Effect of spironolactone on pharmacological treatment of nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) was recently renamed to metabolic (dysfunction)-associated fatty liver disease (MAFLD) to better characterize its pathogenic origin. NAFLD represents, at least in western societies, a potential epidemic with raising prevalence. Its multifactorial pathogenesis is partially unraveled and till now there is no approved pharmacotherapy for NAFLD. A plethora of various choices are investigated in clinical trials, targeting an arsenal of different pathways and molecules. Since the mineralocorticoid receptor (MR) and renin-angiotensin-aldosterone system (RAAS) appear to be implicated in NAFLD, within this concise review, we focus on a rather classical and inexpensive pharmacological agent, spironolactone. We present the current lines of evidence of MR and RAAS-related preclinical models and human trials reporting an association with NAFLD. In conclusion, evidence about spironolactone of RAAS is commented, as potential future pharmacological management of NAFLD.

Soluble PD-L1 generated by endogenous retroelement exaptation is a receptor antagonist.

Immune regulation is a finely balanced process of positive and negative signals. PD-L1 and its receptor PD-1 are critical regulators of autoimmune, antiviral and antitumoural T cell responses. Although the function of its predominant membrane-bound form is well established, the source and biological activity of soluble PD-L1 (sPD-L1) remain incompletely understood. Here, we show that sPD-L1 in human healthy tissues and tumours is produced by exaptation of an intronic LINE-2A (L2A) endogenous retroelement in the CD274 gene, encoding PD-L1, which causes omission of the transmembrane domain and the regulatory sequence in the canonical 3' untranslated region. The alternatively spliced CD274-L2A transcript forms the major source of sPD-L1 and is highly conserved in hominids, but lost in mice and a few related species. Importantly, CD274-L2A-encoded sPD-L1 lacks measurable T cell inhibitory activity. Instead, it functions as a receptor antagonist, blocking the inhibitory activity of PD-L1 bound on cellular or exosomal membranes.

Hyperhemolytic Syndrome Complicating a Delayed Hemolytic Transfusion Reaction due to anti-P1 Alloimmunization, in a Pregnant Woman with HbO-Arab/ß-Thalassemia.

BACKGROUND: Hyperhemolytic Syndrome or Hyperhemolytic Transfusion Reaction (HHTR), a life-threatening subset of Delayed Hemolytic Transfusion Reaction (DHTR) is characterized by destruction of both transfused and autologous erythrocytes evidenced by a fall in post transfusion hemoglobin below the pre-transfusion level. CASE REPORT: We describe a case of DHTR due to anti-P1 alloimmunization manifesting with hyperhemolysis in a 30-year-old Greek Pomak woman with thalassemia intermedia (HbO-Arab/ß-thalassemia), during the11th week of her first gestation. She was successfully managed with avoidance of further transfusions and administration of IVIG and corticosteroids. CONCLUSION: A high index of suspicion for HHTR is of vital importance among clinicians especially since optimal methods for its prevention and treatment remain yet to be defined. Early recognition of HHTR leading to prompt cessation of additional transfusions and initiation of immunosuppressive treatment can be life-saving, especially in clinical settings where limited therapeutic options are available, such as in pregnancy.

Adaptive Evolution Coupled with Retrotransposon Exaptation Allowed for the Generation of a Human-Protein-Specific Coding Gene That Promotes Cancer Cell Proliferation and Metastasis in Both Haematological Malignancies and Solid Tumours: The Extraordinary Case of MYEOV Gene.

The incidence of cancer in human is high as compared to chimpanzee. However previous analysis has documented that numerous human cancer-related genes are highly conserved in chimpanzee. Till date whether human genome includes species-specific cancer-related genes that could potentially contribute to a higher cancer susceptibility remains obscure. This study focuses on MYEOV, an oncogene encoding for two protein isoforms, reported as causally involved in promoting cancer cell proliferation and metastasis in both haematological malignancies and solid tumours. First we document, via stringent in silico analysis, that MYEOV arose de novo in Catarrhini. We show that MYEOV short-isoform start codon was evolutionarily acquired after Catarrhini/Platyrrhini divergence. Throughout the course of Catarrhini evolution MYEOV acquired a gradually elongated translatable open reading frame (ORF), a gradually shortened translation-regulatory upstream ORF, and alternatively spliced mRNA variants. A point mutation introduced in human allowed for the acquisition of MYEOV long-isoform start codon. Second, we demonstrate the precious impact of exonized transposable elements on the creation of MYEOV gene structure. Third, we highlight that the initial part of MYEOV long-isoform coding DNA sequence was under positive selection pressure during Catarrhini evolution. MYEOV represents a Primate Orphan Gene that acquired, via ORF expansion, a human-protein-specific coding potential.

Three-fold higher frequency of circulating chronic lymphocytic leukemia-like B-cell clones in patients with Ph-Myeloproliferative neoplasms.

Philadelphia chromosome-negative Myeloproliferative neoplasms (Ph-MPN) are accompanied by a markedly increased risk for development of chronic lymphocytic leukemia (CLL) compared to the general population. However, the pattern of onset and the biological characteristics of CLL in patients with coexistent Ph-MPN are highly heterogeneous rendering questionable if the above association reflects a causal relationship between the two disorders or merely represents a random event. By analyzing 82 patients with Ph-MPN and 100 age-matched healthy individuals we demonstrate that MPN patients have an almost threefold higher prevalence of, typically low-count, CLL-like monoclonal B lymphocytosis (MBL) compared to normal adults. The clone size remained unaltered during the disease course and unaffected by the administration of hydroxycarbamide, whereas no patient with Ph-MPN/MBL progressed to CLL during a median follow up of 4 years. Monoclonal B cells in Ph-MPN/MBL patients and normal individuals and in four more patients with coexistence of overt CLL and MPN displayed heterogeneous biological characteristics, while the JAK2V617F mutation was absent in isolated lymphocytes from Ph-MPN patients with coexistence of CLL. Despite its clinical and biological variability, the increased incidence of MBL in Ph-MPN patients along with the one reported for CLL further enforces the notion of a shared pathophysiology among the two malignancies via a common genetic link and/or microenviromental interactions.

A case-control study on the rs3130932 single nucleotide polymorphism in the OCT4B translation initiation codon in association with cancer state.

A previously characterized single nucleotide polymorphism (rs3130932) in the translation initiation codon of the OCT4B isoform of the human OCT4 gene, ATG → AGG, is expected to hamper its expression in individuals carrying the AGG genotype. A case-control association study was conducted to validate the AGG genotype as a risk factor for tumour development. Blood samples were collected from 221 female patients with breast cancer, 100 female patients with ovarian cancer, 109 male patients with lung cancer and 553 age-matched and sex-matched healthy individuals. DNA was tested by restriction fragment length polymorphism-PCR for the presence of rs3130932. Statistical association studies were carried out to investigate any association between hOCT4 genotypes and the onset of cancer. Genotypic and allelic statistical analyses led to no significant case-control differences at a P value of less than 0.05 in all different types of cancer, thus showing no significant correlation of the hOCT4 genotypes tested with breast, ovarian or lung cancer risk. The AGG genotype in rs3130932 is not associated with increased (or decreased) cancer risk in homozygous individuals. Research focusing on the elucidation of the biological roles of each OCT4 isoform is further warranted.

OCT4B1 isoform: the novel OCT4 alternative spliced variant as a putative marker of stemness.

A novel OCT4 alternative spliced variant (OCT 4B1) is deduced to be the isoform present in 59 hESC lines characterised by the International Stem Cell Initiative (ISCI) rather than OCT4A as previously assumed. The new variant may be a more reliable marker of stemness than OCT4A and studies are needed to test this.

Revisiting OCT4 expression in peripheral blood mononuclear cells.

The transcription factor OCT4 (officially POU5F1; alternatively OCT3, OCT3/4, OTF3, and OTF4) is currently considered a main regulator of human embryonic stem cell pluripotency and self-renewal capacities. Importantly, these stemness properties are attributed to OCT4A, which is one of the two isoforms produced by the OCT4 gene. The second OCT4 isoform, OCT4B, does not share the stemness factor characteristics of OCT4A and is currently considered of unknown function. Hence, when investigating OCT4 expression at the mRNA and protein level, it is important to specify which OCT4 isoform is detected by the applied methods, such as polymerase chain reaction assays and immunocytochemistry antibodies. Here, we discuss the need to distinguish between OCT4A and OCT4B when interpreting OCT4 expression in differentiated cells, such as peripheral blood mononuclear cells.