Machine learning for individualized prediction of hepatocellular carcinoma development after the eradication of hepatitis C virus with antivirals.

BACKGROUND AND AIMS: Accurate risk stratification for hepatocellular carcinoma (HCC) after achieving a sustained viral response (SVR) is necessary for optimal surveillance. We aimed to develop and validate a machine learning (ML) model to predict the risk of HCC after achieving an SVR in individual patients. METHODS: In this multicenter cohort study, 1742 patients with chronic hepatitis C who achieved an SVR were enrolled. Five ML models were developed including DeepSurv, gradient boosting survival analysis, random survival forest (RSF), survival support vector machine, and a conventional Cox proportional hazard model. Model performance was evaluated using Harrel' c-index and was externally validated in an independent cohort (977 patients). RESULTS: During the mean observation period of 5.4 years, 122 patients developed HCC (83 in the derivation cohort and 39 in the external validation cohort). The RSF model showed the best discrimination ability using seven parameters at the achievement of an SVR with a c-index of 0.839 in the external validation cohort and a high discriminative ability when the patients were categorized into three risk groups (P <0.001). Furthermore, this RSF model enabled the generation of an individualized predictive curve for HCC occurrence for each patient with an app available online. CONCLUSIONS: We developed and externally validated an RSF model with good predictive performance for the risk of HCC after an SVR. The application of this novel model is available on the website. This model could provide the data to consider an effective surveillance method. Further studies are needed to make recommendations for surveillance policies tailored to the medical situation in each country. IMPACT AND IMPLICATIONS: A novel prediction model for HCC occurrence in patients after hepatitis C virus eradication was developed using machine learning algorithms. This model, using seven commonly measured parameters, has been shown to have a good predictive ability for HCC development and could provide a personalized surveillance system.

Prognostic significance of pathogenic variants in BRCA1, BRCA2, ATM and PALB2 genes in men undergoing hormonal therapy for advanced prostate cancer.

BACKGROUND: The prognostic significance of germline variants in homologous recombination repair genes in advanced prostate cancer (PCa), especially with regard to hormonal therapy, remains controversial. METHODS: Germline DNA from 549 Japanese men with metastatic and/or castration-resistant PCa was sequenced for 27 cancer-predisposing genes. The associations between pathogenic variants and clinical outcomes were examined. Further, for comparison, DNA from prostate biopsy tissue samples from 80 independent patients with metastatic PCa were analysed. RESULTS: Forty-four (8%) patients carried germline pathogenic variants in one of the analysed genes. BRCA2 was most frequently altered (n = 19), followed by HOXB13 (n = 9), PALB2 (n = 5) and ATM (n = 5). Further, the BRCA1, BRCA2, PALB2 and ATM variants showed significant association with a short time to castration resistance and overall survival (hazard ratio = 1.99 and 2.36; 95% CI, 1.15-3.44 and 1.23-4.51, respectively), independent of other clinical variables. Based on log-rank tests, the time to castration resistance was also significantly short in patients with BRCA1, BRCA2, PALB2 or ATM somatic mutations and TP53 mutations. CONCLUSIONS: Germline variants in BRCA1, BRCA2, PALB2 or ATM are independent prognostic factors of the short duration of response to hormonal therapy in advanced PCa.

Increased Frequency of Copy Number Variations Revealed by Array Comparative Genomic Hybridization in the Offspring of Male Mice Exposed to Low Dose-Rate Ionizing Radiation.

There is very little information on the transgenerational or genetic effects of low dose-rate ionizing radiation. We report the detection of the transgenerational effects of chronic low dose-rate irradiation in mice, at the molecular level in the whole genome, using array comparative genomic hybridization technology. We observed that the number of the mice with de novo copy number variations (specifically, deletions) was significantly increased in the offspring of C57BL/6J male mice exposed to 20 mGy/day gamma-rays for 400 days (total dose: 8000 mGy), as compared to non-irradiated controls. We did not detect any difference in the size of the de novo deletions between the irradiated and the non-irradiated groups. An analysis of the life span of the offspring suggested a possibility that de novo copy-number variations may be associated with shorter life spans.

[A Case of Penile Pyoderma Gangrenosum Treated by Urethrocutaneostomy without Penectomy].

We herein report a case of penile pyoderma gangrenosum that was successfully treated with prednisolone and by urethrocutaneostomy without penectomy. A man in his 50s visite dour department because of painful urination. Pyuria and redness of the external urethral meatus were present. Treatment for urethritis with antibiotics did not improve his symptoms, and a painful ulcer and fistula formation between the glans and urethra subsequently developed. Microbiological cultures revealed no growth, and punch biopsy showed only nonspecific inflammation, leading to a diagnosis of penile pyoderma gangrenosum. We initiated prednisolone (PSL) at 40 mg once daily following placement of an indwelling suprapubic cystostomy tube for dysuria. However, the treatment was ineffective. Therefore, the dosage of PSL was increased to 65 mg once daily. The ulcer disappeared， but urethral stricture remained. Six hundred days after PSL treatment, we performed urethrocutaneostomy. The patient became free of the cystostomy and was able to urinate spontaneously. In recent years, there has been an increasing number of reports of penile preservation in the treatment of penile pyoderma gangrenosum, but knowledge regarding which patients require urethral surgery is lacking. Urologists should keep in mind increased susceptibility to infection, pathergy and possible recurrence, when considering urethral surgery for penile pyoderma gangrenosum.

The Reduction in Gastric Atrophy after Helicobacter pylori Eradication Is Reduced by Treatment with Inhibitors of Gastric Acid Secretion.

BACKGROUND: Helicobacter pylori (H. pylori) eradication therapy may improve gastric atrophy and intestinal metaplasia, but the results of previous studies have not always been consistent. The aim of this study was to compare the histological changes of intestinal metaplasia and gastric atrophy among the use of acid-suppressing drugs after H. pylori eradication. METHODS: A cohort of 242 patients who underwent successful eradication therapy for H. pylori gastritis and surveillance endoscopy examination from 1996 to 2015 was analyzed. Changes in the histological scores of intestinal metaplasia and atrophy according to drug use (proton-pump inhibitors (PPIs), H2 receptor antagonists (H2RAs), and non-acid suppressant use) were evaluated in biopsies of the antrum and corpus using a generalized linear mixed model in all patients. RESULTS: The mean follow-up period and number of biopsies were 5.48 ± 4.69 years and 2.62 ± 1.67 times, respectively. Improvement in the atrophy scores of both the antrum (p = 0.042) and corpus (p = 0.020) were significantly superior in patients with non-acid suppressant drug use compared with those of PPI and H2RA use. Metaplasia scores in both the antrum and corpus did not improve in all groups, and no significant differences were observed among groups in the antrum (p = 0.271) and corpus (p = 0.077). CONCLUSIONS: Prolonged acid suppression by PPIs or H2RAs may limit the recovery of gastric atrophy following H. pylori eradication.

New predictive model of rebleeding during follow-up of patents with obscure gastrointestinal bleeding: A multicenter cohort study.

BACKGROUND AND AIM: The long-term recurrence rate of patients with obscure gastrointestinal bleeding (OGIB) who underwent video capsule endoscopy (VCE) remains unknown. Our study aimed to identify the cumulative incidence of rebleeding, develop a predictive model of rebleeding, and evaluate whether the model can be applied in other outcomes among patients with OGIB. METHODS: We conducted a multicenter retrospective cohort study of 320 patients with OGIB who underwent VCE between 2009 and 2014. A rebleeding model was developed using multivariate Cox proportional hazards analysis and evaluated using Harrell's c-index. RESULTS: Rebleeding occurred in 43 patients (13.4%) during a mean follow-up period of 18.3 (standard error, 0.9) months. The rebleeding sources were the small intestine (n = 17), extra-small intestine (n = 13), and unknown (n = 13). The cumulative incidence of rebleeding was 11.0% at 12 months and 35.3% at 60 months. Multivariate analysis revealed that female gender, liver cirrhosis, warfarin use, overt bleeding, and positive VCE findings were significant predictors of rebleeding. The rebleeding rate was 0% in patients with no predictors and 40% in patients with full predictors (P < 0.01). The model presented a high predictive accuracy (c-statistic, 0.733). Patients with higher predictors exhibited higher transfusion requirements, longer length of stay, and higher mortality (P < 0.01). CONCLUSION: The cumulative incidence of rebleeding at 12 and 60 months was 11.0% and 35.3%, respectively. Five factors enable prediction of not only rebleeding but also transfusion requirements, length of stay, and death in OGIB patients.

Evaluation of predictors of unfavorable pathological features in men eligible for active surveillance using radical prostatectomy specimens: a multi-institutional study.

OBJECTIVE: Active surveillance has emerged as an alternative to immediate treatment in men with favorable-risk prostate cancer; however, consensus about defining the appropriate candidates is still lacking. To examine the factors predicting unfavorable pathology among active surveillance candidates, we assessed low-risk radical prostatectomy specimens. METHODS: This retrospective study included 1753 men who had undergone radical prostatectomy at six independent institutions in Japan from 2005 to 2011. Patients who met the active surveillance criteria were categorized depending on the pathological features of the radical prostatectomy specimens. 'Reclassification' was defined as upstaging (≥pT3) or upgrading (radical prostatectomy Gleason score ≥7), and 'adverse pathology' was defined as pathological stage ≥pT3 or radical prostatectomy Gleason score ≥4 + 3. Multivariate analysis was used to analyze the preoperative factors for reclassification and adverse pathology. The rates of reclassification and adverse pathology were evaluated by classifying patients according to biopsy core numbers. RESULTS: The active surveillance criteria were met by 284 cases. Reclassification was identified in 154 (54.2%) cases, while adverse pathology in 60 (21.1%) cases. Prostate-specific antigen density and percentage of positive cores were independently associated with reclassification and adverse pathology. The rates of reclassification and adverse pathology were significantly higher among patients with <10 biopsy cores than among others. Thus, focusing on 149 patients with ≥10 biopsy cores, prostate-specific antigen density was the only independent predictor of unfavorable pathological features. The receiver operating characteristic curve analysis determines an optimal cut-off value of prostate-specific antigen density as 0.15 ng/ml2. CONCLUSIONS: Prostate-specific antigen density is the most important predictor of unfavorable pathological features in active surveillance candidates.

[Complete Response in a Patient with HER2-Positive Gastric Cancer and Multiple Lung Metastases with Trastuzumab-Containing Chemotherapy].

We report the case ofa 79-year-old Japanese woman diagnosed with human epidermal growth factor receptor 2 (HER2)-positive gastric cancer of the cardia with multiple lung metastases that showed complete response to trastuzumab-containing chemotherapy. First, we administered tegafur/gimeracil/oteracil (S-1) and cisplatin (CDDP) concurrently to the patient. Next, we switched to trastuzumab in combination with capecitabine and CDDP because gastric cancer tissue indicated HER2-positivity. Considering the patient's age and renal function, the dose of CDDP was decreased to 50% after starting the medication. Before the 2nd course of trastuzumab-containing chemotherapy, oral mucositis (Grade 3) and hand-foot syndrome (Grade 1) were observed. Therefore, a one-step dose reduction of capecitabine was necessary. After the 4th course, the primary gastric tumor was no longer visible endoscopically. After the 7th course, computed tomography (CT) showed the disappearance of all lung metastases. Accordingly, the patient was considered to be completely responsive to the medication. After the 12th course, recurrence of the tumor was not identified and at the request of the patient, the trastuzumab-containing chemotherapy was discontinued. Regular follow-up showed no evidence of recurrence 8 months after discontinuing treatment and the patient was in good condition 21 months after her initial diagnosis.

Discovery and SAR study of 2-(4-pyridylamino)thieno[3,2-d]pyrimidin-4(3H)-ones as soluble and highly potent PDE7 inhibitors.

The discovery and SAR study of a new series of soluble and highly potent phosphodiesterase (PDE) 7 inhibitors are described herein. We explored a new lead compound with improved solubility, which led to the discovery of a 2-(4-pyridylamino)thieno[3,2-d]pyrimidin-4(3H)-one series. The introduction of 3-piperidines at the 7-position resulted in the significant enhancement of PDE7 activity. In particular, compound 32 also showed strong PDE7 inhibitory activity; good selectivity against PDE3, 4, and 5; and good aqueous solubility.

Development of caged non-hydrolyzable phosphoamino acids and application to photo-control of binding affinity of phosphopeptide mimetic to phosphopeptide-recognizing protein.

The design and synthesis of caged non-hydrolyzable phospho-serine, -threonine, and -tyrosine derivatives that generate parent non-hydrolyzable phosphoamino acids, containing a difluoromethylene unit instead of the oxygen of a phosphoester, after UV-irradiation are described. The caged non-hydrolyzable amino acids were incorporated into peptides by standard Fmoc solid-phase peptide synthesis, and the obtained peptides were successfully converted to the parent non-hydrolyzable phosphopeptides by UV-irradiation. Application of the caged non-hydrolyzable phosphoserine-containing peptide to photo-control the binding affinity of the peptide to 14-3-3ß protein is also reported.

[Usefulness of comparing of magnetic resonance imaging (MRI) findings prior to repeat biopsy and negative initial biopsy as a decision-making method for repeat prostate biopsy].

We retrospectively reviewed the data from a cohort of 44 patients with one initial negative transrectal ultrasound-guided prostate biopsy who underwent a repeat biopsy from 2006 to 2013. At each biopsy session, we checked patient age, serum prostate specific antigen (PSA), prostate volume, PSA density, PSA velocity, months from the initial biopsy session, multiparametric magnetic resonance imaging (MRI) findings (T2-weighted, dynamic contrast-enhanced and diffusion-weighted, 1.5 Tesla pelvic-phased array) prior to repeat biopsy and initial negative biopsy. Mean age was 68.2±8.82 years. PSA was 11.5±7.65 ng/ml before repeat biopsy. Prostate cancer was detected in 15 (34.0%) patients at repeat biopsy. In univariate and multivariate analysis, positive MRI findings before repeat biopsy were significant independent predictors of a positive repeat biopsy. At per patient analysis, the sensitivity, specificity, positive and negative predictive values were 66.6, 68.9, 71.4 and 80.0% for MRI before repeat biopsy. No suspicious lesion on MRI before repeat biopsy was relevant to negative biopsy. According to the comparison of MRI findings prior to repeat biopsy and negative initial biopsy, suspicious MRI findings at the peripheral zone before repeat biopsy and initial negative biopsy were relevant to a high cancer detection rate (83.3%) at repeat prostate biopsy. These results suggested that the absence of a suspicious lesion on MRI before repeat biopsy could guide the avoidance of repeat biopsy and suspicious MRI findings at the peripheral zone before repeat biopsy and initial negative biopsy could guide repeat biopsy.

A prospective comparative study of intravesical bacillus Calmette-Guérin therapy with the Tokyo or Connaught strain for nonmuscle invasive bladder cancer.

PURPOSE: We prospectively compared the efficacy and adverse events of the bacillus Calmette-Guérin Tokyo 172 and Connaught strains for nonmuscle invasive bladder cancer. MATERIALS AND METHODS: Between January 2004 and May 2012 patients with pTa/T1 and pTis, multiple tumors and a recurrence-free period of 3 months or less who required intravesical bacillus Calmette-Guérin therapy were prospectively allocated randomly to receive the Tokyo or Connaught strain. The primary study end points were the complete response rate in patients with pTis and concomitant carcinoma in situ (pTa or pT1), recurrence-free survival in patients with pTa, pT1 and carcinoma in situ who achieved a complete response after therapy and the frequency of adverse events. RESULTS: Administration of the Connaught strain ceased because its production was suspended in June 2012. Therefore, analysis was performed using data gathered to date. Overall, 66 and 63 patients who received the Tokyo and Connaught strains, respectively, were included in efficacy analysis. Patient and tumor characteristics were well balanced between the 2 groups. Median followup was 855 days. Adverse events were similar in the groups. The complete response rate was 90.3% and 85.0% in patients given the Tokyo and Connaught strains, respectively, which did not significantly differ (p = 0.896). The 2-year recurrence-free survival rate was 73.2% and 68.8%, respectively. CONCLUSIONS: Results suggest no significant differences between the Tokyo and Connaught strains in the complete response, recurrence-free survival or adverse event rate.

Antimicrobial prophylaxis to prevent perioperative infection in urological surgery: a multicenter study.

We prospectively investigated the rates of incidence of surgical site infection (SSI), urinary tract infection (UTI), and remote infection (RI) in 4,677 patients who underwent urological surgery from January to December 2010, including 2,507 endourological cases, 1,276 clean cases, 807 clean-contaminated cases, and 87 contaminated cases involving bowel segments. A single dose of antimicrobial prophylaxis (AMP) was administered in the endourological, clean, and clean-contaminated surgery cases, except for patients who underwent transurethral resection of the prostate (TURP) or percutaneous nephrolithotripsy (PNL). AMP was administered within 72 h in TURP and PNL, and AMP was administered within 48 h in contaminated surgery cases. In cases of endourological surgery, UTI was observed in 4% and RI in 0%, and SSI, UTI, and RI were seen in 1%, 1%, and 1%, respectively, of clean surgery cases, in 3%, 3%, and 2%, respectively, of clean-contaminated surgery cases, and in 17%, 30%, and 10%, respectively, of contaminated surgery cases. In multivariate analysis of the risk factors for infection, operative time was a significant risk factor for UTI in endourological surgery, and American Society of Anesthesiologists score and operative time were significant risk factors for RI in clean surgery. No significant risk factor was found in analyses of clean-contaminated and contaminated surgery cases. A single-dose AMP regimen was shown to be effective and feasible for prevention of perioperative infection in urological surgery.

[Percutaneous renal mass biopsy after indeterminate diagnostic imaging results].

We conducted a retrospective study to examine the efficacy of renal mass biopsies in our hospital. Twenty-six patients (18 male, 8 female ; median age, 69 years ; range, 42-85 years) with renal masses were divided into two groups. Group 1 (n＝9) underwent renal mass biopsies after completion of diagnostic imaging tests that needed a pathological diagnosis before treatment other than extirpative surgery, and group 2 (n＝17) underwent renal mass biopsies after completion of indeterminate diagnostic imaging tests that did not rule out malignancy. The median tumor size was 2.8cm (range, 0.8-15 cm), and the median number of biopsy cores obtained was two (range, 2-4). There were no biopsy-associated complications that required intervention. In group 1, 100% (9 of 9) of the renal mass biopsies were diagnostic, and the pathological findings corresponded to the respective diagnosis obtained by imaging tests, most of which were clear cell carcinoma. In group 2, 59% (10 of 17) of the biopsies were diagnostic. The imaging characteristics of the seven nondiagnostic biopsies in group 2 were low blood flow and poor peripheral clarity. On the other hand, renal mass biopsies were indispensable for some patients in group 2 in whom the pathological findings led to a decision of treatment strategy. In conclusion, renal mass biopsies should be considered in view of their ability to compensate for limitations of imaging tests and their low frequency of complications.

Development of a reduction-responsive amino acid that induces peptide bond cleavage in hypoxic cells.

Hypoxia-responsive amino acids are indispensable in the preparation of hypoxic tumor-specific peptidyl prodrugs. In this paper, the design and synthesis of a reduction-responsive amino acid that induces peptide bond cleavage after reduction of the nitro group are described. Application to hypoxia-responsive peptide bond cleavage system is also reported.

Endoscopic submucosal dissection is an effective and safe therapy for early gastric neoplasms: a multicenter feasible study.

BACKGROUND AND AIM: The technique of endoscopic submucosal dissection (ESD) was introduced to obtain en bloc specimens of large early gastrointestinal neoplasms. The drawback of ESD is its technical difficulty and, consequently, its higher rate of complication. In this multicenter study, we investigated the therapeutic outcomes of ESD in consecutive patients. METHODS: From January 2002 to December 2008, 485 early gastric neoplasms in 418 patients were consecutively treated by using ESD procedure performed by 6 endoscopists in 4 institutions in Tokyo. Demorgraphics, tumor location, therapeutic outcomes, and complication rates were analyzed. RESULTS: The rates of en bloc resection, complete en bloc resection, submucosal invasion, and piecemeal resection were 93.6%, 85.4%, 10.9%, and 5.4%, respectively. In multivariate analysis, the en bloc resection rate was independently lower in lesions in upper portion than in lower portion (P<0.01), lower in larger lesions (>30 mm, P<0.05; 20 to 30 mm, P<0.05), and lower in lesions with a scar (P<0.01). Delayed bleeding occurrence was independently high in larger lesions (>30 mm, P<0.01; 20 to 29 mm, P<0.01) than in small lesions (<20 mm). Institution and endoscopists were not risk factors of en bloc resection and complications CONCLUSIONS: ESD is an effective and safe therapy in the management of early gastric neoplasms when performed by well-trained endoscopists. Endoscopists should recognize the difficulty to perform ESD for en bloc resection of upper lesion, and the risk of delayed bleeding in cases of lesions >2 cm in size.

[The factors for continuing docetaxel-based chemotherapy for castration-resistant prostate cancer].

A cohort of patients with castration-resistant prostate cancer (CRPC) that were treated with docetaxel (DOC) were retrospectively analyzed in order to examine the factors for continuing DOC therapy. In total, 26 patients treated with DOC at our hospital from August 2007 to August 2011 were recruited into the study. The participants were divided into two groups ; the first comprising 13 patients who received short-term DOC therapy (less than 5 cycles) and the second comprising 13 who received long-term DOC therapy (5 or more cycles). There was no significant difference in the indicators including age, prostate specific antigen level (at initial diagnosis), clinical stage and Gleason score between the groups. Patients with pain or poor performance status were more likely to be found in the short-term DOC group. The Hemoglobin-level was significantly higher in the long-term DOC group. In contrast, alkaline phosphatase, lactate dehydrogenase and C-reactive protein levels were significantly higher in the short-term DOC group. The period from the start of primary endocrine therapy to CRPC diagnosis was significantly longer in the long-term DOC group (p=0.0008). This latter finding suggests that DOC therapy can be continued for a longer time, in CRPC cases which have a long-term response to endocrine therapy, and may be associated with a more favorable survival outcome. However, to validate this suggestion, further investigation with a larger cohort of cases is necessary.

[A multi-institutional questionnaire survey on surgical treatment for a small renal mass: factors related with decision-making in indications for partial nephrectomy].

This study aimed to investigate factors taken into account when considering the indication of partial nephrectomy (PN). In October 2011, a questionnaire prepared with reference to the American Urological Association small renal mass survey and RENAL nephrometry score, and focusing on the factors taken into account when considering the use of PN, such as differences among candidates for open PN or laparoscopic PN was sent to 40 institutions. We received replies from 32 of the 40 institutions (average 611 beds) to which the questionnaire was sent. The total number of surgeries performed for renal tumors at the 32 institutions was 844 in 2009 and 889 in 2010. The number of PNs performed was 174 in 2009 (open : 61, laparoscopic : 113), and 241 in 2010 (open : 103, laparoscopic : 138), which represents a 38.3% increase. All respondents reported that renal function prior to PN was considered to be important, followed by tumor size, tumor number, and hereditariness. There were significantly more indications for open PN than for laparoscopic PN, and they were based on tumor size, degree of protrusion, and distance from the renal sinus. In addition, a clear tendency toward avoiding laparoscopic PN for cystic renal cancer was found. In addition, the institutions with a larger number of PNs tended to indicate more complicated cases including larger tumor size or entirely endophytic cases. This study has a limitation in that it was intended for a relatively large hospital, but these results can be useful information for institutions that are considering the introduction of open or laparoscopic PN.

Apoptosis signal-regulating kinase 1 regulates colitis and colitis-associated tumorigenesis by the innate immune responses.

BACKGROUND & AIMS: Mitogen-activated protein kinase (MAPK) signaling pathways regulate multiple cellular functions and are implicated in the pathogenesis of inflammatory bowel disease and colitis-associated cancer (CAC). Apoptosis signal-regulating kinase 1 (ASK1) is a MAPK kinase kinase; little is known about the role of ASK1 in colonic disease. We assessed the involvement of ASK1 in the development of intestinal inflammation and CAC. METHODS: Dextran sodium sulfate (DSS) or Citrobacter rodentium was used to induce colitis in wild-type (WT) and ASK1 knock-out (ASK1(-/-)) mice; CAC was induced by azoxymethane injection followed by repeated intake of DSS by the mice. Primary macrophages were isolated from WT and ASK1(-/-) mice and used to investigate the involvement of ASK1 in innate immune responses. Bone marrow chimeric mice were used to study the contribution of myeloid cells to colitis activity. RESULTS: ASK1 deficiency increased susceptibility to colonic inflammation in both models of colitis. In vitro, ASK1(-/-) macrophages were impaired in their ability to kill bacteria and had increased susceptibility to bacterial-induced apoptosis, because p38 was inactivated. Expression of antiapoptotic genes was greatly reduced in ASK1(-/-) macrophages. WT mice given transplants of ASK1(-/-) mouse-derived bone marrow cells developed more severe DSS-induced colitis than mice with WT-derived bone marrow cells. In the CAC model, ASK1(-/-) mice developed more numerous and larger tumors than WT mice through increased colonic inflammation. CONCLUSIONS: ASK1 controls the development of intestinal inflammation and CAC through the regulation of innate immunity.

Inhibitor of kappaB kinase beta regulates gastric carcinogenesis via interleukin-1alpha expression.

BACKGROUND & AIMS: Nuclear factor-kappaB (NF-kappaB) is an important transcription factor involved in various biological processes, including carcinogenesis. However, it is unknown whether NF-kappaB activation is involved in gastric carcinogenesis. METHODS: To explore the roles of inhibitor of kappaB kinase (IKKbeta), the key kinase for NF-kappaB activation, in gastric epithelium, we established a conditional gastric mucosal epithelium knockout mouse (Ikkbeta(DeltaST)). Gastric cancer was induced using N-methyl-N-nitrosourea (MNU). After 8 months, the number of tumors and their sizes were evaluated. Apoptosis was analyzed by terminal deoxynucleotidyl transferase-mediated deoxyuridine nick-end labeling staining, and levels of inflammatory cytokines were measured. RESULTS: No phenotypical or histologic difference was observed between untreated Ikkbeta(DeltaST) and controls (Ikkbeta(F/F)). The number of tumors was significantly less in the MNU-treated Ikkbeta(DeltaST) group than in the Ikkbeta(F/F) group (mean +/- standard error, 2.21 +/- 0.48 vs 0.80 +/- 0.23), and the size of the tumors did not differ (2.75 +/- 0.99 vs 2.89 +/- 1.12 mm). After a single oral dose of MNU, interleukin (IL)-1alpha was up-regulated significantly in control mice compared with Ikkbeta(DeltaST) mice, whereas the levels of IL-1beta, IL-6, and tumor necrosis factor-alpha were unchanged. MNU significantly increased apoptotic cell death in Ikkbeta(DeltaST) mice compared with Ikkbeta(F/F) mice, and apoptosis was dependent on decreased IL-1alpha expression. IL-1alpha also induced the proliferation of gastric cancer cells. Fewer tumors were observed in IL-1-receptor knockout mice (Il-1r(-/-); 1.17 +/- 0.44) than in control mice (2.42 +/- 0.52). CONCLUSIONS: IKKbeta regulates gastric carcinogenesis via IL-1alpha expression, which is associated with anti-apoptotic signaling and cell proliferation.