Genedata (Switzerland)

We agree with the commentary that distinguishing between incident and prevalent patients with CeD is important for understanding the disease’s economic implications. However, the limited timeframe of the available data restricts our ability to accurately identify adult CeD patients who are genuinely newly diagnosed, since most individuals with CeD are diagnosed during childhood or adolescence. The available observation period for patients with CeD is not long enough to follow patients from childhood diagnosis until adulthood. Thus, there is a risk of misclassifying incident patients as prevalent cases, but it should be acceptable regarding the overall evaluation, since the probability of incident patients at older age groups is lower.Given our interest in incident patients, we are currently preparing another publication focused specifically on newly diagnosed children with CeD.

Volume-regulated anion channels (VRACs) are multimeric proteins composed of different paralogs of the LRRC8 family. They are activated in response to hypotonic swelling, but little is known about their specific functions. We studied two human individuals with the same congenital syndrome affecting blood vessels, brain, eyes, and bones. The LRRC8C gene harbored de novo variants in both patients, located in a region of the gene encoding the boundary between the pore and a cytoplasmic domain, which is depleted of sequence variations in control subjects. When studied by cryo-EM, both LRRC8C mutant proteins assembled as their wild-type counterparts, but showed increased flexibility, suggesting a destabilization of subunit interactions. When co-expressed with the obligatory LRRC8A subunit, the mutants exhibited enhanced activation, resulting in channel activity even at isotonic conditions in which wild-type channels are closed. We conclude that structural perturbations of LRRC8C impair channel gating and constitute the mechanistic basis of the dominant gain-of-function effect of these pathogenic variants. The pleiotropic phenotype of this novel clinical entity associated with monoallelic LRRC8C variants indicates the fundamental roles of VRACs in different tissues and organs.

Экзосомы, небольшие двухслойные мембраны, полученные из эукариотических клеток, были идентифицированы как полезная естественная платформа доставки благодаря их подходящему размеру, биосовместимости, структурной стабильности, высокой нагрузочной способности и возможности редактирования поверхности. Из-за сложности поддержания высокой чистоты экзосомы было предпринято несколько попыток использовать методы выделения экзосом. В настоящем исследовании был проведен процесс мягкой литографии для создания каналов для разделения экзосом с функцией иммуноаффинности. Тесты как по биохимическим, так и по биофизическим категориям были проведены для проверки качества экстрагированных экзосом из различных источников (сыворотка, клеточный супернатант и моча) и сравнения их с коммерчески доступным набором. Результаты показали, что нынешний метод способен изолировать экзосомы с высоким выходом, чистотой и низкими затратами времени. Все формы экзосом, нагруженных иматинибом, проявляли противоопухолевую активность в отношении клеточной линии KYO-1.

En este artículo, se identifican tanto el importante papel como las posibilidades de las diputaciones para fortalecer los Gobiernos locales y la buena gobernanza local, y con ello la democracia de proximidad y el compromiso cívico de la ciudadanía. Se señalan, además, las características y potencialidades de la planificación estratégica de 2.ª generación para que las diputaciones puedan lograr grandes avances en esta dirección, en unos momentos difíciles para los ayuntamientos, y en que la propia existencia de las diputaciones es puesta en cuestión.

Infertility is a medical and psychosocial problem that affects one in six couples worldwide. Infertility is increasing largely due to people starting families later, adecrease in the quality of sperm due to environmental and lifestyle factors and rising rates of obesity in both men and women. As a result, general practitioners (GPs) are increasingly seeing patients for fertility-related consultations. Nearly half of these GP consultations will result in a referral to a fertility clinic or relevant specialist. Approximately 5% of children now born in Australia are born as a result of assisted reproductive treatment. In Australia, GPs are the primary access point for reproductive care. They can play a central role in educating, preparing and supporting their patients andensuring timely and appropriate intervention and referral. This paper describes the lived experience of those dealing with infertility, particularly the emotional challenges of infertility and its treatment, to help GPs support their patients throughout treatment and beyond. Infertility and fertility treatment can have a significant impact on the psychological wellbeing of both men and women, as well as their relationships with one another, their family and friends. GPs are well placed to establish a trusting and supportive relationship during one of the most stressful periods of their patients' lives, to notice changes in wellbeing, functioning and relationship satisfaction and to facilitate timely referral to appropriate resources.

The data currently described was generated within the EU/FP7 HeCaToS project (Hepatic and Cardiac Toxicity Systems modeling). The project aimed to develop an in silico prediction system to contribute to drug safety assessment for humans. For this purpose, multi-omics data of repeated dose toxicity were obtained for 10 hepatotoxic and 10 cardiotoxic compounds. Most data were gained from in vitro experiments in which 3D microtissues (either hepatic or cardiac) were exposed to a therapeutic (physiologically relevant concentrations calculated through PBPK-modeling) or a toxic dosing profile (IC20 after 7 days). Exposures lasted for 14 days and samples were obtained at 7 time points (therapeutic doses: 2-8-24-72-168-240-336 h; toxic doses 0-2-8-24-72-168-240 h). Transcriptomics (RNA sequencing & microRNA sequencing), proteomics (LC-MS), epigenomics (MeDIP sequencing) and metabolomics (LC-MS & NMR) data were obtained from these samples. Furthermore, functional endpoints (ATP content, Caspase3/7 and O2 consumption) were measured in exposed microtissues. Additionally, multi-omics data from human biopsies from patients are available. This data is now being released to the scientific community through the BioStudies data repository (https://www.ebi.ac.uk/biostudies/).

Combined first-trimester screening (cFTS) for fetal anomalies involves maternal serum screening for biochemical markers and measurement of the nuchal translucency (NT) by ultrasound. Noninvasive prenatal screening (NIPS) analyses cell-free DNA present in a maternal blood sample for presence of fetal chromosomal aneuploidies. To compare NIPS with cFTS as frontline screening in a public hospital in Australia. Women were offered NIPS in addition to the usual cFTS routinely offered to all women at a public hospital in NSW, Australia. The cFTS sample was collected at tenweeks' gestation and the NIPS sample at 12 weeks' gestation at the ultrasound appointment. In a low-risk population of 997 women, frontline NIPS had a screen-positive rate of 0.5% (5/997) vs 4.2% (42/997) with cFTS. cFTS correctly identified one trisomy 21 case and one trisomy 18 case; however, there were two trisomy 18 false negatives. Of five positive NIPS calls, four were correctly identified as trisomy 21 (one) and trisomy 18 (three); there were no NIPS false negatives. Overall, the false-positive rate with NIPS was 0.1% vs 4.0% by cFTS. The lower screen-positive rate with NIPS for common trisomies was a result of the significantly lower false-positive rate with NIPS. Consequently, NIPS as first-line screening, even if funded by the hospital, may provide cost savings. We believe NIPS should be used from tenweeks' gestation in conjunction with morphology ultrasound for routine first-trimester prenatal management.

The cover image is based on the Original Article Microparticles globally reprogram Streptomyces albus toward accelerated morphogenesis, streamlined carbon core metabolism, and enhanced production of the antituberculosis polyketide pamamycin by Martin Kuhl et al., https://doi.org/10.1002/bit.27537.

187 Background: ICD is an immune response against dead-cell antigens from cancer cells treated with cytotoxic and/or targeted therapies. Oxaliplatin (OHP) and cetuximab (Cet) are distinct drugs to elicit ICD, while most other anticancer agents kill cancer cells in a nonimmunogenic manner. We hypothesized that genetic variants in ICD-related genes could predictive efficacy of OHP and/or Cet in mCRC. Methods: We analyzed data of mCRC patients enrolled in three 1st-line randomized trials [FIRE-3: FOLFIRI+Cet vs FOLFIRI+bevacizumab (Bev), TRIBE: FOLFOXIRI+Bev vs FOLFIRI+Bev and MAVERICC: FOLFOX+Bev vs FOLFIRI+Bev]. Genomic DNA from blood samples was genotyped through the OncoArray, a custom array manufactured by Illumina. Candidate 14 SNPs in five ICD-related genes ( CALR, HMGB1, ANXA1, LRP1 and P2RX7) were tested for association with progression-free survival (PFS) and overall survival (OS), using Cox proportional hazards model. We tested treatment-by-SNP interactions in the following cohorts: combined TRIBE and MAVERICC (OHP-containing treatment vs non-OHP-containing treatment), and FIRE-3 (FOLFIRI+Cet vs FOLFIRI+Bev). An interaction p-value (i p) < 0.05 was considered significant. Results: Totally, 890 patients’ SNPs were available (FIRE-3: n = 236, TRIBE: n = 324, and MAVERICC: n = 330). In the combined TRIBE and MAVERICC cohorts [the reference of hazard ratio (HR) is non-OHP-containing treatment], a significant interaction was observed in ANXA1 rs1050305 (A/A: HR 0.96, Any G: HR 2.62, i p < 0.01), LRP1 rs1466535 (G/G: HR 1.39, Any A: HR 0.91, i p = 0.02), P2RX7 rs2230911 (C/C: HR 0.98, Any G: HR 1.76, i p = 0.03) and P2RX7 rs208294 (C/C: HR 1.82, Any T: HR 0.93, i p < 0.01) on OS. For PFS, that was observed in CALR rs110222 (G/G: HR 1.30, Any A: HR 0.87, i p = 0.02), HMGB1 rs1045411 (C/C: HR 0.85, Any T: HR 1.30, i p = 0.04) and HMGB1 rs1360485 (T/T: HR 0.81, Any C: HR 1.40, i p < 0.01). However, in the FIRE-3 cohort, no significant interactions were observed in any SNPs. Conclusions: Our results showed for the first time that SNPs in ICD-related genes may predict efficacy of OHP-containing treatment in mCRC. But the predictive values for Cet efficacy was not evident.