CST2 promotes cell proliferation and regulates cell cycle by activating Wnt-ß-catenin signalling pathway in serous ovarian cancer.

BACKGROUND: Cystatin SA (CST2) plays multiple roles in different types of malignant tumours; however, its role in serous ovarian cancer (SOC) remains unclear. Therefore, we aimed to investigate the expression levels, survival outcomes, immune cell infiltration, proliferation, cell cycle, and underlying molecular mechanisms associated with the CST2 signature in SOC. METHODS: The Cancer Genome Atlas database was used to acquire clinical information and CST2 expression profiles from patients with SOC. Wilcoxon rank-sum tests were used to compare CST2 expression levels between SOC and normal ovarian tissues. A prognostic assessment of CST2 was conducted using Cox regression analysis and the Kaplan-Meier method. Differentially expressed genes were identified using functional enrichment analysis. Immune cell infiltration was examined using a single-sample gene set enrichment analysis. Cell cycle characteristics and proliferation were assessed using a colony formation assay, flow cytometry, and a cell counting kit-8 assay. Western blots and quantitative reverse transcription PCR analyses were employed to examine CST2 expressions and related genes involved in the cell cycle and the Wnt-ß-catenin signalling pathway. RESULTS: Our findings revealed significant upregulation of CST2 in SOC, and elevated CST2 expression was correlated with advanced clinicopathological characteristics and unfavourable prognoses. Pathway enrichment analysis highlighted the association between the cell cycle and the Wnt signalling pathway. Moreover, increased CST2 levels were positively correlated with immune cell infiltration. Functionally, CST2 played vital roles in promoting cell proliferation, orchestrating the G1-to-S phase transition, and driving malignant SOC progression through activating the Wnt-ß-catenin signalling pathway. CONCLUSIONS: The elevated expression of CST2 may be related to the occurrence and progression of SOC by activating the Wnt-ß-catenin pathway. Additionally, our findings suggest that CST2 is a promising novel biomarker with potential applications in therapeutic, prognostic, and diagnostic strategies for SOC.

Serous ovarian cancer is a type of gynecological malignant tumour with high mortality rates. Understanding this disease is crucial for improving treatments and enhancing patient survival. In our study, we investigated a protein called CST2 and its role in serous ovarian cancer. We found that CST2 levels vary among patients and are associated with the progression of cancer and the prognosis of the patient, which could be valuable for future diagnosis and treatment strategies. However, further research is needed to validate these findings. Despite its limitations, our findings suggest that CST2 holds promise as a potential biomarker for detecting serous ovarian cancer and as a therapeutic target in the management of patients with this type of cancer.

Associations between dietary habits and bipolar disorder: a diet-wide mendelian randomization study.

Background: Diet/nutrition is critically important in the pathogenesis, progression, and treatment outcomes of various mental disorders. Current research predominantly focuses on the role of diet in the development and treatment of depression, with less attention given to the relationship between diet and Bipolar Disorder (BD). Method: We employed Mendelian Randomization (MR) to investigate the relationship between 28 dietary habits and BD. An analysis was conducted using publicly available genome-wide association study data from the UK Biobank dataset. Various dietary habits were analyzed as exposures with BD as the outcome, mainly using the Inverse Variance Weighted (IVW) method. Results: Intake of non-oily fish and sponge pudding both have a positive association with BD. Oily fish, dried fruit, apples, salt, and cooked vegetables intake also appeared potentially risky for BD, although the possibility of false positives cannot be ruled out. Sensitivity analysis further confirmed the robustness of these findings. Conclusion: Our research provides evidence of a relationship between various dietary habits and BD. It underscores the need for careful dietary management and balance to reduce the risk of BD, suggesting caution with dietary preferences for fish and sponge pudding. Furthermore, more detailed studies are needed to further understand the potential impacts of high-sugar and high-protein diets on BD development.

Seasonal patterns in Chinese population: Validating the seasonal pattern assessment questionnaire and exploring associations with psychiatric diagnoses and biological rhythms.

Seasonal patterns (SP) exert a notable influence on the course and prognosis of patients with affective disorders, serving as a specifier in diagnosis. However, there is limited exploration of seasonality among psychotic patients, and the distinctions in seasonality among psychiatric patients remain unclear. In this study, we enrolled 198 psychiatric patients with anxiety and depressive disorders (A&D), bipolar disorder (BD), and schizophrenia (SZ), as well as healthy college students. Online questionnaires, including the Seasonal Pattern Assessment Questionnaire (SPAQ) for seasonality, the Morningness and Eveningness Questionnaire-5 (MEQ-5) for chronotypes, and the Pittsburgh Sleep Quality Index (PSQI), were administered. The validity and reliability of the Chinese version of the SPAQ were thoroughly analyzed, revealing a Cronbach's alpha of 0.896 with a two-factor structure. Results indicated that higher seasonality was correlated with poorer sleep quality and a more delayed chronotype (p < 0.05). Significant monthly variations were particularly evident in BD, specifically in mood, appetite, weight, social activities, and sleep dimensions (p < 0.001). In summary, the Chinese version of SPAQ is validated, demonstrating moderate correlations between seasonality, chronotype, and sleep quality. BD patients exhibited the strongest seasonality, while mood disorder patients displayed more delayed chronotypes than SZ.

Associations between ADHD and risk of six psychiatric disorders: a Mendelian randomization study.

BACKGROUND: Observational studies and diagnostic criteria have indicated that Attention Deficit Hyperactivity Disorder (ADHD) frequently comorbid with various psychiatric disorders. Therefore, we conducted a Mendelian randomization (MR) study to explore this potential genetic association between ADHD and six psychiatric disorders. METHODS: Using a two-sample Mendelian randomization (MR) design, this study systematically screened genetic instrumental variables (IVs) based on the genome-wide association studies (GWAS) of ADHD and six psychiatric disorders, with the inverse variance weighted (IVW) method as the primary approach. RESULTS: The study revealed a positive and causal association between ADHD and the risk of ASD, with an odds ratio (OR) of 2.328 (95%CI: 1.241-4.368) in the IVW MR analysis. Additionally, ADHD showed a positive causal effect on an increased risk of schizophrenia, with an OR of 1.867 (95%CI: 1.260-2.767) in the IVW MR analysis. However, no causal effect of Tic disorder, Mental retardation, Mood disorders and Anxiety disorder with ADHD was found in the analysis mentioned above. CONCLUSION: Our MR analysis provides robust evidence of the causal role of ADHD in increasing the risk of ASD and schizophrenia. However, ADHD is not associated with the risk of Tic Disorder, Mental Retardation, Mood Disorders and Anxiety Disorder. This suggests the need for increased attention to the co-occurrence of ADHD-ASD or ADHD-schizophrenia and the implementation of timely intervention and treatment.

Immune checkpoint inhibitors enhanced the antitumor efficacy of disitamab vedotin for patients with HER2-positive or HER2-low advanced or metastatic gastric cancer: a multicenter real-world study.

BACKGROUND: Novel ADC drugs provide a new therapeutic strategy for gastric cancer.The present study aimed to analyze the clinical efficacy and drug toxicities of disitamab vedotin (RC48) plus immune checkpoint inhibitors(ICIs) and RC48 as third-line therapies and beyond for advanced and metastatic gastric cancer patients. METHODS: This was an observational multicenter real-world study.From August 2021 to January 2022,patients with HER2-positive or HER2-low advanced and metastatic gastric cancer and failed from two or more lines of prior therapy were enrolled and treated with RC48 plus ICIs or RC48. In this study, progression free survival(PFS) was the primary end point. Other evaluation indicators were objective response rate(ORR),disease control rate(DCR),overall survival(OS) and drug toxicities. RESULTS: 45 patients were enrolled,of which 25 patients received RC48 plus ICIs,20 patients received RC48.Patients who received RC48 plus ICIs obtained better ORR (36.0% vs. 10.0%, P = 0.044) and DCR (80.0% vs. 50.0%, P = 0.034) compared with RC48,and simultaneously,the median PFS in RC48 plus ICIs group were superior to RC48 group(6.2 m vs. 3.9 m).The median OS was not reached.No statistically differences were found between HER2-positive and HER2-low group with respect to ORR (27.3% vs. 16.7%, P = 0.464),DCR (66.7% vs. 66.7%, P = 1.000),median PFS(5.7 m vs. 4.3 m, P = 0.299).The most common adverse events (AEs) were decreased white blood count,decreased neutrophil count,fatigue,hypoaesthesia and alopecia.Grade 3-4 AEs occurred in 7(35.0%) patients of RC48 group and 10(40.0%) patients of RC48 plus ICIs group,respectively. CONCLUSION: Compared with RC48 monotherapy, ICIs plus RC48 demonstrated superior third-line and beyond therapeutic efficacy for HER2-positive or HER2-low advanced and metastatic gastric cancer patients with manageable safety.

Real-world effectiveness and safety of RC48-ADC alone or in combination with PD-1 inhibitors for patients with locally advanced or metastatic urothelial carcinoma: A multicenter, retrospective clinical study.

INTRODUCTION: Previous RC48 (Disitamab Vedotin) studies established that the safety and efficacy of RC48-antibody-drug conjugate (ADC), either alone or combined with toripalimab, for metastatic urothelial carcinoma (mUC) patients exhibiting human epidermal growth factor receptor 2 (HER2)-positive or even HER2-negative status after standard chemotherapy failure. METHODS: With locally advanced or metastatic urothelial carcinoma (la/mUC), patients who received RC48-ADC monotherapy or a combination with programmed cell death protein 1 (PD-1) inhibitors between August 2021 and October 2022 were enrolled in this retrospective observational study to evaluate the real-world antitumor effectiveness and safety. RESULTS: Among the 38 enrolled patients (29 males; median age 67.5 years [38-93]), 8 received RC48-ADC monotherapy, while 30 received combination therapy. Initially, 63.2% (24/38) of the patients had received ≥1 line of prior treatment, and 63.2% (24/38) had visceral metastasis. UC of the bladder represented the majority type in 68.4% (26/38) of cases. By the data cutoff in March 2023, the overall objective response rate (ORR) was 63.2% (95% CI, 47.1%-79.2%), with a disease control rate (DCR) of 89.5% (95% CI, 79.3%-99.7%). Median follow-up time was 10.6 months. The median progression-free survival (PFS) was 8.2 months (95% CI, 5.9-10.5), with a 6-month PFS rate of 63.2% and a 12-month PFS rate of 34.1%. Median overall survival (OS) was not reached, with a 12-month OS rate of 76.7%. The median duration of response was 7.3 months (95% CI, 4.6-10.0) among 24 patients evaluated as partial response (PR). The most common treatment-related adverse events (TRAEs) included anemia (71.1%), anorexia (57.9%), asthenia (52.6%), hypoesthesia (52.6%), bone marrow suppression (47.4%), alopecia (47.4%), nausea (44.7%), proteinuria (36.8%), vomiting (34.2%), and hypoalbuminemia (31.6%). No patient experienced TRAEs of Grade ≥3. One patient had an immune-related adverse event (irAE) of rash related to toripalimab. CONCLUSIONS: Both as monotherapy and in combination with PD-1 inhibitors, RC48-ADC exhibits promising effectiveness and manageable safety profile for mUC patients in real-world settings.

Ginsenoside Rg1/ADSCs supplemented with hyaluronic acid as the matrix improves rabbit temporomandibular joint osteoarthrosis.

OBJECTIVE: To investigate whether and how ginsenoside Rg1/ADSCs supplemented with hyaluronic acid as the matrix can improve rabbit temporomandibular joint osteoarthrosis. METHOD: Isolate and culture adipose stem cells, measure the activity of differentiated chondrocytes by MTT assay and expression of type II collagen in these cells by immunohistochemistry, in order to evaluate the effect of ginsenoside Rg1 on adipose stem cell proliferation and differentiation into chondrocytes.32 New Zealand white rabbits were randomly divided into four groups: blank group, model group, control group and experimental group, 8 in each group. Osteoarthritis model was established by intra-articular injection of papain. Two weeks after successful model building, medication was given for the rabbits in control group and experimental group. 0.6 mL ginsenoside Rg1/ ADSCs suspension was injected into superior joint space for the rabbits in control group, once a week; 0.6 mL ginsenoside Rg1/ ADSCs complex was injected for the rabbits in experimental group, once a week. RESULTS: Ginsenoside Rg1 can promote ADSCs-derived chondrocytes' activity and expression of type II collagen. Scanning electron microscopy histology images showed cartilage lesions of the experimental group was significantly improved in comparison with control group. CONCLUSION: Ginsenoside Rg1 can promote ADSCs differentiate into chondrocytes, and Ginsenoside Rg1/ADSCs supplemented with hyaluronic acid as the matrix can significantly improve rabbit temporomandibular joint osteoarthrosis.

The correlation between blood-lipid ratio in the first trimester and large-for-gestational-age infants.

BACKGROUND: To investigate the correlation between maternal glucose and lipid metabolism indexes and blood-lipid ratio in the first trimester and large-for- gestational-age (LGA) infants. METHODS: Women in the first trimester of pregnancy who underwent regular obstetric examination in the obstetric outpatient department of the Affiliated Hospital of Chengde Medical College from June 2018 to March 2019 were included according to the standard. Basic information were collected based on questionnaires at the first visit of pregnant women, including early fasting blood glucose (FBG), fasting insulin (FINS), glycated hemoglobin (HbA1c), high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglyceride (TG), total cholesterol (TC), apolipoprotein A1 (APO-A1), apolipoprotein B (APO-B), lipoprotein a (LP(a)), LDL/HDL, TG/HDL, TC/HDL, APO-B/APO-A1 ratio, birth weight of newborns, gestational age at delivery etc. RESULTS: A total of 418 cases were included for analysis. The incidence rate of LGA infants was 13.88%, and that of small-for-gestational-age (SGA) infants was 4.78%. Univariate analysis revealed that the age, pre-pregnancy body mass index (BMI), weight gain during pregnancy, APO-B/APO-A1 between LGA group and appropriate-for-gestational-age (AGA) group were significantly different (P < 0.05); multivariate stepwise logistic regression analysis indicated that the correlation between maternal age, pre-pregnancy BMI, weight gain during pregnancy, APO-B/APO-A1 level and LGA were statistically significant (P < 0.05); compared with the reference range of APO-B/APO-A1 of 0.46-0.65, values < 0.46 and > 0.65 were protective factor of LGA (P < 0.05). The receiver operating curve(ROC) indicated that the area under the curve (AUC)s for predicting LGA using maternal age, pre-pregnancy BMI, weight gain during pregnancy, and early pregnancy APO-B/APO-A1 were 0.585, 0.606, 0.637, 0.531, respectively. The AUC for a combined prediction model was 0.742, showing greater predictive value than any other factors individually. CONCLUSION: Maternal age, pre-pregnancy BMI, weight gain during pregnancy, and APO-B/APO-A1 levels in first trimester are significant factors influencing the occurrence of LGA infants, and the combination of the four factors would have certain predictive value for LGA.

Identification of the cuproptosis-related molecular subtypes and an immunotherapy prognostic model in hepatocellular carcinoma.

BACKGROUND: Cuproptosis, a newly discovered mode of cell death, has been less studied in hepatocellular carcinoma (HCC). Exploring the molecular characteristics of different subtypes of HCC based on cuproptosis-related genes (CRGs) is meaningful to HCC. In addition, immunotherapy plays a pivotal role in treating HCC. Exploring the sensitivity of immunotherapy and building predictive models are critical for HCC. METHODS: The 357 HCC samples from the TCGA database were classified into three subtypes, Cluster 1, Cluster 2, and Cluster 3, based on the expression levels of ten CRGs genes using consensus clustering. Six machine learning algorithms were used to build models that identified the three subtypes. The molecular features of the three subtypes were analyzed and compared from some perspectives. Moreover, based on the differentially expressed genes (DEGs) between Cluster 1 and Cluster 3, a prognostic scoring model was constructed using LASSO regression and Cox regression, and the scoring model was used to predict the efficacy of immunotherapy in the IMvigor210 cohort. RESULTS: Cluster 3 had the worst overall survival compared to Cluster 1 and Cluster 2 (P = 0.0048). The AUC of the Catboost model used to identify Cluster 3 was 0.959. Cluster 3 was significantly different from the other two subtypes in gene mutation, tumor mutation burden, tumor microenvironment, the expression of immune checkpoint inhibitor genes and N6-methyladenosine regulatory genes, and the sensitivity to sorafenib. We believe Cluster 3 is more sensitive to immunotherapy from the above analysis results. Therefore, based on the DEGs between Cluster 1 and Cluster 3, we obtained a 7-gene scoring prognostic model, which achieved meaningful results in predicting immunotherapy efficacy in the IMvigor210 cohort (P = 0.013). CONCLUSIONS: Our study provides new ideas for molecular characterization and immunotherapy of HCC from machine learning and bioinformatics. Moreover, we successfully constructed a prognostic model of immunotherapy.

Identification and exploration of the pyroptosis-related molecular subtypes of breast cancer by bioinformatics and machine learning.

OBJECTIVES: To classify breast cancer (BRCA) according to the expression of pyroptosis-related genes and explore their molecular characteristics. METHODS: Nonnegative matrix factorization (NMF) was used for subtype classification based on 21 pyroptosis-related genes in the TCGA database. Survival analysis and t-distributed stochastic neighbor embedding (t-SNE) analysis were conducted to assess the NMF results' performance. XGBoost, CatBoost, logistic regression, neural network, random forest, and support vector machine were utilized to perform supervised machine learning and construct prediction models. Genetic mutations, tumor mutational burden, immune infiltration, methylation, and drug sensitivity were analyzed to explore the molecular signatures of different subtypes. Lasso, RF, and Cox regression were operated to construct a prognostic model based on differentially expressed genes. RESULTS: BRCA patients were divided into two subtypes (named Cluster1 and Cluster2). Survival analysis (P = 0.02) and t-SNE analysis demonstrated that Cluster1 and Cluster2 were well classified. The XGBoost model achieved reliable predictions on both training and validation sets. Regarding molecular characteristics, Cluster1 had higher TMB, immune cell infiltration, and m6A methylation-related gene expression than Cluster2. There was also a statistically significant difference between the two subtypes concerning drug susceptibility. Finally, a 5-gene prognostic model was constructed using Lasso, RF, and Cox regression and validated in the GEO database. CONCLUSION: Our study may provide new insights from bioinformatics and machine learning for exploring pyroptosis-related subtypes and their respective molecular signatures in BRCA. In addition, our models may be helpful for the treatment and prognosis of BRCA.

Utilization of 3D Laser Scanning for Stability Evaluation and Deformation Monitoring of Landslides.

Three-dimensional laser scanning technology can comprehensively and accurately monitor slope deformation. To conduct deformation monitoring and stability evaluation of the Changzhou Shunguoshan landslide, in this paper, the causes of the Changzhou Shunguoshan landslide were analyzed. Consequently, 3D laser scanning technology and the traditional monitoring methods such as data from the total station were compared. The point cloud data provides big data support for landslide deformation monitoring and landslide stability early warning. Meanwhile, the landslide stability was evaluated by analogy with existing studies on slope deformation monitoring data. Results show that the three-dimensional laser scanning monitoring data is similar to the total station monitoring data. The overall deformation of the Shunguoshan landslide is no more than ± 0.0015 m; the deformation of the Liyang slope is less than ±0.09 m, which is far less than the analog slope deformation monitoring data. The slope construction and monitoring process are in a stable state.

Pharmacokinetic study of deufruquintinibs in rats by HPLC-MS/MS after oral administration.

A sensitive and specific high-performance liquid chromatography-tandem mass spectrometry method was established to quantitatively determine the pharmacokinetics of fruquintinib (HMPL-013) and its derivatives [deufruquintinib-3D (HMPL-013-3D), deufruquintinib-6D (HMPL-013-6D) and deufruquintinib-9D (HMPL-013-9D)] in rats. Detection was performed on a triple quadrupole mass spectrometer in multiple reaction monitoring mode. The method established in this assay was successfully applied to a pharmacokinetic study of HMPL-013 and HMPL-013-Ds after oral administration. These results showed that HMPL-013-Ds had longer half-life and larger area under the plasma concentration-time curve than HMPL-013, especially HMPL-013-6D, which provides a significant basis for innovative ideas for drug structure transformation to reduce drug administration frequency and dosage.

Effect Mechanism of Electroacupuncture at ST36 on the Injured Extensor Digitorum Longus in the Jumping Rat Model Based on mRNA-Seq Analysis.

The key target and regulatory mechanism of electroacupuncture of Zusanli (ST36) on extensor longus muscle injury in a jumping rat model were investigated. To this end, 24 female SD rats were randomly divided into the following four groups: no-treatment control group (NON), 6-week jumping group (J6O), electroacupuncture group after 6-week jumping (J6A), and natural recovery group after 6-week jumping (J6N). After 6 weeks of jumping, in the electroacupuncture group (J6A), electroacupuncture stimulation was applied at Zusanli(ST36) for 20 min per day over the course of 5 days. In the natural recovery group (J6N), rats were fastened with a special apparatus without electroacupuncture stimulation for 20 min at the same time. Transmission electron microscopy, transcriptome sequencing and analysis, Western blotting assay and immunofluorescence staining were performed at the end of our experiment. The recovery effect of J6A rats was more obvious than that of J6N rats and J6O rats as indicated by changes of infiltration of inflammatory cells and morphological structure. Notably, the morphological structure of J6A rats was closer to NON rats in the observation of transmission electron microscopy. CISH/STAT3 regulation was identified by mRNA-seq. The pro-inflammatory response to STAT3 activation was alleviated through up-regulating the expression of CISH protein in J6A rats relative to J6O rats. The level of BAX was decreased and the level of Bcl-2 level was increased in J6A rats relative to J6O rats. Moreover, when compared to J6N rats, the level of Bcl-2 was significantly up-regulated in J6A rats. Increased caspase-3 expression but decreased CDKN2α expression was shown in J6A rats relative to NON rats. These results indicate that the potential mechanism underlying electroacupuncture stimulation of Zusanli (ST36) in repairing the injured extensor digitorum longus following overused jumping may be attributed to CISH/STAT3 regulation of proteins associated with inflammation, apoptosis, and proliferation.

Low-Dose Apatinib Combined With S-1 in Refractory Metastatic Colorectal Cancer: A Phase 2, Multicenter, Single-Arm, Prospective Study.

PURPOSE: Apatinib is an approved third-line treatment for metastatic gastric cancer in China and demonstrates good safety, tolerability, and efficacy in other advanced solid tumors. The aim of this prospective, single-arm, multicenter, phase 2 study was to assess the efficacy and safety of low-dose apatinib combined with S-1 in the treatment of refractory mCRC. PATIENTS AND METHODS: Patients with refractory mCRC were enrolled and administered apatinib combined with S-1 until disease progression, patient decision to withdraw, or unacceptable toxic effects. The primary endpoint was investigator-evaluated progression-free survival (PFS) and the secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR). RESULTS: From December 2017 to December 2018, 30 patients were enrolled and 29 patients were eligible for the evaluation of efficacy and safety. The median PFS (mPFS) and OS (mOS) were 7.9 and 12.9 months, respectively. Exploratory analysis revealed that patients administered S-1 ≥ 70 days achieved longer mPFS and mOS. Four patients achieved a partial response, 22 achieved stable disease, and three had progressive disease, attributing to an ORR of 13.79% and a DCR of 89.66%. Ten grade 3 adverse events were reported and the frequency of each grade 3 adverse event was less than 5%. No grade 4 side events were observed. CONCLUSIONS: These results indicated that apatinib combined with S-1 showed promising efficacy and manageable toxicity in patients with progressive mCRC after at least 2 prior lines of therapy, making it a promising therapeutic option for mCRC treatment. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT03397199, identifier NCT03397199.

Cinnamolide sesquiterpene lactone suppresses in vitro and in vivo cancer cell growth in cisplatin-resistant human cervical carcinoma cells by inducing mitochondrial mediated apoptosis, caspase activation, loss of MMP and targeting Akt/ß-Catenin signaling pathway.

The Editors of JBUON issue an Expression of Concern to 'Cinnamolide sesquiterpene lactone suppresses in vitro and in vivo cancer cell growth in cisplatin-resistant human cervical carcinoma cells by inducing mitochondrial mediated apoptosis, caspase activation, loss of MMP and targeting Akt/ß-Catenin signaling pathway', by Jing Hou, Changli Kan, Yanju Zhu, Yi Zhang, Bingfeng Zhou, Chunli Ren, Jiuyuan Fu, Yanwei Guo, Jinhuan Zhang; JBUON 2020;25(2):709-715; PMID: 32521857. Following the publication of the above article, readers drew to our attention that part of the data was possibly unreliable. We sent emails to the authors with a request to provide the raw data to prove the originality, but received no reply. Therefore, as we continue to work through the issues raised, we advise readers to interpret the information presented in the article with due caution. We thank the readers for bringing this matter to our attention. We apologize for any inconvenience it may cause.

Pre-pregnancy body mass index in mothers, birth weight and the risk of type I diabetes in their offspring: A dose-response meta-analysis of cohort studies.

BACKGROUND: The incidence of type I diabetes among children has increased significantly and the relationship between maternal pre-pregnancy Body Mass Index (BMI), Birth weight and risk of Type 1 diabetes in children (T1DMC) is controversial. OBJECTIVE: This dose-response meta-analysis was performed to investigate the association between maternal Pre-Pregnancy Body-Mass Index, Birth Weight and the Risk of Childhood Type I Diabetes. SEARCH STRATEGY: A comprehensive systematic search was conducted in MEDLINE/PubMed, SCOPUS, Cochrane, and Web of Science databases from inception to April 2019. Key search terms included "body mass index" OR "Birth weight" AND "Type 1 diabetes". SELECTION CRITERIA: Peer-reviewed studies that reporting association between BMI or birth weight and type I diabetes in a retrospective or prospective study by appropriate estimates such as the hazard ratio (HR), risk ratio (RR), or odds ratio (OR) and the corresponding 95 % confidence intervals (CI). DATA COLLECTION AND ANALYSIS: MOOSE guidelines were followed. Data were extracted by 2 researchers, independently. Combined hazard ratios (HRs) was evaluated by DerSimonian and Laird Random-effects model. RESULTS: Two studies continuing four arms with 1,209,122 participants were eligible for pre-pregnancy BMI section meta-analysis and six studies were eligible for inclusion, providing 10,340,036 participants for birth weight section meta-analysis. Pooled results demonstrated a significant association between obesity and risk of T1DMC (HR: 1.30, 95 % CI: 1.16-1.46, I2 = 7%). The combined HR (95 % CI) showed lower risk of T1DMC in low birth weight infants (HR: 0.78, 95 % CI: 0.69-0.88, I2 = 0%) and higher risk of T1DMC in the high birth weight infants versus the normal category of birth weight (HR: 1.08, 95 % CI: 1.00-1.17, I2 = 31 %). There was a significant non-linear association between birth weight and risk of T1DMC in children (Coef =-0.00032, p = 0.001). CONCLUSIONS AND RELEVANCE: This systematic review and meta-analysis identified high maternal BMI and High birth weight (HBW) increase risk of childhood T1DMC.

Astaxanthin inhibiting oxidative stress damage of placental trophoblast cells in vitro.

Oxidative stress from the trophoblasts is one of the possible pathological mechanisms of Preeclampsia (PE). This study aimed at exploring the potential effects of astaxanthin (ATX) on oxidative stress damaged placental trophoblast cell line HTR-8/SVneo. Oxidative stress-induced damaged through H2O2 treatment was checked by MTS CellTiter 96® cell viability, 2',7'-dichlorofluorescein diacetate (DCFH-DA) induced fluorescence, the level of the intracellular malondialdehyde (MDA), and the detection of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and catalase (CAT). Different concentrations of ATX were applied, and then the proliferation rate, apoptotic percentage, cell cycle distribution, invasion test and relative biological function of the rescued cells were followed. We provide evidence that ATX had an anti-oxidative effect against oxidative stress induced by H2O2 on the trophoblast cell line and had beneficial role in promoting cell proliferation, inhibiting cell apoptosis, and inducing cell invasion.Abbreviations: UV: ultraviolet; DCFH-DA: 2',7'-dichlorofluorescein diacetate; EVT: extravillous trophoblast; MMPs: matrix metalloproteinases; IUGR: intrauterine growth restriction.

Cinnamolide sesquiterpene lactone suppresses in vitro and in vivo cancer cell growth in cisplatin-resistant human cervical carcinoma cells by inducing mitochondrial mediated apoptosis, caspase activation, loss of MMP and targeting Akt/ß-Catenin signaling pathway.

PURPOSE: This study was designed to examine the in vitro and in vivo antitumor effects of Cinnamolide against cisplatin-resistant human cervical cancer cells (HeLa cells). METHODS: Cell viability was examined by WST-1 cell viability assay. Cinnamolide-induced apoptosis was examined by fluorescent microscopy using acridine orange (ΑΟ) /ethidium bromide (EB) staining and flow cytometry in combination with annexin-V/propidium iodide (PI) staining. Western blot was used to study the effects of Cinnamolide on apoptosis-related protein expressions including Bax and Bcl-2 as well as to study effects on numerous caspases and Akt/ß-Catenin signaling pathway. Effects on mitochondrial membrane potential (MMP) were evaluated by flow cytometry. In vivo studies using xenograft mouse model were carried out to evaluate the efficacy of Cinnamolide under in vivo conditions. RESULTS: Cinnamolide decreased the viability of the HeLa human cervical cancer cells and exhibited an IC50 of 16.5 µM. The cytoxicity of Cinnamolide was also investigated on the MDCK normal cervical cells which showed that Cinnamolide exerted very low toxic effects on these cells. Cinnamolide also caused remarkable changes in the morphology of the HeLa cancer cells and suppressed their colony forming potential. The AO/EB staining showed that this molecule inhibits the viability of cancer cells via induction of apoptotic cell death which was associated with increase in Bax and decrease in Bcl-2 levels. The apoptotic cells increased from 3.5% in control to around 59% in HeLa cells at 50 µM concentration. Cinnamolide treatment also led to activation of caspase-3 and caspase-9. It was also seen that Cinnamolide treatment led to a significant and dose-dependent loss of MMP in HeLa cancer cells. It also significantly inhibited the Akt/ß-catenin signalling pathway by reducing the levels of phosphorylated Akt and GSK-3ß. The results also showed that Cinnamolide suppressed the tumor volume and the tumor weight of the xenografted tumors. CONCLUSION: The results of this study indicate that Cinnamolide natural product has the potential to be developed as a promising anticancer agent against human cervical carcinoma.

Hyperpolarized MRI of Human Prostate Cancer Reveals Increased Lactate with Tumor Grade Driven by Monocarboxylate Transporter 1.

Metabolic imaging using hyperpolarized magnetic resonance can increase the sensitivity of MRI, though its ability to inform on relevant changes to biochemistry in humans remains unclear. In this work, we image pyruvate metabolism in patients, assessing the reproducibility of delivery and conversion in the setting of primary prostate cancer. We show that the time to max of pyruvate does not vary significantly within patients undergoing two separate injections or across patients. Furthermore, we show that lactate increases with Gleason grade. RNA sequencing data demonstrate a significant increase in the predominant pyruvate uptake transporter, monocarboxylate transporter 1. Increased protein expression was also observed in regions of high lactate signal, implicating it as the driver of lactate signal in vivo. Targeted DNA sequencing for actionable mutations revealed the highest lactate occurred in patients with PTEN loss. This work identifies a potential link between actionable genomic alterations and metabolic information derived from hyperpolarized pyruvate MRI.

α-Pinene Induces Apoptotic Cell Death via Caspase Activation in Human Ovarian Cancer Cells.

BACKGROUND The plant-derived terpenoid, alpha-pinene is a bicyclic monoterpene potentially useful for the treatment of various diseases which also includes cancer and its types. The present investigation is about finding the anticancer activity of the alpha-pinene extracted from the leaves of Boswellia dalzielii over the PA-1 cancer cells of the human ovary. MATERIAL AND METHODS The cytotoxic activity of the alpha-pinene was evaluated using MTT and LDH assays which indicated that alpha-pinene could induce cytotoxicity in cancer-causing cells in the ovary. The consequences of alpha-pinene on the cell sequence regulation were determined by the staining technique using propidium iodide (PI) followed with flow cytometry. RESULTS The cell cycle distribution analysis showed that alpha-pinene inhibit the cycle progression from G2 to M phase. In addition, apoptosis analysis is done through the double staining investigation using Annexin V-FITC/PI to analyze the controlled growth of alpha-pinene which is associated with the apoptosis. Caspase-3 a crucial enzyme involved in apoptosis was markedly increased in the a-pinene treated PA-1 cells. The apoptosis results reveal, that the cancer cells at the human ovary with alpha-pinene induces the significant populations of apoptotic cells. CONCLUSIONS Overall, alpha-pinene may exert anticancer effects in PA-1 cells by promoting cytotoxicity, suppression of cell sequence progression along with the programmed cell death.