Emerging molecular Therapeutic targets in breast Cancer: Pathologic identification and clinical implications.

Breast carcinoma represents a biologically heterogeneous group of malignancies with diverse clinical behaviors, highlighting the need for robust molecular markers to support accurate diagnosis, prognosis, and therapeutic decision-making. Histopathologic evaluation and assessment of established biomarkers, including estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, remain central to clinical management, yet these biomarkers do not fully capture the disease complexity. Advances in genomics have enabled identification of intrinsic breast cancer subtypes, improving risk stratification and personalization of therapy.

Clinical and mechanistic effects of cladribine in relapsing multiple sclerosis: 2-year results from the MAGNIFY-MS Study.

Background: Cladribine, an oral prodrug, penetrates the blood-brain barrier, impacting biomarkers of disease progression within the central nervous system.

Objectives: Describe disease activity in cladribine tablets (CladT)-treated people with highly active relapsing multiple sclerosis (pwRMS) using clinical outcomes and biomarkers.

Design: MAGNIFY-MS was an open-label, single-arm, phase IV trial with four sub-studies.

Intratumoral vidutolimod as monotherapy or in combination with pembrolizumab in patients with programmed cell death 1 blockade-resistant melanoma: Final analysis from a phase 1b study.

Background: New treatment options are needed for patients with metastatic anti-programmed cell death 1 (PD-1)-resistant melanoma. The final analysis of a phase 1b study evaluating the Toll-like receptor 9 agonist vidutolimod is reported here.

Methods: This two-part, open-label, multicenter, phase 1b study in adults with metastatic/unresectable anti-PD-1-resistant melanoma evaluated the safety and clinical activity of intratumoral vidutolimod plus systemic pembrolizumab (part 1) or vidutolimod alone (part 2).

Pembrolizumab plus axitinib versus sunitinib for advanced clear cell renal cell carcinoma: 5-year survival and biomarker analyses of the phase 3 KEYNOTE-426 trial.

At the first interim analysis of the phase 3 KEYNOTE-426 trial, first-line pembrolizumab plus axitinib showed superior overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) over sunitinib for advanced renal cell carcinoma (RCC). To assess long-term durability of clinical outcomes and elucidate predictive biomarkers for RCC, we performed efficacy and prespecified exploratory biomarker analyses from KEYNOTE-426 with ≥5 years of follow-up. Pembrolizumab plus axitinib showed sustained benefits in OS (hazard ratio: 0.

Proteogenomic characterization unveils biomarkers associated with chemoresistance in muscle-invasive bladder cancer.

To explore potential chemoresistance mechanisms and identify therapeutic opportunities in muscle-invasive bladder cancer (MIBC), we conduct comprehensive proteogenomic characterization of 46 pre- and 14 post-treatment MIBC tumors incorporating genomics, transcriptomics, proteomics, and phosphoproteomics. Multi-omics clustering not only recapitulated established molecular subtypes but also revealed subtypes associated with chemotherapy sensitivity. Protein isoform level analysis identifies protein abundance of a short isoform of ATAD1 and RAF family proteins as biomarkers of chemosensitivity.

Integrative analysis of lung adenocarcinoma across diverse ethnicities and exposures.

Lung adenocarcinomas (LUAD) are a pressing global health problem with enduring lethality and rapidly shifting epidemiology. Proteogenomic studies integrating proteomics and post-translational modifications with genomics can identify clinical strata and oncogenic mechanisms, but have been underpowered to examine effects of ethnicity, smoking and environmental exposures, or sex on this heterogeneous disease. This comprehensive proteogenomic analysis of LUAD tumors and matched normal adjacent tissues from 406 patients across diverse geographic and demographic backgrounds explores the impact of understudied driver mutations, prognostic role of chromosomal instability, patterns of immune signaling, differential and sex-specific effects of endogenous mutagens and environmental carcinogens, and pathobiology of early-stage tumors with "late-like" characteristics.

SARS-CoV-2 spike antibody and T cell response in MS patients on high efficacy therapies post vaccine.

Background: There is limited knowledge about SARS-CoV-2 spike antibody and long-term T cell responses in multiple sclerosis (MS) patients on high efficacy treatments post SARS-CoV-2 vaccine.

Objectives: To assess spike antibody and T cell responses in MS patients on fingolimod (FIN), ocrelizumab (OCR) and healthy controls (HC) post vaccine.

Methods: We studied spike antibody seroconversion rates and T cell responses by flow cytometry in HC and MS patients.

HLA-A∗03:01 as predictive genetic biomarker for glatiramer acetate treatment response in multiple sclerosis: a retrospective cohort analysis.

Background: Glatiramer acetate (GA) is a well-tolerated treatment for multiple sclerosis (MS) and comparable in its efficacy to high-dose interferon beta (IFN). As a lack of validated treatment response biomarkers for MS hampers progress in personalised treatment, the study goal was to search for biomarkers of a successful treatment response utilising the known observation of T-cell expansions after GA treatment.

Methods: T-cell receptor beta chain (TRB) sequencing was performed in 3021 patients with MS: a discovery cohort of 1627 patients with MS, 204 of whom had previously been treated with GA, and then validated in 1394 patients with MS, 424 of whom had previously been treated with GA.

Oral MIB-626 (β Nicotinamide Mononucleotide) Safely Raises Blood Nicotinamide Adenine Dinucleotide Levels in Hospitalized Patients With COVID-19 and Acute Kidney Injury: A Randomized Controlled Trial.

Nicotinamide adenine dinucleotide (NAD) plays an important role in the innate immune response and is depleted during SARS-CoV-2 infection due to increased turnover. It is unknown whether treatment with NAD precursors can safely raise NAD levels in patients with COVID-19. To determine whether MIB-626 (nicotinamide mononucleotide), an NAD precursor, can safely increase blood NAD levels and attenuate acute kidney injury (AKI) and inflammation in hospitalized patients with COVID-19, 42 adults, ≥ 18 years, hospitalized with COVID-19 and AKI, were randomized in a 3:2 ratio to MIB-626 1.

The serum levels of specific autoantibodies in systemic sclerosis predict a more severe skin involvement.

Background: Systemic sclerosis is a severe autoimmune disease characterized by fibrosis of the skin and internal organs. Systemic sclerosis is associated with the presence of three specific autoantibodies: anti-topoisomerase I, anti-centromere, and anti-RNA polymerase III autoantibodies, which have also been identified as prognostic factors. However, it remains unknown whether the prognosis also varies based on their serum levels.

Uterine leiomyosarcoma.

Uterine leiomyosarcoma is a rare and heterogeneous gynecological malignancy that poses a significant clinical challenge due to its aggressive nature and limited treatment options. Its multifactorial etiopathogenesis involves complex cytogenetic and molecular aberrations, including TP53, RB1, and chromothripsis-associated gene alterations. The non-specific clinical presentation, resembling other benign conditions, complicates early and accurate diagnosis, alongside intricate radiological and pathological patterns.

Long-Term Efficacy and Safety of Satralizumab in Patients With Neuromyelitis Optica Spectrum Disorder From the SAkuraMoon Open-Label Extension Study.

Background And Objectives: Satralizumab (SAT), an interleukin-6 receptor inhibitor, reduced the risk of protocol-defined relapse (PDR) vs placebo (PBO) with a favorable safety profile in patients with neuromyelitis optica spectrum disorder (NMOSD) in 2 pivotal phase 3 trials, SAkuraSky and SAkuraStar. We evaluated the long-term safety and efficacy of SAT in patients with NMOSD in the single-arm, open-label, rollover study SAkuraMoon.

Methods: Patients who completed the double-blind periods (DBPs) and open-label extensions (OLEs) of SAkuraSky and SAkuraStar were enrolled in SAkuraMoon, where they continued receiving subcutaneous SAT 120 mg 4 times a week (Q4W) ± immunosuppressive therapy.

Depicting multiple sclerosis disease course using lesion parenchymal fraction: a quantified expression of the topographical model of multiple sclerosis.

The topographical model of multiple sclerosis proposes that functional reserve compensates for multiple sclerosis lesions, and that disability accumulation is the result of an insidious unmasking of deficits referable to lesion burden. To utilize topographical principles to establish an imaging metric-lesion parenchymal fraction (LPF)-defined as lesion volume divided by parenchymal volume in the same regional compartment, and to assess the relationship of LPF with disability. One hundred patients with relapsing-remitting or secondary progressive multiple sclerosis were evaluated; clinical and MRI data were longitudinally acquired from 2011-19.

Tepotinib in patients with MET exon 14 skipping non-small cell lung cancer.

The management of non-small cell lung cancer (NSCLC) has been transformed by the identification of specific therapies which target oncogenic drivers, including MET exon 14 (METex14) skipping, which occurs in 3-4% of patients. The development of selective MET inhibitors, such as tepotinib, has provided much-needed oral, targeted treatment options for these patients who otherwise have poor outcomes. In the largest trial involving patients with METex14 skipping NSCLC, the Phase II VISION study, tepotinib demonstrated robust and durable efficacy, which was especially notable when used in the first-line setting.

Transcriptomic profiling of scleroderma monocytes reveals links with cardiovascular complications, implicating Notch and interferon pathways.

Objectives: Recent research has highlighted the critical role of monocytes and macrophages in driving both inflammatory and fibrotic processes in systemic sclerosis. This study seeks to elucidate the gene expression profiles of systemic sclerosis monocytes and their potential links to disease complications, with the ultimate goal of uncovering novel therapeutic targets.

Methods: A total of 48 systemic sclerosis patients and 15 controls were recruited and monocytes were isolated using CD14+ magnetic beads.

Relationship between brain atrophy and disability in a multi-site multiple sclerosis registry.

Background: In a retrospective multicentre cohort study, we explored the association between brain atrophy and multiple sclerosis (MS) disability using different MRI scanners and protocols at multiple sites.

Methods: Relapse-onset MS patients were included if they had two clinical MRIs 12 months apart and ≥2 Expanded Disability Status Scale (EDSS) scores. Percentage brain volume change (PBVC), percentage grey matter change (PGMC), fluid-attenuated inversion recovery (FLAIR) lesion volume change, whole brain volume (BV), grey matter volume (GMV), FLAIR lesion volume and T1 hypointense lesion volume were assessed by icobrain.

A Semi-Mechanistic Mathematical Model of Immune Tolerance Induction to Support Preclinical Studies of Human Monoclonal Antibodies in Rats.

The administration of human monoclonal antibodies (mAb) in preclinical pharmacokinetics and toxicology studies often triggers an immune response, leading to the formation of anti-drug antibodies (ADA). To mitigate this effect, we have recently performed and reported on studies using short-term immunosuppressive regimens to induce prolonged immune tolerance towards a human mAb, erenumab, in rats. Here, we report on the development of a semi-mechanistic modeling approach that quantitatively integrates pharmacokinetic and immunogenicity assessments from immune tolerance induction studies to provide a framework for the simulation-based evaluation of different immune induction scenarios for the maintenance of prolonged immune tolerance towards human mAbs.

Trends in Human Papillomavirus Testing Among Patients With Oropharyngeal Cancer.

Importance: Due to the prognostic value of human papillomavirus (HPV) status, HPV testing for oropharyngeal squamous cell carcinoma (OPSCC) has been recommended since 2012. However, recent HPV testing rates and associated sociodemographic and clinical factors are unknown.

Objective: To examine HPV testing rates stratified by sociodemographic and clinical factors and factors associated with increased likelihood of not receiving HPV testing from 2013 to 2021.

Long-Term Safety and Efficacy of Risankizumab to Treat Moderate-to-Severe Plaque Psoriasis: Final LIMMitless Phase 3, Open-Label Extension Trial Results.

Background: Psoriasis is a chronic, inflammatory disease requiring long-term therapy. Risankizumab, an anti-interleukin-23 monoclonal antibody, is approved to treat moderate-to-severe plaque psoriasis in adults.

Objective: The aim was to assess the long-term safety and efficacy of continuous risankizumab treatment through 6 years in adults with moderate-to-severe plaque psoriasis.

SGNDV-001: disitamab vedotin with pembrolizumab in HER2-expressing locally advanced or metastatic urothelial carcinoma.

Introduction: Platinum-based chemotherapy for the treatment of locally advanced or metastatic urothelial carcinoma (la/mUC), has been the first-line standard of care for many decades. Enfortumab vedotin, an antibody-drug conjugate, combined with pembrolizumab, a programmed death 1 (PD-1) inhibitor, recently demonstrated improved efficacy versus chemotherapy in la/mUC. Since 60%-80% of patients with UC have tumors expressing human epidermal growth factor receptor 2 (HER2), HER2-directed vedotin-based antibody-drug conjugates may also be beneficial in la/mUC.

B- and T cell receptor sequencing elucidates characteristics of lymphocyte depletion by ocrelizumab.

Ocrelizumab therapy depletes circulating CD20 lymphocytes. To characterize adaptive immune changes, we analyzed blood B- and T cell receptor repertoires of 35 multiple sclerosis (MS) patients before and alongside ocrelizumab therapy, compared to 11 healthy donors and 14 MS patients alongside natalizumab therapy, as well as cerebrospinal fluid and blood single-cell transcriptomics of 29 donors. Tissue-resident memory cells in cerebrospinal fluid revealed gene expression and initial therapy-resistance.

Combining CSF and Serum Biomarkers to Differentiate Mechanisms of Disability Worsening in Multiple Sclerosis.

The combined use of serum and CSF biomarkers for prognostic stratification in multiple sclerosis (MS) remains underexplored. This multicenter observational study investigated associations between serum neurofilament light chain (sNfL), glial fibrillary acidic protein (sGFAP), and CSF lipid-specific IgM oligoclonal bands (LS-OCMB) with different forms of disability worsening, such as relapse-associated worsening (RAW), active progression independent of relapse activity (aPIRA), and non-active PIRA (naPIRA). A total of 535 patients with MS were included, all sampled within one year of disease onset.