[Construction of CD138-targeted chimeric antigen receptor- modified T cells and their effect in multiple myeloma therapy].

Objective: To construct a novel chimeric antigen receptor T (CAR-T) cell targeting CD138 and to investigate its cytotoxicity against myeloma cells. Methods: The hybridoma strain that can stably secrete the CD138 monoclonal antibody (mAb) was prepared and obtained through monoclonal antibody screening technology. The hybridoma strain cells were intraperitoneally injected into mice to produce ascites containing monoclonal antibodies, which were then collected and purified to obtain pure CD138 mAb. Further examinations were performed to assess the biological characteristics of CD138 mAb. The variable region sequence of this antibody was amplified through reverse transcription polymerase chain reaction and was used as the antigen recognition domain of CD138 CAR, which was subsequently expressed on the surface of T cells by lentiviral infection. Flow cytometry was employed to assess the phenotype of CD138 CAR-T cells. In vitro cytotoxicity and degranulation assays were performed to evaluate their antitumor effects. Results: ① We successfully prepared anti-human CD138 antibody hybridoma cell lines and screened a hybridoma cell strain, 5G2, which could persistently and stably secrete the anti-CD138 antibody. ② The purified CD138 (5G2) mAb can especially recognize CD138(+) cells with a binding affinity constant (K(D)) of 6.011×10(-9) mol/L and showed no significant binding activity with CD138(-) cells. ③The variable region sequence of the CD138 (5G2) antibody was obtained using molecular cloning technology, and CD138 (5G2) CAR was successfully constructed and expressed on T cells through lentivirus infection and, concurrently, demonstrated effective binding to recombinant human CD138 protein.④ The proliferation of T cells transduced with the CD138 (5G2) CAR was highly efficient. The phenotype analysis revealed that CD138 (5G2) CAR-T cells exhibited a greater tendency to differentiate into central memory T cells and memory stem T cells, with a reduced proportion of terminally differentiated effector memory subsets. ⑤CD138 (5G2) CAR-T cells demonstrated specific cytotoxicity against CD138(+) myeloma cell line H929, whereas CD138(-) cell line K562 remained unaffected. The percentage of residual H929 cells was (12.92±8.02) % after co-culturing with CD138 (5G2) CAR-T cells, while (54.25±15.79) % was left in the Vector-T group (E∶T=1∶2; P<0.001). ⑥Results of degranulation assays demonstrated a significant activation of CD138 (5G2) CAR-T cells after co-culture with the H929 cell line, whereas no significant activation was observed in Vector-T cells [ (25.78±3.35) % vs (6.13±1.30) %, P<0.001]. ⑦After co-culturing with CD138(+) cells, CD138 (5G2) CAR-T cells exhibited a significant increase in cytokine secretion compared to the Vector-T group [interleukin-2: (1 697.52±599.05) pg/ml vs (5.07±1.17) pg/ml, P<0.001; interferon-γ: (3 312.20±486.38) pg/ml vs (9.28±1.46) pg/ml, P<0.001; and tumor necrosis factor-α: (1 837.43±640.49) pg/ml vs (8.75±1.65) pg/ml, P<0.001]. However, no significant difference was observed in cytokine secretion levels between the two groups after co-culturing with CD138(-) cells. Conclusion: This study successfully prepared a novel monoclonal antibody against CD138, and CAR-T cells constructed with the antigen recognition domain derived from this 5G2 mAb demonstrated effective antitumor activity against myeloma cells. This can be used as a new option for the detection of the CD138 antigen and proposes a novel strategy for multiple myeloma immunotherapy.

[Clinical efficacy of intraarticular vancomycin in preventing early periprosthetic joint infection after primary knee arthroplasty].

Objective: To investigate the clinical effect of intraarticular vancomycin on early periprosthetic joint infection (PJI) in knee arthroplasty and the incidence of postoperative complications. Methods: This is a retrospective cohort study. The clinical data of 1 867 patients who underwent primary knee arthroplasty at Department of Joint Surgery, the Affiliated Hospital of Qingdao University from April 2022 to June 2023 were retrospectively analysed, including total knee arthroplasty (TKA), robotic-assisted total knee arthroplasty (RA-TKA) and unicondylar knee arthroplasty (UKA). There were 687 males and 1 180 females, aged (68.0±11.2)years(range:45 to 87 years). Patients were divided into the vancomycin group and the control group according to whether or not intra-articular injection of 1 g of vancomycin powder dissolved in 30 ml of saline was performed after intraoperative joint capsule closure. In the vancomycin group, 925 patients were included, including 782 TKA, 27 RA-TKA and 116 UKA.In the control group, 942 patients were included, including 767 TKA, 99 RA-TKA and 76 UKA. Early PJI, wound complications, and vancomycin-related toxicity including acute renal collapse, ototoxicity, and allergic reactions were assessed within 3 months postoperatively. The data were compared using the independent sample t test, χ² test, and Fisher's exact probability method, as appropriate. Major Extremity Trauma Research Consortium (METRC). Results: No PJI was found in all patients in the vancomycin group.Five cases (0.7%,5/767) of early PJI were found in TKA patients in the control group, with a statistically significant difference (P=0.030); 1 case of early PJI was found in each RA-TKA and UKA patients, with non-significant difference compared with vancomycin group (all P>0.05). Two cases (0.3%,2/782) of incisional complications were found in TKA patients in the vancomycin group, and 4 cases (0.5%, 4/767) of incisional complications were found in TKA patients in the control group, with non-significant difference(P=0.449); no incisional complication was found in RA-TKA patients in the vancomycin group, and 1 case (1.0%,1/99) of incisional complications were found in RA-TKA patients in the control group, the difference was not statistically significant (P>0.05); no incisional complication was found in both groups of UKA patients.No vancomycin-related acute kidney injury, ototoxicity, or allergic reactions was observed in all patients. Conclusion: Intra-articular injection of 1 g of vancomycin suspension after arthrotomy closure during TKA maybe lower the risk of early PJI without increasing the risk of wound complication and vancomycin-associated systemic toxicity.

[The relationships between functional gastrointestinal diseases and psychological factors, diet and lifestyles: a network analysis].

Objective: To investigate the relationship between common functional gastrointestinal diseases symptoms with psychological factors, diet and lifestyles by using the network analysis method which has achieved great success in the field of psychology in recent years. Method: A questionnaire survey was conducted in two military units using the cluster sampling method during July 2020, and a total of 1 805 subjects were included. Functional gastrointestinal disease symptoms were evaluated with the Gastrointestinal Symptom Rating Scale (GSRS). The state, trait anxiety scale and stress response scale were used to evaluate the mental and psychological state by self-evaluation. R was used to build the network and calculate statistical parameters. Results: 1 486 of the 1 805 subjects (82.3%) had experienced functional gastrointestinal diseases symptoms within 2 weeks, but most of them were mild. Network analysis shows that there was a strong interaction between digestive system symptoms with different clinical manifestations (Spearman coefficient ranges 0.31-0.56). There was a clear relationship between functional gastrointestinal symptoms and mental and psychological factors (Spearman coefficient ranges 0.16-0.27), but there was no clear interaction with diet, age, education level, body mass index, etc. Functional gastrointestinal diseases symptoms were connected with mental and psychological factors through two nodes: stress and indigestion. The stability coefficient of node strength correlation was 0.75, indicating that the network was stable. Conclusions: The current study revealed the network structure and features of functional gastrointestinal diseases symptoms with mental and psychological factors. The key linking nodes provided potential interfering target for controlling functional gastrointestinal symptoms related to mental and psychological factors.

[Current status, challenges and reflections on stem cell therapy for liver diseases].

There are increasing number of clinical studies on the use of stem cells in the treatment of liver diseases. Most studies have shown that stem cells can significantly improve liver function and prolong survival in patients with decompensated cirrhosis and liver failure. However, the current study has high heterogeneity and few mechanistic research data, which cannot answer many key questions about stem cell therapy for liver diseases. This paper reviews the research status of stem cells, in order to clarify the existing problems and challenges, and puts forward some reflections and countermeasures, with hope to promote the clinical application of stem cells in the treatment of liver diseases.

[Study of the effects of long-term outcomes of autologous peripheral blood stem cell reinfusion in patients with decompensated cirrhosis].

Objective: Autologous peripheral blood stem cells (PBSC) derived from bone marrow can promote liver regeneration and improve the liver function of patients, but there are few studies on its effect on the long-term outcomes in patients with decompensated cirrhosis. Based on previous work, this study observed the clinical outcomes of PBSC treatment in patients with decompensated cirrhosis for 10 years, in order to provide more data support for the safety and efficacy of stem cells in clinical applications. Methods: Data of patients with decompensated liver cirrhosis who completed PBSC treatment in the Department of Gastroenterology of the First Affiliated Hospital of Air Force Military Medical University from August 2005 to February 2012 were included. The follow-up endpoint was death or liver transplantation, and patients who did not reach the follow-up endpoint were followed-up for at least 10 years. The patients with decompensated liver cirrhosis who met the conditions for PBSC treatment but did not receive PBSC treatment in our hospital during the same period were used as controls. Results: A total of 287 cases with decompensated liver cirrhosis had completed PBSC treatment, and 90 cases were lost to follow-up within 10 years after surgery. A total of 151 cases with complete survival follow-up data were included in the control group. There were no statistically significant differences in baseline information such as gender, age, etiological composition and liver function score between the two groups. The 10-year survival rate was higher in PBSC than control group (37.56% vs. 26.49%, P<0.05). Cholinesterase, albumin, international normalized ratio, Child-Turcotte-Pugh score, model for end-stage liver disease score, and other indicators were gradually recovered within 3 months to 1 year after PBSC treatment, and stabilized at a more desirable level in the long-term after follow-up for up to 10 years. There was no statistically significant difference in the incidence of liver cancer between the two groups (25.22% vs.31.85%, P=0.267). The age of onset of hepatocellular carcinoma was later in PBSC than control group [(56.66±7.21) years vs. (52.69±8.42) years, P<0.05]. Conclusions: This long-term observational follow-up study of more than ten years confirms that PBSC treatment can bring long-term benefits to patients with decompensated cirrhosis, with good long-term safety, thus providing more data support on the safety and efficacy of stem cells for clinical applications.

[Diagnostic value of platelet associated biomarkers in chronic periprosthetic joint infection].

Objective: To evaluate the diagnostic value of platelet count(PC),PC to mean platelet volume(MPV) ratio(PC/MPV) and plateletcrit(PCT) in chronic periprosthetic joint infection(PJI). Method: The medical records of 159 patients who underwent hip or knee revisions at Department of Joint Surgery,Affiliated Hospital of Qingdao University from August 2013 to June 2019 were retrospectively reviewed. There were 51 patients(26 knees and 25 hips) in the PJI group,which included 28 males and 23 females,aged (68.0±11.8)years (range:32 to 84 years)with a body mass index(BMI)of (26.1±3.6) kg/m².There were 116 patients(19 knees and 97 hips) in the aseptic loosening(AL) group,including 67 males and 49 females,aged (70.3±8.9)years(range:49 to 89 years)with a BMI of (25.0±3.6)kg/m².The plasma C-reactive protein(CRP),erythrocyte sedimentation rate(ESR),PC,MPV,PC/MPV and PCT levels of the two groups were recorded and analyzed. Receiver operating characteristic curve was used to calculate the sensitivity and specificity of each biomarker,expect for MPV,and the diagnostic value of each biomarker was compared according to the area under the curve(AUC).Independent-sample t test or Mann-Whitney U test were used for comparison between groups. Result: Compared with AL group,AJI group had significantly higher levels of CRP,ESR,PC,PC/MPV and PCT(all P<0.05),but lower level of MPV (P<0.05).The AUCs for CRP,ESR,PC,PC/MPV and PCT were 0.820, 0.829, 0.689, 0.668 and 0.676,respectively. Based on the Youden index,the optimal predictive cutoff for CRP was 11.12 mg/L,with a sensitivity of 74.4% and a specificity of 87.1%.The optimal predictive cutoff for ESR was 17.60 mm/1 h,with a sensitivity of 81.4% and a specificity of 75.3%.The optimal predictive cutoff for PC was 243.00×109/L,with a sensitivity of 60.6% and a specificity of 71.8%.The optimal predictive cutoff for PC/MPV was 24.95,the sensitivity was 58.1% and the specificity was 74.1%.And the optimal predictive cutoff for PCT was 0.24%,with a sensitivity of 69.8% and a specificity of 63.5%. Conclusion: PC,PC to MPV ratio and PCT were of limited value to diagnose PJI.

Integrative analysis of the characteristics of lipid metabolism-related genes as prognostic prediction markers for hepatocellular carcinoma.

OBJECTIVE: Dysregulated lipid metabolism has been reported in the progression of hepatocellular carcinoma (HCC). In the present study, we investigated the molecular characteristics of lipid-metabolism-related genes (IMRGs) as prognostic markers for HCC. MATERIALS AND METHODS: Multi-dimensional bioinformatics analyses were performed to comprehensively analyze IMRGs, and to construct prognostic prediction signatures. RESULTS: Data of 770 HCC patients and their corresponding 776 IMRGs were downloaded from three databases. Patients were classified into 2 molecular clusters that were associated with overall survival, clinical characteristics, and immune cells. The biological functions of the IMRGs differentially expressed between the 2 clusters were associated with tumor-related metabolic pathways. A 6 IMRG signature (6-IS), consisting of FMO3, SLC11A1, RNF10, KCNH2, ME1, and ZIC2, was established as an independent prognostic factor for HCC. The performance of the signature of 6-IS prognostic was verified in a validation set and compared to an external data set. It was revealed that the 6-IS could effectively predict the prognosis of patients with HCC. CONCLUSIONS: This study provides new insights into the role of IMRGs in the pathogenesis of HCC, and presents a novel signature (6-IS) to predict the prognosis of HCC.

Seropositivity rate and diagnostic accuracy of serological tests in 2019-nCoV cases: a pooled analysis of individual studies.

OBJECTIVE: Currently, detection of SARS-CoV-2 RNA is standard in the diagnosis of COVID-19 (2019-nCoV). However, reliable and rapid serological diagnostic methods to screen SARS-CoV-2 infected patients, including those who do not have overt symptoms, are urgently needed. Most studies have described serological tests based on the detection of SARS-CoV-2-specific IgM and IgG. Here, we attempted to systematically analyze the positive rates and comprehensive diagnostic efficacy of IgM and IgG in response to SARS-CoV-2 infection. MATERIALS AND METHODS: By systematically searching PubMed, medRxiv, bioRxiv and other databases, studies regarding the detection of peripheral blood IgM and/or IgG related to SARS-CoV-2 were collected. The positive rate, sensitivity (SEN), specificity (SPE), area under the curve (AUC) and corresponding 95% CIs were obtained by weighted quantitative mergence, and the source of heterogeneity was explored by performing a subgroup study and sensitivity analysis. RESULTS: A total of 30 studies were included, which were comprised of 3856 confirmed SARS-CoV-2 RNA positive cases, 368 suspected RNA negative cases, 1167 asymptomatic carriers, and 2526 RNA negative controls. The corresponding meta-analysis showed that in confirmed cases with 2019-nCoV, the positive rates of single IgM, single IgG and their joint detection related to SARS-CoV-2 were 61.2% (95% CI: 53.4%-69.0%), 58.8% (95% CI: 49.6%-68.0%) and 62.1% (52.7%-71.4%), respectively. In suspected RNA negative cases, the positive rates of single IgM, single IgG and their joint detection were 29.0% (95% CI: 14.0%-44.0%), 37.0% (95% CI: 20.0%-55.0%) and 55.0% (95% CI: 19.0%-90.0%), respectively. Interestingly, IgM/IgG detection also demonstrated a positive rate of 19% (95% CI: 10.0%-27.0%) in asymptomatic cases. Using RT-PCR test as reference, the AUCs of IgM, IgG and IgM/IgG in the diagnosis of 2019-nCoV infection were 0.9656, 0.9766, and 0.9838, respectively. The stratified analyses showed that among confirmed cases with 2019-nCoV, the positive rates of IgM and IgG were 27.3% (95%CI: 19.8%-34.8%) and 22.3% (95% CI: 11.3%-33.3%), respectively, 0-7days following the onset of symptoms, whereas the positive rate of parallel IgM/IgG testing attained 39.3% (95% CI: 24.2%-54.4%). Moreover, the efficacy of antibody testing based on CLIA (chemiluminescence enzyme immunoassays) in diagnosing 2019-nCoV infection was higher than that of LFIA (lateral flow immunoassays) and ELISA (enzyme linked immunosorbent assay). CONCLUSIONS: IgM, IgG and their joint testing exhibited high clinical value in the diagnosis of 2019-nCoV, which may assist in making up for the deficiency of throat swab RNA tests.

[Establishment of high-fat diet-induced obesity and insulin resistance model in rats].

OBJECTIVE: To investigate the appropriate conditions and duration for establishing a high-fat diet-induced obesity and insulin resistance model in rats. METHODS: Forty-five 6-week-old male Sprague-Dawley (SD) rats were randomly assigned into 2 groups: (1) control group (CON), (2) high-fat diet group (HFD). HFD was fed with a high-fat diet (45% kcal from fat) while CON with chow diet. After four-weeks of high-fat diet feeding, the rats of obesity resistance (OR) were eliminated according to body weight sorting, whereas obese (OB) rats were continued feeding a high-fat diet until 12 weeks. Body weight and food intake were recorded weekly. Glucose tolerance was evaluated by oral glucose tolerance test (OGTT) in 4 weeks, 8 weeks and 12 weeks. At the end of 12 weeks, insulin releasing test and visceral fat mass were measured and HE staining of the liver, adipose tissue and pancreatic tissue were conducted. RESULTS: After 4 weeks of a high-fat diet, the body weight of HFD was 17.8% higher than that of CON (P=0.001), and the rate of obesity was 67.6%-78.4%. Glucose tolerance of OB rats was impaired with a higher blood glucose concentration at 120 min (P<0.001) and a higher area under the curve (AUC, P=0.037) in OGTT compared with CON. The rate of obesity and insulin-resistance rats was 79.3%. After 8 weeks of feeding, the body weight in OB was 30.4% higher than CON (P<0.001). In OGTT, blood glucose levels at 60 min and 120 min were 35.6% and 36.4% higher than those in CON (both P<0.001), and AUC was 21.7% (P<0.001) higher than that of CON. The rate of obesity and insulin-resistance rats was 100.0%. After 12 weeks of feeding, the body weight in OB was 36.9% higher than that in CON (P<0.001). In OGTT, the blood glucose levels at 60 min and 120 min were 24.8% (P=0.001) and 34.6% (P<0.001) higher than those in CON, and AUC was 16.1% (P=0.019) higher than that of CON. The rate of obesity and insulin-resistance rats was 93.3%. The insulin releasing test showed that serum insulin concentration at each time point (0, 30, 60, 120 min) was higher than that in CON, with a 6.3-times higher than that in CON at 120 min (P=0.008). Pathological changes were observed in islets and liver in the OB rats. CONCLUSION: After 4 weeks of a high-fat diet (45% kcal from fat) feeding in six-weeks SD rats, the rats of OR were eliminated. Impaired glucose tolerance was found in OB rats after 4 weeks of feeding, and the rate was higher after 8-12 weeks of high-fat diet feeding.

[Effects of chlorogenic acid on glucose tolerance and its curve characteristics in high-fat diet-induced obesity rats].

OBJECTIVE: To observe the effect of chlorogenic acid (chlorogenic acid, CGA) on the glucose tolerance and its curve characteristics in high fat diet-induced obesity (diet-induced-obesity, DIO) rats, so as to provide scientific grounds for the development and utilization of CGA in early prevention and reversal of prediabetes. METHODS: Eight of forty-six male Sprague-Dawley rats were randomly selected as the normal diet group (CON group), and the rest were fed with high-fat diet. After 4 weeks, 24 high-fat-induced obese rats were screened according to the criteria and then randomly divided into high fat diet group (HFD group), 50% CGA group and 98% CGA group. The CGA groups received intragastric administrations of 50% CGA and 98% CGA orally via a gavage needle once a day for 8 weeks, respectively, while the CON and HFD groups received a carrier solution (phosphate buffer saline, PBS). Their body weights were measured weekly and oral glucose tolerance test (OGTT) was performed every 4 weeks. Fasting insulin and insulin release were measured at the end of the study. Meanwhile, HOMA-IR and visceral fat percentage were calculated. Histopathological examination by hematoxylin and eosin staining method were evaluated in the pancreatic tissues. RESULTS: Before the intervention of chlorogenic acid, blood glucose levels 120 min after glucose loading (P<0.05) and AUC-G (P<0.05) were increased in the HFD group when compared with the CON group, and the time to glucose peak was delayed after 4 weeks of chlorogenic acid intervention (P<0.05). After 8 weeks of intervention, the HOMA-IR index, the insulin levels at 0 min, 30 min, 60 min, and 120 min after glucose loading and AUC-I increased (P<0.05), and the histopathological examination showed obvious hyperplasia of pancreatic islets (P<0.05). Compared with the HFD group, there was no significant change in glucose tolerance and glucose peak time in 50%CGA and 98%CGA groups at the end of 4 weeks of intervention. However, after 8 weeks of intervention, OGTT-60min,OGTT-120min blood glucose (P<0.05) were lower, HOMA-IR index and OGTT-0min, OGTT-120min serum insulin level decreased (P<0.05), the time to glucose peak shifted to an earlier timepoint (P<0.05), abnormal islet hyperplasia attenuated (P<0.05) in 50% CGA and 98% CGA groups. Also, the OGTT-30min serum insulin level was decreased (P<0.05) in 50% CGA group. CONCLUSION: Delay in time to glucose peak during the OGTT was one of the manifestations of impaired glucose tolerance in DIO rats, and 50% and 98% CGA could improve the glucose tolerance and delay in glucose peak time.

MicroRNA-572 targets CDH1 to promote metastasis of Wilms' tumor.

INTRODUCTION: Wilms' tumor (WT) is the most common childhood tumor, and recent studies have demonstrated that abnormal expression of microRNA (miRNA) plays an important role in the progression of WT. However, the effect of miR-572 on cell metastasis and epithelial-mesenchymal transition (EMT) in WT is unclear. PATIENTS AND METHODS: The alternation of miR-572 and cadherin 1 (CDH1) expression was assessed by quantitative Real-time polymerase chain reaction (qRT-PCR). Transwell assay was performed to explore the effects of miR-572 and CDH1 on the metastasis of WT cells. The EMT markers and CDH1 expressions were detected by Western blot. The relationship between miR-572 and CDH1 was verified by dual-luciferase reporter assay. RESULTS: Upregulation of miR-572 was identified in WT tissues. Increased miR-572 promoted cell metastasis and EMT progress in WT. Moreover, miR-572 directly targeted CDH1 and negatively regulated CDH1 expression in WT tissues. The knockdown of CDH1 showed a promoting effect on cell metastasis and EMT, while overexpression of CDH1 significantly weakened the effect of miR-572. CONCLUSIONS: MiR-572 targeted CDH1 to promote cell metastasis in WT by suppressing EMT.

Monolayer-graphene-based perfect absorption structures in the near infrared.

Subwavelength perfect optical absorption structures based on monolayer-graphene are analyzed and demonstrated experimentally. The perfect absorption mechanism is a result of critical coupling relating to a guided mode resonance of a low index two-dimensional periodic structure. Peak absorption over 99% at wavelength of 1526.5 nm with full-width at half maximum (FWHM) about 18 nm is demonstrated from a fabricated structure with period of 1230 nm, and the measured results agree well with the simulation results. In addition, the influence of geometrical parameters of the structure and the angular response for oblique incidence are analyzed in detail in the simulation. The demonstrated absorption structure in the presented work has great potential in the design of advanced photo-detectors and modulators.

[Regulatory effect of bone marrow mesenchymal stem cells on polarization of macrophages].

Objective: To examine the regulatory effect of bone marrow mesenchymal stem cells (BM-MSCs) on the polarization of bone marrow-derived macrophages, and to provide a theoretical support for the application of mesenchymal stem cells in the treatment of liver fibrosis. Methods: MSCs and macrophages were first isolated from the bone marrow of mice. Macrophages were polarized to M1 macrophages with lipopolysaccharide (LPS) and interferon-γ (IFN-γ), and to M2 macrophages with interleukin-4 (IL-4). The macrophages were then co-cultured with BM-MSCs in a Transwell for 24 h, and changes in the percentages of M1 and M2 macrophages were examined using flow cytometry. The mRNA levels of the M1 macrophage-associated cytokines, tumor necrosis factor-α (TNF-α) and interleukin-23a (IL-23a), and M2 macrophage-associated molecules, arginase-1 (Arg-1) and CD163, were measured by real-time quantitative PCR. The two samples were compared using the t test, and P < 0.05 was considered as statistically significant. Results: Flow cytometry showed that the percentage of M1 macrophages was significantly lower in the (macrophage + LPS + IFN-γ + BM-MSC) co-culture group than in the (macrophage + LPS + IFN-γ) group (62.5% ± 4.6% vs 86.6% ± 6.9%, t = 5.034, P = 0.0073). In addition, the relative mRNA expression of TNF-α and IL-23a was also significantly reduced in the co-culture group compared with those in the macrophage control group as measured by RT-qPCR (t = 11.57 and 10.57, respectively, P < 0.05). Compared with that in the macrophage control group, the percentage of M2 macrophages in the (macrophage+BM-MSC) co-culture group was significantly increased (89.5% ± 5.8% vs 70.1% ± 6.3%, t = 3.924, P = 0.0172), along with significantly elevated relative mRNA expression of Arg1 (14.35±1.05 vs 1.00±0.03, t = 21.96, P < 0.05) and CD163 (3.04 ± 0.27 vs 1.00 ± 0.03, t = 13.14, P < 0.05). Conclusion: BM-MSCs can inhibit LPS + IFN-γ-induced polarization to M1 macrophages and promote polarization to M2 macrophages through the release of paracrine factors.

Association between miR-137 polymorphism and risk of schizophrenia: a meta-analysis.

miR-137, a brain-enriched microRNA, is involved in the control of neuronal proliferation, differentiation, and dendritic arborization, all of which are important for proper neurogenesis and relevant to schizophrenia. miR-137 is also known to regulate many genes implicated in schizophrenia risk. Although reports have associated the miR-137 polymorphism rs1625579 with this disease, their results have been inconsistent. The aim of this meta-analysis was to evaluate the relationship between rs1625579 and schizophrenia. Data were obtained from an electronic database, and pooled odds ratios (ORs) with 95% confidence intervals (95%CI) were used to test the association using the RevMan 5.3 software. Twelve case-control studies comprising 11,583 cases and 14,315 controls were included. An estimated lambda value of 0.46 was recorded, suggesting that a codominant model of inheritance was most likely. A statistically significant association was established under allelic (T vs G: OR = 1.15, 95%CI = 1.10-1.21, P < 0.001) and homogeneous codominant models (TT vs GG: OR = 1.32, 95%CI = 1.13-1.54, P < 0.001), but no such relationship was detected using the heterogeneous codominant model (GT vs GG: OR = 1.14, 95%CI = 0.97-1.34, P = 0.11). This meta-analysis demonstrates that the rs1625579 miR-137 genetic variant significantly increases schizophrenia risk.

Distinct neurobiological signatures of brain connectivity in depression subtypes during natural viewing of emotionally salient films.

BACKGROUND: Establishing an evidence-based diagnostic system informed by the biological (dys)function of the nervous system is a major priority in psychiatry. This objective, however, is often challenged by difficulties in identifying homogeneous clinical populations. Melancholia, a biological and endogenous subtype for major depressive disorder, presents a canonical test case in the search of biological nosology. METHOD: We employed a unique combination of naturalistic functional magnetic resonance imaging (fMRI) paradigms - resting state and free viewing of emotionally salient films - to search for neurobiological signatures of depression subtypes. fMRI data were acquired from 57 participants; 17 patients with melancholia, 17 patients with (non-melancholic) major depression and 23 matched healthy controls. RESULTS: Patients with melancholia showed a prominent loss of functional connectivity in hub regions [including ventral medial prefrontal cortex, anterior cingulate cortex (ACC) and superior temporal gyrus] during natural viewing, and in the posterior cingulate cortex while at rest. Of note, the default mode network showed diminished reactivity to external stimuli in melancholia, which correlated with the severity of anhedonia. Intriguingly, the subgenual ACC, a potential target for treating depression with deep brain stimulation (DBS), showed divergent changes between the two depression subtypes, with increased connectivity in the non-melancholic and decreased connectivity in the melancholic subsets. CONCLUSION: These findings reveal neurobiological changes specific to depression subtypes during ecologically valid behavioural conditions, underscoring the critical need to respect differing neurobiological processes underpinning depressive subtypes.

Association between IL2/IL21 and SH2B3 polymorphisms and risk of celiac disease: a meta-analysis.

Celiac disease (CD) is a common autoimmune disorder characterized by heightened immunological response to ingested gluten. Certain gene polymorphisms of IL2/IL21 (rs6822844 and rs6840978) and SH2B3 (rs3184504) may influence susceptibility to CD, although the effects remain unclear. We performed a meta-analysis of the associations between rs6822844, rs6840978, and rs3184504 polymorphisms and CD risk. PubMed, EMBASE, and the China National Knowledge Infrastructure were searched. ORs and 95%CIs of each single nucleotide polymorphism (SNP) were estimated using the fixed-effect model if I(2) < 50% in the test of heterogeneity; otherwise, the random-effect model was used. Our meta-analysis included 12,986 CD cases and 28,733 controls from 16 independent samples, and the analysis of each SNP contained a subset of the total. We found that the minor allele T of both rs6822844 (T vs G, OR = 0.72, 95%CI = 0.67-0.78, P < 0.001) and rs6840978 (T vs C, OR = 0.76, 95%CI = 0.71-0.83, P < 0.001) in IL2/IL21 significantly decreased the risk of CD. However, the minor allele A of rs3184504 (A vs G, OR = 1.18, 95%CI = 1.12-1.24, P < 0.001) in SH2B3 significantly increased CD susceptibility. The estimated lambda values were 0.49, 0.50, and 0.53 for rs6822844, rs6840978, and rs3184504, respectively, suggesting that a co-dominant model of genotype effect was most appropriate for the three SNPs. Our results support associations between the three SNPs and CD and provide a strong argument for further research.

Serum vitamin D level is associated with disease severity and response to ursodeoxycholic acid in primary biliary cirrhosis.

BACKGROUND: Serum vitamin D levels are associated with bone complications in patients with primary biliary cirrhosis (PBC). Increasing evidence suggests a nonskeletal role of vitamin D in various autoimmune and liver diseases. AIM: To investigate the clinical relevance of vitamin D levels in PBC, especially their association with the therapeutic effects of ursodeoxycholic acid (UDCA). METHODS: Consecutive PBC patients were retrospectively reviewed. 25-hydroxyvitamin D [25(OH)D] levels were determined in frozen serum samples collected before initiation of UDCA treatment. Response to UDCA was evaluated by Paris-I and Barcelona criteria. Logistic regressions were performed to identify the treatment response-associated parameters. RESULTS: Among 98 patients, the mean serum 25(OH)D concentration was 17.9 ± 7.6 ng/mL. 25(OH)D levels decreased with increasing histological stage (P = 0.029) and were negatively correlated with bilirubin and alkaline phosphatase levels. After 1 year of UDCA therapy, 31 patients failed to achieve complete response according to Paris-I criteria. The baseline 25(OH)D level was significantly lower in nonresponders (14.8 ± 6.4 vs. 19.3 ± 7.6 ng/mL, P = 0.005). Vitamin D deficiency at baseline was associated with an increased risk of incomplete response independent of advanced stages (OR = 3.93, 95% CI = 1.02-15.19, P = 0.047). Similar results were obtained when biochemical response was evaluated by Barcelona criteria. Furthermore, 25(OH)D levels were lower in patients who subsequently suffered death or liver transplantation (12.1 ± 4.6 vs. 18.4 ± 7.6 ng/mL, P = 0.023). CONCLUSIONS: 25(OH)D level is associated with biochemical and histological features in PBC. Pre-treatment vitamin D status is independently related to subsequent response to UDCA. Our results suggest that vitamin D status may have important clinical significance in PBC.

Matrix metallopeptidase 2 (MMP2) mediates MHC class I polypeptide-related sequence A (MICA) shedding in renal cell carcinoma.

INTRODUCTION: The MHC class i chain-related molecule A (MICA) is a ligand for the natural killer group 2, member D (NKG2D) immunoreceptor activation. The engagement of tumor cell surface MICA to NKG2D stimulates the NK and T cell antitumor immunity. Shedding of MICA by tumor cells facilitates tumor immune evasion, which might partially contribute to tumor progression. MATERIAL AND METHODS: Inmunohistochemistry was performed on both normal and neoplastic renal tissue. Human renal carcinoma cell lines 786-0 and ACHIN were transfected and target sequences to silence human MMP2 by shRNA expression were established. The degree of MICA shedding was measured and quantitative real-time PCR and Western-blot analysis were performed. RESULTS: The membrane type matrix metalloproteinase 2 (MMP2) mediated the MICA shedding, which was blocked by suppression of MMP2 expression. Concomitantly, MMP2 over-expression enhanced the MICA shedding, indicating that MMP2 was involved in the renal cell carcinoma-associated proteolytic release of soluble MICA (sMICA), which facilitated the tumor immune escape. CONCLUSIONS: These findings suggested that MMP2 might be a new potential target for tumor immune therapy. Elucidation of the mechanisms by which tumors shed MICA could be of a great importance for cancer treatment in order to reinforce the NK and T cell antitumor immunity.

Multimodality imaging of thyroid-like follicular renal cell carcinoma with lung metastases, a new emerging tumor entity.

The International Society of Urological Pathology recently proposed classifying thyroid-like follicular renal cell carcinoma (TLF-RCC) as an emerging entity in renal epithelial tumors. Their entire proposal will be the framework for the next World Health Organization classification of renal tumors. Fewer than 15 cases of TLF-RCC have been reported in the literature up to date. We describe the multimodality imaging features of a patient with TLF-RCC. To our knowledge, this is the first case report in the literature commenting on the multimodality imaging appearance of this tumor.

A computational bioinformatics analysis of gene expression identifies candidate agents for prostate cancer.

Prostate cancer is the second most frequently diagnosed cancer and the sixth leading cause of cancer death in males worldwide. Although great progress has been made, the molecular mechanisms of prostate cancer are far from being fully understood and treatment of this disease remains palliative. In this study, we sought to explore the molecular mechanism of prostate cancer and then identify biologically active small molecules capable of targeting prostate cancer using a computational bioinformatics analysis of gene expression. A total of 3068 genes, involved in cell communication, development, localisation and cell proliferation, were differentially expressed in prostate cancer samples compared with normal controls. Pathways associated with signal transduction, immune response and tumorigenesis were dysfunctional. Further, we identified a group of small molecules capable of reversing prostate cancer. These candidate agents may provide the groundwork for a combination therapy approach for prostate cancer. However, further evaluation for their potential use in the treatment of prostate cancer is still needed.