Synthesis and biological evaluation of N-Alkylamide derivatives as anti-tumor agents

Background:N-Alkylamides(NAAs),derived from Anacyclus pyrethrum(L.)DC,have potential anti-tumor effects.To explore the molecular mechanism and chemo-preventive capacity of NAAs,we synthesized an NAA(H-10)and evaluated whether it could inhibit the proliferation of B16,HepG2,HeLa,and HCT116 cancer cells in 2D culture.Methods:To evaluate the antiproliferative activity of H-10 in 2D and 3D culture of BD,HepG2,HeLa,and HCT116 cells,multicellular tumor spheroids were constructed to more accurately reflect the cell tumor environment.To visualize nuclear changes related to apoptosis,Hoechst 33258 staining and propidium iodide-Annexin V double staining were performed.Results:Compound H-10 strongly inhibited the growth of all tested cell lines.Hoechst 33258 staining and propidium iodide-Annexin V double staining revealed that H-10 did not cause morphological alterations in the nuclei and moderately induced late apoptosis only when treated at 180 mM.The strongest inhibitory effect was observed in HCT116 cells.Flow cytometry analysis indicated that treatment of HCT116 cells with compound H-10 resulted in robust cell growth arrest in G2 phase in 2D and 3D cell culture;in 3D-cultured HCT116 cells,growth arrest occurred in G1 phase.Treatment with compound H-10 also significantly suppressed angiogenesis of chick chorioallantoic membrane in vivo.Conclusion:Treatment with compound H-10 strongly affected clonogenic survival(in the long-term)and migration of HCT116 cells.Therefore,H-10,a compound of NAAs may be useful for treating cancer because of its anti-neoplastic effect and easy synthesis.

Safety and efficacy of anti-tumor necrosis factors α in patients with psoriasis and chronic hepatitis C

Up to date,in literature,it is still debated the role of anti-tumor necrosis factors(TNF)-α treatments in hepatitis C virus(HCV) patients.TNF-α performs a lot of functions,it is an important pro-inflammatory cytokine and it is involved in the host's immunity.Since TNF-α is implicated in the apoptotic signaling pathway of hepatocytes infected by HCV,anti TNF-α therapy may increase the risk of viral replication or their reactivation.However the treatment of anti TNF-α could have a healthful role because TNF-α appears to be engaged in the pathogenesis of liver fibrosis,inducing apoptotic pathways.We describe the case of a patient with plaquetype psoriasis and concomitant chronic HCV,who was treated successfully with anti-TNF agents simultaneously to cyclosporine without sign of reactivation of HCV and increase of liver enzymes.Our personal experience shows that anti-TNF-α agents are not only effective but also safe.Furthermore the combination therapy of cyclosporine and anti-TNF-α appears to be well-tolerated and able to reduce the amount of liver enzymes as well as HCV-viral-load.However systematic,large-scale studies with long follow-ups will be needed to confirm our results,in association with close liver function monitoring.

Optimizing production ofasperolide A,a potential anti-tumor tetranorditerpenoid originally produced by the algal-derived endophytic fungus Aspergillus wentii EN-48

The marine algal-derived endophytic fungus Aspergillus wentii EN-48 produces the potential anti-tumor agent asperolide A, a tetranorlabdane diterpenoid active against lung cancer. However, the fermentation yield of asperolide A was very low and only produced in static cultures. Static fermentation conditions of A. wentii EN-48 were optimized employing response surface methodology to enhance the production of asperolide A. The optimized conditions resulted in a 13.9-fold yield enhancement, which matched the predicted value, and the optimized conditions were successfully used in scale-up fermentation for the production of asperolide A. Exogenous addition of plant hormones （especially 10 pmol/L methyl jasmonate） stimulated asperolide A production. To our knowledge, this is first optimized production of an asperolide by a marine-derived fungus. The optimization is effective and valuable to supply material for further anti-tumor mechanism studies and preclinical evaluation of asperolide A and other norditerpenoids.

Effects of recombinant human canstatin protein in the treatment of pancreatic cancer

AIM: To examine the effect of canstatin, a newly discovered endogenous inhibitor of angiogenesis, in the treatment of pancreatic cancer in vivo. METHODS: The canstatin cDNA fragment was synthesized and amplified from the total RNA extracted from human placenta tissues by RT-PCR. The resulting product was firstly cloned into pUCm-T vector, then into plasmid pET-22b (+) and transformed into E. coli BL21. Isopropyl-1-thio-b-Dgalactopyran-oside (IPTG) was used to induce the expression of canstatin protein and affinity chromatography was used to purify the protein. To determine the activity of purified recombinant human canstatin (rhCanstatin), orthotopic xenograft human pancreatic cancer models were established. Human pancreatic cancer cells (SW1990) were injected into the pancreas of BALB/c nude mice. Twenty-four nude mice with orthotopic xenograft tumor were randomly divided into 3 groups 10 d after the inoculation, and were treated with PBS 0.3 mL, or canstatin 5 mg/kg, or 10 mg/kg per day for 3 wk intraperitoneally. When the experiment was over, all tumors were resected and the effects of rhCanstatin on tumor growth, microvessel density (MVD) were analyzed. RESULTS: After IPTG induction, SDS-PAGE showed a new monomeric 24 kDa protein band. This protein was purified through affinity chromatography and refolded through dialysis with a final concentration of 60 mg/L. In orthotopic pancreatic cancer models, the final tumor volume in groups treated with PBS, canstatin 5 mg/ kg, 10 mg/kg were 355.21 ± 39.54 mm3, 112.73 ±10.47 mm3, and 61.75 ± 6.99 mm3 respectively. The immunohistochemical examination showed that the MVD in tumors treated with canstatin was significantly less than that in other group. CONCLUSION: These findings demonstrate that the rhCanstatin effectively retards the growth of pancreatic cancer in a dose-dependent manner through inhibiting angiogenesis and may be a promising therapeutic agent for pancreatic cancer treatment in the clinic.

Preventing infective complications in inflammatory bowel disease

Over the past decade there has been a dramatic change in the treatment of patients with Crohn’s disease and ulcerative colitis, which comprise the inflammatory bowel diseases (IBD). This is due to the increasing use of immunosuppressives and in particular the biological agents, which are being used earlier in the course of disease, and for longer durations, as these therapies result in better clinical outcomes for patients. This, however, has the potential to increase the risk of opportunistic and serious infections in these patients, most of which are preventable. Much like the risk for potential malignancy resulting from the use of these therapies long-term, a balance needs to be struck between medication use to control the disease with minimization of the risk of an opportunistic infection. This outcome is achieved by the physician’s tailored use of justified therapies, and the patients’ education and actions to minimize infection risk. The purpose of this review is to explore the evidence and guidelines available to all physicians managing patients with IBD using immunomodulating agents and to aid in the prevention of opportunistic infections.

Synthesis and in vitro biological evaluation of nitric oxide-releasing derivatives of hydroxylcinnamic acids as anti-tumor agents

Novel furoxan-based nitric oxide-releasing derivatives 6a-p of hydroxylcinnamic acids were synthesized by coupling the carboxyl group of hydroxylcinnamic acids with furoxan through various alkylol amines.Compounds 6a,e-i and m-p displayed more potent anti-tumor activities superior to control 5-fluorouracil（5-FU） in most cancer cells tested.Furthermore,6f could selectively inhibit tumor cells,but not non-tumor cell proliferation.This inhibition was attributed to high levels of NO released in cancer cells and potentially synergistic effect of NO donor moieties and the bioactivity of hydroxylcinnamic acids.

Herpes simplex induced necrotizing tonsillitis in an immunocompromised patient with ulcerative colitis

We here present the case of a 22-year-old female of Suriname ethnicity with ulcerative colitis who received treatment with mercaptopurine and infliximab.She presented herself with a severe necrotizing tonsillitis due to herpes simplex virus type-1(HSV-1).Combination therapy consisting of immunomodulators and anti-tumor necrosis factor(TNF) agents is increasingly being used.Anti-TNF therapy is associated with an increased risk of developing serious infections,and especially patients receiving combination treatment with thiopurines are at an increased risk.We here show that HSV infections can cause a severe tonsillitis in immunocompromised patients.Early recognition is essential when there is no improvement with initial antibiotic therapy within the first 24 to 72 h.HSV infections should be in the differential diagnosis of immunocompromised patients presenting with a necrotizing tonsillitis and can be confirmed by polymerase chain reaction.Early treatment with antiviral agents should be considered especially if antibiotic treatment fails in such patients.

Synthesis and in vitro biological evaluation of farnesylthiosalicylic acid derivatives as anti-tumor carcinoma agents

Novel farnesylthiosalicylic acid （PTA） derivatives 5a-m with different substituted 1,3,4-thiadiazoles were synthesized. Compounds 5b, 5e, 5e and 5f displayed anti-tumor activities superior to FTA in most cancer cells tested. Furthermore, 5e induced tumor cell apoptosis, which was accompanied by lower Bcl-2 expression, but with higher Bax and caspase 3 expression activities in cancer cells.

Severe cholestasis due to adalimumab in a Crohn's disease patient

Elevation of liver biochemistry has been reported with anti-tumor necrosis factor agents, but overt liver failure rarely reported. Autoimmune hepatitis has been more commonly reported with infliximab than adalimumab(ADA). Our case, however, describes the first reported case of ADA-associated severe cholestatic injury. A 39-year-old female with Crohn's disease developed severe jaundice after initiation of ADA. All serologic tests and imaging studies were normal. Liver biopsy showed prominent pericentral canalicular cholestasis,without features of steatosis or sclerosing cholangitis,consistent with drug-induced cholestasis. The serum total bilirubin peaked at 280 μmol/L, and improvement was seen after 5 wk with eventual normalization of liver enzymes at 10 wk. Our case describes the first reported case of ADA-associated severe cholestatic liver disease and the first histopathologic examination of this adverse drug effect. Clinicians need to be aware of this potential drug-induced liver injury when prescribing this commonly used biologic medication.

Surgery for Crohn's disease in the era of biologicals:A reduced need or delayed verdict?

Crohn's disease(CD) is a chronic inflammatory bowel disease that can affect the entire gastrointestinal tract.Ultimately,up to 70% of all patients will need surgery,despite optimized medical therapy.Moreover,about half of the patients will need redo-surgery because of disease recurrence.The introduction of anti-tumor necrosis factor(TNF) drugs(Infliximab in 1998) revolutionized the treatment of CD.Different randomized trials assessed the efficacy of anti-TNF treatment not only to induce,but also to maintain,steroid-free remission.Furthermore,these agents can rapidly lead to mucosal healing.This aspect is important,as it is a major predictor for long-term disease control.Subgroup analyses of responding patients seemed to suggest a reduction in the need for surgery at median-term follow up(1-3 years).However if one looks at population surveys,one does not observe any decline in the need for surgery since the introduction of Infliximab in 1998.The short follow-up term and the exclusion of patients with imminent surgical need in the randomized trials could bias the results.Only 60% of patients respond to induction of anti-TNF therapy,moreover,some patients will actually develop resistance to biologicals.Many patients are diagnosed when stenosing disease has already occurred,obviating the need for biological therapy.In a further attempt to change the actual course of the disease,top down strategies have been progressively implemented.Whether this will indeed obviate surgery for a substantial group of patients remains unclear.For the time being,surgery will still play a pivotal role in the treatment of CD.

Microscopic colitis

Microscopic colitis may be defined as a clinical syndrome, of unknown etiology, consisting of chronic watery diarrhea, with no alterations in the large bowel at the endoscopic and radiologic evaluation. Therefore, a definitive diagnosis is only possible by histological analysis. The epidemiological impact of this disease has become increasingly clear in the last years, with most data coming from Western countries. Microscopic colitis includes two histological subtypes [collagenous colitis (CC) and lymphocytic colitis (LC)] with no differences in clinical presentation and management. Collagenous colitis is characterized by a thickening of the subepithelial collagen layer that is absent in LC. The main feature of LC is an increase of the density of intra-epithelial lymphocytes in the surface epithelium. A number of pathogenetic theories have been proposed over the years, involving the role of luminal agents, autoimmunity, eosinophils, genetics (human leukocyte antigen), biliary acids, infections, alterations of pericryptal fibroblasts, and drug intake; drugs like ticlopidine, carbamazepine or ranitidine are especially associated with the development of LC, while CC is more frequently linked to cimetidine, non-steroidal antiinflammatory drugs and lansoprazole. Microscopic colitis typically presents as chronic or intermittent watery diarrhea, that may be accompanied by symptoms such as abdominal pain, weight loss and incontinence. Recent evidence has added new pharmacological options for the treatment of microscopic colitis:the role of steroidal therapy, especially oral budesonide, has gained relevance, as well as immunosuppressive agents such as azathioprine and 6-mercaptopurine. The use of anti-tumor necrosis factoragents, infliximab and adalimumab, constitutes a new, interesting tool for the treatment of microscopic colitis, but larger, adequately designed studies are needed to confirm existing data.

Synthesis and in vitro biological evaluation of novel 2-aminoimidazolone derivatives as anti-tumor agents

Novel 2-aminoimidazolone derivatives were synthesized.Most compounds displayed strong anticancer activities against human carcinoma cells in vitro.Compounds 8a,8b and 8j exhibited optimal activity superior to 5-FU in most cancer cells tested.Especially,the lC_（50）s of 8b（12.6-21.5μmol/L） against five tumor cells were 1 -4 fold less than those of 5-FU（18.4-56.1μmol/L） in vitro.Furthermore,comp以ound 8b could induce SMMC-7721 cell apoptosis in a dose-dependent manner.Therefore,our novel findings may provide a new framework for the design of new 2-aminoimidazolone derivatives for the treatment of cancer.

What is the best way to manage screening for infections and vaccination of inflammatory bowel disease patients?

The use of biological agents and immunomodulators for inflammatory bowel disease(IBD) is associated with an increased risk of opportunistic infections, in particular of viral or bacterial etiology. Despite the existence of international guidelines, many gastroenterologists have not adopted routine screening and vaccination in those patients with IBD, which are candidate for biologic therapy. Available strategies to screen, diagnose and prevent bacterial and viral infections in patients with IBD prior to start biological therapy are discussed in this review.

Acute renal artery occlusion following infliximab infusion

We report the case of a 44-year-old male patient who presented with acute renal artery occlusion, 3 d after frst injection of infiximab for steroid refractory attack of ulcerative colitis. Extensive work-up provided no evidence of predisposing factors for arterial thrombosis. Infiximab was thus suspected in the genesis of throm-bosis, based on both intrinsic and extrinsic criteria. At month 3 after thrombosis with ongoing anticoagulation, angio-tomodensitometry showed complete revascularization of the left renal artery with renal atrophy. Renal function remained normal and the patient was still in steroid free remission on mercaptopurin monotherapy at maximal follow-up. Few thromboembolic events have been described with anti- tumor necrosis factor （TNF） agents, but it is the frst case reported of renal artery thrombosis after infiximab infusion. In addition, we re-view thrombosis associated with anti-TNF agents.

Gem-Diphosphonates： The Motif of Diverse Biological and Medicinal Importance

The introduction of gem-diphosphonates （known as bisphosphonates, BPs） in oncology has dramatically changed the management of patients with metastatic bone disease. In this manuscript, we thoroughly scrutinize the available body of clinical trials supporting the use of bisphosphonates in this setting and review new and ongoing research. Additionally, we summarize the data showing the benefits of BP-use in the prevention of treatment-induced bone loss and the intriguing emerging evidence on the antitumor potential of some of these agents when used in the adjuvant setting. Finally, we address the need for a careful consideration of potential benefits of BPs therapy and the risk for osteonecrosis, a recently recognized late-toxicity of their use.

The association between metformin use and colorectal cancer survival among patients with diabetes mellitus:An updated meta-analysis

Objective: Recent studies have reported conflicting results on the correlation between metformin use and outcomes in patients with colorectal cancer (CRC). A meta-analysis was performed to evaluate the efficacy of metformin therapy on the prognosis of CRC patients with type 2 diabetes mellitus (T2DM).Methods: We conducted a systematic search of PubMed, EMBASE, the Cochrane Library, and the Web of Science for related articles up to August 2016. Two investigators independently identified and extracted information. Pooled risk estimates [hazard ratios (HRs)] and 95% confidence intervals (CIs) were calculated using fixed-effects models. The risk of publication bias was assessed by examining funnel plot asymmetry as well as Egger's test and Begg's test.Results: Of 81 articles identified, 8 retrospective cohort studies, representing 6098 cases of CRC patients with T2DM who used metformin and 4954 cases of CRC patients with T2DM who did not use metformin, were included in this meta-analysis. There was no significant heterogeneity and quality difference between studies. Metformin users had significantly improved overall survival (OS) (HR=0.82, 95%CI:0.77-0.87, P=0.000). However, Metformin use cannot affect CRC-specific survival (HR=0.84, 95%CI:0.69-1.02, P=0.079) compared to non-users.Conclusion: This meta-analysis suggests that metformin use may improve survival among CRC patients with T2DM. However, prospective controlled studies are still needed to rigorously evaluate the efficacy of metformin as an anti-tumor agent.

Novel hybrids from N-hydroxyarylamide and indole ring through click chemistry as histone deacetylase inhibitors with potent antitumor activities

Novel hybrid molecules 8a-8o were designed and synthesized by connecting indole ring with N- hydroxyarylamide through alkyl substituted triazole, and their in vitro biological activities were evaluated. It was discovered that most of target compounds showed promising anticancer activities, particularly for 8n, which had a significant HDACs inhibitory and antiproliferative activities comparable to or slightly stronger than SAHA against human carcinoma cells. Furthermore, compound 8n exhibited much better selectivity for HDAC1 over HDAC6 and HDAC8 than SAHA. In addition, compound 8n also could dose-dependently induce cancer cell cycling arrest at G0/G1 phase and promote the expression of the acetylation for histone H3 and tubulin in vitro. Therefore, our novel findings may provide a new framework for the design of new selective HDAC inhibitor for the treatment of cancer.

Vedolizumab in the treatment of Crohn’s disease of the pouch

Background:Our recent study showed the efficacy and safety of vedolizumab in the treatment of chronic antibioticrefractory pouchitis.However,there are no published studies on its efficacy and safety in Crohn’s disease(CD)of the pouch.The aim of this study was to assess the efficacy and safety of vedolizumab in those patients.Methods:This case series included all eligible patients with CD of the pouch from our prospectivelymaintained,IRB-approved Pouchitis Registry from 2015 to 2017.Disease activity in pouch patients can bemonitored using the modified Pouchitis Disease Activity Index(mPDAI).mPDAI is the 18-point pouchitis disease activity index consisting of three principal component scores:symptom(range,0–6 points),endoscopy,(range 0–6 points),and histology(range,2–6 points).Pre-and post-treatment(minimum 6 months)pouchoscopy and clinical visits were used to calculate mPDAI.Results:A total of 12 patients were included in this study,who had restorative proctocolectomy with ileal pouch anal anastomosis for medically refractory ulcerative colitis(UC).The mean age at the time of pre-colectomy diagnosis of UC was 25.0611.5 years.The mean current age was 41.0612.1 years,nine(75.0%)were female,three(25.0%)had smoked and eight(66.7%)had used anti-tumor necrosis factor agents prior to vedolizumab use.The mean duration of vedolizumab use was 1.066.4 years.There was a significant reduction in mPDAI symptom subscores after vedolizumab therapy(3.5061.93 vs 5.0860.79,P=0.015).The pre-and post-treatment mean endoscopy subscores were 1.2561.36 and 0.9161.50 in the afferent limb(P=0.583);2.5861.68 and 2.2762.05(P=0.701)in the pouch body;and 2.6761.93 and 2.0962.12(P=0.511)in the cuff,respectively.None of the patients experienced side effects throughout the vedolizumab therapy.Conclusion:The findings of our study suggests that vedolizumab appears to be effective and safe in reducing the symptoms in patients with CD of the pouch.