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This subgroup analysis of a randomized clinical trial investigates whether tucatinib in combination with trastuzumab and capecitabine provides survival and intracranial benefits for patients with ERBB2-positive metastatic breast cancer and brain metastases.
Circulation, Ahead of Print. BACKGROUND:Cardiac chamber-selective transcriptional programs underpin the structural and functional differences between atrial and ventricular cardiomyocytes (aCMs and vCMs). The mechanisms responsible for these chamber-selective transcriptional programs remain largely undefined.METHODS:We nominated candidate chamber-selective enhancers (CSEs) by determining the genome-wide occupancy of 7 key cardiac transcription factors (GATA4, MEF2A, MEF2C, NKX2-5, SRF, TBX5, TEAD1) and transcriptional coactivator P300 in atria and ventricles. Candidate enhancers were tested using an adeno-associated virus–mediated massively parallel reporter assay. Chromatin features of CSEs were evaluated by performing assay of transposase accessible chromatin sequencing and acetylation of histone H3 at lysine 27-highly integrative chromatin immunoprecipitation on aCMs and vCMs. CSE sequence requirements were determined by systematic tiling mutagenesis of 29 CSEs at 5 bp resolution. Estrogen-related receptor (ERR) function in cardiomyocytes was evaluated by Cre-loxP–mediated inactivation of ERRα and ERRγ in cardiomyocytes.RESULTS:We identified 152 832 and 54 824 regions reproducibly occupied by at least 1 transcription factor or P300, in atria or ventricles, respectively. Enhancer activities of 2639 regions bound by transcription factors or P300 were tested in aCMs and vCMs by adeno-associated virus–mediated massively parallel reporter assay. This identified 1092 active enhancers in aCMs or vCMs. Several overlapped loci associated with cardiovascular disease through genome-wide association studies, and 229 exhibited chamber-selective activity in aCMs or vCMs. Many CSEs exhibited differential chromatin accessibility between aCMs and vCMs, and CSEs were enriched for aCM- or vCM-selective acetylation of histone H3 at lysine 27–anchored loops. Tiling mutagenesis of 29 CSEs identified the binding motif of ERRα/γ as important for ventricular enhancer activity. The requirement of ERRα/γ to activate ventricular CSEs and promote vCM identity was confirmed by loss of the vCM gene profile in ERRα/γ knockout vCMs.CONCLUSIONS:We identified 229 CSEs that could be useful research tools or direct therapeutic gene expression. We showed that chamber-selective multi–transcription factor, P300 occupancy, open chromatin, and chromatin looping are predictive features of CSEs. We found that ERRα/γ are essential for maintenance of ventricular identity. Finally, our gene expression, epigenetic, 3-dimensional genome, and enhancer activity atlas provide key resources for future studies of chamber-selective gene regulation.
Results of a large clinical trial counter previous findings of benefit with torsemide.
Operato a Pinerolo (Torino) ragazzo 14 anni, donatore il padre
Operato a Pinerolo (Torino) ragazzo 14 anni, donatore il padre
This randomized, placebo-controlled platform trial compares the use of low-dose fluvoxamine (50 mg twice daily) for 10 days compared with placebo in outpatients with mild to moderate COVID-19.
To the Editor A recent Research Letter examined temperatures generated with temporal artery thermometers with the goal of identifying systemic bias in medical devices. As one of us (F.P.) is the inventor of the temporal artery thermometer, and as we are scientists working for its manufacturer, we wish to highlight that this study showed that Black and White patients had essentially the same fever rates and temporal temperatures (eg, 38 °C: 10.1% vs 10.8% [P = .49]; mean, 36.98 °C vs 36.97 °C [P = .67]).
In Reply We thank the authors for their comments about our recent article exploring racial differences in the accuracy of temporal thermometers. We agree with Dr Newman that self-reported race is an imperfect proxy for skin color. If differences in skin color are the basis of the temperature differences observed between oral and temporal thermometers, the magnitude of the difference would be better measured using an objective measure of skin color in a prospective study rather than self-reported race in a retrospective data analysis.
To the Editor A recent Research Letter reported that temperatures measured by temporal thermometers are lower than those measured orally in Black patients but not in White patients. However, I am concerned that this study used race as a proxy for skin color. Because people can have a range of skin colors despite their so-called race, the results of this study would have been more meaningful if it had used a biological parameter with one of the more objective measurements of skin color, such as a spectrophotometer or one of the visual scales.
To the Editor We have several comments about the recent study that found that intensity-modulated radiation therapy (IMRT) alone was not inferior for 3-year failure-free survival compared with concurrent chemoradiotherapy in patients with low-risk nasopharyngeal carcinoma (NPC).
To the Editor A recent study assessed the noninferiority of IMRT alone vs concurrent chemoradiotherapy for treating low-risk NPC. The noninferiority claim was based on a 3-year failure-free survival rate with a noninferiority margin of 10% for the absolute failure-free survival rate difference.
To the Editor The National Comprehensive Cancer Network (NCCN) guidelines currently recommend that concurrent chemoradiotherapy be the primary treatment for patients with T1-2N1M0, T3N0M0, and T2N0M0 NPC with high-risk features. A recent study reported that patients with low-risk stage II and T3N0M0 cancer who received IMRT alone had the same oncologic outcomes but better long-term quality of life than those who received concurrent chemoradiotherapy. We have 3 concerns about the definition of the truly low-risk NPC.
This clinical trial compares the efficacy of torsemide vs furosemide in decreasing the risk of death from any cause among patients hospitalized for heart failure (regardless of ejection fraction).
In Reply We agree with Ms Hu and Dr Kao that the current NCCN guidelines recommend definitive radiotherapy with or without concurrent chemotherapy for NPC with stage II and T3N0 disease, and in this subset, induction or adjuvant chemotherapy only for patients with high-risk features including bulky tumor volume or high serum EBV DNA copy number. Our study excluded patients who had NPC with high-risk features, so all patients with low-risk NPC were not treated with induction or adjuvant chemotherapy. Although triweekly delivery of cisplatin has been the standard regimen for concurrent chemotherapy, a phase 2 clinical trial comparing weekly and triweekly cisplatin during radiotherapy reported that the therapeutic effect and acute reactions of triweekly regimen were similar to that of the weekly regimen. However, other studies have reported significantly greater hematological toxicity but lower gastrointestinal reactions with a weekly cisplatin regimen.
This randomized clinical trial compares the effect of early high-flow oxygen therapy vs standard oxygen therapy on length of hospital stay in children with acute hypoxemic respiratory failure.
Tissue fibrosis results from uncontrolled healing responses that results in excessive mesenchymal cell activation, collagen and other extracellular matrix (ECM) deposition. In the gastrointestinal (GI) tract, fibrosis leads to narrowing of the lumen and stricture formation. A drug treatment to prevent fibrosis and strictures in the GI tract would be transformational for patient care. Here, we aimed to develop a stricture treatment with following characteristics and components: (1) a small molecule with strong antifibrotic effects; (2) that is delivered locally at the site of the stricture to ensure correct lesional targeting while protecting the systemic circulation and that is (3) formulated with sustained release properties to act throughout the wound healing processes.
