Epigenetic histone modifications in a clinically relevant rat model of chronic ethanol-binge-mediated liver injury

Purpose

Ethanol binge augments liver injury after chronic ethanol consumption in humans, but the mechanism behind the enhanced liver injury by ethanol binge is not known. In this study we used a clinically relevant rat model in which liver injury is amplified by binge after chronic ethanol treatment and investigated the importance of histone modifications.

Methods

Eight-week-old Sprague-Dawley rats were fed ethanol in a liquid diet for 4 weeks. Control rats were fed an isocaloric liquid diet. This was followed by three binge administrations of ethanol (intragastric 5 g/kg body weight, 12 h apart). In the control, ethanol was replaced by water. Four hours after the last binge administration, liver samples were analyzed for histone modifications and parameters of liver injury.

Results

Chronic ethanol administration alone caused an increase in histone H3 ser10 and ser28 (H3S10 or S28) phosphorylation, and binge ethanol reduced their levels. Levels of dually modified phosphoacetylated histone H3 (H3AcK9/PS10) increased after acute binge ethanol and remained same after chronic ethanol binge. In contrast, histone H3 lysine-9 acetylation (H3AcK9) was not increased after chronic ethanol but increased significantly after acute binge and chronic ethanol binge. Increase in histone acetylation was accompanied by increased phospho-ERK1/2 in the nuclear extracts. Increased acetylation after chronic ethanol binge was also accompanied by increased protein levels of GCN5 histone acetyl transferase and a modest increase in HDAC3 in the nucleus. Histone lysine-9 dimethylation was significantly increased after chronic ethanol binge. Chronic ethanol binge also resulted in a decrease in the SAM:SAH ratio with a relative decrease of SAM levels and a corresponding increase in SAH levels.

Conclusions

Ethanol binge after chronic ethanol altered the profile of site-specific histone modifications and may underlie the mechanism of augmented liver injury by chronic-ethanol-binge-treated rats.

     

Endoscopic Management of Barrett’s Esophagus: Advances in Endoscopic Techniques

Barrett??s esophagus (BE) is a well-known premalignant condition that can be associated with the development of dysplasia and adenocarcinoma. In the past, esophagectomy was the standard treatment for patients with BE with high grade dysplasia (HGD) and early cancer (EC). However, esophagectomy is not necessarily the only treatment response to HGD and EC anymore. Over the past decade, a number of endoscopic therapies have been developed for management of BE. These include endoscopic mucosal resection, thermal ablation techniques that use laser irradiation, multipolar electrocoagulation, argon plasma coagulation, photodynamic therapy, and the recently developed cryotherapy and radiofrequency ablation.     

Risk of Colorectal Adenomas in Women with Prior Breast Cancer

Background and Aims

Longer life expectancy in patients with prior breast cancer may increase their risk of developing other primary cancers, including colorectal cancer (CRC). Whether the risk of developing CRC in this patient population is higher in comparison to those with no prior cancer remains unclear. The purpose of this study was to compare the prevalence of colorectal adenomas and any CRC in breast cancer survivors with those who have no history of prior cancer and assess any difference with use of antiestrogen therapy.

Methods

We compared the prevalence of colorectal cancer and adenomas in breast cancer survivors with that of a group of matched controls. Eligible survivors were ??85?years of age; had initially been diagnosed with stage 0, I, II, or III breast cancer; had completed all cancer treatments with the exception of adjuvant antiestrogen therapy; and had no evidence of recurrence on follow-up. We used the screening colonoscopy database at our institution to identify age-, sex-, and race-matched controls with no history of cancer.

Results

We identified 302 study-eligible breast cancer survivors and 302 matched controls. No colorectal cancers were found in either group. Forty-one breast cancer survivors and 30 controls had tubular adenomas; four survivors and three controls had villous adenoma; and eight survivors and ten controls had advanced adenoma. Multivariate regression analysis revealed that adjuvant antiestrogen therapy was not significantly associated with an increased risk of advanced adenoma.

Conclusions

The prevalence of colorectal adenomas in breast cancer survivors and controls was similar. Breast cancer survivors, including those receiving adjuvant antiestrogen therapies may follow the colorectal screening guidelines used for average-risk population.     

Ingestion of a carbonated beverage decreases lower esophageal sphincter pressure and increases frequency of transient lower esophageal sphincter relaxation in normal subjects

Transient lower esophageal sphincter relaxation (tLESR) and decreased basal lower esophageal sphincter (LES) pressure are postulated mechanisms of gastroesophageal reflux (GER). There is conflicting evidence on the effect of carbonated drinks on lower esophageal sphincter function. This study was conducted to assess the effect of a carbonated beverage on tLESR and LES pressure. High resolution manometry tracings (16 channel water-perfused, Trace 1.2, Hebbard, Australia) were obtained in 18 healthy volunteers (6 men) for 30 min each at baseline, and after 200 mL of chilled potable water and 200 mL of chilled carbonated cola drink (Pepsi [Pepsico India Ltd]). The sequence of administration of the drinks was determined by random number method generated by a computer. The analysis of tracings was done using TRACE 1.2 software by a physician who was unaware of the sequence of administration of fluids. The mean (SD) age of the participant was 37.3 (12.9) years. The median (range) frequency of tLESr was higher after the carbonated beverage (10.5 [0-26]) as compared to baseline (0 [0-3], p?=?0.005) as well as after water (1 [0-14], p?=?0.010). The LES pressure decreased after ingestion of the carbonated beverage (18.5 [11-37] mmHg) compared to baseline (40.5 [25-66] mmHg, p?=?0.0001) and after water (34 [15-67] mmHg, p?=?0.003). Gastric pressure was not different in the three groups. Ingestion of a carbonated beverage increases tLESr and lowers LES pressure in healthy subjects.