Piplartine attenuates aminoglycoside-induced TRPV1 activity and protects from hearing loss in mice.

Hearing loss is a major health concern in our society, affecting more than 400 million people worldwide. Among the causes, aminoglycoside therapy can result in permanent hearing loss in 40% to 60% of patients receiving treatment, and despite these high numbers, no drug for preventing or treating this type of hearing loss has yet been approved by the US Food and Drug Administration. We have previously conducted high-throughput screenings of bioactive compounds, using zebrafish as our discovery platform, and identified piplartine as a potential therapeutic molecule.

Co-targeting SOS1 enhances the antitumor effects of KRAS inhibitors by addressing intrinsic and acquired resistance.

Combination approaches are needed to strengthen and extend the clinical response to KRAS inhibitors (KRASi). Here, we assessed the antitumor responses of KRAS mutant lung and colorectal cancer models to combination treatment with a SOS1 inhibitor (SOS1i), BI-3406, plus the KRAS inhibitor, adagrasib. We found that responses to BI-3406 plus adagrasib were stronger than to adagrasib alone, comparable to adagrasib with SHP2 (SHP2i) or EGFR inhibitors and correlated with stronger suppression of RAS-MAPK signaling.

Glucosylceramide synthase modulation ameliorates murine renal pathologies and promotes macrophage effector function in vitro.

While significant advances have been made in understanding renal pathophysiology, less is known about the role of glycosphingolipid (GSL) metabolism in driving organ dysfunction. Here, we used a small molecule inhibitor of glucosylceramide synthase to modulate GSL levels in three mouse models of distinct renal pathologies: Alport syndrome (Col4a3 KO), polycystic kidney disease (Nek8), and steroid-resistant nephrotic syndrome (Nphs2 cKO). At the tissue level, we identified a core immune-enriched transcriptional signature that was shared across models and enriched in human polycystic kidney disease.

Time to Glaucoma Progression Detection by Optical Coherence Tomography and Visual Field in Glaucoma Individuals of African Descent.

Purpose: To examine the time to glaucoma progression detection by retinal nerve fiber layer thickness (RNFLT) and visual field (VF) among individuals of African descent (AD).

Design: Retrospective cohort study.

Methods: This multicenter study included eyes with glaucoma from individuals of AD from the Diagnostic Innovations in Glaucoma Study and the African Descent and Glaucoma Evaluation Study with ≥2 years/5 visits of optic nerve head RNFLT and 24-2 VF examinations.

Mass Spectrometry Identifies Taenia solium Proteins in Sera of Patients With and Without Parenchymal Neurocysticercosis.

Neurocysticercosis (NCC), a major cause of global acquired epilepsy, results from Taenia solium larval brain infection. T. solium adult worms release large numbers of infective eggs into the environment contributing to high levels of exposure in endemic areas.

Accurate non-ceruloplasmin bound copper: a new biomarker for the assessment and monitoring of Wilson disease patients using HPLC coupled to ICP-MS/MS.

Objectives: Assessment of Wilson disease is complicated, with neither ceruloplasmin, nor serum or urine copper, being reliable. Two new indices, accurate non-ceruloplasmin copper (ANCC) and relative ANCC were developed and applied to a cohort of 71 patients, as part of a Wilson Disease Registry Study.

Methods: Elemental copper-protein speciation was developed for holo-ceruloplasmin quantitation using strong anion exchange chromatography coupled to triple quadrupole inductively coupled plasma mass spectrometry.

Application of MALDI-TOF MS to Identify and Detect Antimicrobial-Resistant Associated with Bovine Mastitis.

is a common bovine mastitis pathogen in dairy cattle. The rapid identification and characterization of antimicrobial resistance (AMR) in plays an important role in its diagnosis, treatment, and prevention. In this study, matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) was used to identify and screen for potential AMR biomarkers.

Comorbid neuropathology and atypical presentation of Alzheimer's disease.

Introduction: Alzheimer's disease (AD) neuropathological changes present with amnestic and nonamnestic (atypical) syndromes. The contribution of comorbid neuropathology as a substratum of atypical expression of AD remains under investigated.

Methods: We examined whether atypical AD exhibited increased comorbid neuropathology compared to typical AD and if such neuropathologies contributed to the accelerated clinical decline in atypical AD.

Baseline biomarkers of efficacy and on-treatment immune-profile changes associated with bempegaldesleukin plus nivolumab.

In PIVOT IO 001 (NCT03635983), the combination of the investigational interleukin-2 agonist bempegaldesleukin (BEMPEG) with nivolumab (NIVO) had no added clinical benefit over NIVO monotherapy in unresectable/metastatic melanoma. Pre-defined baseline and on-treatment changes in selected biomarkers were analyzed to explore the potential mechanisms underlying the clinical observations. In each treatment arm, higher baseline tumor mutational burden or immune infiltration/inflammation was associated with improved efficacy compared with lower levels.

Effects of preprandial versus postprandial nutritional insulin administration in the inpatient setting.

Aims: Hospitalized patients can have inconsistent nutritional intake due to acute illness, changing diet, or unpredictable meal delivery. The aim of this study was to evaluate whether implementation of a hospital-wide policy shifting nutritional insulin administration from pre-meal to post-meal was associated with changes in glycemic control or length of stay (LOS).

Methods: This retrospective study performed at a community hospital evaluated adult inpatients receiving nutritional insulin across three time periods.

Mucosal Healing Among Black and White Patients With Inflammatory Bowel Disease.

Introduction: Crohn's disease and ulcerative colitis are characterized by chronic inflammation of the gastrointestinal tract. Mucosal healing (MH) is a therapeutic goal in patients with inflammatory bowel disease (IBD). Current data suggest that Black patients may experience worse clinical outcomes than White patients with IBD.

Single-Frequency Ion Parking in a Digital 3D Quadrupole Ion Trap.

Single-frequency ion parking, a useful technique in electrospray mass spectrometry (ESI-MS), involves gas-phase charge-reduction ion/ion reactions in an electrodynamic ion trap in conjunction with the application of a supplementary oscillatory voltage to selectively inhibit the reaction rate of an ion of interest. The ion parking process provides a means for limiting the extent of charge reduction in a controlled fashion and allows for ions distributed over a range of charge states to be concentrated into fewer charge states (a single charge state under optimal conditions). As charge reduction inherently leads to an increase in the mass-to-charge () ratio of the ions, it is important that the means for storing and analyzing ions be able to accommodate ions of high ratios.

Predictors of High Healthcare Cost Among Patients with Generalized Myasthenia Gravis: A Combined Machine Learning and Regression Approach from a US Payer Perspective.

Background: High healthcare costs could arise from unmet needs. This study used random forest (RF) and regression methods to identify predictors of high costs from a US payer perspective in patients newly diagnosed with generalized myasthenia gravis (gMG).

Methods: Adults with gMG (first diagnosis = index) were selected from the IQVIA PharMetrics Plus database (2017-2021).

Differential Serum Peptidomics Reveal Multi-Marker Models That Predict Breast Cancer Progression.

Here, we assess how the differential expression of low molecular weight serum peptides might predict breast cancer progression with high confidence. We apply an LC/MS-MS-based, unbiased 'omics' analysis of serum samples from breast cancer patients to identify molecules that are differentially expressed in stage I and III breast cancer. Results were generated using standard and machine learning-based analytical workflows.

Differentiation of regioisomers of sulfobenzoic acid by traveling-wave ion mobility mass spectrometry.

An ion mobility mass spectrometry (IM-MS) investigation using a Synapt G2 mass spectrometer was conducted to separate anions generated from the three regioisomers of sulfobenzoic acid. The results revealed that the differences in arrival time distributions (ATDs) were inadequate to differentiate the isomers unambiguously. However, the ATD profiles of the product ions, generated by fragmenting the respective mass-selected m/z 201 precursor ions in the Trap region of the three-compartment traveling-wave ion guide of the Synapt G2 mass spectrometer, were distinctly different, enabling definitive differentiation of the isomers.

Rates of Choriocapillaris Microvascular Dropout and Macular Structural Changes in Glaucomatous Optic Neuropathy With and Without Myopia.

Purpose: To evaluate the association between rates of juxtapapillary choriocapillaris microvasculature dropout (MvD) change and rates of ganglion cell inner plexiform layer (GCIPL) loss in primary open-angle glaucoma (POAG) and glaucoma suspect eyes with and without myopia.

Design: Cohort study from clinical trial data.

Methods: 238 eyes from 155 POAG and glaucoma suspect patients were stratified into no-myopia (axial length (AL) ≤ 24 mm; n = 78 eyes), mild myopia (24 mm < AL ≤ 26 mm; n = 114 eyes), and high myopia (AL > 26 mm; n = 46 eyes).

Florbetaben amyloid PET acquisition time: Influence on Centiloids and interpretation.

Introduction: Amyloid positron emission tomography (PET) acquisition timing impacts quantification.

Methods: In florbetaben (FBB) PET scans of 245 adults with and without cognitive impairment, we investigated the impact of post-injection acquisition time on Centiloids (CLs) across five reference regions. CL equations for FBB were derived using standard methods, using FBB data collected between 90 and 110 min with paired Pittsburgh compound B data.

Isolation and Identification of a Urinary Biomarker for Lung Cancer: 27-Nor-5β-Cholestane-3α,7α,12α,24,25 Pentol Glucuronide and Its Deuterated Analog.

An untargeted metabolomic study identified four potential lung cancer diagnostic biomarkers in human urine. One of the potential biomarkers was an unidentified feature possessing a / value of 561+. "561+" was isolated from human urine and tentatively identified as 27-nor-5β-cholestane-3α,7α,12α,24,25 pentol glucuronide with unknown C24,25 stereochemistry using H NMR and mass spectrometry.

Can a Novel Device with Pure Dry Air Increase the Shear Bond Strength of Dental Composites to Dentin? An Experimental Study.

Modern conservative dentistry is taking the lead in daily clinical practice and is relying on adhesion. Whether it is a simple composite, ceramic inlays, onlays, veneers or crowns, the common factor for a successful outcome is a good bonding of these elements to dental structures. Thus, the purpose of this study was to evaluate the bond strength of resin composite to dentin when using a new device, the DENTIPURE KM™ (KM, Beirut, Lebanon), which provides a pure air flow, free of any contaminants and without humidity, when compared to other dental equipment.

Chemokine-mediated cell migration into the central nervous system in progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) has been associated with different forms of immune compromise. This study analyzes the chemokine signals and attracted immune cells in cerebrospinal fluid (CSF) during PML to define immune cell subpopulations relevant for the PML immune response. In addition to chemokines that indicate a general state of inflammation, like CCL5 and CXCL10, the CSF of PML patients specifically contains CCL2 and CCL4.

Enhancing gas chromatography-mass spectrometry resolution and pure analyte discovery using intra-chromatogram elution profile matching.

Chemometric decomposition methods like multivariate curve resolution-alternating least squares (MCR-ALS) are often employed in gas chromatography-mass spectrometry (GC-MS) to improve analyte identification and quantitation. However, these methods can perform poorly for analytes with a low chromatographic resolution (R) and a high degree of spectral contamination from noise and background interferences. Thus, we propose a novel computational algorithm, termed mzCompare, to improve analyte identification and quantitation when coupled to MCR-ALS.