Ethical aspects in managing patients diagnosed with digestive cancers; a review of literature

Numerous bioethical recommendations are now available in the complex process of communication with cancer patients. In this review, we have focused on the complex process of managing patients with different types of oncologic digestive diseases, immediately after the diagnosis is made. We have analyzed the literature data on the topic. MEDSCAPE and PubMed databases have been studied. Issues such as telling the truth to patients with digestive cancer, the physician\u27s responsibility in the psychological management of patients and their relatives, the nurses’ duties, the consented death, the practice of euthanasia and physician-assisted suicide (PAS) as well as the clinical research have been the main targets of our study

Modern Tools for Diagnosis in Tuberculous Ascites

Tuberculosis (TB) is a highly contagious bacterial infection caused by Mycobacterium tuberculosis (MTB), affecting about 1/3rd of the world population and being responsible for lot of deaths worldwide, despite the progress achieved in the diagnosis and treatment fields. TB can affect the peritoneum, the TB ascites being a concern for physicians, especially when dealing with immunocompromised patients. The clinical presentation of TB ascites is challenging, due to nonspecific symptoms that make confusion with other diseases and the late results of cultures from ascites. The late diagnosis leads to a delayed treatment and high mortality. This manuscript describes recent tools used for early diagnosis in TB ascites. Molecular methods based on mycobacterial nucleic acid amplification tests (NAATs), polymerase chain reaction (PCR) detecting minimal amounts of bacterial DNA, or interferongamma release assays (IGRA) and biochemical methods such as the serum-ascites albumin gradient (SAAG) 40 UI/ml were recently considered more accurate diagnostic procedures. These methods allow a rapid and accurate differential diagnosis of ascites fluid, making possible the early treatment with appropriate drugs

Ethical aspects in managing patients diagnosed with digestive cancers; a review of literature

Numerous bioethical recommendations are now available in the complex process of communication with cancer patients. In this review, we have focused on the complex process of managing patients with different types of oncologic digestive diseases, immediately after the diagnosis is made. We have analyzed the literature data on the topic. MEDSCAPE and PubMed databases have been studied. Issues such as telling the truth to patients with digestive cancer, the physician\u27s responsibility in the psychological management of patients and their relatives, the nurses’ duties, the consented death, the practice of euthanasia and physician-assisted suicide (PAS) as well as the clinical research have been the main targets of our study

METTL13 methylation of eEF1A increases translational output to promote tumorigenesis

Increased protein synthesis plays an etiologic role in diverse cancers. Here, we demonstrate that METTL13 (methyltransferase-like 13) dimethylation of eEF1A (eukaryotic elongation factor 1A) lysine 55 (eEF1AK55me2) is utilized by Ras-driven cancers to increase translational output and promote tumorigenesis in vivo. METTL13-catalyzed eEF1A methylation increases eEF1A's intrinsic GTPase activity in vitro and protein production in cells. METTL13 and eEF1AK55me2 levels are upregulated in cancer and negatively correlate with pancreatic and lung cancer patient survival. METTL13 deletion and eEF1AK55me2 loss dramatically reduce Ras-driven neoplastic growth in mouse models and in patient-derived xenografts (PDXs) from primary pancreatic and lung tumors. Finally, METTL13 depletion renders PDX tumors hypersensitive to drugs that target growth-signaling pathways. Together, our work uncovers a mechanism by which lethal cancers become dependent on the METTL13-eEF1AK55me2 axis to meet their elevated protein synthesis requirement and suggests that METTL13 inhibition may constitute a targetable vulnerability of tumors driven by aberrant Ras signaling.We thank Pal Falnes, Jerry Pelletier, and Julien Sage for helpful discussion, Lauren Brown and William Devine for SDS-1-021, and members of the Gozani and Mazur laboratories for critical reading of the manuscript. This work was supported in part by grants from the NIH to S.M.C. (K99CA190803), M.P.K. (5K08CA218690-02), J.A.P. (R35GM118173), M.C.B. (1DP2HD084069-01), J.S. (1R35GM119721), I.T. (R01CA202021), P.K.M. (R00CA197816, P50CA070907, and P30CA016672), and O.G. (R01GM079641). J.E.E. received support from Stanford ChEM-H, and A.M. was supported by the MD Anderson Moonshot Program. I.T. is a Junior 2 Research Scholar of the Fonds de Recherche du Quebec - Sante (FRQ-S). P.K.M. is supported by the Neuroendocrine Tumor Research Foundation and American Association for Cancer Research and is the Andrew Sabin Family Foundation Scientist and CPRIT scholar (RR160078). S.H. is supported by a Deutsche Forschungsgemeinschaft Postdoctoral Fellowship. J.W.F. is supported by 5T32GM007276. (K99CA190803 - NIH; 5K08CA218690-02 - NIH; R35GM118173 - NIH; 1DP2HD084069-01 - NIH; 1R35GM119721 - NIH; R01CA202021 - NIH; R00CA197816 - NIH; P50CA070907 - NIH; P30CA016672 - NIH; R01GM079641 - NIH; Stanford ChEM-H; MD Anderson Moonshot Program; Neuroendocrine Tumor Research Foundation; American Association for Cancer Research; Deutsche Forschungsgemeinschaft Postdoctoral Fellowship; 5T32GM007276)Supporting documentationAccepted manuscrip

Ethical aspects in managing patients diagnosed with digestive cancers; a review of literature

Numerous bioethical recommendations are now available in the complex process of communication with cancer patients. In this review, we have focused on the complex process of managing patients with different types of oncologic digestive diseases, immediately after the diagnosis is made. We have analyzed the literature data on the topic. MEDSCAPE and PubMed databases have been studied. Issues such as telling the truth to patients with digestive cancer, the physician's responsibility in the psychological management of patients and their relatives, the nurses’ duties, the consented death, the practice of euthanasia and physician-assisted suicide (PAS) as well as the clinical research have been the main targets of our study

The oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathway

The identification of cancer-associated mutations in the tricarboxylic acid (TCA) cycle enzymes isocitrate dehydrogenases 1 and 2 (IDH1/2) highlights the prevailing notion that aberrant metabolic function can contribute to carcinogenesis. IDH1/2 normally catalyse the oxidative decarboxylation of isocitrate into α-ketoglutarate (αKG). In gliomas and acute myeloid leukaemias, IDH1/2 mutations confer gain-of-function leading to production of the oncometabolite R-2-hydroxyglutarate (2HG) from αKG. Here we show that generation of 2HG by mutated IDH1/2 leads to the activation of mTOR by inhibiting KDM4A, an αKG-dependent enzyme of the Jumonji family of lysine demethylases. Furthermore, KDM4A associates with the DEP domain-containing mTOR-interacting protein (DEPTOR), a negative regulator of mTORC1/2. Depletion of KDM4A decreases DEPTOR protein stability. Our results provide an additional molecular mechanism for the oncogenic activity of mutant IDH1/2 by revealing an unprecedented link between TCA cycle defects and positive modulation of mTOR function downstream of the canonical PI3K/AKT/TSC1-2 pathway

Multiple roles of CUX1 in the DNA damage response

The short isoforms of the CUX1 transcription factor have been implicated in various cancer-related processes in tissues culture experiments and were found to contribute to tumorigenicity in transgenic mice. In addition, CUX1 is over-expressed in many human cancers. The functions attributed so far to CUX1 stem from its activity as a transcription factor. However, it is possible that CUX1 plays a non-transcriptional role in the cell. Tandem affinity purification, followed by mass spectrometry, identified numerous binding partners of CUX1. The aim of my studies was to validate and further characterize the interactions of CUX1 with some of these proteins: REV1, PARP1 and Ku70/Ku80. REV1 is an error-prone DNA polymerase involved in translesion synthesis and is responsible for most point mutations in yeast and mammalian cells. We showed that the REV1-CUX1 interaction required the REV1 BRCT domain and was increased following irradiation. I have shown that CUX1 was phosphorylated following DNA damage. My results indicated that ATM phosphorylated CUX1 and that phosphorylation of CUX1 at serines 861, 868 and 1100 promoted its interaction with REV1. ChIP-on-chip experiments showed that REV1 preferentially localized to transcribed regions, that the recruitment increased after gamma-irradiation and that 12.9% of REV1 binding sites overlapped CUX1 binding sites. I have optimized and characterized two reporter assays for point mutations (GFPstop and ouabain resistance) and showed that point mutation frequency correlated, at least in part, with the ability of a promoter to recruit REV1. Reduction in REV1 expression led to a decrease in expression of numerous genes. We propose that the physiological purpose for REV1 recruitment to transcribed regions is to enable efficient transcription of actively transcribed genes, by preventing stalled replication forks from blocking the passage of the transcription machinery. Ku and PARP1 are sensors of DNA damage and promote DNA damage repair. I have validated the interaction of CUX1 with Ku and PARP1 and showed that expression of CUX1 fragments led to their displacement from known promoter targets. Using various experimental approaches, my results indicated that in addition to its transcriptional role, CUX1 might play a non-transcriptional role in the repair of strand breaks.Le facteur de transcription CUX1, et plus particulièrement ses isoformes courtes, sont impliquées dans différents processus associés au développement cancéreux dans des expériences de culture de tissus et dans des modèles de souris transgéniques. De plus, CUX1 est sur-exprimé dans de nombreux cancers humains. Les fonctions attribuées jusqu'à présent à CUX1 sont associées à son activité transcriptionelle. Cependant, il est possible que CUX1 joue un rôle non-transcriptionel dans la cellule. La purification par affinité en tandem, couplée à la spectrométrie de masse, a permis d'identifier plusieurs partenaires d'interaction de CUX1. Le but de mes études a été de valider et caractériser les interactions de CUX1 avec certaines de ces protéines, plus précisément REV1, PARP1 et Ku70/Ku80. REV1 est une ADN polymérase de faible fidélité lors de la synthèse d'ADN impliqué dans le processus de synthèse à travers les lésions (translesion synthesis) et responsable de la plupart des mutations ponctuelles chez la levure, ainsi que chez les mammifères. Nous avons montré que l'interaction entre REV1 et CUX1 nécessitait le domaine BRCT de REV1 et que leur affinité respective augmentait suite à l'irradiation. J'ai montré que CUX1 était phosphorylé suite aux dommages à l'ADN. Mes résultats ont indiqué que ATM phosphorylait CUX1 et que les phosphorylations de CUX1 sur les serines 861, 868 et 1100 favorisaient son interaction avec REV1. Des expériences de localisation génomique par puce ont montré que REV1 était localisé de manière préférentielle dans des régions transcrites, que cette localisation augmentait suite à l'irradiation aux rayons gamma et que 12.9% des sites de localisation de REV1 se superposaient aux sites de localisation de CUX1.J'ai optimisé et j'ai caractérisé deux essais rapporteurs pour l'analyse des mutations ponctuelles (GFPstop et résistance à l'ouabain) et j'ai montré que la fréquence des mutations ponctuelles corrélait, en partie, avec la capacité des promoteurs à recruter REV1. Une réduction de l'expression de REV1 a induit la réduction de l'expression des nombreux gènes. Nous suggérons que le rôle physiologique du recrutement de REV1 au sein de régions génomiques transcrites est de permettre la transcription efficace des gènes transcrits activement, en prévenant le blocage du passage du complexe transcriptionel normalement induit par les fourches de réplication arrêtées à cause du dommage à l'ADN. Ku et PARP1 sont des détecteurs du dommage à l'ADN et stimulent la réparation de l'ADN. J'ai validé l'interaction de CUX1 avec Ku et PARP1 et j'ai montré que, suite à l'expression des fragments de CUX1, Ku et PARP1 ne se localisaient plus sur certaines de leurs cibles génomiques. En utilisant différentes approches expérimentales, mes résultats ont indiqué que, en plus de son rôle transcriptionel, CUX1 pourrait jouer un rôle non-transcriptionel dans la réparation des cassures de l'ADN

Biomedical Potential of mTOR Modulation by Nanoparticles

Modulation of the mammalian target of rapamycin (mTOR), the principal regulator of cellular homeostasis, underlies the biological effects of engineered nanoparticles, including regulation of cell death/survival and metabolic responses. Understanding the mechanisms and biological actions of nanoparticle-mediated mTOR modulation may help in developing safe and efficient nano therapeutics to fight human disease