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Identification of an epithelial member of the protease family, supporting the potential diagnostic and therapeutic role of serine proteases in IBS

2017-09-06T02:02:06-07:00

The quest for appropriate diagnostic tools and therapies for IBS runs in parallel with the different pathogenic mechanisms investigated. One of these mechanisms is visceral hypersensitivity, resulting from a disturbed neuronal signalling at the peripheral and/or central levels.1 2 Rolland-Fourcade et al3 show, in this issue of Gut, that intestinal epithelial cells (Caco-2 cells) release a trypsin-like activity at the basolateral side of the cells after stimulation with a classical inflammatory stimulus (lipopolysaccharide) or with a stress-related stimulus (epinephrine), and they identified it as trypsin-3. They confirmed the clinical relevance of trypsin-3 by proving its presence in colonic tissue from patients with IBS (all subgroups). Besides, trypsin-3 increased epithelial permeability in the Caco-2 monolayers and increased the excitability of mouse dorsal root ganglia neurons in vitro. Moreover, it induced Ca+2 transients in human submucosal neurons in vitro and caused visceral hyperalgesia in response...




What if Prometheus had steatosis? Potential use of FGF19 to promote regeneration of the fatty liver

2017-09-06T02:02:06-07:00

Non-alcoholic fatty liver disease (NAFLD), the excess accumulation of triglycerides in the liver, can lead to liver-associated morbidity and mortality1 and is associated with extrahepatic disorders such as diabetes, obesity and increased cardiovascular risk. NAFLD is becoming extremely prevalent, estimated to affect 30%–45% of the population in the USA.2 3 Given this high prevalence, the impact of NAFLD has become important in other aspects of medical care; one such aspect is liver surgery. Patients with steatosis who undergo major hepatic resection are at an increased risk for perioperative complications and mortality,4 and the regeneration of the liver postresection is slower in the obese and those with NAFLD.5 6 Furthermore, in liver transplantation, steatotic grafts show decreased graft survival and function.7

Fibroblast growth factor 19 (FGF19) and its mouse ortholog Fgf15 are peptide hormones with myriad...




Microbiomarkers in inflammatory bowel diseases: caveats come with caviar

2017-09-06T02:02:06-07:00

The largest numbers of commensal bacteria reside within our intestinal tract, with an increasing density from mouth to anus. Recently, a new estimate for the total number of bacteria (3.8x1013) in the 70 kg ‘reference man’ was reported.1 For human cells, the same authors revised past estimates to 3.0x1013 cells, out of which approximately 90% belong to the haematopoietic lineage. Hence, the widely cited 10:1 ratio of bacteria versus human cells received an update, showing that the number of bacteria in the body is actually of the same order as the number of human cells, and that the cumulative bacterial mass is about 200 g. Still, this large number of bacteria highlights their importance in maintaining health and metabolism. Different parts of the intestinal tract have different functions, tissue structure varies accordingly and gradients exist for several physicochemical parameters such as nutrients, pH or oxygen levels.2 Consequently,...




Germline variation in inflammation-related pathways and risk of Barrett's oesophagus and oesophageal adenocarcinoma

2017-09-06T02:02:06-07:00

Objective

Oesophageal adenocarcinoma (OA) incidence has risen sharply in Western countries over recent decades. Local and systemic inflammation is considered an important contributor to OA pathogenesis. Established risk factors for OA and its precursor, Barrett's oesophagus (BE), include symptomatic reflux, obesity and smoking. The role of inherited genetic susceptibility remains an area of active investigation. Here, we explore whether germline variation related to inflammatory processes influences susceptibility to BE/OA.

Design

We used data from a genomewide association study of 2515 OA cases, 3295 BE cases and 3207 controls. Our analysis included 7863 single-nucleotide polymorphisms (SNPs) in 449 genes assigned to five pathways: cyclooxygenase (COX), cytokine signalling, oxidative stress, human leucocyte antigen and nuclear factor-B. A principal components-based analytic framework was employed to evaluate pathway-level and gene-level associations with disease risk.

Results

We identified a significant signal for the COX pathway in relation to BE risk (p=0.0059, false discovery rate q=0.03), and in gene-level analyses found an association with microsomal glutathione-S-transferase 1 (MGST1); (p=0.0005, q=0.005). Assessment of 36 MGST1 SNPs identified 14 variants associated with elevated BE risk (q<0.05). Four of these were subsequently confirmed (p<5.5x10–5) in a meta-analysis encompassing an independent set of 1851 BE cases and 3496 controls, and are known strong expression quantitative trait loci for MGST1. Three such variants were associated with similar elevations in OA risk.

Conclusions

This study provides the most comprehensive evaluation of inflammation-related germline variation in relation to risk of BE/OA and suggests that variants in MGST1 influence disease susceptibility.




Hemidesmosome integrity protects the colon against colitis and colorectal cancer

2017-09-06T02:02:06-07:00

Objective

Epidemiological and clinical data indicate that patients suffering from IBD with long-standing colitis display a higher risk to develop colorectal high-grade dysplasia. Whereas carcinoma invasion and metastasis rely on basement membrane (BM) disruption, experimental evidence is lacking regarding the potential contribution of epithelial cell/BM anchorage on inflammation onset and subsequent neoplastic transformation of inflammatory lesions. Herein, we analyse the role of the α6β4 integrin receptor found in hemidesmosomes that attach intestinal epithelial cells (IECs) to the laminin-containing BM.

Design

We developed new mouse models inducing IEC-specific ablation of α6 integrin either during development (α6IEC) or in adults (α6IEC-TAM).

Results

Strikingly, all α6IEC mutant mice spontaneously developed long-standing colitis, which degenerated overtime into infiltrating adenocarcinoma. The sequence of events leading to disease onset entails hemidesmosome disruption, BM detachment, IL-18 overproduction by IECs, hyperplasia and enhanced intestinal permeability. Likewise, IEC-specific ablation of α6 integrin induced in adult mice (α6IEC-TAM) resulted in fully penetrant colitis and tumour progression. Whereas broad-spectrum antibiotic treatment lowered tissue pathology and IL-1β secretion from infiltrating myeloid cells, it failed to reduce Th1 and Th17 response. Interestingly, while the initial intestinal inflammation occurred independently of the adaptive immune system, tumourigenesis required B and T lymphocyte activation.

Conclusions

We provide for the first time evidence that loss of IECs/BM interactions triggered by hemidesmosome disruption initiates the development of inflammatory lesions that progress into high-grade dysplasia and carcinoma. Colorectal neoplasia in our mouse models resemble that seen in patients with IBD, making them highly attractive for discovering more efficient therapies.




Reassuring results on birth outcomes in children fathered by men treated with azathioprine/6-mercaptopurine within 3 months before conception: a nationwide cohort study

2017-09-06T02:02:06-07:00

Objective

Information on the safety of paternal use of azathioprine (AZA) and 6-mercaptopurine (6-MP) prior to conception is limited. Based on nationwide data from the Danish health registries, we examined the association between paternal use of AZA/6-MP within 3 months before conception and adverse birth outcomes.

Design

This nationwide cohort study is based on data from all singletons born in Denmark from 1 January 1997 through 2013. Children fathered by men who used AZA/6-MP within 3 months before conception constituted the exposed cohort (N=699), and children fathered by men who did not use AZA/6-MP 3 months prior to conception constituted the unexposed cohort (N=1 012 624). The outcomes were congenital abnormalities (CAs), preterm birth and small for gestational age (SGA). We adjusted for multiple covariates and performed a restricted analysis of men with IBD.

Results

There were no significantly increased risks of CAs, preterm birth or SGA in exposed versus unexposed cohorts of children. The adjusted ORs were 0.82 (95% CI 0.53 to 1.28) for CAs, 1.17 (95% CI 0.72 to 1.92) for preterm birth and 1.38 (95% CI 0.76 to 2.51) for SGA. Restricting our analysis to fathers with IBD showed similar results with no significantly increased risk of adverse birth outcomes.

Conclusions

This nationwide study is the largest to date, examining the effect of preconceptual paternal use of AZA/6-MP on birth outcomes in live born singletons. The results of no significantly increased risks of adverse birth outcomes are reassuring and support the continuation of paternal AZA/6-MP treatment during conception.




Epithelial expression and function of trypsin-3 in irritable bowel syndrome

2017-09-06T02:02:06-07:00

Objectives

Proteases are key mediators of pain and altered enteric neuronal signalling, although the types and sources of these important intestinal mediators are unknown. We hypothesised that intestinal epithelium is a major source of trypsin-like activity in patients with IBS and this activity signals to primary afferent and enteric nerves and induces visceral hypersensitivity.

Design

Trypsin-like activity was determined in tissues from patients with IBS and in supernatants of Caco-2 cells stimulated or not. These supernatants were also applied to cultures of primary afferents. mRNA isoforms of trypsin (PRSS1, 2 and 3) were detected by reverse transcription-PCR, and trypsin-3 protein expression was studied by western blot analysis and immunohistochemistry. Electrophysiological recordings and Ca2+ imaging in response to trypsin-3 were performed in mouse primary afferent and in human submucosal neurons, respectively. Visceromotor response to colorectal distension was recorded in mice administered intracolonically with trypsin-3.

Results

We showed that stimulated intestinal epithelial cells released trypsin-like activity specifically from the basolateral side. This activity was able to activate sensory neurons. In colons of patients with IBS, increased trypsin-like activity was associated with the epithelium. We identified that trypsin-3 was the only form of trypsin upregulated in stimulated intestinal epithelial cells and in tissues from patients with IBS. Trypsin-3 was able to signal to human submucosal enteric neurons and mouse sensory neurons, and to induce visceral hypersensitivity in vivo, all by a protease-activated receptor-2-dependent mechanism.

Conclusions

In IBS, the intestinal epithelium produces and releases the active protease trypsin-3, which is able to signal to enteric neurons and to induce visceral hypersensitivity.




A case of heart failure and diarrhoea

2017-09-06T02:02:06-07:00

Clinical presentation

A 20-year-old man with no significant medical history presented with a 5-day history of intermittent chest pain and dyspnoea. He also reported a 3-month history of daily diarrhoea characterised by multiple, loose, watery, non-bloody stools. Physical examination was notable for tachycardia and a soft systolic murmur at the apex. Laboratory evaluation was significant for microcytic anaemia (serum iron 17 μg/dL; normal range 50–150 μg/dL) and an NT-proBNP (N-terminal pro-brain natriuretic peptide) of 18 995 pg/mL (normal <51 pg/mL). A colonoscopy with random biopsies for evaluation of diarrhoea was unremarkable. Esophagogastroduodenoscopy demonstrated a scalloped and mosaic pattern in the second and third portions of the duodenum (figure 1A), while biopsies showed a malabsorption pattern with total villous atrophy, increased intraepithelial lymphocytes and crypt hyperplasia (figure 1B). During hospitalisation, the patient experienced 2:1 heart block and non-sustained ventricular tachycardia. Transthoracic echocardiogram demonstrated an ejection fraction of 21% and severe...




Deep mural injury and perforation after colonic endoscopic mucosal resection: a new classification and analysis of risk factors

2017-09-06T02:02:06-07:00

Objectives

Perforation is the most serious complication associated with endoscopic mucosal resection (EMR). We propose a new classification for the appearance and integrity of the muscularis propria (MP) after EMR including various extents of deep mural injury (DMI). Risk factors for these injuries were analysed.

Design

Endoscopic images and histological specimens of consecutive patients undergoing EMR of colonic laterally spreading lesions ≥20 mm at a large Australian tertiary referral endoscopy unit were retrospectively analysed using our new DMI classification system. DMI was graded according to MP injury (I/II intact MP without/with fibrosis, III target sign, IV/V obvious transmural perforation without/with contamination). Histological specimens were examined for included MP and patient outcomes were recorded. All type III–V DMI signs were clipped if possible, types I and II DMI were clipped at the endoscopists’ discretion.

Results

EMR was performed in 911 lesions (mean size 37 mm) in 802 patients (male sex 51.4%, mean age 67 years). DMI signs were identified in 83 patients (10.3%). Type III–V DMI was identified in 24 patients (3.0%); clipping was successfully performed in all patients. A clinically significant perforation occurred in two patients (0.2%). Only one of the 59 type I/II cases experienced a delayed perforation. 85.5% of patients with DMI were discharged on the same day, all without sequelae. On multivariable analysis, type III–V DMI was associated with transverse colon location (OR 3.55, p=0.028), en bloc resection (OR 3.84, p=0.005) and high-grade dysplasia or submucosal invasive cancer (OR 2.97, p 0.014).

Conclusions

In this retrospective analysis, use of the new classification and management with clips appeared to be a safe approach. Advanced DMI types (III–V) occurred in 3.0% of patients and were associated with identifiable risk factors. Further prospective clinical studies should use this new classification.

Trial registration number

NCT01368289; results.




Marine {omega}-3 polyunsaturated fatty acid intake and survival after colorectal cancer diagnosis

2017-09-06T02:02:06-07:00

Objective

Experimental evidence supports an antineoplastic activity of marine -3 polyunsaturated fatty acids (-3 PUFAs; including eicosapentaenoic acid, docosahexaenoic acid and docosapentaenoic acid). However, the influence of -3 PUFAs on colorectal cancer (CRC) survival is unknown.

Design

Within the Nurses' Health Study and Health Professionals Follow-up Study, we prospectively studied CRC-specific and overall mortality in a cohort of 1659 patients with CRC according to intake of marine -3 PUFAs and its change after diagnosis.

Results

Higher intake of marine -3 PUFAs after CRC diagnosis was associated with lower risk of CRC-specific mortality (p for trend=0.03). Compared with patients who consumed <0.10 g/day of marine -3 PUFAs, those consuming at least 0.30 g/day had an adjusted HR for CRC-specific mortality of 0.59 (95% CI 0.35 to 1.01). Patients who increased their marine -3 PUFA intake by at least 0.15 g/day after diagnosis had an HR of 0.30 (95% CI 0.14 to 0.64, p for trend <0.001) for CRC deaths, compared with those who did not change or changed their intake by <0.02 g/day. No association was found between postdiagnostic marine -3 PUFA intake and all-cause mortality (p for trend=0.47).

Conclusions

High marine -3 PUFA intake after CRC diagnosis is associated with lower risk of CRC-specific mortality. Increasing consumption of marine -3 PUFAs after diagnosis may confer additional benefits to patients with CRC.




High prevalence of adenomatous colorectal polyps in young cancer survivors treated with abdominal radiation therapy: results of a prospective trial

2017-09-06T02:02:06-07:00

Objective

Cancer survivors treated with abdominal/pelvic radiation therapy (ART) have increased the risks of colorectal cancer (CRC), although evidence supporting early CRC screening for these patients is lacking. We sought to determine whether there is an elevated prevalence of adenomatous colorectal polyps in young survivors prior to the age when screening would be routinely recommended.

Design

We conducted a prospective study of early colonoscopic screening in cancer survivors aged 35–49 who had received ART ≥10 years previously. The planned sample size was based on prior studies reporting a prevalence of adenomatous polyps of approximately 20% among the average-risk population ≥50 years of age, in contrast to ≤10% among those average-risk people aged 40–50 years, for whom screening is not routinely recommended.

Results

Colonoscopy was performed in 54 survivors, at a median age of 45 years (range 36–49) and after median interval from radiation treatment of 19 years (10.6–43.5). Forty-nine polyps were detected in 24 patients, with 15 patients (27.8%; 95% CI 17.6% to 40.9%) having potentially precancerous polyps. Fifty-three per cent of polyps were within or at the edge of the prior ART fields.

Conclusions

Young survivors treated with ART have a polyp prevalence comparable with the average-risk population aged ≥50 years and substantially higher than previously reported for the average-risk population aged 40–50 years. These findings lend support to the early initiation of screening in these survivors.

Clinical trial registration number

NCT00982059; results.




Circulating tumour cells from patients with colorectal cancer have cancer stem cell hallmarks in ex vivo culture

2017-09-06T02:02:06-07:00

Objective

Although counting of circulating tumour cells (CTC) has attracted a broad interest as potential markers of tumour progression and treatment response, the lack of functional characterisation of these cells had become a bottleneck in taking these observations to the clinic. Our objective was to culture these cells in order to understand them and exploit their therapeutic potential to the full.

Design

Here, hypothesising that some CTC potentially have cancer stem cell (CSC) phenotype, we generated several CTC lines from the blood of patients with advanced metastatic colorectal cancer (CRC) based on their self-renewal abilities. Multiple standard tests were then employed to characterise these cells.

Results

Our CTC lines self-renew, express CSC markers and have multilineage differentiation ability, both in vitro and in vivo. Patient-derived CTC lines are tumorigenic in subcutaneous xenografts and are also able to colonise the liver after intrasplenic injection. RNA sequencing analyses strikingly demonstrate that drug metabolising pathways represent the most upregulated feature among CTC lines in comparison with primary CRC cells grown under similar conditions. This result is corroborated by the high resistance of the CTC lines to conventional cytotoxic compounds.

Conclusions

Taken together, our results directly demonstrate the existence of patient-derived colorectal CTCs that bear all the functional attributes of CSCs. The CTC culture model described here is simple and takes <1 month from blood collection to drug testing, therefore, routine clinical application could facilitate access to personalised medicine.

Clinical Trial Registration

ClinicalTrial.gov NCT01577511.




Fukuoka criteria accurately predict risk for adverse outcomes during follow-up of pancreatic cysts presumed to be intraductal papillary mucinous neoplasms

2017-09-06T02:02:06-07:00

Objective

Fukuoka consensus guidelines classify pancreatic cystic lesions (PCLs) presumed to be intraductal papillary mucinous neoplasms (IPMNs) into Fukuoka positive (FP) (subgroups of high-risk (HR) and worrisome features (WFs)) and Fukuoka negative (FN) (non-HR feature/WF cysts). We retrospectively estimated 5-year risk of pancreatic cancer (PC) in FN, WF and HR cysts of patients with PCL-IPMN.

Design

From Mayo Clinic databases, we randomly selected 2000 patients reported to have a PCL; we excluded inflammatory or suspected non-IPMN cysts and those without imaging follow-up. We re-reviewed cross-sectional imaging and abstracted clinical and follow-up data on PCL-IPMNs. The study contained 802 patients with FN cysts and 358 with FP cysts.

Results

Patients with PCL-IPMN had median (IQR) follow-up of 4.2 (1.8–7.1) years. Among FN cysts, 5-year PC risk was low (2–3%) regardless of cyst size (p=0.67). After excluding events in the first 6 months, 5-year PC risk remained low (0–2%) regardless of cyst size (p=0.61). Among FP cysts, HR cysts (n=66) had greater 5-year PC risk than WF cysts (n=292) (49.7% vs 4.1%; p<0.001). In HR cysts, 3-year PC risk was greatest for obstructive jaundice versus enhancing solid component or main pancreatic duct >10 mm (79.8% vs 37.3% vs 39.4%, respectively; p=0.01).

Conclusions

Fukuoka guidelines accurately stratify PCL-IPMNs for PC risk, with FN cysts having lowest and HR cysts having greatest risk. After 6-month follow-up, WF and FN cysts had a low 5-year PC risk. Surveillance strategies should be tailored appropriately.




Fibroblast growth factor 15/19 (FGF15/19) protects from diet-induced hepatic steatosis: development of an FGF19-based chimeric molecule to promote fatty liver regeneration

2017-09-06T02:02:06-07:00

Objective

Fibroblast growth factor 15/19 (FGF15/19), an enterokine that regulates synthesis of hepatic bile acids (BA), has been proposed to influence fat metabolism. Without FGF15/19, mouse liver regeneration after partial hepatectomy (PH) is severely impaired. We studied the role of FGF15/19 in response to a high fat diet (HFD) and its regulation by saturated fatty acids. We developed a fusion molecule encompassing FGF19 and apolipoprotein A-I, termed Fibapo, and evaluated its pharmacological properties in fatty liver regeneration.

Design

Fgf15–/– mice were fed a HFD. Liver fat and the expression of fat metabolism and endoplasmic reticulum (ER) stress-related genes were measured. Influence of palmitic acid (PA) on FGF15/19 expression was determined in mice and in human liver cell lines. In vivo half-life and biological activity of Fibapo and FGF19 were compared. Hepatoprotective and proregenerative activities of Fibapo were evaluated in obese db/db mice undergoing PH.

Results

Hepatosteatosis and ER stress were exacerbated in HFD-fed Fgf15–/– mice. Hepatic expression of Ppar2 was elevated in Fgf15–/– mice, being reversed by FGF19 treatment. PA induced FGF15/19 expression in mouse ileum and human liver cells, and FGF19 protected from PA-mediated ER stress and cytotoxicity. Fibapo reduced liver BA and lipid accumulation, inhibited ER stress and showed enhanced half-life. Fibapo provided increased db/db mice survival and improved regeneration upon PH.

Conclusions

FGF15/19 is essential for hepatic metabolic adaptation to dietary fat being a physiological regulator of Ppar2 expression. Perioperative administration of Fibapo improves fatty liver regeneration.




Sex-specific effects of TLR9 promoter variants on spontaneous clearance of HCV infection

2017-09-06T02:02:06-07:00

Objective

As pathogen sensors, Toll-like receptors (TLR) play a role in the first defence line during HCV infection. However, the impact of the DNA sensor TLR9 on the natural course of HCV infection is unknown. To address this, TLR9 promoter polymorphisms (single nucleotide polymorphisms (SNPs)) rs187084 and rs5743836 were investigated for their effect on disease progression.

Design

Therefore, the TLR9 SNPs and the interferon lambda 4 (IFNL4) rs12979860 were genotyped in chronically HCV type 1 infected (n=333), in patients who spontaneously cleared the infection (n=161), in the Swiss HCV cohort (n=1057) and the well-characterised German (n=305) and Irish (n=198) ‘anti-D’ cohorts. Functional analyses were done with promoter reporter constructs of human TLR9 in B cells and assessing TLR9 mRNA levels in whole blood of healthy volunteers.

Results

The TLR9 rs187084 C allele was associated with spontaneous virus clearance in women of the study cohort (OR=2.15 (95% CI 1.18 to 3.90) p=0.012), of the Swiss HCV cohort (OR=2.06 (95% CI 1.02 to 4.18) p=0.044) and in both ‘anti-D’ cohorts (German: OR=2.01 (95% CI 1.14 to 3.55) p=0.016; Irish: OR=1.93 (95% CI 1.10 to 3.68) p=0.047). Multivariate analysis in the combined study and Swiss HCV cohorts supported the results (OR=1.99 (95% CI 1.30 to 3.05) p=0.002). Functional analyses revealed higher transcriptional activities for both TLR9 variants and an association of the C allele of rs5743836 with allele-specific TLR9 mRNA regulation by oestrogens in women.

Conclusions

TLR9 promoter SNPs are associated with the natural course of HCV infection and show higher transcriptional activities. Our results imply the DNA sensor TLR9 in natural immunity against the RNA virus, HCV.




Carvedilol delays the progression of small oesophageal varices in patients with cirrhosis: a randomised placebo-controlled trial

2017-09-06T02:02:06-07:00

Background and aims

Carvedilol is effective in the primary prophylaxis for large oesophageal varices. We investigated its use in preventing progression of small to large oesophageal varices.

Methods

Consecutive cirrhotics with small oesophageal varices were prospectively randomised to either carvedilol (n=70) or placebo (n=70) and followed up for a minimum of 24 months. Endoscopy was done at baseline and six monthly intervals. Hepatic vein pressure gradient (HVPG) was measured at baseline and at 12 months. The primary endpoint was development of large varices.

Results

Baseline characteristics in two groups were comparable. The predominant aetiology of cirrhosis was non-alcoholic fatty liver disease in both the groups. The mean dose of carvedilol administered was 12±1.67 mg/day and the target heart rate achieved was 58±3 bpm. A higher proportion of patients in carvedilol group had non-progression to large varices than placebo (79.4% vs 61.4%; p=0.04); the mean time of non-progression to large varices was 20.8 months (95% CI 19.4 to 22.4) in carvedilol group and 18.7 months (95% CI 17.1 to 20.4) in placebo group (p=0.04). There was a modest reduction of HVPG at 1 year in carvedilol group (–8.64%) compared with placebo (+0.33%) (p=0.22). None of the patients in either group died of variceal bleeding or liver-related causes. No major adverse events were observed in either group.

Conclusions

Carvedilol is safe and effective in delaying the progression of small to large oesophageal varices in patients with cirrhosis.

Trial registration number

NCT01196507; post-results.




Effectiveness and safety of sofosbuvir plus ribavirin for the treatment of HCV genotype 2 infection: results of the real-world, clinical practice HCV-TARGET study

2017-09-06T02:02:06-07:00

Objective

Due to a high efficacy in clinical trials, sofosbuvir (SOF) and ribavirin (RBV) for 12 or 16 weeks is recommended for treatment of patients with HCV genotype (GT) 2 infection. We investigated safety and effectiveness of these regimens for GT2 in HCV-TARGET participants.

Design

HCV-TARGET, an international, prospective observational study evaluates clinical practice data on novel antiviral therapies at 44 academic and 17 community medical centres in North America and Europe. Clinical data were centrally abstracted from medical records. Selection of treatment regimen and duration was the investigator's choice. The primary efficacy outcome was sustained virological response 12 weeks after therapy (SVR12).

Results

Between December 2013 and April 2015, 321 patients completed 12 weeks (n=283) or 16 weeks (n=38) of treatment with SOF and RBV. Prior treatment experience and cirrhosis was more frequent among patients in the 16-week regimen compared with 12 weeks (52.6% vs 27.6% and 63.2% vs 21.9%, respectively). Overall, SVR12 was 88.2%. The SVR12 in patients without cirrhosis was 91.0% and 92.9% for 12 or 16 weeks of therapy, respectively. In patients with cirrhosis treated for 12 or 16 weeks, SVR12 was 79.0% and 83%. In the multivariate analysis, liver cirrhosis, lower serum albumin and RBV dose at baseline were significantly associated with SVR12. Common adverse events (AEs) included fatigue, anaemia, nausea, headache, insomnia, rash and flu-like symptoms. Discontinuation due to AEs occurred in 2.8%.

Conclusions

In this clinical practice setting, SOF and RBV was safe and effective for treatment of patients with HCV GT2 infection.

Trial registration number

NCT01474811.




Highly bioavailable silibinin nanoparticles inhibit HCV infection

2017-09-06T02:02:06-07:00

Objective

Silibinin is a flavonolignan that is well established for its robust antiviral activity against HCV infection and has undergone several clinical trials for the management of hepatitis C. Despite its potency, silibinin suffers from poor solubility and bioavailability, restricting its clinical use. To overcome this limitation, we developed highly bioavailable silibinin nanoparticles (SB-NPs) and evaluated their efficiency against HCV infection.

Design

SB-NPs were prepared using a nanoemulsification technique and were physicochemically characterised. Infectious HCV culture systems were used to evaluate the influence of SB-NP on the virus life cycle and examine their antioxidant activity against HCV-induced oxidative stress. The safety profiles of SB-NP, in vivo pharmacokinetic studies and antiviral activity against infection of primary human hepatocytes were also assessed.

Results

SB-NP consisted of nanoscale spherical particles (<200 nm) encapsulating amorphous silibinin at >97% efficiency and increasing the compound's solubility by >75%. Treatment with SB-NP efficiently restricted HCV cell-to-cell transmission, suggesting that they retained silibinin's robust anti-HCV activity. In addition, SB-NP exerted an antioxidant effect via their free radical scavenging function. Oral administration of SB-NP in rodents produced no apparent in vivo toxicity, and pharmacokinetic studies revealed an enhanced serum level and superior biodistribution to the liver compared with non-modified silibinin. Finally, SB-NP efficiently reduced HCV infection of primary human hepatocytes.

Conclusions

Due to SB-NP's enhanced bioavailability, effective anti-HCV activity and an overall hepatoprotective effect, we suggest that SB-NP may be a cost-effective anti-HCV agent that merits further evaluation for the treatment of hepatitis C.




GI highlights from the literature

2017-09-06T02:02:06-07:00

Basic scienceColonic organoids: no longer be-hind in modelling disease

Crespo M, Vilar E, Tsai SY, et al. Colonic organoids derived from human induced pluripotent stem cells for modelling colorectal cancer and drug testing. Nat Med 2017. doi: 10.1038/nm.4355. (Epub ahead of print)

The ability to grow gastric and small intestinal organoids from human-induced pluripotent stem cells (hiPSCs) has allowed us to model intestinal biology adeptly. To date, although colonic organoids (COs) can be grown from adult tissue, they have not been obtained from hiPSCs as the hindgut has proved more challenging a source. The authors have accomplished this from both human embryonic stem cells and hiPSCs. They first cultured heSCs with GSK3β inhibitor; modulating the Wnt pathway in this way gave rise to cells positive for CDX2, a hindgut marker. When hindgut cells were treated with a small molecule inhibitor of BMP, they gave rise to COs,...




Water activity does not shape the microbiota in the human colon

2017-09-06T02:02:06-07:00

We recently reported an association between stool consistency as measured by the Bristol Stool Scale (BSS) and major markers of the gut ecosystem, including microbial richness, enterotypes and bacterial growth rates in 53 healthy women.1 Meanwhile, the link between stool consistency and colon microbiota composition has been confirmed in two large-scale (n>1000) cohorts including individuals of both sexes, different age and varying health statuses.2 3 In our original manuscript, we hypothesised on mechanisms that would explain the associations observed. Two potential mechanisms were put forward, namely colon ecosystem differentiation through passage rate variation and reduction of water availability. While the impact of passage rate on ecosystem composition has recently been shown to partially account for BSS-associated microbiota variation,4 the potential correlation with water availability remains unexplored.

Water activity (aw) is a dimensionless variable that reflects the availability of water in a...




Vedolizumab safety in pregnancy and newborn outcomes

2017-09-06T02:02:06-07:00

We read with interest the study by Colombel et al1 on vedolizumab (VDZ) safety in Crohn's disease (CD) and ulcerative colitis (UC). These data were derived from pivotal clinical trials which naturally exclude pregnant women, leaving this important area of pharmacovigilance unaddressed. Epidemiologically, the first age peak of IBD frequently overlaps with family planning. Thus, there is considerable interest among couples and healthcare providers on how VDZ impacts on pregnant women and newborns. Here we report the first four fully VDZ exposed and documented pregnancies and newborns.

VDZ (MLN0002, MLN02, LDP-02, anti-α4β7) is a humanised monoclonal IgG1 antibody targeting α4β7 integrin. IgG1 is the predominant means of fetal immunity and maternal–fetal transport across the placenta, which increases linearly throughout pregnancy.2 Therefore, it can be expected that the fetuses are increasingly VDZ exposed towards the delivery date.

The first two patients display typical IBD demographics, while...




Toward chronic hepatitis C eradication in HIV-positive patients, including those cirrhotic and infected with genotype 3 viruses

2017-09-06T02:02:06-07:00

Direct-acting agents (DAA) have proved dramatic efficiency to cure chronic hepatitis C.1 2 Extensive assessment of their real-life effectiveness is now required, including in cirrhotic and genotype 3 HCV-infected patients who are under-represented in real-world studies but are considered the still hard-to-cure population.1–5 We read therefore with interest the article by Welzel et al1 about the achievement of sustained virological response (SVR) in 91% of cases in a real-world cohort treated with sofosbuvir plus daclatasvir with or without ribavirin for 12–24 weeks. Indeed, remarkably, SVR was 92% in patients infected with HCV-3 (n=102), 97% in cirrhotics (n=389), 98% in HIV-infected individuals (n=55) and 96% in case of prior HCV therapy (n=341).

We analysed the efficacy and safety of DAA-based anti-HCV therapies administered during 2 years (May 2014–April 2016) to a real-world cohort of 170 HCV-HIV-coinfected...




Routine assessment of the gut microbiome to promote preclinical research reproducibility and transparency

2017-09-06T02:02:06-07:00

The irreproducibility of preclinical, biomedical research is becoming increasingly problematic, as recently highlighted by Omary et al,1 in the June issue of Gut. As discussed, variations in study design, mouse strain, sex and age are important factors that should be adequately described to promote study reproducibility.1 In line with recent speculation,2 authors also emphasised the gut microbiome as a potential confounder underlying inconsistencies in preclinical research data.

Recently, there has been a large influx of studies reporting dysbiotic changes in many preclinical models of human disease, both GI and non-GI.3 4 Although informative, much of this research continues to be associative. To dissect causative disease mechanisms, the impact of benign environmental factors relating to study design and rodent husbandry must be acknowledged.

Based on twin studies,5 it is understood that a core subset of bacteria are hereditary.




Delayed severe bleeding complications after treatment of pancreatic fluid collections with lumen-apposing metal stents

2017-09-06T02:02:06-07:00

With interest we read the paper by Bang et al,1 who observed delayed severe adverse events after endoscopic treatment of pancreatic fluid collections (PFCs) with the Hot AXIOS lumen-apposing metal stent (LAMS), which was unrelated to the initial procedure, in a randomised controlled trial. LAMS are increasingly used for transmural endoscopic ultrasound-guided drainage of PFC and infected walled-off pancreatic necrosis (WOPN).2 Procedure associate bleeding is a frequent adverse event after transmural drainage.3 While our experience confirms our colleagues' findings we would like to emphasize that complications are not restricted to Hot AXIOS stents and that certain insertion techniques may be more prone to early bleeding while non-pigtail, LAMS can cause late bleeding complications.

From June 2013 to October 2016, we treated 46 patients with LAMS (8xHot AXIOS 15x10 mm (Boston Scientific); 38xTAEWOONG MEDICAL Niti-S biliary covered stent (NAGI) 10.5F 14x20 mm) for infected WOPNs. The...