Tianyu Zhang

mTOR Inhibition Attenuates Dextran Sulfate Sodium-Induced Colitis by Suppressing T Cell Proliferation and Balancing TH1/TH17/Treg Profile

It has been established that mammalian target of Rapamycin (mTOR) inhibitors have anti-inflammatory effects in models of experimental colitis. However, the underlying mechanism is largely unknown. In this research, we investigate the anti-inflammatory effects of AZD8055, a potent mTOR inhibitor, on T cell response in dextran sulfate sodium (DSS)-induced colitis in mice, a commonly used animal model of inflammatory bowel diseases (IBD). Severity of colitis is evaluated by changing of body weight, bloody stool, fecal consistency, histology evaluation and cytokine expression. We find that AZD8055 treatment attenuates DSS-induced body weight loss, colon length shortening and pathological damage of the colon. And AZD8055 treatment decreases colonic expression of genes encoding the pro-inflammatory cytokines interferon-γ, interleukin (IL)-17A, IL-1β,IL-6 and tumor necrosis factor(TNF)-a and increases colonic expression of anti-inflammatory cytokines IL-10. We show that AZD8055 treatment decreases the percentages of CD4+ T cells and CD8+ T cells in spleen, lymph nodes and peripheral blood of mice. We also find that AZD8055 treatment significantly reduces the number of T helper 1(TH1) cells and TH17 cells and increases regulatory T (Treg) cells in the lamina propria and mesenteric lymph nodes. Furthermore, we demonstrates that AZD8055 suppresses the proliferation of CD4+ and CD8+ T cells and the differentiation of TH1/TH17 cells and expands Treg cells in vitro. The results suggest that, in experimental colitis, AZD8055 exerts anti-inflammatory effect by regulating T helper cell polarization and proliferation.

Potential model for differential diagnosis between Crohn's disease and primary intestinal lymphoma

AIM To evaluate the usefulness of different parameters to differentiate Crohn’s disease (CD) from primary intestinal lymphoma (PIL). METHODS The medical records of 85 patients with CD and 56 patients with PIL were reviewed retrospectively. Demographic, clinical, laboratory, endoscopic, and computed tomographic enterography (CTE) parameters were collected. The univariate value of each parameter was analyzed. A differentiation model was established by pooling all the valuable parameters. Diagnostic efficacy was analyzed, and a receiver operating characteristic (ROC) curve was plotted. RESULTS The demographic and clinical parameters that showed significant values for differentiating CD from PIL included age of onset, symptom duration, presence of diarrhea, abdominal mass, and perianal lesions (P < 0.05). Elevated lactate dehydrogenase and serum β2-microglobulin levels suggested a PIL diagnosis (P < 0.05). The endoscopic parameters that showed significant values for differentiating CD from PIL included multiple-site lesions, longitudinal ulcer, irregular ulcer, and intraluminal proliferative mass (P < 0.05). The CTE parameters that were useful in the identification of the two conditions included involvement of ≤ 3 segments, circular thickening of the bowel wall, wall thickness > 8 mm, aneurysmal dilation, stricture with proximal dilation, “comb sign”, mass showing the “sandwich sign”, and intussusceptions (P < 0.05). The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of the differentiation model were 91.8%, 96.4%, 93.6%, 97.5%, and 88.5%, respectively. The cutoff value was 0.5. The area under the ROC curve was 0.989. CONCLUSION The differentiation model that integrated the various parameters together may yield a high diagnostic efficacy in the differential diagnosis between CD and PIL.

Inhibition of neddylation regulates dendritic cell functions via Deptor accumulation driven mTOR inactivation.

Neddylation, a newly identified post-translational modification, is significant for the activity and stability of target proteins. The exact role of neddylation in the pathogenesis of inflammatory bowel disease, specifically those mediated by dendritic cells (DCs), was still rarely reported. Here, we showed that inhibition of neddylation protected mice from mucosal inflammation. Targeting neddylation also inhibited DC maturation characterized by reduced cytokine production, down-regulated costimulatory molecules and suppressed capacity in allogeneic T cell stimulation. Additionally, inactivation of neddylation promotes caspase dependent apoptosis of DCs. These phenomena were attributed to the inactivation of mTOR, which was caused by Cullin-1 deneddylation induced Deptor accumulation. Together, our findings revealed that neddylation inhibition suppressed DC functions through mTOR signaling pathway and provided a potential therapeutic opportunity in inflammatory bowel diseases.

Comparison between Intestinal Behçet’s Disease and Crohn’s Disease in Characteristics of Symptom, Endoscopy, and Radiology

Aim To evaluate different parameters in differentiating intestinal BD from CD. Methods The medical records of inpatients with intestinal BD and CD were retrospectively reviewed. The univariate value of different parameters was analyzed, respectively. A differentiation model was established by pooling all valuable parameters together. Diagnostic efficacy was evaluated, and a receiver operating curve (ROC) was plotted. Results Forty-two BD patients and ninety-seven CD patients were reviewed. Demographic and clinical parameters that showed significant value included diarrhea, fever, perianal disease, oral ulcers, genital ulcers, skin lesions, and musculoskeletal lesions. Endoscopic parameters reaching clinical significance included multiple-site lesions, lesions confined to the ileocecal region, longitudinal ulcers, round or oval ulcers, punch-out ulcers, ulcers with discrete margin, ulcer size > 2 cm, stricture of bowel, and anorectal involvement. Radiologic parameters aiding the differentiation included involvement segments ≤ 3, asymmetrical pattern of involvement, intraluminal pseudopolyp formation, target sign, stricture with proximal dilation, comb sign, and fistula. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of the differentiation model were 90.5%, 93.8%, 92.8%, 86.4%, and 95.8%, respectively. The cutoff value was 0.5 while the area under the ROC curve was 0.981. Conclusion The differentiation model that integrated the various parameters together may yield a high diagnostic efficacy in the differential diagnosis between intestinal BD and CD.

Improvement of psychological status after infliximab treatment in patients with newly diagnosed Crohn’s disease

Background Patients with newly diagnosed Crohn’s disease (CD) are associated with impaired physical and psychological well-being. These psychological characteristics are dynamic with the course of disease and could be influenced by medical treatment. Infliximab is effective and widely used in moderate-to-severe CD patients. The aim of this study was to evaluate the improvement of psychological status after infliximab treatment in patients with newly diagnosed CD. Methods Newly diagnosed moderate-to-severe CD patients were prospectively enrolled in our study. Infliximab 5 mg/kg was administered at weeks 0, 2, 6, 14, 22, and 30. Outcomes including disease severity, illness perceptions, coping strategies, anxiety, depression, and quality of life (QoL) were measured at baseline, week 14, and week 30. Results Eighty-two patients completed our study. The rates of clinical remission at weeks 14 and 30 were 59/82 (72.0%) and 58/82 (70.7%), respectively. Patients who achieved clinical remission at weeks 14 and 30 significantly improved in illness perceptions (P<0.001 and <0.001), maladaptive coping (P=0.005 and 0.004), anxiety (P<0.001 and <0.001), depression (P=0.004 and 0.004), and QoL (P<0.001 and <0.001). However, emotion-focused coping and problem-focused coping remained unchanged. For infliximab nonresponders, no significant changes were seen in illness perceptions, coping strategies, anxiety, depression, or QoL at week 14 or 30. Conclusion Effective infliximab treatment not only led to clinical remission in patients with newly diagnosed moderate-to-severe CD but also improved their psychological status including illness perceptions, maladaptive coping, anxiety, depression, and QoL.

Prognostic Analysis of Duodenal Gastrointestinal Stromal Tumors

Aim This study aims to analyze factors possibly related to the prognosis of duodenal gastrointestinal stromal tumors (DGISTs). Methods We collected and retrospectively analyzed clinical and pathological data of 62 patients with primary DGISTs. All the patients were hospitalized and received complete surgical resection at Shanghai Ruijin Hospital from September 2003 to April 2015. We followed up the patients to determine survival outcomes. We also analyzed the effect of clinical and pathological factors on disease-free survival (DFS) and overall survival (OS) of the patients. Results Kaplan-Meier univariate survival analysis demonstrated that tumor size, mitotic index, Ki-67 index, and pathological risk were correlated with the DFS and OS of the patients (DFS P = 0.039, 0.001, <0.001, and 0.005, resp.; OS P = 0.027, 0.007, <0.001, and 0.012, resp.). Cox multivariate regression analysis revealed that Ki-67 index was an independent prognostic factor affecting DFS and OS (P = 0.007 and 0.028, resp.). Moreover, Kaplan-Meier survival analysis showed that imatinib treatment for patients with recurrence was correlated with prolonged OS (P = 0.002). Conclusion Prognosis for DGIST treated by R0 resection is favorable. High level of Ki-67 can be an independent risk factor of DGIST prognosis. Adjuvant imatinib therapy for patients with tumor recurrence could probably lead to prolonged survival.

Comparison of patients’ tolerance between computed tomography enterography and double-balloon enteroscopy

Background Computed tomography enterography (CTE) and double-balloon enteroscopy (DBE) are widely used in diagnosis of small bowel diseases. Both of these examinations bring discomfort to patients. The aim of this study was to compare patients’ tolerance and preference between CTE and DBE. Methods From August 1, 2014 to December 31, 2016, patients with suspected or known small bowel diseases who underwent both CTE and DBE were prospectively enrolled in our study. They were asked to fill out a questionnaire evaluating discomfort of the procedure after each examination. Results One hundred and seven patients completed our study. Abdominal distension, painfulness, tenesmus, general discomfort, prolonged duration, difficulty in completing the test, and discomfort after the examination were significantly lower with CTE than with DBE (P<0.001, respectively). Mannitol intake (47.7%), bowel preparation (31.9%), and radiation exposure (15.0%) were regarded as the three most intolerable burdens in CTE. Painfulness (38.3%), bowel preparation (26.2%), and invasiveness (16.8%) were considered as the three most unacceptable parts of DBE. More patients (61.7%) preferred to repeat CTE rather than DBE (P<0.001). Conclusion Compared to DBE, CTE was a more tolerable and less burdensome examination and enjoyed higher preference by most patients.

A retrospective analysis of clinical pathological characteristics and prognosis of 82 patients of primary intestinal lymphoma

Background: To evaluate the histological type, clinical presentation, treatment and prognosis of primary intestinal lymphoma (PIL). Methods: From 2003 to 2015, in a single institution in China, 82 patients with a diagnosis of PIL were enrolled in our study. According to World Health Organization (WHO) classification and Lugano staging system for gastrointestinal lymphoma, we divided patients into different subtypes and stages. Results: Male to female ratio was 1.8:1 and the median age was 59.5 years. Of the 82 patients, 68 patients (82.9%) suffered from intestinal B-cell lymphoma (IBCL) and 14 patients (17.1%) suffered from intestinal T-cell lymphoma (ITCL). Diffuse large B cell lymphoma (DLBCL) was the predominant histological subtype (59.8%) in all of the PIL cases. Mucosa-associated lymphoid tissue-type lymphoma (MALT) was the second most common subtype (15.9%). From the study we also concluded that PIL mostly occurred in the small intestine (45.1%), followed by colon and rectum (26.8%). The univariate prognosis analysis revealed that Lugano stage I/II, B-cell phenotype and treatment based on surgery plus chemotherapy were independent prognostic factors (P=0.003, 0.000 and 0.000, respectively). According to multivariate analysis, age of onset, Lugano stage, immunophenotype and the method of treatment were significant predictive factors for better survival (P=0.005, 0.005, 0.000 and 0.000, respectively). Conclusions: The patients with younger age of onset, B cell lymphoma, earlier stages, and treatment based on surgery plus chemotherapy have a better prognosis. To ensure the diagnosis of PIL to be made as soon as possible, we should make efforts to select the proper laboratory parameters and imaging findings of PIL.

Illness perceptions and stress: mediators between disease severity and psychological well-being and quality of life among patients with Crohn’s disease

Background Disease severity, illness perceptions, coping strategies, stress, psychological well-being, and quality of life were reported to have close relationships. According to the Common Sense Model, illness perceptions and coping strategies could mediate the relationship between illness stimuli and illness outcomes such as psychological health and quality of life. Stress was also associated with the individual’s disease severity, anxiety, depression, and quality of life. Objectives The study aimed to explore the influencing factors of illness outcomes, and to what extent illness perceptions, coping strategies, and stress mediate the relationship between disease severity and anxiety, and depression and quality of life. Methods Our study included 159 patients with Crohn’s disease who were attending a tertiary hospital outpatient clinic or who were hospitalized. Disease severity was measured with the Crohn’s Disease Activity Index. Illness perceptions were measured with the Brief Illness Perceptions Questionnaire. Coping strategies were measured with the Carver Brief Coping Questionnaire. Stress was measured with the Perceived Stress Questionnaire. Anxiety and depression were measured with the Hospital Anxiety and Depression Scale. Quality of life was measured with the Inflammatory Bowel Disease Questionnaire. Results Disease severity, illness perceptions, maladaptive coping, stress, anxiety, depression and quality of life were significantly correlated with each other among patients with Crohn’s disease. Using structural equation modeling to describe the inner relationship of the aforementioned variables, an excellent-fitted model was drawn. (χ2[10]=13.83, P=0.18, χ2/N=1.38, standardized root mean square residual [SRMR] <0.05, root mean square error of approximation [RMSEA] <0.05, goodness of fit index [GFI] >0.97, comparative fit index [CFI] >0.99). Disease severity had a direct influence on illness perceptions. Illness perceptions had a direct influence on stress. Both illness perceptions and stress had direct influences on anxiety, depression, and quality of life, while maladaptive coping did not directly influence anxiety, depression, or quality of life. Stress had a direct influence on maladaptive coping. Quality of life was also directly influenced by disease severity and anxiety. Conclusion Interrelationships between disease stimuli, disease perceptions and management and disease outcomes could be found in patients with Crohn’s disease. Illness perceptions and stress mediated an individual’s disease severity and anxiety, depression and quality of life, while coping strategy was not an applicable mediator.

The Efficacy of Infliximab Monotherapy versus Infliximab-Azathioprine Sequential Treatment in Crohn’s Disease: Experience from a Tertiary Medical Center in China

Objective. To evaluate the efficacy of infliximab (IFX) monotherapy versus infliximab-azathioprine sequential treatment in Crohns disease (CD) patients. Methods. Patients newly diagnosed with CD using IFX as induction therapy were enrolled. After 6 times of IFX infusions, they were divided into IFX monotherapy group and IFX-AZA sequential therapy group. Clinical remission rates were assessed at weeks 57, 84, 111, and 138 while endoscopic remission rates were assessed at weeks 84 and 138 to evaluate the efficacy of these two groups. Results. A total of seventy-nine patients had accomplished 138-week follow-up. At weeks 84 and 138, the deep remission rate (18/22 and 17/22) of IFX monotherapy group was significantly higher compared to IFX-AZA sequential therapy group (26/57 and 21/57) (P = 0.004 and 0.001, resp.). Similar findings were found in complete endoscopic remission rate. The clinical remission rates of IFX monotherapy group were similar to that of IFX-AZA sequential therapy group (P > 0.05). At weeks 84 and 138, the endoscopic remission rate and the endoscopic improvement rate between these two groups displayed no significant difference (P > 0.05). Conclusion. IFX monotherapy provides higher deep remission rate compared with IFX-AZA sequential therapy in two-year maintenance therapy. For patients who could not receive prolonged IFX therapy, IFX-AZA sequential therapy is acceptable, though long-term efficacy remains to be seen.