Clinical Characteristics of COVID-19 in Gynecological Cancer Patients during Chemotherapy-An Observational Study.

BACKGROUND: Infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affects multiple organs throughout the body, which puts chemotherapy patients at even greater risk. This study aims to identify the clinical characteristics of gynecological cancer patients infected with SARS-CoV-2 during chemotherapy. METHODS: Gynecological cancer patients infected with SARS-CoV-2 during chemotherapy from August 1, 2022, to January 31, 2023, were enrolled in this observational cohort study. Patients in the control group were not infected with SARS-CoV-2. All continuous variables, including blood cells (leukocytes, neutrophils, lymphocytes) and biochemical indices (alanine transaminase (ALT), Aspartate transferase (AST), lactate dehydrogenase (LDH), albumin and creatinine) were repeatedly measured and analyzed statistically by the generalized additive mixed model (GAMM). Latent class analysis was estimated for the high-risk factors of severe COVID-19. The primary outcome was to develop a severe condition. RESULTS: During the study period, there were 71 patients with chemotherapy in our center. Of the 57 cases infected with SARS-CoV-2, 14 patients without infection, the infection rate was 80.28%. 52 cases out of the 57 infected patients were included in this study, 9.62% (5/52) cases showed severe disease, and 1 patient died. 51 cases survived during the acute coronavirus disease 2019 (COVID-19) phase. If chemotherapy is given after SARS-CoV-2 infection, tissues and organs that are sensitive to chemotherapy are more likely to be re-damaged by COVID-19. The plasma levels of leukocytes, neutrophils, lymphocytes, ALT, and AST decreased; LDH and creatinine in plasma showed a linear increase, while plasma albumin decreased, and platelets showed no apparent trend. The changes in blood cells and biochemical indices were most evident in relapsed patients and patients with COVID-19 within 2 weeks after chemotherapy. Latent class analysis showed that all severe COVID-19 patients were classified into class 1; the patients of class 1 showed a shorter interval between chemotherapy and COVID-19, and the higher baseline of AST, ALT, and LDH, the more cycles of chemotherapy and the advanced stage. CONCLUSIONS: The interval between chemotherapy and COVID-19 is associated with damage to tissues and organs. Clinical factors and laboratory factors indicate poor health conditions among patients with gynecological cancer and COVID-19.

Tn antigen promotes breast cancer metastasis via impairment of CASC4.

Breast cancer is one of the most serious and deadly cancers in women worldwide, with distant metastases being the leading cause of death. Tn antigen, a tumor-associated carbohydrate antigen, was frequently detected in breast cancer, but its exact role in breast cancer metastasis has not been well elucidated. Here we investigated the impact of Tn antigen expression on breast cancer metastasis and its underlying mechanisms. The expression of Tn antigen was induced in two breast cancer cell lines by deleting T-synthase or Cosmc, both of which are required for normal O-glycosylation. It showed that Tn-expressing cancer cells promoted epithelial-mesenchymal transition (EMT) and metastatic features as compared to Tn(-) control cells both in vitro and in vivo. Mechanistically, we found that cancer susceptibility candidate 4 (CASC4), a heavily O-glycosylated protein, was significantly downregulated in both Tn(+) cells. Overexpression of CASC4 suppressed Tn-induced activation of EMT and cancer metastasis via inhibition of Cdc42 signaling. Furthermore, we confirmed that O-glycosylation is essential for the functional role of CASC4 because defective O-glycosylated CASC4 (mutant CASC4, which lacks nine O-glycosylation sites) exerted marginal metastatic-suppressing effects in comparison with WT CASC4. Collectively, these data suggest that Tn-mediated aberrant O-glycosylation contributes to breast cancer metastasis via impairment of CASC4 expression and function.

miR-24-3p regulation of retinol binding protein 4 in trophoblast biofunction and preeclampsia.

Preeclampsia (PE) is a pregnancy-related disease and is the leading cause of overall maternal mortality and morbidity. Our previous studies have shown that the serum and placental levels of retinol-binding protein 4 (RBP4) in PE are reduced. Our previous bioinformatics analysis predicted that RBP4 is a target of the microRNA miRNA-24-3p. In this study, our database analysis also indicated that RBP4 is a miR-24-3p target. Compared with that of the normal placenta, the expression level of RBP4 in human PE placenta was significantly reduced, and miR-24-3p was highly expressed. In HTR-8/SVneo cells, transfection of exogenous miR-24-3p reduced RBP4 expression. A dual-luciferase reporter assay validated RBP4 as a direct target of miR-24-3p, indicating that it directly binds to the 3'-untranslated region of RBP4. This binding was reversed by a mutation in the microRNA-binding site. Transwell invasion experiments and CCK8 assay showed that inhibitory effect of miR-24-3p reduced RBP4 mediated HTR-8/SVneo cell invasion and proliferation. These data provide a new overarching perspective on the physiological role played by miR-24-3p in regulating RBP4 during trophoblast dysfunction and PE development.

NRF2, a Transcription Factor for Stress Response and Beyond.

Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that regulates the cellular defense against toxic and oxidative insults through the expression of genes involved in oxidative stress response and drug detoxification. NRF2 activation renders cells resistant to chemical carcinogens and inflammatory challenges. In addition to antioxidant responses, NRF2 is involved in many other cellular processes, including metabolism and inflammation, and its functions are beyond the originally envisioned. NRF2 activity is tightly regulated through a complex transcriptional and post-translational network that enables it to orchestrate the cell's response and adaptation to various pathological stressors for the homeostasis maintenance. Elevated or decreased NRF2 activity by pharmacological and genetic manipulations of NRF2 activation is associated with many metabolism- or inflammation-related diseases. Emerging evidence shows that NRF2 lies at the center of a complex regulatory network and establishes NRF2 as a truly pleiotropic transcription factor. Here we summarize the complex regulatory network of NRF2 activity and its roles in metabolic reprogramming, unfolded protein response, proteostasis, autophagy, mitochondrial biogenesis, inflammation, and immunity.

Cosmc Disruption-Mediated Aberrant O-glycosylation Suppresses Breast Cancer Cell Growth via Impairment of CD44.

BACKGROUND: Breast cancer remains the most lethal malignancy in women worldwide. Aberrant O-glycosylation is closely related to many human diseases, including breast carcinoma; however, its precise role in cancer development is insufficiently understood. Cosmc is an endoplasmic reticulum-localized chaperone that regulates the O-glycosylation of proteins. Cosmc dysfunction results in inactive T-synthase and expression of truncated O-glycans such as Tn antigen. Here we investigated the impact of Cosmc disruption-mediated aberrant O-glycosylation on breast cancer cell development through in vitro and in vivo experiments. MATERIALS AND METHODS: We deleted the Cosmc gene in two breast cancer cell lines (MCF7, T47D) using the CRISPR/Cas-9 system and then measured the expression levels of Tn antigen. The proliferation of Tn-positive cells was examined by RTCA, colony formation and in vivo experiments. The effects of Cosmc deficiency on glycoprotein CD44 and MAPK pathway were also determined. RESULTS: Both in vitro and in vivo studies showed that Cosmc deficiency markedly suppressed breast cancer cell growth compared with the corresponding controls. Mechanistically, Cosmc disruption impaired the protein expression of CD44 and the associated MAPK signaling pathway; the latter plays a crucial role in cell proliferation. Reconstitution of CD44 substantially reversed the observed alterations, confirming that CD44 requires normal O-glycosylation for its proper expression and activation of the related signaling pathway. CONCLUSION: This study showed that Cosmc deficiency-mediated aberrant O-glycosylation suppressed breast cancer cell growth, which was likely mediated by the impairment of CD44 expression.

ATAD2 predicts poor outcomes in patients with ovarian cancer and is a marker of proliferation.

The oncogene ATPase family AAA domain­â€‹containing protein 2 (ATAD2) has been demonstrated to promote malignancy in a number of different types of tumor; however, its expression and role in ovarian cancer (OC) remain unknown. In the present study, it was demonstrated that ATAD2 acts as both a marker and a driver of cell proliferation in OC. Immunohistochemistry (IHC) and bioinformatics analyses were used to evaluate ATAD2 expression in OC, and multi­omics integrated analyses were used to dissect which factor resulted in its upregulation. Multiplex IHC assay was used to reveal the specific expression of ATAD2 in proliferating OC cells. CRISPR­Cas9­mediated gene editing was performed to investigate the effect of ATAD2 deletion on OC proliferation. The results demonstrated that ATAD2 is elevated in primary OC tissues compared with the adjacent normal tissue and metastases from the stomach. Genetic copy number amplification is a primary cause resulting in upregulation of ATAD2, and this was most frequently observed in OC. High ATAD2 expression was associated with advanced progression and predicted an unfavorable prognosis. ATAD2 could be used to identify cases of OC with a high proliferation signature and could label proliferating cells in OC. CRISPR­Cas9­mediated ATAD2 deletion resulted in a significant decrease in both cell proliferation and colony formation ability. Mechanistically, ATAD2­knockdown resulted in deactivation of the mitogen­activated protein kinase (MAPK) pathways, particularly the JNK­MAPK pathway, resulting in suppression of proliferation. Collectively, the data from the present study demonstrated that the ATD2 gene was frequently amplified and protein expression levels were upregulated in OC. Therefore, ATAD2 may serve as an attractive diagnostic and prognostic OC marker, which may be used to identify patients with primary OC, whom are most likely to benefit from ATAD2 gene­targeted proliferation intervention therapies.