Women's and Partners' Experiences With a Closed-loop Insulin Delivery System to Manage Type 1 Diabetes in the Postpartum Period.

OBJECTIVES: Closed-loop insulin delivery has the potential to offer women with type 1 diabetes a break from intense diabetes self-care efforts postpartum. Our aim in this study was to explore the views and opinions of hybrid closed-loop users and their partners in the first 24 weeks postpartum. METHODS: This qualitative study was embedded in a controlled study of women with type 1 diabetes randomized to closed-loop insulin delivery (MiniMed™ 670G or 770G) or sensor-augmented pump use for 1 to 11 weeks 6 days postpartum, with all on closed-loop delivery from 12 to 24 weeks postpartum. Semistructured interviews were conducted with 16 study participants and their partners at 12 and 24 weeks postpartum. Thematic analyses were used to examine participants' and partners' experiences. RESULTS: Participants' positive perceptions of closed-loop use related to reduced hypoglycemia, in contrast to previous experiences with nonautomated insulin delivery. These perceptions were balanced against frustrations with the system, allowing blood glucose levels to be higher than desired. Closed-loop use did not influence infant feeding choice, but infant feeding and care impacted participants' diabetes management. Partners expressed uncertainty about the closed loop taking away control from participants who were highly skilled with diabetes self-management. CONCLUSIONS: Participants reported that closed-loop insulin delivery resulted in less time spent in hypoglycemia when compared with the previously used nonautomated delivery. Yet, participants desired a greater understanding of the workings of the closed-loop algorithm. Our study provides potential users with realistic expectations about the experience with the MiniMed 670G or 770G closed-loop system in the postpartum period.

Obesity facilitated colon cancer progression is mediated by increased diacylglycerol o-acyltransferases 1 and 2 (DGAT1/2) levels.

BACKGROUND & AIMS: The obesity epidemic is associated with increased colon cancer progression. As lipid droplets (LDs) fuel tumor growth, we aim to determine the significance of diacyltransferases, DGAT1/2, responsible for LDs biogenesis, in obesity-mediated colonic tumorigenesis. METHODS: Human colon cancer samples, colon cancer cells, colonospheres, and ApcMin/+ colon cancer mouse model on a high-fat diet were employed. For DGAT1/2 inhibition, enzymatic inhibitors and siRNA were used. Expression, pathways, cell cycle, and growth were assessed. Bioinformatic analyses of CUT&RUN and RNAseq data were performed. RESULTS: DGAT1/2 levels in human colon cancer tissue are significantly elevated with disease severity and obesity (vs normal). Their levels are increased in human colon cancer cells (vs non-transformed) and further enhanced by fatty acids prevalent in obesity; augmented DGAT2 expression is MYC-dependent. Inhibition of DGAT1/2 improves FOXO3 activity by attenuating PI3K, resulting in reduced MYC-dependent DGAT2 expression and LDs accumulation, suggesting feedback. This inhibition attenuated growth in colon cancer cells and colonospheres via FOXO3/p27kip1 cell cycle arrest and reduced colonic tumors in ApcMin/+ mice on a high-fat diet. Transcriptomic analysis revealed that DGAT1/2 inhibition targeted metabolic and tumorigenic pathways in human colon cancer and colon cancer crypts, stratifying human colon cancer samples from normal. Further analysis revealed that this inhibition is predictive of advanced disease-free state and survival in colon cancer patients. CONCLUSION: This is a novel mechanism of DGAT1/2-dependent metabolic and tumorigenic remodeling in obesity-facilitated colon cancer, providing a platform for the future development of effective treatments for colon cancer patients.

Glycaemic patterns during breastfeeding with postpartum use of closed-loop insulin delivery in women with type 1 diabetes.

AIMS/HYPOTHESIS: This study aimed to describe the relationship between breastfeeding episodes and maternal glucose levels, and to assess whether this differs with closed-loop vs open-loop (sensor-augmented pump) insulin therapy. METHODS: Infant-feeding diaries were collected at 6 weeks, 12 weeks and 24 weeks postpartum in a trial of postpartum closed-loop use in 18 women with type 1 diabetes. Continuous glucose monitoring (CGM) data were used to identify maternal glucose patterns within the 3 h of breastfeeding episodes. Generalised mixed models adjusted for breastfeeding episodes in the same woman, repeat breastfeeding episodes, carbohydrate intake, infant age at time of feeding and early pregnancy HbA1c. This was a secondary analysis of data collected during a randomised trial (ClinicalTrials.gov registration no. NCT04420728). RESULTS: CGM glucose remained above 3.9 mmol/l in the 3 h post-breastfeeding for 93% (397/427) of breastfeeding episodes. There was an overall decrease in glucose at nighttime within 3 h of breastfeeding (1.1 mmol l-1 h-1 decrease on average; p=0.009). A decrease in nighttime glucose was observed with open-loop therapy (1.2 ± 0.5 mmol/l) but was blunted with closed-loop therapy (0.4 ± 0.3 mmol/l; p<0.01, open-loop vs closed-loop). CONCLUSIONS/INTERPRETATION: There is a small decrease in glucose after nighttime breastfeeding that usually does not result in maternal hypoglycaemia; this appears to be blunted with the use of closed-loop therapy.

Infiltrating lipid-rich macrophage subpopulations identified as a regulator of increasing prostate size in human benign prostatic hyperplasia.

Macrophages exhibit marked phenotypic heterogeneity within and across disease states, with lipid metabolic reprogramming contributing to macrophage activation and heterogeneity. Chronic inflammation has been observed in human benign prostatic hyperplasia (BPH) tissues, however macrophage activation states and their contributions to this hyperplastic disease have not been defined. We postulated that a shift in macrophage phenotypes with increasing prostate size could involve metabolic alterations resulting in prostatic epithelial or stromal hyperplasia. Single-cell RNA-seq of CD45+ transition zone leukocytes from 10 large (>90 grams) and 10 small (<40 grams) human prostates was conducted. Macrophage subpopulations were defined using marker genes. BPH macrophages do not distinctly categorize into M1 and M2 phenotypes. Instead, macrophages with neither polarization signature preferentially accumulate in large versus small prostates. Specifically, macrophage subpopulations with altered lipid metabolism pathways, demarcated by TREM2 and MARCO expression, significantly accumulate with increased prostate volume. TREM2+ and MARCO+ macrophage abundance positively correlates with patient body mass index and urinary symptom scores. TREM2+ macrophages have significantly higher neutral lipid than TREM2- macrophages from BPH tissues. Lipid-rich macrophages were observed to localize within the stroma in BPH tissues. In vitro studies indicate that lipid-loaded macrophages increase prostate epithelial and stromal cell proliferation compared to control macrophages. These data define two new BPH immune subpopulations, TREM2+ and MARCO+ macrophages, and suggest that lipid-rich macrophages may exacerbate lower urinary tract symptoms in patients with large prostates. Further investigation is needed to evaluate the therapeutic benefit of targeting these cells in BPH.

Prenatal findings in 11 cases with craniofacial microsomia using the Alberta Congenital Anomalies Surveillance System, 1997-2019.

Craniofacial microsomia (CFM) primarily includes specific head and neck anomalies that co-occur more frequently than expected. The anomalies are usually asymmetric and affect craniofacial features; however, there are frequently additional anomalies of variable severity. Published prenatal findings for CFM are limited. This study contributes 11 cases with CFM and their anomalies identified prenatally. Cases born between January 1, 1997 and December 31, 2019 with CFM were abstracted from the Alberta Congenital Anomalies Surveillance System, which is a population-based program ascertaining congenital anomalies for livebirths, stillbirths, and termination of pregnancies for fetal anomalies. There were 11 cases ascertained with prenatal findings including facial anomalies: one each with left cleft lip, right microtia, and bilateral microphthalmia. Two cases had vertebral anomalies. In addition, anomalies of the kidneys, brain, heart, and radial ray were identified. Six (55%) had a single umbilical artery, five (45%) were small for gestational age, and three (27%) were from a twin pregnancy that were discordant for anomalies. Four (36%) overlapped another proposed recurrent constellations of embryonic malformation condition. This study describes prenatal findings for 11 cases with CFM. Comparable to prior published cases, there were recurring anomalies on prenatal imaging, including anomalies of the brain, eye, heart, kidneys, and radial ray, which may aid in the prenatal diagnosis of CFM.

Publicly funded healthcare costs associated with orofacial clefts for children born in Alberta, Canada between 2002 and 2018.

BACKGROUND: Orofacial clefts (OFCs) include cleft palate (CP), cleft lip (CL), and cleft lip with cleft palate (CLP) and require multidisciplinary healthcare services. Alberta, Canada has a publicly funded, universal access healthcare system. This study determined publicly funded healthcare costs for children with an OFC and compared these costs to children without congenital anomalies. METHODS: This retrospective population-based cohort analysis used the Alberta Congenital Anomalies Surveillance System to identify children born between 2002 and 2018 with an isolated OFC. They were matched 1:1 to a reference cohort based on sex and year of birth. The study population included 1614 children, from birth to 17 years of age linked to administrative databases to estimate annual inpatient and outpatient costs. Average annual all-cause costs were compared using two-sample independent t tests. RESULTS: The mean total cleft-related costs per patient were highest for children with CLP ($74,138 CAD, standard deviation (SD) $43,447 CAD), followed by CP ($53,062 CAD, SD $74,366 CAD), and CL ($35,288 CAD, SD $49,720 CAD). The mean total all-cause costs per child were statistically significantly higher (p < .001) in children with an OFC ($56,305 CAD, SD $57,744 CAD) compared to children without a congenital anomaly ($18,600 CAD, SD $61,300 CAD). CONCLUSIONS: Despite public health strategies to mitigate risk factors, the trend for OFCs has remained stable in Alberta, Canada for over 20 years. The costs reported are useful to other jurisdictions for comparison, and to families, healthcare professionals, service planners, and policy makers.

Gut-liver axis calibrates intestinal stem cell fitness.

The gut and liver are recognized to mutually communicate through the biliary tract, portal vein, and systemic circulation. However, it remains unclear how this gut-liver axis regulates intestinal physiology. Through hepatectomy and transcriptomic and proteomic profiling, we identified pigment epithelium-derived factor (PEDF), a liver-derived soluble Wnt inhibitor, which restrains intestinal stem cell (ISC) hyperproliferation to maintain gut homeostasis by suppressing the Wnt/ß-catenin signaling pathway. Furthermore, we found that microbial danger signals resulting from intestinal inflammation can be sensed by the liver, leading to the repression of PEDF production through peroxisome proliferator-activated receptor-α (PPARα). This repression liberates ISC proliferation to accelerate tissue repair in the gut. Additionally, treating mice with fenofibrate, a clinical PPARα agonist used for hypolipidemia, enhances colitis susceptibility due to PEDF activity. Therefore, we have identified a distinct role for PEDF in calibrating ISC expansion for intestinal homeostasis through reciprocal interactions between the gut and liver.

A Randomized Trial of Closed-Loop Insulin Delivery Postpartum in Type 1 Diabetes.

OBJECTIVE: This study aimed to evaluate the efficacy of closed-loop insulin delivery postpartum. RESEARCH DESIGN AND METHODS: In this open-label, randomized controlled trial, postpartum individuals with type 1 diabetes were randomized to hybrid closed-loop insulin delivery with the MiniMed 670G/770G system in automode or sensor-augmented pump therapy in the first 12-weeks postpartum followed by a continuation phase with closed-loop insulin delivery for all until 24 weeks postpartum. RESULTS: Eighteen participants (mean ± SD age 32 ± 3.5 years, diabetes duration 22 ± 7.3 years, and early pregnancy HbA1c 52 ± 6.8 mmol/mol [6.9 ± 0.9%]) completed 24 weeks of postpartum follow-up. In the randomized phase, percent time in range 70-180 mg/dL (3.9-10 mmol/L) did not differ between groups (79.2 ± 8.7% vs. 78.2 ± 6.0%; P = 0.41). Participants randomized to closed-loop insulin delivery spent less time <70 mg/dL (3.9 mmol/L) and <54 mg/dL (3.0 mmol/L) (1.7 ± 0.8% vs. 5.5 ± 3.3% [P < 0.001] and 0.3 ± 0.2% vs. 1.1 ± 0.9% [P = 0.008]). Time >180 mg/dL (10 mmol/L) was not different between groups (18.7 ± 8.8% vs. 15.9 ± 7.7%; P = 0.21). In the continuation phase, those initially randomized to sensor-augmented pump therapy had less time <70 mg/dL after initiation of closed-loop insulin delivery (5.5 ± 3.3% vs. 3.3 ± 2.2%; P = 0.039). The closed-loop group maintained similar glycemic metrics in both study phases. There were no episodes of diabetic ketoacidosis or severe hypoglycemia in the randomized or continuation phase in either group. CONCLUSIONS: Women randomized to closed-loop insulin delivery postpartum had less hypoglycemia than those randomized to sensor-augmented pump therapy. There were no safety concerns. These findings are reassuring for use of closed-loop insulin delivery postpartum because of its potential to reduce hypoglycemia.

Perinatal and early life factors and asthma control among preschoolers: a population-based retrospective cohort study.

BACKGROUND: Preventing poor childhood asthma control is crucial for short-term and long-term respiratory health. This study evaluated associations between perinatal and early-life factors and early childhood asthma control. METHODS: This retrospective study used administrative health data from mothers and children born 2010-2012 with a diagnosis of asthma before age 5 years, in Alberta, Canada. The outcome was asthma control within 2 years after diagnosis. Associations between perinatal and early-life factors and risk of partly and uncontrolled asthma were evaluated by multinomial logistic regression. RESULTS: Of 7206 preschoolers with asthma, 52% had controlled, 37% partly controlled and 12% uncontrolled asthma 2 years after diagnosis. Compared with controlled asthma, prenatal antibiotics (adjusted risk ratio (aRR): 1.19; 95% CI 1.06 to 1.33) and smoking (aRR: 1.18; 95% CI 1.02 to 1.37), C-section delivery (aRR: 1.11; 95% CI 1.00 to 1.25), summer birth (aRR: 1.16; 95% CI 1.00 to 1.34) and early-life hospitalisation for respiratory illness (aRR: 2.24; 95% CI 1.81 to 2.76) increased the risk of partly controlled asthma. Gestational diabetes (aRR: 1.41; 95% CI 1.06 to 1.87), C-section delivery (aRR: 1.18; 95% CI 1.00 to 1.39), antibiotics (aRR: 1.32; 95% CI 1.08 to 1.61) and hospitalisation for early-life respiratory illness (aRR: 1.65; 95% CI 1.19 to 2.27) were associated with uncontrolled asthma. CONCLUSION: Maternal perinatal and early-life factors including antibiotics in pregnancy and childhood, gestational diabetes, prenatal smoking, C-section and summertime birth, and hospitalisations for respiratory illness are associated with partly or uncontrolled childhood asthma. These results underline the significance of perinatal health and the lasting effects of early-life experiences on lung development and disease programming.

Craniofacial Microsomia, Associated Congenital Anomalies, and Risk Factors in 63 Cases from the Alberta Congenital Anomalies Surveillance System.

OBJECTIVE: To report associated congenital anomalies with unexplained craniofacial microsomia (CFM) and the phenotypic overlap with other recurrent constellations of embryonic malformations (RCEM), and to assess prenatal and perinatal risk factors. STUDY DESIGN: This is a retrospective cross-sectional study. Cases with CFM, delivered between January 1, 1997, and December 31, 2019, were abstracted from the population-based Alberta Congenital Anomalies Surveillance System. Livebirths, stillbirths, and early fetal losses were reviewed to include all types of pregnancy outcomes along the spectrum of this condition. Prenatal and perinatal risk factors were compared with the Alberta birth population to assess differences between the 2 groups. RESULTS: There were 63 cases with CFM, yielding a frequency of 1 per 16 949. There was a high rate of cases (65%) with anomalies outside the craniofacial and vertebral regions. Congenital heart defects were the most common (33.3%). A single umbilical artery was found in 12.7% of cases. The twin/triplet rate of 12.7% was significantly higher than the Alberta rate of 3.3% (P < .0001). There was an overlap with a second RCEM condition in 9.5% of cases. CONCLUSIONS: Although CFM is primarily a craniofacial condition, the majority of cases have congenital anomalies affecting other systems requiring additional assessments, including an echocardiogram, renal ultrasound examination, and a complete vertebral radiograph. The high rate of an associated single umbilical artery raises the possibility of a related etiological mechanism. Our findings support the proposed concept of RCEM conditions.

The REDUCED trial: a cluster randomized trial for REDucing the utilization of CEsarean delivery for dystocia.

BACKGROUND: To reduce cesarean delivery rates in nulliparous women, guidelines for diagnosing nonprogressive labor have been developed by the National Institute of Child Health and Human Development, the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine. These are mainly based on data from the Consortium for Safe Labor study. The guidelines have not been tested in a clinical trial, so the efficacy and safety of this new approach is uncertain. OBJECTIVE: This study aimed to assess whether adoption of new guidelines for diagnosing nonprogressing labor would reduce cesarean delivery rates. STUDY DESIGN: We conducted a cluster randomized controlled trial of a knowledge translation program of the guidelines in 26 Canadian hospitals (13 control sites and 13 intervention sites). The sites included all intrapartum care sites in Alberta that perform cesarean delivery and deliver at least 70 nulliparous women annually. The baseline period started on January 1, 2015. The intervention was initiated at the first intervention site in January 2017. The follow-up period began at the first intervention site in February 2017 and lasted till February 2020. The primary outcome was the rate of cesarean delivery in nulliparous women with vertex presentation in labor at term. The secondary outcomes included spontaneous vaginal birth and maternal and neonatal safety. The main data source for the primary and secondary outcomes was the Alberta Perinatal Health Program database. The cesarean delivery rates were assessed using repeated measures mixed effects logistic regression applied to individual births. RESULTS: The analysis was based on 45,193 deliveries at intervention sites and 43,725 deliveries at control sites. There was no evidence of a decrease in the rate of cesarean delivery in association with the intervention (baseline-adjusted odds ratio, 0.94; 95% confidence interval [0.85-1.05]; P=.259). The rate of spontaneous vaginal delivery increased slightly (baseline-adjusted odds ratio, 1.10; 95% confidence interval, [1.01-1.18]; P=.024). We did not observe any differences in adverse maternal or neonatal outcomes. CONCLUSION: Cesarean delivery rates in nulliparous women were not reduced by the application of recent guidelines for the diagnosis of nonprogressive labor. Spontaneous vaginal delivery-a secondary outcome-was increased in the intervention group. The intervention appears to be safe.

The Alberta Congenital Anomalies Surveillance System: a 40-year review with prevalence and trends for selected congenital anomalies, 1997-2019. / Le système de surveillance des anomalies congénitales de l'Alberta : compte rendu des données sur 40 ans avec prévalence et tendances de certaines anomalies congénitales entre 1997 et 2019.

INTRODUCTION: Current published long-term provincial or territorial congenital anomaly data are lacking for Canada. We report on prevalence (per 1000 total births) and trends in 1997-2019, in Alberta, Canada, for selected congenital anomalies. Associated risk factors are also discussed. METHODS: We used data from the Alberta Congenital Anomalies Surveillance System (ACASS) to calculate the prevalence and perform chi-square linear trend analyses. RESULTS: From 1997 to 2019, the overall prevalence of neural tube defects was stable, at 0.74 per 1000 total births. The same was true for spina bifida (0.38), orofacial clefts (1.99), more severe CHDs (transposition of the great arteries, 0.38; tetralogy of Fallot, 0.33; and hypoplastic left heart syndrome, 0.32); and gastroschisis (0.38). Anencephaly, cleft palate and anorectal malformation significantly decreased with a prevalence of 0.23, 0.75 and 0.54 per 1000 total births, respectively. Significantly increasing trends were reported for anotia/microtia (0.24), limb reduction anomalies (0.73), omphalocele (0.36) and Down syndrome (2.21) and for hypospadias and undescended testes (4.68 and 5.29, respectively, per 1000 male births). CONCLUSION: Congenital anomalies are an important public health concern with significant social and societal costs. Surveillance data gathered by ACASS for over 40 years can be used for planning and policy decisions and the evaluation of prevention strategies. Contributing genetic and environmental factors are discussed as is the need for continued surveillance and research.

Emergency Department Visits During Pregnancy.

STUDY OBJECTIVE: Pregnant women often seek care in an emergency department (ED). We sought to describe the frequency, characteristics, and factors associated with increased ED visits during pregnancy. METHODS: We conducted a retrospective cohort study using administrative health data of all pregnancies resulting in a live birth at 20 or more weeks of gestation in Alberta, Canada, from 2011 to 2017. The primary outcome was the occurrence of any ED visit during pregnancy. The secondary outcomes were ED visit characteristics and discharge disposition. We calculated rate ratios (RRs) and 95% confidence intervals (CIs) for associations between sociodemographic and clinical factors and increased ED visits during pregnancy using random-effect negative binomial regression adjusting for multiple pregnancies per person during the study period. RESULTS: We included 255,929 pregnancies from 193,965 women. Of all the pregnancy episodes followed, 37.3% (95% CI 37.1 to 37.5) had at least 1 ED visit, resulting in a total of 226,811 ED visits and an overall ED visit rate of 94.0 visits per 100 pregnancies (95% CI 93.6 to 94.3). Most visits were nonobstetric (46.4%) and resulted in ED discharge (85.3%). Increased ED visits were associated with living in remote (RR 6.9; 95 %CI 6.7 to 7.1) or rural (RR 3.4; 95% CI 3.4 to 3.5) areas, younger age (RR 1.9; 95% CI 1.8 to 2.0), intensive prenatal care (RR 1.5; 95% CI 1.5 to 1.5), major/moderate health conditions (RR 1.6; 95% CI 1.6 to 1.6), mental health conditions (RR 1.6; 95% CI 1.5 to 1.6), and high antepartum risk score (RR 1.1; 95% CI 1.1 to 1.1). CONCLUSION: Approximately 1 in 3 women in our sample visited the ED during pregnancy. A higher number of visits occurred in those with rural/remote residence, younger maternal age, and concomitant health conditions.

Shared Inherited Genetics of Benign Prostatic Hyperplasia and Prostate Cancer.

Background: The association between benign prostatic hyperplasia (BPH) and prostate cancer (PCa) remains controversial, largely due to a detection bias in traditional observational studies. Objective: To assess the association between BPH and PCa using inherited single nucleotide polymorphisms (SNPs). Design setting and participants: The participants were White men from the population-based UK Biobank (UKB). Outcome measurements and statistical analysis: The association between BPH and PCa was tested for (1) phenotypic correlation using chi-square, (2) genetic correlation (r g) based on genome-wide SNPs using linkage disequilibrium score regression, and (3) cross-disease genetic associations based on known risk-associated SNPs (15 for BPH and 239 for PCa), individually and cumulatively using genetic risk score (GRS). Results and limitations: Among 214 717 White men in the UKB, 24 623 (11%) and 14 311 (6.7%) had a diagnosis of BPH and PCa, respectively. Diagnoses of these two diseases were significantly correlated (χ2 = 1862.80, p < 0.001). A significant genetic correlation was found (r g = 0.16; 95% confidence interval 0.03-0.28, p = 0.01). In addition, significant cross-disease genetic associations for established risk-associated SNPs were also found. Among the 250 established genome-wide association study-significant SNPs of PCa or BPH, 49 were significantly associated with the risk of the other disease at p < 0.05, significantly more than expected by chance (N = 12, p < 0.001; χ2 test). Furthermore, significant cross-disease GRS associations were also found; GRSBPH was significantly associated with PCa risk (odds ratio [OR] = 1.26 [1.18-1.36], p < 0.001), and GRSPCa was significantly associated with BPH risk (OR = 1.03 [1.02-1.04], p < 0.001). Moreover, GRSBPH was significantly and inversely associated with lethal PCa risk in a PCa case-case analysis (OR = 0.58 [0.41-0.81], p = 0.002). Only White men were studied. Conclusions: BPH and PCa share common inherited genetics, which suggests that the phenotypic association of these two diseases in observational studies is not entirely caused by the detection bias. Patient summary: For the first time, we found that benign prostatic hyperplasia and prostate cancer are genetically related. This finding may have implications in disease etiology and risk stratification.

PEDF Deletion Induces Senescence and Defects in Phagocytosis in the RPE.

The retinal pigment epithelium (RPE) expresses the Serpinf1 gene to produce pigment epithelium-derived factor (PEDF), a retinoprotective protein that is downregulated with cell senescence, aging and retinal degenerations. We determined the expression of senescence-associated genes in the RPE of 3-month-old mice that lack the Serpinf1 gene and found that Serpinf1 deletion induced H2ax for histone H2AX protein, Cdkn1a for p21 protein, and Glb1 gene for ß-galactosidase. Senescence-associated ß-galactosidase activity increased in the Serpinf1 null RPE when compared with wild-type RPE. We evaluated the subcellular morphology of the RPE and found that ablation of Serpinf1 increased the volume of the nuclei and the nucleoli number of RPE cells, implying chromatin reorganization. Given that the RPE phagocytic function declines with aging, we assessed the expression of the Pnpla2 gene, which is required for the degradation of photoreceptor outer segments by the RPE. We found that both the Pnpla2 gene and its protein PEDF-R declined with the Serpinf1 gene ablation. Moreover, we determined the levels of phagocytosed rhodopsin and lipids in the RPE of the Serpinf1 null mice. The RPE of the Serpinf1 null mice accumulated rhodopsin and lipids compared to littermate controls, implying an association of PEDF deficiency with RPE phagocytosis dysfunction. Our findings establish PEDF loss as a cause of senescence-like changes in the RPE, highlighting PEDF as both a retinoprotective and a regulatory protein of aging-like changes associated with defective degradation of the photoreceptor outer segment in the RPE.

Ephrin B Activate Src Family Kinases in Fibroblasts Inducing Stromal Remodeling in Prostate Cancer.

Through stromal-epithelial interactions, carcinoma associated fibroblasts (CAF) play a critical role in tumor growth and progression. Activation of erythrophoyetin-producing human hepatocellular (Eph) receptors has been implicated in cancer. Eph receptor interactions with Ephrin ligands lead to bidirectional signals in the recipient and effector cells. The consequences of continuous reverse Ephrin signaling activation in fibroblasts on prostate cancer (PCa) is unknown. When compared to benign prostate fibroblast, CAF displayed higher expression of Ephrin B1, B2, and B3 ligands (EFNB1, EFNB2, and EFNB3). In this study, we found that continuous activation of EFNB1 and EFNB3 in a benign human prostate stromal cell line (BHPrS1) increased the expression of CAF markers and induced a CAF phenotype. BHPrS1EFNB1 and BHPrS1EFNB3 displayed a pro-tumorigenic secretome with multiple effects on neovascularization, collagen deposition, and cancer cell proliferation, overall increasing tumorigenicity of a premalignant prostate epithelial cell line BPH1 and PCa cell line LNCaP, both in vitro and in vivo. Inhibition of Src family kinases (SFK) in BHPrS1EFNB1 and BHPrS1EFNB3 suppressed EFNB-induced ɑ-SMA (Alpha-smooth muscle actin) and TN-C (Tenascin-C) in vitro. Our study suggests that acquisition of CAF characteristics via SFK activation in response to increased EFNB ligands could promote carcinogenesis via modulation of TME in PCa.

TNF is a potential therapeutic target to suppress prostatic inflammation and hyperplasia in autoimmune disease.

Autoimmune (AI) diseases can affect many organs; however, the prostate has not been considered to be a primary target of these systemic inflammatory processes. Here, we utilize medical record data, patient samples, and in vivo models to evaluate the impact of inflammation, as seen in AI diseases, on prostate tissue. Human and mouse tissues are used to examine whether systemic targeting of inflammation limits prostatic inflammation and hyperplasia. Evaluation of 112,152 medical records indicates that benign prostatic hyperplasia (BPH) prevalence is significantly higher among patients with AI diseases. Furthermore, treating these patients with tumor necrosis factor (TNF)-antagonists significantly decreases BPH incidence. Single-cell RNA-seq and in vitro assays suggest that macrophage-derived TNF stimulates BPH-derived fibroblast proliferation. TNF blockade significantly reduces epithelial hyperplasia, NFκB activation, and macrophage-mediated inflammation within prostate tissues. Together, these studies show that patients with AI diseases have a heightened susceptibility to BPH and that reducing inflammation with a therapeutic agent can suppress BPH.

Antagonism Between PEDF and TGF-ß Contributes to Type VI Osteogenesis Imperfecta Bone and Vascular Pathogenesis.

Osteogenesis imperfecta (OI) is a heterogeneous genetic disorder of bone and connective tissue, also known as brittle bone disease. Null mutations in SERPINF1, which encodes pigment epithelium-derived factor (PEDF), cause severe type VI OI, characterized by accumulation of unmineralized osteoid and a fish-scale pattern of bone lamellae. Although the potent anti-angiogenic activity of PEDF has been extensively studied, the disease mechanism of type VI OI is not well understood. Using Serpinf1(-/-) mice and primary osteoblasts, we demonstrate that loss of PEDF delays osteoblast maturation as well as extracellular matrix (ECM) mineralization. Barium sulfate perfusion reveals significantly increased vessel density in the tibial periosteum of Serpinf1(-/-) mouse compared with wild-type littermates. The increased bone vascularization in Serpinf1(-/-) mice correlated with increased number of CD31(+)/Endomucin(+) endothelial cells, which are involved in the coupling angiogenesis and osteogenesis. Global transcriptome analysis by RNA-Seq of Serpinf1(-/-) mouse osteoblasts reveals osteogenesis and angiogenesis as the biological processes most impacted by loss of PEDF. Intriguingly, TGF-ß signaling is activated in type VI OI cells, and Serpinf1(-/-) osteoblasts are more sensitive to TGF-ß stimulation than wild-type osteoblasts. TGF-ß stimulation and PEDF deficiency showed additive effects on transcription suppression of osteogenic markers and stimulation of pro-angiogenic factors. Furthermore, PEDF attenuated TGF-ß-induced expression of pro-angiogenic factors. These data suggest that functional antagonism between PEDF and TGF-ß pathways controls osteogenesis and bone vascularization and is implicated in type VI OI pathogenesis. This antagonism may be exploited in developing therapeutics for type VI OI utilizing PEDF and TGF-ß antibody. © 2022 American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Recurrence risk of villitis of unknown etiology: Analysis of a large retrospective cohort study, systematic review and meta-analysis.

INTRODUCTION: Recurrence risk of villitis of unknown etiology (VUE) remains uncertain because of few studies and their methodologic limitations. We calculated recurrence risk in a large population of deliveries after minimizing important biases and compared it to others via systematic review and meta-analysis. METHODS: Over 11 years of placenta pathology reports on singleton deliveries were retrieved and searched for 'villitis' or 'VUE'. Cases of acute villitis and chronic villitis from infections were eliminated via pathologist review. Reports were merged to data containing gestational age, parity and gravida. Recurrence risk of VUE per patient, per parity and per gravida was determined among patients with ≥2 placentas examined for deliveries ≥20 weeks gestation. Results were compared to those from articles and their references identified by a MEDLINE® search. Recurrence risks among methodologically similar studies were pooled using a random effects model. RESULTS: Among 29 124 placenta pathology reports from 27 087 patients, there were 2423 cases of VUE among 2382 patients, of which 153 had ≥2 placentas examined. There were 41 recurrent cases of VUE for a recurrence risk of 27% per patient, 22% per parity, and 19% per gravida. We identified 64 articles, of which 4 were retained. One examined all placentas from all births over a ∼3-year period, finding a recurrence risk of 27%. The remaining 3 studies, along with our own, used indications for placental examination and had a pooled recurrence risk of 30% (95% Confidence Interval: 0.21-0.41). DISCUSSION: In our study, which is the largest, most comprehensive, and methodologically robust to date, VUE recurrence risk was ∼30%.