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.
ObjectivesBasaloid-squamous-carcinomas (BSCC) have been considered as aggressive variants of common squamous-cell-carcinomas (HNSCC). Recent studies demonstrated a different clinical course depending on the tumour site. The aim of the study is to analyze the histopathologic/clinical features of BSCC/HNSCC resolved by the HPV-status.MethodsWe analysed the histopathologic/clinical features of BSCC (n=59) and HNSCC (n=981), subdivided due to the HPV status. Differences were analysed using Chi square, Fisher exact, and student's t-test. Survival rates were calculated by Kaplan–Meier and log-rank test. Prognostic variables were subsequently evaluated by Cox regression.ResultsOur cohort was congruent with the literature regarding sex, age, metastases, and a predilection in the oropharynx. HNSCC/BSCC did not show a different disease-specific-survival. After UICC matching, univariate analysis revealed a better survival of UICC stage IVa BSCC compared to HNSCC (69% vs. 42%, p=0.022) that was associated with a better response to radio-chemotherapy (p = 0.009). These results referred to the high prevalence of HPV+ (86%) oropharyngeal BSCC. Subgroup analysis demonstrated a better survival of HPV+ oropharyngeal BSCC than HPV-BSCC (p=0.017).ConclusionThe clinical outcome in BSCC depends on the tumour site and HPV-status. Prospective studies have to evaluate the beneficial application of postoperative radio-chemotherapy in HPV+ BSCC.
ObjectivesDespite modern treatment regimens, overall survival in head and neck squamous cell carcinomas (HNSCC) is less than 50% due to local and systemic disease recurrency. The current study aims to identify molecular markers in primary tumor specimens that predict the risk for local and systemic recurrency at the time of initial diagnosis.MethodsThe study included clinic-pathological data of 1,057 HNSCC. MMP2/9, TIMP1/2, CXCR4, and CXCL12 immunohistochemistry was done in 150 randomly selected specimens. For statistics, we employed Chi square, Fisher exact, and Student's t-test. Overall survival (OS) was calculated by Kaplan–Meier and log-rank test. Prognostic variables were subsequently evaluated by Cox regression for forward selection.ResultsCXCR4 positive specimens demonstrated a significant increased risk for tumor recurrency associated death (rT: HR 10.07; p=0.001 / rN: HR 5.04; p=0.013 / rM: HR 2.49; p=0.029) when compared with their unaltered counterparts. Expression of MMP9, TIMP2, CXCR4, and CXCL12 was significantly increased in distant metastasized patients (p<0.0001) and showed significant cross-correlation. In addition, CXCR4 positivity was associated with an increased risk to die due to enhanced T or N status (T1/2 vs. T3/4: HR 5.78; p=0.017; N0 vs. N+: HR 5.18; p=0.033).ConclusionCXCR4 positivity in tumor samples at initial diagnosis were associated with reduced overall survival, in particular with respect to increasing T/N status, local and systemic recurrency.
The liver is the central metabolic organ of the body. The plethora of anabolic and catabolic pathways in the liver is tightly regulated by physiological signaling but may become imbalanced as a consequence of malnutrition or exposure to certain chemicals, so-called metabolic endocrine disrupters, or metabolism-disrupting chemicals (MDCs). Among different metabolism-related diseases, obesity and non-alcoholic fatty liver disease (NAFLD) constitute a growing health problem, which has been associated with a western lifestyle combining excessive caloric intake and reduced physical activity. In the past years, awareness of chemical exposure as an underlying cause of metabolic endocrine effects has continuously increased. Within this review, we have collected and summarized evidence that certain environmental MDCs are capable of contributing to metabolic diseases such as liver steatosis and cholestasis by different molecular mechanisms, thereby contributing to the metabolic syndrome. Despite the high relevance of metabolism-related diseases, standardized mechanistic assays for the identification and characterization of MDCs are missing. Therefore, the current state of candidate test systems to identify MDCs is presented, and their possible implementation into a testing strategy for MDCs is discussed.
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