The molecular events and transcriptional plasticity driving brain metastasis in clinically relevant breast tumor subtypes has not been determined. Here we comprehensively dissect genomic, ...transcriptomic and clinical data in patient-matched longitudinal tumor samples, and unravel distinct transcriptional programs enriched in brain metastasis. We report on subtype specific hub genes and functional processes, central to disease-affected networks in brain metastasis. Importantly, in luminal brain metastases we identify homologous recombination deficiency operative in transcriptomic and genomic data with recurrent breast mutational signatures A, F and K, associated with mismatch repair defects, TP53 mutations and homologous recombination deficiency (HRD) respectively. Utilizing PARP inhibition in patient-derived brain metastatic tumor explants we functionally validate HRD as a key vulnerability. Here, we demonstrate a functionally relevant HRD evident at genomic and transcriptomic levels pointing to genomic instability in breast cancer brain metastasis which is of potential translational significance.
We evaluated measures to protect healthcare workers (HCWs) in Vancouver, Canada, where variants of concern (VOC) went from <1% VOC in February 2021 to >92% in mid-May. Canada has amongst the longest ...periods between vaccine doses worldwide, despite Vancouver having the highest P.1 variant rate outside Brazil.
With surveillance data since the pandemic began, we tracked laboratory-confirmed SARS-CoV-2 infections, positivity rates, and vaccine uptake in all 25,558 HCWs in Vancouver Coastal Health, by occupation and subsector, and compared to the general population. Cox regression modelling adjusted for age and calendar-time calculated vaccine effectiveness (VE) against SARS-CoV-2 in fully vaccinated (≥ 7 days post-second dose), partially vaccinated infection (after 14 days) and unvaccinated HCWs; we also compared with unvaccinated community members of the same age-range.
Only 3.3% of our HCWs became infected, mirroring community rates, with peak positivity of 9.1%, compared to 11.8% in the community. As vaccine coverage increased, SARS-CoV-2 infections declined significantly in HCWs, despite a surge with predominantly VOC; unvaccinated HCWs had an infection rate of 1.3/10,000 person-days compared to 0.89 for HCWs post first dose, and 0.30 for fully vaccinated HCWs. VE compared to unvaccinated HCWs was 37.2% (95% CI: 16.6-52.7%) 14 days post-first dose, 79.2% (CI: 64.6-87.8%) 7 days post-second dose; one dose provided significant protection against infection until at least day 42. Compared with community infection rates, VE after one dose was 54.7% (CI: 44.8-62.9%); and 84.8% (CI: 75.2-90.7%) when fully vaccinated.
Rigorous droplet-contact precautions with N95s for aerosol-generating procedures are effective in preventing occupational infection in HCWs, with one dose of mRNA vaccination further reducing infection risk despite VOC and transmissibility concerns. Delaying second doses to allow more widespread vaccination against severe disease, with strict public health, occupational health and infection control measures, has been effective in protecting the healthcare workforce.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Patients with non-small-cell lung cancer (NSCLC) that is resistant to PD-1 and PD-L1 (PDL-1)-targeted therapy have poor outcomes. Studies suggest that radiotherapy could enhance antitumour immunity. ...Therefore, we investigated the potential benefit of PD-L1 (durvalumab) and CTLA-4 (tremelimumab) inhibition alone or combined with radiotherapy.
This open-label, multicentre, randomised, phase 2 trial was done by the National Cancer Institute Experimental Therapeutics Clinical Trials Network at 18 US sites. Patients aged 18 years or older with metastatic NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, and progression during previous PD(L)-1 therapy were eligible. They were randomly assigned (1:1:1) in a web-based system by the study statistician using a permuted block scheme (block sizes of three or six) without stratification to receive either durvalumab (1500 mg intravenously every 4 weeks for a maximum of 13 cycles) plus tremelimumab (75 mg intravenously every 4 weeks for a maximum of four cycles) alone or with low-dose (0·5 Gy delivered twice per day, repeated for 2 days during each of the first four cycles of therapy) or hypofractionated radiotherapy (24 Gy total delivered over three 8-Gy fractions during the first cycle only), 1 week after initial durvalumab–tremelimumab administration. Study treatment was continued until 1 year or until progression. The primary endpoint was overall response rate (best locally assessed confirmed response of a partial or complete response) and, along with safety, was analysed in patients who received at least one dose of study therapy. The trial is registered with ClinicalTrials.gov, NCT02888743, and is now complete.
Between Aug 24, 2017, and March 29, 2019, 90 patients were enrolled and randomly assigned, of whom 78 (26 per group) were treated. This trial was stopped due to futility assessed in an interim analysis. At a median follow-up of 12·4 months (IQR 7·8–15·1), there were no differences in overall response rates between the durvalumab–tremelimumab alone group (three 11·5%, 90% CI 1·2–21·8 of 26 patients) and the low-dose radiotherapy group (two 7·7%, 0·0–16·3 of 26 patients; p=0·64) or the hypofractionated radiotherapy group (three 11·5%, 1·2–21·8 of 26 patients; p=0·99). The most common grade 3–4 adverse events were dyspnoea (two 8% in the durvalumab–tremelimumab alone group; three 12% in the low-dose radiotherapy group; and three 12% in the hypofractionated radiotherapy group) and hyponatraemia (one 4% in the durvalumab–tremelimumab alone group vs two 8% in the low-dose radiotherapy group vs three 12% in the hypofractionated radiotherapy group). Treatment-related serious adverse events occurred in one (4%) patient in the durvalumab–tremelimumab alone group (maculopapular rash), five (19%) patients in the low-dose radiotherapy group (abdominal pain, diarrhoea, dyspnoea, hypokalemia, and respiratory failure), and four (15%) patients in the hypofractionated group (adrenal insufficiency, colitis, diarrhoea, and hyponatremia). In the low-dose radiotherapy group, there was one death from respiratory failure potentially related to study therapy.
Radiotherapy did not increase responses to combined PD-L1 plus CTLA-4 inhibition in patients with NSCLC resistant to PD(L)-1 therapy. However, PD-L1 plus CTLA-4 therapy could be a treatment option for some patients. Future studies should refine predictive biomarkers in this setting.
The US National Institutes of Health and the Dana-Farber Cancer Institute.
The importance of heat stress as a consequence of climate climate change is often overlooked for seabirds. As endotherms, seabirds must actively thermoregulate at temperatures above their ...thermoneutral zone, or risk lethal hyperthermia. Although essential activities (e.g. foraging, breeding) may be traded off for thermoregulatory behaviors during periods of heat stress, a recent report by Olin et al. (2024; Mar Ecol Prog Ser 737:147-160 in this Theme Section) is one of very few that directly link this to demography. We argue that heat stress effects, which have strong theoretical support, are underreported directly because large-scale mortality events are rare, and small-scale events are hard to identify and easily obscured by indirect trophic effects. Quantifying heat stress effects on seabirds is necessary to understand fully the threats from climate change but requires prioritizing research in the following areas: developing methods to attribute heat mortality, determining baseline levels of heat mortality, elucidating ecological and organismal differences that underlie heat stress sensitivity, investigating the importance of possible sublethal mechanisms, and separating heat stress trade-offs from indirect effects of climate.
Abstract
Skeletal muscle serves fundamental roles in organismal health. Gene expression fluctuations are critical for muscle homeostasis and the response to environmental insults. Yet, little is ...known about post-transcriptional mechanisms regulating such fluctuations while impacting muscle proteome. Here we report genome-wide analysis of mRNA methyladenosine (m
6
A) dynamics of skeletal muscle hypertrophic growth following overload-induced stress. We show that increases in METTL3 (the m
6
A enzyme), and concomitantly m
6
A, control skeletal muscle size during hypertrophy; exogenous delivery of METTL3 induces skeletal muscle growth, even without external triggers. We also show that METTL3 represses activin type 2 A receptors (ACVR2A) synthesis, blunting activation of anti-hypertrophic signaling. Notably, myofiber-specific conditional genetic deletion of METTL3 caused spontaneous muscle wasting over time and abrogated overload-induced hypertrophy; a phenotype reverted by co-administration of a myostatin inhibitor. These studies identify a previously unrecognized post-transcriptional mechanism promoting the hypertrophic response of skeletal muscle via control of myostatin signaling.
Approximately 70% of the aquatic-based production of animals is fed aquaculture, whereby animals are provided with high-protein aquafeeds. Currently, aquafeeds are reliant on fish meal and fish oil ...sourced from wild-captured forage fish. However, increasing use of forage fish is unsustainable and, because an additional 37.4 million tons of aquafeeds will be required by 2025, alternative protein sources are needed. Beyond plant-based ingredients, fishery and aquaculture byproducts and insect meals have the greatest potential to supply the protein required by aquafeeds over the next 10–20 years. Food waste also has potential through the biotransformation and/or bioconversion of raw waste materials, whereas microbial and macroalgal biomass have limitations regarding their scalability and protein content, respectively. In this review, we describe the considerable scope for improved efficiency in fed aquaculture and discuss the development and optimization of alternative protein sources for aquafeeds to ensure a socially and environmentally sustainable future for the aquaculture industry.
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Approximately 70% of the aquatic-based production of animals is fed aquaculture, whereby animals are provided with high-protein aquafeeds. Currently, aquafeeds are reliant on fish meal and fish oil sourced from wild-captured forage fish. However, increasing use of forage fish is unsustainable and, because an additional 37.4 million tons of aquafeeds will be required by 2025, alternative protein sources are needed. Beyond plant-based ingredients, fishery and aquaculture byproducts and insect meals have the greatest potential to supply the protein required by aquafeeds over the next 10–20 years. Food waste also has potential through the biotransformation/bioconversion of raw waste materials, whereas microbial and macroalgal biomass have limitations regarding their scalability and protein content, respectively. In this review, we describe the considerable scope for improved efficiency in fed aquaculture and discuss the development and optimization of alternative protein sources for aquafeeds to ensure a socially and environmentally sustainable future for the aquaculture industry.
Dietary specialization, exploiting a small fraction of available food resources, is commonly reported for gulls and skuas. Predation of birds by these species is usually considered a specialist ...strategy employed by the minority of the population but non-specialists also predate birds and may actually have a greater impact on the prey species. To date, most studies have focused on predatory bird-specialists, down-playing the possible importance of opportunistic predation by non-specialists. We addressed this by studying diet (regurgitated pellets and prey remains) and behavior of breeding Herring Gulls (Larus argentatus) over three summers at Gull Island, a mixed-species breeding colony in Lake Ontario. One-third of all pellets analyzed contained bird remains, primarily the most numerous breeding bird: Ring-billed Gull (L. delawarensis) chicks (51%) and adults (36%). Although all but one pair of Herring Gulls ate birds, all pairs maintained broad and mostly similar diets, with birds accounting for at most one-third of prey. Behavior also indicated that Herring Gulls at Gull Island were not predatory bird-specialists because predation was too infrequent to meet energetic requirements, was largely unsuccessful and was only ever observed when Ring-billed Gulls strayed into Herring Gull breeding territories. Instead, bird predation appeared mainly opportunistic, increasing with seasonal availability, access to shoreline, proximity to nesting Ring-billed Gulls and breeding territory size. Compared with predatory specialist Herring Gulls in the same region, individuals that predated birds at Gull Island did not display specialist behaviors and killed six times fewer birds (0.1-0.4 per day, on average) but were over 20 times more numerous (98% of the population versus 4%). Thus, our results indicate that opportunistic predation by non-specialists may have important consequences for prey species. Since opportunistic predation cannot be effectively managed using techniques widely advocated for specialist predators, it is essential to investigate cause of predation by large gulls prior to lethal management.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We aimed to evaluate the impact of health care vaccine mandates on vaccine uptake and infection risk in a cohort of Canadian health care workers (HCWs).
We conduct interrupted time series analysis ...through a regression discontinuity in time approach to estimate the immediate and delayed impact of the mandate. Multilevel mixed effect modeling fitted with restricted maximum likelihood was used to estimate impact on infection risk.
The immediate and sustained effects of the mandate was a 0.19% (P < .05) and a 0.012% (P < .05) increase in the daily proportion of unvaccinated HCWs getting their first dose, respectively. An additional 623 (95% confidence interval: 613-667) HCWs received first doses compared to the predicted uptake absent the mandate. Adjusted test positivity declined by 0.053% (95% confidence interval: 0.035%, 0.069) for every additional day the mandate was in effect.
Our results indicate that the mandate was associated with significant increases in vaccine uptake and infection risk reduction in the cohort.
Given the benefit that vaccination could bring to HCWs, understanding strategies to enhance uptake is crucial for bolstering health system resilience, but steps must be taken to avert approaches that sacrifice trust, foster animosity, or exacerbate staffing constraints for short-term results.
•The mandate was effective in increasing vaccine uptake healthcare workers (HCWS).•Effectiveness was also shown for lowering infection risk.•Impact was greater in subgroups of HCWs including those who work in long-term care.•Context and epidemiology should be considered when utilizing vaccine mandates.
Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disease caused by a mutation in
. A G608G mutation in exon 11 of
is responsible for most HGPS cases, generating a truncated ...protein called "progerin". Progerin is permanently farnesylated and accumulates in HGPS cells, causing multiple cellular defects such as nuclear dysmorphism, a thickened lamina, loss of heterochromatin, premature senescence, and clustering of Nuclear Pore Complexes (NPC). To identify the mechanism of NPC clustering in HGPS cells, we evaluated post-mitotic NPC assembly in control and HGPS cells and found no defects. Next, we examined the occurrence of NPC clustering in control and HGPS cells during replicative senescence. We reported that NPC clustering occurs solely in the dysmorphic nuclei of control and HGPS cells. Hence, NPC clustering occurred at a higher frequency in HGPS cells compared to control cells at early passages; however, in late cultures with similar senescence index, NPCs clustering occurred at a similar rate in both control and HGPS. Our results show that progerin does not disrupt post-mitotic reassembly of NPCs. However, NPCs frequently cluster in dysmorphic nuclei with a high progerin content. Additionally, nuclear envelope defects that arise during replicative senescence cause NPC clustering in senescent cells with dysmorphic nuclei.
Identifying Research Domain Criteria (RDoC) constructs in early childhood is essential for understanding etiological pathways of psychopathology. Our central goal was to identify early emotion ...knowledge and self-regulation difficulties across different RDoC domains and examine how they relate to typical versus atypical symptom trajectories between ages 3 and 10. Particularly, we assessed potential contributions of children's gender, executive control, delay of gratification, and regulation of frustration, emotion recognition, and emotion understanding at age 3 to co-occurring patterns of internalizing and externalizing across development. A total of 238 3-year-old boys and girls were assessed using behavioral tasks and parent reports and reassessed at ages 5 and 10 years. Results indicated that very few children developed "pure" internalizing or externalizing symptoms relative to various levels of co-occurring symptoms across development. Four classes of co-occurring internalizing and externalizing problems were identified: low, low-moderate, rising, and severe-decreasing trajectories. Three-year-old children with poor executive control but high emotion understanding were far more likely to show severe-decreasing than low/low-moderate class co-occurring internalizing and externalizing symptom patterns. Child gender and poor executive control differentiated children in rising versus low trajectories. Implications for early intervention targeting self-regulation of executive control are discussed.
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