Vanillic acid restores homeostasis of intestinal epithelium in colitis through inhibiting CA9/STIM1-mediated ferroptosis.

The damage of integrated epithelial epithelium is a key pathogenic factor and closely associated with the recurrence of ulcerative colitis (UC). Here, we reported that vanillic acid (VA) exerted potent therapeutic effects on DSS-induced colitis by restoring intestinal epithelium homeostasis via the inhibition of ferroptosis. By the CETSA assay and DARTS assay, we identified carbonic anhydrase IX (CAIX, CA9) as the direct target of VA. The binding of VA to CA9 causes insulin-induced gene-2 (INSIG2) to interact with stromal interaction molecule 1 (STIM1), rather than SREBP cleavage-activating protein (SCAP), leading to the translocation of SCAP-SREBP1 from the endoplasmic reticulum (ER) to the Golgi apparatus for cleavage into mature SREBP1. The activation of SREBP1 induced by VA then significantly facilitated the transcription of stearoyl-CoA desaturase 1 (SCD1) to exert an inhibitory effect on ferroptosis. By inhibiting the excessive death of intestinal epithelial cells caused by ferroptosis, VA effectively preserved the integrity of intestinal barrier and prevented the progression of unresolved inflammation. In conclusion, our study demonstrated that VA could alleviate colitis by restoring intestinal epithelium homeostasis through CA9/STIM1-mediated inhibition of ferroptosis, providing a promising therapeutic candidate for UC.

COVID-19 vaccination affects short-term anti-coagulation levels in warfarin treatment.

Vaccines against SARS-CoV-2 have been recommended across the world, yet no study has investigated whether COVID-19 vaccination influences short-term warfarin anti-coagulation levels. Patients on stable warfarin treatment who received anti-SARS-CoV-2 vaccination were prospectively enrolled and followed up for three months. INR values less than 10 days before vaccination (baseline), 3-5 days (short-term) and 6-14 days (medium-term) after vaccination were recorded as INR0, INR1, and INR2, respectively. The variations of INR values within individuals were compared, and the linear mixed effect model was used to evaluate the variations of INR values at different time points. Logistic regression analysis was performed to determine covariates related to INR variations after COVID-19 vaccination. Vaccination safety was also monitored. There was a significant difference in INR values between INR0 and INR1 (2.15 vs. 2.26, p = 0.003), yet no marked difference was found between INR0 and INR2. The linear mixed effect model also demonstrated that INR variation was significant in short-term but not in medium-term or long-term period after vaccination. Logistic regression analysis showed that no investigated covariates, including age, vaccine dose, genetic polymorphisms of VKORC1 and CYP2C9 etc., were associated with short-term INR variations. Two patients (2.11%) reported gingival hemorrhage in the short-term due to increased INR values. The overall safety of COVID-19 vaccines for patients on warfarin was satisfying. COVID-19 vaccines may significantly influence warfarin anticoagulation levels 3-5 days after vaccination. We recommend patients on warfarin to perform at least one INR monitoring within the first week after COVID-19 vaccination.

Genomic characterization of thymic epithelial tumors reveals critical genes underlying tumorigenesis and poor prognosis.

Thymic epithelial tumors (TETs) are rare mediastinal tumors whose tumorigenesis mechanism is poorly understood. Characterization of molecular alterations in TETs may contribute to a better understanding of tumorigenesis and prognosis. Hybrid capture-based next-generation sequencing was performed on tumor tissues from 47 TETs (39 thymomas and 8 thymic carcinomas) to detect mutations in 315 tumor-associated genes. In total, 178 nonsynonymous mutations were identified, with a median of 3.79 per tumor in 47 TETs. Higher tumor mutation burden (TMB) level was more common in older TET patients, and significantly associated with the more advanced pathological type, especially in thymic carcinomas (TC) patients. The gene mutation profiles of B1-3, A/AB, and TC patients varied greatly. In the actionable mutations analysis, we found 32 actionable mutations in 24 genes. Among them, NFKBIA and TP53 mutations was the most frequently, which were only identified in TCs. Additionally, TCGA database analysis found that the expression of NFKBIA mRNA in the TCs were significantly higher than thymomas. TET patients with high NFKBIA expression had shorter overall survival compared with patients with low/medium NFKBIA expression, thus providing insights to consider NFKBIA as a potential prognosis biomarker and therapeutic target in TETs.

[Effects of urogenital mycoplasma and chlamydial infections on male fertility].

Objective： This study aimed to assess the impact of urogenital ureaplasma urealyticum (Uu), Mycoplasma hominis (Mh), and Chlamydia trachomatis (Ct) infections on semen quality in men.Methods： In this study, 1022 males were enrolled at the Department of Reproductive Medicine, Rizhao People's Hospital, Shandong Province from October 2014 to January 2023. The participants included 393 in the infertility group, 139 in the recurrent miscarriage group, and 490 in the control group. Based on age, 852 cases were < 36 years old, and 170 cases were ≥ 36 years old. All patients underwent routine semen analysis and tests for Uu, Mh, and Ct, with results statistically analyzed for their impact on semen quality and compared among different age groups. Results: Among the 1022 patients, 344 (33.6%) were Uu-positive, 49 (4.7%) were Mh-positive, and 31 (3.0%) were Ct positive. The sperm concentration, total sperm count, forward sperm motility rate (PR), sperm motility rate (PR+NP) and normal sperm morphology rate of Uu Mh and/or Ct-positive patients were significantly lower than those of the negative group, and the overall difference between the two groups was statistically significant (P<0.05). The positive rate of Uu infection was 41.7% in the infertility group, 30.2% in the recurrent miscarriage group and 28.2% in the control group, and the overall positive rate of the three groups was statistically significant(P<0.05). The positive rate of Mh infection was 6.9% in the infertility group, 8.6% in the recurrent miscarriage group and 2.0% in the control group, and the overall positive rate of the three groups was statistically significant (P<0.001). The positive rate of Ct infection was 6.1% in the infertility group, 2.9% in the recurrent miscarriage group and 0.6% in the control group, and the overall positive rate of the three groups was statistically significant (P<0.001). The positivity rate of Uu infection was 35.8% at the age of <36 years and 22.9% at the age ≥ 36 years, and there was a statistically significant difference in the positivity rate between the two groups (P<0.05). Conclusion: The prevalence of Uu infection in the male urogenital tract is significantly higher than that of Mh and Ct, which is the main pathogen of urogenital tract infection in men. Uu, Mh and Ct infections have adverse effects on sperm concentration, total sperm count, sperm forward motility rate (PR), sperm motility rate (PR+NP) and normal sperm morphology rate, which will lead to a decrease in semen quality and affect male fertility. Genital tract infections are closely related to age, and the prevalence of Uu infection is higher in the younger age group.

Establishing and evaluating physician-pharmacist collaborative clinics to manage patients with type 2 diabetes in primary hospitals in Hunan province: study protocol of a multi-site randomized controlled trial in the era of COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has exerted an unprecedented and universal impact on global health system, resulting in noticeable challenges in traditional chronic disease care, of which diabetes was reported to be most influenced by the reduction in healthcare resources in the pandemic. China has the world's largest diabetes population, and current diabetes management in China is unsatisfactory, particularly in rural areas. Studies in developed countries have demonstrated that physician-pharmacist collaborative clinics are efficient and cost-effective for diabetes management, but little is known if this mode could be adapted in primary hospitals in China. The aim of this proposed study is to develop and evaluate physician-pharmacist collaborative clinics to manage type 2 diabetes mellitus (T2DM) in primary hospitals in Hunan province. METHODS: A multi-site randomized controlled trial will be conducted to evaluate the effectiveness and cost-effectiveness of the physician-pharmacist collaborative clinics compared with usual care for Chinese patients with T2DM. Six primary hospitals will participate in the study, which will recruit 600 eligible patients. Patients in the intervention group will receive services from both physicians and pharmacists in the collaborative clinics, while the control group will receive usual care from physicians. Patients will be followed up at the 3rd, 6th, 9th and 12th month. Comparison between the two groups will be conducted by assessing the clinical parameters, process indicators and costs on diabetes. A satisfaction survey will also be carried out at the end of the study. DISCUSSION: If effective, the physician-pharmacist collaborative clinics can be adapted and used in primary hospitals of China to improve glycemic control, enhance medication adherence, decrease incidence of complications and reduce patients' dependence on physicians. Findings from the present study are meaningful for developing evidence-based diabetes care policy in rural China, especially in the COVID-19 pandemic era. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2000031839 , Registered 12 April 2020.

Development of a novel gout treatment patient decision aid by patient and physician: A qualitative research study.

BACKGROUND: Gout treatment is not optimized globally, often due to therapeutic inertia by physicians or poor adherence to urate-lowering medications by patients. A patient decision aid (PDA) to facilitate shared decision making (SDM) in gout treatment may overcome these physician-patient barriers. OBJECTIVE: The study explored the views of physicians and patients on a novel locally designed gout treatment PDA prototype. DESIGN: Qualitative descriptive design was used to gather data from in-depth-interviews (IDI) and focus group discussions (FGD). Data analysis was via thematic analysis. Emergent themes shaped a revised version of the PDA. SETTING AND PARTICIPANTS: Adult Asian patients with recent acute gout exacerbations and local Primary Care Physicians (PCP) in Singapore were purposefully chosen. 15 patients with gout and 11 PCPs participated across three IDIs and six FGDs, with the investigators exploring their views of a prototype gout treatment PDA. RESULTS: Patients and physicians generally concurred with the content and design of the PDA prototype. However, while patients preferred fewer treatment details, the PCPs desired more information. Patients preferred the display of statistics, while PCPs felt that numbers were not relevant to patients. The latter were hesitant to include treatment options that were unavailable in primary care. Both stakeholders indicated that they would use the PDA during a consultation. PCPs would need further training in SDM, given a lack of understanding of it. CONCLUSION AND PATIENT CONTRIBUTION: Patients will be the prime users of the PDA. While their views differed partially from the physicians, both have jointly developed the novel gout treatment PDA.

Evaluation of the "safe multidisciplinary app-assisted remote patient-self-testing (SMART) model" for warfarin home management during the COVID-19 pandemic: study protocol of a multi-center randomized controlled trial.

BACKGROUND: Warfarin treatment requires frequent monitoring of INR (international normalized ratio) to adjust dosage in a therapeutic range. In China, patients living in small towns usually go to tertiary hospitals to get warfarin monitoring and dosing, resulting in low frequencies of follow-ups and high incidence of complications. Influenced by the COVID-19 pandemic, patients on warfarin have further reduced their visits to healthcare institutions. While patient self-testing (PST) via using a point-of-care testing device for INR measuring at home has been widely used in developed countries and demonstrated improved clinical outcomes compared to usual care in clinics, it is rarely applied in developing countries, including China. This proposed study will develop and assess the "Safe Multidisciplinary App-assisted Remote patient-self-Testing (SMART) model" for warfarin home management in China during the COVID-19 pandemic. METHODS: This is a multi-center randomized controlled trial. We will carry out the study in three county hospitals, three small tertiary hospitals and three large tertiary hospitals with anticoagulation clinics in Hunan province of China. Eligible patients will be randomly assigned to the SMART model group (n = 360) or the control group (usual care clinic group, n = 360; anticoagulation clinic group, n = 120). Patients in the SMART model group do PST at home once every two to 4 weeks. Controls receive usual care in the clinics. All the patients will be followed up through outpatient clinics, phone call or online interviews at the 3rd, 6th, 9th and 12th month. The percentage of time in therapeutic range (TTR), incidence of warfarin associated major bleeding and thromboembolic events and costs will be compared between the SMART model group and control groups. DISCUSSION: Patients in the SMART model group would show improved TTR, lower incidence of complications and better quality of life compared to the control groups. Our design, implementation and usage of the SMART model will provide experience and evidence in developing a novel model for chronic disease management to solve the problem of healthcare service maldistribution, an issue particularly obvious in developing countries during the COVID-19 pandemic. TRIAL REGISTRATION: ChiCTR, ChiCTR 2000038984 . Registered 11 October, 2020.

Globally learning gene regulatory networks based on hidden atomic regulators from transcriptomic big data.

BACKGROUND: Genes are regulated by various types of regulators and most of them are still unknown or unobserved. Current gene regulatory networks (GRNs) reverse engineering methods often neglect the unknown regulators and infer regulatory relationships in a local and sub-optimal manner. RESULTS: This paper proposes a global GRNs inference framework based on dictionary learning, named dlGRN. The method intends to learn atomic regulators (ARs) from gene expression data using a modified dictionary learning (DL) algorithm, which reflects the whole gene regulatory system, and predicts the regulation between a known regulator and a target gene in a global regression way. The modified DL algorithm fits the scale-free property of biological network, rendering dlGRN intrinsically discern direct and indirect regulations. CONCLUSIONS: Extensive experimental results on simulation and real-world data demonstrate the effectiveness and efficiency of dlGRN in reverse engineering GRNs. A novel predicted transcription regulation between a TF TFAP2C and an oncogene EGFR was experimentally verified in lung cancer cells. Furthermore, the real application reveals the prevalence of DNA methylation regulation in gene regulatory system. dlGRN can be a standalone tool for GRN inference for its globalization and robustness.

Neuroblastoma patient-derived cultures are enriched for a mesenchymal gene signature and reflect individual drug response.

Ex vivo evaluation of personalized models can facilitate individualized treatment selection for patients, and advance the discovery of novel therapeutic options. However, for embryonal malignancies, representative primary cultures have been difficult to establish. We developed patient-derived cell cultures (PDCs) from chemo-naïve and post-treatment neuroblastoma tumors in a consistent and efficient manner, and characterized their in vitro growth dynamics, histomorphology, gene expression, and functional chemo-response. From 34 neuroblastoma tumors, 22 engrafted in vitro to generate 31 individual PDC lines, with higher engraftment seen with metastatic tumors. PDCs displayed characteristic immunohistochemical staining patterns of PHOX2B, TH, and GD2 synthase. Concordance of MYCN amplification, 1p and 11q deletion between PDCs and patient tumors was 83.3%, 72.7%, and 80.0% respectively. PDCs displayed a predominantly mesenchymal-type gene expression signature and showed upregulation of pro-angiogenic factors that were similarly enriched in culture medium and paired patient serum samples. When tested with standard-of-care cytotoxics at human Cmax -equivalent concentrations, MYCN-amplified and non-MYCN-amplified PDCs showed a differential response to cyclophosphamide and topotecan, which mirrored the corresponding patients' responses, and correlated with gene signatures of chemosensitivity. In this translational proof-of-concept study, early-phase neuroblastoma PDCs enriched for the mesenchymal cell subpopulation recapitulated the individual molecular and phenotypic profile of patient tumors, and highlighted their potential as a platform for individualized ex vivo drug-response testing.

How Micro-/Nanostructure Evolution Influences Dynamic Wetting and Natural Deicing Abilities of Bionic Lotus Surfaces.

Anti-icing materials have become increasingly urgent for many fields such as power transmission, aviation, energy, telecommunications, and so on. Bionic lotus hydrophobic surfaces with hierarchical micro-/nanostructures show good potential of delaying ice formation; however, their icephobicity (deicing ability) has been controversial. It is mainly attributed to lack of deep understanding of the correlation between micro-/nanoscale structures, wettability, and icephobicity, as well as effective methods for evaluating the deicing ability close to natural environments. In this article, the natural deicing ability is innovatively proposed on the basis of ice adhesion and the influence of microscale structure evolution on dynamic wetting and deicing ability (both ice adhesion strength and natural deicing time) was systematically investigated. Interestingly, different modes (sticky or slippery) were found in natural deicing of hierarchical hydrophobic surfaces, although their ice adhesion strength was higher than that of smooth surfaces. The mechanism was analyzed from three aspects: mechanics, heat transfer, and dynamic wetting. It is highlighted that the sliding of melted interface is not equal to water droplet sliding (dynamic wetting) before freezing or after deicing but significantly depends on the microscale structure. The fundamental understanding on natural deicing of bionic hydrophobic surfaces will open up a new window for developing new anti-icing materials and technology.

Chromatin accessibility analysis reveals that TFAP2A promotes angiogenesis in acquired resistance to anlotinib in lung cancer cells.

Anlotinib, a multitarget tyrosine kinase inhibitor, is effective as a third-line treatment against non-small cell lung cancer (NSCLC). However, acquired resistance occurs during its administration. To understand the molecular mechanisms of anlotinib resistance, we characterized chromatin accessibility in both the parental and anlotinib-resistant lung cancer cell line NCI-H1975 through ATAC-seq. Compared with the parental cells, we identified 2666 genomic regions with greater accessibility in anlotinib-resistant cells, in which angiogenesis-related processes and the motifs of 21 transcription factors were enriched. Among these transcription factors, TFAP2A was upregulated. TFAP2A knockdown robustly diminished tumor-induced angiogenesis and partially rescued the anti-angiogenic activity of anlotinib. Furthermore, transcriptome analysis indicated that 2280 genes were downregulated in anlotinib-resistant cells with TFAP2A knocked down, among which the PDGFR, TGF-ß, and VEGFR signaling pathways were enriched. Meanwhile, we demonstrated that TFAP2A binds to accessible sites within BMP4 and HSPG2. Collectively, this study suggests that TFAP2A accelerates anlotinib resistance by promoting tumor-induced angiogenesis.

GSE1 predicts poor survival outcome in gastric cancer patients by SLC7A5 enhancement of tumor growth and metastasis.

Gastric cancer remains a malignancy with poor survival outcome. We herein report that GSE1, a proline-rich protein, possesses a role in the progression of human gastric cancer. The expression of GSE1 was observed to be much higher in human gastric cancer tissues compared with normal gastric tissues, and GSE1 expression correlated positively with lymph node metastasis, histological grade, depth of invasion, and clinical stage in gastric cancer patients. Moreover, GSE1 expression was also associated with decreased post-operative relapse-free survival and overall survival in the cohort. The forced expression of GSE1 in gastric cancer cell lines resulted in increased cell proliferation, increased colony formation, enhanced cell migration, and invasion. Furthermore, forced expression of GSE1 also increased tumor size and enhanced lung metastasis in xenograft models. The depletion of endogenous GSE1 with shRNAs decreased the oncogenicity and invasiveness of gastric cancer cells both in vitro and in vivo In addition, GSE1 was determined to be a direct target of miR-200b and miR-200c. Furthermore, GSE1 positively regulated the downstream gene SLC7A5 (also known as LAT-1), which was scanned and verified from mRNA sequencing. GSE1 therefore possesses an oncogenic role in human gastric cancer, and targeted therapeutic approaches to inhibit GSE1 function in gastric cancer warrant further consideration.

Different memory patterns of digits: a functional MRI study.

BACKGROUND: Psychological investigations and functional imaging technology have been used to describe neural correlations of different types of memory with various stimuli. Memory with limited storage capacity and a short retention time can be classified as short-term memory (STM) while long-term memory (LTM) can be life-long without defined capacity. METHODS: To identify brain activation pattern associated with different modes of memory for numerical figures, we detected brain activities from twenty-two healthy subjects when performing three types of memory tasks for numbers, namely STM, LTM and working memory (WM), by using functional magnetic resonance imaging (fMRI) technique. RESULTS: The result revealed variable patterns of activation in different brain regions responding to different types of memory tasks. The activation regions with primary processing and transient maintenance of STM for numerical figures are located in the visual cortex and mainly encoded by visual representations, while LTM was encoded by semantics and mainly recruiting left frontal cortex. We also found that subcortical structures, such as the caudate nucleus and the marginal division of the striatum, plays important roles in working memory. CONCLUSIONS: Activation of different brain regions in these three kinds of memories, indicating that different kinds of memories rely on different neural correlates and mental processes.

Measurement method by inferring the thrust from the stress of the cantilever beam based on the photoelasticity theory.

A new, to the best of our knowledge, thrust measurement system based on the photoelasticity theory has been developed to infer the thrust from the stress of the cantilever beam. In this method, the cantilever beam is employed as the loading element to convert the low thrust into high stress, and the modified dynamic photoelasticity is used to infer the stress value of the cantilever beam from the Stokes parameters of the emergent light. The experimental results validated that the thrust stand could measure the thrust in the range of millinewton or millisecond, and the thickness of the beam was negatively correlated with the measurement accuracy. The average errors of the experimental measurements for ampere forces were higher than 25 mN and the pulse ampere forces whose widths were longer than 45 ms were less than ${\pm 5}\% .$±5%. As for the real plasma discharges, the errors of the measured thrust were less than ${\pm 10}\% $±10%.

Post-transcriptional regulation of ERBB2 by miR26a/b and HuR confers resistance to tamoxifen in estrogen receptor-positive breast cancer cells.

Tamoxifen-resistant (TAMR) estrogen receptor-positive (ER+) breast cancer is characterized by elevated Erb-B2 receptor tyrosine kinase 2 (ERBB2) expression. However, the underlying mechanisms responsible for the increased ERBB2 expression in the TAMR cells remain poorly understood. Herein, we reported that the ERBB2 expression is regulated at the post-transcriptional level by miR26a/b and the RNA-binding protein human antigen R (HuR), both of which associate with the 3'-UTR of the ERBB2 transcripts. We demonstrated that miR26a/b inhibits the translation of ERBB2 mRNA, whereas HuR enhances the stability of the ERBB2 mRNA. In TAMR ER+ breast cancer cells with elevated ERBB2 expression, we observed a decrease in the level of miR26a/b and an increase in the level of HuR. The forced expression of miR26a/b or the depletion of HuR decreased ERBB2 expression in the TAMR cells, resulting in the reversal of tamoxifen resistance. In contrast, the inactivation of miR26a/b or forced expression of HuR decreased tamoxifen responsiveness of the parental ER+ breast cancer cells. We further showed that the increase in HuR expression in the TAMR ER+ breast cancer cells is attributable to an increase in the HuR mRNA isoform with shortened 3'-UTR, which exhibits increased translational activity. This shortening of the HuR mRNA 3'-UTR via alternative polyadenylation (APA) was observed to be dependent on cleavage stimulation factor subunit 2 (CSTF2/CstF-64), which is up-regulated in the TAMR breast cancer cells. Taken together, we have characterized a model in which the interplay between miR26a/b and HuR post-transcriptionally up-regulates ERBB2 expression in TAMR ER+ breast cancer cells.

Real-time Microwave Exposure Induces Calcium Efflux in Primary Hippocampal Neurons and Primary Cardiomyocytes.

OBJECTIVE: To detect the effects of microwave on calcium levels in primary hippocampal neurons and primary cardiomyocytes by the real-time microwave exposure combined with laser scanning confocal microscopy. METHODS: The primary hippocampal neurons and primary cardiomyocytes were cultured and labeled with probes, including Fluo-4 AM, Mag-Fluo-AM, and Rhod-2, to reflect the levels of whole calcium [Ca2+], endoplasmic reticulum calcium [Ca2+]ER, and mitochondrial calcium [Ca2+]MIT, respectively. Then, the cells were exposed to a pulsed microwave of 2.856 GHz with specific absorption rate (SAR) values of 0, 4, and 40 W/kg for 6 min to observe the changes in calcium levels. RESULTS: The results showed that the 4 and 40 W/kg microwave radiation caused a significant decrease in the levels of [Ca2+], [Ca2+]ER, and [Ca2+]MIT in primary hippocampal neurons. In the primary cardiomyocytes, only the 40 W/kg microwave radiation caused the decrease in the levels of [Ca2+], [Ca2+]ER, and [Ca2+]MIT. Primary hippocampal neurons were more sensitive to microwave exposure than primary cardiomyocytes. The mitochondria were more sensitive to microwave exposure than the endoplasmic reticulum. CONCLUSION: The calcium efflux was occurred during microwave exposure in primary hippocampal neurons and primary cardiomyocytes. Additionally, neurons and mitochondria were sensitive cells and organelle respectively.

Genome-wide profiling of polyadenylation sites reveals a link between selective polyadenylation and cancer metastasis.

Alternative polyadenylation (APA) is an important post-transcriptional modification implicated in many diseases, including cancer. Although extensively characterized, the functional consequence of APA modulation on tumorigenesis remains elusive. Here, we developed a deep sequencing-based approach that specifically profiles 3' termini of polyadenylated RNAs (herein termed 3T-seq) and analyzed APA events in two gastric cancer cell lines and one non-transformed counterpart. Overall, we identified >28 000 poly(A) sites, 70% of which are potentially novel. Further, we observed widespread APA-mediated 3' UTR shortening of 513 genes (false discovery rate < 0.05) across gastric cancer genome. We characterized one of these genes, NET1, in detail and found that the shortening of NET1 3' UTR significantly enhances transcriptional activity. Moreover, the NET1 isoform with short 3' UTR promotes cellular migration and invasion in vitro. Collectively, our work provides an effective approach for genome-wide APA site profiling and reveals a link between APA modulation and gastric cancer metastasis.

Impact of CYP2C19 Genotype and Liver Function on Voriconazole Pharmacokinetics in Renal Transplant Recipients.

BACKGROUND: Invasive fungal infection (IFI) is one of the leading causes of early death after renal transplantation. Voriconazole (VRC) is the first-line drug of IFI. Because of the large inter- and intraindividual variability in VRC plasma concentrations and the narrow therapeutic window for treating patients with IFIs, it is crucial to study the factors which could influence pharmacokinetic variability. We performed a population pharmacokinetics (PPK) study of VRC for personalized medicine. METHODS: A total of 125 trough concentrations (Cmin) from 56 patients were evaluated, retrospectively. Nonlinear mixed effect model was used to describe a PPK model that was internally validated by bootstrap method. Potential covariates included demographic characteristics, physiological and pathological data, concomitant medications, and CYP2C19 genotype. RESULTS: A 1-compartment model with first-order absorption and elimination was fit to characterize the VRC pharmacokinetics in renal transplant recipients (RTRs). Aspartate aminotransferase (AST) had a significant influence on clearance (CL) while CYP2C19 genotype had a major impact on the volume of distribution (V). The parameters of CL and V were 4.76 L/h and 22.47 L, respectively. The final model was V (L) = 22.47 × [1 + 2.21 × (EM = 1)] × [1 + 4.67 × (IM = 1)] × [1 + 3.30 × (PM = 1)] × exp (0.96); CL (L/h) = 4.76 × (AST/33)^(-0.23) × exp (0.14). VRC Cmin in intermediate metabolizers was significantly higher than in extensive metabolizers. CONCLUSIONS: Liver function and CYP2C19 polymorphism are major determinants of VRC pharmacokinetic variability in RTRs. Genotypes and clinical biomarkers can determine the initial scheme. Subsequently, therapeutic drug monitoring can optimize clinical efficacy and minimize toxicity. Hence, this is a feasible way to facilitate personalized medicine in RTRs. In addition, it is the first report about PPK of VRC in RTRs.

Reduced inflammatory responses of follicular helper T cell promote the development of regulatory B cells after Roux-en-Y gastric bypass.

Bariatric surgery is currently the most effective strategy in treating severe obesity and its comorbidities, such as type 2 diabetes (T2D). However, the mechanism through which bariatric surgery mediates its benefits is not completely understood. Since obesity and T2D represent yet another inflammatory disease, and follicular helper T (Tfh) cells play important roles in inflammatory disorders, we investigated whether the Tfh activity was altered after Roux-en-Y gastric bypass (RYGB), one of the most common bariatric surgery procedures. We found that the Tfh cells after RYGB were not significantly changed in number, but presented altered cytokine secretion profile, including lower interferon (IFN)-γ, interleukin (IL)-2, IL-4, and IL-17 secretion. Tfh cells after RYGB also downregulated inducible co-stimulator and programmed death-1. Interestingly, after Tfh cell-naive B cell coculture, Tfh cells after RYGB secreted more IL-10 than autologous Tfh cells before RYGB. The frequencies of IL-10-expressing and transforming growth factor (TGF)-ß-expressing regulatory B cells after Tfh cell-naive B cell coculture were directly correlated with the frequency of IL-10-expressing Tfh cells. Depletion of IL-10 in the coculture, however, resulted in fewer regulatory B cells. Finally, patients with greater increase in IL-10-expressing Tfh cells presented further reductions in body mass index, glycaemia, and body fat percentage. Together, these data demonstrated that the Tfh cells after RYGB presented lower inflammatory status and secreted higher IL-10, through which these Tfh cells promoted the development of regulatory B cells. Higher IL-10-expressing Tfh cell level also predicted better patient response to RYGB.