Effects of thiazolidinedione in patients with active bladder cancer.

OBJECTIVE: To examine the influence of perioperative thiazolidinedione (TZD) on cancer-specific outcomes in patients with diabetes mellitus (DM) undergoing radical cystectomy (RC) for urothelial carcinoma (UC). PATIENTS AND METHODS: A retrospective cohort of 173 patients with DM undergoing RC from 2005 to 2010 was identified. Of those, 53 were on TZD treatment at the time of RC, with 33 patients taking pioglitazone. Baseline clinicopathological characteristics, as well as cancer-specific survival (CSS), recurrence-free survival (RFS), and overall survival (OS) were compared between the patients on and off TZD therapy at the time of RC. In subgroup analysis, outcomes in patients specifically taking pioglitazone at the time of RC were compared to those not on a TZD. RESULTS: Baseline clinicopathological characteristics were similar between patients on and off TZD therapy at the time of RC. Overall, the median CSS rate was not reached in either group (P = 0.7). The estimated 5-year CSS was 67.8% in the non-TZD group and 66.3% in the TZD group. On multivariate analysis incorporating patient age, pathological T-staging, and adjuvant chemotherapy, TZD use was found not to be a significant predictor for CSS (hazard ratio 1.20, 95% confidence interval 0.66-2.17; P = 0.5). Additionally, RFS (P= 0.3) and OS (P = 0.2) were also similar between the two groups without adjusting for other variables. Comparison between patients taking pioglitazone vs patients not taking TZD yielded similar CSS (P = 0.2), RFS (P = 0.5), and OS (P= 0.2). CONCLUSIONS: CSS, as well as RFS and OS after RC were not compromised in patients on TZD therapy at the time of RC. Additional investigation is warranted in patients with non-muscle-invasive bladder cancer and muscle-invasive bladder cancer undergoing bladder-sparing procedures to assess the safety of using TZD in the setting of active UC.

Intimate partner violence and pregnancy: epidemiology and impact.

Intimate partner violence is a significant public health problem in our society, affecting women disproportionately. Intimate partner violence takes many forms, including physical violence, sexual violence, stalking, and psychological aggression. While the scope of intimate partner violence is not fully documented, nearly 40% of women in the United States are victims of sexual violence in their lifetimes and 20% are victims of physical intimate partner violence. Other forms of intimate partner violence are likely particularly underreported. Intimate partner violence has a substantial impact on a woman's physical and mental health. Physical disorders include the direct consequences of injuries sustained after physical violence, such as fractures, lacerations and head trauma, sexually transmitted infections and unintended pregnancies as a consequence of sexual violence, and various pain disorders. Mental health impacts include an increased risk of depression, anxiety, posttraumatic stress disorder, and suicide. These adverse health effects are amplified in pregnancy, with an increased risk of pregnancy outcomes such as preterm birth, low birthweight, and small for gestational age. In many US localities, suicide and homicide are leading causes of pregnancy-associated mortality. We herein review the issues noted previously in greater depth and introduce the basic principles of intimate partner violence prevention. We separately address current recommendations for intimate partner violence screening and the evidence surrounding effectiveness of intimate partner violence interventions.

Intimate partner violence and pregnancy: screening and intervention.

In the first part of this review, we provided currently accepted definitions of categories and subcategories of intimate partner violence and discussed the prevalence and health impacts of intimate partner violence in nonpregnant and pregnant women. Herein we review current recommendations for intimate partner violence screening and the evidence surrounding the effectiveness of intimate partner violence interventions. Screening for intimate partner violence may include exclusively identification of victims of intimate partner violence or both the identification of and intervention for victims. Until recently, many professional organizations did not recommend universal screening for intimate partner violence because of a lack of evidence of effectiveness of screening, lack of evidence demonstrating that screening is not harmful, and/or a lack of consensus regarding the most effective screening tool. The lack of evidence supporting an intervention posed an additional barrier to screening. The American College of Obstetricians and Gynecologists has been a staunch advocate for universal intimate partner violence screening, even when other groups either did not endorse screening or recommended it only for high-risk women. Recent published data confirm that screening is more reliable than usual care in identifying victims of intimate partner violence, both during pregnancy and in nonpregnant women. Likewise, recent published data show that there are no apparent harms of screening for intimate partner violence and that the act of screening may have an empowering effect on women and improve their relationship with and trust in their health care providers. Despite these findings, the implementation rate of intimate partner violence screening remains low. Most encouraging are the recent data showing that interventions performed after screening for intimate partner violence are effective in reducing depression symptoms and episodes of violence as well as improving some outcomes of pregnancy. Although there remains a lack of consensus regarding which screening tool may be the most effective, we exhort all obstetrician-gynecologists to screen all women for intimate partner violence at regular intervals and to familiarize themselves with available community resources to assist those women who have been identified as experiencing intimate partner violence through screening.

A checklist for timeout on labor and delivery: a pilot study to improve communication and safety.

OBJECTIVE: To assess the impact on staff communication of a standardized checklist for timeout for patients undergoing a trial of labor after cesarean section and/or elective induction at term. STUDY DESIGN: A comparison of presurvey and postsurvey questionnaire results for labor and delivery personnel assessing communication before and after checklist implementation. RESULTS: From October 2011 through March 2012, 52.9% (N=37) of 70 eligible patients had the standardized checklist for timeout performed. Prior to implementation of the checklist, 66% of respondents (48.8% of nurses, 100% of residents, 90% of attendings) slightly or strongly agreed that their opinions were heard versus 83% of respondents during the study period (73.7% of nurses, 100% of residents, 100% of attendings). Following the intervention, nurses reported that they were more likely to feel as though their opinions were heard (p = 0.05). CONCLUSION: Implementation of a formalized obstetric timeout improved the subjective perception of communication among obstetric staff. This tool has the potential to improve patient safety in labor and delivery.

Postoperative Outcomes and Analgesic Requirements of Single-Port vs Multiport Robotic-Assisted Radical Cystectomy.

Objective: To compare outcomes in patients undergoing robotic-assisted radical cystectomy (RARC) with urinary diversion for bladder cancer with either the single-port (SP) or multiport (MP) robotic platform. Methods: All patients who underwent SP and MP RARC at our institution between January 2018 and January 2023 were retrospectively reviewed. Postoperative analgesia was administered by a departmentwide narcotic stewardship protocol, and inpatient and outpatient narcotic use was tracked. The available preoperative clinical, operative, and postoperative outcomes were analyzed using t-test, chi-square, and Fischer exact statistical measures. Kaplan-Meier analysis with log-rank testing was used to determine the freedom from high-grade (Clavien-Dindo grade ≥3) postoperative complications stratified by SP or MP robotic use. Results: Overall, 96 patients underwent RARC with urinary diversion at our institution, with 49 MP and 47 SP procedures performed. Preoperative clinical parameters including age, body mass index, prior abdominal surgery, and use of neoadjuvant chemotherapy were similar between the two groups. Patients undergoing SP RARC had a shorter operative time (386.0 ± 90.9 minutes vs 453.6 ± 94.8 minutes, p < 0.01) and faster return of bowel function (3.4 ± 1.4 days vs 4.5 ± 2.2 days, p < 0.01). However, both cohorts had similar length of hospitalization, postoperative narcotic use, pathologic staging, and rate of positive surgical margin. Within 3 months postoperatively, both cohorts had a similar high-grade complication, hospital readmission, and cancer recurrence rate. Conclusions: The SP robot allows a safe alternative surgical approach for RARC and offers similar postoperative outcomes compared to the MP robot.

Analysis of treatment of muscle invasive bladder cancer using the national cancer database: Factors associated with receipt of aggressive therapy.

OBJECTIVES: To characterize the treatments received by muscle-invasive bladder cancer (MIBC) patients, analyze their use according to sociodemographic, clinical, pathologic, and facility variables, and identify possibilities for improvement in care, with the understanding that patients with MIBC face a potentially lethal disease, yet often do not receive guideline-concordant potentially curative therapies. MATERIALS AND METHODS: Using the National Cancer Data Base (NCDB), we analyzed 102,119 patients with MIBC diagnosed from 2009 to 2018. Treatments included cystectomy, radiation, chemotherapy (CT), or observation. Treatments including cystectomy or radiotherapy (RT) ≥50 Gy were considered aggressive therapy (AT). A multivariable generalized estimating equation model was used to assess the impact of the independent variables with receiving AT, using SAS version 9.4. RESULTS: The median age was 73 years, with 72.9% male, 84.3% White, and 7.1% Black. Stage distribution was 59.4% stage II, 23.0% stage III, and 17.6% stage IV. Overall, 55.2% of patients received AT, while 41.1% did not, with 26.6% receiving observation alone after transurethral resection of bladder tumor. 45.4% received cystectomy, 9.8% received RT, and 12.8% received CT as primary treatment. Notably, over 30% of patients ages 50 to 70 did not receive aggressive therapy. On multivariate analysis, factors associated with nonreceipt of AT included age >70 (OR < 0.79, P < 0.0001), Black race (OR 0.70, P < 0.0001), underinsured status (OR 0.62, P < 0.0001), high comorbidity (OR 0.74, P < 0.0001), and treatment at low volume (OR 0.72 P < 0.0001) or nonacademic cancer program (OR 0.54, P < 0.0001). Long-term trends included increases in utilization of perioperative CT (17.5% in 2009 to 46.7% in 2018, P < 0.001), and chemoradiation (5.4% in 2009 to 8.8% in 2018, P < 0.001). Using Cox regression analysis to control for confounding variables, receipt of aggressive therapy was associated with improved overall survival. CONCLUSIONS: Over a third of patients did not receive AT for MIBC, with many of these patients seemingly eligible by age and comorbidity status. Prospective studies are needed to determine why these patients do not receive AT. A better understanding of patient vs. access to care vs. provider factors will help to focus efforts to improve care for MIBC patients.

Effectively training pediatric residents to deliver diagnoses of Down syndrome.

Physicians and parents report a need for pediatricians to have additional training in delivering a diagnosis of Down syndrome (DS). This study tested a web-based tutorial to assess its effectiveness in improving physicians' perceived comfort with both ambiguous and more medically factual situations as they deliver diagnoses of DS. Based on this web tutorial that integrated prenatal and postnatal information into virtual patient scenarios, the study assessed pediatrics residents' knowledge and comfort in delivering a diagnosis of DS pre and postnatally. A separate survey, given at the same time, asked for residents' perception of their need for this training. Ninety-one volunteer residents from 10 pediatric training programs across the country participated. The tutorial yielded significant improvement in knowledge and a significant decrease in perceived level of discomfort in both ambiguous situations and more medically certain contexts related to a DS diagnosis. In addition, across all pediatric resident groups (by year, gender, and performance on the knowledge test and the comfort scale), residents strongly agreed that this type of training was beneficial for themselves, other residents, practicing physicians, and other medical professionals. This study suggests that web-based, interactive, multi-media training may be an effective tool for improving resident physician comfort with both ambiguous and more medically certain situations in delivering a diagnosis of DS to families.

SDF-1alpha stimulates JNK3 activity via eNOS-dependent nitrosylation of MKP7 to enhance endothelial migration.

The chemokine stromal cell-derived factor-1alpha (SDF-1alpha) is a pivotal player in angiogenesis. It is capable of influencing such cellular processes as tubulogenesis and endothelial cell migration, yet very little is known about the actual signaling events that mediate SDF-1alpha-induced endothelial cell function. In this report, we describe the identification of an intricate SDF-1alpha-induced signaling cascade that involves endothelial nitric oxide synthase (eNOS), JNK3, and MAPK phosphatase 7 (MKP7). We demonstrate that the SDF-1alpha-induced activation of JNK3, critical for endothelial cell migration, depends on the prior activation of eNOS. Specifically, activation of eNOS leads to production of NO and subsequent nitrosylation of MKP7, rendering the phosphatase inactive and unable to inhibit the activation of JNK3. These observations reinforce the importance of nitric oxide and S-nitrosylation in angiogenesis and provide a mechanistic pathway for SDF-1alpha-induced endothelial cell migration. In addition, the discovery of this interactive network of pathways provides novel and unexpected therapeutic targets for angiogenesis-dependent diseases.

ARID1A-deficient bladder cancer is dependent on PI3K signaling and sensitive to EZH2 and PI3K inhibitors.

Metastatic urothelial carcinoma is generally incurable with current systemic therapies. Chromatin modifiers are frequently mutated in bladder cancer, with ARID1A-inactivating mutations present in about 20% of tumors. EZH2, a histone methyltransferase, acts as an oncogene that functionally opposes ARID1A. In addition, PI3K signaling is activated in more than 20% of bladder cancers. Using a combination of in vitro and in vivo data, including patient-derived xenografts, we show that ARID1A-mutant tumors were more sensitive to EZH2 inhibition than ARID1A WT tumors. Mechanistic studies revealed that (a) ARID1A deficiency results in a dependency on PI3K/AKT/mTOR signaling via upregulation of a noncanonical PI3K regulatory subunit, PIK3R3, and downregulation of MAPK signaling and (b) EZH2 inhibitor sensitivity is due to upregulation of PIK3IP1, a protein inhibitor of PI3K signaling. We show that PIK3IP1 inhibited PI3K signaling by inducing proteasomal degradation of PIK3R3. Furthermore, ARID1A-deficient bladder cancer was sensitive to combination therapies with EZH2 and PI3K inhibitors in a synergistic manner. Thus, our studies suggest that bladder cancers with ARID1A mutations can be treated with inhibitors of EZH2 and/or PI3K and revealed mechanistic insights into the role of noncanonical PI3K constituents in bladder cancer biology.

ASB4 is a hydroxylation substrate of FIH and promotes vascular differentiation via an oxygen-dependent mechanism.

The molecular mechanisms of endothelial differentiation into a functional vascular network are incompletely understood. To identify novel factors in endothelial development, we used a microarray screen with differentiating embryonic stem (ES) cells that identified the gene for ankyrin repeat and SOCS box protein 4 (ASB4) as the most highly differentially expressed gene in the vascular lineage during early differentiation. Like other SOCS box-containing proteins, ASB4 is the substrate recognition molecule of an elongin B/elongin C/cullin/Roc ubiquitin ligase complex that mediates the ubiquitination and degradation of substrate protein(s). High levels of ASB4 expression in the embryonic vasculature coincide with drastic increases in oxygen tension as placental blood flow is initiated. However, as vessels mature and oxygen levels stabilize, ASB4 expression is quickly downregulated, suggesting that ASB4 may function to modulate an endothelium-specific response to increasing oxygen tension. Consistent with the hypothesis that ASB4 function is regulated by oxygen concentration, ASB4 interacts with the factor inhibiting HIF1alpha (FIH) and is a substrate for FIH-mediated hydroxylation via an oxygen-dependent mechanism. Additionally, overexpression of ASB4 in ES cells promotes differentiation into the vascular lineage in an oxygen-dependent manner. We postulate that hydroxylation of ASB4 in normoxia promotes binding to and degradation of substrate protein(s) to modulate vascular differentiation.

Physiologic and pharmacologic factors related to the provision of dental care during pregnancy.

During pregnancy, numerous physiologic changes occur that allow the mother to accommodate the needs of the developing fetus. Oral health care professionals should be knowledgeable about these changes and the impact they have on the safe provision of prophylactic and therapeutic dental care to pregnant women. Herein, the authors describe maternal physiologic adaptations and discuss changes in drug processing and placental drug transfer in order to enhance the knowledge base of oral health care professionals.

EZH2-Targeted Therapies in Cancer: Hype or a Reality.

Next-generation genomic sequencing has identified multiple novel molecular alterations in cancer. Since the identification of DNA methylation and histone modification, it has become evident that genes encoding epigenetic modifiers that locally and globally regulate gene expression play a crucial role in normal development and cancer progression. The histone methyltransferase enhancer of zeste homolog 2 (EZH2) is the enzymatic catalytic subunit of the polycomb-repressive complex 2 (PRC2) that can alter gene expression by trimethylating lysine 27 on histone 3 (H3K27). EZH2 is involved in global transcriptional repression, mainly targeting tumor-suppressor genes. EZH2 is commonly overexpressed in cancer and shows activating mutations in subtypes of lymphoma. Extensive studies have uncovered an important role for EZH2 in cancer progression and have suggested that it may be a useful therapeutic target. In addition, tumors harboring mutations in other epigenetic genes such as ARID1A, KDM6, and BAP1 are highly sensitive to EZH2 inhibition, thus increasing its potential as a therapeutic target. Recent studies also suggest that inhibition of EZH2 enhances the response to tumor immunotherapy. Many small-molecule inhibitors have been developed to target EZH2 or the PRC2 complex, with some of these inhibitors now in early clinical trials reporting clinical responses with acceptable tolerability. In this review, we highlight the recent advances in targeting EZH2, its successes, and potential limitations, and we discuss the future directions of this therapeutic subclass.

Neoadjuvant pazopanib and molecular analysis of tissue response in renal cell carcinoma.

BACKGROUNDSurgery remains the frontline therapy for patients with localized clear cell renal cell carcinoma (ccRCC); however, 20%-40% recur. Angiogenesis inhibitors have improved survival in metastatic patients and may result in responses in the neoadjuvant setting. The impact of these agents on the tumor genetic heterogeneity or the immune milieu is largely unknown. This phase II study was designed to evaluate safety, response, and effect on tumor tissue of neoadjuvant pazopanib.METHODSccRCC patients with localized disease received pazopanib (800 mg daily; median 8 weeks), followed by nephrectomy. Five tumors were examined for mutations by whole exome sequencing from samples collected before therapy and at nephrectomy. These samples underwent RNA sequencing; 17 samples were available for posttreatment assessment.RESULTSTwenty-one patients were enrolled. The overall response rate was 8 of 21 (38%). No patients with progressive disease. At 1-year, response-free survival and overall survival was 83% and 89%, respectively. The most frequent grade 3 toxicity was hypertension (33%, 7 of 21). Sequencing revealed strong concordance between pre- and posttreatment samples within individual tumors, suggesting tumors harbor stable core profiles. However, a reduction in private mutations followed treatment, suggesting a selective process favoring enrichment of driver mutations.CONCLUSIONNeoadjuvant pazopanib is safe and active in ccRCC. Future genomic analyses may enable the segregation of driver and passenger mutations. Furthermore, tumor infiltrating immune cells persist during therapy, suggesting that pazopanib can be combined with immune checkpoint inhibitors without dampening the immune response.FUNDINGSupport was provided by Novartis and GlaxoSmithKline as part of an investigator-initiated study.

Therapeutically actionable PAK4 is amplified, overexpressed, and involved in bladder cancer progression.

Muscle-invasive bladder carcinomas (MIBCs) are aggressive genitourinary malignancies. Metastatic urothelial carcinoma of the bladder is generally incurable by current chemotherapy and leads to early mortality. Recent studies have identified molecular subtypes of MIBCs with different sensitivities to frontline therapy, suggesting tumor heterogeneity. We have performed multi-omic profiling of the kinome in bladder cancer patients with the goal of identify therapeutic targets. Our analyses revealed amplification, overexpression, and elevated kinase activity of P21 (RAC1) activated kinase 4 (PAK4) in a subset of Bladder cancer (BLCA). Using bladder cancer cells, we confirmed the role of PAK4 in BLCA cell proliferation and invasion. Furthermore, we observed that a PAK4 inhibitor was effective in curtailing growth of BLCA cells. Transcriptomic analyses identified elevated expression of another kinase, protein tyrosine kinase 6 (PTK6), upon treatment with a PAK4 inhibitor and RNA interference of PAK4. Treatment with a combination of kinase inhibitors (vandetanib and dasatinib) showed enhanced sensitivity compared with either drug alone. Thus, PAK4 may be therapeutically actionable for a subset of MIBC patients with amplified and/or overexpressed PAK4 in their tumors. Our results also indicate that combined inhibition of PAK4 and PTK6 may overcome resistance to PAK4. These observations warrant clinical investigations with selected BLCA patients.

Treatment of periodontal disease and the risk of preterm birth.

BACKGROUND: Maternal periodontal disease has been associated with an increased risk of preterm birth and low birth weight. We studied the effect of nonsurgical periodontal treatment on preterm birth. METHODS: We randomly assigned women between 13 and 17 weeks of gestation to undergo scaling and root planing either before 21 weeks (413 patients in the treatment group) or after delivery (410 patients in the control group). Patients in the treatment group also underwent monthly tooth polishing and received instruction in oral hygiene. The gestational age at the end of pregnancy was the prespecified primary outcome. Secondary outcomes were birth weight and the proportion of infants who were small for gestational age. RESULTS: In the follow-up analysis, preterm birth (before 37 weeks of gestation) occurred in 49 of 407 women (12.0%) in the treatment group (resulting in 44 live births) and in 52 of 405 women (12.8%) in the control group (resulting in 38 live births). Although periodontal treatment improved periodontitis measures (P<0.001), it did not significantly alter the risk of preterm delivery (P=0.70; hazard ratio for treatment group vs. control group, 0.93; 95% confidence interval [CI], 0.63 to 1.37). There were no significant differences between the treatment and control groups in birth weight (3239 g vs. 3258 g, P=0.64) or in the rate of delivery of infants that were small for gestational age (12.7% vs. 12.3%; odds ratio, 1.04; 95% CI, 0.68 to 1.58). There were 5 spontaneous abortions or stillbirths in the treatment group, as compared with 14 in the control group (P=0.08). CONCLUSIONS: Treatment of periodontitis in pregnant women improves periodontal disease and is safe but does not significantly alter rates of preterm birth, low birth weight, or fetal growth restriction. (ClinicalTrials.gov number, NCT00066131 [ClinicalTrials.gov].).

Improving residents' understanding of issues, comfort levels, and patient needs regarding screening for and diagnosing Down syndrome.

OBJECTIVE: This study assessed obstetrics and gynecology and pediatrics residents' knowledge about Down syndrome (DS) and their comfort in delivering a prenatal or postnatal diagnosis of DS before and after interaction with a web-based tutorial. STUDY DESIGN: A team of physicians, parents, and educational specialists developed an interactive tutorial that asked resident physicians to provide their own responses to "virtual patient" cases related to DS diagnoses in utero and at birth. We tested resident knowledge and comfort-level changes and their satisfaction with the web-based tool. RESULTS: The study yielded significant improvement in knowledge and level of comfort changes with both obstetrics and gynecology and pediatric resident physicians at 16 programs nationally. There were no significant differences between the 2 specialties. CONCLUSION: This interactive tutorial is effective in improving physicians' knowledge of and comfort level with imparting accurate, balanced information about DS pre- and postnatally.

Change in periodontitis during pregnancy and the risk of pre-term birth and low birthweight.

AIM: Determine whether periodontitis progression during pregnancy is associated with adverse birth outcomes. METHODS: We used clinical data and birth outcomes from the Obstetrics and Periodontal Therapy Study, in which randomly selected women received periodontal treatment before 21 weeks of gestation (N=413) or after delivery (410). Birth outcomes were available for 812 women and follow-up periodontal data for 722, including 75 whose pregnancies ended <37 weeks. Periodontitis progression was defined as >or=3 mm loss of clinical attachment. Birth outcomes were compared between non-progressing and progressing groups using the log rank and t tests, separately in all women and in untreated controls. RESULTS: The distribution of gestational age at the end of pregnancy (p>0.1) and mean birthweight (3295 versus 3184 g, p=0.11) did not differ significantly between women with and without disease progression. Gestational age and birthweight were not associated with change from baseline in percentage of tooth sites with bleeding on probing or between those who did versus did not progress according to a published definition of disease progression (p>0.05). CONCLUSIONS: In these women with periodontitis and within this study's limitations, disease progression was not associated with an increased risk for delivering a pre-term or a low birthweight infant.

Systemic immune responses in pregnancy and periodontitis: relationship to pregnancy outcomes in the Obstetrics and Periodontal Therapy (OPT) study.

BACKGROUND: Our previous studies reported on the obstetric, periodontal, and microbiologic outcomes of women participating in the Obstetrics and Periodontal Therapy (OPT) Study. This article describes the systemic antibody responses to selected periodontal bacteria in the same patients. METHODS: Serum samples, obtained from pregnant women at baseline (13 to 16 weeks; 6 days of gestation) and 29 to 32 weeks, were analyzed by enzyme-linked immunosorbent assay for serum immunoglobulin G (IgG) antibody to Aggregatibacter actinomycetemcomitans (previously Actinobacillus actinomycetemcomitans), Campylobacter rectus, Fusobacterium nucleatum, Porphyromonas gingivalis, Prevotella intermedia, Tannerella forsythia (previously T. forsythensis), and Treponema denticola. RESULTS: At baseline, women who delivered live preterm infants had significantly lower total serum levels of IgG antibody to the panel of periodontal pathogens (P = 0.0018), to P. gingivalis (P = 0.0013), and to F. nucleatum (P = 0.0200) than women who delivered at term. These differences were not significant at 29 to 32 weeks. Changes in IgG levels between baseline and 29 to 32 weeks were not associated with preterm birth when adjusted for treatment group, clinical center, race, or age. In addition, delivery of low birth weight infants was not associated with levels of antibody at baseline or with antibody changes during pregnancy. CONCLUSIONS: Live preterm birth is associated with decreased levels of IgG antibody to periodontal pathogens in women with periodontitis when assessed during the second trimester. Changes in IgG antibody during pregnancy are not associated with birth outcomes.

Targeted delivery at 34 versus 35 weeks in women with preterm prelabor rupture of membranes.

Objective: To compare planned delivery at 34 versus 35 weeks for women with preterm prelabor rupture of membranes (PPROM). Materials and methods: We performed a retrospective cohort study of singleton pregnancies with PPROM after 24 weeks delivered from 2006 to 2014. In 2009, an institutional practice change established 35 weeks as the target gestational age before induction of labor was initiated after PPROM. Demographic and outcome measures were compared for two cohorts: women delivered 2006-2008 - target 34 weeks (T34) and women delivered 2009-2014 - target 35 weeks (T35). The primary outcome was neonatal intensive care unit (NICU) admission. Results: Of the 382 women with PPROM, 153 (40%) comprized the T34 cohort and 229 (60%) comprized the T35 cohort. Demographic characteristics were similar between groups. There were no differences between groups in gestational age at PPROM (31.0 ± 3.3 weeks versus 31.2 ± 3.1 weeks; p = .50) or maternal complications. The mean gestational age at delivery was earlier in the T34 group (31.8 ± 3.2 weeks versus 32.4 ± 2.7 weeks; p = .04). The median predelivery maternal length of stay (LOS) was 1 day longer in the T35 group (p = .03); the total and postpartum LOS were similar between groups (p > .05). There were no differences in the rate of NICU admission (T34 89.5% versus T35 92.1%; p = .38) or median neonatal LOS (T34 14 days versus T35 17 days; p = .15). In those patients who reached their target gestational age, both maternal predelivery LOS and total LOS were longer in the T35 group (p > .05). The frequency of NICU admission in those reaching their target gestational age was similar between groups (T34 83.37% versus T35 76.19%; p = .46). Conclusions: A 35-week target for delivery timing for women with PPROM does not decrease NICU admissions or neonatal LOS. This institutional change increased maternal predelivery LOS, but did not increase maternal or neonatal complications.

Expression and Role of Methylenetetrahydrofolate Dehydrogenase 1 Like (MTHFD1L) in Bladder Cancer.

Cancer cells utilize vitamin folate to fulfill their excessive demand for nucleotides and amino acids. Dihydrofolate reductase (DHFR), an enzyme involved in folate metabolism converts dihydrofolate into tetrahydrofolate, which is required for the de novo synthesis of purines, and certain amino acids. DHFR inhibitors are used as a chemotherapeutic agent. Cancer sequencing analysis has identified additional enzymes in folate metabolism that are dysregulated in cancer. Methylenetetrahydrofolate dehydrogenase 1 like (MTHFD1L), one such enzyme is overexpressed in bladder cancer. MTHFD1L is a mitochondrial enzyme involved in the folate cycle by catalyzing the reaction of formyl-tetrahydrofolate to formate and tetrahydrofolate (THF). THF is crucial for de novo purine and thymidylate synthesis and is also involved in the regeneration of methionine. Cancer cells rely on purines derived from the de novo pathway for the nucleotides whereas normal cells favor the salvage pathway. In this study we examined MTHFD1L expression in bladder cancer. By using publicly available cancer transcriptome data analysis web-portal UALCAN, we found overexpression of MTHFD1L in bladder cancer and expression was associated with overall survival. RT-PCR and immunoblot analysis confirmed the overexpression of MTHFD1L in muscle invasive bladder cancer tissues compared to normal urothelium. Furthermore, our investigations suggested a critical role for MTHFD1L in bladder cancer cell proliferation, colony formation and invasion. Thus, in this study, we show the significance of the folate metabolic enzyme MTHFD1L in aggressive bladder cancers and suggest that being an enzyme, MTHFD1L serves as a valuable therapeutic target.