Fatty Acid Binding Protein 1 is an Independent Prognostic Biomarker for Gallbladder Cancer with Direct Hepatic Invasion.

Background: Direct liver invasion (DI) is a predominant pathway of gallbladder cancer (GBC) metastasis, but the molecular alterations associated with DI remain addressed. This study identified specific genes correlated with DI, which may offer a potential biomarker for the diagnosis and prognosis of advanced GBC. Methods: RNA samples from 3 patients with DI of GBC were used for RNA-seq analysis. Differentially expressed genes and metabolic pathways between primary tumor (T) and DI tissue was used to analyze aberrant gene expressions. Immunohistochemistry (IHC) of fatty acid binding protein 1 (FABP1) in 62 patients with DI was engaged to evaluate its association with clinicopathological characteristics and prognosis. IHC of CD3+ and CD8+ T cells was analyzed for their correlation with FABP1 expression, clinicopathological features and prognosis. Univariate and multivariate Cox hazards regression analyses were performed to identify independent prognostic factors for disease-free survival (DFS) and overall survival (OS). Results: FABP1 mRNA levels were significantly upregulated in DI region compared to T tissue. IHC results showed identical results with elevated FABP1 (p < 0.0001). Expression of FABP1 in DI region was significantly associated with lymph node metastasis (P = 0.028), reduced DFS (P = 0.013) and OS (P = 0.022); in contrast, its expression in T region was not associated with clinicopathological characteristics and prognosis (P > 0.05). The density of CD8+ T cells in DI region with higher FABP1 expression was significantly lower than that with lower FABP1 expression (p = 0.0084). Multivariate analysis unveiled those hepatic metastatic nodules (HR = 3.35, 95%CI: 1.37-8.15, P = 0.008) and FABP1 expression in DI region (HR = 2.01, 95%CI: 1.05-3.88, P = 0.036) were high risk factors for OS, and FABP1(HR = 2.05, 95%CI: 1.04-4.06, P = 0.039) was also a high risk factor for DFS. Conclusions: Elevated expression of FABP1 in DI region serves as a potential prognostic biomarker for advanced GBC with DI.

Association of serum folic acid levels in response to fasting blood glucose in early pregnancy with the risk of gestational diabetes mellitus: A retrospective cohort study.

OBJECTIVE: With increasingly prevalent folic acid consumption in early pregnancy, concerns about its potentially negative effect on maternal metabolism have been raised. Recent findings regarding folic acid levels in the first trimester and the risk of gestational diabetes mellitus have been inconclusive. The aim of this study was to investigate the association of folic acid status in early pregnancy with gestational diabetes mellitus as well as examine whether glucose levels can be modulated by folic acid status during the same first trimester. METHODS: This was a retrospective cohort study based on 27 128 Chinese pregnant women who registered during their first prenatal visit from January 2015 to December 2019. Serum folic acid and fasting blood glucose concentrations were measured during the 9th to 13th gestational weeks. Binary logistic regression was applied to estimate the odds ratios of gestational diabetes mellitus by using the serum folic acid levels quartiles with adjustment for major confounders. To investigate the potential effect of modifying key risk factors for gestational diabetes mellitus, we established subgroups, in which analyses were stratified by age (<25, 25-29, 30-34, and ≥35 y), parity (nulliparous and parous), prepregnancy body mass index (< 18.5, 18.5-23.9, and ≥ 24 kg/m2), and family history of diabetes (yes and no). RESULTS: The positive association between maternal folate concentrations and fasting blood glucose was observed: the risk for hyperglycemia was higher in those in the middle (Q3) and higher (Q4) quartiles compared with those in Q1 and Q2. A higher risk for gestational diabetes mellitus was found in hyperglycemia of early pregnant women with high folate concentrations (Q3: odds ratio = 5.63; 95% CI, 4.56-6.95, and Q4: odds ratio = 5.57; 95% CI, 4.68-6.64) compared with normal fasting glucose mothers with folate concentrations in Q1 and Q2 after accounting for multiple covariables. Similar patterns were observed for different subgroups. Restricted cubic spline plots had a positive correlation of serum folic acid level with fasting blood glucose concentration as well as risk of gestational diabetes mellitus in a nonlinear pattern, with 32.5 nmol/L as the cutoff point for folic acid level. CONCLUSIONS: Our findings underscore the importance of maintaining an appropriate folic acid concentration for preserving a lower risk of gestational diabetes mellitus, especially in women with relatively higher blood glucose in early pregnancy. Additionally, folic acid concentration > 32.5 nmol/L may be considered a risk factor for gestational diabetes mellitus. This research suggested that folic acid levels should be monitored during the first trimester from the first prenatal checkup to prevent adverse effects of excessive folic acid intake.

POSS hybrid bioactive glass dental composite resin materials: Synthesis and analysis.

INTRODUCTION: This study create a dental composite by hybirding polyhedral oligo-sesquioxide nano monomers and bioactive glass BG 45S5. METHODS: Make an experimental composite resin material with a 60 % filler content overall by substituting 20 % of the filler with BG 45S5. The experimental resins are grouped and named P0, P2, P4, P6 and P8 based on the reactive nanomonomer methacrylic acid-based multifaceted oligomeric sesquisiloxane (POSS) added by 2 %-8 % in the resin matrix portion of each group. Utilize a universal testing machine to analyze and compare the mechanical properties of these, then perform Fourier infrared spectrum analysis, double bond conversion analysis, and scanning electron microscope analysis. Based on this, after soaking the experimental materials artificial saliva solution or lactic acid solution for a while, the pH changes of the solution, the release of Ca2+ and PO43- ions, and the precipitation of apatite on the resin material's surface were tested and analyzed. Cell viability tests were used to assess sample cell viability and quantify the cytotoxicity of biological cells. The independent sample t-test was used to examine the group comparisons, and a difference was considered statistically significant at P<0.05. RESULTS: Outstanding mechanical and the double bond conversion are demonstrated by the nanocomposites when the POSS concentration hits 4 wt%. Agglomeration will cause the performance to deteriorate if the concentration beyond this threshold. In the P4 group, the double bond conversion, CS, and FS rose by a large margin, respectively, in comparison to the blank control group P0. Thankfully, the data demonstrate that adding POSS increases adhesive ability when compared to the blank group P0, however, there is no discernible difference between the other experimental groups. The acid neutralization capacity of the P4 group is essentially the same as that of the control group (P0). Ca2+ and PO43- ions are released in significant amounts following treatment with lactic acid solution, although this tendency is clearly less pronounced in artificial saliva. SEM and EDX data indicate that when the experimental resin is soaked in lactic acid solution and artificial saliva, apatite precipitation will happen on its surface. The results of the cell viability test indicated that there was no statistically significant difference between the experimental groups, and the viability of the cells increased after 24hours and 48 hours. CONCLUSIONS: POSS was included into the composite resin along with 20% bioactive glass as a filler. When the proportion of POSS is less than 4%, the indices of composite resin materials rise in a dose-dependent way. When this value is surpassed, performance begins to deteriorate. The inclusion of POSS has no influence on the biological activity of the composites, which means that the hybrid composite resin is capable of acid neutralization, ion release, and apatite precipitation. CLINICAL SIGNIFICANCE: The experimental composite resin can be used as an intelligent material in clinical treatment. It has the clinical application potential of preventing demineralization of tooth hard tissue, promoting remineralization, and improving edge sealing through apatite precipitation.

Seven New Lobane Diterpenoids from the Soft Coral Lobophytum catalai.

Seven new lobane diterpenoids, namely, lobocatalens A-G (1-7), were isolated from the Xisha soft coral Lobophytum catalai. Their structures, including their absolute configurations, were elucidated via spectroscopic analysis, comparison with the literature data, QM-MNR, and TDDFT-ECD calculations. Among them, lobocatalen A (1) is a new lobane diterpenoid with an unusual ether linkage between C-14 and C-18. In addition, compound 7 showed moderate anti-inflammatory activity in the zebrafish models and cytotoxic activity against the K562 human cancer cell line.

A disposable impedance-based sensor for in-line cell growth monitoring in CAR-T cell manufacturing.

This paper presents the development of low-cost, disposable impedance-based sensors for real-time, in-line monitoring of suspension cell culture. The sensors consist of electrical discharge machining (EDM) cut aluminum electrodes and polydimethylsiloxane (PDMS) spacers, both of which are low-cost materials that can be safely disposed of. Our research demonstrates the capability of these low-cost sensors for in-line, non-invasive monitoring of suspension cell growth in cell manufacturing. We use a hybrid equivalent circuit model to extract key features/parameters from intertwined impedance signals, which are then fed to a novel physics-inspired (gray-box) model designed for α-relaxation. This model determines viable cell count (VCC), a critical quality attribute (CQA) in cell manufacturing. Predicted VCC trends are then compared with image-based cell count data to verify their accuracy.

Terpenoids from the Sponge Sarcotragus sp. Collected in the South China Sea.

Sarcotragusolides A-D (1-4), four new butenolide sesterterpenes featuring a rare methyl-transferred 6/6/6-tricyclic fused ring system with a butyrolactone moiety, and echinohalimane B (8), an unprecedented monocyclic diterpenoid featuring a 2,7-ring-opened halimane-type skeleton, were isolated from the sponge Sarcotragus sp. A γ-hydroxybutenolide sesterterpene derivative (5), a new scalarane sesterterpene (7), a new subersin-type diterpenoid (10), and two known terpenoids were also isolated and identified. The discovery of sarcotragusolides C and D (3 and 4) with an unprecedented inversion of configuration implied a distinct biosynthetic pathway. The structures of these compounds were elucidated based on their spectroscopic data, single-crystal X-ray diffraction, chemical derivatization, and quantum chemical calculations. Compounds 1a, 1b, and 2 presented modest cytotoxic activities against several human cancer cell lines.

Association between paternal age and subtypes of preterm birth: a retrospective study.

RESEARCH QUESTION: Is advanced paternal age (APA) associated with preterm birth overall and with the subtypes of preterm birth? DESIGN: A total of 66,167 pregnancies were included. Linear regression and logistic regression models were used to analyse the association between paternal age and subtypes of preterm birth. RESULTS: APA was associated with a higher risk of preterm birth (35-44 years: odds ratio [OR] 1.16 [1.04-1.28], P = 0.006; >44 years: OR 1.40 [1.10-1.78], P = 0.007) and very early preterm birth (VPTB; <34 weeks) (35-44 years: OR 1.46 [1.17-1.81], P = 0.002; >44 years: OR 1.65 [1.01-2.69], P = 0.045). The increased risk of preterm birth was mostly associated with preterm birth with premature rupture of membranes (PROM-PTB) (35-44 years: OR 1.23 [1.03-1.48], P = 0.021) and medically induced preterm birth (MI-PTB) (>44 years: OR 1.55 [1.12-2.15], P = 0.008). For women who carried a male fetus, having the father in the 35- to 44-year-old group carried a 1.29-fold risk of PROM-PTB (OR 1.29 [1.02-1.63], P = 0.031) and a 1.26-fold risk of MI-PTB (OR 1.26 [1.04-1.52], P = 0.017). There was no evidence of a higher risk of PROM-PTB among women carrying a female fetus, but there was a 1.67-fold higher risk of MI-PTB for the 45-or-older paternal age group (OR 1.67 [1.04-2.67], P = 0.035). CONCLUSIONS: These results suggest that APA is associated with a higher risk of preterm birth and VPTB, mainly related to PROM-PTB and MI-PTB. The study also indicates a fetal sex-specific association between APA and a higher risk of PROM-PTB for male fetuses.

MiRNAs in Gestational Diabetes Mellitus: Potential Mechanisms and Clinical Applications.

Gestational diabetes mellitus (GDM) is a common pregnancy complication which is normally diagnosed in the second trimester of gestation. With an increasing incidence, GDM poses a significant threat to maternal and offspring health. Therefore, we need a deeper understanding of GDM pathophysiology and novel investigation on the diagnosis and treatment for GDM. MicroRNAs (miRNAs), a class of endogenic small noncoding RNAs with a length of approximately 19-24 nucleotides, have been reported to exert their function in gene expression by binding to proteins or being enclosed in membranous vesicles, such as exosomes. Studies have investigated the roles of miRNAs in the pathophysiological mechanism of GDM and their potential as noninvasive biological candidates for the management of GDM, including diagnosis and treatment. This review is aimed at summarizing the pathophysiological significance of miRNAs in GDM development and their potential function in GDM clinical diagnosis and therapeutic approach. In this review, we summarized an integrated expressional profile and the pathophysiological significance of placental exosomes and associated miRNAs, as well as other plasma miRNAs such as exo-AT. Furthermore, we also discussed the practical application of exosomes in GDM postpartum outcomes and the potential function of several miRNAs as therapeutic target in the GDM pathological pathway, thus providing a novel clinical insight of these biological signatures into GDM therapeutic approach.

Periodontal disease and the risk of Alzheimer's disease and mild cognitive impairment: a systematic review and meta-analysis.

BACKGROUND: Results of studies on the association between periodontal disease (PD) and Alzheimer's disease (AD) or mild cognitive impairment (MCI) are inconsistent, and a previous meta-analysis published in 2017 included inadequate studies and is thus outmoded. This study aims to systematically evaluate the correlation between PD and the risk of AD or MCI. METHODS: The following electronic databases were screened by two investigators independently, without restriction of language: CENTRAL (Cochrane library), PubMed (MEDLINE), EMBASE, China National Knowledge Interne, China Science and Technology Journal Database, Wanfang Data, www.ClinicalTrials.gov, and WHO International Clinical Trials Registry Platform. Meta-analysis was conducted using random-effects model or fixed-effects model according to the heterogeneity of included studies. RESULTS: Thirteen eligible studies, of which eight reported AD (291 114 participants) and eight reported MCI (4805 participants), were included in this meta-analysis. The pooled results showed that compared with the non-PD population, the risk of AD and MCI in PD patients was significantly higher (for AD: odds ratio (OR) = 1.78, 95% CI 1.15-2.76; for MCI: OR = 1.60, 95% CI 1.24-2.06), and especially in those with severe PD (for AD: OR = 4.89, 95% CI 1.60-14.97; for MCI, OR = 2.32, 95% CI 1.24-4.36). CONCLUSIONS: This meta-analysis indicated that PD was related to an elevated risk of AD and cognitive impairment, and that it should receive early intervention.

CRISPR interference-guided modulation of glucose pathways to boost aconitic acid production in Escherichia coli.

BACKGROUND: One major mission of microbial breeding is high-level production of desired metabolites. Overproduction of intermediate metabolites in core pathways is challenging as it may impair cell growth and viability. RESULTS: Here we report that aconitic acid, an intermediate metabolite in tricarboxylic acid (TCA) cycle, can be overproduced by an engineered CRISPR interference (CRISPRi) system in Escherichia coli. This CRISPRi system was designed to simultaneously target pyruvate kinase (PK) and isocitrate dehydrogenase (IDH), two enzymes in glycolytic pathway and TCA cycle, respectively. Reverse transcription and quantitative PCR and enzyme activity assays showed that this engineered CRISPRi system significantly repressed the genes encoding IDH and PK, resulting in simultaneous reduction in the activities of IDH and PK. In shake-flask and fed-batch cultivation, this CRISPRi strain produced 60-fold (362.80 ± 22.05 mg/L) and 15-fold (623.80 ± 20.05 mg/L) of aconitic acid relative to the control strain, respectively. In addition, this two-target CRISPRi strain maintained low levels of acetate and lactate, two problematic byproducts. CONCLUSIONS: This work demonstrates that CRISPRi system can improve aconitic acid production by coordinating glycolysis and TCA cycle. This study provides insights for high-level production of the intermediate metabolites in central pathways.

Complete response to the combination of Lenvatinib and Pembrolizumab in an advanced hepatocellular carcinoma patient: a case report.

BACKGROUND: The majority of patients diagnosed with hepatocellular carcinoma (HCC) have advanced diseases and many are not eligible for curative therapies. CASE PRESENTATION: We report a rare case of HCC from a patient who had a complete response (CR) with the use of combination of Lenvatinib and Pembrolizumab. A 63-year-old man presented at the hospital with serious abdominal pain and was found to have a mass with heterogeneous enhancement and with hemorrhage in segment III of the liver after the examination of abdominal computerized tomography (CT) scan. The patient's history of viral hepatitis B infection, liver cirrhosis and the ɑ-fetoprotein (AFP) level of 14,429.3 ng/ml supported the clinical diagnosis of HCC and laboratory results demonstrated liver function damage status (Child-Pugh class B, Score 8). The patient first received hepatic arterial embolization treatment on 28th November 2017. At this stage supportive care was recommended for poor liver function. In February 2018, combined immunotherapy of Pembrolizumab (2 mg/kg, q3w) and Lenvatinib (8 mg-4 mg, qd) were performed. Nine months following the treatment he had a CR and now, 22 months since the initial treatment, there is no clinical evidence of disease progression. The current overall survival is 22 months. CONCLUSIONS: HCC is a potentially lethal malignant tumor and the combination of immunotherapy plus anti-angiogenic inhibitors shows promising outcome for advanced diseases.

New strategies for the treatment of neurotoxic side effects in CAR-T cell therapy / 中国肿瘤生物治疗杂志

@# Chimeric antigen receptor modified T (CAR-T) cell therapy is one of the important methods of tumor immunotherapy. The targeting, killing, proliferation and persistence of CAR-T cells are significantly enhanced than that of conventional T cells.After continuous improvement and evolution, CAR-T cell treatment has achieved excellent progress in hematological tumors and has received extensive attention. However, neurotoxicity arising from the treatment, also known as CAR-T cell relevant encephalopathy syndrome (CRES), has affected its clinical application. Exploring the pathogenesis of CRES and high-risk factors, and finding appropriate strategies is therefore critical for the prevention and treatment of CRES. Here, we take CD19-CAR-T cell treatment as example to review the symptoms and pathogenesis of CRES, discuss high-risk factors as well as coping strategies, in an effort to provide a reference for clinical treatment.

Measurement and decomposition of energy efficiency of Northeast China-based on super efficiency DEA model and Malmquist index.

Nowadays, environment problem has become the international hot issue. Experts and scholars pay more and more attention to the energy efficiency. Unlike most studies, which analyze the changes of TFEE in inter-provincial or regional cities, TFEE is calculated with the ratio of target energy value and actual energy input based on data in cities of prefecture levels, which would be more accurate. Many researches regard TFP as TFEE to do analysis from the provincial perspective. This paper is intended to calculate more reliably by super efficiency DEA, observe the changes of TFEE, and analyze its relation with TFP, and it proves that TFP is not equal to TFEE. Additionally, the internal influences of the TFEE are obtained via the Malmquist index decomposition. The external influences of the TFFE are analyzed afterward based on the Tobit models. Analysis results demonstrate that Heilongjiang has the highest TFEE followed by Jilin, and Liaoning has the lowest TFEE. Eventually, some policy suggestions are proposed for the influences of energy efficiency and study results.