Recent advances in the structure, function and regulation of the volume-regulated anion channels and their role in immunity.

Volume-regulated anion channels (VRACs) are heteromeric complexes formed by proteins of the leucine-rich repeat-containing 8 (LRRC8) family. LRRC8A (also known as SWELL1) is the core subunit required for VRAC function, and it must combine with one or more of the other paralogues (i.e.

CUX1 regulates human hematopoietic stem cell chromatin accessibility via the BAF complex.

CUX1 is a homeodomain-containing transcription factor that is essential for the development and differentiation of multiple tissues. CUX1 is recurrently mutated or deleted in cancer, particularly in myeloid malignancies. However, the mechanism by which CUX1 regulates gene expression and differentiation remains poorly understood, creating a barrier to understanding the tumor-suppressive functions of CUX1.

Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions.

To identify credible causal risk variants (CCVs) associated with different histotypes of epithelial ovarian cancer (EOC), we performed genome-wide association analysis for 470,825 genotyped and 10,163,797 imputed SNPs in 25,981 EOC cases and 105,724 controls of European origin. We identified five histotype-specific EOC risk regions (p value <5 × 10) and confirmed previously reported associations for 27 risk regions. Conditional analyses identified an additional 11 signals independent of the primary signal at six risk regions (p value <10).

Exome sequencing identifies as a novel susceptibility gene for non-mucinous, non-high-grade-serous epithelial ovarian cancer.

Rare, germline loss-of-function variants in a handful of genes that encode DNA repair proteins have been shown to be associated with epithelial ovarian cancer with a stronger association for the high-grade serous hiostotype. The aim of this study was to collate exome sequencing data from multiple epithelial ovarian cancer case cohorts and controls in order to systematically evaluate the role of coding, loss-of-function variants across the genome in epithelial ovarian cancer risk. We assembled exome data for a total of 2,573 non-mucinous cases (1,876 high-grade serous and 697 non-high grade serous) and 13,925 controls.

Harnessing Antitumor Immunity in Ovarian Cancer.

Despite progress in other tumor types, immunotherapy is not yet part of the standard of care treatment for high-grade serous ovarian cancer patients. Although tumor infiltration by T cells is frequently observed in patients with ovarian cancer, clinical responses to immunotherapy remain low. Mechanisms for immune resistance in ovarian cancer have been explored and may provide insight into future approaches to improve response to immunotherapy agents.

Utilizing geospatial artificial intelligence to map cancer disparities across health regions.

We have developed an innovative tool, the Intelligent Catchment Analysis Tool (iCAT), designed to identify and address healthcare disparities across specific regions. Powered by Artificial Intelligence and Machine Learning, our tool employs a robust Geographic Information System (GIS) to map healthcare outcomes and disease disparities. iCAT allows users to query publicly available data sources, health system data, and treatment data, offering insights into gaps and disparities in diagnosis and treatment paradigms.

Natural Killer Cell Infiltration in Prostate Cancers Predict Improved Patient Outcomes.

Background: Natural killer (NK) cells are non-antigen specific innate immune cells that can be redirected to targets of interest using multiple strategies, although none are currently FDA-approved. We sought to evaluate NK cell infiltration into tumors to develop an improved understanding of which histologies may be most amenable to NK cell-based therapies currently in the developmental pipeline.

Methods: DNA (targeted/whole-exome) and RNA (whole-transcriptome) sequencing was performed from tumors from 45 cancer types (N = 90,916 for all cancers and N = 3365 for prostate cancer) submitted to Caris Life Sciences.

Assessing the Landscape in Medical Education Literature in Medical Oncology: A Scoping Review.

Purpose: Medical oncology and medical education (ME) have both expanded exponentially over the past 50 years; thus, it is important to understand the current status of postgraduate medical oncology education and develop ways to advance this field. This study undertakes a scoping review of ME literature in medical oncology to inform future scholarship in this area.

Methods: MEDLINE, Embase, ERIC, and Web of Science were searched to find peer-reviewed English language articles on postgraduate ME in medical oncology published from 2009 to 2020.

Data gaps and opportunities for modeling cancer health equity.

Population models of cancer reflect the overall US population by drawing on numerous existing data resources for parameter inputs and calibration targets. Models require data inputs that are appropriately representative, collected in a harmonized manner, have minimal missing or inaccurate values, and reflect adequate sample sizes. Data resource priorities for population modeling to support cancer health equity include increasing the availability of data that 1) arise from uninsured and underinsured individuals and those traditionally not included in health-care delivery studies, 2) reflect relevant exposures for groups historically and intentionally excluded across the full cancer control continuum, 3) disaggregate categories (race, ethnicity, socioeconomic status, gender, sexual orientation, etc.

Haploinsufficient Transcription Factors in Myeloid Neoplasms.

Many transcription factors (TFs) function as tumor suppressor genes with heterozygous phenotypes, yet haploinsufficiency generally has an underappreciated role in neoplasia. This is no less true in myeloid cells, which are normally regulated by a delicately balanced and interconnected transcriptional network. Detailed understanding of TF dose in this circuitry sheds light on the leukemic transcriptome.

PARK7 Catalyzes Stereospecific Detoxification of Methylglyoxal Consistent with Glyoxalase and Not Deglycase Function.

The protein PARK7 (also known as DJ-1) has been implicated in several diseases, with the most notable being Parkinson's disease. While several molecular and cellular roles have been ascribed to DJ-1, there is no real consensus on what its true cellular functions are and how the loss of DJ-1 function may contribute to the pathogenesis of Parkinson's disease. Recent reports have implicated DJ-1 in the detoxification of several reactive metabolites that are produced during glycolytic metabolism, with the most notable being the α-oxoaldehyde species methylglyoxal.

Cancer Relevance of Circulating Antibodies Against LINE-1 Antigens in Humans.

Unlabelled: Long interspersed nuclear element-1 (LINE-1 or L1), the most abundant family of autonomous retrotransposons occupying over 17% of human DNA, is epigenetically silenced in normal tissues by the mechanisms involving p53 but is frequently derepressed in cancer, suggesting that L1-encoded proteins may act as tumor-associated antigens recognized by the immune system. In this study, we established an immunoassay to detect circulating autoantibodies against L1 proteins in human blood. Using this assay in >2,800 individuals with or without cancer, we observed significantly higher IgG titers against L1-encoded ORF1p and ORF2p in patients with lung, pancreatic, ovarian, esophageal, and liver cancers than in healthy individuals.

Community Outreach and Engagement at U.S. Cancer Centers: Notes from the Third Cancer Center Community Impact Forum.

Community outreach and engagement (COE) is a fundamental activity of cancer centers as they aim to reduce cancer disparities in their geographic catchment areas. As part of COE, NCI-Designated Cancer Centers must monitor the burden of cancer in their catchment area, implement and evaluate evidence-based strategies, stimulate catchment area relevant research, support clinical trial enrollment, and participate in policy and advocacy initiatives, in addition to other responsibilities. The Cancer Center Community Impact Forum (CCCIF) is a national annual meeting of COE professionals who work at or with cancer centers across the country.

BiTE secretion by adoptively transferred stem-like T cells improves FRα+ ovarian cancer control.

Background: Cancer immunotherapies can produce complete therapeutic responses, however, outcomes in ovarian cancer (OC) are modest. While adoptive T-cell transfer (ACT) has been evaluated in OC, durable effects are rare. Poor therapeutic efficacy is likely multifactorial, stemming from limited antigen recognition, insufficient tumor targeting due to a suppressive tumor microenvironment (TME), and limited intratumoral accumulation/persistence of infused T cells.

Perspectives in Immunotherapy: meeting report from Immunotherapy Bridge (Naples, November 30th-December 1st, 2022).

The discovery and development of novel treatments that harness the patient's immune system and prevent immune escape has dramatically improved outcomes for patients across cancer types. However, not all patients respond to immunotherapy, acquired resistance remains a challenge, and responses are poor in certain tumors which are considered to be immunologically cold. This has led to the need for new immunotherapy-based approaches, including adoptive cell transfer (ACT), therapeutic vaccines, and novel immune checkpoint inhibitors.

Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of gynecologic cancer.

Advanced gynecologic cancers have historically lacked effective treatment options. Recently, immune checkpoint inhibitors (ICIs) have been approved by the US Food and Drug Administration for the treatment of cervical cancer and endometrial cancer, offering durable responses for some patients. In addition, many immunotherapy strategies are under investigation for the treatment of earlier stages of disease or in other gynecologic cancers, such as ovarian cancer and rare gynecologic tumors.

Data envelopment analysis to evaluate the efficiency of tobacco treatment programs in the NCI Moonshot Cancer Center Cessation Initiative.

Background: The Cancer Center Cessation Initiative (C3I) is a National Cancer Institute (NCI) Cancer Moonshot Program that supports NCI-designated cancer centers developing tobacco treatment programs for oncology patients who smoke. C3I-funded centers implement evidence-based programs that offer various smoking cessation treatment components (e.g.

Racial and Ethnic Disparities in Cervical Cancer Screening From Three U.S. Healthcare Settings.

Introduction: This study sought to characterize racial and ethnic disparities in cervical cancer screening and follow-up of abnormal findings across 3 U.S. healthcare settings.

Adoptive Cell Therapy for Nonhematologic Solid Tumors.

The long-term benefits demonstrated by immunotherapy in select tumors have failed to generalize to most nonhematologic solid tumors. Adoptive cell therapy (ACT)-a treatment on the basis of the isolation and engineering of living T cells and other immune cells-has shown early clinical advances. ACT, through tumor-infiltrating lymphocyte therapy, has shown activity in traditionally immunogenic tumors such as melanoma and cervical cancers, and has the potential to improve immune reactivity in these tumor types where traditional therapies have failed.

The "Great Debate" at Immunotherapy Bridge 2022, Naples, November 30th-December 1st, 2022.

The 2022 Immunotherapy Bridge congress (November 30-December 1, Naples, Italy) featured a Great Debate session which addressed three contemporary topics in the field of immunotherapy. The debates included counterpoint views from leading experts and considered whether adoptive cell therapy (ACT) has a role in the treatment of solid tumors, the use of peripheral/blood biomarkers versus tumor microenvironment biomarkers for cancer immunotherapy and the role of chimeric antigen receptor T cell versus natural killer cell therapy. As is the tradition in the Immunotherapy Bridge Great Debates, speakers are invited by the meeting Chairs to express one side of the assigned debate and the opinions given may not fully reflect their own personal views.

Measurement of Perceived Risk of Developing Diabetes Mellitus: A Systematic Literature Review.

Background: This systematic review describes approaches to measuring perceived risk of developing type 2 diabetes among individuals without diagnoses and describes the use of theories, models, and frameworks in studies assessing perceived risk. While a systematic review has synthesized perceived risk of complications among individuals with diabetes, no reviews have systematically assessed how perceived risk is measured among those without a diagnosis.

Methods: Medline, PubMed, PsycINFO, and CINAHAL databases were searched for studies conducted through October 2022 with measures of perceived risk among adults ≥ 18 years without a diabetes diagnosis.

Perspectives on Disparities and Equity in Cancer Outcomes: A Call to Action.

Despite remarkable progress in cancer prevention, treatment, and survivorship in the United States over the past 3 decades, there remain considerable disparities in cancer incidence and mortality among various groups based on race, ethnicity, and other social determinants of health. For most cancer types, African Americans have the highest mortality rate and lowest survival rate of any racial and ethnic group. Here the author highlights some of the factors responsible for cancer health disparities and proposes that cancer health equity is a fundamental human right.