Résumé
La prise en charge de l’adénocarcinome pancréatique est un enjeu majeur. En effet, malgré les progrès de la chirurgie et de la chimiothérapie, son pronostic reste sombre. Les essais ...thérapeutiques de phase III évaluant des thérapies ciblées ont été jusqu’à présent des échecs, peut-être en raison de la sélection des patients sur des facteurs prédictifs d’efficacité. Des analyses systématiques du génome tumoral pour le développement d’un traitement personnalisé en maintenance après réponse à un traitement d’induction pourraient être plus concluantes. Enfin, les résultats préliminaires publiés et les essais thérapeutiques à venir permettront, au travers de collaborations transversales, de faire avancer nos connaissances.
Abstract
Deaths from malaria remain staggering despite global support that drives research into new territories. One major gap is our understanding of the sexual biological aspects of the male ...mosquito, which maintain the vector population solidity. Although
Anopheles funestus s.s.
is an extremely efficient African vector, little is known about the network between its sexual physiology and gene expression. The Culicidae male’s sexual maturity involves a suite of physiological changes, such as genitalia rotation that is necessary for successful mating to occur. We show that mating success is guided by genes and physiological plasticity. Transcriptome analysis between newly emerged males (immature) versus males with rotating genitalia (maturing) provides insight into possible molecular mechanisms regulating male sexual behaviour. Putative transcripts that were associated with male sexual maturation were identified and validated. The discovery of the functions of these transcripts could lead to identifying potential targets for innovative vector control interventions, and mosquito population suppression.
Chemotherapy is the only systemic treatment approved for pancreatic ductal adenocarcinoma (PDAC), with a selection of regimens based on patients' performance status and expected efficacy. The ...establishment of a potent stratification associated with chemotherapeutic efficacy could potentially improve prognosis by tailoring treatments.
Concomitant chemosensitivity and genome-wide RNA profiles were carried out on preclinical models (primary cell cultures and patient-derived xenografts) derived from patients with PDAC included in the PaCaOmics program (NCT01692873). The RNA-based stratification was tested in a monocentric cohort and validated in a multicentric cohort, both retrospectively collected from resected PDAC samples (67 and 368 patients, respectively). Forty-three (65%) and 203 (55%) patients received adjuvant gemcitabine in the monocentric and the multicentric cohorts, respectively. The relationships between predicted gemcitabine sensitivity and patients' overall survival (OS) and disease-free survival were investigated.
The GemPred RNA signature was derived from preclinical models, defining gemcitabine sensitive PDAC as GemPred+. Among the patients who received gemcitabine in the test and validation cohorts, the GemPred+ patients had a higher OS than GemPred− (P = 0.046 and P = 0.00216). In both cohorts, the GemPred stratification was not associated with OS among patients who did not receive gemcitabine. Among gemcitabine-treated patients, GemPred+ patients had significantly higher OS than the GemPred−: 91.3 months 95% confidence interval (CI): 61.2-not reached versus 33 months (95% CI: 24-35.2); hazard ratio 0.403 (95% CI: 0.221-0.735, P = 0.00216). The interaction test for gemcitabine and GemPred+ stratification was significant (P = 0.0245). Multivariate analysis in the gemcitabine-treated population retained an independent predictive value.
The RNA-based GemPred stratification predicts the benefit of adjuvant gemcitabine in PDAC patients.
•An RNA signature of gemcitabine-sensitivity is developed from in vitro and in vivo models of pancreatic cancer.•The resulting GemPred signature identifies a subgroup of patients who are sensitive to adjuvant gemcitabine.•The predictive value of GemPred is validated in two cohorts on both OS and disease-free survival.
Résumé
Avec une mortalité proche de l’incidence, le cancer du pancréas a un taux de survie globale à cinq ans autour de 5 %. C’est le sixième cancer le plus fréquent en France (11 600 nouveaux cas ...annuels en 2012) et la quatrième cause de mortalité par cancer en France et en Europe. La chirurgie d’exérèse, seul traitement curatif, concerne seulement 20 % des patients. Le traitement chirurgical, qui permet d’espérer un taux de survie à cinq ans autour de 10 % dans les essais multicentriques, ne peut plus être utilisé isolément: en effet, la chimiothérapie adjuvante permet de doubler les taux de survie à cinq ans dans deux essais de phase III: elle est devenue un standard et est recommandée chez tous les patients opérés quel que soit le statut ganglionnaire; deux options sont possibles, le 5-FU modulé par l’acide folinique (AF) ou la gemcitabine. En revanche, la radiochimiothérapie adjuvante ou néoadjuvante n’a pas montré à ce jour de bénéfice en termes de survie et n’est plus recommandée. Les essais en cours évaluent les associations FOLFIRINOX et gemcitabine–Nab-paclitaxel qui ont permis d’allonger la survie des patients en situation métastatique. Les travaux sur les facteurs prédictifs de réponse et de toxicité des molécules actives sont prometteurs mais non encore utilisables en routine.
Implantable neural prosthetics devices offer a promising opportunity for the restoration of lost functions in patients affected by brain or spinal cord injury, by providing the brain with a ...non-muscular channel able to link machines to the nervous system. Nevertheless current neural microelectrodes suffer from high initial impedance and low charge-transfer capacity because of their small-feature geometry (Abidian et al., 2010; Cui and Zhou, 2007). In this work we have developed PEDOT-modified neural probes based on flexible substrate capable to answer to the three critical requirements for neuroprosthetic device: efficiency, lifetime and biocompatibility. We propose a simple procedure for the fabrication of neural electrodes fully made of Parylene-C, followed by an electropolymerization of the active area with the conductive polymer PEDOT that is shown to greatly enhance the electrical performances of the device. In addition, the biocompatibility and the very high SNR exhibited during signal recording make our device suitable for long-term implantation.
Microbiota identified from preserved Anopheles E Silva, Bianca; Matsena Zingoni, Zvifadzo; Koekemoer, Lizette L ...
Malaria journal,
05/2021, Volume:
20, Issue:
1
Journal Article, Web Resource
Peer reviewed
Open access
Abstract
Background
Mosquito species from the
Anopheles gambiae
complex and the
Anopheles funestus
group are dominant African malaria vectors. Mosquito microbiota play vital roles in physiology and ...vector competence. Recent research has focused on investigating the mosquito microbiota, especially in wild populations. Wild mosquitoes are preserved and transported to a laboratory for analyses. Thus far, microbial characterization post-preservation has been investigated in only
Aedes vexans
and
Culex pipiens
. Investigating the efficacy of cost-effective preservatives has also been limited to AllProtect reagent, ethanol and nucleic acid preservation buffer. This study characterized the microbiota of African
Anopheles
vectors:
Anopheles arabiensis
(member of the
An. gambiae
complex) and
An. funestus
(member of the
An. funestus
group), preserved on silica desiccant and RNA
later
®
solution.
Methods
Microbial composition and diversity were characterized using culture-dependent (midgut dissections, culturomics, MALDI-TOF MS) and culture-independent techniques (abdominal dissections, DNA extraction, next-generation sequencing) from laboratory (colonized) and field-collected mosquitoes. Colonized mosquitoes were either fresh (non-preserved) or preserved for 4 and 12 weeks on silica or in RNA
later
®
. Microbiota were also characterized from field-collected
An. arabiensis
preserved on silica for 8, 12 and 16 weeks.
Results
Elizabethkingia anophelis
and
Serratia oryzae
were common between both vector species, while
Enterobacter cloacae
and
Staphylococcus epidermidis
were specific to females and males, respectively. Microbial diversity was not influenced by sex, condition (fresh or preserved), preservative, or preservation time-period; however, the type of bacterial identification technique affected all microbial diversity indices.
Conclusions
This study broadly characterized the microbiota of
An. arabiensis
and
An. funestus
. Silica- and RNA
later
®
-preservation were appropriate when paired with culture-dependent and culture-independent techniques, respectively. These results broaden the selection of cost-effective methods available for handling vector samples for downstream microbial analyses.
Sorafenib is an oral anticancer agent targeting Ras-dependent signaling and angiogenic pathways. A phase I trial demonstrated that the combination of gemcitabine and sorafenib was well tolerated and ...had activity in advanced pancreatic cancer (APC) patients. The BAYPAN study was a multicentric, placebo-controlled, double-blind, randomized phase III trial comparing gemcitabine/sorafenib and gemcitabine/placebo in the treatment of APC.
The patient eligibility criteria were locally advanced or metastatic pancreatic adenocarcinoma, no prior therapy for advanced disease and a performance status of zero to two. The primary end point was progression-free survival (PFS). The patients received gemcitabine 1000 mg/m2 i.v., weekly seven times followed by 1 rest week, then weekly three times every 4 weeks plus sorafenib 200 mg or placebo, two tablets p.o., twice daily continuously.
Between December 2006 and September 2009, 104 patients were enrolled on the study (52 pts in each arm) and 102 patients were treated. The median and the 6-month PFS were 5.7 months and 48% for gemcitabine/placebo and 3.8 months and 33% for gemcitabine/sorafenib (P = 0.902, stratified log-rank test), respectively. The median overall survivals were 9.2 and 8 months, respectively (P = 0.231, log-rank test). The overall response rates were similar (19 and 23%, respectively).
The addition of sorafenib to gemcitabine does not improve PFS in APC patients.
The Democratic Republic of the Congo (DRC) is characterized as a holoendemic malaria area with the main vectors being Anopheles funestus and members of the Anopheles gambiae complex. Due to political ...instability and socio-economic challenges in the region, knowledge of insecticide resistance status and resistance mechanisms in these vectors is limited. Mosquitoes were collected from a mining site in the north-eastern part of the country and, following identification, were subjected to extensive testing for the target-site and biochemical basis of resistance. Quantitative real-time PCR was used to assess a suite of 10 genes frequently involved in pyrethroid and dichlorodiphenyltrichloroethane (DDT) resistance in An. gambiae females and males. In An. funestus, gene expression microarray analysis was carried out on female mosquitoes.
In both species, deltamethrin resistance was recorded along with high resistance and suspected resistance to DDT in An. gambiae and An. funestus, respectively. A total of 85% of An. gambiae carried the kdr mutations as either homozygous resistant (RR) (L1014S, L1014F or both) or heterozygous (RS), however only 3% carried the rdl mutant allele (RS) and no ace-1 mutations were recorded. Synergist assays indicated a strong role for P450s in deltamethrin resistance in both species. In An. gambiae, analysis of transcription levels showed that the glutathione-S-transferase, GSTS1-2, produced the highest fold change in expression (7.6-fold in females and 31-fold in males) followed by GSTE2, thioredoxin peroxidase (TPX2), and cytochrome oxidases (CYP6M2 and CYP6P1). All other genes tested produced fold change values below 2. Microarray analysis revealed significant over-transcription of cuticular proteins as well as CYP6M7, CYP6P9a and CYP6P9b in insecticide resistant An. funestus.
These data show that high levels of deltamethrin resistance in the main malaria vector species, conferred by enzymatic detoxification, are present in the DRC.
The role of chemotherapy has not been established in the treatment of metastatic squamous cell oesophageal cancer (mESCC).
E-DIS is a discontinuation trial, aimed at estimating efficacy, quality of ...life and safety of chemotherapy continuation (CT-CONT) in patients with mESCC who are free from progression after a selection phase of chemotherapy. The primary end-point was overall survival.
Sixty-seven patients were randomised. The 9-month survival rate was 50% (85% confidence interval CI: 37–62%) and 48% (85% CI: 35–60%) in the CT-CONT arm and in the chemotherapy discontinuation (CT-DISC) arm, respectively. The time until definitive deterioration of the global health status (European Organisation for Research and Treatment of Cancer EORTC core quality of life questionnaire) was 6.6 months (95% CI: 3.3–12.4) for the CT-CONT arm and 4.2 months (95% CI: 2.9–6.3) for the CT-DISC arm, with a hazard ratio (HRCT-DISC/CT-CONT) = 1.44 (95% CI: 0.82–2.53). We observed a beneficial trend in favour of CT-CONT (HR > 1) for most dimensions, including an improvement for three dimensions (dysphagia, eating and oesophageal pain) of the EORTC Oesophageal Cancer Module QLQ-OES18.
CT-CONT provides an overall survival rate that is similar to CT-DISC. E-DIS trial provides valuable data to support shared decision-making between physicians and patients regarding CT-CONT/DISC.
•The efficacy of chemotherapy in the treatment of metastatic oesophageal squamous carcinoma has not been demonstrated so far.•In this setting, chemotherapy until progression provides a 9-month survival rate that is similar to chemotherapy interruption.•Chemotherapy until progression is associated with a numerically extended delay in the worsening of some symptoms.
Abstract Background Diagnosis and management of poorly differentiated gastro-entero-pancreatic (GEP) neuroendocrine carcinomas (NECs) remain challenging. Recent studies suggest prognostic ...heterogeneity. We designed within the French Group of Endocrine Tumours a prospective cohort to gain insight in the prognostic stratification and treatment of GEP-NEC. Patients and methods All patients with a diagnosis of GEP-NEC between 1st January 2010 and 31st December 2013 could be included in this national cohort. Adenoneuroendocrine tumours were excluded. Results 253 patients from 49 centres were included. Median age was 66 years. Main primary locations were pancreas (21%), colorectal (27%), oesophagus-stomach (18%); primary location was unknown in 20%. Tumours were metastatic at diagnosis in 78% of cases. Performance status (PS) at diagnosis was 0–1 in 79% of patients. Among the 147 (58%) cases reviewed by an expert pathological network, 39% were classified as small cell NEC and 61% as large cell NEC. Median Ki67 index was 75% (range, 20–100). Median overall survival was 15.6 (13.6–17.0) months. Significant adverse prognostic factors in univariate analysis were PS > 1 (hazard ratio HR = 2.5), metastatic disease (HR = 1.6), NSE > 2 upper limit of normal ULN; HR = 3.2), CgA > 2 ULN (HR = 1.7) and lactate dehydrogenase >2 ULN (HR = 2.1). After first-line palliative chemotherapy (CT1) with platinum-etoposide (n = 152), objective response, progression-free survival and overall survival were 50%, 6.2 and 11.6 months; they were 24%, 2.9 and 5.9, respectively, after post-CT1 FOLFIRI regimen (n = 72). Conclusions We report a large prospective series of GEP-NEC which show the predominance of large cell type and advanced stage at diagnosis. Prognosis was found more homogeneous than previously reported, mainly impacted by PS and tumour burden.
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