Since myeloproliferative neoplasms (MPN) pose a significant risk for vascular and thrombotic complications, cytoreductive therapies, such as hydroxyurea (HU), interferon (IFN) inhibitors, and Janus kinase (JAK) inhibitors are recommended for patients at high risk. However, these agents also place patients at increased risk for drug-related cutaneous adverse events. Herein, we review the literature on skin toxicity related to the use of drugs for the treatment of MPN. Overall, the cytoreductive agents used for MPN are generally well tolerated and considered to be safe, except IFN, for which dropout rates as high as 25% have been reported. While IFN is known to give rise to flu syndrome, it rarely leads to hematological alterations. The most common hematological side effects of HU are mild and include granulocytopenia, anemia, and thrombocytopenia. The JAK inhibitor ruxolitinib has been associated with cytopenia and a higher incidence of viral infections, as well as increased risk for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Based on the present analysis, it can be concluded that cutaneous toxicity is not a negligible complication of commonly used treatments for MPN. While further research is needed, patients on these agents, and especially those with a history of cutaneous malignancies, should undergo thorough skin examination before and during therapy. In addition, detailed history is critical since many patients who develop non-melanoma skin cancer have multiple preexisting risk factors for cutaneous carcinogenesis.

Chromosome 16 is one of the most gene-rich chromosomes of our genome, and 10% of its sequence consists of segmental duplications, which give instability and predisposition to rearrangement by the recurrent mechanism of non-allelic homologous recombination. Microarray technologies have allowed for the analysis of copy number variations (CNVs) that can contribute to the risk of developing complex diseases. By array comparative genomic hybridization (CGH) screening of 1476 patients, we detected 27 cases with CNVs on chromosome 16. We identified four smallest regions of overlapping (SROs): one at 16p13.11 was found in seven patients; one at 16p12.2 was found in four patients; two close SROs at 16p11.2 were found in twelve patients; finally, six patients were found with atypical rearrangements. Although phenotypic variability was observed, we identified a male bias for Childhood Apraxia of Speech associated to 16p11.2 microdeletions. We also reported an elevated frequency of second-site genomic alterations, supporting the model of the second hit to explain the clinical variability associated with CNV syndromes. Our goal was to contribute to the building of a chromosome 16 disease-map based on disease susceptibility regions. The role of the CNVs of chromosome 16 was increasingly made clear in the determination of developmental delay. We also found that in some cases a second-site CNV could explain the phenotypic heterogeneity by a simple additive effect or a pejorative synergistic effect.

Tumor necrosis factor (TNF) alpha is a major proinflammatory cytokine involved in the immune response in inflammatory bowel disease (IBD). Anti-TNF drugs such as infliximab and adalimumab are used to treat IBD; however, approximately 30% of patients do not respond to treatment. Individual genetic differences could contribute to lack of efficacy. Genetic studies have tried to uncover the factors underlying differences in response, however, knowledge remains limited, and the results obtained should be validated, so that pharmacogenetic information can be applied in clinical practice. In this review, we gather current knowledge in the pharmacogenetics of anti-TNF drugs in patients with IBD. We observed a connection between the major genes described as possible predictors of response to anti-TNF drugs in IBD and the cytokines and molecules involved in the T helper (Th) 17 pathway.

The clinical phenotype of LMNA-associated dilated cardiomyopathy (DCM) varies even among individuals who share the same mutation. LMNA encodes lamin AC, which interacts with the lamin-associated protein 2 alpha (LAP2α) encoded by the TMPO gene. The LAP2α/Arg690Cys polymorphism is frequent in Latin America and was previously found to disrupt LAP2α-Lamin AC interactions in vitro. We identified a DCM patient heterozygous for both a lamin AC truncating mutation (Ser431*) and the LAP2α/Arg690Cys polymorphism. We performed protein modeling and docking experiments, and used confocal microscopy to compare leukocyte nuclear morphology among family members with different genotype combinations (wild type, LAP2α Arg690Cys heterozygous, lamin AC/Ser431* heterozygous, and LAP2α Arg690Cys/lamin AC Ser431* double heterozygous). Protein modeling predicted that 690Cys destabilizes the LAP2α homodimer and impairs lamin AC-LAP2α docking. Lamin AC-deficient nuclei (Ser431* heterozygous) showed characteristic blebs and invaginations, significantly decreased nuclear area, and increased elongation, while LAP2α/Arg690Cys heterozygous nuclei showed a lower perimeter and higher circularity than wild-type nuclei. LAP2α Arg690Cys apparently attenuated the effect of LMNA Ser431* on the nuclear area and fully compensated for its effect on nuclear circularity. Altogether, the data suggest that LAP2α/Arg690Cys may be one of the many factors contributing to phenotype variation of LMNA-associated DCM.

Drought is a serious problem, which causes heavy yield losses for rice. Heat-shock factors (HSFs) had been implicated in tolerance to drought and high temperature. However, there has not been much functional characterization and mechanism clarification in rice. Previously, we found an HSF gene, OsHSFA3, was highly related with drought tolerance after screening from 10,000 different samples. Herein, we cloned the OsHSFA3 from rice and overexpressed it in Arabidopsis thaliana to study its regulatory mechanism of drought tolerance. Phenotypic and physiological assays of the transgenic Arabidopsis lines showed that overexpression of OsHSFA3 confers drought tolerance by reducing water loss and reactive oxygen species (ROS) levels, whereas it increases abscisic acid (ABA) levels. However, enzymatic antioxidants such as activity levels of superoxide dismutase, peroxidase and catalase were not significantly different between wild type and transgenic lines. Instead, we observed a significant increase in polyamine content, which was correlated with increased AtADC1, AtADC2, SPDS1 and SPMS expression levels. In silico and in vivo analyses confirmed that OsHSFA3 is a nuclear-localized gene. In addition, OsHSFA3 can bind to the promoter of AtADC1 and OsADC via a yeast one-hybrid assay. Overall, this study reveals that OsHSFA3 improves drought tolerance in Arabidopsis not only by increasing ABA levels, but also by modulating polyamine levels to maintain ROS homeostasis, therefore it could be a strong candidate to develop drought-tolerant rice cultivars.

Splanchnic vein thrombosis (SVT) encompasses thrombosis in the vessels of the splanchnic basin and has a relatively rare occurrence with a reported frequency in the general population of 1-2%. An episode of seemingly unprovoked SVT almost always triggers a diagnostic work-up for a Philadelphia chromosome-negative myeloproliferative neoplasm (MPN), since atypical site thrombosis is a hallmark of MPN-associated thrombophilia. Primary myelofibrosis (PMF) is a rare MPN with an estimated incidence between 0.1 and 1/100,000 per year. Although prothrombotic tendency in PMF is not envisioned as a subject of specific therapeutic management, unlike other MPNs, such as polycythemia vera (PV) and essential thrombocythemia (ET), thrombotic risk and SVT prevalence in PMF may be comparably high. Additionally, unlike PV and ET, SVT development in PMF may depend more on procoagulant mechanisms involving endothelium than on blood cell activation. Emerging results from registry data also suggest that PMF patients with SVT may exhibit lower risk and better prognosis, thus highlighting the need for better thrombotic risk stratification and identifying a subset of patients with potential benefit from antithrombotic prophylaxis. This review highlights specific epidemiological, pathogenetic, and clinical features pertinent to SVT in myelofibrosis.

The CACNA1G gene encodes the low-voltage-activated Cav3.1 channel, which is expressed in various areas of the CNS, including the cerebellum. We studied two missense CACNA1G variants, p.L208P and p.L909F, and evaluated the relationships between the severity of Cav3.1 dysfunction and the clinical phenotype. The presentation was of a developmental and epileptic encephalopathy without evident cerebellar atrophy. Both patients exhibited axial hypotonia, developmental delay, and severe to profound cognitive impairment. The patient with the L909F mutation had initially refractory seizures and cerebellar ataxia, whereas the L208P patient had seizures only transiently but was overall more severely affected. In transfected mammalian cells, we determined the biophysical characteristics of L208P and L909F variants, relative to the wild-type channel and a previously reported gain-of-function Cav3.1 variant. The L208P mutation shifted the activation and inactivation curves to the hyperpolarized direction, slowed the kinetics of inactivation and deactivation, and reduced the availability of Ca2+ current during repetitive stimuli. The L909F mutation impacted channel function less severely, resulting in a hyperpolarizing shift of the activation curve and slower deactivation. These data suggest that L909F results in gain-of-function, whereas L208P exhibits mixed gain-of-function and loss-of-function effects due to opposing changes in the biophysical properties. Our study expands the clinical spectrum associated with CACNA1G mutations, corroborating further the causal association with distinct complex phenotypes.

Recent genome-wide association studies identified single nucleotide polymorphisms (SNPs) on the chromosome 9p21.3 conferring the risk for CAD (coronary artery disease) in individuals of Caucasian ancestry. We performed a genetic association study to investigate the effect of 12 candidate SNPs within 9p21.3 locus on the risk of CAD in the Saudi population of the Eastern Province of Saudi Arabia. A total of 250 Saudi CAD patients who had experienced an myocardial infarction (MI) and 252 Saudi age-matched healthy controls were genotyped using TaqMan assay. Controls with evidenced lack of CAD provided 90% of statistical power at the type I error rate of 0.05. Five percent of the results were rechecked for quality control using Sanger sequencing, the results of which concurred with the TaqMan genotyping results. Association analysis of 12 SNPs indicated a significant difference in the genotype distribution for four SNPs between cases and controls (rs564398 p = 0.0315, χ² = 4.6, odds ratio (OD) = 1.5; rs4977574 p = 0.0336, χ² = 4.5, OD = 1.4; rs2891168 p = 1.85 × 10 - 10, χ² = 40.6, OD = 2.1 and rs1333042 p = 5.14 × 10 - 9, χ² = 34.1, OD = 2.2). The study identified three protective haplotypes (TAAG p = 1.00 × 10 - 4; AGTA p = 0.022 and GGGCC p = 0.0175) and a risk haplotype (TGGA p = 2.86 × 10 - 10) for the development of CAD. This study is in line with others that indicated that the SNPs located in the intronic region of the CDKN2B-AS1 gene are associated with CAD.

Jasmonate ZIM-domain (JAZ) proteins are key repressors of a jasmonic acid signaling pathway. They play essential roles in the regulation of plant growth and development, as well as environmental stress responses. However, this gene family has not been explored in sweet potato. In this study, we identified 14, 15, and 14 JAZs in cultivated hexaploid sweet potato (Ipomoea batatas, 2n = 6x = 90), and its two diploid relatives Ipomoea trifida (2n = 2x = 30) and Ipomoea triloba (2n = 2x = 30), respectively. These JAZs were divided into five subgroups according to their phylogenetic relationships with Arabidopsis. The protein physiological properties, chromosome localization, phylogenetic relationship, gene structure, promoter cis-elements, protein interaction network, and expression pattern of these 43 JAZs were systematically investigated. The results suggested that there was a differentiation between homologous JAZs, and each JAZ gene played different vital roles in growth and development, hormone crosstalk, and abiotic stress response between sweet potato and its two diploid relatives. Our work provided comprehensive comparison and understanding of the JAZ genes in sweet potato and its two diploid relatives, supplied a theoretical foundation for their functional study, and further facilitated the molecular breeding of sweet potato.

Gastrointestinal stromal tumors (GIST) carrying the D842V activating mutation in the platelet-derived growth factor receptor alpha (PDGFRA) gene are a very rare subgroup of GIST (about 10%) known to be resistant to conventional tyrosine kinase inhibitors (TKIs) and to show an indolent behavior. In this study, we performed an integrated molecular characterization of D842V mutant GIST by whole-transcriptome and whole-exome sequencing coupled with protein-ligand interaction modelling to identify the molecular signature and any additional recurrent genomic event related to their clinical course. We found a very specific gene expression profile of D842V mutant tumors showing the activation of G-protein-coupled receptor (GPCR) signaling and a relative downregulation of cell cycle processes. Beyond D842V, no recurrently mutated genes were found in our cohort. Nevertheless, many private, clinically relevant alterations were found in each tumor (TP53, IDH1, FBXW7, SDH-complex). Molecular modeling of PDGFRA D842V suggests that the mutant protein binds imatinib with lower affinity with respect to wild-type structure, showing higher stability during the interaction with other type I TKIs (like crenolanib). D842V mutant GIST do not show any actionable recurrent molecular events of therapeutic significance, therefore this study supports the rationale of novel TKIs development that are currently being evaluated in clinical studies for the treatment of D842V mutant GIST.

Transgenic expression of Cre recombinase driven by a specific promoter is normally used to conditionally knockout a gene in a tissue- or cell-type-specific manner. In αMHC-Cre transgenic mouse model, expression of Cre recombinase is controlled by the myocardial-specific α-myosin heavy chain (αMHC) promoter, which is commonly used to edit myocardial-specific genes. Toxic effects of Cre expression have been reported, including intro-chromosome rearrangements, micronuclei formation and other forms of DNA damage, and cardiomyopathy was observed in cardiac-specific Cre transgenic mice. However, mechanisms associated with Cardiotoxicity of Cre remain poorly understood. In our study, our data unveiled that αMHC-Cre mice developed arrhythmias and died after six months progressively, and none of them survived more than one year. Histopathological examination showed that αMHC-Cre mice had aberrant proliferation of tumor-like tissue in the atrial chamber extended from and vacuolation of ventricular myocytes. Furthermore, the αMHC-Cre mice developed severe cardiac interstitial and perivascular fibrosis, accompanied by significant increase of expression levels of MMP-2 and MMP-9 in the cardiac atrium and ventricular. Moreover, cardiac-specific expression of Cre led to disintegration of the intercalated disc, along with altered proteins expression of the disc and calcium-handling abnormality. Comprehensively, we identified that the ferroptosis signaling pathway is involved in heart failure caused by cardiac-specific expression of Cre, on which oxidative stress results in cytoplasmic vacuole accumulation of lipid peroxidation on the myocardial cell membrane. Taken together, these results revealed that cardiac-specific expression of Cre recombinase can lead to atrial mesenchymal tumor-like growth in the mice, which causes cardiac dysfunction, including cardiac fibrosis, reduction of the intercalated disc and cardiomyocytes ferroptosis at the age older than six months in mice. Our study suggests that αMHC-Cre mouse models are effective in young mice, but not in old mice. Researchers need to be particularly careful when using αMHC-Cre mouse model to interpret those phenotypic impacts of gene responses. As the Cre-associated cardiac pathology matched mostly to that of the patients, the model could also be employed for investigating age-related cardiac dysfunction.

Fructose-1,6-bisphosphate aldolase (FBA) is a versatile metabolic enzyme involved in multiple important processes of glycolysis, gluconeogenesis, and Calvin cycle. Despite its significance in plant biology, the identity of this gene family in oil crops is lacking. Here, we performed genome-wide identification and characterization of FBAs in an allotetraploid species, oilseed rape Brassica napus. Twenty-two BnaFBA genes were identified and divided into two groups based on integrative analyses of functional domains, phylogenetic relationships, and gene structures. Twelve and ten B. napus FBAs (BnaFBAs) were predicted to be localized in the chloroplast and cytoplasm, respectively. Notably, synteny analysis revealed that Brassica-specific triplication contributed to the expansion of the BnaFBA gene family during the evolution of B. napus. Various cis-acting regulatory elements pertinent to abiotic and biotic stresses, as well as phytohormone responses, were detected. Intriguingly, each of the BnaFBA genes exhibited distinct sequence polymorphisms. Among them, six contained signatures of selection, likely having experienced breeding selection during adaptation and domestication. Importantly, BnaFBAs showed diverse expression patterns at different developmental stages and were preferentially highly expressed in photosynthetic tissues. Our data thus provided the foundation for further elucidating the functional roles of individual BnaFBA and also potential targets for engineering to improve photosynthetic productivity in B. napus.

Carotid paragangliomas (CPGLs) are rare neuroendocrine tumors often associated with mutations in SDHx genes. The immunohistochemistry of succinate dehydrogenase (SDH) subunits has been considered a useful instrument for the prediction of SDHx mutations in paragangliomas/pheochromocytomas. We compared the mutation status of SDHx genes with the immunohistochemical (IHC) staining of SDH subunits in CPGLs. To identify pathogenic/likely pathogenic variants in SDHx genes, exome sequencing data analysis among 42 CPGL patients was performed. IHC staining of SDH subunits was carried out for all CPGLs studied. We encountered SDHx variants in 38% (16/42) of the cases in SDHx genes. IHC showed negative (5/15) or weak diffuse (10/15) SDHB staining in most tumors with variants in any of SDHx (94%, 15/16). In SDHA-mutated CPGL, SDHA expression was completely absent and weak diffuse SDHB staining was detected. Positive immunoreactivity for all SDH subunits was found in one case with a variant in SDHD. Notably, CPGL samples without variants in SDHx also demonstrated negative (2/11) or weak diffuse (9/11) SDHB staining (42%, 11/26). Obtained results indicate that SDH immunohistochemistry does not fully reflect the presence of mutations in the genes; diagnostic effectiveness of this method was 71%. However, given the high sensitivity of SDHB immunohistochemistry, it could be used for initial identifications of patients potentially carrying SDHx mutations for recommendation of genetic testing.