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The addition of pertuzumab to trastuzumab plus standard chemotherapy as adjuvant therapy following surgery significantly improved invasive disease-free survival (IDFS) in patients with HER2-positive early breast cancer in the multinational randomized APHINITY trial (NCT01358877, BIG 4-11/BO25126/TOC4939G). We analyzed clinical outcomes in the subgroup of patients recruited at Chinese sites.

Patients were randomized to standard adjuvant chemotherapy plus 1year of trastuzumab with pertuzumab or placebo. Patients recruited in mainland China, Hong Kong and Taiwan are included in this descriptive analysis.

Chinese patients had similar demographic characteristics to the global population, but a higher proportion had nodal involvement. Although this subgroup analysis was not powered to detect statistical significance, a numerical improvement in IDFS was observed with the addition of pertuzumab to trastuzumab in Chinese patients (hazard ratio, 0.69; 95% confidence interval 0.39-1.19; 3-year IDFS event-free estie patients was consistent with that of the global population.

ANGPTL8 (A8) plays a key role in determining the tissue fate of circulating triglycerides (TGs). Plasma A8 levels are associated with several parameters of glucose and TG metabolism, but the causality of these relationships and the contribution of genetic variants to differences in A8 levels have not been explored.

To characterize the frequency distribution of plasma A8 levels in a diverse population using a newly-developed enzyme-linked immunosorbent assay (ELISA) and to identify genetic factors contributing to differences in plasma A8 levels.

We studied a population-based sample of Dallas County, comprising individuals in the Dallas Heart Study (DHS-1, n = 3538; DHS-2, n = 3283), including 2131 individuals with repeated measurements 7 to 9 years apart (age 18-85 years; >55% female; 52% Black; 29% White; 17% Hispanic; and 2% other). The main outcome measures were associations of A8 levels with body mass index (BMI), plasma levels of glucose, insulin, lipids, and hepatic TGs, as well as DNA variants types.

Scholar photoprotection campaigns are among the most effective strategies for preventing skin cancer. Analysis of the target population constitutes a valuable starting point for the implementation of primary prevention strategies. Our aim is to study photoprotection habits, attitudes and knowledge among a Spanish school community.

Descriptive cross-sectional study targeting schoolchildren, parents and teachers at 20 schools in the area of the Costa del Sol Health Agency in southern Spain. Two population-specific, validated questionnaires were used the CHRESI (for children aged 0-10 years) and CHACES Questionnaire(for adults and adolescents aged > 11 years). We collected demographic data, skin colour, skin phototype, sunburn episodes, sun exposure and photoprotection practices, attitudes and knowledge.

1728 questionnaires were analyzed (22% parents, 14.5% teachers, 44.8% adolescents and 18.6% children). The average ages were 8 years (children), 16 years (adolescents), 39 years (teachers) and 42 years essed in campaigns to promote healthy sun exposure habits, thus reducing skin cancer-related morbidity and mortality in this region.In most taxa, halving of chromosome numbers during meiosis requires that homologous chromosomes (homologues) pair and form crossovers. Crossovers emerge from the recombination-mediated repair of programmed DNA double-strand breaks (DSBs). DSBs are generated by SPO11, whose activity requires auxiliary protein complexes, called pre-DSB recombinosomes. To elucidate the spatiotemporal control of the DSB machinery, we focused on an essential SPO11 auxiliary protein, IHO1, which serves as the main anchor for pre-DSB recombinosomes on chromosome cores, called axes. We discovered that DSBs restrict the DSB machinery by at least four distinct pathways in mice. Firstly, by activating the DNA damage response (DDR) kinase ATM, DSBs restrict pre-DSB recombinosome numbers without affecting IHO1. Secondly, in their vicinity, DSBs trigger IHO1 depletion mainly by another DDR kinase, ATR. Thirdly, DSBs enable homologue synapsis, which promotes the depletion of IHO1 and pre-DSB recombinosomes from synapsed axes. Finally, DSBs and three DDR kinases, ATM, ATR and PRKDC, enable stage-specific depletion of IHO1 from all axes. We hypothesize that these four negative feedback pathways protect genome integrity by ensuring that DSBs form without excess, are well-distributed, and are restricted to genomic locations and prophase stages where DSBs are functional for promoting homologue pairing and crossover formation.

Previous work has demonstrated the role of the circadian clock in ovarian steroid hormone synthesis and attributed embryo implantation failure associated with arrhythmic circadian clock genes to insufficient ovarian-derived progesterone synthesis. Research on expression of core circadian clock genes in the endometrium itself and possible roles in compromised endometrial receptivity and recurrent implantation failure (RIF) are limited.

We aimed to assess the core circadian clock gene profiling in human endometrium across the menstrual cycle and the possible gene interaction networks in the endometrial receptivity of window of implantation (WOI) as well as RIF.

The study was initially an in silico study, with confirmatory lab-based data from primary human endometrial stromal cells (hESCs) as well as endometrial biopsies obtained from 60 women undergoing gynecological surgery in a clinical research center. The study included 30 RIF women and 30 age-matched and body mass index-matched controls.

Initial data mining and bioinformatics analysis of human endometrial microarray datasets across the menstrual cycle and between RIF women versus controls demonstrated the varied expression of core circadian clock genes across menstrual cycle, including the key role of PER2 in WOI and RIF. A PER2-centered network was investigated in the regulation of endometrial receptivity. We also confirmed the evidently increased mRNA expression of SHTN1, RXFP1, KLF5, and STEAP4 in the endometrium of RIF women, displaying the same trend as PER2 did, without any changes in MT1E and FKBP5. Treatment of PER2 siRNA in hESCs verified the positive regulation of PER2 to SHTN1, KLF5, and STEAP4.

Aberrant expression of endometrial PER2 might contribute to impaired endometrial receptivity and development of RIF via regulating SHTN1, KLF5, and STEAP4.

Aberrant expression of endometrial PER2 might contribute to impaired endometrial receptivity and development of RIF via regulating SHTN1, KLF5, and STEAP4.

In heart failure (HF) iron deficiency (ID) is frequently observed and represents a major mortality risk factor. Purpose of this study was to evaluate the correlation between mortality and ID in a cohort of 661 consecutive patients hospitalized for HF worsening.

Patients were grouped (i)according to presence(+)/absence(-) of anaemia (A) and ID defined following World Health Organization (WHO) and European Society of Cardiology (ESC)-American College of Cardiology/American Heart Association/HF society of America (ACC/AHA/HFSA) definitions, respectively Group A-ID- (n = 123), Group A+ID- (n = 80), Group A+ID+ (n = 247), and Group A-ID+ (n = 211); (ii) according to presence of absolute (serum ferritin < 100μg/L) and functional ID [ferritin between 100 and 300μg/L and transferrin saturation (TSAT) < 20%]; and (iii) according to TSAT <20% and ≥20%. Groups were not different for several clinical features but age, gender, kidney function, and chronic obstructive pulmonary disease. Average follow-up was 1to those with TSAT ≥20% but the composite of ferritin between 100 and 300 μg/L and TSAT less then 20% identifies HF patients with the poorest survival rate.Several existing technologies enable short genomic alterations including generating indels and short nucleotide variants, however, engineering more significant genomic changes is more challenging due to reduced efficiency and precision. Here, we developed RecT Editor via Designer-Cas9-Initiated Targeting (REDIT), which leverages phage single-stranded DNA-annealing proteins (SSAP) RecT for mammalian genome engineering. Relative to Cas9-mediated homology-directed repair (HDR), REDIT yielded up to a 5-fold increase of efficiency to insert kilobase-scale exogenous sequences at defined genomic regions. We validated our REDIT approach using different formats and lengths of knock-in templates. We further demonstrated that REDIT tools using Cas9 nickase have efficient gene-editing activities and reduced off-target errors, measured using a combination of targeted sequencing, genome-wide indel, and insertion mapping assays. Our experiments inhibiting repair enzyme activities suggested that REDIT has the potential to overcome limitations of endogenous DNA repair steps. Finally, our REDIT method is applicable across cell types including human stem cells, and is generalizable to different Cas9 enzymes.CRISPR technologies increasingly require spatiotemporal and dosage control of nuclease activity. One promising strategy involves linking nuclease activity to a cell's transcriptional state by engineering guide RNAs (gRNAs) to function only after complexing with a 'trigger' RNA. However, standard gRNA switch designs do not allow independent selection of trigger and guide sequences, limiting gRNA switch application. Here, we demonstrate the modular design of Cas12a gRNA switches that decouples selection of these sequences. The 5' end of the Cas12a gRNA is fused to two distinct and non-overlapping domains one base pairs with the gRNA repeat, blocking formation of a hairpin required for Cas12a recognition; the other hybridizes to the RNA trigger, stimulating refolding of the gRNA repeat and subsequent gRNA-dependent Cas12a activity. Using a cell-free transcription-translation system and Escherichia coli, we show that designed gRNA switches can respond to different triggers and target different DNA sequences. Modulating the length and composition of the sensory domain altered gRNA switch performance. Finally, gRNA switches could be designed to sense endogenous RNAs expressed only under specific growth conditions, rendering Cas12a targeting activity dependent on cellular metabolism and stress. Our design framework thus further enables tethering of CRISPR activities to cellular states.

Medical institutions are using barrier enclosure devices during intubation procedures and other aerosol-generating medical procedures without evidence of their effectiveness or usability, potentially compromising patient care, and provider safety. Our objective was to determine the degree of protection offered by these devices and explore other usability factors for two popular barrier systems.

A simulated trial comparing an intubation box, a frame and plastic tarp system, and unprotected intubation was performed in an academic emergency department. Ten emergency physicians were recruited to participate. Our primary outcome was the degree of contamination from secretions measured by average surface area exposed to phosphorescent material. AS2863619 Secondary outcomes included laryngoscopy time and time to barrier application, unsuccessful intubation attempts, and usability ratings for each system. Descriptive statistics were reported for all variables of interest and a linear mixed model was used to analyze contamination and laryngoscopy time.