CUX1 regulates human hematopoietic stem cell chromatin accessibility via the BAF complex.

CUX1 is a homeodomain-containing transcription factor that is essential for the development and differentiation of multiple tissues. CUX1 is recurrently mutated or deleted in cancer, particularly in myeloid malignancies. However, the mechanism by which CUX1 regulates gene expression and differentiation remains poorly understood, creating a barrier to understanding the tumor-suppressive functions of CUX1. Here, we demonstrate that CUX1 directs the BAF chromatin remodeling complex to DNA to increase chromatin accessibility in hematopoietic cells. CUX1 preferentially regulates lineage-specific enhancers, and CUX1 target genes are predictive of cell fate in vivo. These data indicate that CUX1 regulates hematopoietic lineage commitment and homeostasis via pioneer factor activity, and CUX1 deficiency disrupts these processes in stem and progenitor cells, facilitating transformation.

Survival in Patients With De Novo Metastatic Prostate Cancer.

This cross-sectional study investigates trends in overall survival among patients with newly diagnosed metastatic prostate cancer in 2 national registries in the United States.

The impact of marital status on tumor aggressiveness, treatment, and screening among black and white men diagnosed with prostate cancer.

PURPOSE: To examine the association of marital status with prostate cancer outcomes in a racially-diverse cohort. METHODS: The study population consisted of men (1010 Black; 1070 White) with incident prostate cancer from the baseline North Carolina-Louisiana Prostate Cancer (PCaP) cohort. Marital status at time of diagnosis and screening history were determined by self-report. The binary measure of marital status was defined as married (including living as married) vs. not married (never married, divorced/separated, or widowed). High-aggressive tumors were defined using a composite measure of PSA, Gleason Score, and stage. Definitive treatment was defined as receipt of radical prostatectomy or radiation. Multivariable logistic regression was used to examine the association of marital status with (1) high-aggressive tumors, (2) receipt of definitive treatment, and (3) screening history among Black and White men with prostate cancer. RESULTS: Black men were less likely to be married than White men (68.1% vs. 83.6%). Not being married (vs. married) was associated with increased odds of high-aggressive tumors in the overall study population (adjusted Odds Ratio (aOR): 1.56; 95% Confidence Interval (CI): 1.20-2.02) and both Black and White men in race-stratified analyses. Unmarried men were less likely to receive definitive treatment in the overall study population (aOR: 0.68; 95% CI: 0.54-0.85). In race-stratified analyses, unmarried Black men were less likely to receive definitive treatment. Both unmarried Black and White men were less likely to have a history of prostate cancer screening than married men. CONCLUSION: Lower rates of marriage among Black men might signal decreased support for treatment decision-making, symptom management, and caregiver support which could potentially contribute to prostate cancer disparities.

Shark fish oil prevents scopolamine-induced memory impairment in an experimental model.

Fish oil has been known for its antioxidant, cardioprotective, anti-inflammatory, and neuroprotective characteristics due to the presence of polyunsaturated fatty acids (PUFAs) that are essential for optimal brain function and mental health. The present study investigated the effect of Carcharhinus Bleekeri (Shark Fish) oil on learning and memory functions in scopolamine-induced amnesia in rats. Locomotor and memory-enhancing activity in scopolamine-induced amnesic rats was investigated by assessing the open field and passive avoidance paradigm. Forty male Albino mice were divided into 4 equal groups (n = 10) as bellow: 1 - control (received 0.9% saline), 2 - SCOP (received scopolamine 2 mg/kg for 21 days), 3 - SCOP + SFO (received scopolamine and fish oil 5 mg/kg/ day for 21 days), 4 - SCOP + Donepezil groups (received 3 mg/kg/day for 21 days). SFO produced significant (P < 0.01) locomotor and memory-enhancing activities in open-field and passive avoidance paradigm models. Additionally, SFO restored the Acetylcholine (ACh) concentration in the hippocampus (p < 0.05) and remarkably prevented the degradation of monoamines. Histology of brain tissue showed marked cellular distortion in the scopolamine-treated group, while the SFO treatment restored distortion in the brain's hippocampus region. These results suggest that the SFO significantly ameliorates scopolamine-induced spatial memory impairment by attenuating the ACh and monoamine concentrations in the rat's hippocampus.

Local Treatment and Treatment-Related Adverse Effects Among Patients With Advanced Prostate Cancer.

Importance: Recent data suggest that local treatment with radical prostatectomy or radiation may improve survival outcomes in men with advanced prostate cancer. However, evidence is lacking on treatment-related adverse effects among men with advanced prostate cancer. Objective: To assess the association of local treatment on treatment-related adverse effects among men diagnosed with advanced prostate cancer. Design, Setting, and Participants: This cohort study assessed men diagnosed with advanced prostate cancer (defined as T4, N1, and/or M1 prostate cancer) between January 1, 1999, and December 31, 2013, with follow-up through December 31, 2021, who were treated at Veterans Health Administration medical centers. Exposure: Local treatment with radical prostatectomy or radiation. Main Outcomes and Measures: Main outcomes were treatment-related adverse effects, including constitutional, gastrointestinal, pain, sexual function, and urinary function conditions, at 3 intervals after initial treatment (≤1 year, >1 to ≤2 years, and >2 to ≤5 years) after initial treatment. Results: This cohort study consisted of 5502 men (mean [SD] age, 68.7 [10.3] years) diagnosed with advanced prostate cancer. Of the cohort, 1705 men (31.0%) received local treatment. There was a high prevalence of adverse conditions in men receiving both local and nonlocal treatment, and these adverse conditions persisted for more than 2 years to 5 years or less after initial treatment. A total of 916 men (75.2%) with initial local treatment and 897 men (67.1%) with initial nonlocal treatment reported the presence of at least 1 adverse condition for more than 2 years to 5 years or less after initial treatment. In the first year, local treatment (vs nonlocal) was associated with adverse gastrointestinal (multivariable-adjusted odds ratio [AOR], 4.08; 95% CI, 3.06-5.45), pain (AOR, 1.57; 95% CI, 1.35-1.83), sexual (AOR, 2.96; 95% CI, 2.42-3.62), and urinary (AOR, 2.25; 95% CI, 1.90-2.66) conditions. Local treatment (without secondary treatment) remained significantly associated with adverse gastrointestinal (AOR, 2.39; 95% CI, 1.52-3.77), sexual (AOR, 3.36; 95% CI, 2.56-4.41), and urinary (AOR, 1.39; 95% CI, 1.09-1.78) conditions at more than 2 years to 5 years or less after treatment. Conclusions and Relevance: In this cohort study of men with advanced prostate cancer, local treatment was associated with persistent treatment-related adverse effects across multiple domains. These results suggest that patients and clinicians should consider the adverse effects of local treatment when making treatment decisions in the setting of advanced prostate cancer.

Lifetime Body Weight Trajectories and Risk of Renal Cell Cancer: A Large U.S. Prospective Cohort Study.

BACKGROUND: Body mass index (BMI) is a known risk factor for renal cell cancer (RCC), but data are limited as to the effect of lifetime exposure to excess body weight. METHODS: Using the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (N = 138,614, 527 incident RCCs), we identified several anthropometric measures to capture the lifetime BMI patterns: (i) BMI at specific ages; (ii) adulthood BMI trajectories; (iii) cumulative exposure to overweight/obesity denoted as weighted years of living overweight/obese (WYO); and (iv) weight change during each age span. We conducted multivariable Cox model to quantify the association between each anthropometric metric and incident RCC. RESULTS: A higher BMI at ages 20 and 50 and at baseline was associated with a greater hazard of RCC. Compared with individuals who retained normal BMI throughout adulthood, we observed an increased hazard of RCC for BMI trajectory of progressing from normal BMI to overweight [HR, 1.49; 95% confidence interval (CI), 1.19-1.87], from normal BMI to obesity (HR, 2.22; 95% CI, 1.70-2.90), and from overweight to obesity (HR, 2.78; 95% CI, 1.81-4.27). Compared with individuals who were never overweight (WYO = 0), elevated HRs were observed among individuals who experienced low (HR, 1.31; 95% CI, 0.99-1.74), medium (HR, 1.57; 95% CI, 1.20-2.05), and high (HR, 2.10; 95% CI, 1.62-2.72) WYO tertile. Weight gain of ≥10 kg was associated with increased RCC incidence for each age span. CONCLUSIONS: Across the lifespan, being overweight/obese, weight gain, and higher cumulative exposure to excess weight were all associated with increased RCC risk. IMPACT: It is important to avoid weight gain and assess BMI from a life-course perspective to reduce RCC risk.

A Case Report on the Atypical Symptoms of the Synovitis, Acne, Pustulosis, Hyperostosis, and Osteitis (SAPHO) Syndrome: Could COVID-19 Be a Cause?

Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome, a rare disorder with a spectrum of manifestations and overlapping osseous and cutaneous symptoms, shares pathogenesis with various autoimmune diseases. SARS-CoV-2 has been previously linked to various autoimmune diseases like Guillain-Barré syndrome (GBS), a multi-inflammatory syndrome in children (MIS-C), or rheumatoid arthritis, but there is no existing work showing a link between SAPHO syndrome and COVID-19 yet. Here, we present a case of a middle-aged Asian male who presented with minimum swelling of his right second toe, 21 days post-COVID. After a series of investigations, namely, MRI scans, 99mTc-methylene diphosphonate three-phase bone scan, and bone biopsy, followed by a positive culture and sensitivity test of the same toe, a trial of vancomycin was given to the patient to treat bacterial osteomyelitis. This resulted in no improvement, pointing toward a misdiagnosis. A conclusion of sterile osteomyelitis of his right second and third metatarsal heads and phalanges due to SAPHO syndrome, as a possible complication of SARS-CoV-2 infection, was made. There are a number of classification systems for diagnosing this syndrome, one of which was modified by Kahn and was used in our case. Atypical presentations of rare disorders like SAPHO syndrome and their relation to SARS-CoV-2 infection are still to be fully discovered and investigated. Their prevention, timely diagnosis, and management may help in alleviating the discomfort and fear associated with the unknown for the patients.

Post-diagnostic metformin and statin use and risk of biochemical recurrence in Veterans diagnosed with prostate cancer.

OBJECTIVE: To evaluate the impact of post-diagnostic metformin or statin use and duration on risk of biochemical recurrence in a racially-diverse cohort of Veterans. METHODS: The population consisted of men diagnosed with prostate cancer in the Veterans Health Administration and treated with either radical prostatectomy or radiation (Full cohort n = 65,759, Black men n = 18,817, White men n = 46,631, Other = 311). The association between post-diagnostic (1) metformin and (2) statin use with biochemical recurrence was assessed using multivariable, time-varying Cox Proportional Hazard Models for the overall cohort and by race. In a secondary analysis, metformin and statin duration were evaluated. RESULTS: Post-diagnostic metformin use was not associated with biochemical recurrence (multivariable-adjusted hazard ratio [aHR]: 1.01; 95% confidence interval [CI]: 0.94, 1.09), with similar results observed for both Black and White men. However, duration of metformin use was associated with a reduced risk of biochemical recurrence in the cohort overall (HR: 0.94; 95% CI: 0.92, 0.95) as well as both Black and White men. By contrast, statin use was associated with a reduced risk of biochemical recurrence (HR: 0.83; 95% CI: 0.79, 0.88) in the overall cohort as well as both White and Black men. Duration of statin use was also inversely associated with biochemical recurrence in all groups. CONCLUSION: Post-diagnostic metformin and statin use have the potential to prevent biochemical recurrence in men diagnosed with prostate cancer.

The Role of BMI in Allostatic Load and Risk of Cancer Death.

INTRODUCTION: Obesity and proinflammatory conditions are associated with increased risks of cancer. The associations of baseline allostatic load with cancer mortality and whether this association is modified by body mass index (BMI) were examined. METHODS: A retrospective analysis was performed in March-September 2022 using National Health and Nutrition Examination Survey years 1988 through 2010 linked with the National Death Index through December 31, 2019. Fine and Gray Cox proportional hazard models were stratified by BMI status to estimate subdistribution hazard ratios of cancer death between high and low allostatic load status (adjusted for age, sociodemographics, and health factors). RESULTS: In fully adjusted models, high allostatic load was associated with a 23% increased risk of cancer death (adjusted subdistribution hazard ratio=1.23; 95% CI=1.06, 1.43) among all participants, a 3% increased risk of cancer death (adjusted subdistribution hazard ratio=1.03; 95% CI=0.78, 1.34) among underweight/healthy weight adults, a 31% increased risk of cancer death (adjusted subdistribution hazard ratio=1.31; 95% CI=1.02, 1.67) among overweight adults, and a 39% increased risk of death (adjusted subdistribution hazard ratio=1.39; 95% CI=1.04, 1.88) among obese adults, when compared to those with low allostatic load. CONCLUSIONS: The risk of cancer death is highest among those with high allostatic load and obese BMI, but this effect was attenuated among those with high allostatic load and underweight/healthy or overweight BMI.

Oncogenic RAS promotes leukemic transformation of CUX1-deficient cells.

-7/del(7q) is prevalent across subtypes of myeloid neoplasms. CUX1, located on 7q22, encodes a homeodomain-containing transcription factor, and, like -7/del(7q), CUX1 inactivating mutations independently carry a poor prognosis. As with loss of 7q, CUX1 mutations often occur early in disease pathogenesis. We reported that CUX1 deficiency causes myelodysplastic syndrome in mice but was insufficient to drive acute myeloid leukemia (AML). Given the known association between -7/del(7q) and RAS pathway mutations, we mined cancer genome databases and explicitly linked CUX1 mutations with oncogenic RAS mutations. To determine if activated RAS and CUX1 deficiency promote leukemogenesis, we generated mice bearing NrasG12D and CUX1-knockdown which developed AML, not seen in mice with either mutation alone. Oncogenic RAS imparts increased self-renewal on CUX1-deficient hematopoietic stem/progenitor cells (HSPCs). Reciprocally, CUX1 knockdown amplifies RAS signaling through reduction of negative regulators of RAS/PI3K signaling. Double mutant HSPCs were responsive to PIK3 or MEK inhibition. Similarly, low expression of CUX1 in primary AML samples correlates with sensitivity to the same inhibitors, suggesting a potential therapy for malignancies with CUX1 inactivation. This work demonstrates an unexpected convergence of an oncogene and tumor suppressor gene on the same pathway.

Definitive treatment and risk of death among men diagnosed with metastatic prostate cancer at the Veterans Health Administration.

PURPOSE: To assess the potential survival benefit associated with receipt of definitive treatment (radical prostatectomy or radiation), compared to non-definitive treatment (hormonal therapy or chemotherapy) among men with metastatic prostate cancer. METHODS: A cohort of men diagnosed with metastatic (T4/M1/N1 or T4/M1) prostate cancer from 1999 to 2013 in the Veterans Health Administration were identified and followed to December 28, 2014. All-cause and prostate cancer-specific mortality were evaluated at 10 years for the T4/M1/N1 cohort and 8 years for the T4/M1/ cohort. The association of definitive treatment (radical prostatectomy or radiation), compared to non-definitive (hormonal therapy or chemotherapy) with both all-cause and prostate cancer-specific mortality was assessed using inverse probability of treatment weighted (IPTW) multivariable survival analyses. RESULTS: The cohort included 2919 with T4/M1/N1 disease and 1479 men with T4/M1 disease. Receipt of definitive treatment was associated with a reduced risk of 10-year all-cause (Hazard Ratio (HR): 0.61; 95% Confidence Interval (CI): 0.57-0.65) and prostate cancer-specific mortality (HR: 0.50; 95% CI: 0.46-0.55) among men diagnosed with T4/M1/N1 met-astatic disease. Definitive treatment was similarly associated with a reduced risk of all-cause (HR: 0.84; 95% CI: 0.77-0.91) and prostate cancer-specific (HR: 0.81; 95% CI: 0.73-0.90) mortality among men diagnosed with T4/M1 only metastatic disease. CONCLUSIONS: Definitive treatment may improve survival in men diagnosed with metastatic prostate cancer.

Prostate cancer aggressiveness and financial toxicity among prostate cancer patients.

INTRODUCTION: Financial toxicity (FT) is a growing concern among cancer survivors that adversely affects the quality of life and survival. Individuals diagnosed with aggressive cancers are often at a greater risk of experiencing FT. The objectives of this study were to estimate FT among prostate cancer (PCa) survivors after 10-15 years of diagnosis, assess the relationship between PCa aggressiveness at diagnosis and FT, and examine whether current cancer treatment status mediates the relationship between PCa aggressiveness and FT. METHODS: PCa patients enrolled in the North Carolina-Louisiana Prostate Cancer Project (PCaP) were recontacted for long-term follow-up. The prevalence of FT in the PCaP cohort was estimated. FT was estimated using the COmprehensive Score for Financial Toxicity, a validated measure of FT. The direct effect of PCa aggressiveness and an indirect effect through current cancer treatment on FT was examined using causal mediation analysis. RESULTS: More than one-third of PCa patients reported experiencing FT. PCa aggressiveness was significantly independently associated with high FT; high aggressive PCa at diagnosis had more than twice the risk of experiencing FT than those with low or intermediate aggressive PCa (adjusted odds ratio [aOR] = 2.13, 95% CI = 1.14-3.96). The proportion of the effect of PCa aggressiveness on FT, mediated by treatment status, was 10%, however, the adjusted odds ratio did not indicate significant evidence of mediation by treatment status (aOR = 1.05, 95% CI = 0.95-1.20). CONCLUSIONS: Aggressive PCa was associated with high FT. Future studies should collect more information about the characteristics of men with high FT and identify additional risk factors of FT.

Using health insurance claims data to assess long-term disease progression in a prostate cancer cohort.

BACKGROUND: Long-term population-based cohort studies of men diagnosed with prostate cancer are limited. However, adverse outcomes can occur many years after treatment. Herein, we aim to assess the utility of using claims data to identify prostate cancer progression 10-15 years after diagnosis. METHODS: The study population was derived from the North Carolina-Louisiana Prostate Cancer Project (PCaP). PCaP-North Carolina (NC) included 1031 men diagnosed with prostate cancer from 2004 to 2009. An initial follow-up with a survey and manual medical record abstraction occurred from 2008 to 2011 (Follow-up 1). Herein, we extended this follow-up with linkage to healthcare claims data from North Carolina (2011-2017) and a second, supplementary 10-year follow-up survey (2018-2020) (Follow-up 2). Vital statistics data also were utilized. Long-term oncological progression was determined using these data sources in combination with expert clinical input. RESULTS: Among the 1031 baseline PCaP-NC participants, 652 were linked to medical claims. Forty-two percent of the men had insurance coverage for the entire 72 months of follow-up. In addition, 275 baseline participants completed the supplementary 10-year follow-up survey. Using all sources of follow-up data, we identified a progression event in 259 of 1031 (25%) men with more than 10 years of follow-up data after diagnosis. CONCLUSIONS: Understanding long-term clinical outcomes is essential for improving the lives of prostate cancer survivors. However, access and utility of long-term clinical outcomes with claims alone remain a challenge due to individualized agreements required with each insurer for data access, lack of detailed clinical information, and gaps in insurance coverage. We were able to utilize claims data to determine long-term progression due to several unique advantages that included the availability of detailed baseline clinical characteristics and treatments, detailed manually abstracted clinical data at 5 years of follow-up, vital statistics data, and a supplementary 10-year follow-up survey.

Racial and Ethnic Differences in Rural-Urban Trends in 5-Year Survival of Patients With Lung, Prostate, Breast, and Colorectal Cancers: 1975-2011 Surveillance, Epidemiology, and End Results (SEER).

Importance: Considering reported rural-urban cancer incidence and mortality trends, rural-urban cancer survival trends are important for providing a comprehensive description of cancer burden. Furthermore, little is known about rural-urban differences in survival trends by racial and ethnic groups. Objective: To examine national rural-urban trends in 5-year cancer-specific survival probabilities for lung, prostate, breast, and colorectal cancers in a diverse sample of racial and ethnic groups. Design, Setting, and Participants: This cross-sectional study used an epidemiologic assessment with 1975 to 2016 Surveillance, Epidemiology, and End Results (SEER) data to analyze patients diagnosed no later than 2011. Patients were classified as living in rural and urban counties based on the 2013 Rural-Urban Continuum Codes. Main Outcomes and Measures: The 5-year cancer-specific survival probability of urban and rural patients for each cancer type was estimated by fitting Cox proportional hazard regression models accounting for race, ethnicity, tumor characteristics, and other sociodemographic characteristics. A generalized linear regression model was used to estimate the mean estimated probability of survival for each stratum. Joinpoint regression analysis estimated periods of significant change in survival. Results: In this study, data from 3 659 417 patients with cancer (median [IQR] age, 67 [58-76]; 1 918 609 [52.4%] male; 237 815 [6.5%] Hispanic patients; 396 790 [10.8%] Black patients; 2 825 037 [77.2%] White patients) were analyzed, including 888 338 patients with lung cancer (24.3%), 750 704 patients with colorectal cancer (20.5%), 987 826 patients with breast cancer (27.0%) breast, and 1 023 549 patients with prostate cancer (28.0%). There were 430 353 rural patients (11.8%). Overall, there was an equal representation of rural and urban men. Rural patients were likely to be non-Hispanic White individuals, have more cases of distant tumors, and be older. Rural and non-Hispanic Black patients for all cancer types often had shorter survival. From 1975 to 2016, the 5-year lung cancer survival rate was shorter for non-Hispanic Black rural patients in 1975 at 48%, while increasing to 57% for both non-Hispanic Black urban and rural patients in 2011, but still the shortest among all cancer types. In 1975, the longest survival rate was observed in urban Asian and Pacific Islander patients with breast cancer at 86%, and in 2011, the longest survival rate was observed in urban non-Hispanic White patients with XX cancer at 92%. Conclusions and Relevance: Even after accounting for sociodemographic and tumor characteristics, these findings suggest that non-Hispanic Black patients with cancer are particularly vulnerable to cancer burden, and resources are urgently needed to reverse decades-old survival trends.

Genomic studies controvert the existence of the CUX1 p75 isoform.

CUX1, encoding a homeodomain-containing transcription factor, is recurrently deleted or mutated in multiple tumor types. In myeloid neoplasms, CUX1 deletion or mutation carries a poor prognosis. We have previously established that CUX1 functions as a tumor suppressor in hematopoietic cells across multiple organisms. Others, however, have described oncogenic functions of CUX1 in solid tumors, often attributed to truncated CUX1 isoforms, p75 and p110, generated by an alternative transcriptional start site or post-translational cleavage, respectively. Given the clinical relevance, it is imperative to clarify these discrepant activities. Herein, we sought to determine the CUX1 isoforms expressed in hematopoietic cells and find that they express the full-length p200 isoform. Through the course of this analysis, we found no evidence of the p75 alternative transcript in any cell type examined. Using an array of orthogonal approaches, including biochemistry, proteomics, CRISPR/Cas9 genomic editing, and analysis of functional genomics datasets across a spectrum of normal and malignant tissue types, we found no data to support the existence of the CUX1 p75 isoform as previously described. Based on these results, prior studies of p75 require reevaluation, including the interpretation of oncogenic roles attributed to CUX1.

Improved survival with post-diagnostic metformin and statin use in a racially diverse cohort of US Veterans with advanced prostate cancer.

OBJECTIVE: To examine the association between post-diagnostic metformin or statin use with all-cause and prostate cancer (PCa)-specific mortality in men with advanced prostate cancer. METHODS: Our study consisted of 4572 men (Black = 1352, White = 3192, Other Race = 28) diagnosed with advanced cancer (T4/M1/N1) between 1999 and 2013 in the Veteran Health Administration. The association between post-diagnostic (1) metformin and (2) statin use with all-cause and PCa-specific mortality was examined using multivariable, time-varying Cox Proportional Hazard Models. In a secondary analysis, models were stratified by race. RESULTS: Post-diagnostic metformin use was associated with a reduced risk of all-cause (Hazard Ratio (HR) 0.84, 95% Confidence Interval (CI): 0.73, 0.96) and PCa-specific death (HR: 0.76, 95% CI: 0.63, 0.91). In stratified analyses, the inverse association between post-diagnostic metformin use and both all-cause PCa-specific mortality was limited to White men. Post-diagnostic statin use was associated with a reduced risk of all-cause (HR: 0.75, 95% CI: 0.68, 0.83) and PCa-specific mortality (HR: 0.72; 95% CI: 0.64, 0.81). In stratified analyses, similar inverse associations were observed for post-diagnostic statin use and all-cause and PCa-specific mortality in both Black and White men. CONCLUSION: Post diagnostic metformin and statin use may prevent progression to lethal prostate cancer in men with advanced prostate cancer.

Loss of a 7q gene, CUX1, disrupts epigenetically driven DNA repair and drives therapy-related myeloid neoplasms.

Therapy-related myeloid neoplasms (t-MNs) are high-risk late effects with poorly understood pathogenesis in cancer survivors. It has been postulated that, in some cases, hematopoietic stem and progenitor cells (HSPCs) harboring mutations are selected for by cytotoxic exposures and transform. Here, we evaluate this model in the context of deficiency of CUX1, a transcription factor encoded on chromosome 7q and deleted in half of t-MN cases. We report that CUX1 has a critical early role in the DNA repair process in HSPCs. Mechanistically, CUX1 recruits the histone methyltransferase EHMT2 to DNA breaks to promote downstream H3K9 and H3K27 methylation, phosphorylated ATM retention, subsequent γH2AX focus formation and propagation, and, ultimately, 53BP1 recruitment. Despite significant unrepaired DNA damage sustained in CUX1-deficient murine HSPCs after cytotoxic exposures, they continue to proliferate and expand, mimicking clonal hematopoiesis in patients postchemotherapy. As a consequence, preexisting CUX1 deficiency predisposes mice to highly penetrant and rapidly fatal therapy-related erythroleukemias. These findings establish the importance of epigenetic regulation of HSPC DNA repair and position CUX1 as a gatekeeper in myeloid transformation.

Impact of the COVID-19 pandemic on trauma activations at a pediatric level 1 trauma center in New York.

BACKGROUND: The disruptive effects on society and medical systems due to the coronavirus disease 2019 (COVID-19) pandemic are substantial and far-reaching. The effect of the pandemic on the quantity and quality of pediatric traumas is unclear and has a direct bearing on how scarce hospital resources should be allocated in a pandemic situation. METHODS: A retrospective review of the trauma registry was performed for trauma activations in the years 2018 through 2020 during the months of March, April, and May. Demographic and injury specific datapoints were compared across calendar years. RESULTS: There were 111, 100, and 52 trauma activations during the study interval in 2018, 2019, and 2020, respectively. There were fewer highest severity level activations in 2020 compared to 2018 and 2019 (1 vs 5 and 9; p < 0.01). The median Injury Severity Score was 5 in 2020 compared to 4 in both 2018 and 2019 (p < 0.01). More patients went directly to the operating room in 2020 compared to prior years (21.2% vs 8% and 6.1%; p < 0.01). There were fewer discharges from the emergency department (ED) (12.1% vs 36.6% and 32.7%). No increase in the number of child abuse reports and investigations was noted. There was no difference in the proportion of blunt versus penetrating trauma between years (p = 0.57). No pedestrians were struck by automobiles in 2020 compared to 12 and 14 in 2018 and 2019. However, there were a greater proportion of injuries from falls during 2020 compared to prior years. CONCLUSIONS: There were fewer trauma activations during the peak of the COVID pandemic compared to prior years. Due to the decrease in trauma volume during the peak of the pandemic, hospital resources could potentially be reallocated toward areas of greater need. LEVEL OF EVIDENCE: IV; Retrospective cohort study using historical controls.

Comparative antioxidant and analgesic effect of sesame oil, fish oil and their combination in experimental animal model.

Natural oils are rich in polyunsaturated fatty acids (PUFs) like omega 3, omega 6 and other nutrients that boost physical and mental health. Traditionally these oils have been used to treat joint pain associated with several inflammatory conditions. In this study, we investigated the antioxidant and analgesic properties of the sesame oil (SO), fish oil (FO) and combination of these two oils (SO+FO). Different concentrations of the SO, FO and SO+FO combination 0.02-4mg/ml were used for assessing the free radical scavenging activity by DPPH method and the IC50 value was calculated. Acetic acid-induced abdominal writhing test, tail immersion and hot plate models were used to determined analgesic effect. Results showed that both oils were well tolerated as no signs of toxicity or death were noticed during the observational study period. SO+FO combination showed the best antioxidant properties as shown by DPPH assay. Similarly in analgesic models, SO and FO significantly reduced the number of abdominal contractions (p<0.05) however, SO+FO (1:1) exhibited highly significant results (p<0.001) in writhing reflex test. Furthermore, SO and FO both increased the reaction time on a hot plate as well as in tail flick test (p<0.05) whereas, SO+FO significantly increased reaction time (p<0.001) in hot plate and in tail flick test as compared to SO and FO single treatments. Conclusively, our results suggest that the combination of both oils (SO+FO) exhibited significant antioxidant and analgesic potential that it could be considered as one of the active combinations for relieving pain in adjunctive treatment for joint pain associated with rheumatoid arthritis.