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Heart failure (HF) is characterized by frequent hospital admissions due to acute decompensation and shortened life span with a progressive clinical course leading to an advanced stage where traditional therapies become ineffective. Due to aging of the population and improved therapies, only a small of proportion of patients with advanced HF are candidates for surgical treatments, such as mechanical circulatory support or heart transplantation. In most cases, prompt identification and management of congestion is paramount to improving symptoms and quality of life and avoiding progression to severe multiorgan dysfunction and death.

Acute heart failure (AHF) is a complex, heterogeneous, clinical syndrome with high morbidity and mortality, incurring significant health care costs. Patients transition from home to the emergency department, the hospital, and home again and require decisions surrounding diagnosis, treatment, and prognosis at each step of the way. The purpose of this review is to examine the epidemiology, etiology, and classifications of AHF and specifically focus on practical information relevant to the clinician. We examine the mechanisms of decompensation relevant to clinical presentations-including precipitating factors, neuroendocrine interactions, and inflammation-along with how consideration of these factors may help select therapies for an individual patient. The prevalence and significance of end-organ manifestations such as renal, gastrointestinal, respiratory, and neurologic manifestations are discussed. We also highlight how the development of renal dysfunction relates to the choice of a variety of diuretics that may be useful in specific circumstances and review guideline-directed medical therapy. We discuss the practical use (and pitfalls) of a variety of evidence-based clinical scoring criteria available to risk stratify patients with AHF. Finally, evidence-based management of AHF is discussed, including both pharmacologic and nonpharmacologic therapies, including the lack of evidence for using old and new vasodilators and the recent evidence regarding initiation of newer therapies in hospital. Overall, we suggest that clinicians consider implementing the newer data in AHF and subject existing practice patterns and treatments to the same rigour as new therapies.

Mucopolysaccharidosis type I (MPS-I) is a severe genetic disease caused by a deficiency of the alpha-L-iduronidase (IDUA) enzyme. Ex vivo hematopoietic stem cell (HSC) gene therapy is a promising therapeutic approach for MPS-I, as demonstrated by preclinical studies performed in naive MPS-I mice. However, after enzyme replacement therapy (ERT), several MPS-I patients develop anti-IDUA immunity that may jeopardize ex vivo gene therapy efficacy. Here we treat MPS-I mice with an artificial immunization protocol to mimic the ERT effect in patients, and we demonstrate that IDUA-corrected HSC engraftment is impaired in pre-immunized animals by IDUA-specific CD8+ T cells spared by pre-transplant irradiation. Conversely, humoral anti-IDUA immunity does not impact on IDUA-corrected HSC engraftment. The inclusion of lympho-depleting agents in pre-transplant conditioning of pre-immunized hosts allowes rescue of IDUA-corrected HSC engraftment, which is proportional to CD8+ T cell eradication. Overall, these data demonstrate the relevance of pre-existing anti-transgene T cell immunity on ex vivo HSC gene therapy, and they suggest the application of tailored immune-depleting treatments, as well as a deeper immunological characterization of patients, to safeguard the therapeutic effects of ex vivo HSC gene therapy in immunocompetent hosts., MPS-I patients receiving enzyme replacement therapy develop an anti-IDUA immune response that may affect ex vivo gene therapy. Squeri et al. show, in the MPS-I murine model, that pre-existing IDUA-specific CD8+ T cell response impairs LV-transduced HSC engraftment and that the efficacy of ex vivo gene therapy is rescued by lympho-depleting drugs.

Ovarian carcinoma arises from the ovarian surface epithelium, which undergoes phenotypic changes characteristic of mullerian epithelium during the first stages of tumorigenesis. The variant isoform of the hepatocyte nuclear factor 1 (vHNF1) is a transcription factor involved in the development of tissues derived from the mullerian duct. Here, we show that vHNF1 knockdown in two ovarian carcinoma cell lines, SKOV3 and IGROV1, leads to reduced E-cadherin (E-cadh) expression and decreased proliferation rate. Accordingly, SKOV3 cells ectopically expressing a dominant-negative (DN) vHNF1 mutant undergo an epithelial-mesenchymal-like transition, acquiring a spindle-like morphology, loss of E-cadh, and disrupted cell-cell contacts. Gene expression profiling of DNvHNF1 cells on the basis of a newly compiled list of epithelial-mesenchymal transition-related genes revealed a correlation between vHNF1 loss-of-function and acquisition of the mesenchymal phenotype. Indeed, phenotypic changes were associated with increased Slug transcription and functionality. Accordingly, vHNF1-transfected immortalized ovarian surface epithelial cells showed down-regulation of Snail and Slug transcripts. In DNvHNF1-transfected SKOV3 cells, growth rate decreased, and in vHNF1-transfected immortalized ovarian surface epithelial cells, growth rate increased. By immunohistochemistry, we found a strong association of vHNF1 with E-cadh in clear cell and in a subset of serous carcinomas, data that could potentially contribute in distinguishing different types of ovarian tumors. Our results may help in understanding the biology of ovarian carcinoma, identifying early detection markers, and opening potential avenues for therapeutic intervention.