Hepatic inflammation facilitates transcription-associated mutagenesis via AID activity and enhances liver tumorigenesis.

First published online: May 12, 2015Chronic inflammation triggers the aberrant expression of a DNA mutator enzyme, activation-induced cytidine deaminase (AID), and contributes to tumorigenesis through the accumulation of genetic aberrations. To gain further insight into the inflammation-mediated genotoxic events required for carcinogenesis, we examined the role of chronic inflammation in the emergence of genetic aberrations in the liver with constitutive AID expression. Treatment with thioacetamide (TAA) at low-dose concentrations caused minimal hepatic inflammation in both wild-type (WT) and AID transgenic (Tg) mice. None of the WT mice with low-dose TAA administration or AID Tg mice without hepatic inflammation developed cancers in their liver tissues over the 6 month study period. In contrast, all the AID Tg mice with TAA treatment developed multiple macroscopic hepatocellular carcinomas during the same observation period. Whole exome sequencing and additional deep-sequencing analyses revealed the enhanced accumulation of somatic mutations in various genes, including dual specificity phosphatase 6 (Dusp6), early growth response 1 (Egr1) and inhibitor of DNA binding 2 (Id2), which are putative tumor suppressors, in AID-expressing liver with TAA-mediated hepatic inflammation. Microarray and quantitative reverse transcription-polymerase chain reaction analyses showed the transcriptional upregulation of various genes including Dusp6, Egr1 and Id2 under hepatic inflammatory conditions. Together, these findings suggest that inflammation-mediated transcriptional upregulation of target genes, including putative tumor suppressor genes, enhances the opportunity for inflamed cells to acquire somatic mutations and contributes to the acceleration of tumorigenesis in the inflamed liver tissues

In vitro Activities of Oral Cephem and Telithromycin Against Clinical Isolates of Major Respiratory Pathogens in Japan

The in vitro antibacterial activities of oral cephem antibiotics and ketolide telithromycin against major respiratory pathogens possessing β-lactam-resistant mutations (within the pbp gene) and/or macrolide-resistant genes (erm and mef) were examined in clinical isolates collected at 66 institutes in all over the Japan between 2002 and 2003. Telithromycin showed the strongest antibacterial activity against methicillin-susceptible Staphylococcus aureus strains with and without macrolide-resistant genes, such as ermA or ermC gene. All the cephem antibiotics showed potent antibacterial activity against Streptococcus pyogenes, with minimum inhibitory concentrations (MICs) of 0.015 mg/L or lower. Cefdinir had a much higher MIC90 against genotypic penicillin-resistant Streptococcus pneumoniae (gPRSP) than cefditoren and cefcapene (8 mg/L cefdinir vs. 1 mg/L cefditoren and cefcapene). The majority of gPRSP harbored either ermB or mefA, and the antibacterial activity of telithromycin against these strains was decreased however some susceptibility was still sustained. Cefditoren exerted the strongest antibacterial activity against β-lactamase-negative ampicillin-resistant Haemophilus influenzae, with an MIC90 of 0.5 mg/L. These results underline the importance of checking the susceptibility and selecting an appropriate antibiotic against target pathogens

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

A Crowdsourcing Method for Obtaining Rephrased Questions

We propose a method for obtaining and ranking paraphrased questions from crowds to be used as a part of instructions in microtask-based crowdsourcing. With our method, we are able to obtain questions that differ in expression yet have the same semantics with respect to the crowdsourcing task. This is done by generating tasks that give hints and elicit instructions from workers. We conducted experiments with data used for a real set of gold standard questions submitted to a commercial crowdsourcing platform and compared the results with those from a direct-rewrite method

Leptin receptor somatic mutations are frequent in HCV-infected cirrhotic liver and associated with hepatocellular carcinoma.

[Background & Aims]Hepatocellular carcinoma develops in patients with chronic hepatitis or cirrhosis via a stepwise accumulation of various genetic alterations. To explore the genetic basis of development of hepatocellular carcinoma in hepatitis C virus (HCV)-associated chronic liver disease, we evaluated genetic variants that accumulate in nontumor cirrhotic liver. [Methods]We determined the whole exome sequences of 7 tumors and background cirrhotic liver tissues from 4 patients with HCV infection. We then performed additional sequencing of selected exomes of mutated genes, identified by whole exome sequencing, and of representative tumor-related genes on samples from 22 cirrhotic livers with HCV infection. We performed in vitro and in vivo functional studies for one of the mutated genes. [Results]Whole exome sequencing showed that somatic mutations accumulated in various genes in HCV-infected cirrhotic liver tissues. Among the identified genes, the leptin receptor gene (LEPR) was one of the most frequently mutated in tumor and nontumor cirrhotic liver tissue. Selected exome sequencing analyses detected LEPR mutations in 12 of 22 (54.5%) nontumorous cirrhotic livers. In vitro, 4 of 7 (57.1%) LEPRmutations found in cirrhotic livers reduced phosphorylation of STAT3 to inactivate LEPR-mediated signaling. Moreover, 40% of Lepr-deficient (C57BL/KsJ-db/db) mice developed liver tumors after administration of thioacetamide compared with none of the control mice. [Conclusions]Based on analysis of liver tissue samples from patients, somatic mutations accumulate in LEPR in cirrhotic liver with chronic HCV infection. These mutations could disrupt LEPR signaling and increase susceptibility to hepatocarcinogenesis

An Empirical Study on Short- and Long-Term Effects of Self-Correction in Crowdsourced Microtasks

Self-correction for crowdsourced tasks is a two-stage setting that allows a crowd worker to review the task results of other workers; the worker is then given a chance to update his/her results according to the review.Self-correction was proposed as an approach complementary to statistical algorithms in which workers independently perform the same task. It can provide higher-quality results with few additional costs. However, thus far, the effects have only been demonstrated in simulations, and empirical evaluations are needed. In addition, as self-correction gives feedback to workers, an interesting question arises: whether perceptual learning is observed in self-correction tasks. This paper reports our experimental results on self-corrections with a real-world crowdsourcing service.The empirical results show the following: (1) Self-correction is effective for making workers reconsider their judgments. (2) Self-correction is more effective if workers are shown task results produced by higher-quality workers during the second stage. (3) Perceptual learning effect is observed in some cases. Self-correction can give feedback that shows workers how to provide high-quality answers in future tasks.The findings imply that we can construct a positive loop to improve the quality of workers effectively.We also analyze in which cases perceptual learning can be observed with self-correction in crowdsourced microtasks

A Pediatric Case of Inverted Meckel’s Diverticulum Presenting with Cyclic Vomiting-like Symptoms: A Case Report and Literature Review

Asymptomatic Meckel’s diverticulum cases are not uncommon, leading to diagnostic difficulties in cases of atypical presentations with only gastrointestinal symptoms other than bloody stool. A nine-year-old boy diagnosed as having cyclic vomiting because of recurrent abdominal pain and vomiting for 6 months was referred to our institute and hospitalized due to worsening symptoms. After admission, abdominal ultrasonography showed the multiple concentric ring sign and a pseudokidney sign at the lower ileum, leading to the diagnosis of ileo-ileal intussusception, but the gastrointestinal symptoms and ultrasonic findings disappeared spontaneously. Transanal, double-balloon, intestinal endoscopy demonstrated a pedunculated polyp-like structure, and surgical resection was performed. An inverted diverticulum was found in the resected intestinal lumen, and ectopic gastric mucosa was identified histologically, leading to the diagnosis of inverted Meckel’s diverticulum. In pediatric cases involving periodic attacks of vomiting and abdominal pain, unnecessary emergent surgery could be avoided by cautious imaging evaluation and consideration of ileo-ileal intussusception with advanced lesions of an inverted Meckel’s diverticulum as a differential diagnosis, without facilely diagnosing cyclic vomiting. In addition, previous reports of inverted Meckel’s diverticulum were reviewed, and the results were compared between adult and pediatric groups in each category