Inhibition of Pck1 in intestinal epithelial cells alleviates acute pancreatitis via modulating intestinal homeostasis.

Intestinal barrier dysfunction usually occurred in acute pancreatitis (AP) but the mechanism remains unclear. In this study, RNA sequencing of ileum in L-arginine-induced AP mice demonstrated that phosphoenolpyruvate kinase 1 (Pck1) was significantly up-regulated. Increased Pck1 expression in intestinal epithelial cells (IECs) was further validated in ileum of AP mice and duodenum of AP patients. In AP mice, level of Pck1 was positively correlated with pancreatic and ileal histopathological scores, serum amylase activity, and intestinal permeability (serum diamine oxidase (DAO), D-lactate, and endotoxin). In AP patients, level of Pck1 had a positive correlation with Ranson scores, white blood cell count and C-reactive protein. Inhibition of Pck1 by 3-Mercaptopicolinic acid hydrochloride (3-MPA) alleviated pancreatic and ileal injuries in AP mice. AP + 3-MPA mice showed improved intestinal permeability, including less epithelial apoptosis, increased tight junction proteins (TJPs) expression, decreased serum DAO, D-lactate, endotoxin, and FITC-Dextran levels, and reduced bacteria translocation. Lysozyme secreted by Paneth cells and mucin2 (MUC2) secretion in goblet cells were also partly restored in AP + 3-MPA mice. Meanwhile, inhibition of Pck1 improved intestinal immune response during AP, including elevation of M2/M1 macrophages ratio and secretory immunoglobulin A (sIgA) and reduction in neutrophils infiltration. In vitro, administration of 3-MPA dramatically ameliorated inflammation and injuries of epithelial cells in enteroids treated by LPS. In conclusion, inhibition of Pck1 in IECs might alleviate AP via modulating intestinal homeostasis.

Bacteroides thetaiotaomicron and Faecalibacterium prausnitzii served as key components of fecal microbiota transplantation to alleviate colitis.

Fecal microbiota transplantation (FMT) is a promising therapy for inflammatory bowel disease (IBD) via rectifying gut microbiota. The aim of this study was to identify a mechanism of how specific bacteria-associated immune response contributes to alleviated colitis. Forty donors were divided into high (donor H) and low (donor L) groups according to the diversity and the abundance of Bacteroides and Faecalibacterium by 16S rRNA sequencing. FMT was performed on dextran sulfate sodium (DSS)-induced colitis in mice. Mice with colitis showed significant improvement in intestinal injury and immune imbalance after FMT with group donor H (P < 0.05). Bacteroides thetaiotaomicron and Faecalibacterium prausnitzii were identified as targeted strains in donor feces by real-time PCR and droplet digital PCR. Mice with colitis were treated with mono- or dual-bacterial gavage therapy. Dual-bacterial therapy significantly ameliorated intestinal injury compared with mono-bacterial therapy (P < 0.05). Dual-bacterial therapy increased the M2/M1 macrophage polarization and improved the Th17/Treg imbalance and elevated IL-10 production by Tregs compared with the DSS group (P < 0.05). Metabolomics showed increased abundance of lecithin in the glycerophospholipid metabolism pathway. In conclusion, B. thetaiotaomicron and F. prausnitzii, as the key bacteria in donor feces, alleviate colitis in mice. The mechanism may involve increasing lecithin and regulating IL-10 production of intestinal Tregs.NEW & NOTEWORTHY We demonstrate that donors with high abundance of Bacteroides and Faecalibacterium ameliorate dextran sulfate sodium (DSS)-induced colitis in mice by fecal microbiota transplantation (FMT). The combination therapy of Bacteroides thetaiotaomicron and Faecalibacterium prausnitzii is superior to mono-bacterial therapy in ameliorating colitis in mice, of which mechanism may involve promoting lecithin and inducing IL-10 production of intestinal Tregs.

The effect of immunomodulatory drugs on bone metabolism of patients with multiple myeloma.

INTRODUCTION: Immunomodulatory drugs (IMiDs) are widely used in the management of newly diagnosed and relapsed/refractory multiple myeloma patients. These agents show their potential effect on myeloma bone disease (MBD), including inhibition of osteoclasts activity and effects on osteoblasts differentiation. It is unclear whether these effects are direct, which may have an impact on bone formation markers when combined with proteasome inhibitors. AREAS COVERED: This review summarizes the available evidence on the role of IMiDs in microenvironment regulation and their potential effects on bone metabolism. The literature search methodology consisted of searching PubMed for basic and clinical trials using medical subject terms. Included articles were screened and evaluated by the coauthors of this review. EXPERT OPINION: As a therapeutic option, IMiDs directly affect preosteoblast/osteoclast differentiation. The combination of proteasome inhibitors may counteract the short-term up-regulation of osteogenic activity markers, and therefore intravenous zoledronic acid is recommended, however, obtaining a more significant myeloma response will have a long-term positive impact on myeloma bone disease.

[Clinical Efficacy and Safety of Flumatinib in the Treatment of Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase].

OBJECTIVE: To explore the clinical efficacy and safety of flumatinib mesylate produced in China in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). METHODS: 32 newly diagnosed CML-CP patients admitted to the Hematology Department of the Affiliated Hospital of Southwest Medical University from March 1, 2020 to March 31, 2022, who had never received any tyrosine kinase inhibitor (TKI) were included in the study. The patients were treated by flumatinib mesylate 600mg once daily. The hematologic, cytogenetic and molecular responses were assessed at 3-, 6- and 12-month, and adverse effects of the drug were evaluated. RESULTS: 31 patients were treated with flumatinib for≥3 months, of which 24 patients were treated for ≥6 months and 14 patients were treated for≥12 months. At 3rd month of treatment, 30 out of 31 patients achieved complete hematologic response (CHR); 24 patients underwent cytogenetic testing and 22 cases achieved major cytogenetic response(MCyR), of which 21 cases achieved complete cytogenetic response (CCyR); Among 25 patients who underwent molecular testing, 22 patients had BCR-ABLIS≤10%, including 10 patients with BCR-ABLIS≤0.1%, and 6 patients with BCR-ABLIS≤0.01%. At 6th month of treatment, 23 out of 24 patients achieved CHR; 17 patients underwent cytogenetic testing and all achieved CCyR; Among 23 patients who underwent molecular testing, 20 patients had BCR-ABLIS≤1%, including 16 patients with BCR-ABLIS≤0.1% and 12 patients with BCR-ABLIS≤0.01%. At 12nd month of treatment, all 14 patients achieved CHR and CCyR; Among them, 10 patients had BCR-ABLIS≤0.1%, including 9 patients with BCR-ABLIS≤0.01%. The grade Ⅲ/Ⅳ leukopenia, thrombocytopenia and anemia rates in the patients were 13.3%, 20.0% and 3.3%, respectively. One patient stopped flumatinib therapy due to severe and persistent hematologic toxicity. The major non-hematologic adverse events were abnormal liver function (20%), diarrhea (10%), bone/joint pain (10%), muscle spasm (10%), rash (6.7%), acute kidney injury (6.7%) and nausea(3.3%), most of which were grade I-II. No patient experienced grade Ⅳ non-hematologic adverse events. No drug toxicity-related death occurred. CONCLUSION: Flumatinib mesglate, as the first-line treatment for newly diagnosed CML-CP, can enable the patients to achieve early and deep molecular and cytogenetic responses, and shows good safety.

[Efficacy and Recurrence Factors of Veneclax Combined with Aza- citidine in the Treatment of Acute Myeloid Leukemia].

OBJECTIVE: To observe the efficacy of veneclax combined with azacitidine in acute myeloid leukemia(AML) patients and explore the predictors of treatment response and recurrence. METHODS: The clinical data of 30 AML patients who received venetecla combined with azacitidine in the Affiliated Hospital of Southwest Medical University from January 2021 to September 2022 were retrospectively analyzed, composite complete remission (CRc) rate, overall response rate(ORR), and disease free survival(DFS) of patients were observed. RESULTS: After one course of trea- tment, CRc was 16 cases and ORR was 23/30. Patients with TP53 mutation had poor treatment response (P=0.009). After 1-2 courses, 25 patients reached CR/CRi. Finally, 24 patients who obtained CR/CRi were included to observe the duration of remission. 17 patients had relapse, with a median recurrence time of 3.9 (0.6-15.9) months. The Kaplan-Meier curve showed that MRD negative was a favorable factor for maintaining DFS status (HR=0.5647,95%CI:0.2179-1.464,P=0.007), while NRAS mutation was an adverse factor for maintaining DFS (HR=2.036,95%CI:0.6639-6.245,P=0.0003). Univariate combined multivariate cox regression analysis showed that NRAS mutation was an independent risk factor affecting DFS in patients (HR=5.569, P<0.05). In addition, the cases number of early recurrence in MRD negative group (n=8) and MRD non-negative group (n=9) was 0 and 5, respectively, the difference was statistically significant (P=0.012). There were 3 cases of early recurrence in the NRAS mutant group (n=4) and 2 cases in the NRAS wild-type group (n=13), the difference was statistically significant (P=0.022). CONCLUSION: TP53 mutation is a predictor of poor response to veneclax in combination with azacitidine. With the conti-nuation of the combination chemotherapy regimen described above, NRAS mutation is an independent risk factor for DFS in patients. Moreover, the patients with non-negative MRD and NRAS mutations are at high risk of early recurrence.

Short-Term Exposure to Nitrogen Dioxide Modifies Genetic Predisposition in Blood Lipid and Fasting Plasma Glucose: A Pedigree-Based Study.

(1) Background: Previous studies suggest that exposure to nitrogen dioxide (NO2) has a negative impact on health. But few studies have explored the association between NO2 and blood lipids or fasting plasma glucose (FPG), as well as gene-air pollution interactions. This study aims to fill this knowledge gap based on a pedigree cohort in southern China. (2) Methods: Employing a pedigree-based design, 1563 individuals from 452 families participated in this study. Serum levels of triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDLC), high-density lipoprotein cholesterol (HDLC), and FPG were measured. We investigated the associations between short-term NO2 exposure and lipid profiles or FPG using linear mixed regression models. The genotype-environment interaction (GenoXE) for each trait was estimated using variance component models. (3) Results: NO2 was inversely associated with HDLC but directly associated with TG and FPG. The results showed that each 1 µg/m3 increase in NO2 on day lag0 corresponded to a 1.926% (95%CI: 1.428-2.421%) decrease in HDLC and a 1.400% (95%CI: 0.341-2.470%) increase in FPG. Moreover, we observed a significant genotype-NO2 interaction with HDLC and FPG. (4) Conclusion: This study highlighted the association between NO2 exposure and blood lipid profiles or FPG. Additionally, our investigation suggested the presence of genotype-NO2 interactions in HDLC and FPG, indicating potential loci-specific interaction effects. These findings have the potential to inform and enhance the interpretation of studies that are focused on specific gene-environment interactions.

A pedigree-based cohort to study the genetic risk factors for cardiometabolic diseases: study design, baseline characteristics and preliminary results.

Background: We initiated the Fujian Tulou Pedigree-based Cohort (FTPC) as the integration of extended pedigrees and prospective cohort to clarify the genetic and environmental risk factors of cardiometabolic diseases. Methods: FTPC was carried out in Nanjing County, Fujian Province, China from August 2015 to December 2017 to recruit probands with the same surnames and then enroll their first-degree and more distant relatives. The participants were asked to complete questionnaire interview, physical examination, and blood collection. According to the local genealogical booklets and family registry, we reconstructed extended pedigrees to estimate the heritability of cardiometabolic traits. The follow-up of FTPC is scheduled every 5 years in the future. Results: The baseline survey interviewed 2,727 individuals in two clans. A total of 1,563 adult subjects who completed all baseline examinations were used to reconstruct pedigrees and 452 extended pedigrees were finally identified, including one seven-generation pedigree, two five-generation pedigrees, 23 four-generation pedigrees, 186 three-generation pedigrees, and 240 two-generation pedigrees. The average age of the participants was 57.4 years, with 43.6% being males. The prevalence of hypertension, diabetes and dyslipidemia in FTPC were 49.2, 10.0, and 45.2%, respectively. Based on the pedigree structure, the heritability of systolic blood pressure, diastolic blood pressure, fast blood glucose, total cholesterol, triglyceride, high-density lipoprotein, and low-density lipoprotein was estimated at 0.379, 0.306, 0.386, 0.452, 0.568, 0.852, and 0.387, respectively. Conclusion: As an extended pedigree cohort in China, FTPC will provide an important source to study both genetic and environmental risk factors prospectively.

18F­FDG PET/CT based radiomics features improve prediction of prognosis: multiple machine learning algorithms and multimodality applications for multiple myeloma.

PURPOSE: Multiple myeloma (MM), the second most hematological malignancy, have been studied extensively in the prognosis of the clinical parameters, however there are only a few studies have discussed the role of dual modalities and multiple algorithms of 18F-FDG (18F-fluorodeoxyglucose) PET/CT based radiomics signatures for prognosis in MM patients. We hope to deeply mine the utility of raiomics data in the prognosis of MM. METHODS: We extensively explored the predictive ability and clinical decision-making ability of different combination image data of PET, CT, clinical parameters and six machine learning algorithms, Cox proportional hazards model (Cox), linear gradient boosting models based on Cox's partial likelihood (GB-Cox), Cox model by likelihood based boosting (CoxBoost), generalized boosted regression modelling (GBM), random forests for survival model (RFS) and support vector regression for censored data model (SVCR). And the model evaluation methods include Harrell concordance index, time dependent receiver operating characteristic (ROC) curve, and decision curve analysis (DCA). RESULTS: We finally confirmed 5 PET based features, and 4 CT based features, as well as 6 clinical derived features significantly related to progression free survival (PFS) and we included them in the model construction. In various modalities combinations, RSF and GBM algorithms significantly improved the accuracy and clinical net benefit of predicting prognosis compared with other algorithms. For all combinations of various modalities based models, single-modality PET based prognostic models' performance was outperformed baseline clinical parameters based models, while the performance of models of PET and CT combined with clinical parameters was significantly improved in various algorithms. CONCLUSION: 18F­FDG PET/CT based radiomics models implemented with machine learning algorithms can significantly improve the clinical prediction of progress and increased clinical benefits providing prospects for clinical prognostic stratification for precision treatment as well as new research areas.

Colonic mucin-2 attenuates acute necrotizing pancreatitis in rats by modulating intestinal homeostasis.

Mucin-2 (MUC2) secreted by goblet cells participates in the intestinal barrier, but its mechanism in acute necrotizing pancreatitis (ANP) remains unclear. In acute pancreatitis (AP) patients, the functions of goblet cells (MUC2, FCGBP, CLCA1, and TFF3) decreased, and MUC2 was negatively correlated with AP severity. ANP rats treated with pilocarpine (PILO) (PILO+ANP rats) to deplete MUC2 showed more serious pancreatic and colonic injuries, goblet cell dysfunction, gut dysbiosis, and bacterial translocation than those of ANP rats. GC-MS analysis of feces showed that PILO+ANP rats had lower levels of butyric acid, isobutyric acid, isovaleric acid, and hexanoic acid than those of ANP rats. The expression of MUC2 was associated with colonic injury and gut dysbiosis. All these phenomena could be relieved, and goblet cell functions were also partially reversed by MUC2 supplementation in ANP rats. TNF-α-treated colonoids had exacerbated goblet cell dysfunction. MUC2 expression was negatively correlated with the levels of pro-inflammatory cytokines (IL-1ß and IL-6) (p < .05) and positively related to the expression of tight junction proteins (Claudin 1, Occludin, and ZO1) (p < .05). Downregulating MUC2 by siRNA increased the levels of the pro-inflammatory cytokines in colonoids. MUC2 might maintain intestinal homeostasis to alleviate ANP.

Novel chemical-structure TPOR agonist, TMEA, promotes megakaryocytes differentiation and thrombopoiesis via mTOR and ERK signalings.

BACKGROUND: Non-peptide thrombopoietin receptor (TPOR) agonists are promising therapies for the mitigation and treatment of thrombocytopenia. However, only few agents are available as safe and effective for stimulating platelet production for thrombocytopenic patients in the clinic. PURPOSE: This study aimed to develop a novel small molecule TPOR agonist and investigate its underlying regulation of function in megakaryocytes (MKs) differentiation and thrombopoiesis. METHODS: A potential active compound that promotes MKs differentiation and thrombopoiesis was obtained by machine learning (ML). Meanwhile, the effect was verified in zebrafish model, HEL and Meg-01 cells. Next, the key regulatory target was identified by Drug Affinity Responsive Target Stabilization Assay (DARTS), Cellular Thermal Shift Assay (CETSA), and molecular simulation experiments. After that, RNA-sequencing (RNA-seq) was used to further confirm the associated pathways and evaluate the gene expression induced during MK differentiation. In vivo, irradiation (IR) mice, C57BL/6N-TPORem1cyagen (Tpor-/-) mice were constructed by CRISPR/Cas9 technology to examine the therapeutic effect of TMEA on thrombocytopenia. RESULTS: A natural chemical-structure small molecule TMEA was predicted to be a potential active compound based on ML. Obvious phenotypes of MKs differentiation were observed by TMEA induction in zebrafish model and TMEA could increase co-expression of CD41/CD42b, DNA content, and promote polyploidization and maturation of MKs in HEL and Meg-01 cells. Mechanically, TMEA could bind with TPOR protein and further regulate the PI3K/AKT/mTOR/P70S6K and MEK/ERK signal pathways. In vivo, TMEA evidently promoted platelet regeneration in mice with radiation-induced thrombocytopenia but had no effect on Tpor-/- and C57BL/6 (WT) mice. CONCLUSION: TMEA could serve as a novel TPOR agonist to promote MKs differentiation and thrombopoiesis via mTOR and ERK signaling and could potentially be created as a promising new drug to treat thrombocytopenia.

Comparison between ixazomib+cyclophosphamide+dexamethasone regimen and ixazomib+dexamethasone regimen for elderly and frail patients having newly diagnosed multiple myeloma.

AIMS: The purpose of this prospective, randomized study was to investigate the effectiveness and safety of the ixazomib+cyclophosphamide+dexamethasone (ICd) and ixazomib+dexamethasone (Id) regimens in newly diagnosed multiple myeloma (NDMM) who were elderly and frail and to compare the two regimens. METHODS: Patients were randomly grouped into ICd and Id group. The primary end point was ORR, and patients who received at least two cycles were analyzed. The median follow-up was 13.5 months. After nine induction cycles, patients were instructed to take single ixazomib for maintenance. RESULTS: The overall response rate in the ICd and Id groups was 78.9% and 70.6%, respectively, whereas the very good partial remission or better rate was 47.4% and 23.5%, respectively. For the ICd and Id groups, the response rate after 4 cycles was 76.5% and 57.1%, and the median duration to response was 2 and 4 months, respectively. Adverse events (AEs) included gastrointestinal intolerance, rash, fatigue, and thrombocytopenia, with severe AEs occurring in 21.1% and 23.5% patients in the ICd and Id groups, respectively, and the AEs were manageable. Both the QLQ-C30 and QLQ-MY20 scales indicated that ICd and Id regimens could help maintain and improve the quality of life(QoL). CONCLUSIONS: The ICd and Id regimens might be effective and well-tolerated in elderly and frail patients with NDMM. In addition, a favorable outcome was observed that ICd might tend to cause faster and higher remission than Id regimen without increasing the risk of AEs. The long-term effectiveness and safety of the two regimens need further investigation.

[miR-29a-3p Targets Hepatoma-Derived Growth Factor to Inhibit the Proliferation and Promote the Apoptosis of E6-1 Cells].

OBJECTIVE: To investigate the regulatory effect of miRNA-29a-3p (miR-29a-3p ) on hepatoma-derived growth factor (HDGF), and its influences on the proliferation and apoptosis of acute lymphoblastic leukemia (ALL) cell line E6-1. METHODS: Thirty-five patients with ALL treated in our hospital from January 2017 to January 2019 were selected as research objects, and 35 adults who underwent physical examination in the same period were selected as healthy control group. The miR-29a-3p overexpression vector, miR-29a-3p inhibitory expression vector, and miR-29a-3p and HDGF co-overexpression vector were transfected into E6-1 cells. The expression levels of miR-29a-3p and HDGF mRNA were detected by RT-qPCR. The expression of protein was detected by Western blot. The targeting relationship between miR-29a-3p and HDGF was detected by dual luciferase reporter assay. The cell proliferation was detected by CCK-8 method, while apoptosis detected by flow cytometry. RESULTS: Compared with healthy control group, HDGF was highly expressed in serum of patients with ALL and leukemia cells HuT 78, E6-1, CCRF-CEM, while miR-29a-3p was low expressed (P<0.05). After overexpression of miR-29a-3p , the expression levels of CyclinD1 and Bcl-2 in leukemia cells E6-1 were significantly reduced, while the expression levels of p21 and Bax were significantly increased (P<0.05). The activity of E6-1 cells was also significantly reduced, while the apoptosis rate of E6-1 cells was significantly increased (P<0.05). miR-29a-3p could target and regulate the expression of HDGF, while overexpression of HDGF reversed the inhibitory effect of miR-29a-3p overexpression on the proliferation and promotion effect on the apoptosis of leukemia cells E6-1. CONCLUSION: Overexpression of miR-29a-3p can inhibit the proliferation and promote the apoptosis of ALL cells E6-1, and its mechanism may be related to the regulation of HDGF expression.

Serum metabolomics reveals the effects of accompanying treatment on fatigue in patients with multiple myeloma.

PURPOSE: The renewal and iteration of chemotherapy drugs have resulted in more frequent long-term remissions for patients with multiple myeloma (MM). MM has transformed into a chronic illness for many patients, but the cancer-related fatigue (CRF) of many MM convalescent patients experience is frequently overlooked. We investigated whether the accompanying treatment of family members would affect MM patients' CRF and explore their serum metabolomics, so as to provide clinicians with new ideas for identifying and treating CRF of MM patients. METHODS: This was a single-center study, and a total of 30 MM patients were included in the study. Patients were divided into two groups based on whether they have close family members accompanying them through the whole hospitalization treatment. These patients received regular chemotherapy by hematology specialists, and long-term follow-up was done by general practitioners. Patients' CRF assessment for several factors used the Chinese version of the Brief Fatigue Inventory (BFI-C). Face-to-face questionnaires were administered at a time jointly determined by the patient and the investigator. All questionnaires were conducted by a general practitioner. The LC-MS-based metabolomics analysis determined whether the patients' serum metabolites were related to their fatigue severity. A correlation analysis investigated the relationship between serum metabolites and clinical laboratory indicators. RESULTS: The fatigue severity of MM patients whose family members participated in the treatment process (group A) was significantly lower than patients whose family members did not participate in the treatment process (group B). There was a statistically significant difference (fatigue severity composite score: t = - 2.729, p = 0.011; fatigue interference composite score: t = - 3.595, p = 0.001). There were no differences between the two groups of patients' gender, age, regarding clinical staging, tumor burden, blood routine, biochemical, or coagulation indexes. There were 11 metabolites, including guanidine acetic acid (GAA), 1-(Methylthio)-1-hexanethiol, isoeucyl-asparagine, L-agaritine, tryptophyl-tyrosine, and betaine, which significantly distinguished the two groups of MM patients. GAA had the strongest correlation with patient fatigue, and the difference was statistically significant (fatigue severity composite score: r = 0.505, p = 0.0044; fatigue interference composite score: r = 0.576, p = 0.0009). The results showed that GAA negatively correlated with albumin (r = - 0.4151, p = 0.0226) and GGT (r = - 0.3766, p = 0.0402). Meanwhile, GAA positively correlated with PT (r = 0.385, p = 0.0473), and the difference was statistically significant. CONCLUSION: The study is the first to report that family presence throughout the whole hospitalization may alleviate CRF in MM patients. Moreover, the study evaluated serum metabolites linked to CRF in MM patients and found that CRF has a significant positive correlation with GAA. GAA may be a more sensitive biomarker than liver enzymes, PT, and serum albumin in predicting patient fatigue. While our sample may not represent all MM patients, it proposes a new entry point to help clinicians better identify and treat CRF in MM patients.

Fecal microbiota transplantation versus glucocorticoids for the induction of remission in mild to moderate ulcerative colitis.

OBJECTIVE: To compare efficacy and safety of fecal microbiota transplantation (FMT) with glucocorticoid as induction therapy in ulcerative colitis (UC). METHODS: The patients with active mild to moderate UC were recruited into the single-center, prospective cohort study. The patients were treated with either FMT (FMT group) or glucocorticoids (GCs group). Patients received FMT administration for 3 days. The primary outcome was clinical and endoscopic remission at week 12. Inflammatory parameters were assessed by routine blood tests. Safety was assessed by adverse events recorded. The serum levels of TNF-α, IFN-γ, IL-1ß, IL-4, IL-5, IL-6, IL-10 IL-8, IL-12p70, IL-13, IL-17A and IL-23 following FMT were measured by Luminex multiplex assay. RESULTS: Of the 122 patients, 62 patients were treated with FMT and 60 with glucocorticoids. 34 patients in FMT group (54.8%) and 29 in GCs group (48.3%) reached the primary outcome (p = 0.30). The incidence of adverse events in GCs group (35/60, 58.3%) was significantly higher than that in FMT group (14/62, 22.6%) and two serious adverse events were observed following GCs. Patients in FMT group were stratified into responders (RE) and non-responders (NR) groups. The level of TNF-α and IL-6 decreased significantly in RE group, while IL-10 decreased significantly in NR group. CONCLUSION: FMT therapy was as effective as glucocorticoids to induce remission in active mild to moderate UC, accompanied by fewer adverse events. The modification of serum TNF-α, IL-6 and IL-10 might be related to the efficacy of FMT in UC. Trial registration This study was registered with ClinicalTrials.gov (NCT02435160). Registered on 6 April, 2015. https://clinicaltrials.gov/ct2/results?cond=&term=NCT02435160&cntry=&state=&city=&dist=.

MALDI-TOF MS-Based Clustering and Antifungal Susceptibility Tests of Talaromyces marneffei Isolates from Fujian and Guangxi (China).

Introduction: Talaromyces marneffei is a life-threatening pathogen that causes systemic talaromycosis in immunocompromised and acquired immunodeficiency syndrome (AIDS) patients. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) as a tool to cluster T. marneffei isolates is rarely reported and the data on antifungal susceptibility of T. marneffei isolated in the southern region of China, especially in Fujian, is hardly found. Methods: MALDI-TOF MS was used to cluster 135 T. marneffei isolates, and the minimum inhibitory concentration (MIC) values of amphotericin B, itraconazole, posaconazole, voriconazole, fluconazole, anidulafungin, micafungin, caspofungin and 5-fluorocytosine with Sensititre YeastOne™ YO10 assay were measured during January 2017 to October 2020 in Fujian and Guangxi. Results: MALDI-TOF MS correctly identified 100% of the T. marneffei isolates. Hierarchical clustering of MALDI-TOF peak profiles identified four different clusters. MICs for itraconazole, posaconazole, voriconazole and amphotericin B were as follows: ≤0.015-0.03 µg/mL, ≤0.008-0.03 µg/mL, ≤0.008-0.06 µg/mL, ≤0.12-1 µg/mL, respectively. MICs for echinocandins and fluconazole were comparatively high. Conclusion: Since only simple sample preparation is required and since results are available in a short period of time, MALDI-TOF MS can be considered as a method for identification and clustering of T. marneffei. Itraconazole, posaconazole, voriconazole and amphotericin B can be used to treat T. marneffei infected patients due to the low MICs.

Is RDW a clinically relevant prognostic factor for newly diagnosed multiple myeloma? A systematic review and meta-analysis.

BACKGROUND: Multiple myeloma (MM) is an incurable plasma cell malignancy. Red cell distribution width (RDW) is a prognostic marker in various diseases, solid tumors, and hematologic neoplasms, but its prognostic significance in MM is controversial. In this study, we aimed to assess the relationship between RDW and the clinical prognosis of MM patients through a meta-analysis. METHODS: Relevant literature were retrieved from PubMed, Embase, and Web of Science databases according to PRISMA guideline. All relevant parameters were extracted and combined for statistical analysis. The effect size was presented as hazard ratio (HR)/odds ratio (OR) and 95% confidence interval (CI). HR/OR > 1 in MM patients with high RDW suggested a worse prognosis. Heterogeneity test evaluation was performed using Cochran's Q test and I2 statistics. A Pheterogeneity < 0.10 or I2 > 50% suggested significant heterogeneity. P < 0.05 was considered statistically significant. Statistical analysis was performed using Stata 12.0 software. RESULTS: 8 articles involving 9 studies with 1165 patients were included in our meta-analysis. Our results suggested that elevated RDW is significantly associated with poor prognosis in MM (OS: HR = 1.91, 95%CI: 1.48-2.46; PFS: HR = 2.87, 95% CI: 2.02-4.07). A significant correlation was not found between RDW and International Staging System (ISS) staging (ISS III VS ISS I-II: OR:1.53; 95%CI:0.97-2.42). CONCLUSION: Our results suggested that RDW is a robust predictor of newly diagnosed MM outcomes.

The Prognostic Significance of the BIN1 and CCND2 Gene in Adult Patients with Acute Myeloid Leukemia.

To investigate the expression and clinical significance of Bridging INtegrator 1 (BIN1) and cyclin D2 (CCND2) in newly diagnosed cytogenetically heterogenous adult acute myeloid leukemia patients. Methods Real-time quantitative PCR (RQ-PCR) was used to detect the expression of BIN1 and CCND2 genes in 49 newly diagnosed adult patients with AML, and their clinical significance was analyzed. Results BIN1 and CCND2 genes are highly expressed in patients with AML, which suggest their potential as molecular markers. A statistical significant correlation was found between BIN1 expression with bone marrow blasts (P = 0.012), CD34 expression (P = 0.026), NLR (P = 0.019) and Karyotype risk (P = 0.005). There was a statistically significant correlation between CCND2 and age (P = 0.001), NLR (P = 0.046) Karyotype risk (P = 0.033). The expression level of BIN1 was related to early treatment response (CR or not) (P = 0.043). CCND2 expression was significantly correlated with overall survival (P = 0.013), but not with CR (P = 0.731). Conclusion BIN1 and CCND2 genes are highly expressed in patients with AML, suggesting the potential of these two genes as molecular markers. Moreover, high levels of CCND2 are associated with better prognosis, suggesting the possibility of these two genes as prognostic markers.

Ulcerative Colitis in Response to Fecal Microbiota Transplantation via Modulation of Gut Microbiota and Th17/Treg Cell Balance.

Background: Fecal microbiota transplantation (FMT) may contribute to disease remission in ulcerative colitis (UC). We studied the microbiota change and its regulation on T cells after FMT. Methods: Patients with mild to moderately active UC were included to receive FMT. The intestinal histopathological changes and barrier function were evaluated. The fecal samples of donors and patients were analyzed by 16S rRNA gene-based microbiota analysis, and the colon Th17 and Treg cells were assessed. Results: Fifteen patients completed the 8-week-follow-up. A total of 10 patients (66.7%) were in the responders (RE) group and five in the non-responders (NR) group. The Nancy histological index and fecal calprotectin decreased (p < 0.001, p = 0.06, respectively) and Occludin and Claudin1 increased in the RE group. The abundance of Faecalibaterium increased significantly by 2.3-fold in the RE group at week 8 (p = 0.043), but it was suppressed in the NR group. Fecal calprotectin (r = −0.382, p = 0.003) and Nancy index (r = −0.497, p = 0.006) were correlated inversely with the abundance of Faecalibacterium, respectively. In the RE group the relative mRNA expression of RORγt decreased and Foxp3 increased. Significantly decreased CD4+ RORγt+ Th17 and increased CD4+ Foxp3+ Treg were also observed in the RE group. The relative abundance of Faecalibacterium correlated with CD4+ RORγt+ Th17 (r = −0.430, p = 0.018) and CD4+ Foxp3+ Treg (r = 0.571, p = 0.001). Conclusions: The long-term Faecalibaterium colonization following FMT plays a crucial role in UC remission by alleviating intestinal inflammation. This anti-inflammatory effect of Faecalibacterium may be achieved by regulating the imbalance of Th17/Treg levels in UC.

Serum Metabolomics Coupling With Clinical Laboratory Indicators Reveal Taxonomic Features of Leukemia.

Metabolic abnormality has been considered to be the seventh characteristic in cancer cells. The potential prospect of using serum biomarkers metabolites to differentiate ALL from AML remains unclear. The purpose of our study is to probe whether the differences in metabolomics are related to clinical laboratory-related indicators. We used LC-MS-based metabolomics analysis to study 50 peripheral blood samples of leukemia patients from a single center. Then Chi-square test and T test were used to analyze the clinical characteristics, laboratory indicators and cytokines of 50 patients with leukemia. Correlation analysis was used to explore the relationship between them and the differential metabolites of different types of leukemia. Our study shows that it is feasible to better identify serum metabolic differences in different types and states of leukemia by metabolomic analysis on existing clinical diagnostic techniques. The metabolism of choline and betaine may also be significantly related to the patient's blood lipid profile. The main enrichment pathways for distinguishing differential metabolites in different types of leukemia are amino acid metabolism and fatty acid metabolism. All these findings suggested that differential metabolites and lipid profiles might identify different types of leukemia based on existing clinical diagnostic techniques, and their rich metabolic pathways help us to better understand the physiological characteristics of leukemia.

Paneth Cells Protect against Acute Pancreatitis via Modulating Gut Microbiota Dysbiosis.

Acute pancreatitis (AP) is usually accompanied by intestinal failure, but its mechanism is still unclear. In AP patients, the functions of Paneth cells (lysozyme, HD5, Reg3γ, and Wnt3a) decreased. Compared with AP mice, injuries and inflammation of the pancreas and ileum were aggravated in AP mice treated with dithizone (Dith) (Dith+AP mice). Intestinal permeability and bacterial translocation were also increased. 16S rRNA sequencing showed that the gut microbiota of Dith mice and Dith+AP mice exhibited a marked increase in the pathogenic bacterium Helicobacter and a significant decrease in the probiotic bacterium Blautia. Lysozyme gavage in Dith+AP mice effectively alleviated injuries of the pancreas and small intestine. The beneficial effect of lysozyme was associated with a significant increase in the probiotic bacterium Blautia and a virtual absence of the pathogenic bacterium Helicobacter. The severity of AP in antibiotic-treated mice (ABX mice) was significantly aggravated when receiving feces from Dith mice and was markedly alleviated when receiving feces from lysozyme-gavaged mice. In vitro, lysozyme increased the proliferation of enteroids by promoting the activation of the Wnt pathway and Lgr5 expression in intestinal stem cells. IMPORTANCE We demonstrate that AP patients and experimental AP mice exhibited a dysfunction of Paneth cells. Our in vivo research showed that the severity of AP was exacerbated by the long-term dysfunction of Paneth cells, which was associated with gut microbiota disorder. Restoring part of Paneth cell functions through lysozyme supplementation alleviated the severity of AP and gut microbiota dysbiosis. This study provides novel insight into the link of pancreas-gut interactions in the pathogenesis of AP, providing a new direction for the clinical treatment of intestinal complications during AP.