Percutaneous Liver Biopsy after Living Donor Liver Transplantation Resulting in Fulminant Hepatic Failure: The First Reported Case of Hepatic Compartment Syndrome

A 28-year-old female who underwent live donor liver transplantation 3 years prior presented after percutaneous liver biopsy with abdominal and shoulder pain, nausea, vomiting, and elevated liver enzymes. Computed tomography (CT) showed an intrahepatic and subcapsular hematoma. There was a progressive increase in liver enzymes, bilirubin, and INR and a decline in hemoglobin. Subsequent CT imaging revealed flattening of the portal vein consistent with compression by the enlarging hematoma. Liver failure ensued and the patient required urgent retransplantation. The explant demonstrated ischemic necrosis of greater than 90% of the liver parenchyma. We report this case of “Hepatic Compartment Syndrome” leading to fulminant hepatic failure

Percutaneous mechanical circulatory support and survival in patients resuscitated from Out of Hospital cardiac arrest: A study from the CARES surveillance group

INTRODUCTION: Maintenance of cardiac function is required for successful outcome after out-of-hospital cardiac arrest (OHCA). Cardiac function can be augmented using a mechanical circulatory support (MCS) device, most commonly an intra-aortic balloon pump (IABP) or Impella®. OBJECTIVE: Our objective is to assess whether the use of a MCS is associated with improved survival in patients resuscitated from OHCA in Michigan. METHODS: We matched cardiac arrest cases during 2014-2017 from the Cardiac Arrest Registry to Enhance Survival (CARES) in Michigan and the Michigan Inpatient Database (MIDB) using probabilistic linkage. Multilevel logistic regression tested the association between MCS and the primary outcome of survival to hospital discharge. RESULTS: A total of 3790 CARES cases were matched with the MIDB and 1131 (29.8%) survived to hospital discharge. A small number were treated with MCS, an IABP (n = 183) or Impella® (n = 50). IABP use was associated with an improved outcome (unadjusted OR = 2.16, 95%CI [1.59, 2.93]), while use of Impella® approached significance (OR = 1.72, 95% CI [0.96, 3.06]). Use of MCS was associated with improved outcome (unadjusted OR = 2.07, 95% CI [1.55, 2.77]). In a multivariable model, MCS use was no longer independently associated with improved outcome (OR(adj) = 0.95, 95% CI [0.69, 1.31]). In the subset of subjects with cardiogenic shock (N = 725), MCS was associated with improved survival in univariate (unadjusted OR = 1.84, 95% CI [1.24, 2.73]) but not multi-variable modeling (OR(adj) = 1.14, 95% CI [0.74, 1.77]). CONCLUSION: Use of MCS was infrequent in patients resuscitated from OHCA and was not independently associated with improvement in post arrest survival after adjusting for covariates

Transforming Epidemiology for 21st Century Medicine and Public Health

In 2012, the National Cancer Institute (NCI) engaged the scientific community to provide a vision for cancer epidemiology in the 21st century. Eight overarching thematic recommendations, with proposed corresponding actions for consideration by funding agencies, professional societies, and the research community emerged from the collective intellectual discourse. The themes are (i) extending the reach of epidemiology beyond discovery and etiologic research to include multilevel analysis, intervention evaluation, implementation, and outcomes research; (ii) transforming the practice of epidemiology by moving towards more access and sharing of protocols, data, metadata, and specimens to foster collaboration, to ensure reproducibility and replication, and accelerate translation; (iii) expanding cohort studies to collect exposure, clinical and other information across the life course and examining multiple health-related endpoints; (iv) developing and validating reliable methods and technologies to quantify exposures and outcomes on a massive scale, and to assess concomitantly the role of multiple factors in complex diseases; (v) integrating “big data” science into the practice of epidemiology; (vi) expanding knowledge integration to drive research, policy and practice; (vii) transforming training of 21st century epidemiologists to address interdisciplinary and translational research; and (viii) optimizing the use of resources and infrastructure for epidemiologic studies. These recommendations can transform cancer epidemiology and the field of epidemiology in general, by enhancing transparency, interdisciplinary collaboration, and strategic applications of new technologies. They should lay a strong scientific foundation for accelerated translation of scientific discoveries into individual and population health benefits

Role & alternative splicing regulation of HBZ & Fra-2 protein isoforms in Adult T-cell Leukemia (ATL) development

Le virus T-lymphotropique humain de type 1 (HTLV-1) a été le premier rétrovirus associé à une pathologie humaine. Il infecte aujourd'hui 5 à 10 millions de personnes dans le monde et est responsable chez 5% d'entre eux d'un cancer rare mais très agressif et incurable : la Leucémie à cellules T de l'Adulte (ATL). Parmi les protéines virales importantes pour l'infection et la survenue du cancer, la protéine antisens HBZ (HTLV-1 bZIP factor) joue un rôle majeur. Cette protéine est codée sur le brin complémentaire du génome proviral à partir du LTR-3'et existe sous deux isoformes : usHBZ et HBZ_SP1. Si les fonctions d'HBZ dans la pathogénèse et l'oncogénèse associées à HTLV-1 ne sont pas discutables, très peu d'études ont fait la distinction entre ces deux isoformes. Ce projet de thèse révèle dans une première partie qu'usHBZ et HBZ_SP1 possèdent des propriétés oncogéniques similaires, mais qu'HBZ_SP1 est exprimée de façon largement majoritaire à usHBZ (ratio de 1:300) chez les patients ATL. Trois facteurs régulateurs de l'épissage d'HBZ ont également été identifiés : les hnRNPs A1, H1 et E1 ; dont l'un (A1) semble faire partie d'une boucle de régulation qui maintient l'épissage d'HBZ_SP1. Plusieurs essais de minigènes ont ensuite révélé que cette isoforme est elle-même capable de moduler l'épissage alternatif en induisant l'inclusion d'exons. Dans une seconde partie, l'étude s'est intéressée au rôle du facteur de transcription Fra-2, surexprimé dans l'ATL. Deux isoformes putatives de Fra-2 (X1 et X4) ont été décrites pour la première fois de façon expérimentale au cours de cette thèse. L'isoforme X4 est celle qui confère aux cellules les propriétés oncogéniques (prolifération, transformation et migration) et de résistance aux drogues (via une augmentation de l'efflux) les plus importantes. La construction d'un minigène Fra-2 X4 révèle que le facteur d'épissage RNPS1, qui semble interagir avec HBZ, active l'épissage vers cette isoforme oncogénique. Comme HBZ_SP1 promeut l'inclusion d'exon, son implication dans l'inclusion de l'exon 4 de Fra-2 reste à confirmer. Ce travail contribue à une meilleure compréhension du rôle que jouent différentes isoformes de protéines oncogéniques dans la transformation cellulaire, et souligne l'importance de l'étude de l'épissage alternatif dans un contexte infectieux et cancéreux.The human T-lymphotropic virus type 1 (HTLV-1) was the first retrovirus associated with a human malignancy. It infects 5 to 10 million individuals worldwide and is responsible, in 5% of cases, for a rare but highly aggressive and incurable cancer named Adult T-cell Leukemia (ATL). Among viral proteins implicated in the infection and cancer onset, antisense protein HBZ (HTLV-1 bZIP factor) plays a major role. It is encoded on the complementary strand of proviral genome from the 3'-LTR and exists under two proteins isoforms: usHBZ (unspliced) and HBZ_SP1 (spliced). If there are no doubts about HBZ functions in HTLV-1 associated pathogenesis and oncogenesis, very few studies have distinguished the two isoforms so far. We reveal in the first part of this thesis work that both usHBZ and HBZ_SP1 have oncogenic properties, but that HBZ_SP1 is ~300 times more expressed than usHBZ in ATL patients' samples. Three HBZ-splicing factors have been identified: hnRNPs A1, H1 and E1; and A1 seems to be part of a regulation loop to maintain HBZ splicing toward HBZ_SP1 isoform. Various minigene-assays also revealed that HBZ_SP1 modulates splicing by promoting exon inclusion. In the second part, we approached a transcription factor overexpressed in ATL: Fra-2. We managed to describe experimentally for the first time the expression of two isoforms (X1 and X4) in ATL patients' samples. X4 is the most oncogenic isoforms of all, given its cell proliferation, transformation and migration properties, and also gives a drug resistance advantage to cells by promoting drug efflux. Fra-2 X4 minigene construction then revealed that splicing factor RNPS1 seemingly interacts with HBZ, and induces Fra-2 splicing toward the X4 oncogenic isoform. As HBZ_SP1 also promotes exon inclusion, its role in the inclusion of the exon 4 of Fra-2 remains to be confirmed. This work contributes to a better understanding of the role of different oncogenic proteins isoforms in cell transformation and underlines the importance of studying alternative splicing regulation in infections and cancers

Rôles et régulation des isoformes protéiques d'HBZ du HTLV-1 & de Fra-2 dans la Leucémie T de l'Adulte

The human T-lymphotropic virus type 1 (HTLV-1) was the first retrovirus associated with a human malignancy. It infects 5 to 10 million individuals worldwide and is responsible, in 5% of cases, for a rare but highly aggressive and incurable cancer named Adult T-cell Leukemia (ATL). Among viral proteins implicated in the infection and cancer onset, antisense protein HBZ (HTLV-1 bZIP factor) plays a major role. It is encoded on the complementary strand of proviral genome from the 3'-LTR and exists under two proteins isoforms: usHBZ (unspliced) and HBZ_SP1 (spliced). If there are no doubts about HBZ functions in HTLV-1 associated pathogenesis and oncogenesis, very few studies have distinguished the two isoforms so far. We reveal in the first part of this thesis work that both usHBZ and HBZ_SP1 have oncogenic properties, but that HBZ_SP1 is ~300 times more expressed than usHBZ in ATL patients' samples. Three HBZ-splicing factors have been identified: hnRNPs A1, H1 and E1; and A1 seems to be part of a regulation loop to maintain HBZ splicing toward HBZ_SP1 isoform. Various minigene-assays also revealed that HBZ_SP1 modulates splicing by promoting exon inclusion. In the second part, we approached a transcription factor overexpressed in ATL: Fra-2. We managed to describe experimentally for the first time the expression of two isoforms (X1 and X4) in ATL patients' samples. X4 is the most oncogenic isoforms of all, given its cell proliferation, transformation and migration properties, and also gives a drug resistance advantage to cells by promoting drug efflux. Fra-2 X4 minigene construction then revealed that splicing factor RNPS1 seemingly interacts with HBZ, and induces Fra-2 splicing toward the X4 oncogenic isoform. As HBZ_SP1 also promotes exon inclusion, its role in the inclusion of the exon 4 of Fra-2 remains to be confirmed. This work contributes to a better understanding of the role of different oncogenic proteins isoforms in cell transformation and underlines the importance of studying alternative splicing regulation in infections and cancers.Le virus T-lymphotropique humain de type 1 (HTLV-1) a été le premier rétrovirus associé à une pathologie humaine. Il infecte aujourd'hui 5 à 10 millions de personnes dans le monde et est responsable chez 5% d'entre eux d'un cancer rare mais très agressif et incurable : la Leucémie à cellules T de l'Adulte (ATL). Parmi les protéines virales importantes pour l'infection et la survenue du cancer, la protéine antisens HBZ (HTLV-1 bZIP factor) joue un rôle majeur. Cette protéine est codée sur le brin complémentaire du génome proviral à partir du LTR-3'et existe sous deux isoformes : usHBZ et HBZ_SP1. Si les fonctions d'HBZ dans la pathogénèse et l'oncogénèse associées à HTLV-1 ne sont pas discutables, très peu d'études ont fait la distinction entre ces deux isoformes. Ce projet de thèse révèle dans une première partie qu'usHBZ et HBZ_SP1 possèdent des propriétés oncogéniques similaires, mais qu'HBZ_SP1 est exprimée de façon largement majoritaire à usHBZ (ratio de 1:300) chez les patients ATL. Trois facteurs régulateurs de l'épissage d'HBZ ont également été identifiés : les hnRNPs A1, H1 et E1 ; dont l'un (A1) semble faire partie d'une boucle de régulation qui maintient l'épissage d'HBZ_SP1. Plusieurs essais de minigènes ont ensuite révélé que cette isoforme est elle-même capable de moduler l'épissage alternatif en induisant l'inclusion d'exons. Dans une seconde partie, l'étude s'est intéressée au rôle du facteur de transcription Fra-2, surexprimé dans l'ATL. Deux isoformes putatives de Fra-2 (X1 et X4) ont été décrites pour la première fois de façon expérimentale au cours de cette thèse. L'isoforme X4 est celle qui confère aux cellules les propriétés oncogéniques (prolifération, transformation et migration) et de résistance aux drogues (via une augmentation de l'efflux) les plus importantes. La construction d'un minigène Fra-2 X4 révèle que le facteur d'épissage RNPS1, qui semble interagir avec HBZ, active l'épissage vers cette isoforme oncogénique. Comme HBZ_SP1 promeut l'inclusion d'exon, son implication dans l'inclusion de l'exon 4 de Fra-2 reste à confirmer. Ce travail contribue à une meilleure compréhension du rôle que jouent différentes isoformes de protéines oncogéniques dans la transformation cellulaire, et souligne l'importance de l'étude de l'épissage alternatif dans un contexte infectieux et cancéreux

Alternative RNA splicing in cancer: what about adult T-cell leukemia?

International audienceEukaryotic cells employ a broad range of mechanisms to regulate gene expression. Among others, mRNA alternative splicing is a key process. It consists of introns removal from an immature mRNA (pre-mRNA) via a transesterification reaction to create a mature mRNA molecule. Large-scale genomic studies have shown that in the human genome, almost 95% of protein-encoding genes go through alternative splicing and produce transcripts with different exons combinations (and sometimes retained introns), thus increasing the proteome diversity. Considering the importance of RNA regulation in cellular proliferation, survival, and differentiation, alterations in the alternative splicing pathway have been linked to several human cancers, including adult T-cell leukemia/lymphoma (ATL). ATL is an aggressive and fatal malignancy caused by the Human T-cell leukemia virus type 1 (HTLV-1). HTLV-1 genome encodes for two oncoproteins: Tax and HBZ, both playing significant roles in the transformation of infected cells and ATL onset. Here, we review current knowledge on alternative splicing and its link to cancers and reflect on how dysregulation of this pathway could participate in HTLV-1-induced cellular transformation and adult T-cell leukemia/lymphoma development

Job Creation: A Review of Policies and Strategies

Public Affairs, Public Policy and Public Administration