Impact of the interplay between stemness features, p53 and pol iota on replication pathway choices.

Using human embryonic, adult and cancer stem cells/stem cell-like cells (SCs), we demonstrate that DNA replication speed differs in SCs and their differentiated counterparts. While SCs decelerate DNA replication, differentiated cells synthesize DNA faster and accumulate DNA damage. Notably, both replication phenotypes depend on p53 and polymerase iota (POLι). By exploring protein interactions and newly synthesized DNA, we show that SCs promote complex formation of p53 and POLι at replication sites. Intriguingly, in SCs the translocase ZRANB3 is recruited to POLι and required for slow-down of DNA replication. The known role of ZRANB3 in fork reversal suggests that the p53-POLι complex mediates slow but safe bypass of replication barriers in SCs. In differentiated cells, POLι localizes more transiently to sites of DNA synthesis and no longer interacts with p53 facilitating fast POLι-dependent DNA replication. In this alternative scenario, POLι associates with the p53 target p21, which antagonizes PCNA poly-ubiquitination and, thereby potentially disfavors the recruitment of translocases. Altogether, we provide evidence for diametrically opposed DNA replication phenotypes in SCs and their differentiated counterparts putting DNA replication-based strategies in the spotlight for the creation of therapeutic opportunities targeting SCs.

Evaluating compliance and applicability of postpartum pessary use for preventing and treating pelvic floor dysfunction: a prospective multicenter study.

PURPOSE: Pelvic floor disorders are common and associated with pregnancy and childbirth. For restitution of pelvic floor connective tissue and thereby therapy of postpartum pelvic organ prolapse and stress urinary incontinence, the Restifem® pessary is approved. It supports the anterior vaginal wall behind the symphysis, the lateral sulci and the sacro-uterine ligaments and stabilises the connective tissue. We evaluated the compliance and applicability of Restifem® use in women postpartum in a preventive and therapeutic approach. METHODS: Restifem® pessary was handed out to 857 women. Six weeks after birth, they started the pessary use. After 8 weeks, 3 and 6 months postpartum, women received a questionnaire via online survey for evaluation of pessary applicability and efficacy. RESULTS: After 8 weeks, 209 women answered the questionnaire. 119 women used the pessary. Common problems were discomfort, pain and the pessary use was to circuitous. Vaginal infections were rare. After 3 months, 85 women and after 6 months, 38 women still used the pessary. 3 months postpartum, 94% of women with POP, 72% of women with UI and 66% of women with OAB stated to have an improvement of their symptoms using the pessary. 88% women without any disorder felt an improvement of stability. CONCLUSIONS: Use of the Restifem® pessary in the postpartum period is feasible and accompanied with less complications. It reduces POP and UI and leads to an increased sense of stability. So, Restifem® pessary can be offered to women postpartum to improve pelvic floor dysfunction.

The effect of pelvic floor muscle training on pelvic floor function and sexuality postpartum. A randomized study including 300 primiparous.

PURPOSE: Although pregnancy and childbirth are physiological processes they may be associated with pelvic floor disorders. The aim of this study was to evaluate the influence of pelvic floor muscle training on postpartum pelvic floor and sexual function of primiparous. METHODS: This is a randomized prospective study including 300 primiparous women. Due to the dropout 200 women were analyzed. Inclusion criteria were the delivery of the first, mature baby, the ability to speak and understand German. The participants were evaluated by clinical examinations and questionnaires after 6 and 12 months postpartum. After 6 months, the women were randomized in two groups. Compared to the control group the intervention groups participated in 45-min pelvic floor muscle training and pelvic floor perception once a week over 6 weeks. RESULTS: The results of the questionnaires showed no significant differences between the groups after 12 months. A significant stronger pelvic floor muscle strength was found for the intervention group after 12 months. The improvement of the pelvic floor and sexual function over the time showed a significant improvement in both groups. CONCLUSION: Supervised pelvic floor muscle training did not improve both the pelvic floor and the female sexual function in comparison to the control group. After 12 months, the pelvic floor and sexual function improved significant in all women. TRIAL REGISTRATION: German Clinical Trials Register (DRKS00024725), retrospectively registrated.

Utilization of Aminoguanidine Prevents Cytotoxic Effects of Semen.

Studies of human semen in cell or tissue culture are hampered by the high cytotoxic activity of this body fluid. The components responsible for the cell damaging activity of semen are amine oxidases, which convert abundant polyamines, such as spermine or spermidine in seminal plasma into toxic intermediates. Amine oxidases are naturally present at low concentrations in seminal plasma and at high concentrations in fetal calf serum, a commonly used cell culture supplement. Here, we show that, in the presence of fetal calf serum, seminal plasma, as well as the polyamines spermine and spermidine, are highly cytotoxic to immortalized cells, primary blood mononuclear cells, and vaginal tissue. Thus, experiments investigating the effect of polyamines and seminal plasma on cellular functions should be performed with great caution, considering the confounding cytotoxic effects. The addition of the amine oxidase inhibitor aminoguanidine to fetal calf serum and/or the utilization of serum-free medium greatly reduced this serum-induced cytotoxicity of polyamines and seminal plasma in cell lines, primary cells, and tissues and, thus, should be implemented in all future studies analyzing the role of polyamines and semen on cellular functions.

Fishing for (in)continence: long-term follow-up of women with OASIS-still a taboo.

PURPOSE: Obstetric anal sphincter injuries (OASIS) increase the risk for pelvic floor dysfunctions. The goal of this study was to examine the long-term outcomes after OASIS on pelvic floor functions and quality of life. MATERIAL AND METHODS: Between 2005 and 2013, 424 women had an OASIS at the Women University Hospital Ulm. Out of these 71 women completed the German pelvic floor questionnaire, which includes questions regarding prolapse symptoms as well as bladder, bowel and sexual function. In addition, 64 women were physically examined, including a speculum examination to evaluate the degree of prolapse, a cough test to evaluate urinary stress incontinence (SI) and an evaluation of both pelvic floor sphincter (modified Oxford score) and anal sphincter contraction. RESULTS: A high rate of pelvic floor disorders after OASIS was found, as 74.6% of women reported SI, 64.8% flatus incontinence and 18.3% stool incontinence, respectively. However, only few women stated a substantial negative impact on quality of life. The clinical examination showed that a positive cough test, a weak anal sphincter tone and a diagnosed prolapse correlated with the results of the self-reported questionnaire. CONCLUSION: On one hand, OASIS has an influence on pelvic floor function going along with lots of complaints, while on the other hand, it still seems to be a taboo topic, as none of the participants spoke about the complaints after OASIS with a doctor. Therefore, the gynecologist should actively address these issues and offer therapy options for the women with persisting problems.

Gemcitabine as adjuvant chemotherapy in patients with high-risk early breast cancer-results from the randomized phase III SUCCESS-A trial.

BACKGROUND: When chemotherapy is indicated in patients with early breast cancer, regimens that contain anthracyclines and taxanes are established standard treatments. Gemcitabine has shown promising effects on the response and prognosis in patients with metastatic breast cancer. The SUCCESS-A trial (NCT02181101) examined the addition of gemcitabine to a standard chemotherapy regimen in high-risk early breast cancer patients. METHODS: A total of 3754 patients with at least one of the following characteristics were randomly assigned to one of the two treatment arms: nodal positivity, tumor grade 3, age ≤ 35 years, tumor larger than 2 cm, or negative hormone receptor status. The treatment arms received either three cycles of 5-fluorouracil, epirubicin, and cyclophosphamide, followed by three cycles of docetaxel (FEC → Doc); or three cycles of FEC followed by three cycles of docetaxel and gemcitabine (FEC → Doc/Gem). The primary study aim was disease-free survival (DFS), and the main secondary objectives were overall survival (OS) and safety. RESULTS: No differences were observed in the 5-year DFS or OS between FEC → Doc and FEC → Doc/Gem. The hazard ratio was 0.93 (95% CI, 0.78 to 1.12; P = 0.47) for DFS and 0.94 (95% CI, 0.74 to 1.19; P = 0.60) for OS. For patients treated with FEC → Doc and FEC → Doc/Gem, the 5-year probabilities of DFS were 86.6% and 87.2%, and the 5-year probabilities of OS were 92.8% and 92.5%, respectively. CONCLUSION: Adding gemcitabine to a standard chemotherapy does not improve the outcomes in patients with high-risk early breast cancer and should therefore not be included in the adjuvant treatment setting. TRIAL REGISTRATION: Clinicaltrials.gov NCT02181101 and EU Clinical Trials Register EudraCT 2005-000490-21. Registered September 2005.

Quality of life during and after adjuvant anthracycline-taxane-based chemotherapy with or without Gemcitabine in high-risk early breast cancer: results of the SUCCESS A trial.

PURPOSE: In high-risk early breast cancer, adjuvant taxane-Gemcitabine combinations result in a recurrence-free survival similar to single-agent taxanes. However, haematologic toxicities and need for dose reductions are more frequent in combinations. Which option ultimately provides a better quality of life (QoL) is unknown. We compared the QoL curves before, during, and up to one year after three cycles of Fluorouracil-epirubicin-cyclophosphamide followed by three cycles of Docetaxel-Gemcitabine or Docetaxel. METHODS: Overall, 3691 women with recent R0-resection of a primary epithelial breast cancer participated in the nationwide SUCCESS A clinical trial. The centres sent QoL questionnaires of the European Organisation for Research and Treatment of Cancer before and up to 15 months after randomisation to Docetaxel-Gemcitabine versus Docetaxel. Multilevel analysis by chemotherapy arm estimated the QoL time curves, questionnaire return, and dropout. RESULTS: The combination caused one-point higher global QoL (95% confidence ±1; p = 0.05) and 1.1 lower odds of adherence to the outcome (95% confidence 1.0-1.1; p = 0.23) than the monotherapy. In both groups, a 10-point decrease during therapy preceded a 16-point increase after chemotherapy (p < 0.001). The secondary QoL outcomes showed transient superiority of the combination at the end of chemotherapy. Discontinuation from chemotherapy and its reasons were equal in both groups. CONCLUSIONS: While patients perceive a one-point QoL difference as meaningless, a six-point increase is clinically relevant for them. That is, both regimens cause the same relevant long-term QoL improvement. With the similar recurrence-free survival, the lower toxicity, and the shorter chemotherapy duration in mind, taxanes without Gemcitabine are the preference. This challenges previous recommendations supporting combinations.

In vitro model for DNA double-strand break repair analysis in breast cancer reveals cell type-specific associations with age and prognosis.

Dysfunction of homologous recombination is a common denominator of changes associated with breast cancer-predisposing mutations. In our previous work, we identified a functional signature in peripheral blood lymphocytes from women who were predisposed that indicated a shift from homologous recombination to alternative, error-prone DNA double-strand break (DSB) repair pathways. To capture both hereditary and nonhereditary factors, we newly established a protocol for isolation and ex vivo analysis of epithelial cells, epithelial-mesenchymal transition cells (EMTs), and fibroblasts from breast cancer specimens (147 patients). By applying a fluorescence-based test system, we analyzed the error-prone DSB repair pathway microhomology-mediated end joining in these tumor-derived cell types and peripheral blood lymphocytes. In parallel, we investigated DNA lesion processing by quantitative immunofluorescence microscopy of histone H2AX phosphorylated on Ser139 focus after radiomimetic treatment. Our study reveals elevated histone H2AX phosphorylated on Ser139 damage removal in epithelial cells, not EMTs, and poly(ADP-ribose)polymerase inhibitor sensitivities, which suggested a DSB repair pathway shift with increasing patient age. Of interest, we found elevated microhomology-mediated end joining in EMTs, not epithelial cells, from patients who received a treatment recommendation of adjuvant chemotherapy, that is, those with high-risk tumors. Our discoveries of altered DSB repair activities in cells may serve as a method to further classify breast cancer to predict responsiveness to adjuvant chemotherapy and/or therapeutics that target DSB repair-dysfunctional tumors.-Deniz, M., Kaufmann, J., Stahl, A., Gundelach, T., Janni, W., Hoffmann, I., Keimling, M., Hampp, S., Ihle, M., Wiesmüller, L. In vitro model for DNA double-strand break repair analysis in breast cancer reveals cell type-specific associations with age and prognosis.

The influence of obesity on survival in early, high-risk breast cancer: results from the randomized SUCCESS A trial.

INTRODUCTION: Obese breast cancer patients have worse prognosis than normal weight patients, but the level at which obesity is prognostically unfavorable is unclear. METHODS: This retrospective analysis was performed using data from the SUCCESS A trial, in which 3754 patients with high-risk early breast cancer were randomized to anthracycline- and taxane-based chemotherapy with or without gemcitabine. Patients were classified as underweight/normal weight (body mass index (BMI) < 25.0), overweight (BMI 25.0-29.9), slightly obese (BMI 30.0-34.9), moderately obese (BMI 35.0-39.9) and severely obese (BMI ≥ 40.0), and the effect of BMI on disease-free survival (DFS) and overall survival (OS) was evaluated (median follow-up 65 months). In addition, subgroup analyses were conducted to assess the effect of BMI in luminal A-like, luminal B-like, HER2 (human epidermal growth factor 2)-positive and triple-negative tumors. RESULTS: Multivariate analyses revealed an independent prognostic effect of BMI on DFS (p = 0.001) and OS (p = 0.005). Compared with underweight/normal weight patients, severely obese patients had worse DFS (hazard ratio (HR) 2.70, 95 % confidence interval (CI) 1.71-4.28, p < 0.001) and OS (HR 2.79, 95 % CI 1.63-4.77, p < 0.001), while moderately obese, slightly obese and overweight patients did not differ from underweight/normal weight patients with regard to DFS or OS. Subgroup analyses showed a similar significant effect of BMI on DFS and OS in patients with triple-negative breast cancer (TNBC), but not in patients with other tumor subtypes. CONCLUSIONS: Severe obesity (BMI ≥ 40) significantly worsens prognosis in early breast cancer patients, particularly for triple-negative tumors. TRIAL REGISTRATION: Clinicaltrials.gov NCT02181101 . Registered September 2005.

Phosphatidylserine-exposing extracellular vesicles in body fluids are an innate defence against apoptotic mimicry viral pathogens.

Some viruses are rarely transmitted orally or sexually despite their presence in saliva, breast milk, or semen. We previously identified that extracellular vesicles (EVs) in semen and saliva inhibit Zika virus infection. However, the antiviral spectrum and underlying mechanism remained unclear. Here we applied lipidomics and flow cytometry to show that these EVs expose phosphatidylserine (PS). By blocking PS receptors, targeted by Zika virus in the process of apoptotic mimicry, they interfere with viral attachment and entry. Consequently, physiological concentrations of EVs applied in vitro efficiently inhibited infection by apoptotic mimicry dengue, West Nile, Chikungunya, Ebola and vesicular stomatitis viruses, but not severe acute respiratory syndrome coronavirus 2, human immunodeficiency virus 1, hepatitis C virus and herpesviruses that use other entry receptors. Our results identify the role of PS-rich EVs in body fluids in innate defence against infection via viral apoptotic mimicries, explaining why these viruses are primarily transmitted via PS-EV-deficient blood or blood-ingesting arthropods rather than direct human-to-human contact.

The power of DNA double-strand break (DSB) repair testing to predict breast cancer susceptibility.

Most presently known breast cancer susceptibility genes have been linked to DSB repair. To identify novel markers that may serve as indicators for breast cancer risk, we performed DSB repair analyses using a case-control design. Thus, we examined 35 women with defined familial history of breast and/or ovarian cancer (first case group), 175 patients with breast cancer (second case group), and 245 healthy women without previous cancer or family history of breast cancer (control group). We analyzed DSB repair in peripheral blood lymphocytes (PBLs) by a GFP-based test system using 3 pathway-specific substrates. We found increases of microhomology-mediated nonhomologous end joining (mmNHEJ) and nonconservative single-strand annealing (SSA) in women with familial risk vs. controls (P=0.0001-0.0022) and patients with breast cancer vs. controls (P=0.0004-0.0042). Young age (<50) at initial diagnosis of breast cancer, which could be indicative of genetic predisposition, was associated with elevated SSA using two different substrates, amounting to similar odds ratios (ORs=2.54-4.46, P=0.0059-0.0095) as for familial risk (ORs=2.61-4.05, P=0.0007-0.0045). These findings and supporting validation data underscore the great potential of detecting distinct DSB repair activities in PBLs as method to estimate breast cancer susceptibility beyond limitations of genotyping and to predict responsiveness to therapeutics targeting DSB repair-dysfunctional tumors.

The role of preoperative ultrasound evaluation of inguinal lymph nodes in patients with vulvar malignancy.

OBJECTIVES: Inguinal lymphadenectomy in vulvar malignancies is associated with significant morbidity, especially in patients over 70 years old. Under certain conditions, surgical guidelines recommend biopsy and evaluation of the sentinel node in early vulvar cancer. The purpose of our study is to evaluate ultrasonography as a predictor of inguinal lymph node involvement. METHODS: A retrospective study was performed with 60 patients who had vulvar malignancies (92% of which were squamous cell carcinomas) and who were treated at our hospital between 2002 and 2012. The patients ranged in age from 35 to 89 years, with a median age of 76 years. In total, 118 groin scans were retrospectively evaluated for sonographic evidence of lymph node involvement (i.e., absence of fatty hilum, irregular shape, cortical region diameter and vascularization pattern). The results were then compared with histopathologically confirmed lymph node status. RESULTS: Histopathologically confirmed lymph node status was available for 107 of the inguinal nodes examined by ultrasound, and lymph node metastases were found in 38 (35.5%) cases. The presence or absence of inguinal lymph node metastases was correctly identified by sonography in 92 (86.0%) of the scanned areas. Sensitivity was 76.3%, specificity was 91.3%, and positive and negative predictive values were 82.9% and 87.5%, respectively. CONCLUSIONS: Ultrasonography of the inguinal lymph nodes showed a relatively high sensitivity and specificity for predicting inguinal tumor metastases. However, our results indicate that surgical lymph node staging is still needed to precisely determine inguinal lymph node status in vulvar cancer, especially because a missed lymph node-metastasis is often fatal.

Functional analysis-make or break for cancer predictability.

Copy number variations (CNVs) encompass a variety of genetic alterations including deletions and amplifications and cluster in regions of the human genome with intrinsic instability. Small-sized CNVs can act as initial genetic changes giving rise to larger CNVs such as acquired somatic copy number aberrations (CNAs) promoting cancer formation. Previous studies provided evidence for CNVs as an underlying cause of elevated breast cancer risk when targeting breast cancer susceptibility genes and of accelerated breast cancer progression when targeting oncogenes. With the development of novel techniques for genome-wide detection of CNVs at increasingly higher resolution, it became possible to qualitatively and quantitatively analyse manifestation of DNA damage resulting from defects in any of the large variety of DNA double-strand break (DSB) repair mechanisms. Breast carcinogenesis, particularly in familial cases, has been linked with a defect in the homologous recombination (HR) pathway, which in turn switches damage removal towards alternative, more error-prone DSB repair pathways such as microhomology-mediated non-homologous end joining (mmNHEJ). Indeed, increased error-prone DSB repair activities were detected in peripheral blood lymphocytes from individuals with familial breast cancer risk independently of specific gene mutations. Intriguingly, sequence analysis of breakpoint regions revealed that the majority of genome aberrations found in breast cancer specimens are formed by mmNHEJ. Detection of pathway-specific error-prone DSB repair activities by functional testing was proposed to serve as biomarker for hereditary breast cancer risk and responsiveness to therapies targeting HR dysfunction. Identification of specific error-prone DSB repair mechanisms underlying CNAs and ultimately mammary tumour formation highlights potential targets for future breast cancer prevention regimens.

Ovarian cancer: in search of better marker systems based on DNA repair defects.

Ovarian cancer is the fifth most common female cancer in the Western world, and the deadliest gynecological malignancy. The overall poor prognosis for ovarian cancer patients is a consequence of aggressive biological behavior and a lack of adequate diagnostic tools for early detection. In fact, approximately 70% of all patients with epithelial ovarian cancer are diagnosed at advanced tumor stages. These facts highlight a significant clinical need for reliable and accurate detection methods for ovarian cancer, especially for patients at high risk. Because CA125 has not achieved satisfactory sensitivity and specificity in detecting ovarian cancer, numerous efforts, including those based on single and combined molecule detection and "omics" approaches, have been made to identify new biomarkers. Intriguingly, more than 10% of all ovarian cancer cases are of familial origin. BRCA1 and BRCA2 germline mutations are the most common genetic defects underlying hereditary ovarian cancer, which is why ovarian cancer risk assessment in developed countries, aside from pedigree analysis, relies on genetic testing of BRCA1 and BRCA2. Because not only BRCA1 and BRCA2 but also other susceptibility genes are tightly linked with ovarian cancer-specific DNA repair defects, another possible approach for defining susceptibility might be patient cell-based functional testing, a concept for which support came from a recent case-control study. This principle would be applicable to risk assessment and the prediction of responsiveness to conventional regimens involving platinum-based drugs and targeted therapies involving poly (ADP-ribose) polymerase (PARP) inhibitors.

The Transobturator Tape Versus Retropubic Tension-Free Vaginal Tape in the Treatment of Comorbid and Elderly Women With Stress Urinary Incontinence: A Retrospective Analysis of Over 800 Women.

Background and objective The first-line surgical treatment for female stress urinary incontinence (SUI) involves midurethral slings (MUS), including the transobturator tape (TOT) and the retropubic tension-free vaginal tape (TVT). However, whether offering these procedures to older and comorbid women could lead to increased complications is a question that needs to be seriously addressed. In this retrospective cohort study, we aimed to compare the two procedures and evaluate the impact of age, BMI, and comorbidities on complications. Materials and methods A total of 873 procedures (306 TVTs/567 TOTs) performed between 2007 and 2017 were compared and correlated with regard to age, BMI, and comorbidities. Intraoperative complications included bleeding >50 ml, bladder injury, and anesthesia-associated complications. Postoperative complications included post-void residual volume, pain, hematoma, lower urinary tract infection, revision for loosening tape, and bladder infections. The comorbidities were evaluated based on the American Society of Anesthesiologists (ASA) and Charlson scores. Results A total of 873 MUS were conducted during the study period: 306 TVTs and 567 TOTs. Groupwise comparison between these procedures showed that women in the TOT group were older (p<0.001) with a higher BMI (p<0.001) and a higher ASA score (p<0.001) compared to the TVT group. Nevertheless, significantly more intraoperative complications, especially bladder injuries, were recorded in the TVT group. Postoperative complications occurred in 19.4% of the entire cohort, especially increased post-void residual volume. Postoperative hematoma and tape loosening were significantly more frequent in the TOT group. Age, BMI, and comorbidities showed no significant impact on intraoperative complications; however, the TOT procedure was associated with significantly fewer intraoperative complications [p=0.001, odds ratio (OR): 0.281]. Conclusions Overall, both procedures were associated with a low number of perioperative complications. The TOT technique had a lower incidence of intraoperative complications. It must be highlighted that age and comorbidities had no influence on either the intra- or postoperative complication rates. Hence, we recommend that TOT is employed to treat SUI in older, more obese, and comorbid women.

Effect of the Delivery Mode on Pelvic Floor Function and Coping With Birth-Related Pain and Fear: A Prospective Survey Six Months Postpartum.

Background and objective Delivering a baby is one of the most decisive events in a woman`s life and brings along psychological and physical challenges. Therefore, the question arises: which mode of delivery is the best for the woman's health and her future life? The aim of this study was to evaluate the influence of the delivery mode on pelvic floor function and coping with birth-related pain and fear six months postpartum. Materials and methods A total of 200 primiparous women, who delivered during 2018-2019, were included in this prospective case-control study and were asked to fill out the "Pelvic floor questionnaire for pregnant women and women after childbirth" six months after delivery. The women were separated into the following groups: spontaneous vaginal delivery (n = 113), operative vaginal delivery (n = 44), and cesarean section (n = 41). The pelvic floor function as well as coping with birth-related pain and fear six months after delivery was compared. Results A significantly higher body mass index was found in the cesarean section group. A significantly worse bladder score was shown in the group with an operative vaginal delivery (p = 0.006). The total score of the questionnaire as well as the anal, prolapse, and sexual subscores showed no difference between the delivery modes. Concerning coping with birth-related pain and fear postpartum, significant differences could be seen between the modes of delivery (pain: p < 0.001; fear: p < 0.001). Women with spontaneous vaginal delivery showed better coping with pain and fear postpartum. Conclusion It must be highlighted that women who have had a surgical delivery, including the operative vaginal delivery and cesarean section, stated a lower coping with birth-related pain and fear. This study showed that an operative vaginal delivery has a negative influence on bladder function and the use should be well-indicated. Obstetricians should always be aware of this, as they can contribute to better coping. It is essential to give women the opportunity to talk about the delivery and individual experiences both in pre- and postnatal situations.

ABRAXAS1 orchestrates BRCA1 activities to counter genome destabilizing repair pathways-lessons from breast cancer patients.

It has been well-established that mutations in BRCA1 and BRCA2, compromising functions in DNA double-strand break repair (DSBR), confer hereditary breast and ovarian cancer risk. Importantly, mutations in these genes explain only a minor fraction of the hereditary risk and of the subset of DSBR deficient tumors. Our screening efforts identified two truncating germline mutations in the gene encoding the BRCA1 complex partner ABRAXAS1 in German early-onset breast cancer patients. To unravel the molecular mechanisms triggering carcinogenesis in these carriers of heterozygous mutations, we examined DSBR functions in patient-derived lymphoblastoid cells (LCLs) and in genetically manipulated mammary epithelial cells. By use of these strategies we were able to demonstrate that these truncating ABRAXAS1 mutations exerted dominant effects on BRCA1 functions. Interestingly, we did not observe haploinsufficiency regarding homologous recombination (HR) proficiency (reporter assay, RAD51-foci, PARP-inhibitor sensitivity) in mutation carriers. However, the balance was shifted to use of mutagenic DSBR-pathways. The dominant effect of truncated ABRAXAS1 devoid of the C-terminal BRCA1 binding site can be explained by retention of the N-terminal interaction sites for other BRCA1-A complex partners like RAP80. In this case BRCA1 was channeled from the BRCA1-A to the BRCA1-C complex, which induced single-strand annealing (SSA). Further truncation, additionally deleting the coiled-coil region of ABRAXAS1, unleashed excessive DNA damage responses (DDRs) de-repressing multiple DSBR-pathways including SSA and non-homologous end-joining (NHEJ). Our data reveal de-repression of low-fidelity repair activities as a common feature of cells from patients with heterozygous mutations in genes encoding BRCA1 and its complex partners.

Diagnosis and Therapy of Female Urinary Incontinence. Guideline of the DGGG, OEGGG and SGGG (S2k Level, AWMF Registry No. 015/091, January 2022): Part 2 with Recommendations on Interventional/Surgical Therapy of Overactive Bladder, Surgical Treatment of Stress Urinary Incontinence and Diagnosis and Therapy of Iatrogenic Urogenital Fistula.

Aim This completely revised interdisciplinary S2k-guideline on the diagnosis, therapy, and follow-up care of female patients with urinary incontinence (AWMF registry number: 015-091) was published in December 2021. This guideline combines and summarizes earlier guidelines such as "Female stress urinary incontinence," "Female urge incontinence" and "Use of Ultrasonography in Urogynecological Diagnostics" for the first time. The guideline was coordinated by the German Society for Gynecology and Obstetrics (Deutsche Gesellschaft für Gynäkologie und Geburtshilfe, DGGG) and the Working Group for Urogynecology and Plastic Pelvic Floor Reconstruction (Arbeitsgemeinschaft für Urogynäkologie und plastische Beckenbodenrekonstruktion e. V., AGUB). Methods This S2k-guideline was developed using a structured consensus process involving representative members from different medical specialties and was commissioned by the Guidelines Commission of the DGGG, OEGGG and SGGG. The guideline is based on the current version of the guideline "Urinary Incontinence in Adults" published by the European Association of Urology (EAU). Country-specific items associated with the respective healthcare systems in Germany, Austria and Switzerland were also incorporated. Recommendations The short version of this guideline consists of recommendations and statements on the surgical treatment of female patients with stress urinary incontinence and urge incontinence. Specific solutions for the diagnostic workup and treatment of uncomplicated and complicated urinary incontinence are discussed. The diagnostics and surgical treatment of iatrogenic urogenital fistula are presented.

Diagnosis and Therapy of Female Urinary Incontinence. Guideline of the DGGG, OEGGG and SGGG (S2k-Level, AWMF Registry No. 015/091, January 2022): Part 1 with Recommendations on Diagnostics and Conservative and Medical Treatment.

Aim This completely revised interdisciplinary S2k-guideline on the diagnosis, therapy, and follow-up care of female patients with urinary incontinence (AWMF registry number: 015-091) was published in December 2021. This guideline combines and summarizes earlier guidelines such as "Female stress urinary incontinence," "Female urge incontinence" and "Use of Ultrasonography in Urogynecological Diagnostics" for the first time. The guideline was coordinated by the German Society for Gynecology and Obstetrics (Deutsche Gesellschaft für Gynäkologie und Geburtshilfe, DGGG) and the Working Group for Urogynecology and Plastic Pelvic Floor Reconstruction (Arbeitsgemeinschaft für Urogynäkologie und plastische Beckenbodenrekonstruktion e. V., AGUB). Methods This S2k-guideline was developed using a structured consensus process involving representative members from different medical specialties and was commissioned by the Guidelines Commission of the DGGG, OEGGG and SGGG. The guideline is based on the current version of the guideline "Urinary Incontinence in Adults" published by the European Association of Urology (EAU). Country-specific items associated with the respective healthcare systems in Germany, Austria and Switzerland were also incorporated. Recommendations The short version of this guideline consists of recommendations and statements on the epidemiology, etiology, classification, symptoms, diagnostics, and treatment of female patients with urinary incontinence. Specific solutions for the diagnostic workup and appropriate conservative and medical therapies for uncomplicated and complication urinary incontinence are discussed.

Impact of postpartum pain and birth pain management on the pelvic floor function. A retrospective study including over 300 mothers.

OBJECTIVES: It is known that pregnancy and childbirth bring biological, psychological and social changes in a woman's life. Studies regarding the pelvic floor function focus on the year after delivery, but unfortunately, long-term studies are rare. Furthermore, an association between postpartum pain and birth pain management on the pelvic floor function has rarely been examined. The aim of this study is the evaluation of the pelvic floor function years after delivery in order to detect possible risk factors. STUDY DESIGN: This is a retrospective cohort study. All women who delivered in our hospital between 2015 and 2016 were contacted by mail between 2018 and 2019 and asked to participate. The letters included study information, declaration of consent, the "Pelvic floor questionnaire for pregnant women and women after childbirth" (PFQ), contact information and pre-paid envelopes. Questions about pain after childbirth and the management of birth related fear and pain were particularly of interest in the surveys. The interested participants were asked to return the completed declaration of consent and the questionnaire. Overall, 308 women were included in the analysis. Due to the large number of participants, different subgroups were defined in order to compare influencing factors adequately. RESULTS: No significant association between the mode of delivery and the total score of the PFQ was found after 3-4 years in primiparous women (p = 0.688). Our study also showed that recorded pain after childbirth and insufficient pain and fear management after childbirth had a negative impact on the pelvic floor function (total scores: pain after childbirth p = 0.00; no pain management p = 0.04; no fear management p = 0.021). CONCLUSION: No association was found between delivery mode and pelvic floor function in primiparous women three to four years after childbirth. On the other hand, a negative impact of birth related pain and fears on the pelvic floor function years after delivery was significant. Therefore, these revealing findings should certainly be considered in postpartum management.