Mcgowanbaird9103
Developing non-statin-based small compounds to battle the global epidemic of hyperlipidemia remains challenging. Here, we report the discovery of DC371739, an indole-containing tetrahydroisoquinoline compound with promising lipid-lowering effects, both in vitro and in vivo, and with good tolerability in a Phase I clinical trial (NCT04927221). DC371739 significantly reduced the plasma levels of total cholesterol, low-density lipoprotein cholesterol, and triglycerides simultaneously in several animal models and showed preliminary positive results in the Phase I trial. Mechanistically, DC371739 acts in a distinct manner from other known lipid-lowering reagents. We show that it physically binds HNF-1α, impeding the transcription of both PCSK9 and ANGPTL3, two genes that are known to contribute to hypercholesterolemia and dyslipidemia. Moreover, the distinct mechanism of action of DC371739 allows its combination with atorvastatin treatment to additively improve dyslipidemia, while providing a potential alternative therapeutic strategy for individuals with statin intolerance.Induced pluripotent stem cell (iPSC) and gene editing technologies have revolutionized the field of in vitro disease modeling, granting us access to disease-pertinent human cells of the central nervous system. These technologies are particularly well suited for the study of diseases with strong monogenic etiologies. Epilepsy is one of the most common neurological disorders in children, with approximately half of all genetic cases caused by mutations in ion channel genes. These channelopathy-associated epilepsies are clinically diverse, mechanistically complex, and hard to treat. Here, we review the genetic links to epilepsy, the opportunities and challenges of iPSC-based approaches for developing in vitro models of channelopathy-associated disorders, the available tools for effective phenotyping of iPSC-derived neurons, and discuss the potential therapeutic approaches for these devastating diseases.
Pembrolizumab has shown improved progression-free survival versus chemotherapy in patients with newly diagnosed microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. However, the treatment's effect on overall survival in this cohort of patients was unknown. Here, we present the final overall survival analysis of the KEYNOTE-177 study.
This randomised, open-label, phase 3 study was done in 193 academic medical centres and hospitals in 23 countries. We recruited patients aged at least 18 years, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously untreated microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. Patients were randomly assigned (11) in blocks of four using an interactive voice response system or integrated web response system to intravenous pembrolizumab 200 mg every 3 weeks or to the investigator's choice of intravenous mFOLFOX6 (oxaliplatin 85 mg/m
on day 1, leucovorin 400 mgb were increased alanine aminotransferase, colitis, diarrhoea, and fatigue in three (2%) patients each, and those attributed to chemotherapy were decreased neutrophil count (in 24 [17%] patients), neutropenia (22 [15%]), diarrhoea (14 [10%]), and fatigue (13 [9%]). Serious adverse events attributed to study treatment occurred in 25 (16%) patients in the pembrolizumab group and in 41 (29%) patients in the chemotherapy group. No deaths attributed to pembrolizumab occurred; one death due to intestinal perforation was attributed to chemotherapy.
In this updated analysis, although pembrolizumab continued to show durable antitumour activity and fewer treatment-related adverse events compared with chemotherapy, there was no significant difference in overall survival between the two treatment groups. These findings support pembrolizumab as an efficacious first-line therapy in patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer.
MSD.
MSD.
Two dimensional (2D) full-field digital mammography is the current standard of breast cancer screening. Digital breast tomosynthesis generates pseudo-three dimensional datasets of the breast from which synthesised 2D (s2D) mammograms can be reconstructed. This innovative approach reduces the likelihood of overlapping breast tissues that can conceal features of malignancy. We aimed to compare digital breast tomosynthesis plus s2D mammography with digital screening mammography for the detection of invasive breast cancer.
TOSYMA was a randomised, open-label, superiority trial done at 17 screening units in two federal states of Germany. Eligible participants were women aged 50-69 years who had been invited to participate in a population-wide, quality-controlled mammography screening programme. Women were randomly assigned (11) to digital breast tomosynthesis plus s2D mammography or digital mammography alone using block randomisation (block size of 32), stratified by site. Deutivacaftor concentration The primary endpoints were the detect of 49 762 women in the digital mammography group (4·8 cases per 1000 women screened; odds ratio 1·48 [95% CI 1·25-1·75]; p<0·0001). Adverse events and device deficiencies were rare (six adverse events in each group; 23 device deficiencies in the digital breast tomosynthesis plus s2D group vs five device deficiencies in the digital mammography group) and no serious adverse events were reported.
The results from this study indicate that the detection rate for invasive breast cancer was significantly higher with digital breast tomosynthesis plus s2D mammography than digital mammography alone. Evaluation of interval cancer rates in the follow-up study will further help to investigate incremental long-term benefits of digital breast tomosynthesis screening.
Deutsche Forschungsgemeinschaft (German Research Foundation).
Deutsche Forschungsgemeinschaft (German Research Foundation).
The optimal duration of androgen deprivation combined with high-dose radiotherapy in prostate cancer remains controversial. The DART 01/05 trial was designed to determine whether long-term androgen deprivation is superior to short-term androgen deprivation when combined with high-dose radiotherapy. The 5-year results showed that 2 years of adjuvant androgen deprivation combined with high-dose radiotherapy significantly improved biochemical control, metastasis, and overall survival, especially in patients with high-risk disease. In this report, we present the 10-year final results of the trial.
This open-label, phase 3, randomised, controlled trial was done in ten hospitals in Spain. The eligibility criteria included patients aged 18 years or older with histologically confirmed T1c to T3, N0, and M0 adenocarcinoma of the prostate, according to the 2002 classification of the American Joint Committee on Cancer, with intermediate-risk and high-risk factors, prostate-specific antigen (PSA) less than 100 ng/mL,l characterisation with the inclusion of genomic testing is needed in the decision-making process.
Grupo de Investigación en Oncología Radioterápica and Sociedad Española de Oncología Radioterápica, the National Health Investigation Fund, and AstraZeneca.
Grupo de Investigación en Oncología Radioterápica and Sociedad Española de Oncología Radioterápica, the National Health Investigation Fund, and AstraZeneca.Cellular mRNA-binding proteins (mRBPs) are major posttranscriptional regulators of gene expression. Although many posttranslational modification sites in mRBPs have been identified, little is known about how these modifications regulate mRBP function. Here, we developed quantitative RNA-interactome capture (qRIC) to quantify the fraction of mRBPs pulled down with polyadenylated mRNAs. Combining qRIC with phosphoproteomics allowed us to systematically compare pull-down efficiencies of phosphorylated and nonphosphorylated forms of mRBPs. Almost 200 phosphorylation events affected pull-down efficiency compared with the unmodified mRBPs and thus have regulatory potential. Our data capture known regulatory phosphorylation sites in ELAVL1, SF3B1, and UPF1 and identify potential regulatory sites. Follow-up experiments on the splicing regulator RBM20 revealed multiple phosphorylation sites in the C-terminal disordered region affecting nucleocytoplasmic localization, association with cytoplasmic ribonucleoprotein granules, and alternative splicing. Together, we show that qRIC in conjunction with phosphoproteomics is a scalable method to identify functional posttranslational modification sites in mRBPs.The SARS-CoV-2 pandemic has been the main public health issue since the end of 2019. The vaccination campaign in Bosnia and Herzegovina started in April 2021, with several vaccines available. Our study aimed to evaluate the acceptance, effects, and tolerability of vaccines against SARS-COV-2 among cancer patients. We conducted a cross-sectional, observational study between 22 October and 30 November 2021, at the Clinic of Oncology, Clinical Center University of Sarajevo. Patients were enrolled during their regular visit to the Clinic of Oncology by agreeing to completean individual paper questionnaire. The study included 1063 patients with malignant diseases, of whom 681 (64.1%) were adequately vaccinated patients. In the study population, 76.9% of patients reported that they did not experience any side effects due to vaccination, while only 0.5% had side effects, causing a delay in their treatment. Among adequately vaccinated patients, there were 40 patients (3.8%) who were infected with SARS-CoV-2 after the second or booster dose of the vaccine. Five patients (0.5%) were hospitalized due to COVID-19 after being adequately vaccinated. The findings of our study suggest that cancer patients have a higher acceptance of vaccines against SARS-CoV-2 than the general population in Bosnia and Herzegovina. Vaccination side effects are tolerable and do not cause major delays in specific cancer treatment. The protective effects of COVID-19 vaccines in the cancer patients presented in our study are comparable to available results of similar studies, which included the general population.
Psychotic experiences have been framed as a marker of mental and physical health status; however, more research is needed to confirm these associations in university populations.
We analyzed data from the Healthy Minds Survey (Fall Semester Cohort 2020), which is a non-probability sample of students attending one of 28 universities in the United States, who completed an online survey (September 2020-December 2020). We used multivariable logistic regression to examine the associations between several mental and physical health conditions and psychotic experiences, adjusting for age, gender, sexual orientation race/ethnicity, and international student status.
In terms of mental health, all conditions were associated with greater odds of having lifetime psychotic experiences. Having at least one mental health condition was associated with 2.18 times greater odds of having lifetime psychotic experiences (aOR 2.18; 95% CI 1.96-2.42). In terms of physical health, having at least one physical health condition y benefit from targeted preventive interventions.
