Recent ucsdsom_obgyn_oapdeposits items

Haploinsufficiency of Sox2 causes fewer GnRH neurons and delayed puberty in mice

Thu, 4 Jun 2026 00:00:00 +0000

Mutations in the SOX2 gene have been previously linked to a syndromic form of isolated hypogonadotropic hypogonadism, with additional ocular and neurodevelopmental phenotypes. Recently, we reported a functional role for SOX2 in hypothalamic kisspeptin-expressing neurons and established a mechanistic relationship between SOX2 heterozygous variants and isolated hypogonadotropic hypogonadism. To further test the role of Sox2 in the hypothalamic-pituitary-gonadal axis, we generated mice with a whole-body heterozygous knockout of Sox2 (Sox2WT/KO). We found that heterozygous loss of Sox2 significantly delayed pubertal onset in both male and female Sox2WT/KO mice compared to wild-ype (WT) controls. In females, fertility was also compromised, with fewer estrous cycles and a significant delay in time to first litter of Sox2WT/KO dams compared to WT controls. Circulating levels of gonadotropins were normal in both male and female Sox2WT/KO mice, suggesting a functional pituitary. Finally,...

Surging towards a better understanding of ovulation.

Thu, 4 Jun 2026 00:00:00 +0000

The ability to record the real-time activity of specialized neurons in the brains of female mice is providing new insights into the hormonal control of ovulation.

FAK inhibition in ovarian cancer releases omega-3 fatty acids to program CXCL13-producing anti-tumor resident peritoneal macrophages

Fri, 15 May 2026 00:00:00 +0000

High-grade serous ovarian cancer (HGSOC) is a lethal malignancy characterized by therapy resistance. Focal adhesion kinase (FAK) is highly expressed in HGSOC, yet its impact on tumor-immune communication remains incompletely defined. Using three syngeneic ovarian cancer models, we show that FAK inhibition (FAKi) increased macrophage CXCL13 expression and promoted peritoneal B cell infiltration. Combining FAKi with low-dose pegylated doxorubicin and anti-T cell immunoreceptor with Ig and ITIM domains (TIGIT) checkpoint blockade suppressed orthotopic ovarian tumor growth, extended survival, and induced tertiary lymphoid structures. Macrophage lineage factor GATA6 inactivation reduced CXCL13 expression, enhanced FAK-knockout tumor growth, and limited ascites B cell accumulation. Mechanistically, FAKi-treated or FAK-deficient tumor cells release exosomes enriched in omega-3 fatty acids that stimulated macrophage CXCL13 production. Exposure of macrophages to tumor-derived omega-3 lipids...

Liposomal Doxorubicin, but Not Platinum-Taxane, Supports MHC-II Expression and Immune Maturation in the Ovarian Tumor Microenvironment

Fri, 15 May 2026 00:00:00 +0000

BACKGROUND: Ovarian cancer is an immunologically cold tumor that is treated with surgery and a chemotherapy regimen of platinum agents with taxanes. Paradoxically, elevated levels of several immune markers are effective at predicting prognosis for patients with ovarian cancer, though it is not clear how chemotherapy might influence this. Chemotherapy elicits immunogenic cell death, yet tumor-controlling doses of chemotherapy are also immunotoxic. OBJECTIVES: To evaluate interactions of chemotherapy with the immune system, we studied the impact of chemotherapy in an aggressive mouse model of ovarian cancer developed within our lab. METHODS: Using a single-cell transcriptomics sequencing approach, supported by flow cytometry, we evaluated the influence of a first-line therapy, cisplatin and docetaxel, and a second-line therapy, pegylated liposomal doxorubicin (PLD), on control of tumor growth and on tumor-associated immune populations of cells. RESULTS: Both chemotherapy approaches...

Kisspeptin made in the preoptic area is required for normal estradiol-induced LH surges and optimal fertility in females

Thu, 7 May 2026 00:00:00 +0000

Ovulation is triggered by a surge in luteinizing hormone (LH) secretion from the pituitary. The LH surge is itself driven by a surge in GnRH release induced by estrogen positive feedback action in the hypothalamus. While ERα-expressing kisspeptin (Kiss1) neurons in the preoptic area (in mice, the rostral periventricular region of the third ventricle [RP3V]) are proposed to mediate this estrogen positive feedback event, the functional necessity of RP3V-derived kisspeptin for the LH surge has not been directly tested. Here we leveraged Cre/lox technology and the known high co-expression of tyrosine hydroxylase (TH) with Kiss1 in only the RP3V region to generate novel transgenic mice with selective knockout (KO) of the Kiss1 gene in just RP3V neurons (Kiss1RP3V KO mice). In situ hybridization confirmed a significant 70% reduction in cells expressing Kiss1 in the RP3V region, but not in the arcuate nucleus, along with no change in RP3V Th expression. Kiss1RP3V KO females exhibited...

Mode of delivery among pregnant people with obesity undergoing labor induction in the late preterm period

Tue, 14 Apr 2026 00:00:00 +0000

Introduction: Pregnant people with obesity are more likely than those without obesity to undergo induction of labor and to require unplanned cesarean delivery during induction at term. Whether they are more likely to undergo unplanned cesarean delivery during preterm induction of labor is unknown. This study examines the induction of labor success among people with obesity undergoing indicated late preterm induction of labor. Methods: This is a secondary analysis of a multicenter, randomized trial of betamethasone versus placebo among pregnancies at risk for late preterm delivery, defined as delivery between 34 weeks and 0 days and 36 weeks and 6 days between 2010 and 2015. This study included pregnant people with live singleton nonanomalous gestations at high risk for late preterm delivery before 36 weeks and 6 days. This secondary analysis included all participants who underwent a medically indicated preterm induction of labor starting before 36 weeks and 5 days. We excluded...

Induction of Labor Is Not Associated with Decreased Rates of Breastfeeding in Late Preterm Pregnancies

Tue, 14 Apr 2026 00:00:00 +0000

Background Some studies suggest that induction of labor at term is associated with lower rates of breastfeeding than spontaneous labor. Objective Our objective was to evaluate whether late preterm medically indicated induction of labor is associated with decreased rates of breastfeeding and/or increased rates of breastfeeding complications at the time of discharge from the delivery hospitalization. Study Design This secondary analysis of a randomized trial of individuals at high risk for late preterm delivery, defined as delivery between 34+0 and 36+6 weeks, included non-anomalous, singleton pregnancies and excluded those with unlabored cesareans or preterm prelabor rupture of membranes. The parent study collected detailed data on breastfeeding and the presence of breastfeeding difficulties, defined as issues in milk production or infant feeding. Subjects with incomplete breastfeeding data were additionally excluded. Participants undergoing late preterm indicted inductions were...

Menstrual Dysfunction Is Associated With Elevated Liver Enzymes in Adolescent Females: A United States Population-Based Study

Tue, 3 Mar 2026 00:00:00 +0000

Purpose Polycystic ovary syndrome and metabolic dysfunction–associated steatotic liver disease (MASLD) both emerge during adolescence; however, it remains unknown whether menstrual abnormalities and hyperandrogenism signals increased hepatic risk. Methods We analyzed 2011–2020 National Health and Nutrition Examination Survey data for 1,651 females aged 12–19 years in the United States who were at least 2 years postmenarche. Amenorrhea was defined as self-reported absence of menses in the past 12 months. Biochemical hyperandrogenism was defined as free androgen index ≥5. Elevated alanine aminotransferase (ALT; >22 U/L) was the primary hepatic outcome; suspected MASLD was defined as elevated ALT plus ≥1 cardiometabolic risk factor. Survey-weighted logistic regression models adjusted for age, race and ethnicity, and body mass index (BMI) percentile. Results Amenorrhea was reported by 2.8% of participants and was associated with higher odds of elevated ALT (adjusted odds ratio...

Workup and Management of Polycystic Ovary Syndrome

Tue, 3 Mar 2026 00:00:00 +0000

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in females. It is a heterogeneous condition that frequently manifests in adolescence. Signs and symptoms include various combinations of hyperandrogenism, ovulatory dysfunction, and polycystic ovaries. The etiology of PCOS is still largely unknown, although genetic and environmental factors, including insulin resistance and obesity, have been implicated. Diagnosis is based on the fulfillment of the 2003 Rotterdam criteria, which require two of three cardinal features – hyperandrogenism, oligomenorrhea, or amenorrhea – and polycystic ovaries on ultrasound. Careful history and physical examination are critical first steps in evaluation. Initial evaluation also involves documenting the presence of hyperandrogenism and ruling out other diagnoses. Ultrasound imaging should be considered as part of the initial evaluation and monitoring but is not necessary for all patients. Treatment remains largely empirical with an...

Genetic variants reshape the m6A epitranscriptome and drive transcriptomic reprogramming in colorectal cancer

Thu, 26 Feb 2026 00:00:00 +0000

Genome-wide association studies (GWAS) have identified numerous single-nucleotide polymorphisms (SNPs) associated with various diseases, including cancer. However, the mechanisms by which these SNPs contribute to disease susceptibility remain largely unclear. While recent studies have explored the transcriptional impact of disease-associated SNPs, their role in post-transcriptional regulation has been less extensively investigated. In this study, we investigated whether cancer-associated SNPs influence gene expression by altering N6-methyladenosine (m6A) RNA methylation. We collected GWAS-identified SNPs across nine cancer types and integrated these with matched tumor and normal m6A RNA immunoprecipitation sequencing (m6A-seq) and RNA sequencing (RNA-seq) datasets. We first identified differentially methylated m6A sites and assessed whether cancer-associated SNPs were enriched within these regions. These analyses revealed that cancer-associated SNPs were significantly enriched...

Malignant a-to-I RNA Editing By ADAR1 Drives T-Cell Acute Lymphoblastic Leukemia Relapse Via Attenuating dsRNA Sensing

Thu, 12 Feb 2026 00:00:00 +0000

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that frequently occurs in children, adolescents, and young adults. Approximately 10-20% of T-ALL patients will experience relapse months or years following remission and will often become refractory to further treatments. The survival of relapsed/refractory patients is very poor, with an overall survival rate of less than a 25% overall survival rate. Relapsed patients often have enriched pools of leukemia initiating cells (LICs) with enhanced pro-survival and self-renewal capacity, suggesting a potential vulnerable population for effective targeted therapies with less toxicity. An emerging research topic in LIC biology is the identification of RNA modifying enzymes that are important for LIC self-renewal and survival. ADAR1 enzymes catalyze the transition of adenosine (A) to inosine (I) in precursor double-stranded RNA (dsRNA). Epitranscriptomic A-to-I RNA editing events are widespread in the...

Barriers to specialty care among patients with vulvovaginal symptoms: findings from a retrospective cohort of vulvovaginal clinic patients

Thu, 12 Feb 2026 00:00:00 +0000

Barriers to specialty care among patients with vulvovaginal symptoms: findings from a retrospective cohort of vulvovaginal clinic patients

Joint, multifaceted genomic analysis enables diagnosis of diverse, ultra-rare monogenic presentations

Mon, 26 Jan 2026 00:00:00 +0000

Genomics for rare disease diagnosis has advanced at a rapid pace due to our ability to perform in-depth analyses on individual patients with ultra-rare diseases. The increasing sizes of ultra-rare disease cohorts internationally newly enables cohort-wide analyses for new discoveries, but well-calibrated statistical genetics approaches for jointly analyzing these patients are still under development. The Undiagnosed Diseases Network (UDN) brings multiple clinical, research and experimental centers under the same umbrella across the United States to facilitate and scale case-based diagnostic analyses. Here, we present the first joint analysis of whole genome sequencing data of UDN patients across the network. We introduce new, well-calibrated statistical methods for prioritizing disease genes with de novo recurrence and compound heterozygosity. We also detect pathways enriched with candidate and known diagnostic genes. Our computational analysis, coupled with a systematic clinical...

Integrating community perspectives to improve survey completion rates in public health research by refining controversial survey elements

Thu, 4 Dec 2025 00:00:00 +0000

Background: Many factors can impact survey completion rates, including survey length, sensitivity of the topics addressed, and clarity of wording. This study used cognitive interviews (CIs), a methodological tool that can aid in developing and refining elements for multi-faceted assessments, and previous survey response patterns to refine, streamline, and increase response rates of RADx-UP Common Data Elements (CDEs) for survey/questionnaire use. Methods: Ten previously enrolled CO-CREATE study participants were interviewed between May-June 2023. Interviewees identified CDEs that were "confusing, uncomfortable, and/or not applicable," along with their reasoning. Interview data were analyzed using a rapid qualitative analytic approach, resulting in a summary matrix categorized by language. For further contextualization, CDE response rates were calculated for the 9147 surveys administered during the CO-CREATE study (May 2021-March 2023) and compared against their survey position. Results:...

Sources of successful participant engagement in a public health research study: A focus on a Latino community

Thu, 4 Dec 2025 00:00:00 +0000

BACKGROUND: Latino populations remain vastly underrepresented in clinical and translational research. This study aims to characterize the most common sources of successful participant engagement within our sample. METHODS: Between February 2022 and March 2023, research staff systematically recorded how participants learned about an ongoing study (which we term source of successful participant engagement) designed to co-create and implement a COVID-19 testing program in a U.S./Mexico border community. Demographic characteristics were correlated with each source of participant engagement at the univariate level using a chi-squared test and, if significant, were included in a multinomial logistic regression model to determine the association between participant characteristics and source of participant engagement. RESULTS: A total of 2836 individuals responded to questions regarding source of participant engagement; the most common responses were: Word of Mouth (32%), Clinic/Provider...

Exploratory analysis of placenta accreta spectrum content on TikTok using #placentaaccreta, #accreta, and #placentaprevia

Fri, 7 Nov 2025 00:00:00 +0000

Exploratory analysis of placenta accreta spectrum content on TikTok using #placentaaccreta, #accreta, and #placentaprevia

Postpartum Hemorrhage

Fri, 7 Nov 2025 00:00:00 +0000

This JAMA Insights discusses risk factors for, assessment, and management of postpartum hemorrhage.

Predictive Capacity of First-Trimester Diagnosis of Placenta Previa

Thu, 9 Oct 2025 00:00:00 +0000

First-trimester transabdominal ultrasound (TAUS) is sometimes used to diagnose placenta previa and counsel patients accordingly. We aimed to determine the predictive capacity of a first-trimester transabdominal ultrasonographic placenta previa diagnosis for persistence to the second trimester.Retrospective cohort study of patients with singleton pregnancies and first-trimester transabdominal ultrasonographic placenta previa diagnoses from January to December 2022. The primary outcome was the predictive capacity of a first-trimester TAUS diagnosis of placenta previa for placenta previa persistence into the second trimester. Secondary outcomes included the predictive capacity of a first-trimester TAUS for placenta previa persistence to delivery and risk factors associated with placenta previa persistence. Chi-square and student's t-test were used to determine statistical significance, and a multivariable logistic regression determined the strength of associations.Of the 185...

Real-world impact of COVID-19 vaccination, household exposure, and circulating SARS-CoV-2 variants on infection risk and symptom presentation in a U.S./Mexico border community

Thu, 28 Aug 2025 00:00:00 +0000

Background: San Ysidro, a densely populated primarily Latino community near the U.S./Mexico border, reported the highest rate of COVID-19 infection in San Diego County. In this increased infection risk environment, we explored the impact of COVID-19 vaccine status, household exposure, and primary circulating SARS-CoV-2 variant on the probability of infection and symptom presentation while controlling for temporal and sociodemographic factors. Methods: Data were collected as part of CO-CREATE (Community-Driven Optimization of COVID-19 Testing to Reach and Engage underserved Areas for Testing Equity), a collaborative implementation study between University of California San Diego, a local Federally Qualified Health Center, and the Global Action Research Center. Self-reported sociodemographic factors, household exposure, vaccine status, and symptoms were extracted from a cross-sectional questionnaire completed by participants; PCR test results were used for analysis. Multi-level...

Novel direct effect of CCR2 receptor on follicle activation process

Thu, 14 Aug 2025 00:00:00 +0000

Introduction: The regulation of primordial follicle activation is crucial for maintaining ovarian function, the duration of the reproductive phase, and fertility in women; therefore, we propose as our general objective to determine the physiological role of the chemokine receptor CCR2 within the follicular activation process. Methods: Ovarian cortex fragments from adult domestic cats (Felis catus) were cultured under different experimental groups: control (media alone), CCR2 antagonist (1µM), and recombinant chemokine CC-motif ligand 2 (CCL2) at two concentrations (10 ng/ml and 100 ng/ml) for 4 h or 48 h. At the end of the culture, the fragments were collected for RNA extraction, cDNA synthesis, and quantitative real-time PCR (4 h) or fixed and processed for paraffin embedding (48 h) for hematoxylin and eosin staining or immunohistochemistry for Ki67, bromodeoxyuridine (BrdU) and AKTp. Results: Stimulation of CCR2 significantly increased the normalized mRNA expression of...

55 MHz constant field dielectric warming of kidneys and ovaries cryopreserved by vitrification

Thu, 14 Aug 2025 00:00:00 +0000

Organs cryopreserved by vitrification benefit from fast warming to avoid growth and recrystallization of ice that may nucleate during cooling and during warming. Rapid warming is especially important for tissue that doesn't absorb the full concentration of perfused cryoprotectants. Nanowarming uses an oscillating magnetic field to heat magnetic nanoparticles introduced into blood vessels during cryoprotectant perfusion. Dielectric warming uses an oscillating electric field to directly heat water and cryoprotectant molecules everywhere inside an organ. The efficiency of dielectric warming peaks at a particular solution viscosity and temperature that depends on the field oscillation frequency. Below that temperature, field uniformity is very important for uniform warming. An 800 W 55 MHz dielectric warming system was constructed that reached peak warming efficiency at -60 °C instead of -70 °C previously observed at 27 MHz when using the M22 vitrification...

Bacterial vaginosis toxins impair sperm capacitation and fertilization

Fri, 1 Aug 2025 00:00:00 +0000

STUDY QUESTION: What effect do toxins produced by bacterial vaginosis (BV) bacteria have on sperm function? SUMMARY ANSWER: BV toxins dysregulate sperm capacitation and intracellular calcium homeostasis, and impair the ability of sperm to fertilize oocytes. WHAT IS KNOWN ALREADY: In BV, which is linked to infertility, overgrowth of Prevotella and Gardnerella in the vagina is accompanied by elevated concentrations of the toxins lipopolysaccharide (LPS) and vaginolysin (VLY). STUDY DESIGN, SIZE, DURATION: This was a laboratory study in which human semen samples were collected from consenting healthy donors with normal semen parameters. Mouse sperm samples were obtained from the caudal epididymis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Motile mouse and human sperm were isolated via swim-up and treated under non-capacitating or capacitating conditions. LPS from Escherichia coli was commercially available. VLY was produced by cloning the Gardnerella VLY protein in the ClearColi...

Understanding adaptations in a community-vetted COVID-19 testing program

Mon, 21 Jul 2025 00:00:00 +0000

Background: Adaptations are expected when complex public health interventions are implemented in dynamically and rapidly changing real-world settings, as seen for many programs during the COVID-19 pandemic. Systematic documentation of adaptations to intervention components and strategies are critical when assessing their impact on implementation. Here, we report processes used for tracking and evaluating adaptations made during the CO-CREATE project, which aimed to address COVID-19 testing disparities in the San Ysidro US/Mexico border community. Methods: The study utilized a longitudinal, prospective, mixed methods approach to systematically document and assess adaptations across the pre-implementation, early and mid/late-implementation phases of the project. Aggregated from a combination of sources (i.e., meeting notes, Advisory Board transcripts, and periodic reflections), adaptations were entered weekly into an electronic database that captured information on 16 characteristics...

Sustained dual delivery of metronidazole and viable Lactobacillus crispatus from 3D-printed silicone shells

Wed, 11 Jun 2025 00:00:00 +0000

Bacterial vaginosis (BV) is an imbalance of the vaginal microbiome in which there are limited lactobacilli and an overgrowth of anaerobic and fastidious bacteria such as Gardnerella. The propensity for BV recurrence is high, and therapies involving multiple treatment modalities are emerging to meet this need. However, current treatments requiring frequent therapeutic administration are challenging for patients and impact user compliance. Three-dimensional (3D)-printing offers a novel alternative to customize platforms to facilitate sustained therapeutic delivery to the vaginal tract. This study designed a novel vehicle intended for dual sustained delivery of both antibiotic and probiotic. 3D-printed compartmental scaffolds consisting of an antibiotic-containing silicone shell and a core containing probiotic Lactobacillus were developed with multiple formulations including biomaterials sodium alginate (SA), polyethylene glycol (PEG), polyvinyl alcohol (PVA), polyethylene oxide...

Preclinical validation of electrospun fibers to achieve vaginal colonization by Lactobacillus crispatus

Wed, 11 Jun 2025 00:00:00 +0000

Communities of bacteria collectively known as the vaginal microbiota reside in the human vagina. Bacterial vaginosis (BV) describes an imbalance of this microbiota, affecting more than 25% of women worldwide, and is linked to health problems such as infertility, cervical cancer, and preterm birth. Following antibiotic treatment, BV becomes recurrent in many individuals. Lactobacillus crispatus is widely believed to contribute to a healthy vaginal microbiome, and its therapeutic application has shown promise in early clinical trials investigating adjunct therapies for lasting treatment of conditions such as BV. There is a pressing need for therapeutic platforms that apply biologically active agents such as probiotic bacteria, to the vagina with little user effort but lasting effect. Here, we use a mouse model to investigate the functional utility and potential harms of soft, slow-dissolving fibers made by electrospinning polyethylene oxide (PEO) and poly(lactic-co-glycolic...

Nulliparous with Class III Obesity at Term: Labor Induction or Cesarean Delivery without Labor

Thu, 5 Jun 2025 00:00:00 +0000

OBJECTIVE: This study aimed to compare maternal and neonatal outcomes between labor induction versus cesarean delivery (CD) without labor among nulliparous individuals with class III obesity (body mass index [BMI] ≥40 kg/m²). STUDY DESIGN: A retrospective cohort study of all nulliparous singleton deliveries at ≥37 weeks with a BMI of ≥40 kg/m² at delivery between March 2020 and February 2022. We excluded individuals with spontaneous labor, fetal malformations, and stillbirths. The primary outcome was a composite of maternal mortality and morbidity, including infectious and hemorrhagic morbidity. The secondary outcome was a neonatal composite. A subgroup analysis evaluated patients with a BMI of ≥50 kg/m². Another subgroup analysis compared outcomes between CD without labor and an indicated CD following induction. A multivariable logistic regression was applied. For adjustment, we used possible confounders identified in a univariate analysis. RESULTS:...

Phylogeographic and genetic network assessment of COVID-19 mitigation protocols on SARS-CoV-2 transmission in university campus residences

Thu, 22 May 2025 00:00:00 +0000

BACKGROUND: Congregate living provides an ideal setting for SARS-CoV-2 transmission in which many outbreaks and superspreading events occurred. To avoid large outbreaks, universities turned to remote operations during the initial COVID-19 pandemic waves in 2020 and 2021. In late-2021, the University of California San Diego (UC San Diego) facilitated the return of students to campus with comprehensive testing, vaccination, masking, wastewater surveillance, and isolation policies. METHODS: We performed molecular epidemiological and phylogeographic analysis of 4418 SARS-CoV-2 genomes sampled from UC San Diego students during the Omicron waves between December 2021 and September 2022, representing 58% of students with confirmed SARS-CoV-2 infection. We overlaid these analyses across on-campus residential information to assess the spread and persistence of SARS-CoV-2 within university residences. FINDINGS: Within campus residences, SARS-CoV-2 transmission was frequent among students...

Wastewater-integrated pathogen surveillance dashboards enable real-time, transparent, and interpretable public health risk assessment and dissemination

Thu, 22 May 2025 00:00:00 +0000

Timely pathogen surveillance and reporting is essential for effective public health guidance. Web dashboards have become a key tool for communicating public health information to stakeholders, health care workers, and the broader community. Over the SARS-CoV-2 pandemic, wastewater surveillance has increasingly been incorporated into public health workflows for outbreak monitoring and response, enabling community-representative and low-cost monitoring to supplement clinical surveillance. However, the methods used for visualization and dissemination of clinical and wastewater surveillance data differ across programs, and best practices are yet to be defined. In this work, we demonstrate data workflows and dashboards used to perform wastewater-based public health surveillance in tandem with clinical data across local and national scales, leveraging custom-built, reproducible, and open-source software. Using a centralized data aggregation and analysis hub approach, we establish multiple...

Impact of mismatch repair (MMR) status on recurrence in high intermediate risk endometrial cancer

Thu, 22 May 2025 00:00:00 +0000

BACKGROUND: Approximately 25 % of endometrial cancers harbor deficiencies in mismatch repair (dMMR). The clinical impact of this molecular aberration remains undefined in patients with high intermediate risk (HIR) endometrial cancer. METHODS: We conducted a retrospective chart review of women diagnosed with Stage I high-intermediate risk endometrioid endometrial cancer in two hospital systems in Southern California between 2016 and 2018. We collected demographic information, mismatch repair status, pathology reports, and time to recurrence. RESULTS: 244 patients met inclusion criteria, of which 86 (35 %) were found to be dMMR. The dMMR patient population had higher relative risks of lymphovascular space invasion (relative risk 1.63, 95 % confidence interval 1.26-2.10, p-value 0.0002) but were less likely to have deep myometrial invasion (relative risk 0.81, 95 % confidence interval 0.66-0.99, p-value 0.047) when compared to the pMMR EC cohort. No differences...

OC 33.2 Maladaptive Lymphangiogenesis is Associated with Synovial Iron Accumulation and Delayed Clearance in FVIII-/- Mice After Induced Hemarthrosis

Thu, 24 Apr 2025 00:00:00 +0000

OC 33.2 Maladaptive Lymphangiogenesis is Associated with Synovial Iron Accumulation and Delayed Clearance in FVIII-/- Mice After Induced Hemarthrosis

Gut bacterial lactate stimulates lung epithelial mitochondria and exacerbates acute lung injury

Thu, 24 Apr 2025 00:00:00 +0000

Acute respiratory distress syndrome (ARDS) is an often fatal critical illness where lung epithelial injury leads to intrapulmonary fluid accumulation. ARDS became widespread during the COVID-19 pandemic, motivating a renewed effort to understand the complex etiology of this disease. Rigorous prior work has implicated lung endothelial and epithelial injury in response to an insult such as bacterial infection; however, the impact of microorganisms found in other organs on ARDS remains unclear. Here, we use a combination of gnotobiotic mice, cell culture experiments, and re-analyses of a large metabolomics dataset from ARDS patients to reveal that gut bacteria impact lung cellular respiration by releasing metabolites that alter mitochondrial activity in lung epithelium. Colonization of germ-free mice with a complex gut microbiota stimulated lung mitochondrial gene expression. A single human gut bacterial species, Bifidobacterium adolescentis, was sufficient to replicate this...

Increasing capacity for ethnically-based community leaders to engage in policy change: assessing the impact of a train-the-trainer approach

Sat, 19 Apr 2025 00:00:00 +0000

BackgroundThe COVID-19 pandemic exacerbated existing disparities in healthcare access and outcomes, particularly among underserved communities. As one site participating in the NIH-funded Community Engagement Alliance Against COVID-19, our focus was to address COVID-19 disparities by training immigrant and refugee communities to advocate for their needs by increasing capacity to campaign for policy-level changes.ObjectiveTo evaluate the impact of a train-the-trainer policy advocacy program for ethnically-based community leaders within San Diego County using a mixed-methods evaluation.MethodsWe partnered with a non-profit social change, intermediary organization to adapt a five-session, 4-hour per session training that was conducted over five weeks. A baseline survey, pre- and post-training surveys, and ethnographic documentation were employed during each session.ResultsAmong participants (n = 16), 50% were Latino(a), 25% were Somali Bantu, and 25% were Karen. Training results...

Considerations for prenatal and postpartum management of a female patient with ornithine transcarbamylase deficiency

Fri, 11 Apr 2025 00:00:00 +0000

We report on pregnancy management and outcomes in a 27-year-old female patient with ornithine transcarbamylase (OTC) deficiency, the most common inherited enzyme deficiency in the urea cycle. Our patient was diagnosed during childhood after hyperammonemia associated with surgery and steroid treatment and was well-controlled with nitrogen scavenger treatment, low-protein diet, and L-citrulline supplementation. OTC gene sequencing identified a variant of unknown significance that has more recently been classified as likely pathogenic. Women with OTC deficiency are at increased risk of hyperammonemia during pregnancy and the postpartum period, therefore monthly follow up and laboratory assessments are critical in management decision making. Our patient was maintained on glycerol phenylbutyrate, L-citrulline and essential amino acid supplements, along with restricted protein intake during pregnancy. A multidisciplinary approach with the obstetrics, prenatal genetics, high risk...

Prospermatogonia

Thu, 10 Apr 2025 00:00:00 +0000

Prospermatogonia

Extracellular microRNAs associated with psychiatric symptoms in the Normative Aging Study

Mon, 7 Apr 2025 00:00:00 +0000

Earlier studies have revealed microRNAs (miRNAs) as potential biomarkers for neurological conditions, however, such evidence on psychiatric outcomes is limited. We utilized the Normative Aging Study (NAS) cohort to investigate the associations between extracellular miRNAs (ex-miRNA) and psychiatric symptoms among a group of older male adults, along with the targeted genes and biological pathways. We studied 569 participants with miRNA profile primarily measured in extracellular vesicles isolated from plasma, and psychiatric symptoms reported over 1996-2014 with repeated measures. Global and dimension scales of psychiatric symptoms were measured via the administration of Brief Symptom Inventory (BSI) per visit covering nine aspects of psychiatric health, such as anxiety, depression, hostility, psychoticism, etc. Ex-miRNAs were profiled using small RNA sequencing. Associations of expression of 395 ex-miRNAs (present in >70% samples) with current mental status were assessed using...

Inhibition of human-HPV hybrid ecDNA enhancers reduces oncogene expression and tumor growth in oropharyngeal cancer

Fri, 4 Apr 2025 00:00:00 +0000

Extrachromosomal circular DNA (ecDNA) has been found in most types of human cancers, and ecDNA incorporating viral genomes has recently been described, specifically in human papillomavirus (HPV)-mediated oropharyngeal cancer (OPC). However, the molecular mechanisms of human-viral hybrid ecDNA (hybrid ecDNA) for carcinogenesis remains elusive. We characterize the epigenetic status of hybrid ecDNA using HPVOPC cell lines and patient-derived tumor xenografts, identifying HPV oncogenes E6/E7 in hybrid ecDNA are flanked by previously unrecognized somatic DNA enhancers and HPV L1 enhancers, with strong cis-interactions. Targeting of these enhancers by clustered regularly interspaced short palindromic repeats interference or hybrid ecDNA by bromodomain and extra-terminal inhibitor reduces E6/E7 expression, and significantly inhibites in vitro and/or in vivo growth only in ecDNA(+) models. HPV DNA in hybrid ecDNA structures are associated with previously unrecognized somatic and HPV enhancers...

Themis suppresses the effector function of CD8+ T cells in acute viral infection

Fri, 4 Apr 2025 00:00:00 +0000

CD8+ T cells play a central role in antiviral immune responses. Upon infection, naive CD8+ T cells differentiate into effector cells to eliminate virus-infected cells, and some of these effector cells further differentiate into memory cells to provide long-term protection after infection is resolved. Although extensively investigated, the underlying mechanisms of CD8+ T-cell differentiation remain incompletely understood. Themis is a T-cell-specific protein that plays critical roles in T-cell development. Recent studies using Themis T-cell conditional knockout mice also demonstrated that Themis is required to promote mature CD8+ T-cell homeostasis, cytokine responsiveness, and antibacterial responses. In this study, we used LCMV Armstrong infection as a probe to explore the role of Themis in viral infection. We found that preexisting CD8+ T-cell homeostasis defects and cytokine hyporesponsiveness do not impair viral clearance in Themis T-cell conditional knockout mice. Further...

Preclinical evaluation of a regimen combining chidamide and ABT-199 in acute myeloid leukemia

Thu, 27 Mar 2025 00:00:00 +0000

Acute myeloid leukemia (AML) is a heterogeneous myeloid neoplasm with poor clinical outcome, despite the great progress in treatment in recent years. The selective Bcl-2 inhibitor venetoclax (ABT-199) in combination therapy has been approved for the treatment of newly diagnosed AML patients who are ineligible for intensive chemotherapy, but resistance can be acquired through the upregulation of alternative antiapoptotic proteins. Here, we reported that a newly emerged histone deacetylase inhibitor, chidamide (CS055), at low-cytotoxicity dose enhanced the anti-AML activity of ABT-199, while sparing normal hematopoietic progenitor cells. Moreover, we also found that chidamide showed a superior resensitization effect than romidepsin in potentiation of ABT-199 lethality. Inhibition of multiple HDACs rather than some single component might be required. The combination therapy was also effective in primary AML blasts and stem/progenitor cells regardless of disease status and genetic...

Risk of meningomyelocele mediated by the common 22q11.2 deletion

Fri, 21 Mar 2025 00:00:00 +0000

Meningomyelocele is one of the most severe forms of neural tube defects (NTDs) and the most frequent structural birth defect of the central nervous system. We assembled the Spina Bifida Sequencing Consortium to identify causes. Exome and genome sequencing of 715 parent-offspring trios identified six patients with chromosomal 22q11.2 deletions, suggesting a 23-fold increased risk compared with the general population. Furthermore, analysis of a separate 22q11.2 deletion cohort suggested a 12- to 15-fold increased NTD risk of meningomyelocele. The loss of Crkl, one of several neural tube-expressed genes within the minimal deletion interval, was sufficient to replicate NTDs in mice, where both penetrance and expressivity were exacerbated by maternal folate deficiency. Thus, the common 22q11.2 deletion confers substantial meningomyelocele risk, which is partially alleviated by folate supplementation.

Offering extended use of the contraceptive implant via an implementation science framework: a qualitative study of clinicians’ perceived barriers and facilitators

Fri, 21 Mar 2025 00:00:00 +0000

BackgroundThe etonogestrel contraceptive implant is currently approved by the United States Food and Drug Administration (FDA) for the prevention of pregnancy up to 3 years. However, studies that suggest efficacy up to 5 years. There is little information on the prevalence of extended use and the factors that influence clinicians in offering extended use. We investigated clinician perspectives on the barriers and facilitators to offering extended use of the contraceptive implant. MethodsUsing the Consolidated Framework for Implementation Research (CFIR), we conducted semi-structured qualitative interviews. Participants were recruited from a nationwide survey study of reproductive health clinicians on their knowledge and perspective of extended use of the contraceptive implant. To optimize the diversity of perspectives, we purposefully sampled participants from this study. We used content analysis and consensual qualitative research methods to inform our coding and data analysis....

Time from first clinical contact to abortion in Texas and California

Tue, 18 Mar 2025 00:00:00 +0000

OBJECTIVE: To assess whether having an abortion in Texas, a U.S. state with many restrictive abortion laws, is associated with increased time between contacting an abortion provider and receiving an abortion, compared to having an abortion in California, a less restrictive U.S. state. STUDY DESIGN: This is a multisite, cross-sectional survey of 434 patients in 12 abortion facilities (ambulatory surgical centers and clinics) in Texas (n = 291) and three abortion clinics in California (n = 143) from 2018 to 2019. At 11 facilities in Texas the response rate was 76%. The response rate was not collected at other sites. We compare the clinical-contact-to-abortion time interval between the facilities in these two states using mixed-effects multivariable logistic regression, adjusting for age, race, education, household income, parity, marital status, and insurance status. We also compare barriers to scheduling and traveling to abortion appointments. RESULTS: Median...

Norepinephrine Neurons in the Nucleus of the Solitary Tract Suppress Luteinizing Hormone Secretion in Female Mice

Sat, 1 Mar 2025 00:00:00 +0000

Stress impairs fertility, at least in part, via inhibition of gonadotropin secretion. Luteinizing hormone (LH) is an important gonadotropin that is released in a pulsatile pattern in males and in females throughout the majority of the ovarian cycle. Several models of stress, including acute metabolic stress, suppress LH pulses via inhibition of neurons in the arcuate nucleus of the hypothalamus that coexpress kisspeptin, neurokinin B, and dynorphin (termed KNDy cells) which form the pulse generator. The mechanism for inhibition of KNDy neurons during stress, however, remains a significant outstanding question. Here, we investigated a population of catecholamine neurons in the nucleus of the solitary tract (NTS), marked by expression of the enzyme dopamine beta-hydroxylase (DBH), in female mice. First, we found that a subpopulation of DBH neurons in the NTS is activated (express c-Fos) during metabolic stress. Then, using chemogenetics, we determined that activation of these cells...

Splicing does the two-step

Sat, 15 Feb 2025 00:00:00 +0000

An intricate recursive RNA splicing mechanism that removes especially long introns (non-coding sequences) from genes has been found to be evolutionarily conserved and more prevalent than previously thought. See Letters p.371 & p.376

The RHOX Homeodomain Proteins Regulate the Expression of Insulin and Other Metabolic Regulators in the Testis*

Sat, 15 Feb 2025 00:00:00 +0000

Defects in cellular metabolism have been widely implicated in causing male infertility, but there has been little progress in understanding the underlying mechanism. Here we report that several key metabolism genes are regulated in the testis by Rhox5, the founding member of a large X-linked homeobox gene cluster. Among these Rhox5-regulated genes are insulin 2 (Ins2), resistin (Retn), and adiponectin (Adipoq), all of which encode secreted proteins that have profound and wide-ranging effects on cellular metabolism. The ability of Rhox5 to regulate their levels in the testis has the potential to dictate metabolism locally in this organ, given the existence of the blood-testes barrier. We demonstrate that Ins2 is a direct target of Rhox5 in Sertoli cells, and we show that this regulation is physiologically significant, because Rhox5-null mice fail to up-regulate Ins2 expression during the first wave of spermatogenesis and have insulin-signaling defects. We identify other Rhox family...

Posttranscriptional Control of the Stem Cell and Neurogenic Programs by the Nonsense-Mediated RNA Decay Pathway

Sat, 15 Feb 2025 00:00:00 +0000

The mechanisms dictating whether a cell proliferates or differentiates have undergone intense scrutiny, but they remain poorly understood. Here, we report that UPF1, a central component in the nonsense-mediated RNA decay (NMD) pathway, plays a key role in this decision by promoting the proliferative, undifferentiated cell state. UPF1 acts, in part, by destabilizing the NMD substrate encoding the TGF-β inhibitor SMAD7 and stimulating TGF-β signaling. UPF1 also promotes the decay of mRNAs encoding many other proteins that oppose the proliferative, undifferentiated cell state. Neural differentiation is triggered when NMD is downregulated by neurally expressed microRNAs (miRNAs). This UPF1-miRNA circuitry is highly conserved and harbors negative feedback loops that act as a molecular switch. Our results suggest that the NMD pathway collaborates with the TGF-β signaling pathway to lock in the stem-like state, a cellular state that is stably reversed when neural differentiation...

Epigenetic regulation of the RHOX homeobox gene cluster and its association with human male infertility

Sat, 15 Feb 2025 00:00:00 +0000

The X-linked RHOX cluster encodes a set of homeobox genes that are selectively expressed in the reproductive tract. Members of the RHOX cluster regulate target genes important for spermatogenesis promote male fertility in mice. Studies show that demethylating agents strongly upregulate the expression of mouse Rhox genes, suggesting that they are regulated by DNA methylation. However, whether this extends to human RHOX genes, whether DNA methylation directly regulates RHOX gene transcription and how this relates to human male infertility are unknown. To address these issues, we first defined the promoter regions of human RHOX genes and performed gain- and loss-of-function experiments to determine whether human RHOX gene transcription is regulated by DNA methylation. Our results indicated that DNA methylation is necessary and sufficient to silence human RHOX gene expression. To determine whether RHOX cluster methylation associates with male infertility, we evaluated the methylation...

RNA degradation drives stem cell differentiation

Sat, 15 Feb 2025 00:00:00 +0000

The mechanisms by which multi‐potent stem cells switch their program to become functional differentiated cells have intrigued biologists for decades. Most focus has been on transcriptional pathways, but whether they have sufficient dynamic range to cause discrete shifts in cell state is not clear. Because the steady‐state level of RNAs is also dictated by their decay rate, an attractive possibility is that specific RNA decay mechanisms also have a role in promoting differentiation mechanisms. In this issue of The EMBO Journal, Li et al (2015) obtained evidence that a highly conserved RNA degradation pathway called nonsense‐mediated RNA decay (NMD) is critical for the differentiation of embryonic stem (ES) cells.

Hormone-induced and DNA Demethylation-induced Relief of a Tissue-specific and Developmentally Regulated Block in Transcriptional Elongation*

Sat, 15 Feb 2025 00:00:00 +0000

Genome-wide studies have revealed that genes commonly have a high density of RNA polymerase II just downstream of the transcription start site. This has raised the possibility that genes are commonly regulated by transcriptional elongation, but this remains largely untested in vivo, particularly in vertebrates. Here, we show that the proximal promoter from the Rhox5 homeobox gene recruits polymerase II and begins elongating in all tissues and cell lines that we tested, but it only completes elongation in a tissue-specific and developmentally regulated manner. Relief of the elongation block is associated with recruitment of the elongation factor P-TEFb, the co-activator GRIP1, the chromatin remodeling factor BRG1, and specific histone modifications. We provide evidence that two mechanisms relieve the elongation block at the proximal promoter: demethylation and recruitment of androgen receptor. Together, our findings support a model in which promoter proximal pausing helps confer...

Nonsense-mediated mRNA decay: Inter-individual variability and human disease

Sat, 15 Feb 2025 00:00:00 +0000

Nonsense-mediated mRNA decay (NMD) is a regulatory pathway that functions to degrade transcripts containing premature termination codons (PTCs) and to maintain normal transcriptome homeostasis. Nonsense and frameshift mutations that generate PTCs cause approximately one-third of all known human genetic diseases and thus NMD has a potentially important role in human disease. In genetic disorders in which the affected genes carry PTC-generating mutations, NMD acts as a double-edge sword. While it can benefit the patient by degrading PTC-containing mRNAs that encode detrimental, dominant-negative truncated proteins, it can also make the disease worse when a PTC-containing mRNA is degraded that encodes a mutant but still functional protein. There is evidence that the magnitude of NMD varies between individuals, which, in turn, has been shown to correlate with both clinical presentations and the patients' responses to drugs that promote read-through of PTCs. In this review, we examine...

Transcriptional control of spermatogonial maintenance and differentiation

Sat, 15 Feb 2025 00:00:00 +0000

Spermatogenesis is a multistep process that generates millions of spermatozoa per day in mammals. A key to this process is the spermatogonial stem cell (SSC), which has the dual property of continually renewing and undergoing differentiation into a spermatogonial progenitor that expands and further differentiates. In this review, we will focus on how these proliferative and early differentiation steps in mammalian male germ cells are controlled by transcription factors. Most of the transcription factors that have so far been identified as promoting SSC self-renewal (BCL6B, BRACHYURY, ETV5, ID4, LHX1, and POU3F1) are upregulated by glial cell line-derived neurotrophic factor (GDNF). Since GDNF is crucial for promoting SSC self-renewal, this suggests that these transcription factors are responsible for coordinating the action of GDNF in SSCs. Other transcription factors that promote SSC self-renewal are expressed independently of GDNF (FOXO1, PLZF, POU5F1, and TAF4B) and thus may...

Barriers and facilitators to telemedicine contraception among patients that speak Spanish: a qualitative study

Thu, 13 Feb 2025 00:00:00 +0000

Background: Telemedicine contraception services have increased since the COVID-19 pandemic. There may be unique equity implications and language barriers for patients who speak Spanish. Objective: To identify the barriers and facilitators of telemedicine for contraception care among patients who speak Spanish using a community-based participatory research approach. Study Design: The study was designed and conducted in consultation with a community advisory board. We interviewed 20 patients after telemedicine and in-person contraception visits conducted in Spanish at Planned Parenthood of the Pacific Southwest in Southern California between April 2022 and May 2023. Telemedicine visits were conducted by audio only. Two coders analyzed the data using thematic analysis. Results: The average age of the participants was 32.5 years old (range 19-45). Most participants had some college education (13/20, 65.0%) and public insurance (18/20, 90.0%). Most chose a short-acting contraceptive...

Selective depletion of kisspeptin neurons in the hypothalamic arcuate nucleus in early juvenile life reduces pubertal LH secretion and delays puberty onset in mice

Wed, 12 Feb 2025 00:00:00 +0000

Puberty is the critical developmental transition to reproductive capability driven by the activation of gonadotropin-releasing hormone (GnRH) neurons. The complex neural mechanisms underlying pubertal activation of GnRH secretion still remain unknown, yet likely include kisspeptin neurons. However, kisspeptin neurons reside in several hypothalamic areas and the specific kisspeptin population timing pubertal onset remains undetermined. To investigate this, we strategically capitalized on the differential ontological expression of the Kiss1 gene in different hypothalamic nuclei to selectively ablate just arcuate kisspeptin neurons (aka KNDy neurons) during the early juvenile period, well before puberty, while sparing RP3V kisspeptin neurons. Both male and female transgenic mice with a majority of their KNDy neurons ablated (KNDy^ABL) by diphtheria toxin treatment in juvenile life demonstrated significantly delayed puberty onset and lower peripubertal LH secretion than...

Androgen Inhibition of Reproductive Neuroendocrine Function in Females and Transgender Males

Wed, 12 Feb 2025 00:00:00 +0000

Ovarian function is controlled by pituitary secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH), which in turn are governed by gonadotropin releasing hormone (GnRH) secreted from the brain. A fundamental principle of reproductive axis regulation is negative feedback signaling by gonadal sex steroids back to the brain to fine-tune GnRH and gonadotropin secretion. Endogenous negative feedback effects can be mimicked by exogenous steroid treatments, including androgens, in both sexes. Indeed, a growing number of clinical and animal studies indicate that high levels of exogenous androgens, in the typically male physiological range, can inhibit LH secretion in females, as occurs in males. However, the mechanisms by which male-level androgens inhibit GnRH and LH secretion still remain poorly understood, and this knowledge gap is particularly pronounced in transgender men (individuals designated female at birth but identifying as male). Indeed, many transgender...

Immediate skin‐to‐skin contact and postpartum hemorrhagic morbidity

Thu, 30 Jan 2025 00:00:00 +0000

OBJECTIVE: To examine rates of postpartum hemorrhagic (PPH) morbidity among patients who did and did not have immediate skin-to-skin contact (SSC). METHODS: This study was a retrospective cohort of all non-anomalous, term singleton vaginal births at a Level IV center over 2 years. Exclusion criteria included COVID-19. Immediate SSC was defined as at least 60 min of direct contact initiated between parturient and neonate within 10 min of birth. The primary outcome was a composite of maternal morbidity related to PPH compared among those with and without immediate SSC. We used multivariable Poisson regression adjusted for possible confounders with robust error variance to determine the strength of the association. RESULTS: Of 8623 deliveries during the study period, 3520 (40.8%) deliveries were included; of which 2428 (55.5%) had immediate SSC and 1028 (31.0%) did not. Immediate SSC reduced the overall rate of composite morbidity (adjusted relative risk 0.78, 95% confidence interval...

Genomic surveillance reveals dynamic shifts in the connectivity of COVID-19 epidemics

Sat, 4 Jan 2025 00:00:00 +0000

The maturation of genomic surveillance in the past decade has enabled tracking of the emergence and spread of epidemics at an unprecedented level. During the COVID-19 pandemic, for example, genomic data revealed that local epidemics varied considerably in the frequency of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineage importation and persistence, likely due to a combination of COVID-19 restrictions and changing connectivity. Here, we show that local COVID-19 epidemics are driven by regional transmission, including across international boundaries, but can become increasingly connected to distant locations following the relaxation of public health interventions. By integrating genomic, mobility, and epidemiological data, we find abundant transmission occurring between both adjacent and distant locations, supported by dynamic mobility patterns. We find that changing connectivity significantly influences local COVID-19 incidence. Our findings demonstrate a complex...

Nuclear Focal Adhesion Kinase Protects against Cisplatin Stress in Ovarian Carcinoma

Sat, 28 Dec 2024 00:00:00 +0000

ABSTRACT: Tumor chemotherapy resistance arises frequently and limits high-grade serous ovarian cancer (HGSOC) patient survival. Focal adhesion kinase (FAK) is an intracellular protein–tyrosine kinase encoded by PTK2, a gene that is often gained in HGSOC. Canonically, FAK functions at the cell periphery. However, FAK also transits to the nucleus to modulate gene expression. We find that FAK is tyrosine-phosphorylated and nuclear-localized in tumors of patients with HGSOC surviving neoadjuvant platinum–paclitaxel chemotherapy and that FAK nuclear accumulation occurs upon subcytotoxic cisplatin exposure to ovarian tumor cells in vitro. FAK nuclear localization sequence (NLS) mutational inactivation resulted in tumor cell sensitization to cisplatin in vitro and in vivo relative to wild-type FAK-reconstituted ovarian tumor cells. Cisplatin cytotoxicity was associated with elevated ERK MAPK activation in FAK NLS− cells, cisplatin-stimulated ERK activation was also enhanced upon loss...

Durable antitumor response via an oncolytic virus encoding decoy-resistant IL-18

Tue, 24 Dec 2024 00:00:00 +0000

BACKGROUND: Interleukin-18 (IL-18), or interferon (IFN)-γ-inducing factor, potentiates T helper 1 and natural killer cell activation as well as CD8⁺ T-cell proliferation. Recombinant IL-18 has displayed limited clinical efficacy in part due to the expression of the decoy receptor, IL-18 binding protein (IL-18BP). A series of IL-18 variants that are devoid of IL-18BP binding, termed DR18 (decoy-resistant IL-18), was developed via directed evolution. We tested DR18 using oncolytic adenovirus (oAd) as a platform for delivery in syngeneic mouse tumor models. METHODS: oAd harboring wild-type IL-18 or DR18 (oAdDR18) was constructed by inserting IL-18 mutant into modified oAd backbone with Ad5/3 chimeric fiber. The delivery effect and IFN-γ induction were determined by ELISA. The antitumor efficiency of oAdDR18 was tested in CT26, B16BL6 and 4T1 tumor-bearing mice, or athymic nude mice and compared with recombinant DR18 protein (rDR18). 4T1 lung metastasis model was used to...

Community utilization of a co-created COVID-19 testing program in a US/Mexico border community

Mon, 16 Dec 2024 00:00:00 +0000

BackgroundThe COVID-19 pandemic exposed several health disparities experienced by underserved and Latino/a communities, including inequitable access to COVID-19 testing.Objective and GoalsTo describe the utilization of a community-driven and culturally-tailored testing model on COVID-19 testing in an underserved Latino/a community in San Diego.MethodsThe Community-driven Optimization of COVID-19 testing to Reach and Engage Underserved Areas for Testing Equity (CO-CREATE) project implemented a community co-designed COVID-19 testing program in partnership with a Federally Qualified Health Center in a US/Mexico border community.ResultsBetween May 2021 and March 2023, 24, 422 COVID-19 PCR tests were administered to 13,253 individuals, among whom 93% percent identified as Latino/a, 57% spoke Spanish in the home, and 38% resided in our target community adjacent to the US/Mexico border, San Ysidro. Based on a subset of available county testing data, CO-CREATE accounted for nearly 12%...

Aspirin resistance in pregnancy is associated with reduced interleukin-2 (IL-2) concentrations in maternal serum: Implications for aspirin prophylaxis for preeclampsia

Mon, 16 Dec 2024 00:00:00 +0000

OBJECTIVES: To evaluate the impact of aspirin resistance on the incidence of preeclampsia and maternal serum biomarker levels in pregnant individuals at high-risk of preeclampsia receiving low dose aspirin (LDA). STUDY DESIGN: We performed a secondary analysis of a randomized, placebo-controlled trial of LDA (60 mg daily) for preeclampsia prevention in high-risk individuals (N = 524) on pregnancy outcomes and concentrations of PLGF, IL-2, IL-6, thromboxane B2 (TXB₂), sTNF-R1 and sTNF-R2 from maternal serum. MAIN OUTCOME MEASURES: LDA-resistant individuals were defined as those having a TXB₂ concentration >10 ng/ml or <75 % reduction in concentration at 24-28 weeks after LDA administration. Comparisons of outcomes were performed using a Fisher's Exact Test. Mean concentrations of maternal serum biomarkers were compared using a Student's t-test. Pearson correlation was calculated for all pairwise biomarkers. Longitudinal...

An optimized fractionation method reveals insulin-induced membrane surface localization of GLUT1 to increase glycolysis in LβT2 cells

Sun, 8 Dec 2024 00:00:00 +0000

Insulin is an important regulator of whole-body glucose homeostasis. In insulin sensitive tissues such as muscle and adipose, insulin induces the translocation of glucose transporter 4 (GLUT4) to the cell membrane, thereby increasing glucose uptake. However, insulin also signals in tissues that are not generally associated with glucose homeostasis. In the human reproductive endocrine axis, hyperinsulinemia suppresses the secretion of gonadotropins from gonadotrope cells of the anterior pituitary, thereby linking insulin dysregulation to suboptimal reproductive health. In the mouse, gonadotropes express the insulin receptor which has the canonical signaling response of IRS, AKT, and mTOR activation. However, the functional outcomes of insulin action on gonadotropes are unclear. Here, we demonstrate through use of an optimized cell fractionation protocol that insulin stimulation of the LβT2 gonadotropic cell line results in the unexpected translocation of GLUT1 to the plasma membrane....

Resident microbes shape the vaginal epithelial glycan landscape

Tue, 3 Dec 2024 00:00:00 +0000

Epithelial cells are covered in carbohydrates (glycans). This glycan coat or "glycocalyx" interfaces directly with microbes, providing a protective barrier against potential pathogens. Bacterial vaginosis (BV) is a condition associated with adverse health outcomes in which bacteria reside in direct proximity to the vaginal epithelium. Some of these bacteria, including Gardnerella, produce glycosyl hydrolase enzymes. However, glycans of the human vaginal epithelial surface have not been studied in detail. Here, we elucidate key characteristics of the "normal" vaginal epithelial glycan landscape and analyze the impact of resident microbes on the surface glycocalyx. In human BV, glycocalyx staining was visibly diminished in electron micrographs compared to controls. Biochemical and mass spectrometric analysis showed that, compared to normal vaginal epithelial cells, BV cells were depleted of sialylated N- and O-glycans, with underlying galactose residues exposed...

Development, Usability Testing, and Implementation Assessment of Cancer Related Infertility Score Predictor, an Online Cancer Related Infertility Risk Counseling Tool

Tue, 3 Dec 2024 00:00:00 +0000

Purpose: Oncofertility counseling of female cancer patients lacks efficient access to tailored and valid infertility risk estimates to support shared decision-making on fertility preservation treatments. The objective was to develop, conduct user-centered design, and plan clinic-based implementation of the Cancer Related Infertility Score Predictor (CRISP), a web-based tool to support infertility risk counseling. Methods: Using a mixed methods design, literature review was undertaken to abstract data on infertility, primary ovarian insufficiency, and amenorrhea risks of common cancer treatments. The CRISP website was programmed to take user input about patient ages and cancer treatments and generate a risk summary. Using user experience methodology and semistructured interviews, usability testing and implementation assessment were conducted with 12 providers recruited from 5 medical centers in Southern California. Results: The web-based...

Uterine fibroids with heavy menstrual bleeding stratified by race in a commercial and Medicaid database

Sat, 23 Nov 2024 00:00:00 +0000

Background: Historically, the clinical characteristics and treatment pathways for patients with uterine fibroids and heavy menstrual bleeding have differed between White and Black women. Objective: To provide a contemporary comparison of patient characteristics and treatment patterns among White and Black women with uterine fibroids and heavy menstrual bleeding in the United States. Study Design: This retrospective cohort study included administrative claims data from 46,139 White and 17,297 Black women with uterine fibroids and heavy menstrual bleeding from the Optum Clinformatics database (January 2011-December 2020) and 7353 White and 16,776 Black women from the IBM MarketScan Multi-State Medicaid Insurance database (January 2010-December 2019). Patients were indexed at their initial uterine fibroid diagnosis claim and were required to have a claim for heavy menstrual bleeding and ≥12 months of continuous enrollment pre- and postindex. Patients were followed until the earliest...

Predictors of treatment failure in young patients undergoing in vitro fertilization