Metformin as a Therapeutic Target in Endometrial Cancers.

Endometrial cancer is the most common gynecologic malignancy in developed countries. Its increasing incidence is thought to be related in part to the rise of metabolic syndrome, which has been shown to be a risk factor for the development of hyperestrogenic and hyperinsulinemic states. This has consequently lead to an increase in other hormone-responsive cancers as well e.g., breast and ovarian cancer. The correlation between obesity, hyperglycemia, and endometrial cancer has highlighted the important role of metabolism in cancer establishment and persistence. Tumor-mediated reprogramming of the microenvironment and macroenvironment can range from induction of cytokines and growth factors to stimulation of surrounding stromal cells to produce energy-rich catabolites, fueling the growth, and survival of cancer cells. Such mechanisms raise the prospect of the metabolic microenvironment itself as a viable target for treatment of malignancies. Metformin is a biguanide drug that is a first-line treatment for type 2 diabetes that has beneficial effects on various markers of the metabolic syndrome. Many studies suggest that metformin shows potential as an adjuvant treatment for uterine and other cancers. Here, we review the evidence for metformin as a treatment for cancers of the endometrium. We discuss the available clinical data and the molecular mechanisms by which it may exert its effects, with a focus on how it may alter the tumor microenvironment. The pleiotropic effects of metformin on cellular energy production and usage as well as intercellular and hormone-based interactions make it a promising candidate for reprogramming of the cancer ecosystem. This, along with other treatments aimed at targeting tumor metabolic pathways, may lead to novel treatment strategies for endometrial cancer

RIPK3 restricts viral pathogenesis via cell death-independent neuroinflammation

Receptor-interacting protein kinase-3 (RIPK3) is an activator of necroptotic cell death, but recent work has implicated additional roles for RIPK3 in inflammatory signaling independent of cell death. However, while necroptosis has been shown to contribute to antiviral immunity, death-independent roles for RIPK3 in host defense have not been demonstrated. Using a mouse model of West Nile virus (WNV) encephalitis, we show that RIPK3 restricts WNV pathogenesis independently of cell death. Ripk3(-/-) mice exhibited enhanced mortality compared to wild-type (WT) controls, while mice lacking the necroptotic effector MLKL, or both MLKL and caspase-8, were unaffected. The enhanced susceptibility of Ripk3(-/-) mice arose from suppressed neuronal chemokine expression and decreased central nervous system (CNS) recruitment of T lymphocytes and inflammatory myeloid cells, while peripheral immunity remained intact. These data identify pleiotropic functions for RIPK3 in the restriction of viral pathogenesis and implicate RIPK3 as a key coordinator of immune responses within the CNS

Untangling the Sources of Abundance Dispersion in Low-metallicity Stars

We measure abundances of 12 elements (Na, Mg, Si, Ca, Sc, Ti, V, Cr, Mn, Fe, Co, Ni) in a sample of 86 metal-poor (−2 ≲ [Fe/H] ≲ −1) subgiant stars in the solar neighborhood. Abundances are derived from high-resolution spectra taken with the Potsdam Echelle Polarimetric and Spectroscopic Instrument on the Large Binocular Telescope, modeled using iSpec and MOOG. By carefully quantifying the impact of photon-noise (<0.05 dex for all elements), we robustly measure the intrinsic scatter of abundance ratios. At fixed [Fe/H], the rms intrinsic scatter in [X/Fe] ranges from 0.04 (Cr) to 0.16 dex (Na), with a median of 0.08 dex. Scatter in [X/Mg] is similar, and accounting for [α/Fe] only reduces the overall scatter moderately. We consider several possible origins of the intrinsic scatter with particular attention to fluctuations in the relative enrichment by core-collapse supernovae (CCSN) and Type Ia supernovae and stochastic sampling of the CCSN progenitor mass distribution. The stochastic sampling scenario provides a good quantitative explanation of our data if the effective number of CCSN contributing to the enrichment of a typical sample star is N ∼ 50. At the median metallicity of our sample, this interpretation implies that the CCSN ejecta are mixed over a gas mass ∼6 × 104 M ⊙ before forming stars. The scatter of elemental abundance ratios is a powerful diagnostic test for simulations of star formation, feedback, and gas mixing in the early phases of the Galaxy

Enhancing diversity of clinical trial populations in multiple sclerosis

BACKGROUND: Demographic characteristics, social determinants of health (SDoH), health inequities, and health disparities substantially influence the general and disease-specific health outcomes of people with multiple sclerosis (MS). Participants in clinical trials do not represent all people with MS treated in practice. Objective: To provide recommendations for enhancing diversity and inclusion in clinical trials in MS. METHODS: We held an international workshop under the Auspices of the International Advisory Committee on Clinical Trials in MS (the “Committee”) to develop recommendations regarding diversity and inclusivity of participants of clinical trials in MS. Workshop attendees included members of the Committee as well as external participants. External participants were selected based on expertise in trials, SDoH, health equity and regulatory science, and diversity with respect to gender, race, ethnicity, and geography. RESULTS: Recommendations include use of diversity plans, community engagement and education, cultural competency training, biologically justified rather than templated eligibility criteria, adaptive designs that allow broadening of eligibility criteria over the course of a trial, and logistical and practical adjustments to reduce study participant burden. Investigators should report demographic and SDoH characteristics of participants. CONCLUSION: These recommendations provide sponsors and investigators with methods of improving diversity and inclusivity of clinical trial populations in MS

Effect of starvation and subsequent feeding on glycogen concentration, behavior and mortality in the golden mussel Limnoperna Fortunei (Dunker, 1857) (Bivalvia: Mytilidae)

The success of Limnoperna fortunei as an invasive species is related to its physiological plasticity that allows them to endure adverse environmental conditions. Starvation tolerance is considered to be an important trait associated with bivalve invasiveness. In natural ecosystems, food resources can vary during the year, exposing mussels to variable periods of starvation or limited food availability. Thus, mussels have developed physiological strategies to tolerate fluctuations in food availability. Glycogen concentration has been used in different monitoring studies as an indicator of the nutritional condition of bivalves. The aim of this study was to investigate the physiological responses of L. fortunei based on the glycogen concentrations of specimens under four treatments, comprising differentcombinations of feeding and starvation, during 125 days. The experiment was carried out in two phases. In the phase I, mussels were divided in two treatments: starvation (S) and feeding (F). After 100 days, tissue samples were collected to quantify glycogen concentrations and, each phase I group was divided in two subgroups: starvation (S) and feeding (F), resulting in four treatments. In the phase II, that lasted 25 days, starvation specimens (S) from phase I were allowed to feed (starvation-feeding treatment, or S-F), or continued to undergo starvation (starvation-starvation treatment, or S-S) and the feeding specimens (F) continued feeding (feeding-feeding group, or F-F), or were subjected to starvation (feeding-starvation treatment, or F-S). Behavior (valve-closing) and mortality were recorded in 24 h intervals. After the 25 days (phase II) all specimens were killed, and thei r soft tissue was removed to quantify glycogen concentrations. The glycogen concentration of the S-F treatment was lower than that of the F-S treatment, which was initially allowed to feed (phase I) and then subjected to starvation (phase II). Stability in the glycogen concentrations was observed when the phase II feeding conditions were maintained during the experiments, as observed in the S-S (continued starvation) and F-F (continued feeding) treatments. Based on our glycogen concentrations results, the golden mussel shows a higher tolerance to starvation (125 days) than has previously been published, which suggests that its tolerance strongly influences its invasive behavior.Facultad de Ciencias Naturales y Muse

Effect of starvation and subsequent feeding on glycogen concentration, behavior and mortality in the golden mussel Limnoperna Fortunei (Dunker, 1857) (Bivalvia: Mytilidae)

The success of Limnoperna fortunei as an invasive species is related to its physiological plasticity that allows them to endure adverse environmental conditions. Starvation tolerance is considered to be an important trait associated with bivalve invasiveness. In natural ecosystems, food resources can vary during the year, exposing mussels to variable periods of starvation or limited food availability. Thus, mussels have developed physiological strategies to tolerate fluctuations in food availability. Glycogen concentration has been used in different monitoring studies as an indicator of the nutritional condition of bivalves. The aim of this study was to investigate the physiological responses of L. fortunei based on the glycogen concentrations of specimens under four treatments, comprising differentcombinations of feeding and starvation, during 125 days. The experiment was carried out in two phases. In the phase I, mussels were divided in two treatments: starvation (S) and feeding (F). After 100 days, tissue samples were collected to quantify glycogen concentrations and, each phase I group was divided in two subgroups: starvation (S) and feeding (F), resulting in four treatments. In the phase II, that lasted 25 days, starvation specimens (S) from phase I were allowed to feed (starvation-feeding treatment, or S-F), or continued to undergo starvation (starvation-starvation treatment, or S-S) and the feeding specimens (F) continued feeding (feeding-feeding group, or F-F), or were subjected to starvation (feeding-starvation treatment, or F-S). Behavior (valve-closing) and mortality were recorded in 24 h intervals. After the 25 days (phase II) all specimens were killed, and thei r soft tissue was removed to quantify glycogen concentrations. The glycogen concentration of the S-F treatment was lower than that of the F-S treatment, which was initially allowed to feed (phase I) and then subjected to starvation (phase II). Stability in the glycogen concentrations was observed when the phase II feeding conditions were maintained during the experiments, as observed in the S-S (continued starvation) and F-F (continued feeding) treatments. Based on our glycogen concentrations results, the golden mussel shows a higher tolerance to starvation (125 days) than has previously been published, which suggests that its tolerance strongly influences its invasive behavior.Facultad de Ciencias Naturales y Muse

Effect of starvation and subsequent feeding on glycogen concentration, behavior and mortality in the golden mussel Limnoperna Fortunei (Dunker, 1857) (Bivalvia: Mytilidae)

The success of Limnoperna fortunei as an invasive species is related to its physiological plasticity that allows them to endure adverse environmental conditions. Starvation tolerance is considered to be an important trait associated with bivalve invasiveness. In natural ecosystems, food resources can vary during the year, exposing mussels to variable periods of starvation or limited food availability. Thus, mussels have developed physiological strategies to tolerate fluctuations in food availability. Glycogen concentration has been used in different monitoring studies as an indicator of the nutritional condition of bivalves. The aim of this study was to investigate the physiological responses of L. fortunei based on the glycogen concentrations of specimens under four treatments, comprising differentcombinations of feeding and starvation, during 125 days. The experiment was carried out in two phases. In the phase I, mussels were divided in two treatments: starvation (S) and feeding (F). After 100 days, tissue samples were collected to quantify glycogen concentrations and, each phase I group was divided in two subgroups: starvation (S) and feeding (F), resulting in four treatments. In the phase II, that lasted 25 days, starvation specimens (S) from phase I were allowed to feed (starvation-feeding treatment, or S-F), or continued to undergo starvation (starvation-starvation treatment, or S-S) and the feeding specimens (F) continued feeding (feeding-feeding group, or F-F), or were subjected to starvation (feeding-starvation treatment, or F-S). Behavior (valve-closing) and mortality were recorded in 24 h intervals. After the 25 days (phase II) all specimens were killed, and thei r soft tissue was removed to quantify glycogen concentrations. The glycogen concentration of the S-F treatment was lower than that of the F-S treatment, which was initially allowed to feed (phase I) and then subjected to starvation (phase II). Stability in the glycogen concentrations was observed when the phase II feeding conditions were maintained during the experiments, as observed in the S-S (continued starvation) and F-F (continued feeding) treatments. Based on our glycogen concentrations results, the golden mussel shows a higher tolerance to starvation (125 days) than has previously been published, which suggests that its tolerance strongly influences its invasive behavior.Fil: Cordeiro, Nelmara I. S.. Universidade Federal de Minas Gerais; BrasilFil: Andrade, Jennifer T. M.. Universidade Federal de Minas Gerais; BrasilFil: Montresor, Lângia C.. Fundación Oswaldo Cruz; BrasilFil: Luz, Dalva M. R.. Universidade Federal de Minas Gerais; BrasilFil: Martinez, Carlos B.. Universidade Federal de Minas Gerais; BrasilFil: Darrigran, Gustavo Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de la Plata. Facultad de Ciencias Naturales y Museo. División Zoología Invertebrados; ArgentinaFil: Pinheiro, Jairo. Universidade Federal Rural Do Rio de Janeiro;Fil: Vidigal, Teofânia H. D. A.. Universidade Federal de Minas Gerais; Brasi

Bax and Bak function as the outer membrane component of the mitochondrial permeability pore in regulating necrotic cell death in mice

A critical event in ischemia-based cell death is the opening of the mitochondrial permeability transition pore (MPTP). However, the molecular identity of the components of the MPTP remains unknown. Here, we determined that the Bcl-2 family members Bax and Bak, which are central regulators of apoptotic cell death, are also required for mitochondrial pore-dependent necrotic cell death by facilitating outer membrane permeability of the MPTP. Loss of Bax/Bak reduced outer mitochondrial membrane permeability and conductance without altering inner membrane MPTP function, resulting in resistance to mitochondrial calcium overload and necrotic cell death. Reconstitution with mutants of Bax that cannot oligomerize and form apoptotic pores, but still enhance outer membrane permeability, permitted MPTP-dependent mitochondrial swelling and restored necrotic cell death. Our data predict that the MPTP is an inner membrane regulated process, although in the absence of Bax/Bak the outer membrane resists swelling and prevents organelle rupture to prevent cell death

Hematopoietic Cell Transplantation in Patients With Primary Immune Regulatory Disorders (PIRD): A Primary Immune Deficiency Treatment Consortium (PIDTC) Survey.

Primary Immune Regulatory Disorders (PIRD) are an expanding group of diseases caused by gene defects in several different immune pathways, such as regulatory T cell function. Patients with PIRD develop clinical manifestations associated with diminished and exaggerated immune responses. Management of these patients is complicated; oftentimes immunosuppressive therapies are insufficient, and patients may require hematopoietic cell transplant (HCT) for treatment. Analysis of HCT data in PIRD patients have previously focused on a single gene defect. This study surveyed transplanted patients with a phenotypic clinical picture consistent with PIRD treated in 33 Primary Immune Deficiency Treatment Consortium centers and European centers. Our data showed that PIRD patients often had immunodeficient and autoimmune features affecting multiple organ systems. Transplantation resulted in resolution of disease manifestations in more than half of the patients with an overall 5-years survival of 67%. This study, the first to encompass disorders across the PIRD spectrum, highlights the need for further research in PIRD management