SLUG transcription factor : a pro-survival and prognostic factor in gastrointestinal stromal tumour

Background: The SLUG transcription factor has been linked with the KIT signalling pathway that is important for gastrointestinal stromal tumour (GIST) tumourigenesis. Its clinical significance in GIST is unknown. Methods: Influence of SLUG expression on cell proliferation and viability were investigated in GIST48 and GIST882 cell lines. The association between tumour SLUG expression in immunohistochemistry and recurrence-free survival (RFS) was studied in two clinical GIST series, one with 187 patients treated with surgery alone, and another one with 313 patients treated with surgery and adjuvant imatinib. Results: SLUG downregulation inhibited cell proliferation, induced cell death in both cell lines, and sensitised GIST882 cells to lower imatinib concentrations. SLUG was expressed in 125 (25.0%) of the 500 clinical GISTs evaluated, and expression was associated with several factors linked with unfavourable prognosis. SLUG expression was associated with unfavourable RFS both when patients were treated with surgery alone (HR = 3.40, 95% CI = 1.67-6.89, P = 0.001) and when treated with surgery plus adjuvant imatinib (HR = 1.83, 95% CI = 1.29-2.60, P = 0.001). Conclusions: GIST patients with high tumour SLUG expression have unfavourable RFS. SLUG may mediate pro-survival signalling in GISTs.Peer reviewe

Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer

Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors1,2, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8+ T-cell infiltrates, but neither alone, stratified patients with the longest survival. Investigating the specific neoantigen qualities promoting T-cell activation in long-term survivors, we discovered that these individuals were enriched in neoantigen qualities defined by a fitness model, and neoantigens in the tumour antigen MUC16 (also known as CA125). A neoantigen quality fitness model conferring greater immunogenicity to neoantigens with differential presentation and homology to infectious disease-derived peptides identified long-term survivors in two independent datasets, whereas a neoantigen quantity model ascribing greater immunogenicity to increasing neoantigen number alone did not. We detected intratumoural and lasting circulating T-cell reactivity to both high-quality and MUC16 neoantigens in long-term survivors of pancreatic cancer, including clones with specificity to both high-quality neoantigens and predicted cross-reactive microbial epitopes, consistent with neoantigen molecular mimicry. Notably, we observed selective loss of high-quality and MUC16 neoantigenic clones on metastatic progression, suggesting neoantigen immunoediting. Our results identify neoantigens with unique qualities as T-cell targets in pancreatic ductal adenocarcinoma. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumours that may guide the application of immunotherapies

A Piperidine Chiron for the <i>Veratrum</i> Alkaloids

A <i>Veratrum</i> piperidine chiron was prepared over 11 steps (7.9% yield) from (−)-citronellal. Three methods for the installation of the propargylic side chain onto a cyclic enamide are presented

A Piperidine Chiron for the <i>Veratrum</i> Alkaloids

A <i>Veratrum</i> piperidine chiron was prepared over 11 steps (7.9% yield) from (−)-citronellal. Three methods for the installation of the propargylic side chain onto a cyclic enamide are presented

A Piperidine Chiron for the <i>Veratrum</i> Alkaloids

A <i>Veratrum</i> piperidine chiron was prepared over 11 steps (7.9% yield) from (−)-citronellal. Three methods for the installation of the propargylic side chain onto a cyclic enamide are presented

A Piperidine Chiron for the <i>Veratrum</i> Alkaloids

A <i>Veratrum</i> piperidine chiron was prepared over 11 steps (7.9% yield) from (−)-citronellal. Three methods for the installation of the propargylic side chain onto a cyclic enamide are presented

A Piperidine Chiron for the <i>Veratrum</i> Alkaloids

A <i>Veratrum</i> piperidine chiron was prepared over 11 steps (7.9% yield) from (−)-citronellal. Three methods for the installation of the propargylic side chain onto a cyclic enamide are presented

A Piperidine Chiron for the <i>Veratrum</i> Alkaloids

A <i>Veratrum</i> piperidine chiron was prepared over 11 steps (7.9% yield) from (−)-citronellal. Three methods for the installation of the propargylic side chain onto a cyclic enamide are presented

Derivatives of 1,2,4-Triazole Imines Acting as Dual iNOS and Tumor Cell Growth Inhibitors

A set of 4-(R2-imino)-3-mercapto-5-(R1)-4H-1,2,4-triazoles derivatives were synthesized, characterized and evaluated for their ability to inhibit nitric oxide (NO) production in PAM212 mouse keratinocytes, which led to the discovery and the subsequent evaluation of their growth inhibitory cytotoxic potency toward that same mouse cell line together with a number of human cells lines (PC3, HT-29 and HeLa). Some limited SAR could be established for both NO production inhibition potency and growth inhibition cytotoxicity. Noticeably, the compounds designed to be nitrofurantoin mimics were the most potent anti-neoplastic agents