Citations

Targeting the main protease of SARS-CoV-2 Inside host cells, the RNA genome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is translated into two polyproteins that are cleaved to give the individual viral proteins. The main viral protease, known as Mpro or 3CLpro, plays a key role in these cleavages, making it an important drug target. Drayman et al . identified eight drugs that target 3CLpro from a library of 1900 clinically safe drugs. Because of the challenge of working with SARS-CoV-2, they started by screening for drugs that inhibit the replication of a human coronavirus that causes the common cold. They then evaluated the top hits for inhibiting SARS-CoV-2 replication and for inhibiting 3CLpro. Masitinib, a broad antiviral, inhibited the main proteases of coronaviruses and picornaviruses and was effective in reducing SARS-CoV-2 replication in mice. —VV

Abstract Background: The influence of prenatal diethylstilbestrol (DES) exposure on cancer incidence among middle-aged men has not been well-characterized. We investigated whether exposure to DES before birth impacts overall cancer risk, and risk of site-specific cancers. Methods: Men (mean age in 2016 = 62.0 years) who were or were not prenatally DES exposed were identified between 1953 and 1994 and followed for cancer primarily via questionnaire approximately every 5 years between 1994 and 2016. The overall and site-specific cancer rates of the two groups were compared using Poisson regression and proportional hazards modeling with adjustment for age. Results: DES exposure was not associated with either overall cancer [hazard ratio (HR), 0.94; 95% confidence interval (CI), 0.77–1.15] or total prostate cancer rates (HR, 0.95; 95% CI, 0.68–1.33), but was inversely associated with urinary tract cancer incidence (HR, 0.48; 95% CI, 0.23–1.00). Conclusions: There was no increase in either overall or prostate cancer rates among men prenatally DES exposed relative to those unexposed. An unexpected risk reduction was observed for urinary system cancers among the exposed relative to those unexposed. These findings suggest that prenatal DES exposure is unlikely to be an important contributor to cancer development in middle-aged men. Impact: The results of this study could lend reassurance to middle-aged men who were prenatally DES exposed that their exposure does not adversely influence their overall cancer risk.

SummaryRuxolitinib for steroid‐refractory acute graft‐versus‐host disease (SR‐aGVHD) results in resistance or intolerance in 1/5 of patients. Outcomes of such patients are undefined. We identified these patients in a multicentre review and reported outcomes. Ruxolitinib‐resistant aGVHD was identified in 48/307 patients. Among patients receiving additional therapy, the overall response rate to next therapy was 36%. Median survival was 21 days. Ruxolitinib intolerance led to treatment discontinuation in 16/307 patients. Ten intolerant patients received additional therapy with 50% experiencing continued improvement of aGVHD. Median survival was 50 days in these patients. These data serve as a baseline for future SR‐aGVHD studies.

The AML14 cell line and its AML14.3D10 subclone was established as a model cell system that exhibits phenotypic characteristics similar to that of human eosinophils. We investigated the effects of purinergic receptor stimulation on the physiological response of the AML 14.3D10 cell line to better evaluate its role as a suitable model for eosinophils using both molecular and functional approaches. Ca 2+ imaging experiments using Fura‐2 demonstrated the existence of purinergic receptors responsive to UTP (EC 50 of 8.9 x 10 −8 ), ATP γ‐s (EC 50 of 1.87 x 10 −7 ), and UDP (EC 50 of 7.44x 10 −6 ). Molecular identification of the purinergic receptor subtypes was confirmed by QRT‐PCR which demonstrated the presence of P2Y 1 , P2Y 2 , P2Y 4 , and P2Y 6 receptors. Ratio imaging experiments using the membrane potential sensitive indicator DiBAC‐3 showed that stimulation with UTP produced a membrane hyperpolarization of approximately 10 mV that returned to the original resting potential within 10 minutes after stimulation. Whole cell perforated patch clamp experiments using amphotericin B revealed the presence of voltage‐gated potassium channel currents that were stimulated following treatment with UTP. Analysis of mRNA by QRT‐PCR indicated the existence of several voltage‐gated potassium channel α subunits including, Kv1.2, Kv1.3, Kv1.4, and Kv1.6. Previous studies of Kv1.3 channel function in T‐lymphocytes showed that the channel was involved in activation and proliferation, suggesting the possibility of a similar role related to tumorogenesis in the AML 14.3D10 cell line.

OBJECTIVE Scoliosis is common in patients with Chiari malformation type I (CM-I)–associated syringomyelia. While it is known that treatment with posterior fossa decompression (PFD) may reduce the progression of scoliosis, it is unknown if decompression with duraplasty is superior to extradural decompression. METHODS A large multicenter retrospective and prospective registry of 1257 pediatric patients with CM-I (tonsils ≥ 5 mm below the foramen magnum) and syrinx (≥ 3 mm in axial width) was reviewed for patients with scoliosis who underwent PFD with or without duraplasty. RESULTS In total, 422 patients who underwent PFD had a clinical diagnosis of scoliosis. Of these patients, 346 underwent duraplasty, 51 received extradural decompression alone, and 25 were excluded because no data were available on the type of PFD. The mean clinical follow-up was 2.6 years. Overall, there was no difference in subsequent occurrence of fusion or proportion of patients with curve progression between those with and those without a duraplasty. However, after controlling for age, sex, preoperative curve magnitude, syrinx length, syrinx width, and holocord syrinx, extradural decompression was associated with curve progression > 10°, but not increased occurrence of fusion. Older age at PFD and larger preoperative curve magnitude were independently associated with subsequent occurrence of fusion. Greater syrinx reduction after PFD of either type was associated with decreased occurrence of fusion. CONCLUSIONS In patients with CM-I, syrinx, and scoliosis undergoing PFD, there was no difference in subsequent occurrence of surgical correction of scoliosis between those receiving a duraplasty and those with an extradural decompression. However, after controlling for preoperative factors including age, syrinx characteristics, and curve magnitude, patients treated with duraplasty were less likely to have curve progression than patients treated with extradural decompression. Further study is needed to evaluate the role of duraplasty in curve stabilization after PFD.

Significance By evaluating children with a malformed cerebral cortex, we identified an ATPase pump (ATP1A3) with an early role in brain development. The ATP1A3 pump maintains the physiological concentration of sodium and potassium ions in cells, a process critical for osmotic equilibrium and membrane potential across several developing cell populations. We employed single-cell sequencing approaches to identify key enrichments for ATP1A3 expression during human cortex development. Unravelling this early cell-type–specific pathophysiology in the developing brain offers a potential basis for the treatment of ATP1A3 -related diseases affecting prenatal and early childhood development.

PURPOSE This study assessed the joint association of pathogenic variants (PVs) in breast cancer (BC) predisposition genes and polygenic risk scores (PRS) with BC in the general population. METHODS A total of 26,798 non-Hispanic white BC cases and 26,127 controls from predominately population-based studies in the Cancer Risk Estimates Related to Susceptibility consortium were evaluated for PVs in BRCA1, BRCA2, ATM, CHEK2, PALB2, BARD1, BRIP1, CDH1, and NF1. PRS based on 105 common variants were created using effect estimates from BC genome-wide association studies; the performance of an overall BC PRS and estrogen receptor–specific PRS were evaluated. The odds of BC based on the PVs and PRS were estimated using penalized logistic regression. The results were combined with age-specific incidence rates to estimate 5-year and lifetime absolute risks of BC across percentiles of PRS by PV status and first-degree family history of BC. RESULTS The estimated lifetime risks of BC among general-population noncarriers, based on 10th and 90th percentiles of PRS, were 9.1%-23.9% and 6.7%-18.2% for women with or without first-degree relatives with BC, respectively. Taking PRS into account, more than 95% of BRCA1, BRCA2, and PALB2 carriers had > 20% lifetime risks of BC, whereas, respectively, 52.5% and 69.7% of ATM and CHEK2 carriers without first-degree relatives with BC, and 78.8% and 89.9% of those with a first-degree relative with BC had > 20% risk. CONCLUSION PRS facilitates personalization of BC risk among carriers of PVs in predisposition genes. Incorporating PRS into BC risk estimation may help identify > 30% of CHEK2 and nearly half of ATM carriers below the 20% lifetime risk threshold, suggesting the addition of PRS may prevent overscreening and enable more personalized risk management approaches.

10016 Background: The impact of race and socioeconomic status (SES) on cancer mortality has been elucidated in adult patients, but is not well described in pediatric oncology. We hypothesize that racial and socioeconomic disparities exist in pediatric cancer patients, resulting in higher rates of hospitalization and mortality. Methods: We analyzed the Kids’ Inpatient Database (KID) which shows national estimates of inpatient stays for pediatric patients. Inclusion criteria included patients who were ≤20 with a cancer diagnosis identified through the Clinical Classifications Software (CCS). Variables analyzed were discharge status, patient demographics, hospital characteristics, expected payment source, total visit charge, and length of stay. Initial comparisons between cancer and non-cancer related discharges were performed using a chi-square test. To estimate disparities by race, clinical comparisons were performed across five racial groups: White, Black, Hispanic, Asian/Pacific Islander, and Native American/Other. A multivariable logistic regression model was used to examine predictors of hospitalization and mortality. Results: From 2006-2012, there were 9,488,477 non-cancer related pediatric inpatient stays and 242,489 cancer related stays. Patients with cancer related visits were more likely to be white, male (54.9% vs 46.1%, p < 0.0001), older at admission, have private insurance (52.5% vs 41.7%), and were from a higher income quartile (76th-100th percentile, 25.2% vs 19.9%, p < 0.001). These patients also had a higher rate of death during admission (1.2% vs 0.5%, p < 0.0001), higher cost of visit charge ($25,097 vs $8,267, p < 0.001), longer length of stay (4 vs 2 days), and were less likely to be discharged (85.5% vs 92.0%, p < 0.0001).The four most frequent cancer diagnoses associated with hospital admission were leukemia (n = 75,807), Other and Unspecified Primary (n = 50,076), bone/connective tissue tumor (n = 42,477), and central nervous system tumor (n = 27,958). Patients who were non-white were more likely to die during their inpatient stay (1.5% Non-white versus 0.9% White, p < 0.001). On multivariate logistic regression, Black (OR: 1.61, 95% CI: 1.57-1.66, p < 0.0001) and Native American (OR: 1.39, 95% CI: 1.34-1.44, p < 0.0001) race, as well as lower income quartile (OR: 1.24, 95% CI: 1.19-1.28, p < 0.001) were associated with increased odds of death during admission. Conclusions: This is the largest observational study to date to identify the impact of race and SES on pediatric cancer hospitalization and mortality in the United States. Non-white race and lower SES was associated with significantly increased odds of death during admission. Given the significant difference in mortality by race, healthcare policy makers and insurance companies should investigate the specific drivers of increased admission and mortality and develop strategies to address inequity in cancer care.

e19040 Background: Clinical trials investigating JAK1/JAK2 inhibitors for myelofibrosis (MF) subjects have measured symptom improvement as a minimum 50% reduction in total symptom score (TSS) at the end of a 24-week treatment period. This landmark analysis is based on post-baseline score changes from Weeks 21 (W21) to 24 and requires vastly different absolute TSS improvements for patients with very high or low baseline (BL) TSS to reach responder status. A phase 3 clinical study, SIMPLIFY-1, randomized 432 intermediate and high risk JAK inhibitor (JAKi) naive MF patients 1:1 to momelotinib (MMB) or ruxolitinib (RUX). Non-inferiority on the MPN-SAF TSS response rate endpoint at W24 was not met (MMB: 28% vs RUX: 42%); however, improvement in each of the 7 TSS items was similar for MMB vs RUX. To understand the discrepancy, we applied item analysis and mixed effect models for repeated measures (MMRM) to SIMPLIFY-1. Methods: Analyses were conducted in the intention-to-treat (ITT) population and in a symptomatic subset (selected as subjects with BL TSS ≥ 10). The distributions of TSS items were examined at BL and shift in scores at W24 (health state shifts) were assessed. GEE models were used to estimate item-level odds ratios using multiple predictive imputations for missing data. MMRM compared mean change in TSS from BL to W24 using data from all visits. The meaningful change threshold (MCT) was determined using Patient Global Impression of Change. Results: BL scores across items were heterogenous in the MMB and RUX groups; the proportion of subjects with no or mild symptoms (0–3 on a 0-10 point scale) ranged from 44% (tiredness) to 81% (itching). Distributions of BL scores were different across arms with 6 out of 7 items in the MMB arm reporting more severe or very severe symptoms (scores of 7-10) at BL. Despite the imbalance in BL scores, item-level health state shifts showed similar improvements for MMB and RUX. Categorical responder analysis showed no significant differences on any items. Odds ratios for each between-group comparison ranged from 0.74 to 1.20. MMRM mean TSS change at W24 was 6.35 (MMB) vs 7.87 (RUX) in the ITT and 8.80 (MMB) vs 10.46 (RUX) in the symptomatic subset. Mean TSS were near the within-subject MCT of 8 points in the ITT and exceeded the MCT in the symptomatic subset. The between-group difference was 1.52 (95% CI: (0.196, 2.847)) in the ITT and 1.67 (95% CI: -0.134, 3.468) in the symptomatic subset. Conclusions: Comparable item health state shifts at W24 and similar improvements in mean TSS as shown by MMRM, with a minimal between-group difference of 1.52 on the 70 point scale in context of an 8-point MCT suggest MMB provides clinically relevant and comparable symptom improvements to RUX; these analyses require further validation in independent data sets. Imbalance in BL symptom scores in MMB subjects may have contributed to the inability to demonstrate non-inferiority in TSS response rate at W24. Clinical trial information: NCT01969838.