Phase 2A Proof-of-Concept Double-Blind, Randomized, Placebo-Controlled Trial of Nicotinamide in Early Alzheimer Disease.

Background And Objectives: Nicotinamide is a coenzyme involved in cellular oxidation-reduction reactions that can inhibit Class III histone deacetylases (HDACs) or sirtuins. HDAC inhibition can affect numerous therapeutic pathways, including tau phosphorylation. We tested the hypothesis that nicotinamide treatment could reduce tau phosphorylation in early Alzheimer disease (AD).

Salivary CD44 and Total Protein Levels to Detect Risk for Oral and Oropharyngeal Cancer Recurrence: A Nonrandomized Clinical Trial.

Importance: Oral and oropharyngeal cancer have low survival rates, and incidence continues to increase.

Objective: To determine whether soluble CD44 and total protein (TP) are useful for monitoring head and neck cancer recurrence, either used in a point-of-care (POC) test or as individual laboratory-based biomarkers.

Design, Setting, And Participants: This multi-institutional nonrandomized clinical trial testing a novel diagnostic/screening assay took place across the University of California, San Diego; Johns Hopkins University; the Greater Baltimore Medical Center; New York University; and the San Diego Veterans Affairs Hospital.

Structure-Activity Relationship Studies in Benzothiadiazoles as Novel Vaccine Adjuvants.

Extracellular vesicles (EVs) can transfer antigens and immunomodulatory molecules, and such EVs released by antigen-presenting cells equipped with immunostimulatory functions have been utilized for vaccine formulations. A prior high-throughput screening campaign led to the identification of compound (), which enhanced EV release and increased intracellular Ca influx. Here, we performed systematic structure-activity relationship (SAR) studies to investigate the scaffold for its potency as a vaccine adjuvant.

Cigarette smoking decline among US young adults from 2000 to 2019, in relation to state-level cigarette price and tobacco control expenditure.

Objective: To investigate the association of state-level cigarette price and tobacco control expenditure with the large 2000-2019 decline in cigarette smoking among US 18-24 year-olds.

Methods: Smoking behaviour was assessed in the 24 most populous US states using the 1992-2019 Tobacco Use Supplements to the Current Population Survey; association with price and expenditure was tested using adjusted logistic regression. States were ranked by inflation-adjusted average price and tobacco control expenditure and grouped into tertiles.

A phase 1b study of zilovertamab in combination with paclitaxel for locally advanced/unresectable or metastatic Her2-negative breast cancer.

Background: Zilovertamab is a humanized monoclonal antibody targeting ROR1, an onco-embryonic antigen expressed by malignant cells of a variety of solid tumors, including breast cancer. A prior phase 1 study showed that zilovertamab was well tolerated and effective in inhibiting ROR1-signaling, which leads to activation of ERK1/2, NF-κB, and NRF2 target genes. This phase 1b study evaluated the safety and tolerability of zilovertamab with paclitaxel in patients with advanced breast cancer.

Declines in cigarette smoking among US adolescents and young adults: indications of independence from e-cigarette vaping surge.

Objective: To compare trends in cigarette smoking and nicotine vaping among US population aged 17-18 years and 18-24 years.

Methods: Regression analyses identified trends in ever and current use of cigarettes and e-cigarettes, using three US representative surveys from 1992 to 2022.

Results: From 1997 to 2020, cigarette smoking prevalence among those aged 18-24 years decreased from 29.

Lead Time to Recurrence After Posttreatment Plasma and Saliva HPV DNA Testing in Patients With Low-Risk HPV Oropharynx Cancer.

Importance: Head and neck squamous cell carcinoma is a highly lethal cancer that is often associated with human papillomavirus (HPV). Recent studies have shown promise in the use of HPV DNA detection in salivary rinses and plasma as a factor associated with a future diagnosis of HPV-positive oropharynx cancer (HPVOPC). However, the use of plasma and salivary HPV DNA detection in defining risk for recurrence in the context of a prospective, phase 3, clinical trial coupled with standardized clinical surveillance has not been reported.

Method for estimation of apoptotic cell fraction of cytotherapy using in vivo fluorine-19 magnetic resonance: pilot study in a patient with head and neck carcinoma receiving tumor-infiltrating lymphocytes labeled with perfluorocarbon nanoemulsion.

Background: Adoptive transfer of T cells is a burgeoning cancer therapeutic approach. However, the fate of the cells, once transferred, is most often unknown. We describe the first clinical experience with a non-invasive biomarker to assay the apoptotic cell fraction (ACF) after cell therapy infusion, tested in the setting of head and neck squamous cell carcinoma (HNSCC).

Identification of a Novel Small Molecule That Enhances the Release of Extracellular Vesicles with Immunostimulatory Potency via Induction of Calcium Influx.

Extracellular vesicles (EVs) transfer antigens and immunomodulatory molecules in immunologic synapses as a part of intracellular communication, and EVs equipped with immunostimulatory functions have been utilized for vaccine formulation. Hence, we sought small-molecule compounds that increase immunostimulatory EVs released by antigen-presenting dendritic cells (DCs) for enhancement of vaccine immunogenicity. We previously performed high-throughput screening on a 28K compound library using three THP-1 reporter cell lines with CD63 Turbo-Luciferase, NF-κB, and interferon-sensitive response element (ISRE) reporter constructs, respectively.

Trends in cigarette consumption across the United States, with projections to 2035.

Objectives: To make projections of cigarette consumption that incorporate state-specific trends in smoking behaviors, assess the potential for states to reach an ideal target, and identify State-specific targets for cigarette consumption.

Methods: We used 70 years (1950-2020) of annual state-specific estimates of per capita cigarette consumption (expressed as packs per capita or "ppc") from the Tax Burden on Tobacco reports (N = 3550). We summarized trends within each state by linear regression models and the variation in rates across states by the Gini coefficient.

A generalized covariate-adjusted top-scoring pair algorithm with applications to diabetic kidney disease stage classification in the Chronic Renal Insufficiency Cohort (CRIC) Study.

Background: The growing amount of high dimensional biomolecular data has spawned new statistical and computational models for risk prediction and disease classification. Yet, many of these methods do not yield biologically interpretable models, despite offering high classification accuracy. An exception, the top-scoring pair (TSP) algorithm derives parameter-free, biologically interpretable single pair decision rules that are accurate and robust in disease classification.

Treatment of pancreatic cancer with irreversible electroporation and intratumoral CD40 antibody stimulates systemic immune responses that inhibit liver metastasis in an orthotopic model.

Background: Pancreatic cancer (PC) has a poor prognosis, and most patients present with either locally advanced or distant metastatic disease. Irreversible electroporation (IRE) is a non-thermal method of ablation used clinically in locally advanced PC, but most patients eventually develop distant recurrence. We have previously shown that IRE alone is capable of generating protective, neoantigen-specific immunity.

Imaging Non-alcoholic Fatty Liver Disease Model Using H-1 and F-19 MRI.

Purpose: We explore the use of intravenously delivered perfluorocarbon (PFC) nanoemulsion and F MRI for detecting inflammation in a mouse model of non-alcoholic fatty liver disease (NAFLD). Correlative studies of H-based liver proton density fat fraction (PDFF) and T measurements and histology are also evaluated.

Procedures: C57BL/6 mice were fed standard or high-fat diet (HFD) for 6 weeks to induce NAFLD.

A phase I study of avelumab, palbociclib, and cetuximab in patients with recurrent or metastatic head and neck squamous cell carcinoma.

Objectives: We aimed to test the safety of the CDK4/6 inhibitor palbociclib in combination with the EGFR inhibitor cetuximab and the PD-L1 inhibitor avelumab in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC).

Materials And Methods: This phase I study enrolled eligible adult patients with R/M HNSCC into three sequential single dose-escalation cohorts of palbociclib (75, 100, and 125 mg) PO daily on days 1 to 21 of a 28-day cycle in combination with avelumab 10 mg/kg IV every 2 weeks and cetuximab 400 mg/mIV on day 1, then 250 mg/mweekly thereafter. The study followed a 3 + 3 design with no intra-patient escalation.

Adenoma Detection Rate and Clinical Characteristics Influence Advanced Neoplasia Risk After Colorectal Polypectomy.

Background And Aims: Postpolypectomy risk stratification for subsequent metachronous advanced neoplasia (MAN) is imprecise and does not account for colonoscopist adenoma detection rate (ADR). Our aim was to assess association of ADR with MAN and create a prediction model for postpolypectomy risk stratification incorporating ADR and other factors.

Methods: We conducted a retrospective cohort study of individuals with baseline polypectomy and subsequent surveillance colonoscopy from 2004 to 2016 within the U.

Alvimopan for Enhanced Gastrointestinal Recovery after Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: A Randomized Controlled Trial.

Background: Surgical management of peritoneal metastases with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is associated with prolonged length of stay and time to return of bowel function. Alvimopan is a peripherally acting opioid antagonist that reduces postoperative ileus. We sought to determine the efficacy of alvimopan on return of bowel function in patients undergoing CRS-HIPEC.

Patient Blood Type Is Associated With Response to Immune Checkpoint Blockade in Metastatic Cancer.

Background: Immune checkpoint blockade (ICB) has transformed cancer therapy, with long-term responses and a favorable safety profile; however, only a minority of patients respond. Response to ICB is influenced by immune-related genetic factors such as HLA haplotype, potentially including patient blood type and associated differences in diversity of the T-cell repertoire. A minority of patients experience immune-related adverse events (irAEs), with unclear relation to response or resistance.

Daily E-cigarette Use and the Surge in JUUL Sales: 2017-2019.

Objectives: To identify how the 2017 rapid surge in sales of JUUL e-cigarettes affected usage among US youth and young adults.

Methods: Annual surveys in the Population Assessment of Tobacco and Health Study assess tobacco use by product and brand among the US population. We identified 2 cohorts aged 14 to 34 years, 1 with baseline survey in 2014 before the rapid surge of JUUL and the other in 2017 as the surge in JUUL sales was occurring.

A Triple High Throughput Screening for Extracellular Vesicle Inducing Agents With Immunostimulatory Activity.

Extracellular vesicles (EVs) play an important role in intercellular communication and regulation of cells, especially in the immune system where EVs can participate in antigen presentation and may have adjuvant effects. We aimed to identify small molecule compounds that can increase EV release and thereby enhance the immunogenicity of vaccines. We utilized a THP-1 reporter cell line engineered to release EV-associated tetraspanin (CD63)-Turbo-luciferase to quantitatively measure EVs released in culture supernatants as a readout of a high throughput screen (HTS) of 27,895 compounds.

Effectiveness of e-cigarettes as aids for smoking cessation: evidence from the PATH Study cohort, 2017-2019.

Objective: To assess the effectiveness of e-cigarettes in smoking cessation in the USA from 2017 to 2019, given the 2017 increase in high nicotine e-cigarette sales.

Methods: In 2017, the PATH Cohort Study included data on 3578 previous year smokers with a recent quit attempt and 1323 recent former smokers. Respondents reported e-cigarettes or other products used to quit cigarettes and many covariates associated with e-cigarette use.

Small Molecule Calcium Channel Activator Potentiates Adjuvant Activity.

There remains an unmet need for reliable fully synthetic adjuvants that increase lasting protective immune responses from vaccines. We previously reported a high-throughput screening for small molecules that extended nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) activation after a Toll-like receptor 4 (TLR4) ligand, lipopolysaccharide (LPS), stimulation using a human myeloid reporter cell line. We identified compounds with a conserved aminothiazole scaffold including [-(4-(2,5-dimethylphenyl)thiazol-2-yl)-4-(piperidin-1-ylsulfonyl)benzamide], which increased murine antigen-specific antibody responses when used as a co-adjuvant with LPS.

Impact of potential modifications to Alzheimer's disease clinical trials in response to disruption by COVID-19: a simulation study.

Background: The COVID-19 pandemic disrupted Alzheimer disease randomized clinical trials (RCTs), forcing investigators to make changes in the conduct of such trials while endeavoring to maintain their validity. Changing ongoing RCTs carries risks for biases and threats to validity. To understand the impact of exigent modifications due to COVID-19, we examined several scenarios in symptomatic and disease modification trials that could be made.