Despite recent efforts to dissect the inter-tumor heterogeneity of pancreatic ductal adenocarcinoma (PDAC) by determining prognosis-predictive gene expression signatures for specific subtypes, their functional differences remain elusive. Here, we established a pancreatic tumor organoid library encompassing 39 patient-derived PDACs and identified 3 functional subtypes based on their stem cell niche factor dependencies on Wnt and R-spondin. A Wnt-non-producing subtype required Wnt from cancer-associated fibroblasts, whereas a Wnt-producing subtype autonomously secreted Wnt ligands and an R-spondin-independent subtype grew in the absence of Wnt and R-spondin. Transcriptome analysis of PDAC organoids revealed gene-expression signatures that associated Wnt niche subtypes with GATA6-dependent gene expression subtypes, which were functionally supported by genetic perturbation of GATA6. Furthermore, CRISPR-Cas9-based genome editing of PDAC driver genes (KRAS, CDKN2A, SMAD4, and TP53) demonstrated non-genetic acquisition of Wnt niche independence during pancreas tumorigenesis. Collectively, our results reveal functional heterogeneity of Wnt niche independency in PDAC that is non-genetically formed through tumor progression.

The RR could continue to increase for 7 years even under MST. Based on our analysis of the side effects of steroid therapy, MST at 5 mg/day for 2 (total 4625 mg) to 3 (total 6425 mg) years might be a rational and safe therapeutic strategy in terms of keeping the RR to <30% while avoiding potential steroid toxicity.

A high resistance rate (47.9%) to gatifloxacin (GAT; 8-methoxy fluoroquinolone) in Helicobacter pylori (H. pylori) strains from 48 Japanese patients is observed after unsuccessful H. pylori eradication. A significant association between MICs for GAT equal to or above 1 g/ml and mutations of the gyrA gene of H. pylori was demonstrated.Resistance to antibiotics is the major cause of the failure to eradicate Helicobacter pylori. For such cases, alternative regimens need to be developed.Perri et al. have reported an unacceptable low eradication rate of only 68% with a 7-day regimen of levofloxacin (LVX), amoxicillin (AMX), and pantoprazole (12). However, Sharara et al. have recently reported an excellent eradication rate of 92% with a 7-day regimen of gatifloxacin (GAT), AMX, and rabeprazole (14). It is important to note the superior in vitro activity of GAT over that of LVX against H. pylori (1). Therefore, GAT-based triple therapy might be a promising option for an alternative treatment regimen.Several studies have shown that the "quinolone resistancedetermining region" (QRDR) of the gyrA gene plays a critical role in the resistance of H. pylori to ciprofloxacin (CIP) (8,15). H. pylori does not contain genes for topoisomerase IV, an important fluoroquinolone target in other bacteria (15). The present study demonstrated a correlation between MICs to GAT and mutations of the gyrA and gyrB genes in H. pylori isolated from Japanese patients after unsuccessful eradication of infection.A total of 48 patients (32 males and 16 females; mean age, 57.8) with H. pylori infection after treatment failure were enrolled at Keio University Hospital between September 2004 and June 2005. Of the total, 42 patients had one treatment failure, 4 patients had two treatment failures, and 2 patients had three treatment failures (first-line treatment, triple therapy with clarithromycin [CLR], AMX, and proton pump inhibitor [PPI]; second-line treatment, triple therapy with metronidazole [MNZ], AMX, and PPI; and third-line treatment, triple therapy with LVX, AMX, and PPI). All patients underwent upper gastrointestinal endoscopy and gastric biopsy at Keio University Hospital.The susceptibility of H. pylori isolates to CRL, GAT, and MNZ was determined by the agar dilution method according to the guidelines established by the CLSI (formerly NCCLS) (9). Isolates were considered resistant to MNZ if the MIC of the drug was Ն8 g/ml and resistant to CLR and GAT if the MIC of these drugs was Ն1 g/ml (3, 7, 10). The resistance rates to GAT, CLR, and MNZ were 47.9%, 79.2%, and 6.3%, respectively. The GAT resistance rates were 22.2% (2/9) in the strains susceptible to both CLR and MNZ, 50% (18/36) in the strains resistant to CLR but susceptible to MNZ, 100% (1/1) in the strains resistant to MNZ but susceptible to CLR, and 100% (2/2) in the strains resistant to both CLR and MNZ.Studies in Europe have suggested that the primary resistance rate might be as low as 8% for CIP (2, 16) and that only 9% of the isolates show resistance to CIP after failure of pr...

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Helicobacter pylori is now well known as an important pathogen related to the development of gastric cancer. However, some clinicians still doubt the causal association of H. pylori with the development of gastric cancer. To summarize the recent clinical data on the link between H. pylori and gastric cancer, we reviewed related articles published over the past 3 years, after the award of the Nobel Prize for Physiology or Medicine to Drs. J.R. Warren and B.J. Marshall for the first culture and isolation of H. pylori and the investigation of their relevance to peptic ulcer disease. This updated summary of the relationship between H. pylori and gastric cancer highlights the strong link between the organism and the development of gastric cancer, and suggests eradication of this bacterial infection as a possible prophylactic measure against the development of this lethal malignancy. At present, clinicians and researchers in the field emphasize the strong need for H. pylori eradication from the human stomach.