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Abstract Background Müllerian duct anomalies (MDAs) are congenital developmental disorders that present as a series of abnormalities within the reproductive tracts of females. Genetic factors are linked to MDAs and recent advancements in whole-exome sequencing (WES) provide innovative perspectives in this field. However, relevant mechanism has only been investigated in a restricted manner without clear elucidation of respective observations. Methods Our previous study reported that 2 of 12 patients with MDAs harbored the CHD1L variant c.348-1G>C. Subsequently, an additional 85 MDAs patients were recruited. Variants in CHD1L were screened through the in-house database of WES performed in the cohort and two cases were identified. One presented with partial septate uterus with left renal agenesis and the other with complete septate uterus, duplicated cervices and longitudinal vaginal septum. The pathogenicity of the discovered variants was further assessed by molecular dynamics simulation and various functional assays. Results Ultimately, two novel heterozygous CHD1L variants, including a missense variant c.956G>A (p.R319Q) and a nonsense variant c.1831C>T (p.R611*) were observed. The variants were absent in 100 controls. Altogether, the contribution yield of CHD1L to MDAs was calculated as 4.12% (4/97). All three variants were assessed as pathogenic through various functional analysis. The splice-site variant c.348-1G>C resulted in a 11 bp sequence skipping in exon 4 of CHD1L and led to nonsense mediated decay of its transcripts. Unlike WT CHD1L, the truncated R611* protein mislocalized to the cytoplasm, abolish the ability of CHD1L to promote cell migration and failed to interact with PARP1 owing to the loss of macro domain. The R319Q variant exhibited conformational disparities and showed abnormal protein recruitment behavior through laser microirradiation comparing with the WT CHD1L. All these variants impaired the CHD1L function in DNA damage repair, thus participating in MDAs. Conclusions The current study not only expands the mutational spectrum of CHD1L in MDAs but determines three variants as pathogenic according to ACMG guidelines with reliable functional evidence. Additionally, the impairment in DNA damage repair is an underlying mechanism involved in MDAs.

The combination of photodynamic therapy (PDT)-immunotherapy has brought much hope for cancer patients. However, the hypoxia tumor microenvironment (TME) can regulate tumor angiogenesis and inhibit immune response, thus limiting the therapeutic effects. In this paper, engineered cyanobacteria-M2-like tumor-associated macrophages (TAMs) targeting peptide modified Fe3O4 nanoparticles hybrid system (ECyano@Fe3O4-M2pep) was constructed for alleviating hypoxia and relieving immune suppression to achieve synergistic cancer PDT-immunotherapy. With the irradiation of red laser, oxygen was produced by the photosynthesis of ECyano to alleviate the hypoxia TME. Then, ECyano could secret 5-aminolevulinic acid (5-ALA) under the induction of theophylline for controllable PDT. In the process of PDT, the disulfide bond between ECyano and Fe3O4-M2pep was broken in response to reactive oxygen species (ROS), and then Fe3O4-M2pep was released to target M2-like TAMs, corresponding by the polarization of M2-like TAMs to M1-like TAMs for the killing of tumor cells. Compared with other groups, ECyano@Fe3O4-M2pep + theophylline + laser (ECyano@Fe3O4-M2pep + T + L) group displayed the lowest tumor volume (159.3 mm3) and the highest M1/M2 ratio (1.25- fold). We believe that this hybrid system will offer a promising way for the biomedical application of bacterial therapy.

Abstract Background Premature ovarian insufficiency (POI) is a severe disorder leading to female infertility. Genetic mutations are important factors causing POI. TP63-truncating mutation has been reported to cause POI by increasing germ cell apoptosis, however what factors mediate this apoptosis remains unclear. Methods Ninety-three patients with POI were recruited from Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Whole-exome sequencing (WES) was performed for each patient. Sanger sequencing was used to confirm potential causative genetic variants. A minigene assay was performed to determine splicing effects of TP63 variants. A TP63-truncating plasmid was constructed. Real-time quantitative PCR, western blot analyses, dual luciferase reporter assays, immunofluorescence staining, and cell apoptosis assays were used to study the underlying mechanism of a TP63-truncating mutation causing POI. Results By WES of 93 sporadic patients with POI, we found a 14-bp deletion covering the splice site in the TP63 gene. A minigene assay demonstrated that the 14-bp deletion variant led to exon 13 skipping during TP63 mRNA splicing, resulting in the generation of a truncated TP63 protein (TP63-mut). Overexpression of TP63-mut accelerated cell apoptosis. Mechanistically, the TP63-mut protein could bind to the promoter region of CLCA2 and activate the transcription of CLCA2 several times compared to that of the TP63 wild-type protein. Silencing CLCA2 using a specific small interfering RNA (siRNA) or inhibiting the Ataxia Telangiectasia Mutated (ATM) pathway using the KU55933 inhibitor attenuated cell apoptosis caused by TP63-mut protein expression. Conclusion Our findings revealed a crucial role for CLCA2 in mediating apoptosis in POI pathogenesis, and suggested that CLCA2 is a potential therapeutic target for POI.

Poly ADP-ribose polymerase (PARP) inhibitors are effective therapies for cancer patients with homologous recombination (HR) deficient tumors. The imipridone ONC206 is an orally bioavailable dopamine receptor D2 antagonist and mitochondrial protease ClpP agonist that has anti-tumorigenic effects in endometrial cancer via induction of apoptosis, activation of the integrated stress response and modulation of PI3K/AKT signaling. Both PARP inhibitors and imipridones are being evaluated in endometrial cancer clinical trials but have yet to be explored in combination. In this manuscript, we evaluated the effects of the PARP inhibitor olaparib in combination with ONC206 in human endometrioid endometrial cancer cell lines and in a genetically engineered mouse model of endometrial cancer. Our results showed that simultaneous exposure of endometrial cancer cells to olaparib and ONC206 resulted in synergistic anti-proliferative effects and increased cellular stress and apoptosis in both cell lines, compared to either drug alone. The combination treatment also decreased expression of the anti-apoptotic protein Bcl-2 and reduced phosphorylation of AKT and S6, with greater effects compared to either drug alone. In the transgenic model of endometrial cancer, the combination of olaparib and ONC206 resulted in a more significant reduction in tumor weight in obese and lean mice compared to ONC206 alone or olaparib alone, together with a considerably decreased Ki-67 and enhanced H2AX expression in obese and lean mice. These results suggest that this novel dual therapy may be worthy of further exploration in clinical trials.

Ferroptosis is an important pathological process in acute kidney injury (AKI) which could lead to chronic kidney disease (CKD) and end-stage renal disease (ESRD). As an active ingredient of Chinese medicine Tripterygium wilfordii, celastrol has been reported to alleviate inflammation and preclinical studies have confirmed its anticancer effect. In the present study, we investigated the renal protective effects of celastrol against cisplatin induced AKI. Mice were administrated cisplatin by intraperitoneal injection and we found that celastrol reduced serum levels of BUN and creatinine, inhibited renal dysfunction, inflammation and oxidative stress. In addition, renal iron accumulation and ferroptosis were significantly reduced by celastrol treatment. Further mechanistic analyses suggested that Nrf2 is essential for celastrol upregulated GPX4 to alleviate ferroptosis and reduction of LDH release, intracellular iron accumulation and lipid peroxidation. These findings expand the potential uses of celastrol for treatment of various kinds of AKI associated with ferroptosis.

BackgroundCertain metabolites are closely related to the occurrence and development of pulmonary fibrosis, and the related mechanism has not been fully elucidated. It is necessary to explore the trends of various metabolites and causes of pulmonary fibrosis.ObjectiveTo discuss the trends of publication and research hotspots of pulmonary fibrosis-related metabolites by bibliometrics.MethodsWith "pulmonary fibrosis" and "metabolites" in both Chinese and English as primary keywords, literature search was conducted through public online databases: PubMed, Web of Science, SinoMed, and CNKI. NoteExpress 3.0 and Excel 2019 were used to store and organize the collected literature. Analyses included publication year, number of papers, institution, country/region, and journal title. VOSviewer 1.6.10 was used for visual analysis. Keyword co-occurrence was analyzed by setting the minimum threshold for the occurrence of keywords to 5 times.ResultsThe research on pulmonary fibrosis and associated metabolites in foreign language was earlier than that in Chinese language. Since the 1990s, the number of literature showed an increasing trend in both foreign and Chinese language literature. A total of 1 062 articles were published in foreign languages, of which 864 articles contained the authors’ address information. The authors in the United States published 340 articles, followed by China with 196 articles, and then Japan, Germany, and Italy. There were 728 relevant pieces of literature published in Chinese, 709 of which included the authors’ institution information and 350 institutions were involved. North China University of Science and Technology, Shanxi Medical University, Peking University, Zhengzhou University, China Medical University，and Soochow University were the top 6 by number of publication. A total of 255 Chinese journals published 728 Chinese articles, and among them 242 articles (33.24%) were published by 12 journals having published more than ten articles per journal. A total of 1062 articles were published in 609 foreign language journals, and among them 179 articles (16.85%) were published by 8 journals with more than 15 articles published by each journal. The results of keywords co-occurrence analysis suggested that pulmonary fibrosis in association with glucose metabolism, lipid metabolism, amino acid metabolism, nucleotide metabolism, and biological oxidation were the common themes studied at home and abroad.ConclusionThe number of publications on pulmonary fibrosis and metabolites has been on the rise in recent years, and the research hotspots include glucose metabolism, lipid metabolism, amino acid metabolism, nucleotide metabolism, and biological oxidation.

Abstract Background Although several histological studies have documented airway inflammation and remodelling in the small airways of dust-exposed workers, little is known regarding the prevalence and risk factors of small airway dysfunction (SAD) in pneumoconiosis. The present study investigated the prevalence and characteristics of spirometry-defined SAD in pneumoconiosis and assessed the risk factors for associated with SAD. Methods A total of 1255 patients with pneumoconiosis were invited to participate, of whom 1115 patients were eligible for final analysis. Spirometry was performed to assess SAD using the following three indicators: maximal mid-expiratory flow and forced expiratory flow 50% and 75%. SAD was defined as at least two of these three indicators being less than 65% of predicted value. Logistic regression analyses were used to analyse the relationships between clinical variables and SAD. Results Overall, 66.3% of patients with pneumoconiosis had SAD, among never-smokers the prevalence of SAD was 66.7%. The proportion of SAD did not differ among the subtypes of pneumoconiosis. In addition, SAD was present across the patients with all stages of pneumoconiosis. Even among those with forced expiratory volume in 1 s (FEV1) ≥ 80% and FEV1/forced vital capacity ratio ≥ 70%, 40.8% of patients had SAD. Patients with SAD were older than patients without SAD, more likely to be women and heavy smokers. Importantly, patients with SAD had more severe airflow obstruction, air trapping, and diffusion dysfunction. All patients with both pneumoconiosis and chronic obstructive pulmonary disease had SAD. Based on multivariate analysis, overall, aged 40 years and older, female sex, heavy smoking, body mass index ≥ 25.0 kg/m2 and pneumoconiosis stage III were significantly associated with increased risk of SAD. Among the never smokers, risk factors for SAD included female sex, BMI ≥ 25.0 kg/m2, pneumoconiosis stage II and stage III Conclusion Spirometry-defined SAD is one of the common functional abnormalities caused by occupational dust exposure and should be taken into account when monitoring respiratory health of workers to guide the early precautions and management in pneumoconiosis.

Ovarian cancer is the deadliest gynecological malignancy of the reproductive organs in the United States. Cyclin-dependent kinase 1 (CDK1) is an important cell cycle regulatory protein that specifically controls the G2/M phase transition of the cell cycle. RO-3306 is a selective, ATP-competitive, and cell-permeable CDK1 inhibitor that shows potent anti-tumor activity in multiple pre-clinical models. In this study, we investigated the effect of CDK1 expression on the prognosis of patients with ovarian cancer and the anti-tumorigenic effect of RO-3306 in both ovarian cancer cell lines and a genetically engineered mouse model of high-grade serous ovarian cancer (KpB model). In 147 patients with epithelial ovarian cancer, the overexpression of CDK1 was significantly associated with poor prognosis compared with a low expression group. RO-3306 significantly inhibited cellular proliferation, induced apoptosis, caused cellular stress, and reduced cell migration. The treatment of KpB mice with RO-3306 for four weeks showed a significant decrease in tumor weight under obese and lean conditions without obvious side effects. Overall, our results demonstrate that the inhibition of CDK1 activity by RO-3306 effectively reduces cell proliferation and tumor growth, providing biological evidence for future clinical trials of CDK1 inhibitors in ovarian cancer.

Background: Limited data are available regarding the entire spectrum of interstitial lung disease with a progressive fibrosing feature. We investigated the prevalence and prognostic predictive characteristics in patients with PF-ILD.Methods: This retrospective cohort study included patients with fibrosing ILD who were investigated between 1 January 2015 and 30 April 2021. We recorded clinical features and outcomes to identify the possible risk factors for fibrosing progression as well as mortality.Results: Of the 579 patients with fibrosing ILD, 227 (39.21%) met the criteria for progression. Clubbing of fingers [odds ratio (OR) 1.52, 95% confidence interval (CI) 1.03 to 2.24, p = 0.035] and a high-resolution computed tomography (HRCT)-documented usual interstitial pneumonia (UIP)-like fibrotic pattern (OR 1.95, 95% CI 1.33 to 2.86, p = 0.001) were risk factors for fibrosis progression. The mortality was worse in patients with PF with hypoxemia [hazard ratio (HR) 2.08, 95% CI 1.31 to 3.32, p = 0.002], in those with baseline diffusion capacity of the lung for carbon monoxide (DLCO) % predicted

Abstract Background Silicosis is a progressive pneumoconiosis characterized by interstitial fibrosis following exposure to silica dust. The role of metabolic dysregulation in the pathogenesis of silicosis has not been investigated in detail. This study aimed to identify different metabolic features in the plasma of patients with silicosis and dust-exposed workers without silicosis in metabolomics studies. Methods Patients with silicosis, dust-exposed workers (DEWs) without silicosis and age-matched healthy controls were recruited in a case–control study. The metabolomics analyses by ultra-high performance liquid chromatography-mass spectrometry were conducted. Distinct metabolic features (DMFs) were identified in the pilot study and were validated in the validation study. The enriched signalling pathways of these DMFs were determined. The ability of DMFs to discriminate among the groups was analysed through receiver operating characteristic (ROC) curves. The correlations between DMFs and clinical features were also explored. Results Twenty-nine DMFs and 9 DMFs were detected and had the same trend in the pilot study and the validation study in the plasma of the DEW and silicosis groups, respectively. Sphingolipid metabolism was the major metabolic pathway in the DEWs, and arginine and proline metabolism was associated with silicosis. Twenty DMFs in the DEWs and 3 DMFs in the patients with silicosis showed a discriminatory ability with ROC curve analysis. The abundance of kynurenine was higher in Stage III silicosis than in Stage I or Stage II silicosis. l-arginine and kynurenine were both negatively correlated with the percentage of forced vital capacity predicted in silicosis. Conclusions Distinct metabolic features in the plasma of DEWs and the patients with silicosis were found to be different. Sphingolipid metabolism and arginine and proline metabolism were identified as the major metabolic pathway in the DEW and silicosis groups, respectively. l-arginine and kynurenine were correlated with the severity of silicosis.

Abstract Background ONC201 is a dopamine receptor D2 (DRD2) antagonist that inhibits tumor growth in preclinical models through ClpP activation to induce integrated stress response pathway and mitochondrial events related to inhibition of cell growth, which is being explored in clinical trials for solid tumors and hematological malignancies. In this study, we investigated the anti-tumorigenic effect of ONC201 in endometrial cancer cell lines and a genetically engineered mouse model of endometrial cancer. Methods Cell proliferation was assessed by MTT and colony formation assays. Cell cycle and apoptosis were evaluated by Cellometer. Invasion capacity was tested using adhesion, transwell and wound healing assays. LKB1fl/flp53fl/fl mouse model of endometrial cancer were fed a control low fat diet versus a high fat diet to mimic diet-induced obesity. Following tumor onset, mice were treated with placebo or ONC201. Metabolomics and lipidomics were used to identify the obesity-dependent effects of ONC201 in the mouse endometrial tumors. DRD2 expression was analyzed by immunohistochemistry in human endometrioid and serous carcinoma specimens. DRD2 mRNA expression from the Cancer Genome Atlas (TCGA) database was compared between the four molecular subtypes of endometrial cancer. Results Increasing DRD2 expression in endometrial cancer was significantly associated with grade, serous histology and stage, as well as worse progression free survival and overall survival. Higher expression of DRD2 mRNA was found for the Copy Number High (CNH) subtype when compared to the other subtypes. ONC201 inhibited cell proliferation, induced cell cycle G1 arrest, caused cellular stress and apoptosis and reduced invasion in endometrial cancer cells. Diet-induced obesity promoted endometrial tumor growth while ONC201 exhibited anti-tumorigenic efficacy in the obese and lean LKB1fl/fl/p53fl/fl mice. Metabolomic analysis demonstrated that ONC201 reversed the obesity-driven upregulation of lipid biosynthesis and reduced protein biosynthesis in obese and lean mice. Conclusion ONC201 has anti-tumorigenic effects in endometrial cancer cells and a transgenic mouse model of endometrial cancer, and DRD2 expression was documented in both human serous and endometrioid endometrial cancer. These studies support DRD2 antagonism via ONC201 as a promising therapeutic strategy for endometrial cancer that has already demonstrated pharmacodynamic activity and clinical benefit in both serous and endometrioid endometrial cancer patients.

Pregnant women are at high risk of developing subclinical hypothyroidism (SCH), and anti-thyroid peroxidase antibody (TPOAb) positivity can further inhibit thyroxine synthesis. Emerging evidence indicates that intestinal flora can modulate metabolic and immune homeostasis. The characteristics of intestinal flora of TPOAb-positive women with SCH in their second trimester of pregnancy have not been reported. This single-center prospective observational cohort study investigated gut microbial composition and metabolic function using sequencing of the 16S rRNA gene in fecal samples from 75 TPOAb-positive women with SCH and 90 TPOAb-negative women with SCH during their second trimester of pregnancy. Women were treated with no levothyroxine (LT4), low-dose LT4 (≤50ug/d), or high-dose LT4 (>50ug/d). Taxonomic analysis showed Firmicutes and Bacteroidetes were the dominant phyla, followed by Actinobacteria and Proteobacteria. Faecalibacterium, Bacteroides, Prevotella 9, Bifidobacterium, Subdoligranulum, Lachnospira, and Megamonas were the predominant genera. The intestinal flora of TPOAb-positive women with SCH who received no LT4 was characterized by bacterial amplicon sequence variants (ASVs)/operational taxonomic units (OTUs) enriched in the genus Subdoligranulum. The intestinal flora of TPOAb-positive women with SCH who received low-dose or high-dose LT4 were characterized by bacterial ASVs/OTUs depleted of the species Ruminococcus sp._or Bacteroides massiliensis, respectively. A total of 19 metabolic functions of intestinal flora, mainly involving lipid and amino acid metabolism, discriminated TPOAb-positive and TPOAb-negative women with SCH. Our study suggests that there are differences in the composition and metabolic function of intestinal flora of TPOAb-positive and TPOAb-negative women with SCH treated with different doses of LT4 in the second trimester of pregnancy. The findings provide insight into intestinal flora as novel targets for the treatment of TPOAb-positive women with SCH during pregnancy.

ONC201 is a promising first-in-class small molecule that has been reported to have anti-neoplastic activity in various types of cancer through activation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as well as activation of mitochondrial caseinolytic protease P (ClpP). The present study was to explore the anti-tumor potential effect of ONC201 in ovarian cancer cell lines and in a transgenic mouse model of high grade serous ovarian cancer under obese (high fat diet) and lean (low fat diet) conditions. ONC201 significantly suppressed cell proliferation, induced arrest in G1 phase, and increased cellular stress and apoptosis, accompanied by dual inhibition of the AKT/mTOR/S6 and MAPK pathways in OC cells. ONC201 also resulted in inhibition of adhesion and invasion via epithelial–mesenchymal transition and reduction of VEGF expression. Pre-treatment with the anti-oxidant, N-acetylcysteine (NAC), reversed the ONC201-induced oxidative stress response, and prevented ONC201-reduced VEGF and cell invasion by regulating epithelial–mesenchymal transition protein expression. Knockdown of ClpP in ovarian cancer cells reduced ONC201 mediated the anti-tumor activity and cellular stress. Diet-induced obesity accelerated ovarian tumor growth in the KpB mouse model. ONC201 significantly suppressed tumor growth, and decreased serum VEGF production in obese and lean mice, leading to a decrease in tumoral expression of Ki-67, VEGF and phosphorylation of p42/44 and S6 and an increase in ClpP and DRD5, as assessed by immunohistochemistry. These results suggest that ONC201 may be a promising therapeutic agent to be explored in future clinical trials in high-grade serous ovarian cancer.

In this study, CTS-GSH was prepared by grafting thiol (–SH) groups onto chitosan (CTS), which was characterized through Fourier Transform Infrared (FT-IR) spectra, Scanning Electron Microscopy (SEM) and Differential Thermal Analysis–Thermogravimetric Analysis (DTA-TG). The performance of CTS-GSH was evaluated by measuring Cr(VI) removal efficiency. The –SH group was successfully grafted onto CTS, forming a chemical composite, CTS-GSH, with a rough, porous and spatial network surface. All of the molecules tested in this study were efficient at removing Cr(VI) from the solution. The more CTS-GSH added, the more Cr(VI) removed. When a suitable dosage of CTS-GSH was added, Cr(VI) was almost completely removed. The acidic environment at pH 5–6 was beneficial for the removal of Cr(VI), and at pH 6, the maximum removal efficiency was achieved. Further experimentation showed that with 100.0 mg/L CTS-GSH for the disposal of 5.0 mg/L Cr(VI) solution, the removal rate of Cr(VI) reached 99.3% with a slow stirring time of 8.0 min and sedimentation time of 3 h; the presence of four common ions, including Mg2+, Ca2+, SO42− and CO32−, had an inhibitory effect on CTS-GSH’s ability to remove Cr(VI) from the aqueous solution, and more CTS-GSH was needed to reduce this inhibiting action. Overall, CTS-GSH exhibited good results in Cr(VI) removal, and thus has good potential for the further treatment of heavy metal wastewater.

Mechanical factors in the tumor microenvironment play an important role in response to a variety of cellular activities in cancer cells. Here, we utilized polyacrylamide hydrogels with varying physical parameters simulating tumor and metastatic target tissues to investigate the effect of substrate stiffness on the growth, phenotype, and chemotherapeutic response of ovarian cancer cells (OCCs). We found that increasing the substrate stiffness promoted the proliferation of SKOV-3 cells, an OCC cell line. This proliferation coincided with the nuclear translocation of the oncogene Yes-associated protein. Additionally, we found that substrate softening promoted elements of epithelial-mesenchymal transition (EMT), including mesenchymal cell shape changes, increase in vimentin expression, and decrease in E-cadherin and β-catenin expression. Growing evidence demonstrates that apart from contributing to cancer initiation and progression, EMT can promote chemotherapy resistance in ovarian cancer cells. Furthermore, we evaluated tumor response to standard chemotherapeutic drugs (cisplatin and paclitaxel) and found antiproliferation effects to be directly proportional to the stiffness of the substrate. Nanomechanical studies based on atomic force microscopy (AFM) have revealed that chemosensitivity and chemoresistance are related to cellular mechanical properties. The results of cellular elastic modulus measurements determined by AFM demonstrated that Young’s modulus of SKOV-3 cells grown on soft substrates was less than that of cells grown on stiff substrates. Gene expression analysis of SKOV-3 cells showed that mRNA expression can be greatly affected by substrate stiffness. Finally, immunocytochemistry analyses revealed an increase in multidrug resistance proteins, namely, ATP binding cassette subfamily B member 1 and member 4 (ABCB1 and ABCB4), in the cells grown on the soft gel resulting in resistance to chemotherapeutic drugs. In conclusion, our study may help in identification of effective targets for cancer therapy and improve our understanding of the mechanisms of cancer progression and chemoresistance.

Ovarian cancer is one of the leading causes of female cancer death. Emerging evidence suggests that many dietary natural products have anti-tumorigenic activity, including that of asparagus officinalis. The current study aimed to assess the anti-tumorigenic and anti-metastatic effects of asparagus officinalis on serous ovarian cancer cell lines and a transgenic mouse model of high grade serous ovarian cancer. Asparagus officinalis decreased cellular viability, caused cell cycle G1 phase arrest and induced apoptosis in the OVCAR5 and SKOV3 cells. Induction of apoptosis and inhibition of cell proliferation was rescued by the pan-caspase inhibitor, Z-VAD-FMK, implying that its cytotoxic effects were mainly dependent on caspase pathways. Asparagus officinalis increased levels of ROS and decreased mitochondrial membrane potential with corresponding increases in PERK, Bip, Calnexin PDI and ATF4 in both cell lines. Treatment with asparagus officinalis also reduced ability of adhesion and invasion through epithelial–mesenchymal transition and reduction of VEGF expression. The combination of Asparagus officinalis with paclitaxel had synergistic anti-proliferative activity. Furthermore, Asparagus officinalis significantly inhibited tumor growth and reduced serum VEGF in a genetically engineered mouse model of ovarian cancer under obese and lean conditions, accompanied with a decrease in the expression of Ki67, VEGF and phosphorylated S6, and in an increase in phosphorylation of AMPK in the ovarian tumor tissues. Overall, our data provide a pre-clinical rationale for asparagus officinalis in the prevention and treatment of ovarian cancer as a novel natural product.

ONC206 (Oncoceutics) is an imipiridone with nanomolar potency and analogue of ONC201, a selective dopamine receptor D2 (DRD2) antagonist currently being investigated in phase II clinical trials for serous endometrial cancer (SEC). This study investigated the anti-proliferative efficacy of ONC206 in SEC cell lines as well as its impact on cellular stress and adhesion/invasion. ONC206 inhibited cellular proliferation in a dose-dependent manner and was more potent than ONC201 in the ARK1 (IC50 = 0.33µM vs. IC50 = 1.59uM) and SPEC-2 (IC50 = 0.24uM vs. IC50 = 0.81uM) cell lines. Treatment with ONC206 resulted in induction of ROS production and reduction of mitochondrial membrane potential, accompanied by an increase in cleaved caspase-3 and caspase-9 activity (p < 0.01). ONC206 also significantly inhibited cellular adhesion and migration in both cell lines (p < 0.01). Pretreatment with the stress inhibitor N-acetylcysteine (NAC) significantly attenuated the efficacy of ONC206 on cell proliferation, ROS production and cellular invasion. ONC206 demonstrates nanomolar potency for the inhibition of proliferation in SEC cells. Specifically, ONC206 utilizes ISR activation as a significant pathway in the propagation of its anti-proliferative and anti-metastatic effects. Thus, ONC206 may be a promising agent in future SEC clinical trials as was its predecessor ONC201.

Temperature is an extremely important environmental condition in the application of microbial denitrification for nitrate removal from groundwater. Understanding the nitrate removal efficiency of groundwater and the diversity, composition, and structure of microbial communities under different temperature conditions is of great significance for effective mitigation of groundwater nitrate pollution. This study investigated the effects of temperature on denitrification at 15 °C, 25 °C, 40 °C, and 45 °C. Moreover, the characteristics of microbial community structure and diversity were analyzed by combining high-throughput sequencing and polymerase chain reaction methods in order to fully clarify the denitrification efficiency under different temperature conditions. According to laboratory batch experiments and the findings of previous research, glucose was set as the carbon source and changes in “three nitrogen” indicators of the four temperature systems were mainly tested to clarify the effectiveness of nitrate removal. The maximum removal rates of nitrate nitrogen at 15 °C, 25 °C, 40 °C, and 45 °C were 44.05%, 87.03%, 99.26%, and 92.79%, respectively. Therefore, the most efficient nitrate removal can be achieved at 40℃. The Chao abundance indexes in the denitrification systems at 15 °C, 25 °C, 40 °C, and 45 °C were 1873, 352, 466, and 640, respectively. Therefore, the highest species richness was observed at 15 °C, but there were only a few dominant bacteria species. The composition of the bacterial community and the most dominant phylum varied at different temperatures. Among them, Gammaproteobacteria in Proteobacteria phylum plays an important role in the degradation of nitrate nitrogen. The relative abundance of Gammaproteobacteria at 15 °C, 25 °C, 40 °C, and 45 °C were 25.32%, 66.56%, 72.83%, and 3.47%. Tolumonas belongs to Gammaproteobacteria. The relative abundance of Tolumonas at 15 °C, 25 °C, 40 °C, and 45 °C were 9.41%, 65.47%, 62.49%, and 0.03%, respectively. The results of this study show that different temperature conditions affect the diversity, composition, and structure of the microbial community, thereby affecting the efficiency of denitrification for nitrate removal from groundwater.

Premature infants have a fragile ecology of the gut microbiota, which is associated with many health problems and may be influenced by formula versus breast feeding. The present study investigated differences in the process of gut microbiota colonisation in preterm infants fed with breastmilk or formula with or without probiotics before 12 weeks. This cohort study recruited 138 premature infants; 31 in the breastmilk (BM) group, 59 in the probiotics formula (PF) group and 48 in the non-probiotics formula (NPF) group, according to the feeding practice they received at birth. Gut bacterial composition was identified with 16S rRNA gene sequencing in faecal samples collected at 1 week, 6 weeks and 12 weeks after birth. The alpha diversity was higher in the PF group compared to the other groups at week 1 and 6 (both p < 0.01) but showed no difference at week 12. The beta diversity of the three groups showed a trend towards similarity at the first two stages (p < 0.001 and p = 0.009, respectively) and finally showed no difference at week 12. Canonical redundancy analysis showed that feeding type could explain the difference in gut microbiota composition at week one and six (both p < 0.01). At genus level, Bifidobacterium was enriched in the PF group, while the Enterococcus and Streptococcus was enriched in the NPF group. In summary, formula with probiotics feeding after birth can affect gut microbiota colonisation and lead to a bacterial community with less potential pathogens.

Long non-coding RNAs (lncRNAs) are emerging as important modulators of cancer progression, among which prostate cancer-associated transcript 1 (PCAT1) has been shown to be an oncogene in several tumors. However, the clinical significance and biological function of PCAT1 in endometrial carcinoma (EC) remain unclear. In this study, we used 89 EC tissues and HEC-1B, Ishikawa, RL95-2 and AN3CA EC cell lines. We found elevated expression levels of PCAT1 in EC tissues and cell lines using reverse transcription qPCR (RT-qPCR). The prognostic value of PCAT1 was determined using Kaplan–Meier survival and Cox regression analysis. The results showed that higher PCAT1 expression was positively correlated with FIGO stage, myometrial invasion, lymph node metastasis, and a shorter overall survival. A series of functional assays showed that the knockdown of PCAT1 by small interfering RNA (siRNA) targeting PCAT1 (siPCAT1) suppressed cell proliferation, migration and invasion, but promoted apoptosis. Western blot analysis further showed that B-cell lymphoma 2 (Bcl-2), vimentin and N-cadherin were downregulated, but E-cadherin and Bcl-2-associated death promoter (Bad) were upregulated in PCAT1-silenced EC cells. Taken together, our results underscore the oncogenic role of PCAT1 in EC and show that PCAT1 may be a potential therapeutic target in EC treatment.

As an important vector of dengue and Zika, Aedes albopictus has been the fastest spreading invasive mosquitoes in the world over the last 3-4 decades. Cold tolerance is important for survival and expansion of insects. Ae. albopictus adults are generally considered to be cold-intolerant that cannot survive at subzero temperature. However, we found that Ae. albopictus could survive for several hours' exposure to -9 to -19 oC so long as it was exposed with water. Median lethal time (LT50) of Ae. albopictus exposed to -15 and -19 oC with water increased by more than 100 times compared to those exposed to the same subzero temperature without water. This phenomenon also existed in adult Aedes aegypti and Culex quinquefasciatus. Ae. albopictus female adults which exposed to low subzero temperature at -9 oC with water had similar longevity and reproductive capacity to those of females without cold exposure. Cold exposure after a blood meal also have no detrimental impact on survival capacity of female adult Ae. albopictus compared with those cold exposed without a blood meal. Moreover, our results showed that rapid cold hardening (RCH) was induced in Ae. albopictus during exposing to low subzero temperature with water. Both the RCH and the relative high subzero temperature of water immediate after cold exposure might provide this strong protection against low subzero temperature. The molecular basis of water-induced protection for Ae. albopictus might refer to the increased glycerol during cold exposure, as well as the increased glucose and hsp70 during recovery from cold exposure. Our results suggested that the water-induced strong protection against acute decrease of air temperature for adult mosquitoes might be important for the survival and rapid expansion of Ae. albopictus.

Objective: The prevalence of depression in children with severe bronchial asthma is a significant concern due to its potential effects on illness burden and quality of life. This cross-sectional study aims to explore the relationship between depression and severe bronchial asthma in children, focusing on the impact of alexithymia and somatic symptoms. Methods: The study includes a total of 186 children aged 6-14 years diagnosed with severe bronchial asthma between 2008 and 2022 in our institute. Alexithymia was assessed using the Toronto Alexithymia Scale--20 items (TAS-20). Somatization symptoms were measured using the children's somatization inventory (CSI). The Hamilton depression scale (HAMD) was used to evaluate depression. Spearman correlation analysis was used to describe the correlation between alexithymia, somatization symptoms, and depression. Results: Children with bronchial asthma are found to have a significantly higher prevalence of depression, estimated to be around 16.67%. Approximately 98.92% of children exhibit varying degrees of somatic symptoms. Approximately 3.23% of children have alexithymia. The Spearman correlation analysis revealed that somatic symptoms and alexithymia were positive correlated with the depression. The correlation coefficients were 0.986 and 0.981 (P < .01), respectively. moreover, according to the results of multiple linear regression analysis, somatization symptoms and alexithymia significantly affects depression in children with severe bronchitis asthma (P < .01). Conclusion: These findings suggest that children with severe bronchial asthma experience a higher prevalence of depression, impacting their overall quality of life. In addition, the presence of somatic symptoms is prevalent among these children, further contributing to the burden on their quality of life. Moreover, somatization symptoms and alexithymia have been identified as a significant factor positive affecting depression in this population. Addressing these factors in clinical interventions may be beneficial for improving the overall well-being in this population. [ABSTRACT FROM AUTHOR]

This article considers the efficient and robust estimators for linear regression models. In this article, we develop an adaptive efficient and double-robust estimator based on generalized empirical likelihood framework and weighted least squares. Efficiency is ensured through minimizing the discrepancy statistics and the double robustness is obtained via weighted least-square as well as downweighting the impact of leverage points. We introduce a tuning parameter which is chosen adaptively through the robustified generalized cross-validation statistics. The constrained optimization problem concerned is solved through nonlinear programming approaches. Theoretical results show the asymptotic normality. It is presented in the finite-sample studies that the proposed estimator possesses relatively high efficiency and comparable robustness in comparison with some existing robust regression estimators. Simulation results also indicate that the proposed estimator is double-robust toward both outliers and leverage points. An application to a real data set is also presented for further illustration and comparison. [ABSTRACT FROM AUTHOR]

Poly ADP-ribose polymerase (PARP) inhibitors are effective therapies for cancer patients with homologous recombination (HR) deficient tumors. The imipridone ONC206 is an orally bioavailable dopamine receptor D2 antagonist and mitochondrial protease ClpP agonist that has anti-tumorigenic effects in endometrial cancer via induction of apoptosis, activation of the integrated stress response and modulation of PI3K/AKT signaling. Both PARP inhibitors and imipridones are being evaluated in endometrial cancer clinical trials but have yet to be explored in combination. In this manuscript, we evaluated the effects of the PARP inhibitor olaparib in combination with ONC206 in human endometrioid endometrial cancer cell lines and in a genetically engineered mouse model of endometrial cancer. Our results showed that simultaneous exposure of endometrial cancer cells to olaparib and ONC206 resulted in synergistic anti-proliferative effects and increased cellular stress and apoptosis in both cell lines, compared to either drug alone. The combination treatment also decreased expression of the anti-apoptotic protein Bcl-2 and reduced phosphorylation of AKT and S6, with greater effects compared to either drug alone. In the transgenic model of endometrial cancer, the combination of olaparib and ONC206 resulted in a more significant reduction in tumor weight in obese and lean mice compared to ONC206 alone or olaparib alone, together with a considerably decreased Ki-67 and enhanced H2AX expression in obese and lean mice. These results suggest that this novel dual therapy may be worthy of further exploration in clinical trials. [ABSTRACT FROM AUTHOR]