Acute cholecystitis (AC) is one of the most common surgical diseases. Bacterial infection accounts for 50% to 85% of the disease's onset. Since there is a close relationship between the biliary system and the gut, the aims of this study were to characterize and determine the influence of gut microbiota on AC, to detect the pathogenic microorganism in the biliary system, and to explore the relationship between the gut and bile microbiota of patients with AC. A total of 185 713 high-quality sequence reads were generated from the faecal samples of 15 patients and 13 healthy controls by 16S rRNA gene pyrosequencing. Patients' samples were significantly enriched in Akkermansia, Enterobacter and Escherichia/Shigella group. The healthy controls, however, showed significant enrichment of Clostridiales, Coprococcus, Coprobacillaceae, Paraprevotella, Turicibacter and TM7-3 in their faecal samples. Escherichia coli was the main biliary pathogenic microorganism, among others such as Klebsiella spp., Clostridium perfringens, Citrobacter freundii and Enterobacter cloacae in the bile of the patients. Additionally, the amount of bile endotoxin significantly correlated with the number of Enterobacteriaceae, especially E. coli. Our data indicate that Enterobacteriaceae might play essential role in the pathogenesis and/or progress of AC. This was verified in an in vivo model using a pathogenic E. coli isolated from one of the patients in guinea pigs and observed marked gallbladder inflammation and morphologic changes. This study thus provides insight which could be useful for the prevention, diagnosis and treatment of AC and related diseases by controlling the growth of Enterobacteriaceae to alleviate the infection.
18173 Background: There has been increasing interest in the use of weekly administration of docetaxel as a way of reducing its hemotologic toxicity. Weekly docetaxel plus cisplatin has also shown promising efficacy and well tolerability for first-line treatment of advanced or metastatic NSCLC in our previous phase I study (2002 ASCO, abstract No 2744). We conducted this phase II trial to further evaluate this regimen’s efficacy and toxicity. Methods: Patients with histologically confirmed stage IIIB or IV NSCLC were treated with docetaxel (35 mg/m2, 30 min. iv. infusion) on days 1, 8, 15 and cisplatin (75 mg/m2, 30 min. iv. infusion) on day 1 repeated every 4 weeks for up to 6 cycles. Pts received oral dexamethasone 7.5 mg twice daily from the day before chemotherapy and consecutive two days thereafter. The primary endpoint of this phase II study is efficacy of the regimen. Results: A total of 83 patients were enrolled from July 2002 to June 2004, 75 patients were evaluable for response and 83 for safety. Median age was 55 years (range 29–70 years); and 69.9% were male; adenocarcinoma/squamous cell carcinoma/others (65/12/6); stage IIIB /IV( 47/36); ECOG PS 0/1(52/31). Median number of chemotherapy cycles was 3(1–5). One CR (complete response) and 22 PR (partial response) were achieved with an ORR of 30.7% in the evaluable patients. The 1-year survival was 48.6% with a median survival of 10.7 months (range: 3–34 months). Neutropenia was the most common adverse event, though most were mild; Grade III/IV toxicities per patient were: Neutropenia (15.6%), asthenia (11%), skin/nail toxicity (10.8%) and vomiting (9.6%). Febrile neutropenia was not observed. Conclusions: In the present study, the combination of weekly administration docetaxel combining with cisplatin appears well tolerated with very low frequency of severe hematologic toxicity and similarly efficacious as 3-weekly docetaxel in NSCLC pts. No significant financial relationships to disclose.
PD-L1 on melanoma cells can bind to PD-1 on cytotoxic T cells, which inhibits the antitumor immune response. Immune checkpoint therapy such as PD-1 blockade has shown exciting results to treat melanoma, but relapse after initial tumor regression still occur. Mechanisms of relapse are currently unknown. In T cells, the pro-apoptotic BCL-2 family protein BIM is a downstream signaling molecule of the PD-1 pathway. High levels of BIM in T cells are associated with clinical benefit in patients with metastatic melanoma treated with antiePD-1 drugs. However, it has not been explored whether the expression of BIM in tumor cells affects immunotherapy response. We investigate if BIM expression levels in tumor cells influences PD-L1 expression, a known positive predictive marker for immunotherapy. We used shRNA to knock-down (KD) or CRISPR/Cas9 genome-editing to knock out (KO) BIM expression in multiple melanoma cell lines. We examined PD-L1 expression with immunoblot and FACS analyses. Our data indicate that KD/KO of BIM alone increased the basal level of PD-L1 in some melanoma lines. Further, PD-L1 is dramatically induced in response to Interferon-g treatment (24 hrs) in all KD/KO lines tested (P < 0.05). Moreover, we also looked at two additional biomarkers on tumor cells that independently predict positive response to immunotherapy: (a) HLA-DR (which facilitates recognition by T-cells) and (b) growth inhibition of tumor cells induced by Interferon-g treatment (by means of cytokine induced killing). We found that BIM KO/KD increased the basal level of HLA-DR and inhibited cell viability in a subset of melanoma cell lines. Currently, we are testing the role of BIM in patient samples which have either responded or relapsed from immunotherapy treatment. Taken together, data here indicate that BIM in tumor cells significantly modulate factors that influence immunotherapy response.
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