Estrogens increase cancer cell efferocytosis to establish an immunosuppressive tumor microenvironment.

Phagocytic clearance of apoptotic cancer cells (efferocytosis) by tumor-associated macrophages (TAMs) contributes in a substantial manner to the establishment of an immunosuppressive tumor microenvironment. This puts in context our observation that the female steroid hormone 17β-estradiol (E2) facilitates tumor immune resistance through cancer cell extrinsic Estrogen Receptor (ERalpha;) signaling in TAMs. Notable was the finding that E2 induces the expression of CX3CR1 in TAMs to enable efferocytosis of apoptotic cancer cells which results in the suppression of type I interferon (IFN) signaling.

Orthoses Effect on Radiographic Measurements of Hallux Abducto Valgus: A Systematic Review.

Background: Hallux abducto valgus (HAV), commonly referred to as a bunion, is a prevalent foot deformity with multifactorial etiology, including genetic predisposition, biomechanical abnormalities, and footwear choices. HAV is often managed conservatively with orthotic devices aimed at reducing deformity progression and alleviating associated pain. However, the effectiveness of orthotics in altering radiographic measurements of HAV remains debated.

Androgen receptor monomers and dimers regulate opposing biological processes in prostate cancer cells.

Most prostate cancers express the androgen receptor (AR), and tumor growth and progression are facilitated by exceptionally low levels of systemic or intratumorally produced androgens. Thus, absolute inhibition of the androgen signaling axis remains the goal of current therapeutic approaches to treat prostate cancer (PCa). Paradoxically, high dose androgens also exhibit considerable efficacy as a treatment modality in patients with late-stage metastatic PCa.

Persistent hyperbilirubinemia following preoperative biliary stenting in patients undergoing anatomic hepatectomy predicts serious complications.

Background: Biliary obstruction before liver resection is a known risk factor for post-operative complications. The aim of this study was to determine the impact of persistent hyperbilirubinemia following preoperative biliary drainage before liver resection.

Methods: The ACS-NSQIP (2016-2021) database was used to extract patients with cholangiocarcinoma who underwent anatomic liver resection with preoperative biliary drainage comparing those with persistent hyperbilirubinemia (> 1.

Discovery and Preclinical Characterization of BIIB129, a Covalent, Selective, and Brain-Penetrant BTK Inhibitor for the Treatment of Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic disease with an underlying pathology characterized by inflammation-driven neuronal loss, axonal injury, and demyelination. Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase and member of the TEC family of kinases, is involved in the regulation, migration, and functional activation of B cells and myeloid cells in the periphery and the central nervous system (CNS), cell types which are deemed central to the pathology contributing to disease progression in MS patients. Herein, we describe the discovery of BIIB129 (), a structurally distinct and brain-penetrant targeted covalent inhibitor (TCI) of BTK with an unprecedented binding mode responsible for its high kinome selectivity.

Adeno-Associated Virus-Mediated Dorsal Root Ganglion Toxicity in the New Zealand White Rabbit.

Recombinant adeno-associated virus (AAV)-mediated degeneration of sensory neurons in the dorsal root ganglia (DRG) and trigeminal ganglia (TG) has been observed in non-human primates (NHPs) following intravenous (IV) and intrathecal (IT) delivery. Administration of recombinant AAV encoding a human protein transgene via a single intra-cisterna magna (ICM) injection in New Zealand white rabbits resulted in histopathology changes very similar to NHPs: mononuclear cell infiltration, degeneration/necrosis of sensory neurons, and nerve fiber degeneration of sensory tracts in the spinal cord and of multiple nerves. AAV-associated clinical signs and incidence/severity of histologic findings indicated that rabbits were equally or more sensitive than NHPs to sensory neuron damage.

A novel Shiga toxin 2a neutralizing antibody therapeutic with low immunogenicity and high efficacy.

Shiga toxin-producing infections are difficult to treat due to the risk of antibiotic-induced stress upregulating the production of toxins, medical treatment is consequently limited to supportive care to prevent the development of hemolytic uremic syndrome (HUS). Here, we introduce a potentially therapeutic humanized mouse monoclonal antibody (Hu-mAb 2-5) targeting Stx2a, the most common Shiga toxin subtype identified from outbreaks. We demonstrate that Hu-mAb 2-5 has low immunogenicity in healthy adults and high neutralizing efficacy , protecting mice from mortality and HUS-related tissue damage.

Preclinical safety, toxicokinetics and metabolism of BIIB131, a novel prothrombolytic agent for acute stroke.

BIIB131, a small molecule, is currently in Phase 2 for the treatment of acute ischemic stroke. Safety and metabolism of BIIB131 were evaluated following intravenous administration to rats and monkeys. Exposure increased dose-proportionally in rats up to 60 mg/kg and more than dose-proportionally in monkeys at greater than 10 mg/kg accompanied by prolonged half-life and safety findings.

Development, validation and application of a capillary microsampling LC-MS/MS method for the quantification of BIIB131 (SMTP-7) in rat plasma.

Capillary microsampling (CMS) is a technique that can significantly reduce the blood collection volume compared to conventional sampling methods, and thus is much preferred for studies in rats and mice. BIIB131 (SMTP-7) is a novel thrombolytic drug candidate currently under Phase 2 clinical development for the treatment of acute ischemic stroke. To support the safety studies in rats, an accurate and reliable CMS LC-MS/MS assay for the quantification of BIIB131 in rat plasma was developed and validated.

Development of Thermally Stable Nanobodies for Detection and Neutralization of Staphylococcal Enterotoxin B.

In this study, sixteen unique staphylococcal enterotoxin B (SEB)-reactive nanobodies (nbs), including ten monovalent and six bivalent nbs, were developed. All characterized nbs were highly specific for SEB and did not cross-react with other staphylococcal enterotoxins (SE). Several formats of highly sensitive enzyme-linked immunosorbent assays (ELISAs) were established using SEB nbs and a polyclonal antibody (pAb).

Spring arrival of the common cuckoo at breeding grounds is strongly determined by environmental conditions in tropical Africa.

Failure to adapt migration timing to changes in environmental conditions along migration routes and at breeding locations can result in mismatches across trophic levels, as occurs between the brood parasitic common cuckoo and its hosts. Using satellite tracking data from 87 male cuckoos across 11 years, we evaluate why the cuckoo has not advanced its arrival to the UK. Across years, breeding ground arrival was primarily determined by timing of departure from stopover in West Africa before northward crossing of the Sahara.

Oral care reduces incidence of pneumonia after esophagectomy: systematic review and meta-analysis.

Purpose: Post-operative pneumonia after esophagectomy is a major contributor to morbidity and mortality. Prior studies have demonstrated a link between the presence of pathologic oral flora and the development of aspiration pneumonia. The objective of this systematic review and meta-analysis was to evaluate the effect of pre-operative oral care on the incidence of post-operative pneumonia after esophagectomy.

Landscape fires disproportionally affect high conservation value temperate peatlands, meadows, and deciduous forests, but only under low moisture conditions.

Landscape fires are a natural component of the Earth System. However, they are of growing global concern due to climate change exacerbating their multiple impacts on biodiversity, ecosystems, carbon storage, human health, economies, and wider society. Temperate regions are predicted to be at greatest risk of increasing fire activity due to climate change, where fires can seriously impact important ecosystems for biodiversity and carbon storage, such as peatlands and forests.

Gut microbiota modulates lung fibrosis severity following acute lung injury in mice.

Independent studies demonstrate the significance of gut microbiota on the pathogenesis of chronic lung diseases; yet little is known regarding the role of the gut microbiota in lung fibrosis progression. Here we show, using the bleomycin murine model to quantify lung fibrosis in C57BL/6 J mice housed in germ-free, animal biosafety level 1 (ABSL-1), or animal biosafety level 2 (ABSL-2) environments, that germ-free mice are protected from lung fibrosis, while ABSL-1 and ABSL-2 mice develop mild and severe lung fibrosis, respectively. Metagenomic analysis reveals no notable distinctions between ABSL-1 and ABSL-2 lung microbiota, whereas greater microbial diversity, with increased Bifidobacterium and Lactobacilli, is present in ABSL-1 compared to ABSL-2 gut microbiota.

Transcranial magnetic stimulation maps the neurophysiology of chronic noncancer pain: A scoping review.

Background: Chronic noncancer pain is a global public health challenge. It is imperative to identify biological markers ("biomarkers") to understand the mechanisms underlying chronic pain and to monitor pain over time and after interventions. Transcranial magnetic stimulation (TMS) is a promising method for this purpose.

The influence of age and sex in sarcoidosis.

Purpose Of Review: This review aims to describe how the clinical manifestations of sarcoidosis may be shaped by the effects of sex hormones and by age dependent changes in immune functions and physiology This review is intended to highlight the need to consider the effects of sex and sex in future studies of sarcoidosis.

Recent Findings: The clinical manifestations of sarcoidosis differ based on sex and gender There is emerging evidence that female and male hormones and X-linked genes are important determinants of immune responses to environmental antigens, which has important implications for granuloma formation in the context of sarcoidosis Furthermore, sex hormone levels predictably change throughout adolescence and adulthood, and this occurs in parallel with the onset immune senescence and changes in physiology with advanced age.

Summary: Recent studies indicate that sex and age are important variables shaping the immune response of humans to environmental antigens We posit herein that sex and age are important determinants of sarcoidosis clinical phenotypes Many gaps in our understanding of the roles played by sex and gender in sarcoidosis, and these need to be considered in future studies.

Better cognitive function predicts maintenance of dual-task walking ability over time among people with relapsing-remitting MS.

Objective: Physical fitness and preserved cognitive function may provide neuroprotection in multiple sclerosis (MS), but few studies have examined their role in symptom progression over time. Dual-task paradigms can be useful to detect subtle impairment among people with MS in early stages of the disease. The present study investigated whether higher aerobic fitness or greater cognitive function could predict performance in dual-task walking 1-2 years later among people with mild or no MS-related walking impairment.

A model for self-organization of sensorimotor function: the spinal monosynaptic loop.

Recent spinal cord literature abounds with descriptions of genetic preprogramming and the molecular control of circuit formation. In this paper, we explore to what extent circuit formation based on learning rather than preprogramming could explain the selective formation of the monosynaptic projections between muscle spindle primary afferents and homonymous motoneurons. We adjusted the initially randomized gains in the neural network according to a Hebbian plasticity rule while exercising the model system with spontaneous muscle activity patterns similar to those observed during early fetal development.

Effect of expansion of human umbilical cord blood CD34 + cells on neurotrophic and angiogenic factor expression and function.

The use of CD34 + cell-based therapies has largely been focused on haematological conditions. However, there is increasing evidence that umbilical cord blood (UCB) CD34 + -derived cells have neuroregenerative properties. Due to low cell numbers of CD34 + cells present in UCB, expansion is required to produce sufficient cells for therapeutic purposes, especially in adults or when frequent applications are required.

Host Lung Environment Limits Aspergillus fumigatus Germination through an SskA-Dependent Signaling Response.

Aspergillus fumigatus isolates display significant heterogeneity in growth, virulence, pathology, and inflammatory potential in multiple murine models of invasive aspergillosis. Previous studies have linked the initial germination of a fungal isolate in the airways to the inflammatory and pathological potential, but the mechanism(s) regulating A. fumigatus germination in the airways is unresolved.

Assessing the Impact of Structured Reports for Fluoroscopic Double-Contrast Barium Esophagrams.

Fluoroscopic barium swallow examinations are a commonly performed radiologic study in the evaluation of dysphagia. These studies remain essential in the diagnostic work-up despite the increasing utilization of endoscopy, but current residents are often less experienced with fluoroscopy. Structured reporting has been demonstrated to improve comprehensiveness of reports in multiple settings, but has not been evaluated for barium swallow examinations.

Multi-Task Deep Learning for Image Segmentation Using Recursive Approximation Tasks.

Fully supervised deep neural networks for segmentation usually require a massive amount of pixel-level labels which are manually expensive to create. In this work, we develop a multi-task learning method to relax this constraint. We regard the segmentation problem as a sequence of approximation subproblems that are recursively defined and in increasing levels of approximation accuracy.