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The transition zones of the squamous and columnar epithelia constitute hotspots for the emergence of cancer, often preceded by metaplasia, in which one epithelial type is replaced by another. It remains unclear how the epithelial spatial organization is maintained and how the transition zone niche is remodelled during metaplasia. Here we used single-cell RNA sequencing to characterize epithelial subpopulations and the underlying stromal compartment of endo- and ectocervix, encompassing the transition zone. Mouse lineage tracing, organoid culture and single-molecule RNA in situ hybridizations revealed that the two epithelia derive from separate cervix-resident lineage-specific stem cell populations regulated by opposing Wnt signals from the stroma. Using a mouse model of cervical metaplasia, we further show that the endocervical stroma undergoes remodelling and increases expression of the Wnt inhibitor Dickkopf-2 (DKK2), promoting the outgrowth of ectocervical stem cells. Our data indicate that homeostasis at the transition zone results from divergent stromal signals, driving the differential proliferation of resident epithelial lineages. Chumduri, Gurumurthy et al. show that cervical squamous and columnar epithelia derive from two stem cell populations, regulated by opposing Wnt signals, and that a Wnt-repressive environment can induce metaplasia.

Coinfections with pathogenic microbes continually confront cervical mucosa, yet their implications in pathogenesis remain unclear. Lack of in-vitro models recapitulating cervical epithelium has been a bottleneck to study coinfections. Using patient-derived ectocervical organoids, we systematically modeled individual and coinfection dynamics of Human papillomavirus (HPV)16 E6E7 and Chlamydia, associated with carcinogenesis. The ectocervical stem cells were genetically manipulated to introduce E6E7 oncogenes to mimic HPV16 integration. Organoids from these stem cells develop the characteristics of precancerous lesions while retaining the self-renewal capacity and organize into mature stratified epithelium similar to healthy organoids. HPV16 E6E7 interferes with Chlamydia development and induces persistence. Unique transcriptional and post-translational responses induced by Chlamydia and HPV lead to distinct reprogramming of host cell processes. Strikingly, Chlamydia impedes HPV-induced mechanisms that maintain cellular and genome integrity, including mismatch repair in the stem cells. Together, our study employing organoids demonstrates the hazard of multiple infections and the unique cellular microenvironment they create, potentially contributing to neoplastic progression. Here, Koster et al ., model human papillomavirus and Chlamydia coinfection dynamics in patient-derived ectocervical organoids, and characterize the effects of multiple infections in the cellular microenvironment, potentially contributing to neoplasia.

Chronic infections of the fallopian tubes with Chlamydia trachomatis ( Ctr ) cause scarring and can lead to infertility. Here we use human fallopian tube organoids and genital Ctr serovars D, K and E for long-term in vitro analysis. The epithelial monolayer responds with active expulsion of the bacteria into the lumen and with compensatory cellular proliferation—demonstrating a role of epithelial homeostasis in the defense against this pathogen. In addition, Ctr infection activates LIF signaling, which we find to be an essential regulator of stemness in the organoids. Infected organoids exhibit a less differentiated phenotype with higher stemness potential, as confirmed by increased organoid forming efficiency. Moreover, Ctr increases hypermethylation of DNA, which is an indicator of accelerated molecular aging. Thus, the chronic organoid infection model suggests that Ctr has a long-term impact on the epithelium. These heritable changes might be a contributing factor in the development of tubal pathologies, including the initiation of high grade serous ovarian cancer. Chronic infections of the fallopian tubes with Chlamydia trachomatis can cause scarring and infertility. Here, the authors show that the pathogen alters stem cell differentiation and DNA methylation in human fallopian tube organoids, suggesting a potential link to cellular ageing and malignant transformation.

The epithelial lining of the fallopian tube is of critical importance for human reproduction and has been implicated as a site of origin of high-grade serous ovarian cancer. Here we report on the establishment of long-term, stable 3D organoid cultures from human fallopian tubes, indicative of the presence of adult stem cells. We show that single epithelial stem cells in vitro can give rise to differentiated organoids containing ciliated and secretory cells. Continuous growth and differentiation of organoids depend on both Wnt and Notch paracrine signalling. Microarray analysis reveals that inhibition of Notch signalling causes downregulation of stem cell-associated genes in parallel with decreased proliferation and increased numbers of ciliated cells and that organoids also respond to oestradiol and progesterone treatment in a physiological manner. Thus, our organoid model provides a much-needed basis for future investigations of signalling routes involved in health and disease of the fallopian tube. The mechanisms underlying fallopian tube epithelial renewal are unclear. Here, Kessler et al. isolate adult stem cells from the human fallopian tube epithelium and generate 3D organoids from these cells in vitro that have a similar architecture to that of the fallopian tube.

Cervical cancer is a leading cause of death among women globally, primarily driven by high-risk papillomaviruses. However, the effectiveness of chemotherapy is limited, underscoring the potential of personalized immunotherapies. Patient-derived organoids, which possess cellular heterogeneity, proper epithelial architecture and functionality, and long-term propagation capabilities offer a promising platform for developing viable strategies. In addition to αβ T cells and natural killer (NK) cells, γδ T cells represent an immune cell population with significant therapeutic potential against both hematologic and solid tumours. To evaluate the efficacy of γδ T cells in cervical cancer treatment, we generated patient-derived healthy and cancer ectocervical organoids. Furthermore, we examined transformed healthy organoids, expressing HPV16 oncogenes E6 and E7. We analysed the effector function of in vitro expanded γδ T cells upon co-culture with organoids. Our findings demonstrated that healthy cervical organoids were less susceptible to γδ T cell-mediated cytotoxicity compared to HPV-transformed organoids and cancerous organoids. To identify the underlying pathways involved in this observed cytotoxicity, we performed bulk-RNA sequencing on the organoid lines, revealing differences in DNA-damage and cell cycle checkpoint pathways, as well as transcription of potential γδ T cell ligands. We validated these results using immunoblotting and flow cytometry. We also demonstrated the involvement of BTN3A1 and BTN2A1, crucial molecules for γδ T cell activation, as well as differential expression of PDL1/CD274 in cancer, E6/E7+ and healthy organoids. Interestingly, we observed a significant reduction in cytotoxicity upon blocking MSH2, a protein involved in DNA mismatch-repair. In summary, we established a co-culture system of γδ T cells with cervical cancer organoids, providing a novel in vitro model to optimize innovative patient-specific immunotherapies for cervical cancer.

Background To evaluate the diagnostic value of adding human epididymis protein 4 (HE4), cancer antigen 125 (CA125) and risk of malignancy algorithm (ROMA) to ultrasound for detecting ovarian cancer in patients with a pelvic mass. Methods This was a prospective, observational, multicenter study. Patients aged > 18 years who were scheduled to undergo surgery for a suspicious pelvic mass had CA125 and HE4 levels measured prior to surgery, in addition to a routine transvaginal ultrasound scan. The diagnostic performance of CA125, HE4 and ROMA for distinguishing between benign and malignant adnexal masses was assessed using receiver operating characteristic (ROC) analysis and the corresponding area under the curve (AUC). Results Of 965 evaluable patients, 804 were diagnosed with benign tumors and 161 were diagnosed with ovarian cancer. In late-stage ovarian cancer, CA125, HE4 and ROMA all had an excellent diagnostic performance (AUC > 0.92), whereas in stage I and II, diagnostic performance of all three biomarkers was less adequate (AUC < 0.77). In the differential diagnosis of ovarian cancer and endometriosis, ROMA and HE4 performed better than CA125 with 99 and 98.1% versus 75.0% sensitivity, respectively, at 75.4% specificity. Conclusions ROMA and HE4 could be valuable biomarkers to help with the diagnosis of ovarian cancer in premenopausal patients in order to differentiate from endometriosis, whereas CA125 may be more adequate for postmenopausal patients. Highlights • Serum biomarkers can help to distinguish benign from malignant pelvic masses • We evaluated the diagnostic value of adding HE4, CA125 and ROMA to ultrasound for detecting ovarian cancer • In stage III and IV ovarian cancer all three biomarkers showed excellent performance • ROMA and HE4 performed better than CA125 in the differential diagnosis of ovarian cancer and endometriosis

Nausea and vomiting in pregnancy (NVP) affect up to 85% of pregnant individuals, predominantly in the first trimester. While most cases are mild, moderate to severe NVP can significantly impair quality of life and require medical intervention. Besides, safety concerns often influence decision-making. This study examines the perceptions, concerns, and information-seeking behaviors of women in Germany regarding NVP and its treatment. A nationwide cross-sectional online study was conducted from March 18-28, 2024, targeting pregnant individuals and mothers in Germany via the \" \" online community. Participants completed an anonymous online questionnaire comprising 15 items covering sociodemographic data, NVP severity (using the PUQE-24 score for pregnant individuals currently suffering from NVP), treatment attitudes, and information-seeking behavior. Data were analyzed using descriptive statistics and subgroup analyses were performed to investigate differences in NVP severity. Among 506 respondents (completion rate: 83.9%), 81.9% reported experiencing NVP, with 40% reporting moderate, 30.6% mild and 29.4% severe symptoms. Hospitalization was required in 12.4% of cases, predominantly among those with severe NVP, with 76.3% of those receiving medication post-discharge. Participants primarily sought information from physicians (53.4%), the internet (50.6%), and midwives (44.5%), with more severe NVP prompting greater information-seeking behavior. Safety concerns dominated treatment preferences, with participants prioritizing drug approval (on-label prescription) for pregnancy and rapid symptom relief. This study emphasizes the need for proactive communication from healthcare providers about safe and effective NVP treatments. Tailored, patient-centered strategies that address safety concerns and provide evidence-based guidance are essential for informed decision-making.

OBJECTIVEThe oncological outcome regarding disease-free survival and overall survival after radical vaginal trachelectomy (RVT) is the same as the rates after radical hysterectomy. We aim to analyze predictive and risk factors and death in patients with cervical cancer undergoing fertility preservation by laparoscopic lymphadenectomy and RVT. METHODSThree hundred twenty patients with cervical cancer underwent RVT between March 1995 and February 2013. In our study, we examined recurrence rates analyzed by risk factors. We classified the presence of lymphovascular space invasion, depth of tumor infiltration, tumor size, and tumor grading as risk factors. The mean follow-up time was 48 months. RESULTSTen of the 320 patients had cancer recurrence. Recurrence appeared at a mean time of 26.1 months (3–108 months) after RVT. Five patients died within 8.8 months (4–15 months) after recurrence was diagnosed. Two of these 5 patients had distant metastasis at the time of recurrence. Five patients were treated successfully by surgery, and 4 patients were treated successfully by chemotherapy. The mean follow-up after the recurrence of these 5 patients is 76 months (6–120 months). None of the 10 patients with recurrences in our series showed significant high-risk factors. CONCLUSIONThere seems to be no pattern in the recurrence of cancer after RVT. It is strictly mandatory to follow up the patients closely every 3 months after RVT to diagnose recurrence at an early stage so therapeutic options such as chemoradiation are still available. Once distant metastasis occurs, prognosis is not good.

PurposePatients after radical vaginal trachelectomy (RVT) need specific follow-up treatment because their problems differ from those of other gyneco-oncologic patients. Anatomic changes after surgery complicate examinations. Recognition and treatment of these issues require physician’s expertise.Patients and methodsWe evaluated the follow-up data of 70 patients who underwent RVT for early cervical cancer between 03/2010 and 12/2013. The follow-up interval in the first 2 years was 3 and 6 months in the following 2 years. We used a tailored protocol to describe the special problems after RVT.ResultsCervical stenosis was one of the central problems independent of time interval to RVT. Physicians’ most significant problem was to locate the exact position of the neo-cervix and thus to receive valid pap smears.ConclusionsFollow-up of patients after RVT needs special expertise because the symptoms differ from those after hysterectomy and examinations ensuring oncologic safety require special attention.

Objectives: We aimed to examine the efficacy of two psycho-oncological interventions in anxiety, depression, and self-perceived as well as physiological stress in inpatients with gynaecological cancer. Methods: Forty-five women were included in the trial. Thirty-five were categorized as being at high risk of anxiety and depression, and were randomized to either a single psycho-oncological therapy session or a single-session relaxation intervention. Results: A significant decrease in anxiety [mean (t₀) = 12, mean (t 1 ) = 7.47, p = 0.001] and depression [mean (t₀) = 9.71, mean (t 1 ) = 6.35, p < 0.001] was observed in the psycho-oncological intervention group. In the relaxation group, anxiety also significantly decreased [mean (t₀) = 11.67, mean (t 1 ) = 8.22, p = 0.003], whereas depression did not. A comparative analysis of both interventions showed a trend in favour of psycho-oncological therapy for the treatment of depression (F = 3.3, p = 0.078). However, self-reported stress (p = 0.031) and different objective stress parameters only significantly decreased in the relaxation group. Conclusions: Psycho-oncological interventions should represent an essential part of interdisciplinary care for gynaecological cancer patients. Both types of intervention may reduce anxiety. However, the single psycho-oncological therapy session might be slightly more effective in treating depression, whereas the single-session relaxation intervention seems to have a stronger effect on physiological stress parameters.