After surgical resection of pancreatic ductal adenocarcinoma (PDAC), patients are predominantly treated with adjuvant chemotherapy, commonly consisting of gemcitabine (GEM)-based regimens or the ...modified FOLFIRINOX (mFFX) regimen. While mFFX regimen has been shown to be more effective than GEM-based regimens, it is also associated with higher toxicity. Current treatment decisions are based on patient performance status rather than on the molecular characteristics of the tumor. To address this gap, the goal of this study was to develop drug-specific transcriptomic signatures for personalized chemotherapy treatment.
We used PDAC datasets from preclinical models, encompassing chemotherapy response profiles for the mFFX regimen components. From them we identified specific gene transcripts associated with chemotherapy response. Three transcriptomic artificial intelligence signatures were obtained by combining independent component analysis and the least absolute shrinkage and selection operator-random forest approach. We integrated a previously developed GEM signature with three newly developed ones. The machine learning strategy employed to enhance these signatures incorporates transcriptomic features from the tumor microenvironment, leading to the development of the ‘Pancreas-View’ tool ultimately clinically validated in a cohort of 343 patients from the PRODIGE-24/CCTG PA6 trial.
Patients who were predicted to be sensitive to the administered drugs (n = 164; 47.8%) had longer disease-free survival (DFS) than the other patients. The median DFS in the mFFX-sensitive group treated with mFFX was 50.0 months stratified hazard ratio (HR) 0.31, 95% confidence interval (CI) 0.21-0.44, P < 0.001 and 33.7 months (stratified HR 0.40, 95% CI 0.17-0.59, P < 0.001) in the GEM-sensitive group when treated with GEM. Comparatively patients with signature predictions unmatched with the treatments (n = 86; 25.1%) or those resistant to all drugs (n = 93; 27.1%) had shorter DFS (10.6 and 10.8 months, respectively).
This study presents a transcriptome-based tool that was developed using preclinical models and machine learning to accurately predict sensitivity to mFFX and GEM.
•Transcriptomic signatures were developed for key pancreatic cancer drugs to enable personalized treatment.•The Pancreas-View tool integrates four drug signatures to assist informed therapeutic decisions.•Signatures accurately identify high responder patients, indicative of improved DFS and cancer-specific survival.•Clinical validation involving a cohort of 343 patients confirms the efficacy of this signature approach.•Transcriptomic signatures that integrate predictors from preclinical models and machine learning offer a rationalized treatment strategy.
Previous studies have shown that IFN-γ is essential for the pathogenesis of cerebral malaria (CM) induced by Plasmodium berghei ANKA (PbA) in mice. However, the exact role of IFN-γ in the pathway (s) ...leading to CM has not yet been described. Here, we used 129P2Sv/ev mice which develop CM between 7 and 14 days post-infection with PbA. In this strain, both CD4⁺ and CD8⁺ T cells were involved in the effector phase of CM. When 129P2Sv/ev mice deficient in the IFN-γ receptor α chain (IFN-γR1) were infected with PbA, CM did not occur. Migration of leucocytes to the brain at the time of CM was observed in wild type (WT) but not in deficient mice. However, in the latter, there was an accumulation of T cells in the lungs. Analysis of chemokines and their receptors in WT and in deficient mice revealed a complex, organ-specific pattern of expression. Up-regulation of RANTES/CCL5, IP-10/CCL3 and CCR2 was associated with leucocyte migration to the brain and increased expression of MCP-1/CCL2, IP-10/CCL3 and CCR5 with leucocyte migration to the lung. This shows that IFN-γ controls trafficking of pathogenic T cells in the brain, thus providing an explanation for the organ-specific pathology induced by PbA infection.
The synthesis of an ionic liquid-supported olefin metathesis catalyst derived from Grubb's ruthenium carbene complex is described. This new supported catalyst has been used in BMI·PF6 solvent, and ...this allowed success in solving the challenging problem of catalyst recycling. The IL catalyst in BMI·PF6 can be recovered and reused up to 10 consecutive cycles in RCM reactions of several dienes with excellent conversions. Moreover, the IL catalyst shows a remarkable stability in BMI·PF6 and can be stored several months without loss of activity. These results clearly demonstrate the importance of anchoring an imidazolium ionic liquid pattern to the catalyst to avoid its leaching from the BMI·PF6 phase.
A new complex of ruthenium bearing the unsaturated N-heterocyclic carbene IMes (IMes = 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene) and an ionic alkylidene moiety was synthesized and fully ...characterized. The X-ray structure of this catalyst and that of its SIMes (SIMes = 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene) analogue were determined. The catalytic performances of these catalysts and their recyclability were investigated for olefin cross-metathesis in a BmimPF6/organic solvent biphasic medium. The results show the importance of the proper choice of organic solvent. The solvent effect/catalytic behavior could be explained in terms of clathrate formation.
Cycloaddition between γ,δ-unsaturated β-enamino ester 9 and camphor-derived oxazoline N-oxide 8 afforded a single adduct, 14. Dipolarophile 9 proved to be very reactive despite the substitution on ...the double bond. Stereoselective sodium cyanoborohydride reduction of the imminium intermediate 14a gave rise stereoselectively to β-amino ester derivative 15a. Oxidative acidic hydrolysis, oxidation of the resulting aldehyde 18, deprotection, and cyclization afforded the β-lactam 23, a direct precursor of (+)-carpetimycin A.
This work reports the development of efficient imidazolium-tagged ruthenium catalysts to perform metathesis reactions in ionic liquids. Whereas a high level of recyclability combined with a high ...reactivity were obtained with the first generation catalyst
8, the second generation of
N-heterocyclic carbene ruthenium complex
9 appeared to be more suitable to perform ring-closing metathesis reactions of less reactive substrates.
New recyclable imidazolium-tagged ruthenium catalysts have been developed to perform olefin metathesis in room temperature ionic liquids (RTILs). High level of recyclability combined with a high reactivity were obtained in the ring-closing metathesis (RCM) of a variety of di- or tri-substituted and/or oxygen-containing dienes. Extremely low residual ruthenium levels were detected in the RCM products (average of 7.3
ppm per run). Several examples of olefin cross-metathesis (CM) have been also studied.
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Chiral alkoxy-imidazolinium salts are easily available via a five-step procedure starting from β-aminoalcohols. This new family of alkoxy-N-heterocyclic carbene (NHC) precursors is ...shown to be highly active in the enantioselective copper-catalysed conjugate addition to cyclic enones. Complete conversion with low catalyst loading and good enantiomeric excesses up to 93% were obtained at room temperature.
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