High dimensional proteomic mapping of bone marrow immune characteristics in immune thrombocytopenia.

To investigate the role of co-stimulatory and co-inhibitory molecules on immune tolerance in immune thrombocytopenia (ITP), this study mapped the immune cell heterogeneity in the bone marrow of ITP at the single-cell level using Cytometry by Time of Flight (CyTOF). Thirty-six patients with ITP and nine healthy volunteers were enrolled in the study. As soluble immunomodulatory molecules, more sCD25 and sGalectin-9 were detected in ITP patients. On the cell surface, co-stimulatory molecules like ICOS and HVEM were observed to be upregulated in mainly central memory and effector T cells. In contrast, co-inhibitory molecules such as CTLA-4 were significantly reduced in Th1 and Th17 cell subsets. Taking a platelet count of 30×109 L-1 as the cutoff value, ITP patients with high and low platelet counts showed different T cell immune profiles. Antigen-presenting cells such as monocytes and B cells may regulate the activation of T cells through CTLA-4/CD86 and HVEM/BTLA interactions, respectively, and participate in the pathogenesis of ITP. In conclusion, the proteomic and soluble molecular profiles brought insight into the interaction and modulation of immune cells in the bone marrow of ITP. They may offer novel targets to develop personalized immunotherapies.

SET domain containing 2 promotes megakaryocyte polyploidization and platelet generation through methylation of α-tubulin.

BACKGROUND: Megakaryocytes (MKs) are polyploid cells responsible for producing ∼1011 platelets daily in humans. Unraveling the mechanisms regulating megakaryopoiesis holds the promise for the production of clinical-grade platelets from stem cells, overcoming significant current limitations in platelet transfusion medicine. Previous work identified that loss of the epigenetic regulator SET domain containing 2 (SETD2) was associated with an increased platelet count in mice. However, the role of SETD2 in megakaryopoiesis remains unknown. OBJECTIVES: Here, we examined how SETD2 regulated MK development and platelet production using complementary murine and human systems. METHODS: We manipulated the expression of SETD2 in multiple in vitro and ex vivo models to assess the ploidy of MKs and the function of platelets. RESULTS: The genetic ablation of Setd2 increased the number of high-ploidy bone marrow MKs. Peripheral platelet counts in Setd2 knockout mice were significantly increased ∼2-fold, and platelets exhibited normal size, morphology, and function. By knocking down and overexpressing SETD2 in ex vivo human cell systems, we demonstrated that SETD2 negatively regulated MK polyploidization by controlling methylation of α-tubulin, microtubule polymerization, and MK nuclear division. Small-molecule inactivation of SETD2 significantly increased the production of high-ploidy MKs and platelets from human-induced pluripotent stem cells and cord blood CD34+ cells. CONCLUSION: These findings identify a previously unrecognized role for SETD2 in regulating megakaryopoiesis and highlight the potential of targeting SETD2 to increase platelet production from human cells for transfusion practices.

Differentiation route determines the functional outputs of adult megakaryopoiesis.

Emerging evidence has revealed a direct differentiation route from hematopoietic stem cells to megakaryocytes (direct route), in addition to the classical differentiation route through a series of restricted hematopoietic progenitors (stepwise route). This raises the question of the importance of two alternative routes for megakaryopoiesis. Here, we developed fate-mapping systems to distinguish the two routes, comparing their quantitative and functional outputs. We found that megakaryocytes were produced through the two routes with comparable kinetics and quantity under homeostasis. Single-cell RNA sequencing of the fate-mapped megakaryocytes revealed that the direct and stepwise routes contributed to the niche-supporting and immune megakaryocytes, respectively, but contributed to the platelet-producing megakaryocytes together. Megakaryocytes derived from the two routes displayed different activities and were differentially regulated by chemotherapy and inflammation. Our work links differentiation route to the heterogeneity of megakaryocytes. Alternative differentiation routes result in variable combinations of functionally distinct megakaryocyte subpopulations poised for different physiological demands.

Bone mesenchymal stem cell-derived exosomal miR-26a-3p promotes autophagy to attenuate LPS-induced apoptosis and inflammation in pulmonary microvascular endothelial cells.

Acute lung injury (ALI) is a serious lung disease. The apoptosis and inflammation of pulmonary microvascular endothelial cells (PMVECs) are the primary reasons for ALI. This study aimed to explore the treatment effect and regulatory mechanism of bone mesenchymal stem cell-derived exosomes (BMSC-expos) on ALI. PMVECs were stimulated by Lipopolysaccharide (LPS) to imitate ALI environment. Cell viability was determined by CCK-8 assay. Cell apoptosis was evaluated by TUNEL and flow cytometry. ELISA was utilized for testing the contents of TNF-α, IL-1ß, IL-6, and IL-17. Western blot was applied for testing the levels of autophagy-related proteins LC3, p62, and Beclin-1. RNA interaction was determined by luciferase reporter assay. The ALI rat model was established by intratracheal injection of LPS. Evans blue staining was utilized for detecting pulmonary vascular permeability. Our results showed that LPS stimulation notably reduced cell viability, increased cell apoptosis rate, and enhanced the contents of inflammatory factors in PMVECs. However, BMSC-exo treatment significantly abolished the promoting effects of LPS on cell injury. In addition, we discovered that BMSC-exo treatment notably activated autophagy in LPS-induced PMVECs. Furthermore, BMSC-expos upregulated miR-26a-3p expression and downregulated PTEN in PMVECs. MiR-26a-3p was directly bound to PTEN. MiR-26a-3p overexpression reduced cell apoptosis, and inflammation and promoted autophagy by silencing PTEN. Animal experiments proved that miR-26a-3p overexpression effectively improved LPS-induced lung injury in rats. The results proved that BMSC-expos promotes autophagy to attenuate LPS-induced apoptosis and inflammation in pulmonary microvascular endothelial cells via miR-26a-3p/PTEN axis.

Causal relationship between the gut microbiota and insomnia: a two-sample Mendelian randomization study.

Background: Changes in the gut microbiota are closely related to insomnia, but the causal relationship between them is not yet clear. Objective: To clarify the relationship between the gut microbiota and insomnia and provide genetic evidence for them, we conducted a two-sample Mendelian randomization study. Methods: We used a Mendelian randomized two-way validation method to discuss the causal relationship. First, we downloaded the data of 462,341 participants relating to insomnia, and the data of 18,340 participants relating to the gut microbiota from a genome-wide association study (GWAS). Then, we used two regression models, inverse-variance weighted (IVW) and MR-Egger regression, to evaluate the relationship between exposure factors and outcomes. Finally, we took a reverse MR analysis to assess the possibility of reverse causality. Results: The combined results show 19 gut microbiotas to have a causal relationship with insomnia (odds ratio (OR): 1.03; 95% confidence interval (CI): 1.01, 1.05; p=0.000 for class. Negativicutes; OR: 1.03; 95% CI: 1.01, 1.05; p=0.000 for order.Selenomonadales; OR: 1.01; 95% CI: 1.00, 1.02; p=0.003 for genus.RikenellaceaeRC9gutgroup). The results were consistent with sensitivity analyses for these bacterial traits. In reverse MR analysis, we found no statistical difference between insomnia and these gut microbiotas. Conclusion: This study can provide a new direction for the causal relationship between the gut microbiota (class.Negativicutes, order.Selenomonadales, genus.Lactococcus) and insomnia and the treatment or prevention strategies of insomnia.

LRG1 predicts the prognosis and is associated with immune infiltration in thyroid cancer: a bioinformatics study.

Background: The diagnostic and prognostic value of the leucine-rich alpha-2-glycoprotein 1 (LRG1) gene in thyroid cancer remains unclear. Using the Cancer Genome Atlas (TCGA) database, we conducted a bioinformatics analysis to determine the role of LRG1 in thyroid cancer. Methods: Data from 512 patients with thyroid cancer and 59 normal individuals were collected from TCGA database. The Kruskal-Wallis test and logistic analysis were used to examine the relationship between LRG1 expression and clinicopathologic characteristics. Cox regression and Kaplan-Meier analysis were used to determine the predictive value of LRG1 on clinical outcomes. Single-sample gene set enrichment analysis (ssGSEA) was used to reveal associations between LRG1 expression and immune infiltration levels in thyroid cancer. Results: LRG1 was highly expressed in thyroid cancer (P < 0.001) and could effectively distinguish tumor tissue (area under the curve = 0.875) from normal tissue. Moreover, LRG1 was significantly correlated with pathological N stage (odds ratio (OR) = 2.411 (1.659-3.505), P < 0.001). Kaplan-Meier survival analysis revealed that patients with high LRG1 expression had better overall survival (hazard ratio (HR) = 0.30, P = 0.038). Cox regression analysis indicated that pathological M stage was a risk factor for progression-free interval (HR = 5.964 (2.010-17.694), P < 0.001). Using ssGSEA, we found that LRG1 expression was positively correlated with the number of T helper 1 cells (R = 0.435, P < 0.001), dendritic cells (R = 0.442, P < 0.001), and macrophages (R = 0.459, P < 0.001). Conclusion: LRG1 may be an important biomarker for predicting the prognosis of thyroid cancer and represent a suitable target for immunotherapy associated with immune infiltration.

The Association of Rural Residence With Surgery and Adjuvant Radiation in Medicare Beneficiaries With Rectal Cancer.

Purpose: Radiation therapy and surgery are fundamental site-directed therapies for nonmetastatic rectal cancer. To understand the relationship between rurality and access to specialized care, we characterized the association of rural patient residence with receipt of surgery and radiation therapy among Medicare beneficiaries with rectal cancer. Methods and Materials: We identified fee-for-service Medicare beneficiaries aged 65 years or older diagnosed with nonmetastatic rectal cancer from 2016 to 2018. Beneficiary place of residence was assigned to one of 3 geographic categories (metropolitan, micropolitan, or small town/rural) based on census tract and corresponding rural urban commuting area codes. Multivariable regression models were used to determine associations between levels of rurality and receipt of both radiation and proctectomy within 180 days of diagnosis. In addition, we explored associations between patient rurality and characteristics of surgery and radiation such as minimally invasive surgery (MIS) or intensity modulated radiation therapy (IMRT). Results: Among 13,454 Medicare beneficiaries with nonmetastatic rectal cancer, 3926 (29.2%) underwent proctectomy within 180 days of being diagnosed with rectal cancer, and 1792 (13.3%) received both radiation and proctectomy. Small town/rural residence was associated with an increased likelihood of receiving both radiation and proctectomy within 180 days of diagnosis (adjusted subhazard ratio, 1.15; 95% CI, 1.02-1.30). Furthermore, small town/rural radiation patients were significantly less likely to receive IMRT (adjusted odds ratio, 0.62; 95% CI, 0.48-0.80) or MIS (adjusted odds ratio, 0.80; 95% CI, 0.66-0.97) than metropolitan patients. Conclusions: Although small town/rural Medicare beneficiaries were overall more likely to receive both radiation and proctectomy for their rectal cancer, they were less likely to receive preoperative IMRT or MIS as part of their treatment regimen. Together, these findings clarify that among Medicare beneficiaries, there appeared to be a similar utilization of radiation resources and time to radiation treatment regardless of rural/urban status.

Experimental verification and identifying biomarkers related to insomnia.

Introduction: Insomnia is the most common form of sleep deprivation (SD) observed in clinics. Although there are differences between insomnia and SD, they have similar symptoms and the same animal model. Currently, there is a lack of microarray data on insomnia. Therefore, for now, we are going to apply the SD data to insomnia. Although many studies have explained the possible mechanisms associated with insomnia, no previous studies have considered the key genes associated with insomnia or the relationship between insomnia and immune cells. In this study, we analyzed the relationship between key genes and immune cells by identifying biomarkers for the diagnosis of insomnia. Next, we verified the efficacy of these biomarkers experimentally. Methods: First, we downloaded four microarrays (GSE11755, GSE12624, GSE28750, and GSE48080) from the Gene Expression Omnibus (GEO) database, which included data from 239 normal human blood samples and 365 blood specimens from patients with SD. Then, we analyzed two groups of differentially expressed genes (DEGs) and used Support Vector Machine Recursive Feature Elimination (SVM-RFE) analysis and the Least Absolute Shrinkage and Selection Operator (LASSO) regression model to investigate these key genes. Next, we used CIBERSORT to investigate the composition of 22 immune cell components of key genes in SD patients. Finally, the expression levels of key biomarkers in sleep-deprived patients were examined by quantitative real-time polymerase chain reaction (qRT-PCR). Results: A total of 50 DEGs were identified: six genes were significantly upregulated, and 44 genes were significantly downregulated. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that Salmonella infection, NOD-like receptor (NLR) signaling pathway, Kaposi sarcoma-associated herpesvirus infection, and Th17 cell differentiation were significant. Based on machine learning, we identified C2CD2L, SPINT2, APOL3, PKNOX1, and A2M as key genes for SD; these were confirmed by receiver operating characteristic (ROC) analysis. Immune cell infiltration analysis showed that C2CD2L, SPINT2, APOL3, PKNOX1, and A2M were related in different degrees to regulatory T cells (Tregs), follicular T helper cells, CD8 cells, and other immune cells. The qRT-PCR experiments confirmed that the expression levels of C2CD2L concurred with the results derived from machine learning, but PKNOX1 and APOL3 did not. Discussion: In summary, we identified a key gene (C2CD2L) that may facilitate the development of biomarkers for insomnia.

A bibliometric analysis of insomnia in adolescent.

Background: The negative effects of insomnia on adolescents' development, academic performance, and quality of life place a burden on families, schools, and society. As one of the most important research directions for insomnia, adolescent insomnia has significant research value, social value, and practical significance. Unfortunately, there is no bibliometric analysis in this field of study. This study aims to analyze published articles using bibliometrics, summarize the current research progress and hot topics in this field systematically and exhaustively, and predict the future direction and trend of research. Methods: For this study, the Web of Science Core Collection (WoSCC) database was searched between 2002 and 2022 for publications related to adolescent insomnia. The R-bibliometrix, VOSViewer, and CiteSpace software were utilized for bibliometric analysis. Results: This investigation included 2468 publications from 3102 institutions in 87 countries, led by China and the United States. This field of research has entered a period of rapid development since 2017. The journal with the most publications on adolescent insomnia is Sleep, which is also the most co-cited journal. American Journal of Psychology has the highest impact factor among the top 10 journals. These papers were written by 10605 authors; notably, Liu Xianchen emerged as the author with the highest frequency of publications, while Mary A. Carskadon was the most frequently co-cited author. Mental health and comorbid diseases were the main research directions in this field. "Depression," "anxiety," "mental health," "COVID-19," "stress," "quality of life," "heart rate variability," and "attention-deficit hyperactivity disorder" were hot spots and trends in this field at the current moment. Conclusion: The research on adolescent insomnia has social value, research value, and research potential; its development is accelerating, and an increasing number of researchers are focusing on it. This study summarized and analyzed the development process, hot spots, and trends of adolescent insomnia research using bibliometric analysis, which identified the current hot topics in this field and predicted the development trend for the future.

A life-threatening bleeding prediction model for immune thrombocytopenia based on personalized machine learning: a nationwide prospective cohort study.

Rare but critical bleeding events in primary immune thrombocytopenia (ITP) present life-threatening complications in patients with ITP, which severely affect their prognosis, quality of life, and treatment decisions. Although several studies have investigated the risk factors related to critical bleeding in ITP, large sample size data, consistent definitions, large-scale multicenter findings, and prediction models for critical bleeding events in patients with ITP are unavailable. For the first time, in this study, we applied the newly proposed critical ITP bleeding criteria by the International Society on Thrombosis and Hemostasis for large sample size data and developed the first machine learning (ML)-based online application for predict critical ITP bleeding. In this research, we developed and externally tested an ML-based model for determining the risk of critical bleeding events in patients with ITP using large multicenter data across China. Retrospective data from 8 medical centers across the country were obtained for model development and prospectively tested in 39 medical centers across the country over a year. This system exhibited good predictive capabilities for training, validation, and test datasets. This convenient web-based tool based on a novel algorithm can rapidly identify the bleeding risk profile of patients with ITP and facilitate clinical decision-making and reduce the occurrence of adversities.

Single-cell transcriptomics reveals multiple chemoresistant properties in leukemic stem and progenitor cells in pediatric AML.

BACKGROUND: Cancer patients can achieve dramatic responses to chemotherapy yet retain resistant tumor cells, which ultimately results in relapse. Although xenograft model studies have identified several cellular and molecular features that are associated with chemoresistance in acute myeloid leukemia (AML), to what extent AML patients exhibit these properties remains largely unknown. RESULTS: We apply single-cell RNA sequencing to paired pre- and post-chemotherapy whole bone marrow samples obtained from 13 pediatric AML patients who had achieved disease remission, and distinguish AML clusters from normal cells based on their unique transcriptomic profiles. Approximately 50% of leukemic stem and progenitor populations actively express leukemia stem cell (LSC) and oxidative phosphorylation (OXPHOS) signatures, respectively. These clusters have a higher chance of tolerating therapy and exhibit an enhanced metabolic program in response to treatment. Interestingly, the transmembrane receptor CD69 is highly expressed in chemoresistant hematopoietic stem cell (HSC)-like populations (named the CD69+ HSC-like subpopulation). Furthermore, overexpression of CD69 results in suppression of the mTOR signaling pathway and promotion of cell quiescence and adhesion in vitro. Finally, the presence of CD69+ HSC-like cells is associated with unfavorable genetic mutations, the persistence of residual tumor cells in chemotherapy, and poor outcomes in independent pediatric and adult public AML cohorts. CONCLUSIONS: Our analysis reveals leukemia stem cell and OXPHOS as two major chemoresistant features in human AML patients. CD69 may serve as a potential biomarker in defining a subpopulation of chemoresistant leukemia stem cells. These findings have important implications for targeting residual chemo-surviving AML cells.

Identification of biomarkers related to sepsis diagnosis based on bioinformatics and machine learning and experimental verification.

Sepsis is a systemic inflammatory response syndrome caused by bacteria and other pathogenic microorganisms. Every year, approximately 31.5 million patients are diagnosed with sepsis, and approximately 5.3 million patients succumb to the disease. In this study, we identified biomarkers for diagnosing sepsis analyzed the relationships between genes and Immune cells that were differentially expressed in specimens from patients with sepsis compared to normal controls. Finally, We verified its effectiveness through animal experiments. Specifically, we analyzed datasets from four microarrays(GSE11755、GSE12624、GSE28750、GSE48080) that included 106 blood specimens from patients with sepsis and 69 normal human blood samples. SVM-RFE analysis and LASSO regression model were carried out to screen possible markers. The composition of 22 immune cell components in patients with sepsis were also determined using CIBERSORT. The expression level of the biomarkers in Sepsis was examined by the use of qRT-PCR and Western Blot (WB). We identified 50 differentially expressed genes between the cohorts, including 2 significantly upregulated and 48 significantly downregulated genes, and KEGG pathway analysis identified Salmonella infection, human T cell leukemia virus 1 infection, Epstein-Barr virus infection, hepatitis B, lysosome and other pathways that were significantly enriched in blood from patients with sepsis. Ultimately, we identified COMMD9, CSF3R, and NUB1 as genes that could potentially be used as biomarkers to predict sepsis, which we confirmed by ROC analysis. Further, we identified a correlation between the expression of these three genes and immune infiltrate composition. Immune cell infiltration analysis revealed that COMMD9 was correlated with T cells regulatory (Tregs), T cells follicular helper, T cells CD8, et al. CSF3R was correlated with T cells regulatory (Tregs), T cells follicular helper, T cells CD8, et al. NUB1 was correlated with T cells regulatory (Tregs), T cells gamma delta, T cells follicular helper, et al. Taken together, our findings identify potential new diagnostic markers for sepsis that shed light on novel mechanisms of disease pathogenesis and, therefore, may offer opportunities for therapeutic intervention.

Fructus gardeniae ameliorates anxiety-like behaviors induced by sleep deprivation via regulating hippocampal metabolomics and gut microbiota.

Fructus gardeniae (FG) is a traditional Chinese medicine and health food for thousands of years of application throughout Chinese history and is still widely used in clinical Chinese medicine. FG has a beneficial impact on anxiety, depression, insomnia, and psychiatric disorders; however, its mechanism of action requires further investigation. This study aimed to investigate the effects and mechanisms of FG on sleep deprivation (SD)-induced anxiety-like behavior in rats. A model of SD-induced anxiety-like behavior in rats was established by intraperitoneal injection of p-chlorophenylalanine (PCPA). This was accompanied by neuroinflammation and metabolic abnormalities in the hippocampus and disturbance of intestinal microbiota. However reduced SD-induced anxiety-like behavior and decreased levels of pro-inflammatory cytokines including TNF-α and IL-1ß were observed in the hippocampus of rats after 7 days of FG intervention. In addition, metabolomic analysis demonstrated that FG was able to modulate levels of phosphatidylserine 18, Phosphatidylinositol 18, sn-glycero-3-phosphocholine, deoxyguanylic acid, xylose, betaine and other metabolites in the hippocampus. The main metabolic pathways of hippocampal metabolites after FG intervention involve carbon metabolism, glycolysis/gluconeogenesis, pentose phosphate, and glycerophospholipid metabolism. 16S rRNA sequencing illustrated that FG ameliorated the dysbiosis of gut microbiota in anxious rats, mainly increased the abundance of Muribaculaceae and Lactobacillus, and decreased the abundance of Lachnospiraceae_NK4A136_group. In addition, the correlation analysis demonstrated that there was a close relationship between hippocampal metabolites and intestinal microbiota. In conclusion, FG improved the anxiety behavior and inhibited of neuroinflammation in sleep-deprived rats, and the mechanism may be related to the FG regulation of hippocampal metabolites and intestinal microflora composition.

Association of rurality, socioeconomic status, and race with pancreatic cancer surgical treatment and survival.

BACKGROUND: Pancreatectomy is a necessary component of curative intent therapy for pancreatic cancer, and patients living in nonmetropolitan areas may face barriers to accessing timely surgical care. We evaluated the intersecting associations of rurality, socioeconomic status (SES), and race on treatment and outcomes of Medicare beneficiaries with pancreatic cancer. METHODS: We conducted a retrospective cohort study, using fee-for-service Medicare claims of beneficiaries with incident pancreatic cancer (2016-2018). We categorized beneficiary place of residence as metropolitan, micropolitan, or rural. Measures of SES were Medicare-Medicaid dual eligibility and the Area Deprivation Index. Primary study outcomes were receipt of pancreatectomy and 1-year mortality. Exposure-outcome associations were assessed with competing risks and logistic regression. RESULTS: We identified 45 915 beneficiaries with pancreatic cancer, including 78.4%, 10.9%, and 10.7% residing in metropolitan, micropolitan, and rural areas, respectively. In analyses adjusted for age, sex, comorbidity, and metastasis, residents of micropolitan and rural areas were less likely to undergo pancreatectomy (adjusted subdistribution hazard ratio = 0.88 for rural, 95% confidence interval [CI] = 0.81 to 0.95) and had higher 1-year mortality (adjusted odds ratio = 1.25 for rural, 95% CI = 1.17 to 1.33) compared with metropolitan residents. Adjustment for measures of SES attenuated the association of nonmetropolitan residence with mortality, and there was no statistically significant association of rurality with pancreatectomy after adjustment. Black beneficiaries had lower likelihood of pancreatectomy than White, non-Hispanic beneficiaries (subdistribution hazard ratio = 0.80, 95% CI = 0.72 to 0.89, adjusted for SES). One-year mortality in metropolitan areas was higher for Black beneficiaries (adjusted odds ratio = 1.15, 95% CI = 1.05 to 1.26). CONCLUSIONS: Rurality, socioeconomic deprivation, and race have complex interrelationships and are associated with disparities in pancreatic cancer treatment and outcomes.

Benzene metabolite hydroquinone enhances self-renewal and proliferation of preleukemic cells through the Ppar-γ pathway.

Benzene is a known hematotoxic and leukemogenic chemical. Exposure to benzene cause inhibition of hematopoietic cells. However, the mechanism of how the hematopoietic cells inhibited by benzene undergo malignant proliferation is unknown. The cells carrying leukemia-associated fusion genes are present in healthy individuals and predispose the carriers to the development of leukemia. To identify the effects of benzene on hematopoietic cells, preleukemic bone marrow (PBM) cells derived from transgenic mice carrying the Mll-Af9 fusion gene were treated with benzene metabolite hydroquinone in serial replating of colony-forming unit (CFU) assay. RNA sequencing was further employed to identify the potential key genes that contributed to benzene-initiated self-renewal and proliferation. We found that hydroquinone induced a significant increase in colony formation in PBM cells. Peroxisome proliferator-activated receptor gamma (Ppar-γ) pathway, which plays a critical role in carcinogenesis in multiple tumors, was significantly activated after hydroquinone treatment. Notably, the increased numbers of the CFUs and total PBM cells induced by hydroquinone were significantly reduced by a specific Ppar-γ inhibitor (GW9662). These findings indicated that hydroquinone can enhance self-renewal and proliferation of preleukemic cells by activating the Ppar-γ pathway. Our results provide insight into the missing link between premalignant status and development of benzene-induced leukemia, which can be intervened and prevented.

Association of Life Expectancy With Surveillance Colonoscopy Findings and Follow-up Recommendations in Older Adults.

Importance: Surveillance after prior colon polyps is the most frequent indication for colonoscopy in older adults. However, to our knowledge, the current use of surveillance colonoscopy, clinical outcomes, and follow-up recommendations in association with life expectancy, factoring in both age and comorbidities, have not been studied. Objective: To evaluate the association of estimated life expectancy with surveillance colonoscopy findings and follow-up recommendations among older adults. Design, Setting, and Participants: This registry-based cohort study used data from the New Hampshire Colonoscopy Registry (NHCR) linked with Medicare claims data and included adults in the NHCR who were older than 65 years, underwent colonoscopy for surveillance after prior polyps between April 1, 2009, and December 31, 2018, and had full Medicare Parts A and B coverage and no Medicare managed care plan enrollment in the year prior to colonoscopy. Data were analyzed from December 2019 to March 2021. Exposures: Life expectancy (<5 years, 5 to <10 years, or ≥10 years), estimated using a validated prediction model. Main Outcomes and Measures: The main outcomes were clinical findings of colon polyps or colorectal cancer (CRC) and recommendations for future colonoscopy. Results: Among 9831 adults included in the study, the mean (SD) age was 73.2 (5.0) years and 5285 (53.8%) were male. A total of 5649 patients (57.5%) had an estimated life expectancy of 10 or more years, 3443 (35.0%) of 5 to less than 10 years, and 739 (7.5%) of less than 5 years. Overall, 791 patients (8.0%) had advanced polyps (768 [7.8%]) or CRC (23 [0.2%]). Among the 5281 patients with available recommendations (53.7%), 4588 (86.9%) were recommended to return for future colonoscopy. Those with longer life expectancy or more advanced clinical findings were more likely to be told to return. For example, among patients with no polyps or only small hyperplastic polyps, 132 of 227 (58.1%) with life expectancy of less than 5 years were told to return for future surveillance colonoscopy vs 940 of 1257 (74.8%) with life expectancy of 5 to less than 10 years and 2163 of 2272 (95.2%) with life expectancy of 10 years or more (P < .001). Conclusions and Relevance: In this cohort study, the likelihood of finding advanced polyps and CRC on surveillance colonoscopy was low regardless of life expectancy. Despite this observation, 58.1% of older adults with less than 5 years' life expectancy were recommended to return for future surveillance colonoscopy. These data may help refine decision-making about pursuing or stopping surveillance colonoscopy in older adults with a history of polyps.

Rural Disparities in Lung Cancer-directed Surgery: A Medicare Cohort Study.

OBJECTIVE: The primary objective of this study was to determine the influence of rural residence on access to and outcomes of lung cancer-directed surgery for Medicare beneficiaries. SUMMARY OF BACKGROUND DATA: Lung cancer is the leading cause of cancerrelated death in the United States and rural patients have 20% higher mortality. Drivers of rural disparities along the continuum of lung cancercare delivery are poorly understood. METHODS: Medicare claims (2015-2018) were used to identify 126,352 older adults with an incident diagnosis of nonmetastatic lung cancer. Rural Urban Commuting Area codes were used to define metropolitan, micropolitan, small town, and rural site of residence. Multivariable logistic regression models evaluated influence of place of residence on 1) receipt of cancer-directed surgery, 2) time from diagnosis to surgery, and 3) postoperative outcomes. RESULTS: Metropolitan beneficiaries had higher rate of cancer-directed surgery (22.1%) than micropolitan (18.7%), small town (17.5%), and isolated rural (17.8%) (P < 0.001). Compared to patients from metropolitan areas, there were longer times from diagnosis to surgery for patients living in micropolitan, small, and rural communities. Multivariable models found nonmetropolitan residence to be associated with lower odds of receiving cancer-directed surgery and MIS. Nonmetropolitan residence was associated with higher odds of having postoperative emergency department visits. CONCLUSIONS: Residence in nonmetropolitan areas is associated with lower probability of cancer-directed surgery, increased time to surgery, decreased use of MIS, and increased postoperative ED visits. Attention to timely access to surgery and coordination of postoperative care for nonmetropolitan patients could improve care delivery.

Association of rurality with utilization of palliative care and hospice among Medicare beneficiaries who died from pancreatic cancer: A cohort study.

BACKGROUND: Pancreatic cancer has a 5-year survival of just 10%. Services such as palliative care and hospice are thus crucial in this population, yet their geographic accessibility and utilization remains unknown. AIM: We studied the association between rurality of patient residence and the use of palliative care and hospice. DESIGN, SETTING, AND PARTICIPANTS: Cohort study of continuously enrolled fee-for-service Medicare beneficiaries aged ≥65 diagnosed with incident pancreatic cancer between 04/01/2016-08/31/2018 and who died by 12/31/2018. RESULTS: In this decedent cohort of 31,460 patients, 77% lived in metropolitan areas, 11% in micropolitan areas, 7% in small towns, and 5% in rural areas. Patient demographics were largely similar across rurality; however, the proportion of White, non-Hispanic patients and social deprivation was highest in rural areas and lowest in metropolitan areas. Overall, 33% of patients used any palliative care and 77% received hospice services. After risk adjustment, there were no statistically significant differences in the use of palliative care for patients residing in metropolitan versus micropolitan, small town, or rural areas. Patients in small town (OR = 0.77, 95% CI: 0.69-0.86) and rural areas (OR = 0.75, 95% CI: 0.66-0.85) had lower adjusted odds of receiving hospice care compared to patients in metropolitan areas. CONCLUSIONS: The use of palliative care services captured in Medicare was low, representing either underutilization or failure to accurately measure the extent of services used. While the overall level of hospice enrollment was high, patients in rural communities had relatively lower use of hospice services compared to those in metropolitan areas.

Clinical and genetic characterization of Epstein-Barr virus-associated T/NK-cell lymphoproliferative diseases.

BACKGROUND: Epstein-Barr virus (EBV)-associated T-/natural killer (T/NK)-cell lymphoproliferative diseases clinically take on various forms, ranging from an indolent course to an aggressive condition. OBJECTIVE: Clinically, failure to establish precise diagnosis and provide proper treatment makes it difficult to help patients. We sought to better understand the underlying pathogenesis and to identify genetic prognostic factors to achieve better treatment efficacy. METHODS: In this study, 119 cases of EBV-associated lymphoproliferative diseases, including EBV-associated hemophagocytic lymphohistiocytosis (n = 46) and chronic active EBV disease of T/NK cell type (n = 73), were retrospectively examined. RESULTS: Adults aged >20 years at onset accounted for 71.4% of our cohort. About 54.6% patients with unfavorable overall survival developed hemophagocytic lymphohistiocytosis and had higher plasma EBV load. Allogenic hematopoietic stem-cell transplantation was the sole independent favorable factor. We systematically screened germline and somatic aberrations by whole-exome and targeted sequencing. Among 372 antiviral immunity genes, germline variants of 8 genes were significantly enriched. From a panel of 24 driver genes, somatic mutations were frequently identified in dominant EBV-infected T/NK cells. Patients carrying any germline/somatic aberrations in epigenetic modifiers and RIG-I-like receptor (RLR) pathway had worse overall survival than those without 2 type aberrations. Importantly, patients with IFIH1 and/or DDX3X aberrations in the RLR pathway had higher plasma and NK-cell EBV load. Knockdown of DDX3X in NKYS cells downregulated RLR signaling activities and elevated the expression of EBV-encoded oncogenes such as LMP1 and EBNA1. CONCLUSION: Genetic defects were prevalent in adult EBV-associated hemophagocytic lymphohistiocytosis patients and patients with chronic active EBV disease of T/NK cell type; these defects were associated with unfavorable prognosis. These findings can help clinicians work out more precise staging of the condition and provide new insights into these EBV-associated diseases.

The roles of serum vitamin D and tobacco smoke exposure in insomnia: a cross-sectional study of adults in the United States.

Aim: Tobacco smoke exposure and vitamin D (VD) status were both associated with insomnia. However, the combined effect of smoking and VD on insomnia has not been discussed. This study aimed to explore the role of VD in the association between tobacco smoke exposure and insomnia. Methods: Data on adults were extracted from the National Health and Nutrition Examination Surveys (NHANES) database in 2005-2008 for this cross-sectional study. Weighted univariate and multivariate logistic regression analyses were used to explore the associations between serum cotinine, serum VD, and insomnia. A surface diagram was drawn to reflect the effect of VD on the association between serum cotinine and insomnia. In addition, the potential regulating effect of VD in subgroups of smoking status was also performed. The evaluation index was odds ratios (ORs) with 95% confidence intervals (CIs). Results: Among the eligible participants, 1,766 had insomnia. After adjusting for covariates, we found that elevated serum cotinine levels were associated with higher odds of insomnia [OR = 1.55, 95% CI: (1.22, 1.97)]. However, the relationship between serum VD level and insomnia was not significant (P = 0.553). Higher serum cotinine levels were also associated with higher odds of insomnia [OR = 1.52, 95% CI: (1.17, 1.98)] when serum VD level was <75 nmol/L; however, this relationship became non-significant when serum VD concentration was elevated (P = 0.088). Additionally, the potential regulating effect of VD was also found in adults who were not smoking. Conclusion: VD may play a potential regulative role in the association between tobacco smoke exposure and insomnia. Further studies are needed to clarify the causal relationships between VD, tobacco smoke exposure, and insomnia.