NLRC5/CITA expression correlates with efficient response to checkpoint blockade immunotherapy.

Checkpoint blockade-mediated immunotherapy is emerging as an effective treatment modality for multiple cancer types. However, cancer cells frequently evade the immune system, compromising the effectiveness of immunotherapy. It is crucial to develop screening methods to identify the patients who would most benefit from these therapies because of the risk of the side effects and the high cost of treatment. Here we show that expression of the MHC class I transactivator (CITA), NLRC5, is important for efficient responses to anti-CTLA-4 and anti-PD1 checkpoint blockade therapies. Melanoma tumors derived from patients responding to immunotherapy exhibited significantly higher expression of NLRC5 and MHC class I-related genes compared to non-responding patients. In addition, multivariate analysis that included the number of tumor-associated non-synonymous mutations, predicted neo-antigen load and PD-L2 expression was capable of further stratifying responders and non-responders to anti-CTLA4 therapy. Moreover, expression or methylation of NLRC5 together with total somatic mutation number were significantly correlated with increased patient survival. These results suggest that NLRC5 tumor expression, alone or together with tumor mutation load constitutes a valuable predictive biomarker for both prognosis and response to anti-CTLA-4 and potentially anti-PD1 blockade immunotherapy in melanoma patients.

Comparison of a novel predictor of venous thromboembolic complications in inflammatory bowel disease with current predictors.

BACKGROUND AND AIM: Venous thromboembolism (VTE) is a common complication of inflammatory bowel disease (IBD). The aim of the present study was to identify predictors of VTE in hospitalized patients with IBD. METHODS: Patients with IBD who were hospitalized from February 2015 to March 2016 at the Chiba University Hospital were included. VTE was detected using enhanced computed tomography, and VTE onset within 2 months after admission was assessed. Predictors of VTE onset were investigated with clinical factors during hospitalization. Availability of the Caprini risk assessment model and Padua prediction score at the time of admission was also assessed. RESULTS: Seventy-two patients with IBD were hospitalized, and central venous catheters were placed in 43 of the 72 patients. During the observation period, VTE occurred in six patients (8.3%); however, none died as a result of the condition. Cox proportional hazards regression analysis identified D-dimer values on admission as a risk factor that was highly associated with VTE onset (hazard ratio = 1.590; 95% confidence interval, 1.132-2.233; P = 0.007) and significantly predicted the occurrence of VTE using the receiver operating characteristic curve (P = 0.005, area under the curve = 0.893). However, Caprini risk assessment model and Padua prediction scores were not useful tools for predicting VTE onset in patients with IBD. CONCLUSION: In hospitalized patients with IBD, D-dimer values were highly associated with VTE onset. Therefore, measurement of D-dimer values on admission is critical for the management of thromboembolic complications in patients with IBD.

NLRC5/CITA: A Key Player in Cancer Immune Surveillance.

Cancer cells need to escape immune surveillance for successful tumor growth. Loss of MHC class I has been described as a major immune evasion strategy in many cancers. MHC class I transactivator (CITA), NLRC5 [nucleotide-binding domain and leucine-rich repeats containing (NLR) family, caspase activation and recruitment domain (CARD) domain containing 5], is a key transcription coactivator of MHC class I genes. Recent genetic studies have revealed that NLRC5 is a major target for cancer immune evasion mechanisms. The reduced expression or activity of NLRC5 caused by promoter methylation, copy number loss, or somatic mutations is associated with defective MHC class I expression, impaired cytotoxic T cell activation, and poor patient prognosis. Here, we review the role of NLRC5 in cancer immune evasion and the future prospects for cancer research.

Mesenteric findings of CT enterography are well correlated with the endoscopic severity of Crohn's disease.

BACKGROUND: Maintenance of mucosal healing is a primary goal when treating Crohn's disease (CD). Endoscopy is the most precise method for the assessment of mucosal healing, but is considered overly invasive for patients with CD. In contrast, CT enterography (CTE) is less invasive, but little is known about the correlation between mucosal status and CTE parameters. METHODS: We recruited CD patients who underwent CTE and double balloon endoscopy (DBE) on the same day at our hospital between 2012 and 2014. CTE parameters evaluated included bowel-wall thickening, mural hyperenhancement, mural stratification (target sign), submucosal fat deposition, mesenteric hypervascularity (comb sign), increased fat density, mesenteric fibrofatty proliferation, enlarged mesenteric lymph nodes, and stenosis/sacculation. Endoscopic findings were evaluated using the Simple Endoscopic Score for Crohn's Disease (SES-CD). CTE parameters that were predictive of higher values in the SES-CD were extracted statistically. RESULTS: Forty-one patients were recruited, from which 191 intestinal segments were evaluated. Spearman's rank correlation coefficients showed that the majority of CTE values exhibited mild to moderate correlations with SES-CD values. Notably, multiple ordinal logistic regression analysis demonstrated that CTE findings obtained from the mesenteric area, such as mesenteric hypervascularity (comb sign) and enlarged mesenteric lymph nodes, were more critical predictors of endoscopic mucosal ulceration than those obtained from the bowel wall. CONCLUSIONS: This study was the first of its kind to assess correlations between CTE values and SES-CD values. Mesenteric findings of CTE, rather than mural findings, were highly correlated with the endoscopically evaluated severity of ulceration.

Nod2: A Critical Regulator of Ileal Microbiota and Crohn's Disease.

The human intestinal tract harbors large bacterial community consisting of commensal, symbiotic, and pathogenic strains, which are constantly interacting with the intestinal immune system. This interaction elicits a non-pathological basal level of immune responses and contributes to shaping both the intestinal immune system and bacterial community. Recent studies on human microbiota are revealing the critical role of intestinal bacterial community in the pathogenesis of both systemic and intestinal diseases, including Crohn's disease (CD). NOD2 plays a key role in the regulation of microbiota in the small intestine. NOD2 is highly expressed in ileal Paneth cells that provide critical mechanism for the regulation of ileal microbiota through the secretion of anti-bacterial compounds. Genome mapping of CD patients revealed that loss of function mutations in NOD2 are associated with ileal CD. Genome-wide association studies further demonstrated that NOD2 is one of the most critical genetic factor linked to ileal CD. The bacterial community in the ileum is indeed dysregulated in Nod2-deficient mice. Nod2-deficient ileal epithelia exhibit impaired ability of killing bacteria. Thus, altered interactions between ileal microbiota and mucosal immunity through NOD2 mutations play significant roles in the disease susceptibility and pathogenesis in CD patients, thereby depicting NOD2 as a critical regulator of ileal microbiota and CD.

Retention of the cellophane wall of a patency capsule by intestinal stenosis: a report of three cases.

Here we report three cases in which the cellophane wall of the PillCam® patency capsule (tag-less PC), lacking a radio frequency identification tag, was retained. Case 1 A 33-year-old man with Crohn's disease (CD) who was administered the tag-less PC, subsequently underwent resection for perforated colon. We recovered the cellophane wall that could perforate the intestine and cause peritonitis. Case 2 A 34-year-old man with a recurring intestinal obstruction of unknown cause was administered the tag-less PC test. Computed tomography (CT) detected the cellophane wall at the oral side of an ileal stenosis. He was subsequently diagnosed with CD. Case 3 A 60-year-old woman with recurrent diarrhea was examined using CT, which revealed a thickened ileal wall. She was administered the tag-less PC test. CT detected the cellophane wall at the oral side of an ileal stenosis. Double-balloon enteroscopy revealed that the stenosis was caused by a malignant lymphoma, and the cellophane wall was simultaneously removed. Although there are numerous studies that report the usefulness and safety of tag-less PCs, few studies mention entrapment of the cellophane wall. Our present report indicated that tag-less PCs may cause such adverse effects and illustrated the usefulness of CT for detecting the trapped cellophane wall.

NLRC5/MHC class I transactivator is a target for immune evasion in cancer.

Cancer cells develop under immune surveillance, thus necessitating immune escape for successful growth. Loss of MHC class I expression provides a key immune evasion strategy in many cancers, although the molecular mechanisms remain elusive. MHC class I transactivator (CITA), known as "NLRC5" [NOD-like receptor (NLR) family, caspase recruitment (CARD) domain containing 5], has recently been identified as a critical transcriptional coactivator of MHC class I gene expression. Here we show that the MHC class I transactivation pathway mediated by CITA/NLRC5 constitutes a target for cancer immune evasion. In all the 21 tumor types we examined, NLRC5 expression was highly correlated with the expression of MHC class I, with cytotoxic T-cell markers, and with genes in the MHC class I antigen-presentation pathway, including LMP2/LMP7, TAP1, and ß2-microglobulin. Epigenetic and genetic alterations in cancers, including promoter methylation, copy number loss, and somatic mutations, were most prevalent in NLRC5 among all MHC class I-related genes and were associated with the impaired expression of components of the MHC class I pathway. Strikingly, NLRC5 expression was significantly associated with the activation of CD8(+) cytotoxic T cells and patient survival in multiple cancer types. Thus, NLRC5 constitutes a novel prognostic biomarker and potential therapeutic target of cancers.

Irsogladine Maleate Prevents Colitis in Interleukin-10 Gene-Deficient Mice by Reducing Interleukin-12 and -23 Production.

Irsogladine maleate (2,4-diamino-6-[2,5-dichlorophenyl]-s-triazine maleate; IM), an anti-peptic ulcer drug, may have a protective effect on the gastrointestinal mucosa. This study investigated the effects of IM on spontaneous colitis in interleukin-10 gene-deficient (IL-10(-/-)) mice. Five-week-old IL-10(-/-) mice were fed a control diet or one containing 100 ppm of IM for 10 weeks. Colonic tissues were evaluated morphologically and histologically. J774A.1 murine monocyte/macrophage cells were incubated with IM after lipopolysaccharide stimulation. mRNA expression was assessed by quantitative polymerase chain reaction (PCR) and protein concentration by enzyme-linked immunosorbent assay (ELISA). Colonic length, weight, and histological scores clearly demonstrated that spontaneous colitis was prevented in IL-10(-/-) mice fed a diet containing IM compared with those fed control diet. Levels of tumor necrosis factor-alpha (TNF-α) (-2.5-fold), IL-1ß (-5.4), interferon-gamma (IFN-γ) (-4.5), IL-17 (-113.0), IL-12p35 (-21.0), IL-12p40 (-3.4), and IL-23p19 (-4.2) mRNA expression were significantly decreased in the colonic tissues of IM-treated animals, suggesting that oral treatment with IM suppressed the T-helper (Th)1/Th17 immune response in the colonic mucosa. An in vitro study using monocyte/macrophage cells to clarify the pharmacological action of IM indicated that IL-12p40 and IL-23p19 mRNA expression levels were dose-dependently decreased by IM treatment. ELISA showed that IL-12p40 and IL-23 protein secretion were significantly decreased by IM in a dose-dependent manner. Oral treatment with IM prevented spontaneous colitis in IL-10(-/-) mice by suppressing the colonic mucosal Th1/Th17 immune response through inhibition of IL-12 and -23 production in monocyte/macrophage cells.

A Case of Blind Loop Syndrome Caused by Infection with Giardia duodenalis Diagnosed with Double Balloon Enteroscopy.

A 75-year-old man who had undergone partial gastrectomy was referred to our hospital due to worsening leg edema, loose stools and malnutrition. Double balloon enteroscopy followed by insertion of an indwelling ileus tube was performed to investigate the microbial flora and for washing inside the blind loop. Trophozoites of Giardia were detected in the sampled fluid from the blind loop and DNA analysis disclosed an assemblage of genotype A-II of Giardia duodenalis. Treatment with oral metronidazole was effective. This case emphasizes the importance of a correct diagnosis when treating patients with blind loop syndrome in the digestive tract.

Severe diffuse duodenitis successfully treated with intravenous tacrolimus after colectomy for ulcerative colitis.

We encountered a rare case of severe diffuse duodenitis associated with ulcerative colitis (UC). A 23-year-old man underwent total proctocolectomy with ileal J-pouch anal anastomosis for UC. He suffered from severe abdominal pain, fever and bloody diarrhea for six months after the surgery. Upper double-balloon enteroscopy disclosed severe diffuse duodenitis, of which the findings were endoscopically and histologically similar to those of colonic lesions of UC. Although the administration of prednisolone was ineffective, treatment with intravenous tacrolimus markedly improved the clinical findings. This is the first report of the successful treatment of severe UC-associated diffuse duodenitis with intravenous tacrolimus.