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Background: Prenatal and postpartum depression may be influenced by the composition of host associated microbiomes. As such, the objective of this study was to elucidate the relationship between the human gut or vaginal microbiomes in pregnancy with prenatal or postpartum depression., Methods: 140 female participants were recruited at their first prenatal visit and completed the Edinburgh Postnatal Depression Scale (EPDS) to screen for depression and anxiety, in addition the EPDS was completed one month postpartum. Vaginal and stool biospecimens were collected in the third trimester, analyzed using 16S rRNA gene sequencing, and assessed for alpha and beta diversity. Individual taxa differences and clustering using the k-medoids algorithm enabled community state type classification., Results: Participants with higher postpartum EPDS scores had higher species richness and lower abundance of L. crispatus in the vaginal microbiota compared to those with lower EPDS scores. Participants with a higher prenatal EPDS score had lower species richness of the gut microbiome. Participants with a vaginal community state type dominated by L. iners had the highest mean prenatal EPDS scores, whereas postpartum EPDS scores were similar regardless of prenatal vaginal state type., Limitations: Our small sample size and participant's self-report bias limits generalizability of results., Conclusions: Depression in the prenatal and postpartum period is associated with the composition and diversity of the gut and vaginal microbiomes in the third trimester of pregnancy. These results provide a foundational understanding of the microbial relationships between maternal health and depression for identifying potential therapeutic treatments., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Deaf and hard-of-hearing (DHH) people are at higher risk than their non-DHH counterparts of experiencing adverse birth outcomes. There is a lack of research focusing on social, linguistic, and medical factors related to being DHH which may identify groups of DHH people who experience more inequity., Objective: Examine difference in prevalence of cesarean and adverse birth outcomes among diverse sub-groups of DHH people., Methods: We conducted a cross-sectional survey of DHH birthing people in the U.S. who gave birth within the past 10 years. The sample was predominantly white, college educated, and married. We assessed cesarean birth and three adverse birth outcomes: preterm birth, low birthweight, and NICU admission post-delivery. DHH-specific variables were genetic etiology of hearing loss, preferred language (i.e., American Sign Language, English, or bilingual), severity of hearing loss, age of onset of hearing loss, and self-reported quality of perinatal care communication. We estimated prevalence, 95 % confidence intervals, and unadjusted prevalence ratios., Results: Thirty-one percent of our sample reported a cesarean birth. Overall, there were no significant differences in prevalence across the outcome variables with respect to preferred language, genetic etiology, severity, and age of onset. Poorer perinatal care communication quality was associated with higher prevalence of preterm birth (PR = 2.37) and NICU admission (PR = 1.91)., Conclusions: Our study found no evidence supporting differences in obstetric outcomes among DHH birthing people across medical factors related to deafness. Findings support the important role of communication access for DHH people in healthcare environments., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: This study aimed to investigate antenatal depression and drug use among deaf and hard-of-hearing (DHH) birthing parents who use American Sign Language (ASL), spoken English, or bilingually both ASL and English., Methods: DHH participants in the United States responded to the Survey on Pregnancy Experiences of Deaf and Hard-of-Hearing Women. Respondents self-reported their antenatal depression diagnoses and drug use (i.e., pain relievers, cannabis, or illicit drugs) during their last pregnancy. Poisson regression models were used to estimate prevalence ratios, adjusting for age, race/ethnicity, education, marital status, and parity., Results: The average age of respondents (n = 587) was 35 years. Respondents were predominantly non-Hispanic white (80%), college educated (60%), and married (74%). Relative to DHH English-speakers, DHH ASL-users had lower prevalence of reporting antenatal depression diagnosis (aPR = 0.40, 95% CI: 0.23 to 0.72). DHH people who reported antenatal depression diagnosis had higher prevalence of reporting antenatal drug use (PR = 2.34, 95% CI: 1.65 to 3.33). There were no significant associations between preferred language and antenatal drug use., Conclusions: DHH ASL-users are less likely to report receiving an antenatal depression diagnosis compared to DHH English-speakers. Given well-documented patient-provider communication barriers among DHH ASL-users, it is unclear if the lower prevalence observed in this study is the result of inadequate or inaccessible screening during pregnancy. Future work should consider universal use of linguistically appropriate screening tools for DHH birthing parents in both clinical and research settings., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Objective: We sought to evaluate the impact of the coronavirus disease 2019 (COVID-19) pandemic on perinatal outcomes while accounting for maternal depression or perceived stress and to describe COVID-specific stressors, including changes in prenatal care, across specific time periods of the pandemic., Study Design: Data of dyads from 41 cohorts from the National Institutes of Health Environmental influences on Child Health Outcomes Program ( N  = 2,983) were used to compare birth outcomes before and during the pandemic ( n  = 2,355), and a partially overlapping sample ( n  = 1,490) responded to a COVID-19 questionnaire. Psychosocial stress was defined using prenatal screening for depression and perceived stress. Propensity-score matching and general estimating equations with robust variance estimation were used to estimate the pandemic's effect on birth outcomes., Results: Symptoms of depression and perceived stress during pregnancy were similar prior to and during the pandemic, with nearly 40% of participants reporting mild to severe stress, and 24% reporting mild depression to severe depression. Gestations were shorter during the pandemic ( B  =  - 0.33 weeks, p  = 0.025), and depression was significantly associated with shortened gestation ( B  =  - 0.02 weeks, p  = 0.015) after adjustment. Birth weights were similar ( B  =  - 28.14 g, p  = 0.568), but infants born during the pandemic had slightly larger birth weights for gestational age at delivery than those born before the pandemic ( B  = 0.15 z-score units, p  = 0.041). More women who gave birth early in the pandemic reported being moderately or extremely distressed about changes to their prenatal care and delivery (45%) compared with those who delivered later in the pandemic. A majority (72%) reported somewhat to extremely negative views of the impact of COVID-19 on their life., Conclusion: In this national cohort, we detected no effect of COVID-19 on prenatal depression or perceived stress. However, experiencing the COVID-19 pandemic in pregnancy was associated with decreases in gestational age at birth, as well as distress about changes in prenatal care early in the pandemic., Key Points: · COVID-19 was associated with shortened gestations.. · Depression was associated with shortened gestations.. · However, stress during the pandemic remained unchanged.. · Most women reported negative impacts of the pandemic.., Competing Interests: C.M. served as Chair of the Data Safety Monitoring Board (DSMB) for an Aerogen-supported trial: A Partially-Blind, Randomized, Controlled, Parallel-Group Dose Ranging Study to Determine the Efficacy, Safety and Tolerability of AeroFactTM (SF-RI 1 surfactant for inhalation combined with a dedicated drug delivery system) in Preterm Infants at Risk for Worsening Respiratory Distress Syndrome; Chair of the DSMB for the NIH RCT evaluating Sildenafil in Preterm Infants with Pulmonary Hypertension. J.N. served on the Advisory Board for the Twin Life Study (Germany); received royalties or licenses from Macmillan and consulting fees from the University of Southern California. J.H. served on the New York State Drinking Water Quality Council. The other authors have no conflicts of interest to disclose., (Thieme. All rights reserved.)

To assess the public health impact of the COVID-19 pandemic on mental health, investigators from the National Institutes of Health Environmental influences on Child Health Outcomes (ECHO) research program developed the Pandemic-Related Traumatic Stress Scale (PTSS). Based on the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) acute stress disorder symptom criteria, the PTSS is designed for adolescent (13-21 years) and adult self-report and caregiver-report on 3-12-year-olds. To evaluate psychometric properties, we used PTSS data collected between April 2020 and August 2021 from non-pregnant adult caregivers ( n = 11,483), pregnant/postpartum individuals ( n = 1,656), adolescents ( n = 1,795), and caregivers reporting on 3-12-year-olds ( n = 2,896). We used Mokken scale analysis to examine unidimensionality and reliability, Pearson correlations to evaluate relationships with other relevant variables, and analyses of variance to identify regional, age, and sex differences. Mokken analysis resulted in a moderately strong, unidimensional scale that retained nine of the original 10 items. We detected small to moderate positive associations with depression, anxiety, and general stress, and negative associations with life satisfaction. Adult caregivers had the highest PTSS scores, followed by adolescents, pregnant/postpartum individuals, and children. Caregivers of younger children, females, and older youth had higher PTSS scores compared to caregivers of older children, males, and younger youth, respectively. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Objectives: Deaf or hard of hearing (DHH) women are at a higher risk of adverse pregnancy and birth outcomes compared with other women. However, little is known about postpartum outcomes among DHH women. The objective was to compare the risk of postpartum hospitalizations for DHH compared with non-DHH women and the leading indications for postpartum admissions. Materials and Methods: We analyzed data from the 1998-2017 Massachusetts Pregnancy to Early Life Longitudinal Data System and identified 3,546 singleton deliveries to DHH women and 1,381,439 singleton deliveries to non-DHH women. We used Cox proportional hazard models to compare the first hospital admission and ≥2 hospital admissions between DHH and non-DHH women within 1-42, 43-90, and 91-365 days after delivery. Results: DHH women had a higher risk for any hospital admissions across all periods (hazard ratios [HR] = 1.84; 95% confidence intervals [CI] 1.46-2.34 within 1-42 days; HR = 2.76; 95%CI 1.99-3.83 within 43-90 days; and HR = 3.10; 95%CI 2.66-3.60 91-365 days) after childbirth compared with non-DHH women. They had an almost seven times higher risk for repeated hospital admissions within 43-90 days (HR = 6.84; 95%CI 1.66-28.21) and nearly four times higher the risk within 91-365 days (HR = 3.63; 95%CI 2.00-6.59) after delivery compared with non-DHH women. The leading indications for readmission among DHH women included: conditions complicating the puerperium/hemorrhage and soft tissues disorders. Conclusion: Compared with other women, DHH women had significantly higher readmissions across all postpartum periods and for repeated admissions >42 days. Leading postpartum indications were distinct from those of non-DHH women.

Objective: To evaluate contraceptive provision and contraceptive care quality measures for individuals who are deaf or hard of hearing and compare these outcomes to those individuals who are not., Methods: We conducted a claims analysis with data from the 2014 Massachusetts All-Payer Claims Database. Among premenopausal enrollees aged 15-44, we determined provision of any contraception (yes or no) and provision by contraception type: prescription contraception (pills, patch, ring, injectables, or diaphragm), long-acting reversible contraceptive (LARC) devices, and permanent contraception (tubal sterilization). We compared these outcomes by deaf or hard-of-hearing status (yes or no). The odds of contraceptive provision were calculated with regression models adjusted for age, Medicaid insurance, a preventive health visit, and deaf or hard-of-hearing status. We calculated contraceptive care quality measures, per the U.S. Office of Population Health, as the percentage of enrollees who used: 1) LARC methods or 2) most effective or moderately effective methods (tubal sterilization, pills, patch, ring, injectables, or diaphragm)., Results: We identified 1,171,838 enrollees at risk for pregnancy; 13,400 (1.1%) were deaf or hard of hearing. Among individuals who were deaf or hard of hearing, 31.4% were provided contraception (23.5% prescription contraception, 5.4% LARC, 0.7% tubal sterilization). Individuals who were deaf or hard of hearing were less likely to receive prescription contraception (adjusted odds ratio 0.92, 95% CI 0.88-0.96) than individuals who were not deaf or hard of hearing. The percentage of individuals who were deaf or hard of hearing who received most effective or moderately effective methods was less than that for individuals who were not (24.2% vs 26.3%, P<.001). There were no differences in provision of LARC or permanent contraception by deaf and hard-of-hearing status., Conclusion: Individuals who were deaf or hard of hearing were less likely to receive prescription contraception than individuals who were not; factors underlying this pattern need to be examined. Provision of LARC or permanent contraception did not differ by deaf or hard-of-hearing status. These findings should be monitored and compared with data from states with different requirements for contraceptive coverage., Competing Interests: Financial Disclosure The authors did not report any potential conflicts of interest., (Copyright © 2021 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background: The relationship between the vaginal microbiota, high-risk human papillomavirus infection, and abnormal cervical cytology has not been well characterized. Our objective was to characterize the vaginal microbiota in a stratified random sample of women from a population-based study in Appalachia., Methods: We analyzed a random sample of 308 women in the Community Access, Resources and Education: Project 3 study across 16 clinics in Ohio and West Virginia. Using Illumina MiSeq sequencing of 16S rRNA gene amplicons, we characterized the vaginal microbiota among (I) 109 women randomly chosen with abnormal cervical cytology (i.e., the majority were atypical squamous cells of undetermined significance (n=55) and low-grade squamous intraepithelial lesions (n=45) while n=6 were high-grade squamous intraepithelial lesions and n=3 were atypical glandular cells); (II) 110 high-risk human papillomavirus infection only without cytologic abnormality; and (III) 89 women from a stratified random sample without cytologic abnormalities (negative for intraepithelial lesion or malignancy or any human papillomavirus infection). Among the women with abnormal cervical cytology (n=109), 80 had human papillomavirus infection, the majority of which were positive for a high-risk type (n=61)., Results: Nearly all of the women were non-Hispanic White (94.5%), and the mean age was 26 (IQR=21-39) years. Women with abnormal cervical cytology or who were HPV+ were more likely to have a diverse vaginal microbiota characterized by higher Gardnerella vaginalis relative abundance, compared to women without cytologic abnormalities whose communities were more likely to be Lactobacillus spp . dominant (P<0.04). Women without cytologic abnormalities had a higher prevalence of L. iners dominated communities than women with abnormal cervical cytology and HR HPV+ respectively (P<0.04), and L. gasseri relative abundance was differentially greater among these women compared to women with abnormal cervical cytology or who were high-risk HPV+ (Linear discriminant analysis effect size =4.17; P=0.0009). After adjustment for age, white race, current smoking, and ≥2 male partners in the last year, however, we did not detect differences in the vaginal microbiota community states across the three outcome groups., Conclusions: Compared to women without cytologic abnormalities, the vaginal microbiota of women with abnormal cervical cytology or who were high-risk HPV+ were characterized by a diverse community with increased relative abundance of G. vaginalis and reduced relative abundance of L. gasseri . However, these differences were attenuated after adjustment for other factors. Further study and validation of these differences for prognostic use is warranted.

Background: Risk factors for vulvodynia continue to be elusive. We evaluated the association between past environmental exposures and the presence of vulvodynia., Materials and Methods: The history of 28 lifetime environmental exposures was queried in the longitudinal population-based Woman-to-Woman Health Study on the 24-month follow-up survey. Relationships between these and vulvodynia case status were assessed using multinomial logistic regression., Results: Overall, 1585 women completed the 24-month survey, the required covariate responses, and questions required for case status assessment. Screening positive as a vulvodynia case was associated with history of exposures to home-sprayed chemicals (insecticides, fungicides, herbicides-odds ratio [OR] 2.47, 95% confidence interval [CI] 1.71-3.58, p < 0.0001), home rodent poison and mothballs (OR 1.62, 95% CI 1.25-2.09, p < 0.001), working with solvents and paints (OR 2.49, 95% CI 1.68-3.70, p < 0.0001), working as a housekeeper/maid (OR 2.07, 95% CI 1.42-3.00, p < 0.0001), working as a manicurist/hairdresser (OR 2.00, 95% CI 1.14-3.53, p < 0.05), and working at a dry cleaning facility (OR 2.13, 95% CI 1.08-4.19, p < 0.05). When classified into nine individual environmental exposure categories and all included in the same model, significant associations remained for four categories (home-sprayed chemicals, home rodent poison or mothballs, paints and solvents, and working as a housekeeper)., Conclusions: This preliminary evaluation suggests a positive association between vulvodynia and the reported history of exposures to a number of household and work-related environmental toxins. Further investigation of timing and dose of environmental exposures, relationship to clinical course, and treatment outcomes is warranted.

Context: Women with disabilities experience a higher rate of adverse pregnancy outcomes than women without disabilities. Preventing or delaying pregnancy when that is the best choice for a woman is a critical strategy to reducing pregnancy-related disparities, yet little is known about current contraceptive use among women with disabilities., Methods: A cohort of 545 reproductive-age women with physical disabilities (i.e., difficulty walking, climbing, dressing or bathing) or sensory disabilities (i.e., difficulty with vision or hearing) was identified from among participants in the 2011-2013 National Survey of Family Growth. Those at risk for unplanned pregnancy were categorized by whether they were using highly effective reversible contraceptive methods (IUD, implant), moderately effective ones (pill, patch, ring, injectable), less effective ones (condoms, withdrawal, spermicides, diaphragm, natural family planning) or no method. Multinomial regression was conducted to examine the association between disability and type of contraceptive used., Results: Some 39% of women with disabilities were at risk of unplanned pregnancy, and 27% of those at risk were not using contraceptives. The presence of disability was associated with decreased odds of using highly effective methods or moderately effective methods, rather than less effective ones (odds ratio, 0.6 for each), but had no association with using no method., Conclusion: There is a significant need to reduce contraceptive disparities related to physical or sensory disabilities. Future research should explore the extent to which contraceptive use differs by type and severity of disability, as well as identify contextual factors that contribute to any identified differences., (Copyright © 2017 by the Guttmacher Institute.)

Background: Female sterilization accounts for 50% of all contraceptive use in the U.S. The extent to which U.S. women with physical and/or sensory disabilities have undergone female sterilization is unknown., Objective: Our primary objective was to determine the prevalence of sterilization for women with physical/sensory disabilities, and compare this to the prevalence for women without disabilities. We also compared use of long-acting reversible contraceptive (LARC) methods between women with and without disabilities., Methods: We conducted a secondary analysis of data from the National Survey of Family Growth 2011-2013, a population-based survey of U.S. women aged 15-44. Bivariate comparisons between women with and without disabilities by female sterilization and LARC use were conducted using chi-square tests. Using logistic regression, we estimated the odds of female sterilization based upon disability status., Results: Women with physical/sensory disabilities accounted for 9.3% of the total sample (N = 4966). Among women with disabilities only, 28.2% had undergone female sterilization, representing 1.2 million women nationally. LARC use was lower among women with disabilities than those without disabilities (5.4%, 9.3%, respectively, p < 0.01). After adjusting for age, race/ethnicity, education, insurance, marital status, parity, and self-reported health, women with disabilities had higher odds of sterilization (OR 1.36, 95% CI 1.03, 1.79)., Conclusions: The odds of female sterilization is higher among women with physical/sensory disabilities than those without disabilities. Future research is necessary to understand factors contributing to this finding, including possible underutilization of LARC methods., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective To characterize cumulative physiologic dysfunction (CPD) in pregnancy as a measure of the biological effects of chronic stress and to examine its associations with gestational age and birth weight. Methods Women ≤28 weeks gestation were enrolled from obstetric clinics in Rochester, NY and followed through their delivery. CPD parameters included total cholesterol, Interleukin 6 (IL-6), high sensitivity-C-reactive protein (hs-CRP), systolic and diastolic blood pressure, body mass index at <14 weeks gestation, glucose tolerance, and urinary albumin collected in the third trimester. Linear regression was used to estimate the association between physiologic dysfunction and birth weight and gestational age, respectively (N = 111). Results CPD scores ranged from 0 to 6, out of a total of 8 parameters (Mean 2.09; SD = 1.42). Three-fourths of the participants had a CPD score of 3.0 or lower. The mean birth weight was 3397 g (SD = 522.89), and the mean gestational age was 39.64 weeks (SD = 1.08). CPD was not significantly associated with either birth weight or gestational age (p = 0.42 and p = 0.44, respectively). Conclusion CPD measured at >28 weeks was not associated with birth weight or gestational age. Refinement of a CPD score for pregnancy is needed, taking into consideration both the component parameters and clinical and pre-clinical cut-points for risk scoring.

Background: We investigated cytokines and angiogenic factors (CAFs) in patients with metastatic renal cell carcinoma (mRCC) treated in a randomized phase II clinical trial of sorafenib versus sorafenib+ interferon-α (IFN-α) that yielded no differences in progression-free survival (PFS). We aimed to link the CAF profile to PFS and select candidate predictive and prognostic markers for further study., Methods: The concentrations of 52 plasma CAFs were measured pretreatment (n = 69), day 28, and day 56 using multiplex bead arrays and enzyme-linked immunosorbent assay. We investigated the association between baseline levels of CAFs with PFS and posttreatment changes., Results: Unsupervised CAF clustering analysis revealed two distinct mRCC patient groups with elevated proangiogenic or proinflammatory mediators. A six-marker baseline CAF signature [osteopontin, vascular endothelial growth factor (VEGF), carbonic anhydrase 9, collagen IV, VEGF receptor-2, and tumor necrosis factor-related apoptosis-inducing ligand] correlated with PFS benefit (hazard ratio 0.20 versus 2.25, signature negative versus positive, respectively; P = 0.0002). While changes in angiogenic factors were frequently attenuated by the sorafenib+ IFN combination, most key immunomodulatory mediators increased., Conclusions: Using CAF profiling, we identified two mRCC patient groups, a candidate plasma signature for predicting PFS benefit, and distinct marker changes occurring with each treatment. This platform may provide valuable insights into renal cell carcinoma biology and the molecular consequences of targeted therapies.

Background: State worksite breastfeeding statutes are thought to play a role in increasing rates of breastfeeding duration, which remain below Healthy People 2010 goals. As of 2010 24 states including the District of Columbia had such worksite statutes. Of these only 18 required both break time and a site. This preliminary analysis assessed if infants born in states with worksite breastfeeding statutes had longer breastfeeding duration., Methods: Using the 2009 National Immunization Survey we analyzed infants comparing breastfeeding duration at 6 months with type of worksite breastfeeding statute in place, while adjusting for year enacted and other state characteristics (years since founding of state breastfeeding coalition, breastfeeding supportive hospital practices). Other covariates included maternal and infant characteristics. Only those infants whose mothers were at least 18 years old and who had not changed state of residence since birth were included (n=16,145)., Results: Although requiring a site and/or break time for breastfeeding increased the likelihood of breastfeeding at 6 months (odds ratio, 1.20; 95% confidence interval, 1.07-1.35; p=0.002), after accounting for other factors this relationship remained positive but was not significant (adjusted odd ratio, 1.07; 95% confidence interval, 0.92-1.24). Because all mothers, not just those in or returning to the workforce, were included in the analysis this relationship could be underestimated. Breastfeeding at 6 months was associated with being from a state that had had a breastfeeding coalition for a longer period of time (adjusted odds ratio, 1.25; 95% confidence interval, 1.04-1.49; p<0001)., Conclusions: State worksite breastfeeding statutes alone may not directly affect breastfeeding duration. Analysis of breastfeeding duration using the multiple levels of the social-ecological model is a potentially useful approach to understanding the impact of state breastfeeding statutes. The impact of state breastfeeding coalitions warrants further study.

Purpose: There is an unmet need for biomarkers for identifying patients likely to benefit from anticancer treatments, selecting dose, and understanding mechanisms of resistance. Plasma vascular endothelial growth factor (VEGF) and soluble VEGF receptor 2 (sVEGFR-2) are known to be modulated by VEGF pathway inhibitors. It is unknown whether chemotherapy or VEGFR inhibitor/chemotherapy combinations induce changes in these or other cytokines and angiogenic factors (CAFs) and whether such changes could be markers of benefit., Methods: Thirty-five plasma CAFs were analyzed using multiplexed bead arrays and enzyme-linked immunosorbent assays from 123 patients with non-small-cell lung cancer in a randomized phase II study who received vandetanib, a VEGFR and epidermal growth factor receptor inhibitor, monotherapy carboplatin and paclitaxel (CP), or the combination (VCP). Changes in CAFs at days 8, 22, and 43 from baseline were correlated with progression risk., Results: VEGF increased and sVEGFR-2 decreased by day 43 in the vandetanib arm, whereas a distinct pattern was observed in the CP and VCP arms, with significant decreases in interleukin (IL) -12, IL-1 receptor antagonist, and matrix metalloproteinase 9 (MMP-9) and increased macrophage chemoattractant protein 1. In each treatment arm, changes in different markers were associated with progression risk. For example, increases in IL-8 with VCP, MMP-9 with CP, and VEGF with vandetanib monotherapy were associated with increased progression risk, and increase in intercellular adhesion molecule 1 with vandetanib was associated with decreased risk., Conclusion: Vandetanib and chemotherapy treatment led to distinct patterns of CAF changes; the combination resembled chemotherapy alone. Changes in specific CAFs correlated with clinical outcome, but markers differed for each treatment arm. CAF profiling may provide insights into the biologic effects of treatment and identify drug-specific markers of activity and clinical benefit.

CD26 is an antigen with key role in T-cell biology and is expressed on selected subsets of aggressive T-cell malignancies. To elucidate the role of CD26 in tumor behavior, we examine the effect of CD26 depletion by small interfering RNA transfection of T-anaplastic large cell lymphoma Karpas 299. We show that the resultant CD26-depleted clones lose the ability to adhere to fibronectin and collagen I. Because anti-integrin beta1 blocking antibodies also prevent binding of Karpas 299 to fibronectin and collagen I, we then evaluate the CD26-integrin beta1 association. CD26 depletion does not decrease integrin beta1 expression but leads to dephosphorylation of both integrin beta1 and p38 mitogen-activated protein kinase (MAPK). Moreover, our data showing that the p38MAPK inhibitor SB203580 dephosphorylates integrin beta1 and that binding of the anti-CD26 antibody 202.36 dephosphorylates both p38MAPK and integrin beta1 on Karpas 299, leading to loss of cell adhesion to the extracellular matrix, indicate that CD26 mediates cell adhesion through p38MAPK-dependent phosphorylation of integrin beta1. Finally, in vivo experiments show that depletion of CD26 is associated with loss of tumorigenicity and greater survival. Our findings hence suggest that CD26 plays an important role in tumor development and may be a novel therapeutic target for selected neoplasms.

CD26 is a Mr 110,000 surface-bound glycoprotein with diverse functional properties, including having a key role in normal T-cell physiology and the development of certain cancers. In this article, we show that surface expression of CD26, especially its intrinsic dipeptidyl peptidase IV (DPPIV) enzyme activity, results in enhanced topoisomerase IIalpha level in the B-cell line Jiyoye and subsequent in vitro sensitivity to doxorubicin-induced apoptosis. In addition, we show that expression of CD26/DPPIV is associated with increased phosphorylation of p38 and its upstream regulators mitogen-activated protein kinase kinase 3/6 and apoptosis signal-regulating kinase 1 and that p38 signaling pathway plays a role in the regulation of topoisomerase IIalpha expression. Besides demonstrating that CD26 effect on topoisomerase IIalpha and doxorubicin sensitivity is applicable to cell lines of both B-cell and T-cell lineages, the potential clinical implication of our work lies with the fact that we now show for the first time that our in vitro results can be extended to a severe combined immunodeficient mouse model. Our findings that CD26 expression can be an in vivo marker of tumor sensitivity to doxorubicin treatment may lead to future treatment strategies targeting CD26/DPPIV for selected human cancers in the clinical setting. Our article thus characterizes the biochemical linkage among CD26, p38, and topoisomerase IIalpha while providing evidence that CD26-associated topoisomerase IIalpha expression results in greater in vitro and in vivo tumor sensitivity to the antineoplastic agent doxorubicin.

CD26/dipeptidyl peptidase IV (DPPIV) is a cell surface-bound ectopeptidase with important roles in T-cell activation and tumour biology. We now report that CD26/DPPIV enhances sensitivity to apoptosis induced by the antineoplastic agents doxorubicin and etoposide. In particular, CD26/DPPIV presence is associated with increased susceptibility to the mitochondrial pathway of apoptosis, documented by enhanced cleavage of poly (ADP ribose) polymerase (PARP), caspase-3 and caspase-9, Bcl-xl, and Apaf-1, as well as increased expression of death receptor 5 (DR5). We also show that the caspase-9-specific inhibitor z-LEHD-fmk inhibits drug-mediated apoptosis, leading to decreased PARP and caspase-3 cleavage, and reduced DR5 expression. Importantly, through detailed studies that demonstrate the association between topoisomerase II alpha expression and DPPIV activity, our data provide further evidence of the key role played by CD26 in biological processes.

CD26 is a M(r) 110,000 surface glycoprotein with diverse functional properties, including having a potentially significant role in tumor development, and antibodies to CD26 mediate pleomorphic cellular functions. In this report, we show that binding of soluble anti-CD26 monoclonal Ab 1F7 inhibits the growth of the human CD30+ anaplastic large cell T-cell lymphoma cell line Karpas 299 in both in vitro and in vivo experiments. In vitro experiments show that 1F7 induces cell cycle arrest at the G1-S checkpoint, associated with enhanced p21 expression that is dependent on de novo protein synthesis. Furthermore, experiments with a severe combined immunodeficient mouse tumor model demonstrate that 1F7 treatment significantly enhances survival of tumor-bearing mice by inhibiting tumor formation. Our data therefore suggest that anti-CD26 treatment may have potential clinical use for CD26+ hematological malignancies.

Lactoferrin has been identified as a factor in human colostrum that accounts for increased incorporation of thymidine into the DNA in an in vitro rat crypt enterocyte bioassay. We have examined lactoferrin-stimulated thymidine incorporation by comparing the effects of iron-free lactoferrin (apolactoferrin) with those of iron-saturated lactoferrin (diferric lactoferrin) under conditions that inhibit the transfer of iron between these iron-binding proteins in the bioassay system. In addition, we have compared the dose-response relationships of diferric lactoferrin and apolactoferrin. The results demonstrated that lactoferrin, independent of iron-binding states, promoted the incorporation of thymidine into the DNA of rat crypt enterocytes. These observations suggest a previously unreported nutritional role for lactoferrin that is independent of its iron-binding capacity.

Limited information exists regarding the pattern of left ventricular diastolic filling in moderate to severe chronic aortic regurgitation (AR). The left ventricular diastolic filling curve derived from gated blood pool scans was evaluated in 24 normal subjects and 29 patients with AR. The peak filling rate (PFR), mean filling rate (MFR), peak ejection rate (PER), PFR/MFR, PFR/PER, and the time of the rapid filling period divided by the diastolic time were determined. PFR, MFR and PER were calculated as end-diastolic volumes per second (EDV/s). PFR was lower in the AR group than in the normal subjects (2.24 +/- 0.70 vs 3.09 +/- 0.71 EDV/s, p less than 0.001). Similarly, MFR was lower in the AR group (1.31 +/- 0.40 vs 1.63 +/- 0.29 EDV/s, p less than 0.01). PER was also reduced in the AR group. Both PFR/MFR and PFR/PER were reduced, while the ratio of rapid filling period to diastolic time was longer in the AR group than in normal subjects. Clinical evidence of congestive heart failure occurred in 8 patients in the AR group. Diastolic filling variables were not significantly different from the asymptomatic subgroup of patients with AR, but were abnormal when compared with those of normal subjects. In patients with AR, an abnormal pattern of diastolic filling was noted, consisting of a reduced PFR, MFR and PFR/ with a more linear pattern of filling (reduced PFR/MFR) during a longer rapid filling period.

In a search for dietary factors that might stimulate enterocyte proliferation, we developed an assay for thymidine incorporation into DNA using harvested crypt cells from mature rat small intestine. Human colostrum stimulated a significant increase in thymidine incorporation into rat crypt cell DNA during a 60-min period of incubation. When the protein with biological activity was purified to a single peak by sequential ion exchange and gel filtration chromatography, it was found to have the characteristics of lactoferrin. The protein was identical to lactoferrin standards by sodium dodecyl sulfate polyacrylamide gel electrophoresis, isoelectric focusing, and double-diffusion immunologic precipitation. All available human lactoferrins stimulated thymidine uptake and all reacted with a lactoferrin polyclonal antibody. Human lactoferrin appears to be a potent activator of thymidine incorporation into DNA in incubated rat crypt cells, a nutritional function not previously reported.