Cooneyherskind4043

Studies have shown that the byproducts from Latin American vegetables, such as passion-fruit (Passiflora edulis), pineapple (Ananas comosus) and pumpkin (Cucurbita spp.), for example, could represent interesting tools against IBDs, judging by the results of in vitro and animal studies. Therefore, the aim of this review is to discuss the potential role of non-phenolic compounds from native Latin American food byproducts in the prevention or treatment of IBDs, by highlighting their anti-inflammatory, anti-oxidative and/or anti-dysbiotic effects.Phenyllactic acid (PLA) as a phenolic acid by lactic acid (LA) bacteria shows enhanced antibacterial activity when coexisting with LA, while the antibacterial mechanism of PLA combined with LA was unknown. Hence, the antibacterial mechanism of PLA and LA was investigated against Bacillus cereus. Flow cytometry and TEM analysis demonstrated that single PLA and LA disrupted the membrane integrity and the morphology, while combined PLA and LA synergistically enhanced the damage. iTRAQ-based proteomic analysis suggested that PLA down-regulated kdpB and inhibited K+ transport, disturbed the function of ribosome and expression of competence genes; LA down-regulated periplasmic phosphorus-binding proteins and inhibited phosphorus transport, disturbed the function of ribosome, TCA cycle, as well as purine and pyrimidine metabolism; and combined PLA and LA inhibited K+ and phosphorus transport, and influenced the synthesis of purine and pyrimidine metabolism. The investigation could provide some insights into the application of PLA in food preservation.Mutations in the group of epigenetic modifiers are the largest group of mutated genes in Myelodysplastic Syndromes (MDS) and are very frequently found in Acute Myeloid Leukemia (AML). Our advancements in the understanding of epigenetics in these diseases have helped develop groundbreaking therapeutics that have changed the treatment landscape of MDS and AML, significantly improving outcomes. In this review we describe the most common epigenetic aberrations in MDS and AML, and current treatments that target mutations in epigenetic modifiers, as well as novel treatment combinations, from standard therapies to investigational treatments.The DNA methyltransferase inhibitor azacytidine (aza) may reactivate pathways associated with plasma cell differentiation, cell cycle control, apoptosis, and immune recognition and thereby restore sensitivity to lenalidomide (len) and dexamethasone (dex) in relapsed and/or refractory multiple myeloma (RRMM). We aimed to develop an aza regimen that reaches epigenetically active levels 8 times in 28 days with less bone marrow toxicity than the myeloid malignancy standard of 7 consecutive doses to enable safe combination with len. Aza was escalated from 30 mg/m2 once a week up to a predefined maximum of 50 mg/m2 twice a week in combination with GFR-adjusted len (≥ 60 mL/min 25 mg, 3059 mL/min 10 mg) day 1 to 21 every 28 days and dex 40 mg once a week followed by a limited expansion study to a total N of 23 at the highest tolerated dose. Fifty-one patients (pts) with RRMM were screened, 42 were treated and 41 were evaluable for response based on at least 1 response assessment or progression after treatment start.e optimized further and pt selection may be required to maximize benefit.Interest in the role of epigenetic mechanisms in human biology has exponentially increased over the past several decades. The multitude of opposing and context-dependent chromatin-modifying enzymes/coregulator complexes is just beginning to be understood at a molecular level. This science has benefitted tremendously from studies of erythropoiesis, in which a series of β-globin genes are in sequence turned "on" and "off," serving as a fascinating model of coordinated gene expression. We, therefore, describe here epigenetic complexes about which we know most, using erythropoiesis as the context. The biochemical insights lay the foundation for proposing and developing novel treatments for diseases of red cells and of erythropoiesis, identifying for example epigenetic enzymes that can be drugged to manipulate β-globin locus regulation, to favor activation of unmutated fetal hemoglobin over mutated adult β-globin genes to treat sickle cell disease and β-thalassemias. Other potential translational applications are in redirecting hematopoietic commitment decisions, as treatment for bone marrow failure syndromes.One mechanism by which lymphoid malignancies resist standard apoptosis-intending (cytotoxic) treatments is genetic attenuation of the p53/p16-CDKN2A apoptosis axis. Depletion of the epigenetic protein DNA methyltransferase 1 (DNMT1) using the deoxycytidine analog decitabine is a validated approach to cytoreduce malignancy independent of p53/p16. In vivo decitabine activity, however, is restricted by rapid catabolism by cytidine deaminase (CDA). We, therefore, combined decitabine with the CDA-inhibitor tetrahydrouridine and conducted a pilot clinical trial in patients with relapsed lymphoid malignancies the doses of tetrahydrouridine/decitabine used (∼10/0.2 mg/kg orally (PO) 2×/week) were selected for the molecular pharmacodynamic objective of non-cytotoxic, S-phase dependent, DNMT1-depletion, guided by previous Phase 1 studies. Patients with relapsed/refractory B- or T-cell malignancies (n = 7) were treated for up to 18 weeks. Neutropenia without concurrent thrombocytopenia is an expected toxicity of DNMT1-depletion and occurred in all patients (Grade 3/4). Subjective and objective clinical improvements occurred in 4 of 7 patients, but these responses were lost upon treatment interruptions and reductions to manage neutropenia. We thus performed parallel experiments in a preclinical in vivo model of lymphoma to identify regimen refinements that might sustain DNMT1-targeting in malignant cells but limit neutropenia. We found that timed-alternation of decitabine with the related molecule 5-azacytidine, and combination with inhibitors of CDA and de novo pyrimidine synthesis could leverage feedback responses of pyrimidine metabolism to substantially increase lymphoma cytoreduction but with less neutropenia. In sum, regimen innovations beyond incorporation of a CDA-inhibitor are needed to sustain decitabine DNMT1-targeting and efficacy against chemo-resistant lymphoid malignancy. Such potential solutions were explored in preclinical in vivo studies.TET2 is one of the most frequently mutated genes in myeloid neoplasms. TET2 loss-of-function perturbs myeloid differentiation and causes clonal expansion. Despite extensive knowledge regarding biochemical mechanisms underlying distorted myeloid differentiation, targeted therapies are lagging. Here we review known biochemical mechanisms and candidate therapies that emerge from this. Specifically, we discuss the potential utility of vitamin C to compensate for TET-dioxygenase deficiency, to thereby restore the biochemical function. An alternative approach exploits the TET-deficient state for synthetic lethality, exploiting the fact that a minimum level of TET-dioxygenase activity is required for cell survival, rendering TET2-mutant malignant cells selectively vulnerable to inhibitors of TET-function.Erythroid differentiation program is comprised of lineage commitment, erythroid progenitor proliferation, and termination differentiation. Each stage of the differentiation program is heavily influenced by epigenetic modifiers that alter the epigenome in a dynamic fashion influenced by cytokines/humeral factors and are amicable to target by drugs. The epigenetic modifiers can be classified as DNA modifiers (DNMT, TET), mRNA modifiers (RNA methylases and demethylases) and histone protein modifiers (methyltransferases, acetyltransferases, demethylases, and deacetylases). Here we describe mechanisms by which these epigenetic modifiers influence and guide erythroid-lineage differentiation during normal and malignant erythropoiesis and also benign diseases that arise from their altered structure or function.Human hemoglobin switching describes the highly regulated, sequential expression of the 5 β-like globin genes (HBE, HBG2, HBG1, HBD and HBB) of the human β-globin gene complex. The sequential activation of these β or β-like globin genes during human development from early embryonic through late fetal ('adult') stages, and during erythroid maturation, occurs in an order corresponding to their 5' to 3' location on chromosome 11. The β-hemoglobinopathies are the most common inherited diseases in humanity, and are diseases of mutated HBB or its altered regulation. Since the other β-like globin genes can potentially substitute for defective HBB, much translational research is directed toward understanding and manipulating sequential activation at the human β-globin gene complex to treat β-hemoglobinopathies. Non-human primates provide a vital contribution to such efforts because of their recapitulation of the developmental/maturational switch in hemoglobin production as observed in humans (mice do not model this switch). Valuable insights into druggable epigenetic forces that mediate the switch have been thereby gained. We review important lessons learned in non-human primates, complemented by other studies, and suggest rational next steps.A common thread through malignant and nonmalignant diseases alerts us to a therapeutic opportunity to seize disease may originate from genetic mutations, but resulting maladaptive/unhealthy cell fates and functions are mediated by epigenetic enzymes, that are druggable. Epigenetic enzymes modify DNA, and/or the histones around which DNA is organized, to regulate access to genes by the basal transcription factor machinery that transcribes genes. Epigenetic enzymes can be divided usefully into those that facilitate gene transcription ("on" enzymes or coactivators) and those that favor gene repression ("off" enzymes or corepressors). DNA-binding master transcription factors cooperate to recruit coactivators, and repulse corepressors, from thousands of genes, to thereby activate the gene expression programs that define cell fates and functions. In malignancy, this usual exchange of corepressors for coactivators fails, because of mutations to master transcription factors or the coactivators they recruit. Inhibiting corepressor enzymes using small molecules uses pharmacology to redress this coactivator/corepressor imbalance that originates from genetics, to in this way release cancer cells to the terminal lineage-fates intended by their master transcription factor content. Similarly, in nonmalignant β-hemoglobinopathies, inhibiting corepressors exploits transcription factor and lineage-context to activate unmutated fetal over mutated adult globin genes, to thereby treat these nonmalignant genetic diseases. Master transcription factors then are the "natural forces" in the Hippocratic dictum "Natural forces within us are the true healers of disease," and drugging epigenetic enzymes (corepressors) a way to harness these forces to heal.Surveillance data obtained by public health agencies for COVID-19 are likely inaccurate due to undercounting and misdiagnosing. Using a Bayesian approach, we sought to reduce bias in the estimates of prevalence of COVID-19 in Philadelphia, PA at the ZIP code level. selleck chemicals After evaluating various modeling approaches in a simulation study, we estimated true prevalence by ZIP code with and without conditioning on an area deprivation index (ADI). As of June 10, 2020, in Philadelphia, the observed citywide period prevalence was 1.5%. After accounting for bias in the surveillance data, the median posterior citywide true prevalence was 2.3% when accounting for ADI and 2.1% when not. Overall the median posterior surveillance sensitivity and specificity from the models were similar, about 60% and more than 99%, respectively. Surveillance of COVID-19 in Philadelphia tends to understate discrepancies in burden for the more affected areas, potentially misinforming mitigation priorities.