Modulators affecting the immune dialogue between human immune and colon cancer cells

The link between chronic inflammation and colorectal cancer has been well established. The events proceeding along tumorigenesis are complicated and involve cells activated at the cancer microenvironment, tumor infiltrating polymorphonuclears, immune cells including lymphocyte subtypes and peripheral blood mononuclear cells(PBMC), as well as tumor-associated macrophages. The immune cells generate inflammatory cytokines, several of them playing a crucial role in tumorigenesis. Additional factors, such as gene expression regulated by cytokines, assembling of tumor growth- and transforming factors, accelerated angiogenesis, delayed apoptosis, contribute all to initiation, development and migration of tumor cells. Oxygen radical species originating from the inflammatory area promote cell mutation and cancer proliferation. Tumor cells may over-express pro-inflammatory mediators that in turn activate immune cells for inflammatory cytokines production. Consequently, an immune dialogue emerges between immune and cancer cells orchestrated through a number of activated molecular pathways. Cytokines, encompassing migration inhibitory factor, transforming growth factor beta 1, tumor necrosisfactor-α, Interleukin(IL)-6, IL-10, IL-12, IL-17, IL-23 have been reported to be involved in human cancer development. Some cytokines, namely IL-5, IL-6, IL-10, IL-22 and growth factors promote tumor development and metastasis, and inhibit apoptosis via activation of signal transducer activator transcription-3 transcription factor. Colon cancer environment comprises mesenchymal, endothelial and immune cells. Assessment of the interaction between components in the tumor environment and malignant cells requires a reconsideration of a few topics elucidating the role of chronic inflammation in carcinogenesis, the function of the immune cells expressed by inflammatory cytokine production, the immunomodulation of cancer cells and the existence of a cross-talk between immune and malignant cells leading to a balance in cytokine production. It is conceivable that the prevalence of anti-inflammatory cytokine production by PBMC in the affected colonic mucosa will contribute to the delay, or even to halt down malignant expansion. Targeting the interplay between immune and cancer cells by mediators capable to alter cytokine secretion toward increased anti-inflammatory cytokine release by PBMC and tumor associated macrophages, may serve as an additional strategy for treatment of malignant diseases. This review will focus on the inflammatory events preceding tumorigenesis in general, and on a number of modulators capable to affect colon cancer cell-induced production of inflammatory cytokines by PBMC through alteration of the immune crosstalk between PBMC and cancer cells.

Co-occurrence of type 1 diabetes mellitus and celiac disease

The co-occurrence of celiac disease(CD) and type 1 diabetes(T1DM) has been reported as 5-7 times more prevalent than CD alone.The clinical presentation and natural history of CD in patients with T1 DM may vary considerably.Less than 10% of patients with T1 DM and CD show gastrointestinal symptoms.Therefore,experts support screening for CD in T1 DM patients,though there is no consensus as to the recommended frequency of screening.When stratified by time since CD diagnosis,longer follow-up and coexistence of CD are associated with significant increased risk of diabetic associated morbidity and mortality.Early CD diagnosis and treatment with a gluten-free diet are essential.

Antiviral therapy in cytomegalovirus-positive ulcerative colitis:A systematic review and meta-analysis

AIM:To evaluate the impact of antiviral treatment on cytomegalovirus(CMV)-positive ulcerative colitis patients.METHODS:We performed a systematic review and meta-analysis(MA)of comparative cohort and casecontrol studies published between January 1966 and March 2013.Studies focusing on colectomy series and studies including only less than 3 patients in the treated or non-treated arm were excluded.The primary outcome was colectomy within 30 d of diagnosis.Secondary outcomes included colectomy during the follow-up period Subgroup analyses by method of detection of CMV,study design,risk of bias and country of origin were performed.Quality of studies was evalu-ated according to modified New-Castle Ottawa Scale.RESULTS:After full-text review,nine studies with a total of 176 patients were included in our MA.All the included studies were of low to moderate quality.Patients who have received antiviral treatment had a higher risk of 30-d colectomy(OR=2.40;95%CI:1.05-5.50;I2=37.2%).A subgroup analysis including only patients in whom CMV diagnosis was based did not demonstrate a significant difference between the groups(OR=3.41;95%CI:0.39-29.83;I2=56.9%).Analysis of long-term colectomy rates was possible for 6 studies including110 patients.No statistically significant difference was found between the treated and untreated groups(OR=1.71;95%CI:0.71-4.13;6 studies,I2=0%).Analysis of mortality rate was not possible due to a very limited number of cases.Stratification of the outcomes by disease severity was not possible.CONCLUSION:No positive association between antiviral treatment and a favorable outcome was demonstrated.These findings should be interpreted cautiously due to primary studies’quality and potential biases.

Atorvastatin and rosuvastatin do not prevent thioacetamide induced liver cirrhosis in rats

AIM:To examine whether the administration of atorvastatin and rosuvastatin would prevent experimentallyinduced hepatic cirrhosis in rats.METHODS:Liver cirrhosis was induced by injections of thioacetamide(TAA).Rats were treated concurrently with TAA alone or TAA and either atorvastatin(1,10 and 20 mg/kg) or rosuvastatin(1,2.5,5,10 and 20 mg/kg) given daily by nasogastric gavage.RESULTS:Liver fibrosis and hepatic hydroxyproline content,in the TAA-treated group was significantly higher than those of the controls [11.5 ± 3.2 vs 2.6 ± 0.6 mg/g protein(P = 0.02)].There were no differences in serum aminotransferase levels in the TAA controls compared to all the groups treated concomitantly by statins.Both statins used in our study did not prevent liver fibrosis or reduce portal hypertension,and had no effect on hepatic oxidative stress.Accordingly,the hepatic level of malondialdehyde was not lower in those groups treated by TAA + statins compared to TAA only.In vitro studies,using the BrdU method have shown that atorvastatin had no effect of hepatic stellate cells proliferation.Nevertheless,statin treatment was not associated with worsening of liver damage,portal hypertension or survival rate.CONCLUSION:Atorvastatin or rosuvastatin did not inhibit TAA-induced liver cirrhosis or oxidative stress in rats.Whether statins may have therapeutic applications in hepatic fibrosis due to other etiologies deserve further investigation.

Flare-up of ulcerative colitis after systemic corticosteroids: A strong case for Strongyloides

Super-imposed infection with intestinal organisms can mimic a flare-up of underlying disease in patients with inflammatory bowel disease (IBD). We report a case of patient with long standing ulcerative colitis (UC), who presented with abdominal pain, diarrhea and low- grade fever after receiving systemic corticosteroids for an unrelated disorder. Despite a negative stool examination, a peripheral eosinophilia reappeared upon tapering down of a corticosteroid dose. Subsequently, duodenal biopsies showed evidence for Strongyloides, presumably acquired 20 years ago when the patient was residing in Brazil. The patient fully recovered following anti-helmintic therapy. This case underscores the importance of considering Strongyloides in the work-up of flaring-up IBD patients, even if a history of residing or traveling to endemic areas is in the distant past.

Eating disorders in adolescents with type 1 diabetes:Challenges in diagnosis and treatment

Eating disorders(ED) are characterized by a persistent disturbance of eating that impairs health or psychosocial functioning.They are associated with increased rates of medical complications and mortality.Insulin omission is a unique purging behavior available to individuals with type 1 diabetes mellitus(T1DM).The standard treatment regimen for T1 DM requires a major focus on food andeating patterns.Moreover,intensive insulin therapy is associated with increasing body weight.These factors,combined with the psychological burden of chronic disease management and depression,may contribute to ED.The comorbidity of ED in T1 DM patients is associated with poorer glycemic control and consequently higher rates of diabetes complications.Early recognition and adequate treatment of ED in T1 DM is essential.

Combination of corticosteroids and 5-aminosalicylates or corticosteroids alone for patients with moderate-severe active ulcerative colitis:A global survey of physicians'practice

AIM To examine treatment decisions of gastroenterologists regarding the choice of prescribing 5-aminosalycilates(5ASA) with corticosteroids(CS) versus corticosteroids alone for patients with active ulcerative colitis(UC). METHODS A cross-sectional questionnaire exploring physicians' attitude toward 5ASA + CS combination therapy vs CS alone was developed and validated. The questionnaire was distributed to gastroenterology experts in twelve countries in five continents. Respondents' agreement with stated treatment choices were assessed by standardized Likert scale. Background professional characteristics of respondents were analyzed for correlation with responses. RESULTS Six hundred and sixty-four questionnaires were distributed and 349 received(52.6% response rate). Of 340 eligible respondents, 221(65%) would continue 5ASA in a patient hospitalized for intravenous CS treatment due to a moderate-severe UC flare, while 108(32%) would stop the 5ASA(P < 0.001), and 11(3%) are undecided. Similarly, 62% would continue 5ASA in an out-patient starting oral CS. However, only 140/340(41%) would proactively start 5ASA in a hospitalized patient not receiving 5ASA before admission. Most(94%) physicians consider the safety profile of 5ASA as very good. Only 52% consider them inexpensive, 35% perceive them to be expensive and 12% are undecided. On multi-variable analysis, less years of practice and perception of a plausible additive mechanistic effect of 5ASA + CS were positively associated with the decision to continue 5ASA with CS. CONCLUSION Despite the absence of data supporting its benefit, most gastroenterologists endorse combination of 5ASA + CS for patients with active moderate-to-severe UC. Randomized controlled trials are needed to assess if 5ASA confer any benefit for these patients.

Significance of low level infliximab in the absence of anti-infliximab antibodies

AIM:To evaluate the prevalence of double negative(DN)sera and the mechanisms responsible for DN status.METHODS:Sera of inflammatory bowel disease patients treated with infliximab(IFX)were tested for drug/antibodies to infliximab(ATI)trough levels and the proportion of DN results was compared between a commercially available double antigen ELISA(with labeled IFX as the detection antibody)and an antilambda ELISA(with anti-human lambda chain detection antibody).Repeat testing with lower than customary serum dilution(1:10)was performed.Patients with DN status were matched with IFX+/ATI-controls and were followed-up for subsequent development of nontransient ATI to investigate if DN status precedes ATI.RESULTS:Of 67 sera obtained at time of loss of response,only 6/67(9%)were DN by anti-lambda ELISA compared to 27/67(40%)with double antigen ELISA(P<0.001,Fisher’s Exact test).Of the latter27 sera,22%were also DN by anti-lambda ELISA,whereas 44%were actually IFX positive(IFX+ATI-),30%were ATI positive(IFX-ATI+)and 4%were double positive(IFX+ATI+).Re-testing using a 1:10 dilution converted most DN results into IFX+and/or ATI+status.Patients with DN status had shorter survival free of non-transient ATI compared with matched controls(log rank test,P<0.001).In 9/30(30%)of these patients,non transient ATI occurred before and after the event at which the DN serum was obtained,supporting the view that a DN result may represent aparticular time-point along the two curves of ATI titer rise and infliximab drug level decline.CONCLUSION:DN status may result from false negative detection of IFX or ATI by double antigen ELISA,suggesting a transitional state of low-level immunogenicity,rather than non-immunological clearance.

Atherogenesis, the oxidative LDL modification hypothesis revisited

The commonly-accepted “oxidized LDL hypothesis of atherogenesis” is based on a large number of indirect evidence that shows that oxidatively-modified LDL plays a role in atherogenesis. Yet, the exact role is not clear. Some researchers think that oxidatively modified biomolecules initiate atherogenesis;others believe that they “only” promote this multifactorial process. Regardless of the exact mechanism responsible for the effect of peroxidation on atherogenesis, the “oxidative theory of AS” is apparently inconsistent with the results of meta-analysis, in which (the “expected”) significant correlation between CVD and oxidative stress (OS) was found only when the OS was evaluated on the basis of the plasma concentrations of malondialdehyde (MDA), often based on the concentration of thiobarbituric acid reactive substances (TBARS). Notably, even this association is questionable due to 1) poor reliability of the laboratory assay of MDA and 2) possible publication bias. Hence, it appears that the commonly accepted paradigm regarding the role of oxidative damage in the pathogenesis of CVD has been overestimated. Furthermore, the hypothesis is apparently inconsistent with the disappointing results of most of the clinical trials that were designed to reduce OS by means of supplementation of antioxidants, mostly vitamin E. These apparent inconsistencies do not contradict the oxidative modification hypothesis of AS. The source of the apparent contradictions is probably the oversimplified considerations on which the predictions have been based. Many reasonable arguments can be raised to explain the apparent contradictions, which means that our current knowledge is insufficient to test the relationship of oxidative stress to cardiovascular disease.

Physicians’ Life Satisfaction in Bhutan: A Nationwide Survey

Objectives: Bhutan was the first country to invest in “gross national happiness”. Health care professionals usually report higher levels of happiness. In the last decade many physicians were reportedly dissatisfied with their lives and careers: “unhappy physicians”. We aimed to assess levels of happiness amongst Bhutanese physicians. Methods: Bhutanese physicians endorsed the Satisfaction with Life Scale (SWLS) and a demographic questionnaire. Results: Of 176 physicians in Bhutan, 110 physicians completed the survey: 25.5% women and 74.5% men. Mean age was 36.9 years. Mean SWLS score for all physicians was 23.5 ± 6.9. Conclusions: Only two thirds (66.5%) of the Bhutanese physicians who have participated in this study were satisfied with life, which was significantly lower than rate in the Bhutanese general population or among Israeli Physicians participating in a similar study.

Harnessing class II histone deacetylases in macrophages to combat breast cancer

Viewing the tumor microenvironment(TME)as a critical factor in cancer biology has been a central paradigm shift in the field in the past two decades.1 During this time,the roles of tumor-infiltrating immune cells have gradually been elucidated.

Adenosquamous carcinoma arising in a duplication cyst of the gallbladder

A 52-year-old woman,previously healthy was admitted to another hospital due to right upper quadrant abdominal pain,fever and leukocytosis.An ultrasound demonstrated acute cholecystitis and lesion 8 cm.in diameter near the gallbladder.An abdominal CT scan showed the lesion in close proximity to the gallbladder,with fat infiltration.A percutaneous drainage of the lesion under CT guidance yielded a substance which was bloody and purulent in content.The patient improved clinically under antibiotics and was discharged from hospital with a recommendation for elective exploratory laparoscopy.

Signal-induced PARP1-Erk synergism mediates IEG expression

A recently disclosed Erk-induced PARP1 activation mediates the expression of immediate early genes(IEG)in response to a variety of extra-and intra-cellular signals implicated in memory acquisition,development and proliferation.Here,we review this mechanism,which is initiated by stimulation-induced binding of PARP1 to phosphorylated Erk translocated into the nucleus.Their binding maintains their long-lasting activity in a synergism,which offers a new pattern for targeted therapy.

Characterization of functional transposable element enhancers in acute myeloid leukemia

Transposable elements(TEs)have been shown to have important gene regulatory functions and their alteration could lead to disease phenotypes.Acute myeloid leukemia(AML)develops as a consequence of a series of genetic changes in hematopoietic precursor cells,including mutations in epigenetic factors.Here,we set out to study the gene regulatory role of TEs in AML.We first explored the epigenetic landscape of TEs in AML patients using ATAC-seq data.We show that a large number of TEs in general,and more specifically mammalian-wide interspersed repeats(MIRs),are more enriched in AML cells than in normal blood cells.We obtained a similar finding when analyzing histone modification data in AML patients.Gene Ontology enrichment analysis showed that genes near MIRs in open chromatin regions are involved in leukemogenesis.To functionally validate their regulatory role,we selected 19 MIR regions in AML cells,and tested them for enhancer activity in an AML cell line(Kasumi-1)and a chronic myeloid leukemia(CML)cell line(K562);the results revealed several MIRs to be functional enhancers.Taken together,our results suggest that TEs are potentially involved in myeloid leukemogenesis and highlight these sequences as potential candidates harboring AML-associated variation.