State of the Science of Scale-Up of Cancer Prevention and Early Detection interventions in Low- and Middle-income Countries: a Scoping Review

PURPOSE: Cancer deaths in low- and middle-income countries (LMICs) will nearly double by 2040. Available evidence-based interventions (EBIs) for cancer prevention and early detection can reduce cancer-related mortality, yet there is a lack of evidence on effectively scaling these EBIs in LMIC settings. METHODS: We conducted a scoping review to identify published literature from six databases between 2012 and 2022 that described efforts for scaling cancer prevention and early detection EBIs in LMICs. Included studies met one of two definitions of scale-up: (1) deliberate efforts to increase the impact of effective intervention to benefit more people or (2) an intervention shown to be efficacious on a small scale expanded under real-world conditions to reach a greater proportion of eligible population. Study characteristics, including EBIs, implementation strategies, and outcomes used, were summarized using frameworks from the field of implementation science. RESULTS: This search yielded 3,076 abstracts, with 24 studies eligible for inclusion. Included studies focused on a number of cancer sites including cervical (67%), breast (13%), breast and cervical (13%), liver (4%), and colon (4%). Commonly reported scale-up strategies included developing stakeholder inter-relationships, training and education, and changing infrastructure. Barriers to scale-up were reported at individual, health facility, and community levels. Few studies reported applying conceptual frameworks to guide strategy selection and evaluation. CONCLUSION: Although there were relatively few published reports, this scoping review offers insight into the approaches used by LMICs to scale up cancer EBIs, including common strategies and barriers. More importantly, it illustrates the urgent need to fill gaps in research to guide best practices for bringing the implementation of cancer EBIs to scale in LMICs

#ColorOurCollections Page 14

McGoverrn Historical Center joins other libraries, archives, and cultural heritage institutions sharing coloring pages created from our historical materials the first time. This annual celeberatiion is hosted by The New York Academy of Medicine. Images selected for this coloring book come from The Heart Bulletin. The McGovern Historical Center is home to the Medical Arts Publishing Foundation\u27s archives,k including an extensive collection of original artwork created for its publications.https://digitalcommons.library.tmc.edu/colorourcollections/1013/thumbnail.jp

#ColorOurCollections Page 7

McGoverrn Historical Center joins other libraries, archives, and cultural heritage institutions sharing coloring pages created from our historical materials the first time. This annual celeberatiion is hosted by The New York Academy of Medicine. Images selected for this coloring book come from The Heart Bulletin. The McGovern Historical Center is home to the Medical Arts Publishing Foundation\u27s archives,k including an extensive collection of original artwork created for its publications.https://digitalcommons.library.tmc.edu/colorourcollections/1006/thumbnail.jp

#ColorOurCollections Page 4

McGoverrn Historical Center joins other libraries, archives, and cultural heritage institutions sharing coloring pages created from our historical materials the first time. This annual celeberatiion is hosted by The New York Academy of Medicine. Images selected for this coloring book come from The Heart Bulletin. The McGovern Historical Center is home to the Medical Arts Publishing Foundation\u27s archives,k including an extensive collection of original artwork created for its publications.https://digitalcommons.library.tmc.edu/colorourcollections/1003/thumbnail.jp

#ColorOurCollections Page 10

McGoverrn Historical Center joins other libraries, archives, and cultural heritage institutions sharing coloring pages created from our historical materials the first time. This annual celeberatiion is hosted by The New York Academy of Medicine. Images selected for this coloring book come from The Heart Bulletin. The McGovern Historical Center is home to the Medical Arts Publishing Foundation\u27s archives,k including an extensive collection of original artwork created for its publications.https://digitalcommons.library.tmc.edu/colorourcollections/1009/thumbnail.jp

OXIDATIVE PHOSPHORYLATION IN MELANOMA BRAIN METASTASES: A REGULATOR OF THE TUMOR IMMUNE LANDSCAPE

Previously, we demonstrated via RNA-sequencing analysis of murine intracranial melanoma tumors that pharmacologic inhibition of oxidative phosphorylation (OXPHOS) results in increased expression of genes consistent with activated anti-tumor immune responses. The central hypothesis of this dissertation is that OXPHOS plays a critical role in the pathogenesis and immune regulation of melanoma brain metastases (MBMs). The functional significance of OXPHOS was assessed through genetic inhibition, involving knockout (KO) of key regulatory genes such as Ppargc1a (PGC1a) and Ndfus4 (NDUFS4), a component of mitochondrial complex I. PGC1a KO in an RCAS-TVA mouse model of autochthonous lung and brain tumors developing from primary melanomas significantly reduced the incidence of lung and brain tumor formation. Further characterization of OXPHOS at later stages of metastasis (circulation and growth in the metastatic niche) was evaluated using murine melanoma tumors. NDUFS4 KO resulted in decreased tumor burden in the lungs and brain, however there was no impact on incidence of tumor formation in this model, underscoring the critical role of OXPHOS specifically in early tumorigenesis and metastasis formation. Multiplex cytokine analysis of tissue culture supernatants of Wildtype (WT) and NDUFS4 KO murine melanoma cells identified increased secretion of anti-tumor cytokines after OXPHOS inhibition. Multiplex flow cytometry analysis of tumor-infiltrating lymphocytes from intracranial WT and NDUFS4 KO murine melanoma tumors further demonstrated that tumor OXPHOS results in less activated CD4+ T cells. Single cell RNAseq analysis of intracranial WT and NDUFS4 KO murine melanoma tumors indicated that OXPHOS inhibition results in increased levels of adaptive and innate immune cell subsets. Treatment of mice bearing concurrent subcutaneous and intracranial murine melanoma WT or NDUFS4 KO tumors with anti-PD1 and anti-LAG3 demonstrated the most significant increase in overall survival when immunotherapy treatment was combined with OXPHOS inhibition. Together, these findings highlight the significance of tumor OXPHOS in modulating metastatic melanoma progression and the MBM immune microenvironment. Melanoma OXPHOS at early stages of tumorigenesis impacts incidence of MBM and plays a crucial role in immune cell signaling and activation. Further, these studies highlight the potential of melanoma OXPHOS as a therapeutic target to enhance response to checkpoint immunotherapy in MBMs

MUTATIONAL LANDSCAPE OF NONCODING ULTRACONSERVED ELEMENTS IN HUMAN CANCERS: FUNCTIONAL RELEVANCE AND CLINICAL UTILITY

The mutational landscape of phylogenetically ultraconserved elements (UCEs), especially those in noncoding DNA regions (ncUCEs), and their functional and clinical relevance in cancers remain poorly characterized. In this thesis, we perform a systematic analysis of whole-genome sequencing (WGS) data from the International Cancer Genome Consortium (ICGC) and in-house targeted sequencing of 13,736 UCEs and demonstrate that ncUCE somatic alterations are pervasive. Using a genome-wide multiplexed CRISPR knockout screen in colorectal cancer (CRC) cell lines, we show that the loss of several mutated ncUCEs impacts cancer cell proliferation. In-depth functional studies in vitro and in vivo further reveal that UCE_11311 is an enhancer of the tumor suppressor ARID1B and UCE_2272 is a silencer of the oncogene RPS13. Moreover, several miRNAs located in ncUCEs are recurrently mutated in cancer, including MIR142, whose mutations affect the Drosha-mediated processing of the pre-miR-142 by preventing SRSF3 binding to the CNNC motif in the 3p flanking sequence, resulting in a downregulation of the mature sequences of miR-142. To explore potential clinical utility, we develop a targeted UCE sequencing assay and characterize well-annotated tumor cohorts of CRC and chronic lymphocytic leukemia (CLL) patients. The ncUCE mutation rate correlates well with clinical features of CRC, while CLL patients with the worst prognosis, Richter Transformation, harbor ncUCE mutations in regulators of key cancer genes for leukemogenesis, such as the B-cell lineage specific activator PAX5. These results provide the first supporting evidence that some ncUCEs play important regulatory roles through diverse mechanisms and that analyzing their mutational status in cancer may suggest new biomarkers and therapeutic strategie

Revealing chronic disease progression patterns using Gaussian process for stage inference.

OBJECTIVE: The early stages of chronic disease typically progress slowly, so symptoms are usually only noticed until the disease is advanced. Slow progression and heterogeneous manifestations make it challenging to model the transition from normal to disease status. As patient conditions are only observed at discrete timestamps with varying intervals, an incomplete understanding of disease progression and heterogeneity affects clinical practice and drug development. MATERIALS AND METHODS: We developed the Gaussian Process for Stage Inference (GPSI) approach to uncover chronic disease progression patterns and assess the dynamic contribution of clinical features. We tested the ability of the GPSI to reliably stratify synthetic and real-world data for osteoarthritis (OA) in the Osteoarthritis Initiative (OAI), bipolar disorder (BP) in the Adolescent Brain Cognitive Development Study (ABCD), and hepatocellular carcinoma (HCC) in the UTHealth and The Cancer Genome Atlas (TCGA). RESULTS: First, GPSI identified two subgroups of OA based on image features, where these subgroups corresponded to different genotypes, indicating the bone-remodeling and overweight-related pathways. Second, GPSI differentiated BP into two distinct developmental patterns and defined the contribution of specific brain region atrophy from early to advanced disease stages, demonstrating the ability of the GPSI to identify diagnostic subgroups. Third, HCC progression patterns were well reproduced in the two independent UTHealth and TCGA datasets. CONCLUSION: Our study demonstrated that an unsupervised approach can disentangle temporal and phenotypic heterogeneity and identify population subgroups with common patterns of disease progression. Based on the differences in these features across stages, physicians can better tailor treatment plans and medications to individual patients

The BMAL1/HIF2A heterodimer modulates circadian variations of myocardial injury

Acute myocardial infarction stands as a prominent cause of morbidity and mortality worldwid

Social Determinants of Health Predict Readmission Following Covid-19 Hospitalization: a Health information Exchange-Based Retrospective Cohort Study

INTRODUCTION: Since February 2020, over 104 million people in the United States have been diagnosed with SARS-CoV-2 infection, or COVID-19, with over 8.5 million reported in the state of Texas. This study analyzed social determinants of health as predictors for readmission among COVID-19 patients in Southeast Texas, United States. METHODS: A retrospective cohort study was conducted investigating demographic and clinical risk factors for 30, 60, and 90-day readmission outcomes among adult patients with a COVID-19-associated inpatient hospitalization encounter within a regional health information exchange between February 1, 2020, to December 1, 2022. RESULTS AND DISCUSSION: In this cohort of 91,007 adult patients with a COVID-19-associated hospitalization, over 21% were readmitted to the hospital within 90  days