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Frequent p53 gene involvement in splenic B-cell leukemia/lymphomas of possible marginal zone origin.

A phenotypic and molecular evaluation was made of 15 patients with mature B-cell leukemia/lymphoma showing exclusive spleen and bone marrow … ns 5, 6, and 8 were found in 6 cases (6 of 15, 40%). In 4 cases, the p53 alterations consisted of a point mutation leading to amino acid substitution. In the remaining 2 cases, an insertion or deletion resulting in a frame-shift of the protein was observed. In all but 1 of the cases, the wild-type sequence at the mutation site was barely visible, implying the lo …

Genetic analysis of faropenem-resistant Enterococcus faecalis in urinary isolates.

We isolated faropenem-resistant Enterococcus faecalis in urine specimens and studied the mechanisms of resistance to faropenem in these isolates. Three mechanisms of penicillin resistance have been reported in E. faecalis; (1) beta-lactamase production, (2) overproduction of penicillin-binding protein (PBP) 4 or PBP5, and (3) decreasing affinities of penicillins for PBP4 by the occurrence of point mutations of the penicillin-binding domain. None of the E. faecalis isolates examined produced beta-lactamase or overproduced any PBPs, but the affinities of faropenem for PBP4 were decreased in faro…

Neurological disorders due to mutations of the mitochondrial genome.

The rapidly expanding list of human diseases due to lesions of mitochondrial DNA includes myopathies, encephalopathies, cardiomyopathies, or various combinations of the latter, leading to multisystem disorders, which can also affect visceral organs. Five maternally inherited diseases, mainly affecting muscle and brain, are due to point mutations of mitochondrial genes encoding either respiratory chain polypeptides or transfer RNAs. On the other hand, three sporadic entities, Chronic Progressive External Ophthalmoplegia, Kearns-Sayre syndrome, and Pearson's pancreas-bone marrow syndrome, are du…

Clinicopathological characteristics and mutation profiling in primary cutaneous melanoma.

BACKGROUND: The incidence of mutations in malignant melanoma varies remarkably according to the subtype of melanoma, and this in itself is affected by racial and geographical factors. Studies screening melanoma case series for different types of mutations are relatively rare. METHOD: The authors analyzed the frequency of various somatic point mutations of 10 genes in 106 primary cutaneous melanoma cases. The mutations (BRAF, NRAS, KIT, CDKN2A, KRAS, HRAS, PIK3CA, STK11, GNAQ, CTNNB1) were evaluated with real-time PCR-based PCR-Array through allele-specific amplification, and the results were …

Mutations in SKI in Shprintzen-Goldberg syndrome lead to attenuated TGF-β responses through SKI stabilization.

Shprintzen-Goldberg syndrome (SGS) is a multisystemic connective tissue disorder, with considerable clinical overlap with Marfan and Loeys-Dietz syndromes. These syndromes have commonly been associated with enhanced TGF-β signaling. In SGS patients, heterozygous point mutations have been mapped to the transcriptional co-repressor SKI, which is a negative regulator of TGF-β signaling that is rapidly degraded upon ligand stimulation. The molecular consequences of these mutations, however, are not understood. Here we use a combination of structural biology, genome editing, and biochemistry to sho…

Genetic diseases of the Kennedy pathways for membrane synthesis.

The two branches of the Kennedy pathways (CDP-choline and CDP-ethanolamine) are the predominant pathways responsible for the synthesis of the most abundant phospholipids, phosphatidylcholine and phosphatidylethanolamine, respectively, in mammalian membranes. Recently, hereditary diseases associated with single gene mutations in the Kennedy pathways have been identified. Interestingly, genetic diseases within the same pathway vary greatly, ranging from muscular dystrophy to spastic paraplegia to a childhood blinding disorder to bone deformations. Indeed, different point mutations in the same ge…

Complex multisystem phenotype associated with the mitochondrial DNA m.5522G>A mutation.

Mitochondrial tRNAs are responsible for more than half of pathogenic point mutations in the mitochondrial genome (mtDNA). Different mutations give rise to widely differing phenotypes, ranging from isolated organ-specific diseases to multisystem conditions. Herein, we report a 40-year-old woman presenting with a complex multisystem phenotype including sensorineural hearing loss, retinopathy, severe dilated cardiomyopathy, non-insulin dependent diabetes mellitus, and renal failure. Sequence analysis of mtDNA identified the m.5522G>A mutation in MT-TW, the gene encoding mitochondrial tRNA for try…

Mutational analysis of varicella-zoster virus (VZV) immediate early protein (IE62) subdomains and their importance in viral replication.

VZV IE62 is an essential, immediate-early, tegument protein and consists of five domains. We generated recombinant viruses carrying mutations in the first three IE62 domains and tested their influence on VZV replication kinetics. The mutations in domain I did not affect replication kinetics while domain II mutations, disrupting the DNA binding and dimerization domain (DBD), were lethal for VZV replication. Mutations in domain III of the nuclear localization signal (NLS) and the two phosphorylation sites S686A/S722A resulted in slower growth in early and late infection respectively and were ass

Mitochondrial fusion is required for mtDNA stability in skeletal muscle and tolerance of mtDNA mutations.

Mitochondria are highly mobile and dynamic organelles that continually fuse and divide. These processes allow mitochondria to exchange conte … ological abnormalities. Moreover, the mitochondrial genomes of the mutant muscle rapidly accumulate point mutations and deletions. In a related experiment, we find that disruption of mitochondrial fusion strongly increases mitochondrial dysfunction and lethality in a mouse model with high levels of mtDNA mutations. With its dual function in safeguarding mtDNA in …

The calcium-sensing receptor and related diseases.

The calcium-sensing receptor (CASR) adjusts the extracellular calcium set point regulating PTH secretion and renal calcium excretion. The receptor is expressed in several tissues and is also involved in other cellular functions such as proliferation, differentiation and other hormonal secretion. High extracellular calcium levels activate the receptor resulting in modulation of several signaling pathways depending on the target tissues. Mutations in the CASR gene can result in gain or loss of receptor function. Gain of function mutations are associated to Autossomal dominant hypocalcemia and Ba

Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2.

Tumor suppressor genes evolved as negative effectors of mitogen and nutrient signaling pathways, such that mutations in these genes can lead … on MAPK phosphorylation. Finally, coexpression of a human TSC2 cDNA harboring a disease-associated point mutation in the GAP domain, failed to stimulate Rheb GTPase activity or block Rheb activation of S6K1.

Comparison of Pleomorphic Dermal Sarcoma to Advanced Cutaneous Squamous Cell Carcinoma and Soft-Tissue Sarcoma.

IMPORTANCE: Pleomorphic dermal sarcomas (PDSs) are classified as sarcomas; however, they share features with cutaneous carcinomas, such as presentation on sun-exposed areas and high tumor mutational burden (TMB). Data regarding management of PDS are limited, and it is unclear whether sarcoma or cutaneous cancer treatment paradigms should apply. At present, there are no published data comparing the mutational genetics of PDSs to other cutaneous tumors and to other soft-tissue sarcomas (STSs). OBJECTIVE: To compare TMB, UV signature, and single-nucleotide and pathway-level mutational profiles o

Engineering a Stable Grb2 Monomer: The W60A Mutation Disrupts Dimerization but Preserves Structural Integrity.

The adaptor protein Grb2 is a critical regulator in signaling pathways responsible for cell growth and proliferation, making it a key target … red. Here, we demonstrate that the W60 residue is a critical link for dimerization. We engineered a point mutation (W60A) and employed a comprehensive biophysical approach (including SAXS, NMR, and molecular dynamics) to characterize its structural and dynamic consequences. Our results are definitive: the W60A mutation successfully disrupts the dimer interface, …

BCR::ABL1 kinase domain mutations and their predictive value for treatment outcomes in patients with chronic myeloid leukemia treated with first-line imatinib in a low-income setting: Experience from Côte d'Ivoire.

BACKGROUND: We aimed to analyse the incidence of BCR::ABL1 kinase domain mutations in patients newly diagnosed with or undergoing treatment … enter, Seattle, USA. RESULTS: Among the 42 patients, 16 (38.1%) were found to have known BCR::ABL1 point mutations. A total of nine distinct mutations were identified, with T315I being the most common (5). Three patients harbored compound mutations: one had T315I + M244V, another had G250E + E459K, and the third had H396P + E459K. The 5-year overall survival (O …

Aldehyde dehydrogenase-2 deficiency aggravates neuroinflammation, nociception, and motor impairment in a mouse model of multiple sclerosis.

Aldehyde dehydrogenase-2 deficiency (ALDH2∗2) found in 36 % of Han Chinese, affects approximately 8 % of the world population. ALDH2 is a mi … nonenal (4-HNE), contribute to MS pathogenesis. Here, using knock-in mice carrying the inactivating point mutation in ALDH2, identical to the mutation found in Han Chinese, we showed that the impairment in ALDH2 activity heightens motor disabilities, and hypernociception induced by experimental autoimmune encephalomyelitis (EAE). The deleterious clinical signs a …

Clinical outcome of bevacizumab or ramucirumab combined with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors as the first line therapy in susceptible EGFR-mutated advanced non-small-cell lung.

Combining epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with an anti- vascular endothelial growth factor (VEGF) agent, bevacizumab or ramucirumab, is indicated for advanced lung adenocarcinoma harboring EGFR mutation. This study aimed to show the real-world data of combination therapy and compare the effectiveness between bevacizumab and ramucirumab in combination with an EGFR-TKI. This retrospective study enrolled 47 patients diagnosed of stage IV lung adenocarcinoma with exon 19 deletion or L858R point mutation, receiving a first-line EGFR-TKI with anti-VEGF agent, …

Diagnosis of Resistance to Thyroid Hormone due to a Rare Mutation in the Thyroid Hormone Receptor Beta Gene in a Patient Previously Presumed to Have Graves' Disease.

Clinicians may confuse an impaired sensitivity to thyroid hormone with hyperthyroidism and offer an inappropriate treatment. We report a diagnosis of resistance to thyroid hormone (RTH) caused by a rare mutation in the thyroid hormone receptor beta gene in a patient previously presumed to have Graves' disease. We have found only one published case of a novel point mutation, c.749T>C (p.Ile250Thr variant) associated with 50% reduction in thyroid hormone receptor binding affinity for triiodothyronine in the I250T mutant; it was found in this patient. A 66-year-old male veteran, with a history of…

Молекулярная динамическая симуляция диких и мутантных протеиновых субъектов бета-белка типа 8 (PSMB8): Последствия для восстановления воспаления в экспериментальном аутоиммунном энцефаломиэлите патогенез.

Множественный склероз (MS) — аутоиммунное и хроническое заболевание мозга и спинного мозга. В НР наблюдается подстрекательский прогресс, характеризующийся своими отличительными подстрекательскими знаками. Гистологические и клинические характеристики MS разделяются экспериментальным аутоиммунным энцефаломелитом (EAE). Генетические и экологические факторы способствуют развитию НР. В болезни EAE-MS уровень протеазонного компонента бета-типа 8 (PSMB8), закодированного геном PSMB8, увеличивается и регулирует подстрекательскую реакцию в этой болезни. У людей синдром Накахо-Нишимура вызван мутации в

Совпадение в аннотации оригинала
Multiple Sclerosis (MS) is an autoimmune and chronic disease in the brain and spinal cord. MS has inflammatory progression characterized by … ults using another Google Colab system. The energy analysis ensures the structural deviation due to point mutation. The trajectory of the fundamental simulation (RMSD, RMSF, and Rg) describes that the G210V mutated protein is more flexible and less stable than the wild type. We observed the conformational changes due to mutation by analyzing the RMSD average lin …

Advanced multiparametric MRI-based scoring for isocitrate dehydrogenase mutation prediction of gliomas.

PURPOSE: To propose an advanced multiparametric magnetic resonance imaging (MRI)-based scoring system and evaluate its diagnostic accuracy with respect to the isocitrate dehydrogenase (IDH) mutation status of gliomas. MATERIAL AND METHODS: This prospective observational study included 50 consecutive patients with suspected gliomas, enrolled for pre-operative MRI. The exclusion criteria were previous surgery, biopsy, or chemo/radiotherapy and contraindications to the gadolinium-based contrasts or MRI acquisition. A standardized brain-MRI protocol using a 3-Tesla machine and 16-channel head coi

Road-blocker HSP disease mutation disrupts pre-organization for ATP hydrolysis in kinesin through a second sphere control.

Kinesin motor proteins perform several essential cellular functions powered by the adenosine triphosphate (ATP) hydrolysis reaction. Several single-point mutations in the kinesin motor protein KIF5A have been implicated to hereditary spastic paraplegia disease (HSP), a lethal neurodegenerative disease in humans. In earlier studies, we have shown that a series of HSP-related mutations can impair the kinesin's long-distance displacement or processivity by modulating the order-disorder transition of the linker connecting the heads to the coiled coil. On the other hand, the reduction of kinesin's …