Napabucasin is an NAD(P)H:quinone oxidoreductase 1 (NQO1)bioactivatable small molecule hypothesized to affect multiple oncogenic pathways. In a prespecified, retrospective analysis of the napabucasin phase III CO.23 study, overall survival was longer for napabucasin versus placebo in patients expressing phosphorylated STAT3 (pSTAT3) in tumor cells and cells of the tumor microenvironment (TME). We hypothesized that a connection may exist between NQO1 expression in cancer cells and pSTAT3 in tumor cells and the TME. In 3D spheroid cocultures of cancer cells and cancer-associated fibroblasts, the antitumor activity of napabucasin was NQO1 dependent. The levels of cytokines such as IL6, CXCL10, and GM-CSF were higher in NQO1-positive versus NQO1deleted cocultures. These differentially secreted cytokines promoted STAT3 phosphorylation in tumor cells and the TME. NQO1-expressing, napabucasin-sensitive tumor cells can modify tumor cells and the TME to promote STAT3 phosphorylation, suggesting that pSTAT3 may be used to identify a subpopulation of patients who would likely respond to napabucasin. Implications: pSTAT3 is a potential biomarker for patient response to the anticancer drug napabucasin.

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The normal function of mitochondria in the hepatic parenchyma can be disrupted by ischemia/reperfusion (I/R) damage during liver transplantation. The pathology of these insults involves various cellular and molecular steps of events that have been extensively researched over decades but are yet to provide complete answers. This review discusses the brief mechanism of the pathophysiology following ischemia/reperfusion injury (IRI) and various targeting strategies that could result in improved graft function.The traditional treatment for end-stage liver disease i.e., liver transplantation, has been complicated by I/R damage. The poor graft function or primary non-function found after liver transplantation may be due to mitochondrial dysfunction following IRI. As a result, determining the sequence of incidents that cause human hepatic mitochondrial dysfunction is crucial; it might contribute to further improvements in the outcome of liver transplantation. Early discovery of novel prognostic factors involved in IRI could serve as a primary endpoint for predicting the outcome of liver grafts as well as promoting the early implementation of novel IRI-prevention strategies. In this review, recent developments in the study of mitochondrial dysfunction and I/R damage are discussed, specifically those concerning liver transplantation. Furthermore, we also explore different pharmacological therapeutic methods that may be used and their connections to mitochondrion-related processes and goals.Although significant progress has been made in our understanding of IRI and mitochondrial dysfunction, further research is needed to elucidate the cellular and molecular pathways underlying these processes to help identify biomarkers that can aid donor organ evaluation.

Anemia is a common complication of cancer. Treatment of anemia in cancer is crucial as anemia adversely affects the quality of life, therapeutic outcomes, and overall survival. Erythropoiesis stimulating agents (ESAs) are valuable drugs for treating cancer-related anemia. Cardiovascular adverse effects are a significant concern with ESA therapy, and there is wide variability in therapeutic goals and characteristics of patients who undergo treatment with ESAs. As a result, a careful analysis of the currently available data on the efficacy and safety of these drugs is necessary. This data analysis will aid in the rational use of ESAs for the treatment of anemia in cancer. The objective of this systematic review is to elucidate the pathogenesis of anemia in cancer, assess the effectiveness of ESAs in treating anemia in cancer, and the overall risk of cardiovascular adverse effects associated with the use of ESAs and their impact on prognosis. We searched literature from online databases - PubMed, PubMed Central, MEDLINE, Cochrane Library, and clinical trials register ( clinicaltrials.gov ) to identify prospective phase II and phase III randomized controlled trials (RCTs). We chose RCTs that directly compared patients with cancer who were treated with ESAs to those who were not treated with ESAs. January 2008 was taken as the lower date limit and May 2021 as the upper date limit. Only English language literature and human studies were included. The quality appraisal was completed using the Cochrane risk bias assessment tool, and data from a total of 10,738 patients with cancer in 17 RCTs were identified and included for systematic review. Our review concludes that ESAs effectively reduce the necessity for blood transfusions and increase mean hemoglobin levels in anemic cancer patients. ESA therapy is associated with cardiovascular adverse effects, including venous thromboembolism, thrombophlebitis, hypertension, ischemic heart disease, cardiac failure, arrhythmia, arterial thromboembolism, and cardiac arrest. Aggressive ESA dosing to achieve higher hemoglobin levels and preexisting uncontrolled hypertension increases these cardiovascular side effects. Venous thromboembolism is the most significant adverse effect attributed to ESA therapy. However, there is no major change in overall survival with ESA therapy, and administration of ESAs can be carried out in anemic cancer patients with careful assessment of thromboembolism risk factors, risk-benefit ratio, and monitoring of hemoglobin levels.

Traumatic brain injury of any severity can result in post-concussion syndrome (PCS). Although the postconcussive symptoms are complex, there is an emerging scientific consensus regarding the initiation of the treatment for these symptoms to improve quality of life and prevent long-term effects. The objective of this systematic review is to assess the comprehensive interventions used for the PCS and it aims to appraise if these interventions could prevent the development of depression as a complication. This research has used randomized controlled trials (RCTs) that evaluate the treatment of PCS and its effect on long-term complications like depression. We searched PubMed/MEDLINE, PubMed Central, Cochrane Central Register of Controlled Trials (CENTRAL), and EMBASE from January 1, 2016 to May 31, 2021 for our literature search. A quality check was conducted on the identified studies using the Cochrane risk of bias quality assessment tool (modified Cochrane RoB 2). In total, we included 11 RCTs and used Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines for the reporting of this systematic review. Most of the studies reinforced early initiation of the treatment by providing education to the patients and conducting their risk assessment. Strong evidence for the multidisciplinary treatment consisting of cognitive-behavioral therapy, psychoeducation, and physiotherapy is emphasized by some studies. More studies with a longer follow-up period are required to assess the effectiveness of intervention more accurately on depression. Regardless, this study will discuss guidelines and provide direction to physicians. It will help in developing future guidelines by addressing the clinical gaps in the implementation of these guidelines.

Clinical and basic research addressing the long-term outcomes of the increasing and high-risk population of pediatric cancer survivors requires large cohorts with high quality information. We have assembled the largest group of pediatric cancer survivors to date with comprehensive clinical characterization and germline whole-genome sequencing (WGS), and made these data available through the Survivorship Portal on St. Jude Cloud (https://survivorship.stjude.cloud). The Portal contains data from 7302 survivors from two large studies, including 4402 from the St. Jude Lifetime Cohort Study (SJLIFE) with clinically-assessed outcome phenotypes, and 2900 from the Childhood Cancer Survivor Study (CCSS) with self-reported outcome phenotypes. High-quality germline variants and genotype calls from WGS were generated and curated by an in-house pipeline with corrected indel alleles and read counts. Germline variants of individual survivors are linked with standardized phenotypes described by >300 variables, spanning cancer-related data including diagnosis, length of follow-up, treatment (cumulative doses of chemotherapy, region-specific radiation therapy doses, surgery), demographic characteristics, selected health behaviors, and long-term outcomes (severity-graded chronic health conditions including second cancers). In addition, clinically-relevant genetic variables including ancestry admixture, HLA alleles, leukocyte telomere length, and blood type have been computed from WGS. Both phenotypic and genetic variables are represented by the Dictionary Browser that allows to quickly identify variables of interest, view summary graphics, cross-tabulate variables by default or user-defined categories and test for association between categories. Using GenomePaint on the Portal, investigators can navigate to a locus of interest and explore the presence and frequencies of variants in the cohort, filter variants with multiple criteria including LD r2 values, and identify DNA binding motif change for non-coding variants. Combining GenomePaint with Dictionary Browser, the real-time association analysis allows to identify trait-associated variants at a locus, through the definition of traits, covariates, and inclusion/exclusion criteria using the Dictionary Browser. Future implementation includes supporting copy number and structural variations, characterization of pharmacogenetic diplotypes, gene-level rare variant analysis, polygenic scores, time-to-event survival analysis, and data download and session management enabled by user login. We envision this cohort with high quality phenotypic and genetic information, together with an enabling software platform co-developed with multidisciplinary principal investigators, will accelerate the discovery in both survivorship research and human genetics in general. Citation Format: Xin Zhou, Nickhill Bhakta, Jian Wang, Edgar Sioson, Jaimin Patel, Kyla Shelton, Zhaoming Wang, Shaohua Lei, Alexander M. Gout, Carmen L. Wilson, Wendy Leisenring, Smita Bhatia, Yutaka Yasui, Melissa M. Hudson, Gregory T. Armstrong, Leslie L. Robison, Jinghui Zhang. The St. Jude Survivorship Portal links whole-genome genetic data with clinical therapy and outcome phenotypes for 7302 pediatric cancer survivors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1198.

Background : Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality throughout the world. It is characterized by slow emptying of the lung during forced expiration and measured by FEV1/FVC ratio. Objectives: To assess the difference in the patient's level of symptoms (MMRC Grading), psychological assessment (PHQ9),objective parameters (6 Minute Walk Test, Spirometry) after giving modied pulmonary rehabilitation. Material and Methods:An analytical study was carried out on 150 participants attending our hospital who were enrolled after their informed and written consent, Demographic data, history, physical examination, and psychological assessment were conducted of all the patients. The total duration of the study is of 18 months. Out of that one patient is followed for 12 weeks during which during the rst 6 weeks of the study patients were given pharmacotherapy as per Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines and for the next 6 weeks patients were given pharmacotherapy with pulmonary rehabilitation. Results: Out of 150 patients , the majority of the patients presented with MMRC grade 2 or 3 at the initiation of study and at the end of the study, their grades were improved. The value of spirometry testing, 6 Minute walk test, and the PHQ9(Psychological assessment) score was also improved at the end of the study as compared to the initiation of the study. Conclusion: Pulmonary rehabilitation plays a sentinel role in management of COPD and it increases the survival of COPD patients

Survivors of childhood cancer are at risk for developing various adverse health conditions as adults that are attributable to the cancer and treatments they were exposed to as children. Cancer survivorship research relies on large-scale, longitudinal studies that generate a wide range of demographic, clinical, and genetic data on cancer survivors at multiple time points. To maximize the utility of these comprehensive datasets, we must be able to store and share these datasets in a web-based environment that can be accessed by the broader survivorship research community. Furthermore, this environment should be integrated with analytical tools for performing statistical analyses on the stored data without needing to download the data and import it into third-party analytical software. To address this need, we have created the St. Jude Survivorship Portal (https://survivorship.stjude.cloud > Clinical Data Browser), a web-based data portal for exploring, sharing, and analyzing data from survivors of pediatric cancer. The portal hosts data from two large cohorts of pediatric cancer survivors: the St. Jude Lifetime Cohort Study and the Childhood Cancer Survivor Study. The data stored on the portal consists of demographic data, clinical data, including cancer diagnosis, cancer treatment, clinical outcomes, and patient-reported data, and genetic data, including whole-genome-sequencing-derived genotypes and published polygenic risk scores computed for >500 traits. This data is organized hierarchically in a data dictionary that can be easily explored by the user. Charts and plots of variables can be quickly created, customized, and stratified with other variables, all within the portal environment. Statistical analyses, including cumulative incidence analysis and regression analysis, may also be performed within the portal. In cumulative incidence analysis, users can analyze the incidence of a variety of CTCAE-graded adverse events (e.g., cardiovascular dysfunction, neurological disorders, subsequent neoplasms) in survivors and can also compare them across different survivor populations defined by other variables. In regression analysis, users have the option to perform either a linear, logistic, or cox regression analysis and may use any of the demographic, clinical, or genetic variables on the portal as outcome or explanatory variables in the analysis. In this way, users can assess any risk factor associations within a survivor cohort and generate predictive models for outcomes of interest. Lastly, we also provide the user with the option to download the data on the portal for use in any future analyses. The St. Jude Survivorship Portal provides a comprehensive, powerful, and easy-to-use interface for sharing and analyzing childhood cancer survivorship data that will serve as a valuable research tool for the broader survivorship research community. Citation Format: Gavriel Matt, Edgar Sioson, Jaimin Patel, Jian Wang, Robin Paul, Colleen Reilly, Congyu Lu, Kyla Shelton, Qi Liu, Weiyu Qiu, Cindy Im, Zhaoming Wang, Carmen L. Wilson, Nickhill Bhakta, Kirsten Ness, Gregory T. Armstrong, Melissa M. Hudson, Leslie L. Robison, Jinghui Zhang, Yutaka Yasui, Xin Zhou. St. Jude Survivorship Portal: A data portal for storing, analyzing, and sharing large and complex cancer survivorship datasets. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4513.