The prion-like protein Doppel: A soluble biomarker steering ovarian cancer's peritoneal to circulatory dissemination.

Detecting ovarian cancer (OC) early using existing biomarkers, e.g., cancer antigen 125 (CA125), is challenging due to its ubiquitous expression in many tissues. Doppel, a prion-like protein, expresses in male reproductive organ but absent in female reproductive systems and healthy tissues, but plays an important role in neoangiogenesis. Here, we have shown two platforms, soluble Doppel in sera/ascites and Doppel expressed circulating tumor cells ( Dpl+ CTC) in the whole blood, to detect subsets of epithelial OC (EOC). Increased level of Doppel in the sera of OC patients, in three different cohorts, confirm Doppel as OC specific biomarker. Serum Doppel level distinguishes EOC subtypes and early stages HGSOCs from non-cancerous conditions with high sensitivity and specificity. Stratifying the EOCs based on Doppel level, we categorized them into Doppel-high (Dpl hi ) and Doppel-low (Dpl low ) groups. Using ascites-derived organoids and single cell sequencing of whole ascites of Dpl hi and Dpl low patients, we identify that Doppel induces epithelial-mesenchymal transition (EMT) and creates an immunosuppressive microenvironment, respectively. Doppel levels in the sera/ascites correlate with the changes of Dpl+ CTC number in whole blood, highlighting the association of Doppel-induced EMT with CTC dissemination in circulation. Thus, Doppel-based detection of EOC subtypes could be a promising platform as clinical biomarker and link Doppel-axis with OC dissemination.

Associations of sex hormone ratios with metabolic syndrome and inflammation in US adult men and women.

Background: Sex hormones play a critical role in sex differences and cardiovascular disease risk associated with metabolic syndrome (MS) and inflammation. However, the associations of sex hormone ratios with metabolic and inflammatory markers are unclear according to sex and age differences. We evaluated the associations of sex hormone ratios with MS and inflammation among males and females. Methods: A retrospective cross-sectional study was conducted by including all adults from the National Health and Nutrition Examination Survey cycles 2013-2016 and excluding any pregnant women, heart disease, diabetes, and those currently taking insulin. MS was defined using the National Cholesterol Education Program criteria and a high-sensitivity C-reactive protein (CRP) level>3 mg/L was defined as a high CRP. Measures of MS components and CRP concentrations were also analyzed. The primary exposures were testosterone to estradiol (excess androgen index), testosterone to sex hormone-binding globulin (free androgen index), and estradiol to sex hormone-binding globulin (free estradiol index). The adjusted associations were summarized with a relative risk (RR) and 95% confidence interval (CI). Results: This study included 9167 subjects with 4360 males and 4807 females. Increases in free estradiol index were positively associated with MS (RR=1.48; 95%CI: 1.39, 1.58; RR=1.31; 95%CI: 1.22, 1.40) and high CRP (RR=1.49; 95%CI: 1.25, 1.77; RR=1.26; 95%CI: 1.06, 1.50) in men with age<50 years and age≥50 years, respectively. Similarly, higher free estradiol index was also robustly associated with increased prevalence of MS (RR=1.22; 95%CI: 1.15, 1.28) and high CRP (RR=1.68; 95%CI: 1.48, 1.90) in women with age ≥50 years. Among women with age<50 years, a higher free androgen index was associated with MS (RR=1.34; 95%CI: 1.25, 1.42) and high CRP (RR=1.13; 95%CI: 1.02, 1.25). These associations were unchanged even after adjusting for all sex hormones. Conclusion: Free estradiol index was consistently and positively associated with MS and high CRP in males of all ages and older females. Free androgen index was positively associated with MS and high CRP in females with age<50 years.

Air Pollution and the Heart: Updated Evidence from Meta-analysis Studies.

PURPOSE OF REVIEW: Although environmental exposure such as air pollution is detrimental to cardiovascular disease (CVD), the effects of different air pollutants on different CVD endpoints produced variable findings. We provide updated evidence between air pollutants and CVD outcomes including mitigation strategies with meta-analytic evidence. RECENT FINDINGS: An increased exposure to any class of air pollutants including particulate matter (PM), gas, toxic metals, and disruptive chemicals has been associated with CVD events. Exposure to PM < 2.5 µm has been consistently associated with most heart diseases and stroke as well as CVDs among at-risk individuals. Despite this, there is no clinical approach available for systemic evaluation of air pollution exposure and management. A large number of epidemiological evidence clearly suggests the importance of air pollution prevention and control for reducing the risk of CVDs and mortality. Cost-effective and feasible strategies for air pollution monitoring, screening, and necessary interventions are urgently required among at-risk populations and those living or working, or frequently commuting in polluted areas.

Association of Exposure to Phthalate Metabolites With Sex Hormones, Obesity, and Metabolic Syndrome in US Women.

Importance: Obesity and metabolic syndrome are highly prevalent among the US population and are associated with the dysregulation of sex hormones. An increase in obesity and metabolic syndrome may also be associated with exposure to phthalates. The association of exposure to phthalate metabolites with sex hormones and metabolic health has been understudied in the female population. Objective: To evaluate the association between exposure to common phthalate metabolites with total testosterone (TT) levels, sex hormone-binding globulin (SHBG) levels, obesity, and metabolic syndrome among women. Design, Setting, and Participants: This cross-sectional study used data collected from the National Health and Nutrition Examination Survey during 2013 to 2016. Female participants aged 15 years or older with urinary profiles containing common phthalate metabolites were included in this study. Statistical analyses were performed from March 15, 2021, to April 30, 2022. Exposures: Urinary concentrations of phthalate metabolites were classified into tertiles, and the lowest tertile was used as a reference category. The concentrations of phthalate metabolites and their composite scores based on clustering were also used in the analysis. Main Outcomes and Measures: Serum concentrations of TT and SHBG were dichotomized into high TT levels (>46 ng/dL [to convert to nanomoles per liter, multiply by 0.0347] for age <50 years and >32 ng/dL for age ≥50 years) and low SHBG levels (<2.85 µg/mL [to convert to nanomoles per liter, multiply by 10.53]) as established for the female population. Obesity was defined as a body mass index of 30 or more (calculated as weight in kilograms divided by height in meters squared), and metabolic syndrome was defined using the National Cholesterol Education Program criteria. The serum concentrations of TT and SHBG were also included in the validation analyses. Modified Poisson models were used to estimate the adjusted relative risk (RR) with 95% CIs for the associations. Results: Among the 2004 women included in this study, the mean (SD) age was 46.6 (18.5) years (14.7% Hispanic participants, 62.7% non-Hispanic White participants, and 13.2% non-Hispanic Black participants; 17.4% of participants were born outside the US [weighted percentages]; 230 (11.8%) had high TT levels, 210 (10.4%) had low SHBG levels, 825 (39.8%) had obesity, and 965 (45.5%) had metabolic syndrome (weighted percentages). Of the 13 phthalate metabolites, 8 had the highest tertile level greater than 6.2 ng/mL (range, 0.5-75.2 ng/mL). High levels of exposure to mono(2-ethyl-5-carboxypentyl) phthalate (RR, 1.84 [95% CI, 1.33-2.54]), mono(2-ethyl-5-oxohexyl) phthalate (RR, 1.77 [95% CI, 1.21-2.59]), mono(2-ethyl-5-hydroxyhexyl) phthalate (RR, 1.94 [95% CI, 1.34-2.81]), and monobenzyl phthalate (RR, 1.75 [95% CI, 1.21-2.54]) were associated with low SHBG levels but not with high TT levels. High levels of exposure to some of these metabolites were also associated with obesity and metabolic syndrome. Most associations were specific to premenopausal or postmenopausal women. Conclusions and Relevance: In this cross-sectional study, exposure to certain phthalate metabolites could be associated with low SHBG levels, obesity, and metabolic syndrome depending on menopausal status.

Associations of Glycemic Index and Glycemic Load with Cardiovascular Disease: Updated Evidence from Meta-analysis and Cohort Studies.

PURPOSE OF REVIEW: Diet and lifestyle patterns are considered major contributory factors for cardiovascular disease (CVD) and mortality. In particular, consuming a diet higher in carbohydrates (not inclusive of fruits and vegetables, but more processed carbohydrates) has been associated with metabolic abnormalities that subsequently may increase the risk of CVD and related mortality. Glycemic index (GI) and glycemic load (GL) are values given to foods based on how fast the body converts carbohydrates into glucose also referred to as the glycemic burden of carbohydrates from foods. Conflicting associations of how high GI and GL influence CVDs have been observed even in high-quality meta-analysis studies. We synthesize and report the associations of high GI and GL with various CVDs by sex, obesity, and geographical locations using an updated review of meta-analysis and observational studies. RECENT FINDINGS: We identified high GI or high GL is associated with an increased risk of CVD events including diabetes (DM), metabolic syndrome (MS), coronary heart disease (CHD), stroke, and stroke mortality in the general population, and the risk of CVD outcomes appears to be stratified by sex, obesity status, and preexisting CVD. Both high GI and GL are associated with DM and CHD in the general population. However, high GI is strongly associated with DM/MS, while high GL is strongly associated with an increased risk of CHD in females. In addition, high GL is also associated with incident stroke, and appears to be associated with CVD mortality in subjects with preexisting CVD or high BMI and all-cause mortality in non-obese DM subjects. However, high GI appears to be associated with CVD or all-cause mortality only in females without CVD. High GI/GL is an important risk factor for CVD outcomes in the general population. High GI seems to be markedly associated with DM/MS, and it may enhance the risk of CVD or all-cause mortality in both sexes and predominately females. Although both high GI and high GL are risk factors for CHD in females, high GL is associated with CVD outcomes in at-risk populations for CVD. These data suggest that while high GI increases the propensity of CVD risk factors and mortality in healthy individuals, high GL contributes to the risk of severe heart diseases including CVD or all-cause mortality, particularly in at-risk populations. These data indicate dietary interventions designed for focusing carbohydrate quality by lowering both GI and GL are recommended for preventing CVD outcomes across all populations.

Targeting angiogenic growth factors using therapeutic glycosaminoglycans on doppel-expressing endothelial cells for blocking angiogenic signaling in cancer.

Growth factors (GF) regulate normal development to cancer progression. GFs interact with extracellular matrix (ECM) biomolecules, such as heparin sulfate (HS) glycosaminoglycan (GAG), to enhance their stability and angiogenic signaling. Biomaterials that modulate GF activity by mimicking interactions observed in the native ECM could be designed as an effective treatment strategy. However, these materials failed to attenuate angiogenic signaling site-specifically without sparing normal tissues. In this work, we investigated the effect of a GAG-based biomaterial, which binds to the tumor endothelial cells (TEC), on the interaction among vascular endothelial growth factor (VEGF), its receptors-VEGFR2 and HS-and angiogenesis. Heparin-bile acid based conjugates, as ECM-mimicking component, were synthesized to selectively target the TEC marker doppel and doppel/VEGFR2 axis. The most effective compound LHbisD4 (low molecular weight heparin conjugated with 4 molecules of dimeric dexocholic acid) reduced tumor volume concentrated over doppel-expressing EC, and decreased tumor-interstitial VEGF without affecting its plasma concentration. Doppel-destined LHbisD4 captured VEGF, formed an intermediate complex with doppel, VEGFR2, and VEGF but did not induce active VEGFR2 dimerization, and competitively inhibited HS for VEGF binding. We thus show that GAG-based materials can be designed to imitate and leverage to control tumor microenvironment via bio-inspired interactions.

Prevalence of at-risk hyperandrogenism by age and race/ethnicity among females in the United States using NHANES III.

OBJECTIVE: Hyperandrogenism in females leads to multiple endocrine and metabolic disorders including polycystic ovary syndrome (PCOS) that yields adverse health outcomes across all ages. We sought to estimate the prevalence of hyperandrogenemia and at-risk hyperandrogenism among the US females of different age groups, racial/ethnic, and metabolic characteristics. MATERIALS AND METHODS: A retrospective population-based cross-sectional study of females 6 years or older having serum testosterone measures using the National Health and Nutrition Examination Surveys, 2013-2016 was conducted. Age-appropriate thresholds as per assay methods were used for evaluating high total testosterone, low sex hormone binding globulin (SHBG), and high free androgen index (FAI) levels. The weighted analysis was performed to estimate prevalence and 95 % confidence interval (CI). RESULTS: The prevalence of at-risk hyperandrogenism was estimated as 19.8 % (95 %CI: 18.6 %, 21.2 %) in the overall sample, 11.8 % (95 %CI: 9.5 %, 14.5 %) in prepubertal, 20.5 % (95 %CI: 18.9 %, 22.2 %) in premenopausal, and 21.1 % (95 %CI: 18.7 %-23.7 %) in postmenopausal females with considerable heterogeneity by racial/ethnic and metabolic characteristics. In the entire sample, hyperandrogenemia was estimated as 10.4 % and 4.3 % using total testosterone and FAI respectively while 10.7 % cases had a low SHBG. CONCLUSIONS: At-risk hyperandrogenism is equally prevalent in premenopausal and postmenopausal women with a considerable amount in prepubertal females and varied by racial/ethnic groups depending on specific ages. Regular screening of hyperandrogenism using SHBG and total testosterone measures among at-risk subjects for specific ages is critical for treating and preventing adverse consequences of abnormal hormonal parameters.

Maternal and neonatal characteristics and outcomes among COVID-19 infected women: An updated systematic review and meta-analysis.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) has become a global pandemic and may adversely affect pregnancy outcomes. We estimated the adverse maternal and neonatal characteristics and outcomes among COVID-19 infected women and determined heterogeneity in the estimates and associated factors. STUDY DESIGNS: PubMed search was performed of confirmed COVID-19 pregnant cases and related outcomes were ascertained prior to July 8, 2020, in this systematic review and meta-analysis. Studies reporting premature birth, low birth weight, COVID-19 infection in neonates, or mode of delivery status were included in the study. Two investigators independently performed searches, assessed quality of eligible studies as per the Cochrane handbook recommendations, extracted and reported data according to PRISMA guidelines. Pooled proportions of maternal and neonatal outcomes were estimated using meta-analyses for studies with varying sample sizes while a systematic review with descriptive data analysis was performed for case report studies. Maternal and neonatal outcomes included C-section, premature birth, low birth weight, adverse pregnancy events and COVID transmission in neonates. RESULTS: A total of 790 COVID-19 positive females and 548 neonates from 61 studies were analyzed. The rates of C-section, premature birth, low birth weight, and adverse pregnancy events were estimated as 72 %, 23 %, 7 %, and 27 % respectively. In the heterogeneity analysis, the rate of C-section was substantially higher in Chinese studies (91 %) compared to the US (40 %) or European (38 %) studies. The rates of preterm birth and adverse pregnancy events were also lowest in the US studies (12 %, 15 %) compared to Chinese (17 %, 21 %), and European studies (19 %, 19 %). In case reports, the rates of C-section, preterm birth, and low birth weight were estimated as 69 %, 56 %, and 35 %, respectively. Adverse pregnancy outcomes were associated with infection acquired at early gestational ages, more symptomatic presentation, myalgia symptom at presentation, and use of oxygen support therapy. CONCLUSIONS: Adverse pregnancy outcomes were prevalent in COVID-19 infected females and varied by location, type, and size of the studies. Regular screening and early detection of COVID-19 in pregnant women may provide more favorable outcomes.

Association Between Obesity and Cardiovascular Outcomes: Updated Evidence from Meta-analysis Studies.

PURPOSE OF REVIEW: The prevalence of obesity and cardiovascular disease (CVD) has been increasing worldwide. Studies examining the association between adiposity and CVD outcomes have produced conflicting findings. The interplay between obesity and CVD outcomes in the general population and in specific subpopulations is complex and requires further elucidation. RECENT FINDINGS: We report updated evidence on the association between obesity and CVD events through a review of meta-analysis studies. This review identified that obesity or high body mass index (BMI) was associated with an increased risk of CVD events, including mortality, in the general population and that cardiac respiratory fitness (CRF) and metabolic health status appear to stratify the risk of CVD outcomes. In patients with diabetes, hypertension, or coronary artery disease, mortality displayed a U-shaped association with BMI. This U-shaped association may result from the effect of unintentional weight loss or medication use. By contrast, patients with other severe heart diseases or undergoing cardiac surgery displayed a reverse J-shaped association suggesting the highest mortality associated with low BMI. In these conditions, a prolonged intensive medication use might have attenuated the risk of mortality associated with high BMI. For the general population, a large body of evidence points to the importance of obesity prevention and maintenance of a healthy weight. However, for those with diagnosed cardiovascular diseases or diabetes, the relationship between BMI and cardiovascular outcomes is more complex and varies with the type of disease. More studies are needed to define how heterogeneity in the longitudinal changes in BMI affects mortality, especially in patients with severe heart diseases or going under cardiac surgery, in order to target subgroups for tailored interventions. Interventions for managing body weight, in conjunction with improving CRF and metabolic health status and avoiding unintentional weight loss, should be used to improve CVD outcomes.

Review of hot flash diaries.

Currently, there is only 1 published hot flash diary. This diary rates hot flash severity according to 4 categories: mild, moderate, severe, and very severe. The descriptions of these 4 severity categories are located on a separate form from the main data form. For each 24-h period, subjects record the number of hot flashes experienced for each of the 4 severity categories either by recollection or from a separate data source on which hot flashes have been tallied. This diary has been validated but does not conform to the FDA and EMEA guidance for industry. After we observed a high percentage of subjects reporting confusion when using this 4-category diary, we constructed and used a hot flash diary containing 3 severity categories that offered real-time recording of hot flashes, contained all severity definitions on the principle data form and also conformed to the FDA and EMEA guidance for industry. We compare these 2 diaries here and provide a sample of the 3-category diary, which has not been formally validated but is considered valid by the FDA and EMEA in support of drug approval. Either diary is acceptable for use in clinical trials.

Abiotrophia/Granulicatella tubo-ovarian abscess in an adolescent virginal female.

Tubo-ovarian abscess (TOA) is a common acute complication of pelvic inflammatory disease (PID). It can also develop as a complication of pelvic or abdominal surgery, malignancy, and intra-abdominal processes such as appendicitis. In premenopausal women, PID is the most common cause of tubo-ovarian abscess. We report a case of tubo-ovarian abscess in a virginal adolescent female with no past surgical history and no known history of appendicitis, inflammatory bowel disease, or cancer. Cultures of the tubo-ovarian abscess drainage grew Abiotrophia/Granulicatella species. This case supports including TOA in the broad differential diagnosis for abdominal pain with fever in adolescent females regardless of sexual history.

The ectopic appendicolith from perforated appendicitis as a cause of tubo-ovarian abscess.

Acute appendicitis is a common surgical cause of abdominal pain in the pediatric population. History and physical examination are atypical in up to a third of patients. Known potential complications of untreated or delayed management of acute appendicitis include appendiceal perforation, periappendiceal abscess formation, peritonitis, bowel obstruction and rarely septic thrombosis of mesenteric vessels. We report an unusual complication of perforated appendicitis. A tubo-ovarian abscess developed secondary to appendicolith migration into the right fallopian tube in a patient who had undergone interval laparoscopic appendectomy for perforated appendicitis. The retained appendicolith was visualized within the obstructed and dilated fallopian tube on contrast-enhanced CT. We discuss the CT imaging features of this unusual complication of perforated appendicitis.

Gabapentin, estrogen, and placebo for treating hot flushes: a randomized controlled trial.

OBJECTIVE: To compare the efficacy of gabapentin, estrogen, and placebo in the treatment of hot flushes. METHODS: We performed a randomized, double-blind, placebo-controlled trial of 60 postmenopausal women to assess the efficacy of estrogen and gabapentin in the treatment of moderate-to-severe hot flushes. Participants were randomly assigned to receive either 0.625 mg/d of conjugated estrogens (n = 20), placebo (n = 20), or gabapentin titrated to 2,400 mg/d (n = 20) for 12 weeks. Participants recorded frequency and severity of baseline hot flushes on a hot flush diary for 2 weeks before randomization and for 12 weeks after randomization. The primary outcome measure was the weekly hot flush composite score, which takes into account both severity and frequency of hot flushes. Secondary outcome measures were differences in pre- and posttreatment scores pertaining to depression (Zung Depression Scale) and other climacteric symptoms (Greene Climacteric Scale). RESULTS: Intention-to-treat analysis showed that the reduction in the hot flush composite score for both estrogen (72%, P = .016) and gabapentin (71%, P = .004) was greater than the reduction associated with placebo (54%) at the conclusion of the 12th week. The extent of reduction in hot flush composite score, however, was not significantly different between estrogen and gabapentin (P = .63). No differences were seen between groups in the Zung Depression Scale, or in any of the Greene Climacteric subscales except for the Somatic Symptom cluster, which was significantly greater in the gabapentin arm than in the placebo arm. Despite a lack of group differences in adverse events, the Headache, Dizziness, and Disorientation cluster appeared with greater frequency in the gabapentin group. Estimation of the number needed to harm in this cluster suggests that these symptoms may occur with every fourth patient treated with gabapentin. CONCLUSION: Despite the small scale of this study, gabapentin appears to be as effective as estrogen in the treatment of postmenopausal hot flushes. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, NCT 00276081. LEVEL OF EVIDENCE: I.

Isolation and phenotypic characterization of lung fibroblasts.

Primary fibroblasts represent a heterogeneous population of cells that can be separated into subsets on the basis of cell surface markers such as Thy-1. Deriving fibroblasts initially involves obtaining tissue explants from tissues such as the lung, heart, cornea, skin, and orbit. The tissue is mechanically dissociated and cells are allowed to proliferate from the fragments. Following establishment of a primary culture of fibroblasts, it is necessary to characterize the new strain of cells to ensure their purity and fibroblastic phenotype using immunofluorescence and immunohistochemistry to detect the presence or absence of cell-specific surface markers. Characterizing the cells as expressing or lacking Thy-1 can also be performed by immunofluorescence in concert with microscopy or by flow cytometry using an anti-human Thy-1 antibody. In addition, fibroblasts may be sorted according to their expression of Thy-1 by fluorescence-activated cell sorting and/or magnetic beading; use of these techniques can yield greater than 99% purity. Once separated, the pure Thy-1 expressing or lacking fibroblast subsets can be propagated. These subsets can then be used for experimentation to determine functional differences between fibroblasts derived from normal and pathological tissue such as scarred lung.