Treatment duration of immune checkpoint inhibitors and overall survival in U.S. veterans with Cancer.

BackgroundOptimal treatment duration for immune checkpoint inhibitors (ICI) remains a clinical debate. The objective of this study was to contrast mortality rates between 2-year fixed versus indefinite treatment duration among patients initiating ICIs across a variety cancer types.MethodsThis retrospective observational study used national administrative data from the Veterans Health Administration to select patients who initiated an ICI between January 1, 2014, and December 31, 2020.

Exposure-Informed Care Following Toxic Environmental Exposures: A Lifestyle Medicine Approach.

Exposure to environmental toxins presents substantial health risks, particularly for individuals facing heightened exposure due to occupational hazards. This analytic review highlights the critical need to address these risks through a lifestyle medicine approach, advocating for integrated care strategies to mitigate the long-term health impacts of toxic environmental exposures. We explore exposures to environmental toxins in 2 at-risk populations, military service members exposed to airborne hazards and burn pits during overseas deployments and first responders to the World Trade Center terrorist attack.

Veterans Affairs Military Toxic Exposure Research Conference: Veteran-centric Approach and Community of Practice.

The U.S. Sergeant First Class Heath Robinson Honoring our Promise to Address Comprehensive Toxics (PACT) Act expands benefits and services to U.

Targeting RET alterations in non-small cell lung cancer.

Rearranged during transfection (RET) alterations, which lead to aberrant activation of the RET proto-oncogene, have been identified in various cancers. In non-small cell lung cancer (NSCLC), RET mutations often manifest as RET fusion genes and are observed in 1-2 % of patients with NSCLC. In recent years, selective RET inhibitors such as selpercatinib and pralsetinib, approved by the Food and Drug Administration (FDA) in 2020, have been part of the revolutionary changes in the treatment landscape for non-small cell lung cancer.

Cyclin D1 extensively reprograms metabolism to support biosynthetic pathways in hepatocytes.

Cell proliferation requires metabolic reprogramming to accommodate biosynthesis of new cell components, and similar alterations occur in cancer cells. However, the mechanisms linking the cell cycle machinery to metabolism are not well defined. Cyclin D1, along with its main partner cyclin-dependent kinase 4 (Cdk4), is a pivotal cell cycle regulator and driver oncogene that is overexpressed in many cancers.

Luciferase Calibrants Enable Absolute Quantitation of Bioluminescence Power.

Bioluminescence emitted from a luciferase-catalyzed oxidation of luciferin has been broadly utilized to report on biological events, predominantly through relative changes in the light output. Recent advances in protein engineering and synthetic chemistry have yielded bioluminescent systems with markedly improved brightness and bioavailability. These developments have enabled not only the detection of biological events at far lower expression levels but also new opportunities utilizing bioluminescence to power photochemistry in cells.

Trajectory of Healthcare Contact Days for Veterans With Advanced Gastrointestinal Malignancy.

How and where patients with advanced cancer facing limited survival spend their time is critical. Healthcare contact days (days with healthcare contact outside the home) offer a patient-centered and practical measure of how much of a person's life is consumed by healthcare. We retrospectively analyzed contact days among decedent veterans with stage IV gastrointestinal cancer at the Minneapolis Veterans Affairs Healthcare System from 2010 to 2021.

Gross Hematuria and Lower Urinary Tract Symptoms Associated With Military Burn Pits Exposures in US Veterans Deployed to Iraq and Afghanistan.

Objective: The aim of the study is to describe rates of hematuria and other lower urinary tract symptoms, including self-reported cancer rates, among veterans postburn pits emissions exposure during deployment to Iraq and Afghanistan.

Methods: US post-9/11 veterans with burn pits emissions exposure confirmed via DD214 forms in the Burn Pits360.org Registry were sent a modified survey.

Inhibition of Mitochondrial Antioxidant Defense and CDK4/6 in Mesothelioma.

Advanced mesothelioma is considered an incurable disease and new treatment strategies are needed. Previous studies have demonstrated that mitochondrial antioxidant defense proteins and the cell cycle may contribute to mesothelioma growth, and that the inhibition of these pathways may be effective against this cancer. We demonstrated that the antioxidant defense inhibitor auranofin and the cyclin-dependent kinase 4/6 inhibitor palbociclib could decrease mesothelioma cell proliferation alone or in combination.

An optimized bioluminescent substrate for non-invasive imaging in the brain.

Bioluminescence imaging (BLI) allows non-invasive visualization of cells and biochemical events in vivo and thus has become an indispensable technique in biomedical research. However, BLI in the central nervous system remains challenging because luciferases show relatively poor performance in the brain with existing substrates. Here, we report the discovery of a NanoLuc substrate with improved brain performance, cephalofurimazine (CFz).

Protein kinase CK2 - diverse roles in cancer cell biology and therapeutic promise.

The association of protein kinase CK2 (formerly casein kinase II or 2) with cell growth and proliferation in cells was apparent at early stages of its investigation. A cancer-specific role for CK2 remained unclear until it was determined that CK2 was also a potent suppressor of cell death (apoptosis); the latter characteristic differentiated its function in normal versus malignant cells because dysregulation of both cell growth and cell death is a universal feature of cancer cells. Over time, it became evident that CK2 exerts its influence on a diverse range of cell functions in normal as well as in transformed cells.

Potent Activation of NAD-Dependent Deacetylase Sirt7 by Nucleosome Binding.

Sirtuin-7 (Sirt7) is a nuclear NAD-dependent deacetylase with a broad spectrum of biological functions. Sirt7 overexpression is linked to several pathological states and enhances anticancer drug resistance, making the enzyme a promising target for the development of novel therapeutics. Despite a plethora of reported functions, the biochemical characterization of recombinant Sirt7 remains inadequate for the development of novel drug candidates.

Sirt6 regulates lifespan in .

Sirt6 is a multifunctional enzyme that regulates diverse cellular processes such as metabolism, DNA repair, and aging. Overexpressing Sirt6 extends lifespan in mice, but the underlying cellular mechanisms are unclear. are an excellent model to study genetic regulation of lifespan; however, despite extensive study in mammals, very little is known about Sirt6 function in flies.

Use of Comprehensive Geriatric Assessment in Oncology Patients to Guide Treatment Decisions and Predict Chemotherapy Toxicity.

Purpose: Our objective was to review the utility of pretreatment comprehensive geriatric assessment (CGA) and its impact on decision making regarding choice and intensity of oncologic therapeutic regimens for older, frail, or poor-functional-status patients, as well as using this prospective assessment to predict chemotherapy-related toxicities. Database searches were conducted in Medline, PubMed, and Ovid for clinical studies, review articles, and journal publications. Search terms included , , , , , and .

CX-4945 and siRNA-Mediated Knockdown of CK2 Improves Cisplatin Response in HPV(+) and HPV(-) HNSCC Cell Lines.

Head and neck squamous cell carcinoma (HNSCC) can be categorized into human papillomavirus (HPV) positive or negative disease. Elevated protein kinase CK2 level and activity have been historically observed in HNSCC cells. Previous studies on CK2 in HNSCC did not generally include consideration of HPV(+) and HPV(-) status.

Multivalent interactions drive nucleosome binding and efficient chromatin deacetylation by SIRT6.

The protein deacetylase SIRT6 maintains cellular homeostasis through multiple pathways that include the deacetylation of histone H3 and repression of transcription. Prior work suggests that SIRT6 is associated with chromatin and can substantially reduce global levels of H3 acetylation, but how SIRT6 is able to accomplish this feat is unknown. Here, we describe an exquisitely tight interaction between SIRT6 and nucleosome core particles, in which a 2:1 enzyme:nucleosome complex assembles via asymmetric binding with distinct affinities.

Biological and catalytic functions of sirtuin 6 as targets for small-molecule modulators.

Sirtuin 6 (SIRT6) is a nuclear NAD-dependent deacetylase of histone H3 that regulates genome stability and gene expression. However, nonhistone substrates and additional catalytic activities of SIRT6, including long-chain deacylation and mono-ADP-ribosylation of other proteins, have also been reported, but many of these noncanonical roles remain enigmatic. Genetic studies have revealed critical homeostatic cellular functions of SIRT6, underscoring the need to better understand which catalytic functions and molecular pathways are driving SIRT6-associated phenotypes.

Cyclin-dependent kinase inhibition: an opportunity to target protein-protein interactions.

Cyclin-dependent kinases (CDKs) play an integral part in cellular activities. To date, most of the activities have been evaluated in the cell cycle and transcription. Several diseases are affected by abnormalities in CDKs, related-pathways, or proteins that regulate CDK activity.

Cyclin-Dependent Kinase and Antioxidant Gene Expression in Cancers with Poor Therapeutic Response.

Pancreatic cancer, hepatocellular carcinoma (HCC), and mesothelioma are treatment-refractory cancers, and patients afflicted with these cancers generally have a very poor prognosis. The genomics of these tumors were analyzed as part of The Cancer Genome Atlas (TCGA) project. However, these analyses are an overview and may miss pathway interactions that could be exploited for therapeutic targeting.

Mechanism of activation for the sirtuin 6 protein deacylase.

The histone deacetylase sirtuin 6 (SIRT6) regulates numerous biological functions, including transcriptional repression, DNA repair, and telomere maintenance. Recombinant SIRT6 displays catalytic efficiencies 2 orders of magnitude greater for long-chain deacylation than deacetylation against peptide substrates; however, deacetylation can be enhanced by allosteric small-molecule activators. Here, we investigated the mechanisms of activated lysine deacetylation and enhanced long-chain acyl-group removal by SIRT6.

An inactivating mutation in the histone deacetylase SIRT6 causes human perinatal lethality.

It has been well established that histone and DNA modifications are critical to maintaining the equilibrium between pluripotency and differentiation during early embryogenesis. Mutations in key regulators of DNA methylation have shown that the balance between gene regulation and function is critical during neural development in early years of life. However, there have been no identified cases linking epigenetic regulators to aberrant human development and fetal demise.

Impact of educational intervention on management of periprocedural anticoagulation.

Purpose: The effect of education regarding new evidence in periprocedural anticoagulation, with a focus on reducing use in patients at only moderate thromboembolic risk, is presented.

Methods: A retrospective cohort analysis and quasiexperimental design were used. The initial review identified the current state of practice regarding bridging anticoagulation.