BACKGROUND: Most mutations in the myelin protein zero gene (MPZ) typically cause a severe demyelinating/dysmyelinating neuropathy that begins in infancy or an adult-onset axonal neuropathy. Axonal degeneration in the late-onset H10P mutation may be caused by the disruption of axoglial interaction. OBJECTIVE: To evaluate sural nerve biopsy samples from a patient with early-onset Charcot-Marie-Tooth disease type 1B caused by an arg69-to-cys (R69C) mutation. Design and PARTICIPANTS: Biopsies of sural nerves were performed 20 years apart in a patient with an R69C mutation (early onset). In addition, peripheral nerves were obtained from autopsy material from a patient with a T95M mutation (late onset). These nerves were analyzed using light microscopy of semithin sections, teased nerve fiber immunohistochemical analysis, electron microscopy, and immunologic electron microscopy. MAIN OUTCOME MEASURES: Pathological changes in sural nerve. RESULTS: Both R69C biopsy samples showed prominent demyelination and onion bulb formation, unlike the late-onset T95M mutation, which showed primarily axonal degeneration with no onion bulbs. The sural biopsy sample obtained 20 years earlier from the R69C patient showed minimal difference from the present sample, consistent with the lack of clinical progression during the 2 decades. Teased fiber immunohistochemical analysis of R69C revealed voltage-gated sodium channel subtype 1.8 expressions at the nodes of Ranvier around the areas of segmental demyelination. Internodal length in all R69C nerve fibers was invariably short (>94% of all internodes are <150 mum). CONCLUSIONS: Morphologic abnormalities in this early-onset R69C neuropathy were severe in childhood but progressed very slowly after adolescence. The switch to voltage-gated sodium channel subtype 1.8 expression at the nodes may provide clues into the pathogenesis of this case of early-onset neuropathy, and the short internodes may contribute to the extremely slowed conduction velocities in this case (<10 m/s).

• MeSH
• axony patologie   MeSH
• Charcotova-Marieova-Toothova nemoc genetika   patofyziologie   MeSH
• elektronová mikroskopie MeSH
• gating iontového kanálu fyziologie   MeSH
• imunoelektronová mikroskopie MeSH
• imunohistochemie MeSH
• iontové kanály fyziologie   metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• myelinová pochva * fyziologie   MeSH
• myelinový P0 protein * genetika   MeSH
• nervová vlákna patologie   MeSH
• nervus suralis patologie   MeSH
• nervus ulnaris patologie   MeSH
• progrese nemoci MeSH
• senioři nad 80 let MeSH
• substituce aminokyselin MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Úvod: Celkový počet karcinómov endometria (CaE) má celosvetovo narastajúci trend. Podstatnú časť CaE tvorí endometrioidný histologický podtyp. Vo všeobecnosti má dobrú prognózu, ako aj liečbu. Serózny histologický podtyp CaE tvorí menšiu časť karcinómov endometria. Má horšiu prognózu a diagnostikuje sa v neskorších štádiách ochorenia. Vzhľadom na prognózu serózneho CaE je potrené a užitočné identifikovať tento podtyp karcinómov aj v zmiešaných typoch CaE. Materiál a metódy: Analyzovali sme tkanivo endometria – skupinu tvorilo 24 pacientok; pacientky boli vo veku od 44 do 88 rokov. Histologický diagnostický nález skúmaných vzoriek bol od jednoduchej hyperplázie bez atypie buniek po endometrioidný CaE s výrazným prenikaním do myometria. Vzorky sme analyzovali priamym sekvenovaním, ako aj restrikčnou analýzou. Výsledky: Vo všetkých vzorkách od 24 pacientok s karcinómom endometria alebo prekanceróznou léziou sme identifikovali polymorfizmus CCC/CGC Pro72Arg v exóne 4. Pomer homozygotných a heterozygotných polymorfizmov bol 14:10. Výsledky naznačujú, že môže ísť o zmiešané typy karcinómu endometria.

Introduction: The total number of carcinoma of the endometrium (CaE) has a growing global trend. Most cases of CaE are classified as endometrioid histological subtype, which generally has a good prognosis and is treatable. The serous histological subtype of CaE is a rarer form of endometrial carcinomas; it has a worse prognosis and is diagnosed at later stages of disease. Given the prognosis of serous CaE it is useful and necessary to identify this subtype of carcinomas in mixed types of CaE. Material and Methods: We analyzed endometrial tissue in a group of 24 patients – the patients were between 44 and 88 years old. The histological findings of the samples studied varied from simple hyperplasia without atypia to endometrioid CaE with significant infiltration into myometria. The samples were also analyzed by direct sequencing and restriction analysis. Results: In all of the samples from the 24 patients with endometrial cancer or precancerous lesions, we identified a CCC/CGC Pro72Arg polymorphism in Exon 4. The ratio of heterozygous and homozygous polymorphisms was 14:10. The results suggest that there may be a mixed type of endometrial cancer.

• MeSH
• DNA nádorová MeSH
• financování organizované MeSH
• lidé MeSH
• mutační analýza DNA MeSH
• nádory endometria genetika   patologie   MeSH
• polymorfismus genetický MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH

• Publikační typ
• abstrakt z konference MeSH

U čtyřletého chlapce byla náhodně změřena glykémie 6,9 mmol/l. V následujících sedmi letech sledování glykémie nalačno kolísala mezi 5,7 a 8,8 mmol/l. Průběh oGTT nesplňoval kritéria pro diabetes mellitus, první fáze inzulínové sekrece nebyla významně narušena. Hladiny HbA1c jsou trvale v horním pásmu normálního rozmezí (5,4 – 6,7 %; norma 4,0 – 6,4 %). Chlapec není léčen, má běžnou stravu. Otec chlapce měl náhodně zjištěnou hyperglykémii 7,7 mmol/l ve 34 letech, dědeček chlapce (otec otce) 6,2 mmol/l ve 33 letech. Oba jsou léčeni dietou. U dědečka se tíže poruchy nezměnila po dobu 29 let sledování. U mladšího bratra pacienta jsme ve 4 měsících věku změřili glykémii 8,0 mmol/l mezi kojením. Následná glykémie nalačno byla 5,8 mmol/l, hladina HbA1c 6,0 %. U pacienta, jeho bratra i jeho otce jsme nalezli novou nonsense mutaci genu pro glukokinázu Glu268Stop, která vede k významnému zkrácení molekuly enzymu. V rodině se tedy přenáší autozomálně dominantně MODY 2, benigní forma diabetu MODY. Dle současných názorů tato porucha v průběhu života obvykle neprogreduje a nepřináší svým nositelům klinické obtíže. Léčení zřejmě není nutné.

Glycaemia 6.9 mmol/L was randomly found in a 4-year-old boy. Within the subsequent 7 years, his fasting blood glucose varied between 5.7 and 8.8 mmol/L. OGTT did not meet criteria for diabetes mellitus and first phase insulin release was not significantly decreased. HbA1c fluctuated at the upper normal range (5.4 – 6.7 %; normal values 4.0 – 6.4 %). The boy is not being treated and has no diet restrictions. In the boy‘s father, glycaemia 7.7 mmol/L was randomly estimated at age 34 years, and in the boy‘s grandfather (father‘s father), 6.2 mmol/L at 33 years. Both were recommended to comply with diabetic diet. The grandfather’s status remained unchanged within the subsequent 29 years. In the younger patient‘s brother, blood glucose 8.0 mmol/L was measured between two breast-feedings at age 4 months. His fasting glycaemia was 5.8 mmol/L and the HbA1c level 6.0 %. We found a novel nonsense mutation of the glucokinase gene Glu268Stop in the patient, in his brother and in their father. This mutation leads to a dramatic truncation of the enzyme molecule. Thus, autosomal dominant transmission of MODY 2, a benign subtype of MODY diabetes, occurs within the family. According to recent views, this disorder is usually not progressive and does not cause clinical symptoms throughout the lifespan. No therapy is probably required.

• MeSH
• anamnéza MeSH
• diabetes mellitus diagnóza   farmakoterapie   MeSH
• dítě MeSH
• dospělí MeSH
• finanční podpora výzkumu jako téma MeSH
• geny MeSH
• glukokinasa genetika   MeSH
• hyperglykemie diagnóza   farmakoterapie   genetika   MeSH
• lidé MeSH
• mutace MeSH
• rodina MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH

MicroRNAs (miRNAs) are short, non-coding RNAs, which function as evolutionary conserved regulators of a gene expression. They have essential roles in development, cell differentiation, proliferation, apoptosis and chromosome structure. MiRNAs constitute about 3-5% of predicted genes in the human genome (i.e. about 1000); and 20-30% of the protein-coding genes are estimated to be regulated by the miRNAs. The primary evidence that miRNAs possibly act as a novel class of oncogenes/tumor-suppressors comes from the discovery of the miR-15a and miR-16-1 in 13q14 region deleted in chronic lymphocytic leukemia (CLL). Moreover, miRNA signatures have been used to classify tumor types. There have recently been several reports on the miRNAs role in CLL pathogenesis and disease subtypes (according to IgV(H) mutation status). In this report, we will review the published observations and present our miRNA profiling data in aggressive CLL with TP53 abnormalities (deletion and/or mutation of p53 gene). We have identified a deregulated miRNA expression pattern (down regulation of miR-34a, miR-29 and miR-17-5p) in these samples, compared to cells with wild-type TP53. It has previously been shown that miR-34a is directly regulated by p53 and targets BCL-2, miR-29c regulates the MCL-1 and TCL-1 proto-oncogenes and the miR-17-5p targets important cell cycle regulatory molecules. Consequently, these three miRNAs could potentially play important roles in the pathogenesis of aggressive CLL.

• MeSH
• chronická lymfatická leukemie etiologie   genetika   MeSH
• down regulace MeSH
• lidé MeSH
• mikro RNA genetika   MeSH
• mutace MeSH
• nádorový supresorový protein p53 genetika   MeSH
• regulace genové exprese u nádorů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH

PURPOSE: Noonan syndrome (NS) is an autosomal-dominant disorder characterized by craniofacial dysmorphism, growth retardation, cardiac abnormalities, and learning difficulties. It belongs to the RASopathies, which are caused by germ-line mutations in genes encoding components of the RAS mitogen-activated protein kinase (MAPK) pathway. RIT1 was recently reported as a disease gene for NS, but the number of published cases is still limited. METHODS: We sequenced RIT1 in 310 mutation-negative individuals with a suspected RASopathy and prospectively in individuals who underwent genetic testing for NS. Using a standardized form, we recorded clinical features of all RIT1 mutation-positive patients. Clinical and genotype data from 36 individuals with RIT1 mutation reported previously were reviewed. RESULTS: Eleven different RIT1 missense mutations, three of which were novel, were identified in 33 subjects from 28 families; codons 57, 82, and 95 represent mutation hotspots. In relation to NS of other genetic etiologies, prenatal abnormalities, cardiovascular disease, and lymphatic abnormalities were common in individuals with RIT1 mutation, whereas short stature, intellectual problems, pectus anomalies, and ectodermal findings were less frequent. CONCLUSION: RIT1 is one of the major genes for NS. The RIT1-associated phenotype differs gradually from other NS subtypes, with a high prevalence of cardiovascular manifestations, especially hypertrophic cardiomyopathy, and lymphatic problems.Genet Med 18 12, 1226-1234.

• MeSH
• fenotyp MeSH
• genetické asociační studie MeSH
• genotyp MeSH
• hypertrofická kardiomyopatie genetika   patologie   MeSH
• lidé MeSH
• Noonanové syndrom genetika   patologie   MeSH
• ras proteiny genetika   MeSH
• rodokmen MeSH
• vrozené srdeční vady genetika   patologie   MeSH
• zárodečné mutace MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Since its first official detection in the Guangdong province of China in 1996, the highly pathogenic avian influenza virus of H5N1 subtype (HPAI H5N1) has reportedly been the cause of outbreaks in birds in more than 60 countries, 24 of which were European. The main issue is still to develop effective antiviral drugs. In this case, single point mutation in the neuraminidase gene, which causes resistance to antiviral drug and is, therefore, subjected to many studies including ours, was observed. In this study, we developed magnetic electrochemical bar code array for detection of single point mutations (mismatches in up to four nucleotides) in H5N1 neuraminidase gene. Paramagnetic particles Dynabeads® with covalently bound oligo (dT)₂₅ were used as a tool for isolation of complementary H5N1 chains (H5N1 Zhejin, China and Aichi). For detection of H5N1 chains, oligonucleotide chains of lengths of 12 (+5 adenine) or 28 (+5 adenine) bp labeled with quantum dots (CdS, ZnS and/or PbS) were used. Individual probes hybridized to target molecules specifically with efficiency higher than 60%. The obtained signals identified mutations present in the sequence. Suggested experimental procedure allows obtaining further information from the redox signals of nucleic acids. Moreover, the used biosensor exhibits sequence specificity and low limits of detection of subnanogram quantities of target nucleic acids.

• MeSH
• bodová mutace * MeSH
• elektrochemické techniky metody   MeSH
• lidé MeSH
• magnetismus metody   MeSH
• mutantní proteiny genetika   MeSH
• neuraminidasa genetika   MeSH
• taxonomické DNA čárové kódování metody   MeSH
• virologie metody   MeSH
• virová léková rezistence MeSH
• virové proteiny genetika   MeSH
• virus chřipky A, podtyp H5N1 klasifikace   enzymologie   genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Čína MeSH

Differences in survival according to the pTERT mutation subtypes (-124C > T, -146C > T, and tandem -138_139CC > TT) have been observed. The present study aimed to describe the clinical as the histopathological and molecular cutaneous melanoma features according to the presence of the three most prevalent pTERT mutation subtypes (-124C > T, -146C > T, and tandem -138_139CC > TT). A retrospective cross-sectional study including 684 patients was designed, and a Partial Least-Squares Discriminant Analysis (PLS-DA) was performed. After the PSL-DA, it was observed that the tandem -138_139CC > TT subtype differs from the other subtypes. The model demonstrated that the -124C > T and the -138_139 CC > TT subtypes were associated with fast-growing melanomas (OR 0.5, CI 0.29-0.86, p = .012) and with Breslow >2 mm (OR 0.6, CI 0.37-0.97, p = .037), compared to the -146C > T mutation. Finally, the -124C > T appeared to be more associated with the presence of TILs (non-brisk) than the -146C > T (OR 0.6, CI 0.40-1.01, p = .05). These findings confirmed that the -124C > T and the tandem -138_139 CC > TT subtypes are both highly associated with the presence of features of aggressiveness; however, only the -124C > T was highly associated with TILs. This difference could explain the worse survival rate associated with the tandem -138_139CC > TT mutations.

• MeSH
• lidé MeSH
• melanom * genetika   patologie   mortalita   MeSH
• mutace MeSH
• nádory kůže genetika   patologie   mortalita   MeSH
• promotorové oblasti (genetika) * genetika   MeSH
• průřezové studie MeSH
• retrospektivní studie MeSH
• telomerasa * genetika   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

There have been few clinical or scientific reports of autosomal dominant tubulointerstitial kidney disease due to REN mutations (ADTKD-REN), limiting characterization. To further study this, we formed an international cohort characterizing 111 individuals from 30 families with both clinical and laboratory findings. Sixty-nine individuals had a REN mutation in the signal peptide region (signal group), 27 in the prosegment (prosegment group), and 15 in the mature renin peptide (mature group). Signal group patients were most severely affected, presenting at a mean age of 19.7 years, with the prosegment group presenting at 22.4 years, and the mature group at 37 years. Anemia was present in childhood in 91% in the signal group, 69% prosegment, and none of the mature group. REN signal peptide mutations reduced hydrophobicity of the signal peptide, which is necessary for recognition and translocation across the endoplasmic reticulum, leading to aberrant delivery of preprorenin into the cytoplasm. REN mutations in the prosegment led to deposition of prorenin and renin in the endoplasmic reticulum-Golgi intermediate compartment and decreased prorenin secretion. Mutations in mature renin led to deposition of the mutant prorenin in the endoplasmic reticulum, similar to patients with ADTKD-UMOD, with a rate of progression to end stage kidney disease (63.6 years) that was significantly slower vs. the signal (53.1 years) and prosegment groups (50.8 years) (significant hazard ratio 0.367). Thus, clinical and laboratory studies revealed subtypes of ADTKD-REN that are pathophysiologically, diagnostically, and clinically distinct.

• MeSH
• anemie * MeSH
• dítě MeSH
• dospělí MeSH
• kohortové studie MeSH
• lidé MeSH
• mladý dospělý MeSH
• mutace MeSH
• polycystická choroba ledvin * genetika   MeSH
• renin genetika   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

I přes narůstající preventivní opatření a povědomí o maligním melanomu incidence tohoto onemocnění celosvětově stoupá. Raná stadia se s dobrým efektem léčí chirurgicky, ale ve fázi generalizace se melanom řadí mezi nejobtížněji léčitelné diagnózy. Tento tradiční pohled se s přibývajícími znalostmi o patogenezi melanomu na molekulárně biologické úrovni začíná měnit příznivým směrem. Nyní je zřejmé, že melanom není homogenní choroba s jednotnou sadou genetických změn. V rámci personalizované medicíny lze dnes pacientům s C-KIT mutací v režimu klinického zkoušení nabídnout inhibitor kinázy C-KIT (imatinib) nebo inhibitor kinázy BRAF u pacientů se specifickou mutací BRAFV600E (vemurafenib). Vemurafenib byl schválen FDA v srpnu 2011 a v únoru 2012 lékovou agenturou EMA pro léčbu první i dalších linií pacientů s neresekovatelným nebo metastatickým melanomem s pozitivní mutací genu BRAF. V roce 2011 schválila americká FDA a následně evropská EMA pro léčbu metastazujícího melanomu použití ipilimumabu, tedy protilátky proti cytotoxickému T lymfocytárnímu antigenu 4 (CTLA-4). Ten je klíčovým negativním regulátorem imunitní odpovědi. Terapie ipilimumabem ovlivňuje přirozenou funkci imunitního systému, protože podporuje protinádorovou aktivitu T lymfocytů. Je účinný i u pacientů rezistentních k C-KIT a BRAF inhibitorům a představuje nového perspektivního hráče na poli imunomodulační léčby.

The incidence of malignant melanoma is increasing worldwide, despite our best efforts in prevention and early detection. The locally advanced disease may be treated surgically with good results, however, metastatic melanoma is considered to be one of the most therapeutically challenging malignancies. The increasing knowledge of molecular changes in melanoma may change this picture. Malignant melanoma is not a singular, homogeneous disease but rather a mixture of subtypes characterized by specific mutations. Tumors with C-KIT mutation respond to therapy with C-KIT kinase inhibitor imatinib and the ones characterized by BRAF mutations respond to BRAF kinase inhibitor vemurafenib. Vemurafenib was approved by US FDA in 2011 and EMA in 2012 for therapy of patients with advanced melanoma, harboring mutation in BRAFV600E gene. Ipilimumab, an antibody to cytotoxic T-lymphocyte antigen 4 (CTLA-4), was registered in 2011 by both US FDA and European Medicines Agency for treatment of metastatic melanoma. This therapy promotes the anti-tumor T-cell activity by blocking a CTLA-4 antigen, a key negative regulator of immune response. Key words: melanoma – targeted therapy – BRAF kinase – vemurafenib – immunotherapy – neoplasm metastasis Submitted: 2. 3. 2012 Accepted: 11. 4. 2012

• Klíčová slova
• cílená léčba, vemurafenib, Zelboraf, Plexxikon, Roche, Yervoy,
• MeSH
• analýza přežití MeSH
• biologická terapie klasifikace   metody   MeSH
• geny * MeSH
• hodnocení léčiv MeSH
• humanizované monoklonální protilátky MeSH
• imunologické faktory MeSH
• individualizovaná medicína MeSH
• indoly terapeutické užití   MeSH
• ipilimumab MeSH
• klinické zkoušky jako téma MeSH
• léková rezistence MeSH
• lidé MeSH
• MAP kinasový signální systém účinky léků   MeSH
• melanom * farmakoterapie   MeSH
• metastázy nádorů farmakoterapie   MeSH
• mutace * MeSH
• progrese nemoci MeSH
• protoonkogenní proteiny B-raf * antagonisté a inhibitory   genetika   účinky léků   MeSH
• sulfonamidy terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH