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Cancer progression is driven in part by genomic alterations1. The genomic characterization of cancers has shown interpatient heterogeneity regarding driver alterations2, leading to the concept that generation of genomic profiling in patients with cancer could allow the selection of effective therapies3,4. Although DNA sequencing has been implemented in practice, it remains unclear how to use its results. A total of 1,462 patients with HER2-non-overexpressing metastatic breast cancer were enroled to receive genomic profiling in the SAFIR02-BREAST trial. Two hundred and thirty-eight of these patients were randomized in two trials (nos. NCT02299999 and NCT03386162) comparing the efficacy of maintenance treatment5with a targeted therapy matched to genomic alteration. Targeted therapies matched to genomics improves progression-free survival when genomic alterations are classified as level I/II according to the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT)6(adjusted hazards ratio (HR): 0.41, 90% confidence interval (CI): 0.27–0.61, P< 0.001), but not when alterations are unselected using ESCAT (adjusted HR: 0.77, 95% CI: 0.56–1.06, P= 0.109). No improvement in progression-free survival was observed in the targeted therapies arm (unadjusted HR: 1.15, 95% CI: 0.76–1.75) for patients presenting with ESCAT alteration beyond level I/II. Patients with germline BRCA1/2mutations (n= 49) derived high benefit from olaparib (gBRCA1: HR = 0.36, 90% CI: 0.14–0.89; gBRCA2: HR = 0.37, 90% CI: 0.17–0.78). This trial provides evidence that the treatment decision led by genomics should be driven by a framework of target actionability in patients with metastatic breast cancer.

L’instabilité génomique est une des caractéristiques centrales du développement tumoral favorisant, initialement, l’acquisition d’altérations génétiques promouvant la carcinogenèse. Puis, la prolifération chronique et rapide des cellules cancéreuses contribue également à cette instabilité favorisant un auto-entretien et une évolution tumorale continuelle. L’accumulation de mutations en résultant contribue à l’hétérogénéité tumorale et s’inscrit dans un environnement précis. Ainsi, la diversité des mutations oncogéniques rend alors plus difficile la caractérisation de l’origine du dysfonctionnement dans la cellule tumorale, indispensable à la décision thérapeutique. Pourtant, la prise en considération du contexte moléculaire en oncologie a initié le développement de thérapies dites « ciblées ». Basés sur les concepts d’addiction oncogénique et de létalité synthétique, ces nouveaux médicaments requièrent la caractérisation de biomarqueurs spécifiques prédictifs de leur efficacité. Les thérapies ciblées ont ainsi considérablement optimisé la prise en charge des patients, améliorant la survie globale de certains cancers avec, souvent, un profil de tolérance meilleure que les chimiothérapies conventionnelles. Cependant, malgré les bénéfices cliniques considérables, certaines limitations majeures à leur administration demeurent. L’étude des enjeux actuels associés à ce type de molécules thérapeutiques devient capitale pour une amélioration de la prise en charge des patients vers une médecine toujours plus personnalisée.

La détection des altérations génétiques du domaine tyrosine kinase de l’EGFR est un enjeu majeur dans la prise en charge des cancers bronchiques non à petites cellules, car elle conditionne l’accès aux inhibiteurs de tyrosine kinase. En pratique, il est possible de faire une caractérisation restreinte aux mutations bien documentées ou de séquencer tous les exons concernés de l’EGFRet aussi d’autres cibles d’intérêt théranostique. Cette étude prospective compare la caractérisation ciblée de l’EGFRsur automate Idylla (Biocartis) ou plus étendue par séquençage nouvelle génération par la technologie Ion Torrent.

5-Fluorouracil (5-FU)–based treatments can lead to early-onset severe (4%–5%) even fatal (0.3%) toxicities in patients with dihydropyrimidine dehydrogenase (DPD) deficiency. This multicenter prospective cohort study aimed to assess the clinical benefit of pretherapeutic screening for DPD deficiency using a multiparametric approach. Two parallel cohorts of patients treated with 5-FU–based chemotherapy for colorectal carcinoma were compared in a prospective nonrandomized study. In arm A, patients had DPD deficiency screening before treatment, whereas in arm B no pretherapy screening was performed. Dosing was based on 5-FU administration guidelines of each institution. DPD deficiency screening was performed using a combined multiparametric approach (5-FUODPM Tox). The frequency of early grade 4–5 toxic events potentially induced by 5-FU was compared in the two groups. At total of 1,142 patients (n = 1,116 evaluable) were enrolled. In arm A, out of 718 evaluable patients, nine grade 4 early toxicities potentially related to 5-FU were reported in nine patients (1.2%) with no toxic death despite one complete DPD deficiency and 24 partial deficiencies. The 24 patients with partial deficiency had safe pharmacokinetics (PK)-monitored 5-FU. In arm B, among 398 evaluable patients, 17 grade 4–5 toxic early events potentially related to 5-FU were reported in 12 patients (4.2%). The incidence of early severe toxicity was significantly higher in arm B (P= .0019), confirming the positive impact of pretherapeutic DPD assessment. The percent of patients with a toxicity grade 3 or higher observed in arm A was 10.8% (n = 78) compared to 17.55% (n = 69)  in arm B (P= .0497). The percentage of death was reduced from 2.5/1,000 in arm B to 0 in arm A. The time to occurrence of all grade ≥3 toxicities was determined in both arms and the difference between the two arms was significant (P= .047). Overall, one patient with complete DPD deficiency confirmed retrospectively died within 13 days from grade 5 multivisceral toxicity. Enrollment was prematurely closed after external experts’ decision. In conclusion, multiparametric pretherapeutic DPD deficiency screening significantly lowered the risk of early severe toxicity and avoided an early toxic death. This approach should be used for safe administration of 5-FU–based treatments.

We conducted a multicenter proof of concept phase II trial in patients with advanced colorectal cancer receiving FOLFIRI-cetuximab regimens to explore individual drug tailoring using pharmacogenetics and pharmacokinetics (PK) monitoring. Patients were stratified by their pharmacogenetic/phenotypic status: the irinotecan dose was adjusted according to the number of TA tandem repeats in the UGT1A1 promoter, while the 5-fluorouracil (5-FU) dose was initially adjusted according to dihydropyrimidine dehydrogenase (DPD) activity at initial screening (5-FUODPM Tox) followed by PK-guided dose optimization (5-FUODPM Protocol). An advanced cetuximab PK/pharmacodynamics (PD) study was performed but dosage remained unchanged. Eighty-five patients receiving second-line chemotherapy were enrolled. Mean irinotecan doses at 3 months were 247 ± 50, 210 ± 53 and 140 ± 21 mg/m2for those with 6/6 (33), 6/7 (26), and 7/7 (7) TATA repeats in the UGT1A1 promoter region, respectively. The 5-FU dose was initially reduced in four patients with DPD deficiency, but mean 5-FU dose at 3 months was 2,412 ± 364 mg/m2(1,615–3,170 mg/m2). Grade 4 toxicities were not encountered and grade 4 neutropenia occurred in 6.8%, 5.9%, and 0% of patients with 6/6, 6/7, and 7/7 UGT1A1 genotypes. The objective response rate was 25.8% among the 85 patients, 57.3% in patients with tumors wild type (WT) for KRAS, and 25% in those whose tumor harbored a mutant-KRAS. Secondary resection of hepatic metastases was performed in 31.7% of patients. Median progression-free survival (PFS) for all 85 patients was 181 days and 200, 132, and 121 days for patients with 6/6, 6/7, and 7/7 UGT1A1 genotypes, respectively; these differences were not statistically different. In parallel, a strong relationship was shown between cetuximab AUC and regimen efficacy. We conclude that personalized drug tailoring when administering in FOLFIRI + cetuximab allows for safe and efficient individual dose intensification.

La première édition du code RCC-MR, ensemble de règles complètes et précises relatives à la conception, à la fabrication et au contrôle des chaudières de réacteurs à neutrons rapides, date de l'été 1985. Les auteurs analysent les actions de recherche et développement engagées dans ce cadre illustrant la communication indispensable entre la codification et la R et D.

Background: Although methadone maintenance treatment (MMT) is recognized as the treatment of reference for opioid dependence, little information is available regarding the dynamic adherence to methadone and its determinants. With data from the Methaville trial we investigated the evolution of non-adherence to methadone and the effect of pre-treatment and in-treatment factors on longterm non-adherence to methadone. Methods: We selected 145 patients to study adherence to methadone at 3, 6 and 12 months (M3, M6 and M12, respectively) using a multidimensional questionnaire and a 3-level variable “adherent”/”non adherent”/”highly nonadherent”. We then identified the pre-treatment and in-treatment variables associated with long-term non-adherence to methadone at the M12 visit using a univariate logistic regression and two different multivariate models: the first incorporating only the pre-treatment variables, the second adding the in-treatment variables to the pre-treatment ones. Results: At the M12 visit, 35.2% of the participants remained adherent, 55.9% and 9% were non-adherent and highly non-adherent, respectively. The multivariate analysis of long-term non-adherence to methadone showed 4 pre-treatment predictors and 1 in-treatment predictor as follows: being female, not having stable housing, alcohol consumption, cocaine use and perceiving methadone dose as inadequate. Conclusions: Our findings highlight that pretreatment predictors are important to consider when starting maintenance treatment for opioid dependence, such as cocaine use and problematic alcohol consumption but also low socio-economic levels. In addition, during maintenance treatment, in-treatment predictors such as methadone dose adequacy is a crucial issue to achieve good adherence to MMT.

SUMMARY 5-fluorouracil (5-FU) is widely used in chemotherapeutic treatments of solid tumors. However, adverse events after its administration occur in about 30% of patients. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in the 5-FU catabolic pathway: several studies have focused on its genetics and/or pharmacokinetics in order to explain the wide interpatient variability in the DPD activity, including the rare event of its complete absence of activity. The pretreatment screening for DPD activity with a multiparametric approach (genotyping, phenotyping, clinico–pathological characteristics) shows the greatest specificity and sensitivity to avoid severe early-onset toxicity to fluoropyrimidines. In addition, using the pharmacokinetics of 5-FU, the dose adaptation can be used to properly dose each cycle for optimal efficacy and reduction of early-onset toxicities.

Utility partnerships with small-scale providers (SSPs) are becoming increasingly important as utilities struggle to serve a growing population and the poor in particular. This article explores a delegated management approach as one type of partnership, in which 'master opererators' purchase bulk supplies of water and are then responsible for collecting in water payments from their customers, and introduces the case study of this approach in Nyalenda, the largest slum of Kisumu, Kenya. The authors explore why such partnership innovations in service delivery are needed and what the impact has been on the Kisumu Water and Sewerage Company and on consumers. Here 'unaccounted-for' water has decreased dramatically as both the master operators as well as the utility share an interest in preventing illegal connections. The authors also provide recommendations for the scale-up of this approach in Kisumu and the replication of the delegated management model in other cities facing similar challenges to improve services to the poor.

De nombreuses toxicités, parfois sévères sont rapportées chez les patients traités par du 5-fluorouracile (5-FU) mais aussi avec les fluoropyrimidines orales disponibles, l’UFT® et la capécitabine, en situation conventionnelle, adjuvante ou métastatique. Ces effets toxiques sont dus à une large variabilité interindividuelle du métabolisme, dépendant principalement de l’activité de la dihydropyrimidine déhydrogénase (DPD) l’enzyme majeure de catabolisme du 5-FU. Ainsi, les patients présentant un déficit de l’activité de cette enzyme ont un risque accru de toxicité aiguë, précoce et grave avec cette famille de médicaments. Ces toxicités peuvent aboutir à une toxicité polyviscérale grave, potentiellement mortelle. Les fréquences de déficits en DPD, partiels ou complets, sont estimées à 3–5 % et 0,2 % respectivement, et leur existence est le plus souvent liée à un polymorphisme d’origine génétique. Différentes techniques de détection de tels déficits avant tout traitement ont été décrites : phénotypiques, telles que le rapport plasmatique dihydoruracile/uracile, ou génotypiques, telles que la recherche de variants par génotypage ciblé du gène de la DPD retentissant sur l’activité de l’enzyme. Le dépistage génétique préthérapeutique systématique des patients porteurs d’un tel déficit, en lui-même totalement asymptomatique, permettrait d’éviter la quasi-totalité des effets toxiques aigus sévères. Cependant, il ne s’agit pas alors d’un simple rendu de résultats, de présence ou d’absence de déficit enzymatique puisque la découverte d’un déficit métabolique ne contre-indique que rarement l’utilisation du médicament. Ce dépistage doit s’accompagner d’un véritable conseil thérapeutique.

CNS-resident macrophages (microglia and CNS-associated macrophages) are the main immunocompetent cells of the central nervous system (CNS) and respond by rapid activation to brain injury. Molecular events occurring during IFNγ-activation and identification of potential markers of the CNS-resident macrophage subsets were investigated using microglial-derived clones (EOC) differing in their morphology and their antigen presenting activities for CD4+and CD8+T-cells. By applying the subtractive process of cDNA representational difference analysis (cRDA), 16 differentially expressed mRNAs were isolated and sequenced, revealing 8 known and 8 novel molecules; 15 of these messages were unpreviously reported in microglia. Two markers of all activated microglial EOC cells were identified (iNOS; IRG-1) and specific subpopulation markers were highlighted, including molecules known to be closely expressed in perivascular spaces. Moreover, some messages could support the distinct morphology, adhesive characteristics, and potential functions of the different clones.

The structural requirements for internalization and signalling of the vasopressin V1a receptor were investigated in stably transfected HEK‐293 cells. Removal of the 51 C‐terminal amino acids did not affect vasopressin binding, calcium signalling, heterologous desensitization or internalization of the receptor. Deletion of 14 additional amino acids reduced vasopressin‐dependent calcium increase and impaired receptor internalization. Substitution of cysteines 371‐372 did not affect intracellular signalling, but decreased endocytosis by 26%. Substitution of the 361‐362 leucine by alanine residues reduced by 56% V1a receptor sequestration without affecting calcium signalling. These results indicate that di‐cysteine and mostly di‐leucine motifs present in the C‐terminal region of the V1a receptor are involved in its internalization.

A new somatostatin-28 has been isolated from the Teleostean fish ( Lophius piscatorius) Brockmann organs. Determination of its aminoacid sequence indicates that it corresponds to an octacosapeptide containing in its C-terminal end the Tyr-7 Gly-10 derivative of somatostatin-14 I. This structure is in agreement with the one predicted by Hobart et al. (Nature (1980) 288, 137-141) from a cDNA nucleotide sequence. It demonstrates that, since the corresponding somatostatin-14 II cannot be detected in this organ, S-28 II is a terminal product of prosomatostatin II processing in anglerfish pancreatic islets.

The in vivo incorporation of [3H]phenylalanine into an apparent 15 kDa prosomatostatin was observed in the hypothalamus of rats injected with the labeled amino acid in the third ventricle. Precursor‐product relationships were established between this newly synthesized material and both somatostatin‐28 and ‐14.

Abstract: Expression and regulation of vasopressin V2 and V1a receptors were studied at the mRNA level in the rat kidney. Two V2 mRNA variants were identified and shown to arise from a single gene by alternative splicing using one donor and two different acceptor sites. The long (V2L) form encodes the adenylyl cyclase-coupled receptor. The short (V2S) form lacks the nucleotide sequence encoding the putative seventh transmembrane domain and undergoes a frame shift in its 3'end coding region; it is inactive on the cyclase pathway in transfected cells. Measurement of mRNAs, carried out by quantitative reverse transcription-polymerase chain reaction (RT-PCR) on microdissected nephrons, demonstrated that neither V2L, V2S nor V1A mRNAs are expressed in glomeruli and proximal tubules (<100 mRNA copies/glomerulus or mm of tubular length), whereas they are present in the ascending limb of Henle's loop and in the collecting tubule. The V2L mRNA, which is always predominant in these structures, is expressed throughout the collecting tubule at 10 times higher levels (30,000 copies/mm) than in the thin and thick ascending limbs. The ratio of the V2S over V2L mRNA is constant (15%) in all nephron segments; hence high V2S levels are only observed in the collecting tubule. The V1A mRNA is slightly expressed in the thin ascending limb, absent in the thick ascending limb and reaches its maximum in the cortical collecting duct (4,000 copies/mm), before gradually decreasing to undetectable levels in the terminal collecting duct. Finally, in vivo administration of a vasopressin V2 agonist decreased by 50% V2L and V2S mRNAs, but did not alter the V1A mRNA level. We conclude that this study provides the quantitation, on a molar basis, of vasopressin receptor mRNAs in kidney tubules and demonstrates the occurence of two V2 mRNA spliced variants which are similarly down-regulated.

The in vivo incorporation of [ 3H]phenylalanine into an apparent 15 kDa prosomatostatin was observed in the hypothalamus of rats injected with the labeled amino acid in the third ventricle. Precursor-product relationships were established between this newly synthesized material and both somatostatin-28 and -14.

The role of protein kinase C activation and carboxyl‐terminal region in rapid desensitization of the vasopressin V1a receptor was investigated in Xenopusoocytes. Preincubation of the oocytes with vasopressin or with the diacylglycerol analog 1‐oleoyl‐2‐acetyl‐sn‐glycerol (OAG), or direct injection of active protein kinase C, all blunted the calcium response of the V1a receptor. Truncation of the 51 terminal amino acids (S374STOP) modified neither the intracellular calcium response to vasopressin nor its desensitization by vasopressin or OAG. These data suggest that desensitization of the V1a receptor is mediated by PKC activation and that its carboxyl‐terminal domain is not required for signal transduction and rapid desensitization.

Cross-talk between the phospholipase C and adenylyl cyclase signalling pathways was investigated in Chinese hamster ovary (CHO) cells transfected with the V1a and V2 vasopressin receptors. Cell lines expressing V1a, V2, or both V1a and V2 receptors, were established and characterized. Stimulation of V2 receptors by vasopressin induced a dose-dependent increase in cAMP accumulation, whereas stimulation of V1a receptor resulted in an increase in intracellular calcium without any change in basal cAMP. The simultaneous stimulation of V2 and V1a receptors by vasopressin elicited an intracellular cAMP accumulation which was twice that induced by stimulation of V2 receptor alone with deamino-[D-Arg8]vasopressin. This potentiation between V1a and V2 receptors was mimicked by activation of protein kinase C (PKC) with PMA, and was suppressed when PKC activity was inhibited by bisindolylmaleimide. The potentiation was observed in the presence or absence of 1 mM 3-isobutyl-1-methylxanthine, a phosphodiesterase inhibitor, implying that an alteration in cAMP hydrolysis was not involved. Vasopressin, as well as PMA, had no effect on the forskolin-induced cAMP accumulation, suggesting that PKC did not directly stimulate the cyclase activity. On the other hand, vasopressin, like PMA, potentiated the cAMP accumulation induced by cholera toxin, an activator of Gαs protein. These results suggest that, in CHO cells, vasopressin V1a receptor potentiates the cAMP accumulation induced by the V2 receptor through a PKC-dependent increase in the coupling between Gs protein and adenylyl cyclase.

A new somatostatin‐28 has been isolated from the Teleostean fish (Lophius piscatorius) Brockmann organs. Determination of its aminoacid sequence indicates that it corresponds to an octacosapeptide containing in its C‐terminal end the Tyr‐7 Gly‐10 derivative of somatostatin‐14 I. This structure is in agreement with the one predicted by Hobart et al. (Nature (1980) 288, 137‐141) from a cDNA nucleotide sequence. It demonstrates that, since the corresponding somatostatin‐14 II cannot be detected in this organ, S‐28 II is a terminal product of prosomatostatin II processing in anglerfish pancreatic islets.

Ausgehend von morphologischen und sedimentologischen Befunden im Nigertal, im Tal des Azawagh und im Airgebirge läßt sich eine Abfolge paläoklimatischer Phasen von feuchttropischen tertiären zu ariden quartären Klimaten unterscheiden. Sie entsprechen denen, die schon aus anderen Teilen Westafrikas, von Senegal bis zum Tchad, bekannt sind. Dank K/Ar-Datierungen an Basaltlaven des Air, die das Altrelief überdecken, lassen sich diese Phasen zeitlich festlegen. Die Rumpffläche, in die die Täler eingetieft sind, wurde bis vor 3.8 Mill. Jahren BP gebildet. Die Erosion war zuerst schnell, dann langsamer, aber immer unter dem Einfluß jahreszeitlich kontrastierender Klimate. Feuchtere und trockenere Phasen wechselten sich ab und bedingten entweder Bodenbildung oder Erosion. Die erste aride Phase liegt vor dem Ende des Pliozän, aber Klimate, unter denen Hydrolyse der vorherrschende Verwitterungsprozeß war, gab es auch noch zu Anfang des unteren Pleistozän: 2 Mill. J. alte Basaltflüsse zeigen noch mäßige chemische Verwitterung; solche, die auf 1 Mill. J. datiert worden sind, erscheinen unverändert. Eine extreme Tiefenerosion, bedingt durch torrentiellen Abfluß, war noch bis vor etwa 1 Mill. J. wirksam. Insgesamt ist das Klima zunehmend trockener geworden, aber diese Entwicklung vollzog sich im Wechsel von humiden und ariden Phasen.

Group R streptococci have caused many cases of septicaemia and meningitis in patients handling live or slaughtered pigs which were the only known reservoir of group R streptococci. A human case, due to a wild boar, is reported here and it is therefore concluded that there exist both a domestic (pig) and a wild (wild boar) reservoir of group R streptococci.

Group R streptococci have caused many cases of septicaemia and meningitis in patients handling live or slaughtered pigs which were the only known reservoir of group R streptococci. A human case, due to a wild boar, is reported here and it is therefore concluded that there exist both a domestic (pig) and a wild (wild boar) reservoir of group R streptococci.

Expression profiles represent new molecular tools that are useful to characterize the successive steps of tumor progression and the prediction of recurrence or chemotherapy response. In this study, we have used quantitative proteomic analysis to compare different stages of colorectal cancer. A combination of laser microdissection, OFFGEL separation, iTRAQ labeling, and MALDI-TOF/TOF MS was used to explore the proteome of 28 colorectal cancer tissues. Two software packages were used for identification and quantification of differentially expressed proteins: Protein Pilot and iQuantitator. Based on ∼1,190,702 MS/MS spectra, a total of 3138 proteins were identified, which represents the largest database of colorectal cancer realized to date and demonstrates the value of our quantitative proteomic approach. In this way, individual protein expression and variation have been identified for each patient and for each colorectal dysplasia and cancer stage (stages I–IV). A total of 555 proteins presenting a significant fold change were quantified in the different stages, and this differential expression correlated with immunohistochemistry results reported in the Human Protein Atlas database. To identify a candidate biomarker of the early stages of colorectal cancer, we focused our study on secreted proteins. In this way, we identified olfactomedin-4, which was overexpressed in adenomas and in early stages of colorectal tumors. This early stage overexpression was confirmed by immunohistochemistry in 126 paraffin-embedded tissues. Our results also indicate that OLFM4 is regulated by the Ras-NF-κB2 pathway, one of the main oncogenic pathways deregulated in colorectal tumors.

Expression profiles represent new molecular tools that are useful to characterize the successive steps of tumor progression and the prediction of recurrence or chemotherapy response. In this study, we have used quantitative proteomic analysis to compare different stages of colorectal cancer. A combination of laser microdissection, OFFGEL separation, iTRAQ labeling, and MALDI-TOF/TOF MS was used to explore the proteome of 28 colorectal cancer tissues. Two software packages were used for identification and quantification of differentially expressed proteins: Protein Pilot and iQuantitator. Based on ∼1,190,702 MS/MS spectra, a total of 3138 proteins were identified, which represents the largest database of colorectal cancer realized to date and demonstrates the value of our quantitative proteomic approach. In this way, individual protein expression and variation have been identified for each patient and for each colorectal dysplasia and cancer stage (stages I–IV). A total of 555 proteins presenting a significant fold change were quantified in the different stages, and this differential expression correlated with immunohistochemistry results reported in the Human Protein Atlas database. To identify a candidate biomarker of the early stages of colorectal cancer, we focused our study on secreted proteins. In this way, we identified olfactomedin-4, which was overexpressed in adenomas and in early stages of colorectal tumors. This early stage overexpression was confirmed by immunohistochemistry in 126 paraffin-embedded tissues. Our results also indicate that OLFM4 is regulated by the Ras-NF-κB2 pathway, one of the main oncogenic pathways deregulated in colorectal tumors.