scholarly journals TheKAT6B-related disorders genitopatellar syndrome and Ohdo/SBBYS syndrome have distinct clinical features reflecting distinct molecular mechanisms

2012 ◽  
Vol 33 (11) ◽  
pp. 1520-1525 ◽  
Author(s):  
Philippe M. Campeau ◽  
James T. Lu ◽  
Brian C. Dawson ◽  
Ivo F. A. C. Fokkema ◽  
Stephen P. Robertson ◽  
...  
Keyword(s):  
Clinical Features ◽  
Molecular Mechanisms

CACNA1A Mutation Linking Hemiplegic Migraine and Alternating Hemiplegia of Childhood

Cephalalgia ◽  
2008 ◽  
Vol 28 (8) ◽  
pp. 887-891 ◽  
Author(s):  
B de Vries ◽  
AH Stam ◽  
F Beker ◽  
AMJM van den Maagdenberg ◽  
KRJ Vanmolkot ◽  
...  
Keyword(s):  
Clinical Features ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Monozygotic Twin ◽  
Familial Hemiplegic Migraine ◽  
Hemiplegic Migraine ◽  
Mutation Scanning ◽  
Alternating Hemiplegia Of Childhood ◽  
Neurological Phenotype ◽  
Cacna1a Mutation

Familial hemiplegic migraine (FHM) and alternating hemiplegia of childhood (AHC) are severe neurological disorders that share clinical features. Therefore, FHM genes are candidates for AHC. We performed mutation analysis in the CACNA1A gene in a monozygotic twin pair with clinical features overlapping with both AHC and FHM and identified a novel de novo CACNA1A mutation. We provide the first evidence that a CACNA1A mutation can cause atypical AHC, indicating an overlap of molecular mechanisms causing AHC and FHM. These results also suggest that CACNA1A mutation scanning is indicated in patients with a severe neurological phenotype that includes paroxysmal (alternating) hemiplegia.

Inhibition of Heat Shock Factor 1 Enhances Repressive Molecular Mechanisms on the POMC Promoter

2019 ◽  
Vol 109 (4) ◽  
pp. 362-373
Author(s):  
Denis Ciato ◽  
Ran Li ◽  
Jose Luis Monteserin Garcia ◽  
Lilia Papst ◽  
Sarah D’Annunzio ◽  
...  
Keyword(s):  
Heat Shock ◽  
Clinical Features ◽  
Transcriptional Activation ◽  
Molecular Mechanisms ◽  
Primary Cultures ◽  
Heat Shock Protein 90 ◽  
Heat Shock Factor ◽  
Heat Shock Factor 1 ◽  
Promising Treatment ◽  
Acth Secreting

Background: Cushing’s disease (CD) is caused by adrenocorticotropic hormone (ACTH)-secreting pituitary tumours. They express high levels of heat shock protein 90 and heat shock factor 1 (HSF1) in comparison to the normal tissue counterpart, indicating activated cellular stress. Aims: Our objectives were: (1) to correlate HSF1 expression with clinical features and hormonal/radiological findings of CD, and (2) to investigate the effects of HSF1 inhibition as a target for CD treatment. Patients/Methods: We examined the expression of total and pSer326HSF1 (marker for its transcriptional activation) by Western blot on eight human CD tumours and compared to the HSF1 status of normal pituitary. We screened a cohort of 45 patients with CD for HSF1 by immunohistochemistry and correlated the HSF1 immunoreactivity score with the available clinical data. We evaluated the effects of HSF1 silencing with RNA interference and the HSF1 inhibitor KRIBB11 in AtT-20 cells and four primary cultures of human corticotroph tumours. Results: We show that HSF1 protein is highly expressed and transcriptionally active in CD tumours in comparison to normal pituitary. The immunoreactivity score for HSF1 did not correlate with the typical clinical features of the disease. HSF1 inhibition reduced proopiomelanocortin (Pomc) transcription in AtT-20 cells. The HSF1 inhibitor KRIBB11 suppressed ACTH synthesis from 75% of human CD tumours in primary cell culture. This inhibitory action on Pomc transcription was mediated by increased glucocorticoid receptor and suppressed Nurr77/Nurr1 and AP-1 transcriptional activities. Conclusions: These data show that HSF1 regulates POMC transcription. Pharmacological targeting of HSF1 may be a promising treatment option for the control of excess ACTH secretion in CD.

scholarly journals An Update on Silent Corticotroph Adenomas: Diagnosis, Mechanisms, Clinical Features, and Management

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 6134
Author(s):  
Shenzhong Jiang ◽  
Xiaokun Chen ◽  
Yinzi Wu ◽  
Renzhi Wang ◽  
Xinjie Bao
Keyword(s):  
Clinical Features ◽  
Molecular Mechanisms ◽  
Early Recognition ◽  
World Health ◽  
Pituitary Hormone ◽  
Endocrine Tumors ◽  
Tissue Samples ◽  
Management Approaches ◽  
Health Organization ◽  
Corticotroph Adenomas

With the introduction of 2017 World Health Organization (WHO) classification of endocrine tumors, T-PIT can serve as a complementary tool for identification of silent corticotroph adenomas (SCAs) in some cases if the tumor is not classifiable by pituitary hormone expression in pathological tissue samples. An increase of the proportion of SCAs among the non-functioning pituitary adenomas (NFPAs) has been witnessed under the new rule with the detection of T-PIT-positive ACTH-negative SCAs. Studies of molecular mechanisms related to SCA pathogenesis will provide new directions for the diagnosis and management of SCAs. A precise pathological diagnosis can help clinicians better identify SCAs. Understanding clinical features in the context of the pathophysiology of SCAs is critical for optimal management. It could provide information on appropriate follow-up time and aid in early recognition and treatment of potentially aggressive forms. Management approaches include surgical, radiation, and/or medical therapies.

The Clinical Features and Molecular Mechanisms of ACTH-secreting Pancreatic Neuroendocrine Tumors

2020 ◽  
Vol 105 (11) ◽  
Author(s):  
Cui Zhang ◽  
Jiabin Jin ◽  
Jing Xie ◽  
Lei Ye ◽  
Tingwei Su ◽  
...  
Keyword(s):  
Clinical Features ◽  
Neuroendocrine Tumors ◽  
Molecular Mechanisms ◽  
Transarterial Embolization ◽  
Cpg Methylation ◽  
Pancreatic Neuroendocrine Tumors ◽  
Ectopic Acth ◽  
Primary Tumors ◽  
Free Cortisol ◽  
Acth Secreting

Abstract Objective Pancreatic neuroendocrine tumors (pNETs) causing ectopic adrenal corticotropic hormone (ACTH) syndrome (EAS) are rare and aggressive with little known information. We aimed to elucidate the clinical features and molecular mechanisms of pNETs with EAS by methylation analysis. Methods Seven patients with ectopic ACTH-secreting pNETs who were diagnosed at Shanghai Clinical Endocrine and Metabolic Diseases Center and Pancreatic Disease Center in Ruijin Hospital between 2001 and 2019 were enrolled. Twenty patients with ectopic ACTH-secreting thymic neuroendocrine tumors (TNETs) and 7 with nonfunctional pNETs (nf-pNETs) were also enrolled as controls. We collected clinical data and measured POMC promoter CpG methylation. Results All 7 patients had elevated ACTH and urinary free cortisol (UFC) levels with positive ACTH staining in the pancreas and were diagnosed with ectopic ACTH-secreting pNET. Of the 7 patients, 6 underwent surgery and 1 underwent transarterial embolization (TAE). Two patients were free of disease after surgery; 2 died within 90 days after surgery; and 3 had metastases and died within 1 year. Compared with ACTH-secreting TNETs, ACTH-secreting pNETs had similar clinical and biochemical features but a significantly poorer prognosis. POMC promoter CpG methylation was significantly lower in ACTH-secreting pNETs than in nf-pNETs and normal pancreas. Conclusions ACTH-secreting pNETs are aggressive and fatal. Surgery is definitively curative for patients with resectable primary tumors without metastasis. Pro-opiomelanocortin (POMC) promoter hypomethylation caused pNETs to produce ACTH. This study further supplements the genetic features of ACTH-secreting NETs.

scholarly journals Crosstalk among DNA Damage, Mitochondrial Dysfunction, Impaired Mitophagy, Stem Cell Attrition, and Senescence in the Accelerated Ageing Disorder Werner Syndrome

2021 ◽  
Vol 161 (6-7) ◽  
pp. 297-304
Author(s):  
Ruben Gudmundsrud ◽  
Tarjei H. Skjånes ◽  
Brian C. Gilmour ◽  
Domenica Caponio ◽  
Sofie Lautrup ◽  
...  
Keyword(s):  
Dna Damage ◽  
Stem Cell ◽  
Mitochondrial Dysfunction ◽  
Clinical Features ◽  
Molecular Mechanisms ◽  
Werner Syndrome ◽  
Dna Helicase ◽  
Accelerated Ageing ◽  
Metabolic Dysfunction ◽  
Underlying Mechanisms

Werner syndrome (WS) is an accelerated ageing disease caused by multiple mutations in the gene encoding the Werner DNA helicase (WRN). The major clinical features of WS include wrinkles, grey hair, osteoporosis, and metabolic phenomena such as atherosclerosis, diabetes, and fatty liver, and resemble those seen in normal ageing, but occur earlier, in middle age. Defective DNA repair resulting from mutations in WRN explain the majority of the clinical features of WS, but the underlying mechanisms driving the larger metabolic dysfunction remain elusive. Recent studies in animal models of WS and in WS patient cells and blood samples suggest the involvement of impaired mitophagy, NAD<sup>+</sup> depletion, and accumulation of damaged mitochondria in metabolic dysfunction. This mini-review summarizes recent progress in the understanding of the molecular mechanisms of metabolic dysfunction in WS, with the involvement of DNA damage, mitochondrial dysfunction, mitophagy reduction, stem cell impairment, and senescence. Future studies on NAD<sup>+</sup> and mitophagy may shed light on potential therapeutic strategies for the WS patients.

Molecular Mechanisms of TanshinoneIIA in Hepatocellular carcinomatherapy via WGCNA-based Network Pharmacology Analysis

2021 ◽  
Author(s):  
Han Zhao ◽  
Jing Guo ◽  
Qingjia Chi ◽  
Meng Fang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Features ◽  
Molecular Mechanisms ◽  
Tanshinone Iia ◽  
Network Pharmacology ◽  
Specific Gene ◽  
Advanced Tumor Stage ◽  
Overlapping Genes ◽  
Hub Genes ◽  
Advanced Tumor

Abstract Background: Hepatocellular carcinoma (HCC) is a worldwide malignant tumor that caused irreversible consequences. The studies of Tanshinone IIA showed that Tanshinone IIA has played a notable role in HCC treatment. However, it is still to be investigated to discover the potential targets and associating mechanism of Tanshinone IIA against HCC. Methods: To analyze the correlation between genes and specific clinical features, we applied weighted gene co-expression network analysis (WGCNA), which can help us identify the targets of Tanshinone IIA related to the clinical features of Hepatocellular carcinoma. Results: We screened out 105 overlapping genes by integrating the predicted targets of Tanshinone IIA and the gene expression profile of HCC from the Cancer Genome Atlas (TCGA) database. For WGCNA, we used the RNA-seq profile of the overlapping genes and the related clinical information of HCC from TCGA. And 23 genes related to clinical tumor grade in the important module (R2 = 0.37) were imported for Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and protein-protein interaction (PPI) analysis. Compared to the key genes in the significant module from WGCNA with the high connectivity nodes from the PPI network, we can analyze three hub genes, AURKB, KIF11, and PLK1, for further verification. We tested the binding of Tanshinone IIA to the targets of Hepatocellular carcinoma using Autodock Vina. The survival curve validated that the three hub genes represented a poor prognosis. Receiver operating characteristic (ROC) curves demonstrated that the three hub genes were effective in diagnosis. The mRNA expression of the three hub genes was upregulated in the HCC than the normal. AURKB, KIF11 and PLK1 were further upregulated in advanced tumor stage and grade. Moreover, AURKB, KIF11 and PLK1 also had higher protein expression in HCC tissues. Conclusions: In the study, WGCNA revealed grade-specific gene modules, indicating that Tanshinone IIA probably plays its therapeutical effect in the differentiation process of HCC. And the study partly interpreted the pharmacological mechanism of Tanshinone IIA against HCC.

scholarly journals COVID-19 in Elderly Adults: Clinical Features, Molecular Mechanisms, and Proposed Strategies

2020 ◽  
Vol 11 (6) ◽  
pp. 1481 ◽  
Author(s):  
Ya Yang ◽  
Yalei Zhao ◽  
Fen Zhang ◽  
Lingjian Zhang ◽  
Lanjuan Li
Keyword(s):  
Clinical Features ◽  
Molecular Mechanisms ◽  
Elderly Adults

scholarly journals Aspirin Sensitivity and Chronic Rhinosinusitis with Polyps: A Fatal Combination

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Hendrik Graefe ◽  
Christina Roebke ◽  
Dirk Schäfer ◽  
Jens Eduard Meyer
Keyword(s):  
Chronic Rhinosinusitis ◽  
Respiratory Disease ◽  
Clinical Features ◽  
Nasal Polyposis ◽  
Molecular Mechanisms ◽  
Molecular Pathogenesis ◽  
Surgical Interventions ◽  
Aspirin Sensitivity ◽  
Aspirin Exacerbated Respiratory Disease ◽  
Lower Airways

Aspirin-exacerbated respiratory disease (AERD) refers to aspirin sensitivity, chronic rhinosinusitis (CRS), nasal polyposis, asthma, eosinophil inflammation in the upper and lower airways, urticaria, angioedema, and anaphylaxis following the ingestion of NSAIDs. Epidemiologic and pathophysiological links between these diseases are established. The precise pathogenesis remains less defined, even though there is some progress in the understanding of several molecular mechanisms. Nevertheless, these combinations of diseases in patients classified by AERD constitute a fatal combination and may be difficult to treat with standard medical and surgical interventions. This paper reviews in brief the epidemiology, clinical features, diagnosis, molecular pathogenesis, and specific therapies of patients classified by AERD and postulates future attempts to gain new insights into this disease.

scholarly journals Comprehensive review of molecular mechanisms and clinical features of invasive lobular cancer

2021 ◽  
Author(s):  
Nikhil Pramod ◽  
Akanksha Nigam ◽  
Mustafa Basree ◽  
Resham Mawalkar ◽  
Saba Mehra ◽  
...  
Keyword(s):  
Clinical Features ◽  
Molecular Mechanisms ◽  
Comprehensive Review ◽  
Invasive Lobular Cancer ◽  
Lobular Cancer

Clinical Features and Molecular Mechanisms of Spinal and Bulbar Muscular Atrophy (SBMA)

2010 ◽  
pp. 64-74 ◽  
Author(s):  
Masahisa Katsuno ◽  
Haruhiko Banno ◽  
Keisuke Suzuki ◽  
Hiroaki Adachi ◽  
Fumiaki Tanaka ◽  
...  
Keyword(s):  
Clinical Features ◽  
Molecular Mechanisms ◽  
Muscular Atrophy
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