Mutation of SMARCA4 (BRG1), the ATPase of BAF (mSWI/SNF) and PBAF complexes, contributes to a range of malignancies and neurologic disorders. Unfortunately, the effects of SMARCA4 missense mutations have remained uncertain. Here we show that SMARCA4 cancer missense mutations target conserved ATPase surfaces and disrupt the mechanochemical cycle of remodeling. We find that heterozygous expression of mutants alters the open chromatin landscape at thousands of sites across the genome. Loss of DNA accessibility does not directly overlap with Polycomb accumulation, but is enriched in 'A compartments' at active enhancers, which lose H3K27ac but not H3K4me1. Affected positions include hundreds of sites identified as superenhancers in many tissues. Dominant-negative mutation induces pro-oncogenic expression changes, including increased expression of Myc and its target genes. Together, our data suggest that disruption of enhancer accessibility represents a key source of altered function in disorders with SMARCA4 mutations in a wide variety of tissues.

• MeSH
• Adenosine Triphosphatases metabolism   MeSH
• Chromatin chemistry   MeSH
• DNA Helicases genetics   MeSH
• Genes, Dominant * MeSH
• Epigenomics MeSH
• Genotype MeSH
• Heterozygote MeSH
• Nuclear Proteins genetics   MeSH
• Culture Media MeSH
• Humans MeSH
• Mutation, Missense MeSH
• Multivariate Analysis MeSH
• Mutation * MeSH
• Mouse Embryonic Stem Cells cytology   MeSH
• Mice, Transgenic MeSH
• Mice MeSH
• Neoplasms genetics   MeSH
• Polycomb-Group Proteins genetics   MeSH
• Chromatin Assembly and Disassembly MeSH
• Sequence Analysis, RNA MeSH
• Transcription Factors genetics   MeSH
• Enhancer Elements, Genetic MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

The role of KRAS mutations in molecular targeted therapy by epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC) has not been fully understood. The present investigation is aimed at an elucidation of the role of specific KRAS mutation types in predicting outcomes of patients with advanced NSCLC receiving EGFR-TKI therapy. Initially, 448 NSCLC patients were tested for the presence of KRAS mutations, to obtain frequencies of specific KRAS mutation types. Subsequently, the clinical outcome of treatment was evaluated in a subgroup of 38 KRAS-positive patients receiving EGFR-TKI therapy. KRAS mutations were detected in 69 of 448 patients (15.4%), mostly in smokers (17.86% vs. 5.8%, P = 0.0048), and appeared more frequently in adenocarcinomas than in squamous cell NSCLC or NSCLC that is not otherwise specified (21% vs. 6.99% vs. 4.4%, P = 0.0004). The most frequent type of KRAS mutation was G12C. The progression-free survival (PFS) was doubled in a group of non-G12C patients compared with that of the G12C group (9.0 wk vs. 4.3 wk, P = 0.009). The overall survival (OS) was not significantly different between non-G12C and G12C groups (12.1 wk vs. 9.3 wk, P = 0.068). The G12C KRAS mutation is a strong negative predictor for EGFR-TKI treatment, whereas other KRAS mutation types have not negatively predicted treatment efficacy compared with that for the wild-type KRAS genotype.

• MeSH
• Biomarkers, Pharmacological metabolism   MeSH
• Drug Resistance, Neoplasm genetics   MeSH
• Cysteine genetics   MeSH
• Adult MeSH
• ErbB Receptors antagonists & inhibitors   MeSH
• Glycine genetics   MeSH
• Protein Kinase Inhibitors therapeutic use   MeSH
• Cohort Studies MeSH
• Middle Aged MeSH
• Humans MeSH
• Mutation, Missense physiology   MeSH
• Biomarkers, Tumor genetics   physiology   MeSH
• Lung Neoplasms diagnosis   drug therapy   genetics   MeSH
• Carcinoma, Non-Small-Cell Lung diagnosis   drug therapy   genetics   MeSH
• Prognosis MeSH
• Antineoplastic Agents therapeutic use   MeSH
• Proto-Oncogene Proteins genetics   metabolism   physiology   MeSH
• ras Proteins genetics   metabolism   physiology   MeSH
• Aged MeSH
• Case-Control Studies MeSH
• Amino Acid Substitution physiology   MeSH
• Protein-Tyrosine Kinases antagonists & inhibitors   MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Evaluation Study MeSH
• Research Support, Non-U.S. Gov't MeSH

Growth hormone (GH) insensitivity syndrome (GHIS) is a rare clinical condition in which production of insulin-like growth factor 1 is blunted and, consequently, postnatal growth impaired. Autosomal-recessive mutations in signal transducer and activator of transcription (STAT5B), the key signal transducer for GH, cause severe GHIS with additional characteristics of immune and, often fatal, pulmonary complications. Here we report dominant-negative, inactivating STAT5B germline mutations in patients with growth failure, eczema, and elevated IgE but without severe immune and pulmonary problems. These STAT5B missense mutants are robustly tyrosine phosphorylated upon stimulation, but are unable to nuclear localize, or fail to bind canonical STAT5B DNA response elements. Importantly, each variant retains the ability to dimerize with wild-type STAT5B, disrupting the normal transcriptional functions of wild-type STAT5B. We conclude that these STAT5B variants exert dominant-negative effects through distinct pathomechanisms, manifesting in milder clinical GHIS with general sparing of the immune system.

• MeSH
• Cell Line MeSH
• Child MeSH
• Eczema genetics   MeSH
• Genetic Predisposition to Disease genetics   MeSH
• HEK293 Cells MeSH
• Immunoglobulin E blood   MeSH
• Insulin-Like Growth Factor I biosynthesis   MeSH
• Infant MeSH
• Laron Syndrome genetics   MeSH
• Humans MeSH
• Human Growth Hormone metabolism   MeSH
• Mutation, Missense genetics   MeSH
• Adolescent MeSH
• Response Elements genetics   MeSH
• STAT5 Transcription Factor genetics   MeSH
• Germ-Line Mutation genetics   MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

Dominance hierarchy is often established via repeated agonistic encounters where consistent winners are considered dominant. Human body odour contains cues to psychological dominance and competition, but it is not known whether competition outcome (a marker of a change in dominance hierarchy) affects the hedonic quality of human axillary odour. Therefore, we investigated the effect of winning and losing on odour quality. We collected odour samples from Mixed Martial Arts fighters approximately 1 h before and immediately after a match. Raters then assessed samples for pleasantness, attractiveness, masculinity and intensity. We also obtained data on donors' affective state and cortisol and testosterone levels, since these are known to be associated with competition and body odour quality. Perceived body odour pleasantness, attractiveness and intensity significantly decreased while masculinity increased after a match irrespective of the outcome. Nonetheless, losing a match affected the pleasantness of body odour more profoundly, though bordering formal level of significance. Moreover, a path analysis revealed that match loss led to a decrease in odour attractiveness, which was mediated by participants' negative affective states. Our study suggests that physical competition and to some extent also its outcome affect the perceived quality of human body odour in specific real-life settings, thus providing cues to dominance-related characteristics. This article is part of the Theo Murphy meeting issue 'Olfactory communication in humans'.

• MeSH
• Martial Arts MeSH
• Smell * MeSH
• Olfactory Perception * MeSH
• Adult MeSH
• Hydrocortisone blood   MeSH
• Competitive Behavior physiology   MeSH
• Humans MeSH
• Young Adult MeSH
• Odorants analysis   MeSH
• Testosterone blood   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Czech Republic MeSH

Rare autosomal dominant tubulointerstitial kidney disease is caused by mutations in the genes encoding uromodulin (UMOD), hepatocyte nuclear factor-1β (HNF1B), renin (REN), and mucin-1 (MUC1). Multiple names have been proposed for these disorders, including 'Medullary Cystic Kidney Disease (MCKD) type 2', 'Familial Juvenile Hyperuricemic Nephropathy (FJHN)', or 'Uromodulin-Associated Kidney Disease (UAKD)' for UMOD-related diseases and 'MCKD type 1' for the disease caused by MUC1 mutations. The multiplicity of these terms, and the fact that cysts are not pathognomonic, creates confusion. Kidney Disease: Improving Global Outcomes (KDIGO) proposes adoption of a new terminology for this group of diseases using the term 'Autosomal Dominant Tubulointerstitial Kidney Disease' (ADTKD) appended by a gene-based subclassification, and suggests diagnostic criteria. Implementation of these recommendations is anticipated to facilitate recognition and characterization of these monogenic diseases. A better understanding of these rare disorders may be relevant for the tubulointerstitial fibrosis component in many forms of chronic kidney disease.

• MeSH
• Gout * classification   diagnosis   genetics   therapy   MeSH
• Phenotype MeSH
• Genetic Predisposition to Disease MeSH
• Hyperuricemia * classification   diagnosis   genetics   therapy   MeSH
• Consensus MeSH
• Humans MeSH
• Mutation MeSH
• DNA Mutational Analysis MeSH
• Nephrology standards   MeSH
• Kidney Diseases * classification   diagnosis   genetics   therapy   MeSH
• Polycystic Kidney, Autosomal Dominant * classification   diagnosis   genetics   therapy   MeSH
• Predictive Value of Tests MeSH
• Terminology as Topic MeSH
• Uromodulin classification   deficiency   genetics   MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Consensus Development Conference MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Practice Guideline MeSH

INTRODUCTION: Impaired baroreflex function is associated with a shift in autonomic balance towards sympathetic dominance, which may play important role in the development of arterial hypertension and consequent target organ damage. AIM: To determine the effect of treatment on the cardiovascular autonomic modulation expressed by baroreflex sensitivity (BRS) in hypertensives. METHODS: A total of one hundred fourteen hypertensive patients (58 male/56 female, 65 ± 13 years of age, BMI 30 ± 3.4 kg/m(2)) were enrolled. Control group of 20 subjects with normal blood pressure (BP) (ten male/ten female, 59 ± 8 years of age, body mass index 28.3 ± 2.5 kg/m(2)) without any treatment was also studied. BRS and BRSf were determined by the sequence and spectral method: a 5-min on-invasive beat-to-beat recording of blood pressure and R-R interval with use of Collin CBM-7000 monitor, controlled breathing at a frequency of 0.1 Hz. RESULTS: Significant negative correlation between spontaneous BRS and BP was present in hypertensives (r = -0.52, p < 0.001). All cohort of hypertensive patients had significantly lower BRS than subjects with normal blood pressure (p < 0.05). The greatest decline in BRS values was in hypertensive patients with metabolic syndrome, who had BRS values <5 ms/mmHg. Hypertensives with hypercholesterolaemia on low dose statin therapy (atrovastatin 20 mg) had higher BRS/BRSf values than statin free patients (p < 0.05). Only BRSf not BRS was significantly increased in hypertensives with beta-blockers. CONCLUSION: An inverse correlation between blood pressure and BRS is present in hypertensives. BRS and BRSf is higher in low dose statin-treated patients with essential hypertension.

• MeSH
• Antihypertensive Agents administration & dosage   MeSH
• Arterial Pressure drug effects   MeSH
• Atorvastatin administration & dosage   MeSH
• Autonomic Nervous System drug effects   physiopathology   MeSH
• Baroreflex drug effects   MeSH
• Time Factors MeSH
• Hyperlipidemias diagnosis   drug therapy   physiopathology   MeSH
• Hypertension diagnosis   drug therapy   physiopathology   MeSH
• Cardiovascular System innervation   MeSH
• Middle Aged MeSH
• Humans MeSH
• Aged MeSH
• Hydroxymethylglutaryl-CoA Reductase Inhibitors administration & dosage   MeSH
• Treatment Outcome MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

OBJECTIVE: Mean platelet volume is arousing increasing interest as a new independent cardiovascular risk factor. Large platelets are likely to be more reactive. If mean platelet volume would drop after LDL-lowering therapy, decreased MPV could be one of the markers of successful therapy. Therefore, we investigated mean platelet volume after extracorporeal LDL-cholesterol elimination. METHODS: Mean platelet volume was investigated in patients with severe familial hypercholesterolemia long-term treated (3-12 years) by LDL-apheresis (immunoapheresis) or cascade filtration. Plasma was obtained by centrifugation. Adsorbers Lipopak 400 were used for immunoapheresis and filters Evaflux 4A were used for cascade filtration. 95 pair samples were measured (before and after the procedures) in a group of 12 patients--each patient 8 times in 4 years. RESULTS: Mean platelet volume before the procedures was 10.891 fl, CI 10.25-11.53. Mean platelet volume after the procedures decreased--10.478 fl, CI 09.84-11.11. The difference is statistically significant (p = 0.036). Mean platelet volume did not correlate with age, sex, platelet count, duration of therapy. At the same time, we used rheohemapheresis in the therapy of 40 patients with age-related macular degeneration. But mean platelet volume was not changed. CONCLUSION: Mean platelet volume is easily available and is often disregarded, and sometimes may suggest the need for a careful assessment in patients with familial hypercholesterolemia. Mean platelet volume could be one of the markers of therapeutic efficacy in patients with familial hypercholesterolemia treated by extracorporeal LDL-cholesterol elimination that is simple and inexpensive.

• MeSH
• Biomarkers blood   MeSH
• Time Factors MeSH
• Adult MeSH
• Hyperlipoproteinemia Type II blood   diagnosis   therapy   MeSH
• Cholesterol, LDL blood   MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Predictive Value of Tests MeSH
• Blood Component Removal * MeSH
• Blood Platelets pathology   MeSH
• Cell Size * MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Plant-plant interactions (competition and facilitation) in terrestrial ecosystems include: (1) short-term effects, primarily quantified with experimental removals; and (2) long-term effects, mostly due to soil weathering processes, primarily quantified with observational methods. It has been argued that these effects are likely to vary in contrasting directions with increasing drought stress in arid systems. However, few studies have used appropriate methodology to assess both types of effects and their variation across nurse species and environmental conditions, in particular in arid systems. This knowledge is crucial for predicting variation in the mediating role of facilitation with climate change and assessing the importance of nurse effects in ecological restoration. In the arid climate of central-south Tunisia, understory species' biomass, abundance and composition and soil parameters were compared in shrub-control, shrub-removed and open areas for three shrub species and in two habitats with contrasting soil moisture conditions. Long-term effects were dominant, positive for all three shrub species and associated with increasing nutrient content in shrub patches. Short-term effects, mainly related to water consumption, were weaker, mostly negative and dependent on shrub species. Additionally, long-term effects were less positive and short-term effects more negative in the dry habitat than in the wet habitat. Our study provides evidence of the primary influence of positive (facilitative) long-term effects in this arid system. However, the net effects of shrubs could be less beneficial for other species with increasing aridity under climate change, due to both a decrease in positive long-term effects and an increase in negative short-term effects.

• MeSH
• Biomass * MeSH
• Time MeSH
• Species Specificity MeSH
• Ecology MeSH
• Ecosystem * MeSH
• Stress, Physiological MeSH
• Climate Change * MeSH
• Desert Climate * MeSH
• Soil chemistry   MeSH
• Plants * MeSH
• Water * MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Tunisia MeSH

Mechanická nálož aktivuje remodelaci kosti a zvyšuje její pevnost. Fyzická zátěž má tedy mimořádný význam pro kostní zdraví. Objem svalové hmoty i její kontrakce jsou v těsném vztahu ke kostní denzitě u mužů i žen, přestože u mužů je tento vztah těsnější. Svalově-
-kostní jednotka tvoří vývojový funkční celek, jehož obě komponenty jsou pod společnou kontrolou systému somatotropin-IGF-1, androgenů a D hormonu. Tyto endokrinní systémy prostřednictvím svalově-kostní jednotky hrají významnou roli ve vývoji kosti i její stabilitě v dospělosti. Proto deficit kteréhokoli z těchto systémů, podobně jako omezená fyzická aktivita (především v dětství), mohou negativně ovlivnit kostní denzitu i kvalitu. Kost je také pod kontrolou tukové tkáně, která moduluje kostní metabolizmus mechanicky, ale především prostřednictvím adipocytokinů (leptin, adiponektin nebo rezistin). Leptin zrychluje novotvorbu kosti aktivací osteoblastů. Tento přímý efekt hormonu je amplifikován stimulací β-1 adrenergního systému, který ruší negativní osteotropní efekt neuropeptidu Y. Na druhé straně leptin aktivuje také β-2 adrenerní receptory, které zrychlují resorpci kosti. Nicméně u člověka převládá osteoanabolický efekt hormonu. Leptin má zásadní význam pro nastartování puberty u dívek a pro vývoj ženské kosti. Adiponektin (a pravděpodobně také rezistin) má na kost vliv jednoznačně negativní. Klinický význam měkkých tkání a regulačních hormonů pro integritu skeletu potvrdí další studie.

Mechanical load activates bone modeling and increases bone strength. Thus physical activity is extremely important for overall bone health. Muscle volume and muscle contraction are closely related to bone mineral density in men and women, although these relationships are more significat in men. The muscle-bone unit has been defined as a functional system, in which both components are under control of the somatotropin-IGF-I system, androgens and D hormone. These endocrine systems play, via the muscle-bone unit, an important role in development of the skeleton and its stability in adulthood. That is why deficiency of any of these hormonal systems, or reduced physical activity (mainly in childhood) could seriously affect bone density and quality. Bone is also under control of adipose tissue, which modulates its metabolism via mechanical load and more importantly via adipocytokines (leptin, adiponectin and rezistin). Leptin increases bone formation by activation of osteoblasts. This direct effect of leptin is amplified by stimulation of the β-1 adrenergic system, which inhibits the negative osteotropic effects of neuropeptide Y. On the other hand, leptin also activates β-2 adrenergic receptors, which increase bone resorption. In humans, the overall osteo-anabolic effect of leptin tends to be dominant. Furthermore, leptin has a principal role in the start of puberty in girls and maturation, remodeling and development of the female skeleton. Adiponectin (and probably rezistin) has an unambiguous deteriorating effect on the skeleton. Further studies are needed to confirm the clinical importance of soft tissues relative to the integrity of the skeleton.

• Keywords
• sval, kost, tuk, IGF1,
• MeSH
• Adiponectin physiology   metabolism   MeSH
• Androgens physiology   MeSH
• Child MeSH
• Adult MeSH
• Estrogens physiology   MeSH
• Insulin-Like Growth Factor I MeSH
• Leptin physiology   metabolism   MeSH
• Humans MeSH
• Adolescent MeSH
• Musculoskeletal Development MeSH
• Nicotinamide Phosphoribosyltransferase MeSH
• Motor Activity MeSH
• Child, Preschool MeSH
• Resistin MeSH
• Growth Hormone physiology   deficiency   MeSH
• Steroids MeSH
• Vitamin D physiology   MeSH
• Bone Development MeSH
• Muscle Development MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Review MeSH

Práce je zaměřena na dostupnou léčbu farmakorezistentní schizofrenie v běžné klinické praxi. Literární údaje a klinické zkušenosti ukazují na nutnost vyloučení pseudorezistence, která je často dána nonadherencí. Zlatým standardem je klozapin. Další možnosti zahrnují augmentaci a kombinaci antipsychotik, pro tyto strategie však máme málo důkazů o jejich účinnosti a výsledky jsou inkonzistentní. Augmentace je převážně cílena na přetrvávající a převládající příznaky (depresivní a negativní příznaky, kognitivní deficit). Nejčastěji užívanou kombinací je klozapin a antipsychotikum, které je k němu z hlediska farmakologického profilu komplementární.

The paper is focused on available therapeutic approaches to schizophrenia in common clinical practice. The literature and clinical experience stress the exclusion of pseudoresistance, caused mainly by nonadherence. The gold standard is clozapine. Further possibilities include augmentation and combination of antipsychotics; however, for these strategies there is not enough evidence and results are inconsistent. Augmentation is aimed mostly on persistent and dominant symptoms (depressive and negative symptoms, cognitive deficit). The most frequently used combination is combination of clozapine with an antipsychotic with complementary pharmacological profile.

• MeSH
• Antipsychotic Agents administration & dosage   classification   therapeutic use   MeSH
• Clozapine administration & dosage   therapeutic use   MeSH
• Drug Therapy, Combination MeSH
• Drug Resistance * MeSH
• Humans MeSH
• Schizophrenia * drug therapy   complications   MeSH
• Healthy Lifestyle MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH