Autobiographical memory, self, and stress-related psychiatric disorders: which implications in cancer patients?

International audienceAutobiographical memory refers to information and memories of personal life events, accumulated since childhood, which enable the construction of a feeling of identity and continuity. Autobiographical memory retrieval is a dynamic and reconstructive process, as mental representations change with the passage of time. This flexible aspect of memory is linked to one's changing self and aspirations over time, that evolve according to our personal status and environment. Hence, any breakdown in the continuity of life involves a distortion of memory. Such distortions can be observed in stress-related psychiatric disorders, such as major depression or post-traumatic stress disorder, where autobiographical memory retrieval is characterized by overgenerality (i.e., the tendency to recall generic memories rather than specific events in response to cue words). Such memory disorders can be observed at different degrees in cancer patients. We will report studies focusing on the above-mentioned psychiatric disorders and cancer, and will attempt to establish a relation with autobiographical memory disturbances. The better understanding of such memory deficits could permit new pathophysiological hypotheses to emerge. Recommendations for future research that will enhance understanding of the factors that contribute to autobiographical memory in cancer are suggested

Chronic Dietary Exposure to a Low-Dose Mixture of Genistein and Vinclozolin Modifies the Reproductive Axis, Testis Transcriptome, and Fertility

Background: The reproductive consequences and mechanisms of action of chronic exposure to low-dose endocrine disruptors are poorly understood.[br/] Objective: We assessed the effects of a continuous, low-dose exposure to a phytoestrogen (genistein) and/or an antiandrogenic food contaminant (vinclozolin) on the male reproductive tract and fertility.[br/] Methods: Male rats were exposed by gavage to genistein and vinclozolin from conception to adulthood, alone or in combination, at low doses (1 mg/kg/day) or higher doses (10 and 30 mg/kg/day). We studied a number of standard reproductive toxicology end points and also assessed testicular mRNA expression profiles using long-oligonucleotide microarrays.[br/] Results: The low-dose mixture and high-dose vinclozolin produced the most significant alterations in adults: decreased sperm counts, reduced sperm motion parameters, decreased litter sizes, and increased post implantation loss. Testicular mRNA expression profiles for these exposure conditions were strongly correlated. Functional clustering indicated that many of the genes induced belong to the “neuroactive ligand-receptor interactions” family encompassing several hormonally related actors (e.g., follicle-stimulating hormone and its receptor). All exposure conditions decreased the levels of mRNAs involved in ribosome function, indicating probable decreased protein production.[br/] Conclusions: Our study shows that chronic exposure to a mixture of a dose of a phytoestrogen equivalent to that in the human diet and a low dose—albeit not environmental—of a common anti-androgenic food contaminant may seriously affect the male reproductive tract and fertility

A Pilot Initiative to Deliver Community-based Psychiatric Services in Rural Haiti After the 2010 Earthquake

Background: Worldwide, there is a gap between the burden of mental distress and disorder and access to mental health care. This gap is particularly large in low- and middle-income countries (LMICs). After the 2010 earthquake in Haiti, the international health care organizations Partners in Health and Zanmi Lasante worked to expand local mental health services in rural Haiti. Objective: The aims of this study are to describe clinical characteristics of the patients served during a pilot project to deliver community-based psychiatric services in rural Haiti and to show how this experience complements the Mental Health Gap Action Programme (“mhGAP”), a tool developed by the World Health Organization to support mental health care delivery by nonspecialists in LMICs. Methods: The pilot was conducted in March 2011. A visiting psychiatrist traveled to rural Haiti and paired with local clinicians to evaluate patients and to support quality improvement practices in psychiatric care. Patients received a standard neuropsychiatric evaluation. mhGAP was an important clinical reference. To assess the experience, we conducted a retrospective chart review of outpatient encounters. Findings: Sixty-five patients presented with a wide range of common psychiatric, neurologic, and general medical conditions. Forty-nine of these patients (75%) reported primary problems subsumed by an mhGAP module. Fifteen patients (23%) reported headache as their chief complain, a condition that is not currently covered by mhGAP. Surprisingly, only 3 patients (5%), reported earthquake-related distress. Conclusions: Our clinical data reinforce the need for provision of standard psychiatric and neurologic services in LMICs. Such services ought to accompany interventions targeted specifically at disaster-related problems. Clinical situations falling outside existing mhGAP modules inspired the development of supplemental treatment protocols. These observations informed coordinated efforts at Zanmi Lasante to build a sustainable, integrated mental health system in Haiti that may be relevant to other resource-limited settings

Experimental evidence that immune trypanolysis using the LiTat 1.3 and LiTat 1.5 variant antigen types is not specific to Trypanosoma brucei gambiense in pigs

In the context of the human African trypanosomiasis elimination process, reliable and accurate diagnostic tools are crucial for exploring the role of a potential animal reservoir of Trypanosoma brucei gambiense. The immune trypanolysis test (TL) using the variant antigen types (VAT) LiTat 1.3 and LiTat 1.5, described as a specific serological method to detect people infected by T. b. gambiense, seems to be a promising tool. However, its specificity was recently questioned during field animal surveys. The present study evaluates the performance of TL during experimental T. b. brucei infection in pigs. Eight infected pigs and four uninfected pigs were followed up with blood and plasma collection. Blood was used for parasitological investigation. TL was performed on the plasma with the LiTat 1.3, LiTat 1.5 and LiTat 1.6 VATs. All control pigs remained negative to parasitological investigation and TL. Trypanosomes were detected in all the infected pigs and the first detection was between 10 and 14 days post infection (dpi). TL results showed that infected pigs developed antibodies against the three VATs. The first antibody detections by TL occurred between 14 and 21 dpi for antibodies directed against LiTat 1.6, 21 and 168 dpi for antibodies directed against LiTat 1.5 and 70, and 182 dpi for antibodies directed against LiTat 1.3. This study highlights for the first time that TL using LiTat 1.3 and LiTat 1.5 VATs is not specific to T. b. gambiense. Development of specific diagnostic tools for the detection of T. b. gambiense infections in animals, especially in pigs, is still needed

Parallel assessment of male reproductive function in workers and wild rats exposed to pesticides in banana plantations in Guadeloupe

<p>Abstract</p> <p>Background</p> <p>There is increasing evidence that reproductive abnormalities are increasing in frequency in both human population and among wild fauna. This increase is probably related to exposure to toxic contaminants in the environment. The use of sentinel species to raise alarms relating to human reproductive health has been strongly recommended. However, no simultaneous studies at the same site have been carried out in recent decades to evaluate the utility of wild animals for monitoring human reproductive disorders. We carried out a joint study in Guadeloupe assessing the reproductive function of workers exposed to pesticides in banana plantations and of male wild rats living in these plantations.</p> <p>Methods</p> <p>A cross-sectional study was performed to assess semen quality and reproductive hormones in banana workers and in men working in non-agricultural sectors. These reproductive parameters were also assessed in wild rats captured in the plantations and were compared with those in rats from areas not directly polluted by humans.</p> <p>Results</p> <p>No significant difference in sperm characteristics and/or hormones was found between workers exposed and not exposed to pesticide. By contrast, rats captured in the banana plantations had lower testosterone levels and gonadosomatic indices than control rats.</p> <p>Conclusion</p> <p>Wild rats seem to be more sensitive than humans to the effects of pesticide exposure on reproductive health. We conclude that the concept of sentinel species must be carefully validated as the actual nature of exposure may varies between human and wild species as well as the vulnerable time period of exposure and various ecological factors.</p

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Approches synthétiques de tétrahydroisoquinoléines par cyclisation Pallado-Catalysée & synthèse de composés spirocétaliques par RRM

Après avoir exposé les enjeux de ce travail en présentant dans le chapitre 1 les produits naturels possédant le motif tétrahydroisoquinoléinique, leurs intérêts pharmacologiques et leur unique voie d'accès via la réaction de Pictet Spengler, nous avons présenté la synthèse énantiosélective de tétrahydroisoquinoléine 1,3-disubstituées et différentes tentatives d'obtention des motifs pentacycliques de différents alcaloïdes d'intérêt biologique. La synthèse énantiosélective de tétrahydroisoquinoléines 1,3-disubstituées a été effectuée en 6 étapes utilisant deux étapes clés. Une alkylation catalysée par transfert de phase permet de créer un centre asymétrique et une cyclisation pallado-catalysée permet d'accéder au motif tétrahydroisoquinoléinique. Dans la suite, les différentes voies d'accès testées permettant d'accéder au motif pentacyclique n'ont pas été couronnées de succès. Dans un second temps ont été exposées les différentes sources de composés possédant un motif spirocétalique, leurs propriétés électroniques et conformationnelles. Les différentes voies de synthèse de spirocétals ont été présentées. Les différentes voies de synthèse d'a-hétérofuranes ont été introduites en se concentrant sur les dérivés soufrés, azotés et oxygénés. L'utilisation des a alcoxyfuranes en réaction de cycloaddition a ensuite été présentée ainsi que l'utilisation des adduits. Enfin la réaction de RRM a été étudiée en se focalisant sur les réactifs à forte tension de cycle. Différentes voies de synthèse des a-alcoxyfuranes ont été exposées. Une voie d'accès générale a été développée par réaction d'addition/élimination sur le 2,5-diméthoxy-2,5-dihydro-2-furanoate de méthyle. La séquence cycloaddition [4+2] ou [4+3]1 RRM a été ensuite présentée permettant d'accéder aux spirocétals (5,6) et (6,6). L'application de cette méthodologie à la synthèse des aculéatines et des aculéatols, est étudiée.Alkaloids from the family of the tetrahydroisoquinolins exhibit powerful antitumor and antibiotic activities. For 25 years, numerous laboratories led their efforts to synthesize these functionalized polycyclic molecules. Usually the strategy used to prepare these is based on a Pictet-Spengler reaction allowing the first ring system of the tetrahydroisoquinoline moiety to be installed. The main drawback of this reaction is the need of an electron rich aromatic ring to attack the iminium intermediate. The main purpose of this thesis is the synthesis of compounds of this family of natural substances without the limited step to access to new analogs. The total synthesis of the Jorumycine is based on a key step of a ring closing metathesis, a reaction developed by R. Grubbs, R. Shrock and Y. Chauvin who obtained the Nobel prize of Chemistry in 2005. This reaction has been successfully done on a corresponding substrate in the laboratory but the next steps involving a ring contraction and a transannular cyclization seemed to be problematic. This strategy includes an enantioselective synthesis of 1,3-disubstitued tetrahydroisoquinoline that have been done for the first time to our knowledge. In the same time, we tried to synthesize the tetracyclic structure of the Lemonomycine through a nitroso Diels-Alder strategy. This molecule has already been prepared in other groups but the methods didn t allowed the scale up nor the synthesis of analogs. The strategy was focused on the synthesis of a dihydropinoisoquinolinone moiety that has never yet been prepared via a ring closing metathesis reaction. Spiroketal compounds are widely present in nature as pheromones of insects, steroids of the family of the saponins and in a lot of natural products isolated from marine organisms. A lot of natural substances are bearing the spiroketalic moiety in the non-anomeric configuration meaning that at least one oxygen atom is in the axial conformation despite the stabilization by anomeric effect. To our knowledge, there are only two published strategies to prepare contrathermodynamic non-anomeric spiroketals but these methods are neither general nor rationalized. The Ring Rearrangement Metathesis reaction allows access to these structures from alpha-alkoxyfuran derivatives. Although the alpha-alkoxyfuran derivatives are relatively simple structures, there are no efficient and general synthetic methods to prepare them. We developed a simple access that will be presented along with their use in a [4+2] cycloaddition/RRM sequence.MULHOUSE-SCD Sciences (682242102) / SudocSudocFranceF

Nouvelles Métathèses avec Réarrangement de Cycles : Application à la Synthèse d Oligosaccharides Rares

Ce travail présente une nouvelle voie d'accès aux polysaccharides polyinsaturés via une étape clé de réarrangement de cycle par métathèse (Rn de type RCM-ROM-RCM). En effet au départ de composés triéniques comportant un relais central sous forme d'un cycle à 5 ou 6 chaînons, la synthès de disaccharides liés de manière 1,6 et diversement fonctionnalisés à été réalisée. De même, la synthèse de disaccharides triinsaturés au départ d'un composé tétraénique comportant deux relais cycliques à été réalisée via cette méthode. Au cours de ce travail, nous avons également mis en évidence k premier enchaînement RCM-ROM-RCM-ROM-RCM efficace de la littérature.This work describes a new method for the synthesis of polyunsaturated-polysaccharides The synthesis relies on a ring-rearrangement metathesis (RRM) key step usnrg a RCM-ROM-RCM sequence. Thus, trienic compounds containing a 5- or 6- membered ring as relay moiety allowed us to synthesise several 1,6-linked disaccharides. The method was extended to the synthesis of a trisaccharide via RRM of a tetraenic precusor, featuring tw< cyclic, relay moieties. This is the first reported example of a synthetically useful efficient RCM-ROM-RCM-ROM-RCM sequence.MULHOUSE-SCD Sciences (682242102) / SudocSudocFranceF

Synthèse d'inhibiteurs potentiels de la D-arabinosyltransférase (vers de nouveaux antibiotiques contre la tuberculose)

La tuberculose est un problème majeur pour la santé mondiale. Son agent pathogène, Mycobacterium tuberculosis, utilise un phospholipide particulier, le béta-D-arabinofuranosyl-1-monophosphodécaprénol (DPA), pour construire sa paroi cellulaire. Le DPA est spécifique des mycobactéries et le sucre qu'il contient n'est pas présent chez les mammifères. Il constitue une cible de choix pour le développement de nouveaux antituberculeux. Cette thèse expose la synthèse d'analogues du DPA pouvant inhiber l'arabinosyltranférase, une des enzymes bâtissant la paroi mycobactérienne. Dans un premier temps, nous avons préparé des analogues dont la liaison phosphate du substrat naturel est remplacé par une liaison phosphonate non sécable par le processus enzymatique naturel. La seconde série d'analogues est constituée de produits dont le cycle furanne a été remplacé par un cycle pyrrolidine. Les iminosucres sont connus pour être de bons inhibiteurs de glycosidases, une classe d'enzymes dont le mécanisme est similaire à l'arabinosyltranférase. Les premiers tests effectués sur l'enzyme seule montrent une inactivité de nos produits qu'il reste à confirmer.Tuberculosis is a major worldwide health problem. Its pathogen agent, Mycobacterium tuberculosis, uses a particular phospholipid, decaprenolphosphoarabinose (DPA), to build its cell wall. DPA is a specific mycobacterial phospholipid and the sugar that it contains is not found in mammalians. It is a good therapeutic target to develop new antituberculosis drugs. This thesis reports the synthesis of DPA analogues, aimed at inhibiting arabinosyltransferase, a key-enzyme involved in the building of mycobacterial cell wall. At first, we have synthesized analogues in which the phosphate linkage has been replaced by a phosphonate linkage. This linkage is not cut by natural enzymatic processes. Products in which the furan cycle of natural substrate cycle has been replaced by a pyrrolidine cycle constitute the second series of analogues. Iminosugars are known to be excellent inhibitors of the related glycosidases. Preliminary tests on crude enzymatic preparation show that our products are inactive but this remains to be confirmed in vivo using Mycobacterium smegmatis as a model of non pathogenic mycobacteria.MULHOUSE-SCD Sciences (682242102) / SudocSudocFranceF

Synthèse de carbo et hétérocycles à partir d'hydrates de carbone par la chimie des métaux de transition (Zr, Mo, Ru)

MULHOUSE-SCD Sciences (682242102) / SudocSudocFranceF