Postpartum uterine involution promoted by penetrating-moxibustion therapy: a randomized controlled trial. / é€ç¸æ³•ä¿ƒè¿›äº§åŽå­å®«å¤æ—§ï¼šéšæœºå¯¹ç §è¯•éªŒ.

OBJECTIVES: To observe the effect of penetrating-moxibustion therapy on postpartum uterine involution. METHODS: Eighty puerpera were randomized into an observation group and a control group, 40 cases in each one. In the control group, oxytocin injection was administered by intravenous drip, 20 U each time, once daily. In the observation group, on the base of the treatment as the control group, the penetrating-moxibustion therapy was used at Shenque (GV 8), Qihai (CV 6) and Guanyuan (CV 4), 30 min to 40 min each time, twice a day. The intervention of each group started from the first day after childbirth and lasted 3 days. The uterine volume before and after treatment, and in 42 days of postpartum, the height decrease of the fundus of the uterus, the score of visual analogue scale (VAS) for uterine contraction, the volume of lochia rubra in 1 to 3 days of treatment, and lochia duration were compared between the two groups; and the clinical effect was evaluated. RESULTS: The uterine volume in the observation group was smaller than that of the control group after treatment (P<0.01). In 1 to 3 days of treatment, the height decrease of the fundus of the uterus in the observation group was larger (P<0.01), VAS scores of uterine contraction were lower (P<0.05, P<0.01), the lochia rubra volume was less (P<0.01) than those in the control group. The duration of lochia rubra and lochia was shorter (P<0.01) in the observation group when compared with that of the control group. The favorable rate of uterine involution in the observation group was 95.0% (38/40), higher than that of the control group (75.0%, 30/40, P<0.05). CONCLUSIONS: Penetrating-moxibustion therapy accelerates the recovery of the uterine volume, relieves uterine contraction, shortens the duration of lochia, reduces the lochia volume and promotes the postpartum uterine involution.

TP63 truncating mutation causes increased cell apoptosis and premature ovarian insufficiency by enhanced transcriptional activation of CLCA2.

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.

Oleic Acid Exhibits Anti-Proliferative and Anti-Invasive Activities via the PTEN/AKT/mTOR Pathway in Endometrial Cancer.

Reprogramming of fatty acid metabolism promotes cell growth and metastasis through a variety of processes that stimulate signaling molecules, energy storage, and membrane biosynthesis in endometrial cancer. Oleic acid is one of the most important monounsaturated fatty acids in the human body, which appears to have both pro- and anti-tumorigenic activities in various pre-clinical models. In this study, we evaluated the potential anti-tumor effects of oleic acid in endometrial cancer cells and the LKB1fl/flp53fl/fl mouse model of endometrial cancer. Oleic acid increased lipogenesis, inhibited cell proliferation, caused cell cycle G1 arrest, induced cellular stress and apoptosis, and suppressed invasion in endometrial cancer cells. Targeting of diacylglycerol acyltransferases 1 and 2 effectively increased the cytotoxicity of oleic acid. Moreover, oleic acid significantly increased the expression of wild-type PTEN, and knockdown of PTEN by shRNA partially reversed the anti-proliferative and anti-invasive effects of oleic acid. Inhibition of the AKT/mTOR pathway by ipatasertib effectively increased the anti-tumor activity of oleic acid in endometrial cancer cells. Oleic acid treatment (10 mg/kg, daily, oral) for four weeks significantly inhibited tumor growth by 52.1% in the LKB1fl/flp53fl/fl mice. Our findings demonstrated that oleic acid exhibited anti-tumorigenic activities, dependent on the PTEN/AKT/mTOR signaling pathway, in endometrial cancer.

MMP19 Variants in Familial and Sporadic Idiopathic Pulmonary Fibrosis.

BACKGROUND: Gene variants have been identified in patients with familial or sporadic idiopathic pulmonary fibrosis (IPF). These variants may partially account for the genetic risk of IPF. The aim of this study was to identify potential genes involved in both familial and sporadic IPF. METHODS: A Han family in northern China with four members diagnosed with IPF was investigated in this observational study. Whole-exome sequencing (WES) was used to identify germline variants underlying disease phenotypes in five members of this family. Candidate rare variants were validated by Sanger sequencing in samples from 16 family members and 119 patients with sporadic IPF. The plasma levels of proteins encoded by the above candidate genes were also examined in 16 family members, 119 other patients with sporadic IPF and 120 age- and sex-matched healthy controls. RESULTS: In a Chinese Han family, MMP19 c.1222 C > T was identified in all familial IPF patients and six offspring from generations III and IV. This variant introduces a premature stop codon, which may damage protein function. Sanger sequencing revealed that 7.6% (9/119) of sporadic IPF patients harbored three MMP19 variants. The genetic risk analysis for pulmonary fibrosis showed that MMP19 c.1499 C > T and c.1316G > A were significantly associated with an increased risk of IPF (OR 3.66, p = 0.028 and OR 8.64, p < 0.001, respectively). The plasma levels of MMP19 were significantly higher in patients with sporadic or familial IPF than in healthy controls (all p < 0.001). CONCLUSIONS: MMP19 variants were identified in familial or sporadic IPF, thus providing a potential new clue into IPF pathogenesis.

Celastrol alleviated acute kidney injury by inhibition of ferroptosis through Nrf2/GPX4 pathway.

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.

Inhibition of CDK1 by RO-3306 Exhibits Anti-Tumorigenic Effects in Ovarian Cancer Cells and a Transgenic Mouse Model of Ovarian Cancer.

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.

Ipatasertib exhibits anti­tumorigenic effects and enhances sensitivity to paclitaxel in endometrial cancer in vitro and in vivo.

Endometrial cancer is the most common gynecologic cancer and one of the only cancers for which incidence and mortality is steadily increasing. Although curable with surgery in the early stages, endometrial cancer presents a significant clinical challenge in the metastatic and recurrent setting with few novel treatment strategies emerging in the past fifty years. Ipatasertib (IPAT) is an orally bioavailable pan­AKT inhibitor, which targets all three AKT isoforms and has demonstrated anti­tumor activity in pre­clinical models, with clinical trials emerging for many cancer types. In the present study, the MTT assay was employed to evaluate the therapeutic efficacy of IPAT or IPAT in combination with paclitaxel (PTX) in endometrial cancer cell lines and primary cultures of endometrial cancer. The effect of IPAT and PTX on the growth of endometrial tumors was evaluated in a transgenic mouse model of endometrial cancer. Apoptosis was assessed using cleaved caspase assays and cellular stress was assessed using ROS, JC1 and tetramethylrhodamine ethyl ester assays. The protein expression levels of markers of apoptosis and cellular stress, and DNA damage were evaluated using western blotting and immunohistochemistry. IPAT significantly inhibited cell proliferation, caused cell cycle G1 phase arrest, and induced cellular stress and mitochondrial apoptosis in a dose dependent manner in human endometrial cancer cell lines. Combined treatment with low doses of IPAT and PTX led to synergistic inhibition of cell proliferation and induction of cleaved caspase 3 activity in the human endometrial cancer cell lines and the primary cultures. Furthermore, IPAT effectively reduced tumor growth, accompanied by decreased protein expression levels of Ki67 and phosphorylation of S6 in the Lkb1fl/flp53fl/fl mouse model of endometrioid endometrial cancer. The combination of IPAT and PTX resulted in increased expression of phosphorylated­H2AX and KIF14, markers of DNA damage and microtubule dysfunction respectively, as compared with IPAT alone, PTX alone or placebo­treated mice. The results of the present study provide a biological rationale to evaluate IPAT and the combination of IPAT and PTX in future clinical trials for endometrial cancer.

Gut microbiota disorder induces liver dysfunction in polycystic ovary syndrome rats' model by regulating metabolite rosmarinic acid.

AIMS: The present study aims to investigate the impact of the gut microbiota and serum metabolites on the regulation of liver dysfunction in PCOS. MATERIALS AND METHODS: PCOS rat models were established by treating Sprague Dawley (SD) rats with DHEA (an androgen, 60 mg/kg) and LET (a nonsteroidal aromatase inhibitor, 1 mg/kg) for 90 days. Hematoxylin and eosin staining (H&E), Western blotting, and radioimmunoassay were employed to test ovarian and liver functions. Gut microbiome and serum metabolites were assessed using 16S rRNA amplicon sequencing and non-targeted metabolomics, respectively. The association between gut microbiota and serum metabolites was examined using Spearman analysis. Finally, using HepG2 cells to investigate the function of the serum metabolite rosmarinic acid (RA). KEY FINDINGS: Both Dehydroepiandrosterone (DHEA) and letrozole (LET) treatments induced a PCOS phenotype and liver dysfunction. However, LET resulted in more severe lipid accumulation and liver cell apoptosis than DHEA. 16S rRNA sequencing and non-targeted metabolomics analysis revealed significant differences in beta diversity and serum metabolite profiles among the three groups. Furthermore, among the significantly changed metabolites, RA was found to have a significant correlation with the levels of serum aspartate transaminase (AST) and lactate dehydrogenase (LDH) and could promote HepG2 cell apoptosis. SIGNIFICANCE: Restoring gut microbiota, altering serum metabolites and/or decreasing RA may provide a new insight to treat this complication.

A novel dopamine receptor D2 antagonist (ONC206) potentiates the effects of olaparib in endometrial cancer.

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.

Study on Flocculation Behavior of Cr(VI) Using a Novel Chitosan Functionalized with Thiol Groups.

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.

Lipid dysregulation associated with progression of silica-induced pulmonary fibrosis.

Silicosis is an irreversible, progressive, fibrotic lung disease caused by long-term exposure to dust-containing silica particles at the workplace. Despite the precautions enforced, the rising incidence of silicosis continues to occur globally, particularly in developing countries. A better understanding of the disease progression and potential metabolic reprogramming of silicosis is warranted. The low- or high-dose silica-induced pulmonary fibrosis in mice was constructed to mimic chronic or accelerated silicosis. Silica-induced mice lung fibrosis was analyzed by histology, lung function, and computed tomography scans. Non-targeted metabolomics of the lung tissues was conducted by ultra-high-performance liquid chromatography-mass spectrometry to show the temporal metabolic trajectory. The low-dose silica-induced silicosis characterized inflammation for up to 42 days, with the onset of cellular silicon nodules. Conversely, the high-dose silica-induced silicosis characterized inflammation for up to 14 days, after which the disease developed rapidly, with a large volume of collagen deposition, presenting progressive massive fibrosis. Both low- and high silica-induced fibrosis had aberrant lipid metabolism. Combined with the RNA-Seq data, this multiomics study demonstrated alterations in the enzymes involved in sphingolipid metabolism. Time-dependent metabolic reprogramming revealing abnormal glycerophospholipid metabolism was intimately associated with the process of inflammation, whereas sphingolipid metabolism was crucial during lung fibrosis. These findings suggest that lipid dysregulation, especially sphingolipid metabolism, was involved in the process of silicosis.

Discovery of novel hydroxyamidine based indoleamine 2,3-dioxygenase 1 (IDO1) and thioredoxin reductase 1 (TrxR1) dual inhibitors.

In order to take advantage of both immunotherapeutic and metabolic antitumor agents, novel dual indoleamine 2,3- dioxygenase 1 (IDO1) and thioredoxin reductase 1 (TrxR1) inhibitors were designed. Thioredoxin reductase 1 (TrxR1) is a main ROS modulator within CRC cells. Indoleamine 2,3-dioxygenase (IDO1) is crucial controller for tryptophan (Trp) metabolism that is also important for CRC immunotherapy. Herein, ten compounds 12a-j containing hydroxyamidine scaffold were designed, synthesized and evaluated for inhibitory activities against IDO1/TrxR1 enzyme and CRC cells. Among these compounds, the most active compound 12d (ZC0109) showed excellent and balanced activity against both IDO1 (IC50 = 0.05 µM) and TrxR1 (IC50 = 3.00 ± 0.25 µM) were selected for further evaluation. Compound ZC0109 exhibited good dual inhibition against IDO1 and TrxR1 both in vitro and in vivo. Further mechanistic studies reveal that, through IDO1 and TrxR1 inhibition by ZC0109 treatment, accumulated ROS effectively induced apoptosis and G1/S cell cycle arrest in cancer cells. In vivo evaluation demonstrated excellent anti-tumor effect of ZC0109 with the notable ability of promoting ROS-induced apoptosis, reducing kynurenine level in plasma and restoring anti-tumor immune response. Thus, ZC0109 represents a potential CRC therapy agent for further development.

Asparagus officinalis combined with paclitaxel exhibited synergistic anti-tumor activity in paclitaxel-sensitive and -resistant ovarian cancer cells.

PURPOSE: Although paclitaxel is a promising first-line chemotherapeutic drug for ovarian cancer, acquired resistance to paclitaxel is one of the leading causes of treatment failure, limiting its clinical application. Asparagus officinalis has been shown to have anti-tumorigenic effects on cell growth, apoptosis, cellular stress and invasion of various types of cancer cells and has also been shown to synergize with paclitaxel to inhibit cell proliferation in ovarian cancer. METHODS: Human ovarian cancer cell lines MES and its PTX-resistant counterpart MES-TP cell lines were used and were treated with Asparagus officinalis and paclitaxel alone as well as in combination. Cell proliferation, cellular stress, invasion and DMA damage were investigated and the synergistic effect of a combined therapy analyzed. RESULTS: In this study, we found that Asparagus officinalis combined with low-dose paclitaxel synergistically inhibited cell proliferation, induced cellular stress and apoptosis and reduced cell invasion in paclitaxel-sensitive and -resistant ovarian cancer cell lines. The combined treatment effects were dependent on DNA damage pathways and suppressing microtubule dynamics, and the AKT/mTOR pathway and microtubule-associated proteins regulated the inhibitory effect through different mechanisms in paclitaxel-sensitive and -resistant cells. CONCLUSION: These findings suggest that the combination of Asparagus officinalis and paclitaxel have potential clinical implications for development as a novel ovarian cancer treatment strategy.

Fine mapping of powdery mildew and stripe rust resistance genes Pm5V/Yr5V transferred from Dasypyrum villosum into wheat without yield penalty.

KEY MESSAGE: The novel wheat powdery mildew and stripe rust resistance genes Pm5V/Yr5V are introgressed from Dasypyrum villosum and fine mapped to a narrowed region in 5VS, and their effects on yield-related traits were characterized. The powdery mildew and stripe rust seriously threaten wheat production worldwide. Dasypyrum villosum (2n = 2x = 14, VV), a relative of wheat, is a valuable resource of resistance genes for wheat improvement. Here, we describe a platform for rapid introgression of the resistance genes from D. villosum into the wheat D genome. A complete set of new wheat-D. villosum V (D) disomic substitution lines and 11 D/V Robertsonian translocation lines are developed and characterized by molecular cytogenetic method. A new T5DL·5V#5S line NAU1908 shows resistance to both powdery mildew and stripe rust, and the resistances associated with 5VS are confirmed to be conferred by seedling resistance gene Pm5V and adult-plant resistance gene Yr5V, respectively. We flow-sort chromosome arm 5VS and sequence it using the Illumina NovaSeq 6000 system that allows us to generate 5VS-specific markers for genetic mapping of Pm5V/Yr5V. Fine mapping shows that Pm5V and Yr5V are closely linked and the location is narrowed to an approximately 0.9 Mb region referencing the sequence of Chinese Spring 5DS. In this region, a NLR gene in scaffold 24,874 of 5VS orthologous to TraesCS5D02G044300 is the most likely candidate gene for Pm5V. Soft- and hard-grained T5DL·5V#5S introgressions confer resistance to both powdery mildew and stripe rust in diverse wheat genetic backgrounds without yield penalty. Meanwhile, significant decrease in plant height and increase in yield were observed in NIL-5DL·5V#5S compared with that in NIL-5DL·5DS. These results indicate that Pm5V/Yr5V lines might have the potential value to facilitate wheat breeding for disease resistance.

Prognostic Predictive Characteristics in Patients With Fibrosing Interstitial Lung Disease: A Retrospective Cohort Study.

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 <50% (HR 2.25, 95% CI 1.45 to 3.50, p < 0.001), or in those with UIP-like fibrotic pattern (HR 1.68, 95% CI 1.04 to 2.71, p < 0.001). Conclusion: Clubbing of fingers and an HRCT-documented UIP-like fibrotic pattern were more likely to be associated with progressive fibrosing with varied prevalence based on the specific diagnosis. Among patients with progressive fibrosing, those with hypoxemia, lower baseline DLCO% predicted, or UIP-like fibrotic pattern showed poor mortality.

Ipatasertib, an oral AKT inhibitor, inhibits cell proliferation and migration, and induces apoptosis in serous endometrial cancer.

Ipatasertib (IPAT) is an orally administered, selective protein kinase B (AKT) inhibitor with promising data in solid tumors in both pre-clinical studies and clinical trials. Given that the PI3K/AKT/mTOR pathway is frequently dysregulated in uterine serous carcinoma (USC), we aimed to explore the functional impact of IPAT on anti-tumorigenic activity in USC cell lines and primary cultures of USC. We found that IPAT significantly inhibited cell proliferation and colony formation in a dose-dependent manner in USC cells. Induction of cell cycle arrest and apoptosis was observed in IPAT-treated ARK1 and SPEC-2 cells. Treatment with IPAT resulted in reduced adhesion and invasion of both cell lines with a concomitant decrease in the expression of Snail, Slug, and N-Cadherin. Compared with single-drug treatment, the combination of IPAT and paclitaxel synergistically reduced cell proliferation and increased the activity of cleaved caspase 3 in both cell lines. Additionally, IPAT inhibited growth in four of five primary USC cultures, and three of five primary cultures also exhibited synergistic growth inhibition when paclitaxel and IPAT were combined. These results support that IPAT appears to be a promising targeted agent in the treatment of USC.

Characteristics of the Intestinal Flora of TPOAb-Positive Women With Subclinical Hypothyroidism in the Second Trimester of Pregnancy: A Single-Center Prospective Cohort Study.

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.

Pulmonary hypertension in patients with pneumoconiosis with progressive massive fibrosis.

OBJECTIVES: This study aims to explore the prevalence and clinical features of pulmonary hypertension (PH) in patients with progressive massive fibrosis (PMF) and its correlation with large opacities on CT scans. METHODS: This retrospective study collected 235 patients with PMF, and 199 were eligible for analysis. The probability of PH development was estimated based on tricuspid regurgitation velocity measured by echocardiogram. The size and the location of large opacities on chest CT were recorded. Potential risk factors for PH secondary to PMF were analysed using regression analysis. RESULTS: The prevalence of a high or intermediate probability of PH was 39.7% in patients with PMF. Type C of large opacities (OR 6.99, 95% CI 2.34 to 23.00, p<0.001) and central type of the large opacities (OR 8.12, 95% CI 2.89 to 24.71, p<0.001) were identified as the risk factors for PH secondary to PMF. Over a median follow-up of 32.8 months, the survival rate was 73.3% in the PH group, significantly lower than that in the non-PH group (96.6%, p<0.001). CONCLUSIONS: Over one-third of patients with PMF developed PH. The increased size and the central distribution of large opacities were identified as the risk factors.

The combination of metabolic syndrome and inflammation increased the risk of colorectal cancer.

BACKGROUND: Inflammation and metabolic syndrome (MetS) may act synergistically and possibly accelerate the initiation and progression of colorectal cancer (CRC). We prospectively examined the joint effect of MetS and inflammation on the risk of CRC. METHODS: We studied 92,770 individuals from the Kailuan study. MetS was defined based on the presence of three or more of the following components. (1) high glucose: FPG > 5.6 mmol/L; (2) high blood pressure: SBP ≥ 130 mmHg or DBP ≥ 85 mmHg; (3) high triglycerides: triglycerides > 1.69 mmol/L; (4) low HDL-C: HDL-C < 1.04 mmol/L in men or 1.29 mmol/L in women; and (5) visceral adiposity: waist circumference ≥ 85 cm in men or 80 cm in women. Inflammation was defined as hs-CRP ≥ 3 mg/L. We divided participants into four groups for the primary exposure according to the presence/absence of inflammation and presence/absence of MetS. Cox proportional hazards regression models were used to evaluate the association of MetS and/or inflammation with the risk of CRC. RESULTS: Compared with metabolically healthy noninflammatory individuals, inflammatory participants without MetS and inflammatory participants with MetS were associated with a 1.3-fold and 4.18-fold increased risk of CRC with corresponding HRs (95% CI) of 1.34 (1.09, 1.64) and 4.18 (3.11, 5.62), respectively. The combination of MetS and inflammation was associated with the highest risk of CRC in all subgroups, especially among participants who were female, in younger age, and obese. Sensitivity analyses further validated our primary findings. CONCLUSIONS: We found the combination of MetS and inflammation could significantly increase the risk of CRC. Including CRP in the diagnosis of MetS may help to identify additional high-risk participants who should be targeted for early diagnosis and prevention of CRC. Trial registration Kailuan study, ChiCTR-TNRC-11001489. Registered 24 August, 2011-Retrospectively registered, http:// www.chictr.org.cn/showprojen.aspx?proj=8050.