Cholestenoic acid as endogenous epigenetic regulator decreases hepatocyte lipid accumulation in vitro and in vivo.

Cholestenoic acid (CA) has been reported as an important biomarker of many severe diseases, but its physiological and pathological roles remain unclear. This study aimed to investigate the potential role of CA in hepatic lipid homeostasis. Enzyme kinetic studies revealed that CA specifically activates DNA methyltransferases 1 (DNMT1) at low concentration with EC50 = 1.99 × 10-6 M and inhibits the activity at higher concentration with IC50 = 9.13 × 10-6 M, and specifically inhibits DNMT3a, and DNMT3b activities with IC50= 8.41 × 10-6 M and IC50= 4.89 × 10-6 M, respectively. In a human hepatocyte in vitro model of high glucose (HG)-induced lipid accumulation, CA significantly increased demethylation of 5mCpG in the promoter regions of over 7,000 genes, particularly those involved in master signaling pathways such as calcium-AMPK and 0.0027 at 6 h. RNA sequencing analysis showed that the downregulated genes are affected by CA encoding key enzymes, such as PCSK9, MVK, and HMGCR, which are involved in cholesterol metabolism and steroid biosynthesis pathways. In addition, untargeted lipidomic analysis showed that CA significantly reduced neutral lipid levels by 60% in the cells cultured in high-glucose media. Administration of CA in mouse metabolic dysfunction-associated steatotic liver disease (MASLD) models significantly decreases lipid accumulation, suppresses the gene expression involved in lipid biosynthesis in liver tissues, and alleviates liver function. This study shows that CA as an endogenous epigenetic regulator decreases lipid accumulation via epigenetic regulation. The results indicate that CA can be considered a potential therapeutic target for the treatment of metabolic disorders.NEW & NOTEWORTHY To our knowledge, this study is the first to identify the mitochondrial monohydroxy bile acid cholestenoic acid (CA) as an endogenous epigenetic regulator that regulates lipid metabolism through epigenome modification in human hepatocytes. The methods used in this study are all big data analysis, and the results of each part show the global regulation of CA on human hepatocytes rather than narrow point effects.

Daisy-chain gene drives for the alteration of local populations.

If they are able to spread in wild populations, CRISPR-based gene-drive elements would provide new ways to address ecological problems by altering the traits of wild organisms, but the potential for uncontrolled spread tremendously complicates ethical development and use. Here, we detail a self-exhausting form of CRISPR-based drive system comprising genetic elements arranged in a daisy chain such that each drives the next. "Daisy-drive" systems can locally duplicate any effect achievable by using an equivalent self-propagating drive system, but their capacity to spread is limited by the successive loss of nondriving elements from one end of the chain. Releasing daisy-drive organisms constituting a small fraction of the local wild population can drive a useful genetic element nearly to local fixation for a wide range of fitness parameters without self-propagating spread. We additionally report numerous highly active guide RNA sequences sharing minimal homology that may enable evolutionarily stable daisy drive as well as self-propagating CRISPR-based gene drive. Especially when combined with threshold dependence, daisy drives could simplify decision-making and promote ethical use by enabling local communities to decide whether, when, and how to alter local ecosystems.

Real-world economic value of a 21-gene assay in early-stage breast cancer.

OBJECTIVES: Value-based payment reforms shift cost-containment responsibilities to the physician. Although gene expression profiling (GEP) utilizing a 21-gene panel among patients with early-stage, axillary lymph node-negative, hormone receptor-positive, HER2/neu oncogene-negative breast cancer is able to identify a cohort that may achieve excellent outcomes without adjuvant chemotherapy, high up-front costs (list price, $4175) could dissuade usage. STUDY DESIGN: Retrospective review of consecutive patients with breast cancer treated at a single cancer center. METHODS: Chart review of 227 patients 70 years or younger with outpatient costs (ie, drug average sales price, reagent costs, physician charges) during first 6 months of treatment. RESULTS: Of these patients, 68% underwent GEP, with 52%, 43%, and 5% having low, intermediate, and high recurrence risk scores, respectively. Adjuvant chemotherapy was utilized less in genomically profiled cohorts (19% vs 29%; P = .08) and was consistent with recommendations of the recurrence scores. The mean 6-month outpatient costs were $24,955 with adjuvant chemotherapy and $2654 with hormonal therapy. Patients with stage II cancer undergoing GEP received adjuvant chemotherapy at a lower frequency (28.6% vs 86.7%), but patients with stage I cancer who underwent testing were slightly more likely to receive chemotherapy (15.8% vs 14%) because the test identified patients with higher-risk tumors. Universal GEP testing of patients with stage II cancer would have resulted in net savings of $11,494 per patient inclusive of test cost; stage I testing would have increased costs by $4505. Similar trends for grade 2/3 tumors (-$2394) and grade 1 tumors (+$6047) were noted. CONCLUSIONS: Universal GEP testing of women 70 years or younger with stage II or grade 2/3 lymph node-negative breast cancers would result in lower outpatient costs, inclusive of the diagnostic test, within the first 6-month episode of care.

Designing DNA Nanotube Liquid Crystals as a Weak-Alignment Medium for NMR Structure Determination of Membrane Proteins.

Thirty percent of the human proteome is composed of membrane proteins that can perform a wide range of cellular functions and communications. They represent the core of modern medicine as the targets of about 50 % of all prescription pharmaceuticals. However, elucidating the structure of membrane proteins has represented a constant challenge, even in the modern era. To date, only a few hundred high-resolution structural models of membrane proteins are available. This chapter describes the emergence of DNA nanotechnology as a powerful tool for the structural characterization of membrane protein using solution-state nuclear magnetic resonance (NMR) spectroscopy. Here, we detail the large-scale synthesis of detergent-resistant DNA nanotubes that can be assembled into a dilute liquid crystal to be used as a weak-alignment media in solution NMR structure determination of membrane proteins.

Acute Pancreatitis after Extracorporeal Shock Wave Lithotripsy for a Urolithiasis / 대한췌담도학회지

48-year-old woman was admitted to emergency room due to left flank pain. It was diagnosed with left ureteral stone and underwent extracorporeal shock wave lithotripsy (ESWL). However, 12 hours later, the patient complained acute upper abdominal pain with pulmonary edema and low blood pressure. A diagnosis of moderate acute pancreatitis with local complication was considered and we decided conservative therapy including fluid resuscitation, inotropics and antibiotics. It was suggested that ESWL was responsible for the acute pancreatitis. The patient gradually recovered and was discharged on 13th day of admission. ESWL is considered the standard treatment for urolithiasis. Although, it has proved to be safe and effective, serious complications have been reported in 1% of patients, including acute pancreatitis, perirenal hematoma, urosepsis, venous thrombosis, biliary obstruction, bowel perforation, lung injury, and cardiac arrhythmia. Although the possibility of post-ESWL acute pancreatitis is extremely low, physicians should take care of this complication.

Spontaneous Dissolution of Isolated Superior Mesenteric Vein Thrombosis in Acute Pancreatitis / 대한소화기학회지

Acute pancreatitis can result in many vascular complications in both artery and vein. Venous complication usually occurs as a form of splenic or portal vein thrombosis, and also can simultaneously occur in superior mesenteric vein as well. Rarely, isolated superior mesenteric vein thrombosis occurs as a venous complication. Although it is uncommon, mesenteric vein thrombosis is an important clinical entity because of the possibility of mesenteric ischemia and infarction of small bowel. The treatments of mesenteric venous thrombosis include anticoagulation therapy, transcatheter therapy and surgical intervention. We report a case of 45-year-old man who had acute pancreatitis with isolated superior mesenteric vein thrombosis, which was spontaneously dissolved with the resolution of underlying inflammation without anticoagulation or surgical intervention.

A Case of Duodenal Diverticulitis / 대한소화기내시경학회지

Duodenal diverticulitis is difficult to diagnose because it can mimic other common diseases such as cholecystitis and perforated ulcer. Recently, we experienced a rare case of duodenal diverticulitis that was initially suspected on abdominal computed tomography as focal pancreatitis. Although duodenal diverticulitis has been increasingly recognizable before surgery, with the advent of multi-detector computed tomography, misdiagnosis remains problematic since duodenal diverticulitis is commonly not considered in the differential diagnosis of acute abdominal pain. We have to consider this rare disease entity because delayed diagnosis might be a cause of substantial morbidity and mortality.

A Case of Early Bile Duct Cancer Arising from Villous Adenoma in Choledochal Cyst / 대한소화기학회지

Choledochal cyst is an uncommon premalignant anomaly. The morphology and pathogenesis of the premalignant lesion of cholangiocarcinoma arising from the choledochal cyst has not been well described. Herein, we report a rare case of bile duct adenoma arising from choledochal cyst with anomalous union of pancreaticobiliary duct (AUPBD). 50-year-old woman was admitted to our hospital with the complaint of epigastric pain. She had received common bile duct (CBD) exploration and choledocholithotomy and cholecystectomy 3 months earlier under the diagnosis of multiple CBD stones. Intraoperalive cholangiogram was not remarkable except CBD dilatation at that time. Endoscopic retrograde cholangiopancreatography revealed choledochal cyst with AUPBD and round filling defect which disappeared easily on the balloon cholaniogram. On magnetic resonance cholangiopancreatography, the filling defect was confirmed as 2 cm polypoid mass attached to the distal bile duct wall. At laparotomy, a soft whitish mass was palpable on the lower CBD. On histological examination, adenoma with focal carcinoma change arising from choledochal cyst was diagnosed.

A Case of Anti-LKM 1 Positive Autoimmune Hepatitis Accompanied by Systemic Lupus Erythematosus / 대한소화기학회지

Overlap of autoimmune hepatitis and systemic lupus erythematosus (SLE) is a comparatively rare condition. Although both autoimmune hepatitis and SLE can share common autoimmune features such as polyarthralgia, hypergammaglobulinemia and positive ANA, it has been considered as two different entities. We report a case of anti-LKM1 positive autoimmune hepatitis who developed SLE two years later. The presence of interface hepatitis with lymphoplasma cell infiltrates and rosette formation points to the autoimmune hepatitis rather than SLE hepatitis. Autoimmune hepatitis is infrequently accompanied by SLE, therefore, it could be recommended to investigate for SLE in patients with autoimmune hepatitis.

A Case of Carcinoid Tumor of the Common Bile Duct / 대한소화기학회지

Majority of malignant neoplasms arising from the extrahepatic bile duct are adenocarcinomas. Carcinoid tumors at this site are extremely rare. We report a 67-year-old woman with malignant carcinoid tumor of the common bile duct. She presented with obstructive jaundice of 1 week's duration. Abdominal CT and ERCP revealed a common bile duct mass. She underwent Whipple's operation and was diagnosed as malignant carcinoid tumor histologically and immunohistochemically.

A Case of Limy Bile Associated with Cholangitis and Calcified Gallbladder / 대한소화기내시경학회지

Limy bile is characterized by excessive precipitation of calcium carbonate, and generally preceded by gallbladder obstruction. Three case reports have been found in the domestic literatures. It is rare that limy bile syndrome associates cholangitis or calcified gallbladder. We report the case of a patient with limy bile, located in the gallbladder, common bile duct, and intrahepatic duct, with association of calcified gallbladder. This case showed characteristic radiologic and endoscopic findings. The patient was treated by endoscopic sphincterotomy and laparoscopic cholecystectomy.

Liver Abscess Caused by Gemella morbillorum / 대한소화기학회지

Gemella morbillorum, an anaerobic-to-aerotolerant Gram-positive coccus, is a normal flora of the oral cavity, respiratory tract, urogenital organ and gastrointestinal tract, and infections caused by this organism are unusual. It has been associated mainly with endocarditis and bacteremia, and rarely with arthritis, spondylodiscitis, meningitis, brain abscess and septic shock. Liver abscess caused by G. morbillorum is very rare, and only a few cases were reported. We experienced a case of liver abscess by G. morbillorum in a 56-year-old woman presented with fever. We report this case with a review of literatures.

Choledocho-duodenal Fistula Caused by Tuberculosis / 대한소화기내시경학회지

Choledocho-duodenal fistula is a rare condition. It is usually developed as a complication of the gallstone disease, and rarely developed by penetrating peptic ulcer, trauma and neoplasm. Tuberculosis as a etiology of choledocho-duodenal fistula is very rare, and only a few cases were reported. We experienced a case of choledocho-duodenal fistula due to tuberculous lymphadenitis in a 26 year-old man presented with epigastric pain. After 6 months of anti-tuberculous medication, He was free of symptom and the fistula was closed spontaneously. We report the case with a review of literatures.

A Case of Subphrenic Abscess with Ileal Fistula Caused by Metastatic Adenocarcinoma of Unknown Origin / 대한소화기학회지

Usual sources of subphrenic abscess with intestinal fistula are previous abdominal operation, inflammatory bowel disease and malignancy. Reported cases of intestinal fistula caused by adenocarcinoma were complicated by direct invasion. In this report, a 70-year-old male had a subphrenic abscess with intestinal fistula and the cause was a metastatic adenocarcinoma of unknown origin. As far as we know, this has not been reported previously in the literatures. The abscess went on chronic course for six months because intermittent administration of antibiotics modified its clinical presentation. The fistulous tract between the abscess and ileum was demonstrated by tubogram via the drainage catheter in abscess. The patient underwent surgical treatment because the cause of fistula was obscure. Invasion of the ileum by metastatic adenocarcinoma was diagnosed by the histologic examination of surgical specimen. Therefore, when a fistula develops without any apparent cause, there is a possibility of malignancy, and surgical approach must be considered. An early surgical approach will prevent the delay in treatment and reduce the mortality.

A Case of Chronic Recurrent Small Bowel Bleeding in Neurofibromatosis Type 1 Diagnosed by Capsule Endoscopy / 대한소화기내시경학회지

Small bowel diseases comprised of neoplasm, inflammatory disease, vascular abnormality, absorption dysfunction, and iatrogenic causes. Among those, vascular abnormality is perhaps the most important clinical disease entity. Obscure gastrointestinal bleeding accounts for 5% of chronic gastrointestinal bleeding, but conventional endoscopy and radiologic study may fail to diagnose the cause in certain cases. Patients with neurofibromatosis type 1 have a lot of gastrointestinal tumor, with a high incidence of small bowel involvement. We experienced a case presenting with chronic bleeding due to jejunal gastrointestinal stromal tumor diagnosed by capsule endoscopy in a seventy-two year old female patient with sporadic neurofibromatosis type 1.

Portal vein thrombosis that successfully treated with low molecular weight heparin in acute pancreatitis / 대한내과학회지

Portal vein thrombosis is an uncommon cause for presinusoidal hypertension, which results from inherited thrombotic disorder, neoplasm, and intra-abdominal inflammation like pancreatitis. It could develop portal hypertension, culminating in variceal bleeding from esophagus or stomach. One of the medical management of portal vein thrombosis is intravenous heparinization followed by long term oral anticoagulation. Intravenous heparinization using unfractionated heparin requires aPTT monitoring for dose adjustment which is not needed for low molecular weight heparin, and has higher risk of bleeding than using low molecular weight heparin. However, the standard protocol for anticoagulation in portal vein thrombosis has not been determined yet. We experienced a case of portal vein thrombosis in acute necrotizing pancreatitis, which was successfully treated with low molecular weight heparin, as herein reported.