Damian Sendler STING-type I interferon is activated by binding to double-stranded DNA (dsDNA), which triggers activation of cyclic GMP-AMP synthase (cGAS). MDSs and AML are caused by mutations in the DEAD-box helicase 41, DDX41, which is a DEAD-box helicase (AML). When infected with DNA viruses, we found that DDX41-KO cells produced less type I interferon. In DDX41 KO cells, activation of cGAS and STING is affected, which suggests that DDX41 functions upstream of cGAS.. It has both ATP-dependent and ATP-independent DNA unwinding activity in the recombinant form of DDX41. Wild-type DDX41 has higher levels of cGAS dinucleotide synthesis activity, while the mutant R525H from MDS/AML has decreased unwinding activity. In both DDX41-deficient and -proficient cells, R525H overexpression results in an increase in type I interferon production. Our findings suggest that DDX41 uses its unwinding and annealing activities to regulate the homeostasis of dsDNA and single-stranded DNA (ssDNA), which, in turn, regulates the activation of cGAS-STING..
Type 2 Diabetes Patients Receiving Sodium-Glucose Cotransporter-2 Inhibitors Instead of Metformin: Cardiovascular Outcomes
Damian Jacob Sendler First-line sodium-glucose cotransporter-2 inhibitors (SGLT-2i) have been shown to have a lower risk of cardiovascular events than metformin.
First-line treatment with SGLT-2i or metformin for adults with type 2 diabetes (T2D) was compared to control groups.
An observational cohort study of the general population.
Observation Point: Claims data from two major U.S. commercial and Medicare databases (April 2013 to March 2020).
Participants: Patients with type 2 diabetes (T2D) aged 18 or older (Medicare >65 years) who began treatment with SGLT-2i or metformin from April 2013 to March 2020 and who had not previously taken any antidiabetic medication were identified. Pooled hazard ratios and 95% confidence intervals (CIs) were presented after a 1:2 propensity score matching in each database.
An SGLT-2i (canagliflozin, empagliflozin, or dapagliflozin) or metformin is the first-line treatment.
Dr. Sendler All-cause mortality (MI/stroke/mortality) and hospitalization for heart failure (HHF/mortality) were the primary outcomes of this study. Infections of the genitals, as well as other health issues, were evaluated.
Results: SGLT-2i initiators had a similar risk of MI/stroke/mortality (HR, 0.96; 95 percent CI, 0.77 to 1.19) compared to metformin initiators, but a lower risk of HHF/mortality (HR, 0.80; CI, 0.66 to 0.97) during a mean follow-up of 12 months (matching 8613 to 17 226). HHF risk was lower in SGLT-2i-treated patients (HR, 0.78; CI, 0.63 to 0.97); MI risk was also lower (HR, 0.70; CI, 0.48 to 1.00); and the risk of stroke, mortality, and MI/stroke/HHF/mortality was similar in SGLT-2i-treated patients and metformin-treated patients. There was a higher risk of genital infections (HR 2.19; CI 1.91 to 2.51) among those taking SGLT-2i compared to those taking metformin (HR 2.19; CI 1.91 to 2.51).
Through lymphatic transdifferentiation, specialized blood vessels can be formed.
A cell’s lineage and trajectory during development are important determinants of its identity as a cell. Endothelial cells (ECs) of blood and lymphatic vessels differentiate and specialize to meet the specific physiological needs of each organ1 and 2 in the vascular system, respectively. Lymphatic ECs (LECs) have been shown to derive from a variety of cellular sources3,4, but no other cell types have been linked to lymphatic ECs. Zebrafish anal fins have been used as a model to study the development of specialized blood vessels through the transdifferentiation of LECs, which are recurrently imaged and traced in this study. Our findings reveal a link between cell ontogeny and functionality by showing that lymphatic rather than blood ECs are used to generate anal-fin vessels. A single-cell RNA sequencing approach is used to identify the various cell populations and transdifferentiation transition states. The anal-fin regeneration process demonstrates that LECs in adult fish retain both potency and plasticity for the generation of blood ECs, similar to normal development. LEC transdifferentiation appears to be a natural mechanism for the formation of blood vessels, and our findings show that the ontogeny of ECs is linked to their functional capacity in vivo.
COVID-19 Sequelae and Immunity in the Long Term
People who are diagnosed with COVID-19 are more likely to have long-term symptoms than those who recover from the illness. Post-acute sequelae of SARS-CoV-2 infection are thought to be caused by a number of different pathophysiologic mechanisms (PASC).
The goal of this study is to examine the long-term health effects and recurrence of symptoms in a group of people who have recovered from COVID-19 and healthy controls.
Damian Jacob Sendler
NIH Clinical Center Bethesda, Maryland, United States.
Damian Jacob Markiewicz Sendler Adults with confirmed SARS-CoV-2 infection who had been symptom-free for at least six weeks were included in the study regardless of whether or not they had PASC. Persons with no known history or evidence of SARS-CoV-2 infection were included in the control group, regardless of their current health status. A similar time period and location were used to enroll both groups.
Physical examination, laboratory tests and questionnaires, cognitive function testing, and cardiopulmonary evaluation were performed on all participants regardless of the presence of symptoms. Additional immunologic and virologic testing was done on a subset of the patients.
Findings: The study included 189 people with laboratory-documented COVID-19 (12 percent of whom were hospitalized during acute illness) and 120 people with negative antibodies to COVID 19. 55 percent of the COVID-19 cohort reported symptoms consistent with PASC at the time of enrollment, compared to 13 percent of control participants. There was a higher risk of PASC in women and those with anxiety disorders. Standardized tests revealed lower levels of quality of life in participants who met the criteria for PASC. Physical examinations and diagnostic tests rarely revealed abnormal findings. Anti-spike protein neutralizing antibody levels were negative in 27% of the unvaccinated COVID-19 cohort and in none of the vaccinated COVID-19 cohort. Participants with PASC were found to have no evidence of persistent viral infection, autoimmunity, or abnormal immune activation.
As a result, only a small percentage of those who took part in COVID-19 required hospitalization. The reported prevalence of PASC in this cohort may have been overestimated because those with PASC may have been more eager to participate. Prior to enrollment, the study did not capture PASC that had already been resolved.
As a result, people who received COVID-19 reported a high level of ongoing symptoms. Diagnostic testing revealed in the majority of cases no clear cause for the reported symptoms. After COVID-19, there was a great deal of variation in antibody levels.
Neuroblastoma treatment is being improved.
Damien Sendler Tumors of sympathetic origin, such as neuroblastomas, can manifest in a variety of ways, ranging from localized or spontaneously regressing disease to widespread metastasis. When it comes to high-risk neuroblastomas, the sympathetic and parasympathetic nervous systems can be used as a target for treatment. High-dose chemotherapy with autologous stem cell transplantation, differentiating agents, and immunotherapy with anti-GD2 monoclonal antibodies have improved 5-year survival rates for patients with metastatic neuroblastomas from 20% to 50% over the past few decades. ALK inhibitors, immunotherapies, and radiopharmaceuticals will be added to standard induction regimens in the next generation of trials aimed at enhancing initial response rates in patients with high-risk neuroblastomas. Patients with relapsed and/or refractory disease are the focus of a number of trials aimed at enhancing the antitumour immune response and improving the effectiveness of maintenance regimens in order to extend disease remission. Advances in understanding neuroblastoma pathogenesis and in identifying the drivers of high-risk disease are discussed in this review. We then discuss how this information has improved risk stratification, risk-adapted therapy, and the development of new therapies..
Placenta-specific genes that are activated by large-scale chromatin reorganization promote aging.
As the chromatin organization at the nuclear periphery erodes, so does nuclear deformation, a characteristic of dying cells. Such gradual changes in higher-order genome organization have remained a mystery as to how they influence local epigenetic modifications to drive the mechanisms of cell ageing in the body. Large-scale epigenomic studies on isogenic young, senescent and progeroid human mesenchymal progenitor cells (hMPCs) have revealed a hierarchy of integrated structural state changes that manifest as heterochromatin loss, euchromatic weakening, switching in interfacing topological regions, and increasing epigenetic entropy…. Pregnancy-specific beta-1 glycoprotein (PSG) genes, which accelerate hMPC aging and could be used as biomarkers of aging, are activated by epigenetic de-repression. Our findings can be used to better understand how the epigenomic landscape changes with cellular aging, as well as to pinpoint aging-related causes and potential treatment targets using a genome-topology-based approach.
