Discovery of lirafugratinib (RLY-4008), a highly selective irreversible small-molecule inhibitor of FGFR2.

Fibroblast growth factor receptor (FGFR) kinase inhibitors have been shown to be effective in the treatment of intrahepatic cholangiocarcinoma and other advanced solid tumors harboring FGFR2 alterations, but the toxicity of these drugs frequently leads to dose reduction or interruption of treatment such that maximum efficacy cannot be achieved. The most common adverse effects are hyperphosphatemia caused by FGFR1 inhibition and diarrhea due to FGFR4 inhibition, as current therapies are not selective among the FGFRs. Designing selective inhibitors has proved difficult with conventional approaches because the orthosteric sites of FGFR family members are observed to be highly similar in X-ray structures. In this study, aided by analysis of protein dynamics, we designed a selective, covalent FGFR2 inhibitor. In a key initial step, analysis of long-timescale molecular dynamics simulations of the FGFR1 and FGFR2 kinase domains allowed us to identify differential motion in their P-loops, which are located adjacent to the orthosteric site. Using this insight, we were able to design orthosteric binders that selectively and covalently engage the P-loop of FGFR2. Our drug discovery efforts culminated in the development of lirafugratinib (RLY-4008), a covalent inhibitor of FGFR2 that shows substantial selectivity over FGFR1 (~250-fold) and FGFR4 (~5,000-fold) in vitro, causes tumor regression in multiple FGFR2-altered human xenograft models, and was recently demonstrated to be efficacious in the clinic at doses that do not induce clinically significant hyperphosphatemia or diarrhea.

[Targeted newborn screening for sickle-cell anemia: Sickling test (Emmel test) boundaries in the prenatal assessment in West African area]. / Dépistage néonatal ciblé de la drépanocytose : limites du test de falciformation (test d'Emmel) dans le bilan prénatal en zone ouest africaine.

BACKGROUND: Newborn screening for sickle cell anemia is necessary in Africa where the disease is more frequent. Hemoglobin electrophoresis is used for screening, but is limited by a high cost and difficult access. Sickling test (Emmel test), which is more affordable and technically more accessible, is often requested for prenatal assessment of pregnant women in West African areas to reserve screening for newborns from mothers in whom the positive sickling test attests the presence of hemoglobin S. This study aims to evaluate the number of undetected sickle cell anemia newborns by a screening policy targeting only newborns from mothers in whom a sickling test would have been positive. METHODS: From 2010 to 2012, in Bamako, Mali, West Africa, 2489 newborns were routinely screened for sickle cell anemia at the umbilical cord or heel by isoelectrofocusing and, if necessary, by high-performance liquid chromatography. These newborns were born from 2420 mothers whose hemoglobin was studied by isoelectrofocusing. The data was recorded and processed using Excel software version 14.0.0. We calculated the frequency of the sickle cell gene in mothers and newborns as well as the number of SCA newborns from heterozygous or C homozygous mothers. RESULTS: Of the 2489 newborns, 16 had sickle cell anemia (6 SS and 10 SC); 198 had the sickle cell trait; 139 were AC and 1 was CC. Of the 10 newborns with SC profile, 3 were born from mothers not carrying the S gene but the C gene of hemoglobin and in which an Emmel test would have been negative. CONCLUSION: Targeted newborn screening, based on the results of sickling test in pregnant women, would misdiagnose more than one of six sickle cell anemia newborns who would not benefit from early care. Cost-effectiveness studies of routine newborn screening for sickle cell anemia should lead to a better screening strategy in contexts where hemoglobin S and other hemoglobin defect genes coexist.

[Fortuitous discovery of a Stafne bone cavity in the Cone Beam CT sialography]. / Découverte fortuite d'une lacune de Stafne à la sialographie Cone Beam CT.

The Stafne defect is a benign, asymptomatic, non-progressive and rare bone depression, mainly discovered by chance in the posterior mandibular region. It is described radiographically as an oval radiolucency located below the mandibular canal, in the molar region, close to the submandibular gland. Sialography is a traditional technique in the radiographic examination of salivary glands that involves the injection of an iodine-based contrast medium into the main salivary duct. The Cone Beam Computed Tomography (CBCT) is a 3D imaging technique that has modernized the dental and maxillofacial practice with its advantages such as high speed, good spatial resolution and low radiation exposure. The CBCT Sialography that consists in a 3D Sialography with cone beam offers the same benefits as traditional sialography and allows three-dimensional viewing. It is a new imaging test for an accurate anatomical study of the major salivary glands and their relationships with their environments. The aim of this report is to present a case of Stafne bone cavity containing right submandibular gland tissue, occurring in a 58-year-old man and diagnosed by using CBCT sialography.

Accessing Drug Metabolites via Transition-Metal Catalyzed C-H Oxidation: The Liver as Synthetic Inspiration.

Can classical and modern chemical C-H oxidation reactions complement biotransformation in the synthesis of drug metabolites? We have surveyed the literature in an effort to try to answer this important question of major practical significance in the pharmaceutical industry. Drug metabolites are required throughout all phases of the drug discovery and development process; however, their synthesis is still an unsolved problem. This Review, not intended to be comprehensive or historical, highlights relevant applications of chemical C-H oxidation reactions, electrochemistry and microfluidic technologies to drug templates in order to access drug metabolites, and also highlights promising reactions to this end. Where possible or appropriate, the contrast with biotransformation is drawn. In doing so, we have tried to identify gaps where they exist in the hope to spur further activity in this very important research area.

Complementation of biotransformations with chemical C-H oxidation: copper-catalyzed oxidation of tertiary amines in complex pharmaceuticals.

The isolation, quantitation, and characterization of drug metabolites in biological fluids remain challenging. Rapid access to oxidized drugs could facilitate metabolite identification and enable early pharmacology and toxicity studies. Herein, we compared biotransformations to classical and new chemical C-H oxidation methods using oxcarbazepine, naproxen, and an early compound hit (phthalazine 1). These studies illustrated the low preparative efficacy of biotransformations and the inability of chemical methods to oxidize complex pharmaceuticals. We also disclose an aerobic catalytic protocole (CuI/air) to oxidize tertiary amines and benzylic CH's in drugs. The reaction tolerates a broad range of functionalities and displays a high level of chemoselectivity, which is not generally explained by the strength of the C-H bonds but by the individual structural chemotype. This study represents a first step toward establishing a chemical toolkit (chemotransformations) that can selectively oxidize C-H bonds in complex pharmaceuticals and rapidly deliver drug metabolites.

[Practice of reconstructive plastic surgery of the clitoris after genital mutilation in Burkina Faso. Report of 94 cases]. / Pratique de la chirurgie plastique reconstructrice du clitoris après mutilations génitales au Burkina Faso. À propos de 94cas.

PURPOSE OF THE STUDY: To describe and evaluate the results of reconstructive plastic surgery of the clitoris in order to promote reproductive health. PATIENTS AND METHOD: We conducted a retrospective study from 2007 to 2010. Ninety-four women were included in our study. RESULTS: The mean age was 32.3 years. The evaluation of the experience of sexuality before reconstruction showed that 41.5 % of patients had never had a sexual desire before surgery, more than half did not have a clitoral orgasm and dyspareunia was experienced by about a third of them. The main reason for consultation in our series was related to sexual dysfunction in more than half of our study population. All patients were operated using the technique of Dr Pierre Foldès. Evaluation with a decline of at least 6 months after surgery showed us a massive restoration of the clitoris at 89.7 %. There was a significant difference between sexual desire before and after surgery. A significant improvement in sexuality was observed in 83.6 % of patients. However, there was no significant difference between orgasm before and after surgery. This showed us that getting an orgasm is multifactorial and it is not enough to have a clitoris to have an orgasm, you have to use it. CONCLUSION: Regardless of the anatomical and functional results, all women were satisfied with respect to body found.

RLY-4008, the First Highly Selective FGFR2 Inhibitor with Activity across FGFR2 Alterations and Resistance Mutations.

Oncogenic activation of fibroblast growth factor receptor 2 (FGFR2) drives multiple cancers and represents a broad therapeutic opportunity, yet selective targeting of FGFR2 has not been achieved. Although the clinical efficacy of pan-FGFR inhibitors (pan-FGFRi) validates FGFR2 driver status in FGFR2 fusion-positive intrahepatic cholangiocarcinoma, their benefit is limited by incomplete target coverage due to FGFR1- and FGFR4-mediated toxicities (hyperphosphatemia and diarrhea, respectively) and the emergence of FGFR2 resistance mutations. RLY-4008 is a highly selective, irreversible FGFR2 inhibitor designed to overcome these limitations. In vitro, RLY-4008 demonstrates >250- and >5,000-fold selectivity over FGFR1 and FGFR4, respectively, and targets primary alterations and resistance mutations. In vivo, RLY-4008 induces regression in multiple xenograft models-including models with FGFR2 resistance mutations that drive clinical progression on current pan-FGFRi-while sparing FGFR1 and FGFR4. In early clinical testing, RLY-4008 induced responses without clinically significant off-isoform FGFR toxicities, confirming the broad therapeutic potential of selective FGFR2 targeting. SIGNIFICANCE: Patients with FGFR2-driven cancers derive limited benefit from pan-FGFRi due to multiple FGFR1-4-mediated toxicities and acquired FGFR2 resistance mutations. RLY-4008 is a highly selective FGFR2 inhibitor that targets primary alterations and resistance mutations and induces tumor regression while sparing other FGFRs, suggesting it may have broad therapeutic potential. See related commentary by Tripathi et al., p. 1964. This article is featured in Selected Articles from This Issue, p. 1949.

Cervical human papillomavirus and HIV infection in women of child-bearing age in Abidjan, Côte d'Ivoire, 2010.

BACKGROUND: We sought to document the association of Human immunodeficiency Virus (HIV) infection and immunodeficiency with oncogenic Human Papillomavirus (HPV) infection in women with no cervical neoplastic lesions identified through a cervical cancer screening programme in Côte d'Ivoire. METHODS: A consecutive sample of women stratified on their HIV status and attending the national blood donor clinic or the closest HIV clinic was recruited during a cervical cancer screening programme based on the visual inspection. Diagnosis of HPV infection and genotype identification were based on the Linear Array; HPV test. RESULTS: A total of 445 (254 HIV-positive and 191 HIV-negative) women were included. The prevalence of oncogenic HPV infection was 53.9% (95% confidence interval (CI) 47.9-59.9) in HIV-positive women and 33.7% (95% CI 27.1-40.3) in HIV-negative women (odds ratio (OR)=2.3 (95% CI 1.5-3.3)). In multivariate analysis, HIV-positive women with a CD4 count <200 cells mm(3) or between 200 and 499 cells mm(3) were more likely to harbour an oncogenic HPV compared with women with a CD4 count ≥500 cells mm(3) with OR of 2.8 (95% CI 1.1-8.1) and 1.7 (95% CI 1.0-2.9), respectively. CONCLUSION: A high prevalence of oncogenic HPV was found in women with no cervical neoplastic lesions, especially in HIV-positive women. Despite antiretroviral use, immunodeficiency was a main determinant of the presence of oncogenic HPV.

[Medicinal plants in Senegal and oral diseases: use and interest]. / Plantes médicinales au Sénégal et affections bucco-dentaires: utilisation et intérêt.

The end of the last century and the present decade is characterized by an evolution of the concept of health and illness in the public domain. The World Health Organization defines traditional medicine as "comprising various practices, approaches, knowledge and beliefs incorporating medicinal herbal, animal and/or mineral, spiritual therapies, applied alone or in combination to maintain well-being and to treat, diagnose or prevent disease. In dentistry, the plants used are numerous. The objective of this work is to describe the herbal medicine used against oral diseases. To conduct this study, 10 articles and theses, a brief, 2 books, 4 reports and 2 clippings on traditional medicine/herbal medicine were consulted. Several African plants, in the form of use, can help relieve or treat dental pain and have positive effects against dental caries and periodontal diseases. The geographic and financial accessibility associated with the lack of qualified personnel are the plants could be an alternative in the management of certain oral diseases.

C-H bonds as ubiquitous functionality: a general approach to complex arylated imidazoles via regioselective sequential arylation of all three C-H bonds and regioselective N-alkylation enabled by SEM-group transposition.

Imidazoles are an important group of the azole family of heterocycles frequently found in pharmaceuticals, drug candidates, ligands for transition metal catalysts, and other molecular functional materials. Owing to their wide application in academia and industry, new methods and strategies for the generation of functionalized imidazole derivatives are in demand. We here describe a general and comprehensive approach for the synthesis of complex aryl imidazoles, where all three C-H bonds of the imidazole core can be arylated in a regioselective and sequential manner. We report new catalytic methods for selective C5- and C2-arylation of SEM-imidazoles and provide a mechanistic hypothesis for the observed positional selectivity based on electronic properties of C-H bonds and the heterocyclic ring. Importantly, aryl bromides and low-cost aryl chlorides can be used as arene donors under practical laboratory conditions. To circumvent the low reactivity of the C-4 position, we developed the SEM-switch that transfers the SEM-group from N-1 to N-3 nitrogen and thus enables preparation of 4-arylimidazoles and sequential C4-C5-arylation of the imidazole core. Furthermore, selective N3-alkylation followed by the SEM-group deprotection (trans-N-alkylation) allows for regioselective N-alkylation of complex imidazoles. The sequential C-arylation enabled by the SEM-switch allowed us to produce a variety of mono-, di-, and triarylimidazoles using diverse bromo- and chloroarenes. Using our approach, the synthesis of individual compounds or libraries of analogues can begin from either the parent imidazole or a substituted imidazole, providing rapid access to complex imidazole structures.

Factors limiting the use of modern contraceptive methods in mothers with children aged 12-23 months at the Yalgado Ouedraogo University Hospital in Ouagadougou, Burkina Faso.

Knowledge of the factors of non-use of modern contraceptive methods should help to reduce the number of infants born after short interpregnancy intervals, which are associated with adverse effects for mothers, children, and families. For this reason, this study aimed to determine the factors associated with this non-use among mothers of infants aged 12 to 23 months. This case-control study included a sample of mothers of children aged 12 to 23 months. The case mothers were users of modern contraceptive methods and the control mothers were non-users. Data were collected from January 1 through March 31, 2018. Six factors were significantly associated with the use of modern contraceptive methods: age younger than 25 years, lack of gainful activity, desire for a family size ≥ 4 children, BMI greater than 25, opposition by husband, and failure to attend the 45-day postnatal consultation. Modifiable socio-economic factors were significantly associated with the non-use of modern contraceptive methods by mothers of children aged 12 to 23 months.

[Radiographic study of the canal anatomy of mandibular premolars in a Senegalese population]. / Etude radiographique de l'anatomie canalaire des premolaires mandibulaires dans une population Senegalaise.

AIM: The purpose of this study was to assess the canal anatomy of mandiblar premolars in Senegalese population. MATERIALS AND METHODS: Retroalveolar radiographs of mandibular premolars of 208 patients in Senegal were obtained. Two experienced practitioners using a long cone tube and the parallel plane technique with angulators took the radiographs. The canal morphology of each tooth was determined in terms of the number of canals radiologically visible to the apex. Any anatomic structure emanating from the pulp chamber or the principal canal to the apex and measuring more than 3 millimetres was considered to be a supplementary canal. RESULTS: For the 208 patients studied, 412 first premolars were present and 4 were absent.Among the 412 teeth, 335 (81.3%) had a single canal, 62 (15.1%) 2 canals, and 17 (3.6%) 3 canals. For the second premolars 408 were present. Of the 408 teeth, 352 (86%) had one canal, 49 (12%) 2 canals, and 8 (2%) 3 canals. CONCLUSION: The prevalence of two or more canals in premolar mandibular from Senegalese patients was similar to that found in the others ethnic population.

[Evaluation of the canal shaping duration with Pro Taper: 50 cases--clinical experience]. / Article original evaluation de la duree de preparation canalaire au Pro Taper: experience clinique a propos de 50 cas.

INTRODUCTION: Shaping canal is one of the most important steps in endodontic treatment. It allows the cleaning solutions to reach the totality of the canal and to control any infection of the canal system. To achieve this goal is not without difficulty with the steel instruments, because of their rigidity. Recently, the Nickel Titanium instruments were introduced in Endodontics, to allow a setting form technically simplified and faster The aim of this study was to evaluate the duration of the canal shaping with the Pro Taper system. MATERIALS AND METHODS: This exploratory study was carried out in Conservative Odontology and Endodontics service (OCE) of the department of Odontology of Faculty of Medicine, Pharmacy and Odonto-Stomatology of the University CheikhAnta Diop of Dakar in 2006. Sixty nine root canals (50 teeth) were shaped with ProTaper. RESULTS: The results showed that an average time of 17.35 minutes was necessary for the shaping of the long canals against 15.38 minutes for the middle canals and 14.29 minutes for the short canals. The average duration of canal shaping of the one-root teeth is 13.76 minutes and 17.77 minutes for the plural root teeth. CONCLUSION: Taking into account the necessity of maintaining the teeth on the arcade during long year; include that we have now to respect imperatively the biological principles during the canal shaping in a restricted duration to realize a dense and hermetic canal obturation of the canal system in the same meeting. The Pro Taper system is so a reliable means.

[Prevalence of fixed prosthesis-related periodontitis in Senegal]. / Prévalence de la prothèse fixèe et des parodontites apicales associées au Sénégal.

The purpose of this study was to determine radiographically the prevalence of periapical periodontitis in teeth restored with crown in a Senegalese population. Full mouth periapical radiographs were obtained from 208 consecutive adult patients (6234 teeth) presenting as new patients to the Dental Service of the University. The presence of crown restorations, the periapical status and technical quality of root fillings associated were evaluated. 7.69% (n = 16) of patients had at least one tooth that was crowned. The total number of crowns assessed was 0.95% (n = 59). The molars were the teeth most crowned 40.67% (n = 24) followed by anterior teeth 30.50% (n = 18) and premolars 28.81% (n = 17). All the crowned teeth had previous root canal treatment of which only 16.94% (n = 10) were acceptable. 53 % (n = 32) of the teeth had apical periodontitis (PAI > 2). Unacceptable root fillings were associated with a higher prevalence of periapical disease (p < 0.05). Crown with a post extending more than 4 millimetres from the apex were associated with more periapical lesions 64.28% (p < 0.05). The results indicate a low prevalence of crowned teeth, an absence of vital preparation, a high prevalence of radiographic periapical disease and unacceptable root fillings associated.

[Yaws in Côte d'lvoire: health problem forgotten and neglected]. / Le pian en Côte d'Ivoire: problème de santé oublié et négligé.

Yaws is endemic in Côte d'Ivoire, with an hospital incidence estimated by the medical statistics at 0.58 per thousand in 2000; cases of yaws were notified in all medical districts. This study describes the yaws situation in Côte d'Ivoire based on available hospital statistics and a cross section investigation. The yaws diagnoses during the investigation were based on clinic lesions. The yaws prevalence found at the end of the investigation was 5 per thousand: the majority of the patients were children under 15 years old (82%) and male (91%). Only 27% of diagnosed patients had a medical treatment at the time of the study. Yaws is still endemic in Côte d'Ivoire which underlines the need for an implementation of a national control strategy.

"Addition" and "Subtraction": Selectivity Design for Type II Maternal Embryonic Leucine Zipper Kinase Inhibitors.

While adding the structural features that are more favored by on-target activity is the more common strategy in selectivity optimization, the opposite strategy of subtracting the structural features that contribute more to off-target activity can also be very effective. Reported here is our successful effort of improving the kinase selectivity of type II maternal embryonic leucine zipper kinase inhibitors by applying these two complementary approaches together, which clearly demonstrates the powerful synergy between them.

[Prevalence and risk factors for sickle retinopathy in a sub-Saharan comprehensive Sickle Cell Center]. / Prévalence et facteurs de risque de la rétinopathie drépanocytaire dans un centre de suivi drépanocytaire d'Afrique subsaharienne.

INTRODUCTION: Retinopathy is a chronic complication with severe functional consequences in patients with sickle cell disease. Its prevalence is not well known in sub-Saharan Africa because of the absence of screening. We report here the results of a routine screening for sickle retinopathy in a Comprehensive Sickle Cell Center in Sub-Saharan Africa. METHODS: Screening of sickle retinopathy was carried out in all sickle cell patients aged 10 and over, followed between 2010 and 2012. Retinopathy was screened by dilated indirect fundoscopic examination and retinal angiography, if necessary. The gender, age and hematological parameters of patients with sickle retinopathy were compared with those of controls randomly selected from the cohort of sickle cell patients without retinopathy followed during the same period. RESULTS: The overall prevalence of sickle cell retinopathy was 8.8% (142/1604): 12.4% (91/731) in SC, 5.2% (38/734) in SS, 9.4% (5/53) in Sß°-thalassemia patients and 9.3% (8/86) in Sß+-thalassemia patients. Proliferative retinopathy was more common in SC patients (P<0.01). High levels of hemoglobin or of hematocrit were associated with retinopathy in all patients and with proliferative retinopathy in SC patients. In SS or Sß0thalassemia patients, high leukocyte count was associated with proliferative retinopathy. Low fetal hemoglobin level was associated with retinopathy in all groups. CONCLUSION: The prevalence of sickle cell retinopathy is high and negatively associated to the level of fetal hemoglobin. The efficiency of a routine screening for sickle cell retinopathy must be assessed in Africa as well as the benefit of phlebotomy and hydroxyurea therapy as a preventive treatments.

Allosteric Mutant IDH1 Inhibitors Reveal Mechanisms for IDH1 Mutant and Isoform Selectivity.

Oncogenic IDH1 and IDH2 mutations contribute to cancer via production of R-2-hydroxyglutarate (2-HG). Here, we characterize two structurally distinct mutant- and isoform-selective IDH1 inhibitors that inhibit 2-HG production. Both bind to an allosteric pocket on IDH1, yet shape it differently, highlighting the plasticity of this site. Oncogenic IDH1R132H mutation destabilizes an IDH1 "regulatory segment," which otherwise restricts compound access to the allosteric pocket. Regulatory segment destabilization in wild-type IDH1 promotes inhibitor binding, suggesting that destabilization is critical for mutant selectivity. We also report crystal structures of oncogenic IDH2 mutant isoforms, highlighting the fact that the analogous segment of IDH2 is not similarly destabilized. This intrinsic stability of IDH2 may contribute to observed inhibitor IDH1 isoform selectivity. Moreover, discrete residues in the IDH1 allosteric pocket that differ from IDH2 may also guide IDH1 isoform selectivity. These data provide a deeper understanding of how IDH1 inhibitors achieve mutant and isoform selectivity.

Optimization of 3-Pyrimidin-4-yl-oxazolidin-2-ones as Allosteric and Mutant Specific Inhibitors of IDH1.

High throughput screening and subsequent hit validation identified 4-isopropyl-3-(2-((1-phenylethyl)amino)pyrimidin-4-yl)oxazolidin-2-one as a potent inhibitor of IDH1R132H. Synthesis of the four separate stereoisomers identified the (S,S)-diastereomer (IDH125, 1f) as the most potent isomer. This also showed reasonable cellular activity and excellent selectivity vs IDH1wt. Initial structure-activity relationship exploration identified the key tolerances and potential for optimization. X-ray crystallography identified a functionally relevant allosteric binding site amenable to inhibitors, which can penetrate the blood-brain barrier, and aided rational optimization. Potency improvement and modulation of the physicochemical properties identified (S,S)-oxazolidinone IDH889 (5x) with good exposure and 2-HG inhibitory activity in a mutant IDH1 xenograft mouse model.