Targeted SPP1 Inhibition of Tumor-Associated Myeloid Cells Effectively Decreases Tumor Sizes.

Secreted phosphosprotein 1 (SPP1) tumor-associated macrophages (TAM) are abundant tumor myeloid cells that are immunosuppressive, pro-tumorigenic, and have a highly negative prognostic factor. Despite this, there is a lack of efficient TAM-specific therapeutics capable of reducing SPP1 expression. Here, on a phenotypic screen is reported to identify small molecule SPP1 modulators in macrophages.

Targeted protein degradation with bifunctional molecules as a novel therapeutic modality for Alzheimer's disease & beyond.

Alzheimer's disease (AD) is associated with memory and cognitive impairment caused by progressive degeneration of neurons. The events leading to neuronal death are associated with the accumulation of aggregating proteins in neurons and glia of the affected brain regions, in particular extracellular deposition of amyloid plaques and intracellular formation of tau neurofibrillary tangles. Moreover, the accumulation of pathological tau proteoforms in the brain concurring with disease progression is a key feature of multiple neurodegenerative diseases, called tauopathies, like frontotemporal dementia (FTD) where autosomal dominant mutations in the tau encoding MAPT gene provide clear evidence of a causal role for tau dysfunction.

Study protocol for a pilot randomised controlled trial of a virtually delivered behavioural intervention (ACTION) for adults with cancer at risk for opioid use disorder.

Introduction: Opioid therapy is often central to pain management during cancer care. However, opioid exposure and unaddressed psychological suffering jointly amplify opioid use disorder risk. Therefore, we iteratively developed a behavioural, individually delivered intervention to mitigate the risk of opioid use disorder during cancer care (Acceptance and Commitment Therapy Intervention when Opioids are Necessary (ACTION)).

An integrative TAD catalog in lymphoblastoid cell lines discloses the functional impact of deletions and insertions in human genomes.

The human genome is packaged within a three-dimensional (3D) nucleus and organized into structural units known as compartments, topologically associating domains (TADs), and loops. TAD boundaries, separating adjacent TADs, have been found to be well conserved across mammalian species and more evolutionarily constrained than TADs themselves. Recent studies show that structural variants (SVs) can modify 3D genomes through the disruption of TADs, which play an essential role in insulating genes from outside regulatory elements' aberrant regulation.

Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): one cohort of a phase 2, multicentre, open-label, non-comparative study.

Background: Alpelisib, a PI3Kα-selective inhibitor and degrader, plus fulvestrant showed efficacy in hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer in SOLAR-1; limited data are available in the post-cyclin-dependent kinase 4/6 inhibitor setting. BYLieve aimed to assess alpelisib plus endocrine therapy in this setting in three cohorts defined by immediate previous treatment; here, we report results from cohort A.

Methods: This ongoing, phase 2, multicentre, open-label, non-comparative study enrolled patients with hormone receptor-positive, HER2-negative, advanced breast cancer with tumour PIK3CA mutation, following progression on or after previous therapy, including CDK4/6 inhibitors, from 114 study locations (cancer centres, medical centres, university hospitals, and hospitals) in 18 countries worldwide.

Discovery of Gene Fusions in Driver-Negative Cancer Samples From the National Cancer Institute-Molecular Analysis for Therapy Choice Screening Cohort.

Purpose: The National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH) trial was implemented to identify actionable genetic alterations across cancer types and enroll patients accordingly onto treatment arms, irrespective of tumor histology. Using multiplex polymerase chain reaction (PCR) next-generation sequencing, NCI-MATCH genotyped 5,540 patients, discovering gene fusions in 202/5,540 tumors (3.65%).

Estimation of Cancer Deaths Averted From Prevention, Screening, and Treatment Efforts, 1975-2020.

Importance: Cancer mortality has decreased over time, but the contributions of different interventions across the cancer control continuum to averting cancer deaths have not been systematically evaluated across major cancer sites.

Objective: To quantify the contributions of prevention, screening (to remove precursors [interception] or early detection), and treatment to cumulative number of cancer deaths averted from 1975 to 2020 for breast, cervical, colorectal, lung, and prostate cancers.

Design, Setting, And Participants: In this model-based study using population-level cancer mortality data, outputs from published models developed by the Cancer Intervention and Surveillance Modeling Network were extended to quantify cancer deaths averted through 2020.

Reddit for research recruitment? Social media as a novel clinical trial recruitment tool for adolescent and young adult (AYA) cancer survivors.

Purpose: Adolescent and young adult cancer survivors (AYAs) have been considered a hard-to-reach population with low enrollment rates in cancer clinical trials. Race, ethnicity, socioeconomic status, and inaccessibility have been identified as barriers impacting research participation. Social media has the potential to overcome these barriers and increase AYA enrollment.

Overcoming Resistance Mechanisms to Melanoma Immunotherapy.

The advent of immune checkpoint inhibition has revolutionized treatment of advanced melanoma. While most patients derive survival benefit from established immunotherapies, notably monoclonal antibodies blocking cytotoxic T-lymphocyte antigen 4 and programmed cell death protein 1, a subset does not optimally respond due to the manifestation of innate or acquired resistance to these therapies. Combination regimens have proven efficacious relative to single-agent blockade, but also yield high-grade treatment toxicities that are often dose-limiting for patients.

Non-canonical CDK6 activity promotes cilia disassembly by suppressing axoneme polyglutamylation.

Tubulin polyglutamylation is a posttranslational modification that occurs primarily along the axoneme of cilia. Defective axoneme polyglutamylation impairs cilia function and has been correlated with ciliopathies, including Joubert Syndrome (JBTS). However, the precise mechanisms regulating proper axoneme polyglutamylation remain vague.

Significant Disparities in Hepatocellular Carcinoma Outcomes by Race/Ethnicity and Sociodemographic Factors.

Background: Hepatocellular carcinoma (HCC) disproportionately affects racial/ethnic minorities. We evaluated the impact of income and geography on racial/ethnic disparities across the HCC care cascade in the U.S.

The Role of Functional Health Literacy in Terms of Hazardous Alcohol Use in Adults with Probable Posttraumatic Stress Disorder and Alcohol Use Disorder.

Co-occurring posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) represents a prevalent and problematic comorbidity. Functional health literacy (FHL) may play a role in this comorbidity based on its previously documented role in hazardous drinking. The current study examined functional health literacy (FHL) regarding hazardous drinking among a sample with probable posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD).

First results of migoprotafib, a potent and highly selective Src homology-2 domain-containing phosphatase 2 (SHP2) inhibitor in patients with advanced solid tumors.

Src homology-2 domain-containing phosphatase 2 (SHP2) promotes RAS-MAPK signaling and tumorigenesis and is a promising therapeutic target for multiple solid tumors. Migoprotafib is a potent and highly selective SHP2 inhibitor designed for the treatment of RAS-MAPK driven cancers, particularly in combination with other targeted agents. Here we report first-in-human study results of single agent migoprotafib in advanced solid tumor patients.

Best Practices for Delivering Neoadjuvant Therapy in Pancreatic Ductal Adenocarcinoma.

Importance: Neoadjuvant therapy (NT) is an increasingly used treatment strategy for patients with localized pancreatic ductal adenocarcinoma (PDAC). Little research has been conducted on cancer care delivery during NT, and the standards for optimal delivery of NT have not been defined.

Objective: To develop consensus best practices for delivering NT to patients with localized PDAC.

The Potential Utility of RAS Q61R Immunohistochemistry as a Screening Tool in Pre-operative Fine Needle Aspirates of Medullary Thyroid Carcinoma.

Medullary thyroid carcinoma (MTC) can either be sporadic, often via mutually exclusive RET or RAS alterations, or inherited via a RET germline alteration. Germline testing is recommended for all patients diagnosed with MTC. RAS p.

Deciphering the effects of radiopharmaceutical therapy in the tumor microenvironment of prostate cancer: an in-silico exploration with spatial transcriptomics.

Radiopharmaceutical therapy (RPT) is an emerging prostate cancer treatment that delivers radiation to specific molecules within the tumor microenvironment (TME), causing DNA damage and cell death. Given TME heterogeneity, it's crucial to explore RPT dosimetry and biological impacts at the cellular level. We integrated spatial transcriptomics (ST) with computational modeling to investigate the effects of RPT targeting prostate-specific membrane antigen (PSMA), fibroblast activation protein (FAP), and gastrin-releasing peptide receptor (GRPR) each labelled with beta-emitting lutetium-177 (Lu) and alpha-emitting actinium-225 (Ac).

Elotuzumab in combination with pomalidomide, bortezomib, and dexamethasone in relapsed and refractory multiple myeloma.

Elotuzumab is an approved monoclonal antibody targeting SLAMF7 on plasma and NK cells that enhances the activity of lenalidomide, pomalidomide, and bortezomib in multiple myeloma (MM). The OPTIMISMM study showed improved outcomes with the combination of pomalidomide, bortezomib, and dexamethasone (PVd) in relapsed/refractory MM. We therefore studied adding elotuzumab to PVd (elo-PVd) in relapsed/refractory MM in a multicenter phase 2 trial.

The Society for Immunotherapy of Cancer Perspective on Tissue-Based Technologies for Immuno-Oncology Biomarker Discovery and Application.

With immuno-oncology becoming the standard of care for a variety of cancers, identifying biomarkers that reliably classify patient response, resistance, or toxicity becomes the next critical barrier towards improving care. Multi-parametric, multi-omics, and computational platforms generating an unprecedented depth of data are poised to usher in the discovery of increasingly robust biomarkers for enhanced patient selection and personalized treatment approaches. Deciding which developing technologies to implement in clinical settings ultimately, applied either alone or in combination, relies on weighing pros and cons, from minimizing patient sampling to maximizing data outputs, and assessing reproducibility and representativeness of findings, while lessening data fragmentation towards harmonization.