Single-Cell Transcriptome Analysis of Small Cell Neuroendocrine Carcinoma of the Endometrium Reveals ISL1 as a Potential Biomarker for Diagnosis and Treatment.

BACKGROUND: As a dedifferentiated tumor, small cell endometrial neuroendocrine tumors (NETs) are rare and frequently diagnosed at an advanced stage with a poor prognosis. Current treatment recommendations are often extrapolated from histologically similar tumors in other sites or based on retrospective studies. The exploration for diagnostic and therapeutic markers in small cell NETs is of great significance. METHODS: In this study, we conducted single-cell RNA sequencing on a specimen obtained from a patient diagnosed with small cell endometrial neuroendocrine carcinoma (SCNEC) based on pathology. We revealed the cell map and intratumoral heterogeneity of the cancer cells through data analysis. Further, we validated the function of ISL LIM Homeobox 1 (ISL1) in vitro in an established neuroendocrine cell line. Finally, we examined the association between ISL1 and tumor staging in small cell lung cancer (SCLC) patient samples. RESULTS: We observed the significant upregulation of ISL1 expression in tumor cells that showed high expression of the neuroepithelial markers. Additionally, in vitro cell function experiments demonstrated that the high ISL1 expression group exhibited markedly higher cell proliferation and migration abilities compared to the low expression group. Finally, we showed that the expression level of ISL1 was correlated with SCLC stages. CONCLUSIONS: ISL1 protein in NETs shows promise as a potential biomarker for diagnosis and treatment.

LATS1/2 loss promote tumor immune evasion in endometrial cancer through downregulating MHC-I expression.

BACKGROUND: LATS1/2 are frequently mutated and down-regulated in endometrial cancer (EC), but the contributions of LATS1/2 in EC progression remains unclear. Impaired antigen presentation due to mutations or downregulation of the major histocompatibility complex class I (MHC-I) has been implicated in tumor immune evasion. Herein, we elucidate the oncogenic role that dysregulation of LATS1/2 in EC leads to immune evasion through the down-regulation of MHC-I. METHODS: The mutation and expression as well as the clinical significance of LATS1/2 in EC was assessed in the TCGA cohort and our sample cohort. CRISPR-Cas9 was used to construct knockout cell lines of LATS1/2 in EC. Differentially expressed genes were analyzed by RNA-seq. The interaction between LATS1/2 and STAT1 was verified using co-immunoprecipitation and GST pull-down assays. Mass spectrometry, in vitro kinase assays, ChIP-qPCR, flow cytometry, immunohistochemistry, immunofluorescence and confocal microscopy were performed to investigate the regulation of LATS1/2 on MHC-I through interaction with and phosphorylate STAT1. The killing effect of activated PBMCs on EC cells were used to monitor anti-tumor activity. RESULTS: Here, we demonstrate that LATS1/2 are frequently mutated and down-regulated in EC. Moreover, LATS1/2 loss was found to be associated with a significant down-regulation of MHC-I, independently of the Hippo-YAP pathway. Instead, LATS1/2 were found to directly interact with and phosphorylate STAT1 at Ser727, a crucial transcription factor for MHC-I upregulation in response to interferon-gamma (IFN-γ) signaling, to promote STAT1 accumulating and moving into the nucleus to enhance the transcriptional activation of IRF1/NLRC5 on MHC-I. Additionally, the loss of LATS1/2 was observed to confer increased resistance of EC cells to immune cell-mediated killing and this resistance could be reversed by over-expression of MHC-I. CONCLUSION: Our findings indicate that dysregulation of LATS1/2 in EC leads to immune evasion through the down-regulation of MHC-I, leading to the suppression of infiltrating activated CD8 + T cells and highlight the importance of LATS1/2 in IFN-γ signaling-mediated tumor immune response, suggesting that LATS1/2 is a promising target for immune checkpoint blockade therapy in EC.

Association between depression or anxiety symptoms and immune-inflammatory characteristics in in-patients with tuberculosis: A cross-sectional study.

Background: Depression and anxiety are major psychological issues among patients with tuberculosis (TB) owing to chronic and complex treatments, have been reported to be closely correlated with immune and inflammation. However, the association of peripheral immune-inflammatory characteristics with depression/anxiety symptoms in in-patients with TB has rarely been reported. Methods: A cross-sectional study of 338 in-patients with TB from 3 hospitals in China were enrolled to investigate their depression and anxiety status by using the nine-item Patient Health Questionnaire (PHQ-9) and seven-item Generalized Anxiety Disorder Scale (GAD-7). Participants were divided into groups based on their PHQ-9 and GAD-7 scores, and differences in demography and immune-inflammatory characteristics were studied. Logistic analysis was performed to explore factors related to depression and anxiety symptoms. Results: Depression and anxiety prevalence among patients with TB was 47.9 and 42.6%, respectively. Furthermore, 38.5% of patients reported a comorbidity of depression and anxiety symptoms. The counts of CD3, CD4, CD8, and lymphocytes decreased, whereas those of neutrophils, platelets, and peripheral blood cells and their derived indices increased among TB patients with depression or anxiety in comparison with those without symptoms (p < 0.05). In addition, increasing age, lower income (monthly income ≤ 3,000 yuan), divorced or widowed, drug resistance, and higher systemic immune inflammation index (SII) were significantly associated with depression or anxiety symptoms (p < 0.05). Conclusion: Approximately half of the patients with TB suffered from depression or/and anxiety symptoms. Patients with depression or anxiety present worse cell immune status and stronger inflammatory responses compared to those without symptoms. We emphasized the importance of paying attention to the dysfunction of immune-inflammation process of TB patients with depression or anxiety symptoms. Especially, SII has a potential application value in guiding the evaluation of TB-related depression or anxiety owing to its easily accessibility and being economical.

Association of Three SNPs Loci of Kelch-Like-ECH-Associated Protein 1 (Human) with Tuberculosis in Chinese Han Population.

Purpose: Progression from latent tuberculosis infection (LTBI) to pulmonary TB (PTB) was associated with genetic polymorphisms, but there were limited genetic polymorphism data on LTBI and PTB. We aimed at examining the association of KEAP1 gene polymorphisms with PTB and LTBI. Patients and Methods: PTB patients and close contacts of PTB patients were recruited from West China Hospital of Sichuan University. After obtaining the patient's consent, we draw 2-5mL of blood from the patient's peripheral vein. Tag-SNPs of KEAP1 were chosen according to previous studies. The genotyping was done by improved multiplex ligase detection reaction (iMLDR). We used logistic regression to assess the association of SNPs with LTBI/PTB, with sex and age as covariates. Results: A total of 209 PTB patients, 201 LTBI, and 204 HCS were included in the present study. Three Tag-SNPs were included in this study. Significant association was found for KEAP1 rs1048290 between LTBI and HCS. Compared with the KEAP1 rs1048290 CC genotype, genotype GC had an 38% decreased risk for development LTBI (P = 0.043, OR = 0.62, 95% CI: 0.039-0.98). We also found that SNPs in KEAP1 were significantly related to PTB compared to LTBI. Compared with the rs11545829G allele, allele A had an 30% decreased risk for development PTB (P = 0.034, OR = 0.70, 95% CI: 0.51-0.97). We also found the rs11668429 polymorphism was related to PTB. Compared with TT, GT had a significantly increased risk of LTBI developing into PTB (P = 0.041, OR = 1.68, 95% CI: 1.02-2.77). Conclusion: Our study suggested that KEAP1 polymorphisms were significantly related to susceptibility to PTB and LTBI subjects.

Compartmentalized localization of 11ß-HSD 1 and 2 at the feto-maternal interface in the first trimester of human pregnancy.

Glucocorticoids are engaged in a number of actions at the feto-maternal interface for the establishment of early pregnancy. However, excessive glucocorticoids can be deleterious to fetal development. Therefore, compartmentalized distribution of 11ß-hydroxysteroid dehydrogenase 1 and 2 (11ß-HSD1 and 2), which regenerates and inactivates cortisol respectively, would ensure an optimal cortisol concentration at the feto-maternal interface for the establishment of early gestation. However, the distribution pattern of 11ß-HSD1 and 2 at the feto-maternal interface in early human pregnancy is not clearly defined. Here we showed that 11ß-HSD1 distributed extensively on the maternal side including decidual stromal cells and epithelial cells but scarcely on the fetal side except for localization in the fetal blood vessels of the chorionic villi. In contrast, 11ß-HSD2 was abundantly localized in syncytial layer of the chorionic villi and the decidual epithelium. In primary cultures, cortisol upregulated not only 11ß-HSD1 expression in decidual stromal cells but also 11ß-HSD2 expression in villous trophoblasts of early pregnancy. Further studies revealed that cortisol inhibited the expression of interleukin-1ß and 6 in decidual stromal cells and villous trophoblasts, and stimulated expression of human chorionic gonadotropin in villous trophoblasts. Collectively, this study has revealed a compartmentalized distribution pattern of 11ß-HSD 1 and 2 at the feto-maternal interface, both of which can be upregulated by glucocorticoids, suggesting that a coordinated interaction between 11ß-HSD 1 and 2 may exist to ensure an optimal cortisol concentration at discrete locations at the feto-maternal interface for the establishment of early pregnancy.

Effect of PFOS on glucocorticoid-induced changes in human decidual stromal cells in the first trimester of pregnancy.

Perfluorooctane sulfonate (PFOS) is a surfactant and used in treating products for waterproofing and non-stick applications. PFOS has potential influence on reproductive function but the effect of PFOS exposure on the decidual functions remains unknown. By using primary human decidual stromal cells of early pregnancy we demonstrated that PFOS inhibited decidualization of the stromal cells as well as decidualization-induced upregulation of 11ß-HSD1, an enzyme that regenerates biologically active cortisol from its inactive counterpart cortisone. Moreover, PFOS attenuated cortisol-induced decidualization and upregulation of 11ß-HSD1 in the stromal cells. Furthermore, PFOS inhibited the reduction of IL-6 and IL-1ß, the key proinflammatory cytokines in maternal-fetal immune intolerance, by cortisone in the decidual stromal cells indicating attenuated conversion of cortisone to cortisol. In conclusion, exposure to PFOS may disrupt the regeneration of cortisol in the decidual tissue thereby impairing the decidualization and immune-tolerance environment of early pregnancy.

The acetyl-CoA carboxylase enzyme: a target for cancer therapy?

As a rate-limiting enzyme, the acetyl-CoA carboxylase (ACC) is essential for fatty acid synthesis. Traditionally, the ACC has been a target of metabolic syndrome and obesity. Recent research has demonstrated that malignant tumors have a high energy flow, thus having a great ability to synthesize fatty acids. ACCs are occasionally found to be overexpressed in cancer cells, and using chemical or RNA interference to inhibit ACC can lead to cancer cell cycle arrest and apoptosis. This suggests that ACC and relative fatty acids may be critical for the survival of cancer cells. In this review, we summarize the role of ACC in tumor development. We also discuss the signaling pathways possibly affected by ACC, which may give insight into future research for cancer therapy.

Inhibition of 11ß-HSD2 expression by triclosan via induction of apoptosis in human placental syncytiotrophoblasts.

CONTEXT: Triclosan is widely used in personal care products for its broad spectrum of antimicrobial effects, but triclosan is a potential endocrine disruptor. 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2) is a cortisol-inactivating enzyme that is highly expressed in human placental syncytiotrophoblasts to ensure normal fetal development in the presence of high levels of maternal cortisol in pregnancy. OBJECTIVE: We investigated the effects of triclosan on 11ß-HSD2 and apoptosis and the relationship between these two events in human placental syncytiotrophoblasts. DESIGN: Primary human placental cytotrophoblasts were isolated from term placenta. After syncytialization, the levels of 11ß-HSD2 and apoptosis-related proteins including caspase3, Bcl-2, and Bax were examined after treatment with triclosan from 0.001 µM to 10 µM or triclosan (0.1 µM) in the presence and absence of apoptosis inhibitor Z-VAD-FMK (30 µM) for 24 h. RESULTS: Triclosan inhibited 11ß-HSD2 mRNA, protein and activity levels in a concentration-dependent manner from 0.001 to 10 µM with a significant inhibition at 0.01 µM and above. Concurrently, triclosan induced apoptosis of human placental syncytiotrophoblasts as demonstrated by observations of increased nuclear condensation, DNA fragmentation and pro-apoptosis proteins such as Bax and cleaved-caspase3, decreased pro-caspase-3 and anti-apoptosis protein such as Bcl-2. Blocking apoptosis with Z-VAD-FMK attenuated the inhibition of 11ß-HSD2 by triclosan significantly. CONCLUSIONS: Triclosan may attenuate the expression of placental 11ß-HSD2 via the induction of apoptosis of placental syncytiotrophoblasts. This is likely to disrupt the placental glucocorticoid barrier and impair fetal development.