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

Eukaryotic 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.

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 (ORadj = 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 (ORadj = 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.

RNA testing for the diagnosis of acute hepatitis A during the 2017 outbreak in France.

Diagnostic of acute hepatitis A virus (HAV) infection is based on the detection of anti-HAV IgM without testing for the pathogen itself. We evaluated the usefulness of HAV RNA testing for confirmation of acute hepatitis A and to provide indications about the level of HAV replication in HIV-positive and HIV-negative subjects during an unprecedented outbreak of HAV observed in France in 2017. HAV RNA was detected in 38 out of 41 (92.6%) subjects with a clinical diagnosis of acute hepatitis A, whereas nine cases tested positive for anti-HAV IgM in whom the diagnosis of acute hepatitis A was not retained were found negative for HAV RNA. All subjects in the control group were also tested negative for HAV RNA. HAV viremia was correlated to ALT peak (r = .64; P < .0001). HIV-infected patients have similar HAV RNA levels but were less likely to have prolonged international normalized ratio of prothrombin time when compared to the HIV-uninfected group (P = .016), suggesting a less severe course of acute hepatitis. HAV RNA was detected in the serum of most of the patients with acute hepatitis A, indicating that the direct detection of HAV can be used to confirm hepatitis A in patients tested positive for anti-HAV IgM antibodies. Nucleic acid tests should serve more broadly during the diagnosis workup of acute hepatitis A to improve the predictive values of HAV in vitro diagnostic tests and to confirm acute hepatitis A in patients tested positive with IgM with moderate or low S/CO values.