Interpretable machine learning model predicting immune checkpoint inhibitor-induced hypothyroidism: A retrospective cohort study.

Hypothyroidism is a known adverse event associated with the use of immune checkpoint inhibitors (ICIs) in cancer treatment. This study aimed to develop an interpretable machine learning (ML) model for individualized prediction of hypothyroidism in patients treated with ICIs. The retrospective cohort of patients treated with ICIs was from the First Affiliated Hospital of Ningbo University. ML methods applied include logistic regression (LR), random forest classifier (RFC), support vector machine (SVM), and extreme gradient boosting (XGBoost). The area under the receiver-operating characteristic curve (AUC) was the main evaluation metric used. Furthermore, the Shapley additive explanation (SHAP) was utilized to interpret the outcomes of the prediction model. A total of 458 patients were included in the study, with 59 patients (12.88%) observed to have developed hypothyroidism. Among the models utilized, XGBoost exhibited the highest predictive capability (AUC = 0.833). The Delong test and calibration curve indicated that XGBoost significantly outperformed the other models in prediction. The SHAP method revealed that thyroid-stimulating hormone (TSH) was the most influential predictor variable. The developed interpretable ML model holds potential for predicting the likelihood of hypothyroidism following ICI treatment in patients. ML technology offers new possibilities for predicting ICI-induced hypothyroidism, potentially providing more precise support for personalized treatment and risk management.

Multi-modal molecular determinants of clinically relevant osteoporosis subtypes.

Due to a rapidly aging global population, osteoporosis and the associated risk of bone fractures have become a wide-spread public health problem. However, osteoporosis is very heterogeneous, and the existing standard diagnostic measure is not sufficient to accurately identify all patients at risk of osteoporotic fractures and to guide therapy. Here, we constructed the first prospective multi-omics atlas of the largest osteoporosis cohort to date (longitudinal data from 366 participants at three time points), and also implemented an explainable data-intensive analysis framework (DLSF: Deep Latent Space Fusion) for an omnigenic model based on a multi-modal approach that can capture the multi-modal molecular signatures (M3S) as explicit functional representations of hidden genotypes. Accordingly, through DLSF, we identified two subtypes of the osteoporosis population in Chinese individuals with corresponding molecular phenotypes, i.e., clinical intervention relevant subtypes (CISs), in which bone mineral density benefits response to calcium supplements in 2-year follow-up samples. Many snpGenes associated with these molecular phenotypes reveal diverse candidate biological mechanisms underlying osteoporosis, with xQTL preferences of osteoporosis and its subtypes indicating an omnigenic effect on different biological domains. Finally, these two subtypes were found to have different relevance to prior fracture and different fracture risk according to 4-year follow-up data. Thus, in clinical application, M3S could help us further develop improved diagnostic and treatment strategies for osteoporosis and identify a new composite index for fracture prediction, which were remarkably validated in an independent cohort (166 participants).

Whole-Exome Sequencing Identifies Mutation Profile and Mutation Signature-Based Clustering Associated with Prognosis in Appendiceal Pseudomyxoma Peritonei.

Pseudomyxoma peritonei (PMP) is a rare malignant clinical syndrome with little known about the global mutation profile. In this study, whole-exome sequencing (WES) was performed in 49 appendiceal PMP to investigate mutation profiles and mutation signatures. A total of 4,020 somatic mutations were detected, with a median mutation number of 56 (1-402). Tumor mutation burden (TMB) was generally low (median 1.55 mutations/Mb, 0.12-11.26 mutations/Mb). Mutations were mainly enriched in the function of cancer-related axonogenesis, extracellular matrix-related processes, calcium signaling pathway, and cAMP signaling pathway. Mutations in FCGBP, RBFOX1, SPEG, RTK-RAS, PI3K-AKT, and focal adhesion pathways were associated with high-grade mucinous carcinoma peritonei. These findings revealed distinct mutation profile in appendiceal PMP. Ten mutation signatures were identified, dividing patients into mutation signature cluster (MSC) 1 (N = 28, 57.1%) and MSC 2 (N = 21, 42.9%) groups. MSC (P = 0.007) was one of the four independent factors associated with 3-year survival. TMB (P = 0.003) and microsatellite instability (P = 0.002) were independent factors associated with MSC 2 grouping. Taken together, our findings provided a broader view in the understanding of molecular pathologic mechanism in appendiceal PMP and may be critical to developing an individualized approach to appendiceal PMP treatment. IMPLICATIONS: This work describes exhaustive mutation profile of PMP based on WES data and derives ten mutation signatures, which divides patients into two clusters and serve as an independent prognostic factor associated with 3-year survival.

Psychological distress and aggression among adolescents with internet gaming disorder symptoms.

The present study aimed to investigate the current situation of internet gaming disorder (IGD) in Chinese adolescents and explore the impact of IGD-related factors on adolescent aggression. We hypothesized that IGD symptoms in adolescents would be associated with aggressive behavior and that risk factors for IGD symptoms could increase the aggressive tendencies of adolescents. To verify the above hypothesis, a cross-sectional survey of junior and senior high school students from southern, southwestern, central, and eastern China was conducted. A total of 9306 valid questionnaires were collected. The results showed that the prevalence of IGD symptoms was 1.78 % among Chinese adolescents. The adolescents in the disordered gamer group had the most severe IGD symptoms, with the highest levels of psychological distress and aggression. Interestingly, adolescents in the casual gamer group had the lowest psychological distress and aggression scores. Linear regression analysis further showed that higher levels of aggression were significantly associated with male sex, younger age, more severe psychological distress and IGD symptoms, and more violent game exposure. Our results suggested that excessive online gaming not only contributes to psychological distress in adolescents but also increases their levels of aggressive behavior. Apart from male sex and younger age, severe IGD symptoms and psychological distress are the most important predictors of the development of aggressive behavior.

A study on molecular mechanism of Xihuang pill in the treatment of glioblastoma based on network pharmacology and validation in vitro and in vivo.

ETHNOPHARMACOLOGICAL RELEVANCE: Xihuang pill has been utilized to treat cancer for more than three hundred years in China. The molecular mechanisms of Xihuang pill in treating glioblastoma remains unclear. AIM OF THE STUDY: This study aimed to explore the core molecular mechanisms of Xihuang pill in treating glioblastoma by an integrative pharmacology-based investigation. MATERIALS AND METHODS: The main active compounds of Xihuang pill were identified from TCMSP, BATMAN-TCM, TCMID and CNKI. Glioblastoma-related therapeutic targets were retrieved from GeneCards and UniProt. Subsequently, a protein-protein interaction (PPI) network analysis was constructed using STRING. GO and KEGG enrichment were performed to analyze the intersection targets between the active compounds of Xihuang pill and glioblastoma. Based on the above analysis, we built a CTP network. The in vitro and in vivo experiments were further performed to validate the crucial molecular targets of Xihuang pill for the treatment of glioblastoma. RESULTS: A total of sixty active compounds of Xihuang pill and ten potential targets related to glioblastoma were found. Based on topological analysis, fourteen ingredients were selected as the main active compounds, and MY11 might be the most important metabolite in Xihuang pill. PI3K/Akt signaling pathway and receptor tyrosine kinases were considered as crucial targets for Xihuang pill against glioblastoma through KEGG enrichment and CTP analysis. The present experiments indicated that Xihuang pill suppressed the activation of PI3K/Akt/mTOR signaling pathway in glioblastoma cells and mouse xenografts via modulating the expression of PTEN and Rheb proteins, the interaction between TSC2 and Rheb, and the production of PIP3. Meanwhile, after glioblastoma cells treatment with Xihuang pil, the release of IL-1ß, INF-γ was increased and the production of IL-10, TGF-ß1 was decreased in glioblastoma cells after incubated with Xihuang pill. In addition, the activation of the upstream positive modulators of PI3K/Akt/mTOR pathway including PDGF/PDGFR and FGF/FGFR signaling were down-regulated in glioblastoma cells and mouse xenografts after treatment with Xihuang pill. CONCLUSION: Taken together, Xihuang pill inhibiting glioblastoma cell growth might be partly through down-regulating the activation of PDGF/PDGFR or FGF/FGFR-PI3K/Akt/mTOR signaling axis and improving immuno-suppressive micro-environment of glioblastoma.

Xihuang pill in the treatment of cancer: TCM theories, pharmacological activities, chemical compounds and clinical applications.

ETHNOPHARMACOLOGICAL RELEVANCE: Xihuang pill as a famous traditional Chinese formula has long been used as an adjuvant therapy for cancer. AIM OF THE STUDY: This study is aimed at summarizing recent advances in research of Xihuang pill's anti-cancer efficacies from the theoretical basis of traditional Chinese medicine, pharmacological activities, chemical components and its clinical application. MATERIALS AND METHODS: The literature information was obtained from several authoritative databases including PubMed, Embase, Cochrane Library, CNKI and Wan Fang before April 30, 2023. We also analyzed the representatively chemical compounds of Xihuang pill in vivo experiments using HPLC-Q/TOF-MS. RESULTS: The present study indicated that Xihuang pill, a classic anti-tumor prescription, had efficacies of strengthening body resistance, clearing heat and detoxification, and promoting blood circulation for removing blood stasis. Modern basic researches showed that Xihuang pill played anti-cancer roles through inducing cancer cell apoptosis, inhibiting cell proliferation, migration, invasion and angiogenesis, improving immune function and tumor microenvironment, and regulating related signaling pathways. Its chemical components are primarily consisted of amino acids, terpenoids, fatty acids, fatty acid esters, phenolics, bile acids, bile pigments and volatile oil. Clinically, Xihuang pill, as an adjuvant drug for cancer treatment, was mostly combined with chemotherapy, which could prolong survival, enhance response rate, improve patients' life quality, regulate immune function and alleviate chemotherapy-induced toxicities. CONCLUSIONS: This present study suggests that Xihuang pill may be a promising adjuvant therapy for cancer, and proposes the possibility of future research directions for Xihuang pill based on the current research status.

Tick (Acari: Ixodoidea) fauna and zoogeographic division of Jiangxi Province, China.

Tick fauna and zoogeographic distribution of Jiangxi Province remain largely unknown due to the lack of data on distribution, occurrence, and host associations of ticks. Considering this, we collected 1,817 individual samples from natural hosts, humans, and vegetation in 18 counties/districts throughout Jiangxi Province, China, from 2015 to 2021. These 1,817 individuals were found to 13 tick species, 4 genera, and 1 family. In addition, the tick sample data from 8 sampling localities (counties and districts) reported in previous studies were also included in our data. A total of 4,021 individuals, including our sample collection and the previously reported data, were assigned to at least 18 species, 6 genera, and 2 families. One newly recorded species Dermacentor sp. (near D. steini Schulze) was found; three misidentified species (Ixodes acuminatus, Haemaphysalis spinigera, and Haemaphysalis verticalis) reported previously were deleted; and one misidentified species Dermacentor auratus Supino was revised as Dermacentor steini Schulze. In addition, we divided the tick fauna in Jiangxi Province into 5 zoogeographic areas and assigned the 18 tick species collected from 26 localities to these 5 zoogeographic areas. To summarize, our findings provide valuable information on the distribution, tick-host associations, and zoogeographic division of ticks in Jiangxi Province, China. Their molecular characterizations, phylogenetic relationships, and tick-borne pathogens that they may transmit should be further explored.

Guggulsterone from Commiphora mukul potentiates anti-glioblastoma efficacy of temozolomide in vitro and in vivo via down-regulating EGFR/PI3K/Akt signaling and NF-κB activation.

ETHNOPHARMACOLOGICAL RELEVANCE: Myrrh is an aromatic oleo-gum resin extracted from the stem of Commiphora myrrha (Nees) Engl., and has the efficacies to promote blood circulation and remove blood stasis. Myrrh is mainly used for the treatment of chronic diseases including cancer. Guggulsterone, a major active steroid extracted from myrrh, has been found to inhibit cancer cell growth. Glioblastoma is the most common malignancy of central nervous system, and its prognosis remains very poor mainly due to chemotherapeutic resistance. The active status of EGFR/PI3K/Akt and NF-κB signaling in glioblastoma contributed to poor response for chemotherapy, and blocking this signaling with antagonists sensitized glioblastoma cells to chemotherapy. AIM OF THE STUDY: The present study will investigate whether guggulsterone potentiates the anti-glioblastoma efficacy of temozolomide by down-regulating EGFR/PI3K/Akt signaling and NF-κB activation. MATERIALS AND METHODS: Cell viability and proliferation was determined by cell counting Kit-8 and colony formation assays. Cell apoptosis was evaluated by Annexin V/PI and hoechst 33342 staining assays. Molecular techniques such as western blotting and real-time quantitative PCR were used to demonstrate guggulsterone in vitro effect on EGFR/PI3K/Akt signaling and NF-κB activation. Finally, in vivo studies were performed in orthotopic mouse models of glioblastoma. RESULTS: The results demonstrated that guggulsterone enhanced temozolomide-induced growth inhibition and apoptosis in human glioblastoma U251 and U87 cells. Furthermore, the synergistic anti-glioblastoma efficacy between guggulsterone and temozolomide was intimately associated with the inhibition of EGFR/PI3K/Akt signaling and NF-κB activation in U251 and U87 cells. Our in vivo results on orthotopic xenograft models similarly indicated that guggulsterone potentiated temozolomide-induced tumor growth inhibition through suppressing EGFR/PI3K/Akt signaling pathway and NF-кB activity. CONCLUSIONS: The present study suggested that guggulsterone potentiated anti-glioblastoma efficacy of temozolomide through down-regulating EGFR/PI3K/Akt signaling pathway and NF-кB activation.

The relationship between poor glycaemic control at different time points of gestational diabetes mellitus and pregnancy outcomes.

We aimed to identify the complications of gestational diabetes mellitus (GDM) associated with poor control of fasting plasma glucose (FPG) and postload plasma glucose (PPG) on the 75-g oral glucose tolerance test (OGTT). This retrospective study included 997 singleton pregnancy GDM patients who were assigned to poor or good glycaemic control groups. Multivariate analysis indicated that poor FPG control and poor PPG control were both independent predictors of hypertensive disorder complicating pregnancy (HDCP) (odd ratio (OR) of 2.551 (95% CI [1.146-5.682], p = .022) and OR of 2.084 (95% [1.115-3.894], p = .021) compared with good glycaemic control groups, respectively). Poor PPG control promoted the rate of caesarean delivery (1.534 (95% CI [1.063-2.214]), p = .022), whereas good PPG control increased the risk of premature rupture of membranes (PROM) (0.373 (95% CI [0.228-0.611]), p < .001). Conclusively, poor control FPG and PPG dissimilarly affect pregnancy complications in GDM; these findings may help clinicians in the effective implementation of measures to prevent pregnancy complications in GDM.IMPACT STATEMENTWhat is already known on this subject? Previous studies displayed that GDM patients with 2-h PPG elevated at 24-28 week of gestation had a 2.254-fold increased risk of postpartum dysglycaemia. Abnormal plasma glucose in GDM mother increased the probability of childhood obesity in the offspring. With the implementation of China's second-child policy, the incidence of GDM is rising.What do the results of this study add? Our results indicated that the older patients with GDM, the greater the risk of abnormal plasma glucose control. In addition, maternal age and prenatal BMI were notably correlated with poor plasma glucose control of FPG and PPG, respectively. We also found that both poor FPG and PPG control notably increased the incidence of HDCP in pregnant women. The incidence of PROM was higher in the good PPG control group compared with the poor PPG control group.What are the implications of these findings for clinical practice and/or further research? This study displayed that the effects of poor FPG and PPG control on pregnancy complications and newborn outcomes were heterogeneous, which might be related to the specificity of plasma glucose metabolism at different time points. Good glycaemic control, especially PPG control, was of great significance for improving pregnancy complications and perinatal conditions.

Tumor-stroma ratio as a new prognosticator for pseudomyxoma peritonei: a comprehensive clinicopathological and immunohistochemical study.

BACKGROUND: As a rare clinical tumor syndrome with an indolent clinical course and lack of pathognomonic symptoms, pseudomyxoma peritonei (PMP) is usually diagnosed at an advanced stage. In-depth pathological analysis is essential to assess tumor biological behaviors, assist treatment decision, and predict the clinical prognosis of PMP. The tumor-stroma ratio (TSR) is a promising prognostic parameter based on the tumor and stroma. This study explored the relationship between TSR and the pathological characteristics and prognosis of PMP. METHODS: PMP patients with complete data who underwent cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy were enrolled. The TSR of postoperative pathological images was quantitatively analyzed by Image-Pro Plus. Then the relationship between TSR and the clinicopathological characteristics, immunohistochemical characteristics and prognosis of PMP was analyzed. RESULTS: Among the 50 PMP patients included, there were 27 males (54.0%) and 23 females (46.0%), with a median age of 55 (range: 31-76) years. 25 (50.0%) patients were diagnosed with low-grade PMP (LG-PMP), and 25 (50.0%) were diagnosed with high-grade PMP (HG-PMP). There were 4 (8.0%) patients with vascular tumor emboli, 3 (6.0%) patients with nerve invasion, and 5 (10.0%) patients with lymph node metastasis. The immunohistochemical results showed that the Ki67 label index was < 25% in 18 cases (36.0%), 25 - 50% in 18 cases (36.0%) and > 50% in 14 cases (28.0%). The range of TSR was 2 - 24% (median: 8%). The cutoff value of TSR was 10% based on the receiver operating characteristic (ROC) curve and X-Tile analysis. There were 31 (62.0%) cases with TSR < 10% and 19 (38.0%) cases with TSR ≥ 10%. The TSR was closely related to histopathological type (P < 0.001) and Ki67 label index (P < 0.001). Univariate analysis showed that preoperative carcinoembryonic antigen (CEA), preoperative carbohydrate antigen 19-9, pathological type, vascular tumor emboli and TSR influenced the prognosis of PMP patients (P < 0.05). Multivariate analysis showed that preoperative CEA, vascular tumor emboli and the TSR were independent prognostic factors. CONCLUSIONS: The TSR could be a new independent prognosticator for PMP.

Pseudomyxoma peritonei originating from intestinal duplication: A case report and review of the literature.

BACKGROUND: Pseudomyxoma peritonei (PMP) is a rare mucinous neoplasm with a relatively low incidence of 1 to 2 per million individuals. It is typically characterized by a type of gelatinous ascites named "jelly belly". Most cases of PMP occur in association with ruptured primary mucinous tumors of the appendix (90%). Periodically, PMP can originate from mucinous carcinomas at other sites, including the colorectum, gallbladder, and pancreas. However, unusual origin can occur, as noted in this case report. CASE SUMMARY: A 52-year-old woman had an unusual derivation of PMP from intestinal duplication. The patient complained of abdominal distension and increasing abdominal girth. Abdominal contrast-enhanced computed tomography showed a mass in the greater omentum located on the left side of the abdomen, likely to be a cystic mass of peritoneal origin. A PMP diagnosis was presumed based on the specific signs of the mass with flocculent and stripe-like echoes in ultrasound images. Ultrasound-guided percutaneous aspiration suggested a high likelihood of PMP. Once the PMP diagnosis was recognized, identification of the origin of the primary tumor was indicated. Thus, an exploratory laparoscopy was performed. In the absence of a primary tumor of appendix origin, the diagnosis of a low-grade mucinous neoplasm of intestinal duplication origin was finally confirmed by histopathology. CONCLUSION: PMP is secondary to mucinous carcinomas of the appendix mostly. This case resulted from an unusual derivation from intestinal duplication.

[Preparation of Sulfidated Copper-Iron Bimetallic Composited Material and Its Mechanism for Chromium Removal].

Sulfidated copper-iron bimetallic particles (S-Fe-Cu) were prepared by sulfidation of copper-iron bimetallic particles (Fe-Cu) obtained by the replacement reaction in the liquid phase. The influencing factors of S-Fe-Cu in removing Cr(Ⅵ) in water were determined. BET, SEM-EDX, and XPS were used to analyze the superficial structure and mineralogy of S-Fe-Cu. Combined with batch experiments, the mechanisms of Cr removal were analyzed. The results showed that FeSx was successfully loaded on the surface of S-Fe-Cu, and the optimum S/Fe molar ratio and Cu/Fe mass ratio in theory were 0.056 and 0.025, respectively. Compared with Fe-Cu, the specific surface area of S-Fe-Cu increased by 2.1 times, and the Cr removal efficiency increased by 6.1 times under a pH of 5. A high Cr removal efficiency was maintained under alkaline conditions. Meanwhile, chloride ions could penetrate the passivation layer of iron-based material, which was beneficial to the direct oxidation of Fe0 to produce Fe(Ⅱ) and advance the performance of S-Fe-Cu for Cr removal. The XPS results showed that the removal mechanism of Cr(Ⅵ) in water included adsorption, reduction, and coprecipitation.

Effects of grazing intensities on functional traits of Cleistogenes squarrosa in a typical grassland of Inner Mongolia, China.

We examined the response of 11 functional traits of Cleistogenes squarrosa, including plant height and clump width, to the grazing of different intensity (no grazing; twice grazing in May and July; five grazing in the whole growing season). After five-year treatments, the number of reproductive branches, plant height, stem quality, specific leaf area and total leaf area were significantly reduced. Such reduction was significantly increased with the increases of grazing intensity. Under the treatments of grazing in May and July, the declines of each index were 61.7%, 21.5%, 33.3%, 21.6% and 26.7%, respectively; and the declines in the treatment of whole growing season grazing were 75.7%, 24.7%, 46.7%, 28.5% and 43.7%, respectively. The number of vegetative branches, number of leaf, total leaf area, stem quality, total leaf quality and clump width of the C. squarrosa had a synergistic relationship with aboveground biomass of the whole clump under different grazing intensities. The number of vegetative branches was significantly positively correlated with stem quality and total leaf quality. C. squarrosa had a dwarf-dense branching strategy to avoid grazing. The reduction of grazing intensity would be conducive to maintaining the stability of functional traits.

[Bayesian network Meta-analysis of Chinese medicine injections in treatment of chronic renal insufficiency].

In this study, Honghua Injection, Danshen Injection, Shenkang Injection, Shuxuetong Injection, Lulutong Injection, Shenxiong Glucose Injection and Chuanxiong Injection were compared for their clinical efficacy on chronic renal insufficiency by using the method of network Meta-analysis, with Western medicine as the common reference. The randomized controlled trial(RCT) of Hong-hua Injection, Danshen Injection, Shenkang Injection, Shuxuetong Injection, Lulutong Injection, Shenxiong Glucose Injection and Chuanxiong Injection for the treatment of chronic renal insufficiency were obtained by computer-based retrieval. The literature quality was evaluated by using the method in Cochrane Reviewer's Handbook 5.1 after independent screening of the included literature by two reviewers. The RJAGS package and GEMTC package of RevMan 5.3, GEMTC software, R software were used for statistical analysis to compare and sort the different injections in terms of efficacy. A total of 6 197 patients with chronic renal failure were included in 79 RCTs, involving 8 treatment measures. The effective rates of conventional treatment combined with Shenxiong Injection(OR=3.55, 95%CI[1.98, 6.37], P<0.000 1), Honghua Injection(OR=3.77, 95%CI[2.45, 5.81], P<0.000 01), Shuxuetong Injection(OR=6.71, 95%CI[3.30, 13.65], P<0.000 01) and Shenkang Injection(OR=4.14, 95%CI[3.42, 5.03], P<0.000 01) were all better than that in control group, and the effective rate of Honghua Injection combined with conventional treatment(OR=3.89, 95%CI[1.73, 8.74], P=0.001) was better than that in Danshen Injection combined with conventional treatment, all with statistically significant differences. By comprehensive comparison, Shuxuetong Injection, Honghua Injection and Shenkang Injection combined with Western medicine had good clinical effect on the effective rate, serum creatinine reduction and urea nitrogen reduction in patients with chronic renal insufficiency. However, due to the relatively low quality of the included literature, the conclusion has yet to be verified clinically.

Consensuses and controversies on pseudomyxoma peritonei: a review of the published consensus statements and guidelines.

BACKGROUND: Pseudomyxoma peritonei (PMP) is a clinical malignant syndrome mainly originating from the appendix, with an incidence of 2-4 per million people. As a rare disease, an early and accurate diagnosis of PMP is difficult. It was not until the 1980s that the systematic study of this disease was started. MAIN BODY: As a result of clinical and basic research progress over the last 4 decades, a comprehensive strategy based on cytoreductive surgery (CRS) + hyperthermic intraperitoneal chemotherapy (HIPEC) has been established and proved to be an effective treatment for PMP. Currently, CRS + HIPEC was recommended as the standard treatment for PMP worldwide. There are several consensuses on PMP management, playing an important role in the standardization of CRS + HIPEC. However, controversies exist among consensuses published worldwide. A systematic evaluation of PMP consensuses helps not only to standardize PMP treatment but also to identify existing controversies and point to possible solutions in the future. The controversy underlying the consensus and vice versa promotes the continuous refinement and updating of consensuses and continue to improve PMP management through a gradual and continuous process. In this traditional narrative review, we systemically evaluated the consensuses published by major national and international academic organizations, aiming to get a timely update on the treatment strategies of CRS + HIPEC on PMP. CONCLUSION: Currently, consensuses have been reached on the following aspects: pathological classification, terminology, preoperative evaluation, eligibility for surgical treatment, maximal tumor debulking, CRS technical details, and severe adverse event classification system. However, controversies still exist regarding the HIPEC regimen, systemic chemotherapy, and early postoperative intraperitoneal chemotherapy.

Direct growth of m-BiVO4@carbon fibers for highly efficient and recyclable photocatalytic and antibacterial applications.

Owing to photocatalytic and antibacterial properties, bismuth based oxides has drawn much attention in recent past. However, non-recyclability of these oxides has restricted their practical applications. In present work, a novel nanostructured composite monoclinic bismuth vanadate@ activated carbon fibers (BiVO4@ACF) photocatalyst was efficaciously synthesized using a solvothermal method and characterized by X-ray diffraction (XRD), scanning electron microscope (SEM) and Bruner-Emmett-Teller (BET). The specific surface area, phase composition, microstructure, binding and photocatalytic activity of BiVO4@ACF pose great dependence on solvent nature and chelating agents utilized for synthesis. The photocatalytic and antibacterial potential of this composite was evaluated and optimized by using a model pollutant, Reactive Rhodamine Blue (RhB) and pathogenic microbes (Escherichia coli and Staphylococcus aureus). The composite possesses enhanced photocatalytic and antibacterial activity and was reutilized for three rounds of respective reaction without any loss of activity and structure as evident from SEM and XRD results. The photocatalytic mechanism of photodegradation of dye and bactericidal properties of samples under visible light irradiation was determined by scavenger and photoluminescence (PL) spectroscopy. The enhanced photocatalytic and antibacterial activity, chemical stability and most importantly good recyclability of BiVO4@ACFs highlight the potential application of this composite in water purification and other biological applications.

Xihuang pill potentiates the anti-tumor effects of temozolomide in glioblastoma xenografts through the Akt/mTOR-dependent pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Xihuang pill, as a famous traditional Chinese medicine formula, is used for tumor treatment in China. The anti-tumor activities and mechanisms of Xihuang pill still remain unclear. AIM OF THE STUDY: The Akt/mTOR signaling pathway plays an important role in mediating cell proliferation and apoptosis in glioblastoma. This study aimed to investigate whether Xihuang pill could potentiate temozolomide-induced apoptosis of glioblastoma U87 and U251 cells in vivo and its underlying mechanisms related to Akt/mTOR pathway. MATERIALS AND METHODS: Human glioblastoma U87 and U251 xenograft models were established. Immunocytochemistry and Western blot were performed to evaluate the anti-proliferative effect, apoptosis and Akt/mTOR signaling mediators. RESULTS: The results showed that Xihuang pill (0.5, 1 g/kg) or temozolomide (10 mg/kg) treatment alone inhibited tumor growth in glioblastoma U87 and U251 xenografts. When Xihuang pill (1 g/kg) and temozolomide (10 mg/kg) were co-administrated, the activities of antitumor growth were markedly increased. Meanwhile, Xihuang pill (0.5, 1 g/kg) or temozolomide (10 mg/kg) treatment alone decreased the levels of Ki67 and PCNA expression in glioblastoma U87 and U251 xenografts. In combination treatment group, the inhibitory effects on Ki67 and PCNA expression were significantly enhanced in glioblastoma U87 and U251 xenografts compared to temozolomide treatment alone. Examining the apoptotic index by TUNEL assay showed similar results. Furthermore, Xihuang pill markedly down-regulated the Bcl-2/Bax ratio and inhibited the activation of Akt/mTOR pathway in glioblastoma U87 and U251 xenografts. In addition, no significant signs of toxicities were related to Xihuang pill and/or temozolomide treatment. CONCLUSIONS: The present study suggested that Xihuang pill might potentiate temozolomide-induced apoptosis of glioblastoma cells in vivo through inhibiting Akt/mTOR-dependent pathway.

Ginsenoside Rh3 activates Nrf2 signaling and protects endometrial cells from oxygen and glucose deprivation-reoxygenation.

Oxygen and glucose deprivation (OGD)-reoxygenation (OGDR) induces oxidative injury to endometrial cells in vitro. We tested the potential effect of ginsenoside Rh3 (GRh3) in the process. Our results show that GRh3 activated Nrf2 signaling in T-HESC cells and primary murine endometrial cells. GRh3 induced Nrf2 Ser-40 phosphorylation and Keap1-Nrf2 disassociation, causing Nrf2 protein stabilization and nuclear translocation, which led to transcription and expression of antioxidant response element-dependent genes (HO1, NQO1 and GCLC). In T-HESC cells and primary murine endometrial cells, GRh3 potently attenuated OGDR-induced reactive oxygen species production, lipid peroxidation and mitochondrial depolarization, as well as cell viability reduction and necrosis. Activation of Nrf2 is required for GRh3-induced anti-OGDR actions in endometrial cells. Nrf2 inhibition, by Nrf2 shRNA, knockout (through CRISPR-Cas9-editing) or S40T mutation, abolished GRh3-induced endometrial cell protection against OGDR. Additionally, forced activation of Nrf2, by Keap1 knockout, mimicked and nullified GRh3-induced anti-OGDR actions in T-HESC cells. Together, we conclude that GRh3 protects endometrial cells from OGDR via activation of Nrf2 signaling.

Keap1-targeting microRNA-941 protects endometrial cells from oxygen and glucose deprivation-re-oxygenation via activation of Nrf2 signaling.

BACKGROUND: Mimicking ischemia-reperfusion injury, oxygen and glucose deprivation (OGD)-re-oxygenation (OGDR) applied to endometrial cells produces significant oxidative stress and programmed necrosis, which can be inhibited by nuclear-factor-E2-related factor 2 (Nrf2) signaling. MicroRNA (miRNA)-induced repression of Keap1, a Nrf2 suppressor protein that facilitates Nrf2 degradation, is novel strategy to activate Nrf2 cascade. METHODS: MicroRNA-941 (miR-941) was exogenously expressed in HESC and primary human endometrial cells, and the Nrf2 pathway examined by Western blotting and real-time quantitative PCR analysis. The endometrial cells were treated with OGDR, cell programmed necrosis and apoptosis were tested. RESULTS: MiR-941 is a novel Keap1-targeting miRNA that regulates Nrf2 activity. In T-HESC cells and primary human endometrial cells, ectopic overexpression of miR-941 suppressed Keap1 3'-UTR (untranslated region) expression and downregulated its mRNA/protein expression, leading to activation of the Nrf2 cascade. Conversely, inhibition of miR-941 elevated Keap1 expression and activity in endometrial cells, resulting in suppression of Nrf2 activation. MiR-941 overexpression in endometrial cells attenuated OGDR-induced oxidative stress and programmed necrosis, whereas miR-941 inhibition enhanced oxidative stress and programmed necrosis. MiR-941 overexpression and inhibition were completely ineffective in Keap1-/Nrf2-KO T-HESC cells (using CRISPR/Cas9 strategy). Restoring Keap1 expression, using an UTR-depleted Keap1 construct, abolished miR-941-induced anti-OGDR activity in T-HESC cells. Thus Keap1-Nrf2 cascade activation is required for miR-941-induced endometrial cell protection. CONCLUSIONS: Targeting Keap1 by miR-941 activates Nrf2 cascade to protect human endometrial cells from OGDR-induced oxidative stress and programmed necrosis. Video Abstract.

Z-guggulsterone regulates MDR1 expression mainly through the pregnane X receptor-dependent manner in human brain microvessel endothelial cells.

Recently studies showed that pregnane X receptor (PXR) was expressed in human brain microvessel endothelial cells and coordinately induced multidrug resistance protein 1 (MDR1) expression. The present study aimed to investigate the regulatory effect of Z-guggulsterone on MDR1 in human brain microvessel endothelial cells, and explored whether it involved modulation of PXR. The results showed that Z-guggulsterone (30 µM) simultaneously inhibited the expression of PXR and MDR1 at 24 h in human brain-derived microvessel endothelial cells (hBDMECs). Meanwhile, the levels of PXR and MDR1 expression were simultaneously reduced in PXR siRNA-transfected hBDMECs; MDR-1 siRNA-transfected hBDMECs showed significant decrease in MDR1 expression, but no change in PXR expression. Furthermore, Z-guggulsterone inhibited the activation of PXR in hBDMECs through decreasing the release of cAMP/PKA. Z-guggulsterone reduced the co-activator SRC-1 expression in hBDMECs, as to prevent the activation of MDR1 gene transcription. In addition, Z-guggulsterone (30 µM) at 24 h significantly inhibited the expression of human constitutive androstane receptor (CAR) protein in hBDMECs. However, after treatment with Z-guggulsterone (≤30 µM), the level of MDR1 reporter gene activity was lower in human PXR-transfected cells than that in human CAR-transfected cells. The inhibition effect of Z-guggulsterones on MDR1 reporter gene activation was gradually enhanced with the increase of human PXR to CAR ratio, which was greater extent than that with the increase of human CAR to hPXR ratio. The present study suggested that Z-guggulsterone down-regulating the efflux function and expression of MDR1 in hBDMECs might be mainly through the PXR-dependent manner.