Spatiotemporal single-cell analysis decodes cellular dynamics underlying different responses to immunotherapy in colorectal cancer.

Expanding the efficacy of immune checkpoint blockade (ICB) in colorectal cancer (CRC) presses for a comprehensive understanding of treatment responsiveness. Here, we analyze multiple sequential single-cell samples from 22 patients undergoing PD-1 blockade to map the evolution of local and systemic immunity of CRC patients. In tumors, we identify coordinated cellular programs exhibiting distinct response associations. Specifically, exhausted T (Tex) or tumor-reactive-like CD8+ T (Ttr-like) cells are closely related to treatment efficacy, and Tex cells show correlated proportion changes with multiple other tumor-enriched cell types following PD-1 blockade. In addition, we reveal the less-exhausted phenotype of blood-associated Ttr-like cells in tumors and find that their higher abundance suggests better treatment outcomes. Finally, a higher major histocompatibility complex (MHC) II-related signature in circulating CD8+ T cells at baseline is linked to superior responses. Our study provides insights into the spatiotemporal cellular dynamics following neoadjuvant PD-1 blockade in CRC.

[Retracted] Effect of metformin on cell proliferation, apoptosis, migration and invasion in A172 glioma cells and its mechanisms.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that the cell invasion and migration assay data shown in Fig. 6 and the cell proliferation assay experiments shown in Fig. 2 were strikingly similar to data appearing in different form in other articles by different authors; furthermore, in Fig. 2, for the '10 mM metformin' experiment, certain of the glioma cells appeared to be strikingly similar to other cells contained within the same data panels. Owing to the fact that the contentious data in the above article had already been published elsewhere or were under consideration for publication prior to its submission to Molecular Medicine Reports, and owing to concerns with the authenticity of certain of the data, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 20: 887­894, 2019; DOI: 10.3892/mmr.2019.10369].

To explore the protective effect of gastrodin on PC12 cells against oxidative stress induced by lead acetate based on network pharmacology.

Objective: Screening and predicting potential targets for gastrodin antioxidant stress based on network pharmacology methods, and exploring the effect of gastrodin on lead acetate induced oxidative stress in PC12 cells through cell experiments. Methods: Through the Pharmaper database Predict the target of action of gastrodin. Through OMIM and GeneCards to collect oxidative stress targets from database, and intersect with drug targets to obtain drug disease intersection targets; Construct a PPI network diagram using the STRING database. Perform GO enrichment analysis and KEGG pathway enrichment analysis on intersection targets through the DAVID platform. Lead acetate (PbAc) exposure was used to establish a lead poisoning cell model, and intracellular ROS levels, ALB, AKT1, and Caspase-3 levels were measured. Results: A total of 288 targets of gastrodin action, 638 targets related to oxidative stress, and 62 drug disease intersection targets were obtained, among which core targets such as ALB, AKT1, CASP3 may be closely related to oxidative stress. KEGG pathway analysis showed that gastrodin antioxidant stress mainly involved in lipid, cancer pathway and other signaling pathways. The results of the cell experiment showed that 50 µM is the optimal effective concentration for PbAc induced ROS production in PC12 cells. Gastrodin significantly increased the ROS content of PC12 cells treated with PbAc, Upregulation of ALB expression and downregulation of AKT1 and CASP3 expression. Conclusions: Gastrodin may alleviate PbAc-induced ROS in PC12 cells, indicating potential protective effects against oxidative stress. Further studies are needed to confirm these findings and explore the underlying mechanisms.

The quality of guidelines on the pancreatic perioperative enhanced recovery after surgery: a systematic quality appraisal using AGREE II instrument.

PURPOSE: To evaluate the quality of guidelines on the pancreatic perioperative enhanced recovery after surgery both domestically and internationally, providing reference and reference for clinical practice. METHODS: Systemically retrieved in the guideline websites, professional association websites and databases, such as up to date, BMJ Best Practice, PubMed, Embase, The Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), Wan Fang Data, China Science and Technology Journal Database(VIP), China Biology Medicine disc (CBMdisc), Medlive, Guidelines International Network(GIN), National Guideline Clearinghouse(NGC), National Institute for Health and Care Excellence(NICE), Registered Nurses Association of Ontario(RNAO), Scottish Intercollegiate Guidelines Network(SIGN), Joanna Briggs Institute Library(JBI), including guidelines and expert consensus on enhanced postsurgical recovery in pancreatic surgery published as of December 20, 2023. The Appraisal of Guidelines for Research and Evaluation II(AGREE II) tool was applied to evaluate the quality of the guidelines by four assessors. RESULTS: This study included seven guidelines, all of which were rated as Grade B in terms of quality, with ICC coefficients ranging from 0.752 to 0.884, indicating a high level of consistency. CONCLUSION: When formulating guidelines in the future, it is recommended to use AGREE II as a reference, emphasizing the standardization of the guideline development process and methods, fully considering patients' values and preferences, focusing on the applicability of the guidelines, and striving to create high-quality evidence-based recommendations.

[Application of metal cushion block combined with Jumbo cup in reconstruction of acetabular bone defect in revision of artificial hip joint].

OBJECTIVE: To investigate the application effect and imaging changes of metal cushion block combined with Jumbo cup in the reconstruction of acetabular bone defect after revision of artificial hip joint. METHODS: Retrospective analysis was made on the clinical data of 83 patients who underwent revision acetabular bone defect reconstruction of the artificial hip joint in our hospital from September 2019 to October 2021. They were divided into group A and group B according to different surgical methods. There were 42 patients in group A, including 26 males and 16 females, aged from 44 to 72 years old with an average of (60.57±4.62) years, who underwent revision with metal cushion block and Jumbo cup. There were 41 patients in group B, including 22 males and 19 females, aged from 42 to 71 years old with an average of (58.74±4.25) years, who underwent revision with metal cushion block and bone cement mortar cup. The operation related indexes, Harris hip function score and visual analogue scale (VAS) of pain before operation, 1 month and 12 month after operation were compared between two groups. The results of X-ray imaging examination (hip rotation center height, acetabular abduction angle, femoral eccentricity and imaging standard qualification rate) before and 12 month after operation were evaluated, and the incidence of complications was compared between two groups. RESULTS: There was no significant difference in operation time, intraoperative bleeding volume and postoperative drainage volume between two groups (P>0.05). Both groups were followed up for 12 to 36 months with an average of (25.36±3.59) months. The scores of pain, function, deformity and Harris' total score in the two groups at 1 month after operation were higher than those before operation (P<0.05), and the scores of pain, function, deformity, joint activity and Harris' total score in two groups at 1 year after operation were higher than those before operation and 1 month after operation (P<0.05), and the above scores in group A were higher than those in group B at 1 year after operation (P<0.05). The VAS of two groups decreased successively at 1 month and 1 year after operation (P<0.05), but there was no significant difference in both groups at each time point (P>0.05). The femoral eccentricity increased in both groups at 1 year after operation (P<0.05), and group A was higher than group B (P<0.05). The height of rotation center and acetabular abduction angle decreased in both groups at 1 year after operation (P<0.05), and the height of rotation center in group A was lower than that in group B (P<0.05), but there was no significant difference in acetabular abduction angle between two groups (P>0.05). The imaging qualification rate of group A was higher than that of group B (P<0.05). There was no significant difference in the incidence of adverse reactions between two groups (P>0.05). CONCLUSION: Metal cushion block combined with Jumbo cup in the treatment of acetabular bone defects can provide the hip joint function, and restore the hip joint rotation center, femoral eccentricity and acetabular abduction angle, with obvious clinical effect.

Deep learning system for malignancy risk prediction in cystic renal lesions: a multicenter study.

OBJECTIVES: To develop an interactive, non-invasive artificial intelligence (AI) system for malignancy risk prediction in cystic renal lesions (CRLs). METHODS: In this retrospective, multicenter diagnostic study, we evaluated 715 patients. An interactive geodesic-based 3D segmentation model was created for CRLs segmentation. A CRLs classification model was developed using spatial encoder temporal decoder (SETD) architecture. The classification model combines a 3D-ResNet50 network for extracting spatial features and a gated recurrent unit (GRU) network for decoding temporal features from multi-phase CT images. We assessed the segmentation model using sensitivity (SEN), specificity (SPE), intersection over union (IOU), and dice similarity (Dice) metrics. The classification model's performance was evaluated using the area under the receiver operator characteristic curve (AUC), accuracy score (ACC), and decision curve analysis (DCA). RESULTS: From 2012 to 2023, we included 477 CRLs (median age, 57 [IQR: 48-65]; 173 men) in the training cohort, 226 CRLs (median age, 60 [IQR: 52-69]; 77 men) in the validation cohort, and 239 CRLs (median age, 59 [IQR: 53-69]; 95 men) in the testing cohort (external validation cohort 1, cohort 2, and cohort 3). The segmentation model and SETD classifier exhibited excellent performance in both validation (AUC = 0.973, ACC = 0.916, Dice = 0.847, IOU = 0.743, SEN = 0.840, SPE = 1.000) and testing datasets (AUC = 0.998, ACC = 0.988, Dice = 0.861, IOU = 0.762, SEN = 0.876, SPE = 1.000). CONCLUSION: The AI system demonstrated excellent benign-malignant discriminatory ability across both validation and testing datasets and illustrated improved clinical decision-making utility. CRITICAL RELEVANCE STATEMENT: In this era when incidental CRLs are prevalent, this interactive, non-invasive AI system will facilitate accurate diagnosis of CRLs, reducing excessive follow-up and overtreatment. KEY POINTS: The rising prevalence of CRLs necessitates better malignancy prediction strategies. The AI system demonstrated excellent diagnostic performance in identifying malignant CRL. The AI system illustrated improved clinical decision-making utility.

Tumor Necrosis Factor α-Induced Protein 8-Like 1 Binds to Protein Arginine Methyltransferase 1 to Suppress the Methylation of Signal Transducer and Activator of Transcription 3 and Cell Growth in Oral Squamous Cell Carcinoma.

The tumor necrosis factor α-induced protein 8 (TIPE, also TNFAIP8 or OXi-α) family is a newly discovered series of proteins involved in immune regulation and tumorigenesis. TIPE1, a member of the TIPE/TNFAIP8/OXi-α family, has emerged as an anticancer-drug target, as it promotes cancer cell apoptosis and inhibits cell proliferation. The current study aimed to systematically reveal that TIPE1 regulates the activity of protein arginine methyltransferase (PRMT)-1 and the subsequent methylation of signal transducer and activator of transcription (STAT)-3 to suppress oral squamous cell carcinoma (OSCC) growth. TIPE1 was down-regulated in the OSCC cell lines (Tca8113, SCC25, Cal27, SCC15, and HSC27). TIPE1 overexpression significantly inhibited cell proliferation, colony formation, in vivo tumorgenicity, and Ki-67 expression in OSCC. TIPE1 interacted with the catalytic region of PRMT1 and inhibited STAT3 methylation. The effects of TIPE1 on OSCC cells were alleviated after PRMT1 overexpression, confirming the importance of this interaction to the tumor-suppressive effects of TIPE1. Together, these findings confirmed that TIPE1 mediated PRMT1 suppression through direct binding to its catalytic domain and subsequently inhibited the methylation and expression of STAT3 in OSCC cells, thereby inhibiting cell growth and tumorgenicity.

Role of INPP4B in the proliferation, migration, invasion, and survival of human endometrial cancer cells.

BACKGROUND: Inositol polyphosphate 4-phosphatase type II (INPP4B) has been identified as a tumor repressor in several human cancers while its role in endometrial cancer has not been investigated yet. Therefore, the current study was designed to determine whether INPP4B participates in the progression of endometrial cancer by utilizing clinical data and experimental determination. MATERIALS AND METHODS: We first include six chemotherapy-treated patients with recurrent and metastatic endometrioid carcinoma to determine the relationship between INPP4B mutation and relative tumor burden. By using siRNA-mediated gene silencing and vector-mediated gene overexpression, we further determined the effect of manipulating INPP4B expression on the proliferation, invasion, and survival of endometrial cancer cells. Furthermore, the repressing effect of INPP4B together with its role in chemotherapy was further validated by xenograft tumor-bearing mice models. Western blot analysis was used to explore further downstream signaling modulated by INPP4B expression manipulation. RESULTS: Two of the patients were found to have INPP4B mutations and the mutation frequency of INPP4B increased during the progression of chemotherapy resistance. Endometrial cancer cells with silenced INPP4B expression were found to have promoted tumor cell proliferation, invasion, and survival. Endometrial cancer cells overexpressing INPP4B were found to have decreased tumor cell proliferation, invasion, and survival. An in vivo study using six xenograft tumor-bearing mice in each group revealed that INPP4B overexpression could suppress tumor progression and enhance chemosensitivity. Furthermore, INPP4B overexpression was found to modulate the activation of Wnt3a signaling. CONCLUSION: The current study suggested that INPP4B could be a suppressor in endometrial cancer progression and might be a target for endometrial cancer treatment. Also, INPP4B might serve as a predictor of chemosensitivity determination.

Hydrochemistry, quality, and integrated health risk assessments of groundwater in the Huaibei Plain, China.

Groundwater is an essential freshwater resource utilized in industry, agriculture, and daily life. In the Huaibei Plain (HBP), where groundwater significantly influences socio-economic development, information about its quality, hydrochemistry, and related health risks remains limited. We conducted a comprehensive groundwater sampling in the HBP and examined its rock characteristics, water quality index (WQI), and potential health risks. The results revealed that the primary factors shaping groundwater hydrochemistry were rock dissolution and weathering, cation exchange, and anthropogenic activities. WQI assessment indicated that only 73% of the groundwaters is potable, as Fe2+, Mn2+, NO3-, and F- contents in the water could pose non-carcinogenic hazards to humans. Children were more susceptible to these health risks through oral ingestion than adults. Uncertainty analysis indicated that the probabilities of non-carcinogenic risk were approximately 57% and 31% for children and adults, respectively. Sensitivity analysis further identified fluoride as the primary factor influencing non-carcinogenic risks, indicating that reducing fluoride contamination should be prioritized in future groundwater management in the HBP.

Efficacy and safety of Huangqi Jianzhong decoction in the treatment of chronic atrophic gastritis: A meta-analysis.

BACKGROUND: Chronic atrophic gastritis is a persistent disorder of the digestive system where the gastric mucosa epithelium and glands undergo atrophy, leading to a decrease in their number and thinning of the gastric mucosa. It is worth noting that the prevalence of chronic atrophic gastritis is higher in China compared to the global average, and it is also considered a precancerous condition for gastric cancer. AIM: To evaluate the efficacy of Huangqi Jianzhong decoction in treating chronic atrophic gastritis. Chronic atrophic gastritis is a persistent illness characterized by the progressive disappearance of healthy gastric glands due to repeated injury. Huangqi Jianzhong decoctions are widely used in China to treat chronic atrophic gastritis. However, there is limited scientific evidence regarding their efficacy in treating this illness. METHODS: The present meta-analysis adhered to the PRISMA guidelines and used the Cochrane Collaboration methodology. We performed a comprehensive search for clinical trials investigating the use of Huangqi Jianzhong decoction in treating chronic atrophic gastritis published until January 2023. The risk of bias and the quality of the included studies were evaluated using the Cochrane Handbook guidelines. Finally, a meta-analysis was conducted using the RevMan 5.4 software. RESULTS: This study included a total of 13 articles, comprising 1269 samples. The meta-analysis was conducted on these 13 articles, yielding the following results: I2 = 0%, P = 0.60, [RR = 1.24, 95%CI: 1.18 to 1.30, P < 0.00001]. The forest plot analysis of the Helicobacter pylori clearance rate revealed I2 = 0%, P = 0.36, [RR = 1.20, 95%CI: 1.05 to 1.38, P = 0.009]. The forest plot of PG-I level showed I2 = 99%, P < 0.00001, [MD = 4.99, 95%CI: -1.59 to 11.58, P = 0.14]. The forest plot of stomach pain demonstrated I2 = 54%, P = 0.04, [MD = -0.63, 95%CI: -0.68 to -0.58, P < 0.00001]. The forest plot of reflux indicated I2 = 82%, P = 0.0009, [MD = -0.48, 95%CI: -0.63 to -0.33, P < 0.00001]. The forest plot of recurrence rate exhibited I2 = 0%, P = 0.92, [RR = 0.15, 95%CI: 0.04 to 0.66, P = 0.01]. The forest plot of adverse reactions showed no heterogeneity in outcome data, [RR = 1.07, 95%CI: 0.53 to 2.17, P = 0.86]. CONCLUSION: This study demonstrated that Huangqi Jianzhong decoction improved various factors in adults with chronic atrophic gastritis. These factors included the total effective rate, Helicobacter pylori clearance rate, symptoms such as stomachache and acid reflux alleviation, and recurrence rates.

PTP4A1 promotes oral squamous cell carcinoma (OSCC) metastasis through altered mitochondrial metabolic reprogramming.

PTP4A1 (Protein tyrosine phosphatase 4A1) is a protein tyrosine phosphatase that regulates a range of pro-oncogenic signaling pathways. Here, we report a novel role for PTP4A1 in oral squamous cell carcinoma (OSCC) growth and development. We show that PTP4A1 is frequently overexpressed in OSCC cells and tissues compared to adjacent non-tumor tissue. In OSCC, the overexpression of PTP4A1 increased cell growth and invasion in vitro, and enhanced tumor progression in vivo. At the molecular level, PTP4A1 was found to regulate mitochondrial metabolic reprogramming to enhance the invasive capacity of OSCC cells. Mechanistically, these effects were mediated through binding to pyruvate kinase isoenzyme M2 (PKM2) to promote its expression and aconitase 2 (ACO2) to enhance its degradation. Together, these data reveal PTP4A1 as a viable target for OSCC therapeutics.

[Effects of total ginsenosides from Panax ginseng stems and leaves on gut microbiota and short-chain fatty acids metabolism in acute lung injury mice].

This study aimed to investigate the biological effects and underlying mechanisms of the total ginsenosides from Panax ginseng stems and leaves on lipopolysaccharide(LPS)-induced acute lung injury(ALI) in mice. Sixty male C57BL/6J mice were randomly divided into a control group, a model group, the total ginsenosides from P. ginseng stems and leaves normal administration group(61.65 mg·kg~(-1)), and low-, medium-, and high-dose total ginsenosides from P. ginseng stems and leaves groups(15.412 5, 30.825, and 61.65 mg·kg~(-1)). Mice were administered for seven continuous days before modeling. Twenty-four hours after modeling, mice were sacrificed to obtain lung tissues and calculate lung wet/dry ratio. The number of inflammatory cells in bronchoalveolar lavage fluid(BALF) was detected. The levels of interleukin-1ß(IL-1ß), interleukin-6(IL-6), and tumor necrosis factor-α(TNF-α) in BALF were detected. The mRNA expression levels of IL-1ß, IL-6, and TNF-α, and the levels of myeloperoxidase(MPO), glutathione peroxidase(GSH-Px), superoxide dismutase(SOD), and malondialdehyde(MDA) in lung tissues were determined. Hematoxylin-eosin(HE) staining was used to observe the pathological changes in lung tissues. The gut microbiota was detected by 16S rRNA sequencing, and gas chromatography-mass spectrometry(GC-MS) was applied to detect the content of short-chain fatty acids(SCFAs) in se-rum. The results showed that the total ginsenosides from P. ginseng stems and leaves could reduce lung index, lung wet/dry ratio, and lung damage in LPS-induced ALI mice, decrease the number of inflammatory cells and levels of inflammatory factors in BALF, inhibit the mRNA expression levels of inflammatory factors and levels of MPO and MDA in lung tissues, and potentiate the activity of GSH-Px and SOD in lung tissues. Furthermore, they could also reverse the gut microbiota disorder, restore the diversity of gut microbiota, increase the relative abundance of Lachnospiraceae and Muribaculaceae, decrease the relative abundance of Prevotellaceae, and enhance the content of SCFAs(acetic acid, propionic acid, and butyric acid) in serum. This study suggested that the total ginsenosides from P. ginseng stems and leaves could improve lung edema, inflammatory response, and oxidative stress in ALI mice by regulating gut microbiota and SCFAs metabolism.

Effect of humic acid-modified attapulgite on polycyclic aromatic hydrocarbon adsorption and release from paddy soil into the overlying water in a rice-crab coculture paddy ecosystem and the underlying process.

Phenanthrene (Phe), a typical polycyclic aromatic hydrocarbon (PAH) pollutant, poses an enormous safety risk to rice-crab coculture (RC) paddy ecosystems. In this study, humic acid-modified purified attapulgite (HA-ATP) with a composite structure was successfully fabricated to adsorb PAHs released from paddy soil to overlying water in RC paddy ecosystems in Northeast China. The maximum crab bioturbation intensities for dissolved Phe and particulate Phe were 64.83nullng/L·(cm2·d) and 214.29nullng/L·(cm2·d), respectively. The highest concentration of dissolved Phe released from paddy soil to overlying water due to crab bioturbation reached 80.89nullng/L, while the corresponding concentration of particulate Phe reached 267.36nullng/L. The dissolved organic carbon (DOC) and total suspended solid (TSS) concentrations in overlying water increased correspondingly and were strongly correlated with dissolved Phe and particulate Phe concentrations, respectively (P < 0.05). When 6% HA-ATP was added to the surface layer of paddy soil, the efficiency of the adsorption of Phe release was 24.00%-36.38% for particulate Phe and 89.99%-91.91% for dissolved Phe. Because HA-ATP has a large adsorption pore size (11.33 nm) and surface area (82.41nullm2/g) as well as many HA functional groups, it provided multiple hydrophobic adsorption sites for dissolved Phe, which was conducive to competitive adsorption with DOC in the overlying water. In contrast to that adsorbed by DOC, the average proportion of dissolved Phe adsorbed by HA-ATP reached 90.55%, which reduced the dissolved Phe concentration in the overlying water. Furthermore, even though the particulate Phe was resuspended by crab bioturbation, HA-ATP immobilized particulate Phe due to its capacity to inhibit desorption, which achieved the goal of reducing the Phe concentration in the overlying water. This result was confirmed by research on the adsorption-desorption characteristics of HA-ATP. This research provides an environmentally friendly in situ remediation method for reducing agricultural environmental risks and improving rice crop quality.

Design of diversified chimeric antigen receptors through rational module recombination.

Chimeric antigen receptor (CAR)-T cells have shown great promise in cancer therapy. However, the anti-tumor efficiency is limited due to the CAR-induced T cell apoptosis or exhaustion. The intracellular domain of CAR comprised of various signaling modules orchestrates CAR-T cell behaviors. The modularity of CAR signaling domain functions as the "mainboard" to assemble diversified downstream signaling components. Here, we implemented the modular recombination strategy to construct a library of CARs with synthetic co-signaling modules adopted from immunoglobin-like superfamily (IgSF) and tumor necrosis factor receptor superfamily (TNFRSF). We quantitatively characterized the signaling behaviors of these recombinants by both NFAT and NF-κB reporter, and identified a set of new CARs with diverse signaling behaviors. Specifically, the 28(NM)-BB(MC) CAR-T cells exhibited improved cytotoxicity and T cell persistence. The synthetic approach can promote our understanding of the signaling principles of CAR molecule, and provide a powerful tool box for CAR-T cell engineering.

Supramolecular Host-Guest Strategy for the Accelerating Detection of Nitroreductase.

Identifying nitroreductase (NTR) with fluorescent techniques has become a research hotspot, due to its good sensitivity and selectivity toward the early-stage cancer diagnosis and monitoring. Herein, a host-guest reporter (NAQA⊂Zn-MPPB) is successfully achieved by encapsulating the NTR probe NAQA into a new NADH-functioned metal-organic cage Zn-MPPB, which makes the reporter for ultrafast detection of NTR within dozens of seconds in solution. The host-guest strategy fuses the Zn-MPPB and NAQA to form a pseudomolecule material, which changes the reaction process of NTR and NAQA from a double substrates mechanism to a single substrate one, and accelerates the reduction efficiency of NAQA. This advantage make the new host-guest reporter exhibit a linear relationship between emission changes and NTR concentration, and it shows better sensitively toward NTR than that of NAQA. Additionally, the positively charged water-soluble metal-organic cage can encapsulate NAQA in the cavity, promote it to dissolve in an aqueous environment, and facilitate their accumulation into tumor cells. As expected, such host-guest reporter displays a fast and high efficiently imaging capability toward NTR in tumor cells and tumor-bearing mice, and flow cytometry assay is conducted to corroborate the capability as well, implying the considerably potential of host-guest strategy for early tumor diagnosis and treatment.

Follicular fluid progesterone downregulated HPGD and COX2 in granulosa cells via suppressing NF-ĸB in endometriosis†.

Increasing evidences showed that ovulatory dysfunction, possibly caused by luteinized unruptured follicular follicle syndrome (LUFS), is one of the reasons for endometriosis-related infertility. The present study was conducted to explore the potential effect of elevated progesterone in follicular fluid (FF) on ovulation in endometriosis. A prospective study including 50 ovarian endometriosis patients and 50 control patients with matched pairs design was conducted with alterations in FF and peritoneal fluid (PF) components identified by metabolomics analyses and differentially expressed genes in granulosa cells (GCs) identified by transcriptome analysis. Patients with endometriosis exhibited a significantly higher progesterone level in serum, FF, and PF. Granulosa cells from endometriosis patients revealed decreased expression of HPGD, COX-2, and suppressed NF-ĸB signaling. Similarly, progesterone treatment in vitro downregulated HPGD and COX2 expression and suppressed NF-ĸB signaling in granulosa tumor-like cell line KGN (Bena Culture Collection, China) and primarily cultured GCs, as manifested by decreased expressions of IL1R1, IRAK3, reduced pIĸBα/IĸBα ratio, and nucleus translocation of p65. On the contrary, TNF-α treatment increased expression of IL1R1, IRAK3, pIĸBα, p65, and HPGD in GCs. One potential p65 binding site was identified in the promoter region of HPGD by chromatin immunoprecipitation. In conclusion, we found that intrafollicular progesterone might downregulate HPGD and COX-2 in GCs via suppressing the NF-ĸB signaling pathway, shedding light on the mechanism underlying the endometriosis-related ovulatory dysfunction.

NuTracker: a coordinate-based neural network representation of lung motion for intrafraction tumor tracking with various surrogates in radiotherapy.

Objective. Tracking tumors and surrounding tissues in real-time is critical for reducing errors and uncertainties during radiotherapy. Existing methods are either limited by the linear representation or scale poorly with the volume resolution. To address both issues, we propose a novel coordinate-based neural network representation of lung motion to predict the instantaneous 3D volume at arbitrary spatial resolution from various surrogates: patient surface, fiducial marker, and single kV projection.Approach. The proposed model, namely NuTracker, decomposes the 4DCT into a template volume and dense displacement fields (DDFs), and uses two coordinate neural networks to predict them from spatial coordinates and surrogate states. The predicted template is spatially warped with the predicted DDF to produce the deformed volume for a given surrogate state. The nonlinear coordinate networks enable representing complex motion at infinite resolution. The decomposition allows imposing different regularizations on the spatial and temporal domains. The meta-learning and multi-task learning are used to train NuTracker across patients and tasks, so that commonalities and differences can be exploited. NuTracker was evaluated on seven patients implanted with markers using a leave-one-phase-out procedure.Main results. The 3D marker localization error is 0.66 mm on average and <1 mm at 95th-percentile, which is about 26% and 32% improvement over the predominant linear methods. The tumor coverage and image quality are improved by 5.7% and 11% in terms of dice and PSNR. The difference in the localization error for different surrogates is small and is not statistically significant. Cross-population learning and multi-task learning contribute to performance. The model tolerates surrogate drift to a certain extent.Significance. NuTracker can provide accurate estimation for entire tumor volume based on various surrogates at infinite resolution. It is of great potential to apply the coordinate network to other imaging modalities, e.g. 4DCBCT and other tasks, e.g. 4D dose calculation.

Risk-factor model for postpartum hemorrhage after cesarean delivery: a retrospective study based on 3498 patients.

This study aimed to investigate the risk factors of patients with postpartum hemorrhage (PPH) after cesarean delivery (CD) and to develop a risk-factor model for PPH after CD. Patients were selected from seven affiliated medical institutions of Chongqing Medical University from January 1st, 2015, to January 1st, 2020. Continuous and categorical variables were obtained from the hospital's electronic medical record systems. Independent risk factors were identified by univariate analysis, least absolute shrinkage and selection operator and logistic regression. Furthermore, logistic, extreme gradient boosting, random forest, classification and regression trees, as well as an artificial neural network, were used to build the risk-factor model. A total of 701 PPH cases after CD and 2797 cases of CD without PPH met the inclusion criteria. Univariate analysis screened 28 differential indices. Multi-variable analysis screened 10 risk factors, including placenta previa, gestational age, prothrombin time, thrombin time, fibrinogen, anemia before delivery, placenta accreta, uterine atony, placental abruption and pregnancy with uterine fibroids. Areas under the curve by random forest for the training and test sets were 0.957 and 0.893, respectively. The F1 scores in the random forest training and test sets were 0.708. In conclusion, the risk factors for PPH after CD were identified, and a relatively stable risk-factor model was built.

ITGA5 Promotes Tumor Progression through the Activation of the FAK/AKT Signaling Pathway in Human Gastric Cancer.

Background: ITGA5 is an adhesion molecule that integrates the intracellular structures with the extracellular matrix to perform biological functions. However, ITGA5 is highly expressed in a variety of tumors and is involved in tumor progression by promoting cell proliferation and metastasis. Nevertheless, little research has been performed on its function in gastric cancer. Therefore, the aim of this study was to investigate the role of ITGA5 in gastric cancer, focusing on the mechanism regulating the proliferation, invasion and migration. Methods: The expression of ITGA5 in gastric cancer tissues was assessed by the use of molecular bioinformatics databases and high-throughput sequencing of gastric cancer tissues from patients. Western blot, qPCR, and immunohistochemistry were performed to detect the expression of ITGA5 in samples from gastric cancer patients and gastric cancer cell lines. Furthermore, the ITGA5 gene was silenced and overexpressed in gastric cancer cells, and the effect on proliferation, invasion, migration, and tumorigenic ability was assessed. Results: ITGA5 mRNA and protein expression were upregulated in gastric cancer cell lines and tissues from patients, and its expression was closely associated with tumor size, lymph node metastasis, and TNM stage. In vitro and in vivo experiments showed that ITGA5 silencing resulted in the inhibition of proliferation, invasion, migration, and graft growth of gastric cancer cells; conversely, the overexpression resulted in the promotion of these cell functions. Our results finally showed that the effect of ITGA5 on proliferation, invasion, and migration of gastric cancer cells was performed through the activation of the FAK/AKT pathway. Conclusions: ITGA5 promotes proliferation, invasion, and migration of gastric cancer cells through the activation of FAK/AKT signaling pathway, suggesting that ITGA5 may be potentially considered as a new target in gastric cancer therapy.

Salvia chinensis Benth Inhibits Triple-Negative Breast Cancer Progression by Inducing the DNA Damage Pathway.

Objective: Triple-negative breast cancer (TNBC) is distinguished by early recurrence and metastases, a high proclivity for treatment resistance, and a lack of targeted medicines, highlighting the importance of developing innovative therapeutic techniques. Salvia chinensis Benth (SCH) has been widely studied for its anticancer properties in a variety of cancers. However, its significance in TNBC treatment is rarely discussed. Our study investigated the anticancer effect of SCH on TNBC and the underlying mechanisms. Methods: First, we used clonogenic, cell viability, flow cytometry, and Transwell assays to assess the effect of SCH on TNBC. Bioinformatic studies, especially network pharmacology-based analysis and RNA sequencing analysis, were performed to investigate the constituents of SCH and its molecular mechanisms in the suppression of TNBC. High-performance liquid chromatography and thin-layer chromatography were used to identify two major components, quercetin and ß-sitosterol. Then, we discovered the synergistic cytotoxicity of quercetin and ß-sitosterol and assessed their synergistic prevention of cell migration and invasion. Breast cancer xenografts were also created using MDA-MB-231 cells to test the synergistic therapeutic impact of quercetin and ß-sitosterol on TNBC in vivo. The impact on the DNA damage and repair pathways was investigated using the comet assay and Western blot analysis. Results: Our findings showed that SCH decreased TNBC cell growth, migration, and invasion while also inducing cell death. We identified quercetin and ß-sitosterol as the core active components of SCH based on a network pharmacology study. According to RNA sequencing research, the p53 signaling pathway is also regarded as a critical biological mechanism of SCH treatment. The comet assay consistently showed that SCH significantly increased DNA damage in TNBC cells. Our in vivo and in vitro data revealed that the combination of quercetin and ß-sitosterol induced synergistic cytotoxicity and DNA damage in TNBC cells. In particular, SCH particularly blocked the inter-strand cross-link repair mechanism and the double-strand breach repair caused by the homologous recombination pathway, in addition to inducing DNA damage. Treatment with quercetin and ß-sitosterol produced similar outcomes. Conclusion: The current study provides novel insight into the previously unknown therapeutic potential of SCH as a DNA-damaging agent in TNBC.