ABBV-744 induces autophagy in gastric cancer cells by regulating PI3K/AKT/mTOR/p70S6k and MAPK signaling pathways.

The mortality rates of gastric cancer remain high due to limited therapeutic strategies. As a highly selective inhibitor of the BD2 domain of BET family proteins, ABBV-744 has potent chemotherapeutic activity against various human solid tumors. However, whether ABBV-744 has potential anti-tumor effects in gastric cancer remain largely unknown. In this study, we evaluated the effect of ABBV-744 on gastric cancer cells and explored the possible underlying mechanisms. We found that ABBV-744 inhibited the growth of gastric cancer cells and patient-derived tumor organoids in a dose-dependent manner. Cellular experiments revealed that ABBV-744 induced mitochondria damage, reactive oxygen species accumulation, cell cycle arrest and apoptotic cell death in gastric cancer cells. Transcriptomic analysis using RNA-sequencing data identified autophagy as a crucial pathway involved in the cell death caused by ABBV-744. Mechanically, further studies showed that ABBV-744 induced autophagy flux in gastric cancer cells by inactivating PI3K/AKT/mTOR/p70S6k and activating the MAPK signaling pathways. In vivo mouse xenograft studies demonstrated that ABBV-744 significantly suppressed the growth of gastric cancer cells via inducing autophagy. Taken together, our results suggest that ABBV-744 is a novel drug candidate for gastric cancer.

Therapeutic potential of an intestinotrophic hormone, glucagon-like peptide 2, for treatment of type 2 short bowel syndrome rats with intestinal bacterial and fungal dysbiosis.

BACKGROUND: Previous studies showed that type 2 short bowel syndrome (SBS) rats were accompanied by severe intestinal bacterial dysbiosis. Limited data are available for intestinal fungal dysbiosis. Moreover, no effective therapeutic drugs are available for these microbiota dysbiosis. The aims of our study were to investigate the therapeutic potential of glucagon-like peptide 2 (GLP-2) for these microbiota dysbiosis in type 2 SBS rats. METHODS: 8-week-old male SD rats which underwent 80% small bowel resection, ileocecum resection, partial colon resection and jejunocolostomy, were treated with saline (SBS group, n = 5) or GLP-2 (GLP2.SBS group, n = 5). The Sham group rats which underwent transection and re-anastomosis were given a saline placebo (Sham group, n = 5). 16S rRNA and ITS sequencing were applied to evaluate the colonic bacterial and fungal composition at 22 days after surgery, respectively. RESULTS: The relative abundance of Actinobacteria, Firmicutes and proinflammatory Proteobacteria increased significantly in SBS group rats, while the relative abundance of Bacteroidetes, Verrucomicrobia and Tenericutes decreased remarkably. GLP-2 treatment significantly decreased Proteus and increased Clostridium relative to the saline treated SBS rats. The diversity of intestinal fungi was significantly increased in SBS rats, accompanied with some fungi abnormally increased and some resident fungi (e.g., Penicillium) significantly decreased. GLP-2 treatment significantly decreased Debaryomyces and Meyerozyma, and increased Penicillium. Moreover, GLP-2 partially restored the bacteria-fungi interkingdom interaction network of SBS rats. CONCLUSION: Our study confirms the bacterial and fungal dysbiosis in type 2 SBS rats, and GLP-2 partially ameliorated these microbiota dysbiosis.

Extensive small bowel metastasis and peritoneal dissemination 1 year following curative gastrectomy for T1N1 gastric cancer: A case report.

RATIONALE: Metastasis of T1N1 gastric cancer (GC) at early stage after curative gastrectomy is unusual. Reports on the diagnosis, treatment, and prognosis of peritoneal metastasis following curative gastrectomy for T1N1 GC are lacking. PATIENT CONCERNS: A 54-year-old woman was admitted to our hospital with complaints of mild abdominal distension and failure to pass gas and stool for 2 days. She has a history of distal gastrectomy for T1N1 GC. About 1 year after surgery, she presented with persistent abdominal distension and underwent conservative managements. DIAGNOSES: Imaging tests failed to identify the apparent cause of intestinal obstruction. When conservative managements failed to relieve the symptoms, she underwent emergency laparotomy, which revealed extensive small bowel metastasis and peritoneal dissemination. INTERVENTIONS: Peritoneal irrigation and drainage were performed with the consent of the patient's families. OUTCOMES: The patient abandoned further therapy and died 1 week later during the follow-up period. LESSONS: Although the metastasis of T1N1 GC is rare, patients with high risk of metastasis after curative surgery should also be closely followed and be considered as candidates for more aggressive screening strategies. In addition, the use of more effective chemotherapeutic drugs as adjuvant chemotherapy after curative surgery in T1N1 patients may also need to be explored.

[Establishment and application of gastric and gastric cancer organoids].

Gastric organoid is the organotypic cultures of gastric stem cells or pluripotent stem cells. Gastric organoid is comprised of all major types of gastric epithelial cells and represent the architecture and function remarkably similar to those of the gastric epithelium, faithfully recapitulating the functional gastric epithelium ex vivo. As ideal basic experimental model, gastric organoid has advantages over animal models and conventional cell model in many aspects. Gastric organoid derived from human gastric tissue, in particular, allows the investigation of the function of human stomach in the ex vivo setting. It has now been applied in the field of formation and physiology of the stomach, Helicobacter pylori infection-associated diseases, research of the pathogenic gene, screening and development of drugs, and regenerative medicine. What is more, as an innovative pre-clinical cancer model, gastric cancer organoid has provided important insights in the development of gastric cancer and screening of antitumor drugs, such as simulating the occurrence and development of gastric cancer, screening and development of antitumor drugs, personalized medication and targeted therapy for gastric cancer, and combined application with patient-derived xenograft. In this review, we summarize the establishment and application of gastric and gastric cancer organoids, especially in modeling gastric cancer, basic research and drug development.

Recurrent scrotal edema in a patient with radiation enteritis: A case report.

Since its introduction as an alternative treatment technique, radiotherapy has been increasingly used as the medical treatment of choice for patients with malignant tumors. However, radiotherapy is associated with a number of common, well-described side effects, which may compromise the quality of life of the patients. Scrotal edema is an infrequent complication in patients who undergo pelvic irradiation, which is suspected to be due to lymphatic obstruction. An extensive literature search found no previous case report describing this complication in patients receiving pelvic radiotherapy. Herein, we present a case of recurrent scrotal edema in a 59-year-old man with prostate cancer and radiation enteritis. Conservative therapy was applied and was successful in relieving the symptoms. To the best of our knowledge, this is the first case report of scrotal edema in a patient with radiation enteritis.

Coordinated Hospital-Home Fecal Microbiota Transplantation via Percutaneous Endoscopic Cecostomy for Recurrent Steroid-Dependent Ulcerative Colitis.

Since its introduction as an alternative intestinal microbiota alteration approach, fecal microbiota transplantation (FMT) has been increasingly used as a treatment of choice for patients with ulcerative colitis (UC), but no reports exist regarding FMT via percutaneous endoscopic cecostomy (PEC). This report describes the case of a 24-year-old man with a 7-year history of recurrent, steroid-dependent UC. He received FMT via PEC once per day for 1 month in the hospital. After the remission of gastrointestinal symptoms, he was discharged from the hospital and continued FMT via PEC twice per week for 3 months at home. The frequency of stools decreased, and the characteristics of stools improved soon thereafter. Enteral nutrition was regained after 1 week, and an oral diet was begun 1 month later. Two months after the FMT end point, the patient resumed a normal diet, with formed soft stools once per day. The follow-up colonoscopy showed normal mucus membranes; then, the PEC set was removed. On the subsequent 12 months follow-up, the patient resumed orthobiosis without any gastrointestinal discomfort and returned to work. This case emphasizes that FMT via PEC can not only induce remission but also shorten the duration of hospitalization and reduce the medical costs; therefore, this approach should be considered an alternative option for patients with UC.

Low Triiodothyronine Syndrome in Patients With Radiation Enteritis: Risk Factors and Clinical Outcomes an Observational Study.

The implications of low triiodothyronine syndrome (LT3S) in patients with radiation enteritis (RE) have not been properly investigated. As such, we conducted this cohort study to investigate the association between LT3S and RE, to explore the etiology of LT3S in RE, to evaluate the clinical features and clinical outcomes of LT3S patients, and to inspect the correlation of clinical variables and LT3S in RE.This prospective study included 39 RE patients. Medical records and various laboratory parameters (including thyroidal, tumorous, nutritional, and radiotherapy variables) were collected in all participants.Our results showed that the incidence of LT3S was 84.6% in patients with RE. Total protein (71.7 ±â€Š5.7 vs 63.2 ±â€Š9.6 g/L, P = 0.04) and albumin (ALB, 46.0 ±â€Š4.6 vs 38.7 ±â€Š5.3 g/L, P = 0.01) were significantly lower in LT3S group compared with those in euthyroid group. Standard thyroid-stimulating hormone index (-0.89 ±â€Š2.11 vs -2.39 ±â€Š1.33, P = 0.03) and sum activity of deiodinases (19.74 ±â€Š4.19 vs 12.55 ±â€Š4.32 nmol/L, P = 0.01) were significantly lower in LT3S group. Patients with LT3S suffered longer duration of hospitalization (48.25 ±â€Š23.29 days in LT3S vs 26.75 ±â€Š10.56 days in euthyroid, P = 0.036). Low serum ALB (ß = 0.694, 95% CI = 0.007-0.190, P = 0.037) was the only significant predictor of LT3S.LT3S was common in RE patients. A hypodeiodination condition and a potential pituitary-thyrotroph dysfunction might play a role in the pathophysiology of LT3S in RE. Worse nutritional status and clinical outcomes were confirmed in RE patients with LT3S. Furthermore, total protein and ALB were observed as protective and differentiating parameters of LT3S in RE. In summary, this was the 1st investigation to evaluate the clinical correlation between RE and LT3S, investigate the prevalence of LT3S in RE, and explore the pathogenesis of LT3S, despite the limitation of a relatively small sample size. These results will hopefully encourage future research to place greater emphasis on early identification of LT3S in RE patients.

An Unusual Cause of Duodenal Obstruction: Persimmon Phytobezoar.

Duodenal phytobezoar, an unusual cause of acute duodenal obstruction, is rarely seen. The most common cause of this type of bezoar is persimmon. It frequently arises from underlying gastrointestinal tract pathologies (gastric surgery, etc.). Here, we report the case of a 66-year-old man who had undergone distal gastrectomy with Billroth I reconstruction for gastric cancer and experienced severe epigastric discomfort, abdominal pain, and vomiting for a few days. The abdominal computed tomography scan showed a large-sized mass in the horizontal portion of the duodenum. On following endoscopic examination, a large phytobezoar was revealed in the duodenum. He was treated with endoscopic fragmentation combined with nasogastric Coca-Cola. The patient tolerated the procedure well and resumed a normal oral diet 3 days later.

[Advances in diagnosis and treatment of intestinal Behcet's disease].

Behcet's disease (BD) affects gastrointestinal tract is defined as intestinal BD. The diagnosis and therapeutic efficacy of intestinal BD are still lack of specific diagnostic method and effective treatment. Intestinal BD is diagnosed according to established criteria based on colonoscopic features and biopsy. To date, 5-aminosalicylic acid and systemic corticosteroids are established as the first-line therapy, while immunosuppressants and infliximab are used as second-line therapy for patients with glucocorticoid resistant. In the process of therapy, we need to carefully evaluate the patient's condition and be cautious about surgical treatment. Surgical intervention should only be considered in patients with serious complications. In this review, we summarize the recent advances in diagnosis, disease activity index and treatment of intestinal BD, and provide the theoretic proofs to clinical application.

Success of serial transverse enteroplasty in an adult with extreme short bowel syndrome: a case report.

Since its introduction as an alternative intestinal lengthening technique, serial transverse enteroplasty has been increasingly used as the surgical treatment of choice for children with refractory short bowel syndrome, but there have been few reports about the adult patients. This report describes the case of a 71-year-old man with a short bowel after distal gastrectomy with Billroth II reconstruction for gastric cancer, followed by extensive intestinal resection. The serial transverse enteroplasty operation was performed and lengthened the small intestine from 49 to 67 cm. The patient tolerated the procedure well and weaned off total parenteral nutrition. Liver function also improved. This case shows that the serial transverse enteroplasty procedure increases intestinal length. This procedure should be considered a surgical option for adult patients with extreme short bowel syndrome.

Tumor necrosis factor-α suppresses the protein fractional synthesis rate of the small intestine stimulated by glutamine in rats.

The objective of this study was to examine whether and how TNF-α affects glutamine-enhanced protein synthesis and the expression of the amino acid transporter ASCT2 in the small intestine at the mRNA and protein levels. A total of 30 male Sprague-Dawley rats were randomly assigned into three groups, namely the total parenteral nutrition (TPN; control), glutamine-treated (Gln), and glutamine- and tumor necrosis factor-α (TNF-α)-treated (TNF-α) groups. At 30 min prior to examination, all rats were mainlined with [L-15N]leucine. The concentration of TNF-α in plasma and of glutamine in plasma and the small intestine was measured. The fractional synthesis rate (FSR) of protein and the mRNA and protein expression levels of ASCT2 in the small intestine were assessed. The level of TNF-α was highest in the TNF-α group and the glutamine concentration was elevated to a greater extent in the TNF-α group than in the other two groups. However, the FSR of protein in the small intestine was significantly higher in the Gln group compared with that in the TNF-α group. The mRNA and protein expression levels of ASCT2 in the experimental groups were significantly higher that those in the control group, but did not differ significantly between the Gln and TNF-α groups. These results indicate that TNF-α may attenuate glutamine-stimulated protein synthesis in the small intestine in the early stage of sepsis in rats. The mechanism may be that TNF-α inhibits the function of the glutamine transporter in the uptake the glutamine into target cells for protein synthesis. This inhibition may occur at or following protein translation.