An At-labeled alpha-melanocyte stimulating hormone peptide analog for targeted alpha therapy of metastatic melanoma.

Purpose: Patients who develop metastatic melanoma have a very poor prognosis, and new treatments are needed to improve the response rates. Melanocortin-1 receptor (MC1R) is a promising target for radionuclide therapy of metastatic melanoma, and alpha-melanocyte stimulating hormone (α-MSH) peptide analogs show high affinities to MC1Rs. Because targeted alpha therapy (TAT) can be a desirable treatment for metastatic melanoma, this study aimed to develop an At-labeled α-MSH peptide analog for TAT of metastatic melanoma.

Dexamethasone Delivery via Amphiphilic, Low-swelling Hydrogels Treats Postoperative Inflammation in Cervical Spine Applications.

Anterior cervical spine surgeries are often complicated by difficulty swallowing due to local postoperative swelling, pain, scarring, and tissue dysfunction. These postoperative events lead to systemic steroid and narcotic use. Local, sustained drug delivery may address these problems, but current materials are unsafe for tight surgical spaces due to high biomaterial swelling, especially upon degradation.

The Linda Kizazi study: a comparison of morbidity and mortality from birth to 2 years between children who are HIV-unexposed and HIV-exposed, uninfected in the era of universal antiretroviral therapy.

Background: Historically, children who are HIV-exposed, uninfected (CHEU) have been found to have greater morbidity and mortality than children who are HIV-unexposed, uninfected (CHUU). To assess whether this difference persists in the era of universal antiretroviral therapy (ART), we conducted a cohort study to compare the risk of acute diarrhoea, respiratory tract infections (RTI), malaria, hospitalisation, and all-cause mortality between Kenyan CHEU and CHUU from birth to 2 years.

Methods: From December 2018 to March 2020 at Mathare North Health Centre in Nairobi, we recruited pregnant women living with HIV on ART for ≥6 months and pregnant women without HIV from the same community.

Antimicrobial efficacy of alternative root canal disinfection strategies: An evaluation on multiple working models.

Researching disinfection strategies is pivotal because effectively eliminating bacteria and their byproducts during root canal treatment (RCT) remains a challenge. This study investigated the antimicrobial efficacy of natural antimicrobial compounds, propolis (PRO) and copaiba oil-resin (COR), compared to conventional agents in Endodontics. Antimicrobials were tested against endodontic pathogens via macrodilution with standardized inoculums to determine the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC).

Adjuvant Cytotoxic Chemotherapy may not be Associated with a Survival Advantage for Resected Intrahepatic Cholangiocarcinoma.

Background: Randomized data suggest improved survival with adjuvant chemotherapy for biliary tract cancers; however, subset analyses of intrahepatic cholangiocarcinoma (IHC) show limited survival benefit. This study evaluated the impact of adjuvant chemotherapy on recurrence patterns and overall survival (OS) in patients with resected IHC.

Methods: Patients who underwent curative-intent resection for IHC were identified within a bi-institutional dataset and the National Cancer Database (NCDB).

Metagenomics: a new frontier for routine pathology testing of gastrointestinal pathogens.

Background: Accurate and comprehensive identification of enteropathogens, causing infectious gastroenteritis, is essential for optimal patient treatment and effective isolation processes in health care systems. Traditional diagnostic techniques are well established and optimised in low-cost formats. However, thorough testing for a wider range of causal agents is time consuming and remains limited to a subset of pathogenic organisms.

Consistent direction despite wavering policy: reductions in resident physician extended duration shifts over 20 years.

We examined data from 17,498 physicians-in-training who reported on 92,662 months of work over a 20 year study interval that included three major revisions to work hour limits. Extended duration shifts (≥24 hours; EDS) are much less common than they used to be. On average, first-year resident physicians (PGY1s) currently work a total of 4 EDS per year and 3 EDS per month during months in which any EDS are worked.

Somatic CAG repeat expansion in blood associates with biomarkers of neurodegeneration in Huntington's disease decades before clinical motor diagnosis.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease with the age at which characteristic symptoms manifest strongly influenced by inherited HTT CAG length. Somatic CAG expansion occurs throughout life and understanding the impact of somatic expansion on neurodegeneration is key to developing therapeutic targets. In 57 HD gene expanded (HDGE) individuals, ~23 years before their predicted clinical motor diagnosis, no significant decline in clinical, cognitive or neuropsychiatric function was observed over 4.

Interferon-α promotes HLA-B-restricted presentation of conventional and alternative antigens in human pancreatic β-cells.

Interferon (IFN)-α is the earliest cytokine signature observed in individuals at risk for type 1 diabetes (T1D), but the effect of IFN-α on the antigen repertoire of HLA Class I (HLA-I) in pancreatic β-cells is unknown. Here we characterize the HLA-I antigen presentation in resting and IFN-α-exposed β-cells and find that IFN-α increases HLA-I expression and expands peptide repertoire to those derived from alternative mRNA splicing, protein cis-splicing and post-translational modifications. While the resting β-cell immunopeptidome is dominated by HLA-A-restricted peptides, IFN-α largely favors HLA-B and only marginally upregulates HLA-A, translating into increased HLA-B-restricted peptide presentation and activation of HLA-B-restricted CD8 T cells.

First generation vanadium-based PTEN inhibitors: Comparative study in vitro and in vivo and identification of a novel mechanism of action.

PTEN, a tumor suppressor phosphatase, regulates cellular functions by antagonizing the growth promoting PI3K/Akt/mTOR pathway through the dephosphorylation of the second messenger PIP. Many preclinical cellular and animal studies have used PTEN inhibitors to highlight specific disease contexts where acute activation of PI3K/Akt/mTOR pathway might offer therapeutic advantages. In the present study we have re-evaluated first-generation PTEN inhibitors, including established bisperoxo-vanadium complexes (bpVs).

Pan-PPAR agonist lanifibranor improves insulin resistance and hepatic steatosis in patients with T2D and MASLD.

Background & Aims: Lanifibranor is a pan-PPAR agonist that improves glucose/lipid metabolism and reverses steatohepatitis and fibrosis in adults with MASH. We tested its effect on insulin resistance at the level of different target tissues in relationship to change in intrahepatic triglyceride (IHTG) content.

Methods: This phase 2, single center, study randomized (1:1) 38 patients with T2D and MASLD to receive lanifibranor 800 mg or placebo for 24 weeks.

A systematic review of participant diversity in psychedelic-assisted psychotherapy trials.

A lack of diverse and representative participant samples in mental health intervention research perpetuates mental health disparities. This issue has become a salient concern in studies of psychedelic-assisted psychotherapy (PAT), which is emerging as a promising mental health intervention. This systematic review evaluates the reporting, representation, and analysis of participant sociodemographic characteristics in randomized controlled trials (RCTs) of PAT.

Quantitative Assessment of the Effect of Chronic Kidney Disease on Plasma P-Tau217 Concentrations.

Background And Objectives: Chronic kidney disease (CKD) is known to be associated with increased plasma phosphorylated tau217 (p-tau217) concentrations, potentially confounding the utility of plasma p-tau217 measurements as a marker of amyloid pathology in individuals with suspected Alzheimer disease (AD). In this study, we quantitatively investigate the relationship of plasma p-tau217 concentrations vs estimated glomerular filtration rate (eGFR) in individuals with CKD with and without amyloid pathology.

Methods: This was a retrospective examination of data from 2 observational cohorts from either the Mayo Clinic Study of Aging or the Alzheimer's Disease Research Center cohorts.

Speech, Language and Non-verbal Communication in CLN2 and CLN3 Batten Disease.

CLN2 and CLN3 diseases, the most common types of Batten disease (also known as neuronal ceroid lipofuscinosis), are childhood dementias associated with progressive loss of speech, language and feeding skills. Here we delineate speech, language, non-verbal communication and feeding phenotypes in 33 individuals (19 females) with a median age of 9.5 years (range 3-28 years); 16 had CLN2 and 17 CLN3 disease; 8/15 (53%) participants with CLN2 and 8/17 (47%) participants with CLN3 disease had speech and language impairments prior to genetic diagnosis.

Removal of dissolved organic carbon in the West Pacific hadal zones.

The deep oceans are environments of complex carbon dynamics that have the potential to significantly impact the global carbon cycle. However, the role of hadal zones, particularly hadal trenches (water depth > 6 km), in the oceanic dissolved organic carbon (DOC) cycle is not thoroughly investigated. Here we report distinct DOC signatures in the Japan Trench bottom water.

Long-term excessive salt consumption alters villous and crypt morphology and the protein expression of uroguanylin, TRPV6 and PMCA1b in the rat small intestine.

Although long-term high dietary sodium consumption often aggravates hypertension and bone loss, sodium in the intestinal lumen has been known to promote absorption of nutrients and other ions, e.g., glucose and calcium.

Volumetric bioprinting of the osteoid niche.

Volumetric bioprinting has revolutionized the field of biofabrication by enabling the creation of cubic centimeter-scale living constructs at faster printing times (in the order of seconds). However, a key challenge remains: developing a wider variety of available osteogenic bioinks that allow osteogenic maturation of the encapsulated cells within the construct. Herein, the bioink exploiting a step-growth mechanism (norbornene-norbornene functionalized gelatin in combination with thiolated gelatin-GelNBNBSH) outperformed the bioink exploiting a chain-growth mechanism (gelatin methacryloyl-GelMA), as the necessary photo-initiator concentration was three times lower combined with a more than 50% reduction in required light exposure dose resulting in an improved positive and negative resolution.

Alterations in Gut Microbiome-Host Relationships After Immune Perturbation in Patients With Multiple Sclerosis.

Background And Objectives: Gut microbial symbionts have been shown to influence the development of autoimmunity in multiple sclerosis (MS). Emerging research points to an important relationship between the microbial-IgA interface and MS pathophysiology. IgA-secreting B cells are observed in the MS brain, and shifts in gut bacteria-IgA binding have been described in some patients with MS.

Proteomic Profiling Reveals Alterations in Metabolic and Cellular Pathways in Severe Obesity and Following Metabolic Bariatric Surgery.

In this study, we investigated the impact of bariatric surgery on the adipose proteome to better understand the metabolic and cellular mechanisms underlying weight loss following the procedure. A total of 46 patients with severe obesity were included, with samples collected both before and after bariatric surgery. Additionally, 15 healthy, non-obese individuals who did not undergo surgery served as controls and were studied once.

Bacterial Nanovesicles as Interkingdom Signaling Moieties Mediating Pain Hypersensitivity.

Gut dysbiosis contributes to multiple pathologies, yet the mechanisms of the gut microbiota-mediated influence on systemic and distant responses remain largely elusive. This study aimed to identify the role of nanosized bacterial extracellular vesicles (bEVs) in mediating allodynia, i.e.

Impact of Treatment With Trifluridine/Tipiracil in Combination With Bevacizumab on Health-Related Quality of Life and Performance Status in Refractory Metastatic Colorectal Cancer: An Analysis of the Phase III SUNLIGHT Trial.

Background: The efficacy of trifluridine/tipiracil (FTD/TPI) + bevacizumab compared to FTD/TPI for treatment of refractory metastatic colorectal cancer (mCRC) was demonstrated in the SUNLIGHT trial. This analysis of SUNLIGHT investigated the impact of treatment with FTD/TPI + bevacizumab on patient quality of life (QoL) and Eastern Cooperative Oncology Group performance status (ECOG PS).

Methods: Questionnaires (EORTC QLQ-C30 and EQ-5D-5L) and ECOG PS assessments were conducted at baseline and on Day 1 of each treatment cycle.

Metabolomics signatures of serotonin reuptake inhibitor (escitalopram), serotonin norepinephrine reuptake inhibitor (duloxetine) and cognitive-behavioral therapy on key neurotransmitter pathways in major depressive disorder.

Metabolomics provides powerful tools that can inform about heterogeneity in disease and response to treatments. In this exploratory study, we employed an electrochemistry-based targeted metabolomics platform to assess the metabolic effects of three randomly-assigned treatments: escitalopram, duloxetine, and Cognitive-Behavioral Therapy (CBT) in 163 treatment-naïve outpatients with major depressive disorder. Serum samples from baseline and 12 weeks post-treatment were analyzed using targeted liquid chromatography-electrochemistry for metabolites related to tryptophan, tyrosine metabolism and related pathways.

Finerenone and new-onset diabetes in heart failure: a prespecified analysis of the FINEARTS-HF trial.

Background: Data on the effect of mineralocorticoid receptor antagonist therapy on HbA levels and new-onset diabetes are conflicting. We aimed to examine the effect of oral finerenone, compared with placebo, on incident diabetes in the Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure (FINEARTS-HF) trial.

Methods: In this randomised, double-blind, placebo-controlled trial, 6001 participants with heart failure with New York Heart Association functional class II-IV, left ventricular ejection fraction 40% or higher, evidence of structural heart disease, and elevated N-terminal pro-B-type natriuretic peptide levels were randomly assigned to finerenone or placebo, administered orally.

Simulation studies to identify high-affinity probiotic peptides for inhibiting PAK1 gastric cancer protein: A comparative approach.

A major threat to world health is the high death rate from gastrointestinal (GI) cancer, especially in Asia, South America, and Europe. The new approaches are needed because of the complexity and heterogeneity of gastrointestinal (GI) cancer, which has made the development of effective treatments difficult. To investigate the potential of peptide-based therapies that target the P21 Activated Kinase 1 (PAK1) in GI cancer, we are using the DBsORF database to predict peptides from the genomes of two bacterial strains: Lactobacillus plantarum and Pediococcus pentosaceus.