USP21 deubiquitinase promotes pancreas cancer cell stemness via Wnt pathway activation.

The ubiquitin-specific protease (USP) family is the largest group of cysteine proteases. Cancer genomic analysis identified frequent amplification of USP21 (22%) in human pancreatic ductal adenocarcinoma (PDAC). USP21 overexpression correlates with human PDAC progression, and enforced expression of USP21 accelerates murine PDAC tumor growth and drives PanIN to PDAC progression in immortalized human pancreatic ductal cells. Conversely, depletion of USP21 impairs PDAC tumor growth. Mechanistically, USP21 deubiquitinates and stabilizes the TCF/LEF transcription factor TCF7, which promotes cancer cell stemness. Our work identifies and validates USP21 as a PDAC oncogene, providing a potential druggable target for this intractable disease.

Racial disparities in care escalation for postpartum hemorrhage requiring transfusion.

BACKGROUND: Postpartum hemorrhage is a leading cause of maternal morbidity and mortality in the United States and disproportionately affects pregnant persons of color. OBJECTIVE: This study aimed to identify the demographic and obstetrical characteristics of those who received different levels of antihemorrhagic intervention in the setting of severe postpartum hemorrhage requiring blood transfusion. STUDY DESIGN: This was a retrospective cohort study of patients with documented postpartum hemorrhage (estimated blood loss of ≥1000 mL) and blood product transfusion. Moreover, 3 levels of antihemorrhagic intervention were defined as follows: level 1, administration of uterotonics only; level 2, performance of a procedure (ie, B-Lynch suture, O'Leary stitch, Bakri balloon, dilation and curettage, laceration repair, or embolization); and level 3, hysterectomy. Maternal demographics, obstetrical characteristics, and comorbidities were extracted from electronic health records. Ordinal logistic regression was used to estimate the odds of higher intervention levels adjusting for maternal demographic and obstetrical characteristics. RESULTS: Of note, 365 patients were included in this study, with a racial or ethnic composition of 30% White, 42% Black, 18% Hispanic, and 10% other. Moreover, 233 patients (64%) received level 1 intervention, 98 patients (27%) received level 2 intervention, and 34 patients (9%) received level 3 intervention. Patients receiving higher levels of intervention were more likely to have greater estimated blood loss (P<.001), have more transfusions (P<.001), and be of advanced maternal age (P=.004). Black and Hispanic patients were less likely to have received higher levels of intervention than White patients (P=.034). After adjusting for estimated blood loss, advanced maternal age, placenta accreta spectrum, and fibroids, Black patients remained significantly less likely to receive higher levels of intervention (adjusted odds ratio, 0.55; 95% confidence interval, 0.30-0.98). This difference persisted at an estimated blood loss of ≥3000 mL, with Black and Hispanic patients being significantly less likely to receive higher levels of intervention than White patients (odds ratio, 0.31 [95% confidence interval, 0.10-0.92] and 0.10 [95% confidence interval, 0.01-0.53], respectively). CONCLUSION: Among patients experiencing postpartum hemorrhage and receiving transfusion, Black patients are less likely to receive higher levels of antihemorrhagic intervention. This disparity is concerning in this high-risk population and requires further attention and investigation.

Assisted reproductive technology: what are the cardiovascular risks for women?

INTRODUCTION: Infertility affects 15% of women of reproductive age in the United States. The use of assisted reproductive technology (ART) has been rising globally, as well as a growing recognition of reproductive factors that increase risk for cardiovascular disease (CVD). AREAS COVERED: Women with infertility who use ART are more likely to have established CVD risk factors, such as obesity, dyslipidemia, hypertension, and diabetes. They are also more likely to experience adverse pregnancy outcomes, which are associated with both peripartum and long-term cardiovascular complications. ART may lead to increased cardiometabolic demands due to ovarian stimulation, pregnancy itself, and higher rates of multifetal gestation. Preeclampsia risk appears greater with frozen rather than fresh embryo transfers. EXPERT OPINION: The use of ART and its association with long term CVD has not been well-studied. Future prospective and mechanistic studies investigating the association of ART and CVD risk may help determine causality. Nevertheless, CVD risk screening is critical pre-pregnancy and during pregnancy to reduce pregnancy complications that elevate future CVD risk. This also offers a window of opportunity to connect patients to longitudinal care for early management of cardiometabolic risk profile and initiation of preventive lifestyle and pharmacotherapy interventions tailored toward patient-specific risk factors.

Polycystic ovary syndrome: a "risk-enhancing" factor for cardiovascular disease.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age and is hallmarked by hyperandrogenism, oligo-ovulation, and polycystic ovarian morphology. Polycystic ovary syndrome, particularly the hyperandrogenism phenotype, is associated with several cardiometabolic abnormalities, including obesity, dyslipidemia, elevated blood pressure, and prediabetes or type 2 diabetes. Many, but not all, studies have suggested that PCOS is associated with increased risk of cardiovascular disease (CVD), including coronary heart disease and stroke, independent of body mass index and traditional risk factors. Interpretation of the data from these observational studies is limited by the varying definitions and ascertainment of PCOS and CVD across studies. Recent Mendelian randomization studies have challenged the causality of PCOS with coronary heart disease and stroke. Future longitudinal studies with clearly defined PCOS criteria and newer genetic methodologies may help to determine association and causality. Nevertheless, CVD risk screening remains critical in this patient population, as improvements in metabolic profile and reduction in CVD risk are achievable with a combination of lifestyle management and pharmacotherapy. Statin therapy should be implemented in women with PCOS who have elevated atherosclerotic CVD risk. If CVD risk is uncertain, measurement of subclinical atherosclerosis (carotid plaque or coronary artery calcium) may be a useful tool to guide shared decision-making about initiation of statin therapy. Other medications, such as metformin and glucagon-like peptide-1 receptor agonists, also may be useful in reducing CVD risk in insulin-resistant populations. Additional research is needed to determine the best pathways to mitigate PCOS-associated CVD risk.

Trends, Predictors, and Outcomes of Cardiovascular Complications Associated With Polycystic Ovary Syndrome During Delivery Hospitalizations: A National Inpatient Sample Analysis (2002-2019).

Background Women with polycystic ovary syndrome (PCOS) have an increased risk of pregnancy-associated complications. However, data on peripartum cardiovascular complications remain limited. Hence, we investigated trends, outcomes, and predictors of cardiovascular complications associated with PCOS diagnosis during delivery hospitalizations in the United States. Methods and Results We used data from the National Inpatient Sample (2002-2019). International Classification of Diseases, Ninth Revision (ICD-9), or International Classification of Diseases, Tenth Revision (ICD-10), codes were used to identify delivery hospitalizations and PCOS diagnosis. A total of 71 436 308 weighted hospitalizations for deliveries were identified, of which 0.3% were among women with PCOS (n=195 675). The prevalence of PCOS, and obesity among those with PCOS, increased during the study period. Women with PCOS were older (median, 31 versus 28 years; P<0.01) and had a higher prevalence of diabetes, obesity, and dyslipidemia. After adjustment for age, race and ethnicity, comorbidities, insurance, and income, PCOS remained an independent predictor of cardiovascular complications, including preeclampsia (adjusted odds ratio [OR], 1.56 [95% CI, 1.54-1.59]; P<0.01), eclampsia (adjusted OR, 1.58 [95% CI, 1.54-1.59]; P<0.01), peripartum cardiomyopathy (adjusted OR, 1.79 [95% CI, 1.49-2.13]; P<0.01), and heart failure (adjusted OR, 1.76 [95% CI, 1.27-2.45]; P<0.01), compared with no PCOS. Moreover, delivery hospitalizations among women with PCOS were associated with increased length (3 versus 2 days; P<0.01) and cost of hospitalization ($4901 versus $3616; P<0.01). Conclusions Women with PCOS had a higher risk of preeclampsia/eclampsia, peripartum cardiomyopathy, and heart failure during delivery hospitalizations. Moreover, delivery hospitalizations among women with PCOS diagnosis were associated with increased length and cost of hospitalization. This signifies the importance of prepregnancy consultation and optimization for cardiometabolic health to improve maternal and neonatal outcomes.

Quantitative Microstructural Analysis of Cellular and Tissue Remodeling in Human Glaucoma Optic Nerve Head.

Purpose: To measure quantitatively changes in lamina cribrosa (LC) cell and connective tissue structure in human glaucoma eyes. Methods: We studied 27 glaucoma and 19 age-matched non-glaucoma postmortem eyes. In 25 eyes, LC cross-sections were examined by confocal and multiphoton microscopy to quantify structures identified by anti-glial fibrillary acidic protein (GFAP), phalloidin-labeled F-actin, nuclear 4',6-diamidino-2-phenylindole (DAPI), and by second harmonic generation imaging of LC beams. Additional light and transmission electron microscopy were performed in 21 eyes to confirm features of LC remodeling, including immunolabeling by anti-SOX9 and anti-collagen IV. All glaucoma eyes had detailed clinical histories of open-angle glaucoma status, and degree of axon loss was quantified in retrolaminar optic nerve cross-sections. Results: Within LC pores, the proportionate area of both GFAP and F-actin processes was significantly lower in glaucoma eyes than in controls (P = 0.01). Nuclei were rounder (lower median aspect ratio) in glaucoma specimens (P = 0.02). In models assessing degree of glaucoma damage, F-actin process width was significantly wider in glaucoma eyes with more damage (P = 0.024), average LC beam width decreased with worse glaucoma damage (P = 0.042), and nuclear count per square millimeter rose with worse damage (P = 0.019). The greater cell count in LC pores represented 92.3% astrocytes by SOX9 labeling. The results are consistent with replacement of axons in LC pores by basement membrane labeled by anti-collagen IV and in-migrating astrocytes. Conclusions: Alteration in LC structure in glaucoma involves migration of astrocytes into axonal bundles, change in astrocyte orientation and processes, production of basement membrane material, and thinning of connective tissue beams.

Pharmacological characterisation of small molecule C5aR1 inhibitors in human cells reveals biased activities for signalling and function.

The complement fragment C5a is a core effector of complement activation. C5a, acting through its major receptor C5aR1, exerts powerful pro-inflammatory and immunomodulatory functions. Dysregulation of the C5a-C5aR1 axis has been implicated in numerous immune disorders, and the therapeutic inhibition of this axis is therefore imperative for the treatment of these diseases. A myriad of small-molecule C5aR1 inhibitors have been developed and independently characterised over the past two decades, however the pharmacological properties of these compounds has been difficult to directly compare due to the wide discrepancies in the model, read-out, ligand dose and instrumentation implemented across individual studies. Here, we performed a systematic characterisation of the most commonly reported and clinically advanced small-molecule C5aR1 inhibitors (peptidic: PMX53, PMX205 and JPE1375; non-peptide: W545011, NDT9513727, DF2593A and CCX168). Through signalling assays measuring C5aR1-mediated cAMP and ERK1/2 signalling, and ß-arrestin 2 recruitment, this study highlighted the signalling-pathway dependence of the rank order of potencies of the C5aR1 inhibitors. Functional experiments performed in primary human macrophages demonstrated the high insurmountable antagonistic potencies for the peptidic inhibitors as compared to the non-peptide compounds. Finally, wash-out studies provided novel insights into the duration of inhibition of the C5aR1 inhibitors, and confirmed the long-lasting antagonistic properties of PMX53 and CCX168. Overall, this study revealed the potent and prolonged antagonistic activities of selected peptidic C5aR1 inhibitors and the unique pharmacological profile of CCX168, which thus represent ideal candidates to fulfil diverse C5aR1 research and clinical therapeutic needs.