUREMENTS AND MAIN RESULTS: One hundred and sixty (74 HIV(+) and 86 HIV(-)) persons were enrolled. A lower proportion of Mantoux results was positive in HIV-infected subjects compared with HIV-uninfected subjects (p < 0.01). By contrast, the proportion of positive IFNGRAs was not significantly different in HIV-infected persons for the T-SPOT.TB test (52 vs. 59%; p = 0.41) or the QuantiFERON-TB Gold test (43 and 46%; p = 0.89). Fair agreement between the Mantoux test (5- and 10-mm cutoffs) and the IFNGRA was seen in HIV-infected people (kappa = 0.52-0.6). By contrast, poor agreement between the Mantoux and QuantiFERON-TB Gold tests was observed in the HIV-uninfected group (kappa = 0.07-0.30, depending on the Mantoux cutoff). The pattern was similar for T-SPOT.TB (kappa = 0.18-0.24). Interpretation: IFNGRA sensitivity appears relatively unimpaired by moderately advanced HIV infection. However, agreement between the tests and with the Mantoux test varied from poor to fair. This highlights the need for prospective studies to determine which test may predict the subsequent risk of tuberculosis

Violent conflict and breastfeeding: the case of Iraq

Background: This study explores the relationship between armed conflict and breastfeeding practices of Iraqi mothers. To date, the relationship between violent conflict and breastfeeding is surprisingly understudied. Especially in the Middle East, which is conflict-prone and has a young population, research on war and household behavior is critical for promoting recovery and sustainable development. Methods: This study employs a unique pairing of the Iraq Body Count Database and the 2006 and 2011 Multiple Indicator Cluster Surveys for Iraq. We use probit models to explore the association between armed conflict and several breastfeeding outcomes – whether a child was ever breastfed, whether a child was breastfed within 1 h after birth, whether a child is currently breastfed, and whether an infant under 6 months of age is exclusively breastfed. Our proxies for conflict intensity are the average rate of conflict-related casualties across the 3 years prior to survey administration and the rate of casualties averaged across the 2 years prior to the birth of the child, in the governorate in which the family resides. We employ a number of other independent variables important for breastfeeding status, including health controls and characteristics of the household, child and mother. We also use a Cox proportional hazards model to study the association between conflict and breastfeeding duration. We complement this analysis with various robustness checks, including disaggregation by year, controls for household wealth and an analysis of breastmilk substitutes and their potential for an interaction with household wealth. Results: We find in our main results that increases in conflict-related casualties are associated with a significant decline in the probability that a child was ever breastfed and a decline in the probability that a child is currently breastfeeding. There is no significant association with exclusive breastfeeding or with initiation of breastfeeding within 1 h after birth. This result is robust to alternative measures of conflict, although some coefficients from estimation based on the 2006 subsample are positive and not significant, and reverse causation is a potential source of bias in interpreting cross-sectional feeding patterns. Results on breastfeeding duration are mixed. Our results also suggest an increase in the use of breastfeeding substitutes like formula concurrent to higher levels of conflict among wealthier households. Conclusion: The results are informative in the context of designing policy aimed at stabilizing the long-term health and productivity of populations in conflict areas. Infant formula provided with the objective of offering temporary relief creates risks, including reducing the probability and duration of breastfeeding. Attention to the supply of health care and to support systems for women, especially skilled breastfeeding support and targeted support to infants dependent on formula, are matters of the utmost urgency during and after conflict periods

Effectiveness of Resistance Training on the Strength of Scapulo-humeral Muscles and Abdominals in Male Volley Ball Players

Background: Volleyball is a sportive modality that requires strength in the upper and lower extremities along with the trunk musculature. The improvement of muscular strength is very important along with agility and flexibility for a volleyball player. Aim of the study to find the effectiveness of resistance training on the strength of scapulo-humeral muscles and abdominals in male volley ball players. Objectives of this study is find out the effect of resistance training on the strength of the scapulo-humeral muscles by measuring peak torque by using an isokinetic dynamometer and to find out the effect of resistance training on strength of abdominals through 1RM test. Methods: A group of 30 male volleyball players who have fulfilled the inclusion criteria were assigned into two groups control and experimental groups each consisting of 15 subjects. The subjects of the experimental group underwent resistance training under my supervision and the subjects of the control group done the same protocol unsupervised for 6 weeks. Results: There was significant improvement in the strength of scapula-humeral muscles and abdominals in the experimental group when compared to the control group when the pre and post intervention values were measured (p=0.05). Conclusion: Resistance training under supervision of the therapist resulted in significant improvement in strength of the scapulo-humeral muscles and abdominals in the male volleyball players

Emerging Biological Principles of Metastasis

Metastases account for the great majority of cancer-associated deaths, yet this complex process remains the least understood aspect of cancer biology. As the body of research concerning metastasis continues to grow at a rapid rate, the biological programs that underlie the dissemination and metastatic outgrowth of cancer cells are beginning to come into view. In this review we summarize the cellular and molecular mechanisms involved in metastasis, with a focus on carcinomas where the most is known, and we highlight the general principles of metastasis that have begun to emerge

Dietary Conjugated Linoleic Acid and Hepatic Steatosis: Species-Specific Effects on Liver and Adipose Lipid Metabolism and Gene Expression

Objective. To summarize the recent studies on effect of conjugated linoleic acid (CLA) on hepatic steatosis and hepatic and adipose lipid metabolism highlighting the potential regulatory mechanisms. Methods. Sixty-four published experiments were summarized in which trans-10, cis-12 CLA was fed either alone or in combination with other CLA isomers to mice, rats, hamsters, and humans were compared. Summary and Conclusions. Dietary trans-10, cis-12 CLA induces a severe hepatic steatosis in mice with a more muted response in other species. Regardless of species, when hepatic steatosis was present, a concurrent decrease in body adiposity was observed, suggesting that hepatic lipid accumulation is a result of uptake of mobilized fatty acids (FA) from adipose tissue and the liver's inability to sufficiently increase FA oxidation and export of synthesized triglycerides. The potential role of liver FA composition, insulin secretion and sensitivity, adipokine, and inflammatory responses are discussed as potential mechanisms behind CLA-induced hepatic steatosis

Substrate Prediction for RiPP Biosynthetic Enzymes via Masked Language Modeling and Transfer Learning

Ribosomally synthesized and post-translationally modified peptide (RiPP) biosynthetic enzymes often exhibit promiscuous substrate preferences that cannot be reduced to simple rules. Large language models are promising tools for predicting such peptide fitness landscapes. However, state-of-the-art protein language models are trained on relatively few peptide sequences. A previous study comprehensively profiled the peptide substrate preferences of LazBF (a two-component serine dehydratase) and LazDEF (a three-component azole synthetase) from the lactazole biosynthetic pathway. We demonstrated that masked language modeling of LazBF substrate preferences produced language model embeddings that improved downstream classification models of both LazBF and LazDEF substrates. Similarly, masked language modeling of LazDEF substrate preferences produced embeddings that improved the performance of classification models of both LazBF and LazDEF substrates. Our results suggest that the models learned functional forms that are transferable between distinct enzymatic transformations that act within the same biosynthetic pathway. Our transfer learning method improved performance and data efficiency in data-scarce scenarios. We then fine-tuned models on each data set and showed that the fine-tuned models provided interpretable insight that we anticipate will facilitate the design of substrate libraries that are compatible with desired RiPP biosynthetic pathways