Same-day bidirectional endoscopy has been reported to reduce recovery time, and procedure-related cost. The safety of bidirectional endoscopy vs colonoscopy only, while using midazolam and pethidine, ...has never been evaluated. We reviewed 1,202 consecutive patients who underwent bidirectional endoscopy or colonoscopy only with administration of midazolam and pethidine in Toyoshima Ensdoscopy Clinic. We compared the clinical characteristics and adverse events associated with method of endoscopy (colonoscopy only vs bidirectional endoscopy). Furthermore, multivariate logistic regression analyses were conducted to study the role of age, sex, use of sedative, polypectomy, and bidirectional endoscopy in adverse events. In the bidirectional endoscopy group, the doses of pethidine and midazolam, and the incidence rates of hypoxia and posto-endoscopic nausea were significantly higher. On multivariate analysis, age (odds ratio = 1.061, p<0.001), use of pethidine (odds ratio = 4.311, p = 0.003), and bidirectional endoscopy (odds ratio = 3.658, p<0.001) were independently associated with hypoxia. On multivariate analysis, female sex (odds ratio = 10.25, p = 0.027) and bidirectional endoscopy (odds ratio = 6.051, p = 0.022) were independently associated with post-endoscopic nausea. In conclusion, bidirectional endoscopy could increase hypoxia in elderly patients using pethidine and post-endoscopic nausea in female patients.
Overexpression of human progastrin increases colonic mucosal proliferation and colorectal cancer progression in mice. The G-protein coupled receptor 56 (GPR56) is known to regulate cell adhesion, ...migration, proliferation and stem cell biology, but its expression in the gut has not been studied. We hypothesized that the promotion of colorectal cancer by progastrin may be mediated in part through GPR56. Here, we found that GPR56 expresses in rare colonic crypt cells that lineage trace colonic glands consistent with GPR56 marking long-lived colonic stem-progenitor cells. GPR56 was upregulated in transgenic mice overexpressing human progastrin. While recombinant human progastrin promoted the growth and survival of wild-type colonic organoids in vitro, colonic organoids cultured from GPR56-/- mice were resistant to progastrin. We found that progastrin directly bound to, and increased the proliferation of, GPR56-expressing colon cancer cells in vitro, and proliferation was increased in cells that expressed both GPR56 and the cholecystokinin-2 receptor (CCK2R). In vivo, deletion of GPR56 in the mouse germline abrogated progastrin-dependent colonic mucosal proliferation and increased apoptosis. Loss of GPR56 also inhibited progastrin-dependent colonic crypt fission and colorectal carcinogenesis in the azoxymethane (AOM) mouse model of colorectal cancer. Overall, we found that progastrin binds to GPR56 expressing colonic stem cells, which in turn promotes their expansion, and that this GPR56-dependent pathway is an important driver and potential new target in colorectal carcinogenesis.
Pancreatic ductal adenocarcinoma (PDA) has a 5-year survival rate of less than 5% and is the sixth leading cause of cancer death. Although KRAS mutations are one of the major driver mutations in PDA, ...KRAS mutation alone is not sufficient to induce invasive pancreatic cancer in mice model. HER2, also known as ERBB2, is a receptor tyrosine kinase, and overexpression of HER2 is associated with poor clinical outcomes in pancreatic cancer. However, no report has shown whether HER2 and its downstream signaling contributes to the pancreatic cancer development. By immunohistochemical analysis in human cases, HER2 protein expression was detected in 40% of PDAs and 29% of intraductal papillary mucinous carcinomas, another type of pancreatic cancer. In a mouse model, we showed overexpression of activated HER2 (HER2
) in the pancreas, in which cystic neoplastic lesions resembling intraductal papillary mucinous neoplasm-like lesions in humans had developed. We also found that HER2
cooperated with oncogenic Kras to accelerate the development of pancreatic intraepithelial neoplasms. In addition, using pancreatic organoids in 3D cultures, we found that organoids cultured from HER2
/Kras double transgenic mice showed proliferative potential and tumorigenic ability cooperatively. HER2-signaling inhibition was suggested to be an new therapeutic target in some types of PDAs.
Background and Aim
Helicobacter pylori, gastritis, and intestinal metaplasia (IM) are known risk factors for gastric cancer. In the present study, we conducted a cohort study to evaluate the ...predictive value of the distribution of IM for gastric cancer development.
Methods
We conducted a retrospective cohort study at a university hospital. From June 1998 to December 2000, we assessed histological gastritis using biopsy specimens, one from the antrum and one from the corpus, from 1450 patients, among whom 729 revisited for follow‐up endoscopy. Patients were classified into three groups according to the distribution of IM at initial endoscopy. IM group A had no IM, IM group B had IM in the antrum only, and IM group C had IM in the corpus. The development of gastric cancer was assessed by endoscopic examination.
Results
The mean duration of follow‐up was 6.7 ± 4.7 years. The cumulative incidence of gastric cancer at 5 years was 1.5% in total and 0.8%, 3.3%, and 2.7% in IM groups A, B, and C, respectively. The IM group was identified as an independent risk factor by multivariate analysis; compared with IM group A, hazard ratios were 3.6 (95% confidence interval CI 1.1–12.1) in IM group B and 3.8 (95% CI 1.01–14.1) in IM group C. In IM group C, the incidence of gastric cancer in patients who received eradication therapy was significantly lower than that in patients who did not receive (P = 0.021, log‐rank).
Conclusion
IM is a good predictive marker for the development of gastric cancer.
Disturbance of intestinal homeostasis is associated with the development of inflammatory bowel disease IBD, and TGF-β signalling impairment in mononuclear phagocytes MPs causes murine colitis with ...goblet cell depletion. Here, we examined an organoid-MP co-culture system to study the role of MPs in intestinal epithelial differentiation and homeostasis.
Intestinal organoids were co-cultured with lamina propria leukocytes and bone marrow-derived dendritic cells BMDCs from CD11c-cre Tgfbr2fl/fl mice. Organoid-MP adhesive interactions were evaluated by microscopy, RT-PCR, and flow cytometry. Murine colitis models (dextran sodium sulphate DSS, CD11c-cre Tgfbr2fl/fl, T-cell-transfer) were used for histological and immunohistochemical analysis. Anti-E-cadherin antibody treatment or CD11c+-cell-specific CDH1 gene deletion were performed for E-cadherin neutralization or knockout. Colonic biopsies from patients with ulcerative colitis were analysed by flow cytometry.
Intestinal organoids co-cultured with CD11c+ lamina propria leukocytes or BMDCs from CD11c-cre Tgfbr2fl/fl mice showed morphological changes and goblet cell depletion with Notch signal activation, analogous to CD11c-cre Tgfbr2fl/fl colitis. E-cadherin was upregulated in CD11c+ MPs, especially CX3CR1+CCR2+ monocytes, of CD11c-cre Tgfbr2fl/fl mice. E-cadherin-mediated BMDC adhesion promoted Notch activation and cystic changes in organoids. Anti-E-cadherin antibody treatment attenuated colitis in CD11c-cre Tgfbr2fl/fl and T-cell-transferred mice. In addition, E-cadherin deletion in CD11c+ cells attenuated colitis in both CD11c-cre Tgfbr2fl/fl and DSS-treated mice. In patients with ulcerative colitis, E-cadherin expressed by intestinal CD11c+ leukocytes was enhanced compared with that in healthy controls.
E-cadherin-mediated MP-epithelium adhesion is associated with the development of colitis, and blocking these adhesions may have therapeutic potential for IBD.
c‐Jun N‐terminal kinase (JNK) is a member of the mitogen‐activated protein kinase (MAPK) family, and it is reportedly involved in the development of several cancers. However, the role of JNK in ...pancreatic cancer has not been elucidated. We assessed t he involvement of JNK in the development of pancreatic cancer and investigated the therapeutic effect of JNK inhibitors on this deadly cancer. Small interfering RNAs against JNK or the JNK inhibitor SP600125 were used to examine the role of JNK in cellular proliferation and the cell cycles of pancreatic cancer cell lines. Ptf1acre/+;LSL‐KrasG12D/+;Tgfbr2flox/flox mice were treated with the JNK inhibitor to examine pancreatic histology and survival. The effect of JNK inhibition on tumor angiogenesis was also assessed using cell lines and murine pancreatic cancer specimens. JNK was frequently activated in human and murine pancreatic cancer in vitro and in vivo. Growth of human pancreatic cancer cell lines was suppressed by JNK inhibition through G1 arrest in the cell cycle with decreased cyclin D1 expression. In addition, oncogenic K‐ras expression led to activation of JNK in pancreatic cancer cell lines. Treatment of Ptf1acre/+;LSL‐KrasG12D/+;Tgfbr2flox/flox mice with the JNK inhibitor decreased growth of murine pancreatic cancer and prolonged survival of the mice significantly. Angiogenesis was also decreased by JNK inhibition in vitro and in vivo. In conclusion, activation of JNK promotes development of pancreatic cancer, and JNK may be a potential therapeutic target for pancreatic cancer.
Although some molecularly targeted drugs for colorectal cancer are used clinically and contribute to a better prognosis, the current median survival of advanced colorectal cancer patients is not ...sufficient. Autophagy, a basic cell survival mechanism mediated by recycling of cellular amino acids, plays an important role in cancer. Recently, autophagy has been highlighted as a promising new molecular target. The unfolded protein response (UPR) reportedly act in complementary fashion with autophagy in intestinal homeostasis. However, the roles of UPR in colon cancer under autophagic inhibition remain to be elucidated. We aim to clarify the inhibitory effect of autophagy on colon cancer.
We crossed K19 (CreERT) and Atg5 (flox/flox) mice to generate Atg5 (flox/flox)/K19 (CreERT) mice. Atg5 (flox/flox)/K19 (CreERT) mice were first treated with azoxymethane/dextran sodium sulfate and then injected with tamoxifen to inhibit autophagy in CK19-positive epithelial cells. To examine the anti-cancer mechanisms of autophagic inhibition, we used colon cancer cell lines harboring different p53 gene statuses, as well as small interfering RNAs (siRNAs) targeting Atg5 and immunoglobulin heavy-chain binding protein (BiP), a chaperone to aid folding of unfolded proteins.
Colon tumors in Atg5 (flox/flox)/K19 (CreERT) mice showed loss of autophagic activity and decreased tumor size (the total tumor diameter was 28.1 mm in the control and 20.7 mm in Atg5 (flox/flox)/K19 (CreERT) mice, p = 0.036). We found that p53 and UPR/endoplasmic reticulum (ER) stress-related proteins, such as cleaved caspase 3, and CAAT/enhancer-binding protein homologous protein, are up-regulated in colon tumors of Atg5 (flox/flox)/K19 (CreERT) mice. Although Atg5 and BiP silencing, respectively, increased apoptosis in p53 wild type cells, Atg5 silencing alone did not show the same effect on apoptosis in p53 mutant cells. However, co-transfection of Atg5 and BiP siRNAs led to increased apoptosis in p53 mutant cells.
Blocking autophagy has potential in the treatment of colon cancer by inducing apoptosis via p53 and ER stress, and suppressing the UPR pathway is a valid strategy to overcome resistance to autophagic inhibition.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
SNP rs2294008 in
(
) and decreased
expression are associated with gastric cancer. The objective of this study is to investigate the role of rs2294008 and
expression in the gastritis-gastric cancer ...carcinogenic pathway. We conducted a case-control association study of
-infected gastritis and gastric cancer. rs2294008 was associated with the progression to chronic active gastritis (
9.4 × 10
; odds ratio = 3.88, TT + TC vs CC genotype), but not with
infection
nor with the progression from active gastritis to gastric cancer. We also assessed the association of rs2294008 with
mRNA expression in the gastric mucosa at various disease stages and found that rs2294008 was associated with
expression (
1.3 × 10
).
infection (
5.1 × 10
) and eradication therapy (
< 1 × 10
) resulted in the reduced and increased
expression, respectively, indicating negative regulation of
expression by
infection.
expression was decreased in severe gastritis compared with mild gastritis only among T allele carriers. Our findings revealed the regulation of
expression by host genetic variation and bacterial infection might contribute to gastritis progression after
infection.
PDF
