Impact of infliximab therapeutic drug level monitoring on outcomes of patients with inflammatory bowel disease: A real-world experience from a Middle Eastern cohort

Background and study aimTherapeutic drug monitoring (TDM) through measurement of infliximab (IFX) trough levels and antibodies to infliximab (ATI) is performed to guide IFX intensification strategies and improve its efficacy. We conducted this study to explore the relationship between clinical and endoscopic/radiological remission and IFX and ATI levels in patients with inflammatory bowel disease (IBD) treated with IFX and to evaluate the appropriateness of treatment decision post TDM.Patients and methodsThis was a cross-sectional study of a cohort of adult patients with IBD. Serum IFX trough concentrations and ATI were measured.ResultsA total of 129 patients [104] with ulcerative colitis (UC) and 25 with Crohn’s disease (CD)] were included in this study, of whom 61.2% were men. The mean disease duration was 6.7 years, and 72% of patients with UC had extensive colitis. The mean serum IFX trough level was 4.1 µg/mL; the IFX trough levels were subtherapeutic in 75 patients (58%), therapeutic in 37 patients (29%), and supratherapeutic in 17 patients (13%). Positivity to ATI was found in 16 patients (12.4%). Only 43 patients (33.3%) underwent an appropriate change in therapy after TDM, patients with penetrating CD disease had low IFX levels and higher C-reactive protein levels at 12 months before TDM.ConclusionsPatients with IBD with therapeutic IFX levels tend to have increased endoscopic/radiological remission rates. However, an appropriate change in management based on TDM was absent in the majority of patients, potentially reflecting the need to have a dashboard to support and guide clinicians in decision-making.     

The analysis of cell-free DNA concentrations and integrity in serum of initial and treated of lymphoma patients

ObjectiveTo evaluate cell-free DNA (cfDNA) in plasma as a promising biomarker for lymphoma, altered levels of cfDNA and its association with clinical parameters are investigated in patients suffered from lymphomas.MethodsPeripheral blood specimens were collected from 60 patients with lymphoma during initial diagnosis and those of another 107 patients with lymphoma during treated stage were also collected, 93 healthy volunteers were selected as control group. Quantitative PCR was used to detect cfDNA level in each group, cfDNA level in different groups was analyzed to understand its relationship with lymphoma patients' clinical features. After correlation analysis between cfDNA and clinical characteristics, Receiver operator characteristic curve was performed to analyze sensitivity and specificity of cfDNA and LDH.ResultscfDNA concentration and integrity in initial stage of lymphoma patients were significantly higher than those in treated stage, and cfDNA concentration in treated phase was significantly higher than cfDNA concentration in control group. There was no significant difference in cfDNA integrity at treated stage compared with control group. There was no significant correlation between patient's age, gender, extranodal invasion and lymphoma pathological type and cfDNA concentration and integrity; In contrast, there was a significant correlation between ECOG score, LDH content, Ann Arbor stage, IPI, B-symptoms, Ki-67 expression and radiotherapy and cfDNA concentration and integrity, both at the time of initial diagnosis and treated stage. cfDNA concentration detection is an optimal diagnostic indicator, followed by cfDNA integrity detection, the sensitivity and specificity of both are superior to the traditional LDH detection.ConclusioncfDNA level is significantly increased in lymphomas patient plasma and may help lymphoma screening. cfDNA level may serve as a potential indicator of lymphomas treatment efficacy.     

双硫仑对结肠癌细胞SW480生长和侵袭的作用及机制研究

目的：探讨双硫仑（disulfiram）对SW480结肠癌细胞体外增殖、迁移和体内生长的作用及机制。方法：MTS法检测不同浓度双硫仑对结肠癌细胞SW480增殖的作用;划痕实验双硫仑对SW480细胞迁移的影响;Transwell实验双硫仑对SW480细胞侵袭的影响;裸鼠移植瘤模型研究双硫仑对SW480细胞体内增殖的抑制作用;免疫组化检测双硫仑对裸鼠移植瘤组织中低氧诱导因子-1α（hypoxia inducible factor-1,HIF-1α）和葡萄糖转运蛋白1（Glucose transporter 1,GLUT1）蛋白表达的影响。结果：双硫仑对SW480细胞增殖有抑制作用,且呈现剂量依赖性;双硫仑4 μmol·L-1和8 μmol·L-1浓度组均能够抑制SW480细胞迁移和侵袭能力,与对照组相比具有显著性差异（P<0.05）;双硫仑20 mg·kg-1和40 mg·kg-1剂量组均能够抑制SW480细胞裸鼠移植瘤的生长（P<0.01）,且抑制移植瘤中HIF-1α和GLUT1蛋白的表达。结论：双硫仑可抑制SW480结肠癌细胞的增殖和转移,其机制可能与抑制HIF-1α和GLUT1蛋白的表达有关。     

Item Response Model Adaptation for Analyzing Data from Different Versions of Parkinson’s Disease Rating Scales

Pharmaceutical Research - Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel technique delivering drugs into the abdominal cavity as an aerosol under high pressure. It is...     

Risk-based,response-adapted therapy for early-stage extranodal nasal-type NK/T-cell lymphoma in the modern chemotherapy era: A China Lymphoma Collaborative Group study

We aimed to determine the survival benefits of chemotherapy (CT) added to radiotherapy (RT) in different risk groups of patients with early-stage extranodal nasal-type NK/T-cell lymphoma (ENKTCL), and to investigate the risk of postponing RT based on induction CT responses. A total of 1360 patients who received RT with or without new-regimen CT from 20 institutions were retrospectively reviewed. The patients had received RT alone, RT followed by CT (RT + CT), or CT followed by RT (CT + RT). The patients were stratified into different risk groups using the nomogram-revised risk index (NRI). A comparative study was performed using propensity score-matched (PSM) analysis. Adding new-regimen CT to RT (vs RT alone) significantly improved overall survival (OS, 73.2% vs 60.9%, P < .001) and progression-free survival (PFS, 63.5% vs 54.2%, P < .001) for intermediate-risk/high-risk patients, but not for low-risk patients. For intermediate-risk/high-risk patients, RT + CT and CT + RT resulted in non-significantly different OS (77.7% vs 72.4%; P = .290) and PFS (67.1% vs 63.1%; P = .592). For patients with complete response (CR) after induction CT, initiation of RT within or beyond three cycles of CT resulted in similar OS (78.2% vs 81.7%, P = .915) and PFS (68.2% vs 69.9%, P = .519). For patients without CR, early RT resulted in better PFS (63.4% vs 47.6%, P = .019) than late RT. Risk-based, response-adapted therapy involving early RT combined with CT is a viable, effective strategy for intermediate-risk/high-risk early-stage patients with ENKTCL in the modern treatment era.     

exosomes在肺癌细胞对顺铂敏感性降低过程中的作用研究

目的研究肺癌细胞分泌的exosomes在同源细胞对顺铂的敏感性调节过程中的可能作用。方法采用超速离心和Exoquick-TC结合的方法从肺癌细胞系A549和H1975的上清液中分离出exosomes,透射电子显微镜观察其形态,western blot检测其CD63蛋白表达;共聚焦显微镜观察细胞胞吞exosomes过程;分别提取顺铂处理肺癌细胞来源exosomes和未处理肺癌细胞来源exosomes,并使用2种exosomes分别处理肺癌细胞,采用CCK-8法检测上述获得的exosomes对肺癌细胞顺铂敏感性的影响。结果透射电子显微镜下观察肺腺癌细胞来源的exosomes具有特征性的盘状结构,直径30-100 nm,western blot结果显示exosomes富含CD63蛋白;显微镜下可观察到exosomes可进入细胞;同时经顺铂处理过肺癌细胞分泌的exosomes可降低同源细胞对顺铂的敏感性。结论减少exosomes的分泌和传递可能会增加顺铂化疗的疗效,这为肺癌的治疗提供了一种新的思路。     

Investigation of microRNA expression signatures in HCC via microRNA Gene Chip and bioinformatics analysis

BackgroundDysregulation of miRNAs is closely involved with hepatocellular carcinoma (HCC) progression, oncogenesis and signalling pathways. The aim of this study was to investigate differences in expression of miRNAs in HCC tissue in comparison to healthy liver tissue, as well as to explore the key miRNA-targeted genes.MethodsGene Chip microarray analysis was used to analyse differentially expressed miRNAs (DEMs) in tissues, and qRT-PCR was performed to validate the top 9 downregulated miRNAs. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses were performed for target genes using the DAVID database. A protein-protein interaction (PPI) network of the target genes was created by STRING and visualised using Cytoscape. Three online miRNA databases were utilised to aid in the prediction of genes targeted by the top 10 significantly altered DEMs.ResultsIn total, 153 upregulated and 206 downregulated miRNAs were identified in HCC tissue. The genes targeted by the top 10 increased and decreased miRNAs were 6 and 1060, respectively. Moreover, FOXO1 was projected to be regulated by all twenty miRNAs. A PPI network was constructed that consisted of 956 nodes and 1298 edges. Four significant modules, consisting of 66 hub genes, were detected from the PPI system via MCODE. Functional enrichment demonstrated that miRNAs have a vital function in cancer development and advancement.ConclusionIn summary, our study identified DEMs in HCC tissue, major target genes and possible molecular mechanisms that underlie HCC, providing novel insights for treatment approaches.     

Value of multi-parameter flow cytometry immunophenotyping in T/NK-cell neoplasms in cytology specimens: A retrospective study in Chinese patients

BackgroundInnate limitations of morphological diagnosis of T/NK-cell neoplasms mean that they can be misdiagnosed or missed, especially when mixed with a variety of benign and reactive conditions. The aim of this study was to investigate the application value of multiparameter flow cytometry immunophenotyping (MFCI) in screening and diagnosing T/NK-cell neoplasms with cytology specimens.Material and methodsThe clinical and pathological characteristics of 1028 newly diagnosed cases from Fudan University Shanghai Cancer Center who provided a cytology specimen between June 2010 and January 2016 with correlated histology diagnosis and clinical confirmation were retrospectively reviewed. MFCI was used for screening, diagnosis and typing. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) in diagnosis of T/NK-cell neoplasms were calculated.ResultsThere were 606 males and 422 females in 1028cases, with a mean age of 47.5 years (range 9–86 years). Specimens used for cytologic diagnosis included 996 FNAs, 2 US-FNAs, 13 EUS-FNAs and 17 effusions. Screening for types of lymphoma of MFCI, 139 (13.52 %) cases were T/NK cell lymphoma, 3 (0.29 %) cases were B cell lymphoma T-NHL and B-NHL coexist. A total of 146 suspected T/NK-cell neoplasms were screened out (sensitivity = 94.64 %, specificity = 95.63 % PPV = 72.60 %, NPV = 99.32 %) by MFCI, with 112 (76.71 %) histologically confirmed cases and 6 (4.11 %) false-negative cases identified (3 cases diagnosed as B-cell neoplasms and 1 case as T-cell neoplasm with B-cell neoplasm, which also were confirmed by gene rearrangement. 2 cases were suspicious T-cell–immunophenotypic abnormalities). When used at the diagnostic level, a total of 88 T/NK-cell neoplasms were identified (sensitivity = 68.75 %, specificity = 98.80 %, PPV = 87.50 %, NPV = 96.28 %) with 11 false-positive cases recognized, 9 of which showed typical immunophenotypic T-cell neoplasms features, and 2 exhibited aberrant T immunophenotype.ConclusionsMFCI has high sensitivity and specificity in the screening and diagnosis of T/NK-cell neoplasms and may be useful as an alternative diagnosis method in cytology specimens.     

Natural mannosylation of HIV-1 gp120 imposes no immunoregulatory effects in primary human plasmacytoid dendritic cells

Plasmacytoid dendritic cells (pDCs) play a vital role in activation of anti-HIV-1 immunity, and suppression of pDCs might mitigate immune responses against HIV-1. HIV-1 gp120 high-mannose has been attributed immunosuppressive roles in human myeloid DCs, but no receptors for high-mannose have so far been reported on human pDCs. Here we show that upon activation with HIV-1 or by a synthetic compound triggering the same receptor in human pDCs as single-stranded RNA, human pDCs upregulate the mannose receptor (MR, CD206). To examine the functional outcome of this upregulation, inactivated intact or viable HIV-1 particles with various degrees of mannosylation were cultured with pDCs. Activation of pDCs was determined by assaying secretion of IFN-alpha, viability, and upregulation of several pDC-activation markers: CD40, CD86, HLA-DR, CCR7, and PD-L1. The level of activation negatively correlated with degree of mannosylation, however, subsequent reduction in the original mannosylation level had no effect on the pDC phenotype. Furthermore, two of the infectious HIV-1 strains induced profound necrosis in pDCs, also in a mannose-independent manner. We therefore conclude that natural mannosylation of HIV-1 is not involved in HIV-1-mediated immune suppression of pDCs.     

A low level of GPR37 is associated with human hepatocellular carcinoma progression and poor patient survival

GPR37, also known as parkin-associated endothelin-like receptor (Pael-R), is an orphan G protein-coupled receptor (GPCR). It has been reported that GPCRs play vital roles in the development and progression of cancer. To investigate the potential roles of GPR37 in hepatocellular carcinoma (HCC), expression of GPR37 was examined in human HCC samples. Immunohistochemistry and Western blot analyses were performed for GPR37 in 57 hepatocellular carcinoma samples. GPR37 expression was low in hepatocellular carcinoma as compared with the adjacent non-tumorous tissues. Clinicopathological analysis showed that GPR37 expression was significantly correlated with histological grade and the level of alpha fetal protein (AFP) (P = 0.000 and 0.002, respectively). The Kaplan–Meier survival curves revealed that decreasing GPR37 expression was associated with poor prognosis in HCC patients, while in vitro, following the release from serum starvation of HuH7 HCC cell, the expression of GPR37 was downregulated. In addition, the transient GPR37 knockdown by siRNA in HuH7 cells significantly decreased the apoptosis of hepatoma cells with activation of the phosphatidylinositol 3-kinase-Akt signaling pathway. Our data suggest that GPR37 may play an important role in the pathogenesis of hepatocellular carcinoma by affecting the proliferation of H CC cells, and it could be a novel potential molecular therapy target for HCC.