Development and validation of AI-assisted transcriptomic signatures to personalize adjuvant chemotherapy in patients with pancreatic ductal adenocarcinoma.

BACKGROUND: After surgical resection of pancreatic ductal adenocarcinoma (PDAC), patients are predominantly treated with adjuvant chemotherapy, commonly consisting of gemcitabine-based regimens or the modified FOLFIRINOX regimen (mFFX). While mFFX has been shown to be more effective than gemcitabine-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. PATIENTS AND METHODS: 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 AI-signatures were obtained by combining Independent Component Analysis, Least Absolute Shrinkage and the Selection Operator-Random Forest approach. We integrated a previously developed gemcitabine 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. RESULTS: 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 HR: 0.31; 95% 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 gemcitabine sensitive group when treated with gemcitabine. 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). CONCLUSIONS: This study presents a transcriptome-based tool that was developed using preclinical models and machine learning to accurately predict sensitivity to mFFX and gemcitabine.

Control of pathogenic CD8+ T cell migration to the brain by IFN-gamma during experimental cerebral malaria.

Previous studies have shown that IFN-gamma is essential for the pathogenesis of cerebral malaria (CM) induced by Plasmodium berghei ANKA (PbA) in mice. However, the exact role of IFN-gamma 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-gamma receptor alpha chain (IFN-gammaR1) 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-gamma controls trafficking of pathogenic T cells in the brain, thus providing an explanation for the organ-specific pathology induced by PbA infection.

Oxazoline N-oxide mediated [2 + 3] cycloadditions. Application to a formal synthesis of (+)-carpetimycin A.

[formula: see text] Cycloaddition between gamma,delta-unsaturated beta-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 beta-amino ester derivative 15a. Oxidative acidic hydrolysis, oxidation of the resulting aldehyde 18, deprotection, and cyclization afforded the beta-lactam 23, a direct precursor of (+)-carpetimycin A.

[Computerized tomography-guided needle biopsy for the diagnosis of pulmonary nodules: analysis of a series of 41 patients]. / Ponction à visée diagnostique de nodules pulmonaires sous repérage scanographique: analyse d'une série de 41 patients.

This study was aimed at assessing percutaneous biopsy under computerized tomography (CT) guidance, its results in terms of diagnostic value, factors contributing to its complications or success, and its indications. Results obtained from a series of 41 patients and data from previous clinical trials were compared. Patients who were not eligible due to either poor physical condition or a tumor that could not be reached were not included into the study. Various factors, ie, the tumor location, the size of the lesion, the distance between the lesion and the thoracic wall, and the type (histological and/or cytological) of samples, were analyzed. Results were evaluated according to the disease evolution or pathological findings. Tumoral cells were found in 23 samples. Eighteen samples were negative for malignancy, with eight benign lesions and ten false negative. Complications that occurred just after the biopsy were recorded. Failures and complication factors were analyzed and compared to those already described. CT-guided needle biopsy is an admitted alternative to thoracotomy, even for small nodules deeply located. The use of this technique should be discussed when fiberoptic endoscopy leads to negative results. Various tumors cannot be reached using CT-guided needle biopsy and this technique is more efficacious for bulky nodules. The thickness of lung parenchyma passed through does not seem to change the risk of pneumothorax. The use of laser guidance might help locate the tumor with more accuracy.

[Extracorporeal circulation in acute ischemia of the lower limb with late detection]. / Circulation extracorporelle de membre dans l'ischémie aiguë vue tardivement.

The authors report a case of acute limb ischemia in a 19 years old patient seen at 9 hours of the injury. They describe a technique of "washing-reperfusion" by a cardio-pulmonary limb bypass (CPLB). Blood pH and kaliema measurements during CPLB were noted. The good clinical result except on the initial nerves deficit, should lead to think that this technique could take a place in the treatment of acute limb ischemia seen lately.

[Low molecular weight heparin in extracorporeal circulation. 1st clinical applications]. / Etude d'une héparine de bas poids moléculaire au cours des circulations extracorporelles. Premières applications cliniques.

The haemorrhagic complications inherent to the use of heparin during cardiac surgery led us, after a pilot experimental study, to try out a low molecular weight heparin (LMWH), PK 10169, which has weaker haemorrhagic effects in vitro. Our initial experience was confined to 23 patients with differing pathologies, undergoing cardiopulmonary bypass lasting 30 to 165 minutes. The modes of injection of YK 10169 varied according to the results, especially with respect to the limitation of peaks of anti-Xa activity; 8 patients were given one bolus intravenous injection, 9 were given a bolus injection and a continuous infusion, and 6 were only given the continuous infusion. Biological monitoring of anticoagulation was based on anti-Xa activity. Analysis of the biological results showed that the principal feature was the partial correction, and occasionally the non-correction of anti-Xa activity by protamine sulphate, with no correlation between this anti-Xa activity and postoperative bleeding. The authors report cases of severe postoperative bleeding despite the supposed theoretical and experimental weakly haemorrhagic properties of LMWH, and also discuss the inefficacy of protamine sulphate. The indications for LMWH for cardiopulmonary bypass which were retained, were the rare cases of heparin-induced thrombocytopaenia. In conclusion, it is possible to use LMWH during cardiac surgery but we do not advise using it routinely as its theoretical advantages are not confirmed in practice.