RSK1 is an exploitable dependency in myeloproliferative neoplasms and secondary acute myeloid leukemia.

Myeloid malignancies are heterogenous disorders characterized by distinct molecular drivers but share convergence of oncogenic signaling pathways and propagation by ripe pro-inflammatory niches. Here, we establish a comprehensive transcriptional atlas across the spectrum of myeloproliferative neoplasms (MPN) and secondary acute myeloid leukemia (sAML) through RNA-sequencing of 158 primary samples encompassing CD34+ hematopoietic stem/progenitor cells and CD14+ monocytes. Supported by mass cytometry (CyTOF) profiling, we reveal aberrant networks of PI3K/AKT/mTOR signalling and NFκB-mediated hyper-inflammation.

Investigating the implementation of a novel approach to alcohol screening and brief intervention in Mexico: a mixed-methods study using pseudo-patients.

Introduction: Low- and middle-income countries bear disproportionate burdens from excessive alcohol consumption, yet have fewer resources to identify and intervene with risky drinkers. Low-cost screening and brief intervention (SBI) models offer a tool for addressing this health problem and reducing disparities.

Methods: In this mixed-methods study, trained pseudo-patients visited health clinics in Zacatecas, Mexico, where a novel SBI model was used with trained nonmedical health educators (HEs) conducting SBI in waiting areas.

Self-reported drink driving, enforcement, crashes, and crash reporting: A 6-country comparison.

Objective: The objective of this study was to compare drink driving and related road safety issues in 2 urban areas of 6 countries and develop an equation for estimating the rate of crash underreporting to the police in urban areas of countries that lack this information.

Methods: This study is a secondary analysis of 1 to 2 waves of surveys in pairs of matched medium-sized cities in Belgium, Brazil, China, Mexico, South Africa, and Ohio, United States; the surveys supported evaluation of local alcohol harm reduction efforts. Data were from 2017 to 2019 except 2023 for Mexico.

In vivo ablation of NF-κB cascade effectors alleviates disease burden in myeloproliferative neoplasms.

Hyperactivation of the NF-κB cascade propagates oncogenic signaling and proinflammation, which together augments disease burden in myeloproliferative neoplasms (MPNs). Here, we systematically ablate NF-κB signaling effectors to identify core dependencies using a series of primary samples and syngeneic and patient-derived xenograft (PDX) mouse models. Conditional knockout of Rela attenuated Jak2V617F- and MPLW515L-driven onset of polycythemia vera and myelofibrosis disease hallmarks, respectively.

Altered erythropoiesis via JAK2 and ASXL1 mutations in myeloproliferative neoplasms.

Myeloproliferative neoplasms (MPNs) are driven by hyperactivation of JAK-STAT signaling but can demonstrate skewed hematopoiesis upon acquisition of additional somatic mutations. Here, using primary MPN samples and engineered embryonic stem cells, we demonstrate that mutations in JAK2 induced a significant increase in erythroid colony formation, whereas mutations in additional sex combs-like 1 (ASXL1) led to an erythroid colony defect. RNA-sequencing revealed upregulation of protein arginine methyltransferase 6 (PRMT6) induced by mutant ASXL1.

Multiomic profiling reveals metabolic alterations mediating aberrant platelet activity and inflammation in myeloproliferative neoplasms.

Platelets from patients with myeloproliferative neoplasms (MPNs) exhibit a hyperreactive phenotype. Here, we found elevated P-selectin exposure and platelet-leukocyte aggregates indicating activation of platelets from essential thrombocythemia (ET) patients. Single-cell RNA-seq analysis of primary samples revealed significant enrichment of transcripts related to platelet activation, mTOR, and oxidative phosphorylation in ET patient platelets.

Complementary and countervailing actions of Jak2 and Ikk2 in hematopoiesis in mice.

Hyperactivation of JAK2 kinase is a unifying feature of human Ph- myeloproliferative neoplasms (MPNs), most commonly due to the JAK2 V617F mutation. Mice harboring a homologous mutation in the Jak2 locus exhibit a phenotype resembling polycythemia vera. NFκB pathway hyperactivation is present in myeloid neoplasms, including MPNs, despite scarcity of mutations in NFκB pathway genes.

Healthcare costs, resource utilization, and productivity loss associated with colorectal cancer screening.

Objectives: To evaluate healthcare costs, resource utilization, associated costs, and lost productivity for colorectal cancer (CRC) screening in an average-risk population.

Methods: This retrospective cohort study identified average-risk individuals (50-75 years) with claims in the Optum Research Database for CRC screening test between 1 January 2014 to 31 December 2018. Index date was defined as the first date of a claim for colonoscopy, fecal immunochemical test (FIT), guaiac-based fecal occult blood test (FOBT) or multi-target stool DNA test (mt-sDNA).

Patient and provider factors associated with colorectal cancer screening among average risk health plan enrollees in the US, 2015-2018.

Background: To assess patient and primary care provider (PCP) factors associated with adherence to American Cancer Society (ACS) and United States Preventive Services Task Force (USPSTF) guidelines for average risk colorectal cancer (CRC) screening.

Methods: Retrospective case-control study of medical and pharmacy claims from the Optum Research Database from 01/01/2014 - 12/31/2018. Enrollee sample was adults aged 50 - 75 years with ≥ 24 months continuous health plan enrollment.

IMC-Denoise: a content aware denoising pipeline to enhance Imaging Mass Cytometry.

Imaging Mass Cytometry (IMC) is an emerging multiplexed imaging technology for analyzing complex microenvironments using more than 40 molecularly-specific channels. However, this modality has unique data processing requirements, particularly for patient tissue specimens where signal-to-noise ratios for markers can be low, despite optimization, and pixel intensity artifacts can deteriorate image quality and downstream analysis. Here we demonstrate an automated content-aware pipeline, IMC-Denoise, to restore IMC images deploying a differential intensity map-based restoration (DIMR) algorithm for removing hot pixels and a self-supervised deep learning algorithm for shot noise image filtering (DeepSNiF).

DUSP6 mediates resistance to JAK2 inhibition and drives leukemic progression.

Myeloproliferative neoplasms (MPNs) exhibit a propensity for transformation to secondary acute myeloid leukemia (sAML), for which the underlying mechanisms remain poorly understood, resulting in limited treatment options and dismal clinical outcomes. Here, we performed single-cell RNA sequencing on serial MPN and sAML patient stem and progenitor cells, identifying aberrantly increased expression of DUSP6 underlying disease transformation. Pharmacologic dual-specificity phosphatase (DUSP)6 targeting led to inhibition of S6 and Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling while also reducing inflammatory cytokine production.

Colorectal screening among average risk individuals in the United States, 2015-2018.

Colorectal cancer screening rates are important metrics for public health and quality indicators for health care systems; however, published estimates of colorectal cancer screening rates often include both high-risk and average-risk patients, and the use of different epidemiologic methods makes between-study comparisons tenuous. The objective of this study was to measure the proportion of average-risk American adults who are up to date with colorectal cancer screening guidelines and examine the impact of evaluation methods on screening rate estimates. This repeated cross-sectional study used administrative claims to identify individuals aged 50-75 years between 2015 and 2018 with ≥ 1-year of continuous health plan enrollment.

A Cluster Randomized Trial of a Family Health History Platform to Identify and Manage Patients at Increased Risk for Colorectal Cancer.

Background: Obtaining comprehensive family health history (FHH) to inform colorectal cancer (CRC) risk management in primary care settings is challenging.

Objective: To examine the effectiveness of a patient-facing FHH platform to identify and manage patients at increased CRC risk.

Design: Two-site, two-arm, cluster-randomized, implementation-effectiveness trial with primary care providers (PCPs) randomized to immediate intervention versus wait-list control.

Screening and brief intervention for alcohol use disorder risk in three middle-income countries.

Background: This study examined the prevalence of screening and brief intervention (SBI) for alcohol use disorder (AUD) risk in samples of adult drinkers in three middle-income countries (Brazil, China, South Africa), and the extent to which meeting criteria for AUD risk was associated with SBI.

Methods: Cross-sectional survey data were collected from adult samples in two cities in each country in 2018. Survey measures included past-year alcohol use, the CAGE assessment for AUD risk, talking to a health care professional in the past year, alcohol use screening by a health care professional, receiving advice about drinking from a health care professional, and sociodemographic characteristics.

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.

Adherence to colorectal cancer screening and healthcare resource utilization: a longitudinal analysis in Medicare beneficiaries aged 66-75 years.

Objective: In this study, we examined colorectal cancer (CRC) screening adherence in Medicare beneficiaries and associated healthcare resource utilization (HCRU) and Medicare costs.

Methods: Using 20% Medicare random sample data, the study population included Medicare fee-for-service beneficiaries aged 66-75 years on 1 January 2009, at average risk for CRC and continuously enrolled in Medicare Part A/B from 2008 to 2018. We excluded those who had undergone colonoscopy or flexible sigmoidoscopy during 2007-2008 and assumed everyone was due for screening in 2009; screening patterns were determined for 2009-2018.

Diagnosis and Treatment of Lung Cancer in the Setting of Interstitial Lung Disease.

Interstitial lung disease (ILD) including idiopathic pulmonary fibrosis increases the risk of developing lung cancer. Diagnosing and staging lung cancer in patients with ILD is challenging and requires careful interpretation of computed tomography (CT) and fluorodeoxyglucose PET/CT to distinguish nodules from areas of fibrosis. Minimally invasive tissue sampling is preferred but may be technically challenging given tumor location, coexistent fibrosis, and pneumothorax risk.