A real-world clinical experience on the effectiveness of remogliflozin etabonate in management of Indian patients with type II diabetes mellitus

Background: The aim of the study was to evaluate effectiveness and safety of remogliflozin etabonate in a real-world outpatient setting in type 2 diabetes mellitus (T2DM) patients in India.Methods: A retrospective, observational, single-center study wherein medical records of adult patients (≥18 years old) with T2DM managed with remogliflozin 100 mg for at least three months at the diabetes care center in Jharkhand were retrieved. The effectiveness was assessed in terms of change from baseline in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), total body weight, blood pressure (BP, systolic and diastolic), kidney function tests, and lipid parameters after three months of treatment. Safety was assessed by adverse events (AEs) and serious AEs.Results: Half of the patients received ≥3 concomitant antidiabetic drugs, common being sulphonylureas (92%), and metformin (91%). Remogliflozin treatment resulted in a significant mean reduction from baseline in HbA1c [-1.99 (0.12%); p<0.001], FPG [-52.3 (4.31) mg/dl; p<0.001] and PPG [-103.6 (7.10) mg/dl; p<0.001). Bodyweight reduction was not statistically significant [-0.1 (10.12) kg]. A significant reduction was observed in the systolic BP [-15.9 (2.21) mmHg; p<0.001] and diastolic BP [-3.3 (0.95) mmHg; p=0.001]. Commonly reported AE was heartburn (51.4%) and urinary tract infections (34.2%). No serious AEs were reported. The mean estimated glomerular filtration rate showed a statistically significant reduction of -1.55 (0.61) ml/min. The lipid parameter findings were non-significant.Conclusions: The real-world experience of remogliflozin administered concomitantly with other antidiabetic drugs was effective and well-tolerated in Indian patients with T2DM.

Time to Bloom

Bloom Syndrome (BS) is an autosomal recessive disorder due to mutation in Bloom helicase (referred in literature either as BLM helicase or BLM). Patients with BS are predisposed to almost all forms of cancer. BS patients are even today diagnosed in the clinics by hyper-recombination phenotype that is manifested by high rates of Sister Chromatid Exchange. The function of BLM as a helicase and its role during the regulation of homologous recombination (HR) is well characterized. However in the last few years the role of BLM as a DNA damage sensor has been revealed. For example, it has been demonstrated that BLM can stimulate the ATPase and chromatin remodeling activities of RAD54 in vitro. This indicates that BLM may increase the accessibility of the sensor proteins that recognize the lesion. Over the years evidence has accumulated that BLM is one of the earliest proteins that accumulates at the site of the lesion. Finally BLM also acts like a "molecular node" by integrating the upstream signals and acting as a bridge between the transducer and effector proteins (which again includes BLM itself), which in turn repair the DNA damage. Hence BLM seems to be a protein involved in multiple functions - all of which may together contribute to its reported role as a "caretaker tumor suppressor". In this review the recent literature documenting the upstream BLM functions has been elucidated and future directions indicated

Inferring to C or not to C: Evolutionary games with Bayesian inferential strategies

Strategies for sustaining cooperation and preventing exploitation by selfish agents in repeated games have mostly been restricted to Markovian strategies where the response of an agent depends on the actions in the previous round. Such strategies are characterized by lack of learning. However, learning from accumulated evidence over time and using the evidence to dynamically update our response is a key feature of living organisms. Bayesian inference provides a framework for such evidence-based learning mechanisms. It is therefore imperative to understand how strategies based on Bayesian learning fare in repeated games with Markovian strategies. Here, we consider a scenario where the Bayesian player uses the accumulated evidence of the opponent's actions over several rounds to continuously update her belief about the reactive opponent's strategy. The Bayesian player can then act on her inferred belief in different ways. By studying repeated Prisoner's dilemma games with such Bayesian inferential strategies, both in infinite and finite populations, we identify the conditions under which such strategies can be evolutionarily stable. We find that a Bayesian strategy that is less altruistic than the inferred belief about the opponent's strategy can outperform a larger set of reactive strategies, whereas one that is more generous than the inferred belief is more successful when the benefit-to-cost ratio of mutual cooperation is high. Our analysis reveals how learning the opponent's strategy through Bayesian inference, as opposed to utility maximization, can be beneficial in the long run, in preventing exploitation and eventual invasion by reactive strategies.Comment: 13 pages, 9 figure

Inositol pyrophosphate synthesis by inositol hexakisphosphate kinase 1 is required for homologous recombination repair

Inositol pyrophosphates, such as diphosphoinositol pentakisphosphate (IP7), are water-soluble inositol phosphates that contain high energy diphosphate moieties on the inositol ring. Inositol hexakisphosphate kinase 1 (IP6K1) participates in inositol pyrophosphate synthesis, converting inositol hexakisphosphate (IP6) to IP7. In the present study, we show that mouse embryonic fibroblasts (MEFs) lacking IP6K1 exhibit impaired DNA damage repair via homologous recombination (HR). IP6K1 knock-out MEFs show decreased viability and reduced recovery after induction of DNA damage by the replication stress inducer, hydroxyurea, or the radiomimetic antibiotic, neocarzinostatin. Cells lacking IP6K1 arrest after genotoxic stress, and markers associated with DNA repair are recruited to DNA damage sites, indicating that HR repair is initiated in these cells. However, repair does not proceed to completion because these markers persist as nuclear foci long after drug removal. A fraction of IP6K1-deficient MEFs continues to proliferate despite the persistence of DNA damage, rendering the cells more susceptible to chromosomal aberrations. Expression of catalytically active but not inactive IP6K1 can restore the repair process in knock-out MEFs, implying that inositol pyrophosphates are required for HR-mediated repair. Our study therefore highlights inositol pyrophosphates as novel small molecule regulators of HR signaling in mammals

RECQL4 is essential for the transport of p53 to mitochondria in normal human cells in the absence of exogenous stress

Mutations in RECQL4 helicase are associated with Rothmund–Thomson syndrome (RTS). A subset of RTS patients is predisposed to cancer and is sensitive to DNA damaging agents. The enhanced sensitivity of cells from RTS patients correlates with the accumulation of transcriptionally active nuclear p53. We found that in untreated normal human cells these two nuclear proteins, p53 and RECQL4, instead colocalize in the mitochondrial nucleoids. RECQL4 accumulates in mitochondria in all phases of the cell cycle except S phase and physically interacts with p53 only in the absence of DNA damage. p53–RECQL4 binding leads to the masking of the nuclear localization signal of p53. The N-terminal 84 amino acids of RECQL4 contain a mitochondrial localization signal, which causes the localization of RECQL4–p53 complex to the mitochondria. RECQL4–p53 interaction is disrupted after stress, allowing p53 translocation to the nucleus. In untreated normal cells RECQL4 optimizes de novo replication of mtDNA, which is consequently decreased in fibroblasts from RTS patients. Wild-type RECQL4-complemented RTS cells show relocalization of both RECQL4 and p53 to the mitochondria, loss of p53 activation, restoration of de novo mtDNA replication and resistance to different types of DNA damage. In cells expressing Δ84 RECQL4, which cannot translocate to mitochondria, all the above functions are compromised. The recruitment of p53 to the sites of de novo mtDNA replication is also regulated by RECQL4. Thus these findings elucidate the mechanism by which p53 is regulated by RECQL4 in unstressed normal cells and also delineates the mitochondrial functions of the helicase