TET1 and TDG Suppress Inflammatory Response in Intestinal Tumorigenesis: Implications for Colorectal Tumors With the CpG Island Methylator Phenotype.

BACKGROUND & AIMS: Aberrant DNA methylation is frequent in colorectal cancer (CRC), but underlying mechanisms and pathologic consequences are poorly understood. METHODS: We disrupted active DNA demethylation genes Tet1 and/or Tdg from ApcMin mice and characterized the methylome and transcriptome of colonic adenomas. Data were compared to human colonic adenocarcinomas (COAD) in The Cancer Genome Atlas. RESULTS: There were increased numbers of small intestinal adenomas in ApcMin mice expressing the TdgN151A allele, whereas Tet1-deficient and Tet1/TdgN151A-double heterozygous ApcMin colonic adenomas were larger with features of erosion and invasion. We detected reduction in global DNA hypomethylation in colonic adenomas from Tet1- and Tdg-mutant ApcMin mice and hypermethylation of CpG islands in Tet1-mutant ApcMin adenomas. Up-regulation of inflammatory, immune, and interferon response genes was present in Tet1- and Tdg-mutant colonic adenomas compared to control ApcMin adenomas. This up-regulation was also seen in murine colonic organoids and human CRC lines infected with lentiviruses expressing TET1 or TDG short hairpin RNA. A 127-gene inflammatory signature separated colonic adenocarcinomas into 4 groups, closely aligned with their microsatellite or chromosomal instability and characterized by different levels of DNA methylation and DNMT1 expression that anticorrelated with TET1 expression. Tumors with the CpG island methylator phenotype (CIMP) had concerted high DNMT1/low TET1 expression. TET1 or TDG knockdown in CRC lines enhanced killing by natural killer cells. CONCLUSIONS: Our findings reveal a novel epigenetic regulation, linked to the type of genomic instability, by which TET1/TDG-mediated DNA demethylation decreases methylation levels and inflammatory/interferon/immune responses. CIMP in CRC is triggered by an imbalance of methylating activities over demethylating activities. These mice represent a model of CIMP CRC.

Effect of an online educational module incorporating real-time feedback on accuracy of polyp sizing in trainees: a randomized controlled trial.

BACKGROUND: Although polyp size dictates surveillance intervals, endoscopists often estimate polyp size inaccurately. We hypothesized that an intervention providing didactic instruction and real-time feedback could significantly improve polyp size classification. METHODS: We conducted a multicenter randomized controlled trial to evaluate the impact of different components of an online educational module on polyp sizing. Participants were randomized to control (no video, no feedback), video only, feedback only, or video + feedback. The primary outcome was accuracy of polyp size classification into clinically relevant categories (diminutive [1-5mm], small [6-9mm], large [≥10mm]). Secondary outcomes included accuracy of exact polyp size (inmm), learning curves, and directionality of inaccuracy (over- vs. underestimation). RESULTS: 36 trainees from five training programs provided 1360 polyp size assessments. The feedback only (80.1%, P=0.01) and video + feedback (78.9%, P=0.02) groups had higher accuracy of polyp size classification compared with controls (71.6%). There was no significant difference in accuracy between the video only group (74.4%) and controls (P=0.42). Groups receiving feedback had higher accuracy of exact polyp size (inmm) and higher peak learning curves. Polyps were more likely to be overestimated than underestimated, and 29.3% of size inaccuracies impacted recommended surveillance intervals. CONCLUSIONS: Our online educational module significantly improved polyp size classification. Real-time feedback appeared to be a critical component in improving accuracy. This scalable and no-cost educational module could significantly decrease under- and overutilization of colonoscopy, improving patient outcomes while increasing colonoscopy access.

Spectrum of Advanced Colorectal Neoplasia and Anticipated Yield of Average-Risk Screening in Veterans Under Age 50.

The incidence of early onset colorectal cancer, or colorectal cancer (CRC) diagnosed before age 50, is increasing.1 In response, multiple societal guidelines in the United States now recommend initiating CRC screening at age 45 in average-risk individuals (ie, those without high-risk clinical characteristics, such as bleeding, or iron deficiency anemia), inflammatory bowel disease, or family history of colorectal neoplasia.2 The Veterans Health Administration (VHA) is the largest integrated health system in the United States and is contending with how best to expand CRC screening access to this younger population in the setting of limited colonoscopy resources. Understanding the rate and anatomic location of colorectal neoplasia in Veterans younger than age 50 can inform the expected yield of different screening modalities. Prior work has shown that individuals undergoing colonoscopy for low-risk diagnostic indications have equivalent risk of colorectal neoplasia as those undergoing average-risk screening.3 This study and a recent meta-analysis4 reported that 3.6% (95% confidence interval, 1.9%-6.7%) to 3.7% (95% confidence interval, 3.0%-4.7%) of average-risk individuals age 45-49 have advanced colorectal neoplasia (ACN), defined as an advanced polyp or carcinoma; however, data specific to the VHA population are lacking.

Associations of Iron Sucrose and Intradialytic Blood Pressure.

RATIONALE & OBJECTIVE: Intradialytic hypotension and intradialytic hypertension are associated with morbidity and mortality in hemodialysis (HD). Many factors can contribute to intra-HD blood pressure (BP) changes, such as drugs with vasoactive properties that can destabilize an already tenuous BP. Intravenous iron sucrose is commonly administered to correct iron deficiency; however, its reported associations with altered hemodynamics have not been consistent. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 950 outpatients receiving maintenance HD. EXPOSURE: Iron sucrose administered during HD. OUTCOME: Intradialytic hypotension, intradialytic hypertension, systolic blood pressure parameters. ANALYTICAL APPROACH: Unadjusted and adjusted Poisson and linear repeated measures regression models. RESULTS: The mean age of patients included in the study was 53±22 years, 43% were female, and 38% were Black. Mean pre-HD SBP was 152±26 (SD) mm Hg. At baseline, the patients who received higher doses of iron sucrose tended to have diabetes, have longer HD sessions, and have a higher frequency of erythropoiesis-stimulating agent use, compared with those who did not receive iron sucrose. In adjusted models, higher doses of iron sucrose were associated with an 11% lower rate of intradialytic hypotension (incidence rate ratio [IRR] for iron sucrose≥100mg vs 0 mg, 0.89 [95% CI, 0.85-0.94]). In adjusted analyses, the administration of higher doses of iron sucrose during HD was associated with intradialytic hypertension (IRR for iron sucrose≥100mg vs 0 mg, 1.07 [95% CI, 1.04-1.10]). LIMITATIONS: Nonavailability of the precise iron sucrose formulation (volume), laboratory data for each HD session, and outpatient medications. Objective measures of volume status, home medications, and symptom data were not recorded in this study. CONCLUSIONS: We observed an independent association of intravenous iron sucrose administration during HD with a lower risk of intradialytic hypotension and higher risk of intradialytic hypertension. Future studies to better understand the mechanisms underlying these associations are warranted. PLAIN-LANGUAGE SUMMARY: Intradialytic hypotension and intradialytic hypertension are common among patients on hemodialysis, and they are associated with morbidity and mortality. Although many factors may contribute to these risks, medications administered during hemodialysis play an important role. We studied the significance of the intravenous iron sucrose used to treat iron deficiency and the impact it may have on blood pressure during dialysis. In our study of 950 outpatient hemodialysis patients, we observed that administration of iron sucrose was associated with higher systolic blood pressure (during and after hemodialysis sessions) as well as a lower risk of intradialytic hypotension. We also observed that higher doses of iron sucrose are associated with the development of intradialytic hypertension.

Optimizing Endoscopy Procedure Documentation Improves Guideline-Adherent Care in Upper Gastrointestinal Bleeding.

BACKGROUND AND AIMS: Upper GI bleeding (UGIB) is a common indication for inpatient esophagogastroduodenoscopy (EGD). Guideline adherence improves post-EGD care, including appropriate medication dosing/duration and follow-up procedures that reduce UGIB-related morbidity. We aimed to optimize and standardize post-EGD documentation to improve process and clinical outcomes in UGIB-related care. METHODS: We performed a prospective quality improvement study of inpatient UGIB endoscopies at an academic tertiary referral center during 6/2019-7/2021. Guidelines were used to develop etiology/severity-specific electronic health record note templates. Participants (39 faculty/15 trainees) completed 10-min training in template content/use. We collected pre/post-intervention process data on "Minimal Standard Report" (MSR) documentation including patient disposition, diet, and medications. We also recorded documentation of re-bleed precautions and follow-up procedures. Study outcomes included guideline-based medication prescriptions, ordering of follow-up EGD, and post-discharge re-bleeding. Pre/post-intervention analysis was performed using chi-square tests. RESULTS: From a pre-intervention baseline of 199 patients to 459 patients post-intervention, compliance improved with inpatient PPI (53.4-77.9%, p < 0.001) and discharge PPI (31.3-61.0%, p < 0.001) prescriptions. There was improvement in MSR completion (28.6-42.5%, p < 0.001). Compliance improved with octreotide prescriptions (75.0-93.6%, p = 0.002) and follow-up EGD order (61.3-87.1%, p < 0.001). There was no change in post-discharge re-bleeding. 82.6% of cases used templates. CONCLUSIONS: Our project leveraged endoscopy software to standardize documentation, resulting in improved clinical care behavior and efficiency. Our intervention required low burden of maintenance, and sustainability with high utilization over 9 months. Similar endoscopy templates can be applied to other health systems and procedures to improve care.

Nearly complete deletion of BubR1 causes microcephaly through shortened mitosis and massive cell death.

BUB-related 1 (BubR1) encoded by Budding Uninhibited by Benzimidazole 1B (BUB1B) is a crucial mitotic checkpoint protein ensuring proper segregation of chromosomes during mitosis. Mutations of BUB1B are responsible for mosaic variegated aneuploidy (MVA), a human congenital disorder characterized by extensive abnormalities in chromosome number. Although microcephaly is a prominent feature of MVA carrying the BUB1B mutation, how BubR1 deficiency disturbs neural progenitor proliferation and neuronal output and leads to microcephaly is unknown. Here we show that conditional loss of BubR1 in mouse cerebral cortex recapitulates microcephaly. BubR1-deficient cortex includes a strikingly reduced number of late-born, but not of early-born, neurons, although BubR1 expression is substantially reduced from an early stage. Importantly, absence of BubR1 decreases the proportion of neural progenitors in mitosis, specifically in metaphase, suggesting shortened mitosis owing to premature chromosome segregation. In the BubR1 mutant, massive apoptotic cell death, which is likely due to the compromised genomic integrity that results from aberrant mitosis, depletes progenitors and neurons during neurogenesis. There is no apparent alteration in centrosome number, spindle formation or primary cilia, suggesting that the major effect of BubR1 deficiency on neural progenitors is to impair the mitotic checkpoint. This finding highlights the importance of the mitotic checkpoint in the pathogenesis of microcephaly. Furthermore, the ependymal cell layer does not form in the conditional knockout, revealing an unrecognized role of BubR1 in assuring the integrity of the ventricular system, which may account for the presence of hydrocephalus in some patients.

Randomized Controlled Trial of Personalized Colorectal Cancer Risk Assessment vs Education to Promote Screening Uptake.

INTRODUCTION: Risk stratification has been proposed as a strategy to improve participation in colorectal cancer (CRC) screening, but evidence is lacking. We performed a randomized controlled trial of risk stratification using the National Cancer Institute's Colorectal Cancer Risk Assessment Tool (CCRAT) on screening intent and completion. METHODS: A total of 230 primary care patients eligible for first-time CRC screening were randomized to risk assessment via CCRAT or education control. Follow-up of screening intent and completion was performed by record review and phone at 6 and 12 months. We analyzed change in intent after intervention, time to screening, overall screening completion rates, and screening completion by CCRAT risk score tertile. RESULTS: Of the patients, 61.7% of patients were aged <60 years, 58.7% female, and 94.3% with college or higher education. Time to screening did not differ between arms (hazard ratio 0.78 [95% confidence interval (CI) 0.52-1.18], P = 0.24). At 12 months, screening completion was 38.6% with CCRAT vs 44.0% with education (odds ratio [OR] 0.80 [95% CI 0.47-1.37], P = 0.41). Changes in screening intent did not differ between the risk assessment and education arms (precontemplation to contemplation: OR 1.52 [95% CI 0.81-2.86], P = 0.19; contemplation to precontemplation: OR 1.93 [95% CI 0.45-8.34], P = 0.38). There were higher screening completion rates at 12 months in the top CCRAT risk tertile (52.6%) vs the bottom (32.4%) and middle (31.6%) tertiles (P = 0.10). DISCUSSION: CCRAT risk assessment did not increase screening participation or intent. Risk stratification might motivate persons classified as higher CRC risk to complete screening, but unintentionally discourage screening among persons not identified as higher risk.

Acute Pancreatitis Task Force on Quality: Development of Quality Indicators for Acute Pancreatitis Management.

INTRODUCTION: Detailed recommendations and guidelines for acute pancreatitis (AP) management currently exist. However, quality indicators (QIs) are required to measure performance in health care. The goal of the Acute Pancreatitis Task Force on Quality was to formally develop QIs for the management of patients with known or suspected AP using a modified version of the RAND/UCLA Appropriateness Methodology. METHODS: A multidisciplinary expert panel composed of physicians (gastroenterologists, hospitalists, and surgeons) who are acknowledged leaders in their specialties and who represent geographic and practice setting diversity was convened. A literature review was conducted, and a list of proposed QIs was developed. In 3 rounds, panelists reviewed literature, modified QIs, and rated them on the basis of scientific evidence, bias, interpretability, validity, necessity, and proposed performance targets. RESULTS: Supporting literature and a list of 71 proposed QIs across 10 AP domains (Diagnosis, Etiology, Initial Assessment and Risk Stratification, etc.) were sent to the expert panel to review and independently rate in round 1 (95% of panelists participated). Based on a round 2 face-to-face discussion of QIs (75% participation), 41 QIs were classified as valid. During round 3 (90% participation), panelists rated the 41 valid QIs for necessity and proposed performance thresholds. The final classification determined that 40 QIs were both valid and necessary. DISCUSSION: Hospitals and providers managing patients with known or suspected AP should ensure that patients receive high-quality care and desired outcomes according to current evidence-based best practices. This physician-led initiative formally developed 40 QIs and performance threshold targets for AP management. Validated QIs provide a dependable quantitative framework for health systems to monitor the quality of care provided to patients with known or suspected AP.

Genetic Variants That Predispose to DNA Double-Strand Breaks in Lymphocytes From a Subset of Patients With Familial Colorectal Carcinomas.

BACKGROUND & AIMS: DNA structural lesions are prevalent in sporadic colorectal cancer. Therefore, we proposed that gene variants that predispose to DNA double-strand breaks (DSBs) would be found in patients with familial colorectal carcinomas of an undefined genetic basis (UFCRC). METHODS: We collected primary T cells from 25 patients with UFCRC and matched patients without colorectal cancer (controls) and assayed for DSBs. We performed exome sequence analyses of germline DNA from 20 patients with UFCRC and 5 undiagnosed patients with polyposis. The prevalence of identified variants in genes linked to DNA integrity was compared with that of individuals without a family history of cancer. The effects of representative variants found to be associated with UFCRC was confirmed in functional assays with HCT116 cells. RESULTS: Primary T cells from most patients with UFCRC had increased levels of the DSB marker γ(phosphorylated)histone2AX (γH2AX) after treatment with DNA damaging agents, compared with T cells from controls (P < .001). Exome sequence analysis identified a mean 1.4 rare variants per patient that were predicted to disrupt functions of genes relevant to DSBs. Controls (from public databases) had a much lower frequency of variants in the same genes (P < .001). Knockdown of representative variant genes in HCT116 CRC cells increased γH2AX. A detailed analysis of immortalized patient-derived B cells that contained variants in the Werner syndrome, RecQ helicase-like gene (WRN, encoding T705I), and excision repair cross-complementation group 6 (ERCC6, encoding N180Y) showed reduced levels of these proteins and increased DSBs, compared with B cells from controls. This phenotype was rescued by exogenous expression of WRN or ERCC6. Direct analysis of the recombinant variant proteins confirmed defective enzymatic activities. CONCLUSIONS: These results provide evidence that defects in suppression of DSBs underlie some cases of UFCRC; these can be identified by assays of circulating lymphocytes. We specifically associated UFCRC with variants in WRN and ERCC6 that reduce the capacity for repair of DNA DSBs. These observations could lead to a simple screening strategy for UFCRC, and provide insight into the pathogenic mechanisms of colorectal carcinogenesis.

Proteomic profiling of patient-derived glioblastoma xenografts identifies a subset with activated EGFR: implications for drug development.

The development of drugs to inhibit glioblastoma (GBM) growth requires reliable pre-clinical models. To date, proteomic level validation of widely used patient-derived glioblastoma xenografts (PDGX) has not been performed. In the present study, we characterized 20 PDGX models according to subtype classification based on The Cancer Genome Atlas criteria, TP53, PTEN, IDH 1/2, and TERT promoter genetic analysis, EGFR amplification status, and examined their proteomic profiles against those of their parent tumors. The 20 PDGXs belonged to three of four The Cancer Genome Atlas subtypes: eight classical, eight mesenchymal, and four proneural; none neural. Amplification of EGFR gene was observed in 9 of 20 xenografts, and of these, 3 harbored the EGFRvIII mutation. We then performed proteomic profiling of PDGX, analyzing expression/activity of several proteins including EGFR. Levels of EGFR phosphorylated at Y1068 vary considerably between PDGX samples, and this pattern was also seen in primary GBM. Partitioning of 20 PDGX into high (n = 5) and low (n = 15) groups identified a panel of proteins associated with high EGFR activity. Thus, PDGX with high EGFR activity represent an excellent pre-clinical model to develop therapies for a subset of GBM patients whose tumors are characterized by high EGFR activity. Further, the proteins found to be associated with high EGFR activity can be monitored to assess the effectiveness of targeting EGFR. The development of drugs to inhibit glioblastoma (GBM) growth requires reliable pre-clinical models. We validated proteomic profiles using patient-derived glioblastoma xenografts (PDGX), characterizing 20 PDGX models according to subtype classification based on The Cancer Genome Atlas (TCGA) criteria, TP53, PTEN, IDH 1/2, and TERT promoter genetic analysis, EGFR amplification status, and examined their proteomic profiles against those of their parent tumors. Proteins found to be associated with high EGFR activity represent potential biomarkers for GBM monitoring.

Replication stress and mitotic dysfunction in cells expressing simian virus 40 large T antigen.

We previously demonstrated that simian virus 40 (SV40) large T antigen (LT) binds to the Bub1 kinase, a key regulator of the spindle checkpoint and chromosome segregation. Bub1 mutations or altered expression patterns are linked to chromosome missegregation and are considered to be a driving force in some human cancers. Here we report that LT, dependent on Bub1 binding, causes micronuclei, lagging chromatin, and anaphase bridges, which are hallmarks of chromosomal instability (CIN) and Bub1 insufficiency. Using time-lapse microscopy, we demonstrate that LT imposes a Bub1 binding-dependent delay in the metaphase-to-anaphase transition. Kinetochore fibers reveal that LT, via Bub1 binding, causes aberrant kinetochore (KT)-microtubule (MT) attachments and a shortened interkinetochore distance, consistent with a lack of tension. Previously, we showed that LT also induces the DNA damage response (DDR) via Bub1 binding. Using inducible LT cell lines, we show that an activated DDR was observed before the appearance of anaphase bridges and micronuclei. Furthermore, LT induction in serum-starved cells demonstrated γ-H2AX accumulation in cells that had not yet entered mitosis. Thus, DDR activation can occur independently of chromosome segregation defects. Replication stress pathways may be responsible, because signatures of replication stress were observed, which were attenuated by exogenous supplementation with nucleosides. Our observations allow us to propose a model that explains and integrates the diverse manifestations of genomic instability induced by LT.

G Protein-coupled receptor kinase 5 is localized to centrosomes and regulates cell cycle progression.

G protein-coupled receptor kinases (GRKs) are important regulators of G protein-coupled receptor function and mediate receptor desensitization, internalization, and signaling. While GRKs also interact with and/or phosphorylate many other proteins and modify their function, relatively little is known about the cellular localization of endogenous GRKs. Here we report that GRK5 co-localizes with γ-tubulin, centrin, and pericentrin in centrosomes. The centrosomal localization of GRK5 is observed predominantly at interphase and although its localization is not dependent on microtubules, it can mediate microtubule nucleation of centrosomes. Knockdown of GRK5 expression leads to G2/M arrest, characterized by a prolonged G2 phase, which can be rescued by expression of wild type but not catalytically inactive GRK5. This G2/M arrest appears to be due to increased expression of p53, reduced activity of aurora A kinase and a subsequent delay in the activation of polo-like kinase 1. Overall, these studies demonstrate that GRK5 is localized in the centrosome and regulates microtubule nucleation and normal cell cycle progression.

Modeling the renoprotective mechanisms of SGLT2 inhibition in hypertensive chronic kidney disease.

Sodium-glucose cotransporter (SGLT)-2 inhibitors have recently been approved for chronic kidney disease (CKD) based on their ability to lower proteinuria and slow CKD progression independent of diabetes status. In diabetic renal disease, modulation of tubuloglomerular feedback (TGF) leading to lower intraglomerular pressure has been postulated as one of the mechanisms of renal protection with SGLT2 inhibition; however, this mechanism has not been sufficiently explored in non-diabetic CKD. We hypothesized that SGLT2 inhibition exerts renoprotection in CKD through increasing TGF despite normoglycemia. To test this hypothesis, we used an integrative mathematical model of human physiology, HumMod. Stage 3 CKD conditions were simulated by reducing nephron mass which was associated with hypertension, low glomerular filtration rate (GFR) (55 mL/min), hyperfiltration of remnant nephrons, elevated albuminuria (500 mg/day), and minimal levels of urinary glucose (0.02 mmol/L). SGLT2 inhibition was associated with acute reductions in GFR associated with afferent arteriolar vasoconstriction due to TGF. After 12 months, glomerular pressure, nephron damage, and chronic GFR decline were reduced with SGLT2 inhibition with additional SGLT1 inhibitory effects further enhancing these effects. This model supports the use of SGLT2 inhibitors to reduce hyperfiltration in CKD and mitigate renal disease progression, even in the absence of diabetes.

Ultrastructure and regulation of lateralized connexin43 in the failing heart.

RATIONALE: Gap junctions mediate cell-to-cell electric coupling of cardiomyocytes. The primary gap junction protein in the working myocardium, connexin43 (Cx43), exhibits increased localization at the lateral membranes of cardiomyocytes in a variety of heart diseases, although the precise location and function of this population is unknown. OBJECTIVE: To define the subcellular location of lateralized gap junctions at the light and electron microscopic level, and further characterize the biochemical regulation of gap junction turnover. METHODS AND RESULTS: By electron microscopy, we characterized gap junctions formed between cardiomyocyte lateral membranes in failing canine ventricular myocardium. These gap junctions were varied in structure and appeared to be extensively internalizing. Internalized gap junctions were incorporated into multilamellar membrane structures, with features characteristic of autophagosomes. Intracellular Cx43 extensively colocalized with the autophagosome marker GFP-LC3 when both proteins were exogenously expressed in HeLa cells, and endogenous Cx43 colocalized with GFP-LC3 in neonatal rat ventricular myocytes. Furthermore, a distinct phosphorylated form of Cx43, as well as the autophagosome-targeted form of LC3 (microtubule-associated protein light chain 3) targeted to lipid rafts in cardiac tissue, and both were increased in heart failure. CONCLUSIONS: Our data demonstrate a previously unrecognized pathway of gap junction internalization and degradation in the heart and identify a cellular pathway with potential therapeutic implications.

The rising tide of early-onset colorectal cancer: a comprehensive review of epidemiology, clinical features, biology, risk factors, prevention, and early detection.

The incidence of early-onset colorectal cnacer-ie, colorectal cancer diagnosed in patients under the age of 50 years- has been increasing around the world. This Series paper provides a comprehensive review on the topic of early-onset colorectal cancer, including examining the epidemiology of early-onset colorectal cancer around the world, clinical and pathological features, genetic and epigenetic landscapes, and emerging data on the clinical risk factors associated with this malignancy. Evidence-based approaches to prevention and early detection are also presented.

Serum Sodium, Patient Symptoms, and Clinical Outcomes in Hospitalized Patients with COVID-19.

INTRODUCTION: Disorders of serum sodium (SNa) are common in hospitalized patients with COVID-19 and may reflect underlying disease severity. However, the association of SNa with patient-reported outcomes is not clear. METHODS: The Brigham and Women's Hospital COVID-19 Registry is a prospective cohort study of consecutively admitted adult patients with confirmed SARS-CoV-2 infection (n = 809). We examined the associations of SNa (continuous and tertiles) on admission with: (1) patient symptoms obtained from detailed chart review; and (2) in-hospital mortality, length of stay, and intensive care unit (ICU) admission using unadjusted and adjusted logistic regression models. Covariates included demographic data and comorbidities. RESULTS: Mean age was 60 years, 48% were male, and 35% had diabetes. The most frequent symptoms were cough (64%), fever (60%), and shortness of breath (56%). In adjusted models, higher SNa (per mmol/L) was associated with lower odds of GI symptoms (OR 0.96; 95% CI 0.92-0.99), higher odds of confusion (OR 1.08; 95% CI 1.04-1.13), in-hospital mortality (OR 1.06; 95% CI 1.02-1.11), and ICU admission (OR 1.09; 95% CI 1.05-1.13). The highest sodium tertile (compared with the middle tertile) showed similar associations, in addition to lower odds of either anosmia or ageusia (OR 0.30; 95% CI 0.12-0.74). CONCLUSION: In this prospective cohort study of hospitalized patients with COVID-19, hypernatremia was associated with higher odds of confusion and in-hospital mortality. These findings may aid providers in identifying high-risk patients who warrant closer attention, thereby furthering patient-centered approaches to care.

Active DNA demethylation-The epigenetic gatekeeper of development, immunity, and cancer.

DNA methylation is a critical process in the regulation of gene expression with dramatic effects in development and continually expanding roles in oncogenesis. 5-Methylcytosine was once considered to be an inherited and stably repressive epigenetic mark, which can be only removed by passive dilution during multiple rounds of DNA replication. However, in the past two decades, physiologically controlled DNA demethylation and deamination processes have been identified, thereby revealing the function of cytosine methylation as a highly regulated and complex state-not simply a static, inherited signature or binary on-off switch. Alongside these fundamental discoveries, clinical studies over the past decade have revealed the dramatic consequences of aberrant DNA demethylation. In this review we discuss DNA demethylation and deamination in the context of 5-methylcytosine as critical processes for physiological and physiopathological transitions within three states-development, immune maturation, and oncogenic transformation; and we describe the expanding role of DNA demethylating drugs as therapeutic agents in cancer.

Trends in the Incidence of Early-Onset Colorectal Adenocarcinoma Among Black and White US Residents Aged 40 to 49 Years, 2000-2017.

Importance: Early-onset colorectal cancer incidence rates are rising faster in White individuals than Black individuals. However, prior National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) racial stratification analyses used smaller SEER 13 databases, combined patients under age 50 years, did not stratify by sex, and did not focus on adenocarcinoma histologic subtypes (screening target). Objective: To perform a race- and sex-stratified adenocarcinoma incidence rate analysis in individuals aged 40 to 49 years using larger SEER 18 databases with expanded race data to better understand the colorectal cancer burden in those at or approaching screening age. Design, Setting, and Participants: This cross-sectional study used 2000 to 2017 SEER 18 annual age-adjusted colorectal cancer incidence rates stratified by anatomic subsite (colon or rectum), adenocarcinoma histology, race (non-Hispanic Black or non-Hispanic White), and sex for individuals aged 40 to 49 years, and yearly annual percent change (APC) incidence rates were calculated. Annual rate ratios (ARRs) between subgroups were determined. Statistical analysis was performed from January to March 2021. Main Outcomes and Measurements: Early-onset colorectal cancer incidence rates, APCs, and ARRs. Results: In this study, a total of 46 728 colorectal cancer cases were identified in 45 429 patients aged 40 to 49 years from 2000 to 2017. Among the 45 429 patients included in this study, 6480 (14.2%) were Black and 27 426 (60.4%) were White; the mean (SD) age was 45.5 (2.8) years. Among White individuals aged 40 to 49 years, colorectal adenocarcinoma incidence rates increased from 19.6 per 100 000 person-years in 2000 to 25.2 per 100 000 person-years in 2017 (APC, 1.6; 95% CI, 1.3 to 1.9). Among Black individuals aged 40 to 49 years, colorectal adenocarcinoma incidence rates were not significantly changed (26.4 per 100 000 person-years in 2000 and 25.8 per 100 000 person-years in 2017 [APC, -0.03; 95% CI, -0.5 to 0.5]). There were no significant differences in ARRs of absolute colorectal incidence rates between White and Black individuals from 2014 to 2017. Rectal-only absolute adenocarcinoma incidence rates in Black and White individuals remained similar from 2000 to 2008 but significantly diverged in 2009. As of 2017, rectal absolute incidence rates were 39% higher among White individuals than among Black individuals with increasing APC (APC, 2.2; 95% CI, 1.6 to 2.8) whereas rectal adenocarcinoma incidence rates among Black individuals were decreasing, although the APC was not statistically significant (APC, -1.4; 95% CI, -2.6 to 0.1). Absolute colonic adenocarcinoma incidence rates remained higher in Black individuals. The study subgroups with the largest divergence in APCs were rectal adenocarcinoma in White vs Black women (APC of 2.2 [95% CI, 1.6 to 2.8] vs APC of -1.7 [95% CI, -3.6 to 0.3], respectively). Conclusions and Relevance: This study found that colorectal adenocarcinoma incidence rates in people aged 40 to 49 years were increasing among White individuals but stabilized among Black individuals with absolute incidence rates becoming equivalent. Absolute rectal adenocarcinoma incidence rates were 39% lower in Black individuals with a widening disparity in rectal cancer between White and Black women. Possible contributors include introduction of a screening threshold of age 45 years in Black individuals in 2008. Although the average-risk screening age has now shifted to age 45 years in all racial groups, these data can help motivate real-world implementation of guidelines to maximize screening rates that have historically been suboptimal in younger individuals.

HP1 proteins are essential for a dynamic nuclear response that rescues the function of perturbed heterochromatin in primary human cells.

Cellular information is encoded genetically in the DNA nucleotide sequence and epigenetically by the "histone code," DNA methylation, and higher-order packaging of DNA into chromatin. Cells possess intricate mechanisms to sense and repair damage to DNA and the genetic code. However, nothing is known of the mechanisms, if any, that repair and/or compensate for damage to epigenetically encoded information, predicted to result from perturbation of DNA and histone modifications or other changes in chromatin structure. Here we show that primary human cells respond to a variety of small molecules that perturb DNA and histone modifications by recruiting HP1 proteins to sites of altered pericentromeric heterochromatin. This response is essential to maintain the HP1-binding kinetochore protein hMis12 at kinetochores and to suppress catastrophic mitotic defects. Recruitment of HP1 proteins to pericentromeres depends on histone H3.3 variant deposition, mediated by the HIRA histone chaperone. These data indicate that defects in pericentromeric epigenetic heterochromatin modifications initiate a dynamic HP1-dependent response that rescues pericentromeric heterochromatin function and is essential for viable progression through mitosis.