Background: The goal of the study was to evaluate a potential role for tumor necrosis factor alpha (TNF-α) genetic variability as biomarker in sepsis. In particular, we aimed to determine if single nucleotide polymorphisms (SNPs) ofTNF-αgene are associated with sepsis in terms of risk, severity and outcome.Methods: We performed a prospective study on 163 adult critically ill septic patients (septic shock 65, sepsis 98, further divided in 40 survivors and 123 deceased) and 232 healthy controls. Genotyping ofTNF-αSNPs (-308G/A, -238G/A, -376G/A and +489G/A) was performed for all patients and controls and plasma cytokine levels were measured during the first 24 h after sepsis onset.Results: TNF-α +489G/A A-allele carriage was associated with significantly lower risk of developing sepsis and sepsis shock (AA+AG vs GG: OR = 0.53;p = 0.004; 95% CI = 0.34–0.82 and OR = 0.39;p = 0.003; 95% CI = 0.21–0.74, respectively) but not with sepsis-related outcomes. There was no significant association between any of the otherTNF-αpromoter SNPs, or their haplotype frequencies and sepsis or septic shock risk. Circulating TNF-α levels were higher in septic shock; they were not correlated with SNP genotype distribution; GG homozygosity for each polymorphism was correlated with higher TNF-α levels in septic shock.Conclusions: TNF-α +489G/A SNP A-allele carriage may confer protection against sepsis and septic shock development but apparently does not influence sepsis-related mortality. PromoterTNF-αSNPs did not affect transcription and were not associated with distinct sepsis, septic shock risk or outcomes.

Oxidative damage at the DNA level may be promoted by high levels of reactive oxygen species (ROS), leading to genomic instability and increased neoplastic risk. Superoxide dismutase (SOD), glutathione peroxidase (GPX), and catalase (CAT) enzymes are implicated in the prevention of DNA damage by ROS. The aim of the study was to investigate the relationships betweenCATC262T,GPX1Pro198Leu,MnSODAla16Val,GSTM1, GSTT1, andGSTP1Ile105Val polymorphisms and the risk of CML. No association was observed between CML and variant genotypes ofGPX1, MnSOD, GSTM1, andGSTT1polymorphisms in any of the investigated cases. Our study suggests that the homozygous variant genotype of theGSTP1Ile105Val gene polymorphisms may be associated with the risk of developing CML (OR=2.5; 95% CI=1.08–5.7;Pvalue = 0.02), while the heterozygous genotype of theCATC262T polymorphism seems to have a protective effect against CML (OR=0.59, 95% CI=0.39–0.89,Pvalue = 0.01). In most cases, no association was found between laboratory parameters and prognostic factors and the variant genotype of investigated gene polymorphisms. We concluded thatCAT, GPX, MnSOD, GSTM1, andGSTT1gene polymorphisms are not associated with the risk of CML. Variant genotype of theGSTP1Ile105Val gene polymorphisms may contribute to the risk of developing CML.

Background and Aims. Diabetic neuropathy is a frequent complication of type 2 diabetes mellitus (T2DM). Genetic susceptibility and oxidative stress may play a role in the appearance of T2DM and diabetic neuropathy. We investigated the relation between polymorphism in genes related to oxidative stress such asGSTM1,GSTT1, andGSTP1and the presence of T2DM and diabetic neuropathy (DN).Methods. Samples were collected from 84 patients with T2DM (42 patients with DN and 42 patients without DN) and 98 healthy controls and genotyped by using polymerase chain reaction and restriction fragment length polymorphism method.Results.GSTP1Ile105Val polymorphism was associated with the risk of developing T2DM (p=0.05) but not with the risk of developing DN in diabetic cases.GSTM1andGSTT1gene polymorphisms were associated with neither the risk of developing T2DM nor the risk of DN occurrence in diabetic patients. No association was observed between the patients with T2DM and DSPN (diabetic sensorimotor peripheral neuropathy) and T2DM without DSPN regarding investigated polymorphism.Conclusion. Our data suggest thatGSTP1gene polymorphisms may contribute to the development of T2DM in Romanian population.GSTM1,GSTT1, andGSTP1gene polymorphisms are not associated with susceptibility of developing diabetic neuropathy in T2DM patients.

Polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are classical myeloproliferative neoplasms (MPN), characterized by specific somatic mutations in JAK2, CALR or MPL genes. JAK2 46/1 and TERT rs2736100 polymorphisms are known to significantly predispose to MPN. This study aimed to establish the additional contribution of the recently described MECOM rs2201862, HBS1L‐MYB rs9376092 and THRB‐RARB rs4858647 polymorphisms to the occurrence of MPN. These three polymorphisms, along with JAK2 46/1 and TERT rs2736100 were genotyped in 939 MPN patients (454 with ET, 337 with PV and 148 with PMF) and 483 controls. MECOM rs2201862 associated significantly with each MPN entity, except for ET, and with all major molecular sub‐types, especially those CALR‐mutated (OR = 1.4; 95% CI = 1.1‐1.8; P‐value = .005). HBS1L‐MYB rs9376092 associated only with JAK2 V617F‐mutated ET (OR = 1.4; 95% CI = 1.1‐1.7; P‐value = .003). THRB‐RARB rs4858647 had a weak association with PMF only (OR = 1.5; 95% CI = 1‐2.1; P‐value = .04). Surprisingly, JAK2 46/1 haplotype was associated significantly not only with JAK2 V617F‐mutated MPN, but also with CALR‐mutated MPN (OR = 1.4; 95% CI = 1.1‐1.8; P‐value = .01). TERT rs2736100 was associated equally strong with all MPN, regardless of phenotype or molecular sub‐type. In conclusion, JAK2 46/1, TERT rs2736100 and MECOM rs2201862 are the chief predisposing polymorphisms to MPN.

It is well known that critically ill patients require special attention and additional consideration during their treatment and management. The multiple systems and organ dysfunctions, typical of the critical patient, often results in different patterns of enteral absorption in these patients. Anti-platelet drugs are the cornerstone in treating patients with coronary and cerebrovascular disease. Dual anti-platelet therapy with aspirin and clopidogrel is the treatment of choice in patients undergoing elective percutaneous coronary interventions and is still widely used in patients with acute coronary syndromes. However, despite the use of dual anti-platelet therapy, some patients continue to experience cardiovascular ischemic events. Recurrence of ischemic events is partly attributed to the fact that some patients have poor inhibition of platelet reactivity despite treatment. These patients are considered low- or nonresponders to therapy. The underlying mechanisms leading to resistance are not yet fully elucidated and are probably multifactorial, cellular, genetic and clinical factors being implicated. Several methods have been developed to asses platelet function and can be used to identify patients with persistent platelet reactivity, which have an increased risk of thrombosis. In this paper, the concept of anti-platelet therapy resistance, the underlying mechanisms and the methods used to identify patients with low responsiveness to anti-platelet therapy will be highlighted with a focus on aspirin and clopidogrel therapy and addressing especially critically ill patients.

Myelodysplastic neoplasm (MDS) represents a heterogeneous group of myeloid disorders that originate from the hematopoietic stem and progenitor cells that lead to the development of clonal hematopoiesis. MDS was characterized by an increased risk of transformation into acute myeloid leukemia (AML). In recent years, with the aid of next-generation sequencing (NGS), an increasing number of molecular aberrations were discovered, such as recurrent mutations in FLT3, NPM1, DNMT3A, TP53, NRAS, and RUNX1 genes. During MDS progression to leukemia, the order of gene mutation acquisition is not random and is important when considering the prognostic impact. Moreover, the co-occurrence of certain gene mutations is not random; some of the combinations of gene mutations seem to have a high frequency (ASXL1 and U2AF1), while the co-occurrence of mutations in splicing factor genes is rarely observed. Recent progress in the understanding of molecular events has led to MDS transformation into AML and unraveling the genetic signature has paved the way for developing novel targeted and personalized treatments. This article reviews the genetic abnormalities that increase the risk of MDS transformation to AML, and the impact of genetic changes on evolution. Selected therapies for MDS and MDS progression to AML are also discussed.