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The novel Bruton’s tyrosine kinase inhibitor ibrutinib has demonstrated high response rates in B-cell lymphomas; however, a growing number of ibrutinib-treated patients relapse with resistance and fulminant progression. Using chemical proteomics and an organotypic cell-based drug screening assay, we determine the functional role of the tumour microenvironment (TME) in ibrutinib activity and acquired ibrutinib resistance. We demonstrate that MCL cells develop ibrutinib resistance through evolutionary processes driven by dynamic feedback between MCL cells and TME, leading to kinome adaptive reprogramming, bypassing the effect of ibrutinib and reciprocal activation of PI3K-AKT-mTOR and integrin-β1 signalling. Combinatorial disruption of B-cell receptor signalling and PI3K-AKT-mTOR axis leads to release of MCL cells from TME, reversal of drug resistance and enhanced anti-MCL activity in MCL patient samples and patient-derived xenograft models. This study unifies TME-mediated de novo and acquired drug resistance mechanisms and provides a novel combination therapeutic strategy against MCL and other B-cell malignancies. Ibrutinib has demonstrated high response rates in B-cell lymphomas but a lot of ibrutinib-treated patients relapse with resistance. This study unified TME-mediated de novo and acquired drug resistance through B-cell receptor signalling and PI3K-AKT-mTOR axis and provides a combination therapeutic strategy against B-cell malignancies.

The clinical utility of histone/protein deacetylase (HDAC) inhibitors in combinatorial regimens with proteasome inhibitors for patients with relapsed and refractory multiple myeloma (MM) is often limited by excessive toxicity due to HDAC inhibitor promiscuity with multiple HDACs. Therefore, more selective inhibition minimizing off-target toxicity may increase the clinical effectiveness of HDAC inhibitors. We demonstrated that plasma cell development and survival are dependent upon HDAC11, suggesting this enzyme is a promising therapeutic target in MM. Mice lacking HDAC11 exhibited markedly decreased plasma cell numbers. Accordingly, in vitro plasma cell differentiation was arrested in B cells lacking functional HDAC11. Mechanistically, we showed that HDAC11 is involved in the deacetylation of IRF4 at lysine 103 . Further, targeting HDAC11 led to IRF4 hyperacetylation, resulting in impaired IRF4 nuclear localization and target promoter binding. Importantly, transient HDAC11 knockdown or treatment with elevenostat, an HDAC11-selective inhibitor, induced cell death in MM cell lines. Elevenostat produced similar anti-MM activity in vivo, improving survival among mice inoculated with 5TGM1 MM cells. Elevenostat demonstrated nanomolar ex vivo activity in 34 MM patient specimens and synergistic activity when combined with bortezomib. Collectively, our data indicated that HDAC11 regulates an essential pathway in plasma cell biology establishing its potential as an emerging theraputic vulnerability in MM.

To assess influenza symptoms, adherence to mask use recommendations, absenteesm and presenteeism in acute care healthcare workers (HCWs) during influenza epidemics. The TransFLUas influenza transmission study in acute healthcare prospectively followed HCWs prospectively over 2 consecutive influenza seasons. Symptom diaries asking for respiratory symptoms and adherence with mask use recommendations were recorded on a daily basis, and study participants provided midturbinate nasal swabs for influenza testing. In total, 152 HCWs (65.8% nurses and 13.2% physicians) were included: 89.1% of study participants reported at least 1 influenza symptom during their study season and 77.8% suffered from respiratory symptoms. Also, 28.3% of HCW missed at least 1 working day during the study period: 82.6% of these days were missed because of symptoms of influenza illness. Of all participating HCWs, 67.9% worked with symptoms of influenza infection on 8.8% of study days. On 0.3% of study days, symptomatic HCWs were shedding influenza virus while at work. Among HCWs with respiratory symptoms, 74.1% adhered to the policy to wear a mask at work on 59.1% of days with respiratory symptoms. Respiratory disease is frequent among HCWs and imposes a significant economic burden on hospitals due to the number of working days lost. Presenteesm with respiratory illness, including influenza, is also frequent and poses a risk for patients and staff. NCT02478905 (clinicaltrials.gov).

Nosocomial transmission of influenza is a major concern for infection control. We aimed to dissect transmission dynamics of influenza, including asymptomatic transmission events, in acute care. Prospective surveillance study during 2 influenza seasons. Tertiary-care hospital. Volunteer sample of inpatients on medical wards and healthcare workers (HCWs). Participants provided daily illness diaries and nasal swabs for influenza A and B detection and whole-genome sequencing for phylogenetic analyses. Contacts between study participants were tracked. Secondary influenza attack rates were calculated based on spatial and temporal proximity and phylogenetic evidence for transmission. In total, 152 HCWs and 542 inpatients were included; 16 HCWs (10.5%) and 19 inpatients (3.5%) tested positive for influenza on 109 study days. Study participants had symptoms of disease on most of the days they tested positive for influenza (83.1% and 91.9% for HCWs and inpatients, respectively). Also, 11(15.5%) of 71 influenza-positive swabs among HCWs and 3 (7.9%) of 38 influenza-positive swabs among inpatients were collected on days without symptoms; 2 (12.5%) of 16 HCWs and 2 (10.5%) of 19 inpatients remained fully asymptomatic. The secondary attack rate was low: we recorded 1 transmission event over 159 contact days (0.6%) that originated from a symptomatic case. No transmission event occurred in 61 monitored days of contacts with asymptomatic influenza-positive individuals. Influenza in acute care is common, and individuals regularly shed influenza virus without harboring symptoms. Nevertheless, both symptomatic and asymptomatic transmission events proved rare. We suggest that healthcare-associated influenza prevention strategies that are based on preseason vaccination and barrier precautions for symptomatic individuals seem to be effective.

5-Methoxysalicylic acid (MSA) is demonstrated to be a useful matrix for matrix-assisted laser desorption/ionization time-of-flight (TOF) mass spectrometry of oligonucleotides, when desorption/ionization without fragmentation is desired. When MSA is combined with the additive spermine, the need for desalting is reduced. The MSA/spermine matrix yields linear TOF mass spectra with improved resolution, less fragmentation, and less intense alkali ion adduct peaks than those spectra obtained using 3-hydroxypicolinic acid and 6-aza-2-thiothymine with spermine or diammonium hydrogen citrate as additives. Instrumental conditions are discussed to improve the spectral resolution, specifically the use of longer delay times in the delayed-extraction ion source.

Importance Intercenter variation exists in the management of hypoxic-ischemic encephalopathy (HIE). It is unclear whether increased resource utilization translates into improved neurodevelopmental outcomes. Objective To determine if higher resource utilization during the first 4 days of age, quantified by hospital costs, is associated with survival without neurodevelopmental impairment (NDI) among infants with HIE. Design, Setting, and Participants Retrospective cohort analysis of neonates with HIE who underwent therapeutic hypothermia (TH) at US children’s hospitals participating in the Children’s Hospitals Neonatal Database between 2010 and 2016. Data were analyzed from December 2021 to December 2022. Exposures Infants who survived to 4 days of age and had neurodevelopmental outcomes assessed at greater than 11 months of age were divided into 2 groups: (1) death or NDI and (2) survived without NDI. Resource utilization was defined as costs of hospitalization including neonatal neurocritical care (NNCC). Data were linked with Pediatric Health Information Systems to quantify standardized costs by terciles. Main Outcomes and Measures The main outcome was death or NDI. Characteristics, outcomes, hospitalization, and NNCC costs were compared. Results Among the 381 patients who were included, median (IQR) gestational age was 39 (38-40) weeks; maternal race included 79 (20.7%) Black mothers, 237 (62.2%) White mothers, and 58 (15.2%) mothers with other race; 80 (21%) died, 64 (17%) survived with NDI (combined death or NDI group: 144 patients [38%]), and 237 (62%) survived without NDI. The combined death or NDI group had a higher rate of infants with Apgar score at 10 minutes less than or equal to 5 (65.3% [94 of 144] vs 39.7% [94 of 237];P < .001) and a lower rate of infants with mild or moderate HIE (36.1% [52 of 144] vs 82.3% [195 of 237];P < .001) compared with the survived without NDI group. Compared with low-cost centers, there was no association between high– or medium–hospitalization cost centers and death or NDI. High– and medium–EEG cost centers had lower odds of death or NDI compared with low-cost centers (high vs low: OR, 0.30 [95% CI, 0.16-0.57]; medium vs low: OR, 0.29 [95% CI, 0.13-0.62]). High– and medium–laboratory cost centers had higher odds of death or NDI compared with low-cost centers (high vs low: OR, 2.35 [95% CI, 1.19-4.66]; medium vs low: OR, 1.93 [95% CI, 1.07-3.47]). High–antiseizure medication cost centers had higher odds of death or NDI compared with low-cost centers (high vs. low: OR, 3.72 [95% CI, 1.51-9.18]; medium vs low: OR, 1.56 [95% CI, 0.71-3.42]). Conclusions and Relevance Hospitalization costs during the first 4 days of age in neonates with HIE treated with TH were not associated with neurodevelopmental outcomes. Higher EEG costs were associated with lower odds of death or NDI yet higher laboratory and antiseizure medication costs were not. These findings serve as first steps toward identifying aspects of NNCC that are associated with outcomes.

Molecular complexes such as double-stranded oligonucleotides contain non-covalent bonds that are difficult to maintain in the MALDI experiment. Quantifiers are introduced in order to evaluate, summarize, and compare spectra from experiments in which additives are used to stabilize duplex oligonucleotides. Compounds known to complex with and stabilize duplex molecules can be useful as additives in MALDI. Spermine and methylene blue, present at concentrations similar to the matrix, are detected, bound to the duplex. When peptides are used as additives, the duplex is stabilized when the peptide is present at an amount less than that of the duplex.

The TEMPO (Transiting Exosatellites, Moons, and Planets in Orion) Survey is a proposed 30-day observational campaign using the Nancy Grace Roman Space Telescope. By providing deep, high-resolution, short-cadence infrared photometry of a dynamic star-forming region, TEMPO will investigate the demographics of exosatellites orbiting free-floating planets and brown dwarfs -- a largely unexplored discovery space. Here, we present the simulated detection yields of three populations: extrasolar moon analogs orbiting free-floating planets, exosatellites orbiting brown dwarfs, and exoplanets orbiting young stars. Additionally, we outline a comprehensive range of anticipated scientific outcomes accompanying such a survey. These science drivers include: obtaining observational constraints to test prevailing theories of moon, planet, and star formation; directly detecting widely separated exoplanets orbiting young stars; investigating the variability of young stars and brown dwarfs; constraining the low-mass end of the stellar initial mass function; constructing the distribution of dust in the Orion Nebula and mapping evolution in the near-infrared extinction law; mapping emission features that trace the shocked gas in the region; constructing a dynamical map of Orion members using proper motions; and searching for extragalactic sources and transients via deep extragalactic observations reaching a limiting magnitude of \\(m_AB=29.7\\)\\,mag (F146 filter).