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Sample records for mutations hormone status

  1. Oncogenic mutations of thyroid hormone receptor β

    PubMed Central

    Park, Jeong Won; Zhao, Li; Willingham, Mark; Cheng, Sheue-yann

    2015-01-01

    The C-terminal frame-shift mutant of the thyroid hormone receptor TRβ1, PV, functions as an oncogene. An important question is whether the oncogenic activity of mutated TRβ1 is uniquely dependent on the PV mutated sequence. Using four C-terminal frame-shift mutants—PV, Mkar, Mdbs, and AM—we examined that region in the oncogenic actions of TRβ1 mutants. Remarkably, these C-terminal mutants induced similar growth of tumors in mouse xenograft models. Molecular analyses showed that they physically interacted with the p85α regulatory subunit of PI3K similarly in cells. In vitro GST-binding assay showed that they bound to the C-terminal Src-homology 2 (CSH2) of p85α with markedly higher avidity. The sustained association of mutants with p85α led to activation of the common PI3K-AKT-ERK/STAT3 signaling to promote cell proliferation and invasion and to inhibit apoptosis. Thus, these results argue against the oncogenic activity of PV being uniquely dependent on the PV mutated sequence. Rather, these four mutants could favor a C-terminal conformation that interacted with the CSH2 domain of p85α to initiate activation of PI3K to relay downstream signaling to promote tumorigenesis. Thus, we propose that the mutated C-terminal region of TRβ1 could function as an “onco-domain” and TRβ1 is a potential therapeutic target. PMID:25924236

  2. Thyroid hormone resistance: a novel mutation in thyroid hormone receptor beta (THRB) gene - case report.

    PubMed

    Işık, Emregül; Beck Peccoz, Paolo; Campi, Irene; Özön, Alev; Alikaşifoğlu, Ayfer; Gönç, Nazlı; Kandemir, Nurgün

    2013-01-01

    Thyroid hormone resistance (THR) is a dominantly inherited syndrome characterized by reduced sensitivity to thyroid hormones. It is usually caused by mutations in the thyroid hormone receptor beta (THRB) gene. In the present report, we describe the clinical and laboratory characteristics and genetic analysis of patients with a novel THRB gene mutation. The index patient had been misdiagnosed as hyperthyroidism and treated with antithyroid drugs since eight days of age. Thyroid hormone results showed that thyrotropin (thyroid-stimulating hormone, TSH) was never suppressed despite elevated thyroid hormone levels, and there was no symptom suggesting hyperthyroidism. A heterozygous mutation at codon 350 located in exon 9 of the THRB gene was detected in all the affected members of the family. It is important to consider thyroid hormone levels in association with TSH levels to prevent inappropriate treatment and the potential complications, such as clinical hypothyroidism or an increase in goiter size.

  3. Genetic mutations associated with status epilepticus.

    PubMed

    Bhatnagar, M; Shorvon, S

    2015-08-01

    This paper reports the results of a preliminary search of the literature aimed at identifying the genetic mutations reported to be strongly associated with status epilepticus. Genetic mutations were selected for inclusion if status epilepticus was specifically mentioned as a consequence of the mutation in standard genetic databases or in a case report or review article. Mutations in 122 genes were identified. The genetic mutations identified were found in only rare conditions (sometimes vanishingly rare) and mostly in infants and young children with multiple other handicaps. Most of the genetic mutations can be subdivided into those associated with cortical dysplasias, inborn errors of metabolism, mitochondrial disease, or epileptic encephalopathies and childhood syndromes. There are no identified 'pure status epilepticus genes'. The range of genes underpinning status epilepticus differs in many ways from the range of genes underpinning epilepsy, which suggests that the processes underpinning status epilepticus differ from those underpinning epilepsy. It has been frequently postulated that status epilepticus is the result of a failure of 'seizure termination mechanisms', but the wide variety of genes affecting very diverse biochemical pathways identified in this survey makes any unitary cause unlikely. The genetic influences in status epilepticus are likely to involve a wide range of mechanisms, some related to development, some to cerebral energy production, some to diverse altered biochemical pathways, some to transmitter and membrane function, and some to defects in networks or systems. The fact that many of the identified genes are involved with cerebral development suggests that status epilepticus might often be a system or network phenomenon. To date, there are very few genes identified which are associated with adult-onset status epilepticus (except in those with preexisting neurological damage), and this is disappointing as the cause of many adult

  4. Novel mutations associated with combined pituitary hormone deficiency.

    PubMed

    Romero, Christopher J; Pine-Twaddell, Elyse; Radovick, Sally

    2011-06-01

    The pituitary gland produces hormones that play important roles in both the development and the homeostasis of the body. A deficiency of two or several of these pituitary hormones, known as combined pituitary hormone deficiency, may present in infants or children due to an unknown etiology and is considered congenital or idiopathic. Advancements in our understanding of pituitary development have provided a genetic basis to explain the pathophysiological basis of pituitary hormone disease. Nevertheless, there are several challenges to the precise characterization of abnormal genotypes; these exist secondary to the complexities of several of the hypothalamic/pituitary developmental factors and signals, which ultimately integrate in a temporal and spatial dependent manner to produce a mature gland. Furthermore, the clinical presentation of pituitary hormone disease may be dynamic as subsequent hormone deficiencies may develop over time. The characterization of patients with mutations in genes responsible for pituitary development provides an opportunity to discover potential novel mechanisms responsible for pituitary pathophysiology. The focus of this review is to report the most recent mutations in genes responsible for pituitary development in patients with hypopituitarism and emphasize the importance to physicians and researchers for characterizing these patients. Continuing efforts toward understanding the molecular basis of pituitary development as well as genetic screening of patients with pituitary disease will offer new insights into both diagnostic and potential therapeutic options that will decrease the morbidity and mortality in patients with hypopituitarism.

  5. Mutational status of nevus associated-melanomas

    PubMed Central

    Shitara, D.; Tell-Martí, G.; Badenas, C.; Enokihara, M.M.S.S.; Alós, L.; Larque, A.B.; Michalany, Nilceo; Puig-Butille, J.; Carrera, C.; Malvehy, J.; Puig, S.; Bagatin, E.

    2015-01-01

    Introduction Melanoma origin has always been a debated subject, as well as the role of adjacent melanocytic nevi. Epidemiological and histopathological studies point to melanomas arising either de novo or from a nevus. Methods Sixty-one melanomas found in association with a preexisting nevus were microdissected, after careful selection of cell subpopulations and submitted to Sanger sequencing of the BRAF, NRAS, C-KIT, PPP6C, STK19 and RAC1 genes. Each gene was evaluated twice in all samples by sequencing or by sequencing and another confirmation method, allele-specific fluorescent polymerase chain reaction (PCR) and capillary electrophoresis detection, or by SNaPshot Analysis. Only mutations confirmed via two different molecular methods or twice by sequencing were considered positive. Results The majority of cases presented concordance of mutational status between melanoma and the associated nevus for all 6 genes (40/60; 66.7%). Nine cases presented concomitant BRAF and NRAS mutations, including one case, in which both the melanoma and the adjacent nevus harbored V600E and Q61K double mutations. In two cases, both melanoma and associated nevus, located on acral sites were BRAF mutated, including an acral lentiginous melanoma. Conclusions This is the largest nevus-associated melanoma series molecularly evaluated to our knowledge. The majority of melanomas and adjacent nevi in our sample share the same mutational profile, corroborating the theory that the adjacent nevus and melanoma are clonally related and that melanoma originated within a nevus. PMID:25857817

  6. Female sexual dysfunction and hormonal status in multiple sclerosis patients.

    PubMed

    Lombardi, Giuseppe; Celso, Maria; Bartelli, Mario; Cilotti, Antonio; Del Popolo, Giulio

    2011-04-01

    Literature holds no information on a correlation between blood hormonal levels, in particular sex hormones and the sexual response of women with multiple sclerosis (MS). To investigate a possible correlation between hormonal status and the sexual response of females with MS. The Female Sexual Function Index (FSFI) questionnaire was used to determine sexual dysfunctions (SDs). Methods for measuring blood hormones were chemiluminescence immunoassay, electrochemiluminescence immunoassay, enzyme immunoassay, and radioimmunoassay. During the screening phase, 55 women of reproductive age were recruited and completed the FSFI. In the first phase of the study females underwent a hematic hormonal evaluation on the third day of their menstrual cycle. Serum follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), thyroid stimulating hormone (TSH), cortisol, dehydroepiandrosterone sulphate (DHEA-S), androstenedione, 17[alpha]-hydroxyprogesterone, total and free testosterone, 17 beta estradiol, inhibin and sex hormone binding globulin (SHBG), and thyroid hormones (fT3 and fT4) were checked. On the day 20-21 into their menstrual cycle the progesterone hematic value was noted. Patients with amenorrhea had all hormones tested once with a random blood drawing. After a 3-month period patients began phase 2, completing the FSFI again. The same blood hormones were investigated. Fifty-four females completed the study. Thirty-one continued to manifest at least one SD: desire (57.4%) was the most common. Overall, 36.4% showed abnormal hormonal alterations. The most frequent was 40% for 17 beta-estradiol. None of the FSFI domains, including the total score, revealed any statistically significant correlation to the hormones investigated. No statistically significant clinical predictive factors for blood hormone abnormalities were detected; comparing females with and without SD, P = 0.250 using chi-squared test was reached. Notable percentages of blood hormonal

  7. Lifetime, untreated isolated GH deficiency due to a GH-releasing hormone receptor mutation has beneficial consequences on bone status in older individuals, and does not influence their abdominal aorta calcification.

    PubMed

    Souza, Anita H O; Farias, Maria I T; Salvatori, Roberto; Silva, Gabriella M F; Santana, João A M; Pereira, Francisco A; de Paula, Francisco J A; Valença, Eugenia H O; Melo, Enaldo V; Barbosa, Rita A A; Pereira, Rossana M C; Gois-Junior, Miburge B; Aguiar-Oliveira, Manuel H

    2014-09-01

    The GH/IGF-I axis has essential roles in regulating bone and vascular status. The age-related decrease in GH secretion ("somatopause") may contribute to osteoporosis and atherosclerosis, commonly observed in the elderly. Adult-onset GH deficiency (GHD) has been reported to be associated with reduced bone mineral density (BMD), increased risk of fractures, and premature atherosclerosis. We have shown the young adult individuals with isolated GHD (IGHD) due to a homozygous for the c.57+1G>A GHRH receptor gene mutation have normal volumetric BMD (vBMD), and not develop premature atherosclerosis, despite adverse risk factor profile. However, the bone and vascular impact of lifetime GHD on the aging process remains unknown. We studied a group of ten older IGHD subjects (≥60 years) homozygous for the mutation, comparing them with 20 age- and gender-matched controls (CO). Areal BMD was measured, and vBMD was calculated at the lumbar spine and total hip. Vertebral fractures and abdominal aortic calcifications (expressed as calcium score) were also assessed. Areal BMD was lower in IGHD, but vBMD was similar in the two groups. The percent of fractured individuals was similar, but the mean number of fractures per individual was lower in IGHD than CO. Calcium score was similar in the two groups. A positive correlation was found between calcium score and number of fractures. Untreated lifetime IGHD has beneficial consequences on bone status and does not have a deleterious effect on abdominal aorta calcification.

  8. Tumour morphology predicts PALB2 germline mutation status

    PubMed Central

    Teo, Z L; Provenzano, E; Dite, G S; Park, D J; Apicella, C; Sawyer, S D; James, P A; Mitchell, G; Trainer, A H; Lindeman, G J; Shackleton, K; Cicciarelli, L; Buys, S S; Andrulis, I L; Mulligan, A M; Glendon, G; John, E M; Terry, M B; Daly, M; Odefrey, F A; Nguyen-Dumont, T; Giles, G G; Dowty, J G; Winship, I; Goldgar, D E; Hopper, J L; Southey, M C

    2013-01-01

    Background: Population-based studies of breast cancer have estimated that at least some PALB2 mutations are associated with high breast cancer risk. For women carrying PALB2 mutations, knowing their carrier status could be useful in directing them towards effective cancer risk management and therapeutic strategies. We sought to determine whether morphological features of breast tumours can predict PALB2 germline mutation status. Methods: Systematic pathology review was conducted on breast tumours from 28 female carriers of PALB2 mutations (non-carriers of other known high-risk mutations, recruited through various resources with varying ascertainment) and on breast tumours from a population-based sample of 828 Australian women diagnosed before the age of 60 years (which included 40 BRCA1 and 18 BRCA2 mutation carriers). Tumour morphological features of the 28 PALB2 mutation carriers were compared with those of 770 women without high-risk mutations. Results: Tumours arising in PALB2 mutation carriers were associated with minimal sclerosis (odds ratio (OR)=19.7; 95% confidence interval (CI)=6.0–64.6; P=5 × 10−7). Minimal sclerosis was also a feature that distinguished PALB2 mutation carriers from BRCA1 (P=0.05) and BRCA2 (P=0.04) mutation carriers. Conclusion: This study identified minimal sclerosis to be a predictor of germline PALB2 mutation status. Morphological review can therefore facilitate the identification of women most likely to carry mutations in PALB2. PMID:23787919

  9. The effects of thyroid hormone abnormalities on periodontal disease status.

    PubMed

    Zahid, Talal M; Wang, Bing-Yan; Cohen, Robert E

    2011-10-01

    Thyroid hormones play an important role in the regulation of physiologic processes. Thyroid disease can lead to imbalance in the homeostasis of the body and affect the healing capacity of tissues. However, limited data are available regarding the relationship between thyroid hormone imbalance (thyroid disease) and periodontal health. This review is carried out to summarize the relationship between thyroid disease and periodontal status. PUBMED and MEDLINE searches of both human and animal studies were performed to investigate the relationship between thyroid disease, periodontal status, and dental implants. Results suggest that thyroid diseases may affect the status of periodontal diseases, especially in hypothyroid conditions. The duration from disease onset to treatment of thyroid disorders may be critical, since uncontrolled thyroid disease may result in destruction of the periodontium. Further controlled studies are needed to explore the relationship between thyroid hormone imbalance and periodontal status. Periodontal therapies, including dental implant placement, appear to be safe with no increase in treatment failure, so long as the status of the thyroid gland is controlled.

  10. Somatic mutations, acetylator status, and prognosis in colorectal cancer

    PubMed Central

    Hardingham, J; Butler, W; Roder, D; Dobrovic, A; Dymock, R; Sage, R; Roberts-Thomson, I

    1998-01-01

    Background—Somatic mutations in K-ras and TP53 may be associated with both acetylator status and prognosis in colorectal cancer. 
Aims—To determine whether cancers with somatic mutations are more frequent in fast acetylators and whether mutations or acetylator status influence prognosis after colorectal surgery. 
Patients—One hundred consecutive subjects undergoing elective surgery for colorectal cancer. 
Methods—Acetylator status was determined by polymerase chain reaction (PCR) genotyping for polymorphism in the N-acetyltransferase 2 (NAT2) gene. Mutations in K-ras (codon 12) and TP53 were determined by PCR analysis using restriction enzyme digestion and single strand conformation polymorphism respectively. Survival from colorectal cancer for up to five years after diagnosis was analysed using the Kaplan-Meier product limit estimator. Cox proportional hazards regression was used to compare survival rates after adjusting for tumour stage. 
Results—Mutations in K-ras and TP53 were independent of acetylator status. By log rank test, survival was significantly reduced in subjects with TP53 mutations (p=0.003) but was not significantly related to acetylator status or the presence of K-ras mutations. After adjustment for tumour stage, subjects with both TP53 and K-ras mutations had a 4.2-fold case fatality (95% confidence interval 1.5 to 11.6) when compared with that of a TP53 negative reference group. 
Conclusion—The presence of both TP53 and K-ras mutations in colorectal tumours is an adverse prognostic marker which is independent of tumour stage. 

 Keywords: colorectal cancer; TP53 and K-ras mutations; acetylator status; prognosis PMID:9659162

  11. Novel growth hormone receptor gene mutation in a patient with Laron syndrome.

    PubMed

    Arman, Ahmet; Yüksel, Bilgin; Coker, Ajda; Sarioz, Ozlem; Temiz, Fatih; Topaloglu, Ali Kemal

    2010-04-01

    Growth Hormone (GH) is a 22 kDa protein that has effects on growth and glucose and fat metabolisms. These effects are initiated by binding of growth hormone (GH) to growth hormone receptors (GHR) expressed in target cells. Mutations or deletions in the growth hormone receptor cause an autosomal disorder called Laron-type dwarfism (LS) characterized by high circulating levels of serum GH and low levels of insulin like growth factor-1 (IGF-1). We analyzed the GHR gene for genetic defect in seven patients identified as Laron type dwarfism. We identified two missense mutations (S40L and W104R), and four polymorphisms (S473S, L526I, G168G and exon 3 deletion). We are reporting a mutation (W104R) at exon 5 of GHR gene that is not previously reported, and it is a novel mutation.

  12. Thyroid hormone status regulates the expression of secretory phospholipases.

    PubMed

    Sharma, Pragya; Levesque, Tania; Boilard, Eric; Park, Edwards A

    2014-01-31

    Thyroid hormone (T3) stimulates various metabolic pathways and the hepatic actions of T3 are mediated primarily through the thyroid hormone receptor beta (TRβ). Hypothyroidism has been linked with low grade inflammation, elevated risk of hepatic steatosis and atherosclerosis. Secretory phospholipases (sPLA2) are associated with inflammation, hyperlipidemia and atherosclerosis. Due to potential linkage between thyroid hormone and sPLA2, we investigated the effect of thyroid hormone status on the regulation of secretory phospholipases in mice, rats and human liver. T3 suppressed the expression of the sPLA2 group IIa (PLA2g2a) gene in the liver of BALB/c mice and C57BL/6 transgenic mice expressing the human PLA2g2a. PLA2g2a was elevated with hypothyroidism and high fat diets which may contribute to the low grade inflammation associated with hypothyroidism and diet induced obesity. We also examined the effects of the TRβ agonist eprotirome on hepatic gene regulation. We observed that eprotirome inhibited the expression of selected sPLA2 genes and furthermore the cytokine mediated induction PLA2g2a was suppressed. In addition, eprotirome induced genes involved in fatty acid oxidation and cholesterol clearance while inhibiting lipogenic genes. Our results indicate that in vivo thyroid hormone status regulates the abundance of sPLA2 and the inhibition of PLA2g2a by T3 is conserved across species. By regulating sPLA2 genes, T3 may impact processes associated with atherosclerosis and inflammation and TRβ agonists may ameliorate inflammation and hyperlipidemia.

  13. Thyroid hormone status regulates the expression of secretory phospholipases

    PubMed Central

    Sharma, Pragya; Levesque, Tania; Boilard, Eric; Park, Edwards A.

    2014-01-01

    Thyroid hormone (T3) stimulates various metabolic pathways and the hepatic actions of T3 are mediated primarily through the thyroid hormone receptor beta (TRβ). Hypothyroidism has been linked with low grade inflammation, elevated risk of hepatic steatosis and atherosclerosis. Secretory phospholipases (sPLA2) are associated with inflammation, hyperlipidemia and atherosclerosis. Due to potential linkage between thyroid hormone and sPLA2, we investigated the effect of thyroid hormone status on the regulation of secretory phospholipases in mice, rats and human liver. T3 suppressed the expression of the sPLA2 group IIa (PLA2g2a) gene in the liver of BALB/c mice and C57BL/6 transgenic mice expressing the human PLA2g2a. PLA2g2a was elevated with hypothyroidism and high fat diets which may contribute to the low grade inflammation associated with hypothyroidism and diet induced obesity. We also examined the effects of the TRβ agonist eprotirome on hepatic gene regulation. We observed that eprotirome inhibited the expression of selected sPLA2 genes and furthermore the cytokine mediated induction PLA2g2a was suppressed. In addition, eprotirome induced genes involved in fatty acid oxidation and cholesterol clearance while inhibiting lipogenic genes. Our results indicate that in vivo thyroid hormone status regulates the abundance of sPLA2 and the inhibition of PLA2g2a by T3 is conserved across species. By regulating sPLA2 genes, T3 may impact processes associated with atherosclerosis and inflammation and TRβ agonists may ameliorate inflammation and hyperlipidemia. PMID:24440706

  14. DNA methylation and hormone receptor status in breast cancer.

    PubMed

    Benevolenskaya, Elizaveta V; Islam, Abul B M M K; Ahsan, Habibul; Kibriya, Muhammad G; Jasmine, Farzana; Wolff, Ben; Al-Alem, Umaima; Wiley, Elizabeth; Kajdacsy-Balla, Andre; Macias, Virgilia; Rauscher, Garth H

    2016-01-01

    We examined whether differences in tumor DNA methylation were associated with more aggressive hormone receptor-negative breast cancer in an ethnically diverse group of patients in the Breast Cancer Care in Chicago (BCCC) study and using data from The Cancer Genome Atlas (TCGA). DNA was extracted from formalin-fixed, paraffin-embedded samples on 75 patients (21 White, 31 African-American, and 23 Hispanic) (training dataset) enrolled in the BCCC. Hormone receptor status was defined as negative if tumors were negative for both estrogen and progesterone (ER/PR) receptors (N = 22/75). DNA methylation was analyzed at 1505 CpG sites within 807 gene promoters using the Illumina GoldenGate assay. Differential DNA methylation as a predictor of hormone receptor status was tested while controlling for false discovery rate and assigned to the gene closest to the respective CpG site. Next, those genes that predicted ER/PR status were validated using TCGA data with respect to DNA methylation (validation dataset), and correlations between CpG methylation and gene expression were examined. In the training dataset, 5.7 % of promoter mean methylation values (46/807) were associated with receptor status at P < 0.05; for 88 % of these (38/46), hypermethylation was associated with receptor-positive disease. Hypermethylation for FZD9, MME, BCAP31, HDAC9, PAX6, SCGB3A1, PDGFRA, IGFBP3, and PTGS2 genes most strongly predicted receptor-positive disease. Twenty-one of 24 predictor genes from the training dataset were confirmed in the validation dataset. The level of DNA methylation at 19 out 22 genes, for which gene expression data were available, was associated with gene activity. Higher levels of promoter methylation strongly correlate with hormone receptor positive status of breast tumors. For most of the genes identified in our training dataset as ER/PR receptor status predictors, DNA methylation correlated with stable gene expression level. The predictors performed well when

  15. A vital region for human glycoprotein hormone trafficking revealed by an LHB mutation.

    PubMed

    Potorac, Iulia; Rivero-Müller, Adolfo; Trehan, Ashutosh; Kiełbus, Michał; Jozwiak, Krzysztof; Pralong, Francois; Hafidi, Aicha; Thiry, Albert; Ménagé, Jean-Jacques; Huhtaniemi, Ilpo; Beckers, Albert; Daly, Adrian F

    2016-12-01

    Glycoprotein hormones are complex hormonally active macromolecules. Luteinizing hormone (LH) is essential for the postnatal development and maturation of the male gonad. Inactivating Luteinizing hormone beta (LHB) gene mutations are exceptionally rare and lead to hypogonadism that is particularly severe in males. We describe a family with selective LH deficiency and hypogonadism in two brothers. DNA sequencing of LHB was performed and the effects of genetic variants on hormone function and secretion were characterized by mutagenesis studies, confocal microscopy and functional assays. A 20-year-old male from a consanguineous family had pubertal delay, hypogonadism and undetectable LH. A homozygous c.118_120del (p.Lys40del) mutation was identified in the patient and his brother, who subsequently had the same phenotype. Treatment with hCG led to pubertal development, increased circulating testosterone and spermatogenesis. Experiments in HeLa cells revealed that the mutant LH is retained intracellularly and showed diffuse cytoplasmic distribution. The mutated LHB heterodimerizes with the common alpha-subunit and can activate its receptor. Deletion of flanking glutamic acid residues at positions 39 and 41 impair LH to a similar extent as deletion of Lys40. This region is functionally important across all heterodimeric glycoprotein hormones, because deletion of the corresponding residues in hCG, follicle-stimulating hormone and thyroid-stimulating hormone beta-subunits also led to intracellular hormone retention. This novel LHB mutation results in hypogonadism due to intracellular sequestration of the hormone and reveals a discrete region in the protein that is crucial for normal secretion of all human glycoprotein hormones.

  16. Hormone resistance caused by mutations in G proteins and G protein-coupled receptors.

    PubMed

    Spiegel, A M

    1999-04-01

    G proteins couple receptors for many hormones to effectors that regulate second messenger metabolism. Several endocrine disorders have been shown to be caused by either loss or gain of function mutations in G proteins or G protein-coupled receptors. Pseudohypoparathyroidism (PHP), the first described example of a hormone resistance disorder, is characterized by renal resistance to parathyroid hormone (PTH) proximal to generation of the second messenger, cAMP. In PHP Ia there is more generalized hormone resistance (PTH, TSH, gonadotropins) and associated abnormal physical features, Albright hereditary osteodystrophy (AHO). Subjects with PHP Ib are normal in appearance and resistant exclusively to PTH. Germline loss of function mutations have been identified in the Gs-alpha gene in PHP Ia, and recent evidence suggests that the Gs-alpha gene is paternally imprinted in a tissue-specific manner. In PHP Ib, several studies have excluded PTH receptor gene mutations, and the molecular basis has not yet been defined.

  17. Predictive radiogenomics modeling of EGFR mutation status in lung cancer

    PubMed Central

    Gevaert, Olivier; Echegaray, Sebastian; Khuong, Amanda; Hoang, Chuong D.; Shrager, Joseph B.; Jensen, Kirstin C.; Berry, Gerald J.; Guo, H. Henry; Lau, Charles; Plevritis, Sylvia K.; Rubin, Daniel L.; Napel, Sandy; Leung, Ann N.

    2017-01-01

    Molecular analysis of the mutation status for EGFR and KRAS are now routine in the management of non-small cell lung cancer. Radiogenomics, the linking of medical images with the genomic properties of human tumors, provides exciting opportunities for non-invasive diagnostics and prognostics. We investigated whether EGFR and KRAS mutation status can be predicted using imaging data. To accomplish this, we studied 186 cases of NSCLC with preoperative thin-slice CT scans. A thoracic radiologist annotated 89 semantic image features of each patient’s tumor. Next, we built a decision tree to predict the presence of EGFR and KRAS mutations. We found a statistically significant model for predicting EGFR but not for KRAS mutations. The test set area under the ROC curve for predicting EGFR mutation status was 0.89. The final decision tree used four variables: emphysema, airway abnormality, the percentage of ground glass component and the type of tumor margin. The presence of either of the first two features predicts a wild type status for EGFR while the presence of any ground glass component indicates EGFR mutations. These results show the potential of quantitative imaging to predict molecular properties in a non-invasive manner, as CT imaging is more readily available than biopsies. PMID:28139704

  18. Mutation analysis underlying the downregulation of the thyroid hormone receptor β1 gene in the Chinese breast cancer population

    PubMed Central

    Ling, Yaqin; Ling, Xiaoling; Fan, Lu; Wang, Yong; Li, Qing

    2015-01-01

    Purpose There are a growing number of reports suggesting that the aberrant expression and mutation of the thyroid hormone receptor β1 (TRβ1) gene is associated with the development of human neoplasms. However, its exact role in the pathogenesis of breast cancer remains elusive. In the present study, we analyzed the mRNA expression and mutations of the TRβ1 gene in the Chinese breast cancer population. Methods The expression of TRβ1 mRNA was examined by real-time quantitative reverse transcription polymerase chain reaction, and mutations in the TRβ1 gene in the hotspot region that spans exons 7–10 were analyzed by polymerase chain reaction single-strand conformation polymorphism and automated DNA sequencing. Results TRβ1 mRNA expression was significantly reduced in all 105 breast cancer specimens examined. A total of 20 samples showed truncating mutations within the exons 7–10 of the TRβ1 gene, where eight cases harbored a frame shift mutation (five cases of c.850insA in exon 7 and three cases c.1028delA in exon 8), whereas missense mutations were observed in 12 breast cancer cases. The 20 cases with mutation in the TRβ1 gene showed a reduction in TRβ1 mRNA expression compared with that observed in matched normal tissues. The mutation was also correlated with menopausal stage and estrogen receptor status. Conclusion The findings of the present study suggest that the aberrant expression and mutations of the TRβ1 gene are associated with the development of breast cancer and that the mutations in the TRβ1 gene partly serve as the underlying mechanism for TRβ1 inactivation in the Chinese breast cancer population. PMID:26527882

  19. Menopausal status and adjuvant hormonal therapy for breast cancer patients: a practical guideline.

    PubMed

    De Vos, F Y F L; van Laarhoven, H W M; Laven, J S E; Themmen, A P N; Beex, L V A M; Sweep, C G J; Seynaeve, C; Jager, A

    2012-11-01

    Breast cancer is the most common malignancy amongst women in the developed world. For patients with hormone-sensitive breast cancer eligible for adjuvant hormonal therapy, it is important to know if the ovaries are (still) functional or not. Indeed, the choice for a specific adjuvant hormonal treatment depends on the menopausal status of an individual woman. The currently available measures to determine the menopausal status are conflicting. Until better measures become available, we propose a practical guideline enabling an optimal choice of adjuvant hormonal therapy for women with a hormone receptor positive breast cancer taking into account uncertainties about their menopausal status.

  20. Frequency of mutations in PROP-1 gene in Turkish children with combined pituitary hormone deficiency.

    PubMed

    Kandemir, Nurgün; Vurallı, Doğuş; Taşkıran, Ekim; Gönç, Nazlı; Özön, Alev; Alikaşifoğlu, Ayfer; Yılmaz, Engin

    2012-01-01

    Mutations in the prophet of Pit-1 (PROP-1) gene are responsible for most of the cases of combined pituitary hormone deficiencies (CPHD). We performed this study to determine the prevalence of PROP-1 mutations in a group of Turkish children with CPHD. Fifty-three children with the diagnosis of CPHD were included in this study. Clinical data were obtained from medical files, and hormonal evaluation and genetic screening for PROP-1 mutations were performed. A homozygous S109X mutation was found in the second exon in two brothers, and they had growth hormone (GH) and thyroid-stimulating hormone (TSH) deficiencies and normal prolactin levels. In the third exon of the PROP-1 gene, a heterozygous A142T polymorphism was found in 14 patients and a homozygous A142T polymorphism was found in 3 patients. In the first exon, a homozygous A9A polymorphism was found in 7 patients and a heterozygous A9A polymorphism was found in 31 patients. We assumed that mutations in the PROP-1 gene in cases with CPHD were expected to be more prevalent in our population due to consanguinity, but it was found that these mutations were far less than expected and that it was rare in non-familial cases.

  1. Elevation of growth hormone-releasing hormone receptor messenger ribonucleic acid expression in growth hormone-secreting pituitary adenoma with Gsalpha protein mutation.

    PubMed

    Sakai, Naoyuki; Kim, Kyongsong; Sanno, Naoko; Yoshida, Daizo; Teramoto, Akira; Shibasaki, Tamotsu

    2008-01-01

    Growth hormone-releasing hormone (GHRH) stimulates not only the synthesis and secretion of GH but also the proliferation of normal somatotrophs. The expression of GHRH receptor (GHRHR) is regulated by GHRH, both of which are known to be expressed in human GH-secreting pituitary adenoma cells. Somatic mutations in the subunit of Gsalpha protein (gsp), lead to the constitutive activation of adenylyl cyclase in pituitary adenomas that secrete GH. It has not been examined how gsp mutations influence GHRHR expression in GH-secreting adenomas. We therefore analyzed the expression levels of GHRHR messenger ribonucleic acid (mRNA) in GH-secreting pituitary adenomas focusing on a gsp mutation. Furthermore, we investigated the effect of GHRH on the expression of GHRHR mRNA in primary cultures of GH-secreting pituitary adenoma cells. GHRHR mRNA expression levels were significantly elevated in gsp mutation-positive GH-secreting adenomas compared with those in gsp mutation-negative ones. In primary-cultured GH-secreting adenoma cells, the increase of GH secretion in response to GHRH was shown in both gsp mutation-positive and -negative adenoma cells with a significantly higher response in the latter adenoma cells. GHRH increased GHRHR mRNA expression level in gsp mutation-negative adenoma cells while it was not influenced by GHRH in gsp mutation-positive adenoma cells. These results suggest that gsp mutations up-regulate GHRHR mRNA expression in GH-secreting pituitary adenoma cells, and that gsp mutations desensitize the adenoma cells to GHRH in terms of their GHRHR mRNA expression probably because of their saturation of GHRH signaling.

  2. Episodic patterns of growth hormone secretion and growth hormone status of normal and tibial dyschondroplastic chickens.

    PubMed

    Vasilatos-Younken, R; Leach, R M

    1986-01-01

    Growth hormone status of normal and tibial dyschondroplastic (TD) birds was determined in 25 d old male chicks genetically selected for high and low incidence of TD. Birds were surgically prepared with indwelling venous catheters and blood samples remotely removed at 20 min intervals for 6 h to establish secretory patterns. Birds were maintained under a 16L:8D cycle, with free access to feed and water at all times. In a second experiment, secretory capacity was evaluated by administering a 10 micrograms/kg body weight dose of thyrotrophin releasing hormone (TRH). Blood samples were removed at 0, 5, 10, 20, 30, 60 and 120 min post-infusion of either TRH or saline (control). All birds displayed pulsatile patterns of GH secretion, with an average peak duration of 60 min and a 90 min inter-peak interval. Dyschondroplastic birds exhibited 50% higher mean peak amplitudes than normal birds (P less than .06), however, this difference was not translated into overall mean or total (curve area) differences. The magnitude of response to a TRH challenge was greater (P less than .10) for TD than for normal birds. In view of the relationships observed in other species between secretory pattern characteristics such as peak amplitude, and growth characteristics, it is suggested that differences in GH status of dyschondroplastic relative to normal birds may be related to initiation of the TD lesion.

  3. Status of long-acting-growth hormone preparations--2015.

    PubMed

    Høybye, Charlotte; Cohen, Pinchas; Hoffman, Andrew R; Ross, Richard; Biller, Beverly M K; Christiansen, Jens Sandahl

    2015-10-01

    Growth hormone (GH) treatment has been an established therapy for GH deficiency (GHD) in children and adults for more than three decades. Numerous studies have shown that GH treatment improves height, body composition, bone density, cardiovascular risk factors, physical fitness and quality of life and that the treatment has few side effects. Initially GH was given as intramuscular injections three times per week, but daily subcutaneous injections were shown to be more effective and less inconvenient and the daily administration has been used since its introduction in the 1980s. However, despite ongoing improvements in injection device design, daily subcutaneous injections remain inconvenient, painful and distressing for many patients, leading to noncompliance, reduced efficacy and increased health care costs. To address these issues a variety of long-acting formulations of GH have been developed. In this review we present the current status of long-acting GH preparations and discuss the specific issues related to their development.

  4. HFE gene mutations and iron status of Brazilian blood donors.

    PubMed

    Santos, P C J L; Cançado, R D; Terada, C T; Rostelato, S; Gonzales, I; Hirata, R D C; Hirata, M H; Chiattone, C S; Guerra-Shinohara, E M

    2010-01-01

    Mutations of the HFE and TFR2 genes have been associated with iron overload. HFE and TFR2 mutations were assessed in blood donors, and the relationship with iron status was evaluated. Subjects (N = 542) were recruited at the Hemocentro da Santa Casa de São Paulo, São Paulo, Brazil. Iron status was not influenced by HFE mutations in women and was independent of blood donation frequency. In contrast, men carrying the HFE 282CY genotype had lower total iron-binding capacity (TIBC) than HFE 282CC genotype carriers. Men who donated blood for the first time and were carriers of the HFE 282CY genotype had higher transferrin saturation values and lower TIBC concentrations than those with the homozygous wild genotype for the HFE C282Y mutation. Moreover, in this group of blood donors, carriers of HFE 63DD plus 63HD genotypes had higher serum ferritin values than those with the homozygous wild genotype for HFE H63D mutation. Multiple linear regression analysis showed that HFE 282CY leads to a 17.21% increase (P = 0.018) and a 83.65% decrease (P = 0.007) in transferrin saturation and TIBC, respectively. In addition, serum ferritin is influenced by age (3.91%, P = 0.001) and the HFE 63HD plus DD genotype (55.84%, P = 0.021). In conclusion, the HFE 282Y and 65C alleles were rare, while the HFE 63D allele was frequent in Brazilian blood donors. The HFE C282Y and H63D mutations were associated with alterations in iron status in blood donors in a gender-dependent manner.

  5. Three Novel Missense Mutations within the LHX4 Gene Are Associated with Variable Pituitary Hormone Deficiencies

    PubMed Central

    Pfaeffle, Roland W.; Hunter, Chad S.; Savage, Jesse J.; Duran-Prado, Mario; Mullen, Rachel D.; Neeb, Zachary P.; Eiholzer, Urs; Hesse, Volker; Haddad, Nadine G.; Stobbe, Heike M.; Blum, Werner F.; Weigel, Johannes F. W.; Rhodes, Simon J.

    2008-01-01

    Context: The LHX4 LIM-homeodomain transcription factor has essential roles in pituitary gland and nervous system development. Heterozygous mutations in LHX4 are associated with combined pituitary hormone deficiency. Objectives: Our objectives were to determine the nature and frequency of LHX4 mutations in patients with pituitary hormone deficiency and to examine the functional outcomes of observed mutations. Design: The LHX4 gene sequence was determined from patient DNA. The biochemical and gene regulatory properties of aberrant LHX4 proteins were characterized using structural predictions, pituitary gene transcription assays, and DNA binding experiments. Patients: A total of 253 patients from 245 pedigrees with GH deficiency and deficiency of at least one additional pituitary hormone was included in the study. Results: In five patients, three types of heterozygous missense mutations in LHX4 that result in substitution of conserved amino acids were identified. One substitution is between the LIM domains (R84C); the others are in the homeodomain (L190R; A210P). The patients have GH deficiency; some also display reductions in TSH, LH, FSH, or ACTH, and aberrant pituitary morphology. Structural models predict that the aberrant L190R and A210P LHX4 proteins would have impaired DNA binding and gene activation properties. Consistent with these models, EMSAs and transfection experiments using pituitary gene promoters demonstrate that whereas the R84C form has reduced activity, the L190R and A210P proteins are inactive. Conclusions: LHX4 mutations are a relatively rare cause of combined pituitary hormone deficiency. This report extends the range of phenotypes associated with LHX4 gene mutations and describes three novel exonic mutations in the gene. PMID:18073311

  6. ACAN Gene Mutations in Short Children Born SGA and Response to Growth Hormone Treatment.

    PubMed

    van der Steen, Manouk; Pfundt, Rolph; Maas, Stephan J W H; Bakker-van Waarde, Willie M; Odink, Roelof J; Hokken-Koelega, Anita C S

    2017-05-01

    Some children born small for gestational age (SGA) show advanced bone age (BA) maturation during growth hormone (GH) treatment. ACAN gene mutations have been described in children with short stature and advanced BA. To determine the presence of ACAN gene mutations in short SGA children with advanced BA and assess the response to GH treatment. BA assessment in 290 GH-treated SGA children. ACAN sequencing in 29 children with advanced BA ≥0.5 years compared with calendar age. Four of 29 SGA children with advanced BA had an ACAN gene mutation (13.8%). Mutations were related to additional characteristics: midface hypoplasia (P = 0.003), joint problems (P = 0.010), and broad great toes (P = 0.003). Children with one or fewer additional characteristic had no mutation. Of children with two additional characteristics, 50% had a mutation. Of children with three additional characteristics, 100% had a mutation. All GH-treated children with a mutation received gonadotropin-releasing hormone analog (GnRHa) treatment for 2 years from onset of puberty. At adult height, one girl was 5 cm taller than her mother and one boy was 8 cm taller than his father with the same ACAN gene mutation. This study expands the differential diagnosis of genetic variants in children born SGA and proposes a clinical scoring system for identifying subjects most likely to have an ACAN gene mutation. ACAN sequencing should be considered in children born SGA with persistent short stature, advanced BA, and midface hypoplasia, joint problems, or broad great toes. Our findings suggest that children with an ACAN gene mutation benefit from GH treatment with 2 years of GnRHa.

  7. Hormone receptor status and survival of medullary breast cancer patients

    PubMed Central

    Aksoy, Asude; Odabas, Hatice; Kaya, Serap; Bozkurt, Oktay; Degirmenci, Mustafa; Topcu, Turkan O.; Aytekin, Aydın; Arpaci, Erkan; Avci, Nilufer; Pilanci, Kezban N.; Cinkir, Havva Y.; Bozkaya, Yakup; Cirak, Yalcin; Gumus, Mahmut

    2017-01-01

    Objectives: To analyze the relationship between clinical features, hormonal receptor status, and survival in patients who were diagnosed with medullary breast cancer (MBC). Methods: Demographic characteristics, histopathological features, and survival statuses of 201 patients diagnosed with MBC between 1995 and 2015 were retrospectively recorded. Survival analyses were conducted with uni- and multivariate cox regression analysis. Results: Median follow-up time was 54 (4-272) months. Median patient age at the time of diagnosis was 47 years old (26-90). Of the patients, 91.5% were triple negative. Five-year recurrence free survival time (RFS) rate was 87.4% and overalll survival (OS) rate 95.7%. For RFS, progesterone receptor (PR) negativity, atypical histopathological evaluation, absence of lymphovascular invasion, smaller tumor, lower nodal involvement were found to be favourable prognostic factors by univariate analysis (p<0.05). The PR negativity and smaller tumor were found to be favourable factors by univariate analysis (p<0.05). However, none of these factors were determined as significant independent prognostic factors for OS (p>0.05). Conclusion: Turkish MBC patients exhibited good prognosis, which was comparable with survival outcomes achieved in the literature. The PR negativity was related to a better RFS and OS rates. PMID:28133688

  8. Thyroid hormones regulate selenoprotein expression and selenium status in mice.

    PubMed

    Mittag, Jens; Behrends, Thomas; Hoefig, Carolin S; Vennström, Björn; Schomburg, Lutz

    2010-09-22

    Impaired expression of selenium-containing proteins leads to perturbed thyroid hormone (TH) levels, indicating the central importance of selenium for TH homeostasis. Moreover, critically ill patients with declining serum selenium develop a syndrome of low circulating TH and a central downregulation of the hypothalamus-pituitary-thyroid axis. This prompted us to test the reciprocal effect, i.e., if TH status would also regulate selenoprotein expression and selenium levels. To investigate the TH dependency of selenium metabolism, we analyzed mice expressing a mutant TH receptor α1 (TRα1+m) that confers a receptor-mediated hypothyroidism. Serum selenium was reduced in these animals, which was a direct consequence of the mutant TRα1 and not related to their metabolic alterations. Accordingly, hyperthyroidism, genetically caused by the inactivation of TRβ or by oral TH treatment of adult mice, increased serum selenium levels in TRα1+m and controls, thus demonstrating a novel and specific role for TRα1 in selenium metabolism. Furthermore, TH affected the mRNA levels for several enzymes involved in selenoprotein biosynthesis as well as serum selenoprotein P concentrations and the expression of other antioxidative selenoproteins. Taken together, our results show that TH positively affects the serum selenium status and regulates the expression of several selenoproteins. This demonstrates that selenium and TH metabolism are interconnected through a feed-forward regulation, which can in part explain the rapid parallel downregulation of both systems in critical illness.

  9. Resistance to Thyroid Hormone Complicated with Type 2 Diabetes and Cardiomyopathy in a Patient with a TRβ Mutation

    PubMed Central

    Wakasaki, Hisao; Matsumoto, Miyuki; Tamaki, Shinya; Miyata, Kaori; Yamamoto, Shohei; Minaga, Takamasa; Hayashi, Yoshitaka; Komukai, Kenichi; Imanishi, Toshio; Yamaoka, Hiroyuki; Matsuno, Shohei; Nishi, Masahiro; Akamizu, Takashi

    2016-01-01

    Resistance to thyroid hormone (RTH) is a genetic disorder characterized by reduced tissue responsiveness to thyroid hormone. We herein describe a 60-year old man who presented with the clinical features of cardiomyopathy, diabetes mellitus and elevated thyroid hormones with unsuppressed thyroid stimulating hormone. A genetic analysis of thyroid hormone receptor (TR) revealed a missense mutation (A268D) in the TRβ gene. Clinical manifestations of RTH may be variable due to different tissue distributions of TR subtypes and different actions of mutant receptors. The current case demonstrates that patients with a TRβ mutation may have impaired his glucose metabolism and a reduced cardiac function, although patients appear clinically euthyroid. PMID:27853072

  10. A mutation in the receptor Methoprene-tolerant alters juvenile hormone response in insects and crustaceans.

    PubMed

    Miyakawa, Hitoshi; Toyota, Kenji; Hirakawa, Ikumi; Ogino, Yukiko; Miyagawa, Shinichi; Oda, Shigeto; Tatarazako, Norihisa; Miura, Toru; Colbourne, John K; Iguchi, Taisen

    2013-01-01

    Juvenile hormone is an essential regulator of major developmental and life history events in arthropods. Most of the insects use juvenile hormone III as the innate juvenile hormone ligand. By contrast, crustaceans use methyl farnesoate. Despite this difference that is tied to their deep evolutionary divergence, the process of this ligand transition is unknown. Here we show that a single amino-acid substitution in the receptor Methoprene-tolerant has an important role during evolution of the arthropod juvenile hormone pathway. Microcrustacea Daphnia pulex and D. magna share a juvenile hormone signal transduction pathway with insects, involving Methoprene-tolerant and steroid receptor coactivator proteins that form a heterodimer in response to various juvenoids. Juvenile hormone-binding pockets of the orthologous genes differ by only two amino acids, yet a single substitution within Daphnia Met enhances the receptor's responsiveness to juvenile hormone III. These results indicate that this mutation within an ancestral insect lineage contributed to the evolution of a juvenile hormone III receptor system.

  11. Reproductive and hormonal factors, family history, and breast cancer according to the hormonal receptor status.

    PubMed

    Rosato, Valentina; Bosetti, Cristina; Negri, Eva; Talamini, Renato; Dal Maso, Luigino; Malvezzi, Matteo; Falcini, Fabio; Montella, Maurizio; La Vecchia, Carlo

    2014-09-01

    The aim of this study was to investigate the association between breast cancer risk, reproductive factors, and family history of breast cancer by the estrogen receptor (ER) and progesterone receptor (PR) status. We analyzed data from an Italian case-control study including 1075 women with incident breast cancer and 1477 hospital controls. We estimated the odds ratios (ORs) of breast cancer using unconditional logistic regression models including major recognized risk factors for breast cancer. Stronger associations with ER+ than with ER- breast cancer were observed for parity (OR: 0.7 vs. 0.9 for ≥ 3 births vs. nulliparae), age at first birth (OR: 1.6 vs. 1.2 for age ≥ 30 vs. <25 years), menopausal status (OR: 0.7 vs. 0.8 for postmenopause vs. pre/perimenopause), age at menopause (OR: 1.3 vs. 1.2 for menopause at age ≥ 50 vs. <50 years), and family history of breast cancer (OR: 2.2 vs. 1.4). Among the ER+ patients, the presence of PR+ did not appreciably modify any of the risk estimates. The association with age at menarche and hormone replacement therapy use was neither significant nor heterogeneous across ER and PR subtypes. In conclusion, we found stronger associations with selected menstrual and reproductive factors for ER+ (PR+) than for ER- (PR-) breast cancers, though in the absence of significant heterogeneity.

  12. Heterozygous gsp mutation renders ion channels of human somatotroph adenoma cells unresponsive to growth hormone-releasing hormone.

    PubMed

    Yasufuku-Takano, J; Takano, K; Takei, T; Fukumoto, S; Teramoto, A; Takakura, K; Yamashita, N; Fujita, T

    1999-05-01

    Ionic mechanisms play an important role in the regulation of hormone secretion. The GHRH-induced GH release by human GH-secreting cells is transmitted through protein kinase A (PKA), which activates nonselective cation current (NSCC) and induces membrane depolarization, intracellular Ca2+ increase, and GH secretion. To evaluate whether ionic mechanisms have pathophysiological significance in GH oversecretion of GH-secreting pituitary adenomas, we examined four adenomas with constitutively active Gs alpha mutation (gsp mutation) and compared with three gsp-negative adenomas. In primary-cultured cells of gsp-positive adenomas, GHRH did not increase the NSCC under voltage-clamp experiments. Detailed examination showed that NSCC was maximally activated at the basal level and application of GHRH did not increase the current in these adenomas. Furthermore, by using single-cell RT-PCR method, we demonstrated for the first time at the single cell level that gsp mutation is heterozygous in GH-secreting pituitary adenomas. These indicate that heterozygous gsp mutation fully activates NSCC at the basal level, which may account for the GH oversecretion in gsp-positive GH-secreting pituitary adenomas.

  13. NFKB2 mutation in common variable immunodeficiency and isolated adrenocorticotropic hormone deficiency

    PubMed Central

    Shi, Chuan; Wang, Fen; Tong, Anli; Zhang, Xiao-Qian; Song, Hong-Mei; Liu, Zheng-Yin; Lyu, Wei; Liu, Yue-Hua; Xia, Wei-Bo

    2016-01-01

    Abstract Background Common variable immunodeficiency (CVID) with central adrenal insufficiency is a recently defined clinical syndrome caused by mutations in the nuclear factor kappa-B subunit 2 (NFKB2) gene. We present the first case of NFKB2 mutation in Asian population. Methods and Results An 18-year-old Chinese female with adrenocorticotropic hormone (ACTH) deficiency was admitted due to adrenal crisis and pneumonia. She had a history of recurrent respiratory infections since childhood and ectodermal abnormalities were noted during physical examination. Immunologic tests revealed panhypogammaglobulinemia and deficient natural killer (NK)-cell function. DNA sequencing of NFKB2 identified a heterozygous nonsense mutation (c.2563 A>T, p.855: Lys>∗) in the patient but not her parents. Conclusion Clinicians should be alert to comorbidities of adrenal insufficiency and ectodermal dysplasia in CVID patients as these might suggest a rare hereditary syndrome caused by NFKB2 mutation. PMID:27749582

  14. A Mathematical Model of Prostate Tumor Growth Under Hormone Therapy with Mutation Inhibitor

    NASA Astrophysics Data System (ADS)

    Tao, Youshan; Guo, Qian; Aihara, Kazuyuki

    2010-04-01

    This paper extends Jackson’s model describing the growth of a prostate tumor with hormone therapy to a new one with hypothetical mutation inhibitors. The new model not only considers the mutation by which androgen-dependent (AD) tumor cells mutate into androgen-independent (AI) ones but also introduces inhibition which is assumed to change the mutation rate. The tumor consists of two types of cells (AD and AI) whose proliferation and apoptosis rates are functions of androgen concentration. The mathematical model represents a free-boundary problem for a nonlinear system of parabolic equations, which describe the evolution of the populations of the above two types of tumor cells. The tumor surface is a free boundary, whose velocity is equal to the cell’s velocity there. Global existence and uniqueness of solutions of this model is proved. Furthermore, explicit formulae of tumor volume at any time t are found in androgen-deprived environment under the assumption of radial symmetry, and therefore the dynamics of tumor growth under androgen-deprived therapy could be predicted by these formulae. Qualitative analysis and numerical simulation show that controlling the mutation may improve the effect of hormone therapy or delay a tumor relapse.

  15. Novel growth hormone receptor mutation in a Chinese patient with Laron syndrome.

    PubMed

    Hui, Hamilton N T; Metherell, Louise A; Ng, K L; Savage, Martin O; Camacho-Hübner, Cecilia; Clark, Adrian J L

    2005-02-01

    Laron syndrome, growth hormone (GH) insensitivity syndrome, caused by a mutation of the GH receptor (GHR) gene, is extremely rare in the Chinese population. We report a Chinese girl diagnosed with Laron syndrome at age 1.9 years with height -4.9 SDS, basal GH 344 mIU/ml, IGF-I <12 ng/ml, IGFBP-3 <0.2 mg/ml, and undetectable GHBP. A novel mutation of the GHR, not previously described, was identified at the donor splice site of intron 6.

  16. Progress in antiandrogen design targeting hormone binding pocket to circumvent mutation based resistance

    PubMed Central

    Tian, Xiaohong; He, Yang; Zhou, Jinming

    2015-01-01

    Androgen receptor (AR) plays a critical role in the development and progression of prostate cancer (PCa). Current clinically used antiandrogens such as flutamide, bicalutamide, and newly approved enzalutamide mainly target the hormone binding pocket (HBP) of AR. However, over time, drug resistance invariably develops and switches these antiandrogens from antagonist to agonist of the AR. Accumulated evidence indicates that AR mutation is an important cause for the drug resistance. This review will give an overview of the mutation based resistance of the current clinically used antiandrogens and the rational drug design to overcome the resistance, provides a promising strategy for the development of the new generation of antiandrogens targeting HBP. PMID:25852559

  17. Anti-Müllerian hormone serum concentrations of women with germline BRCA1 or BRCA2 mutations.

    PubMed

    Phillips, Kelly-Anne; Collins, Ian M; Milne, Roger L; McLachlan, Sue Anne; Friedlander, Michael; Hickey, Martha; Stern, Catharyn; Hopper, John L; Fisher, Richard; Kannemeyer, Gordon; Picken, Sandra; Smith, Charmaine D; Kelsey, Thomas W; Anderson, Richard A

    2016-05-01

    Do women with ITALIC! BRCA1 or ITALIC! BRCA2 mutations have reduced ovarian reserve, as measured by circulating anti-Müllerian hormone (AMH) concentration? Women with a germline mutation in ITALIC! BRCA1 have reduced ovarian reserve as measured by AMH. The DNA repair enzymes encoded by ITALIC! BRCA1 and ITALIC! BRCA2 are implicated in reproductive aging. Circulating AMH is a biomarker of ovarian reserve and hence reproductive lifespan. This was a cross-sectional study of AMH concentrations of 693 women at the time of enrolment into the Kathleen Cuningham Foundation Consortium for research in the Familial Breast Cancer (kConFab) cohort study (recruitment from 19 August 1997 until 18 September 2012). AMH was measured on stored plasma samples between November 2014 and January 2015 using an electrochemiluminescence immunoassay platform. Eligible women were from families segregating ITALIC! BRCA1 or ITALIC! BRCA2 mutations and had known mutation status. Participants were aged 25-45 years, had no personal history of cancer, retained both ovaries and were not pregnant or breastfeeding at the time of plasma storage. Circulating AMH was measured for 172 carriers and 216 non-carriers from families carrying ITALIC! BRCA1 mutations, and 147 carriers and 158 non-carriers from families carrying ITALIC! BRCA2 mutations. Associations between plasma AMH concentration and carrier status were tested by linear regression, adjusted for age at plasma storage, oral contraceptive use, body mass index and cigarette smoking. Mean AMH concentration was negatively associated with age ( ITALIC! P < 0.001). Mutation carriers were younger at blood draw than non-carriers ( ITALIC! P ≤ 0.031). ITALIC! BRCA1 mutation carriers had, on average, 25% (95% CI: 5%-41%, ITALIC! P = 0.02) lower AMH concentrations than non-carriers and were more likely to have AMH concentrations in the lowest quartile for age (OR 1.84, 95% CI: 1.11-303, ITALIC! P = 0.02). There was no evidence of an association between

  18. Anti-Müllerian hormone serum concentrations of women with germline BRCA1 or BRCA2 mutations

    PubMed Central

    Phillips, Kelly-Anne; Collins, Ian M.; Milne, Roger L.; McLachlan, Sue Anne; Friedlander, Michael; Hickey, Martha; Stern, Catharyn; Hopper, John L.; Fisher, Richard; Kannemeyer, Gordon; Picken, Sandra; Smith, Charmaine D.; Kelsey, Thomas W.; Anderson, Richard A.

    2016-01-01

    STUDY QUESTION Do women with BRCA1 or BRCA2 mutations have reduced ovarian reserve, as measured by circulating anti-Müllerian hormone (AMH) concentration? SUMMARY ANSWER Women with a germline mutation in BRCA1 have reduced ovarian reserve as measured by AMH. WHAT IS KNOWN ALREADY The DNA repair enzymes encoded by BRCA1 and BRCA2 are implicated in reproductive aging. Circulating AMH is a biomarker of ovarian reserve and hence reproductive lifespan. STUDY DESIGN, SIZE, DURATION This was a cross-sectional study of AMH concentrations of 693 women at the time of enrolment into the Kathleen Cuningham Foundation Consortium for research in the Familial Breast Cancer (kConFab) cohort study (recruitment from 19 August 1997 until 18 September 2012). AMH was measured on stored plasma samples between November 2014 and January 2015 using an electrochemiluminescence immunoassay platform. PARTICIPANTS/MATERIALS, SETTING, METHODS Eligible women were from families segregating BRCA1 or BRCA2 mutations and had known mutation status. Participants were aged 25–45 years, had no personal history of cancer, retained both ovaries and were not pregnant or breastfeeding at the time of plasma storage. Circulating AMH was measured for 172 carriers and 216 non-carriers from families carrying BRCA1 mutations, and 147 carriers and 158 non-carriers from families carrying BRCA2 mutations. Associations between plasma AMH concentration and carrier status were tested by linear regression, adjusted for age at plasma storage, oral contraceptive use, body mass index and cigarette smoking. MAIN RESULTS AND THE ROLE OF CHANCE Mean AMH concentration was negatively associated with age (P < 0.001). Mutation carriers were younger at blood draw than non-carriers (P ≤ 0.031). BRCA1 mutation carriers had, on average, 25% (95% CI: 5%–41%, P = 0.02) lower AMH concentrations than non-carriers and were more likely to have AMH concentrations in the lowest quartile for age (OR 1.84, 95% CI: 1.11–303, P = 0

  19. Effect of mutations in putative hormone binding sites on V2 vasopressin receptor function.

    PubMed

    Sebti, Y; Rabbani, M; Sadeghi, H Mir Mohammad; Sardari, S; Ghahremani, M H; Innamorati, G

    2015-01-01

    The vasopressin V2 receptor belongs to the large family of the G-protein coupled receptors and is responsible for the antidiuretic effect of the neurohypophyseal hormone arginine vasopressin (AVP). Based on bioinformatic studies it seems that Ala300 and Asp297 of the V2 vasopressin receptor (V2R) are involved in receptor binding. Ala300Glu mutation resulted in lower energy while Asp297Tyr mutation resulted in higher energy in AVP-V2R docked complex rather than the wild type. Therefore we hypothesized that the Ala300Glu mutation results in stronger and Asp297Tyr mutation leads to weaker ligand-receptor binding. Site directed mutagenesis of Asp297Tyr and Ala300Glu was performed using nested polymerase chain reaction. After restriction enzyme digestion, the inserts were ligated into the pcDNA3 vector and Escherichia coli XL1-Blue competent cells were transformed using commercial kit and electroporation methods. The obtained colonies were analyzed for the presence and orientation of the inserts using proper restriction enzymes. After transient transfection of COS-7 cells using ESCORT™ IV transfection reagent, the adenylyl cyclase activity assay was performed for functional studies. The cell surface expression of V2R was analyzed by indirect ELISA method. Based on the obtained results, the Ala300Glu mutation of V2R led to reduced levels of cAMP production without a marked effect on the receptor expression and the receptor binding. Effect of Asp297Tyr mutation on cell surface expression of V2R was the same as the wild type receptor. Pretreatment with 1 nM vasopressin showed an increased level of Asp297Tyr mutant receptor internalization as compared to the wild type receptor, while the effect of 100 nM vasopressin was similar in the mutant and wild type receptors. These data suggest that alterations in Asp297 but not Ala300 would affect the hormone receptor binding.

  20. Current status of hormone therapy in patients with hormone receptor positive (HR+) advanced breast cancer.

    PubMed

    Dalmau, Elsa; Armengol-Alonso, Alejandra; Muñoz, Montserrat; Seguí-Palmer, Miguel Ángel

    2014-12-01

    The natural history of HR+ breast cancer tends to be different from hormone receptor-negative disease in terms of time to recurrence, site of recurrence and overall aggressiveness of the disease. The developmental strategies of hormone therapy for the treatment of breast cancer have led to the classes of selective estrogen receptor modulators, selective estrogen receptor downregulators, and aromatase inhibitors. These therapeutic options have improved breast cancer outcomes in the metastatic setting, thereby delaying the need for chemotherapy. However, a subset of hormone receptor-positive breast cancers do not benefit from endocrine therapy (intrinsic resistance), and all HR+ metastatic breast cancers ultimately develop resistance to hormonal therapies (acquired resistance). Considering the multiple pathways involved in the HR network, targeting other components of pathologically activated intracellular signaling in breast cancer may prove to be a new direction in clinical research. This review focuses on current and emerging treatments for HR+ metastatic breast cancer. Copyright © 2014 Elsevier Ltd. All rights reserved.

  1. ABCB4 mutations underlie hormonal cholestasis but not pediatric idiopathic gallstones

    PubMed Central

    Jirsa, Milan; Bronský, Jiří; Dvořáková, Lenka; Šperl, Jan; Šmajstrla, Vít; Horák, Jiří; Nevoral, Jiří; Hřebíček, Martin

    2014-01-01

    AIM: To investigate the contribution of ABCB4 mutations to pediatric idiopathic gallstone disease and the potential of hormonal contraceptives to prompt clinical manifestations of multidrug resistance protein 3 deficiency. METHODS: Mutational analysis of ABCB4, screening for copy number variations by multiplex ligation-dependent probe amplification, genotyping for low expression allele c.1331T>C of ABCB11 and genotyping for variation c.55G>C in ABCG8 previously associated with cholesterol gallstones in adults was performed in 35 pediatric subjects with idiopathic gallstones who fulfilled the clinical criteria for low phospholipid-associated cholelithiasis syndrome (LPAC, OMIM #600803) and in 5 young females with suspected LPAC and their families (5 probands, 15 additional family members). The probands came to medical attention for contraceptive-associated intrahepatic cholestasis. RESULTS: A possibly pathogenic variant of ABCB4 was found only in one of the 35 pediatric subjects with idiopathic cholesterol gallstones whereas 15 members of the studied 5 LPAC kindreds were confirmed and another one was highly suspected to carry predictably pathogenic mutations in ABCB4. Among these 16, however, none developed gallstones in childhood. In 5 index patients, all young females carrying at least one pathogenic mutation in one allele of ABCB4, manifestation of LPAC as intrahepatic cholestasis with elevated serum activity of gamma-glutamyltransferase was induced by hormonal contraceptives. Variants ABCB11 c.1331T>C and ABCG8 c.55G>C were not significantly overrepresented in the 35 examined patients with suspect LPAC. CONCLUSION: Clinical criteria for LPAC syndrome caused by mutations in ABCB4 cannot be applied to pediatric patients with idiopathic gallstones. Sexual immaturity even prevents manifestation of LPAC. PMID:24914347

  2. Mutation of thyroid hormone receptor-β in mice predisposes to the development of mammary tumors

    PubMed Central

    Guigon, CJ; Kim, DW; Willingham, MC; Cheng, S-y

    2012-01-01

    Correlative data suggest that thyroid hormone receptor-β (TRβ) mutations could increase the risk of mammary tumor development, but unequivocal evidence is still lacking. To explore the role of TRβ mutants in vivo in breast tumor development and progression, we took advantage of a knock-in mouse model harboring a mutation in the Thrb gene encoding TRβ (ThrbPV mouse). Although in adult nulliparous females, a single ThrbPV allele did not contribute to mammary gland abnormalities, the presence of two ThrbPV alleles led to mammary hyperplasia in ~36% ThrbPV/PV mice. The ThrbPV mutation further markedly augmented the risk of mammary hyperplasia in a mouse model with high susceptibility to mammary tumors (Pten+/− mouse), as demonstrated by the occurrence of mammary hyperplasia in ~60% of Thrbpv/+Pten+/− and ~77% of ThrbPV/PV Pten+/− mice versus ~33% of Thrb+/+Pten+/− mice. The ThrbPV mutation increased the activity of signal transducer and activator of transcription (STAT5) to increase cell proliferation and the expression of the STAT5 target gene encoding β-casein in the mammary gland. We next sought to understand the molecular mechanism underlying STAT5 overactivation by TRβPV. Cell-based studies with a breast cancer cell line (T47D cells) showed that thyroid hormone (T3) repressed STAT5 signaling in TRβ-expressing cells through decreasing STAT5-mediated transcription activity and target gene expression, whereas sustained STAT5 signaling was observed in TRβPV-expressing cells. Collectively, these findings show for the first time that a TRβ mutation promotes the development of mammary hyperplasia via aberrant activation of STAT5, thereby conferring a fertile genetic ground for tumorigenesis. PMID:21399657

  3. Identification of a splice-site mutation in the human growth hormone-variant gene.

    PubMed Central

    MacLeod, J N; Liebhaber, S A; MacGillivray, M H; Cooke, N E

    1991-01-01

    The human growth-hormone-variant (hGH-V) gene normally expresses two alternatively spliced forms of mRNA--hGH-V and hGH-V2--in the placenta. hGH-V2 mRNA differs from hGH-V rDNA by the retention of intron 4 and represents approximately 15% of transcripts at term. In a survey of hGH-V gene expression in 20 placentas of gestational age 8-40 wk, we detected a single placenta that contained, in addition to the two normal hGH-V mRNA species, a set of two slightly larger hGH-V mRNAs. Sequence analysis of the elongated hGH-V mRNA demonstrated retention of the first 12 bases of intron 2, resulting from both a base substitution at the intron 2 splice-donor dinucleotide (GT----AT) and activation of a cryptic splice-donor site 12 bases downstream. Survey of a total of 60 additional chromosomes failed to reveal additional incidence of this mutation. The mutation, which we have designated hGH-Vintron 2, pos 1 (G----A), represents both an initial example of a nondeletional mutation within the hGH-V gene and corresponding structural alteration in the encoded hGH-V hormone. Images Figure 1 Figure 2 Figure 4 PMID:2035535

  4. Hormonal and surgical treatment in trans-women with BRCA1 mutations: a controversial topic.

    PubMed

    Colebunders, Britt; T'Sjoen, Guy; Weyers, Steven; Monstrey, Stan

    2014-10-01

    Male-to-female transgender persons (trans-women) receive livelong cross-sex hormonal treatment in order to induce and maintain secondary female characteristics. One of the concerns of long-term estrogen treatment is the induction of carcinomas of estrogen-sensitive tissues such as the breast. BRCA1 mutations have been shown to account for a large proportion of inherited predispositions to breast cancer. The aim of this case report is to discuss the hormonal and surgical options in the treatment of trans-women with a genetic predisposition for breast cancer. We describe a case of a trans-woman who was found to be a carrier of a BRCA1 mutation. The patient underwent a breast augmentation. She refused a prophylactic mastectomy followed by a primary breast reconstruction. She also underwent a vaginoplasty and a bilateral castration. Androgen blocking treatment was stopped after surgery; estradiol treatment however was continued. This case points to the importance of routine investigation of family history in trans-women. Trans-women with BRCA mutations should be carefully monitored and if cancers develop, this should be reported. Follow-up should be according to the guidelines for breast cancer screening in biological women, and the guidelines for prostate cancer and colon cancer screening in men. © 2014 International Society for Sexual Medicine.

  5. Male hormonal contraceptives: current status and future prospects.

    PubMed

    Amory, John K

    2005-01-01

    Because of the shortcomings of currently available methods of male contraception, efforts have been made to develop additional forms of contraception for men. The most promising approach to male contraceptive development involves hormones, and requires the administration of exogenous testosterone. When administered to a healthy man, testosterone functions as a contraceptive by suppressing the secretion of luteinizing hormone and follicle-stimulating hormone from the pituitary, thereby depriving the testes of the signals required for normal spermatogenesis. After 2-3 months of treatment, low levels of pituitary gonadotropins lead to markedly decreased sperm counts and effective contraception in the majority of men. Treatment with exogenous testosterone has proven not to be associated with serious adverse effects and is well tolerated by men. In addition, sperm counts uniformly normalize when testosterone is discontinued. Thus, male hormonal contraception is safe, effective, and reversible; however, spermatogenesis is not suppressed to zero in all men, meaning that some diminished potential for fertility persists. Because of this, recent studies have combined testosterone with progestogens and/or gonadotropin-releasing hormone antagonists to further suppress pituitary gonadotropins and optimize contraceptive efficacy. Current combinations of testosterone and progestogens completely suppress spermatogenesis in 80-90% of men without severe adverse effects, with significant suppression in the remainder of individuals. Recent trials with newer, long-acting forms of injectable testosterone, which can be administered every 8 weeks, combined with progestogens, administered either orally or by long-acting implant, have yielded promising results and may soon result in the marketing of a safe, reversible, and effective hormonal contraceptive for men.

  6. Identification of a novel mutation in the human growth hormone receptor gene (GHR) in a patient with Laron syndrome.

    PubMed

    Gennero, Isabelle; Edouard, Thomas; Rashad, Mona; Bieth, Eric; Conte-Aurio, Françoise; Marin, Françoise; Tauber, Maithé; Salles, Jean Pierre; El Kholy, Mohamed

    2007-07-01

    Deletions and mutations in the growth hormone receptor (GHR) gene are the underlying etiology of Laron syndrome (LS) or growth hormone (GH) insensitivity syndrome (GHIS), an autosomal recessive disease. Most patients are distributed in or originate from Mediterranean and Middle-Eastern countries. Sixty mutations have been described so far. We report a novel mutation in the GHR gene in a patient with LS. Genomic DNA sequencing of exon 5 revealed a TT insertion at nucleotide 422 after codon 122. The insertion resulted in a frameshift introducing a premature termination codon that led to a truncated receptor. We present clinical, biochemical and molecular evidence of LS as the result of this homozygous insertion.

  7. Identification of novel GHRHR and GH1 mutations in patients with isolated growth hormone deficiency.

    PubMed

    Birla, Shweta; Khadgawat, Rajesh; Jyotsna, Viveka P; Jain, Vandana; Garg, M K; Bhalla, Ashu Seith; Sharma, Arundhati

    2016-08-01

    Human growth is an elementary process which starts at conception and continues through different stages of development under the influence of growth hormone (GH) secreted by the anterior pituitary gland. Variation affecting the production, release and functional activity of GH leads to growth hormone deficiency (GHD), which is of two types: isolated growth hormone deficiency (IGHD) and combined pituitary hormone deficiency (CPHD). IGHD may result from mutations in GH1 and GHRHR while CPHD is associated with defects in transcription factor genes PROP1, POU1F1 and HESX1. The present study reports on the molecular screening of GHRHR and GH1 in IGHD patients. A total of 116 clinically diagnosed IGHD patients and 100 controls were enrolled for the study after taking informed consent. Family history was noted and 5ml blood sample was drawn. Anatomical and/or morphological pituitary gland alterations were studied using magnetic resonance imaging (MRI). DNA from blood samples was processed for screening the GHRHR and GH1 by Sanger sequencing. Mean age at presentation of the 116 patients (67 males and 49 females) was 11.71±3.5years. Mean height standard deviation score (SDS) and weight SDS were -4.5 and -3.5 respectively. Nine (7.8%) were familial and parental consanguinity was present in 21 (19.8%) families. Eighty-three patients underwent MRI and morphological alterations of the pituitary were observed in 39 (46.9%). GH1 and GHRHR screening revealed eleven variations in 24 (21%) patients of which, four were novel deleterious, one novel non-pathogenic and six reported changes. GHRHR contributed more to IGHD in our patients which confirmed that GHRHR should be screened first before GH1 in our population. Identification of GH1 and GHRHR variations helped in defining our mutational spectrum which will play a crucial role in providing predictive and prenatal genetic testing to the patients. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. Anti-Muellerian hormone Bruxelles: A nonsense mutation associated with the persistent Muellerian duct syndrome

    SciTech Connect

    Boussin, L.; Guerrier, D.; Legeai, L.; Josso, N.; Picard, J.Y. ); Knebelmann, B.; Kahn, A. )

    1991-05-01

    The persistent Muellerian duct syndrome (PMDS) is characterized by the persistence of Muellerian derivatives, uterus and tubes, in otherwise normally virilized males. In a previous study, the authors showed that this syndrome is heterogeneous, with lack of production of anti-Muellerian hormone (AMH) by testicular tissue accounting for only some, AMH-negative, cases of this disorder. They have characterized the point mutation responsible for an AMH-negative PMDS in three siblings: a guanine to thymine transversion at position 2096 in the fifth exon changes a GAA triplet, coding for glutamic acid, to a TAA stop codon. The mutation could also be recognized, using the polymerase chain reaction, on RNA produced in trace amounts by a lymphoblastic cell line. The translation product, although undetectable in testicular tissue, could be visualized in culture medium of cells transfected with the mutant gene.

  9. Hormone receptor status of a first primary breast cancer predicts contralateral breast cancer risk in the WECARE study population.

    PubMed

    Reiner, Anne S; Lynch, Charles F; Sisti, Julia S; John, Esther M; Brooks, Jennifer D; Bernstein, Leslie; Knight, Julia A; Hsu, Li; Concannon, Patrick; Mellemkjær, Lene; Tischkowitz, Marc; Haile, Robert W; Shen, Ronglai; Malone, Kathleen E; Woods, Meghan; Liang, Xiaolin; Morrow, Monica; Bernstein, Jonine L

    2017-07-19

    Previous population-based studies have described first primary breast cancer tumor characteristics and their association with contralateral breast cancer (CBC) risk. However, information on influential covariates such as treatment, family history of breast cancer, and BRCA1/2 mutation carrier status was not available. In a large, population-based, case-control study, we evaluated whether tumor characteristics of the first primary breast cancer are associated with risk of developing second primary asynchronous CBC, overall and in subgroups of interest, including among BRCA1/2 mutation non-carriers, women who are not treated with tamoxifen, and women without a breast cancer family history. The Women's Environmental Cancer and Radiation Epidemiology Study is a population-based case-control study of 1521 CBC cases and 2212 individually-matched controls with unilateral breast cancer. Detailed information about breast cancer risk factors, treatment for and characteristics of first tumors, including estrogen receptor (ER) and progesterone receptor (PR) status, was obtained by telephone interview and medical record abstraction. Multivariable risk ratios (RRs) and 95% confidence intervals (CIs) were estimated in conditional logistic regression models, adjusting for demographics, treatment, and personal medical and family history. A subset of women was screened for BRCA1/2 mutations. Lobular histology of the first tumor was associated with a 30% increase in CBC risk (95% CI 1.0-1.6). Compared to women with ER+/PR+ first tumors, those with ER-/PR- tumors had increased risk of CBC (RR = 1.4, 95% CI 1.1-1.7). Notably, women with ER-/PR- first tumors were more likely to develop CBC with the ER-/PR- phenotype (RR = 5.4, 95% CI 3.0-9.5), and risk remained elevated in multiple subgroups: BRCA1/2 mutation non-carriers, women younger than 45 years of age, women without a breast cancer family history, and women who were not treated with tamoxifen. Having a hormone receptor

  10. The origin of the p.E180 growth hormone receptor gene mutation.

    PubMed

    Ostrer, Harry

    2016-06-01

    Laron syndrome, an autosomal recessive condition of extreme short stature, is caused by the absence or dysfunction of the growth hormone receptor. A recurrent mutation in the GHR gene, p.E180, did not alter the encoded amino acid, but activated a cryptic splice acceptor resulting in a receptor protein with an 8-amino acid deletion in the extracellular domain. This mutation has been observed among Sephardic Jews and among individuals in Ecuador, Brazil and Chile, most notably in a large genetic isolate in Loja, Ecuador. A common origin has been postulated based on a shared genetic background of markers flanking this mutation, suggesting that the Lojanos (and others) may have Sephardic (Converso) Jewish ancestry. Analysis of the population structure of Lojanos based on genome-wide analysis demonstrated European, Sephardic Jewish and Native American ancestry in this group. X-autosomal comparison and monoallelic Y chromosomal and mitochondrial genetic analysis demonstrated gender-biased admixture between Native American women and European and Sephardic Jewish men. These findings are compatible with the co-occurrence of the Inquisition and the colonization of the Americas, including Converso Jews escaping the Inquisition in the Iberian Peninsula. Although not found among Lojanos, Converso Jews also brought founder mutations to contemporary Hispanic and Latino populations in the BRCA1 (c.68_69delAG) and BLM (c.2207_2212delATCTGAinsTAGATTC) genes. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. Clinical Implications of ESR1 Mutations in Hormone Receptor-Positive Advanced Breast Cancer

    PubMed Central

    Reinert, Tomas; Saad, Everardo D.; Barrios, Carlos H.; Bines, José

    2017-01-01

    Hormone receptor-positive breast cancer is the most frequent breast cancer subtype. Endocrine therapy (ET) targeting the estrogen receptor (ER) pathway represents the main initial therapeutic approach. The major strategies include estrogen deprivation and the use of selective estrogen modulators or degraders, which show efficacy in the management of metastatic and early-stage disease. However, clinical resistance associated with progression of disease remains a significant therapeutic challenge. Mutations of the ESR1 gene, which encodes the ER, have been increasingly recognized as an important mechanism of ET resistance, with a prevalence that ranges from 11 to 39%. The majority of these mutations are located within the ligand-binding domain and result in an estrogen-independent constitutive activation of the ER and, therefore, resistance to estrogen deprivation therapy such as aromatase inhibition. ESR1 mutations, most often detected from liquid biopsies, have been consistently associated with a worse outcome and are being currently evaluated as a potential biomarker to guide therapeutic decisions. At the same time, targeted therapy directed to ESR1-mutated clones is an appealing concept with preclinical and clinical work in progress. PMID:28361033

  12. Mutations of the Thyroid Hormone Transporter MCT8 Cause Prenatal Brain Damage and Persistent Hypomyelination

    PubMed Central

    López-Espíndola, Daniela; Morales-Bastos, Carmen; Grijota-Martínez, Carmen; Liao, Xiao-Hui; Lev, Dorit; Sugo, Ella; Verge, Charles F.; Refetoff, Samuel

    2014-01-01

    Context: Mutations in the MCT8 (SLC16A2) gene, encoding a specific thyroid hormone transporter, cause an X-linked disease with profound psychomotor retardation, neurological impairment, and abnormal serum thyroid hormone levels. The nature of the central nervous system damage is unknown. Objective: The objective of the study was to define the neuropathology of the syndrome by analyzing brain tissue sections from MCT8-deficient subjects. Design: We analyzed brain sections from a 30th gestational week male fetus and an 11-year-old boy and as controls, brain tissue from a 30th and 28th gestational week male and female fetuses, respectively, and a 10-year-old girl and a 12-year-old boy. Methods: Staining with hematoxylin-eosin and immunostaining for myelin basic protein, 70-kDa neurofilament, parvalbumin, calbindin-D28k, and synaptophysin were performed. Thyroid hormone determinations and quantitative PCR for deiodinases were also performed. Results: The MCT8-deficient fetus showed a delay in cortical and cerebellar development and myelination, loss of parvalbumin expression, abnormal calbindin-D28k content, impaired axonal maturation, and diminished biochemical differentiation of Purkinje cells. The 11-year-old boy showed altered cerebellar structure, deficient myelination, deficient synaptophysin and parvalbumin expression, and abnormal calbindin-D28k expression. The MCT8-deficient fetal cerebral cortex showed 50% reduction of thyroid hormones and increased type 2 deiodinase and decreased type 3 deiodinase mRNAs. Conclusions: The following conclusions were reached: 1) brain damage in MCT8 deficiency is diffuse, without evidence of focal lesions, and present from fetal stages despite apparent normality at birth; 2) deficient hypomyelination persists up to 11 years of age; and 3) the findings are compatible with the deficient action of thyroid hormones in the developing brain caused by impaired transport to the target neural cells. PMID:25222753

  13. Mutations of the thyroid hormone transporter MCT8 cause prenatal brain damage and persistent hypomyelination.

    PubMed

    López-Espíndola, Daniela; Morales-Bastos, Carmen; Grijota-Martínez, Carmen; Liao, Xiao-Hui; Lev, Dorit; Sugo, Ella; Verge, Charles F; Refetoff, Samuel; Bernal, Juan; Guadaño-Ferraz, Ana

    2014-12-01

    Mutations in the MCT8 (SLC16A2) gene, encoding a specific thyroid hormone transporter, cause an X-linked disease with profound psychomotor retardation, neurological impairment, and abnormal serum thyroid hormone levels. The nature of the central nervous system damage is unknown. The objective of the study was to define the neuropathology of the syndrome by analyzing brain tissue sections from MCT8-deficient subjects. We analyzed brain sections from a 30th gestational week male fetus and an 11-year-old boy and as controls, brain tissue from a 30th and 28th gestational week male and female fetuses, respectively, and a 10-year-old girl and a 12-year-old boy. Staining with hematoxylin-eosin and immunostaining for myelin basic protein, 70-kDa neurofilament, parvalbumin, calbindin-D28k, and synaptophysin were performed. Thyroid hormone determinations and quantitative PCR for deiodinases were also performed. The MCT8-deficient fetus showed a delay in cortical and cerebellar development and myelination, loss of parvalbumin expression, abnormal calbindin-D28k content, impaired axonal maturation, and diminished biochemical differentiation of Purkinje cells. The 11-year-old boy showed altered cerebellar structure, deficient myelination, deficient synaptophysin and parvalbumin expression, and abnormal calbindin-D28k expression. The MCT8-deficient fetal cerebral cortex showed 50% reduction of thyroid hormones and increased type 2 deiodinase and decreased type 3 deiodinase mRNAs. The following conclusions were reached: 1) brain damage in MCT8 deficiency is diffuse, without evidence of focal lesions, and present from fetal stages despite apparent normality at birth; 2) deficient hypomyelination persists up to 11 years of age; and 3) the findings are compatible with the deficient action of thyroid hormones in the developing brain caused by impaired transport to the target neural cells.

  14. Differential Effects of Genistein on Prostate Cancer Cells Depend on Mutational Status of the Androgen Receptor

    PubMed Central

    Mahmoud, Abeer M.; Zhu, Tian; Parray, Aijaz; Siddique, Hifzur R.; Yang, Wancai; Saleem, Mohammad; Bosland, Maarten C.

    2013-01-01

    Blocking the androgen receptor (AR) activity is the main goal of therapies for advanced prostate cancer (PCa). However, relapse with a more aggressive, hormone refractory PCa arises, which harbors restored AR activity. One mechanism of such reactivation occurs through acquisition of AR mutations that enable its activation by various steroidal and non-steroidal structures. Thus, natural and chemical compounds that contribute to inappropriate (androgen-independent) activation of the AR become an area of intensive research. Here, we demonstrate that genistein, a soy phytoestrogen binds to both the wild and the Thr877Ala (T877A) mutant types of AR competitively with androgen, nevertheless, it exerts a pleiotropic effect on PCa cell proliferation and AR activity depending on the mutational status of the AR. Genistein inhibited, in a dose-dependent way, cell proliferation and AR nuclear localization and expression in LAPC-4 cells that have wild AR. However, in LNCaP cells that express the T877A mutant AR, genistein induced a biphasic effect where physiological doses (0.5-5 µmol/L) stimulated cell growth and increased AR expression and transcriptional activity, and higher doses induced inhibitory effects. Similar biphasic results were achieved in PC-3 cells transfected with AR mutants; T877A, W741C and H874Y. These findings suggest that genistein, at physiological concentrations, potentially act as an agonist and activate the mutant AR that can be present in advanced PCa after androgen ablation therapy. PMID:24167630

  15. Differential effects of genistein on prostate cancer cells depend on mutational status of the androgen receptor.

    PubMed

    Mahmoud, Abeer M; Zhu, Tian; Parray, Aijaz; Siddique, Hifzur R; Yang, Wancai; Saleem, Mohammad; Bosland, Maarten C

    2013-01-01

    Blocking the androgen receptor (AR) activity is the main goal of therapies for advanced prostate cancer (PCa). However, relapse with a more aggressive, hormone refractory PCa arises, which harbors restored AR activity. One mechanism of such reactivation occurs through acquisition of AR mutations that enable its activation by various steroidal and non-steroidal structures. Thus, natural and chemical compounds that contribute to inappropriate (androgen-independent) activation of the AR become an area of intensive research. Here, we demonstrate that genistein, a soy phytoestrogen binds to both the wild and the Thr877Ala (T877A) mutant types of AR competitively with androgen, nevertheless, it exerts a pleiotropic effect on PCa cell proliferation and AR activity depending on the mutational status of the AR. Genistein inhibited, in a dose-dependent way, cell proliferation and AR nuclear localization and expression in LAPC-4 cells that have wild AR. However, in LNCaP cells that express the T877A mutant AR, genistein induced a biphasic effect where physiological doses (0.5-5 µmol/L) stimulated cell growth and increased AR expression and transcriptional activity, and higher doses induced inhibitory effects. Similar biphasic results were achieved in PC-3 cells transfected with AR mutants; T877A, W741C and H874Y. These findings suggest that genistein, at physiological concentrations, potentially act as an agonist and activate the mutant AR that can be present in advanced PCa after androgen ablation therapy.

  16. [Current status of the treatment with thyroid hormones].

    PubMed

    Laudo Pardos, C; Puigdevall Gallego, V; del Río Mayor, M J; Velasco Martín, A

    1996-11-01

    The main indication of thyroid hormone preparations is the treatment of hypothyroidism, ideally the goal of therapy is to restore the serum thyrotropin (TSH) concentration to a normal value. The optimal doses used to be stable, but several conditions may alter their requirements (reduced intestinal absorption, pregnancy,...). Levothyroxine therapy is also used in the benign nodular disease and after surgery in patients with thyroid cancer. The overtreatment with thyroxine and the problems related to bone mineral density seems of special importance.

  17. Neuronal expression of a thyroid hormone receptor α mutation alters mouse behaviour.

    PubMed

    Richard, S; Aguilera, N; Thévenet, M; Dkhissi-Benyahya, O; Flamant, F

    2017-03-15

    In humans, alterations in thyroid hormone signalling are associated with mood and anxiety disorders, but the neural mechanisms underlying such association are poorly understood. The present study investigates the involvement of neuronal thyroid hormone receptor α (TRα) in anxiety, using mouse genetics and Cre/loxP technology to specifically alter TRα signalling in neurons. We evaluated the behaviour of mice expressing a dominant negative, neuron-specific mutation of TRα (TRα(AMI)/Cre3 mice), using the elevated-plus maze, light-dark box and open-field tests. In a first experiment, mice were housed individually, and the behaviour of TRα(AMI)/Cre3 mice differed significantly from that of control littermates in these 3 tests, suggesting heightened anxiety. In a second experiment, designed to evaluate the robustness of the results with the same 3 tests, mice were housed in groups. In these conditions, the behaviour of TRα(AMI)/Cre3 mice differed from that of control littermates only in the light-dark box. Thus, TRα(AMI)/Cre3 mice appear to be more likely to develop anxiety under stressful housing conditions than control mice. These results suggest that in adult mice, thyroid hormone signalling in neurons, via TRα, is involved in the control of anxiety behaviour.

  18. Congenital Central Hypothyroidism Caused by a Novel Thyroid-Stimulating Hormone-Beta Subunit Gene Mutation in Two Siblings.

    PubMed

    Özhan, Bayram; Boz Anlaş, Özlem; Sarıkepe, Bilge; Albuz, Burcu; Semerci Gündüz, Nur

    2017-09-01

    Congenital central hypothyroidism (CCH) is a very rare disease. Alterations in pituitary development genes as well as mutations of immunoglobulin superfamily member 1 and transducin β-like protein 1 can result in CCH and multiple pituitary hormone deficiencies. However, mutations of the thyrotropin-releasing hormone receptor or thyroid-stimulating hormone-beta (TSHB) gene are responsible for isolated CCH. In this paper, we present the cases of two siblings with a novel mutation of TSHB. Direct sequencing of the coding regions and exon/intron boundaries of the TSHB gene revealed two homozygous nucleotides changes. One of them was c.40A>G (rs10776792) which is a very common variation that is also seen in healthy individuals, the other was c.94G>A at codon 32 of exon 2 which resulted in a change from glutamic acid to lysine (p.E32K). Both patients were homozygous and the parents were heterozygous.

  19. IGSF10 mutations dysregulate gonadotropin-releasing hormone neuronal migration resulting in delayed puberty.

    PubMed

    Howard, Sasha R; Guasti, Leonardo; Ruiz-Babot, Gerard; Mancini, Alessandra; David, Alessia; Storr, Helen L; Metherell, Lousie A; Sternberg, Michael Je; Cabrera, Claudia P; Warren, Helen R; Barnes, Michael R; Quinton, Richard; de Roux, Nicolas; Young, Jacques; Guiochon-Mantel, Anne; Wehkalampi, Karoliina; André, Valentina; Gothilf, Yoav; Cariboni, Anna; Dunkel, Leo

    2016-06-01

    Early or late pubertal onset affects up to 5% of adolescents and is associated with adverse health and psychosocial outcomes. Self-limited delayed puberty (DP) segregates predominantly in an autosomal dominant pattern, but the underlying genetic background is unknown. Using exome and candidate gene sequencing, we have identified rare mutations in IGSF10 in 6 unrelated families, which resulted in intracellular retention with failure in the secretion of mutant proteins. IGSF10 mRNA was strongly expressed in embryonic nasal mesenchyme, during gonadotropin-releasing hormone (GnRH) neuronal migration to the hypothalamus. IGSF10 knockdown caused a reduced migration of immature GnRH neurons in vitro, and perturbed migration and extension of GnRH neurons in a gnrh3:EGFP zebrafish model. Additionally, loss-of-function mutations in IGSF10 were identified in hypothalamic amenorrhea patients. Our evidence strongly suggests that mutations in IGSF10 cause DP in humans, and points to a common genetic basis for conditions of functional hypogonadotropic hypogonadism (HH). While dysregulation of GnRH neuronal migration is known to cause permanent HH, this is the first time that this has been demonstrated as a causal mechanism in DP‡.

  20. Hormones

    MedlinePlus

    Hormones are your body's chemical messengers. They travel in your bloodstream to tissues or organs. They work ... glands, which are special groups of cells, make hormones. The major endocrine glands are the pituitary, pineal, ...

  1. Caffeine and Blood Pressure Response: Sex, Age, and Hormonal Status

    PubMed Central

    Whitsett, Thomas L.; McKey, Barbara S.; Wilson, Michael F.; Vincent, Andrea S.; Everson-Rose, Susan A.; Lovallo, William R.

    2010-01-01

    Abstract Purpose The pressor effect of caffeine has been established in young men and premenopausal women. The effect of caffeine on blood pressure (BP) remains unknown in postmenopausal women and in relation to hormone replacement therapy (HRT) use. Materials and Methods In a randomized, 2-week cross-over design, we studied 165 healthy men and women in 6 groups: men and premenopausal women (35–-49 yrs) vs. men and postmenopausal women (50–-64 yrs), with postmenopausal women divided into those taking no hormone replacements (HR), estrogen alone, or estrogen and progesterone. Testing during one week of the study involved 6 days of caffeine maintenance at home (80 mg, 3x/day) followed by testing of responses to a challenge dose of caffeine (250 mg) in the laboratory. The other week involved ingesting placebos on maintenance and lab days. Resting BP responses to caffeine were measured at baseline and at 45 to 60 min following caffeine vs placebo ingestion, using automated monitors. Results Ingestion of caffeine resulted in a significant increase in systolic BP in all 6 groups (4 ± .6, p < 0.01). Diastolic BP significantly increased in response to caffeine in all (3 ± .4, p < 0.04) but the group of older men (2 ± 1.0, p = 0.1). The observed pressor responses to caffeine did not vary by age. Conclusions Caffeine resulted in an increase in BP in healthy, normotensive, young and older men and women. This finding warrants the consideration of caffeine in the lifestyle interventions recommended for BP control across the age span. PMID:20500126

  2. Hormone- and light-regulated nucleocytoplasmic transport in plants: current status.

    PubMed

    Lee, Yew; Lee, Hak-Soo; Lee, June-Seung; Kim, Seong-Ki; Kim, Soo-Hwan

    2008-01-01

    The gene regulation mechanisms underlying hormone- and light-induced signal transduction in plants rely not only on post-translational modification and protein degradation, but also on selective inclusion and exclusion of proteins from the nucleus. For example, plant cells treated with light or hormones actively transport many signalling regulatory proteins, transcription factors, and even photoreceptors and hormone receptors into the nucleus, while actively excluding other proteins. The nuclear envelope (NE) is the physical and functional barrier that mediates this selective partitioning, and nuclear transport regulators transduce hormone- or light-initiated signalling pathways across the membrane to mediate nuclear activities. Recent reports revealed that mutating the proteins regulating nuclear transport through the pores, such as nucleoporins, alters the plant's response to a stimulus. In this review, recent works are introduced that have revealed the importance of regulated nucleocytoplasmic partitioning. These important findings deepen our understanding about how co-ordinated plant hormone and light signal transduction pathways facilitate communication between the cytoplasm and the nucleus. The roles of nucleoporin components within the nuclear pore complex (NPC) are also emphasized, as well as nuclear transport cargo, such as Ran/TC4 and its binding proteins (RanBPs), in this process. Recent findings concerning these proteins may provide a possible direction by which to characterize the regulatory potential of hormone- or light-triggered nuclear transport.

  3. Effect of Nitric Oxide on Neointimal Hyperplasia based on Sex and Hormone Status

    PubMed Central

    Hogg, Melissa E.; Varu, Vinit N.; Vavra, Ashley K.; Popowich, Daniel A.; Banerjee, Monisha N.; Martinez, Janet; Jiang, Qun; Saavedra, Joseph E.; Keefer, Larry K.; Kibbe, Melina R.

    2011-01-01

    Nitric oxide (NO)-based therapies decrease neointimal hyperplasia; however, studies have only been performed in male animal models. Thus, we sought to evaluate the effect of NO on vascular smooth muscle cells (VSMC) in vitro and neointimal hyperplasia in vivo based on sex and hormone status. In hormone-replete media, male VSMC proliferated at greater rates than female VSMC. In hormone-deplete media, female VSMC proliferated at greater rates than male VSMC. However, in both hormone environments, NO inhibited proliferation and migration to a greater extent in male versus female VSMC. These findings correlated with greater G0/G1 cell cycle arrest and changes in cell cycle protein expression in male versus female VSMC following exposure to NO. Next, the rat carotid artery injury model was performed to assess the effect of NO on neointimal hyperplasia in vivo. Consistent with the in vitro data, NO was significantly more effective at inhibiting neointimal hyperplasia in hormonally intact males versus females using weight-based dosing. An increased weight-based dose of NO in females was able to achieve efficacy equal to that in males. Surprisingly, NO was less effective at inhibiting neointimal hyperplasia in both sexes in castrated animals. In conclusion, these data suggest that NO inhibits neointimal hyperplasia more effectively in males than females and in hormonally-intact compared to castrated rats, indicating that the effect of NO in the vasculature may be sex- and hormone-dependent. PMID:21256959

  4. Effect of nitric oxide on neointimal hyperplasia based on sex and hormone status.

    PubMed

    Hogg, Melissa E; Varu, Vinit N; Vavra, Ashley K; Popowich, Daniel A; Banerjee, Monisha N; Martinez, Janet; Jiang, Qun; Saavedra, Joseph E; Keefer, Larry K; Kibbe, Melina R

    2011-05-01

    Nitric oxide (NO)-based therapies decrease neointimal hyperplasia; however, studies have been performed only in male animal models. Thus, we sought to evaluate the effect of NO on vascular smooth muscle cells (VSMC) in vitro and neointimal hyperplasia in vivo based on sex and hormone status. In hormone-replete medium, male VSMC proliferated at greater rates than female VSMC. In hormone-depleted medium, female VSMC proliferated at greater rates than male VSMC. However, in both hormone environments, NO inhibited proliferation and migration to a greater extent in male compared to female VSMC. These findings correlated with greater G₀/G₁ cell cycle arrest and changes in cell cycle protein expression in male compared to female VSMC after exposure to NO. Next, the rat carotid artery injury model was used to assess the effect of NO on neointimal hyperplasia in vivo. Consistent with the in vitro data, NO was significantly more effective at inhibiting neointimal hyperplasia in hormonally intact males compared to females using weight-based dosing. An increased weight-based dose of NO in females was able to achieve efficacy equal to that in males. Surprisingly, NO was less effective at inhibiting neointimal hyperplasia in castrated animals of both sexes. In conclusion, these data suggest that NO inhibits neointimal hyperplasia more effectively in males compared to females and in hormonally intact compared to castrated rats, indicating that the effects of NO in the vasculature may be sex- and hormone-dependent.

  5. EFFECTS OF PERFLUOROOCTANE SULFONATE (PFOS) ON THYROID HORMONE STATUS IN ADULT AND NEONATAL RATS

    EPA Science Inventory

    EFFECTS OF PERFLUOROOCTANE SULFONATE (PFOS) ON THYROID HORMONE STATUS IN ADULT AND NEONATAL RATS. M.N. Logan1, J.R. Thibodeaux2, R.G. Hanson2, C. Lau2. 1North Carolina Central University, Durham, NC, 2Reprod. Tox. Div. NHEERL, US EPA, Research Triangle Park, NC.

    Perfluor...

  6. Homozygous Thyroid Hormone Receptor β-Gene Mutations in Resistance to Thyroid Hormone: Three New Cases and Review of the Literature

    PubMed Central

    Ferrara, Alfonso Massimiliano; Onigata, Kazumichi; Ercan, Oya; Woodhead, Helen; Weiss, Roy E.

    2012-01-01

    Context: The most common cause of resistance to thyroid hormone (RTH) is heterozygous thyroid hormone receptor β (THRB) gene mutations. Homozygous mutations in the THRB gene are a rare event. Objective: In this study, the clinical findings of three new patients (belonging to two families) homozygous for mutations in the THRB gene are compared to three other families in which affected individuals lack a normal TRβ. Methods: We conducted clinical studies and genetic analyses. Results: The clinical presentation in all three homozygous subjects was unusually severe; their phenotype was characterized by compromised intellectual development, tachycardia, goiter, growth retardation, and hearing loss. This was comparable with one other reported patient homozygous for mutant TRβ, but not in RTH due to THRB gene deletions. Conclusion: We report three new subjects, from two families, in whom RTH was associated with homozygous mutations in the THRB gene. They represent an important addition to the single known patient homozygous for a mutant TRβ. The clinical and laboratory abnormalities indicate a strong dominant-negative effect and are in agreement with data obtained from mice expressing a mutant Thrb in both alleles. This report strengthens the concept that the mutated TRβ interferes with the function of the TRα1 in humans. PMID:22319036

  7. E180splice mutation in the growth hormone receptor gene in a Chilean family with growth hormone insensitivity: a probable common Mediterranean ancestor.

    PubMed

    Espinosa, Claudia; Sjoberg, Marcela; Salazar, Teresa; Rodriguez, Adrian; Cassorla, Fernando G; Mericq, M Veronica; Carvallo, Pilar

    2008-12-01

    Mutations in the GH receptor gene have been identified as the cause of growth hormone insensitivity syndrome (GHIS), a rare autosomal recessive disorder. We studied the clinical and biochemical characteristics and the coding sequence and intron-exon boundaries of the GH receptor gene in a consanguineous family with severe short stature which consisted of two patients, their parents and five siblings. The two adolescents had heights of -4.7 and -5.5 SDS, respectively, with elevated growth hormone associated with low IGF-I, IGFBP-3 and GHBP concentrations. Molecular analysis of the GH receptor gene revealed a mutation in exon 6, present in both patients This mutation, E180 splice, has been previously described in an Ecuadorian cohort, and in one Israeli and six Brazilian patients. We determined the GH receptor haplotypes based on six polymorphic sites in intron 9. Co-segregation of the E180splice mutation with haplotype I was found in this family, compatible with a common Mediterranean ancestor, as shown for previous cases with the E180splice mutation described to date.

  8. Genotype-phenotype relationship in patients with mutations in thyroid hormone transporter MCT8.

    PubMed

    Jansen, Jurgen; Friesema, Edith C H; Kester, Monique H A; Schwartz, Charles E; Visser, Theo J

    2008-05-01

    Loss-of-function mutations in thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to severe X-linked psychomotor retardation and elevated serum T(3) levels. Most patients, for example those with mutations V235M, S448X, insI189, or delF230, cannot stand, walk, or speak. Patients with mutations L434W, L568P, and S194F, however, walk independently and/or develop some dysarthric speech. To study the relationship between mutation and phenotype, we transfected JEG3 and COS1 cells with wild-type or mutant MCT8. Expression and function of the transporter were studied by analyzing T(3) and T(4) uptake, T(3) metabolism (by cotransfected type 3 deiodinase), Western blotting, affinity labeling with N-bromoacetyl-T(3), immunocytochemistry, and quantitative RT-PCR. Wild-type MCT8 increased T(3) uptake and metabolism about 5-fold compared with empty vector controls. Mutants V235M, S448X, insI189, and delF230 did not significantly increase transport. However, S194F, L568P, and L434W showed about 20, 23, and 37% of wild-type activity. RT-PCR did not show significant differences in mRNA expression between wild-type and mutant MCT8. Immunocytochemistry detected the nonfunctional mutants V235M, insI189, and delF230 mostly in the cytoplasm, whereas mutants with residual function were expressed at the plasma membrane. Mutants S194F and L434W showed high protein expression but low affinity for N-bromoacetyl-T(3); L568P was detected in low amounts but showed relatively high affinity. Mutations in MCT8 cause loss of function through reduced protein expression, impaired trafficking to the plasma membrane, or reduced substrate affinity. Mutants L434W, L568P, and S194F showed significant residual transport capacity, which may underlie the more advanced psychomotor development observed in patients with these mutations.

  9. Genotype-Phenotype Relationship in Patients with Mutations in Thyroid Hormone Transporter MCT8

    PubMed Central

    Jansen, Jurgen; Friesema, Edith C. H.; Kester, Monique H. A.; Schwartz, Charles E.; Visser, Theo J.

    2008-01-01

    Loss-of-function mutations in thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to severe X-linked psychomotor retardation and elevated serum T3 levels. Most patients, for example those with mutations V235M, S448X, insI189, or delF230, cannot stand, walk, or speak. Patients with mutations L434W, L568P, and S194F, however, walk independently and/or develop some dysarthric speech. To study the relationship between mutation and phenotype, we transfected JEG3 and COS1 cells with wild-type or mutant MCT8. Expression and function of the transporter were studied by analyzing T3 and T4 uptake, T3 metabolism (by cotransfected type 3 deiodinase), Western blotting, affinity labeling with N-bromoacetyl-T3, immunocytochemistry, and quantitative RT-PCR. Wild-type MCT8 increased T3 uptake and metabolism about 5-fold compared with empty vector controls. Mutants V235M, S448X, insI189, and delF230 did not significantly increase transport. However, S194F, L568P, and L434W showed about 20, 23, and 37% of wild-type activity. RT-PCR did not show significant differences in mRNA expression between wild-type and mutant MCT8. Immunocytochemistry detected the nonfunctional mutants V235M, insI189, and delF230 mostly in the cytoplasm, whereas mutants with residual function were expressed at the plasma membrane. Mutants S194F and L434W showed high protein expression but low affinity for N-bromoacetyl-T3; L568P was detected in low amounts but showed relatively high affinity. Mutations in MCT8 cause loss of function through reduced protein expression, impaired trafficking to the plasma membrane, or reduced substrate affinity. Mutants L434W, L568P, and S194F showed significant residual transport capacity, which may underlie the more advanced psychomotor development observed in patients with these mutations. PMID:18187543

  10. Hormonal status and fluid electrolyte metabolism in motion sickness

    SciTech Connect

    Grigoriev, A.I.; Nichiporuk, I.A.; Yasnetsov, V.V.; Shashkov, V.S.

    1988-04-01

    In the first experimental series, 10 healthy male test subjects with a high susceptibility to motion sickness showed a significant increase of ACTH, cortisol, STH, prolactin, ADH, aldosterone concentrations, and plasma renin activity after vestibular tests. The 10 subjects with a moderate susceptibility exhibited a still higher increase of the hormones, except plasma renin. The 8 test subjects with a low susceptibility displayed a considerable increase in ACTH, cortisol, and STH after vestibular stimulation. In the second experimental series, the increase of STH, cortisol, ADH, aldosterone and renin occurred immediately after rotation in the moderate susceptibility subjects and an hour after exposure in the high susceptibility subjects. This may be indicative of specific immediate adaptation mechanisms or excitation transfer in the CNS in high susceptibility persons. In the third experimental animal series, the permeability of the blood-brain barrier for /sup 125/I and IgG increased after rotation. Greater concentrations of potassium, chloride, and urea in CSF are suggestive of an inhibition process activation in the CNS and, probably, of an active urea transport by the vascular plexus epithelium which maintains constant osmotic pressure of cerebral extracellular fluid and prevents hyper-hydration of CNS neurons.

  11. [Adipose tissue hormones and nutritional status in chronic obstructive pulmonary disease].

    PubMed

    Nevzorova, V A; Barkhatova, D A; Kudriavtseva, V A; Luk'ianov, P A

    2009-01-01

    To study nutritional status in chronic obstructive pulmonary disease (COPD) in relation to the serum content of adipose tissue hormones. Ninety-four patients with Stages II and III COPD and 20 gender- and age-matched healthy non-smoking volunteers were examined. Interviews, analysis of laboratory data, enzyme immunoassay, and somatometry were made. The patients with COPD are characterized by the development of malnutrition, even in the absence of body weight loss and in the presence of normal body mass index (BMI) with predominant lean body mass (LBM) loss, normal serum concentrations of adipose tissue hormones. With more advanced COPD and a worse nutritional status, the level of leptin decreases and that of adiponectin increases. The content of adiponectins is closely related to the indicators of nutritional status, mainly to the value of body weight loss, BMI, LBM, absolute blood lymphocyte count, and degree of malnutrition. The COPD patients with emphysema show the most pronounced changes in nutritional status and higher adiponectin levels. An integrated assessment of the degree of protein-energy malnutrition and measurement of the level of adipose tissue hormones should be made when nutritional status is studied in patients with COPD.

  12. A targeted dominant negative mutation of the thyroid hormone α1 receptor causes increased mortality, infertility, and dwarfism in mice

    PubMed Central

    Kaneshige, Masahiro; Suzuki, Hideyo; Kaneshige, Kumiko; Cheng, Jun; Wimbrow, Heather; Barlow, Carrolee; Willingham, Mark C.; Cheng, Sheue-yann

    2001-01-01

    Mutations in the thyroid hormone receptor β (TRβ) gene result in resistance to thyroid hormone. However, it is unknown whether mutations in the TRα gene could lead to a similar disease. To address this question, we prepared mutant mice by targeting mutant thyroid hormone receptor kindred PV (PV) mutation to the TRα gene locus by means of homologous recombination (TRα1PV mice). The PV mutation was derived from a patient with severe resistance to thyroid hormone that has a frameshift of the C-terminal 14 aa of TRβ1. We knocked in the same PV mutation to the corresponding TRα gene locus to compare the phenotypes of TRα1PV/+ mice with those of TRβPV/+ mice. TRα1PV/+ mice were viable, indicating that the mutation of the TRα gene is not embryonic lethal. In drastic contrast to the TRβPV/+ mice, which do not exhibit a growth abnormality, TRα1PV/+ mice were dwarfs. These dwarfs exhibited increased mortality and reduced fertility. In contrast to TRβPV/+ mice, which have a hyperactive thyroid, TRα1PV/+ mice exhibited mild thyroid failure. The in vivo pattern of abnormal regulation of T3 target genes in TRα1PV/+ mice was unique from those of TRβPV/+ mice. The distinct phenotypes exhibited by TRα1PV/+ and TRβPV/+ mice indicate that the in vivo functions of TR mutants are isoform-dependent. The TRα1PV/+ mice may be used as a tool to uncover human diseases associated with mutations in the TRα gene and, furthermore, to understand the molecular mechanisms by which TR isoforms exert their biological activities. PMID:11734632

  13. Novel mutation involving the translation initiation codon of the growth hormone receptor gene (GHR) in a patient with Laron syndrome.

    PubMed

    Quinteiro, Celsa; Castro-Feijoo, Lidia; Loidi, Lourdes; Barreiro, Jesus; de la Fuente, Maria; Dominguez, Fernando; Pombo, Manuel

    2002-01-01

    Laron syndrome (LS) or growth hormone (GH) insensitivity syndrome (GHIS) is an autosomal recessive disease due to molecular defects in the GH receptor gene (GHR). Most of the identified mutations are located on the extracelular domain of the receptor. We studied the GHR gene in a patient with LS and found a homozygous missense mutation in exon 2. The novel mutation is an A-->T transversion (ATG -->TTG) that abolishes the translation initiation codon of the GHR gene. This mutation is expected to prevent the translation of the protein. We present clinical, biochemical and molecular evidence of Laron syndrome as the result of a mutation (ATG-->TTG) in the codon for the initial methionine of the GHR gene.

  14. Defective erythropoiesis caused by mutations of the thyroid hormone receptor α gene.

    PubMed

    Park, Sunmi; Han, Cho Rong; Park, Jeong Won; Zhao, Li; Zhu, Xuguang; Willingham, Mark; Bodine, David M; Cheng, Sheue-Yann

    2017-09-01

    Patients with mutations of the THRA gene exhibit classical features of hypothyroidism, including erythroid disorders. We previously created a mutant mouse expressing a mutated TRα1 (denoted as PV; Thra1PV/+ mouse) that faithfully reproduces the classical hypothyroidism seen in patients. Using Thra1PV/+ mice, we explored how the TRα1PV mutant acted to cause abnormalities in erythropoiesis. Thra1PV/+ mice exhibited abnormal red blood cell indices similarly as reported for patients. The total bone marrow cells and erythrocytic progenitors were markedly reduced in the bone marrow of Thra1PV/+ mice. In vitro terminal differentiation assays showed a significant reduction of mature erythrocytes in Thra1PV/+ mice. In wild-type mice, the clonogenic potential of progenitors in the erythrocytic lineage was stimulated by thyroid hormone (T3), suggesting that T3 could directly accelerate the differentiation of progenitors to mature erythrocytes. Analysis of gene expression profiles showed that the key regulator of erythropoiesis, the Gata-1 gene, and its regulated genes, such as the Klf1, β-globin, dematin genes, CAII, band3 and eALAS genes, involved in the maturation of erythrocytes, was decreased in the bone marrow cells of Thra1PV/+ mice. We further elucidated that the Gata-1 gene was a T3-directly regulated gene and that TRα1PV could impair erythropoiesis via repression of the Gata-1 gene and its regulated genes. These results provide new insights into how TRα1 mutants acted to cause erythroid abnormalities in patients with mutations of the THRA gene. Importantly, the Thra1PV/+ mouse could serve as a preclinical mouse model to identify novel molecular targets for treatment of erythroid disorders.

  15. Ten-year survival after epithelial ovarian cancer is not associated with BRCA mutation status.

    PubMed

    Kotsopoulos, Joanne; Rosen, Barry; Fan, Isabel; Moody, Joel; McLaughlin, John R; Risch, Harvey; May, Taymaa; Sun, Ping; Narod, Steven A

    2016-01-01

    After a diagnosis of ovarian cancer, positive BRCA mutation status confers a transient mortality benefit that diminishes with time. The majority of women who survive for 10-12 years are effectively cured of their disease. Thus, it is important to estimate the probability of long-term survival by BRCA mutation status and treatment-related factors. We included unselected epithelial ovarian cancers diagnosed in Ontario, Canada from 1995 to 1999 and from 2002 to 2004. Clinical information was obtained from medical records. Survival status was determined by linkage to the Ontario Cancer Registry. We estimated the annual mortality for these patients. We compared women who did and did not survive 10 years for a range of factors including BRCA mutation status and extent of residual disease post-surgery. Of the 1421 patients, 109 (7.7%) had BRCA1 mutations and 68 (4.8%) had BRCA2 mutations. A status of no residual disease was achieved by 39% of non-carriers and 19% of mutation carriers (P<0.0001). By 10-years of follow-up, 43% of non-carriers, 57% of BRCA1 mutation carriers and 69% of BRCA2 mutation carriers had died from ovarian cancer. Among women with stage III/IV serous cancers and no residual disease, the 10-year actuarial survival was 42% for non-carriers and 29% for mutation carriers (P=0.40). The initial survival advantage among women with BRCA mutations may reflect a higher initial sensitivity of BRCA carriers to chemotherapy, but this response does not predict long-term survival. The strongest predictor of long-term survival is status of no residual disease at resection. Copyright © 2015. Published by Elsevier Inc.

  16. Hormone Receptor and ERBB2 Status in Gene Expression Profiles of Human Breast Tumor Samples

    PubMed Central

    Dvorkin-Gheva, Anna; Hassell, John A.

    2011-01-01

    The occurrence of large publically available repositories of human breast tumor gene expression profiles provides an important resource to discover new breast cancer biomarkers and therapeutic targets. For example, knowledge of the expression of the estrogen and progesterone hormone receptors (ER and PR), and that of the ERBB2 in breast tumor samples enables choice of therapies for the breast cancer patients that express these proteins. Identifying new biomarkers and therapeutic agents affecting the activity of signaling pathways regulated by the hormone receptors or ERBB2 might be accelerated by knowledge of their expression levels in large gene expression profiling data sets. Unfortunately, the status of these receptors is not invariably reported in public databases of breast tumor gene expression profiles. Attempts have been made to employ a single probe set to identify ER, PR and ERBB2 status, but the specificity or sensitivity of their prediction is low. We enquired whether estimation of ER, PR and ERBB2 status of profiled tumor samples could be improved by using multiple probe sets representing these three genes and others with related expression. We used 8 independent datasets of human breast tumor samples to define gene expression signatures comprising 24, 51 and 14 genes predictive of ER, PR and ERBB2 status respectively. These signatures, as demonstrated by sensitivity and specificity measures, reliably identified hormone receptor and ERBB2 expression in breast tumors that had been previously determined using protein and DNA based assays. Our findings demonstrate that gene signatures can be identified which reliably predict the expression status of the estrogen and progesterone hormone receptors and that of ERBB2 in publically available gene expression profiles of breast tumor samples. Using these signatures to query transcript profiles of breast tumor specimens may enable discovery of new biomarkers and therapeutic targets for particular subtypes of

  17. FOXL2 Mutation Status in Granulosa Theca Cell Tumors of the Ovary.

    PubMed

    Nolan, Amber; Joseph, Nancy M; Sangoi, Ankur R; Rabban, Joseph; Zaloudek, Charles; Garg, Karuna

    2017-03-17

    Ovarian sex-cord stromal tumors that have between 10% and 50% granulosa cells in a prominent fibrothecomatous background have been referred to as granulosa theca cell tumors or mixed granulosa theca cell tumors. The classification and prognosis of these tumors is not clear. Most adult granulosa cell tumors of the ovary harbor a mutation in the FOXL2 gene, whereas fibromas and thecomas lack this mutation. The aim of our study was to assess the FOXL2 mutation status of ovarian granulosa theca cell tumors and to correlate the mutation status with morphologic and clinical characteristics. A FOXL2 mutation was detected in 6 of 12 (50%) granulosa theca cell tumors. Tumors with higher cellularity of granulosa cells were more likely to harbor a FOXL2 mutation as were tumors in which the granulosa cells formed large lobules. No conclusions could be drawn regarding the clinical and prognostic significance of the presence of a mutation given the small number of cases and limited clinical follow-up. Our study shows that half of granulosa theca cell tumors harbor the same FOXL2 mutation that characterizes adult granulosa cell tumors but there is no outcome evidence to guide whether mutation status should alter the classification of the tumor or the management of the patient.

  18. A new point mutation (C446R) in the thyroid hormone receptor-{beta} gene of a family with resistance to thyroid hormone

    SciTech Connect

    Weiss, R.E.; Chyna, B.; Hayashi, Yoshitaka; Sunthornthepvarakul, T.; Refetoff, S.; Duell, P.B.

    1994-05-01

    Resistance to thyroid hormone (RTH) is a condition of impaired end-organ responsiveness to thyroid hormone characterized by goiter and elevated thyroid hormone levels with an appropriately normal TSH. RTH has been associated with mutations in the thyroid hormone receptor-{beta} (TR{beta}) gene. The authors report studies carried out in 21 members of a family (F119), 12 of whom exhibited the RTH phenotype. A point mutation was detected in the T{sub 3}-binding domain of the TR{beta} gene. It resulted in replacement of the normal cysteine-446 with an arginine (C446R) that has not been previously reported. The clinical characteristics of this family are similar to those reported in other families with RTH, namely goiter, tachycardia, and learning disabilities. Thyroid function tests are also typical of other subjects with RTH. The mean values ({+-}SD) in untreated affected subjects compared to those in unaffected family members were: free T{sub 4} index, 250 {+-} 21 vs. 108 {+-} 13; total T{sub 3}, 4.3 {+-} 0.4 vs. 2.4 {+-} 0.4 nmol/L; and TSH, 4.5 {+-} 1.1 vs. 2.4 {+-} 1.1 mU/L. DNA samples from 18 family members were screened for the TR{beta} mutation, which results in the loss of a BsmI restriction site, and each of the 11 subjects with abnormal thyroid function tests were heterozygous for the mutant allele. The mutant TR{beta} expressed in Cos-I cells did not bind T{sub 3} (K{sub a} of C446R/wild-type, <0.05). T{sub 3} at a concentration up to 100 nmol/L failed to enhance the transactivation of a reporter gene, and the mutant receptor inhibited the T{sub 3}-mediated transcriptional activation of the wild-type TR{beta}. 17 refs., 3 figs., 1 tab.

  19. A new point mutation (C446R) in the thyroid hormone receptor-beta gene of a family with resistance to thyroid hormone.

    PubMed

    Weiss, R E; Chyna, B; Duell, P B; Hayashi, Y; Sunthornthepvarakul, T; Refetoff, S

    1994-05-01

    Resistance to thyroid hormone (RTH) is a condition of impaired end-organ responsiveness to thyroid hormone characterized by goiter and elevated thyroid hormone levels with an inappropriately normal TSH. RTH has been associated with mutations in the thyroid hormone receptor-beta (TR beta) gene. We report studies carried out in 21 members of a family (F119), 12 of whom exhibited the RTH phenotype. A point mutation was detected in the T3-binding domain of the TR beta gene. It resulted in replacement of the normal cysteine-446 with an arginine (C446R) that has not been previously reported. The clinical characteristics of this family are similar to those reported in other families with RTH, namely goiter, tachycardia, and learning disabilities. Thyroid function tests are also typical of other subjects with RTH. The mean values (+/- SD) in untreated affected subjects compared to those in unaffected family members were: free T4 index, 250 +/- 21 vs. 108 +/- 13; total T3, 4.3 +/- 0.4 vs. 2.4 +/- 0.4 nmol/L; and TSH, 4.5 +/- 1.1 vs. 2.4 +/- 1.1 mU/L. DNA samples from 18 family members were screened for the TR beta mutation, which results in the loss of a BsmI restriction site, and each of the 11 subjects with abnormal thyroid function tests were heterozygous for the mutant allele. The mutant TR beta expressed in Cos-I cells did not bind T3 (Ka of C446R/wild-type, < 0.05). T3 at a concentration up to 100 nmol/L failed to enhance the transactivation of a reporter gene, and the mutant receptor inhibited the T3-mediated transcriptional activation of the wild-type TR beta.

  20. Variation in serum biomarkers with sex and female hormonal status: implications for clinical tests

    PubMed Central

    Ramsey, Jordan M.; Cooper, Jason D.; Penninx, Brenda W. J. H.; Bahn, Sabine

    2016-01-01

    Few serum biomarker tests are implemented in clinical practice and recent reports raise concerns about poor reproducibility of biomarker studies. Here, we investigated the potential role of sex and female hormonal status in this widespread irreproducibility. We examined 171 serum proteins and small molecules measured in 1,676 participants from the Netherlands Study of Depression and Anxiety. Concentrations of 96 molecules varied with sex and 66 molecules varied between oral contraceptive pill users, postmenopausal females, and females in the follicular and luteal phases of the menstrual cycle (FDR-adjusted p-value <0.05). Simulations of biomarker studies yielded up to 40% false discoveries when patient and control groups were not matched for sex and up to 41% false discoveries when premenopausal females were not matched for oral contraceptive pill use. High accuracy (over 90%) classification tools were developed to label samples with sex and female hormonal status where this information was not collected. PMID:27240929

  1. Association of copayment and socioeconomic status with hormonal contraceptive adherence in a female veteran population.

    PubMed

    Kazerooni, Rashid; Vu, Khanh; Takizawa, Atsuhiko; Broadhead, Christine; Morreale, Anthony P

    2014-01-01

    There are limited studies available analyzing association between copayment and hormonal contraception adherence. The study was conducted to investigate the association between copayment status and hormonal contraceptive adherence in a female veteran population when stratified by socioeconomic status. This 4-year, retrospective, cohort study of women Veterans from the Veterans Integrated Service Network 22, a network of Veterans Affairs facilities that includes Southern California and Nevada, included patients who received a new hormonal contraceptive prescription between October 1, 2008, and September 30, 2012. Patients were split into five quintiles (one having the lowest income and five the highest) dependent on zip code-based median annual household income from the 2007-2011 American Community Survey data. Medication possession ratio difference of copayment versus no copayment group for each respective quintile was the primary outcome. Analysis was done using multiple linear regression models. A total of 3,622 patients met the inclusion criteria and were included in the analysis. Over the entire population, copayment was significantly associated with reduced adherence (-0.034; 95% confidence interval [CI], -0.06 to -0.008). Patients in the highest socioeconomic group, quintile five, had the largest reduction in adherence associated with having a copayment (-0.073; 95% CI, -0.129 to -0.017). Patients in the other four quintiles saw varying levels of decreased adherence respectively, although the differences did not achieve statistical significance. The association between adherence and copayment status varied by socioeconomic status. Our findings suggest that even affluent patients may be discouraged from adherence when subject to a copayment. If larger studies substantiate these findings, consideration should be given to a policy that exempts women veterans from copayments for hormonal contraceptives. Published by Elsevier Inc.

  2. Novel splice site mutation in the growth hormone receptor gene in Turkish patients with Laron-type dwarfism.

    PubMed

    Arman, Ahmet; Ozon, Alev; Isguven, Pinar S; Coker, Ajda; Peker, Ismail; Yordam, Nursen

    2008-01-01

    Growth hormone (GH) is involved in growth, and fat and carbohydrate metabolism. Interaction of GH with the GH receptor (GHR) is necessary for systemic and local production of insulin-like growth factor-I (IGF-I) which mediates GH actions. Mutations in the GHR cause severe postnatal growth failure; the disorder is an autosomal recessive genetic disease resulting in GH insensitivity, called Laron syndrome. It is characterized by dwarfism with elevated serum GH and low levels of IGF-I. We analyzed the GHR gene for mutations and polymorphisms in eight patients with Laron-type dwarfism from six families. We found three missense mutations (S40L, V125A, I526L), one nonsense mutation (W157X), and one splice site mutation in the extracellular domain of GHR. Furthermore, G168G and exon 3 deletion polymorphisms were detected in patients with Laron syndrome. The splice site mutation, which is a novel mutation, was located at the donor splice site of exon 2/ intron 2 within GHR. Although this mutation changed the highly conserved donor splice site consensus sequence GT to GGT by insertion of a G residue, the intron splicing between exon 2 and exon 3 was detected in the patient. These results imply that the splicing occurs arthe GT site in intron 2, leaving the extra inserted G residue at the end of exon 2, thus changing the open reading frame of GHR resulting in a premature termination codon in exon 3.

  3. Assessing reproductive status in elasmobranch fishes using steroid hormones extracted from skeletal muscle tissue.

    PubMed

    Prohaska, Bianca K; Tsang, Paul C W; Driggers, William B; Hoffmayer, Eric R; Wheeler, Carolyn R; Brown, A Christine; Sulikowski, James A

    2013-01-01

    Elasmobranch fishes (sharks, skates, and rays) are particularly susceptible to anthropogenic threats, making a thorough understanding of their life history characteristics essential for proper management. Historically, elasmobranch reproductive data have been collected by lethal sampling, an approach that is problematic for threatened and endangered species. However, recent studies have demonstrated that non-lethal approaches can be as effective as lethal ones for assessment of the reproductive status of an animal. For example, plasma has been used to examine concentrations of steroid hormones. Additionally, skeletal muscle tissue, which can be obtained non-lethally and with minimal stress, can also be used to quantify concentrations of steroid hormones. Skeletal muscle progesterone, testosterone, and estradiol concentrations were determined to be statistically significant indicators of reproductive status in the oviparous Leucoraja erinacea, the yolk-dependent viviparous Squalus acanthias, and the yolk-sac placental viviparous Rhizoprionodon terraenovae. The results of the present study demonstrate that steroid hormones present in non-lethally harvested skeletal muscle tissue can be used as reliable indicators of reproductive status in elasmobranchs.

  4. Assessing reproductive status in elasmobranch fishes using steroid hormones extracted from skeletal muscle tissue

    PubMed Central

    Prohaska, Bianca K.; Tsang, Paul C. W.; Driggers, William B.; Hoffmayer, Eric R.; Wheeler, Carolyn R.; Brown, A. Christine; Sulikowski, James A.

    2013-01-01

    Elasmobranch fishes (sharks, skates, and rays) are particularly susceptible to anthropogenic threats, making a thorough understanding of their life history characteristics essential for proper management. Historically, elasmobranch reproductive data have been collected by lethal sampling, an approach that is problematic for threatened and endangered species. However, recent studies have demonstrated that non-lethal approaches can be as effective as lethal ones for assessment of the reproductive status of an animal. For example, plasma has been used to examine concentrations of steroid hormones. Additionally, skeletal muscle tissue, which can be obtained non-lethally and with minimal stress, can also be used to quantify concentrations of steroid hormones. Skeletal muscle progesterone, testosterone, and estradiol concentrations were determined to be statistically significant indicators of reproductive status in the oviparous Leucoraja erinacea, the yolk-dependent viviparous Squalus acanthias, and the yolk-sac placental viviparous Rhizoprionodon terraenovae. The results of the present study demonstrate that steroid hormones present in non-lethally harvested skeletal muscle tissue can be used as reliable indicators of reproductive status in elasmobranchs. PMID:27293612

  5. Disruption of Germination and Seedling Development in Brassica napus by Mutations Causing Severe Seed Hormonal Imbalance

    PubMed Central

    Nguyen, Tung C. T.; Obermeier, Christian; Friedt, Wolfgang; Abrams, Suzanne R.; Snowdon, Rod J.

    2016-01-01

    The Brassica napus (oilseed rape) accession 1012-98 shows a disturbed germination phenotype that was thought to be associated with its lack of testa pigmentation and thin seed coat. Here, we demonstrate that the disturbed germination and seedling development are actually due to independent mutations that disrupt the balance of hormone metabolites and their regulators in the seeds. High-throughput UPLC-MS/MS hormone profiling of seeds and seedlings before and after germination revealed that 1012-98 has a severely disturbed hormone balance with extremely atypical, excessive quantities of auxin and ABA metabolites. The resulting hypersensitivity to abscisic acid (ABA) and a corresponding increase in dormancy often results in death of the embryo after imbibition or high frequencies of disturbed, often lethal developmental phenotypes, resembling Arabidopsis mutants for the auxin regulatory factor gene ARF10 or the auxin-overproducing transgenic line iaaM-OX. Molecular cloning of Brassica ARF10 orthologs revealed four loci in normal B. napus, two derived from the Brassica A genome and two from the C genome. On the other hand, the phenotypic mutant 1012-98 exhibited amplification of C-genome BnaC.ARF10 copy number along with a chimeric allele originating from recombination between homeologous A and C genome loci which lead to minor increase of Bna.ARF10 transcription on the critical timepoint for seed germination, the indirect regulator of ABI3, the germinative inhibitor. Bna.GH3.5 expression was upregulated to conjugate free auxin to IAA-asp between 2 and 6 DAS. Functional amino acid changes were also found in important DNA binding domains of one BnaC.ARF10 locus, suggesting that regulatory changes in Bna.ARF10 are collectively responsible for the observed phenotpyes in 1012-98. To our knowledge, this study is the first to report disruption of germination and seedling development in Brassica napus caused by the crosstalk of auxin-ABA and the corresponding regulators Bna

  6. Disruption of Germination and Seedling Development in Brassica napus by Mutations Causing Severe Seed Hormonal Imbalance.

    PubMed

    Nguyen, Tung C T; Obermeier, Christian; Friedt, Wolfgang; Abrams, Suzanne R; Snowdon, Rod J

    2016-01-01

    The Brassica napus (oilseed rape) accession 1012-98 shows a disturbed germination phenotype that was thought to be associated with its lack of testa pigmentation and thin seed coat. Here, we demonstrate that the disturbed germination and seedling development are actually due to independent mutations that disrupt the balance of hormone metabolites and their regulators in the seeds. High-throughput UPLC-MS/MS hormone profiling of seeds and seedlings before and after germination revealed that 1012-98 has a severely disturbed hormone balance with extremely atypical, excessive quantities of auxin and ABA metabolites. The resulting hypersensitivity to abscisic acid (ABA) and a corresponding increase in dormancy often results in death of the embryo after imbibition or high frequencies of disturbed, often lethal developmental phenotypes, resembling Arabidopsis mutants for the auxin regulatory factor gene ARF10 or the auxin-overproducing transgenic line iaaM-OX. Molecular cloning of Brassica ARF10 orthologs revealed four loci in normal B. napus, two derived from the Brassica A genome and two from the C genome. On the other hand, the phenotypic mutant 1012-98 exhibited amplification of C-genome BnaC.ARF10 copy number along with a chimeric allele originating from recombination between homeologous A and C genome loci which lead to minor increase of Bna.ARF10 transcription on the critical timepoint for seed germination, the indirect regulator of ABI3, the germinative inhibitor. Bna.GH3.5 expression was upregulated to conjugate free auxin to IAA-asp between 2 and 6 DAS. Functional amino acid changes were also found in important DNA binding domains of one BnaC.ARF10 locus, suggesting that regulatory changes in Bna.ARF10 are collectively responsible for the observed phenotpyes in 1012-98. To our knowledge, this study is the first to report disruption of germination and seedling development in Brassica napus caused by the crosstalk of auxin-ABA and the corresponding regulators Bna

  7. LINE-1 hypomethylation and mutational status in cutaneous melanomas.

    PubMed

    Pramio, Dimitrius T; Pennacchi, Paula C; Maria-Engler, Silvya S; Campos, Antônio H J F M; Duprat, João P; Carraro, Dirce M; Krepischi, Ana C V

    2016-04-01

    Epigenetic dysregulation is an important emerging hallmark of cutaneous melanoma development. The global loss of DNA methylation in gene-poor regions and transposable DNA elements of cancer cells contributes to increased genomic instability. Long interspersed element-1 (LINE-1) sequences are the most abundant repetitive sequence of the genome and can be evaluated as a surrogate marker of the global level of DNA methylation. In this work, LINE-1 methylation levels were evaluated in cutaneous melanomas and normal melanocyte primary cell cultures to investigate their possible association with both distinct clinicopathological characteristics and tumor mutational profile. A set of driver mutations frequently identified in cutaneous melanoma was assessed by sequencing (actionable mutations in BRAF, NRAS, and KIT genes, and mutations affecting the TER T promoter) or multiplex ligation-dependent probe amplification (MLPA) (CDKN2A deletions). Pyrosequencing was performed to investigate the methylation level of LINE-1 and CDKN2A promoter sequences. The qualitative analysis showed a trend toward an association between LINE-1 hypomethylation and CDKN2A inactivation (p=0.05). In a quantitative approach, primary tumors, mainly the thicker ones (>4 mm), exhibited a trend toward LINE-1 hypomethylation when compared with control melanocytes. To date, this is the first study reporting in cutaneous melanomas a possible link between the dysregulation of LINE-1 methylation and the presence of driver mutations. Copyright © 2016 American Federation for Medical Research.

  8. Influence of Chemotherapy on EGFR Mutation Status Among Patients With Non–Small-Cell Lung Cancer

    PubMed Central

    Bai, Hua; Wang, Zhijie; Chen, Keneng; Zhao, Jun; Lee, J. Jack; Wang, Shuhang; Zhou, Qinghua; Zhuo, Minglei; Mao, Li; An, Tongtong; Duan, Jianchun; Yang, Lu; Wu, Meina; Liang, Zhen; Wang, Yuyan; Kang, Xiaozheng; Wang, Jie

    2012-01-01

    Purpose EGFR mutation is a predictor of epidermal growth factor receptor–tyrosine kinase inhibitor treatment response in patients with non–small-cell lung cancer (NSCLC). However, it remains unclear whether chemotherapy affects EGFR mutation status in NSCLC. We investigated the influence of chemotherapy on EGFR mutations in plasma and tumor tissues from patients with NSCLC. Patients and Methods Samples were derived from three cohorts: one, 264 patients with advanced NSCLC who received first-line chemotherapy with matched pre- and postchemotherapy blood samples; two, 63 patients with stages IIb to IIIb disease with pre– and post–neoadjuvant chemotherapy tumor tissues; and three, 79 patients with advanced NSCLC who underwent palliative surgery. EGFR mutation status was determined and analyzed to reveal potential impact of chemotherapy. Results In the first cohort, EGFR mutations were detected in 34.5% of the prechemotherapy plasma samples (91 of 264) but in only 23.1% of the postchemotherapy plasma samples (61 of 264). The decrease in EGFR mutation rate was statistically significant (P < .001). Patients whose EGFR mutations switched from positive to negative after chemotherapy had a better partial response (PR) than patients with a reverse change (P = .037). A similar decrease in EGFR mutation rate was observed in tissues after neoadjuvant chemotherapy in the second cohort (34.9% [22 of 63] v 19.0% [12 of 63]; P = .013). In the third cohort, 38.0% of the tumors (30 of 79) showed an intratumor heterogeneity of EGFR mutation, whereas 62.0% (49 of 79) were homogeneous, either with EGFR mutation or no mutation. Conclusion Our results suggest that chemotherapy may reduce EGFR mutation frequency in patients with NSCLC, likely the result of a preferential response of subclones with EGFR mutations in tumors with heterogeneous tumor cell populations. PMID:22826274

  9. Mutational status of VHL gene and its clinical importance in renal clear cell carcinoma.

    PubMed

    Alves, Mariana Rezende; Carneiro, Felipe Cavalcanti; Lavorato-Rocha, André Mourão; da Costa, Walter Henriques; da Cunha, Isabela Werneck; de Cássio Zequi, Stênio; Guimaraes, Gustavo Cardoso; Soares, Fernando Augusto; Carraro, Dirce Maria; Rocha, Rafael Malagoli

    2014-09-01

    The most common subtype of renal cell carcinoma is the clear cell type (ccRCC), accounting for 75 % of cases. Inactivation of VHL gene is thought to be an early event in ccRCC carcinogenesis. Our intention was to assess whether VHL mutational status might provide useful predictive or prognostic information in patients with ccRCC. VHL messenger RNA (mRNA) expression was analyzed by in situ hybridization and its protein by immunohistochemistry on a tissue microarray containing samples from 148 cases. This was validated by qRT-PCR on 62 cases, for which RNA was available. The mutation status was assessed in 91 cases by Sanger sequencing. VHL was found mutated in 57 % of cases, with missense mutations in 26 %, nonsense in 5 %, splice site in 13 %, deletions in 39 %, indels in 8 %, duplications in 8 %, and insertions in 2 % of the cases. The prevalence of mutations by exon was the following: exon 1, 47 %; exon 2, 27 %; and exon 3, 13 %. VHL protein was expressed in a high number of cases (80 %), but significant correlations were not found between protein expression, clinical data, and survival. Importantly, of the 91 samples evaluated by sequencing, 45 were mutated, and 87 % of those were strongly positive. We found 32 novel mutations in the VHL gene in ccRCC. The presence of mutations was not concordant with mRNA or protein expression. Nonsense mutations of the VHL gene appear to be related with poorer prognosis and survival.

  10. A meta-analysis of prognostic value of KIT mutation status in gastrointestinal stromal tumors

    PubMed Central

    Jiang, Zhiqiang; Zhang, Jian; Li, Zhi; Liu, Yingjun; Wang, Daohai; Han, Guangsen

    2016-01-01

    Numerous types of KIT mutations have been reported in gastrointestinal stromal tumors (GISTs); however, controversy still exists regarding their clinicopathological significance. In this study, we reviewed the publicly available literature to assess the data by a meta-analysis to characterize KIT mutations and different types of KIT mutations in prognostic prediction in patients with GISTs. Twenty-eight studies that included 4,449 patients were identified and analyzed. We found that KIT mutation status was closely correlated with size of tumors and different mitosis indexes, but not with tumor location. KIT mutation was also observed to be significantly correlated with tumor recurrence, metastasis, as well as the overall survival of patients. Interestingly, there was higher risk of progression in KIT exon 9-mutated patients than in exon 11-mutated patients. Five-year relapse-free survival (RFS) rate was significantly higher in KIT exon 11-deleted patients than in those with other types of KIT exon 11 mutations. In addition, RFS for 5 years was significantly worse in patients bearing KIT codon 557–558 deletions than in those bearing other KIT exon 11 deletions. Our results strongly support the hypothesis that KIT mutation status is another evaluable factor for prognosis prediction in GISTs. PMID:27350754

  11. A meta-analysis of prognostic value of KIT mutation status in gastrointestinal stromal tumors.

    PubMed

    Jiang, Zhiqiang; Zhang, Jian; Li, Zhi; Liu, Yingjun; Wang, Daohai; Han, Guangsen

    2016-01-01

    Numerous types of KIT mutations have been reported in gastrointestinal stromal tumors (GISTs); however, controversy still exists regarding their clinicopathological significance. In this study, we reviewed the publicly available literature to assess the data by a meta-analysis to characterize KIT mutations and different types of KIT mutations in prognostic prediction in patients with GISTs. Twenty-eight studies that included 4,449 patients were identified and analyzed. We found that KIT mutation status was closely correlated with size of tumors and different mitosis indexes, but not with tumor location. KIT mutation was also observed to be significantly correlated with tumor recurrence, metastasis, as well as the overall survival of patients. Interestingly, there was higher risk of progression in KIT exon 9-mutated patients than in exon 11-mutated patients. Five-year relapse-free survival (RFS) rate was significantly higher in KIT exon 11-deleted patients than in those with other types of KIT exon 11 mutations. In addition, RFS for 5 years was significantly worse in patients bearing KIT codon 557-558 deletions than in those bearing other KIT exon 11 deletions. Our results strongly support the hypothesis that KIT mutation status is another evaluable factor for prognosis prediction in GISTs.

  12. Risk of breast cancer in relation to combined effects of hormone therapy, body mass index, and alcohol use, by hormone-receptor status.

    PubMed

    Hvidtfeldt, Ulla Arthur; Tjønneland, Anne; Keiding, Niels; Lange, Theis; Andersen, Ingelise; Sørensen, Thorkild I A; Prescott, Eva; Hansen, Åse Marie; Grønbæk, Morten; Bojesen, Stig Egil; Diderichsen, Finn; Rod, Naja Hulvej

    2015-05-01

    Alcohol consumption, increased body mass index (BMI), and hormone therapy are risk factors for postmenopausal breast cancer, but their combined effects are not well understood. Because hormone therapy is effective for the relief of menopausal symptoms, the identification of "high-risk" users is important for therapeutic reasons. We investigated interactions between hormone therapy use and alcohol-use/high BMI status in relation to invasive breast cancer risk, both overall and according to estrogen receptor (ER) status. Two Danish prospective cohorts were pooled, including 30,789 women ages 50+ years (study period 1981 to 2009). Information on risk factors was obtained in baseline questionnaires. We performed analyses using the Aalen additive hazards model. Serum estradiol and testosterone measurements were obtained in a subsample of approximately 1000 women. During 392,938 person-years of follow-up, 1579 women developed invasive breast cancer. Among nonusers of hormone therapy, the risk of breast cancer was slightly increased with overweight/obesity and increasing alcohol consumption. Compared with normal-weight nonusers, the risk of breast cancer was higher in hormone therapy users across all BMI strata (P for interaction = 0.003). A markedly higher risk of breast cancer was also observed for alcohol combined with hormone therapy use compared with abstinent nonusers (P for interaction = 0.02). These effects were primarily restricted to ER-positive cases. Combined effects of hormone therapy/high BMI and hormone therapy/alcohol on serum estradiol and testosterone supported the hypothesis of a hormonal pathway linking these exposures to breast cancer. These analyses suggest an increased risk of breast cancer associated with hormone therapy use-a risk that may be particularly strong among women consuming alcohol.

  13. EGFR Mutation status in Japanese lung cancer patients: genotyping analysis using LightCycler.

    PubMed

    Sasaki, Hidefumi; Endo, Katsuhiko; Konishi, Akimitsu; Takada, Minoru; Kawahara, Masaaki; Iuchi, Keiji; Matsumura, Akihide; Okumura, Meinoshin; Tanaka, Hisaichi; Kawaguchi, Tomoya; Shimizu, Toshiki; Takeuchi, Hiroshi; Yano, Motoki; Fukai, Ichiro; Fujii, Yoshitaka

    2005-04-15

    Recently, somatic mutations of the epidermal growth factor receptor (EGFR) gene were found in approximately 25% of Japanese lung cancer patients. These EGFR mutations are reported to be correlated with clinical response to gefitinib therapy. However, DNA sequencing using the PCR methods described to date is time-consuming and requires significant quantities of DNA; thus, this existing approach is not suitable for a routine pretherapeutic screening program. We have genotyped EGFR mutation status in Japanese lung cancer patients, including 102 surgically treated lung cancer cases from Nagoya City University Hospital and 16 gefitinib-treated lung cancer cases from Kinki-chuo Chest Medical Center. The presence or absence of three common EGFR mutations were analyzed by real-time quantitative PCR with mutation-specific sensor and anchor probes. In exon 21, EGFR mutations (CTG --> CGG; L858R) were found from 8 of 102 patients from Nagoya and 1 of 16 from Kinki. We also detected the deletion mutations in exon 19 from 7 of 102 patients from Nagoya (all were deletion type 1a) and 4 of 16 patients from Kinki (one was type 1a and three were type 1b). In exon 18, one example of G719S mutation was found from both Nagoya and Kinki. The L858R mutation was significantly correlated with gender (women versus men, P < 0.0001), Brinkman index (600 < or = versus 600, P = 0.001), pathologic subtypes (adenocarcinoma versus nonadenocarcinoma, P = 0.007), and differentiation status of the lung cancers (well versus moderately or poorly, P = 0.0439), whereas the deletion mutants were not. EGFR gene status, including the type of EGFR somatic mutation, was correlated with sensitivity to gefitinib therapy. For example, some of our gefitinib-responsive patients had L858R or deletion type 1a mutations. On the other hand, one of our gefitinib-resistant patients had a G719S mutation. Using the LightCycler PCR assay, the EGFR L858R mutation status might correlate with gender, pathologic subtypes, and

  14. Suppressor of cytokine signaling 1 gene mutation status as a prognostic biomarker in classical Hodgkin lymphoma.

    PubMed

    Lennerz, Jochen K; Hoffmann, Karl; Bubolz, Anna-Maria; Lessel, Davor; Welke, Claudia; Rüther, Nele; Viardot, Andreas; Möller, Peter

    2015-10-06

    Suppressor of cytokine signaling 1 (SOCS1) mutations are among the most frequent somatic mutations in classical Hodgkin lymphoma (cHL), yet their prognostic relevance in cHL is unexplored. Here, we performed laser-capture microdissection of Hodgkin/Reed-Sternberg (HRS) cells from tumor samples in a cohort of 105 cHL patients. Full-length SOCS1 gene sequencing showed mutations in 61% of all cases (n = 64/105). Affected DNA-motifs and mutation pattern suggest that many of these SOCS1 mutations are the result of aberrant somatic hypermutation and we confirmed expression of mutant alleles at the RNA level. Contingency analysis showed no significant differences of patient-characteristics with HRS-cells containing mutant vs. wild-type SOCS1. By predicted mutational consequence, mutations can be separated into those with non-truncating point mutations ('minor' n = 49/64 = 77%) and those with length alteration ('major'; n = 15/64 = 23%). Subgroups did not differ in clinicopathological characteristics; however, patients with HRS-cells that contained SOCS1 major mutations suffered from early relapse and significantly shorter overall survival (P = 0.03). The SOCS1 major status retained prognostic significance in uni-(P = 0.016) and multivariate analyses (P = 0.005). Together, our data indicate that the SOCS1 mutation type qualifies as a single-gene prognostic biomarker in cHL.

  15. Growth hormone deficiency in a dopa-responsive dystonia patient with a novel mutation of guanosine triphosphate cyclohydrolase 1 gene.

    PubMed

    Lin, Yu; Wang, Dan-Ni; Chen, Wan-Jin; Lin, Xiang; Lin, Min-Ting; Wang, Ning

    2015-05-01

    Dopa-responsive dystonia is a rare hereditary movement disorder caused by mutations in the guanosine triphosphate cyclohydrolase 1 (GCH1) gene. This disease typically manifests in dystonia, with marked diurnal fluctuation and a dramatic response to levodopa. However, growth retardation in dopa-responsive dystonia has rarely been reported, and the etiology of short stature is not clarified. Here, we report a 14-year-old patient with extremities dystonia and short stature. Treatment with levodopa relieved his symptoms and resulted in a height increase. We also investigated the mutation in GCH1 and the etiology of short stature in this case. Sequence analysis of GCH1 revealed a novel mutation (c.695G>T). Laboratory examinations and imaging confirmed the diagnosis of growth hormone deficiency. We conclude that our case reveals a rare feature for dopa-responsive dystonia and suggests a possible pathogenic link between growth hormone deficiency and dopa-responsive dystonia. We recommend levodopa as the first choice for treating dopa-responsive dystonia in children with growth hormone deficiency.

  16. The hormonal receptor status of uterine carcinosarcomas (mixed müllerian tumours): an immunohistochemical study.

    PubMed Central

    Ansink, A C; Cross, P A; Scorer, P; de Barros Lopes, A; Monaghan, J M

    1997-01-01

    AIM: To investigate the role of oestrogen and progesterone receptor status in uterine carcinosarcomas (mixed Müllerian tumours) to see whether the receptors were identifiable, and if so whether they were of significance clinically. METHODS: 11 cases of uterine carcinosarcoma were identified from clinical and pathology records. An immunohistochemical method was used to demonstrate oestrogen and progesterone hormone receptors on paraffin embedded material, with suitable tissue controls, staining being recorded. RESULTS: 10 of 11 cases showed staining for one or both hormone receptors in normal tissue adjacent to tumour. In four carcinosarcoma cases, staining for one or both receptors was shown within the epithelial component (appearing to correlate with the degree of epithelial differentiation); two of these cases had staining within sarcomatous areas. Two of the three patients still alive had epithelial hormone receptor positivity. CONCLUSIONS: Receptors for oestrogen and progesterone were found in four of 11 cases of uterine carcinosarcoma, using paraffin embedded material. There may be an association between hormone receptor positivity and clinical outcome. Images PMID:9215151

  17. Expression of neuropeptide W in rat stomach mucosa: regulation by nutritional status, glucocorticoids and thyroid hormones.

    PubMed

    Caminos, Jorge E; Bravo, Susana B; García-Rendueles, María E R; Ruth González, C; Garcés, Maria F; Cepeda, Libia A; Lage, Ricardo; Suárez, Miguel A; López, Miguel; Diéguez, Carlos

    2008-02-07

    Neuropeptide W (NPW) is a recently identified neuropeptide that binds to G-protein-coupled receptor 7 (GPR7) and 8 (GPR8). In rodent brain, NPW mRNA is confined to specific nuclei in hypothalamus, midbrain and brainstem. Expression of NPW mRNA has also been confirmed in peripheral organs such as stomach. Several reports suggested that brain NPW is implicated in the regulation of energy and hormonal homeostasis, namely the adrenal and thyroid axes; however the precise physiological role and regulation of peripheral NPW remains unclear. In this study, we examined the effects of nutritional status on the regulation of NPW in stomach mucosa. Our results show that in this tissue, NPW mRNA and protein expression is negatively regulated by fasting and food restriction, in all the models we studied: males, females and pregnant females. Next, we examined the effect of glucocorticoids and thyroid hormones on NPW mRNA expression in the stomach mucosa. Our data showed that NPW expression is decreased in this tissue after glucocorticoid treatment or hyperthyroidism. Conversely, hypothyroidism induces a marked increase in the expression of NPW in rat stomach. Overall, these data indicate that stomach NPW is regulated by nutritional and hormonal status.

  18. Clinical features and growth hormone receptor gene mutations of patients with Laron syndrome from a Chinese family.

    PubMed

    Ying, Yan-Qin; Wei, Hong; Cao, Li-Zhi; Lu, Juan-Juan; Luo, Xiao-Ping

    2007-08-01

    Laron syndrome is an autosomal recessive disorder caused by defects of growth hormone receptor (GHR) gene. It is characterized by severe postnatal growth retardation and characteristic facial features as well as high circulating levels of growth hormone (GH) and low levels of insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3). This report described the clinical features and GHR gene mutations in 2 siblings with Laron syndrome in a Chinese family. Their heights and weights were in the normal range at birth, but the growth was retarded after birth. When they presented to the clinic, the heights of the boy (8 years old) and his sister (11 years old) were 80.0 cm (-8.2 SDS) and 96.6 cm (-6.8 SDS) respectively. They had typical appearance features of Laron syndrome such as short stature and obesity, with protruding forehead, saddle nose, large eyes, sparse and thin silky hair and high-pitched voice. They had higher basal serum GH levels and lower serum levels of IGF-I, IGFBP-3 and growth hormone binding protein (GHBP) than normal controls. The peak serum GH level after colonidine and insulin stimulations in the boy was over 350 ng/mL. After one-year rhGH treatment, the boy's height increased from 80.0 cm to 83.3 cm. The gene mutation analysis revealed that two patients had same homozygous mutation of S65H (TCA -->CCA) in exon 4, which is a novel gene mutation. It was concluded that a definite diagnosis of Laron syndrome can be made based on characteristic appearance features and serum levels of GH, IGF-I, IGFBP-3 and GHBP. The S65H mutation might be the cause of Laron syndrome in the two patients.

  19. Oestrogen receptor status, treatment and breast cancer prognosis in Icelandic BRCA2 mutation carriers.

    PubMed

    Jonasson, Jon G; Stefansson, Olafur A; Johannsson, Oskar T; Sigurdsson, Helgi; Agnarsson, Bjarni A; Olafsdottir, Gudridur H; Alexiusdottir, Kristin K; Stefansdottir, Hrefna; Munoz Mitev, Rodrigo; Olafsdottir, Katrin; Olafsdottir, Kristrun; Arason, Adalgeir; Stefansdottir, Vigdis; Olafsdottir, Elinborg J; Barkardottir, Rosa B; Eyfjord, Jorunn E; Narod, Steven A; Tryggvadóttir, Laufey

    2016-09-27

    The impact of an inherited BRCA2 mutation on the prognosis of women with breast cancer has not been well documented. We studied the effects of oestrogen receptor (ER) status, other prognostic factors and treatments on survival in a large cohort of BRCA2 mutation carriers. We identified 285 breast cancer patients with a 999del5 BRCA2 mutation and matched them with 570 non-carrier patients. Clinical information was abstracted from patient charts and pathology records and supplemented by evaluation of tumour grade and ER status using archived tissue specimens. Univariate and multivariate hazard ratios (HR) were estimated for breast cancer-specific survival using Cox regression. The effects of various therapies were studied in patients treated from 1980 to 2012. Among mutation carriers, positive ER status was associated with higher risk of death than negative ER status (HR=1.94; 95% CI=1.22-3.07, P=0.005). The reverse association was seen for non-carriers (HR=0.71; 95% CI: 0.51-0.97; P=0.03). Among BRCA2 carriers, ER-positive status is an adverse prognostic factor. BRCA2 carrier status should be known at the time when treatment decisions are made.

  20. TERT Promoter Mutation Status as an Independent Prognostic Factor in Cutaneous Melanoma

    PubMed Central

    Murali, Rajmohan; Puig-Butille, Joan Anton; Schilling, Bastian; Livingstone, Elisabeth; Potrony, Miriam; Carrera, Cristina; Schimming, Tobias; Möller, Inga; Schwamborn, Marion; Sucker, Antje; Hillen, Uwe; Badenas, Celia; Malvehy, Josep; Zimmer, Lisa; Scherag, André; Puig, Susana

    2014-01-01

    Background Recently, TERT promoter mutations were identified at high frequencies in cutaneous melanoma tumor samples and cell lines. The mutations were found to have a UV-signature and to lead to increased TERT gene expression. We analyzed a large cohort of melanoma patients for the presence and distribution of TERT promoter mutations and their association with clinico-pathological characteristics. Methods 410 melanoma tumor samples were analyzed by Sanger sequencing for the presence of TERT promoter mutations. An analysis of associations between mutation status and various clinical and pathologic variables was performed. Results TERT promoter mutations were identified in 154 (43%) of 362 successfully sequenced melanomas. Mutation frequencies varied between melanoma subtype, being most frequent in melanomas arising in nonacral skin (48%) and melanomas with occult primary (50%), and less frequent in mucosal (23%), and acral (19%) melanomas. Mutations carried a UV signature (C>T or CC>TT). The presence of TERT promoter mutations was associated with factors such as BRAF or NRAS mutation (P < .001), histologic type (P = .002), and Breslow thickness (P < .001). TERT promoter mutation was independently associated with poorer overall survival in patients with nonacral cutaneous melanomas (median survival 80 months vs 291 months for wild-type; hazard ratio corrected for other covariates 2.47; 95% confidence interval [CI] = 1.29 to 4.74; P = .006). Conclusions UV-induced TERT promoter mutations are one of the most frequent genetic alterations in melanoma, with frequencies varying depending on melanoma subtype. In nonacral cutaneous melanomas, presence of TERT promoter mutations is independently associated with poor prognosis. PMID:25217772

  1. TERT promoter mutation status as an independent prognostic factor in cutaneous melanoma.

    PubMed

    Griewank, Klaus G; Murali, Rajmohan; Puig-Butille, Joan Anton; Schilling, Bastian; Livingstone, Elisabeth; Potrony, Miriam; Carrera, Cristina; Schimming, Tobias; Möller, Inga; Schwamborn, Marion; Sucker, Antje; Hillen, Uwe; Badenas, Celia; Malvehy, Josep; Zimmer, Lisa; Scherag, André; Puig, Susana; Schadendorf, Dirk

    2014-09-01

    Recently, TERT promoter mutations were identified at high frequencies in cutaneous melanoma tumor samples and cell lines. The mutations were found to have a UV-signature and to lead to increased TERT gene expression. We analyzed a large cohort of melanoma patients for the presence and distribution of TERT promoter mutations and their association with clinico-pathological characteristics. 410 melanoma tumor samples were analyzed by Sanger sequencing for the presence of TERT promoter mutations. An analysis of associations between mutation status and various clinical and pathologic variables was performed. TERT promoter mutations were identified in 154 (43%) of 362 successfully sequenced melanomas. Mutation frequencies varied between melanoma subtype, being most frequent in melanomas arising in nonacral skin (48%) and melanomas with occult primary (50%), and less frequent in mucosal (23%), and acral (19%) melanomas. Mutations carried a UV signature (C>T or CC>TT). The presence of TERT promoter mutations was associated with factors such as BRAF or NRAS mutation (P < .001), histologic type (P = .002), and Breslow thickness (P < .001). TERT promoter mutation was independently associated with poorer overall survival in patients with nonacral cutaneous melanomas (median survival 80 months vs 291 months for wild-type; hazard ratio corrected for other covariates 2.47; 95% confidence interval [CI] = 1.29 to 4.74; P = .006). UV-induced TERT promoter mutations are one of the most frequent genetic alterations in melanoma, with frequencies varying depending on melanoma subtype. In nonacral cutaneous melanomas, presence of TERT promoter mutations is independently associated with poor prognosis. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  2. LC-MS/MS based determination of basal- and ACTH-stimulated plasma concentrations of 11 steroid hormones: implications for detecting heterozygote CYP21A2 mutation carriers.

    PubMed

    Kulle, A E; Riepe, F G; Hedderich, J; Sippell, W G; Schmitz, J; Niermeyer, L; Holterhus, P M

    2015-10-01

    Heterozygosity in 21-hydroxylase deficiency (21OHD) has been associated with hyperandrogenemic symptoms in children and adults. Moreover, the carrier status is mandatory for genetic counseling. We aimed at defining a hormonal parameter for carrier detection by mass spectrometry. Eleven basal and ACTH-stimulated steroid hormones of heterozygous carriers of CYP21A2 mutations and control individuals were compared. Hormones were determined in plasma samples by liquid chromatography tandem mass spectrometry (LC-MS/MS) in 58 carriers (35 males, 23 females, age range 6-78 years) and 44 random controls (25 males, 19 females, age range 8-58 years). Heterozygotes could be identified best applying the 17-hydroxyprogesterone+21-deoxycortisol/cortisol×1000 ((17OHP+21S)/F×1000) equation 30  min after ACTH injection. An optimal cut-off value of 8.4 provided 89% sensitivity and specificity. Considering this data and a published frequency of heterozygotes of 1/50 to 1/61, the positive predictive value (PPV) of this cut-off is 12%. Of note, the negative predictive value (NPV) excluding heterozygosity in a given patient is 99.8%. Considering only marginal biochemical effects anticipated from heterozygosity, the stimulated ((17OHP+21S)/F×1000) identifies and excludes heterozygotes remarkably well. Nevertheless, LC-MS/MS cannot replace genetic testing, since sensitivity and specificity did not reach 100%. However, due to the considerably high NPV of the optimal cut-off and to a specificity of even 100% applying a cut-off higher than 14.7, hormonal assessment of heterozygosity can be of significant aid in conditions with limited access to genetic testing, as in some health care systems. The ((17OHP+21S)/F×1000) equation can guide diagnostic considerations in the differential diagnosis of hyperandrogenism. © 2015 European Society of Endocrinology.

  3. Screening of nineteen unrelated families with generalized resistance to thyroid hormone for known point mutations in the thyroid hormone receptor beta gene and the detection of a new mutation.

    PubMed Central

    Takeda, K; Balzano, S; Sakurai, A; DeGroot, L J; Refetoff, S

    1991-01-01

    Generalized resistance to thyroid hormone (GRTH) is a syndrome characterized by impaired tissue responsiveness to thyroid hormone. Two distinct point mutations in the hormone binding domain of the thyroid hormone receptor (TR) beta have recently been identified in two unrelated families with GRTH. One, Mf, involves a replacement of the normal glycine-345 for arginine in exon 7 and another, Mh, replaces the normal proline-453 for histidine in exon 8. To probe for the presence of the Mf and Mh defect in 19 unrelated families with GRTH, we applied separate polymerase chain reactions using allele-specific oligonucleotide primers containing the normal and each of the two mutant nucleotides at the 3'-position. A total of 24 affected subjects and 13 normal family members were studied. The mode of inheritance was dominant in 13 families, was unknown in 5 families, and was clearly recessive in 1 family in which only the consanguineous subjects were affected. Primers containing the substitutions specific for Mf and Mh amplified exons 7 and 8, respectively, only in affected members of each of the two index families. Primers containing the normal sequences amplified exons 7 and 8 of the TR beta gene in all subjects except affected members of one family. In this family with recessively inherited GRTH, neither exon could be amplified using any combinations of primers and DNA blot revealed absence of all coding exons. These results indicate a major deletion of the TR beta gene, including both DNA and hormone binding domains. Since heterozygous members of this family are not affected, the presence of a single normal allele is sufficient for normal function of the TR beta. These data also support the hypothesis that in the dominant mode of GRTH inheritance the presence of an abnormal TR beta interferes with the function of the normal TR beta. Distinct mutations are probably responsible for GRTH in unrelated families. Images PMID:1991834

  4. Circulating thyroxine, thyroid-stimulating hormone, and hypothyroid status and the risk of prostate cancer.

    PubMed

    Mondul, Alison M; Weinstein, Stephanie J; Bosworth, Tracey; Remaley, Alan T; Virtamo, Jarmo; Albanes, Demetrius

    2012-01-01

    Thyroid hormones may influence risk of cancer through their role in cell differentiation, growth, and metabolism. One study of circulating thyroid hormones supports this hypothesis with respect to prostate cancer. We undertook a prospective analysis of thyroid hormones and prostate cancer risk in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Within the ATBC Study, a randomized controlled trial of α-tocopherol and β-carotene supplements and cancer incidence in male smokers, 402 prostate cancer cases were sampled. Controls were matched 2:1 to cases on age and date of blood collection. Odds ratios (OR) and 95% confidence intervals (CI) of prostate cancer were estimated for quintiles of serum total and free thyroxine (T4), thyroid-stimulating hormone (TSH), thyroid-binding globulin (TBG), and by categories of thyroid status. Men with serum higher TSH had a decreased risk of prostate cancer compared to men with lower TSH (Q5 vs. Q1-4: OR = 0.70, 95% CI: 0.51-0.97, p = 0.03). When the T4 and TSH measurements were combined to define men as hypothyroid, euthyroid or hyperthyroid, hypothyroid men had a lower risk of prostate cancer compared to euthyroid men (OR = 0.48, 95% CI = 0.28-0.81, p = 0.006). We observed no association between hyperthyroid status and risk, although the number of hyperthyroid men with prostate cancer was small (n = 9). In this prospective study of smokers, men with elevated TSH and those classified as being in a hypothyroid state were at decreased risk of prostate cancer. Future studies should examine the association in other populations, particularly non-smokers and other racial/ethnic groups.

  5. [Association between obstetric factors, hormone levels and nutritional status with the development of breast cancer].

    PubMed

    González-Jiménez, Emilio; Montero-Alonso, Miguel Ángel; Schmidt Riovalle, Jacqueline

    2013-12-01

    Recent studies suggest that the age at first pregnancy, number of children and the lapse between births may protect against breast cancer. Furthermore, serum levels of estrogen, prolactin and progesterone appear to contribute to the development of this tumors in obese women. To verify whether the variables age at first pregnancy, number of children, birth interval, hormone levels and nutritional status are associated with the age at diagnosis of breast cancer. Retrospective analysis of medical records of 550 female patients, diagnosed and treated for breast cancer at a hospital in Spain between 2009 and 2012. We found a significant and positive association between age at diagnosis of cancer and the variables age at first pregnancy, parity and interval between pregnancies. There was also a significant correlation (p < 0.000) between serum levels of estrogen, prolactin and progesterone and nutritional status of patients. In this sample, age at first pregnancy or number of children, hormone levels and nutritional status are related to the age of onset of cancer.

  6. How type of parturition and health status influence hormonal and metabolic profiles in newborn foals.

    PubMed

    Panzani, S; Comin, A; Galeati, G; Romano, G; Villani, M; Faustini, M; Veronesi, M C

    2012-04-01

    Thyroid hormones, insulin growth factor I (IGF-I) and non-esterified fatty acids (NEFA) represent important hormonal and metabolic factors associated with perinatal growth and maturation. Their action could be influenced by the type of parturition and the health status of the foal and therefore the aim of this work is to evaluate their plasma concentrations in newborn foals during the first 2 wks of life. Three groups of subjects were enrolled: 15 healthy foals born by spontaneous parturition, 24 healthy foals born by induced parturition and 26 pathologic foals. From each of the healthy foals, blood was collected at 10, 20 and 30 minutes, 3 and 12 hours from birth, daily from Day 1 to Day 7, and at Day 10 and 14 of life. In pathologic foals samples were collected twice a day from the day of admission at the hospital until the day of discharge or death. Thyroid hormones (T3 and T4) and IGF-I were analyzed by radioimmunoassay and NEFA by enzymatic-colorimetric methods. In all the three groups a declining trend of T3 and T4 plasma concentrations was detectable, with lower levels in the pathologic group compared to healthy foals. Spontaneous foals showed higher levels of T3 at 7 d compared to induced foals, while T4 levels were higher in spontaneous vs. induced foals before 6 h of life, at three and seven days. IGF-I showed increasing plasma concentrations in all three considered groups. No differences were found between healthy and pathologic foals. NEFA in spontaneous and induced healthy foals showed a declining trend with higher levels during the first hours of life. Pathologic foals presented higher levels compared to spontaneous foals only at 24 h and 10 d. These data suggest that the type of foaling could influence the reference ranges for thyroid hormones. Moreover, pathologic foals showed some hormonal and metabolic differences related to their health status. Above all changes of thyroid hormones levels, early in postnatal life, could be a cause, and not only a

  7. Survival of Patients with Cystic Fibrosis Depending on Mutation Type and Nutritional Status.

    PubMed

    Szwed, A; John, A; Goździk-Spychalska, J; Czaiński, W; Czerniak, W; Ratajczak, J; Batura-Gabryel, H

    2017-07-19

    The purpose of the study was to evaluate the influence of nutrition and of the severity of mutation type on survival rate in cystic fibrosis (CF) patients. Data were longitudinally collected from 60 hospitalized adult CF patients, aged 18-50. The variables consisted of body mass index (BMI) ratio, Cole's BMI cut-off points, severity of mutation type, and survival rate of CF patients. We found that the mean BMI was strongly associated with the severity of mutation type and was significantly lower in patients with severe mutations of grade I and II. The mutation type significantly affected the patients' survival rate; survival was greater in patients with mild and undefined mutation types. The BMI and Cole's cut-off points also had a significant influence on survival rate. CF patients, who suffered from malnutrition and emaciation, had a shorter survival rate than those with proper nutritional status. In conclusion, the study findings confirmed a significant effect of nutritional status and of mutation type on survival rate of CF patients.

  8. Influence of Hormone Receptor Status on Spinal Metastatic Lesions in Patients with Breast Cancer.

    PubMed

    Lin, Jenny; Goldstein, Leanne; Nesbit, Amanda; Chen, Mike Y

    2016-01-01

    Bony metastasis predominantly affects the spinal column and has been commonly associated in patients with breast cancer. There are two types of lesions that can occur with spine cancer-osteolytic or osteoblastic. Some patients may have mixed lesions, which include lytic and blastic in one vertebra or lytic and blastic in different vertebrae. Previous studies have shown that patients with breast cancer have an increased likelihood for development of lytic spinal metastases. A retrospective chart review was conducted to more closely examine the association between hormone receptor status and spinal lesion type. A total of 195 patients were initially identified through the City of Hope Cancer Registry. Of the 195, only 153 patients had hormone receptor marker status available. Associations between spinal lesion and hormone receptor status were evaluated using χ(2) tests with alpha = 0.05 significance level. In a secondary analysis, the Oncomine Platform was used, which integrated The Cancer Genome Atlas (TCGA) datasets, to identify osteogenic genes that may be relevant to invasive breast cancers. Contrary to previous studies, our findings revealed progesterone receptor positive (PR+) patients were significantly more likely to present with blastic than lytic or mixed lesions. Furthermore, using TCGA analysis, COL1A1 and COL1A2 were found to be up-regulated, which could provide a molecular explanation for the development of blastic metastases. By integrating clinical and bioinformatic techniques, this study provides a novel discovery of the relationship between blastic and PR + breast cancers, which may have important implications for diagnostic strategies concerning vertebral metastases. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Low intelligence but not attention deficit hyperactivity disorder is associated with resistance to thyroid hormone caused by mutation R316H in the thyroid hormone receptor {beta} gene

    SciTech Connect

    Weiss, R.E.; Stein, M.A.; Chyna, B.; Phillips, W.; O`Brien, T.; Gutermuth, L.; Refetoff, S.; Duck, S.C.

    1994-06-01

    Resistance to thyroid hormone (RTH) is a syndrome of reduced responsiveness of tissues to thyroid hormone. The clinical manifestations are variable and 46-50% of children with RTH have attention deficit hyperactivity disorder (ADD). The authors present a new family with RTH (F120) found to have a mutation R316H in the thyroid hormone receptor {beta} (TR{beta}) gene identical for that reported in an unrelated family. Assignment of the mutant allele and haplotyping based on CA repeat polymorphism were done on 16 family members. Semistructured diagnostic interviews and psychometric testing were used to determine the psychiatric diagnosis of 12 family members by examiners blinded to the genotype. Three subjects were identified to have the R316H allele as well as mildly elevated free T{sub 4} index (168 {+-} 12; normal range 77-135) and nonsuppressed TSH (4.1 {+-} 1.7 mU/L). Only 2 of the subjects with RTH were found to have ADD, while one family member homozygous for the wild type TR{beta} and normal thyroid function tests also had ADD. Unaffected family members had higher full scale intelligence quotients ({vert_bar}Q) (93 {+-} 7) than any of the 3 family members with RTH (77 {+-} 5, p = 0.006). These data do not support the genetic linkage of ADD and RTH, but do suggest that RTH is associated with lower IQ scores that may confer a high likelihood of exhibiting ADD symptoms. 20 refs., 2 figs., 2 tabs.

  10. Restraint effects on stress-related hormones and blood natural killer cell cytotoxicity in pigs with a mutated ryanodine receptor.

    PubMed

    Ciepielewski, Z M; Stojek, W; Glac, W; Wrona, D

    2013-05-01

    A mutation in the ryanodine receptor gene (RYR1) of the calcium release channel is responsible for increased stress susceptibility in pigs. In the present study, the relation of a mutation in RYR1 with the neuroendocrine (stress-related hormone) response and the immune defense represented by natural killer cell cytotoxicity (NKCC) during a 4-h restraint and recovery phase in 60 male pigs was investigated. Blood samples were collected from pigs previously divided into RYR1 genotypes (nn, Nn, NN), based on PCR amplification and restriction analyses. The blood samples collected during the restraint and recovery phases of the experiment were used to determine NKCC ((51)Cr-release assay), large granular lymphocyte number (hematologic method), and plasma concentrations of prolactin (PRL), GH, ACTH, and cortisol (COR) (by specific RIA). The greatest degree of NKCC response (P < 0.05) to restraint stress relative to controls was observed for the stress-susceptible homozygote group (nn). Measures of stress-related hormones were positively correlated with NKCC during the entire experimental period (P < 0.001 for all investigated hormones) in the nn group. Immunostimulatory effects in the early (0-60 min) phase of restraint were associated with increased hormone responses, especially PRL and GH. In the late (180-240 min) phase of stress and the recovery phase (480 min), a decrease in immune response was accompanied by an elevated COR response in all RYR1 genotypes. Moreover, divergent responses of both PRL (greatest in nn, P < 0.001) and GH (greatest in NN, P < 0.001) to the 4-h restraint were observed. Our results suggest that stress-susceptible RYR1-mutated homozygotes develop a greater level of immune defense, including cytotoxic activity of NK cells, and accompanied by more pronounced stress-induced changes in neuroendocrine response than stress-resistant heterozygous (Nn) and homozygous (NN) pigs.

  11. Endometrial tumour BRAF mutations and MLH1 promoter methylation as predictors of germline mismatch repair gene mutation status: a literature review.

    PubMed

    Metcalf, Alexander M; Spurdle, Amanda B

    2014-03-01

    Colorectal cancer (CRC) that displays high microsatellite instability (MSI-H) can be caused by either germline mutations in mismatch repair (MMR) genes, or non-inherited transcriptional silencing of the MLH1 promoter. A correlation between MLH1 promoter methylation, specifically the 'C' region, and BRAF V600E status has been reported in CRC studies. Germline MMR mutations also greatly increase risk of endometrial cancer (EC), but no systematic review has been undertaken to determine if these tumour markers may be useful predictors of MMR mutation status in EC patients. Endometrial cancer cohorts meeting review inclusion criteria encompassed 2675 tumours from 20 studies for BRAF V600E, and 447 tumours from 11 studies for MLH1 methylation testing. BRAF V600E mutations were reported in 4/2675 (0.1%) endometrial tumours of unknown MMR mutation status, and there were 7/823 (0.9%) total sequence variants in exon 11 and 27/1012 (2.7%) in exon 15. Promoter MLH1 methylation was not observed in tumours from 32 MLH1 mutation carriers, or for 13 MSH2 or MSH6 mutation carriers. MMR mutation-negative individuals with tumour MLH1 and PMS2 IHC loss displayed MLH1 methylation in 48/51 (94%) of tumours. We have also detailed specific examples that show the importance of MLH1 promoter region, assay design, and quantification of methylation. This review shows that BRAF mutations occurs so infrequently in endometrial tumours they can be discounted as a useful marker for predicting MMR-negative mutation status, and further studies of endometrial cohorts with known MMR mutation status are necessary to quantify the utility of tumour MLH1 promoter methylation as a marker of negative germline MMR mutation status in EC patients.

  12. Infertility in Female Mice with a Gain-of-Function Mutation in the Luteinizing Hormone Receptor Is Due to Irregular Estrous Cyclicity, Anovulation, Hormonal Alterations, and Polycystic Ovaries.

    PubMed

    Hai, Lan; McGee, Stacey R; Rabideau, Amanda C; Paquet, Marilène; Narayan, Prema

    2015-07-01

    The luteinizing hormone receptor, LHCGR, is essential for fertility in males and females, and genetic mutations in the receptor have been identified that result in developmental and reproductive defects. We have previously generated and characterized a mouse model (KiLHR(D582G)) for familial male-limited precocious puberty caused by an activating mutation in the receptor. We demonstrated that the phenotype of the KiLHR(D582G) male mice is an accurate phenocopy of male patients with activating LHCGR mutations. In this study, we observed that unlike women with activating LHCGR mutations who are normal, female KiLHR(D582G) mice are infertile. Mice exhibit irregular estrous cyclicity, anovulation, and precocious puberty. A temporal study from 2-24 wk of age indicated elevated levels of progesterone, androstenedione, testosterone, and estradiol and upregulation of several steroidogenic enzyme genes. Ovaries of KiLHR(D582G) mice exhibited significant pathology with the development of large hemorrhagic cysts as early as 3 wk of age, extensive stromal cell hyperplasia and hypertrophy with luteinization, numerous atretic follicles, and granulosa cell tumors. Ovulation could not be rescued by the addition of exogenous gonadotropins. The body weights of the KiLHR(D582G) mice were higher than wild-type counterparts, but there was no increase in the body fat composition or metabolic abnormalities such as impaired glucose tolerance and insulin resistance. These studies demonstrate that activating LHCGR mutations do not produce the same phenotype in female mice as in humans and clearly illustrate species differences in the expression and regulation of LHCGR in the ovary, but not in the testis. © 2015 by the Society for the Study of Reproduction, Inc.

  13. The prognostic value of IDH mutations and MGMT promoter status in secondary high-grade gliomas.

    PubMed

    Juratli, T A; Kirsch, M; Geiger, K; Klink, B; Leipnitz, E; Pinzer, T; Soucek, S; Schrock, E; Schrok, E; Schackert, G; Krex, D

    2012-12-01

    Reports about the prognostic value of IDH mutations and the promoter region of the O6-Methyl-guanyl-methyl-transferase gene in secondary high-grade gliomas (sHGG) are few in number. We investigated the prognostic value of IDH mutations and methylation of the promoter region of the MGMT gene in 99 patients with sHGG and analyzed the clinical course of those tumors. Patients with sHGG were screened for IDH mutations by direct sequencing, and, for promoter status of MGMT gene, by the methylation-specific polymerase chain reaction. A total of 48 of 99 patients (48.5 %) had secondary anaplastic gliomas (Group 1), while 51 patients had secondary glioblastomas (Group 2). The median survival time after malignant progression of all patients with sHGG and with an IDH mutation was 4 years, which is significantly longer than in patients with wild-type IDH (1.2 years, p = 0.009). Patients' survival was not significantly influenced by the tumors' MGMT promoter status, both in Group 1- 9.7 years vs. 6.1 years, methylated vs. unmethylated promoter (p = 0.330)-as well as in Group 2-1.5 years vs. 1.6 years, methylated versus unmethylated promoter (p = 0.829). In our population, the IDH mutation status was not associated with increased PFS or median survival time in sGBM patients. However, patients with secondary anaplastic glioma and IDH mutation had a significantly improved outcome. In addition, IDH mutations are a more powerful prognostic marker concerning both PFS and MS than the MGMT promoter status in those patients.

  14. Impact of IDH1 mutation status on outcome in clinical trials for recurrent glioblastoma.

    PubMed

    Mandel, Jacob J; Cachia, David; Liu, Diane; Wilson, Charmaine; Aldape, Ken; Fuller, Greg; de Groot, John F

    2016-08-01

    IDH1 mutated glioblastoma (GB) has a better prognosis than IDH1 wildtype GB. However, it remains unknown whether patients (pts) with IDH1 mutated GB have a higher 6-month progression free survival (PFS6) or radiographic response (RR) rate on clinical trials for recurrence. Retrospective review of GB pts at MDACC between 2006 and 2012 identified 330 patients in recurrent GB trials. 93 patients (28 %) had either PFS6 or a complete/partial RR per RANO criteria. 49/93 (53 %) patients with PFS6 or a complete/partial RR had tumor tissue for IDH1 testing. A matched cohort of 49 patients on recurrent GB clinical trials that failed to achieve PFS6 or RR (also with tissue for IDH1 testing) was identified for comparison. IDH1 status was obtained in 92/98 (94 %) patients of which 17 (18 %) had an IDH1 mutation. PFS6 was seen in 26/49 (53 %) patients. IDH status was unknown in two of these patients. 5/24 (21 %) were IDH1 mutated compared to 5/24 (21 %) of their matched cohort without PFS6. RR was found in 47/49 (94 %) patients. IDH status was unknown in four of these patients. IDH1 mutation was present in 7/43 (16 %) patients with RR compared to 10/43 (23 %) in the matched cohort without RR (p = 0.48). Median OS for trials at first recurrence was 9.8 months for IDH1 wildtype GB vs. 19.32 months for IDH1 mutated GB (p = 0.14). IDH1 mutation status was not predictive of PFS6 or RR in recurrent GB trials for this data set. However, further examination in larger randomized prospective studies is needed.

  15. Mutational status predicts the risk of thromboembolic events in lung adenocarcinoma.

    PubMed

    Davidsson, Elsa; Murgia, Nicola; Ortiz-Villalón, Cristian; Wiklundh, Emil; Sköld, Magnus; Kölbeck, Karl Gustav; Ferrara, Giovanni

    2017-01-01

    Precision medicine promises to improve prognosis of patients affected by untreatable diseases. Patients with lung cancer (especially lung adenocarcinoma) bear an increased risk of VTE. Mutations in the EGFR and rearrangement in the ALK genes identify specific subgroups of patients. Aim of this study was to investigate the role of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutational status on the risk of venous thromboembolism (VTE) in lung adenocarcinoma. A retrospective longitudinal design was used. Patients with lung adenocarcinoma diagnosed and undergoing a mutational analysis at the Karolinska University Hospital, Stockholm, Sweden between January 2009 and September 2015 were divided in three subgroups based on their mutational status (EGFR-, ALK-mutated, unexposed group). Event-free time for VTE was assessed using Cox regression analysis based on mutation status and treatment received. Three hundred-ten patients were included. A VTE occurred in 70 (22.6%) patients. Mutation of EGFR was associated with a decreased risk of VTE (HR 0.46, 95% CI 0.23-0.94). Treatment with tyrosine kinase inhibitors (TKI) reduced the risk of VTE compared to other treatment strategies not including TKI (HR 0.42, 95% CI 0.29-0.79). Our study suggests that patients with lung adenocarcinoma bearing a EGFR-mutation have a decreased risk of VTE compared with patients with other forms of lung adenocarcinoma. Targeted therapy with TKI alone or in combination with other treatments seems to reduce the risk of VTE compared to other treatments not including TKI.

  16. An accurate, simple prognostic model consisting of age, JAK2, CALR, and MPL mutation status for patients with primary myelofibrosis.

    PubMed

    Rozovski, Uri; Verstovsek, Srdan; Manshouri, Taghi; Dembitz, Vilma; Bozinovic, Ksenija; Newberry, Kate; Zhang, Ying; Bove, Joseph E; Pierce, Sherry; Kantarjian, Hagop; Estrov, Zeev

    2017-01-01

    In most patients with primary myelofibrosis, one of three mutually exclusive somatic mutations is detected. In approximately 60% of patients, the Janus kinase 2 gene is mutated, in 20%, the calreticulin gene is mutated, and in 5%, the myeloproliferative leukemia virus gene is mutated. Although patients with mutated calreticulin or myeloproliferative leukemia genes have a favorable outcome, and those with none of these mutations have an unfavorable outcome, prognostication based on mutation status is challenging due to the heterogeneous survival of patients with mutated Janus kinase 2. To develop a prognostic model based on mutation status, we screened primary myelofibrosis patients seen at the MD Anderson Cancer Center, Houston, USA, between 2000 and 2013 for the presence of Janus kinase 2, calreticulin, and myeloproliferative leukemia mutations. Of 344 primary myelofibrosis patients, Janus kinase 2(V617F) was detected in 226 (66%), calreticulin mutation in 43 (12%), and myeloproliferative leukemia mutation in 16 (5%); 59 patients (17%) were triple-negatives. A 50% cut-off dichotomized Janus kinase 2-mutated patients into those with high Janus kinase 2(V617F) allele burden and favorable survival and those with low Janus kinase 2(V617F) allele burden and unfavorable survival. Patients with a favorable mutation status (high Janus kinase 2(V617F) allele burden/myeloproliferative leukemia/calreticulin mutation) and aged 65 years or under had a median survival of 126 months. Patients with one risk factor (low Janus kinase 2(V617F) allele burden/triple-negative or age >65 years) had an intermediate survival duration, and patients aged over 65 years with an adverse mutation status (low Janus kinase 2(V617F) allele burden or triple-negative) had a median survival of only 35 months. Our simple and easily applied age- and mutation status-based scoring system accurately predicted the survival of patients with primary myelofibrosis. Copyright© Ferrata Storti Foundation.

  17. An accurate, simple prognostic model consisting of age, JAK2, CALR, and MPL mutation status for patients with primary myelofibrosis

    PubMed Central

    Rozovski, Uri; Verstovsek, Srdan; Manshouri, Taghi; Dembitz, Vilma; Bozinovic, Ksenija; Newberry, Kate; Zhang, Ying; Bove, Joseph E.; Pierce, Sherry; Kantarjian, Hagop; Estrov, Zeev

    2017-01-01

    In most patients with primary myelofibrosis, one of three mutually exclusive somatic mutations is detected. In approximately 60% of patients, the Janus kinase 2 gene is mutated, in 20%, the calreticulin gene is mutated, and in 5%, the myeloproliferative leukemia virus gene is mutated. Although patients with mutated calreticulin or myeloproliferative leukemia genes have a favorable outcome, and those with none of these mutations have an unfavorable outcome, prognostication based on mutation status is challenging due to the heterogeneous survival of patients with mutated Janus kinase 2. To develop a prognostic model based on mutation status, we screened primary myelofibrosis patients seen at the MD Anderson Cancer Center, Houston, USA, between 2000 and 2013 for the presence of Janus kinase 2, calreticulin, and myeloproliferative leukemia mutations. Of 344 primary myelofibrosis patients, Janus kinase 2V617F was detected in 226 (66%), calreticulin mutation in 43 (12%), and myeloproliferative leukemia mutation in 16 (5%); 59 patients (17%) were triple-negatives. A 50% cut-off dichotomized Janus kinase 2-mutated patients into those with high Janus kinase 2V617F allele burden and favorable survival and those with low Janus kinase 2V617F allele burden and unfavorable survival. Patients with a favorable mutation status (high Janus kinase 2V617F allele burden/myeloproliferative leukemia/calreticulin mutation) and aged 65 years or under had a median survival of 126 months. Patients with one risk factor (low Janus kinase 2V617F allele burden/triple-negative or age >65 years) had an intermediate survival duration, and patients aged over 65 years with an adverse mutation status (low Janus kinase 2V617F allele burden or triple-negative) had a median survival of only 35 months. Our simple and easily applied age- and mutation status-based scoring system accurately predicted the survival of patients with primary myelofibrosis. PMID:27686378

  18. Deiodination as an index of chemical disruption of thyroid hormone homeostasis and thyroidal status in fish

    SciTech Connect

    Eales, J.G.; Brown, S.B.; Cyr, D.G.; Adams, B.A.; Finnson, K.R.

    1999-07-01

    Commonly used indices of fish thyroidal status are based on thyroxine (T4) secretion by thyroid tissue under control of the central brain-pituitary-thyroid axis. However, much of the control of the fish thyroid system also occurs in peripheral tissues, such as liver, by regulating T4 prohormone conversion to biologically active 3,5,3{prime}-triiodothyronine (T3) or to biologically inactive 3,3{prime},5{prime}-triiodothyronine and by regulating T3 conversion to inactive 3,3{prime}-diiodothyronine. These extrathyroidal conversions depend on a family of independently-regulated selenocysteine-containing microsomal deiodinases. The authors describe deiodination assays and evaluate their potential as biomarkers for exposure to chemicals that directly or indirectly disrupt thyroid hormone homeostasis or thyroidal status. The authors conclude that deiodination be included in a minimum suite of assays to detect xenobiotic effects on the fish thyroid system.

  19. Mutations in the hormone regulatory element of mouse mammary tumor virus differentially affect the response to progestins, androgens, and glucocorticoids.

    PubMed Central

    Gowland, P L; Buetti, E

    1989-01-01

    Transcription of the mouse mammary tumor virus DNA is known to be induced by several steroid hormones. Using chimeric MMTV plasmids containing mutations within the hormone regulatory element, we have previously studied the regions required for the glucocorticoid response in mouse fibroblasts. Here we report the characterization of elements essential for the stimulation by progestins and androgens as compared with glucocorticoids. The same set of mutant plasmids was transfected into the human mammary tumor cell line T47D, and the specific transcripts were analyzed by an S1 nuclease protection assay. Androgen-mediated stimulation, although weak, showed an extended sensitivity to mutations, with a slight preference for the proximal region. The results with progestin suggest that sequences within all the described sites protected by the receptor in vitro are required and that the promoter-proximal region (-128 to -78 from the RNA start site) is more important than the distal one (-190 to -160). Moreover, a binding site for nuclear factor I was not required for the progestin response, whereas it was required for glucocorticoids. Thus, the various steroid receptors play a role in the differential regulation of mouse mammary tumor virus transcription by recognizing distinct sequence differences in the hormone regulatory element and interacting with different factors bound to the promoter. Images PMID:2550809

  20. The influence of gender and hormone status on the severity and progression of keratoconus.

    PubMed

    Fink, Barbara A; Sinnott, Loraine T; Wagner, Heidi; Friedman, Chad; Zadnik, Karla

    2010-01-01

    To assess the effects of gender and hormone status on the severity and progression of keratoconus in patients enrolled in the Collaborative Longitudinal Evaluation of Keratoconus Study. The severity and progression of keratoconus in both men (M) and women were evaluated over a 4-year period that encompassed menopausal transition for hormone-active women (HA) and hormone-inactive women (HI). Four outcome measures were selected as indicators of the severity of keratoconus: high-contrast best-corrected visual acuity, low-contrast best-corrected visual acuity, the steep keratometric measurement, and corneal scarring (yes/no). There were no statistically significant differences among the 3 groups (M, HA, and HI) in race, history of atopic disease, family history of keratoconus, or rigid contact lens wear in the right and left eyes. At baseline, there were no significant differences among the 3 groups in high-contrast best-corrected visual acuity, low-contrast best-corrected visual acuity, or steep keratometric reading. Progression of keratoconus, as assessed by changes in these 3 continuous variables, was equal for the 3 groups. M had more corneal scarring than did HA or HI; however, there was no progression of scarring for any of the groups. Keratoconus progressed in both men and women, aged 48-59 years; however, there were no differences among the groups in progression.

  1. Audiovisual Stimulation Modulates Physical Performance and Biochemical and Hormonal Status of Athletes.

    PubMed

    Golovin, M S; Golovin, M S; Aizman, R I

    2016-09-01

    We studied the effect of audiovisual stimulation training course on physical development, functional state of the cardiovascular system, blood biochemical parameters, and hormonal status of athletes. The training course led to improvement of physical performance and adaptive capacities of the circulatory system, increase in plasma levels of total protein, albumin, and glucose and total antioxidant activity, and decrease in triglyceride, lipase, total bilirubin, calcium, and phosphorus. The concentration of hormones (cortisol, thyrotropin, triiodothyronine, and thyroxine) also decreased under these conditions. In the control group, an increase in the concentration of creatinine and uric acid and a tendency toward elevation of lowdensity lipoproteins and total antioxidant activity were observed in the absence of changes in cardiac function and physical performance; calcium and phosphorus concentrations reduced. The improvement in functional state in athletes was mainly associated with intensification of anabolic processes and suppression of catabolic reactions after audiovisual stimulation (in comparison with the control). Stimulation was followed by an increase in the number of correlations between biochemical and hormonal changes and physical performance of athletes, which attested to better integration of processes at the intersystem level.

  2. The glucose-dependent insulinotropic polypeptide receptor is overexpressed amongst GNAS1 mutation-negative somatotropinomas and drives growth hormone (GH)-promoter activity in GH3 cells.

    PubMed

    Occhi, G; Losa, M; Albiger, N; Trivellin, G; Regazzo, D; Scanarini, M; Monteserin-Garcia, J L; Fröhlich, B; Ferasin, S; Terreni, M R; Fassina, A; Vitiello, L; Stalla, G; Mantero, F; Scaroni, C

    2011-07-01

    Somatic mutations in the GNAS1 gene, encoding the α-subunit of the heterotrimeric stimulatory G protein (Gαs), occur in approximately 40% of growth hormone (GH)-secreting pituitary tumours. By altering the adenylate cyclase-cAMP-protein kinase A pathway, they unequivocally give somatotroph cells a growth advantage. Hence, the pathogenesis of somatotropinomas could be linked to anomalies in receptors coupled to the cAMP second-messenger cascade. Among them, the glucose-dependent insulinotropic polypeptide receptor (GIPR) is already known to play a primary role in the impaired cAMP-dependent cortisol secretion in patients affected by food-dependent Cushing's syndrome. In the present study, 43 somatotropinomas and 12 normal pituitary glands were investigated for GIPR expression by quantitative reverse transcriptase-polymerase chain reaction, western blotting and immunohistochemistry. Tumoural specimens were also evaluated for GNAS1 mutational status. The effect of GIPR overexpression on cAMP levels and GH transcription was evaluated in an in vitro model of somatotropinomas, the GH-secreting pituitary cell line GH3. GIPR was expressed at higher levels compared to normal pituitaries in 13 GNAS1 mutation-negative somatotropinomas. GIP stimulated adenylyl cyclase and GH-promoter activity in GIPR-transfected GH3 cells, confirming a correct coupling of GIPR to Gαs. In a proportion of acromegalic patients, GIPR overexpression appeared to be associated with a paradoxical increase in GH after an oral glucose tolerance test. Whether GIPR overexpression in acromegalic patients may be associated with this paradoxical response or more generally involved in the pathogenesis of acromegaly, as suggested by the mutually exclusive high GIPR levels and GNAS1 mutations, remains an open question.

  3. Lung adenocarcinoma: Sustained subtyping with immunohistochemistry and EGFR, HER2 and KRAS mutational status.

    PubMed

    Sousa, Vitor; Rodrigues, Carolina; Silva, Maria; Alarcão, Ana Maria; Carvalho, Lina

    2015-01-01

    Pulmonary adenocarcinomas are still in the process of achieving morphological, immunohistochemical and genetic standardization. The ATS/ERS/IASLC proposed classification for lung adenocarcinomas supports the value of the identification of histological patterns, specifically in biopsies. Thirty pulmonary adenocarcinomas were subjected to immunohistochemical study (CK7, CK5, 6, 18, CK20, TTF1, CD56, HER2, EGFR and Ki-67), FISH and PCR followed by sequencing and fragment analysis for EGFR, HER2 and KRAS. Solid pattern showed lower TTF1 and higher Ki-67 expression. TTF1 expression was higher in non-mucinous lepidic and micropapillary patterns when compared to acinar and solid and acinar, solid and mucinous respectively. Higher Ki67 expression was present in lepidic and solid patterns compared to mucinous. EGFR membranous staining had increasing expression from non-mucinous lepidic/BA pattern to solid pattern and micropapillary until acinar pattern. EGFR mutations, mainly in exon 19, were more frequent in females, together with non-smoking status, while KRAS exon 2 mutations were statistically more frequent in males, especially in solid pattern. FISH EGFR copy was correlated gross, with mutations. HER2 copy number was raised in female tumours without mutations, in all cases. Although EGFR and KRAS mutations are generally considered mutually exclusive, in rare cases they can coexist as it happened in one of this series, and was represented in acinar pattern with rates of 42.9% and 17.9%, respectively. EGFR mutations were more frequent in lepidic/BA and acinar patterns. Some cases showed different EGFR mutations. The differences identified between the adenocarcinoma patterns reinforce the need to carefully identify the patterns present, with implications in diagnosis and in pathogenic understanding. EGFR and KRAS mutational status can be determined in biopsies representing bronchial pulmonary carcinomas because when a mutation is present it is generally present in all the

  4. Telomere length shows no association with BRCA1 and BRCA2 mutation status.

    PubMed

    Killick, Emma; Tymrakiewicz, Malgorzata; Cieza-Borrella, Clara; Smith, Paula; Thompson, Deborah J; Pooley, Karen A; Easton, Doug F; Bancroft, Elizabeth; Page, Elizabeth; Leongamornlert, Daniel; Kote-Jarai, Zsofia; Eeles, Rosalind A

    2014-01-01

    This study aimed to determine whether telomere length (TL) is a marker of cancer risk or genetic status amongst two cohorts of BRCA1 and BRCA2 mutation carriers and controls. The first group was a prospective set of 665 male BRCA1/2 mutation carriers and controls (mean age 53 years), all healthy at time of enrollment and blood donation, 21 of whom have developed prostate cancer whilst on study. The second group consisted of 283 female BRCA1/2 mutation carriers and controls (mean age 48 years), half of whom had been diagnosed with breast cancer prior to enrollment. TL was quantified by qPCR from DNA extracted from peripheral blood lymphocytes. Weighted and unweighted Cox regressions and linear regression analyses were used to assess whether TL was associated with BRCA1/2 mutation status or cancer risk. We found no evidence for association between developing cancer or being a BRCA1 or BRCA2 mutation carrier and telomere length. It is the first study investigating TL in a cohort of genetically predisposed males and although TL and BRCA status was previously studied in females our results don't support the previous finding of association between hereditary breast cancer and shorter TL.

  5. Regulation of NR4A by nutritional status, gender, postnatal development and hormonal deficiency.

    PubMed

    Pérez-Sieira, S; López, M; Nogueiras, R; Tovar, S

    2014-03-03

    The NR4A is a subfamily of the orphan nuclear receptors (NR) superfamily constituted by three well characterized members: Nur77 (NR4A1), Nurr1 (NR4A2) and Nor 1 (NR4A3). They are implicated in numerous biological processes as DNA repair, arteriosclerosis, cell apoptosis, carcinogenesis and metabolism. Several studies have demonstrated the role of this subfamily on glucose metabolism, insulin sensitivity and energy balance. These studies have focused mainly in liver and skeletal muscle. However, its potential role in white adipose tissue (WAT), one of the most important tissues involved in the regulation of energy homeostasis, is not well-studied. The aim of this work was to elucidate the regulation of NR4A in WAT under different physiological and pathophysiological settings involved in energy balance such as fasting, postnatal development, gender, hormonal deficiency and pregnancy. We compared NR4A mRNA expression of Nur77, Nurr1 and Nor 1 and found a clear regulation by nutritional status, since the expression of the 3 isoforms is increased after fasting in a leptin-independent manner and sex steroid hormones also modulate NR4A expression in males and females. Our findings indicate that NR4A are regulated by different physiological and pathophysiological settings known to be associated with marked alterations in glucose metabolism and energy status.

  6. Regulation of NR4A by nutritional status, gender, postnatal development and hormonal deficiency

    PubMed Central

    Pérez-Sieira, S.; López, M.; Nogueiras, R.; Tovar, S.

    2014-01-01

    The NR4A is a subfamily of the orphan nuclear receptors (NR) superfamily constituted by three well characterized members: Nur77 (NR4A1), Nurr1 (NR4A2) and Nor 1 (NR4A3). They are implicated in numerous biological processes as DNA repair, arteriosclerosis, cell apoptosis, carcinogenesis and metabolism. Several studies have demonstrated the role of this subfamily on glucose metabolism, insulin sensitivity and energy balance. These studies have focused mainly in liver and skeletal muscle. However, its potential role in white adipose tissue (WAT), one of the most important tissues involved in the regulation of energy homeostasis, is not well-studied. The aim of this work was to elucidate the regulation of NR4A in WAT under different physiological and pathophysiological settings involved in energy balance such as fasting, postnatal development, gender, hormonal deficiency and pregnancy. We compared NR4A mRNA expression of Nur77, Nurr1 and Nor 1 and found a clear regulation by nutritional status, since the expression of the 3 isoforms is increased after fasting in a leptin-independent manner and sex steroid hormones also modulate NR4A expression in males and females. Our findings indicate that NR4A are regulated by different physiological and pathophysiological settings known to be associated with marked alterations in glucose metabolism and energy status. PMID:24584059

  7. Assessing reproductive status of right whales (Eubalaena glacialis) using fecal hormone metabolites.

    PubMed

    Rolland, Rosalind M; Hunt, Kathleen E; Kraus, Scott D; Wasser, Samuel K

    2005-07-01

    Long-term studies of the endangered North Atlantic right whale, Eubalaena glacialis, have revealed declining reproductive parameters over the past two decades, threatening recovery of this small population if current trends continue. Little is known about right whale reproductive physiology, and investigating this reproductive decline has been limited by a lack of non-lethal methods for assessing reproductive status (e.g., sexual maturation, ovarian activity, pregnancy, lactation, and reproductive senescence) in free-swimming whales. This paper describes validation of existing radioimmunoassay techniques to study reproduction in right whales by measuring estrogens, progestins, androgens, and their related metabolites in fecal samples. Over the past decade fecal steroid hormone assays have been used to assess reproductive status and function in a wide range of terrestrial wildlife species, but this is the first application of this methodology in wild cetaceans. Analysis of fecal hormone metabolite levels in combination with life history data from photographically identified whales shows that this non-invasive method can be used to determine gender, detect pregnancy and lactation, and to assess age at sexual maturity in right whales and potentially other endangered whale populations.

  8. Antioxidant status and hormonal profile reflected by experimental feeding of probiotics.

    PubMed

    Ghoneim, Magdy A; Moselhy, Said S

    2016-04-01

    Excessive production of free radicals can result in tissue damage, which mainly involves generation of hydroxyl radical and other oxidants. Such free radical-induced cell damage appears to play a major role in the pathogenesis of many diseases. Probiotics have been used therapeutically to modulate immunity, improve digestive processes, lower cholesterol, treat rheumatoid arthritis, and prevent cancer. The proposed research was designed to evaluate the changes in oxidative and antioxidative profile in addition to metabolic-related hormones of living animal model, which may generally affect the health status. Two groups of rabbits (10 animals each) were allocated in hygienic cages of controlled animal house. Control group received standard diet, and the other group received the same diet containing one probiotic for 30 days. Lactate dehydrogenase (LDH) activity in leukocytes, blood glucose, reduced glutathione (GSH), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) were estimated in different tissues. Malondialdehyde (MDA) and total proteins were also determined in different tissues. Certain hormones related to metabolism and growth were also evaluated. Leukocytic LDH activity was significantly increased along with nonsignificant increase of blood glucose in probiotics-fed animals. Results showed significant decreases in the levels of triiodothyronine and thyroid-stimulating hormone but showed significant elevations in thyroxine, insulin, growth hormone, and testosterone levels in animals fed with probiotics. Total proteins content was highly significantly elevated in liver, kidneys, and muscles of probiotic-administered animals. Microsomal GSH level was significantly decreased only in skeletal muscles of probiotic-treated animals. MDA was significantly lowered in animal tissues fed with probiotics. GSH-Px activity was elevated in hepatic and muscular microsomes of probiotic-supplemented animals while it was nonsignificantly increased in renal

  9. Sesame ingestion affects sex hormones, antioxidant status, and blood lipids in postmenopausal women.

    PubMed

    Wu, Wen-Huey; Kang, Yu-Ping; Wang, Nai-Hung; Jou, Hei-Jen; Wang, Tzong-An

    2006-05-01

    Sesame ingestion has been shown to improve blood lipids in humans and antioxidative ability in animals. Sesamin, a sesame lignan, was recently reported to be converted by intestinal microflora to enterolactone, a compound with estrogenic activity and also an enterometabolite of flaxseed lignans, which are known to be phytoestrogens. Whether sesame can be a source of phytoestrogens is unknown. This study was designed to investigate the effect of sesame ingestion on blood sex hormones, lipids, tocopherol, and ex vivo LDL oxidation in postmenopausal women. Twenty-six healthy subjects attended, and 24 completed, this randomized, placebo-controlled, crossover study. Half of them consumed 50 g sesame seed powder daily for 5 wk, followed by a 3-wk washout period, then a 5-wk 50-g rice powder placebo period. The other half received the 2 supplements in reverse order. After sesame treatment, plasma total cholesterol (TC), LDL-C, the ratio of LDL-C to HDL-C, thiobarbituric acid reactive substances in oxidized LDL, and serum dehydroepiandrosterone sulfate decreased significantly by 5, 10, 6, 23, and 18%, respectively. The ratio of alpha- and gamma-tocopherol to TC increased significantly by 18 and 73%, respectively. All of these variables differed significantly between the 2 treatments. Serum sex hormone-binding globulin and urinary 2-hydroxyestrone (n = 8) increased significantly by 15 and 72%, respectively, after sesame treatment, and these concentrations tended to differ (P = 0.065 and P = 0.090, respectively) from those after the placebo treatment. These results suggest that sesame ingestion benefits postmenopausal women by improving blood lipids, antioxidant status, and possibly sex hormone status.

  10. Novel mutation in MCT8 gene in a Brazilian boy with thyroid hormone resistance and severe neurologic abnormalities.

    PubMed

    Filho, Hamilton Cabral de Menezes; Marui, Suemi; Manna, Thais Della; Brust, Ester Saraiva; Radonsky, Vanessa; Kuperman, Hilton; Dichtchekenian, Vaê; Setian, Nuvarte; Damiani, Durval

    2011-02-01

    MCT8 is a cellular transporter of thyroid hormones important in their action and metabolization. We report a male patient with the novel inactivating mutation 630insG in the coding region in exon 1 of MCT8. He was characterized clinically by severe neurologic impairment (initially with global hypotonia, later evolving with generalized hypertonia), normal growth during infancy, reduced weight gain, and absence of typical signs and symptoms of hypothyroidism, while the laboratory evaluation disclosed elevated T3, low total and free T4, and mildly elevated TSH serum levels. Treatment with levothyroxine improved thyroid hormone profile but was not able to alter the clinical picture of the patient. These data reinforce the concept that the role of MCT8 is tissue-dependent: while neurons are highly dependent on MCT8, bone tissue, adipose tissue, muscle, and liver are less dependent on MCT8 and, therefore, may suffer the consequences of the exposition to high serum T3 levels.

  11. The status of Her2 amplification and Kras mutations in mucinous ovarian carcinoma.

    PubMed

    Chang, Kuang-Leei; Lee, Ming-Yung; Chao, Wan-Ru; Han, Chih-Ping

    2016-12-28

    Jayson GC et al. remarked in Lancet that nearly 100% of mucinous ovarian cancer cases have Kras mutation as well as a high frequency of Her2 amplification. Using the Abbott PathVysion Her2 DNA Probe Kit and Kras mutant-enriched PCR Kits (FemtoPath®), 21 samples of primary ovarian mucinous cystadenocarcinomas from Taiwanese patients were examined to determine the status of Her2 amplification and Kras mutations. Our results showed the Her2 amplification rates were 33.33%, while the Kras mutation rates were 61.90%. We present here our results in order to enlighten the readership that the ~100% Kras mutant frequency and the high Her2 amplification rate reported by Jayson et al. may be too exaggerated to be applicable into all populations. Additionally, we report another 2 novel Kras mutations (A11V, V14I).

  12. Direct mutation analysis of 495 patients for fragile X carrier status/proband diagnosis

    SciTech Connect

    Kaplan, G.; Kung, M.; McClure, M.; Cronister, A.

    1994-07-15

    With the cloning of the FMR-1 gene, direct mutation analysis is possible for fragile X syndrome. We have analyzed 495 patients using the StB12.3 probe/EcoRI/EagI system of Rousseau et al. and 167 of these also with PCR analysis according to Brown et al. For 28 patients requesting carrier status due to a family history of fragile X, 10 were shown to have either premutations or full mutations; for the remainder with varied backgrounds, 1 in 182 was shown to carry a premutation. For proband diagnosis, 7 of 14 with a fragile X family history carried a full mutation; 11 of 271 with other family histories carried the full mutation. 13 refs., 1 tab.

  13. The first case of association between postpartum thyroiditis and thyroid hormone resistance in an Italian patient showing a novel p.V283A THRB mutation.

    PubMed

    Paragliola, Rosa Maria; Concolino, Paola; De Rosa, Annapina; Mello, Enrica; Zuppi, Cecilia; Pontecorvi, Alfredo; Capoluongo, Ettore; Corsello, Salvatore Maria

    2013-04-01

    Postpartum thyroiditis (PPT) is characterized by the development of postpartum thyroid dysfunction, which may occur up to 12 months after delivery. The syndrome usually presents with transient thyrotoxicosis, followed by transient hypothyroidism. The association of this condition with resistance to thyroid hormones (RTH) has never been described. In this report, we describe a 30-year-old patient affected by RTH due to a novel p.V283A thyroid hormone receptor-β (THRB) heterozygous mutation in exon 8, which affects the ligand-binding domain, never before described in literature. A simple polymorphism was excluded through screening of 100 healthy controls. The patient became pregnant twice (in 2008 and in 2009) and developed PPT after both deliveries. Two months after her first pregnancy and one month after her second pregnancy, she presented with severe endogenous thyrotoxicosis and concomitant suppressed thyrotropin (TSH) levels, which represents an unusual finding in patients affected by RTH. Other causes of hyperthyroidism were excluded. After the hyperthyroid phase, she became hypothyroid (TSH >75 mU/L and low free-thyroxine and free-tri-iodothyronine levels), and eventually returned to her usual euthyroid status. During the course of PPT, no specific treatment was required, except for β-blockers used to treat tachycardia during the hyperthyroid phase. We report a unique case of a woman affected by RTH, due to a novel mutation V283A in THRB, who experienced PPT with a severe thyrotoxic phase after both her pregnancies. The association between RTH and PPT has never been reported in the literature. In particular, the marked suppression of TSH occurring when levels of TH are particularly elevated is not a frequent condition during RTH.

  14. Immunohistochemical NF1 analysis does not predict NF1 gene mutation status in pheochromocytoma.

    PubMed

    Stenman, Adam; Svahn, Fredrika; Welander, Jenny; Gustavson, Boel; Söderkvist, Peter; Gimm, Oliver; Juhlin, C Christofer

    2015-03-01

    Pheochromocytomas (PCCs) are tumors originating from the adrenal medulla displaying a diverse genetic background. While most PCCs are sporadic, about 40 % of the tumors have been associated with constitutional mutations in one of at least 14 known susceptibility genes. As 25 % of sporadic PCCs harbor somatic neurofibromin 1 gene (NF1) mutations, NF1 has been established as the most recurrently mutated gene in PCCs. To be able to pinpoint NF1-related pheochromocytoma (PCC) disease in clinical practice could facilitate the detection of familial cases, but the large size of the NF1 gene makes standard DNA sequencing methods cumbersome. The aim of this study was to examine whether mutations in the NF1 gene could be predicted by immunohistochemistry as a method to identify cases for further genetic characterization. Sixty-seven PCCs obtained from 67 unselected patients for which the somatic and constitutional mutational status of NF1 was known (49 NF1 wild type, 18 NF1 mutated) were investigated for NF1 protein immunoreactivity, and the results were correlated to clinical and genetic data. NF1 immunoreactivity was absent in the majority of the PCCs (44/67; 66 %), including 13 out of 18 cases (72 %) with a somatic or constitutional NF1 mutation. However, only a minority of the NF1 wild-type PCCs (18/49; 37 %) displayed retained NF1 immunoreactivity, thereby diminishing the specificity of the method. We conclude that NF1 immunohistochemistry alone is not a sufficient method to distinguish between NF1-mutated and non-mutated PCCs. In the clinical context, genetic screening therefore remains the most reliable tool to detect NF1-mutated PCCs.

  15. IDH-1R132H mutation status in diffuse glioma patients: implications for classification.

    PubMed

    Wang, Peng-Fei; Liu, Ning; Song, Hong-Wang; Yao, Kun; Jiang, Tao; Li, Shou-Wei; Yan, Chang-Xiang

    2016-05-24

    WHO2007 grading of diffuse gliomas in adults is well-established. However, IDH mutations make classification of gliomas according to the WHO2007 edition controversial. Here, we characterized IDH-1R132H mut status in a cohort of 670 adult patients with different WHO2007 grades of diffuse glioma. Patient characteristics, clinical data and prognoses were obtained from medical records. Patients with IDH-1R132H mut were younger and had better clinical outcomes than those without mutations. Differences in age among patients with astrocytomas of different WHO2007 grades were eliminated after patients were grouped based on IDH-1R132H status. IDH-1R132H mut was present more often in patients with lower Ki-67 and MGMT protein levels and higher mutant p53 levels. Ki-67 was also strongly associated with WHO2007 grade independently of IDH-1R132H mut status. Moreover, patients with Ki-67<30 survived longer than those with Ki-67≥30, regardless of IDH-1R132H mut status. Patients in the IDH-1R132H mut group with lower MGMT protein levels also had better clinical outcomes than those in other groups. Our results indicate that to better treat gliomas, IDH mutation status should be included when determining WHO2007 grade in glioma patients.

  16. Hormonal correlates of social status and courtship display in the cooperatively lekking lance-tailed manakin.

    PubMed

    DuVal, Emily H; Goymann, Wolfgang

    2011-01-01

    Though cooperative behavior has long been a focus of evolutionary biology, the proximate hormonal mechanisms underlying cooperative interactions remain poorly understood. Lance-tailed manakins (Chiroxiphia lanceolata) are tropical passerines that form long-term male-male partnerships and cooperate in paired male courtship displays. To elucidate patterns of natural hormonal variation in relation to cooperation and reproductive behavior, we examined circulating androgen levels of male lance-tailed manakins in relation to social status, display behavior, and time of year. We found significantly higher circulating androgen levels in alpha-ranked (breeding) males compared to non-alpha adult males in the population. Beta males, which participated in courtship displays but did not copulate, had androgen levels indistinguishable from those of unpaired adult males that never displayed for females, suggesting that an elevated concentration of plasma testosterone in tropical lekking birds may be associated primarily with copulatory behavior or other status-specific traits, and not the performance of courtship display. Androgens decreased throughout the breeding season for males of all status categories. Interestingly, alphas that displayed for females in the observation session prior to sampling had lower androgen levels than alphas that did not display for females. This pattern may result from female discrimination against alpha males at display areas with high levels of social conflict among males, as social disruption is linked to elevated testosterone in many species. However, recent change of a display partner was not related to alpha androgen levels. We discuss alternative explanations and the possible implications of these results, and generate several testable predictions for future investigations.

  17. Effect of thyroid hormone status and concomitant medication on statin induced adverse effects in hyperlipidemic patients.

    PubMed

    Berta, E; Harangi, M; Zsíros, N; Nagy, E V; Paragh, G; Bodor, M

    2014-06-01

    Statins are effective treatment for the prevention of cardiovascular diseases and used extensively worldwide. However, adverse effects induced by statins are the major barrier of maximalizing cardiovascular risk reduction. Hypothyroidism and administration of drugs metabolized on the same cytochrome P450 (CYPP450) pathways where statin biotransformation occurs represent a significant risk factor for statin induced adverse effects including myopathy. Simvastatin, atorvastatin and lovastatin are metabolized by CYP3A4, fluvastatin by CYP2C9, while rosuvastatin by CYP2C9 and 2C19. We investigated the levels of the free thyroid hormones and CYP metabolism of concomitant medication in 101 hyperlipidemic patients (age 61.3 +/- 9.9 ys) with statin induced adverse effects including myopathy (56 cases; 55.4%), hepatopathy (39 cases; 38.6%) and gastrointestinal adverse effects (24 cases; 23.8%). Abnormal thyroid hormone levels were found in 5 patients (4.95%); clinical hypothyroidism in 2 and hyperthyroidism in 3 cases. 11 patients had a positive history for hypothyroidism (10.9%). Myopathy occured in one patient with hypothyroidism and two patients with hyperthyroidism. There were no significant differences in the TSH, fT4 and fT3 levels between patients with statin induced myopathy and patients with other types of adverse effects. 78 patients (77.2%) were administered drugs metabolized by CYP isoforms also used by statins (3A4: 66 cases (65.3%); 2C9: 67 cases (66.3%); 2C19: 54 cases (53.5%)). Patients with myopathy took significantly more drugs metabolized by CYP3A4 compared to patients with other types of adverse effects (p < 0.05). More myopathy cases were found in patients on simvastatin treatment (52% vs. 38%, ns.), while significantly less patients with myopathy were on fluvastatin treatment (13% vs. 33%, p < 0.05) compared to patients with other types of statin induced adverse effects. Both abnormal thyroid hormone status and administration of drugs metabolized by CYP

  18. Hormone replacement therapy after menopause and risk of breast cancer in BRCA1 mutation carriers: a case-control study.

    PubMed

    Kotsopoulos, Joanne; Huzarski, Tomasz; Gronwald, Jacek; Moller, Pal; Lynch, Henry T; Neuhausen, Susan L; Senter, Leigha; Demsky, Rochelle; Foulkes, William D; Eng, Charis; Karlan, Beth; Tung, Nadine; Singer, Christian F; Sun, Ping; Lubinski, Jan; Narod, Steven A

    2016-01-01

    Many BRCA1 mutation carriers undergo elective surgical oophorectomy (often before menopause) to manage their elevated risk of developing ovarian cancer. It is important to clarify whether or not the use of hormone replacement therapy (HRT) to mitigate the symptoms associated with surgical or natural menopause is safe in women with an inherited BRCA1 mutation and no personal history of breast or ovarian cancer. We conducted a case-control analysis of 432 matched pairs of women with a BRCA1 mutation. Detailed information on HRT use after menopause (duration, type, age at first/last use, formulation) was obtained from a research questionnaire administered at the time of study enrollment. Conditional logistic regression was used to estimate the odds ratio (OR) and 95 % confidence intervals (CI) associated with HRT use. The mean duration of HRT use after menopause was 4.3 years among the cases and 4.4 years among the controls (P = 0.83). The adjusted OR for breast cancer comparing all women who ever used HRT to those who never used HRT was 0.80 (95 % CI 0.55-1.16; P = 0.24). Findings did not differ by type of menopause (natural vs. surgical), by recency of use, by duration of use, and by formulation type. These findings suggest that a short course of HRT should not be contra-indicated for BRCA1 mutation carriers who have undergone menopause and who have no personal history of cancer.

  19. Adult granulosa cell tumours (GCT): clinicopathological outcomes including FOXL2 mutational status and expression.

    PubMed

    Rosario, Roseanne; Wilson, Michelle; Cheng, Wei-Tzu; Payne, Kathryn; Cohen, Paul A; Fong, Peter; Shelling, Andrew N

    2013-11-01

    The aim of this research was to use nucleic acids isolated from formalin-fixed paraffin-embedded (FFPE) tissue to investigate the diagnostic potential and prognostic significance of FOXL2 in adult-type GCTs, particularly as a marker of identifying early stage patients that are likely to relapse. We performed a retrospective review of GCT patients referred to the Auckland Gynae-Oncology Multidisciplinary Team from 1955 to 2012. Baseline characteristics, clinical course, histopathology and survival data was recorded. Using nucleic acids extracted from FFPE tumour blocks, FOXL2 mutation status and expression was determined by DNA sequencing and RT-qPCR, respectively, and correlated with clinical data. 57 adult GCT patients were identified, however FFPE tumour blocks were available for only 37 of these patients. Sequencing results confirmed the presence of the FOXL2 mutation in 70% of patients. FOXL2 mutation positive adult tumours showed a trend towards higher FOXL2 expression than wildtype adult tumours, particularly in stage I patients (p=0.051). In addition, patients with homozygous FOXL2 mutations had a significantly higher relapse rate (p=0.04). There was no significant correlation between FOXL2 mutation status or FOXL2 expression and any other clinical variables. FFPE tumour blocks are a valuable resource of molecular information, especially when studying rare tumours such as GCTs. The FOXL2 mutation appears to have some diagnostic potential, however additional work in a larger cohort needs to be completed to confirm the prognostic significance of this gene mutation, and its expression. © 2013. Published by Elsevier Inc. All rights reserved.

  20. Expanding the Spectrum of Founder Mutations Causing Isolated Gonadotropin-Releasing Hormone Deficiency

    PubMed Central

    Choi, Jin-Ho; Balasubramanian, Ravikumar; Lee, Phil H.; Shaw, Natalie D.; Hall, Janet E.; Plummer, Lacey; Buck, Cassandra L.; Kottler, Marie-Laure; Jarzabek, Katarzyna; Wołczynski, Sławomir; Quinton, Richard; Latronico, Ana Claudia; Dode, Catherine; Ogata, Tsutomu; Kim, Hyung-Goo; Layman, Lawrence C.; Gusella, James F.

    2015-01-01

    Context: Loss of function (LoF) mutations in more than 20 genes are now known to cause isolated GnRH deficiency (IGD) in humans. Most causal IGD mutations are typically private, ie, limited to a single individual/pedigree. However, somewhat paradoxically, four IGD genes (GNRH1, TAC3, PROKR2, and GNRHR) have been shown to harbor LoF founder mutations that are shared by multiple unrelated individuals. It is not known whether similar founder mutations occur in other IGD genes. Objective: The objective of the study was to determine whether shared deleterious mutations in IGD-associated genes represent founder alleles. Setting: This study was an international collaboration among academic medical centers. Methods: IGD patients with shared mutations, defined as those documented in three or more unrelated probands in 14 IGD-associated genes, were identified from various academic institutions, the Human Gene Mutation Database, and literature reports by other international investigators. Haplotypes of single-nucleotide polymorphisms and short tandem repeats surrounding the mutations were constructed to assess genetic ancestry. Results: A total of eight founder mutations in five genes, GNRHR (Q106R, R262Q, R139H), TACR3 (W275X), PROKR2 (R85H), FGFR1 (R250Q, G687R), and HS6ST1 (R382W) were identified. Most founder alleles were present at low frequency in the general population. The estimated age of these mutant alleles ranged from 1925 to 5600 years and corresponded to the time of rapid human population expansion. Conclusions: We have expanded the spectrum of founder alleles associated with IGD to a total of eight founder mutations. In contrast to the approximately 9000-year-old PROKR2 founder allele that may confer a heterozygote advantage, the rest of the founder alleles are relatively more recent in origin, in keeping with the timing of recent human population expansion and any selective heterozygote advantage of these alleles requires further evaluation. PMID:26207952

  1. Cognitive function, stress hormones, heart rate and nutritional status during simulated captivity in military survival training.

    PubMed

    Lieberman, Harris R; Farina, Emily K; Caldwell, John; Williams, Kelly W; Thompson, Lauren A; Niro, Philip J; Grohmann, Kyle A; McClung, James P

    2016-10-15

    Stress influences numerous psychological and physiological processes, and its effects have practical implications in a variety of professions and real-world activities. However, few studies have concurrently assessed multiple behavioral, hormonal, nutritional and heart-rate responses of humans to acute, severe stress. This investigation simultaneously assessed cognitive, affective, hormonal, and heart-rate responses induced by an intensely stressful real-world environment designed to simulate wartime captivity. Sixty males were evaluated during and immediately following participation in U.S. Army Survival, Evasion, Resistance, and Escape (SERE) school, three weeks of intense but standardized training for Soldiers at risk of capture. Simulated captivity and intense mock interrogations degraded grammatical reasoning (p<0.005), sustained-attention (p<0.001), working memory (p<0.05) and all aspects of mood assessed by the Profile of Mood States (POMS) questionnaire: Tension/Anxiety, Depression/Dejection, Anger/Hostility, Vigor/Activity, Fatigue/Inertia; Confusion/Bewilderment, and Total Mood Disturbance (p<0.001) It also elevated heart rate (p<0.001); increased serum and salivary cortisol and dehydroepiandrosterone-sulfate (DHEA-s) (p<0.01); elevated serum epinephrine, norepinephrine, and soluble transferrin receptors (sTfR) (p<0.01); increased salivary neuropeptide-Y (NPY) (p<0.001); and decreased serum prolactin and serum and salivary testosterone (p<0.001). Partial recovery was observed immediately after training, but stress-induced changes, particularly in body weight and several of the biomarkers, persisted. This study demonstrates that when individuals were exposed to realistic and controlled simulated captivity, cognition, mood, stress hormones, nutritional status and heart rate are simultaneously altered, and each of these subsequently recovers at different rates. Published by Elsevier Inc.

  2. Heterogeneity of TERT promoter mutations status in squamous cell carcinomas of different anatomical sites.

    PubMed

    Cheng, Katherine A; Kurtis, Boaz; Babayeva, Sabina; Zhuge, Jian; Tantchou, Irlna; Cai, Dongming; Lafaro, Rocco J; Fallon, John T; Zhong, Minghao

    2015-06-01

    Squamous cell carcinoma (SCC) can arise from different anatomical sites including the skin, head and neck, lung, esophagus, genital area, and so on. Despite the same histopathologic features and immunohistochemistry profile, the SCCs of different body sites can show tremendous differences in their presenting symptoms, risk factor associations, natural history, prognosis, and response to treatment. This may reflect the fact that SCCs are heterogenous and likely have unique molecular characteristics at different anatomical sites. Recurrent somatic mutations in the TERT promoter region were first reported in human melanomas. Subsequently, other tumors including cutaneous SCC were found to demonstrate high frequencies of the same mutations. However, the incidences of TERT promoter mutation in noncutaneous SCCs have not been systemically studied. We investigated the TERT promoter mutation status among SCCs from different sites. We collected 84 cases of SCC from the skin (27), head and neck (12), lung (25), and cervix (10), as well as 10 cases of urothelial carcinoma with squamous differentiation (UC-SqD). We found that the frequencies of TERT promoter mutation among SCC of different sits are quite heterogenous: ~70% in skin SCC and UC-SqD, 16.67% in head and neck SCC, and 0% in lung and cervix SCC. These results may support the hypothesis of different carcinogenesis mechanisms of SCC in different sites. It also indicates that TERT promoter mutation could be a biomarker for distinguishing skin SCC or UC-SqD vs pulmonary SCC. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Functional analysis of a proline to serine mutation in codon 453 of the thyroid hormone receptor {beta}1 gene

    SciTech Connect

    Ozata, M.; Suzuki, Satoru; Takeda, Teiji

    1995-10-01

    Mutations in the gene encoding human thyroid hormone receptor {beta}(hTR{beta}) have been associated with generalized resistance to thyroid hormone (GRTH). This disorder is associated with significant behavoral abnormalities. We examined the hTR{beta} gene in a family with members who manifest inappropriately normal TSH, elevated free T{sub 4}, and free and total T{sub 3}. Sequence analysis showed a cytosine to thymine transition at nucleotide 1642 in one allele of the index patient`s genomic DNA. This altered proline to serine at codon 453. The resulting mutant receptor when expressed in vitro bound DNA with high affinity, but the T{sub 3} affinity of the receptor was impaired. The mutant TR demonstrated a dominant negative effect when cotransfected with two isoforms of wild-type receptor and also in the presence of TR variant {alpha}2 in COS-1 cells. Mutations of codon 453 occur more frequently than at other sites, and four different amino acid substitutions have been reported. Significant differences in phenotype occur among affected individuals, varying from normality to moderately severe GRTH. There is no clear correlation between K{sub a} or in vitro function of the mutant receptor, and phenotype. This study extends the association between GRTH and illness, and indicates that early diagnosis and counseling are needed in families with TR{beta}1 abnormalities. 34 refs., 5 figs., 2 tabs.

  4. [The influence of 24-epibrassidinole on the hormone status of wheat plants under sodium chloride].

    PubMed

    Aval'baev, A M; Iuldashev, R A; Fatkhutdinova, R A; Urusov, F A; Safutdinova, Iu V; Shakirova, F M

    2010-01-01

    We studied the influence of the preconditioning of wheat germ (Triticum aestivum L.) with 0.4 microM 24-epibrassidinole (EB) on the growth and hormone status of plants under the influence of 2% NaCl. The preconditioning with EB promoted the lowering of the extent of the damaging influence of pickling on the growth of germs. The important contribution to the realization of the protective action of EB in the preconditioning of plants is probably that of its ability to lower the level of stress-induced abscisic acid accumulation and the decrease in the content of indole-acetic acid. At the same time, the cytokinin concentration in plants preconditioned with EB under pickling was practically the same as in plants without stress. This fact combined with data about the ability of EB to induce the increase in cytokinin content in wheat, obtained before, allowed us to assume that the protective action of EB on plants is connected, first of all, with the prevention of the increase in level of hormones of cytokinin nature under pickling.

  5. Aging Independently of the Hormonal Status Changes Pain Responses in Young Postmenopausal Women

    PubMed Central

    Tousignant-Laflamme, Yannick; Marchand, Serge

    2012-01-01

    Both aging and hormonal status have an effect on pain perception. The goal of this study was to isolate as much as possible the effect of aging in postmenopausal women. Thirty-two women with regular menstrual cycles (RMW) and 18 postmenopausal women (PMW) underwent a 2-minute cold pressor test (CPT) to activate DNIC with a series of tonic heat pain stimulations with a contact thermode to assess ascending pain pathways. We found that this procedure induced much less pain during the first 15 seconds of stimulation the PMW group (P = 0.03), while the mean thermode pain ratings, pain tolerance, pain threshold, and DNIC analgesia were similar for both groups (P > 0.05). The absence of the peak pain in the PMW was probably due to reduced function of the myelinated Aδ fibers that naturally occurs with age. PMID:22110943

  6. Androgen receptor expression predicts different clinical outcomes for breast cancer patients stratified by hormone receptor status

    PubMed Central

    Xu, Yan; Zheng, Yi-Zi; Liu, Yi-Rong; Lang, Guan-Tian; Qiao, Feng; Hu, Xin; Shao, Zhi-Ming

    2016-01-01

    In this study we sought to correlate androgen receptor (AR) expression with tumor progression and disease-free survival (DFS) in breast cancer patients. We investigated AR expression in 450 breast cancer patients. We found that breast cancers expressing the estrogen receptor (ER) are more likely to co-express AR compared to ER-negative cancers (56.0% versus 28.1%, P < 0.001). In addition, we found that AR expression is correlated with increased DFS in patients with luminal breast cancer (P < 0.001), and decreased DFS in TNBC (triple negative breast cancer, P = 0.014). In addition, patients with HR+ tumors (Hormone receptor positive tumors) expressing low levels of AR have the lowest DFS among all receptor combinations. We also propose a novel prognostic model using AR receptor status, BRCA1, and present data showing that our model is more predictive of disease free survival compared to the traditional TMN staging system. PMID:27285752

  7. Clinical and laboratory parameters predicting a requirement for the reevaluation of growth hormone status during growth hormone treatment: Retesting early in the course of GH treatment.

    PubMed

    Vuralli, Dogus; Gonc, E Nazli; Ozon, Z Alev; Alikasifoglu, Ayfer; Kandemir, Nurgun

    2017-06-01

    We aimed to define the predictive criteria, in the form of specific clinical, hormonal and radiological parameters, for children with growth hormone deficiency (GHD) who may benefit from the reevaluation of GH status early in the course of growth hormone (GH) treatment. Two hundred sixty-five children with growth hormone deficiency were retested by GH stimulation at the end of the first year of GH treatment. The initial clinical and laboratory characteristics of those with a normal (GH≥10ng/ml) response and those with a subnormal (GH<10ng/ml) response were compared to predict a normal GH status during reassessment. Sixty-nine patients (40.6%) out of the 170 patients with isolated growth hormone deficiency (IGHD) had a peak GH of ≥10ng/ml during the retest. None of the patients with multiple pituitary hormone deficiency (MPHD) had a peak GH of ≥10ng/ml. Puberty and sex steroid priming in peripubertal cases increased the probability of a normal GH response. Only one patient with IGHD who had an ectopic posterior pituitary without stalk interruption on MRI analysis showed a normal GH response during the retest. Patients with a peak GH between 5 and 10ng/ml, an age at diagnosis of ≥9years or a height gain below 0.61 SDS during the first year of treatment had an increased probability of having a normal GH response at the retest. Early reassessment of GH status during GH treatment is unnecessary in patients who have MPHD with at least 3 hormone deficiencies. Retesting at the end of the first year of therapy is recommended for patients with IGHD who have a height gain of <0.61 SDS in the first year of treatment, especially those with a normal or 'hypoplastic' pituitary on imaging. Priming can increase the likelihood of a normal response in patients in the pubertal age group who do not show overt signs of pubertal development. Copyright © 2017. Published by Elsevier Ltd.

  8. The impact of HFE mutations on haemoglobin and iron status in individuals experiencing repeated iron loss through blood donation

    PubMed Central

    Mast, Alan E.; Lee, Tzong-Hae; Schlumpf, Karen S.; Wright, David J.; Johnson, Bryce; Carrick, Danielle M.; Cable, Ritchard G.; Kiss, Joseph E.; Glynn, Simone A.; Steele, Whitney R.; Murphy, Edward L.; Sacher, Ronald; Busch, Michael P.

    2012-01-01

    Summary Frequent blood donors become iron deficient. HFE mutations are present in over 30% of donors. A 24-month study of 888 first time/reactivated donors and 1537 frequent donors measured haemoglobin and iron status to assess how HFE mutations impact the development of iron deficiency erythropoiesis. Donors with two HFE mutations had increased baseline haemoglobin and iron stores as did those with one mutation, albeit to a lesser extent. Over multiple donations haemoglobin and iron status of donors with HFE mutations paralleled those lacking mutations. The prevalence of HFE mutations was not increased in higher intensity donors. Thus, in general, HFE mutations do not temper donation-induced changes in haemoglobin and iron status. However, in Black donors there was an increase of H63D carriers at baseline, from 3.7% in first time/reactivated donors to 15.8% in frequent donors, suggesting that the relative effects of HFE mutations on iron absorption may vary between racial/ethnic groups. In secondary analyses, venous haemoglobin decreased more slowly in donors with ferritin ≥ 12 μg/l; and haemoglobin recovery time was shorter in donors with reticulocyte haemoglobin (CHr) ≥ 32.6 pg, indicating that these biochemical measures are better indicators of a donor’s response to phlebotomy than their HFE mutation status. PMID:22118647

  9. The impact of HFE mutations on haemoglobin and iron status in individuals experiencing repeated iron loss through blood donation*.

    PubMed

    Mast, Alan E; Lee, Tzong-Hae; Schlumpf, Karen S; Wright, David J; Johnson, Bryce; Carrick, Danielle M; Cable, Ritchard G; Kiss, Joseph E; Glynn, Simone A; Steele, Whitney R; Murphy, Edward L; Sacher, Ronald; Busch, Michael P

    2012-02-01

    Frequent blood donors become iron deficient. HFE mutations are present in over 30% of donors. A 24-month study of 888 first time/reactivated donors and 1537 frequent donors measured haemoglobin and iron status to assess how HFE mutations impact the development of iron deficiency erythropoiesis. Donors with two HFE mutations had increased baseline haemoglobin and iron stores as did those with one mutation, albeit to a lesser extent. Over multiple donations haemoglobin and iron status of donors with HFE mutations paralleled those lacking mutations. The prevalence of HFE mutations was not increased in higher intensity donors. Thus, in general, HFE mutations do not temper donation-induced changes in haemoglobin and iron status. However, in Black donors there was an increase of H63D carriers at baseline, from 3·7% in first time/reactivated donors to 15·8% in frequent donors, suggesting that the relative effects of HFE mutations on iron absorption may vary between racial/ethnic groups. In secondary analyses, venous haemoglobin decreased more slowly in donors with ferritin ≥12μg/l; and haemoglobin recovery time was shorter in donors with reticulocyte haemoglobin (CHr) ≥32·6pg, indicating that these biochemical measures are better indicators of a donor's response to phlebotomy than their HFE mutation status. © 2011 Blackwell Publishing Ltd.

  10. Congenital adrenal hypoplasia: clinical spectrum, experience with hormonal diagnosis, and report on new point mutations of the DAX-1 gene.

    PubMed

    Peter, M; Viemann, M; Partsch, C J; Sippell, W G

    1998-08-01

    X-linked congenital adrenal hypoplasia (AHC) is a rare developmental disorder of the human adrenal cortex and is caused by deletion or mutation of the DAX-1 gene, a recently discovered member of the nuclear hormone receptor superfamily. Hypogonadotropic hypogonadism is frequently associated with AHC. AHC occurs as part of a contiguous gene syndrome together with glycerol kinase deficiency (GKD) and Duchenne's muscular dystrophy. The present series, collected over the past 2 decades, includes 18 AHC boys from 16 families: 4 with AHC, GKD, and Duchenne's muscular dystrophy; 2 with AHC and GKD; and 12 with AHC (5 young adults with hypogonadotropic hypogonadism). Most of the boys presented with salt wasting and hyperpigmentation during the neonatal period. Plasma steroid determinations performed in the first weeks of life often showed confusing results, probably caused by steroids produced in the neonates' persisting fetocortex. Aldosterone deficiency usually preceded cortisol deficiency, which explains why the patients more often presented with salt-wasting rather than with hypoglycemic symptoms. An ACTH test was often necessary to detect cortisol deficiency in the very young infants. In some patients, serial testing was necessary to establish the correct diagnosis. In 4 boys studied during the first 3 months after birth, we found pubertal LH, FSH, and testosterone plasma levels indicating postnatal transient activation of the hypothalamic-pituitary-gonadal axis as in normal boys. Previous studies have shown that the DAX-1 gene is deleted in the AHC patients with a contiguous gene syndrome and is mutated in nondeletion patients. Most of the point mutations identified in AHC patients were frameshift mutations and stop mutations. In the 15 patients available for molecular analysis of the DAX-1 gene, there were large deletions in 6 patients and point mutations in another 7 patients. All of the point mutations identified in the present study resulted in a nonfunctional

  11. Aberrant methylation of imprinted genes is associated with negative hormone receptor status in invasive breast cancer

    PubMed Central

    Barrow, Timothy M; Barault, Ludovic; Ellsworth, Rachel E; Harris, Holly R; Binder, Alexandra M; Valente, Allyson L; Shriver, Craig D; Michels, Karin B

    2015-01-01

    Epigenetic regulation of imprinted genes enables monoallelic expression according to parental origin, and its disruption is implicated in many cancers and developmental disorders. The expression of hormone receptors is significant in breast cancer as they are indicators of cancer cell growth rate and determine response to endocrine therapies. We investigated the frequency of aberrant events and variation in DNA methylation at nine imprinted sites in invasive breast cancer and examined the association with estrogen and progesterone receptor status. Breast tissue and blood from patients with invasive breast cancer (n=38) and benign breast disease (n=30) were compared to those from healthy individuals (n=36), matched to the cancer patients by age at diagnosis, ethnicity, BMI, menopausal status, and familial history of cancer. DNA methylation and allele-specific expression were analyzed by pyrosequencing. Tumor-specific methylation changes at IGF2 DMR2 were observed in 59% of cancer patients, IGF2 DMR0 in 38%, DIRAS3 DMR in 36%, GRB10 ICR in 23%, PEG3 DMR in 21%, MEST ICR in 19%, H19 ICR in 18%, KvDMR in 8%, and SNRPN/SNURF ICR in 4%. Variation of methylation was significantly greater in breast tissue from cancer patients than healthy individuals and benign breast disease. Aberrant methylation of three or more sites was significantly associated with negative estrogen-alpha (Fisher’s Exact Test, p=0.02) and progesterone-A (p=0.02) receptor status. Aberrant events and increased variation of imprinted gene DNA methylation therefore appear to be frequent in invasive breast cancer and are associated with negative estrogen and progesterone receptor status, without loss of monoallelic expression. PMID:25560175

  12. [The importance of mutational status in prognosis and therapy of GIST].

    PubMed

    Comandone, Alessandro; Boglione, Antonella

    2015-01-01

    mutations appear and the disease progresses. Regorafenib is the third line therapy but too few data relates mutational status and regorafenib activity. In adjuvant setting only imatinib has a role. Two important studies (the USA ACOSOG Z 9001 and the German-Scandinavian study) fail to demonstrate that a specific mutation can predict a better DFS and OS in treated patients. On the contrary, volume of the tumor, number of mitosis and site of GIST are strong prognostic and predictive factors. In conclusion mutational analysis in GIST is at present more useful in metastatic setting than in adjuvant therapy. The insurgence of primary and secondary mutations during therapy is a fundamental step for disease progression.

  13. Prognostic model for brain metastases from lung adenocarcinoma identified with epidermal growth factor receptor mutation status.

    PubMed

    Li, Hongwei; Wang, Weili; Jia, Haixia; Lian, Jianhong; Cao, Jianzhong; Zhang, Xiaqin; Song, Xing; Jia, Sufang; Li, Zhengran; Cao, Xing; Zhou, Wei; Han, Songye; Yang, Weihua; Xi, Yanfen; Lian, Shenming

    2017-09-01

    Several indices have been developed to predict survival of brain metastases (BM) based on prognostic factors. However, such models were designed for general brain metastases from different kinds of cancers, and prognostic factors vary between cancers and histological subtypes. Recently, studies have indicated that epidermal growth factor receptor (EGFR) mutation status may be a potential prognostic biological factor in BM from lung adenocarcinoma. Thus, we sought to define the role of EGFR mutation in prognoses and introduce a prognostic model specific for BM from lung adenocarcinoma. Data of 256 patients with BM from lung adenocarcinoma identified with EGFR mutations were collected. Independent prognostic factors were confirmed using a Cox regression model. The new prognostic model was developed based on the results of multivariable analyses. The score of each factor was calculated by six-month survival. Prognostic groups were divided into low, medium, and high risk based on the total scores. The prediction ability of the new model was compared to the three existing models. EGFR mutation and Karnofsky performance status were independent prognostic factors and were thus integrated into the new prognostic model. The new model was superior to the three other scoring systems regarding the prediction of three, six, and 12-month survival by pairwise comparison of the area under the curve. Our proposed prognostic model specific for BM from lung adenocarcinoma incorporating EGFR mutation status was valid in predicting patient survival. Further verification is warranted, with prospective testing using large sample sizes. © 2017 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

  14. Clinico-pathological nomogram for predicting BRAF mutational status of metastatic colorectal cancer

    PubMed Central

    Loupakis, Fotios; Moretto, Roberto; Aprile, Giuseppe; Muntoni, Marta; Cremolini, Chiara; Iacono, Donatella; Casagrande, Mariaelena; Ferrari, Laura; Salvatore, Lisa; Schirripa, Marta; Rossini, Daniele; De Maglio, Giovanna; Fasola, Gianpiero; Calvetti, Lorenzo; Pilotto, Sara; Carbognin, Luisa; Fontanini, Gabriella; Tortora, Giampaolo; Falcone, Alfredo; Sperduti, Isabella; Bria, Emilio

    2016-01-01

    Background: In metastatic colorectal cancer (mCRC), BRAFV600E mutation has been variously associated to specific clinico-pathological features. Methods: Two large retrospective series of mCRC patients from two Italian Institutions were used as training-set (TS) and validation-set (VS) for developing a nomogram predictive of BRAFV600E status. The model was internally and externally validated. Results: In the TS, data from 596 mCRC patients were gathered (RAS wild-type (wt) 281 (47.1%); BRAFV600E mutated 54 (9.1%)); RAS and BRAFV600E mutations were mutually exclusive. In the RAS-wt population, right-sided primary (odds ratio (OR): 7.80, 95% confidence interval (CI) 3.05–19.92), female gender (OR: 2.90, 95% CI 1.14–7.37) and mucinous histology (OR: 4.95, 95% CI 1.90–12.90) were independent predictors of BRAFV600E mutation, with high replication at internal validation (100%, 93% and 98%, respectively). A predictive nomogram was calculated: patients with the highest score (right-sided primary, female and mucinous) had a 81% chance to bear a BRAFV600E-mutant tumour; accuracy measures: AUC=0.812, SE:0.034, sensitivity:81.2% specificity:72.1%. In the VS (508 pts, RAS wt: 262 (51.6%), BRAFV600E mutated: 49 (9.6%)), right-sided primary, female gender and mucinous histology were confirmed as independent predictors of BRAFV600E mutation with high accuracy. Conclusions: Three simple and easy-to-collect characteristics define a useful nomogram for predicting BRAF status in mCRC with high specificity and sensitivity. PMID:26575603

  15. Predictive Value of GJB2 Mutation Status for Hearing Outcomes of Pediatric Cochlear Implantation.

    PubMed

    Abdurehim, Yasin; Lehmann, Alexandre; Zeitouni, Anthony G

    2017-03-01

    Objective To systematically review and quantify current evidence regarding the association of GJB2 mutation status with outcomes of pediatric cochlear implantation. Data Sources PubMed, Embase, and the Cochrane Library were searched for "GJB2,"pediatric hearing loss," and "cochlear implantation" and their synonyms, with no language restrictions, until December 2, 2015. Review Methods Studies were included that investigated the status of GJB2 mutation and its predictive value for outcomes of pediatric cochlear implantation. Speech recognition scores, Infant-Toddler Meaningful Auditory Integration Scale, Speech Intelligibility Rating, and Categorized Auditory Performance were pooled using weighted mean differences, and a 95% confidence interval. Results Eighteen studies met the inclusion criteria. The differences between GJB2-related deafness and non- GJB2-related deafness due to unidentified causes and other types of genetic deafness without additional disabilities were not statistically significant ( P = .15 and P = .30, respectively); however, the difference between GJB2-related deafness and acquired hearing loss due to environmental etiologies was statistically significant and favored GJB2-related deafness ( P = .03). Conclusion GJB2-related deafness leads to significantly better cochlear implantation outcomes when compared with acquired deafness caused by environmental etiologies. However, GJB2 mutation is not associated with a significantly better prognosis when compared with those whose deafness results from either nonsyndromic hearing loss of unknown origin or other types of genetic mutations in the absence of other neurologic deficits.

  16. Gastrointestinal stromal tumors: clinical significance of p53 expression, MDM2 amplification, and KIT mutation status.

    PubMed

    Wallander, Michelle L; Layfield, Lester J; Tripp, Sheryl R; Schmidt, Robert L

    2013-07-01

    Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. Clinical behavior is best predicted by size and mitotic count (risk index). KIT and platelet-derived growth factor receptor α (PDGFRA) mutations have therapeutic and prognostic value but few other prognostically significant molecular markers have been identified. We investigated the prognostic value of p53 protein expression and MDM2 gene amplification in a series of GISTs. Thirty-five GISTs were tested for KIT and PDGFRA mutations, p53 protein expression (high >10% positive by immunohistochemistry) and MDM2 gene amplification (ratio >1.8). Mitotic index (>5/50 HPF), MDM2 amplification status, p53 protein expression, tumor size, and KIT/PDGFRA mutational status were correlated with clinical outcome. Only a single (3%) GIST was amplified for MDM2. p53 protein expression, mitotic index, and KIT/PDGFRA mutations did not correlate with recurrence or metastasis (P=0.20, 0.50, and 0.08, respectively) but tumor size did (P=0.04). Risk assessment (size and mitotic index) showed a weak association with clinical behavior (P=0.19). MDM2 amplification is uncommon in GISTs. Although high p53 expression occurred in 35% of cases, it did not correlate with clinical behavior. Only GIST size predicted clinical outcome.

  17. US Incidence of Breast Cancer Subtypes Defined by Joint Hormone Receptor and HER2 Status

    PubMed Central

    Altekruse, Sean F.; Li, Christopher I.; Chen, Vivien W.; Clarke, Christina A.; Ries, Lynn A. G.; Cronin, Kathleen A.

    2014-01-01

    Background In 2010, Surveillance, Epidemiology, and End Results (SEER) registries began collecting human epidermal growth factor 2 (HER2) receptor status for breast cancer cases. Methods Breast cancer subtypes defined by joint hormone receptor (HR; estrogen receptor [ER] and progesterone receptor [PR]) and HER2 status were assessed across the 28% of the US population that is covered by SEER registries. Age-specific incidence rates by subtype were calculated for non-Hispanic (NH) white, NH black, NH Asian Pacific Islander (API), and Hispanic women. Joint HR/HER2 status distributions by age, race/ethnicity, county-level poverty, registry, stage, Bloom–Richardson grade, tumor size, and nodal status were evaluated using multivariable adjusted polytomous logistic regression. All statistical tests were two-sided. Results Among case patients with known HR/HER2 status, 36810 (72.7%) were found to be HR+/HER2−, 6193 (12.2%) were triple-negative (HR−/HER2−), 5240 (10.3%) were HR+/HER2+, and 2328 (4.6%) were HR−/HER2+; 6912 (12%) had unknown HR/HER2 status. NH white women had the highest incidence rate of the HR+/HER2− subtype, and NH black women had the highest rate of the triple-negative subtype. Compared with women with the HR+/HER2− subtype, triple-negative patients were more likely to be NH black and Hispanic; HR+/HER2+ patients were more likely to be NH API; and HR−/HER2+ patients were more likely to be NH black, NH API, and Hispanic. Patients with triple-negative, HR+/HER2+, and HR−/HER2+ breast cancer were 10% to 30% less likely to be diagnosed at older ages compared with HR+/HER2− patients and 6.4-fold to 20.0-fold more likely to present with high-grade disease. Conclusions In the future, SEER data can be used to monitor clinical outcomes in women diagnosed with different molecular subtypes of breast cancer for a large portion (approximately 28%) of the US population. PMID:24777111

  18. The use of anti-Müllerian hormone as diagnostic for gonadectomy status in dogs.

    PubMed

    Themmen, Axel P N; Kalra, Bhanu; Visser, Jenny A; Kumar, Ajay; Savjani, Gopal; de Gier, Jeffrey; Jaques, Scott

    2016-10-01

    In the veterinary practice, there is a need for a diagnostic tool to check the gonadal status in female dogs because it may be difficult to determine whether a female animal has been spayed or whether there are ovarian remnants. Although less prevalent, a similar situation pertains to male dogs. Anti-Müllerian hormone (AMH) is an important regulator of gonadal function and is a specific gonadal product that can be determined in circulation. The objective of this study was to develop and test a canine blood AMH assay as a diagnostic tool to determine the presence of functional gonadal tissue in dogs. A prospective study with a training-validation set paradigm was used. A canine AMH assay was developed and serum and plasma AMH concentrations were determined in blood samples from 46 intact female dogs, 48 spayed females, 50 intact males, and 48 castrated males collected at two separate institutes. Using a training-validation set paradigm, it was found that using cutoff values of 1.1 ng/mL (female) and 5.5 ng/mL (male) AMH, the assay reported excellent specificity and sensitivity of 100% and 90% in female dogs, and good specificity and sensitivity of 100% and 76%, in male dogs, respectively. The sensitivity in male dogs could be further enhanced by including a serum testosterone determination. This newly developed canine AMH assay is a valuable diagnostic tool to determine gonadal status in veterinary medicine. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Fruit, Vegetable, and Animal Food Intake and Breast Cancer Risk by Hormone Receptor Status

    PubMed Central

    Bao, Ping-Ping; Shu, Xiao-Ou; Zheng, Ying; Cai, Hui; Ruan, Zhi-Xian; Gu, Kai; Su, Yinghao; Gao, Yu-Tang; Zheng, Wei; Lu, Wei

    2013-01-01

    Background The effects of diet on breast cancer are controversial and whether the effects vary with hormone receptor status has not been well investigated. This study evaluated the associations of dietary factors with risk for breast cancer overall and by hormone receptor status of tumors among Chinese women. Methods The Shanghai Breast Cancer Study, a large, population-based, case-control study, enrolled 3,443 cases and 3,474 controls in 1996–1998 (phase I) and 2002–2004 (phase II); 2,676 cases had ER and PR data. Dietary intake was assessed using a validated, quantitative, food frequency questionnaire (FFQ). Odds ratios (ORs) and 95% confidence intervals (95% CI) were derived from multivariate, polychotomous, unconditional logistic regression models. Results Total vegetable intake was inversely related to breast cancer risk, with an adjusted OR for the highest quintile of 0.80 (95% CI = 0.67–0.95; P trend=0.02). Reduced risk was also related to high intake of allium vegetables (P trend = 0.01) and fresh legumes (P trend = 0.0008). High intake of citrus fruits and rosaceae fruits were inversely associated with breast cancer risk (P trend = 0.003 and P trend = 0.004, respectively), although no consistent association was seen for total fruit intake. Elevated risk was observed for all types of meat and fish intake (all P trend <0.05), while intakes of eggs and milk were associated with a decreased risk of breast cancer (both P trend <0.05). There was little evidence that associations with dietary intakes varied across the four tumor subtypes or between ER+/PR+ and ER−/PR− tumors (P for heterogeneity >0.05). Conclusion Our results suggest that high intake of total vegetables, certain fruits, milk, and eggs may reduce the risk of breast cancer, while high consumption of animal-source foods may increase risk. The dietary associations did not appear to vary by ER/PR status. PMID:22860889

  20. Misfolding Ectodomain Mutations of the Lutropin Receptor Increase Efficacy of Hormone Stimulation

    PubMed Central

    Charmandari, E.; Guan, R.; Zhang, M.; Silveira, L. G.; Fan, Q. R.; Chrousos, G. P.; Sertedaki, A. C.; Latronico, A. C.

    2016-01-01

    We demonstrate 2 novel mutations of the LHCGR, each homozygous, in a 46,XY patient with severe Leydig cell hypoplasia. One is a mutation in the signal peptide (p.Gln18_Leu19ins9; referred to here as SP) that results in an alteration of the coding sequence of the N terminus of the mature mutant receptor. The other mutation (p.G71R) is also within the ectodomain. Similar to many other inactivating mutations, the cell surface expression of recombinant human LHR(SP,G71R) is greatly reduced due to intracellular retention. However, we made the unusual discovery that the intrinsic efficacy for agonist-stimulated cAMP in the reduced numbers of receptors on the cell surface was greatly increased relative to the same low number of cell surface wild-type receptor. Remarkably, this appears to be a general attribute of misfolding mutations in the ectodomains, but not serpentine domains, of the gonadotropin receptors. These findings suggest that there must be a common, shared mechanism by which disparate mutations in the ectodomain that cause misfolding and therefore reduced cell surface expression concomitantly confer increased agonist efficacy to those receptor mutants on the cell surface. Our data further suggest that, due to their increased agonist efficacy, extremely small changes in cell surface expression of misfolded ectodomain mutants cause larger than expected alterations in the cellular response to agonist. Therefore, for inactivating LHCGR mutations causing ectodomain misfolding, the numbers of cell surface mutant receptors on fetal Leydig cells of 46,XY individuals exert a more exquisite effect on the relative severity of the clinical phenotypes than already appreciated. PMID:26554443

  1. Diagnostic implications of TERT promoter mutation status in diffuse gliomas in a routine clinical setting.

    PubMed

    Hewer, Ekkehard; Prebil, Nadine; Berezowska, Sabina; Gutt-Will, Marielena; Schucht, Philippe; Dettmer, Matthias S; Vassella, Erik

    2017-08-19

    IDH (isocitrate dehydrogenase) gene mutations are present in most diffuse low-grade gliomas and define the clinico-pathological core of the respective morphologically defined entities. Conversely, according to the 2016 WHO classification, the majority of glioblastomas belong to the IDH-wildtype category, which is defined by exclusion. TERT (telomerase reverse transcriptase gene) promoter mutations have been suggested as a molecular marker for primary glioblastomas. We analyzed molecular, histopathological, and clinical profiles of a series of 110 consecutive diffuse gliomas (WHO grades II-IV) diagnosed at our institution, in which TERT promoter mutation analysis had been performed as part of diagnostic work-up. A diagnostic algorithm based on IDH, TERT, ATRX, H3F3A, and 1p19q co-deletion status resulted in a consistent molecular classification with only 14 (13%) marker-negative tumors. TERT promoter mutations were present in 77% of IDH-wildtype tumors. The TERT/IDH-wildtype category was highly enriched for tumors with unconventional clinical or histological features. Molecular classes were associated with distinct rates of MGMT promoter methylation. We conclude that, in a routine diagnostic setting, TERT promoter mutations define a relatively homogeneous core group among IDH-wildtype diffuse gliomas that includes the majority of primary glioblastomas as well as their putative precursor lesions.

  2. KRAS mutational status as a predictor of epidermal growth factor receptor inhibitor efficacy in colorectal cancer.

    PubMed

    Baynes, Roy D; Gansert, Jennifer

    2009-01-01

    Inhibitors of the epidermal growth factor receptor (EGFR) have demonstrated promising potential in the treatment of advanced colorectal cancer. However, a proportion of patients do not respond to therapy with EGFR inhibitors, and therefore, there has been interest in identifying those patients most likely to benefit from therapy with these agents. KRAS, a member of the RAS family of signaling proteins, plays an important role in EGFR-mediated regulation of cellular proliferation and survival. Although there is still some debate regarding the prognostic importance of KRAS mutations in patients with metastatic colorectal cancer, several recent phase 2 and 3 studies have identified the presence of mutations at codons 12 and 13 of KRAS as predictors of poor response to the anti-EGFR monoclonal antibodies panitumumab and cetuximab. Patients with wild-type KRAS were found to have significantly better progression-free survival, overall survival, and/or objective response rate compared with patients harboring KRAS mutations. As a result, there has been growing interest in the development of KRAS mutational status as a biomarker for predicting patient response to EGFR-targeted therapy. Screening colorectal tumors for the absence of KRAS mutations may help identify patients most likely to benefit from anti-EGFR therapies.

  3. Epidermal Growth Factor Receptor Mutational Status and Brain Metastases in Non-Small-Cell Lung Cancer.

    PubMed

    Bhatt, Vijaya Raj; D'Souza, Sanyo P; Smith, Lynette M; Cushman-Vokoun, Allison M; Noronha, Vanita; Verma, Vivek; Joshi, Amit; Chougule, Anuradha; Jambhekar, Nirmala; Kessinger, Anne; Marr, Alissa; Patil, Vijay; Banavali, Sripad D; Ganti, Apar Kishor; Prabhash, Kumar

    2017-06-01

    Epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancers (NSCLC) may be more common in patients with brain metastases. Previous studies, however, did not adjust for effects of confounding variables. This retrospective study included 1,522 consecutive patients with NSCLC, whose tumors were diagnosed and tested for EGFR mutations at the University of Nebraska Medical Center (Omaha, NE) and Tata Memorial Hospital (Mumbai, India). Multivariate logistic regression was used to identify any association between EGFR status and clinical factors. EGFR mutations were more common in females than males (38.7% v 24.8%), Asians than whites (31.3% v 13.4%), nonsmokers than smokers (40.2% v 14.6%), alcohol nonconsumers than users (32.4% v 15.8%), adenocarcinoma than other histology types (32.7% v 10.3%), and patients with brain metastases than extracranial or no metastases (39.4% v 29.8% v 15.1%; P < .001 for all comparisons). There was a higher likelihood of an EGFR mutation among patients with brain metastases (odds ratio, 1.8; P < .001). The median overall survival (OS) was 19.8 months. Patients with brain metastases had a shorter median OS (15 v 20.6 months; P = .02). However, in the cohort of EGFR mutation-positive patients, there was no difference in median OS between patients with and without brain metastases (20.8 v 25.1 months; P = .11). There is a nearly two-fold higher incidence of EGFR mutations in NSCLC among patients with brain metastases at diagnosis. EGFR mutations did not predict for outcomes from brain metastases.

  4. [Andrological status of adolescents and its connection to anthropometric and hormonal descriptions in the students of technical college group].

    PubMed

    Lutov, Iu V; Seliatitskaia, V G; Epanchintseva, E A; Riabichenko, T I

    2014-01-01

    The purpose of this investigation was to study the interrelation of andrological status with anthropometric and hormonal descriptions for age-specific features discovery of male sexual system pathological states at technical college students. 147 adolescents aged 15-17 years old were examined. Only 41 of them were found to have no abnormalities in their genital system development; in 35 adolescents sexual development was delayed; and 97 adolescents were found to have various andrological diseases (varicocele, phimosis, gynecomastia, testicular asymmetry, etc.) or clinical signs for development of these diseases. In 26 adolescences delayed sexual development was combined with the andrological pathology. The normal andrological status was usually accompanied with the highest frequency of low values of anthropometric indicators and indices that reflect the influence of various hormonal systems on the bodily constitution, as well as expressed anthropometricheterogeneity. In adolescents with andrological pathology or clinical signs for its development, in all anthropometric parameters the higher values were seen more frequently than low values against the background of highest group anthropometric homogeneity. Summative anthropometric characteristics of the adolescents group with delayed sexual development were between those of the adolescents groups with normal andrological status and andrological pathology The number of correlational relationships of anthropometric and hormonal indicators with the levels of cortisol and dehydroepiandrosteronesulphate was the lowest in the group of adolescents with normal andrological status as compared to their peers with delayed sexual development and andrological pathology. Only in the group of adolescents with normal andrological status the correlation analysis of data showed physiological influence of sexual hormones on anthropometric indicators. Thus, lower influence of sexual system hormones during this ontogenesis stage

  5. The correlation between EGFR mutation status and the risk of brain metastasis in patients with lung adenocarcinoma.

    PubMed

    Li, Bo; Sun, Suo-Zhu; Yang, Ming; Shi, Jian-Ling; Xu, Wei; Wang, Xi-Fan; Song, Mao-Min; Chen, Huo-Ming

    2015-08-01

    To explore the correlation between epidermal growth factor receptor (EGFR) mutation status and the risk of brain metastasis (BM) in patients with lung adenocarcinoma, the clinical data of 100 patients with pathologically confirmed lung adenocarcinoma and known EGFR mutation status at exon 18, 19, 20, or 21 were analyzed retrospectively. The incidence of BM was similar between patients with wild-type EGFR and those with EGFR mutations (p = 0.48). However, among patients with EGFR mutations, the incidence of BM was significantly higher in patients with mutation at exon 19 than in patients with mutation at other sites (p = 0.007). Besides, among patients with heterochronous BM, 66.7 % had EGFR mutations. Regarding brain-metastasis-free survival (BMFS), patients with EGFR sensitive mutations (mutation at exon 19/21/and dual mutation) had significantly shorter BMFS compared with patients with wild-type EGFR (p = 0.018). For patients treated only with chemotherapy, BM was an unfavorable prognostic factor. Patients with BM had worse overall survival compared with those without BM (p = 0.035). However, in patients with BM and EGFR sensitive mutations, those treated with tyrosine kinase inhibitors (TKIs) had significantly longer overall survival compared with those treated with chemotherapy only (p = 0.0081). In conclusion, among patients with EGFR mutations, those mutated at exon 19 had the highest incidence of BM. Furthermore, patients with EGFR mutations are more likely to develop heterochronous BM. The BMFS was significantly shorter in patients with EGFR sensitive mutations. TKIs improved the survival of patients with lung adenocarcinoma and BM who harbored EGFR sensitive mutations.

  6. A domestication related mutation in the thyroid stimulating hormone receptor gene (TSHR) modulates photoperiodic response and reproduction in chickens.

    PubMed

    Karlsson, Anna-Carin; Fallahshahroudi, Amir; Johnsen, Hanna; Hagenblad, Jenny; Wright, Dominic; Andersson, Leif; Jensen, Per

    2016-03-01

    The thyroid stimulating hormone receptor gene (TSHR) has been suggested to be a "domestication locus" in the chicken. A strong selective sweep over TSHR in domestic breeds together with significant effects of a mutation in the gene on several domestication related traits, indicate that the gene has been important for chicken domestication. TSHR plays a key role in the signal transduction of seasonal reproduction, which is characteristically less strict in domestic animals. We used birds from an advanced intercross line between ancestral Red Junglefowl (RJF) and domesticated White Leghorn (WL) to investigate effects of the mutation on reproductive traits as well as on TSHB, TSHR, DIO2 and DIO3 gene expression during altered day length (photoperiod). We bred chickens homozygous for either the mutation (d/d) or wild type allele (w/w), allowing assessment of the effect of genotype at this locus while also controlling for background variation in the rest of the genome. TSHR gene expression in brain was significantly lower in both d/d females and males and d/d females showed a faster onset of egg laying at sexual maturity than w/w. Furthermore, d/d males showed a reduced testicular size response to decreased day length, and lower levels of TSHB and DIO3 expression. Additionally, purebred White Leghorn females kept under natural short day length in Sweden during December had active ovaries and lower levels of TSHR and DIO3 expression compared to Red Junglefowl females kept under similar conditions. Our study indicates that the TSHR mutation affects photoperiodic response in chicken by reducing dependence of seasonal reproduction, a typical domestication feature, and may therefore have been important for chicken domestication. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Thyroid Hormone Status Interferes with Estrogen Target Gene Expression in Breast Cancer Samples in Menopausal Women

    PubMed Central

    Conde, Sandro José; Luvizotto, Renata de Azevedo Melo; de Síbio, Maria Teresa; Nogueira, Célia Regina

    2014-01-01

    We investigated thyroid hormone levels in menopausal BrC patients and verified the action of triiodothyronine on genes regulated by estrogen and by triiodothyronine itself in BrC tissues. We selected 15 postmenopausal BrC patients and a control group of 18 postmenopausal women without BrC. We measured serum TPO-AB, TSH, FT4, and estradiol, before and after surgery, and used immunohistochemistry to examine estrogen and progesterone receptors. BrC primary tissue cultures received the following treatments: ethanol, triiodothyronine, triiodothyronine plus 4-hydroxytamoxifen, 4-hydroxytamoxifen, estrogen, or estrogen plus 4-hydroxytamoxifen. Genes regulated by estrogen (TGFA, TGFB1, and PGR) and by triiodothyronine (TNFRSF9, BMP-6, and THRA) in vitro were evaluated. TSH levels in BrC patients did not differ from those of the control group (1.34 ± 0.60 versus 2.41 ± 1.10 μU/mL), but FT4 levels of BrC patients were statistically higher than controls (1.78 ± 0.20 versus 0.95 ± 0.16 ng/dL). TGFA was upregulated and downregulated after estrogen and triiodothyronine treatment, respectively. Triiodothyronine increased PGR expression; however 4-hydroxytamoxifen did not block triiodothyronine action on PGR expression. 4-Hydroxytamoxifen, alone or associated with triiodothyronine, modulated gene expression of TNFRSF9, BMP-6, and THRA, similar to triiodothyronine treatment. Thus, our work highlights the importance of thyroid hormone status evaluation and its ability to interfere with estrogen target gene expression in BrC samples in menopausal women. PMID:24701358

  8. Generalized resistance to thyroid hormone associated with a mutation in the ligand-binding domain of the human thyroid hormone receptor. beta

    SciTech Connect

    Sakurai, A.; Takeda, K.; Ain, K.; Ceccarelli, P.; Nakai, A.; Seino, S.; Bell, G.I.; Refetoff, S.; DeGroot, L.J. )

    1989-11-01

    The syndrome of generalized resistance to thyroid hormone is characterized by elevated circulating levels of thyroid hormone in the presence of an overall eumetabolic state and failure to respond normally to triiodothyronine. The authors have evaluated a family with inherited generalized resistance to thyroid hormone for abnormalities in the thyroid hormone nuclear receptors. A single guanine {yields} cytosine replacement in the codon for amino acid 340 resulted in a glycine {yields} arginine substitution in the hormone-binding domain of one of two alleles of the patient's thyroid hormone nuclear receptor {beta} gene. In vitro translation products of this mutant human thyroid hormone nuclear receptor {beta} gene did not bind triiodothyronine. Thus, generalized resistance to thyroid hormone can result from expression of an abnormal thyroid hormone nuclear receptor molecule.

  9. Juvenile hormone catabolism and oviposition in the codling moth, Cydia pomonella, as functions of age, mating status, and hormone treatment.

    PubMed

    Cole, Tracey J; Ramaswamy, Sonny B; Srinivasan, Asoka; Dorn, Silvia

    2002-01-01

    In vitro catabolism of juvenile hormone (JH) in haemolymph of adult female Cydia pomonella was ascribed mainly to juvenile hormone esterase (JHE) activity. No significant differences were noted between virgin and mated females 0-96 h post-emergence. Changes in JHE activity did not appear dependent upon fluctuations in JH titre; conversely, changes in JHE activity could not explain the changes in JH titres. Maximal JHE activity was recorded at 24 h (331.47 +/- 47.25 pmol/h/microl; 355.93 +/- 36.68 pmol/h/microl, virgin; mated insects, respectively) and preceded the peak in JH titres at 48 h. Topical application of JH II (10 ng-10 microg) or fenoxycarb (50 ng) enhanced JHE activity up to 640 and 56%, respectively. Treatment upon emergence with 10 microg JH II induced enzymic activity for less than 24 h, and when 10 microg JH II or 50 ng fenoxycarb were applied, circulating JH titres returned to control levels within 24 h. Oviposition was highly sensitive to exogenous JH and declined significantly with dosages >100 pg. To allow a degree of oocyte maturation before JH treatment, the hormone was administered at 6, 12, 24, or 48 h post-emergence and/or females were mated. Neither measure "protected" the system; oviposition declined immediately after JH application.

  10. The relationship between history of hormonal contraceptive use and iron status among women in Tanzania: A population-based study.

    PubMed

    Haile, Zelalem T; Kingori, Caroline; Teweldeberhan, Asli K; Chavan, Bhakti

    2017-10-01

    Approximately 30% of the Tanzanian women in the reproductive age group are iron deficient. At population-level, there is a dearth of research on the relationship between hormonal contraceptive use and iron deficiency. The study objective was to examine the relationship between history of hormonal contraceptive use and iron status among women in Tanzania. We conducted a cross-sectional study analysis including 4186 women who participated in the population-based 2010 Tanzania Demographic and Health Survey. Iron status determined by iron deficiency, anemia, and iron deficiency anemia. Almost 19.0% women reported history of hormonal contraceptive use. Nearly, 30.0%, 39.5%, and 14.3% women had iron deficiency, anemia and iron deficiency anemia respectively. History of hormonal contraceptive use was negatively associated with iron deficiency, anemia and iron deficiency anemia, independent of potential confounders. Compared to non-users, the multivariable-adjusted odds ratio OR (95% CI) among hormonal contraceptive users was 0.73 (0.56-0.94, p<0.05) for iron deficiency, 0.58 (0.46-0.72, p<0.001) for anemia, and 0.53 (0.37-0.74; p<0.001) for iron deficiency anemia. Longer duration of hormonal contraceptive use (>2years) had lesser odds of iron deficiency 0.63 (0.43-0.91, p for trend 0.005), anemia 0.51 (0.36-0.73, p for trend <0.001) and iron deficiency anemia 0.35 (0.19-0.65, p for trend <0.001). Our finding has important implications for educating healthcare providers and women about additional nutritional benefits of the use of hormonal contraceptives. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Adiposity, hormone replacement therapy use and breast cancer risk by age and hormone receptor status: a large prospective cohort study

    PubMed Central

    2012-01-01

    Introduction Associations of hormone-receptor positive breast cancer with excess adiposity are reasonably well characterized; however, uncertainty remains regarding the association of body mass index (BMI) with hormone-receptor negative malignancies, and possible interactions by hormone replacement therapy (HRT) use. Methods Within the European EPIC cohort, Cox proportional hazards models were used to describe the relationship of BMI, waist and hip circumferences with risk of estrogen-receptor (ER) negative and progesterone-receptor (PR) negative (n = 1,021) and ER+PR+ (n = 3,586) breast tumors within five-year age bands. Among postmenopausal women, the joint effects of BMI and HRT use were analyzed. Results For risk of ER-PR- tumors, there was no association of BMI across the age bands. However, when analyses were restricted to postmenopausal HRT never users, a positive risk association with BMI (third versus first tertile HR = 1.47 (1.01 to 2.15)) was observed. BMI was inversely associated with ER+PR+ tumors among women aged ≤49 years (per 5 kg/m2 increase, HR = 0.79 (95%CI 0.68 to 0.91)), and positively associated with risk among women ≥65 years (HR = 1.25 (1.16 to 1.34)). Adjusting for BMI, waist and hip circumferences showed no further associations with risks of breast cancer subtypes. Current use of HRT was significantly associated with an increased risk of receptor-negative (HRT current use compared to HRT never use HR: 1.30 (1.05 to 1.62)) and positive tumors (HR: 1.74 (1.56 to 1.95)), although this risk increase was weaker for ER-PR- disease (Phet = 0.035). The association of HRT was significantly stronger in the leaner women (BMI ≤22.5 kg/m2) than for more overweight women (BMI ≥25.9 kg/m2) for, both, ER-PR- (HR: 1.74 (1.15 to 2.63)) and ER+PR+ (HR: 2.33 (1.84 to 2.92)) breast cancer and was not restricted to any particular HRT regime. Conclusions An elevated BMI may be positively associated with risk of ER-PR- tumors among postmenopausal women

  12. Epidermal Growth Factor Receptor Mutational Status and Brain Metastases in Non–Small-Cell Lung Cancer

    PubMed Central

    Bhatt, Vijaya Raj; D’Souza, Sanyo P.; Smith, Lynette M.; Cushman-Vokoun, Allison M.; Noronha, Vanita; Verma, Vivek; Joshi, Amit; Chougule, Anuradha; Jambhekar, Nirmala; Kessinger, Anne; Marr, Alissa; Patil, Vijay; Banavali, Sripad D.; Prabhash, Kumar

    2017-01-01

    Introduction Epidermal growth factor receptor (EGFR) mutations in non–small-cell lung cancers (NSCLC) may be more common in patients with brain metastases. Previous studies, however, did not adjust for effects of confounding variables. Methods This retrospective study included 1,522 consecutive patients with NSCLC, whose tumors were diagnosed and tested for EGFR mutations at the University of Nebraska Medical Center (Omaha, NE) and Tata Memorial Hospital (Mumbai, India). Multivariate logistic regression was used to identify any association between EGFR status and clinical factors. Results EGFR mutations were more common in females than males (38.7% v 24.8%), Asians than whites (31.3% v 13.4%), nonsmokers than smokers (40.2% v 14.6%), alcohol nonconsumers than users (32.4% v 15.8%), adenocarcinoma than other histology types (32.7% v 10.3%), and patients with brain metastases than extracranial or no metastases (39.4% v 29.8% v 15.1%; P < .001 for all comparisons). There was a higher likelihood of an EGFR mutation among patients with brain metastases (odds ratio, 1.8; P < .001). The median overall survival (OS) was 19.8 months. Patients with brain metastases had a shorter median OS (15 v 20.6 months; P = .02). However, in the cohort of EGFR mutation–positive patients, there was no difference in median OS between patients with and without brain metastases (20.8 v 25.1 months; P = .11). Conclusion There is a nearly two-fold higher incidence of EGFR mutations in NSCLC among patients with brain metastases at diagnosis. EGFR mutations did not predict for outcomes from brain metastases. PMID:28717762

  13. CDKN2A exon-wise deletion status and novel somatic mutations in Indian glioma patients.

    PubMed

    Sibin, M K; Bhat, Dhananjaya I; Lavanya, Ch; Manoj, M Jeru; Aakershita, S; Chetan, G K

    2014-02-01

    Over the years, deletions of CDKN2A (p16) tumor suppressor gene has been studied using FISH and multiplex PCR, with major focus on exon 2 in various cancers, and the frequency of mutation is found to be varied in different studies. In this study, we analyzed the deletion status of all three exons of p16 and frequency of exon 2 somatic point mutations in glioma from the Indian population and its clinical implications. Multiplex PCR was carried out in order to check deletion of all 3 exons in 50 glioma samples. Nonconventional PCR-SSCP analysis and sequencing was done to identify mutations in 48 cases. Deletion of at least one of the three exons of p16 INK4A was observed in ten cases (20 %). The frequencies of exon-wise deletions were 10 % for exon 1, 4 % for exon 2, and 8 % for exon 3. Two out of 48 samples were positive for mutations in p16 exon 2. One sample had a transition of G to C on position 147 with a codon change TGG to TGC which does not contribute to the protein structure. Another sample had a transversion of A to G on the position 154 with a codon change ATG to GTG with change in amino acid methionine to valine in 52nd position. Deletion pattern was found to be varied in three exons. Frequency of p16 gene mutation was less in the Indian population (4.2 %), and this mutation does not contribute to any remarkable change in protein structure.

  14. Effects of HIV Infection on the Metabolic and Hormonal Status of Children with Severe Acute Malnutrition

    PubMed Central

    Hornik, Christoph P.; Kiyimba, Tonny; Bain, James; Muehlbauer, Michael; Kiboneka, Elizabeth; Stevens, Robert; St. Peter, John V.; Newgard, Christopher B.; Bartlett, John; Freemark, Michael

    2014-01-01

    Background HIV infection occurs in 30% of children with severe acute malnutrition in sub-Saharan Africa. Effects of HIV on the pathophysiology and recovery from malnutrition are poorly understood. Methods We conducted a prospective cohort study of 75 severely malnourished Ugandan children. HIV status/CD4 counts were assessed at baseline; auxologic data and blood samples were obtained at admission and after 14 days of inpatient treatment. We utilized metabolomic profiling to characterize effects of HIV infection on metabolic status and subsequent responses to nutritional therapy. Findings At admission, patients (mean age 16.3 mo) had growth failure (mean W/H z-score −4.27 in non-edematous patients) that improved with formula feeding (mean increase 1.00). 24% (18/75) were HIV-infected. Nine children died within the first 14 days of hospitalization; mortality was higher for HIV-infected patients (33% v. 5%, OR = 8.83). HIV-infected and HIV-negative children presented with elevated NEFA, ketones, and even-numbered acylcarnitines and reductions in albumin and amino acids. Leptin, adiponectin, insulin, and IGF-1 levels were low while growth hormone, cortisol, and ghrelin levels were high. At baseline, HIV-infected patients had higher triglycerides, ketones, and even-chain acylcarnitines and lower leptin and adiponectin levels than HIV-negative patients. Leptin levels rose in all patients following nutritional intervention, but adiponectin levels remained depressed in HIV-infected children. Baseline hypoleptinemia and hypoadiponectinemia were associated with increased mortality. Conclusions Our findings suggest a critical interplay between HIV infection and adipose tissue storage and function in the adaptation to malnutrition. Hypoleptinemia and hypoadiponectinemia may contribute to high mortality rates among malnourished, HIV-infected children. PMID:25050734

  15. JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes.

    PubMed

    Rumi, Elisa; Pietra, Daniela; Ferretti, Virginia; Klampfl, Thorsten; Harutyunyan, Ashot S; Milosevic, Jelena D; Them, Nicole C C; Berg, Tiina; Elena, Chiara; Casetti, Ilaria C; Milanesi, Chiara; Sant'antonio, Emanuela; Bellini, Marta; Fugazza, Elena; Renna, Maria C; Boveri, Emanuela; Astori, Cesare; Pascutto, Cristiana; Kralovics, Robert; Cazzola, Mario

    2014-03-06

    Patients with essential thrombocythemia may carry JAK2 (V617F), an MPL substitution, or a calreticulin gene (CALR) mutation. We studied biologic and clinical features of essential thrombocythemia according to JAK2 or CALR mutation status and in relation to those of polycythemia vera. The mutant allele burden was lower in JAK2-mutated than in CALR-mutated essential thrombocythemia. Patients with JAK2 (V617F) were older, had a higher hemoglobin level and white blood cell count, and lower platelet count and serum erythropoietin than those with CALR mutation. Hematologic parameters of patients with JAK2-mutated essential thrombocythemia or polycythemia vera were related to the mutant allele burden. While no polycythemic transformation was observed in CALR-mutated patients, the cumulative risk was 29% at 15 years in those with JAK2-mutated essential thrombocythemia. There was no significant difference in myelofibrotic transformation between the 2 subtypes of essential thrombocythemia. Patients with JAK2-mutated essential thrombocythemia and those with polycythemia vera had a similar risk of thrombosis, which was twice that of patients with the CALR mutation. These observations are consistent with the notion that JAK2-mutated essential thrombocythemia and polycythemia vera represent different phenotypes of a single myeloproliferative neoplasm, whereas CALR-mutated essential thrombocythemia is a distinct disease entity.

  16. JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes

    PubMed Central

    Rumi, Elisa; Pietra, Daniela; Ferretti, Virginia; Klampfl, Thorsten; Harutyunyan, Ashot S.; Milosevic, Jelena D.; Them, Nicole C. C.; Berg, Tiina; Elena, Chiara; Casetti, Ilaria C.; Milanesi, Chiara; Sant’Antonio, Emanuela; Bellini, Marta; Fugazza, Elena; Renna, Maria C.; Boveri, Emanuela; Astori, Cesare; Pascutto, Cristiana; Kralovics, Robert

    2014-01-01

    Patients with essential thrombocythemia may carry JAK2 (V617F), an MPL substitution, or a calreticulin gene (CALR) mutation. We studied biologic and clinical features of essential thrombocythemia according to JAK2 or CALR mutation status and in relation to those of polycythemia vera. The mutant allele burden was lower in JAK2-mutated than in CALR-mutated essential thrombocythemia. Patients with JAK2 (V617F) were older, had a higher hemoglobin level and white blood cell count, and lower platelet count and serum erythropoietin than those with CALR mutation. Hematologic parameters of patients with JAK2-mutated essential thrombocythemia or polycythemia vera were related to the mutant allele burden. While no polycythemic transformation was observed in CALR-mutated patients, the cumulative risk was 29% at 15 years in those with JAK2-mutated essential thrombocythemia. There was no significant difference in myelofibrotic transformation between the 2 subtypes of essential thrombocythemia. Patients with JAK2-mutated essential thrombocythemia and those with polycythemia vera had a similar risk of thrombosis, which was twice that of patients with the CALR mutation. These observations are consistent with the notion that JAK2-mutated essential thrombocythemia and polycythemia vera represent different phenotypes of a single myeloproliferative neoplasm, whereas CALR-mutated essential thrombocythemia is a distinct disease entity. PMID:24366362

  17. Growth hormone receptor gene mutations in two Italian patients with Laron Syndrome.

    PubMed

    Fassone, L; Corneli, G; Bellone, S; Camacho-Hübner, C; Aimaretti, G; Cappa, M; Ubertini, G; Bona, G

    2007-05-01

    Laron Syndrome (LS) represents a condition characterized by GH insensitivity caused by molecular defects in the GH receptor (GHR) gene or in the post-receptor signalling pathway. We report the molecular characterization of two unrelated Italian girls from Sicily diagnosed with LS. The DNA sequencing of the GHR gene revealed the presence of different nonsense mutations, occurring in the same background haplotype. The molecular defects occurred in the extracellular domain of the GHR leading to a premature termination signal and to a truncated non-functional receptor. In one patient, a homozygous G to T transversion, in exon 6, led to the mutation GAA to TAA at codon 180 (E180X), while in the second patient a homozygous C to T transition in exon 7 was detected, causing the CGA to TAA substitution at codon 217 (R217X). Both probands presented the polymorphisms Gly168Gly and Ile544Leu in a homozygous state in exons 6 and 10, respectively. The E180X represents a novel defect of the GHR gene, while the R217X mutation has been previously reported in several patients from different ethnic backgrounds but all from countries located in the Mediterranean and Middle Eastern region.

  18. VE1 immunohistochemistry predicts BRAF V600E mutation status and clinical outcome in colorectal cancer

    PubMed Central

    Schafroth, Christian; Galván, José A.; Centeno, Irene; Koelzer, Viktor H.; Dawson, Heather E.; Sokol, Lena; Rieger, Gregor; Berger, Martin D.; Hädrich, Marion; Rosenberg, Robert; Nitsche, Ulrich; Schnüriger, Beat; Langer, Rupert; Inderbitzin, Daniel; Lugli, Alessandro; Zlobec, Inti

    2015-01-01

    Aim VE1 is a monoclonal antibody detecting mutant BRAFV600E protein by immunohistochemistry. Here we aim to determine the inter-observer agreement and concordance of VE1 with mutational status, investigate heterogeneity in colorectal cancers and metastases and determine the prognostic effect of VE1 in colorectal cancer patients. Methods Concordance of VE1 with mutational status and inter-observer agreement were tested on a pilot cohort of colorectal cancers (n = 34), melanomas (n = 23) and thyroid cancers (n = 8). Two prognostic cohorts were evaluated (n = 259, Cohort 1 and n = 226, Cohort 2) by multiple-punch tissue microarrays. VE1 staining on preoperative biopsies (n = 118 patients) was compared to expression in resections. Primary tumors and metastases from 13 patients were tested for VE1 heterogeneity using a tissue microarray generated from all available blocks (n = 100 blocks). Results Inter-observer agreement was 100% (kappa = 1.0). Concordance between VE1 and V600E mutation was 98.5%. Cohort 1: VE1 positivity (seen in 13.5%) was associated with older age (p = 0.0175) and MLH1 deficiency (p < 0.0001). Cohort 2: VE1 positivity (seen in 12.8%) was associated with female gender (p = 0.0016), right-sided tumor location (p < 0.0001), higher tumor grade (p < 0.0001) and mismatch repair (MMR)-deficiency (p < 0.0001). In survival analysis, MMR status and postoperative therapy were identified as possible confounding factors. Adjusting for these features, VE1 was an unfavorable prognostic factor. Preoperative biopsy staining matched resections in all cases except one. No heterogeneity was found across any primary/metastatic tumor blocks. Conclusion VE1 is highly concordant for V600E and homogeneously expressed suggesting staining can be analysed on resection specimens, preoperative biopsies, metastatic lesions and tissue microarrays. PMID:26496026

  19. The effects of ryanodine receptor (RYR1) mutation on natural killer cell cytotoxicity, plasma cytokines and stress hormones during acute intermittent exercise in pigs.

    PubMed

    Ciepielewski, Z M; Stojek, W; Borman, A; Myślińska, D; Pałczyńska, P; Kamyczek, M

    2016-04-01

    Stress susceptibility has been mapped to a single recessive gene, the ryanodine receptor 1 (RYR1) gene or halothane (Hal) gene. Homozygous (Hal(nn)), mutated pigs are sensitive to halothane and susceptible to Porcine Stress Syndrome (PSS). Previous studies have shown that stress-susceptible RYR1 gene mutated homozygotes in response to restraint stress showed an increase in natural killer cell cytotoxicity (NKCC) accompanied by more pronounced stress-related hormone and anti-inflammatory cytokine changes. In order to determine the relationship of a RYR1 gene mutation with NKCC, plasma cytokines and stress-related hormones following a different stress model - exercise - 36 male pigs (representing different genotypes according to RYR1 gene mutation: NN, homozygous dominant; Nn, heterozygous; nn, homozygous recessive) were submitted to an intermittent treadmill walking. During the entire experiment the greatest level of NKCC and the greatest concentrations of interleukin (IL-) 6, IL-10, IL-12, interferon (IFN-)γ and tumor necrosis factor-α and stress-related hormones (adrenaline, prolactin, beta-endorphin) were observed in nn pigs, and the greatest concentration of IL-1 and growth hormone in NN pigs. Immunostimulatory effects of intermittent exercise on NKCC in nn pigs were concomitant with increases in IL-2, IL-12 and IFN-γ, the potent NKCC activators. Our findings suggest that stress-susceptible pigs RYR1 gene mutated pigs develop a greater level of NKCC and cytokine production in response to exercise stress. These results suggest that the heterogeneity of immunological and neuroendocrine response to exercise stress in pigs could be influenced by RYR1 gene mutation.

  20. Search for genetic variants in the retinoid X receptor-gamma-gene by polymerase chain reaction-single-strand conformation polymorphism in patients with resistance to thyroid hormone without mutations in thyroid hormone receptor beta gene.

    PubMed

    Romeo, Stefano; Menzaghi, Claudia; Bruno, Rocco; Sentinelli, Federica; Fallarino, Mara; Fioretti, Francesca; Filetti, Sebastiano; Balsamo, Armando; Di Mario, Umberto; Baroni, Marco G

    2004-05-01

    Resistance to thyroid hormone (RTH) is an inherited disease characterized by reduced tissue sensitivity to thyroid hormone. Approximately 90% of subjects with RTH have mutation in the thyroid hormone receptor beta (TRbeta) gene. Approximately 10% of subjects diagnosed as having RTH do not carry mutation in the TRbeta gene. A possible linkage was reported with the retinoid X receptor-gamma (RXR-gamma) gene in two families. The aim of this study is to search for mutation within the RXR-gamma gene in unrelated subjects with diagnosed RTH without mutations in the TRbeta gene. Four subjects with RTH were studied, and sequence variants in the RXR-gamma gene were searched by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP). Analysis of all the 10 exons of the RXR-gamma gene, including intron-exon boundaries, promoter region and 3' untranslated region (UTR) reveled two variant bands in subjects II and III. Sequencing of these variants showed two single nucleotide polymorphisms (SNPs): 447C > T in exon 3 for patients II and IVS9 + 6A > G for patient III. Both SNPs were also present at high frequency in a group of normal subjects and in nonaffected relatives of subject III. In conclusion, in patients with RTH we have found two SNPs in the RXR-gamma gene; these SNPS are common in the general population, thus excluding a role for the RXR-gamma gene in these patients.

  1. Association between BRCA Mutation Status, Pathological Findings, and Magnetic Resonance Imaging Features in Patients with Breast Cancer at Risk for the Mutation.

    PubMed

    Noh, Jae Myoung; Han, Boo-Kyung; Choi, Doo Ho; Rhee, Sun Jung; Cho, Eun Yoon; Huh, Seung Jae; Park, Won; Park, Hyojung; Nam, Seok Jin; Lee, Jeong Eon; Kil, Won-Ho

    2013-09-01

    We investigated the relationship between BRCA mutations, pathological findings, and magnetic resonance imaging (MRI) features in patients with breast cancer at risk for the mutation. Genetic testing for BRCA mutations was performed in 275 breast cancer patients with at least one risk factor for the mutation. Using the breast imaging reporting and data system MR lexicon, morphological and kinetic features were reviewed on MRI scans of 230 tumors in 209 patients. The relationship between BRCA mutations, pathologic findings, and MRI data was examined, and disease recurrence was estimated. BRCA mutations were detected in 48 patients (23.0%), of which 21 (10.0%) were in BRCA1, and 25 (12.0%) in BRCA2. Additionally, two patients (1.0%) had mutations in both genes. Cancers in patients with BRCA1 mutations more frequently showed a higher nuclear grade (p=0.0041), and triple-negative (TN) phenotype (p<0.0001). On MRI scans, the cancers were seen as mass-type in 182 out of 230 lesions (79.1%), and nonmass type in 48 cases (20.9%). Among the features indentified by MRI, rim enhancement was significantly associated with molecular subtypes based on immunohistochemistry (p<0.0001), and nuclear grade (p=0.0387) in multiple logistic regression analysis. Rim enhancement on MRI, along with advanced pathologic N stage, was associated with increased disease recurrence (p=0.0023) based on multivariate analysis. However, the proportion of mass and nonmass tumors, and the distribution of morphological shape, margin, internal enhancement, and kinetic features assessed by MRI were not different according to BRCA mutation status. BRCA1 mutations were associated with aggressive pathological characteristics, and the TN phenotype. Rim enhancement was frequently seen on MRI scans of high-grade cancers and in the TN phenotype. And it was a significant predictor of disease recurrence. However, a direct association with BRCA mutations was not observed.

  2. KRAS driven expression signature has prognostic power superior to mutation status in non‐small cell lung cancer

    PubMed Central

    Nagy, Ádám; Pongor, Lőrinc Sándor; Szabó, András; Santarpia, Mariacarmela

    2016-01-01

    KRAS is the most frequently mutated oncogene in non‐small cell lung cancer (NSCLC). However, the prognostic role of KRAS mutation status in NSCLC still remains controversial. We hypothesize that the expression changes of genes affected by KRAS mutation status will have the most prominent effect and could be used as a prognostic signature in lung cancer. We divided NSCLC patients with mutation and RNA‐seq data into KRAS mutated and wild type groups. Mann‐Whitney test was used to identify genes showing altered expression between these cohorts. Mean expression of the top five genes was designated as a “transcriptomic fingerprint” of the mutation. We evaluated the effect of this signature on clinical outcome in 2,437 NSCLC patients using univariate and multivariate Cox regression analysis. Mutation of KRAS was most common in adenocarcinoma. Mutation status and KRAS expression were not correlated to prognosis. The transcriptomic fingerprint of KRAS include FOXRED2, KRAS, TOP1, PEX3 and ABL2. The KRAS signature had a high prognostic power. Similar results were achieved when using the second and third set of strongest genes. Moreover, all cutoff values delivered significant prognostic power (p < 0.01). The KRAS signature also remained significant (p < 0.01) in a multivariate analysis including age, gender, smoking history and tumor stage. We generated a “surrogate signature” of KRAS mutation status in NSCLC patients by computationally linking genotype and gene expression. We show that secondary effects of a mutation can have a higher prognostic relevance than the primary genetic alteration itself. PMID:27859136

  3. Aspirin Use and Risk of Colorectal Cancer According to BRAF Mutation Status

    PubMed Central

    Nishihara, Reiko; Lochhead, Paul; Kuchiba, Aya; Jung, Seungyoun; Yamauchi, Mai; Liao, Xiaoyun; Imamura, Yu; Qian, Zhi Rong; Morikawa, Teppei; Wang, Molin; Spiegelman, Donna; Cho, Eunyoung; Giovannucci, Edward; Fuchs, Charles S.; Chan, Andrew T.; Ogino, Shuji

    2013-01-01

    Importance Aspirin use reduces the risk of colorectal carcinoma. Experimental evidence implicates a role of RAF kinases in upregulation of PTGS2 (cyclooxygenase-2), suggesting that BRAF-mutant colonic cells might be less sensitive to the anti-tumor effects of aspirin than BRAF-wild-type neoplastic cells. Objective To examine if the association of aspirin intake with colorectal cancer risk differs according to status of tumor BRAF oncogene mutation. Design and Setting We collected biennial questionnaire data on aspirin use and followed participants from 1980 (in the Nurses’ Health Study) or 1986 (in the Health Professionals Follow-up Study) until July 1, 2006 for cancer incidence and until January 1, 2012 for cancer mortality. Duplication-method Cox proportional cause-specific hazards regression for competing risks data was used to compute hazard ratio (HR) for colorectal carcinoma incidence according to BRAF mutation status. Results Among 127,865 individuals, with 3,165,985 person-years of follow-up, we identified 1,226 incident rectal and colon cancers with available molecular data. Compared with non-use, regular aspirin use was associated with lower BRAF-wild-type cancer risk (multivariable HR=0.73 [95% CI, 0.64–0.83]; age-adjusted incidence rate difference [IRD]=−9.7 [95% CI, −12.6 to −6.7] per 100,000 person-years). This association was observed irrespective of status of tumor PTGS2 expression or PIK3CA or KRAS mutation. In contrast, regular aspirin use was not associated with a lower risk of BRAF-mutated cancer (multivariable HR=1.03 [95% CI, 0.76–1.38]; age-adjusted IRD=0.7 [95% CI, −0.3 to 1.7] per 100,000 person-years) (Pheterogeneity=0.037, between BRAF-wild-type vs. BRAF-mutated cancer risks). Compared with no aspirin use, aspirin use of >14 tablets per week was associated with a lower risk of BRAF-wild-type cancer (multivariable HR=0.43 [95% CI, 0.25–0.75]; age-adjusted IRD=−19.8 [95% CI, −26.3 to −13.3] per 100,000 person

  4. Pituitary resistance to thyroid hormone associated with a base mutation in the hormone-binding domain of the human 3, 5,3[prime]-triiodothyronine receptor-[beta

    SciTech Connect

    Sasaki, Shigekazu; Nakamura, Hirotoshi; Tagami, Tetsuya; Miyoshi, Yohzi; Nogimori, Tsuyoshi; Mitsuma, Terunori; Imura, Hiroo )

    1993-05-01

    Point mutations in the human T[sub 3] receptor-[beta] (TR[beta]) gene causing single amino acid substitutions have been identified in several different kindred with generalized resistance to thyroid hormone. Until now, no study has been reported on the TR gene in cases of pituitary resistance (PRTH). In the present study, the authors analyzed the TR[beta] gene in a 30-yr-old Japanese female with PRTH. She exhibited clinical features of hyperthyroidism, elevated serum thyroid hormone levels accompanied by inappropriately increased secretion of TSH, mildly elevated basal metabolic rate, and increased urinary excretion of hydroxyproline. No pituitary tumor was detected. DNA fragments of exons 3-8 of the geonomic TR[beta] gene were generated by the polymerase chain reaction and analyzed by a single stranded conformation polymorphism method. Exon 7 of the patient's TR[beta] gene showed an abnormal band, suggesting the existence of mutation(s). By subcloning and sequencing the DNA, a point mutation was identified in one allele at nucleotide 1297 (C to T), which altered the 333rd amino acid, arginine, to tryptophan. Neither of her apparently normal parents had any mutations of the TR[beta] gene. In vitro translation products of the mutant TR[beta] gene showed remarkably decreased T[sub 3]-binding activity (K[sub a], 2.1 [times] 10[sup 8] M[sup [minus]1]; normal TR[beta] K[sub a], 1.1 [times] 10[sup 10] M[sup [minus]1]). Since the molecular defect detected in a patient with PRTH is similar to that seen in subjects with generalized resistance to thyroid hormone, both types of the syndrome may represent a continuous spectrum of the same etiological defect with variable tissue resistance to thyroid hormone.

  5. Different metastatic pattern according to the KRAS mutational status and site-specific discordance of KRAS status in patients with colorectal cancer

    PubMed Central

    2012-01-01

    Background We evaluated the association between a KRAS mutational status and various clinicopathologic features including the metastatic pattern in patients with metastatic or recurrent colorectal cancer (MRCRC). The concordance rates of the KRAS status between primary tumor sites and paired metastatic organs were also analyzed. Methods The KRAS mutational status in codons 12, 13, and 61 from formalin-fixed sections of both primary tumors and related metastases was determined by sequencing analysis. One hundred forty-three Korean patients with MRCRC with available tissues (resection or biopsy) from both primary tumors and related metastatic sites were consecutively enrolled. Results The KRAS mutation rate was 52.4% (75/143) when considering both the primary and metastatic sites. When the relationship between the KRAS status and initial metastatic sites at the time of diagnosis of MRCRC was analyzed, lung metastasis was more frequent as the initial metastatic site in patients with the KRAS mutation than in patients without the KRAS mutation (45.3% vs. 22.1%; P = 0.003). However, liver (37.3% vs. 70.6%; P < 0.001) or distant lymph node metastases (6.7% vs. 19.1%; P = 0.025) were less frequent as the initial metastatic organ in patients with the KRAS mutation than in patients without the KRAS mutation. The discordance rate of KRAS mutational status between primary and paired metastatic sites other than the lung was 12.3% (13/106). Compared with primary tumor sites, the KRAS discordance rate was significantly higher in matched lung metastases [32.4% (12/37)] than in other matched metastatic organs (P = 0.005). Conclusions Organs initially involved by distant metastasis were different according to the KRAS mutational status in MRCRC patients. The concordance rate (87.7%) of the KRAS mutation status at metastatic sites other than the lung was generally high compared with primary tumor sites; however, lung metastasis had a high rate of KRAS discordance (32.4%). PMID

  6. A novel missense mutation in the mouse growth hormone gene causes semidominant dwarfism, hyperghrelinemia, and obesity.

    PubMed

    Meyer, Carola W E; Korthaus, Dirk; Jagla, Wolfgang; Cornali, Emmanuelle; Grosse, Johannes; Fuchs, Helmut; Klingenspor, Martin; Roemheld, Stephanie; Tschöp, Matthias; Heldmaier, Gerhard; De Angelis, Martin Hrabé; Nehls, Michael

    2004-05-01

    The SMA1-mouse is a novel ethyl-nitroso-urea (ENU)-induced mouse mutant that carries an a-->g missense mutation in exon 5 of the GH gene, which translates to a D167G amino acid exchange in the mature protein. Mice carrying the mutation are characterized by dwarfism, predominantly due to the reduction (sma1/+) or absence (sma1/sma1) of the GH-mediated peripubertal growth spurt, with sma1/+ mice displaying a less pronounced phenotype. All genotypes are viable and fertile, and the mode of inheritance is in accordance with a semidominant Mendelian trait. Adult SMA1 mice accumulate excessive amounts of sc and visceral fat in the presence of elevated plasma ghrelin levels, possibly reflecting altered energy partitioning. Our results suggest impaired storage and/or secretion of pituitary GH in mutants, resulting in reduced pituitary GH and reduced GH-stimulated IGF-1 expression. Generation and identification of the SMA1 mouse exemplifies the power of the combination of random mouse mutagenesis with a highly detailed phenotype-analysis as a successful strategy for the detection and analysis of novel gene-function relationships.

  7. MR-determined metabolic phenotype of breast cancer in prediction of lymphatic spread, grade, and hormone status.

    PubMed

    Bathen, Tone F; Jensen, Line R; Sitter, Beathe; Fjösne, Hans E; Halgunset, Jostein; Axelson, David E; Gribbestad, Ingrid S; Lundgren, Steinar

    2007-08-01

    The purpose of the study was to evaluate the use of metabolic phenotype, described by high-resolution magic angle spinning magnetic resonance spectroscopy (HR MAS MRS), as a tool for prediction of histological grade, hormone status, and axillary lymphatic spread in breast cancer patients. Biopsies from breast cancer (n = 91) and adjacent non-involved tissue (n = 48) were excised from patients (n = 77) during surgery. HR MAS MR spectra of intact samples were acquired. Multivariate models relating spectral data to histological grade, lymphatic spread, and hormone status were designed. The multivariate methods applied were variable reduction by principal component analysis (PCA) or partial least-squares regression-uninformative variable elimination (PLS-UVE), and modelling by PLS, probabilistic neural network (PNN), or cascade correlation neural network. In the end, model verification by prediction of blind samples (n = 12) was performed. Validation of PNN training resulted in sensitivity and specificity ranging from 83 to 100% for all predictions. Verification of models by blind sample testing showed that hormone status was well predicted by both PNN and PLS (11 of 12 correct), lymphatic spread was best predicted by PLS (8 of 12), whereas PLS-UVE PNN was the best approach for predicting grade (9 of 12 correct). MR-determined metabolic phenotype may have a future role as a supplement for clinical decision-making-concerning adjuvant treatment and the adaptation to more individualised treatment protocols.

  8. A novel follicle-stimulating hormone receptor mutation causing primary ovarian failure: a fertility application of whole exome sequencing.

    PubMed

    Bramble, Matthew S; Goldstein, Ellen H; Lipson, Allen; Ngun, Tuck; Eskin, Ascia; Gosschalk, Jason E; Roach, Lara; Vashist, Neerja; Barseghyan, Hayk; Lee, Eric; Arboleda, Valerie A; Vaiman, Daniel; Yuksel, Zafer; Fellous, Marc; Vilain, Eric

    2016-04-01

    Can whole exome sequencing (WES) and in vitro validation studies be used to find the causative genetic etiology in a patient with primary ovarian failure and infertility? A novel follicle-stimulating hormone receptor (FSHR) mutation was found by WES and shown, via in vitro flow cytometry studies, to affect membrane trafficking. WES may diagnose up to 25-35% of patients with suspected disorders of sex development (DSD). FSHR mutations are an extremely rare cause of 46, XX gonadal dysgenesis with primary amenorrhea due to hypergonadotropic ovarian failure. A WES study was followed by flow cytometry studies of mutant protein function. The study subjects were two Turkish sisters with hypergonadotropic primary amenorrhea, their parents and two unaffected sisters. The affected siblings and both parents were sequenced (trio-WES). Transient transfection of HEK 293T cells was performed with a vector containing wild-type FSHR as well as the novel FSHR variant that was discovered by WES. Cellular localization of FSHR protein as well as FSH-stimulated cyclic AMP (cAMP) production was evaluated using flow cytometry. Both affected sisters were homozygous for a previously unreported missense mutation (c.1222G>T, p.Asp408Tyr) in the second transmembrane domain of FSHR. Modeling predicted disrupted secondary structure. Flow cytometry demonstrated an average of 48% reduction in cell-surface signal detection (P < 0.01). The mean fluorescent signal for cAMP (second messenger of FSHR), stimulated by FSH, was reduced by 50% in the mutant-transfected cells (P < 0.01). This is an in vitro validation. All novel purported genetic variants can be clinically reported only as 'variants of uncertain significance' until more patients with a similar phenotype are discovered with the same variant. We report the first WES-discovered FSHR mutation, validated by quantitative flow cytometry. WES is a valuable tool for diagnosis of rare genetic diseases, and flow cytometry allows for quantitative

  9. The Effect of a Mutation in the Thyroid Stimulating Hormone Receptor (TSHR) on Development, Behaviour and TH Levels in Domesticated Chickens

    PubMed Central

    Karlsson, Anna-Carin; Svemer, Frida; Eriksson, Jonas; Darras, Veerle M.; Andersson, Leif; Jensen, Per

    2015-01-01

    The thyroid stimulating hormone receptor (TSHR) has been suggested to be a “domestication locus” in the chicken, due to a strong selective sweep over the gene found in domesticated chickens, differentiating them from their wild ancestor the Red Junglefowl (RJF). We investigated the effect of the mutation on development (incubation time), behaviour and thyroid hormone levels in intercross chickens homozygous for the mutation (d/d), wild type homozygotes (w/w) or heterozygotes (d/w). This allowed an assessment of the effect of genotype at this locus against a random mix of RJF and WL genotypes throughout the rest of the genome, controlling for family effects. The d/d genotype showed a longer incubation time, less fearful behaviours, lower number of aggressive behaviours and decreased levels of the thyroid hormone T4, in comparison to the w/w genotype. The difference between TSHR genotypes (d/d vs. w/w) in these respects mirrors the differences in development and behaviour between pure domesticated White Leghorns and pure RJF chickens. Higher individual T3 and T4 levels were associated with more aggression. Our study indicates that the TSHR mutation affects typical domestication traits, possibly through modifying plasma levels of thyroid hormones, and may therefore have been important during the evolution of the domestic chicken. PMID:26053744

  10. The efficacy of IGF-I receptor monoclonal antibody against human gastrointestinal carcinomas is independent of k-ras mutation status.

    PubMed

    Ii, Masanori; Li, Hua; Adachi, Yasushi; Yamamoto, Hiroyuki; Ohashi, Hirokazu; Taniguchi, Hiroaki; Arimura, Yoshiaki; Carbone, David P; Imai, Kohzoh; Shinomura, Yasuhisa

    2011-08-01

    Insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling is required for carcinogenicity and proliferation of gastrointestinal cancers. We have previously shown successful targeting therapy for colorectal, pancreatic, gastric, and esophageal carcinomas using recombinant adenoviruses expressing dominant negative IGF-IR. Mutation in k-ras is one of key factors in gastrointestinal cancers. In this study, we sought to evaluate the effect of a new monoclonal antibody for IGF-IR, figitumumab (CP-751,871), on the progression of human gastrointestinal carcinomas with/without k-ras mutation. We assessed the effect of figitumumab on signal transduction, proliferation, and survival in six gastrointestinal cancer cell lines with/without k-ras mutation, including colorectal and pancreatic adenocarcinoma, esophageal squamous cell carcinoma, and hepatoma. Combination effects of figitumumab and chemotherapy were also studied. Then figitumumab was evaluated in the treatment of xenografts in nude mice. Figitumumab blocked autophosphorylation of IGF-IR and its downstream signals. The antibody suppressed proliferation and tumorigenicity in all cell lines. Figitumumab inhibited survival by itself and up-regulated chemotherapy (5-FU and gemcitabine) induced apoptosis. Moreover, the combination of this agent and chemotherapy was effective against tumors in mice. The effect of figitumumab was not influenced by the mutation status of k-ras. Figitumumab reduced expression of IGF-IR but not insulin receptor in these xenografted tumors. The drug did not affect murine body weight or blood concentrations of glucose, insulin, IGF binding protein 3, and growth hormone. IGF-IR might be a good molecular therapeutic target and figitumumab may thus have therapeutic value in human gastrointestinal malignancies even in the presence of k-ras mutations. ©2011 AACR.

  11. Survival but not brain metastasis response relates to lung cancer mutation status after radiosurgery.

    PubMed

    Shin, Samuel M; Cooper, Benjamin T; Chachoua, Abraham; Butler, James; Donahue, Bernadine; Silverman, Joshua S; Kondziolka, Douglas

    2016-02-01

    We prospectively addressed whether EGFR and KRAS mutations, EML4-ALK, ROS1 and RET rearrangements, or wild-type (WT), affects radiosurgery outcomes and overall survival (OS) in non-small cell lung cancer (NSCLC) patients with brain metastases (BM). Of 326 patients with BM treated in 2012-2014 with Gamma Knife radiosurgery (GKRS), 112 NSCLC patients received GKRS as their initial intracranial treatment. OS, intracranial progression-free survival, and time to intracranial failure were determined. Univariate and multivariate analysis were performed to determine factors affecting OS. Toxicity of treatment was evaluated. Median follow-up was 9 months. Patients with EGFR mutant BM had improved survival compared to WT. Median time to development of BM was higher in EGFR mutant patients, but this difference was not significant (2.2 vs 0.9 months; p = 0.2). Median time to distant brain failure was independent of EGFR mutation status. Karnofsky performance status (KPS), non-squamous histopathology, targeted therapy, systemic disease control, EGFR mutation, and low tumor volume were predictive of increased OS on univariate analysis. KPS (p = 0.001) and non-squamous histopathology (p = 0.03) continued to be significant on multivariate analysis. Patients with EGFR mutant BM underwent salvage treatment more often than those without (p = 0.04). Treatment-related toxicity was no different in patients treated with GKRS combined with targeted therapies versus GKRS alone (5 vs 7%, p = 0.7). Patients with EGFR mutant BM had improved survival compared to a WT cohort. Intracranial disease control following radiosurgery was similar for all tumor subtypes. Radiosurgery is effective for BM and concurrent treatment with targeted therapy appears to be safe.

  12. Two mutations in the hormone binding domain of the vitamin D receptor cause tissue resistance to 1,25 dihydroxyvitamin D3.

    PubMed Central

    Kristjansson, K; Rut, A R; Hewison, M; O'Riordan, J L; Hughes, M R

    1993-01-01

    We have identified and characterized two mutations in the hormone binding domain of the vitamin D receptor (VDR) in patients with hereditary vitamin D-resistant rickets. One patient was found to have a premature stop mutation (CAG to TAG) in the hinge region affecting amino acid 149 (Q149X) and the other demonstrated a missense mutation (CGC to CTC) resulting in the substitution of arginine 271 by leucine (R271L) in the steroid binding domain. Eukaryotic expression analyses in CV-1 cells showed the inability of both patients' VDR to induce transcription from the osteocalcin hormone gene response element at 10(-7) M 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). Normal transcription levels could, however, be elicited by the missense mutated VDR (R271L) in the presence of 1,000-fold higher 1,25-(OH)2D3 concentrations than needed for the wild-type receptor. This shows that Arg 271 directly affects the affinity of the VDR for its ligand and its conversion to leucine decreases its affinity for 1,25(OH)2D3 by a factor of 1,000. Arg 271 is located immediately 3-prime to a 30 amino acid segment (VDR amino acids 241-270) that is conserved among members of the steroid/thyroid/retinoid hormone receptor superfamily. These results represent the first missense mutation identified in the hormone binding domain of VDR and further define the structure-function relationship of 1,25(OH)2D3 ligand binding to its nuclear receptor. Images PMID:8392085

  13. Prognostic role of PIK3CA mutations and their association with hormone receptor expression in breast cancer: a meta-analysis.

    PubMed

    Pang, Bo; Cheng, Shi; Sun, Shi-Peng; An, Cheng; Liu, Zhi-Yuan; Feng, Xue; Liu, Gui-Jian

    2014-09-01

    The phosphatidylinositol-4, 5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) gene is frequently mutated in breast cancer (BCa). Sex hormone receptors (HRs), including estrogen receptor (ER) and progesterone receptor (PR) play pivotal roles in BCa. In this study, we evaluated the association between PIK3CA mutations and ER/PR expression and the prognostic role of PIK3CA mutations in BCa patients, and in particular, HR-positive BCa. Thirty-two studies involving 5719 cases of BCa obtained from database searches were examined. PIK3CA gene mutations correlated significantly with ER/PR expression (p < 0.00001) and relapse-free survival (RFS) (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.59-0.98, p = 0.03) but not overall survival (OS) (HR 1.14, 95%CI 0.72-1.82, p = 0.57) in unsorted BCa patients. PIK3CA mutations were not associated with OS (HR 1.06, 95%CI 0.67-1.67, p = 0.81) or RFS (HR 0.86, 95%CI 0.53-1.40, p = 0.55) in HR-positive BCa patients. In conclusion, PIK3CA mutations were significantly related to ER/PR expression and RFS in unsorted BCa patients. However, the clinical implications of PIK3CA mutations may vary according to different mutant exons. And PIK3CA mutations alone may have limited prognostic value for HR-positive BCa patients.

  14. The Influence of Menopausal Status and Postmenopausal Use of Hormone Therapy on Presentation of Major Depression in Women

    PubMed Central

    Kornstein, Susan G.; Young, Elizabeth A.; Harvey, Annie T.; Wisniewski, Stephen R.; Barkin, Jennifer L.; Thase, Michael E.; Trivedi, Madhukar H.; Nierenberg, Andrew A.; Rush, A. John

    2010-01-01

    Objective: The purpose of this study was to determine whether there are differences in depression characteristics among premenopausal, perimenopausal, and postmenopausal women with major depressive disorder. This study also evaluated these differences between postmenopausal women with major depressive disorder who are taking and not taking hormone therapy. Methods: Analyses conducted with data from the Sequenced Treatment Alternatives to Relieve Depression study focused on female outpatients with non-psychotic major depressive disorder seeking treatment in 41 primary or psychiatric care settings across the United States. Baseline demographic and clinical characteristics were compared among women not taking hormone therapy who were premenopausal (N=950), perimenopausal (N=380), or postmenopausal (N=562). These comparisons were also made between postmenopausal women (n=768) taking (N=171) or not taking (N=562) hormone therapy. Results: After adjusting for sociodemographic and clinical baseline differences, premenopausal women were more likely to present with irritability than either peri- or postmenopausal women, and were more likely to have decreased appetite and less likely to have early morning insomnia than perimenopausal women. Postmenopausal women were more likely to have suicidal ideation and poorer physical functioning than either of the other groups, and were more likely to have sympathetic arousal and gastrointestinal symptoms than premenopausal women. After adjusting for baseline differences, postmenopausal women taking hormone therapy had better physical functioning, fewer melancholic features, less sympathetic arousal, and more lack of involvement in activities than women not taking hormone therapy. Conclusions: Menopausal status and postmenopausal use of hormone therapy may influence the clinical presentation of major depressive episodes in women. PMID:20616669

  15. Novel A219P mutation of hydroxymethylbilane synthase identified in a Chinese woman with acute intermittent porphyria and syndrome of inappropriate antidiuretic hormone.

    PubMed

    Li, Yingjie; Qu, Hua; Wang, Hang; Deng, Huacong; Liu, Ziyan

    2015-07-01

    Acute intermittent porphyria (AIP) is an autosomal dominant metabolic disorder caused by deficiency of the heme biosynthetic enzyme hydroxymethylbilane synthase (approved gene symbol HMBS), also known as porphobilinogen deaminase (PBGD). AIP is characterised by intermittent attacks of abdominal pain, vomiting, and neurological complaints. The highly variable symptomatic presentation of AIP causes confusion with other diseases and results in a high misdiagnosis rate (68% in China) and delayed effective treatments. Based on biochemical and genetic analysis of two Chinese families, a new and a previously reported HMBS mutation were identified in patients with AIP and syndrome of inappropriate antidiuretic hormone (SIADH). The novel HMBS mutation is the 655G>C point mutation (A219P). In addition, the 973C>T point mutation (R325X), which had been previously reported in two Danish families, was identified.

  16. Effect of Inactivating Mutations on Peptide Conformational Ensembles: The Plant Polypeptide Hormone Systemin.

    PubMed

    Chowdhury, Saikat Dutta; Sarkar, Aditya K; Lahiri, Ansuman

    2016-07-25

    As part of their basal immune mechanism against insect/herbivore attacks, plants have evolved systemic response mechanisms. Such a systemic wound response in tomato was found to involve an 18 amino acid polypeptide called systemin, the first polypeptide hormone to be discovered in plants. Systematic alanine scanning and deletion studies showed differential modulation in its activity, particularly a major loss of function due to alanine substitution at positions 13 and 17 and less extentive loss of function due to substitution at position 12. We have studied the conformational ensembles of wild-type systemin along with its 17 variants by carrying out a total of 5.76 μs of replica-exchange molecular dynamics simulation in an implicit solvent environment. In our simulations, wild-type systemin showed a lack of α-helical and β-sheet structures, in conformity with earlier circular dichroism and NMR data. On the other hand, two regions containing diproline segments showed a tendency to adopt polyproline II structures. Examination of conformational ensembles of the 17 variants revealed a change in the population distributions, suggesting a less flexible structure for alanine substitutions at positions 12 and 13 but not for position 17. Combined with the experimental observations that positions 1-14 of systemin are important for the formation of the peptide-receptor complex, this leads to the hypothesis that loss of conformational flexibility may play a role in the loss of activity of systemin due to the P12A and P13A substitutions, while T17A deactivation probably occurs for a different reason, most likely the loss of the threonine phosphorylation site. We also indicate possible structural reasons why the substitution of the prolines at positions 12 and 13 leads to a loss of conformational freedom in the peptide.

  17. Antioxidant status and sex hormones in women with complex endometrial hyperplasia.

    PubMed

    Pejić, S; Todorović, A; Stojiljković, V; Pavlović, I; Gavrilović, L; Popović, N; Pajović, S B

    2016-09-30

    Endometrial tissue is under a strong influence of sex hormones. These hormones are considered as developmental factors of endometrial hyperplasia and endometrial cancer. We examined the influence of gonadotropins (follicle-stimulating and luteinizing hormone) and sex hormones (estradiol, progesterone) on oxidant/antioxidant parameters in blood and endometrial tissue of women with complex endometrial hyperplasia. In blood, superoxide dismutase activity was significantly higher in luteal phase and postmenopause compared to the follicular phase. A significant phase-related difference of glutathione peroxidase and glutathione reductase activity was recorded in the endometrium. Both enzymes had lower activity in luteal phase and postmenopause compared to the follicular phase. The linear regression analysis of individual hormonal variables against antioxidant parameters showed negative correlation between glutathione peroxidase activity and gonadotropin concentrations in the endometrium. The regression of hyperplastic to normal endometrium is the purpose of conservative treatment based on administration of progestogens or gonadotropin-releasing hormone analogues. Our findings indicate that gonadotropins influence the antioxidant enzymes activity in women with complex endometrial hyperplasia, which may affect disease development. Further studies are needed to clarify the molecular basis of hormone action on antioxidant system that may potentially initiate a development of treatments based on redox-dependent mechanism.

  18. Molecular analysis of brazilian patients with combined pituitary hormone deficiency and orthotopic posterior pituitary lobe reveals eight different PROP1 alterations with three novel mutations.

    PubMed

    Madeira, Joao Lo; Nishi, Mirian Y; Nakaguma, Marilena; Benedetti, Anna F; Biscotto, Isabela Peixoto; Fernandes, Thamiris; Pequeno, Thiago; Figueiredo, Thalita; Franca, Marcela M; Correa, Fernanda A; Otto, Aline P; Abrão, Milena; Miras, Mirta B; Santos, Silvana; Jorge, Alexander Al; Costalonga, Everlayny F; Mendonca, Berenice B; Arnhold, Ivo Jp; Carvalho, Luciani R

    2017-07-22

    Mutations in PROP1, HESX1 and LHX3 are associated with combined pituitary hormone deficiency (CPHD) and orthotopic posterior pituitary lobe (OPP). To identify mutations in PROP1, HESX1 and LHX3 in a large cohort of patients with CPHD and OPP (35 Brazilian, two Argentinian). We studied 23 index patients with CPHD and OPP (six familial and 17 sporadic) as well as 14 relatives. PROP1 was sequenced by the Sanger method in all except one sporadic case studied using a candidate gene panel. Multiplex ligation-dependent probe amplification (MLPA) was applied to one familial case in whom PROP1 failed to amplify by PCR. In the 13 patients without PROP1 mutations, HESX1 and LHX3 were sequenced by the Sanger method. We identified PROP1 mutations in 10 index cases. Three mutations were novel: one affecting the initiation codon (c.1A>G) and two affecting splicing sites, c.109+1G>A and c.342+1G>C. The known mutations, c.150delA (p.Arg53Aspfs*112), c.218G>A (p.Arg73His), c.263T>C (p.Phe88Ser) and c.301_302delAG (p.Leu102Cysfs*8), were also detected. MLPA confirmed complete PROP1 deletion in one family. We did not identify HESX1 and LHX3 mutations by Sanger. PROP1 mutations are a prevalent cause of congenital CPHD with OPP, and therefore, PROP1 sequencing must be the first step of molecular investigation in patients with CPHD and OPP, especially in populations with a high frequency of PROP1 mutations. In the absence of mutations, massively parallel sequencing is a promising approach. The high prevalence and diversity of PROP1 mutations is associated with the ethnic background of this cohort. © 2017 John Wiley & Sons Ltd.

  19. Impact of JAK2V617F Mutational Status on Phenotypic Features in Essential Thrombocythemia and Primary Myelofibrosis

    PubMed Central

    Yönal, İpek; Dağlar-Aday, Aynur; Akadam-Teker, Başak; Yılmaz, Ceylan; Nalçacı, Meliha; Yavuz, Akif Selim; Sargın, Fatma Deniz

    2016-01-01

    Objective: The JAK2V617F mutation is present in the majority of patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF). The impact of this mutation on disease phenotype in ET and PMF is still a matter of discussion. This study aims to determine whether there are differences in clinical presentation and disease outcome between ET and PMF patients with and without the JAK2V617F mutation. Materials and Methods: In this single-center study, a total of 184 consecutive Philadelphia-negative chronic myeloproliferative neoplasms, 107 cases of ET and 77 cases of PMF, were genotyped for JAK2V617F mutation using the JAK2 Ipsogen MutaScreen assay, which involves allele-specific polymerase chain reaction. Results: ET patients positive for JAK2V617F mutation had higher hemoglobin (Hb) and hematocrit (Hct) levels, lower platelet counts, and more prevalent splenomegaly at diagnosis compared to patients negative for the JAK2V617F mutation, but rates of major thrombotic events, arterial thrombosis, and venous thrombosis were comparable between the groups. At presentation, PMF patients with JAK2V617F mutation had significantly higher Hb and Hct levels and leukocyte counts than patients without the mutation. Similar to the findings of ET patients, thromboembolic rates were similar in PMF patients with and without theJAK2V617F mutation. For ET and PMF patients, no difference was observed in rates of death with respect to JAK2V617F mutational status. Moreover, leukemic transformation rate was not different in our PMF patients with and without JAK2V617F mutation. Conclusion: We conclude that JAK2V617F-mutated ET patients express a polycythemia vera-like phenotype and JAK2V617F mutation in PMF patients is associated with a more pronounced myeloproliferative phenotype. PMID:25913509

  20. Impact of clinical risk scores and BRAF V600E mutation status on outcome in papillary thyroid cancer.

    PubMed

    Niederer-Wüst, Séverine M; Jochum, Wolfram; Förbs, Diana; Brändle, Michael; Bilz, Stefan; Clerici, Thomas; Oettli, René; Müller, Joachim; Haile, Sarah R; Ess, Silvia; Stoeckli, Sandro J; Broglie, Martina A

    2015-01-01

    To evaluate the relationship between the BRAF V600E mutation and clinicopathologic parameters and to assess the impact of the BRAF V600E mutation and established risk scores on survival in patients with papillary thyroid carcinoma (PTC). Retrospective analysis of a consecutive, single-institutional cohort of patients with PTC larger than 1 cm. Clinical risk scores according to the Metastases, Age, Completeness of Resection, Invasion, Size (MACIS), European Organisation for Research and Treatment of Cancer (EORTC), and tumor, node, metastases (TNM) scoring systems were determined. BRAF exon 15 mutation analysis was performed by polymerase chain reaction and Sanger sequencing. BRAF V600E mutations were found in 75/116 (65%) PTC. The rates for 5- and 10-year overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) were 92% and 87%, 98% and 96%, and 96% and 94%, respectively. Low MACIS scores were associated with longer OS (10 y 95% vs 75%, P = .008), DSS (10 y 100% vs 89%, P = .02) and RFS (100% vs 85%, P = .006). Comparable survival advantages were observed for patients with early EORTC scores and low TNM stage. BRAF V600E mutation status was not associated with clinicopathologic characteristics of aggressive behavior such as extrathyroidal extension, lymph node metastases, higher T-categories, male sex, and greater age. Furthermore, BRAF V600E mutation status was not correlated with clinical risk scores and decreased survival. In concordance with other studies, we did not find a negative prognostic impact of a positive BRAF V600E mutation status on survival. In contrast, the risk algorithms MACIS, EORTC score, and TNM stage were associated with impaired prognosis. Therefore, clinical staging systems represent better tools for risk stratification than BRAF V600E mutation status. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Blood biochemistry, thyroid hormones, and oxidant/antioxidant status of guinea pigs challenged with sodium arsenite or arsenic trioxide.

    PubMed

    Mohanta, Ranjan Kumar; Garg, Anil Kumar; Dass, Ram Sharan; Behera, Suvendu Kumar

    2014-08-01

    The present experiment aimed to compare the two most commonly used compounds of arsenic (sodium arsenite and arsenic trioxide) for their effect on blood metabolites, thyroid hormones, and oxidant/antioxidant status in guinea pigs. Twenty-one adult guinea pigs were randomly divided into three equal groups. Animals in group T1 (control) were fed a basal diet, whereas 50 ppm arsenic was added in the basal diet either as sodium arsenite (T2) or arsenic trioxide (T3) and fed for 11 weeks. Serum aspartate aminotransferase and alanine aminotransferase activities were significantly increased along with a decrease in blood hemoglobin level in both the arsenic-administered groups. The level of erythrocytic antioxidants (catalase, superoxide dismutase, reduced glutathione, glutathione-S-transferase, and glutathione reductase) was decreased and lipid peroxidation was elevated upon arsenic exposure. Serum thyroid hormone levels were reduced and arsenic levels in tissues increased in both the arsenic-exposed groups, irrespective of the arsenic compound. Thus, sodium arsenite and arsenic trioxide exerted similar adverse effects on blood metabolic profile, antioxidant status, and thyroid hormones in guinea pigs.

  2. Women's intercollegiate athletic competition: cortisol, testosterone, and the dual-hormone hypothesis as it relates to status among teammates.

    PubMed

    Edwards, David A; Casto, Kathleen V

    2013-06-01

    Recent research suggests that testosterone and cortisol jointly regulate dominance motivation and, perhaps, the status relationships that are affected by it. For this article, the results of six different studies of women's intercollegiate athletic competition were combined to give a sample size of almost ninety women for whom we had before- and after-competition values for salivary cortisol and testosterone for at least one and sometimes two competitions. For many of these women, we had surveys that allowed us to assess their status with teammates. In no matter what sport (soccer, softball, volleyball, and tennis) levels of salivary cortisol and testosterone increased when women participated in athletic competition. Salivary levels of C and T appear to rise in parallel during competition and increases in levels of one hormone are significantly related to increases in the other. Salivary levels of these hormones typically decreased for teammates who did not play but watched the competition from the sidelines. For women who played in two competitions, individual differences in the positive effect of competition on cortisol and testosterone were conserved from one competition to the next, affirming the personal consistency of endocrine responses to competition. Status with teammates was positively related to before-competition levels of testosterone, but only for women with relatively low before-competition levels of cortisol. This result provides novel support for the "dual-hormone hypothesis" as it relates to predicting social status in women's athletic teams - natural social groups of individuals who know each other and whose social hierarchy has evolved over the course of practice and play for at least one and, in some cases, several years of intercollegiate athletic competition.

  3. Thyroid hormone status and pituitary function in adult rats given oral doses of perfluorooctanesulfonate (PFOS)

    EPA Science Inventory

    Perfluorooctanesulfonate (PFOS) is widely distributed and persistent in humans and wildlife. Prior toxicological studies have reported decreased total and free thyroid hormones in serum without a major compensatory rise in thyrotropin (TSH) or altered thyroid gland histology. Alt...

  4. Thyroid hormone status and pituitary function in adult rats given oral doses of perfluorooctanesulfonate (PFOS)

    EPA Science Inventory

    Perfluorooctanesulfonate (PFOS) is widely distributed and persistent in humans and wildlife. Prior toxicological studies have reported decreased total and free thyroid hormones in serum without a major compensatory rise in thyrotropin (TSH) or altered thyroid gland histology. Alt...

  5. The effects of sex and hormonal status on the physiological response to acute psychosocial stress.

    PubMed

    Kajantie, Eero; Phillips, David I W

    2006-02-01

    Whether one is male or female is one of the most important determinants of human health. While males are more susceptible to cardiovascular and infectious disease, they are outnumbered by women for many autoimmune disorders, fibromyalgia and chronic pain. Recently, individual differences in the physiological response to stress have emerged as a potentially important risk factor for these disorders. This raises the possibility that sex differences in prevalence of disease could at least in part be explained by sex differences in the nature of the physiological response to stress. In a psychophysiological laboratory, the autonomic nervous system response can be provoked by many different stressors including physical, mental and psychosocial tasks, while the hypothalamic-pituitary-adrenal axis (HPAA) response seems to be more specific to a psychosocial challenge incorporating ego involvement. The responses of both systems to different psychosocial challenges have been subject to extensive research, although in respect of sex differences the HPAA response has probably been more systematically studied. In this review, we focus on sex differences in HPAA and autonomic nervous system responses to acute psychosocial stress. Although some differences are dependent on the stressor used, the responses of both systems show marked and consistent differences according to sex, with the phase of the menstrual cycle, menopausal status and pregnancy having marked effects. Between puberty and menopause, adult women usually show lower HPAA and autonomic responses than men of same age. However, the HPAA response is higher in the luteal phase, when for example post stress free cortisol levels approach those of men. After menopause, there is an increase in sympathoadrenal responsiveness, which is attenuated during oral hormone replacement therapy, with most evidence suggesting that HPAA activity shows the same trends. Interestingly, pregnancy is associated with an attenuated response of

  6. Growth hormone insensitivity with immune dysfunction caused by a STAT5B mutation in the south of Brazil: evidence for a founder effect

    PubMed Central

    Scalco, Renata C.; Gonçalves, Fernanda T.; Santos, Hadassa C.; Cardena, Mari M. S. G.; Tonelli, Carlos A.; Funari, Mariana F. A.; Aracava, Rosana M.; Pereira, Alexandre C.; Fridman, Cintia; Jorge, Alexander A. L.

    2017-01-01

    ABSTRACT Homozygous STAT5B mutations causing growth hormone insensitivity with immune dysfunction were described in 10 patients since 2003, including two Brazilian brothers from the south of Brazil. Our objectives were to evaluate the prevalence of their STAT5B mutation in this region and to analyze the presence of a founder effect. We obtained DNA samples from 1,205 local inhabitants, 48 relatives of the homozygous patients and four individuals of another affected family. Genotyping for STAT5B c.424_427del mutation and for two polymorphic markers around it was done through fragment analysis technique. We also determined Y-chromosome and mtDNA haplotypes and genomic ancestry in heterozygous carriers. We identified seven families with STAT5B c.424_427del mutation, with 33 heterozygous individuals. The minor allelic frequency of this mutation was 0.29% in this population (confidence interval 95% 0.08-0.5%), which is significantly higher than the frequency of other pathogenic STAT5B allele variants observed in public databases (p < 0.001). All heterozygous carriers had the same haplotype present in the homozygous patients, found in only 9.4% of non-carriers (p < 0.001), supporting the existence of a founder effect. The Y-chromosome haplotype, mtDNA and genomic ancestry analysis indicated a European origin of this mutation. Our results provide compelling evidence for a founder effect of STAT5B c.424_427del mutation. PMID:28590503

  7. Growth hormone insensitivity with immune dysfunction caused by a STAT5B mutation in the south of Brazil: evidence for a founder effect.

    PubMed

    Scalco, Renata C; Gonçalves, Fernanda T; Santos, Hadassa C; Cardena, Mari M S G; Tonelli, Carlos A; Funari, Mariana F A; Aracava, Rosana M; Pereira, Alexandre C; Fridman, Cintia; Jorge, Alexander A L

    2017-01-01

    Homozygous STAT5B mutations causing growth hormone insensitivity with immune dysfunction were described in 10 patients since 2003, including two Brazilian brothers from the south of Brazil. Our objectives were to evaluate the prevalence of their STAT5B mutation in this region and to analyze the presence of a founder effect. We obtained DNA samples from 1,205 local inhabitants, 48 relatives of the homozygous patients and four individuals of another affected family. Genotyping for STAT5B c.424_427del mutation and for two polymorphic markers around it was done through fragment analysis technique. We also determined Y-chromosome and mtDNA haplotypes and genomic ancestry in heterozygous carriers. We identified seven families with STAT5B c.424_427del mutation, with 33 heterozygous individuals. The minor allelic frequency of this mutation was 0.29% in this population (confidence interval 95% 0.08-0.5%), which is significantly higher than the frequency of other pathogenic STAT5B allele variants observed in public databases (p < 0.001). All heterozygous carriers had the same haplotype present in the homozygous patients, found in only 9.4% of non-carriers (p < 0.001), supporting the existence of a founder effect. The Y-chromosome haplotype, mtDNA and genomic ancestry analysis indicated a European origin of this mutation. Our results provide compelling evidence for a founder effect of STAT5B c.424_427del mutation.

  8. Association of plasma hormones, nutritional status, and stressful life events in anorexia nervosa patients.

    PubMed

    Śmiarowska, Małgorzata; Safranow, Krzysztof; Dziedziejko, Violetta; Bialecka, Monika; Koziołek, Monika; Samochowiec, Jerzy

    2014-02-06

    The aim of the current study was to analyze the relationships between plasma hormones, body weight parameters and stressful life events in anorexia nervosa (AN). 72 females in the active phase of AN were evaluated. 52 healthy women constituted the control group. RIA kits were used to measure plasma hormone levels. The concentrations of leptin, insulin, IGF-1, triiodothyronine, LH, FSH, estradiol, and testosterone were significantly lower and those of cortisol and growth hormone significantly higher in the AN than the control group. No hormonal differences between restrictive and binge-purging AN subtypes were found. Leptin, IGF-1, gonadotropins, and sex steroids correlated significantly negatively and growth hormone positively with total reduction of body weight or the degree of undernutrition. Associations were also found between lower insulin concentration and family violence, lower cortisol and psychiatric diseases in the family, higher testosterone and patient's alcohol or drug abuse. The changed activity of the somatotropin-somatomedin, gonadal, and corticotrophin axes corresponds to the clinical stage of AN. Plasma IGF-1 seems to be the most sensitive and useful independent hormonal marker of cachexia.

  9. Can EGFR mutation status be reliably determined in pre-operative needle biopsies from adenocarcinomas of the lung?

    PubMed

    Lindahl, Kim Hein; Sørensen, Flemming Brandt; Jonstrup, Søren Peter; Olsen, Karen Ege; Loeschke, Siegfried

    2015-04-01

    The identification of EGFR mutations in non-small-cell lung cancer is important for selecting patients, who may benefit from treatment with EGFR tyrosine kinase inhibitors. The analysis is usually performed on cytological aspirates and/or histological needle biopsies, representing a small fraction of the tumour volume. The aim of the present investigation was to evaluate the diagnostic performance of this molecular test. We retrospectively included 201 patients with primary adenocarcinoma of the lung. EGFR mutation status (exon 19 deletions and exon 21 L858R point mutation) was evaluated on both pre-operative biopsies (131 histological and 70 cytological) and on the surgical specimens, using PCR. Samples with low tumour cell fraction were assigned to laser micro-dissection (LMD). We found nine (4.5%) patients with EGFR mutation in the lung tumour resections, but failed to identify mutation in one of the corresponding pre-operative, cytological specimens. Several (18.4%) analyses of the pre-operative biopsies were inconclusive, especially in case of biopsies undergoing LMD and regarding exon 21 analysis. Discrepancy of mutation status in one patient may reflect intra-tumoural heterogeneity or technical issues. Moreover, several inconclusive results in the diagnostic biopsies reveal that attention must be paid on the suitability of pre-operative biopsies for EGFR mutation analysis.

  10. KRAS and BRAF mutational status in primary colorectal tumors and related metastatic sites: biological and clinical implications.

    PubMed

    Italiano, Antoine; Hostein, Isabelle; Soubeyran, Isabelle; Fabas, Thibault; Benchimol, Daniel; Evrard, Serge; Gugenheim, Jean; Becouarn, Yves; Brunet, René; Fonck, Marianne; François, Eric; Saint-Paul, Marie-Christine; Pedeutour, Florence

    2010-05-01

    KRAS and BRAF mutations in primary colorectal tumors (PT) are predictive of nonresponse to anti-epidermal growth factor receptor (EGFR) antibodies in patients with metastatic colorectal cancer (mCRC). The question of primary resistance to anti-EGFR treatment as a result of the presence of KRAS or BRAF mutations only in metastases has been raised but not resolved. We analyzed the mutational status of KRAS and BRAF in 64 new patients with mCRC and performed a systematic review of published data from 285 patients. A total of 285 and 95 matched PT/metastases were available for the analysis of the KRAS and the BRAF status, respectively. An identical mutational pattern of KRAS in PT and the matching metastases were reported in all the cases but 14 (5%). In six cases (2%), KRAS was mutated in the PT and wild type in the metastatic site, whereas in eight cases (3%), KRAS was wild type in the PT and mutated in the metastatic site. An identical mutational pattern of BRAF in PT and the matching metastases was reported in all but two cases (3%). In one case (1.5%), BRAF was mutated in the PT and wild type in the metastatic site, whereas in one case (1.5%), BRAF was wild type in the PT and mutated in the metastatic site. The acquisition by metastases of a KRAS or a BRAF mutation that was not present in the PT is a rare event, occurring in 5% of cases of mCRC. This is not a frequent mechanism of primary resistance to anti-EGFR treatments in mCRC.

  11. ctDNA Determination of EGFR Mutation Status in European and Japanese Patients with Advanced NSCLC: The ASSESS Study.

    PubMed

    Reck, Martin; Hagiwara, Koichi; Han, Baohui; Tjulandin, Sergei; Grohé, Christian; Yokoi, Takashi; Morabito, Alessandro; Novello, Silvia; Arriola, Edurne; Molinier, Olivier; McCormack, Rose; Ratcliffe, Marianne; Normanno, Nicola

    2016-10-01

    To offer patients with EGFR mutation-positive advanced NSCLC appropriate EGFR tyrosine kinase inhibitor treatment, mutation testing of tumor samples is required. However, tissue/cytologic samples are not always available or evaluable. The large, noninterventional diagnostic ASSESS study (NCT01785888) evaluated the utility of circulating free tumor-derived DNA (ctDNA) from plasma for EGFR mutation testing. ASSESS was conducted in 56 centers (in Europe and Japan). Eligible patients (with newly diagnosed locally advanced/metastatic treatment-naive advanced NSCLC) provided diagnostic tissue/cytologic and plasma samples. DNA extracted from tissue/cytologic samples was subjected to EGFR mutation testing using local practices; designated laboratories performed DNA extraction/mutation testing of blood samples. The primary end point was level of concordance of EGFR mutation status between matched tissue/cytologic and plasma samples. Of 1311 patients enrolled, 1288 were eligible. Concordance of mutation status in 1162 matched samples was 89% (sensitivity 46%, specificity 97%, positive predictive value 78%, and negative predictive value 90%). A group of 25 patients with apparent false-positive plasma results was overrepresented for cytologic samples, use of less sensitive tissue testing methodologies, and smoking habits associated with high EGFR mutation frequency, indicative of false-negative tumor results. In cases in which plasma and tumor samples were tested with identical highly sensitive methods, positive predictive value/sensitivity were generally improved. These real-world data suggest that ctDNA is a feasible sample for EGFR mutation analysis. It is important to conduct mutation testing of both tumor and plasma samples in specialized laboratories, using robust/sensitive methods to ensure that patients receive appropriate treatments that target the molecular features of their disease. Copyright © 2016 International Association for the Study of Lung Cancer

  12. Reproductive toxicity after levetiracetam administration in male rats: Evidence for role of hormonal status and oxidative stress.

    PubMed

    Baysal, Merve; Ilgin, Sinem; Kilic, Gozde; Kilic, Volkan; Ucarcan, Seyda; Atli, Ozlem

    2017-01-01

    Levetiracetam (LEV) is an antiepileptic drug commonly used in the treatment of epilepsy because of its excellent safety profile in all age groups. It is remarkable that there are no studies evaluating the toxic effects of this drug on the male reproductive system, as it is commonly used in male patients of reproductive age. From this point of view, our aim was to evaluate the possible toxic effects of LEV on the male reproductive system. Therefore, LEV was administered to male rats orally at 50, 150, and 300 mg/kg for 70 consecutive days. At the end of this period, alterations to body and organ weights were calculated, and sperm concentration, motility, and morphology were investigated by a computer-assisted sperm analysis system. Sperm DNA damage was determined by comet assay and histopathological examination of the testes was carried out. Serum testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels were measured by ELISAs to determine the effects of hormonal status, while glutathione, superoxide dismutase, catalase, and malondialdehyde levels in the testes were measured by colorimetric assay kits to determine the role of oxidative status in potential toxicity. According to the results, sperm quality was decreased by LEV treatment in a dose-dependent manner. LEV induced significant DNA damage in the 150 and 300 mg/kg LEV-administered groups. Histopathology of the testes showed that LEV resulted in testicular injury in the 300 mg/kg LEV-administered group. Serum testosterone, FSH, and LH levels were significantly decreased in the 300 mg/kg LEV-administered group. Glutathione, superoxide dismutase, and catalase levels were significantly decreased in all experimental groups while malondialdehyde levels were significantly increased in 150 and 300 mg/kg LEV-administered groups. According to these results, it was determined that LEV administration decreased sperm quality and it was alleged that hormonal alteration and oxidative stress are

  13. Preoperative inflammation markers and IDH mutation status predict glioblastoma patient survival.

    PubMed

    Wang, Peng-Fei; Song, Hong-Wang; Cai, Hong-Qing; Kong, Ling-Wei; Yao, Kun; Jiang, Tao; Li, Shou-Wei; Yan, Chang-Xiang

    2017-02-09

    Recent studies suggest that inflammation response biomarkers are prognostic indicators of solid tumor outcomes. Here, we quantify the prognostic value of the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) in glioblastomas (GBMs), taking into consideration the role of the isocitrate dehydrogenase (IDH) mutation status. We examined 141 primary glioblastomas (pGBMs) and 25 secondary glioblastomas (sGBMs). NLRs, PLRs, and LMRs were calculated before surgery. IDH mutations were detected immunohistochemically after tumor resection, and patients' clinical outcomes were analyzed after classification into GBM, pGBM, and IDH-wild type glioblastoma (IDH-wt GBM) groups. To make comparisons, we set cutoffs for NLR, PLR and LMR of 4.0, 175.0, and 3.7, respectively. In a multivariate analysis, both NLR (HR=1.712, 95% CI 1.026-2.858, p=0.040) and PLR (HR=2.051, 95% CI 1.288-3.267, p=0.002) had independent prognostic value. While a low NLR was associated with a better prognosis only in the IDH-wt GBM group, PLR was predictive of patient survival in the GBM, pGBM, and IDH-wt GBM groups. By contrast, LMR exhibited no prognostic value for any of the 3 types of GBM.

  14. Hormone, vitamin and contaminant status during the moulting/fasting period in ringed seals (Pusa [Phoca] hispida) from Svalbard.

    PubMed

    Routti, Heli; Jenssen, Bjørn Munro; Lydersen, Christian; Bäckman, Christina; Arukwe, Augustine; Nyman, Madeleine; Kovacs, Kit M; Gabrielsen, Geir Wing

    2010-01-01

    This study investigates the potential effects of moulting, and the concomitant period of fasting undertaken by ringed seals, on hormone, vitamin and contaminant status in adult animals in a population from Svalbard, Norway, which has relatively low contaminant levels. Concentrations of circulating total and free thyroxine and triiodothyronine, circulating and hepatic vitamin A, hepatic persistent organic pollutants and their circulating hydroxyl metabolites were higher in moulting seals compared to pre-moulting seals. The opposite trend was observed for body condition, circulating calcitriol levels and hepatic mRNA expression of thyroid hormone receptor beta. No differences were observed for circulating or hepatic vitamin E levels or hepatic mRNA expressions for deioidinase 1 or 2, or retinoic acid receptor alpha between the two seal groups. The observed differences are likely the result of increased metabolic rates required during moulting to maintain thermal balance and replace the pelage, in combination with mobilization of lipid soluble compounds from blubber stores during the fasting period that is associated with moulting. The present study shows that contaminant levels and their relationships with physiological or endogenous variables can be highly confounded by moulting/fasting status. Thus, moulting status and body condition should be taken into consideration when using variables related to thyroid, calcium or vitamin A homeostasis as biomarkers for contaminant effects.

  15. Vitamin D status and 5-year changes in urine albumin creatinine ratio and parathyroid hormone in a general population.

    PubMed

    Skaaby, Tea; Husemoen, Lise Lotte Nystrup; Pisinger, Charlotta; Jørgensen, Torben; Thuesen, Betina Heinsbæk; Rasmussen, Knud; Fenger, Mogens; Rossing, Peter; Linneberg, Allan

    2013-10-01

    Vitamin D is associated with cardiovascular disease and renal function but the mechanisms are as yet unexplained. Microalbuminuria is associated with a higher risk of kidney function loss, cardiovascular disease, and mortality. Parathyroid hormone is a predictor of cardiovascular mortality and negatively correlated with glomerular filtration rate. We investigated the association between vitamin D status and 5-year changes in urine albumin creatinine ratio (UACR) and parathyroid hormone (PTH). A random sample of 6,784 individuals aged 30-60 years from a general population participated in the Inter99 study in 1999-2001. Vitamin D (serum-25-hydroxyvitamin D) was measured at baseline by high-performance liquid chromatography. UACR and PTH were measured at baseline and follow-up. Increased UACR was defined as UACR >4.0 mg/g reflecting the upper quartile at baseline. We included 4,330 individuals who participated at 5-year follow-up. In multivariable linear regression analysis, a 10-nmol/l higher baseline level of vitamin D was associated with a 5-year decrease in UACR by 0.92 % (95 % confidence interval, CI 0.13, 1.71). In multivariable logistic regression analysis, the odds ratio of developing increased UACR during follow-up was 0.96 (95 % CI 0.92, 0.98) per 10 nmol/l higher baseline vitamin D level. We found a significant inverse cross-sectional (p < 0.0001) but no prospective association (p = 0.6) between baseline vitamin D status and parathyroid hormone. We found low vitamin D status to be a predictor of long-term development of increased UACR. It remains to be proven whether vitamin D deficiency is a causal and reversible factor in the development of albuminuria.

  16. A novel follicle-stimulating hormone receptor mutation causing primary ovarian failure: a fertility application of whole exome sequencing

    PubMed Central

    Bramble, Matthew S.; Goldstein, Ellen H.; Lipson, Allen; Ngun, Tuck; Eskin, Ascia; Gosschalk, Jason E.; Roach, Lara; Vashist, Neerja; Barseghyan, Hayk; Lee, Eric; Arboleda, Valerie A.; Vaiman, Daniel; Yuksel, Zafer; Fellous, Marc; Vilain, Eric

    2016-01-01

    STUDY QUESTION Can whole exome sequencing (WES) and in vitro validation studies be used to find the causative genetic etiology in a patient with primary ovarian failure and infertility? SUMMARY ANSWER A novel follicle-stimulating hormone receptor (FSHR) mutation was found by WES and shown, via in vitro flow cytometry studies, to affect membrane trafficking. WHAT IS KNOWN ALREADY WES may diagnose up to 25–35% of patients with suspected disorders of sex development (DSD). FSHR mutations are an extremely rare cause of 46, XX gonadal dysgenesis with primary amenorrhea due to hypergonadotropic ovarian failure. STUDY DESIGN, SIZE, DURATION A WES study was followed by flow cytometry studies of mutant protein function. PARTICIPANTS/MATERIALS, SETTING, METHODS The study subjects were two Turkish sisters with hypergonadotropic primary amenorrhea, their parents and two unaffected sisters. The affected siblings and both parents were sequenced (trio-WES). Transient transfection of HEK 293T cells was performed with a vector containing wild-type FSHR as well as the novel FSHR variant that was discovered by WES. Cellular localization of FSHR protein as well as FSH-stimulated cyclic AMP (cAMP) production was evaluated using flow cytometry. MAIN RESULTS AND THE ROLE OF CHANCE Both affected sisters were homozygous for a previously unreported missense mutation (c.1222G>T, p.Asp408Tyr) in the second transmembrane domain of FSHR. Modeling predicted disrupted secondary structure. Flow cytometry demonstrated an average of 48% reduction in cell-surface signal detection (P < 0.01). The mean fluorescent signal for cAMP (second messenger of FSHR), stimulated by FSH, was reduced by 50% in the mutant-transfected cells (P < 0.01). LIMITATIONS, REASONS FOR CAUTION This is an in vitro validation. All novel purported genetic variants can be clinically reported only as ‘variants of uncertain significance’ until more patients with a similar phenotype are discovered with the same variant. WIDER

  17. Proliferation and ovarian hormone signaling are impaired in normal breast tissues from women with BRCA1 mutations: benefit of a progesterone receptor modulator treatment as a breast cancer preventive strategy in women with inherited BRCA1 mutations

    PubMed Central

    Communal, Laudine; Courtin, Aurélie; Mourra, Najat; Lahlou, Najiba; Le Guillou, Morwenna; de Jotemps, Muriel Perrault; Chauvet, Marie-Pierre; Chaouat, Marc; Pujol, Pascal; Feunteun, Jean; Delaloge, Suzette; Forgez, Patricia; Gompel, Anne

    2016-01-01

    Women with inherited BRCA1 mutations have an elevated risk (40-80%) for developing breast and ovarian cancers. Reproductive history has been reported to alter this risk, suggesting a relationship between ovarian hormone signaling and BRCA1-related tumor development. BRCA1 interactions with estrogen receptor (ER) and progesterone receptor (PR) signaling were previously described in human breast cancer cell lines and mouse models. However, few studies have examined the effect of ovarian hormone regulation in normal human breast tissues bearing a heterozygous BRCA1 mutation. This study compares the proliferation level (Ki67) and the expression of ER, PR, and of the PR target gene, fatty acid synthase (FASN), in histologically normal breast tissues from women with BRCA1 mutations (BRCA1+/mut, n=23) or without BRCA1 mutations (BRCA1+/+, n=28). BRCA1+/mut tissues showed an increased proliferation and impaired hormone receptor expression with a marked loss of the PR isoform, PR-B. Responses to estradiol and progesterone treatments in BRCA1+/mut and BRCA1+/+ breast tissues were studied in a mouse xenograft model, and showed that PR and FASN expression were deregulated in BRCA1+/mut breast tissues. Progesterone added to estradiol treatment increased the proliferation in a subset of BRCA1+/mut breast tissues. The PR inhibitor, ulipristal acetate (UPA), was able to reverse this aberrant progesterone-induced proliferation. This study suggests that a subset of women with BRCA1 mutations could be candidates for a UPA treatment as a preventive breast cancer strategy. PMID:27246982

  18. Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status.

    PubMed

    Piccio, Laura; Deming, Yuetiva; Del-Águila, Jorge L; Ghezzi, Laura; Holtzman, David M; Fagan, Anne M; Fenoglio, Chiara; Galimberti, Daniela; Borroni, Barbara; Cruchaga, Carlos

    2016-06-01

    Low frequency coding variants in TREM2 are associated with increased Alzheimer disease (AD) risk, while loss of functions mutations in the gene lead to an autosomal recessive early-onset dementia, named Nasu-Hakola disease (NHD). TREM2 can be detected as a soluble protein in cerebrospinal fluid (CSF) and plasma, and its CSF levels are elevated in inflammatory CNS diseases. We measured soluble TREM2 (sTREM2) in the CSF of a large AD case-control dataset (n = 180) and 40 TREM2 risk variant carriers to determine whether CSF sTREM2 levels are associated with AD status or mutation status. We also performed genetic studies to identify genetic variants associated with CSF sTREM2 levels. CSF, but not plasma, sTREM2 was highly correlated with CSF total tau and phosphorylated-tau levels (r = 0.35, P < 1×10(-4); r = 0.40, P < 1×10(-4), respectively), but not with CSF Aβ42. AD cases presented higher CSF sTREM2 levels than controls (P = 0.01). Carriers of NHD-associated TREM2 variants presented significantly lower CSF sTREM2 levels, supporting the hypothesis that these mutations lead to reduced protein production/function (R136Q, D87N, Q33X or T66M; P = 1×10(-3)). In contrast, CSF sTREM2 levels were significantly higher in R47H carriers compared to non-carriers (P = 6×10(-3)), suggesting that this variant does not impact protein expression and increases AD risk through a different pathogenic mechanism than NHD variants. In GWAS analyses for CSF sTREM2 levels the most significant signal was located on the MS4A gene locus (P = 5.45 × 10(-07)) corresponding to one of the SNPs reported to be associated with AD risk in this locus. Furthermore, SNPs involved in pathways related to virus cellular entry and vesicular trafficking were overrepresented, suggesting that CSF sTREM2 levels could be an informative phenotype for AD.

  19. Clinical, hormonal, behavioral, and genetic characteristics of androgen insensitivity syndrome in a Brazilian cohort: five novel mutations in the androgen receptor gene.

    PubMed

    Melo, Karla F S; Mendonca, Berenice B; Billerbeck, Ana Elisa C; Costa, Elaine M F; Inácio, Marlene; Silva, Frederico A Q; Leal, Angela M O; Latronico, Ana C; Arnhold, Ivo J P

    2003-07-01

    Androgen insensitivity syndrome (AIS) is caused by mutations in the androgen receptor gene and is associated with a variety of phenotypes in 46,XY individuals, ranging from phenotypic women [complete form (CAIS)] to men with minor degrees of undervirilization or infertility [partial form (PAIS)]. We studied 32 subjects with male pseudohermaphroditism from 20 families (9 CAIS, 11 PAIS) with the following criteria for AIS: 46,XY karyotype, normal male basal and human chorionic gonadotropin-stimulated levels of serum testosterone and steroid precursors, gynecomastia at puberty, and, in prepubertal patients, a family history suggestive of X-linked inheritance. The entire coding region of the androgen receptor gene was analyzed, and mutations were found in all families with CAIS and in eight of 11 families with PAIS. Fifteen different mutations were identified, including five (S119X, T602P, L768V, I898F, and P904V) that have not been described previously. Detailed clinical and hormonal features were compared with genotype in 25 subjects with AIS and confirmed by mutational analysis. LH hormone levels and the LH x testosterone product were high in all postpubertal subjects with AIS. All subjects with PAIS maintained at postpubertal age the gender identity and social sex that was assigned to them in infancy, in contrast to other forms of pseudohermaphroditism.

  20. TP53 mutational status is a potential marker for risk stratification in Wilms tumour with diffuse anaplasia.

    PubMed

    Maschietto, Mariana; Williams, Richard D; Chagtai, Tasnim; Popov, Sergey D; Sebire, Neil J; Vujanic, Gordan; Perlman, Elizabeth; Anderson, James R; Grundy, Paul; Dome, Jeffrey S; Pritchard-Jones, Kathy

    2014-01-01

    The presence of diffuse anaplasia in Wilms tumours (DAWT) is associated with TP53 mutations and poor outcome. As patients receive intensified treatment, we sought to identify whether TP53 mutational status confers additional prognostic information. We studied 40 patients with DAWT with anaplasia in the tissue from which DNA was extracted and analysed for TP53 mutations and 17p loss. The majority of cases were profiled by copy number (n = 32) and gene expression (n = 36) arrays. TP53 mutational status was correlated with patient event-free and overall survival, genomic copy number instability and gene expression profiling. From the 40 cases, 22 (55%) had TP53 mutations (2 detected only after deep-sequencing), 20 of which also had 17p loss (91%); 18 (45%) cases had no detectable mutation but three had 17p loss. Tumours with TP53 mutations and/or 17p loss (n = 25) had an increased risk of recurrence as a first event (p = 0.03, hazard ratio (HR), 3.89; 95% confidence interval (CI), 1.26-16.0) and death (p = 0.04, HR, 4.95; 95% CI, 1.36-31.7) compared to tumours lacking TP53 abnormalities. DAWT carrying TP53 mutations showed increased copy number alterations compared to those with wild-type, suggesting a more unstable genome (p = 0.03). These tumours showed deregulation of genes associated with cell cycle and DNA repair biological processes. This study provides evidence that TP53 mutational analysis improves risk stratification in DAWT. This requires validation in an independent cohort before clinical use as a biomarker.

  1. Non-invasive in vivo assessment of IDH1 mutational status in glioma.

    PubMed

    Chaumeil, Myriam M; Larson, Peder E Z; Yoshihara, Hikari A I; Danforth, Olivia M; Vigneron, Daniel B; Nelson, Sarah J; Pieper, Russell O; Phillips, Joanna J; Ronen, Sabrina M

    2013-01-01

    Gain-of-function mutations of the isocitrate dehydrogenase 1 (IDH1) gene are among the most prevalent in low-grade gliomas and secondary glioblastoma. They lead to intracellular accumulation of the oncometabolite 2-hydroxyglutarate, represent an early pathogenic event and are considered a therapeutic target. Here we show, in this proof-of-concept study, that [1-(13)C] α-ketoglutarate can serve as a metabolic imaging agent for non-invasive, real-time, in vivo monitoring of mutant IDH1 activity, and can inform on IDH1 status. Using (13)C magnetic resonance spectroscopy in combination with dissolution dynamic nuclear polarization, the metabolic fate of hyperpolarized [1-(13)C] α-ketoglutarate is studied in isogenic glioblastoma cells that differ only in their IDH1 status. In lysates and tumours that express wild-type IDH1, only hyperpolarized [1-(13)C] α-ketoglutarate can be detected. In contrast, in cells that express mutant IDH1, hyperpolarized [1-(13)C] 2-hydroxyglutarate is also observed, both in cell lysates and in vivo in orthotopic tumours.

  2. IDH1/2 mutation status combined with Ki-67 labeling index defines distinct prognostic groups in glioma.

    PubMed

    Zeng, Ailiang; Hu, Qi; Liu, Yanwei; Wang, Zheng; Cui, Xiaoming; Li, Rui; Yan, Wei; You, Yongping

    2015-10-06

    The current World Health Organization (WHO) classification of human gliomas is mainly based on morphology. However, it has limitations in prognostic prediction. We examined whether combining isocitrate dehydrogenase (IDH) 1/2 mutation status with the Ki-67 labeling index would improve the definition of prognostically distinct entities. We investigated the correlation of Ki-67 expression with IDH1/2 mutation status and their impact on clinical outcome in 703 gliomas. Low Ki-67 expression closely overlapped with IDH1/2 mutation in our cohort (P < 0.0001). Patients with IDH1/2 mutation survived significantly longer than patients with wild-type IDH1/2 did (P < 0.0001); higher Ki-67 expression was associated with shorter progression-free survival and overall survival (OS) (P < 0.0001). IDH1/2 combined with Ki-67 was used to re-classify glioma patients into five groups. IDH1/2 mutant patients with low and moderate Ki-67 expression (Group1) had the best prognosis, whereas patients with wild-type IDH1/2 and high Ki-67 expression (Group5) had the worst prognosis (Median OS = 1527 vs. 355 days, P < 0.0001). To summarize, our new classification model distinguishes biologically distinct subgroups and provides prognostic information regardless of the conventional WHO grade. Classification based on IDH1/2 mutation status and Ki-67 expression level could be more convenient for clinical application and guide personalized treatment in malignant gliomas.

  3. Prospective evaluation of tumor size and hormonal status in adrenal incidentalomas.

    PubMed

    Yener, S; Ertilav, S; Secil, M; Demir, T; Akinci, B; Kebapcilar, L; Comlekci, A; Bayraktar, F; Yesil, S

    2010-01-01

    Because of the increased use of imaging interventions, more subjects have been diagnosed with adrenal incidentaloma in recent years. To evaluate the risk of mass enlargement, hormone hypersecretion and development of adrenal carcinomas during short-term followup. There were 317 subjects with incidentally discovered adrenal tumors in the registry. Forty subjects were excluded because of clinically overt hormone secretion at diagnosis and subjects with complete data were included in radiological (no.=150) and hormonal (no.=150) follow- up. Radiological evaluation was performed with computed tomography (CT) and/or magnetic resonance imaging (MRI). There were 143 subjects with adrenal adenomas and 7 subjects with other tumor types (cyst or myelolipoma). Median follow-up duration was 24 months. Increase in tumor size was detected in 25 subjects (17.4%) with adenomas and 1 subject with adrenal myelolipoma (14.3%). Decrease in tumor size was found in 7 subjects (4.8%) with adrenal adenomas. One patient was diagnosed with adrenocortical carcinoma during follow-up. In subjects with non-functioning adrenal adenoma (NFA, no.=120) or subclinical Cushing syndrome (sCS) (no.=30), no subject developed clinically overt hormone hypersecretion, while 8 (6%) subjects in the NFA group developed sCS. Tumor diameter and follow-up duration were significantly higher in subjects who developed sCS. In conclusion, we demonstrated that, despite being infrequent, adrenal tumors may increase in size, develop overt or subclinical hormone secretion or feature malignant transformation. Therefore, radiological and hormonal follow-up should be recommended to the patients. More investigations are needed for the establishment of long-term follow-up protocols.

  4. EGF-Induced Acetylation of Heterogeneous Nuclear Ribonucleoproteins Is Dependent on KRAS Mutational Status in Colorectal Cancer Cells.

    PubMed

    Roda, Desamparados; Castillo, Josefa; Telechea-Fernández, Marcelino; Gil, Anabel; López-Rodas, Gerardo; Franco, Luís; González-Rodríguez, Patricia; Roselló, Susana; Pérez-Fidalgo, J Alejandro; García-Trevijano, Elena R; Cervantes, Andrés; Zaragozá, Rosa

    2015-01-01

    KRAS mutational status is considered a negative predictive marker of the response to anti-EGFR therapies in colorectal cancer (CRC) patients. However, conflicting data exist regarding the variable response to EGFR-targeted therapy. The effects of oncogenic KRAS on downstream targets were studied in cell lines with different KRAS mutations. Cells harboring a single KRASG13D allele showed the most tumorigenic profile, with constitutive activation of the downstream pathway, rendering them EGF-unresponsive. Conversely, KRASA146T cells showed a full EGF-response in terms of signal transduction pathways, cell proliferation, migration or adhesion. Moreover, the global acetylome of CRC cells was also dependent on KRAS mutational status. Several hnRNP family members were identified within the 36 acetylated-proteins. Acetylation status is known to be involved in the modulation of EGF-response. In agreement with results presented herein, hnRNPA1 and L acetylation was induced in response to EGF in KRASA146T cells, whereas acetyl-hnRNPA1 and L levels remained unchanged after growth factor treatment in KRASG13D unresponsive cells. Our results showed that hnRNPs induced-acetylation is dependent on KRAS mutational status. Nevertheless hnRNPs acetylation might also be the point where different oncogenic pathways converge.

  5. EGF-Induced Acetylation of Heterogeneous Nuclear Ribonucleoproteins Is Dependent on KRAS Mutational Status in Colorectal Cancer Cells

    PubMed Central

    Telechea-Fernández, Marcelino; Gil, Anabel; López-Rodas, Gerardo; Franco, Luís; González-Rodríguez, Patricia; Roselló, Susana; Pérez-Fidalgo, J. Alejandro; García-Trevijano, Elena R.; Cervantes, Andrés; Zaragozá, Rosa

    2015-01-01

    KRAS mutational status is considered a negative predictive marker of the response to anti-EGFR therapies in colorectal cancer (CRC) patients. However, conflicting data exist regarding the variable response to EGFR-targeted therapy. The effects of oncogenic KRAS on downstream targets were studied in cell lines with different KRAS mutations. Cells harboring a single KRASG13D allele showed the most tumorigenic profile, with constitutive activation of the downstream pathway, rendering them EGF-unresponsive. Conversely, KRASA146T cells showed a full EGF-response in terms of signal transduction pathways, cell proliferation, migration or adhesion. Moreover, the global acetylome of CRC cells was also dependent on KRAS mutational status. Several hnRNP family members were identified within the 36 acetylated-proteins. Acetylation status is known to be involved in the modulation of EGF-response. In agreement with results presented herein, hnRNPA1 and L acetylation was induced in response to EGF in KRASA146T cells, whereas acetyl-hnRNPA1 and L levels remained unchanged after growth factor treatment in KRASG13D unresponsive cells. Our results showed that hnRNPs induced-acetylation is dependent on KRAS mutational status. Nevertheless hnRNPs acetylation might also be the point where different oncogenic pathways converge. PMID:26110767

  6. Effects of bovine somatotropin and thyroid hormone status on hormone levels, body weight gain, and mohair fiber growth of Angora goats.

    PubMed

    Puchala, R; Prieto, I; Banskalieva, V; Goetsch, A L; Lachica, M; Sahlu, T

    2001-11-01

    Forty-eight Angora goats (24 wethers and 24 doelings; 5 mo old; 16 +/- 0.5 kg initial BW) were used in an experiment with a 2 x 3 factorial treatment arrangement (n = 8) to evaluate effects of recombinant bovine somatotropin (bST) administration and thyroid hormone status (euthyroid, hypothyroid, and hyperthyroid) on hormone levels, ADG, and mohair fiber growth. The bST was a slow-release zinc-based suspension, with sustained delivery (100 microg/[kg BW x d]) over a 14-d period. Hyperthyroidism was maintained by daily treatment with thyroxine (T4; 150 microg/[kg BW x d]), and hypothyroidism was achieved by feeding 6 mg/(kg BW x d) of propylthiouracil. The experiment was conducted in July to September and consisted of a 2-wk pretreatment period and 8 wk of bST treatment. Goats were given ad libitum access to a diet with 15% CP and 2.54 Mcal/ kg ME (DM basis). Concentrations of T4 and T3 were greatest (P < 0.01) among treatments for hyperthyroid-bST and hyperthyroid-control (T4: 38.6 and 38.0 microg/dL; T3: 406 and 385 ng/dL, respectively); similar among euthyroid-control, euthyroid-bST, and hypothyroid-bST (T4: 11.1, 11.5, and 9.8 microg/dL, respectively; T3: 232, 252, and 226 ng/dL, respectively); and lowest (P < 0.01) for hypothyroid-control (T4: 5.1 microg/dL; T3: 144 ng/dL). Plasma concentration of insulin-like growth factor-I was greatest (P < 0.01) for euthyroid-bST (596 ng/mL) and hypothyroid-bST (618 ng/mL); however, concentration for hyperthyroid-bST was similar to those for euthyroid-control, hypothyroid-control, and hyperthyroid-control (188, 178, 187, and 191 ng/mL, respectively). Dry matter intake was greatest (P < 0.05) for euthyroid-bST (794 g/d), similar among hypothyroid treatments (693 and 703 g/d for control and bST, respectively) and euthyroid-control (681 g/d), and lowest for hyperthyroid groups (554 and 518 g/d for control and bST, respectively); ADG for hyperthyroid goats (11 g/d) was lower than with hypothyroidism and euthyroidism (72 and 73

  7. Overexpression of the CC-type glutaredoxin, OsGRX6 affects hormone and nitrogen status in rice plants

    PubMed Central

    El-Kereamy, Ashraf; Bi, Yong-Mei; Mahmood, Kashif; Ranathunge, Kosala; Yaish, Mahmoud W.; Nambara, Eiji; Rothstein, Steven J.

    2015-01-01

    Glutaredoxins (GRXs) are small glutathione dependent oxidoreductases that belong to the Thioredoxin (TRX) superfamily and catalyze the reduction of disulfide bonds of their substrate proteins. Plant GRXs include three different groups based on the motif sequence, namely CPYC, CGFS, and CC-type proteins. The rice CC-type proteins, OsGRX6 was identified during the screening for genes whose expression changes depending on the level of available nitrate. Overexpression of OsGRX6 in rice displayed a semi-dwarf phenotype. The OsGRX6 overexpressors contain a higher nitrogen content than the wild type, indicating that OsGRX6 plays a role in homeostatic regulation of nitrogen use. Consistent with this, OsGRX6 overexpressors displayed delayed chlorophyll degradation and senescence compared to the wild type plants. To examine if the growth defect of these transgenic lines attribute to disturbed plant hormone actions, plant hormone levels were measured. The levels of two cytokinins (CKs), 2-isopentenyladenine and trans-zeatin, and gibberellin A1 (GA1) were increased in these lines. We also found that these transgenic lines were less sensitive to exogenously applied GA, suggesting that the increase in GA1 is a result of the feedback regulation. These data suggest that OsGRX6 affects hormone signaling and nitrogen status in rice plants. PMID:26579177

  8. Refined histopathological predictors of BRCA1 and BRCA2 mutation status: a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia.

    PubMed

    Spurdle, Amanda B; Couch, Fergus J; Parsons, Michael T; McGuffog, Lesley; Barrowdale, Daniel; Bolla, Manjeet K; Wang, Qin; Healey, Sue; Schmutzler, Rita; Wappenschmidt, Barbara; Rhiem, Kerstin; Hahnen, Eric; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Plendl, Hansjoerg; Niederacher, Dieter; Sutter, Christian; Wang-Gohrke, Shan; Steinemann, Doris; Preisler-Adams, Sabine; Kast, Karin; Varon-Mateeva, Raymonda; Ellis, Steve; Frost, Debra; Platte, Radka; Perkins, Jo; Evans, D Gareth; Izatt, Louise; Eeles, Ros; Adlard, Julian; Davidson, Rosemarie; Cole, Trevor; Scuvera, Giulietta; Manoukian, Siranoush; Bonanni, Bernardo; Mariette, Frederique; Fortuzzi, Stefano; Viel, Alessandra; Pasini, Barbara; Papi, Laura; Varesco, Liliana; Balleine, Rosemary; Nathanson, Katherine L; Domchek, Susan M; Offitt, Kenneth; Jakubowska, Anna; Lindor, Noralane; Thomassen, Mads; Jensen, Uffe Birk; Rantala, Johanna; Borg, Åke; Andrulis, Irene L; Miron, Alexander; Hansen, Thomas V O; Caldes, Trinidad; Neuhausen, Susan L; Toland, Amanda E; Nevanlinna, Heli; Montagna, Marco; Garber, Judy; Godwin, Andrew K; Osorio, Ana; Factor, Rachel E; Terry, Mary B; Rebbeck, Timothy R; Karlan, Beth Y; Southey, Melissa; Rashid, Muhammad Usman; Tung, Nadine; Pharoah, Paul D P; Blows, Fiona M; Dunning, Alison M; Provenzano, Elena; Hall, Per; Czene, Kamila; Schmidt, Marjanka K; Broeks, Annegien; Cornelissen, Sten; Verhoef, Senno; Fasching, Peter A; Beckmann, Matthias W; Ekici, Arif B; Slamon, Dennis J; Bojesen, Stig E; Nordestgaard, Børge G; Nielsen, Sune F; Flyger, Henrik; Chang-Claude, Jenny; Flesch-Janys, Dieter; Rudolph, Anja; Seibold, Petra; Aittomäki, Kristiina; Muranen, Taru A; Heikkilä, Päivi; Blomqvist, Carl; Figueroa, Jonine; Chanock, Stephen J; Brinton, Louise; Lissowska, Jolanta; Olson, Janet E; Pankratz, Vernon S; John, Esther M; Whittemore, Alice S; West, Dee W; Hamann, Ute; Torres, Diana; Ulmer, Hans Ulrich; Rüdiger, Thomas; Devilee, Peter; Tollenaar, Robert A E M; Seynaeve, Caroline; Van Asperen, Christi J; Eccles, Diana M; Tapper, William J; Durcan, Lorraine; Jones, Louise; Peto, Julian; dos-Santos-Silva, Isabel; Fletcher, Olivia; Johnson, Nichola; Dwek, Miriam; Swann, Ruth; Bane, Anita L; Glendon, Gord; Mulligan, Anna M; Giles, Graham G; Milne, Roger L; Baglietto, Laura; McLean, Catriona; Carpenter, Jane; Clarke, Christine; Scott, Rodney; Brauch, Hiltrud; Brüning, Thomas; Ko, Yon-Dschun; Cox, Angela; Cross, Simon S; Reed, Malcolm W R; Lubinski, Jan; Jaworska-Bieniek, Katarzyna; Durda, Katarzyna; Gronwald, Jacek; Dörk, Thilo; Bogdanova, Natalia; Park-Simon, Tjoung-Won; Hillemanns, Peter; Haiman, Christopher A; Henderson, Brian E; Schumacher, Fredrick; Le Marchand, Loic; Burwinkel, Barbara; Marme, Frederik; Surovy, Harald; Yang, Rongxi; Anton-Culver, Hoda; Ziogas, Argyrios; Hooning, Maartje J; Collée, J Margriet; Martens, John W M; Tilanus-Linthorst, Madeleine M A; Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volke; Stegmaier, Christa; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Lindblom, Annika; Margolin, Sara; Joseph, Vijai; Robson, Mark; Rau-Murthy, Rohini; González-Neira, Anna; Arias, José Ignacio; Zamora, Pilar; Benítez, Javier; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Peterlongo, Paolo; Zaffaroni, Daniela; Barile, Monica; Capra, Fabio; Radice, Paolo; Teo, Soo H; Easton, Douglas F; Antoniou, Antonis C; Chenevix-Trench, Georgia; Goldgar, David E

    2014-12-23

    The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling. Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of mutation status by histopathological markers were derived using a Mantel-Haenszel approach. ER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years or older (LR = 4.13 (3.70 to 4.62)) versus younger than 50 years (LR = 3.16 (2.96 to 3.37)). For BRCA2, ER-positive grade 3 phenotype modestly predicted positive mutation status irrespective of age (LR = 1.7-fold), whereas ER-negative grade 3 features modestly predicted positive mutation status at 50 years or older (LR = 1.54 (1.27 to 1.88)). Triple-negative tumor status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR = 3.73 (3.43 to 4.05)) and 50 years or older (LR = 4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years or older (LR = 1.79 (1.42 to 2

  9. The Influence of BRAF and KRAS Mutation Status on the Association between Aspirin Use and Survival after Colon Cancer Diagnosis

    PubMed Central

    Reimers, Marlies S.; Swets, Marloes; Bastiaannet, Esther; Prinse, Bianca; van Eijk, Ronald; Lemmens, Valery E. P. P.; van Herk-Sukel, Myrthe P. P.; van Wezel, Tom; Kuppen, Peter J. K.; Morreau, Hans; van de Velde, Cornelis J. H.; Liefers, Gerrit-Jan

    2017-01-01

    Background Use of aspirin after diagnosis of colon cancer has been associated with improved survival. Identification of cancer subtypes that respond to aspirin treatment may help develop personalized treatment regimens. The aim of this study was to investigate the influence of BRAF and KRAS mutation status on the association between aspirin use and overall survival after colon cancer diagnosis. Methods A random selection of 599 patients with colon cancer were analyzed, selected from the Eindhoven Cancer Registry, and BRAF and KRAS mutation status was determined. Data on aspirin use (80 mg) were obtained from the PHARMO Database Network. Parametric survival models with exponential (Poisson) distribution were used. Results Aspirin use after colon cancer diagnosis was associated with improved overall survival in wild-type BRAF tumors, adjusted rate ratio (RR) of 0.60 (95% CI 0.44–0.83). In contrast, aspirin use in BRAF mutated tumors was not associated with an improved survival (RR 1.11, 95% CI 0.57–2.16). P-value for interaction was non-significant. KRAS mutational status did not differentiate in the association between aspirin use and survival. Conclusion Low-dose aspirin use after colon cancer diagnosis was associated with improved survival in BRAF wild-type tumors only. However, the large confidence interval of the rate ratio for the use of aspirin in patients with BRAF mutation does not rule out a possible benefit. These results preclude BRAF and KRAS mutation status to be used as a marker for individualized treatment with aspirin, if aspirin becomes regular adjuvant treatment for colon cancer patients in the future. PMID:28125730

  10. The Influence of BRAF and KRAS Mutation Status on the Association between Aspirin Use and Survival after Colon Cancer Diagnosis.

    PubMed

    Frouws, Martine A; Reimers, Marlies S; Swets, Marloes; Bastiaannet, Esther; Prinse, Bianca; van Eijk, Ronald; Lemmens, Valery E P P; van Herk-Sukel, Myrthe P P; van Wezel, Tom; Kuppen, Peter J K; Morreau, Hans; van de Velde, Cornelis J H; Liefers, Gerrit-Jan

    2017-01-01

    Use of aspirin after diagnosis of colon cancer has been associated with improved survival. Identification of cancer subtypes that respond to aspirin treatment may help develop personalized treatment regimens. The aim of this study was to investigate the influence of BRAF and KRAS mutation status on the association between aspirin use and overall survival after colon cancer diagnosis. A random selection of 599 patients with colon cancer were analyzed, selected from the Eindhoven Cancer Registry, and BRAF and KRAS mutation status was determined. Data on aspirin use (80 mg) were obtained from the PHARMO Database Network. Parametric survival models with exponential (Poisson) distribution were used. Aspirin use after colon cancer diagnosis was associated with improved overall survival in wild-type BRAF tumors, adjusted rate ratio (RR) of 0.60 (95% CI 0.44-0.83). In contrast, aspirin use in BRAF mutated tumors was not associated with an improved survival (RR 1.11, 95% CI 0.57-2.16). P-value for interaction was non-significant. KRAS mutational status did not differentiate in the association between aspirin use and survival. Low-dose aspirin use after colon cancer diagnosis was associated with improved survival in BRAF wild-type tumors only. However, the large confidence interval of the rate ratio for the use of aspirin in patients with BRAF mutation does not rule out a possible benefit. These results preclude BRAF and KRAS mutation status to be used as a marker for individualized treatment with aspirin, if aspirin becomes regular adjuvant treatment for colon cancer patients in the future.

  11. Associations of vitamin D status and vitamin D-related polymorphisms with sex hormones in older men.

    PubMed

    Rafiq, R; van Schoor, N M; Sohl, E; Zillikens, M C; Oosterwerff, M M; Schaap, L; Lips, P; de Jongh, R T

    2016-11-01

    Evidence regarding relationships of serum 25-hydroxyvitamin D (25(OH)D) with sex hormones and gonadotropin concentrations remains inconsistent. Polymorphisms in vitamin D-related genes may underly these relationships. Our aim was to examine the relationship of vitamin D status and polymorphisms in vitamin D-related genes with sex hormone and gonadotropin levels. We analysed data from the Longitudinal Aging Study Amsterdam, an ongoing population-based cohort study of older Dutch individuals (65-89 years). We included data of men with measurements of serum 25-hydroxyvitamin D (25(OH)D) (n=643) and determination of vitamin D-related gene polymorphisms (n=459). 25(OH)D concentrations were classified into four categories: <25, 25-50, 50-75 and >75nmol/L. Outcome measures were total testosterone, calculated bioavailable and free fraction testosterone, SHBG, estradiol, LH and FSH concentrations. Hypogonadism was defined as a total testosterone level <8.0nmol/L. Serum 25(OH)D was positively associated with total and bioavailable testosterone levels. After adjustments for confounders, men with serum 25(OH)D less than 25 (n=56), 25-50 (n=199) and 50-75nmol/L (n=240) had lower total testosterone levels compared to men with serum 25(OH)D higher than 75nmol/L (n=148) (β (95% confidence interval): -2.1 (-3.7 to -0.4nmol/L), -0.8 (-1.9 to 0.4nmol/L) and -1.4 (-2.4 to -0.3nmol/L), respectively). For bioavailable testosterone the association was significant only for men with serum 25(OH)D less than 25nmol/L (-0.8 (-1.4 to -0.1nmol/L)) compared to men with serum 25(OH)D >75nmol/L. Serum 25(OH)D was not related to SHBG, estradiol or gonadotropin levels. Hypogonadism (n=29) was not associated with lower serum 25(OH)D. No significant differences were found in hormone levels between the different genotypes of the vitamin D-related gene polymorphisms. Also, the polymorphisms did not modify the relationships of serum 25(OH)D with sex hormones or gonadotropins. Vitamin D status is

  12. Central obesity increases risk of breast cancer irrespective of menopausal and hormonal receptor status in women of South Asian Ethnicity.

    PubMed

    Nagrani, R; Mhatre, S; Rajaraman, P; Soerjomataram, I; Boffetta, P; Gupta, S; Parmar, V; Badwe, R; Dikshit, R

    2016-10-01

    Current evidence suggests that the relationship between obesity and breast cancer (BC) risk may vary between ethnic groups. A total of 1633 BC cases and 1504 controls were enrolled in hospital-based case-control study in Mumbai, India, from 2009 to 2013. Along with detailed questionnaire, we collected anthropometric measurements on all participants. We used unconditional logistic regression models to estimate odds ratios (ORs) and 95% confidence interval (CI) for BC risk associated with anthropometry measurements, stratified on tumour subtype and menopausal status. Waist-to-hip ratio (WHR) of ≥0.95 was strongly associated with risk of BC compared to WHR ≤0.84 in both premenopausal (OR = 4.3; 95% CI: 2.9-6.3) and postmenopausal women (OR = 3.4; 95% CI: 2.4-4.8) after adjustment for body mass index (BMI). Premenopausal women with a BMI ≥30 were at lower risk compared to women with normal BMI (OR = 0.5; 95% CI: 0.4-0.8). A similar protective effect was observed in women who were postmenopausal for <10 years (OR = 0.6; 95% CI: 0.4-0.9) but not in women who were postmenopausal for ≥10 years (OR = 1.8; 95% CI: 1.1-3.3). Overweight and obese women (BMI: 25-29.9 and ≥ 30 kg/m(2), respectively) were at increased BC risk irrespective of menopausal status if their WHR ≥0.95. Central obesity (measured in terms of WC and WHR) increased the risk of both premenopausal and postmenopausal BCs irrespective of hormone receptor (HR) status. Central obesity appears to be a key risk factor for BC irrespective of menopausal or HR status in Indian women with no history of hormone replacement therapy. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  13. The association between reproductive and hormonal factors and ovarian cancer by estrogen-α and progesterone receptor status.

    PubMed

    Shafrir, Amy L; Rice, Megan S; Gupta, Mamta; Terry, Kathryn L; Rosner, Bernard A; Tamimi, Rulla M; Hecht, Jonathan L; Tworoger, Shelley S

    2016-12-01

    We assessed the association between reproductive and hormonal factors and ovarian cancer incidence characterized by estrogen receptor-α (ERα) and progesterone receptor (PR) status. Tissue microarrays were used to assess ERα and PR expression among 197 Nurses' Health Study (NHS), 42 NHSII and 76 New England Case-Control Study (NECC) ovarian cancer cases. NHS/NHSII cases were matched to up to 4 controls (n=954) on diagnosis date and birth year. NECC controls (n=725) were frequency matched on age. Cases were considered receptor positive if ≥1% of tumor cells stained positive. Associations by ERα and PR status were assessed using polytomous logistic regression. p-Value for heterogeneity was calculated using a likelihood ratio test. 45% of ovarian tumors were PR(+), 78% were ERα(+) and 45% were ERα(+)/PR(+), while 22% were ERα(-)/PR(-). Postmenopausal status was associated with an increased risk of PR(-) tumors (OR: 2.07; 95%CI: 1.15-3.75; p-heterogeneity=0.01) and age at natural menopause was inversely associated with PR(-) tumors (OR, per 5years: 0.77; 95%CI: 0.61-0.96; p-het=0.01). Increasing duration of postmenopause was differentially associated by PR status (p-het=0.0009). Number of children and tubal ligation were more strongly associated with ERα(-) versus ERα(+) tumors (p-het=0.002 and 0.05, respectively). No differential associations were observed for oral contraceptive or hormone therapy use. Postmenopausal women have an increased risk of developing PR(-) ovarian tumors compared to premenopausal women. The associations observed for ovarian cancer differ from those seen for breast cancer suggesting that the biology for tumor development through ERα and PR pathways may differ. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Lung Adenocarcinoma: Predictive Value of KRAS Mutation Status in Assessing Local Recurrence in Patients Undergoing Image-guided Ablation.

    PubMed

    Ziv, Etay; Erinjeri, Joseph P; Yarmohammadi, Hooman; Boas, F Edward; Petre, Elena N; Gao, Song; Shady, Waleed; Sofocleous, Constantinos T; Jones, David R; Rudin, Charles M; Solomon, Stephen B

    2017-01-01

    Purpose To establish the relationship between KRAS mutation status and local recurrence after image-guided ablation of lung adenocarcinoma. Materials and Methods This study consisted of a HIPAA-compliant institutional review board-approved retrospective review of 56 primary lung adenocarcinomas in 54 patients (24 men, 30 women; median age, 72 years; range, 54-87 years) treated with percutaneous image-guided ablation and with available genetic mutational analysis. KRAS mutation status and additional clinical and technical variables-Eastern Cooperative Oncology Group (ECOG) status, smoking history, stage at diagnosis, status (new primary or not), history of radiation, history of surgery, prior systemic treatment, modality of ablation, size of nodule, ablation margin, and presence of ground-glass appearance-were recorded and evaluated in relation to time to local recurrence, which was calculated from the time of ablation to the first radiographic evidence of recurrence. Predictors of outcome were identified by using a proportional hazards model for both univariate and multivariate analysis, with death as a competing risk. Results Technical success was 100%. Of the 56 ablated tumors, 37 (66%) were wild type for KRAS and 19 (34%) were KRAS mutants. The 1-year and 3-year cumulative incidences of recurrence were 20% and 35% for wild-type KRAS compared with 40% and 63% for KRAS mutant tumors. KRAS mutation status was a significant predictor of local recurrence at both univariate (P = .05; subdistribution hazard ratio [sHR], 2.32) and multivariate (P = .006; sHR, 3.75) analysis. At multivariate analysis, size (P = .026; sHR, 2.54) and ECOG status (P = .012; sHR, 2.23) were also independent significant predictors, whereas minimum margin (P = .066) was not. Conclusion The results of this study show that there is a relationship between KRAS mutation status and local recurrence after image-guided ablation of lung adenocarcinoma. Specifically, KRAS mutation status of the ablated

  15. Mammographic breast density and breast cancer risk by menopausal status, postmenopausal hormone use and a family history of breast cancer.

    PubMed

    Yaghjyan, Lusine; Colditz, Graham A; Rosner, Bernard; Tamimi, Rulla M

    2012-05-01

    Few studies have investigated the association between breast density and breast cancer by a family history of breast cancer, menopausal status, and postmenopausal hormone use (PMH). We investigated if associations of breast density and breast cancer differ according to the status of these risk factors. This study included 1,481 incident breast cancer cases diagnosed within the Nurses' Health Study I and II cohorts and 2,779 matched controls. Breast density was measured from digitized film images with computerized techniques. Information on breast cancer risk factors was obtained prospectively from the biennial questionnaires before the date of the cancer diagnosis for cancer cases and their matched controls. The data were analyzed with logistic regression. Breast cancer risk increased with increasing percent breast density in all strata (p for trend in all subsets <0.0001). The density-related risk of breast cancer was similar in women with and without a family history (OR = 4.00 [95 % CI 2.01-7.94] vs. 3.71 [95 % CI 2.79-4.94] for density ≥50 % vs. <10 %, p for interaction = 0.53). The magnitude of the association between density and breast cancer risk, however, appeared to be stronger in premenopausal women than in postmenopausal women without PMH history (OR = 5.49 [95 % CI 2.44-12.39] vs. 3.02 [95 % CI 1.62-5.63] for density ≥50 % vs. <10 %, p-heterogeneity = 0.17) and appeared to be stronger in postmenopausal women currently using hormones compared with postmenopausal women who never used PMH (OR = 4.50 [95 % CI 2.99-6.78] vs. 3.02, p-heterogeneity = 0.20) or with past hormone use (OR = 4.50 vs. 3.71 [95 % CI 1.90-7.23], p-heterogeneity = 0.23). Findings on associations by menopausal status/hormone use are suggestive and should be examined in additional larger studies.

  16. Supraphysiological hormonal status, anxiety disorders, and COMT Val/Val genotype are associated with reduced sensorimotor gating in women.

    PubMed

    Comasco, Erika; Hellgren, Charlotte; Olivier, Jocelien; Skalkidou, Alkistis; Sundström Poromaa, Inger

    2015-10-01

    Pregnancy is a period characterized by a supraphysiological hormonal status, and greater anxiety proneness, which can lead to peripartum affective symptoms with dramatic consequences not only for the woman but also for the child. Clinical psychiatry is heavily hampered by the paucity of objective and biology-based intermediate phenotypes. Prepulse inhibition (PPI) of the startle response, a neurophysiological measure of sensorimotor gating, has been poorly investigated in relation to anxiety and in pregnant women. In the present study, the PPI of healthy non-pregnant women (n = 82) and late pregnant women (n = 217) was investigated. Age, BMI, depression and anxiety symptoms, tobacco use, and antidepressant medication were considered. We investigated and provided evidence of lower PPI: (i) in healthy pregnant women compared to healthy non-pregnant controls, (ii) in pregnant women with anxiety disorders compared to healthy pregnant women, (iii) in pregnant women with anxiety disorders using SSRI compared to un-medicated pregnant women with anxiety disorders, and (iv) in healthy pregnant women carrying the COMT Val158Met Val/Val genotype compared to Met carriers. Altogether, a reduced sensorimotor gating as an effect of supraphysiological hormonal status, anxiety disorders, SSRIs, and catecholaminergic genotype, implicate the putative relevance of lower PPI as an objective biological correlate of anxiety proneness in pregnant women. These findings call for prospective studies to dissect the multifactorial influences on PPI in relation to mental health of pregnant women.

  17. FLT3 mutational status is an independent risk factor for adverse outcomes after allogeneic transplantation in AML

    PubMed Central

    Li, Yumeng; Braun, Thomas; Chang, Lawrence; Bixby, Dale; Hanauer, David A.; Chughtai, Komal A.; Gatza, Erin; Couriel, Daniel; Goldstein, Steven; Pawarode, Attaphol; Reddy, Pavan; Riwes, Mary; Connelly, James; Harris, Andrew; Kitko, Carrie; Levine, John; Yanik, Greg

    2015-01-01

    Allogeneic HCT has been increasingly used in the setting of FLT3 mutated AML. However, its role in conferring durable relapse-free intervals remains in question. Herein, we sought to investigate FLT3 mutational status on transplant outcomes. We conducted a retrospective cohort study of 262 consecutive AML patients who underwent first-time allogeneic HCT (2008-2014), of whom 171 had undergone FLT3-ITD mutational testing. FLT3 mutated AML was associated with nearly twice the relapse risk (RR) compared with those without FLT3 mutation 3 years post-HCT (63% vs. 37%, P<0.001), and with a shorter median time to relapse (100 vs. 121 days). FLT3 mutational status remained significantly associated with this outcome after controlling for patient, disease, and transplant-related risk factors (P<0.05). Multivariate analysis showed a significant association of FLT3 mutation with increased 3-year RR (HR 3.63, 95% CI: 2.13, 6.19, P<0.001), and inferior disease-free survival (HR 2.05, 95% CI: 1.29, 3.27, P<0.01) and overall survival (HR 1.92, 95% CI: 1.14, 3.24, P<0.05). These data demonstrate high risk of early relapse after allogeneic HCT for FLT3 mutated AML that translates into adverse disease-free and overall survival outcomes. Additional targeted and coordinated interventions are needed to maintain durable remission after allogeneic HCT in this high-risk population. PMID:26191952

  18. Influence of feeding status, time of the day, and season on baseline adrenocorticotropic hormone and the response to thyrotropin releasing hormone-stimulation test in healthy horses.

    PubMed

    Diez de Castro, E; Lopez, I; Cortes, B; Pineda, C; Garfia, B; Aguilera-Tejero, E

    2014-07-01

    Equine pituitary pars intermedia function can be assessed by the measurement of baseline and thyrotropin releasing hormone (TRH)-induced concentrations of adrenocorticotropic hormone (ACTH); however, these measurements may be affected by the environment. Therefore, a prospective observational study evaluated the influence of feeding, time of the day, and season on baseline and TRH-induced concentrations of ACTH in healthy horses. Baseline ACTH was measured in 50 horses before and 2 h after feeding. Six research horses were subjected to a crossover study in which 6 TRH tests were performed in 2 different seasons, March-April (MA) and July-September (JS), at 2 different times of the day, 8 AM and 8 PM, and, under 2 different conditions relative to feeding status, fasted and 2 h after feeding. Differences between fasted and fed horses were found in baseline ACTH, 17.1 ± 1.8 versus 46.1 ± 7.6 pg/mL (P = 0.003) and TRH-stimulated ACTH: 124.1 ± 21.3 versus 192.6 ± 33.1 pg/mL (P = 0.029) at 10 min, and 40.1 ± 4.9 versus 73.2 ± 13.4 pg/mL (P = 0.018) at 30 min post TRH injection. No differences were found between tests performed at different times of the day. Basal ACTH concentrations were greater in JS than in MA, 17.1 ± 1.8 versus 11.9 ± 0.6 pg/mL (P = 0.006). A seasonal influence was also found in stimulated ACTH values, which were much greater in JS 122.7 ± 36.7 versus 31.2 ± 7.4 pg/mL, at 10 min (P = 0.03) and 39.0 ± 7.2 versus 19.8 ± 3.1 pg/mL, at 30 min (P = 0.03). In addition to season, feeding is a potential confounding factor when measuring baseline or stimulated ACTH in horses. In conclusion, feeding status should be standardized for the diagnosis of equine pituitary pars intermedia dysfunction.

  19. The effect of red wine consumption on hormonal reproductive parameters and total antioxidant status in young adult male rats.

    PubMed

    Oczkowski, Michał; Średnicka-Tober, Dominika; Stachoń, Małgorzata; Kołota, Aleksandra; Wolińska-Witort, Ewa; Malik, Agnieszka; Hallmann, Ewelina; Rusaczonek, Anna; Gromadzka-Ostrowska, Joanna

    2014-09-01

    Very little is known about the effects of red wine consumption on male reproductive functions. Here we report the effect of regular drinking of different types of red wine on hormonal reproductive parameters and total antioxidant status in young adult male rats. Dry red wine (D-RW) exerted higher antioxidant activity and was characterized by higher concentration of phenolic compounds compared to semi-dry (SD-RW), sweet (S-RW) and semi-sweet (SS-RW) wines. No differences in total antioxidant status of rat plasma after six weeks of drinking of the wines were detected. Increased plasma follicle-stimulating hormone levels in S-RW versus control and D-RW (5.26 vs. 3.06 and 3.21 ng mL(-1)) groups were found. The plasma testosterone concentration was lower in D-RW compared to control, SD-RW, S-RW and SS-RW groups (0.25 vs. 1.12, 1.09, 1.54 and 1.25 ng mL(-1)). Higher plasma 17β-estradiol level in S-RW versus SD-RW and SS-RW (10.94 vs. 7.18 and 6.72 pg mL(-1)) group was stated. The prolactin level was higher in plasma of S-RW versus D-RW and SS-RW (17.35 vs. 9.74 and 8.59 ng mL(-1)) rats. The effects of red wine drinking on the hormonal regulation of the male reproductive system depend on the type and the dose of red wine. Chemical compounds naturally occurring in red wines (i.e. phenolics) may modulate the effects of ethyl alcohol, but also directly affect the male reproduction.

  20. [Epidermal growth factor receptor (EGFR) mutation status before and after acquired resistance to EGFR tyrosine kinase inhibitors in patients with lung adenocarcinoma].

    PubMed

    Ye, S B; Li, R; Shi, S S

    2017-02-08

    Objective: To investigate epidermal growth factor receptor (EGFR) mutation status in lung adenocarcinomas before and after acquiring resistance to EGFR tyrosine kinase inhibitors (TKIs) using ARMS method followed by further verification using droplet digital PCR technique. Methods: Twenty qualified patients were included, among them 13 were male and 7 were female patients. Before EGFR-TKIs treatment, 5 patients were EGFR wild-type by ARMS, and the other 15 patients had L858R or 19-del point mutations. The time to progression varied from 4 to 18 months. Mutation of exons 18, 19, 20 and 21 were detected by ARMS, and were verified by droplet digital PCR system method. Results: EGFR wild-type status was unchanged before and after acquired resistance to EGFR-TKIs in 5 lung adenocarcinoma patients. Alteration of EGFR mutation status occurred in 10 of the 15 patients with pre-treatment L858R or 19-del mutations. Among them, T790M mutation was found in 8 patients, L858R became G719X plus S768I mutation in one patient, and 19-del converted into wild-type in one other patient. Conclusions: T790M mutation is the primary type of EGFR mutation in lung adenocarcinomas with acquired resistance to EGFR-TKIs therapy. Acquired resistance to EGFR-TKIs dose not lead to the alteration of EGFR status in pre-treatment EGFR wild-type patients, but can alter EGFR mutation status in pre-treatment EGFR mutant patients.

  1. Unexpected peripheral markers of thyroid function in a patient with a novel mutation of the MCT8 thyroid hormone transporter gene.

    PubMed

    Herzovich, V; Vaiani, E; Marino, R; Dratler, G; Lazzati, J M; Tilitzky, S; Ramirez, P; Iorcansky, S; Rivarola, M A; Belgorosky, A

    2007-01-01

    The specific thyroid hormone transporter, MCT8, located on the X chromosome, has led to the identification a novel syndrome. The objective is to relate phenotype with several tissue-specific thyroid functions. A 1-year-old boy, who had severe psychological damage and low serum T4, had received l-T4 for 3 months. At admission, body length was normal but weight was low. Off therapy, serum TSH was mildly elevated, serum T4 and free T4 were low, and serum T3 and free T3 were high. Direct sequencing of the MCT8 gene revealed a single nucleotide change that resulted in a novel nonsense mutation at codon 261 (Q261X) in exon 3. Since serum T3 was high, peripheral markers of hyperthyroidism were looked for. Bone age was advanced, despite the presence of malnutrition and low T4. Serum SHBG, a marker of thyroid hormone action in liver, was markedly elevated. Markers of skeletal muscle catabolism, ammonemia and lactic acid, were found to be elevated. The phenotype of MCT 8 mutation might be explained by differences in the entry of thyroid hormones into different cells. In the presence of an inactive MCT8 transporter, the high blood T3 levels might not be enough to prevent brain damage early in life, while they seem to be able to induce a postnatal state of peripheral hyperthyroidism in other tissues, such as liver, bone and skeletal muscle.

  2. Global expression profiling reveals gain-of-function onco-genic activity of a mutated thyroid hormone receptor in thyroid carcinogenesis

    PubMed Central

    Lu, Changxue; Mishra, Alok; Zhu, Yuelin J; Meltzer, Paul; Cheng, Sheue-yann

    2011-01-01

    Thyroid hormone receptors (TRs) are critical in regulating gene expression in normal physiological processes. Decreased expression and/or somatic mutations of TRs have been shown to be associated several types of human cancers including liver, breast, lung, and thyroid. To understand the molecular mechanisms by which mutated TRs promote carcinogenesis, an animal model of follicular thyroid carcinoma (FTC) (Thrbpv/pv mice) was used in the present study. The Thrbpv/pv mouse harbors a knockin dominant negative PV mutation, identified in a patient with resistance to thyroid hormone. To understand whether oncogenic actions of PV involve not only the loss of normal TR functions but also gain-of-function activities, we compared the gene expression profiles of thyroid lesions in Thrbpv/pv mice and Thra1-/- Thrb-/- mice that also spontaneously develop FTC, but with less severe malignancy. Analysis of the cDNA microarray data derived from microdissected thyroid tumor cells of these two mice showed contrasting global gene expression profiles. With stringent selection using 2.5-fold change (p<0.01) in cDNA microarray analysis, 241 genes with altered gene expression were identified. Nearly half of the genes (n=103: 42.7% of total) with altered gene expression in thyroid tumor cells of Thrbpv/pv mice were associated with tumorigenesis and metastasis; some of these genes function as oncogenes in human thyroid cancers. The remaining genes were found to function in transcriptional regulation, RNA processing, cell proliferation, apoptosis, angiogenesis, and cytoskeleton modification. These results indicate that the more aggressive thyroid tumor progression in Thrbpv/pv mice was not due simply to the loss of tumor suppressor functions of TR via mutation but also, importantly, to gain-of-function in the oncogenic activities of PV to drive thyroid carcinogenesis. Thus, the present study identifies a novel mechanism by which a mutated TRβ evolves with an oncogenic advantage to promote

  3. Evaluation of oxidative stress and thyroid hormone status in hemodialysis patients in Gorgan

    PubMed Central

    Velayeti, Javad; Mansourian, Azad Reza; Mojerloo, Mohammad; Marjani, Abdoljalal

    2016-01-01

    Aims: The aim of this study focused on serum malondialdehyde (MDA) levels and erythrocyte superoxide dismutase (SOD) and catalase (CAT) activities in hemodialysis patients and compared with control groups. Materials and Methods: Forty-five hemodialyzed patients and 45 control groups recruited in this study. Serum creatinine and urea, thyroid hormones (THs) levels and erythrocyte antioxidant enzyme activities were determined. Results: Hemodialysis (HD) patients showed higher levels of MDA than control groups (P < 0.01), but the levels of thyroxin (T3), free triiodothyronine (fT3), and free thyroxin (fT4), SOD and CAT were low in HD patients (P < 0.01). Serum T3, fT3, and fT4 levels were significantly negative correlated with MDA (P < 0.01). Conclusion: It is concluded that serum lipid peroxidation is markedly increased in HD patients. This means that elevated reactive oxygen species may interact with the lipid molecules in HD patients. HD may cause significant changes in TH levels. Thyroid-stimulating hormone level in HD patients is slightly similar to that of control groups. This suggests that thyroid is able to resynthesize for hormonal urinary losses. PMID:27186552

  4. Using predictors of hormone therapy use to model the healthy user bias: how does healthy user status influence cognitive effects of hormone therapy?

    PubMed

    Gleason, Carey E; Dowling, N Maritza; Friedman, Elliot; Wharton, Whitney; Asthana, Sanjay

    2012-05-01

    This study investigated the phenomenon known as the healthy user bias by equating hormone therapy (HT) use (past or current) with healthy user status. Data from the Survey of Midlife in the United States were used to identify the predictors of HT use. The unique Survey of Midlife in the United States data include psychological, demographic, health-related, and behavioral variables as well as history of HT use. Predictors of HT use were combined to derive propensity scores, describing the likelihood that a woman was an HT user, based on her psychological, demographic, physical, and behavioral profile (ie, likelihood of being a healthy user) as opposed to her actual use of HT. Finally, cognitive performance on an executive function test was examined in women stratified by propensity score. Using a multiple logistic regression model, nine variables emerged as predictors of HT use. The nine variables were used to estimate the propensity or conditional probability of using HT for each subject; resultant propensity scores were ranked and divided into tertiles. Women in the highest tertile demonstrated shorter median response latencies on a test of executive function than did women who did not use HT. From an array of psychological, medical, and behavioral variables, nine emerged as predictors of HT use. If validated, these features may serve as a means of estimating the phenomenon known as healthy user bias. Moreover, these data suggest that the degree to which a woman fits a model of a healthy user may influence cognitive response to HT.

  5. The impact of concurrent temozolomide with adjuvant radiation and IDH mutation status among patients with anaplastic astrocytoma.

    PubMed

    Kizilbash, Sani H; Giannini, Caterina; Voss, Jesse S; Decker, Paul A; Jenkins, Robert B; Hardie, John; Laack, Nadia N; Parney, Ian F; Uhm, Joon H; Buckner, Jan C

    2014-10-01

    This study assesses the controversial role of temozolomide (TMZ) concurrent with adjuvant radiation (RT) in patients with anaplastic astrocytoma (AA). The impact of isocitrate dehydrogenase (IDH) status on therapy and outcomes is also examined. All adult patients diagnosed with AA from 2001 to 2011 and treated with standard doses of adjuvant RT were identified retrospectively for clinical data extraction. IDH status was determined by IDH1-R132H immunostain and sequencing for other mutations in IDH1/IDH2. Cumulative survival probabilities were estimated using the Kaplan-Meier method. Cox proportional hazards regression models were fit for univariable/multivariable analyses. 136 patients had received concurrent TMZ while 29 had not. Of these, IDH status was determined on 114 and 27 patients, respectively. On univariable analysis, improved five-year survival was independently associated with concurrent TMZ (46.2 vs. 29.3%, p = 0.02) and IDH mutation (78.9 vs. 22.0%, p < 0.001). IDH mutation was additionally associated with a greater likelihood of extensive resection possibly secondary to a more favorable tumor location. Gross total/subtotal resections also led to improved survival when compared to biopsy alone on univariable analysis. On multivariable analysis, the association with five-year survival persisted for both concurrent TMZ and IDH mutation, but not with extent of surgery. Both IDH mutation and concurrent TMZ are associated with improved five-year survival in patients with AA who are receiving adjuvant RT. Secondarily, the association between five-year survival and extent of resection is lost on multivariable analysis. This suggests a possible association between IDH mutation, tumor location and consequent resectability.

  6. Functional characterization of a human POU1F1 mutation associated with isolated growth hormone deficiency: a novel etiology for IGHD.

    PubMed

    Sobrier, Marie-Laure; Tsai, Yu-Cheng; Pérez, Christelle; Leheup, Bruno; Bouceba, Tahar; Duquesnoy, Philippe; Copin, Bruno; Sizova, Daria; Penzo, Alfredo; Stanger, Ben Z; Cooke, Nancy E; Liebhaber, Stephen A; Amselem, Serge

    2016-02-01

    POU1F1, a pituitary-specific POU-homeo domain transcription factor, plays an essential role in the specification of the somatotroph, lactotroph and thyrotroph lineages and in the activation of GH1, PRL and TSHβ transcription. Individuals with mutations in POU1F1 present with combined deficiency of GH, PRL and TSH. Here, we identified a heterozygous missense mutation with evidence of pathogenicity, at the POU1F1 locus, in a large family in which an isolated growth hormone deficiency segregates as an autosomal dominant trait. The corresponding p.Pro76Leu mutation maps to a conserved site within the POU1F1 transactivation domain. Bandshift assays revealed that the mutation alters wild-type POU1F1 binding to cognate sites within the hGH-LCR and hGH1 promoter, but not to sites within the PRL promoter, and it selectively increases binding affinity to sites within the hGH-LCR. Co-immunoprecipitation studies reveal that this substitution enhances interactions of POU1F1 with three of its cofactors, PITX1, LHX3a and ELK1, and that residue 76 plays a critical role in these interactions. The insertion of the mutation at the mouse Pou1f1 locus results in a dramatic loss of protein expression despite normal mRNA concentrations. Mice heterozygous for the p.Pro76Leu mutation were phenotypically normal while homozygotes demonstrated a dwarf phenotype. Overall, this study unveils the involvement of POU1F1 in dominantly inherited isolated GH deficiency and demonstrates a significant impact of the Pro76Leu mutation on DNA-binding activities, alterations in transactivating functions and interactions with cofactors. Our data further highlight difficulties in modeling human genetic disorders in the mouse despite apparent conservation of gene expression pathways and physiologic functions. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  7. Functional characterization of a human POU1F1 mutation associated with isolated growth hormone deficiency: a novel etiology for IGHD

    PubMed Central

    Sobrier, Marie-Laure; Tsai, Yu-Cheng; Pérez, Christelle; Leheup, Bruno; Bouceba, Tahar; Duquesnoy, Philippe; Copin, Bruno; Sizova, Daria; Penzo, Alfredo; Stanger, Ben Z.; Cooke, Nancy E.; Liebhaber, Stephen A.; Amselem, Serge

    2016-01-01

    POU1F1, a pituitary-specific POU-homeo domain transcription factor, plays an essential role in the specification of the somatotroph, lactotroph and thyrotroph lineages and in the activation of GH1, PRL and TSHβ transcription. Individuals with mutations in POU1F1 present with combined deficiency of GH, PRL and TSH. Here, we identified a heterozygous missense mutation with evidence of pathogenicity, at the POU1F1 locus, in a large family in which an isolated growth hormone deficiency segregates as an autosomal dominant trait. The corresponding p.Pro76Leu mutation maps to a conserved site within the POU1F1 transactivation domain. Bandshift assays revealed that the mutation alters wild-type POU1F1 binding to cognate sites within the hGH-LCR and hGH1 promoter, but not to sites within the PRL promoter, and it selectively increases binding affinity to sites within the hGH-LCR. Co-immunoprecipitation studies reveal that this substitution enhances interactions of POU1F1 with three of its cofactors, PITX1, LHX3a and ELK1, and that residue 76 plays a critical role in these interactions. The insertion of the mutation at the mouse Pou1f1 locus results in a dramatic loss of protein expression despite normal mRNA concentrations. Mice heterozygous for the p.Pro76Leu mutation were phenotypically normal while homozygotes demonstrated a dwarf phenotype. Overall, this study unveils the involvement of POU1F1 in dominantly inherited isolated GH deficiency and demonstrates a significant impact of the Pro76Leu mutation on DNA-binding activities, alterations in transactivating functions and interactions with cofactors. Our data further highlight difficulties in modeling human genetic disorders in the mouse despite apparent conservation of gene expression pathways and physiologic functions. PMID:26612202

  8. Do Menopausal Status and Use of Hormone Therapy Affect Antidepressant Treatment Response? Findings from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study

    PubMed Central

    Toups, Marisa; Rush, A. John; Wisniewski, Stephen R.; Thase, Michael E.; Luther, James; Warden, Diane; Fava, Maurizio; Trivedi, Madhukar H.

    2013-01-01

    Abstract Background Menopausal status and use of hormonal contraception or menopausal hormone therapy (HT) may affect treatment response to selective serotonin reuptake inhibitors (SSRIs). This report evaluates whether menopausal status and use of hormonal contraceptives or menopausal HT affect outcome in women treated with citalopram. Methods In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, 896 premenopausal and 544 postmenopausal women were treated with citalopram for 12–14 weeks. Baseline demographic and clinical characteristics were used in adjusted analysis of the effect of menopausal status and use of hormonal contraceptives or menopausal HT on outcomes. Remission was defined as final Hamilton Rating Scale for Depression-17 (HRSD17) ≤7 or Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR16) score ≤5 and response as ≥50% decrease from the baseline QIDS-SR16 score. Results Premenopausal and postmenopausal women differed in multiple clinical and demographic baseline variables but did not differ in response or remission rates. Premenopausal women taking hormonal contraceptives had significantly greater unadjusted remission rates on the HRSD17 and the QIDS-SR16 than women not taking contraception. Response and remission rates were not different between postmenopausal women taking vs. not taking HT. Adjusted results showed no significant difference in any outcome measure across menopause status in women who were not taking contraception/HT. There were no significant differences in adjusted results across HT status in premenopausal or postmenopausal women. Conclusions In this study, citalopram treatment outcome was not affected by menopausal status. Hormonal contraceptives and HT also did not affect probability of good outcome. PMID:23398127

  9. Association of a missense mutation in the luteinizing hormone/choriogonadotropin receptor gene (LHCGR) with superovulation traits in Chinese Holstein heifers

    PubMed Central

    2012-01-01

    Background Upon binding luteinizing hormone in the ovary, the luteinizing hormone/choriogonadotropin receptor (LHCGR) is necessary for follicular maturation and ovulation, as well as luteal function. We detected mutations in the LHCGR gene and evaluated their association with superovulation. Methods Using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and DNA sequencing, we examined polymorphisms in LHCGR and the genotypes associated with superovulation traits in 127 Chinese Holstein heifers. Results A G/T polymorphism (ss52050737) in exon 11 was significantly associated with the total number of ova and the number of transferable embryos. Conclusions LHCGR may be a new predictor for superovulation in Chinese Holstein heifers. PMID:23140330

  10. Impact of KRAS, BRAF, PIK3CA, TP53 status and intraindividual mutation heterogeneity on outcome after liver resection for colorectal cancer metastases.

    PubMed

    Løes, Inger Marie; Immervoll, Heike; Sorbye, Halfdan; Angelsen, Jon-Helge; Horn, Arild; Knappskog, Stian; Lønning, Per Eystein

    2016-08-01

    We determined prognostic impact of KRAS, BRAF, PIK3CA and TP53 mutation status and mutation heterogeneity among 164 colorectal cancer (CRC) patients undergoing liver resections for metastatic disease. Mutation status was determined by Sanger sequencing of a total of 422 metastatic deposits. In univariate analysis, KRAS (33.5%), BRAF (6.1%) and PIK3CA (13.4%) mutations each predicted reduced median time to relapse (TTR) (7 vs. 22, 3 vs. 16 and 4 vs. 17 months; p < 0.001, 0.002 and 0.023, respectively). KRAS and BRAF mutations also predicted a reduced median disease-specific survival (DSS) (29 vs. 51 and 16 vs. 49 months; p <0.001 and 0.008, respectively). No effect of TP53 (60.4%) mutation status was observed. Postoperative, but not preoperative chemotherapy improved both TTR and DSS (p < 0.001 for both) with no interaction with gene mutation status. Among 94 patients harboring two or more metastatic deposits, 13 revealed mutation heterogeneity across metastatic deposits for at least one gene. Mutation heterogeneity predicted reduced median DSS compared to homogeneous mutations (18 vs. 37 months; p = 0.011 for all genes; 16 vs. 26 months; p < 0.001 analyzing BRAF or KRAS mutations separately). In multivariate analyses, KRAS or BRAF mutations consistently predicted poor TRR and DSS. Mutation heterogeneity robustly predicted DSS but not TTR, while postoperative chemotherapy improved both TTR and DSS. Our findings indicate that BRAF and KRAS mutations as well as mutation heterogeneity predict poor outcome in CRC patients subsequent to liver resections and might help guide treatment decisions. © 2016 The Authors International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control.

  11. Discordance of Mutation Statuses of Epidermal Growth Factor Receptor and K-ras between Primary Adenocarcinoma of Lung and Brain Metastasis.

    PubMed

    Rau, Kun-Ming; Chen, Han-Ku; Shiu, Li-Yen; Chao, Tsai-Ling; Lo, Yi-Ping; Wang, Chin-Chou; Lin, Meng-Chih; Huang, Chao-Cheng

    2016-04-07

    Mutations on epidermal growth factor receptor (EGFR) of adenocarcinomas of lung have been found to be associated with increased sensitivity to EGFR tyrosine kinase inhibitors and K-ras mutations may correlate with primary resistance. We aimed to explore the discordant mutation statuses of EGFR and K-ras between primary tumors and matched brain metastases in adenocarcinomas of lung. We used a sensitive Scorpion ARMS method to analyze EGFR mutation, and Sanger sequencing followed by allele-specific real-time polymerase chain reaction to analyze K-ras mutation. Forty-nine paired tissues with both primary adenocarcinoma of lung and matched brain metastasis were collected. Thirteen patients (26.5%) were discordant for the status of EGFR between primary and metastatic sites. K-ras gene could be checked in paired specimens from 33 patients, thirteen patients (39.6%) were discordant for the status of K-ras. In primary lung adenocarcinoma, there were 14 patients of mutant EGFR had mutant K-ras synchronously. This study revealed that the status of EGFR mutation in lung adenocarcinomas is relatively consistent between primary and metastatic sites compared to K-ras mutation. However, there are still a few cases of adenocarcinoma of lung showing discordance for the status of EGFR mutation. Repeated analysis of EGFR mutation is highly recommended if tissue from metastatic or recurrent site is available for the evaluation of target therapy.

  12. Correlation of tumour BRAF mutations and MLH1 methylation with germline mismatch repair (MMR) gene mutation status: a literature review assessing utility of tumour features for MMR variant classification.

    PubMed

    Parsons, Michael T; Buchanan, Daniel D; Thompson, Bryony; Young, Joanne P; Spurdle, Amanda B

    2012-03-01

    Colorectal cancer (CRC) that demonstrates microsatellite instability (MSI) is caused by either germline mismatch repair (MMR) gene mutations, or 'sporadic' somatic tumour MLH1 promoter methylation. MLH1 promoter methylation is reportedly correlated with tumour BRAF V600E mutation status. No systematic review has been undertaken to assess the value of BRAF V600E mutation and MLH1 promoter methylation tumour markers as negative predictors of germline MMR mutation status. A literature review of CRC cohorts tested for MMR mutations, and tumour BRAF V600E mutation and/or MLH1 promoter methylation was conducted using PubMed. Studies were assessed for tumour features, stratified by tumour MMR status based on immunohistochemistry or MSI where possible. Pooled frequencies and 95% CIs were calculated using a random effects model. BRAF V600E results for 4562 tumours from 35 studies, and MLH1 promoter methylation results for 2975 tumours from 43 studies, were assessed. In 550 MMR mutation carriers, the BRAF V600E mutation frequency was 1.40% (95% CI 0.06% to 3%). In MMR mutation-negative cases, the BRAF V600E mutation frequency was 5.00% (95% CI 4% to 7%) in 1623 microsatellite stable (MSS) cases and 63.50% (95% CI 47% to 79%) in 332 cases demonstrating MLH1 methylation or MLH1 expression loss. MLH1 promoter methylation of the 'A region' was reported more frequently than the 'C region' in MSS CRCs (17% vs 0.06%, p<0.0001) and in MLH1 mutation carriers (42% vs 6%, p<0.0001), but not in MMR mutation-negative MSI-H CRCs (40% vs 47%, p=0.12). Methylation of the 'C region' was a predictor of MMR mutation-negative status in MSI-H CRC cases (47% vs 6% in MLH1 mutation carriers, p<0.0001). This review demonstrates that tumour BRAF V600E mutation, and MLH1 promoter 'C region' methylation specifically, are strong predictors of negative MMR mutation status. It is important to incorporate these features in multifactorial models aimed at predicting MMR mutation status.

  13. Chromosome 3 status combined with BAP1 and EIF1AX mutation profiles are associated with metastasis in uveal melanoma.

    PubMed

    Ewens, Kathryn G; Kanetsky, Peter A; Richards-Yutz, Jennifer; Purrazzella, Juliana; Shields, Carol L; Ganguly, Tapan; Ganguly, Arupa

    2014-06-26

    Somatic mutations in GNAQ, GNA11, SF3B1, EIF1AX, and BAP1 have been identified in uveal melanoma (UM). The aim of this study was to determine whether mutations in these genes in primary tumors were associated with metastases in individuals diagnosed with UM. A total of 63 UM cases who developed a metastasis within 48 months of primary treatment and 53 UM controls who were metastasis-free over a similar time period were selected for the study. Primary UM cases were screened for mutations in GNAQ, GNA11, SF3B1, EIF1AX, and BAP1. The association of these mutations with tumor characteristics, chromosome 3 copy number, and metastatic status was analyzed by logistic regression to estimate the odds of developing metastasis within 48 months. As expected, tumor diameter, thickness, cilio-choroidal location, and chromosome 3 monosomy were all significantly (P < 0.02) associated with the presence of metastasis. In univariate analysis, GNA11 (odds ratio [OR] 2.5, 95% confidence interval [CI] 1.1-5.5) and BAP1 (OR 6.3, 95% CI 2.7-14.4) mutations were positively associated and EIF1AX mutation (OR 0.13, 95% CI 0.034-0.47) was inversely associated with metastatic status at 48 months after UM treatment. After adjustment for covariates, a chromosome 3 monosomy/BAP1-mutation/EIF1AX-wild-type (WT) mutation profile was strongly associated (OR 37.5, 95% CI 4.3-414) with the presence of metastasis compared with a chromosome 3 disomy/BAP1-WT/EIF1AX mutation profile. The results suggest that knowledge of mutations in BAP1 and EIF1AX can enhance prognostication of UM beyond that determined by chromosome 3 and tumor characteristics. Tumors with chromosome 3 disomy/BAP1-WT/EIF1AX-WT have a 10-fold increased risk of metastasis at 48 months compared with disomy-3/BAP1-WT/EIF1AX mutant tumors. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

  14. Premenopausal serum sex hormone levels in relation to breast cancer risk, overall and by hormone receptor status - results from the EPIC cohort.

    PubMed

    Kaaks, Rudolf; Tikk, Kaja; Sookthai, Disorn; Schock, Helena; Johnson, Theron; Tjønneland, Anne; Olsen, Anja; Overvad, Kim; Clavel-Chapelon, Françoise; Dossus, Laure; Baglietto, Laura; Rinaldi, Sabina; Chajes, Veronique; Romieu, Isabelle; Boeing, Heiner; Schütze, Madlen; Trichopoulou, Antonia; Lagiou, Pagona; Trichopoulos, Dimitrios; Palli, Domenico; Sieri, Sabina; Tumino, Rosario; Ricceri, Fulvio; Mattiello, Amalia; Buckland, Genevieve; Ramón Quirós, Jose; Sánchez, María-José; Amiano, Pilar; Chirlaque, Maria-Dolores; Barricarte, Aurelio; Bas Bueno-de-Mesquita, H; van Gils, Carla H; Peeters, Petra H; Andersson, Anne; Sund, Malin; Weiderpass, Elisabete; Khaw, Kay-Tee; Wareham, Nick; Key, Timothy J; Travis, Ruth C; Merritt, Melissa A; Gunter, Marc J; Riboli, Elio; Lukanova, Annekatrin

    2014-04-15

    Results from prospective studies on premenopausal serum hormone levels in relation to breast cancer risk have been inconclusive, especially with regard to tumor subtypes. Using a case-control study nested within the prospective European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (801 breast cancer cases and 1,132 matched control subjects), we analyzed the relationships of prediagnostic serum estradiol, free estradiol, progesterone, testosterone, free testosterone and sex hormone-binding globulin (SHBG) levels with the risk of breast cancer by estrogen and progesterone receptor-positive and -negative breast tumors and by age at diagnoses. Higher prediagnostic serum levels of testosterone and free testosterone were associated with an increased overall risk of breast cancer [ORQ4-Q1  = 1.56 (95% CI 1.15-2.13), ptrend  = 0.02 for testosterone and ORQ4-Q1  = 1.33 (95% CI 0.99-1.79), ptrend  = 0.04 for free testosterone], but no significant risk association was observed for estradiol, free estradiol, progesterone and SHBG. Tests for heterogeneity between receptor-positive and -negative tumors were not significant. When analysis were stratified by age at tumor diagnosis, the odds ratios observed for estradiol were stronger and borderline significant for breast cancer diagnosed at age less than 50 [ORQ4-Q1  = 1.32 (95% CI 0.87-2.01), ptrend  = 0.05] compared to breast cancer diagnosed at age 50 or above [ORQ4-Q1  = 0.94 (95% CI 0.60-1.47), ptrend  = 0.34, phet  = 0.04]. In conclusion, our data indicate that higher premenopausal circulating testosterone levels are associated with an increased risk of developing breast cancer, but do not show a significant association of estradiol or progesterone with breast cancer risk, overall, by menstrual cycle phase or by tumor receptor status, although a possible risk increase with higher estradiol levels for tumors diagnosed before age 50 was seen.

  15. Clonal composition of human ovarian cancer based on copy number analysis reveals a reciprocal relation with oncogenic mutation status.

    PubMed

    Sakai, Kazuko; Ukita, Masayo; Schmidt, Jeanette; Wu, Longyang; De Velasco, Marco A; Roter, Alan; Jevons, Luis; Nishio, Kazuto; Mandai, Masaki

    2017-10-01

    Intratumoral heterogeneity of cancer cells remains largely unexplored. Here we investigated the composition of ovarian cancer and its biological relevance. A whole-genome single nucleotide polymorphism array was applied to detect the clonal composition of 24 formalin-fixed, paraffin-embedded samples of human ovarian cancer. Genome-wide segmentation data consisting of the log2 ratio (log2R) and B allele frequency (BAF) were used to calculate an estimate of the clonal composition number (CC number) for each tumor. Somatic mutation profiles of cancer-related genes were also determined for the same 24 samples by next-generation sequencing. The CC number was estimated successfully for 23 of the 24 cancer samples. The mean ± SD value for the CC number was 1.7 ± 1.1 (range of 0-4). A somatic mutation in at least one gene was identified in 22 of the 24 ovarian cancer samples, with the mutations including those in the oncogenes KRAS (29.2%), PIK3CA (12.5%), BRAF (8.3%), FGFR2 (4.2%), and JAK2 (4.2%) as well as those in the tumor suppressor genes TP53 (54.2%), FBXW7 (8.3%), PTEN (4.2%), and RB1 (4.2%). Tumors with one or more oncogenic mutations had a significantly lower CC number than did those without such a mutation (1.0 ± 0.8 versus 2.3 ± 0.9, P = 0.0027), suggesting that cancers with driver oncogene mutations are less heterogeneous than those with other mutations. Our results thus reveal a reciprocal relation between oncogenic mutation status and clonal composition in ovarian cancer using the established method for the estimation of the CC number. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

  16. Family history predictors of BRCA1/BRCA2 mutation status among Tunisian breast/ovarian cancer families.

    PubMed

    Riahi, Aouatef; Ghourabi, Mohamel El; Fourati, Asma; Chaabouni-Bouhamed, Habiba

    2017-03-01

    With the increasing request for BRCA1/BRCA2 mutation tests, several risk models have been developed to predict the presence of mutation in these genes; in this study, we have developed an efficient BRCA genetic testing strategy. As first step, to identify predictor variables associated with BRCA status, we have undertaken a cumulative mutation analysis including data from three Tunisian studies. Then, we have developed a logistic regression model for predicting the likelihood of harboring a BRCA mutation. Using receiver operating characteristic curves (ROC), an effective evaluation was performed. A total of 92 Tunisian families were included. Overall, 27 women were positive for BRCA1/BRCA2 deleterious mutations. Tow recurrent mutations (c.211dupA and c.5266dupC) explained 76 % of BRCA1-related families and three recurrent mutations (c.1310_1313del, c.1542_1547delAAGA and c.7887_7888insA) explained 90 % of BRCA2-related families. Early age at diagnosis of breast cancer, ovarian cancer, bilateral breast cancer were associated with BRCA1, whereas male breast cancer and four or more breast cancer cases in the family were associated with BRCA2. The area under the receiver operating characteristic curve of the risk score was 0.802 (95 % confidence interval = 0.0699-0. 905). Logistic regression reported particular profiles related to BRCA germline mutation carriers in our population, as well as an efficient prediction model that may be a useful tool for increasing the cost-effectiveness of genetic testing strategy.

  17. A novel presentation of inappropriate antidiuretic hormone secretion in Leigh syndrome with the myoclonic epilepsy and ragged red fibers, mitochondrial DNA 8344A>G mutation.

    PubMed

    Swiderska, Nina; Appleton, Richard; Morris, Andrew; Isherwood, David; Selby, Andrew

    2010-06-01

    A 17-month-old infant presented with a 2-week history of lethargy, anorexia, and an abnormal respiratory pattern on a previous 4-month history of hypotonia and gross motor delay, suggesting a clinical phenotype of Leigh syndrome. The patient experienced no epileptic seizures. Biochemical investigations were normal other than showing evidence of inappropriate secretion of antidiuretic hormone, and cerebral magnetic resonance imaging (MRI) showed symmetrical lesions in the cervical cord and lower brain stem. Initial screening investigations for a mitochondrial cytopathy were negative. Muscle histochemistry demonstrated reduced staining of cytochrome c oxidase but no ragged red fibers. Blood and muscle-derived DNA demonstrated a high level (92% and 82%, respectively) of the m.8344A>G mutation seen in patients with the mitochondrial cytopathy, ''myoclonic epilepsy with ragged red fibers on muscle biopsy.'' This infant's early presentation including inappropriate antidiuretic secretion due to presumed renal salt loss and rapid course appears to be unique to this mutation.

  18. A novel point mutation in the hormone binding domain of the androgen receptor associated with partial and minimal androgen insensitivity syndrome.

    PubMed

    Galli-Tsinopoulou, Assimina; Hiort, Olaf; Schuster, Tobias; Messer, Gerald; Kuhnle, Ursula

    2003-02-01

    Mutations in the coding sequence of the androgen receptor (AR) gene result in a wide range of androgen insensitivity syndromes (AIS). We report an extended family in which at least five male individuals in different generations suffer from partial AIS. The index patient presented at birth with ambiguous genitalia; the karyotype was 46,XY and subsequent sex assignment male. Elevated stimulated testosterone (T) and normal baseline gonadotropins were found. Family history revealed four additional adult males affected with various abnormalities of their external genitalia. Molecular analysis of the coding sequence of the AR gene revealed in all a novel point mutation in exon 6, changing threonine to isoleucine at codon position 800 in the hormone-binding domain. We conclude that phenotypic variations in mild AR defects are striking and can remain undetected even until late in life.

  19. Family history and breast cancer hormone receptor status in a Spanish cohort.

    PubMed

    Jiang, Xuejuan; Castelao, Jose Esteban; Chavez-Uribe, Elisabet; Fernandez Rodriguez, Beatriz; Celeiro Muñoz, Catuxa; Redondo, Carmen M; Peña Fernandez, Maite; Novo Dominguez, Alejandro; Pereira, Carina Doris; Martínez, María Elena; García-Caballero, Tomás; Fraga Rodriguez, Máximo; Antúnez, José; Carracedo, Angel; Forteza-Vila, Jerónimo; Gago-Dominguez, Manuela

    2012-01-01

    Breast cancer is a heterogenous disease that impacts racial/ethnic groups differently. Differences in genetic composition, lifestyles, reproductive factors, or environmental exposures may contribute to the differential presentation of breast cancer among Hispanic women. A population-based study was conducted in the city of Santiago de Compostela, Spain. A total of 645 women diagnosed with operable invasive breast cancer between 1992 and 2005 participated in the study. Data on demographics, breast cancer risk factors, and clinico-pathological characteristics of the tumors were collected. Hormone receptor negative tumors were compared with hormone receptor postive tumors on their clinico-pathological characteristics as well as risk factor profiles. Among the 645 breast cancer patients, 78% were estrogen receptor-positive (ER+) or progesterone receptor-positive (PR+), and 22% were ER-&PR-. Women with a family history of breast cancer were more likely to have ER-&PR- tumors than women without a family history (Odds ratio, 1.43; 95% confidence interval, 0.91-2.26). This association was limited to cancers diagnosed before age 50 (Odds ratio, 2.79; 95% confidence interval, 1.34-5.81). An increased proportion of ER-&PR- breast cancer was observed among younger Spanish women with a family history of the disease.

  20. Family History and Breast Cancer Hormone Receptor Status in a Spanish Cohort

    PubMed Central

    Chavez-Uribe, Elisabet; Rodriguez, Beatriz Fernandez; Muñoz, Catuxa Celeiro; Redondo, Carmen M.; Fernandez, Maite Peña; Dominguez, Alejandro Novo; Pereira, Carina Doris; Martínez, María Elena; García-Caballero, Tomás; Rodriguez, Máximo Fraga; Antúnez, José; Carracedo, Angel; Forteza-Vila, Jerónimo; Gago-Dominguez, Manuela

    2012-01-01

    Background Breast cancer is a heterogenous disease that impacts racial/ethnic groups differently. Differences in genetic composition, lifestyles, reproductive factors, or environmental exposures may contribute to the differential presentation of breast cancer among Hispanic women. Materials and Methods A population-based study was conducted in the city of Santiago de Compostela, Spain. A total of 645 women diagnosed with operable invasive breast cancer between 1992 and 2005 participated in the study. Data on demographics, breast cancer risk factors, and clinico-pathological characteristics of the tumors were collected. Hormone receptor negative tumors were compared with hormone receptor postive tumors on their clinico-pathological characteristics as well as risk factor profiles. Results Among the 645 breast cancer patients, 78% were estrogen receptor-positive (ER+) or progesterone receptor-positive (PR+), and 22% were ER−&PR−. Women with a family history of breast cancer were more likely to have ER−&PR− tumors than women without a family history (Odds ratio, 1.43; 95% confidence interval, 0.91–2.26). This association was limited to cancers diagnosed before age 50 (Odds ratio, 2.79; 95% confidence interval, 1.34–5.81). Conclusions An increased proportion of ER−&PR− breast cancer was observed among younger Spanish women with a family history of the disease. PMID:22238615

  1. Sex hormone status in male rats after exposure to 50 Hz, 5 mTesla magnetic field.

    PubMed

    Mostafa, R M; Moustafa, Y M; Ali, F M; Shafik, A

    2006-01-01

    The question of whether extremely low frequency magnetic fields can affect biological system has attracted attention. The theoretical possibility of such an interaction is often questioned and the site of interaction is unknown. The influence of extremely low frequency magnetic field of 50 Hz, 5 mTesla on sex hormone status was studied. 60 male albino rats were divided into 6 groups and were continuously exposed to 50 Hz, 5 mTesla magnetic field generated by magnetic field chamber for periods of 1, 2 and 4 weeks. For each experimental point, sham treated group was used as a control. Assay of serum testosterone LH, FSH, and prolactin were performed. Serum testosterone showed no significant changes. FSH showed significant increase than sham exposed group after 1 week magnetic field exposure. LH showed significant increase than sham exposed group only after 4 weeks magnetic field exposure, while serum prolactin hormone level showed a significant increase in all magnetic field exposed groups than sham exposed animals. Exposure to 50 Hz, 5 mTesla magnetic field for periods of 1, 2 and 4 weeks has no effect on testosterone level, some changes on FSH and LH serum levels and increase in serum prolactin level.

  2. Functional Pathway Analysis Using SCNP of FLT3 Receptor Pathway Deregulation in AML Provides Prognostic Information Independent from Mutational Status

    PubMed Central

    Cesano, Alessandra; Putta, Santosh; Rosen, David B.; Cohen, Aileen C.; Gayko, Urte; Mathi, Kavita; Woronicz, John; Hawtin, Rachael E.; Cripe, Larry; Sun, Zhuoxin; Tallman, Martin S.; Paietta, Elisabeth

    2013-01-01

    FMS-like tyrosine kinase 3 receptor (FLT3) internal tandem duplication (ITD) mutations result in constitutive activation of this receptor and have been shown to increase the risk of relapse in patients with acute myeloid leukemia (AML); however, substantial heterogeneity in clinical outcomes still exists within both the ITD mutated and unmutated AML subgroups, suggesting alternative mechanisms of disease relapse not accounted by FLT3 mutational status. Single cell network profiling (SCNP) is a multiparametric flow cytometry based assay that simultaneously measures, in a quantitative fashion and at the single cell level, both extracellular surface marker levels and changes in intracellular signaling proteins in response to extracellular modulators. We previously reported an initial characterization of FLT3 ITD-mediated signaling using SCNP. Herein SCNP was applied sequentially to two separate cohorts of samples collected from elderly AML patients at diagnosis. In the first (training) study, AML samples carrying unmutated, wild-type FLT3 (FLT3 WT) displayed a wide range of induced signaling, with a fraction having signaling profiles comparable to FLT3 ITD AML samples. Conversely, the FLT3 ITD AML samples displayed more homogeneous induced signaling, with the exception of patients with low (<40%) mutational load, which had profiles comparable to FLT3 WT AML samples. This observation was then confirmed in an independent (verification) cohort. Data from the second cohort were also used to assess the association between SCNP data and disease-free survival (DFS) in the context of FLT3 and nucleophosmin (NPM1) mutational status among patients who achieved complete remission (CR) to induction chemotherapy. The combination of SCNP read outs together with FLT3 and NPM1 molecular status improved the DFS prediction accuracy of the latter. Taken together, these results emphasize the value of comprehensive functional assessment of biologically relevant signaling pathways in AML

  3. Inhibitory effect of aluminium on calcium absorption in small intestine of rats with different thyroid hormone status.

    PubMed

    Orihuela, Daniel

    2009-11-01

    To analyse the influence of thyroid status on the effect of aluminium (Al) upon intestinal calcium (Ca) absorption, adult male Wistar rats with experimentally altered thyroid hormones circulating levels, were orally treated (o.g.) with 0 (control), or 50 mg elemental Al (as chloride)/kg body weight (b.w.) per day, for a 14 d period. Hyper- and hypo-thyroid conditions were respectively achieved by means of administration of either sodium levothyroxine (50 microg/kg b.w. per day, o.g.) or methimazole, a thyroxine synthesis inhibitor (1mg/kg b.w. per day, o.g.). In duodenum-jejunum segments, in vitro mucosa-to-serosa (45)Ca flux (JCa(ms)) and kinetics of (45)Ca uptake in isolated enterocytes, were determined. In serum, concentrations of thyroxine (T4) and triiodothyronine (T3) were measured by chemiluminescent enzyme immunoassay. Unlike non-Al-treated rats, JCa(ms) of Al-exposed rats decreased as serum levels of T4 and T3 increased, showing a significant inverse correlation in both cases (T4: r(2)=0.414, P=0.024; T3: r(2)=0.443, P=0.018). Enterocytes isolated from rats treated with Al plus thyroxine showed a reduction of both maximum Ca uptake (4.86+/-0.44 vs. 6.85+/-1.04 nmol Ca/mg protein, P<0.05) and K(m) (0.84+/-0.18 vs. 1.05+/-0.36 mM, P<0.05) when compared to control. The observed variability in the Al effect on Ca transport with thyroid status of rats could be reflecting a negative interaction of Al with thyroid hormone action mechanisms on intestinal Ca absorption, which would take place mainly at Ca entry into enterocyte from lumen.

  4. Juvenile hormone titers, ovarian status and epicuticular hydrocarbons in gynes and workers of the paper wasp Belonogaster longitarsus.

    PubMed

    Kelstrup, Hans C; Hartfelder, Klaus; Esterhuizen, Nanike; Wossler, Theresa C

    2017-04-01

    The prevailing paradigm for social wasp endocrinology is that of juvenile hormone (JH) functioning pleiotropically in potential and actual queens, where it fuels dominance behaviors, stimulates ovarian growth and/or affects the production of status-linked cuticular compounds. In colonies with annual cycles (e.g., temperate-zone species), female adults produced at the end of the summer (called gynes) are physiologically primed to hibernate. Despite the absence of egg-laying in the pre-overwintering phase, gynes engage in dominance interactions that may affect reproductive potential following hibernation. JH levels have long been inferred to be low in gynes but this has never been tested. In what is the first study to measure JH in gyne-containing colonies of a temperate paper wasp, and the first to incorporate hormone assays in Belonogaster, our results show that the JH titer positively correlates with gyne-specific traits (including oocyte length and a low frequency of foraging trips) in B. longitarsus, a South African paper wasp. Measures of dominance correlated with oocyte length, but not all dominant females possessed activated ovaries. The cuticular hydrocarbon profiles of gynes and workers were distinct, with oocyte length and JH titer showing a positive association with longer-chain methyl-branched alkanes. Nonetheless, evidence for a role of JH in dominance was inconclusive. Finally, the range of JH titers among gynes, and the positive association of JH titers with ovarian status and prospective fertility signals, makes it unlikely that the gyne phenotype is maintained by low JH levels.

  5. Relevance of different cellular models in determining the effects of mutations on SLC16A2/MCT8 thyroid hormone transporter function and genotype-phenotype correlation.

    PubMed

    Capri, Yline; Friesema, Edith C H; Kersseboom, Simone; Touraine, Renaud; Monnier, Aurélie; Eymard-Pierre, Eléonore; Des Portes, Vincent; De Michele, Giusseppe; Brady, Angela F; Boespflug-Tanguy, Odile; Visser, Theo J; Vaurs-Barriere, Catherine

    2013-07-01

    SLC 16A2, the gene for the second member of the solute carrier family 16 (monocarboxylic acid transporter), located on chromosome Xq13.2, encodes a very efficient thyroid hormone transporter: monocarboxylate transporter 8, MCT8. Its loss of function is responsible in males for a continuum of psychomotor retardation ranging from severe (no motor acquisition, no speech) to mild (ability to walk with help and a few words of speech). Triiodothyronine uptake measurement in transfected cells and, more recently, patient fibroblasts, has been described to study the functional consequences of MCT8 mutations. Here, we describe three novel MCT8 mutations, including one missense variation not clearly predicted to be damaging but found in a severely affected patient. Functional studies in fibroblasts and JEG3 cells demonstrate the usefulness of both cellular models in validating the deleterious effects of a new MCT8 mutation if there is still a doubt as to its pathogenicity. Moreover, the screening of fibroblasts from a large number of patient fibroblasts and of transfected mutations has allowed us to demonstrate that JEG3 transfected cells are more relevant than fibroblasts in revealing a genotype-phenotype correlation.

  6. Surrogate molecular markers for IGHV mutational status in chronic lymphocytic leukemia for predicting time to first treatment.

    PubMed

    Morabito, Fortunato; Cutrona, Giovanna; Mosca, Laura; D'Anca, Marianna; Matis, Serena; Gentile, Massimo; Vigna, Ernesto; Colombo, Monica; Recchia, Anna Grazia; Bossio, Sabrina; De Stefano, Laura; Maura, Francesco; Manzoni, Martina; Ilariucci, Fiorella; Consoli, Ugo; Vincelli, Iolanda; Musolino, Caterina; Cortelezzi, Agostino; Molica, Stefano; Ferrarini, Manlio; Neri, Antonino

    2015-08-01

    ZAP-70 is a marker of clinical outcome in chronic lymphocytic leukemia (CLL), however its assessment suffers from a lack of standardization consensus. To identify novel markers able to surrogate IGHV mutational status, CD19(+)CD5(+)-B-lymphocytes from 216 patients enrolled in a prospective study (ClinicalTrial.gov Identifier:NCT00917540), underwent gene expression profiling. Samples were split into CLL-Training (n=102) and CLL-Validation (n=114) sets, and an independent supervised analysis for IGHV mutational status was performed considering all genes with gene expression equal or above that of ZAP-70. Thirty-one genes (23 up- and 8 down-regulated) and 23 genes (18 up- and 5 down-regulated) satisfied these criteria in the CLL-Training and CLL-Validation sets, respectively, and 20 common genes (15 up and 5 down) were found to be differentially regulated in both sets. Two (SNORA70F, NRIP1) of the down-regulated and 6 (SEPT10, ZNF667, TGFBR3, MBOAT1, LPL, CRY1) of the up-regulated genes were significantly associated with a reduced risk of disease progression in both sets. Forcing the afore-mentioned genes in a Cox multivariate model together with IGHV mutational status, only CRY1 (HR=2.3, 95% CI: 1.1-4.9, P=.027) and MBOAT1 (HR=2.1, 95% CI: 1.1-3.7, P=.018) retained their independent prognostic impact, supporting the hypothesis that these genes may potentially act as surrogates for predicting IGHV mutational status.

  7. Infertility in Female Mice with a Gain-of-Function Mutation in the Luteinizing Hormone Receptor Is Due to Irregular Estrous Cyclicity, Anovulation, Hormonal Alterations, and Polycystic Ovaries1

    PubMed Central

    Hai, Lan; McGee, Stacey R.; Rabideau, Amanda C.; Paquet, Marilène; Narayan, Prema

    2015-01-01

    The luteinizing hormone receptor, LHCGR, is essential for fertility in males and females, and genetic mutations in the receptor have been identified that result in developmental and reproductive defects. We have previously generated and characterized a mouse model (KiLHRD582G) for familial male-limited precocious puberty caused by an activating mutation in the receptor. We demonstrated that the phenotype of the KiLHRD582G male mice is an accurate phenocopy of male patients with activating LHCGR mutations. In this study, we observed that unlike women with activating LHCGR mutations who are normal, female KiLHRD582G mice are infertile. Mice exhibit irregular estrous cyclicity, anovulation, and precocious puberty. A temporal study from 2–24 wk of age indicated elevated levels of progesterone, androstenedione, testosterone, and estradiol and upregulation of several steroidogenic enzyme genes. Ovaries of KiLHRD582G mice exhibited significant pathology with the development of large hemorrhagic cysts as early as 3 wk of age, extensive stromal cell hyperplasia and hypertrophy with luteinization, numerous atretic follicles, and granulosa cell tumors. Ovulation could not be rescued by the addition of exogenous gonadotropins. The body weights of the KiLHRD582G mice were higher than wild-type counterparts, but there was no increase in the body fat composition or metabolic abnormalities such as impaired glucose tolerance and insulin resistance. These studies demonstrate that activating LHCGR mutations do not produce the same phenotype in female mice as in humans and clearly illustrate species differences in the expression and regulation of LHCGR in the ovary, but not in the testis. PMID:26040673

  8. Leptin concentration in breast milk and its relationship to duration of lactation and hormonal status

    PubMed Central

    Ilcol, Yesim Ozarda; Hizli, Z Banu; Ozkan, Tanju

    2006-01-01

    Background Leptin, a hormone present in breast milk, is involved in energy regulation and metabolism. The objectives of this study were to assess leptin concentrations in breast milk during the first 180 days postpartum, and to determine the relationship between the concentrations of milk leptin and circulating hormone levels in lactating women. Methods Between April 2005 and January 2006, blood and breast milk samples were collected from 160 breastfeeding women enrolled either in the first three days (n = 37; colostrum), days 4–14 (n = 27; transitional milk), days 15–30 (n = 16; early mature milk), days 31–90 (n = 37; mature milk) or days 91–180 (n = 43; late mature milk) postpartum. Milk and serum leptin levels were measured by immunoradiometric assay. Cortisol was measured by radioimmunoassay method. Serum insulin, estradiol, prolactin and thyroxine were measured by chemiluminescent immunometric method. Results Leptin concentrations in breast milk were highest (3.28 ± 0.41 ng/ml) in colostrum, decreased during the first 180 days of lactation, showing a significant inverse relation (r = -0.694, p < 0.001) with the days of lactation. Colostrum leptin concentrations correlated with maternal serum leptin (r = 0.425, p < 0.01), cortisol (r = 0.549, p < 0.01) and thyroxine (r = -0.530, p < 0.01). Mature milk leptin concentrations correlated with maternal serum leptin (r = 0.547, p < 0.001), insulin (r = 0.331, p < 0.05) and thyroxine (r = -0.329, p < 0.01). Serum leptin concentrations correlated with serum insulin (r = 0.648, p < 0.001), estradiol (r = 0.639, p < 0.001), prolactin (r = 0.530, p < 0.001) and thyroxine (r = -0.327, p < 0.05) concentrations during days 1–3 postpartum. During 15–180 postpartum days, serum leptin concentrations correlated with serum insulin (r = 0.271, p < 0.01), and thyroxine (r = -0.345, p < 0.001). Conclusion Leptin concentrations in breast milk decrease with time during lactation and show significant relationships with

  9. Low parathyroid hormone status induced by high dialysate calcium is an independent risk factor for cardiovascular death in hemodialysis patients.

    PubMed

    Merle, Emilie; Roth, Hubert; London, Gérard M; Jean, Guillaume; Hannedouche, Thierry; Bouchet, Jean-Louis; Drüeke, Tilman; Fouque, Denis; Daugas, Eric

    2016-03-01

    Here we studied a possible association between low parathyroid hormone (PTH) status and mortality in incident patients undergoing hemodialysis . A total of 1983 patients were included at baseline and prospectively followed for 24 months. Patients were classified according to their Kidney Disease: Improving Global Outcomes PTH status at baseline and at 12 months, and mortality evaluated at 12 to 24 months using adjusted Cox analysis. Factors potentially involved in PTH status variability between baseline and 12 months were analyzed. A decrease in serum PTH from normal or high to low values between baseline and 12 months was associated with significantly increased cardiovascular mortality at 12 to 24 months (hazard ratio, 2.03; 95% confidence interval, 1.22-3.36). For patients with high or normal baseline PTH levels, the main independent factor at 6 months for a decrease to low PTH levels at 12 months was high dialysate calcium (1.75 mmol/L), whereas prescription of non-calcium-based phosphate binders was associated with a lower risk of PTH decrease. In the high cardiovascular (CV) mortality risk subgroup of patients who acquired a low PTH status at 12 months, the main independent factor at 12 months associated with significant 12- to 24-month CV mortality was high dialysate calcium (odds ratio, 5.44; 95% CI, 2.52-11.75). Thus, patients with a serum PTH decrease to low values after 1 year of hemodialysis treatment are at high risk of short-term CV death. High dialysate calcium was an important contributor to PTH oversuppression, and continued use was associated with increased CV mortality. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  10. The Effects of Psychological Interventions on Neuroendocrine Hormone Regulation and Immune Status in HIV-Positive Persons

    PubMed Central

    Carrico, Adam W.; Antoni, Michael H.

    2009-01-01

    We reviewed randomized controlled trials (RCTs) that examined the effects of psychological interventions on HIV disease markers including neuroendocrine hormone regulation and immune status. Utilizing both PubMed and PsycINFO, we searched for RCTs published over the past 20 years (1987-2007). Of the 31 RCTs identified, 14 tested effects of psychological interventions on neuroendocrine regulation or immune status. Despite the fact that there are significant methodological limitations of RCTs that have been conducted to date, psychological interventions for HIV-positive persons have been shown to be efficacious in improving psychological adjustment compared with wait-list or treatment as usual control conditions. However, there is little support for differential efficacy of group-based interventions that have been tested to date, even in comparison with semistructured social support groups. Irrespective of the treatment modality, it seems that interventions that are successful in improving psychological adjustment are more likely to have salutary effects on neuroendocrine regulation and immune status. Psychological interventions represent a viable adjuvant treatment that can assist patients with improving psychological adjustment and potentially enhancing immune status. To inform the development of innovative treatments with potentially superior efficacy, deconstruction trials are necessary to examine the effects of distinct components of multimodal psychological interventions compared with nonspecific social support effects. Effectiveness trials of promising psychological interventions with more representative samples of HIV-positive persons are also needed to provide more definitive information on the clinical utility and potential cost-effectiveness of treatments that have been developed to date. PMID:18541907

  11. Correlation between hormone receptor status and age, and its prognostic implications in breast cancer patients in Bahrain.

    PubMed

    AlZaman, Aysha S; Mughal, Saad A; AlZaman, Yahya S; AlZaman, Entisar S

    2016-01-01

    To assess the correlation between hormone receptor status (HRS) and age, and its significance as a predictor of outcome in patients with breast cancer (BC).    This retrospective review was conducted on 109 patients diagnosed with BC at Salmaniya Medical Complex, Manama, Bahrain from 2010-2013. Patients were divided into 2 age groups; under and over 40 years, and were analyzed for tumor histology, lymph node status, stage, and HRS. Younger patients with BC were more likely to be of higher stage, grade, and of larger size. Older women were more likely to be estrogen receptor (ER) positive (72.6% versus 55.3%), and progesterone receptor (PR) positive (71% versus 53.2%) (p=0.03). The human epidermal growth factor receptor (HER)-2 over-expression was seen more in younger women (51% versus 40%) (p=0.2). Younger patients had higher lymph node metastases (88.6% versus 56.1%) (p=0.0004), and higher distant metastases (26.7% versus 6.8%) (p=0.005). The HER-2 over-expression strongly correlated with lymph node status. A total of 63.4% of lymph node positive patients had HER-2 over-expression compared with only 13.3% of lymph node negative patients (p less than 0.00001). Breast cancer is more aggressive and advanced in younger women, a fact that can be significantly attributed to under expression of ER and PR, and over expression of HER-2, which also correlates well with lymph node status, as a measure of aggressiveness. Further studies should evaluate the genetic profile of BC in such population to improve their outcomes.

  12. Etiology of fatty liver in dairy cattle: effects of nutritional and hormonal status on hepatic microsomal triglyceride transfer protein.

    PubMed

    Bremmer, D R; Trower, S L; Bertics, S J; Besong, S A; Bernabucci, U; Grummer, R R

    2000-10-01

    We conducted three experiments to determine the effects of nutritional and hormonal status on microsomal triglyceride transfer protein (MTP) activity and mass. In experiment 1, 18 nonlactating Holstein cows, 75 d before expected calving date, in their second gestation or greater were monitored from d 75 to 55 prepartum. Cows were fed a control diet from d 75 to 62 prepartum for covariable measurements. From d 61 to 55 prepartum, six cows continued to receive the control diet, six cows were restricted to 2.3 kg of grass hay/d, and six cows were fed the control diet plus 1.8 kg of concentrate/d and 500 ml of propylene glycol given 2 times/d as an oral drench. Plasma glucose and serum insulin concentrations were highest in cows that received propylene glycol and lowest in feed restricted cows. Plasma nonesterified fatty acids (NEFA) and liver triglyceride (TG) concentrations were highest in feed restricted cows and not different between cows that received the control diet and cows that received propylene glycol. Hepatic MTP activity and mass were not affected by treatment in experiment 1. In experiment 2, bovine hepatocytes isolated from the caudate process of five preruminating Holstein bull calves were incubated with either 0, 0.5, 1.0, or 2.0 mM NEFA for 48 h. Intracellular TG increased linearly as NEFA concentration in the media increased. Concentration of NEFA in the incubation media had no effect on MTP activity or mass. There was a quadratic effect of concentration of NEFA in the incubation media on MTP mRNA. In experiment 3, bovine hepatocytes isolated from the caudate process of five preruminating Holstein bull calves were incubated with 2 mM [1-14C]oleate for 24 h to accumulate TG, followed by a 36-h period of TG depletion, during which hepatocytes were incubated with no hormone, 10 nM insulin, or 10 nM glucagon. There was no effect of insulin or glucagon on intracellular TG, MTP activity or mass. Cells incubated with no hormone had higher levels of MTP m

  13. Association of antiepileptic drug usage, trace elements and thyroid hormone status.

    PubMed

    Zevenbergen, Chantal; Korevaar, Tim I M; Schuette, Andrea; Peeters, Robin P; Medici, Marco; Visser, Theo J; Schomburg, Lutz; Visser, W Edward

    2016-04-01

    Levels of thyroid hormone (TH) and trace elements (copper (Cu) and selenium (Se)) are important for development and function of the brain. Anti-epileptic drugs (AEDs) can influence serum TH and trace element levels. As the relationship between AEDs, THs, and trace elements has not yet been studied directly, we explored these interactions. In total 898 participants, from the Thyroid Origin of Psychomotor Retardation study designed to investigate thyroid parameters in subjects with intellectual disability (ID), had data available on serum Se, Cu, thyroid stimulating hormone (TSH), free thyroxine (FT4), tri-iodothyronine (T3), reverse T3, T4, and thyroxine-binding globulin (TBG); 401 subjects were on AED treatment. Differences in trace elements according to medication usage was investigated using ANOVA, and associations between trace elements and thyroid parameters were analysed using (non-) linear regression models. Study participants were not deficient in any of the trace elements analyzed. AED (carbamazepine, valproate and phenytoin) usage was negatively associated with serum Se and showed compound-specific associations with Cu levels. After correction for drug usage, Se was positively associated with TSH levels, negatively associated with FT4 levels, and positively with T3 levels. Cu was positively associated with T4, T3, and rT3, which was largely dependent on TBG levels. The subjects with ID did not display profound deficiencies in trace element levels. AEDs were associated with serum Se and Cu levels, while serum Se and Cu were also associated with thyroid parameters. Further studies on the underlying mechanisms and potential clinical importance are warranted. © 2016 European Society of Endocrinology.

  14. Regulation of steroid hormones and energy status with cysteamine and its effect on spermatogenesis.

    PubMed

    Wang, Yandi; Zhao, Yong; Yu, Shuai; Feng, Yanni; Zhang, Hongfu; Kou, Xin; Chu, Meiqiang; Cui, Liantao; Li, Lan; Zhang, Pengfei; Shen, Wei; Min, Lingjiang

    2016-12-15

    Although it is well known that cysteamine is a potent chemical for treating many diseases including cystinosis and it has many adverse effects, the effect of cysteamine on spermatogenesis is as yet unknown. Therefore the objective of this investigation was to explore the effects of cysteamine on spermatogenesis and the underlying mechanisms. Sheep were treated with vehicle control, 10mg/kg or 20mg/kg cysteamine for six months. After that, the semen samples were collected to determine the spermatozoa motility by computer-assisted sperm assay method. Blood samples were collected to detect the levels of hormones and the activity of enzymes. Spermatozoa and testis samples were collected to study the mechanism of cysteamine's actions. It was found that the effects of cysteamine on spermatogenesis were dose dependent. A low dose (10mg/kg) cysteamine treatment increased ovine spermatozoa motility; however, a higher dose (20mg/kg) decreased both spermatozoa concentration and motility. This decrease might be due to a reduction in steroid hormone production by the testis, a reduction in energy in the testis and spermatozoa, a disruption in the blood-testis barrier, or a breakdown in the vital signaling pathways involved in spermatogenesis. The inhibitory effects of cysteamine on sheep spermatogenesis may be used to model its effects on young male patients with cystinosis or other diseases that are treated with this drug. Further studies on spermatogenesis that focus on patients treated with cysteamine during the peripubertal stage are warranted. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Thyroid hormone status affects expression of daily torpor and gene transcription in Djungarian hamsters (Phodopus sungorus).

    PubMed

    Bank, Jonathan H H; Kemmling, Julia; Rijntjes, Eddy; Wirth, Eva K; Herwig, Annika

    2015-09-01

    Thyroid hormones (TH) play a key role in regulation of seasonal as well as acute changes in metabolism. Djungarian hamsters (Phodopus sungorus) adapt to winter by multiple changes in behaviour and physiology including spontaneous daily torpor, a state of hypometabolism and hypothermia. We investigated effects of systemic TH administration and ablation on the torpor behaviour in Djungarian hamsters adapted to short photoperiod. Hyperthyroidism was induced by giving T4 or T3 and hypothyroidism by giving methimazole (MMI) and sodium perchlorate via drinking water. T3 treatment increased water, food intake and body mass, whereas MMI had the opposite effect. Continuous recording of body temperature revealed that low T3 serum concentrations increased torpor incidence, lowered Tb and duration, whereas high T3 serum concentrations inhibited torpor expression. Gene expression of deiodinases (dio) and uncoupling proteins (ucp) were analysed by qPCR in hypothalamus, brown adipose tissue (BAT) and skeletal muscle. Expression of dio2, the enzyme generating T3 by deiodination of T4, and ucps, involved in thermoregulation, indicated a tissue specific response to treatment. Torpor per se decreased dio2 expression irrespective of treatment or tissue, suggesting low intracellular T3 concentrations during torpor. Down regulation of ucp1 and ucp3 during torpor might be a factor for the inhibition of BAT thermogenesis. Hypothalamic gene expression of neuropeptide Y, propopiomelanocortin and somatostatin, involved in feeding behaviour and energy balance, were not affected by treatment. Taken together our data indicate a strong effect of thyroid hormones on torpor, suggesting that lowered intracellular T3 concentrations in peripheral tissues promote torpor.

  16. Hippocampal Transcriptome Profile of Persistent Memory Rescue in a Mouse Model of THRA1 Mutation-Mediated Resistance to Thyroid Hormone

    PubMed Central

    Wang, Yiqiao; Fisahn, André; Sinha, Indranil; Nguyen, Dinh Phong; Sterzenbach, Ulrich; Lallemend, Francois; Hadjab, Saїda

    2016-01-01

    Hypothyroidism due to THRA1 (gene coding for thyroid hormone receptor α1) mutation-mediated Resistance to Thyroid Hormone (RTH) has been recently reported in human and is associated with memory deficits similar to those found in a mouse model for Thra1 mutation mediated RTH (Thra1+/m mice). Here, we show that a short-term treatment of Thra1+/m mice with GABAA receptor antagonist pentylenetetrazol (PTZ) completely and durably rescues their memory performance. In the CA1 region of the hippocampus, improvement of memory is associated with increased in long-term potentiation (LTP) and an augmentation of density of dendritic spines (DDS) onto the apical dendrites of pyramidal cells reflecting an increase in the local excitatory drive. Unbiased gene profiling analysis of hippocampi of treated Thra1+/+ and Thra1+/m mice were performed two weeks and three months post treatment and identified co-expression modules that include differentially expressed genes related with and predicting higher memory, LTP and DDS in the hippocampi of PTZ-treated animals. We observed that PTZ treatment changed similar sets of genes in both Thra1+/+ and Thra1+/m mice, which are known to be involved in memory consolidation and neurotransmission dynamics and could participate in the persistent effects of PTZ on memory recovery. PMID:26743578

  17. BRAFV600E mutation contributes papillary thyroid carcinoma and Hashimoto thyroiditis with resistance to thyroid hormone: A case report and literature review

    PubMed Central

    Xing, Wanjia; Liu, Xiaohong; He, Qingqing; Zhang, Zongjing; Jiang, Zhaoshun

    2017-01-01

    Resistance to thyroid hormone (RTH) is a rare autosomal hereditary disorder characterized by increased serum thyroid hormone (TH) levels with unsuppressed or increased thyrotropin concentration. It remains unknown whether the coexistence of RTH with papillary thyroid carcinoma (PTC) and Hashimoto thyroiditis (HT) is incidental or whether it possesses a genetic or pathophysiological association. In the present study, a case of RTH with PTC and HT in an 11-year-old Chinese patient was examined and the clinical presentation of RTH with PTC was discussed. In addition, the possible associations between RTH, PTC and HT were determined. HT was confirmed in the patient using an autoimmune assay and thyroid ultrasound. RTH was diagnosed on the basis of clinical manifestations, laboratory information and gene analysis, and PTC was diagnosed according to histological results. Results of BRAFV600E mutation analysis were positive. A literature review of 14 cases of RTH with PTC was included for comparison. The present case report indicates an association of RTH with PTC and HT coexistence in the patient. Close follow-up, histological evaluation and BRAFV600E mutation detection should be performed in each RTH case with HT, since a persistent increase in TSH may be a risk factor for the development of thyroid neoplasm. PMID:28928829

  18. Evidence of associations between feto-maternal vitamin D status, cord parathyroid hormone and bone-specific alkaline phosphatase, and newborn whole body bone mineral content

    USDA-ARS?s Scientific Manuscript database

    In spite of a high prevalence of vitamin D inadequacy in pregnant women and neonates, relationships among vitamin D status [25(OH)D], parathyroid hormone (PTH), bone specific alkaline phosphatase (BALP), and whole body bone mineral content (WBBMC) in the newborn are poorly characterized. The purpose...

  19. Clonal status of actionable driver events and the timing of mutational processes in cancer evolution

    PubMed Central

    McGranahan, Nicholas; Favero, Francesco; de Bruin, Elza C.; Birkbak, Nicolai Juul; Szallasi, Zoltan; Swanton, Charles

    2015-01-01

    Deciphering whether actionable driver mutations are found in all or a subset of tumor cells will likely be required to improve drug development and precision medicine strategies. We analyzed nine cancer types to determine the subclonal frequencies of driver events, to time mutational processes during cancer evolution, and to identify drivers of subclonal expansions. Although mutations in known driver genes typically occurred early in cancer evolution, we also identified later subclonal “actionable” mutations, including BRAF(V600E), IDH1(R132H), PIK3CA(E545K), EGFR(L858R), and KRAS(G12D), which may compromise the efficacy of targeted therapy approaches. More than 20% of IDH1 mutations in glioblastomas, and 15% of mutations in genes in the PI3K(phosphatidylinositol 3-kinase)–AKT–mTOR (mammalian target of rapamycin) signaling axis across all tumor types were subclonal. Mutations in the RAS–MEK (mitogen-activated protein kinase kinase) signaling axis were less likely to be subclonal than mutations in genes associated with PI3K-AKT-mTORsignaling. Analysis of late mutations revealed a link between APOBEC-mediated mutagenesis and the acquisition of subclonal driver mutations and uncovered putative cancer genes involved in subclonal expansions, including CTNNA2 and ATXN1. Our results provide a pan-cancer census of driver events within the context of intratumor heterogeneity and reveal patterns of tumor evolution across cancers. The frequent presence of subclonal driver mutations suggests the need to stratify targeted therapy response according to the proportion of tumor cells in which the driver is identified. PMID:25877892

  20. Clonal status of actionable driver events and the timing of mutational processes in cancer evolution.

    PubMed

    McGranahan, Nicholas; Favero, Francesco; de Bruin, Elza C; Birkbak, Nicolai Juul; Szallasi, Zoltan; Swanton, Charles

    2015-04-15

    Deciphering whether actionable driver mutations are found in all or a subset of tumor cells will likely be required to improve drug development and precision medicine strategies. We analyzed nine cancer types to determine the subclonal frequencies of driver events, to time mutational processes during cancer evolution, and to identify drivers of subclonal expansions. Although mutations in known driver genes typically occurred early in cancer evolution, we also identified later subclonal "actionable" mutations, including BRAF (V600E), IDH1 (R132H), PIK3CA (E545K), EGFR (L858R), and KRAS (G12D), which may compromise the efficacy of targeted therapy approaches. More than 20% of IDH1 mutations in glioblastomas, and 15% of mutations in genes in the PI3K (phosphatidylinositol 3-kinase)-AKT-mTOR (mammalian target of rapamycin) signaling axis across all tumor types were subclonal. Mutations in the RAS-MEK (mitogen-activated protein kinase kinase) signaling axis were less likely to be subclonal than mutations in genes associated with PI3K-AKT-mTOR signaling. Analysis of late mutations revealed a link between APOBEC-mediated mutagenesis and the acquisition of subclonal driver mutations and uncovered putative cancer genes involved in subclonal expansions, including CTNNA2 and ATXN1. Our results provide a pan-cancer census of driver events within the context of intratumor heterogeneity and reveal patterns of tumor evolution across cancers. The frequent presence of subclonal driver mutations suggests the need to stratify targeted therapy response according to the proportion of tumor cells in which the driver is identified.

  1. Nutritional factors, physical activity, and breast cancer by hormonal receptor status.

    PubMed

    Rosato, Valentina; Bertuccio, Paola; Bosetti, Cristina; Negri, Eva; Edefonti, Valeria; Ferraroni, Monica; Decarli, Adriano; Talamini, Renato; Dal Maso, Luigino; Falcini, Fabio; Montella, Maurizio; Franceschi, Silvia; La Vecchia, Carlo

    2013-10-01

    To investigate the association between food and nutrient intake, occupational and leisure-time physical activity, and body mass index and breast cancer risk by estrogen receptor (ER) and progesterone receptor (PR) status. We analyzed data from a hospital-based case-control study conducted between 1991 and 1994 in Italy, including 1075 women with incident breast cancer and 1477 controls. The associations with breast cancer risk were similar according to ER status for all risk factors considered. In particular, significant reduced risk of ER- and ER+ breast cancers were observed for raw vegetables (multivariate odds ratio, OR, for high vs low consumption: 0.6 and 0.7, respectively) and for polyunsaturated fats (OR: 0.6 and 0.7, respectively). No significant heterogeneous risk estimates were observed for combinations of ER and PR status. Our study does not suggest major differences risk for various dietary and lifestyle factors according to ER and PR breast cancer subtypes. Copyright © 2013 Elsevier Ltd. All rights reserved.

  2. Correlation between EGFR mutation status and the incidence of brain metastases in patients with non-small cell lung cancer.

    PubMed

    Li, Lina; Luo, Shuimei; Lin, Heng; Yang, Haitao; Chen, Huijuan; Liao, Ziyuan; Lin, Wanzun; Zheng, Weili; Xie, Xianhe

    2017-08-01

    Lung cancer is the leading cause of cancer-related death worldwide. Numerous studies have been performed to investigate the correlation between epidermal growth factor receptor (EGFR) mutation status and the incidence of brain metastases (BMs) in patients with non-small cell lung cancer (NSCLC), however, the outcomes were inconsistent. Thus, we performed this study to establish the role of EGFR mutation status in BMs. Electronic databases PubMed, Embase, Cochrane Library, CBM, WanFang, CNKI were searched to identify relevant trials. The primary endpoint was the incidence of BMs in EGFR mutations or wild type NSCLC and the secondary endpoint was overall survival calculated from the BMs emerging (BMOS). Twenty-two studies incorporating 8,152 participants were eligible. EGFR mutations group possessed a significantly higher risk of BMs (OR =1.99; 95% CI, 1.59-2.48; P=0.000) than EGFR wild type group. In the stratified analysis, compared with EGFR wild type group, EGFR mutations group had a significant higher incidence (OR =2.01; 95% CI, 1.56-2.59; P=0.000) of subsequent BMs while only a trend of increasing the incidence of initial BMs (OR =1.38; 95% CI, 0.98-1.94; P=0.066). Moreover, exon 19 deletion had a trend of increasing the incidence of BMs than exon 21 mutation (OR =1.44; 95% CI, 0.77-2.68; P=0.252). Compared with EGFR wild type group, EGFR mutations group possessed a prolonged overall BMOS (HR =0.68; 95% CI, 0.47-0.98; P=0.038) and a longer BMOS in initial BMs (HR =0.50; 95% CI, 0.31-0.80; P=0.004) but no significant difference in NSCLC with subsequent BMs (HR =0.95; 95% CI, 0.42-2.15; P=0.901). Patients with EGFR mutations were more susceptible to develop into BMs than those with EGFR wild type, especially during the course of disease.

  3. Association Between NRAS and BRAF Mutational Status and Melanoma-Specific Survival Among Patients With Higher Risk Primary Melanoma

    PubMed Central

    Thomas, Nancy E.; Edmiston, Sharon N.; Alexander, Audrey; Groben, Pamela A.; Parrish, Eloise; Kricker, Anne; Armstrong, Bruce K.; Anton-Culver, Hoda; Gruber, Stephen B.; From, Lynn; Busam, Klaus J.; Hao, Honglin; Orlow, Irene; Kanetsky, Peter A.; Luo, Li; Reiner, Anne S.; Paine, Susan; Frank, Jill S.; Bramson, Jennifer I.; Marrett, Lorraine D.; Gallagher, Richard P.; Zanetti, Roberto; Rosso, Stefano; Dwyer, Terence; Cust, Anne E.; Ollila, David W.; Begg, Colin B.; Berwick, Marianne; Conway, Kathleen

    2015-01-01

    Importance NRAS and BRAF mutations in melanoma inform current treatment paradigms but their role in survival from primary melanoma has not been established. Identification of patients at high risk of melanoma-related death based on their primary melanoma characteristics before evidence of recurrence could inform recommendations for patient follow-up and eligibility for adjuvant trials. Objective To determine tumor characteristics and survival from primary melanoma by somatic NRAS and BRAF status. Design, Setting, and Participants A population-based study with median follow-up of 7.6 years for 912 patients with first primary cutaneous melanoma analyzed for NRAS and BRAF mutations diagnosed in the year 2000 from the United States and Australia in the Genes, Environment and Melanoma Study and followed through 2007. Main Outcomes and Measures Tumor characteristics and melanoma-specific survival of primary melanoma by NRAS and BRAF mutational status. Results The melanomas were 13% NRAS+, 30% BRAF+, and 57% with neither NRAS nor BRAF mutation (wildtype). In a multivariable model including clinicopathologic characteristics, NRAS+ melanoma was associated (P<.05) with mitoses, lower tumor infiltrating lymphocyte (TIL) grade, and anatomic site other than scalp/neck and BRAF+ melanoma was associated with younger age, superficial spreading subtype, and mitoses, relative to wildtype melanoma. There was no significant difference in melanoma-specific survival for melanoma harboring mutations in NRAS (HR 1.7, 95% CI, 0.8–3.4) or BRAF (HR, 1.5, 95% CI, 0.8–2.9) compared to wildtype melanoma adjusted for age, sex, site, AJCC tumor stage, TIL grade, and study center. However, melanoma-specific survival was significantly poorer for higher risk (T2b or higher stage) tumors with NRAS (HR 2.9; 95% CI 1.1–7.7) or BRAF (HR 3.1; 95% CI 1.2–8.5) mutations but not for lower risk (T2a or lower) tumors (P=.65) adjusted for age, sex, site, AJCC tumor stage, TIL grade, and study center

  4. Effects of long-term temperature acclimation on thyroid hormone deiodinase function, plasma thyroid hormone levels, growth, and reproductive status of male Atlantic cod, Gadus morhua.

    PubMed

    Cyr, D G; Idler, D R; Audet, C; McLeese, J M; Eales, J G

    1998-01-01

    The recent collapse of the Northwestern Atlantic cod fisheries has coincided with a cooling of water temperatures. During this time the condition factor of cod has been poor. The objective of the present study was to determine the effects of long-term temperature acclimation on growth reproduction and thyroid function in laboratory held Atlantic cod (Gadus morhua). One of the key parameters used to assess thyroid function is the peripheral metabolism of L-thyroxine (T4) by microsomal deiodinase enzymes. Deiodinase function has not been described for gadid fish. T4 outer-ring deiodinating activity (apparent K(m) 1-2 nM) was confined primarily to liver. Its properties resembled those for hepatic T4ORD activity of other teleosts and the mammalian type II deiodinase. The T4ORD activity of cod liver exceeded that of salmonids and could explain the high plasma T3 levels (10-18 ng/ml), which were 2-5 times greater than T4 levels. T4 and T3 inner-ring deiodination was confined mainly to brain. In order to determine the effects of long-term temperature acclimation on cod, somatic growth, reproduction, and thyroidal status were assessed monthly in 400-900-g satiation-fed male Atlantic cod captured in June from the St. Lawrence Estuary and then acclimated from August to the following June under a natural photoperiod at 2-4 degrees C (LT) or 6-10 degrees C (HT). Reproductive status was determined from the gonadosomatic index (GSI), plasma testosterone (T) and 11-ketotestosterone (11-KT) levels, and the appearance of milt; thyroidal status was determined from plasma T4 and 3,5,3'-triiodo-L-thyronine (T3) levels and hepatic T4ORD activity to produce biologically active T3. Testis maturation (high levels of 1 and 11-KT, and milt release) occurred in April and May and was uninfluenced by acclimation temperature. LT cod grew more slowly than HT cod. Differences in body weight were particularly evident from December to February. In conclusion, (i) cod possess outer- and inner

  5. TP53 Mutational Status and Prediction of Benefit from Adjuvant 5-Fluorouracil in Stage III Colon Cancer Patients.

    PubMed

    Kandioler, Daniela; Mittlböck, Martina; Kappel, Sonja; Puhalla, Harald; Herbst, Friedrich; Langner, Cord; Wolf, Brigitte; Tschmelitsch, Jörg; Schippinger, Walter; Steger, Günther; Hofbauer, Friedrich; Samonigg, Hellmut; Gnant, Michael; Teleky, Bela; Kührer, Irene

    2015-08-01

    We investigated the hypothesis that the varying treatment efficacy of adjuvant 5-fluorouracil (5FU) in stage III colon cancer is linked to the TP53 mutational status. ABCSG-90 was a prospective randomized trial in which effect of adjuvant 5FU was studied in stage III colon cancer patients. Tumor material of 70% of these patients (389/572) was available for analysis of the biomarker TP53 using a TP53-gene-specific Sanger sequencing protocol. Median follow-up was 88 months. TP53 mutation frequency was 33%. A significant interaction between TP53 status, outcomes and nodal category was found (P = 0.0095). In the N1 category, TP53 wildtype patients had significantly better overall survival than TP53 mutated (81.0% vs. 62.0% overall survival at 5 years; HR = 2.131; 95% CI: 1.344-3.378; P = 0.0010). In the N2 category, the TP53 status did not affect survival (P = 0.4992). In TP53 wildtype patients, the prognostic significance of N category was significantly enhanced (P = 0.0002). In TP53 mutated patients, survival curves of N1 and N2 patients overlapped and nodal category was no longer prognostic. The biomarker TP53 independently predicted effect of adjuvant 5FU in N1 colon cancer patients. TP53 was not predictive in N2 patients, in whom 5FU is known to have no effect.

  6. Novel C617Y mutation in the 7th transmembrane segment of luteinizing hormone/choriogonadotropin receptor in a Japanese boy with peripheral precocious puberty.

    PubMed

    Nagasaki, Keisuke; Katsumata, Noriyuki; Ogawa, Yohei; Kikuchi, Toru; Uchiyama, Makoto

    2010-01-01

    Testotoxicosis, also known as familial male-limited precocious puberty, is an autosomal dominant form of gonadotropin-independent precocious puberty caused by heterozygous constitutively activating mutations of the LHCGR gene encoding the luteinizing hormone/choriogonadotropin receptor (LH/CGR). The patient is an 8-year-old boy who started to develop pubic hair and penile enlargement at 6 years of age. The patient had elevated serum testosterone levels, but initially exhibited a prepubertal response of gonadotropins to GnRH, which was followed by central activation of the hypothalamo-pituitary-gonadal axis. The father reported having experienced precocious puberty, and is 158 cm tall. There is no history of short stature and precocious puberty in the family except for the father. The LHCGR gene was analyzed by direct DNA sequencing of amplified PCR products from the patient and his parents. The wild-type and mutant LH/CGRs were transiently expressed in COS-1 cells and cAMP levels in the cells were determined with or without hCG stimulation. Genetic analysis revealed a novel C617Y mutation of the LHCGR gene in the patient and his mother, while his father had no mutations. Functional expression study demonstrated around 15% increase in the basal intracellular cAMP level in cells expressing the mutant LH/CGR compared with that in cells expressing the wild-type receptor. We have reported the first missense C617Y mutation located in the 7th transmembrane segment of LH/CGR causing testotoxicosis. The modest phenotype of our patient may be explained, at least in part, by the modest increase in the intracellular cAMP level caused by the C617Y mutation.

  7. Combined pituitary hormone deficiency caused by a novel mutation of a highly conserved residue (F88S) in the homeodomain of PROP-1.

    PubMed

    Osorio, M G; Kopp, P; Marui, S; Latronico, A C; Mendonca, B B; Arnhold, I J

    2000-08-01

    Mutations in the pituitary-specific paired-like homeodomain transcription factor, PROP-1, result in combined pituitary hormone deficiency. We studied a Brazilian girl, offspring of first cousins, who presented with short stature and deficiencies of GH, TSH, PRL, LH, and FSH. Her cortisol response to hypoglycemia was determined at age 4.9, 10.7, and 14.1 yr and remained normal. Magnetic resonance imaging at the age of 9 yr revealed an anterior pituitary lobe of diminished height (3 mm; normal, 4.5 +/- 0.6), but radiography revealed a sella turcica volume above the normal mean. Direct sequencing of the PROP-1 gene revealed homozygosity for a novel 263T>C transition that results in the replacement of a highly conserved phenylalanine by serine at codon 88 (F88S). F88 constitutes the hydrophobic core of the first helix of the homeodomain of PROP-1, and the substitution by the polar residue serine is expected to alter the secondary structure and impair binding of the mutated PROP-1 to DNA target sequences. The F88S mutation (which corresponds to murine F85S) was introduced into the murine Prop-1 complementary DNA and its consequences on DNA binding and trans-activation were assessed in vitro. In contrast to wild-type Prop-1, the F88S mutant showed no significant DNA binding to a PRDQ9 Prop-1 response element in gel shift assays. Transcriptional activation of a luciferase reporter gene containing a PRDQ9 site upstream of a simian virus 40 promoter was reduced to approximately 34% compared with that of wild-type Prop-1 in transiently transfected TSA-201 human embryonic kidney cells. The F88S mutation further expands the repertoire of mutations in PROP-1.

  8. Impaired thyroid hormone status and thermoregulation during cold exposure of zinc-deficient rats.

    PubMed

    Lukaski, H C; Hall, C B; Marchello, M J

    1992-08-01

    Forty-five male, weanling Sprague-Dawley rats were matched by weight into three groups (n = 15). One group was fed ad libitum a semipurified diet containing all essential nutrients and 30 ppm of zinc (control). A second group was fed ad libitum a similar diet but with a deficient zinc intake of less than 1 ppm (ZnD). A third group was pair-fed (PF) the control diet in amounts equal to that consumed by the matched ZnD animals. After 42 days, the animals were fasted for 12 hr then five animals from each group were sacrificed and the remainder was exposed to 3 degrees C for 6 hr. Rectal temperatures were lower (p less than 0.05) in ZnD at 23 degrees C and during cold exposure. Plasma thyroxine (T4) and triiodothyronine (T3) concentrations were reduced (p less than 0.05) at room temperature in ZnD rats. During cold exposure, the ZnD animals had depressed (p less than 0.05) plasma thyrotropin, T4 and T3 concentrations. Thus, ZnD adversely affects thermoregulatory performance of rats acutely exposed to cold by influencing thyroid hormone metabolism.

  9. Vitamin D Status and Its Association with Parathyroid Hormone Concentration in Brazilians

    PubMed Central

    Martins, Juliana Sálvio; Palhares, Magda de Oliveira; Teixeira, Octávio Cury Mayrink

    2017-01-01

    Vitamins are organic compounds that play a vital role in the control of metabolic processes. The D complex is considered a nutrient with a hormonal action and has an important participation in the constant maintenance of serum and extracellular calcium levels. The present study aims to analyze the results of 105.588 vitamin D (25(OH)D) measurements obtained from a database from a clinical analysis laboratory in Brazil, between the years of 2011 and 2013. The values of 25(OH)D were correlated with age, gender, and values of PTH. The results show a high prevalence of values of 25(OH)D considered inadequate, characterizing 76% of the studied population. It was observed that 26,5% of the individuals had deficiency and 49,5% had insufficiency of vitamin D. It was also shown that there was a negative correlation between 25(OH)D and PTH levels. In conclusion, this study is in accordance with others that show a high prevalence of vitamin D deficiency in different populations and alerts us for the importance of these measurements and analysis in clinical practice and as a base for diagnosis and treatment of hypovitaminosis. PMID:28265467

  10. Thyroid hormone status defines brown adipose tissue activity and browning of white adipose tissues in mice

    PubMed Central

    Weiner, Juliane; Kranz, Mathias; Klöting, Nora; Kunath, Anne; Steinhoff, Karen; Rijntjes, Eddy; Köhrle, Josef; Zeisig, Vilia; Hankir, Mohammed; Gebhardt, Claudia; Deuther-Conrad, Winnie; Heiker, John T.; Kralisch, Susan; Stumvoll, Michael; Blüher, Matthias; Sabri, Osama; Hesse, Swen; Brust, Peter; Tönjes, Anke; Krause, Kerstin

    2016-01-01

    The present study aimed to determine the effect of thyroid hormone dysfunction on brown adipose tissue activity and white adipose tissue browning in mice. Twenty randomized female C57BL/6NTac mice per treatment group housed at room temperature were rendered hypothyroid or hyperthyroid. In-vivo small animal 18F-FDG PET/MRI was performed to determine the effects of hypo- and hyperthyroidism on BAT mass and BAT activity. Ex-vivo14C-acetate loading assay and assessment of thermogenic gene and protein expression permitted analysis of oxidative and thermogenic capacities of WAT and BAT of eu-, hyper and hypothyroid mice. 18F-FDG PET/MRI revealed a lack of brown adipose tissue activity in hypothyroid mice, whereas hyperthyroid mice displayed increased BAT mass alongside enhanced 18F-FDG uptake. In white adipose tissue of both, hyper- and hypothyroid mice, we found a significant induction of thermogenic genes together with multilocular adipocytes expressing UCP1. Taken together, these results suggest that both the hyperthyroid and hypothyroid state stimulate WAT thermogenesis most likely as a consequence of enhanced adrenergic signaling or compensation for impaired BAT function, respectively. PMID:27941950

  11. Thyroid hormone status defines brown adipose tissue activity and browning of white adipose tissues in mice.

    PubMed

    Weiner, Juliane; Kranz, Mathias; Klöting, Nora; Kunath, Anne; Steinhoff, Karen; Rijntjes, Eddy; Köhrle, Josef; Zeisig, Vilia; Hankir, Mohammed; Gebhardt, Claudia; Deuther-Conrad, Winnie; Heiker, John T; Kralisch, Susan; Stumvoll, Michael; Blüher, Matthias; Sabri, Osama; Hesse, Swen; Brust, Peter; Tönjes, Anke; Krause, Kerstin

    2016-12-12

    The present study aimed to determine the effect of thyroid hormone dysfunction on brown adipose tissue activity and white adipose tissue browning in mice. Twenty randomized female C57BL/6NTac mice per treatment group housed at room temperature were rendered hypothyroid or hyperthyroid. In-vivo small animal (18)F-FDG PET/MRI was performed to determine the effects of hypo- and hyperthyroidism on BAT mass and BAT activity. Ex-vivo(14)C-acetate loading assay and assessment of thermogenic gene and protein expression permitted analysis of oxidative and thermogenic capacities of WAT and BAT of eu-, hyper and hypothyroid mice. (18)F-FDG PET/MRI revealed a lack of brown adipose tissue activity in hypothyroid mice, whereas hyperthyroid mice displayed increased BAT mass alongside enhanced (18)F-FDG uptake. In white adipose tissue of both, hyper- and hypothyroid mice, we found a significant induction of thermogenic genes together with multilocular adipocytes expressing UCP1. Taken together, these results suggest that both the hyperthyroid and hypothyroid state stimulate WAT thermogenesis most likely as a consequence of enhanced adrenergic signaling or compensation for impaired BAT function, respectively.

  12. Stress hormones in relation to breeding status and territory location in colonial king penguin: a role for social density?

    PubMed

    Viblanc, Vincent A; Gineste, Benoit; Stier, Antoine; Robin, Jean-Patrice; Groscolas, René

    2014-07-01

    Because glucocorticoid (stress) hormones fundamentally affect various aspects of the behaviour, life history and fitness of free-living vertebrates, there is a need to understand the environmental factors shaping their variation in natural populations. Here, we examined whether spatial heterogeneity in breeding territory quality affected the stress of colonial king penguin (Aptenodytes patagonicus). We assessed the effects of local climate (wind, sun and ambient temperature) and social conditions (number of neighbours, distance to neighbours) on the baseline levels of plasma total corticosterone (CORT) in 77 incubating and 42 chick-brooding birds, breeding on territories of central or peripheral colony location. We also assessed the oxidative stress status of a sub-sample of central vs. peripheral chick-brooders to determine whether chronic stress arose from breeding on specific territories. On average, we found that brooders had 55% higher CORT levels than incubators. Regardless of breeding status, central birds experienced greater social density (higher number of neighbours, shorter distance between territories) and had higher CORT levels than peripheral birds. Increasing social density positively explained 40% of the variation in CORT levels of both incubators and brooders, but the effect was more pronounced in brooders. In contrast, climate was similar among breeding territories and did not significantly affect the CORT levels of breeding birds. In brooders, oxidative stress status was not affected by local density or weather conditions. These results highlight that local heterogeneity in breeding (including social) conditions may strongly affect the stress levels of breeding seabirds. The fitness consequences of such variation remain to be investigated.

  13. BI-07HYPERPOLARIZED [1-13C] GLUTAMATE: A METABOLIC IMAGING BIOMARKER OF IDH1 MUTATIONAL STATUS IN GLIOMA

    PubMed Central

    Chaumeil, Myriam; Larson, Peder; Woods, Sarah; Cai, Larry; Eriksson, Pia; Robinson, Aaron; Lupo, Janine; Vigneron, Daniel; Nelson, Sarah; Pieper, Russell; Phillips, Joanna; Ronen, Sabrina

    2014-01-01

    Mutations of the isocitrate dehydrogenase 1 (IDH1) gene are among the most prevalent in low-grade glioma and secondary glioblastoma, represent an early pathogenic event and are being considered a promising therapeutic target. Consequently, non-invasive imaging methods are needed to monitor IDH1 status. Amongst these, we previously demonstrated the use of 13C MR spectroscopic imaging of hyperpolarized [1-13C] α-ketoglutarate (α-KG) to non-invasively assess IDH1 status through the detection of the conversion of hyperpolarized α-ketoglutarate to 2-hydroxyglutarate (2-HG) catalyzed by mutant IDH1. Importantly, in addition to its oncogenic role, IDH1 mutation is also associated with global modulations in metabolism. Interestingly, a study recently uncovered a relationship between presence of IDH1 mutation and decreased activity of the branched chained amino acid transaminase 1 (BCAT1) enzyme, which transaminates amino acids while converting α-KG to glutamate. Given this new study, we decided to expand on our previous findings and investigated the potential of hyperpolarized α-KG as an imaging probe to monitor BCAT1-driven α-KG-to-glutamate conversion and its modulation in the presence of IDH1 mutation. We investigated two isogenic glioblastoma lines that differed only in their IDH1 status, and performed experiments in live cells and in vivo in rat orthotopic tumors. Following injection of hyperpolarized α-KG, hyperpolarized glutamate production was detected both in cells and in vivo, and the level of hyperpolarized glutamate was significantly lower in mutant IDH1 cells and tumors compared to their IDH1-wild-type counterparts. Importantly however, the observed drop in hyperpolarized glutamate was likely mediated not only by a drop in BCAT1 activity, but also by reductions in aspartate transaminase and glutamate dehydrogenase activities, suggesting additional metabolic reprogramming at least in our model. Hyperpolarized glutamate could thus inform on multiple

  14. MYH Gene Status in Polish FAP Patients without APC Gene Mutations

    PubMed Central

    2006-01-01

    Familial Adenomatous Polyposis (FAP) is an inheritable predisposition for the occurrence of numerous polyps in the large intestine. In about 50% of all patients, the occurrence of the disease is conditioned by heterozygotic mutations of the APC gene. Screening for genetic factors in persons without mutations in the APC gene led to the identification of homozygotic mutations of the MYH gene as the cause of the appearance of the polyposis form which is characterized by recessive heritability and a milder course than in the case of the classic form of the disease. The authors examined 90 persons from the DNA bank of patients with FAP from the Institute of Human Genetics of the Polish Academy of Sciences in Poznań in whom no mutations in the APC gene were detected. Two of the most frequent mutations of the MYH gene (Y165C and G382D) were found to be heterozygous in 13% of patients and no other mutations in this gene coding sequence were observed. In the group with heterozygotic occurrence of the mutation in the MYH gene, the disease phenotype was not milder in comparison with the entire examined group and the mean age of the disease manifestation was even lower. This observation allows one to conclude that the employed methods of mutation screening were correct and, in the case of the examined group, the mutation ratio of the MYH gene does not precondition the occurrence of the disease, but it cannot be excluded that it may modify its phenotype. The obtained results indicate that the criteria applied during the process of FAP qualification are more rigorous than those applied in other countries. PMID:20223003

  15. Alternating hemiplegia of childhood in Denmark: clinical manifestations and ATP1A3 mutation status.

    PubMed

    Hoei-Hansen, Christina E; Dali, Christine Í; Lyngbye, Troels J B; Duno, Morten; Uldall, Peter

    2014-01-01

    Alternating hemiplegia of childhood (AHC) is a rare neurodevelopmental disorder characterized by early-onset recurrent distinctive hemiplegic episodes commonly accompanied by other paroxysmal features and developmental impairment. De novo mutations in ATP1A3 were recently identified as a genetic cause of AHC. To describe the entire Danish cohort of paediatric AHC patients we approached neuropaediatricians nationwide. All currently acknowledged Danish patients ≤16 years with AHC were genetically tested and seen by the same child neurologist (PU). Ten patients; seven girls and three boys were identified. Mean present age was 10.0 years (range 1-16). Mean age at presentation was 7.4 months (range 1-18 months). Sequencing of ATP1A3 in all ten patients revealed a pathogenic mutation in seven. Two females with moderate psychomotor impairment were heterozygous for the known p.G947R mutation, whereas one severely retarded boy was heterozygous for the common p.E815K mutation. The prevalent p.D801N mutation was identified in two moderate to severely retarded children. Interestingly, in a set of monochorionic male twins a novel p.D801E mutation was identified, underscoring that the asparagine at position 801 is a mutation hotspot. Three girls aged 5-13 years did not reveal any ATP1A3 mutations. They were rather mildly clinically affected and displayed a normal or near-normal psychomotor development. This is the first study of AHC in the Danish paediatric population. The patients harboured a wide range of psychomotor difficulties. Patients with no mutation detected tended to be less severely affected. Prevalence was approximately 1 per 100,000 children.

  16. Decreased Degradation of Internalized Follicle-Stimulating Hormone Caused by Mutation of Aspartic Acid 6.30550 in a Protein Kinase-CK2 Consensus Sequence in the Third Intracellular Loop of Human Follicle-Stimulating Hormone Receptor1

    PubMed Central

    Kluetzman, Kerri S.; Thomas, Richard M.; Nechamen, Cheryl A.; Dias, James A.

    2011-01-01

    A naturally occurring mutation in follicle-stimulating hormone receptor (FSHR) gene has been reported: an amino acid change to glycine occurs at a conserved aspartic acid 550 (D550, D567, D6.30567). This residue is contained in a protein kinase-CK2 consensus site present in human FSHR (hFSHR) intracellular loop 3 (iL3). Because CK2 has been reported to play a role in trafficking of some receptors, the potential roles for CK2 and D550 in FSHR function were evaluated by generating a D550A mutation in the hFSHR. The hFSHR-D550A binds hormone similarly to WT-hFSHR when expressed in HEK293T cells. Western blot analyses showed lower levels of mature hFSHR-D550A. Maximal cAMP production of both hFSHR-D550A as well as the naturally occurring mutation hFSHR-D550G was diminished, but constitutive activity was not observed. Unexpectedly, when 125I-hFSH bound to hFSHR-D550A or hFSHR-D550G, intracellular accumulation of radiolabeled FSH was observed. Both sucrose and dominant-negative dynamin blocked internalization of radiolabeled FSH and its commensurate intracellular accumulation. Accumulation of radiolabeled FSH in cells transfected with hFSHR-D550A is due to a defect in degradation of hFSH as measured in pulse chase studies, and confocal microscopy imaging revealed that FSH accumulated in large intracellular structures. CK2 kinase activity is not required for proper degradation of internalized FSH because inhibition of CK2 kinase activity in cells expressing hFSHR did not uncouple degradation of internalized radiolabeled FSH. Additionally, the CK2 consensus site in FSHR iL3 is not required for binding because CK2alpha coimmunoprecipitated with hFSHR-D550A. Thus, mutation of D550 uncouples the link between internalization and degradation of hFSH. PMID:21270425

  17. The value of the repeated examination of BRAF V600E mutation status in diagnostics of papillary thyroid cancer.

    PubMed

    Beiša, Augustas; Beiša, Virgilijus; Stoškus, Mindaugas; Ostanevičiūtė, Elvyra; Griškevičius, Laimonas; Strupas, Kęstutis

    2016-01-01

    Nodular thyroid disease is one of the most frequently diagnosed pathologies of the adult population in iodine-deficient regions. Approximately 30% of thyroid aspirates are classified as nondiagnostic/unsatisfactory or indeterminate. However, patients with indeterminate cytology still undergo surgery. The object of this study was to determine the diagnostic value of re-examining the BRAF V600E mutation in papillary thyroid carcinoma patients. All patients underwent ultrasound guided fine-needle aspiration of a thyroid nodule. They were assigned to one of the four groups (indeterminate or positive for malignant cells) of the Bethesda System for Reporting Thyroid Cytopathology. Genetic investigation of the BRAF V600E mutation was performed for all of the fine-needle aspiration cytology specimens. All of the patients underwent surgery. Subsequently, histological investigation of the removed tissues was performed. Additional analysis of the BRAF V600E mutation from the histology specimen was then performed for the initially BRAF-negative cases. Two hundred and fourteen patients were involved in the study. One hundred and six (49.53%) patients were diagnosed with thyroid cancer. Of these 106 patients, 95 (89.62%) patients were diagnosed with papillary thyroid cancer. The BRAF V600E mutation was positive in 62 (65.26%) and negative in 33 (34.74%) histologically confirmed papillary thyroid cancer cases. After the genetic investigation, a total of 74 (77.89%) papillary thyroid cancer cases were positive for the BRAF V600E mutation and 21 (22.11%) were negative. Repeated examination of the BRAF V600E mutation status in the fine-needle aspiration may potentially increase the sensitivity of papillary thyroid cancer diagnostics.

  18. Decreased cellular uptake and metabolism in Allan-Herndon-Dudley syndrome (AHDS) due to a novel mutation in the MCT8 thyroid hormone transporter.

    PubMed

    Maranduba, C M C; Friesema, E C H; Kok, F; Kester, M H A; Jansen, J; Sertié, A L; Passos-Bueno, M R; Visser, T J

    2006-05-01

    We report a novel 1 bp deletion (c.1834delC) in the MCT8 gene in a large Brazilian family with Allan-Herndon-Dudley syndrome (AHDS), an X linked condition characterised by severe mental retardation and neurological dysfunction. The c.1834delC segregates with the disease in this family and it was not present in 100 control chromosomes, further confirming its pathogenicity. This mutation causes a frameshift and the inclusion of 64 additional amino acids in the C-terminal region of the protein. Pathogenic mutations in the MCT8 gene, which encodes a thyroid hormone transporter, results in elevated serum triiodothyronine (T3) levels, which were confirmed in four affected males of this family, while normal levels were found among obligate carriers. Through in vitro functional assays, we showed that this mutation decreases cellular T3 uptake and intracellular T3 metabolism. Therefore, the severe neurological defects present in the patients are due not only to deficiency of intracellular T3, but also to altered metabolism of T3 in central neurones. In addition, the severe muscle hypoplasia observed in most AHDS patients may be a consequence of high serum T3 levels.

  19. Parathyroid Hormone Receptor Type 1/Indian Hedgehog Expression Is Preserved in the Growth Plate of Human Fetuses Affected with Fibroblast Growth Factor Receptor Type 3 Activating Mutations

    PubMed Central

    Cormier, Sarah; Delezoide, Anne-Lise; Benoist-Lasselin, Catherine; Legeai-Mallet, Laurence; Bonaventure, Jacky; Silve, Caroline

    2002-01-01

    The fibroblast growth factor receptor type 3 (FGFR3) and Indian hedgehog (IHH)/parathyroid hormone (PTH)/PTH-related peptide receptor type 1 (PTHR1) systems are both essential regulators of endochondral ossification. Based on mouse models, activation of the FGFR3 system is suggested to regulate the IHH/PTHR1 pathway. To challenge this possible interaction in humans, we analyzed the femoral growth plates from fetuses carrying activating FGFR3 mutations (9 achondroplasia, 21 and 8 thanatophoric dysplasia types 1 and 2, respectively) and 14 age-matched controls by histological techniques and in situ hybridization using riboprobes for human IHH, PTHR1, type 10 and type 1 collagen transcripts. We show that bone-perichondrial ring enlargement and growth plate increased vascularization in FGFR3-mutated fetuses correlate with the phenotypic severity of the disease. PTHR1 and IHH expression in growth plates, bone-perichondrial rings and vascular canals is not affected by FGFR3 mutations, irrespective of the mutant genotype and age, and is in keeping with cell phenotypes. These results indicate that in humans, FGFR3 signaling does not down-regulate the main players of the IHH/PTHR1 pathway. Furthermore, we show that cells within the bone-perichondrial ring in controls and patients express IHH, PTHR1, and type 10 and type 1 collagen transcripts, suggesting that bone-perichondrial ring formation involves cells of both chondrocytic and osteoblastic phenotypes. PMID:12368206

  20. Body Mass Index and Breast Cancer Risk According to Postmenopausal Estrogen-Progestin Use and Hormone Receptor Status

    PubMed Central

    Munsell, Mark F.; Sprague, Brian L.; Berry, Donald A.; Chisholm, Gary; Trentham-Dietz, Amy

    2014-01-01

    To assess the joint relationships among body mass index, menopausal status, and breast cancer according to breast cancer subtype and estrogen-progestin medication use, we conducted a meta-analysis of 89 epidemiologic reports published in English during 1980–2012 identified through a systematic search of bibliographic databases. Pooled analysis yielded a summary risk ratio of 0.78 (95% confidence interval (CI): 0.67, 0.92) for hormone receptor–positive premenopausal breast cancer associated with obesity (body mass index (weight (kg)/height (m)2) ≥30 compared with <25). Obesity was associated with a summary risk ratio of 1.39 (95% CI: 1.14, 1.70) for receptor-positive postmenopausal breast cancer. For receptor-negative breast cancer, the summary risk ratios of 1.06 (95% CI: 0.70, 1.60) and 0.98 (95% CI: 0.78, 1.22) associated with obesity were null for both premenopausal and postmenopausal women, respectively. Elevated postmenopausal breast cancer risk ratios associated with obesity were limited to women who never took estrogen-progestin therapy, with risk ratios of 1.42 (95% CI: 1.30, 1.55) among never users and 1.18 (95% CI: 0.98, 1.42) among users; too few studies were available to examine this relationship according to receptor subtype. Future research is needed to confirm whether obesity is unrelated to receptor-negative breast cancer in populations of postmenopausal women with low prevalence of hormone medication use. PMID:24375928

  1. The interaction between nutritional status and growth hormone in young cattle: differential responsiveness of fat and protein metabolism.

    PubMed

    Dawson, J M; Greathead, H M; Craigon, J; Hachey, D L; Reeds, P J; Pell, J M; Buttery, P J

    1998-03-01

    The effect of dietary intake level on in vivo plasma leucine and plasma palmitate flux rates and on the response to a bolus injection of bovine growth hormone (GH) was investigated in six young steers. Animals were fed on a pelleted diet of dried grass-barley (0.7:0.3, w/w) in quantities sufficient to supply 0.8, 1.2, 1.6, 2.0, 2.4 or 2.65 x maintenance energy requirement, offered in hourly portions. Continuous intravenous infusions of [1-13C]leucine or [1-13C]palmitate were used to determine the flux of amino acid and fatty acid through the plasma pool before, immediately (1-3 h) after and 22-24 h after a subcutaneous injection of bovine GH (0.55 mg/kg body weight). Hourly blood samples were taken for 27 h to monitor the temporal responses of circulating hormones and metabolites following GH administration. The animal on the lowest plane of nutrition had elevated plasma GH and reduced insulin-like growth factor-1 concentrations compared with those fed on higher intake levels. Plasma leucine flux and leucine concentration increased with intake while palmitate flux and plasma non-esterified fatty acid (NEFA) concentrations were inversely related to intake. Leucine flux rate decreased in the animals fed on the two highest intake levels in response to GH 22-24 h after administration, but plasma leucine concentrations were reduced in all animals at this time. Only the animal fed on the lowest intake level showed an immediate response to GH (within 3 h of administration) with increased palmitate flux and plasma NEFA concentrations but a lipolytic response was apparent in other animals 22-24 h post-administration although the magnitude of the response was markedly reduced at high intakes. We conclude that lipid and protein metabolism are differentially responsive to GH and nutritional status.

  2. Combined effect of Hashimoto's thyroiditis and BRAF(V600E) mutation status on aggressiveness in papillary thyroid cancer.

    PubMed

    Kim, Su-jin; Myong, Jun Pyo; Jee, Hyeon-Gun; Chai, Young Jun; Choi, June Young; Min, Hye Sook; Lee, Kyu Eun; Youn, Yeo-Kyu

    2016-01-01

    The purpose of this study was to evaluate the association between Hashimoto's thyroiditis and BRAF(V600E) mutation status in patients with papillary thyroid cancer (PTC) and to determine their combined association with tumor aggressiveness in PTC. A total of 1780 patients with PTC who underwent surgery were enrolled in this study. Simple and multiple analyses were performed to determine the association between Hashimoto's thyroiditis and the BRAF(V600E) mutation in PTC. Hashimoto's thyroiditis was present in 11.5% of patients (204/1780) with PTC. Multiple logistic regressions showed that BRAF(V600E) (odds ratio [OR] = 0.493; 95% confidence interval [CI] = 0.360-0.678) and the female sex (OR = 7.146; 95% CI = 3.408-18.347) were independent factors associated with Hashimoto's thyroiditis in PTC. BRAF(V600E) mutation and the Hashimoto's thyroiditis-negative PTC group were associated with aggressive disease (OR = 3.069; 95% CI = 1.654-5.916). Hashimoto's thyroiditis was associated less frequently with BRAF(V600E) , and frequently with the female sex in patients with PTC. Hashimoto's thyroiditis and BRAF(V600E) status may help to predict clinical outcome of PTC. © 2015 Wiley Periodicals, Inc.

  3. Changes of thyroid hormonal status in patients receiving ketogenic diet due to intractable epilepsy.

    PubMed

    Kose, Engin; Guzel, Orkide; Demir, Korcan; Arslan, Nur

    2017-04-01

    Ketogenic diet (KD), which is high in fat and low in carbohydrates, mimics the metabolic state of starvation and is used therapeutically for pharmacoresistant epilepsy. It is known that generation of triiodothyronine (T3) from thyroxine (T4) decreases during fasting periods. The aim of this study was to evaluate the thyroid function of children receiving KD for at least 1 year due to drug-resistant epilepsy. A total of 120 patients [63 males, 52.5%; mean age 7.3±4.3 years, median interquartile range (IQR): 7.0 (4-10 years)] treated with KD for at least 1 year were enrolled. Seizure control, side effects, and compliance with the diet were recorded, and free T3, free T4, and thyroid-stimulating hormone (TSH) levels were measured at baseline and at post-treatment months 1, 3, 6, and 12. The Mann-Whitney U-test, repeated measures analysis of variance (ANOVA) with post-hoc Bonferroni correction, and logistic regression analysis were used for data analysis. Hypothyroidism was diagnosed and L-thyroxine medication was initiated for eight, seven and five patients (20 patients in total, 16.7%) at 1, 3, and 6 months of KD therapy, respectively. Logistic regression analysis showed that baseline TSH elevation [odds ratio (OR): 26.91, 95% confidence interval (CI) 6.48-111.76, p<0.001] and female gender (OR: 3.69, 95% CI 1.05-12.97, p=0.042) were independent risk factors for development of hypothyroidism during KD treatment in epileptic children. KD causes thyroid malfunction and L-thyroxine treatment may be required. This is the first report documenting the effect of KD treatment on thyroid function. Thyroid function should be monitored regularly in epileptic patients treated with KD.

  4. Cervical mucus characteristics and hormonal status at insemination of Holstein cows

    PubMed Central

    Bernardi, S.; Rinaudo, A.; Marini, P.

    2016-01-01

    The present study was carried out to characterize the cervical mucus (CM) collected when inseminating Holstein cows and to relate the secretion pattern with pregnancy. The mucus was collected from mid-cervix of 64 cows with spontaneus estrus (SE) and induced estrus (IE). The quantity, pattern and consistency of the mucus, pH, arborization patterns and the sperm motility were observed. The levels of progesterone and estradiol 17β in serum were also determined. Pregnancy detection was performed by means of transrectal ultrasonography 60 days after insemination. Mucous secretion of cows with SE was significantly different from those with IE, showing a lower degree of crystallization (SE 2.00; IE 2.75) and a lower level of steroid hormones (P4: SE 0.17 ng/ml and IE 0.33 ng/ml (t 1.99547 α 0.05); E2: SE 30.95 pg/ml and IE 47.76 pg/ml (t 1.99495 α 0.05). Progesterone level was significantly lower and estrogen significantly higher in pregnant cows (P) in relation to that observed in non pregnant females (N) (P4: P 0.20 ng/ml and N 0.44 ng/ml (t 1.99602 α 0.05); E2: P 54.77 pg/ml and N 40.75 pg/ml (t 1.99505 α 0.05). In conclusion pregnancy was associated with acopious, clear and watery discharge (similar to egg white), with an arborization degree of 2.25, presence of atypical fern leaves together with rosette formations and needles or thorns on rails due to low levels of progesterone accompanied by high concentrations of estrogens. PMID:27656229

  5. Bone turnover and mineral density in adult thalassemic patients: relationships with growth hormone secretory status and circulating somatomedins.

    PubMed

    Scacchi, Massimo; Danesi, Leila; Cattaneo, Agnese; Sciortino, Giovanna; Radin, Raffaella; Ambrogio, Alberto Giacinto; Vitale, Giovanni; D'Angelo, Emanuela; Mirra, Nadia; Zanaboni, Laura; Arvigo, Marica; Boschetti, Mara; Ferone, Diego; Marzullo, Paolo; Baldini, Marina; Cassinerio, Elena; Cappellini, Maria Domenica; Persani, Luca; Cavagnini, Francesco

    2016-08-01

    Previous evidence supports a role for growth hormone (GH)-insulin-like growth factor (IGF)-I deficiency in the pathophysiology of osteopenia/osteoporosis in adult thalassemia. Moreover, serum IGF-II has never been studied in this clinical condition. Thus, we elected to study the GH secretory status and the levels of circulating somatomedins, correlating these parameters with bone mineral density (BMD) and biochemical markers of bone turnover. A hundred and thirty-nine normal weight adult thalassemic patients (72 men and 67 women) were studied. Lumbar and femoral neck BMD were measured in 106/139 patients. Sixty-eight patients underwent growth hormone releasing hormone plus arginine testing. Measurement of baseline IGF-I and IGF-II was performed in all patients, while osteocalcin, C-terminal telopeptide of type I collagen (CTx), and urinary cross-linked N-telopeptides of type I collagen (NTx) were assayed in 95 of them. Femoral and lumbar osteoporosis/Z score below the expected range for age were documented in 61.3 and in 56.6 % of patients, respectively. Severe GH deficiency (GHD) was demonstrated in 27.9 % of cases, whereas IGF-I SDS was low in 86.3 %. No thalassemic patients displayed circulating levels of IGF-II below the reference range. GH peaks were positively correlated with femoral, but not lumbar, Z score. No correlations were found between GH peaks and osteocalcin, CTx and NTx. GH peaks were positively correlated with IGF-I values, which in their turn displayed a positive correlation with osteocalcin, CTx, and NTx. No correlations emerged between IGF-I values and either femoral or lumbar Z scores. No correlations were found between IGF-II and any of the following parameters: GH peaks, osteocalcin, CTx, NTx, femoral Z score, and lumbar Z score. Our study, besides providing for the first time evidence of a normal IGF-II production in thalassemia, contributes to a better understanding of the involvement of the somatotropin-somatomedin axis in the

  6. [The effect of the dioxin-containing herbicide 2,4-D on the hormonal status of experimental animals].

    PubMed

    Gil'manov, A Zh; Galimov, Sh N; Kamilov, F Kh; Davletov, E G; Shchepanskiĭ, V O

    1997-01-01

    The article presents studies of hormonal state in rats under daily or 20-day peroral administration of variable doses of 2,4-D herbicide containing dioxine. Changed levels of thyroid hormones, insulin, cortisol, testosterone and estradiol appeared to be divergent and dose-dependent, proving direct toxic effects of the herbicide in endocrine organs, altered hormonal effects in target organs and disorders of peripheral hormonal metabolism.

  7. Novel mutation in the gonadotropin-releasing hormone receptor (GNRHR) gene in a patient with normosmic isolated hypogonadotropic hypogonadism.

    PubMed

    Beneduzzi, Daiane; Trarbach, Ericka B; Latronico, Ana Claudia; Mendonca, Berenice Bilharinho de; Silveira, Letícia F G

    2012-11-01

    We report a novel GNRHR mutation in a male with normosmic isolated hypogonadotropic hypogonadism (nIHH). The coding region of the GNRHR gene was amplified and sequenced. Three variants p.[Asn10Lys;Gln11Lys]; [Tyr283His] were identified in the GNRHR coding region in a male with sporadic complete nIHH. The three variants were absent in the controls (130 normal adults). Familial segregation showed that the previously described p.Asn10Lys and p.Gln11Lys are in the same allele, in compound heterozygozity with the novel variant p.Tyr283His. The p.[Asn10Lys;Gln11Lys] are known inactivating mutations. The p.Tyr283His affects a well-conserved residue, and in silico analysis suggested it is a deleterious variant. We describe a novel GNRHR mutation in a male with nIHH. Absence of the mutation in the control group, conservation among species, in silico analysis, and familial segregation suggest that p.Tyr283His, which was identified in compound heterozygozity with the p.[Asn10Lys;Gln11Lys] variants, is an inactivating mutation.

  8. K-Ras gene mutation status as a prognostic and predictive factor in patients with colorectal cancer undergoing irinotecan- or oxaliplatin-based chemotherapy

    PubMed Central

    Stec, Rafał; Bodnar, Lubomir; Charkiewicz, Radosław; Korniluk, Jan; Rokita, Marta; Smoter, Marta; Ciechowicz, Marzena; Chyczewski, Lech; Nikliński, Jacek; Kozłowski, Wojciech; Szczylik, Cezary

    2012-01-01

    Background: CRC caused more than 600,000 estimated deaths in 2008. Dysregulated signaling through the RAS/RAF/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway due to mutations in K-Ras and B-Raf are common events in CRC. Methods: Incidence of mutations in codons 12 and 13 of K-Ras and exons 11 and 15 of B-Raf were analyzed in amplified PCR products from primary tumors of 273 patients with CRC, and their prognostic and predictive significance was assessed. The prognostic role of clinical and pathological factors was also examined. Results: K-Ras mutations were present in 89 patients (32.6%), of whom 76 (85.4%) had mutations in codon 12 and 10 (11.2%) had mutations in codon 13. B-Raf gene mutations were present in 17 patients (6.9%), of whom 6 (35.3%) had mutations in exon 15. Multivariate analysis revealed a predictive significance for K-Ras mutations with respect to time to progression in patients treated with irinotecan and oxaliplatin as first-line chemotherapy. There was no predictive significance for B-Raf gene mutation status in these patients. The following risk factors were found to affect overall survival (OS) rates: primary tumor location, lymph node involvement grade, carcinoembryonic antigen (CEA) level before treatment, and performance status according to WHO criteria. Conclusions: Based on the results of this study, K-Ras mutation status may be a suitable indicator of patient eligibility and a prognostic indicator for responsiveness to anti-EGFR therapy alone, or in combination with chemotherapy. Also, K-Ras mutation status may predict time to progression in patients treated with irinotecan and oxaliplatin. PMID:22909976

  9. MAX mutations status in Swedish patients with pheochromocytoma and paraganglioma tumours.

    PubMed

    Crona, Joakim; Maharjan, Rajani; Delgado Verdugo, Alberto; Stålberg, Peter; Granberg, Dan; Hellman, Per; Björklund, Peyman

    2014-03-01

    Pheochromocytoma (PCC) and Paraganglioma are rare tumours originating from neuroendocrine cells. Up to 60% of cases have either germline or somatic mutation in one of eleven described susceptibility loci, SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, EPAS1, RET, NF1, TMEM127 and MYC associated factor-X (MAX). Recently, germline mutations in MAX were found to confer susceptibility to PCC and paraganglioma (PGL). A subsequent multicentre study found about 1% of PCCs and PGLs to have germline or somatic mutations in MAX. However, there has been no study investigating the frequency of MAX mutations in a Scandinavian cohort. We analysed tumour specimens from 63 patients with PCC and PGL treated at Uppsala University hospital, Sweden, for re-sequencing of MAX using automated Sanger sequencing. Our results show that 0% (0/63) of tumours had mutations in MAX. Allele frequencies of known single nucleotide polymorphisms rs4902359, rs45440292, rs1957948 and rs1957949 corresponded to those available in the Single Nucleotide Polymorphism Database. We conclude that MAX mutations remain unusual events and targeted genetic screening should be considered after more common genetic events have been excluded.

  10. Vitamin D and parathyroid hormone status in a representative population living in Macau, China.

    PubMed

    Ke, L; Mason, R S; Mpofu, E; Dibley, M; Li, Y; Brock, K E

    2015-04-01

    Associations between documented sun-exposure, exercise patterns and fish and supplement intake and 25-hydroxyvitamin D (25OHD) and parathyroid hormone (PTH) were investigated in a random household survey of Macau residents (aged 18-93). Blood samples (566) taken in summer were analyzed for 25OHD and PTH. In this Chinese population, 55% were deficient (25OHD <50nmol/L: median (interquartile range)=47.7 (24.2) nmol/L). Vitamin D deficiency was greatest in those aged <50 years: median (interquartile range)=43.3 (18.2) nmol/L, females: median (interquartile range)=45.5 (19.4) nmol/L and those with higher educational qualifications: median (interquartile range)=43.1 (18.7) nmol/L. In the total Macau population, statistically significant (p<0.01) modifiable associations with lower 25OHD levels were sunlight exposure (β=0.06), physical activity (PA) (measured as hours(hrs)/day: β=0.08), sitting (measured as hrs/day β=-0.20), intake of fish (β=0.08) and calcium (Ca) supplement intake (β=0.06) [linear regression analysis adjusting for demographic risk factors]. On similar analysis, and after adjustment for 25OHD, the only significant modifiable associations in the total population with PTH were sitting (β=-0.17), Body Mass Index (β=0.07) and Ca supplement intake (β=-0.06). In this Macau population less documented sun exposure, fish and Ca supplement intake and exercise were associated with lower 25OHD levels, especially in the younger population, along with the interesting finding that more sitting was associated with both lower 25OHD and high PTH blood levels. In conclusion, unlike findings from Caucasian populations, younger participants were significantly more vitamin D deficient, in particular highly educated single females. This may indicate the desire of young females to be pale and avoid the sun. There are also big differences in lifestyle between the older generation and the younger, in particular with respect to sun exposure and PA. This article is part of

  11. [Thyroid hormone resistance syndromes].

    PubMed

    Bernal, Juan

    2011-04-01

    Thyroid hormone resistance syndromes are a group of genetic conditions characterized by decreased tissue sensitivity to thyroid hormones. Three syndromes, in which resistance to hormone action is respectively due to mutations in the gene encoding for thyroid hormone receptor TRβ, impaired T4 and T3 transport, and impaired conversion of T4 to T3 mediated by deiodinases. An updated review of each of these forms of resistance is provided, and their pathogenetic mechanisms and clinical approaches are discussed.

  12. Interaction between body mass index and hormone-receptor status as a prognostic factor in lymph-node-positive breast cancer

    PubMed Central

    Chung, Il Yong; Park, Yu Rang; Min, Yul Ha; Lee, Yura; Yoon, Tae In; Sohn, Guiyun; Lee, Sae Byul; Kim, Jisun; Kim, Hee Jeong; Ko, Beom Seok; Son, Byung Ho; Ahn, Sei Hyun

    2017-01-01

    The aim of this study was to determine the relationship between the body mass index (BMI) at a breast cancer diagnosis and various factors including the hormone-receptor, menopause, and lymph-node status, and identify if there is a specific patient subgroup for which the BMI has an effect on the breast cancer prognosis. We retrospectively analyzed the data of 8,742 patients with non-metastatic invasive breast cancer from the research database of Asan Medical Center. The overall survival (OS) and breast-cancer-specific survival (BCSS) outcomes were compared among BMI groups using the Kaplan-Meier method and Cox proportional-hazards regression models with an interaction term. There was a significant interaction between BMI and hormone-receptor status for the OS (P = 0.029), and BCSS (P = 0.013) in lymph-node-positive breast cancers. Obesity in hormone-receptor-positive breast cancer showed a poorer OS (adjusted hazard ratio [HR] = 1.51, 95% confidence interval [CI] = 0.92 to 2.48) and significantly poorer BCSS (HR = 1.80, 95% CI = 1.08 to 2.99). In contrast, a high BMI in hormone-receptor-negative breast cancer revealed a better OS (HR = 0.44, 95% CI = 0.16 to 1.19) and BCSS (HR = 0.53, 95% CI = 0.19 to 1.44). Being underweight (BMI < 18.50 kg/m2) with hormone-receptor-negative breast cancer was associated with a significantly worse OS (HR = 1.98, 95% CI = 1.00–3.95) and BCSS (HR = 2.24, 95% CI = 1.12–4.47). There was no significant interaction found between the BMI and hormone-receptor status in the lymph-node-negative setting, and BMI did not interact with the menopause status in any subgroup. In conclusion, BMI interacts with the hormone-receptor status in a lymph-node-positive setting, thereby playing a role in the prognosis of breast cancer. PMID:28248981

  13. A miniature condition in Brahman cattle is associated with a single nucleotide mutation within the growth hormone gene.

    PubMed

    McCormack, B L; Chase, C C; Olson, T A; Elsasser, T H; Hammond, A C; Welsh, T H; Jiang, H; Randel, R D; Okamura, C A; Lucy, M C

    2009-08-01

    Miniature Brahman cattle at the USDA ARS Subtropical Agriculture Research Station in Brooksville, FL have normal proportioned growth but are approximately 70% of mature height and weight when compared with Brahman cattle in the same herd. Pedigree analyses suggest that the condition is inherited through a recessive allele. The miniature Brahman cattle in the Brooksville herd have been used for studies of growth and reproduction, but the underlying causative mutation is unknown. Presumably, the miniature condition could arise from a mutation in the GH gene. The objective, therefore, was to clone the GH cDNA from Brooksville miniature Brahman cattle, compare its sequence to normal Brahman cattle, and test the biological activity of the native GH protein. Messenger RNA was isolated from the pituitary, and a cDNA for the protein coding region of the GH gene was amplified by reverse-transcription polymerase chain reaction (PCR) from each of 2 miniature Brahman bulls. The cDNA were cloned into plasmid vectors, and top and bottom strands were sequenced by automated DNA sequencing. The sequence of both cDNA clones derived from miniature cattle differed from Bos indicus GH (GenBank AF034386) at base number 641 because there was a cytosine (C) instead of a thymine (T). The C to T change encoded a mutation (threonine to methionine) at amino acid 200 (T200M mutation). The mutation was confirmed by sequencing of an additional 2 miniature cattle and comparing their sequence to 2 normal cattle. The threonine is located in the fourth alpha helix of GH and is 1 of 8 amino acids that participate in binding of GH to the GH receptor. Twelve miniature Brahman and 9 normal Brahman cattle were tested by using a restriction fragment length polymorphism analysis that employed the BsmBI restriction enzyme (specific for the mutated nucleotide). The 12 miniature Brahman cattle were homozygous for the mutation (-/-). Seven of the normal Brahman cattle were homozygous for the wild-type allele

  14. The EGFR mutation status affects the relative biological effectiveness of carbon-ion beams in non-small cell lung carcinoma cells.

    PubMed

    Amornwichet, Napapat; Oike, Takahiro; Shibata, Atsushi; Nirodi, Chaitanya S; Ogiwara, Hideaki; Makino, Haruhiko; Kimura, Yuka; Hirota, Yuka; Isono, Mayu; Yoshida, Yukari; Ohno, Tatsuya; Kohno, Takashi; Nakano, Takashi

    2015-06-11

    Carbon-ion radiotherapy (CIRT) holds promise to treat inoperable locally-advanced non-small cell lung carcinoma (NSCLC), a disease poorly controlled by standard chemoradiotherapy using X-rays. Since CIRT is an extremely limited medical resource, selection of NSCLC patients likely to benefit from it is important; however, biological predictors of response to CIRT are ill-defined. The present study investigated the association between the mutational status of EGFR and KRAS, driver genes frequently mutated in NSCLC, and the relative biological effectiveness (RBE) of carbon-ion beams over X-rays. The assessment of 15 NSCLC lines of different EGFR/KRAS mutational status and that of isogenic NSCLC lines expressing wild-type or mutant EGFR revealed that EGFR-mutant NSCLC cells, but not KRAS-mutant cells, show low RBE. This was attributable to (i) the high X-ray sensitivity of EGFR-mutant cells, since EGFR mutation is associated with a defect in non-homologous end joining, a major pathway for DNA double-strand break (DSB) repair, and (ii) the strong cell-killing effect of carbon-ion beams due to poor repair of carbon-ion beam-induced DSBs regardless of EGFR mutation status. These data highlight the potential of EGFR mutation status as a predictor of response to CIRT, i.e., CIRT may show a high therapeutic index in EGFR mutation-negative NSCLC.

  15. A combination of TERT promoter mutation and MGMT methylation status predicts clinically relevant subgroups of newly diagnosed glioblastomas.

    PubMed

    Arita, Hideyuki; Yamasaki, Kai; Matsushita, Yuko; Nakamura, Taishi; Shimokawa, Asanao; Takami, Hirokazu; Tanaka, Shota; Mukasa, Akitake; Shirahata, Mitsuaki; Shimizu, Saki; Suzuki, Kaori; Saito, Kuniaki; Kobayashi, Keiichi; Higuchi, Fumi; Uzuka, Takeo; Otani, Ryohei; Tamura, Kaoru; Sumita, Kazutaka; Ohno, Makoto; Miyakita, Yasuji; Kagawa, Naoki; Hashimoto, Naoya; Hatae, Ryusuke; Yoshimoto, Koji; Shinojima, Naoki; Nakamura, Hideo; Kanemura, Yonehiro; Okita, Yoshiko; Kinoshita, Manabu; Ishibashi, Kenichi; Shofuda, Tomoko; Kodama, Yoshinori; Mori, Kanji; Tomogane, Yusuke; Fukai, Junya; Fujita, Koji; Terakawa, Yuzo; Tsuyuguchi, Naohiro; Moriuchi, Shusuke; Nonaka, Masahiro; Suzuki, Hiroyoshi; Shibuya, Makoto; Maehara, Taketoshi; Saito, Nobuhito; Nagane, Motoo; Kawahara, Nobutaka; Ueki, Keisuke; Yoshimine, Toshiki; Miyaoka, Etsuo; Nishikawa, Ryo; Komori, Takashi; Narita, Yoshitaka; Ichimura, Koichi

    2016-08-08

    The prognostic impact of TERT mutations has been controversial in IDH-wild tumors, particularly in glioblastomas (GBM). The controversy may be attributable to presence of potential confounding factors such as MGMT methylation status or patients' treatment. This study aimed to evaluate the impact of TERT status on patient outcome in association with various factors in a large series of adult diffuse gliomas. We analyzed a total of 951 adult diffuse gliomas from two cohorts (Cohort 1, n = 758; Cohort 2, n = 193) for IDH1/2, 1p/19q, and TERT promoter status. The combined IDH/TERT classification divided Cohort 1 into four molecular groups with distinct outcomes. The overall survival (OS) was the shortest in IDH wild-type/TERT mutated groups, which mostly consisted of GBMs (P < 0.0001). To investigate the association between TERT mutations and MGMT methylation on survival of patients with GBM, samples from a combined cohort of 453 IDH-wild-type GBM cases treated with radiation and temozolomide were analyzed. A multivariate Cox regression model revealed that the interaction between TERT and MGMT was significant for OS (P = 0.0064). Compared with TERT mutant-MGMT unmethylated GBMs, the hazard ratio (HR) for OS incorporating the interaction was the lowest in the TERT mutant-MGMT methylated GBM (HR, 0.266), followed by the TERT wild-type-MGMT methylated (HR, 0.317) and the TERT wild-type-MGMT unmethylated GBMs (HR, 0.542). Thus, patients with TERT mutant-MGMT unmethylated GBM have the poorest prognosis. Our findings suggest that a combination of IDH, TERT, and MGMT refines the classification of grade II-IV diffuse gliomas.

  16. SDH Subunit Mutation Status in Saliva: Genetic Testing in Patients with Pheochromocytoma.

    PubMed

    Osinga, T E; Xekouki, P; Nambuba, J; Faucz, F R; de la Luz Sierra, M; Links, T P; Kema, I P; Adams, K; Stratakis, C A; van der Horst-Schrivers, A N A; Pacak, K

    2016-04-01

    Germline mutations occur in up to 30-40% of pheochromocytoma/paraganglioma, with mutations in the succinate dehydrogenase (SDH) subunits B (SDHB) and D (SDHD) being the most common. Blood samples are favored for obtaining high quality DNA, however, leukocytes can also be obtained by collecting saliva. The aim of this study was to determine whether SDHB and SDHD gene mutations in patients with pheochromocytoma/paraganglioma could be determined using a salivary sample. Paired blood and salivary samples were collected from 30 patients: 9 SDHB mutation positive, 13 with a SDHD mutation, and 8 without any SDHx mutations. The Oragene DISCOVER kit was used to collect and extract DNA from saliva. Blood DNA was extracted from EDTA blood samples. The DNA purification and concentration were measured by spectrophotometry. The 8 exons of SDHB and the 4 exons of SDHD were amplified and sequenced by PCR-based bidirectional Sanger sequencing. Total DNA yields from blood DNA were similar to those obtained from saliva DNA [mean (±SD) saliva vs. blood DNA concentration 514.6 (±580.8) ng/µl vs. 360.9 (±262.7) ng/µl; p=0.2)]. The purity of the saliva DNA samples was lower than that of blood [mean OD260/OD280 ratio 1.78 (±0.13) vs. 1.87 (±0.04); p=0.001, respectively], indicating more protein contamination in the saliva-extracted DNA. This study shows that salivary DNA collected from patients with pheochromocytoma/paraganglioma is a good alternative for extraction of genomic DNA for its high DNA concentration and acceptable purity and can be used as an alternative to blood derived DNA in screening for SDHB and SDHD mutations.

  17. The Relationship between "MECP2" Mutation Type and Health Status and Service Use Trajectories over Time in a Rett Syndrome Population

    ERIC Educational Resources Information Center

    Young, Deidra; Bebbington, Ami; de Klerk, Nick; Bower, Carol; Nagarajan, Lakshmi; Leonard, Helen

    2011-01-01

    This study aimed to investigate the trajectories over time of health status and health service use in Rett syndrome by mutation type. Data were obtained from questionnaires administered over 6 years to 256 participants from the Australian Rett Syndrome Database. Health status (episodes of illness and medication load) and health service use…

  18. The Relationship between "MECP2" Mutation Type and Health Status and Service Use Trajectories over Time in a Rett Syndrome Population

    ERIC Educational Resources Information Center

    Young, Deidra; Bebbington, Ami; de Klerk, Nick; Bower, Carol; Nagarajan, Lakshmi; Leonard, Helen

    2011-01-01

    This study aimed to investigate the trajectories over time of health status and health service use in Rett syndrome by mutation type. Data were obtained from questionnaires administered over 6 years to 256 participants from the Australian Rett Syndrome Database. Health status (episodes of illness and medication load) and health service use…

  19. Adjuvant Trastuzumab in HER2-Positive Early Breast Cancer by Age and Hormone Receptor Status: A Cost-Utility Analysis.

    PubMed

    Leung, William; Kvizhinadze, Giorgi; Nair, Nisha; Blakely, Tony

    2016-08-01

    -effect data by hormone receptor subtype. Heterogeneity was restricted to age and hormone receptor status; tumour size/grade heterogeneity could be explored in future work. This study highlights how cost-effectiveness can vary greatly by heterogeneity in age and hormone receptor subtype. Resource allocation and licensing of subsidised therapies such as trastuzumab should consider demographic and clinical heterogeneity; there is currently a profound disconnect between how funding decisions are made (largely agnostic to heterogeneity) and the principles of personalised medicine.

  20. Adjuvant Trastuzumab in HER2-Positive Early Breast Cancer by Age and Hormone Receptor Status: A Cost-Utility Analysis

    PubMed Central

    Leung, William; Kvizhinadze, Giorgi; Nair, Nisha; Blakely, Tony

    2016-01-01

    the same result. A key limitation was a lack of treatment-effect data by hormone receptor subtype. Heterogeneity was restricted to age and hormone receptor status; tumour size/grade heterogeneity could be explored in future work. Conclusions This study highlights how cost-effectiveness can vary greatly by heterogeneity in age and hormone receptor subtype. Resource allocation and licensing of subsidised therapies such as trastuzumab should consider demographic and clinical heterogeneity; there is currently a profound disconnect between how funding decisions are made (largely agnostic to heterogeneity) and the principles of personalised medicine. PMID:27504960

  1. Tumour mutation status and sites of metastasis in patients with cutaneous melanoma.

    PubMed

    Adler, Nikki R; Wolfe, Rory; Kelly, John W; Haydon, Andrew; McArthur, Grant A; McLean, Catriona A; Mar, Victoria J

    2017-09-26

    Cutaneous melanoma can metastasise haematogenously and/or lymphogenously to form satellite/in-transit, lymph node or distant metastasis. This study aimed to determine if BRAF and NRAS mutant and wild-type tumours differ in their site of first tumour metastasis and anatomical metastatic pathway. Prospective cohort of patients with a histologically confirmed primary cutaneous melanoma at three tertiary referral centres in Melbourne, Australia from 2010 to 2015. Multinomial regression determined clinical, histological and mutational factors associated with the site of first metastasis and metastatic pathway. Of 1048 patients, 306 (29%) developed metastasis over a median 4.7 year follow-up period. 73 (24%), 192 (63%) and 41 (13%) developed distant, regional lymph node and satellite/in-transit metastasis as the first site of metastasis, respectively. BRAF mutation was associated with lymph node metastasis (adjusted RRR 2.46 95% CI 1.07-5.69, P=0.04) and sentinel lymph node positivity (adjusted odds ratio [aOR] OR 1.55, 95% CI 1.14-2.10, P=0.005). BRAF mutation and NRAS mutation were associated with increased odds of developing liver metastasis (aOR 3.09, 95% CI 1.49-6.42, P=0.003; aOR 3.17, 95% CI 1.32-7.58, P=0.01) and central nervous system (CNS) metastasis (aOR 4.65, 95% CI 2.23-9.69, P<0.001; aOR 4.03, 95% CI 1.72-9.44, P=0.001). NRAS mutation was associated with lung metastasis (aOR 2.44, 95% CI 1.21-4.93, P=0.01). BRAF mutation was found to be associated with lymph node metastasis as first metastasis and sentinel lymph node positivity. BRAF and NRAS mutations were associated with CNS and liver metastasis and NRAS mutation with lung metastasis. If these findings are validated in additional prospective studies, a role for heightened visceral organ surveillance may be warranted in patients with tumours harbouring these somatic mutations.

  2. Growth hormone therapy-related hyperglycaemia in a boy with renal cystic hypodysplasia and a new mutation of the HNF1 beta gene.

    PubMed

    Giglio, Sabrina; Contini, Elisa; Toni, Sonia; Pela, Ivana

    2010-09-01

    We provide a molecular and pathophysiological characterization of an 11-year-old male patient, with a diagnosis of renal hypodysplasia, cysts and chronic renal failure. Although previously normoglycaemic and with a negative familial history for diabetes mellitus, he developed fasting hyperglycaemia within 12 months of the start of treatment with recombinant human growth hormone (rhGH). Direct sequencing of the HNF1 beta gene revealed a de novo heterozygous mutation in exon 2, c.535delC [Pro118LeuX7]+[=]. The appearance of fasting hyperglycaemia following rhGH treatment in children with renal cystic hypodysplasia suggests that investigation of the HNF1 beta gene is warranted, even when familial history is negative for diabetes. This is particularly important in regard to genetic counselling.

  3. An activating mutation of the follicle-stimulating hormone receptor autonomously sustains spermatogenesis in a hypophysectomized man

    SciTech Connect

    Gromoll, J.; Simoni, M.; Nieschlag, E.

    1996-04-01

    As both gonadotropins, LH and FSH, are required for normal spermatogenesis, patients with pituitary insufficiency need hCG plus human menopausal gonadotropin therapy to induce spermatogenesis and establish fertility. In a patient hypophysectomized because of a pituitary tumor, who, despite undetectable serum gonadotropin levels, had normal testis volume and semen parameters and fathered three children under testosterone substitution alone, we hypothesized an activating mutation of the FSH receptor. Exon 10 of the FSH receptor gene was amplified from genomic DNA by PCR, screened by single stranded conformation polymorphism gel electrophoresis, and sequenced. We identified a heterozygous A{r_arrow}G base change at nucleotide position 1700, leading to an Asp,Gly transition in codon 567 in the third intracytoplasmatic loop. COS-7 cells transiently transfected with the mutated receptor displayed a 1.5-fold increase in basal cAMP production compared to wild-type receptor, indicating that this mutation leads to ligand-independent constitutive activation of the FSH receptor. We conclude that this activating mutation of the FSH receptor, the first ever described, autonomously sustains spermatogenesis in the absence of gonadotropins. 31 refs., 5 figs., 1 tab.

  4. Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: implications for classification of gliomas.

    PubMed

    Hartmann, Christian; Hentschel, Bettina; Wick, Wolfgang; Capper, David; Felsberg, Jörg; Simon, Matthias; Westphal, Manfred; Schackert, Gabriele; Meyermann, Richard; Pietsch, Torsten; Reifenberger, Guido; Weller, Michael; Loeffler, Markus; von Deimling, Andreas

    2010-12-01

    WHO grading of human brain tumors extends beyond a strictly histological grading system by providing a basis predictive for the clinical behavior of the respective neoplasm. For example, patients with glioblastoma WHO grade IV usually show a less favorable clinical course and receive more aggressive first-line treatment than patients with anaplastic astrocytoma WHO grade III. Here we provide evidence that the IDH1 status is more prognostic for overall survival than standard histological criteria that differentiate high-grade astrocytomas. We sequenced the isocitrate dehydrogenase 1 gene (IDH1) at codon 132 in 382 patients with anaplastic astrocytoma and glioblastoma from the NOA-04 trial and from a prospective translational cohort study of the German Glioma Network. Patients with anaplastic astrocytomas carried IDH1 mutations in 60%, and patients with glioblastomas in 7.2%. IDH1 was the most prominent single prognostic factor (RR 2.7; 95% CI 1.6-4.5) followed by age, diagnosis and MGMT. The sequence from more favorable to poorer outcome was (1) anaplastic astrocytoma with IDH1 mutation, (2) glioblastoma with IDH1 mutation, (3) anaplastic astrocytoma without IDH1 mutation and (4) glioblastoma without IDH1 mutation (p < 0.0001). In this combined set of anaplastic astrocytomas and glioblastomas both, IDH1 mutation and IDH1 expression status were of greater prognostic relevance than histological diagnosis according to the current WHO classification system. Our data indicate that much of the prognostic significance of patient age is due to the predominant occurrence of IDH1 mutations in younger patients. Immunohistochemistry using a mutation-specific antibody recognizing the R132H mutation yielded similar results. We propose to complement the current WHO classification and grading of high-grade astrocytic gliomas by the IDH1 mutation status and to use this combined histological and molecular classification in future clinical trials.

  5. Trends in 5-year survival rates among breast cancer patients by hormone receptor status and stage

    PubMed Central

    Chen, Lu; Linden, Hannah M.; Anderson, Benjamin O.; Li, Christopher I.

    2014-01-01

    Purpose Improvement in breast cancer survival has been observed in recent decades in the U.S., but it is unclear if similar survival gains are consistent across breast cancer subtypes, especially with regards to more advanced stages of the disease. Methods Data were from 13 population-based cancer registries participating in the Surveillance, Epidemiology and End Results (SEER) program, consisting of women between 20–79 years of age diagnosed with invasive breast cancer between 1992 and 2008. 2-year (1992–2008) and 5-year (1992–2006) breast cancer cause-specific survival rates were calculated and stratified by estrogen receptor (ER)/progesterone receptor (PR) status, stage and race. Annual percent changes in survival rates were assessed. Results From 1992 through 1998–1999, 5-year and 2-year cause specific survival rates significantly improved across ER+/PR+, ER−/PR− and ER+/PR− subtypes, with an annual increase ranging from 0.5%–1.0%. From 1998–1999 to 2006, different patterns were observed by ER/PR subtypes with survival rates slightly improving for ER+/PR+, continuing to improve at a rate of 0.5% per year for ER−/PR−, and dropping 0.3% annually for ER+/PR− No significant survival gains were experienced by patients with ER−/PR+ cancer during the study period. In terms of advanced diseases, greatest annual increases in survival rates were seen for patients with stage III–IV ER+/PR+ and ER−/PR− tumors but less progress was observed for advanced ER+/PR− breast cancers. Conclusion Steady improvements in survival rates for breast cancer have been achieved over the past several decades. However, 5-year survival rates for stage IV disease remained dismally below 20% for most ER/PR subtypes. PMID:25164974

  6. Correlation of EGFR or KRAS mutation status with 18F-FDG uptake on PET-CT scan in lung adenocarcinoma.

    PubMed

    Takamochi, Kazuya; Mogushi, Kaoru; Kawaji, Hideya; Imashimizu, Kota; Fukui, Mariko; Oh, Shiaki; Itoh, Masayoshi; Hayashizaki, Yoshihide; Ko, Weijey; Akeboshi, Masao; Suzuki, Kenji

    2017-01-01

    18F-fluoro-2-deoxy-glucose (18F-FDG) positron emission tomography (PET) is a functional imaging modality based on glucose metabolism. The correlation between EGFR or KRAS mutation status and the standardized uptake value (SUV) of 18F-FDG PET scanning has not been fully elucidated. Correlations between EGFR or KRAS mutation status and clinicopathological factors including SUVmax were statistically analyzed in 734 surgically resected lung adenocarcinoma patients. Molecular causal relationships between EGFR or KRAS mutation status and glucose metabolism were then elucidated in 62 lung adenocarcinomas using cap analysis of gene expression (CAGE), a method to determine and quantify the transcription initiation activities of mRNA across the genome. EGFR and KRAS mutations were detected in 334 (46%) and 83 (11%) of the 734 lung adenocarcinomas, respectively. The remaining 317 (43%) patients had wild-type tumors for both genes. EGFR mutations were more frequent in tumors with lower SUVmax. In contrast, no relationship was noted between KRAS mutation status and SUVmax. CAGE revealed that 4 genes associated with glucose metabolism (GPI, G6PD, PKM2, and GAPDH) and 5 associated with the cell cycle (ANLN, PTTG1, CIT, KPNA2, and CDC25A) were positively correlated with SUVmax, although expression levels were lower in EGFR-mutated than in wild-type tumors. No similar relationships were noted with KRAS mutations. EGFR-mutated adenocarcinomas are biologically indolent with potentially lower levels of glucose metabolism than wild-type tumors. Several genes associated with glucose metabolism and the cell cycle were specifically down-regulated in EGFR-mutated adenocarcinomas.

  7. Functional Assessment of Residues in the Amino- and Carboxyl-Termini of Crustacean Hyperglycemic Hormone (CHH) in the Mud Crab Scylla olivacea Using Point-Mutated Peptides

    PubMed Central

    Liu, Chun-Jing; Huang, Shiau-Shan; Toullec, Jean-Yves; Chang, Cheng-Yen; Chen, Yun-Ru; Huang, Wen-San; Lee, Chi-Ying

    2015-01-01

    To assess functional importance of the residues in the amino- and carboxyl-termini of crustacean hyperglycemic hormone in the mud crab Scylla olivacea (Sco-CHH), both wild-type and point-mutated CHH peptides were produced with an amidated C-terminal end. Spectral analyses of circular dichroism, chromatographic retention time, and mass spectrometric analysis of the recombinant peptides indicate that they were close in conformation to native CHH and were produced with the intended substitutions. The recombinant peptides were subsequently used for an in vivo hyperglycemic assay. Two mutants (R13A and I69A rSco-CHH) completely lacked hyperglycemic activity, with temporal profiles similar to that of vehicle control. Temporal profiles of hyperglycemic responses elicited by 4 mutants (I2A, F3A, D12A, and D60A Sco-CHH) were different from that elicited by wild-type Sco-CHH; I2A was unique in that it exhibited significantly higher hyperglycemic activity, whereas the remaining 3 mutants showed lower activity. Four mutants (D4A, Q51A, E54A, and V72A rSco-CHH) elicited hyperglycemic responses with temporal profiles similar to those evoked by wild-type Sco-CHH. In contrast, the glycine-extended version of V72A rSco-CHH (V72A rSco-CHH-Gly) completely lost hyperglycemic activity. By comparing our study with previous ones of ion-transport peptide (ITP) and molt-inhibiting hormone (MIH) using deleted or point-mutated mutants, detail discussion is made regarding functionally important residues that are shared by both CHH and ITP (members of Group I of the CHH family), and those that discriminate CHH from ITP, and Group-I from Group-II peptides. Conclusions summarized in the present study provide insights into understanding of how functional diversification occurred within a peptide family of multifunctional members. PMID:26261986

  8. Functional Assessment of Residues in the Amino- and Carboxyl-Termini of Crustacean Hyperglycemic Hormone (CHH) in the Mud Crab Scylla olivacea Using Point-Mutated Peptides.

    PubMed

    Liu, Chun-Jing; Huang, Shiau-Shan; Toullec, Jean-Yves; Chang, Cheng-Yen; Chen, Yun-Ru; Huang, Wen-San; Lee, Chi-Ying

    2015-01-01

    To assess functional importance of the residues in the amino- and carboxyl-termini of crustacean hyperglycemic hormone in the mud crab Scylla olivacea (Sco-CHH), both wild-type and point-mutated CHH peptides were produced with an amidated C-terminal end. Spectral analyses of circular dichroism, chromatographic retention time, and mass spectrometric analysis of the recombinant peptides indicate that they were close in conformation to native CHH and were produced with the intended substitutions. The recombinant peptides were subsequently used for an in vivo hyperglycemic assay. Two mutants (R13A and I69A rSco-CHH) completely lacked hyperglycemic activity, with temporal profiles similar to that of vehicle control. Temporal profiles of hyperglycemic responses elicited by 4 mutants (I2A, F3A, D12A, and D60A Sco-CHH) were different from that elicited by wild-type Sco-CHH; I2A was unique in that it exhibited significantly higher hyperglycemic activity, whereas the remaining 3 mutants showed lower activity. Four mutants (D4A, Q51A, E54A, and V72A rSco-CHH) elicited hyperglycemic responses with temporal profiles similar to those evoked by wild-type Sco-CHH. In contrast, the glycine-extended version of V72A rSco-CHH (V72A rSco-CHH-Gly) completely lost hyperglycemic activity. By comparing our study with previous ones of ion-transport peptide (ITP) and molt-inhibiting hormone (MIH) using deleted or point-mutated mutants, detail discussion is made regarding functionally important residues that are shared by both CHH and ITP (members of Group I of the CHH family), and those that discriminate CHH from ITP, and Group-I from Group-II peptides. Conclusions summarized in the present study provide insights into understanding of how functional diversification occurred within a peptide family of multifunctional members.

  9. Germline MC1R status influences somatic mutation burden in melanoma

    PubMed Central

    Robles-Espinoza, Carla Daniela; Roberts, Nicola D.; Chen, Shuyang; Leacy, Finbarr P.; Alexandrov, Ludmil B.; Pornputtapong, Natapol; Halaban, Ruth; Krauthammer, Michael; Cui, Rutao; Timothy Bishop, D.; Adams, David J.

    2016-01-01

    The major genetic determinants of cutaneous melanoma risk in the general population are disruptive variants (R alleles) in the melanocortin 1 receptor (MC1R) gene. These alleles are also linked to red hair, freckling, and sun sensitivity, all of which are known melanoma phenotypic risk factors. Here we report that in melanomas and for somatic C>T mutations, a signature linked to sun exposure, the expected single-nucleotide variant count associated with the presence of an R allele is estimated to be 42% (95% CI, 15–76%) higher than that among persons without an R allele. This figure is comparable to the expected mutational burden associated with an additional 21 years of age. We also find significant and similar enrichment of non-C>T mutation classes supporting a role for additional mutagenic processes in melanoma development in individuals carrying R alleles. PMID:27403562

  10. Germline MC1R status influences somatic mutation burden in melanoma.

    PubMed

    Robles-Espinoza, Carla Daniela; Roberts, Nicola D; Chen, Shuyang; Leacy, Finbarr P; Alexandrov, Ludmil B; Pornputtapong, Natapol; Halaban, Ruth; Krauthammer, Michael; Cui, Rutao; Timothy Bishop, D; Adams, David J

    2016-07-12

    The major genetic determinants of cutaneous melanoma risk in the general population are disruptive variants (R alleles) in the melanocortin 1 receptor (MC1R) gene. These alleles are also linked to red hair, freckling, and sun sensitivity, all of which are known melanoma phenotypic risk factors. Here we report that in melanomas and for somatic C>T mutations, a signature linked to sun exposure, the expected single-nucleotide variant count associated with the presence of an R allele is estimated to be 42% (95% CI, 15-76%) higher than that among persons without an R allele. This figure is comparable to the expected mutational burden associated with an additional 21 years of age. We also find significant and similar enrichment of non-C>T mutation classes supporting a role for additional mutagenic processes in melanoma development in individuals carrying R alleles.

  11. The Bioenergetic Status Relates to Dopamine Neuron Loss in Familial PD with PINK1 Mutations

    PubMed Central

    Hilker, Rüediger; Pilatus, Ulrich; Eggers, Carsten; Hagenah, Johann; Roggendorf, Julia; Baudrexel, Simon; Klein, Johannes C.; Neumaier, Bernd; Fink, Gereon R.; Steinmetz, Helmuth; Klein, Christine; Hattingen, Elke

    2012-01-01

    Mutations in the PINK1 gene cause autosomal recessive familial Parkinson’s disease (PD). The gene encodes a mitochondrial protein kinase that plays an important role in maintaining mitochondrial function and integrity. However, the pathophysiological link between mutation-related bioenergetic deficits and the degenerative process in dopaminergic neurons remains to be elucidated. We performed phosphorous (31P) and proton (1H) 3-T magnetic resonance spectroscopic imaging (MRSI) in 11 members of a German family with hereditary PD due to PINK1 mutations (PARK6) compared to 23 age-matched controls. All family members had prior 18-Fluorodopa (FDOPA) positron emission tomography (PET). The striatal FDOPA uptake was correlated with quantified metabolic brain mapping in MRSI. At group level, the heterozygous PINK1 mutation carriers did not show any MRSI abnormalities relative to controls. In contrast, homozygous individuals with manifest PD had putaminal GPC, PCr, HEP and β-ATP levels well above the 2SD range of controls. Across all subjects, the FDOPA Ki values correlated positively with MI (r = 0.879, p<0.001) and inversely with β-ATP (r = −0.784, p = 0.008) and GPC concentrations (r = −0.651, p = 0.030) in the putamen. Our combined imaging data suggest that the dopaminergic deficit in this family with PD due to PINK1 mutations relates to osmolyte dysregulation, while the delivery of high energy phosphates was preserved. Our results corroborate the hypothesis that PINK1 mutations result in reduced neuronal survival, most likely due to impaired cellular stress resistance. PMID:23251494

  12. The bioenergetic status relates to dopamine neuron loss in familial PD with PINK1 mutations.

    PubMed

    Hilker, Rüediger; Pilatus, Ulrich; Eggers, Carsten; Hagenah, Johann; Roggendorf, Julia; Baudrexel, Simon; Klein, Johannes C; Neumaier, Bernd; Fink, Gereon R; Steinmetz, Helmuth; Klein, Christine; Hattingen, Elke

    2012-01-01

    Mutations in the PINK1 gene cause autosomal recessive familial Parkinson's disease (PD). The gene encodes a mitochondrial protein kinase that plays an important role in maintaining mitochondrial function and integrity. However, the pathophysiological link between mutation-related bioenergetic deficits and the degenerative process in dopaminergic neurons remains to be elucidated. We performed phosphorous ((31)P) and proton ((1)H) 3-T magnetic resonance spectroscopic imaging (MRSI) in 11 members of a German family with hereditary PD due to PINK1 mutations (PARK6) compared to 23 age-matched controls. All family members had prior 18-Fluorodopa (FDOPA) positron emission tomography (PET). The striatal FDOPA uptake was correlated with quantified metabolic brain mapping in MRSI. At group level, the heterozygous PINK1 mutation carriers did not show any MRSI abnormalities relative to controls. In contrast, homozygous individuals with manifest PD had putaminal GPC, PCr, HEP and β-ATP levels well above the 2SD range of controls. Across all subjects, the FDOPA K(i) values correlated positively with MI (r = 0.879, p<0.001) and inversely with β-ATP (r = -0.784, p = 0.008) and GPC concentrations (r = -0.651, p = 0.030) in the putamen. Our combined imaging data suggest that the dopaminergic deficit in this family with PD due to PINK1 mutations relates to osmolyte dysregulation, while the delivery of high energy phosphates was preserved. Our results corroborate the hypothesis that PINK1 mutations result in reduced neuronal survival, most likely due to impaired cellular stress resistance.

  13. KRAS and BRAF mutations and MSI status in precursor lesions of colorectal cancer detected by colonoscopy.

    PubMed

    Yamane, L S; Scapulatempo-Neto, C; Alvarenga, L; Oliveira, C Z; Berardinelli, G N; Almodova, E; Cunha, T R; Fava, G; Colaiacovo, W; Melani, A; Fregnani, J H; Reis, R M; Guimarães, D P

    2014-10-01

    Colorectal cancer (CRC) is one of the most frequent cancers worldwide. Adenoma is the main precursor lesion and, recently, the serrated polyps were described as a group of colorectal lesions with malignant potential. The morphologic and biologic characterizations of serrated polyps remain limited. The aim of the present study was to determine the frequency of KRAS and BRAF mutations and microsatellite instability (MSI) in CRC precursor lesions, to evaluate the association between molecular, pathologic and morphologic alterations in precursor lesions and to compare with the alterations detected in CRC. A series of 342 precursor lesions were removed from 155 patients during colonoscopy. After morphologic classification, molecular analysis was performed in 103 precursor lesions, and their genetic profile compared with 47 sporadic CRCs. Adenomas were the main precursor lesions (70.2%). Among the serrated polyps, the main precursor lesion was hyperplastic polyps (HPs) (82.4%), followed by sessile serrated adenomas (12.7%) and traditional serrated adenomas (2.0%). KRAS mutations were detected in 13.6% of the precursor lesions, namely in adenomas and in HPs, but in no serrated adenoma. BRAF mutations were found in 9 (8.7%) precursor lesions, mainly associated with serrated polyps and absent in adenomas (P<0.001). High MSI (MSI-H) was absent in precursor lesions. In the 47 CCR cases, 46.8% exhibited KRAS mutation, 6.5% BRAF mutations and 10.6% MSI-H. This study confirms the role of KRAS and BRAF mutations in CRC carcinogenesis, a crucial step in implementing CRC screening strategies.

  14. Auxin synthesis gene tms1 driven by tuber-specific promoter alters hormonal status of transgenic potato plants and their responses to exogenous phytohormones.

    PubMed

    Kolachevskaya, Oksana O; Sergeeva, Lidiya I; Floková, Kristyna; Getman, Irina A; Lomin, Sergey N; Alekseeva, Valeriya V; Rukavtsova, Elena B; Buryanov, Yaroslav I; Romanov, Georgy A

    2017-03-01

    Ectopic auxin overproduction in transgenic potato leads to enhanced productivity accompanied with concerted and occasional changes in hormonal status, and causing altered response of transformants to exogenous auxin or cytokinin. Previously, we generated potato transformants expressing Agrobacterium-derived auxin synthesis gene tms1 driven by tuber-specific patatin gene promoter (B33-promoter). Here, we studied the endogenous hormonal status and the response to exogenous phytohormones in tms1 transformants cultured in vitro. Adding indole-3-acetic acid (IAA) or kinetin to culture medium affected differently tuberization of tms1-transformed and control plants, depending also on sucrose content in the medium. Exogenous phytohormones ceased to stimulate the tuber initiation in transformants at high (5-8%) sucrose concentration, while in control plants the stimulation was observed in all experimental settings. Furthermore, exogenous auxin partly inhibited the tuber initiation, and exogenous cytokinin reduced the average tuber weight in most transformants at high sucrose content. The elevated auxin level in tubers of the transformants was accompanied with a decrease in content of cytokinin bases and their ribosides in tubers and most shoots. No concerted changes in contents of abscisic, jasmonic, salicylic acids and gibberellins in tubers were detected. The data on hormonal status indicated that the enhanced productivity of tms1 transformants was due to auxin and not mediated by other phytohormones. In addition, exogenous cytokinin was shown to upregulate the expression of genes encoding orthologs of auxin receptors. Overall, the results showed that tms1 expression and local increase in IAA level in transformants affect both the balance of endogenous cytokinins and the dynamics of tuberization in response to exogenous hormones (auxin, cytokinin), the latter reaction depending also on the carbohydrate supply. We introduce a basic model for the hormonal network

  15. Specific mutations in the ligand binding domain selectively abolish the silencing function of human thyroid hormone receptor beta.

    PubMed Central

    Nawaz, Z; Tsai, M J; O'Malley, B W

    1995-01-01

    Although most nuclear hormone receptors are ligand-dependent transcriptional activators, certain members of this superfamily, such as thyroid hormone receptor (TR) and retinoic acid receptor (RAR), are involved in transcriptional repression. The silencing function of these receptors has been localized to the ligand binding domain (LBD). Previously, we demonstrated that overexpression of either the entire LBD or only the N-terminal region of the LBD (amino acids 168-259) is able to inhibit the silencing activity of TR. From this result we postulated the existence of a limiting factor (corepressor) that is necessary for TR silencing activity. To support this hypothesis, we identified amino acids in the N-terminal region of the LBD of TR that are important for the corepressor interaction and for the silencing function of TR. The silencing activity of TR was unaffected by overexpression of the LBD of mutant TR (V174A/D177A), suggesting that valine at position 174 and/or aspartic acid at position 177 are important for corepressor interaction. This mutant receptor protein, V174/D177, also lost the ability to silence target genes, suggesting that these amino acids are important for silencing function. Control experiments indicate that this mutant TR maintains its wild-type hormone binding and transactivation functions. These findings further strengthen the idea that the N-terminal region of the LBD of TR interacts with a putative corepressor protein(s) to achieve silencing of basal gene transcription. Images Fig. 1 Fig. 2 Fig. 4 PMID:8524830

  16. Effect of hypoxia and TP53 mutation status and cytogenetics of normal and malignant mammary epithelium.

    PubMed

    Vidarsson, Hilmar; Steinarsdóttir, Margrét; Jónasson, Jón Gunnlaugur; Júlíusdóttir, Hildur; Hauksdóttir, Halla; Hilmarsdóttir, Hólmfrídur; Halldórsdóttir, Kristín; Ogmundsdóttir, Helga M

    2006-03-01

    It has been proposed that hypoxia favors the growth of tumor cells over normal cells, particularly tumor cells carrying TP53 mutations. Cytogenetic studies of breast cancer have shown that highly complex karyotypes seen in direct harvest preparations are rarely detected after short-term culture. In this study, 34 paired samples of breast carcinomas and grossly nontumorous tissue from the same breast were cultured at 20 and 5% (12 samples) or 20 and 0% oxygen (22 samples). Both carcinoma samples and nontumorous tissue survived at 0% oxygen. Recovery for 24 hours at 20% produced good yields for cytogenetic analysis. Lower oxygen levels did not specifically stimulate growth of tumor cells. Samples with TP53 mutations showed a consistently increased growth under anaerobic hypoxic conditions. Culture at 5% oxygen did not generally reveal more karyotypic abnormalities than found at 20%. In the samples cultured at 0 and 20%, karyotypic abnormalities were detected only in anaerobic hypoxic culture in two cases. Of the only four samples where more complex karyotypes were detected in the low-oxygen culture, two were TP53 mutated. Hypoxic treatment followed by recovery at 20% oxygen may thus increase the yield of complex karyotypes from a subset of breast carcinomas, particularly those with mutated TP53.

  17. Mutation Status and Immunoglobulin Gene Rearrangements in Patients from Northwest and Central Region of Spain with Chronic Lymphocytic Leukemia

    PubMed Central

    González-Gascón y Marín, I.; Hernández, J. A.; Martín, A.; Alcoceba, M.; Sarasquete, M. E.; Rodríguez-Vicente, A.; Heras, C.; de las Heras, N.; Fisac, R.; García de Coca, A.; de la Fuente, I.; Hernández-Sánchez, M.; Recio, I.; Galende, J.; Martín-Núñez, G.; Alonso, J. M.; Hernández-Rivas, J. M.; González, M.

    2014-01-01

    The aim of this study was to investigate the frequency and mutation status of the immunoglobulin heavy variable chain (IGHV) in a cohort of 224 patients from northwest and central region of Spain diagnosed with chronic lymphocytic leukemia (CLL), and to correlate it with cytogenetic abnormalities, overall survival (OS) and time to first treatment (TTFT). 125 patients had mutated IGHV, while 99 had unmutated IGHV. The most frequently used IGHV family was IGHV3, followed by IGHV1 and IGHV4. The regions IGHV3-30, IGHV1-69, IGHV3-23, and IGHV4-34 were the most commonly used. Only 3.1% of the patients belonged to the subfamily IGHV3-21 and we failed to demonstrate a worse clinical outcome in this subgroup. The IGHV4 family appeared more frequently with mutated pattern, similar to IGHV3-23 and IGHV3-74. By contrast, IGHV1-69 was expressed at a higher frequency in unmutated CLL patients. All the cases from IGHV3-11 and almost all from IGHV5-51 subfamily belonged to the group of unmutated CLL. PMID:24790994

  18. Mutation status and immunoglobulin gene rearrangements in patients from northwest and central region of Spain with chronic lymphocytic leukemia.

    PubMed

    González-Gascón Y Marín, I; Hernández, J A; Martín, A; Alcoceba, M; Sarasquete, M E; Rodríguez-Vicente, A; Heras, C; de Las Heras, N; Fisac, R; García de Coca, A; de la Fuente, I; Hernández-Sánchez, M; Recio, I; Galende, J; Martín-Núñez, G; Alonso, J M; Hernández-Rivas, J M; González, M

    2014-01-01

    The aim of this study was to investigate the frequency and mutation status of the immunoglobulin heavy variable chain (IGHV) in a cohort of 224 patients from northwest and central region of Spain diagnosed with chronic lymphocytic leukemia (CLL), and to correlate it with cytogenetic abnormalities, overall survival (OS) and time to first treatment (TTFT). 125 patients had mutated IGHV, while 99 had unmutated IGHV. The most frequently used IGHV family was IGHV3, followed by IGHV1 and IGHV4. The regions IGHV3-30, IGHV1-69, IGHV3-23, and IGHV4-34 were the most commonly used. Only 3.1% of the patients belonged to the subfamily IGHV3-21 and we failed to demonstrate a worse clinical outcome in this subgroup. The IGHV4 family appeared more frequently with mutated pattern, similar to IGHV3-23 and IGHV3-74. By contrast, IGHV1-69 was expressed at a higher frequency in unmutated CLL patients. All the cases from IGHV3-11 and almost all from IGHV5-51 subfamily belonged to the group of unmutated CLL.

  19. Hormonal status and age differentially affect tolerance to the disruptive effects of delta-9-tetrahydrocannabinol (Δ(9)-THC) on learning in female rats.

    PubMed

    Winsauer, Peter J; Filipeanu, Catalin M; Weed, Peter F; Sutton, Jessie L

    2015-01-01

    The effects of hormone status and age on the development of tolerance to Δ(9)-THC were assessed in sham-operated (intact) or ovariectomized (OVX) female rats that received either intraperitoneal saline or 5.6 mg/kg of Δ(9)-THC daily from postnatal day (PD) 75-180 (early adulthood onward) or PD 35-140 (adolescence onward). During this time, the four groups for each age (i.e., intact/saline, intact/THC, OVX/saline, and OVX/THC) were trained in a learning and performance procedure and dose-effect curves were established for Δ(9)-THC (0.56-56 mg/kg) and the cannabinoid type-1 receptor (CB1R) antagonist rimonabant (0.32-10 mg/kg). Despite the persistence of small rate-decreasing and error-increasing effects in intact and OVX females from both ages during chronic Δ(9)-THC, all of the Δ(9)-THC groups developed tolerance. However, the magnitude of tolerance, as well as the effect of hormone status, varied with the age at which chronic Δ(9)-THC was initiated. There was no evidence of dependence in any of the groups. Hippocampal protein expression of CB1R, AHA1 (a co-chaperone of CB1R) and HSP90β (a molecular chaperone modulated by AHA-1) was affected more by OVX than chronic Δ(9)-THC; striatal protein expression was not consistently affected by either manipulation. Hippocampal brain-derived neurotrophic factor expression varied with age, hormone status, and chronic treatment. Thus, hormonal status differentially affects the development of tolerance to the disruptive effects of delta-9-tetrahydrocannabinol (Δ(9)-THC) on learning and performance behavior in adolescent, but not adult, female rats. These factors and their interactions also differentially affect cannabinoid signaling proteins in the hippocampus and striatum, and ultimately, neural plasticity.

  20. Hormonal status and age differentially affect tolerance to the disruptive effects of delta-9-tetrahydrocannabinol (Δ9-THC) on learning in female rats

    PubMed Central

    Winsauer, Peter J.; Filipeanu, Catalin M.; Weed, Peter F.; Sutton, Jessie L.

    2015-01-01

    The effects of hormone status and age on the development of tolerance to Δ9-THC were assessed in sham-operated (intact) or ovariectomized (OVX) female rats that received either intraperitoneal saline or 5.6 mg/kg of Δ9-THC daily from postnatal day (PD) 75–180 (early adulthood onward) or PD 35–140 (adolescence onward). During this time, the four groups for each age (i.e., intact/saline, intact/THC, OVX/saline, and OVX/THC) were trained in a learning and performance procedure and dose-effect curves were established for Δ9-THC (0.56–56 mg/kg) and the cannabinoid type-1 receptor (CB1R) antagonist rimonabant (0.32–10 mg/kg). Despite the persistence of small rate-decreasing and error-increasing effects in intact and OVX females from both ages during chronic Δ9-THC, all of the Δ9-THC groups developed tolerance. However, the magnitude of tolerance, as well as the effect of hormone status, varied with the age at which chronic Δ9-THC was initiated. There was no evidence of dependence in any of the groups. Hippocampal protein expression of CB1R, AHA1 (a co-chaperone of CB1R) and HSP90β (a molecular chaperone modulated by AHA-1) was affected more by OVX than chronic Δ9-THC; striatal protein expression was not consistently affected by either manipulation. Hippocampal brain-derived neurotrophic factor expression varied with age, hormone status, and chronic treatment. Thus, hormonal status differentially affects the development of tolerance to the disruptive effects of delta-9-tetrahydrocannabinol (Δ9-THC) on learning and performance behavior in adolescent, but not adult, female rats. These factors and their interactions also differentially affect cannabinoid signaling proteins in the hippocampus and striatum, and ultimately, neural plasticity. PMID:26191005

  1. BRAF-Mutated Colorectal Cancer Exhibits Distinct Clinicopathological Features from Wild-Type BRAF-Expressing Cancer Independent of the Microsatellite Instability Status

    PubMed Central

    2017-01-01

    In patients with colorectal cancer (CRC), the BRAF V600E mutation has been reported to be associated with several clinicopathological features and poor survival. However, the prognostic implications of BRAF V600E mutation and the associated clinicopathological characteristics in CRCs remain controversial. Therefore, we reviewed various clinicopathological features, including BRAF status, in 349 primary CRCs and analyzed the relationship between BRAF status and various clinicopathological factors, including overall survival. Similar to previous studies conducted in Eastern countries, the incidence of the BRAF V600E mutation in the current study was relatively low (5.7%). BRAF-mutated CRC exhibits distinct clinicopathological features from wild-type BRAF-expressing cancer independent of the microsatellite instability (MSI) status. This mutation was significantly associated with a proximal tumor location (P = 0.002); mucinous, signet ring cell, and serrated tumor components (P < 0.001, P = 0.003, and P = 0.008, respectively); lymphovascular invasion (P = 0.004); a peritumoral lymphoid reaction (P = 0.009); tumor budding (P = 0.046); and peritoneal seeding (P = 0.012). In conclusion, the incidence of the BRAF V600E mutation was relatively low in this study. BRAF-mutated CRCs exhibited some clinicopathological features which were also frequently observed in MSI-H CRCs, such as a proximal location; mucinous, signet ring cell, and serrated components; and marked peritumoral lymphoid reactions. PMID:27914130

  2. Changes in PIK3CA mutation status are not associated with recurrence, metastatic disease or progression in endocrine-treated breast cancer.

    PubMed

    Arthur, L M; Turnbull, A K; Renshaw, L; Keys, J; Thomas, J S; Wilson, T R; Lackner, M R; Sims, A H; Dixon, J M

    2014-08-01

    The phosphatidylinositol-3-kinase pathway plays an important role in proliferation, migration and survival in breast cancer and may play a role in resistance to endocrine therapy. Pathway activation occurs as a result of mutations in PIK3CA or loss of functional PTEN. Matched primary and recurrent samples from 120 breast cancer patients treated with endocrine therapy were profiled with a qPCR-based mutation assay covering eight mutational hotspots in PIK3CA. PTEN was assayed by immunohistochemistry. Samples were well characterized with respect to anatomic location of recurrence (metastatic nodal or local recurrence as opposed to contralateral or ipsilateral new primary cancers). In total, 43 % of patients had at least one PIK3CA mutation at diagnosis, and 41 % had a mutation at the time of recurrence. Only 8 % of patients with local recurrence, metastatic disease or progression on primary endocrine treatment changed their PIK3CA mutation status (four gains, two losses, total 76). The most common changes in PIK3CA mutation status were seen in patients who developed a new cancer either in the treated or contralateral breast (64 %, three gains, four losses, total 11). PIK3CA mutation status does not change in the majority of patients with breast cancer and the acquisition of mutations in PIK3CA is not responsible for the development of endocrine resistance. PTEN loss at diagnosis is associated with a significantly shorter time to progression compared with tumours in which PTEN was retained. These are the most comprehensive data currently available correlating PIK3CA status, site of recurrence and endocrine resistance.

  3. Response to first-line chemotherapy in patients with non-small-cell lung cancer according to epidermal growth factor receptor and K-RAS mutation status.

    PubMed

    Dong, Xiaopeng; Zhao, Xiaogang; Hao, Yingtao; Wei, Yucheng; Yin, Qiuwei; Du, Jiajun

    2013-11-01

    Epidermal growth factor receptor (EGFR)-targeted therapy has shown a favorable efficacy in patients with non-small-cell lung cancer (NSCLC). Conversely, K-RAS mutations were reported to have an adverse effect on the survival of patients with NSCLC. These studies suggest that the tumor biology of patients with EGFR or K-RAS mutations is different from that of patients with wild-type mutations. Therefore, we hypothesized that the response to cytotoxic chemotherapy may differ among patients with and without EGFR or K-RAS mutations. A total of 229 patients with advanced NSCLC who received platinum doublet chemotherapy were included in this retrospective study, and their clinical outcomes were analyzed according to EGFR and K-RAS mutation status. EGFR and K-RAS mutations were found in 52.4% and 27.9% of patients, respectively. Progression-free survival (PFS) was significantly higher in patients with EGFR mutations than in patients with wild-type EGFR (P = .008), and multivariate analysis showed that EGFR mutation was an independent factor to chemotherapy (P = .01). Among the patients with EGFR mutations, the disease control rate for docetaxel was higher than for gemcitabine-based therapy (P = .031). In addition, docetaxel or vinorelbine showed a longer PFS than gemcitabine-based chemotherapy in patients with EGFR mutations (P = .033 and P = .028). However, no similar differences were found according to the K-RAS mutations. EGFR, but not K-RAS mutation, is associated with improved survival time to platinum-based chemotherapy. In patients with EGFR mutations, PFS for docetaxel and gemcitabine was higher than for vinorelbine-based chemotherapies. The predictive meaning of EGFR mutation for chemotherapy should be further investigated. Copyright © 2013 Elsevier Inc. All rights reserved.

  4. The effects of social isolation on steroid hormone levels are modulated by previous social status and context in a cichlid fish.

    PubMed

    Galhardo, L; Oliveira, R F

    2014-01-01

    Social isolation is a major stressor which impacts the physiology, behaviour and health of individuals in gregarious species. However, depending on conditional and contextual factors, such as social status and group composition, social isolation may be perceived differently by different individuals or even by the same individuals at different times. Here we tested the effects of social status (territorial vs. non-territorial) and previous group composition (i.e. type of social group: mixed sex group with two territorial males, TT vs. mixed sex group with one territorial and one non-territorial male, TnT) on the hormonal response (androgens and cortisol) to social isolation in a cichlid fish (Oreochromis mossambicus). The different steroid hormones measured responded differentially to social isolation, and their response was modulated by social factors. Social isolation elicited a decrease of 11-keto formation only in territorial males, whereas non-territorial males present a non-significant trend for increasing KT levels. Testosterone did not respond to social isolation. Cortisol only increased in isolated individuals from TnT groups irrespective of social status (i.e. both in territorials and non-territorials). These results suggest that it is the perception of social isolation and not the objective structure of the situation that triggers the hormonal response to isolation.

  5. Analysis of 508 infertile male patients in south-western Finland in 1980-2000: hormonal status and factors predisposing to immunological infertility.

    PubMed

    Veräjänkorva, Esko; Laato, Matti; Pöllänen, Pasi

    2003-12-10

    To analyse the factors predisposing to male immunological infertility from the hospital records of 508 patients that had been treated for infertility in the Turku University Central Hospital from 1980 to 2000. In addition, the hormonal status was investigated at the beginning of treatment. Patients with a history of mumps, or either a fresh varicocele or a history of varicocele had statistically significant lower levels of MAR antisperm antibodies (ASAs) than patients with no such conditions. Repair of varicocele (either surgical or embolisation), showed a statistically significant enhancement of the total sperm cell counts in ejaculates, but it appeared not to have any influence on other parameters of the semen analysis (mobility and morphology). Of all male infertility patients, 66.3% had normal hormonal status at the beginning of treatment, 12.6% of patients had hypotestosteronemia and 22.1% had subclinical hypogonadism. Patients with subclinical hypogonadism had lower total sperm cell count in ejaculates than patients with normal hormonal status although they had statistically significant more offspring. In addition, it appeared that mumps orchitis as well as smoking and alcohol abuse are risk factors for subclinical hypogonadism. No clear predisposing factor for male immunological infertility could be found. However, patients with subclinical hypogonadism differed from other male infertility patients and thus may form a special group among the male infertility patients.

  6. Association Between NRAS and BRAF Mutational Status and Melanoma-Specific Survival Among Patients With Higher-Risk Primary Melanoma.

    PubMed

    Thomas, Nancy E; Edmiston, Sharon N; Alexander, Audrey; Groben, Pamela A; Parrish, Eloise; Kricker, Anne; Armstrong, Bruce K; Anton-Culver, Hoda; Gruber, Stephen B; From, Lynn; Busam, Klaus J; Hao, Honglin; Orlow, Irene; Kanetsky, Peter A; Luo, Li; Reiner, Anne S; Paine, Susan; Frank, Jill S; Bramson, Jennifer I; Marrett, Lorraine D; Gallagher, Richard P; Zanetti, Roberto; Rosso, Stefano; Dwyer, Terence; Cust, Anne E; Ollila, David W; Begg, Colin B; Berwick, Marianne; Conway, Kathleen

    2015-06-01

    NRAS and BRAF mutations in melanoma inform current treatment paradigms, but their role in survival from primary melanoma has not been established. Identification of patients at high risk of melanoma-related death based on their primary melanoma characteristics before evidence of recurrence could inform recommendations for patient follow-up and eligibility for adjuvant trials. To determine tumor characteristics and survival from primary melanoma by somatic NRAS and BRAF status. A population-based study with a median follow-up of 7.6 years (through 2007), including 912 patients from the United States and Australia in the Genes, Environment, and Melanoma (GEM) Study, with first primary cutaneous melanoma diagnosed in the year 2000 and analyzed for NRAS and BRAF mutations. Tumor characteristics and melanoma-specific survival of primary melanoma by NRAS and BRAF mutational status. The melanomas were 13% NRAS+, 30% BRAF+, and 57% with neither NRAS nor BRAF mutation (wildtype [WT]). In a multivariable model including clinicopathologic characteristics, relative to WT melanoma (with results reported as odds ratios [95% CIs]), NRAS+ melanoma was associated with presence of mitoses (1.8 [1.0-3.3]), lower tumor-infiltrating lymphocyte (TIL) grade (nonbrisk, 0.5 [0.3-0.8]; and brisk, 0.3 [0.5-0.7] [vs absent TILs]), and anatomic site other than scalp/neck (0.1 [0.01-0.6] for scalp/neck vs trunk/pelvis), and BRAF+ melanoma was associated with younger age (ages 50-69 years, 0.7 [0.5-1.0]; and ages >70 years, 0.5 [0.3-0.8] [vs <50 years]), superficial spreading subtype (nodular, 0.5 [0.2-1.0]; lentigo maligna, 0.4 [0.2-0.7]; and unclassified/other, 0.2 [0.1-0.5] [vs superficial spreading]), and presence of mitoses (1.7 [1.1-2.6]) (P < .05 for all). There was no significant difference in melanoma-specific survival (reported as hazard ratios [95% CIs]) for melanoma harboring mutations in NRAS (1.7 [0.8-3.4]) or BRAF (1.5 [0.8-2.9]) compared with WT melanoma, as adjusted for age

  7. Customized chemotherapy based on epidermal growth factor receptor mutation status for elderly patients with advanced non-small-cell lung cancer: a phase II trial.

    PubMed

    Fujita, Shiro; Katakami, Nobuyuki; Masago, Katsuhiro; Yoshioka, Hiroshige; Tomii, Keisuke; Kaneda, Toshihiko; Hirabayashi, Masataka; Kunimasa, Kei; Morizane, Toshio; Mio, Tadashi

    2012-05-21

    Elderly patients are more vulnerable to toxicity from chemotherapy. Activating epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer (NSCLC) are associated with enhanced response to EGFR tyrosine-kinase inhibitors. We studied patients with advanced NSCLC for whom treatment was customized based on EGFR mutation status. We screened 57 chemotherapy-naïve patients with histologically or cytologically confirmed NSCLC, stage IIIB or IV, aged 70 years or older, and with an Eastern Cooperative Oncology Group performance status 0 or 1, for EGFR exon 19 codon 746-750 deletion and exon 21 L858R mutation. Twenty-two patients with EGFR mutations received gefitinib; 32 patients without mutations received vinorelbine or gemcitabine. The primary endpoint was the response rate. The response rate was 45.5% (95% confidence interval [CI]: 24.4%, 67.8%) in patients with EGFR mutations and 18.8% (95% CI: 7.2%, 36.4%) in patients without EGFR mutations. The median overall survival was 27.9 months (95%CI: 24.4 months, undeterminable months) in patients with EGFR mutations and 14.9 months (95%CI: 11.0 months, 22.4 months) in patients without EGFR mutations. In the gefitinib group, grade 3/4 hepatic dysfunction and dermatitis occurred in 23% and 5% of patients, respectively. In patients treated with vinorelbine or gemcitabine, the most common grade 3 or 4 adverse events were neutropenia (47%; four had febrile neutropenia), anemia (13%), and anorexia (9%). No treatment-related deaths occurred. Treatment customization based on EGFR mutation status deserves consideration, particularly for elderly patients who often cannot receive second-line chemotherapy due to poor organ function or comorbidities. This trial is registered at University hospital Medical Information Network-clinical trial registration (http://www.umin.ac.jp/ctr/index/htm) with the registration identification number C000000436.

  8. Clinical outcome of patients with non-small cell lung cancer receiving front-line chemotherapy according to EGFR and K-RAS mutation status.

    PubMed

    Kalikaki, Aristea; Koutsopoulos, Anastasios; Hatzidaki, Dora; Trypaki, Maria; Kontopodis, Emmanouel; Stathopoulos, Efstathios; Mavroudis, Dimitris; Georgoulias, Vassilis; Voutsina, Alexandra

    2010-07-01

    Somatic mutations in EGFR and K-RAS may predict for sensitivity and resistance to EGFR tyrosine kinase inhibitors (TKIs). Whether EGFR and K-RAS mutations could also predict clinical outcome of non-small cell lung cancer (NSCLC) patients following front-line chemotherapy has not yet been established. One hundred and sixty-two chemotherapy-naïve patients with locally advanced/metastatic NSCLC who received front-line chemotherapy were included in this retrospective study and their clinical outcome data was analyzed according to EGFR and K-RAS mutation status of their tumors. Classical activating EGFR and K-RAS mutations were found in 8.2 and 22.6% of patients respectively and were not associated with patients' clinicopathological characteristics. Patients with classical EGFR mutations had a higher probability of response to front-line chemotherapy as compared to those with wild type EGFR (p=0.023). Multivariate analysis showed that the presence of activating EGFR mutations was an independent factor associated with response to front-line chemotherapy (HR=4.85; 95% CI: 1.13-20.83, p=0.034). K-RAS mutation status was not associated with response to front-line chemotherapy. The presence of activating EGFR but not of K-RAS mutations was associated with a significantly higher overall survival compared to patients without mutations treated with platinum-based front-line chemotherapy (p=0.043). The data indicate that EGFR mutation status could be predictive for response to cytotoxic front-line chemotherapy in patients with NSCLC. Additional prospective studies are needed in order to validate this observation and to define whether these patients should be preferentially treated with front-line TKIs or chemotherapy. Copyright 2009 Elsevier Ireland Ltd. All rights reserved.

  9. Secretion of anti-Müllerian hormone in the Florida manatee Trichechus manatus latirostris, with implications for assessing conservation status

    USGS Publications Warehouse

    Wilson, Rhian C.; Reynolds, John E.; Wetzel, Dana L.; Schwierzke-Wade, Leslie; Bonde, Robert K.; Breuel, Kevin F.; Roudebush, William E.

    2011-01-01

    Environmental and anthropogenic stressors can affect wildlife populations in a number of ways. For marine mammals (e.g. the Florida manatee Trichechus manatus latirostris), certain stressors or conservation risk factors have been identified, but sublethal effects have been very difficult to assess using traditional methods. The development of 'biomarkers' allows us to correlate effects, such as impaired reproduction, with possible causes. A recently developed biomarker (anti-Müllerian hormone, AMH) provides an enzyme-linked immunosorbent assay of gonadal function. The study objective was to determine AMH levels in wild manatees. In total, 28 male and 17 female manatee serum samples were assayed. Animal demographics included collection date, body weight (kg) and total length (cm). In certain cases, age of individuals was also known. AMH levels ranged from 160 to 2451.85 ng ml-1 (mean = 844.65 ng ml-1) in males and 0.00 to 0.38 ng ml-1 (mean = 0.10 ng ml-1) in females. Linear regression analyses revealed a significant relationship between male AMH levels and body weight (R2 = 0.452; p 2 = 0.338; p < 0.001). Due to the small sample size, regression analyses for female AMH and body weight and length were not significant. This represents the first report of AMH detection in a marine mammal. AMH levels in male manatees are the highest of any species observed to date, whereas levels in females are within reported ranges. Further studies will promote improved conservation decision by assessing AMH levels in the manatee as a function of various stressors including, but not limited to, nutritional status, serious injuries (e.g. watercraft collisions), exposure to biotoxins or contaminants, or disease.

  10. Evaluation of hormonal change, biochemical parameters, and histopathological status of uterus in rats exposed to 50-Hz electromagnetic field.

    PubMed

    Aydin, M; Cevik, A; Kandemir, F M; Yuksel, M; Apaydin, A M

    2009-04-01

    This study investigates the effects of the electromagnetic field (EMF) resulting from the 170 kV high-voltage power lines on hormonal status, on progesterone and 17-beta estradiol levels, and on morphology of the uterus and ovaries associated with biochemical parameters of adult Wistar female rats. The rats were assigned to experimental (21) and control groups (7). The rats in the experimental group were housed in a wooden barn with 7.5 m vertical distance to the power line. Groups 1, 2, and 3 were exposed continuously (24 h) to electric-electromagnetic fields (ELF-EMFs) (48.21 +/- 1.58 mG) for 1, 2, and 3 months, respectively. The rats of group 4 served as the control and were placed in laboratory conditions (The average value of the ELF was 0.75 +/- 0.05 V/m. The value of the EMF was calculated to be 0.48 +/- 0.05 mG.). Significant (P < 0.05) decreases were determined among the groups in terms of reproductive organ weights (uterus and ovaries) and progesterone and estrogen levels in relation to the varying periods of the estrous cycle. Although marked reductions (P < 0.05) were observed among the groups in relation to plasma catalase activity, depending on exposure time, no significant differences were found in terms of glutathione and malondialdehyde levels. It is concluded that exposure to the ELF-EMFs for different time periods produced significant decreases in plasma catalase activities in the 3-month exposure groups but no effects on progesterone level, on 17-beta estradiol level, or on the morphology and weight of uterus and ovaries.

  11. The Role of BRCA2 Mutation Status as Diagnostic, Predictive, and Prognosis Biomarker for Pancreatic Cancer

    PubMed Central

    Garcia-Foncillas, Jesus

    2016-01-01

    Pancreatic cancer is one of the deadliest cancers worldwide, and life expectancy after diagnosis is often short. Most pancreatic tumours appear sporadically and have been highly related to habits such as cigarette smoking, high alcohol intake, high carbohydrate, and sugar consumption. Other observational studies have suggested the association between pancreatic cancer and exposure to arsenic, lead, or cadmium. Aside from these factors, chronic pancreatitis and diabetes have also come to be considered as risk factors for these kinds of tumours. Studies have found that 10% of pancreatic cancer cases arise from an inherited syndrome related to some genetic alterations. One of these alterations includes mutation in BRCA2 gene. BRCA2 mutations impair DNA damage response and homologous recombination by direct regulation of RAD51. In light of these findings that link genetic factors to tumour development, DNA damage agents have been proposed as target therapies for pancreatic cancer patients carrying BRCA2 mutations. Some of these drugs include platinum-based agents and PARP inhibitors. However, the acquired resistance to PARP inhibitors has created a need for new chemotherapeutic strategies to target BRCA2. The present systematic review collects and analyses the role of BRCA2 alterations to be used in early diagnosis of an inherited syndrome associated with familiar cancer and as a prognostic and predictive biomarker for the management of pancreatic cancer patients. PMID:28078281

  12. The current status of two-dimensional electrophoresis in germ cell mutation research

    SciTech Connect

    Giometti, C.S.

    1989-01-01

    Previous research demonstrated that isoelectric focusing followed by sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis can be used to resolve hundreds of proteins from a single sample into a pattern of well-defined polypeptide spots. The possible application of this two-dimensional electrophoresis (2DE) technique to the detection of heritable mutations was recognized and demonstrated using mouse tissues. The studies demonstrated that actual implementation of 2DE for large genetic studies, however, required rigorous pattern reproducibility and methods of extracting numerical data from the patterns. The development of equipment for multiple parallel 2DE analyses and of computer software for the analysis of the resulting 2DE patterns during the 10 years since the first description of 2DE have provided the necessary tools for the application of 2DE to genetic studies. We are currently using inbred strains of mice to study the mutation detection capability of 2DE. The levels of sample and pattern reproducibility required for detection of significant changes in protein expression are being defined; the detection of mutations induced by different classes of mutagen (e.g., those causing large versus small alterations in DNA) is being assessed; and the population of proteins (and therefore genes) monitored by 2DE analysis is being characterized. 19 refs., 3 figs.

  13. Parathyroid hormone, calcitonin, and vitamin D 1974: Present status of physiological studies and analysis of calcium homeostasis

    NASA Technical Reports Server (NTRS)

    Potts, J. T., Jr.; Swenson, K. G.

    1975-01-01

    The role of parathyroid hormone, calcitonin, and vitamin D in the control of calcium and bone metabolism was studied. Particular emphasis was placed on the physiological adaptation to weightlessness and, as a potential model for this purpose, on the immobilization characteristic of space flight or prolonged bed rest. The biosynthesis, control of secretion, and metabolism of these hormonal agents is considered.

  14. Parathyroid hormone, calcitonin, and vitamin D 1974: Present status of physiological studies and analysis of calcium homeostasis

    NASA Technical Reports Server (NTRS)

    Potts, J. T., Jr.; Swenson, K. G.

    1975-01-01

    The role of parathyroid hormone, calcitonin, and vitamin D in the control of calcium and bone metabolism was studied. Particular emphasis was placed on the physiological adaptation to weightlessness and, as a potential model for this purpose, on the immobilization characteristic of space flight or prolonged bed rest. The biosynthesis, control of secretion, and metabolism of these hormonal agents is considered.

  15. Assessment of epidermal growth factor receptor and K-ras mutation status in cytological stained smears of non-small cell lung cancer patients: correlation with clinical outcomes.

    PubMed

    Lozano, Maria D; Zulueta, Javier J; Echeveste, Jose I; Gúrpide, Alfonso; Seijo, Luis M; Martín-Algarra, Salvador; Del Barrio, Anabel; Pio, Ruben; Idoate, Miguel Angel; Labiano, Tania; Perez-Gracia, Jose Luis

    2011-01-01

    Epidermal growth factor receptor (EGFR) and K-ras mutations guide treatment selection in non-small cell lung cancer (NSCLC) patients. Although mutation status is routinely assessed in biopsies, cytological specimens are frequently the only samples available. We determined EGFR and K-ras mutations in cytological samples. DNA was extracted from 150 consecutive samples, including 120 Papanicolau smears (80%), 10 cell blocks (7%), nine fresh samples (6%), six ThinPrep® tests (4%), and five body cavity fluids (3.3%). Papanicolau smears were analyzed when they had >50% malignant cells. Polymerase chain reaction and direct sequencing of exons 18-21 of EGFR and exon 2 of K-ras were performed. EGFR mutations were simultaneously determined in biopsies and cytological samples from 20 patients. Activity of EGFR tyrosine kinase inhibitors (TKIs) was assessed. The cytological diagnosis was adenocarcinoma in 110 samples (73%) and nonadenocarcinoma in 40 (27%) samples. EGFR mutations were identified in 26 samples (17%) and K-ras mutations were identified in 18 (12%) samples. EGFR and K-ras mutations were mutually exclusive. In EGFR-mutated cases, DNA was obtained from stained smears in 24 cases (92%), pleural fluid in one case (4%), and cell block in one case (4%). The response rate to EGFR TKIs in patients harboring mutations was 75%. The mutation status was identical in patients who had both biopsies and cytological samples analyzed. Assessment of EGFR and K-ras mutations in cytological samples is feasible and comparable with biopsy results, making individualized treatment selection possible for NSCLC patients from whom tumor biopsies are not available.

  16. Assessment of Epidermal Growth Factor Receptor and K-Ras Mutation Status in Cytological Stained Smears of Non-Small Cell Lung Cancer Patients: Correlation with Clinical Outcomes

    PubMed Central

    Zulueta, Javier J.; Echeveste, Jose I.; Gúrpide, Alfonso; Seijo, Luis M.; Martín-Algarra, Salvador; del Barrio, Anabel; Pio, Ruben; Idoate, Miguel Angel; Labiano, Tania; Perez-Gracia, Jose Luis

    2011-01-01

    Objective. Epidermal growth factor receptor (EGFR) and K-ras mutations guide treatment selection in non-small cell lung cancer (NSCLC) patients. Although mutation status is routinely assessed in biopsies, cytological specimens are frequently the only samples available. We determined EGFR and K-ras mutations in cytological samples. Methods. DNA was extracted from 150 consecutive samples, including 120 Papanicolau smears (80%), 10 cell blocks (7%), nine fresh samples (6%), six ThinPrep® tests (4%), and five body cavity fluids (3.3%). Papanicolau smears were analyzed when they had >50% malignant cells. Polymerase chain reaction and direct sequencing of exons 18–21 of EGFR and exon 2 of K-ras were performed. EGFR mutations were simultaneously determined in biopsies and cytological samples from 20 patients. Activity of EGFR tyrosine kinase inhibitors (TKIs) was assessed. Results. The cytological diagnosis was adenocarcinoma in 110 samples (73%) and nonadenocarcinoma in 40 (27%) samples. EGFR mutations were identified in 26 samples (17%) and K-ras mutations were identified in 18 (12%) samples. EGFR and K-ras mutations were mutually exclusive. In EGFR-mutated cases, DNA was obtained from stained smears in 24 cases (92%), pleural fluid in one case (4%), and cell block in one case (4%). The response rate to EGFR TKIs in patients harboring mutations was 75%. The mutation status was identical in patients who had both biopsies and cytological samples analyzed. Conclusion. Assessment of EGFR and K-ras mutations in cytological samples is feasible and comparable with biopsy results, making individualized treatment selection possible for NSCLC patients from whom tumor biopsies are not available. PMID:21572125

  17. Leydig cell hypoplasia: absent luteinizing hormone receptor cell surface expression caused by a novel homozygous mutation in the extracellular domain.

    PubMed

    Richter-Unruh, A; Verhoef-Post, M; Malak, S; Homoki, J; Hauffa, B P; Themmen, A P N

    2004-10-01

    Leydig cell hypoplasia is a rare autosomal recessive condition that interferes with normal development of male external genitalia in 46,XY individuals. We have studied a family with a 46,XY girl due to a new homozygous mutation (V144F) in the extracellular ligand-binding domain. HEK 293 cells transfected with the mutant LH receptor exhibited a marked impairment of human chorionic gonadotropin binding. Using Western blotting of the expressed V144F mutant LH receptor protein showed the absence of the glycosylated cell surface form. Treatment of the mutant LH receptor with N-glycosidase F or endoglycosidase-H demonstrated that the mutant receptor is retained in the endoplasmic reticulum. Expression and study of enhanced green fluorescent protein-tagged receptors confirmed that the mutant LHR-V144F receptors do not migrate to the cell surface, and the fluorescence remains intracellular and colocalizes with an endoplasmic reticulum marker, ER-tracker Blue-white DPX. Comparison of the theoretical molecular models of the extracellular domain of the wild-type and the mutant receptor suggests that the mutation LHR-V144F, located in the outer circumference in a alpha-helix of the leucine-rich repeat 4, may induce a conformational strain on the molecule. F144 of the mutant LH receptor has overlapping interactions with F119, which V144 in the wild-type receptor has not.

  18. BRCA1 and BRCA2 mutation status and cancer family history of Danish women affected with multifocal or bilateral breast cancer at a young age

    PubMed Central

    Bergthorsson, J; Ejlertsen, B; Olsen, J; Borg, A; Nielsen, K; Barkardottir, R; Klausen, S; Mouridsen, H; Winther, K; Fenger, K; Niebuhr, A; Harboe, T; Niebuhr, E

    2001-01-01

    INTRODUCTION—A small fraction of breast cancer is the result of germline mutations in the BRCA1 and BRCA2 cancer susceptibility genes. Mutation carriers frequently have a positive family history of breast and ovarian cancer, are often diagnosed at a young age, and may have a higher incidence of double or multiple primary breast tumours than breast cancer patients in general.
OBJECTIVES—To estimate the prevalence and spectrum of BRCA1 and BRCA2 mutations in young Danish patients affected with bilateral or multifocal breast cancer and to determine the relationship of mutation status to family history of cancer.
SUBJECTS—From the files of the Danish Breast Cancer Cooperative Group (DBCG), we selected 119 breast cancer patients diagnosed before the age of 46 years with either bilateral (n=59) or multifocal (n=61) disease.
METHODS—DNA from the subjects was screened for BRCA1 and BRCA2 mutations using single strand conformation analysis (SSCA) and the protein truncation test (PTT). Observed and expected cancer incidence in first degree relatives of the patients was estimated using data from the Danish Cancer Registry.
RESULTS—Twenty four mutation carriers were identified (20%), of whom 13 had a BRCA1 mutation and 11 carried a BRCA2 mutation. Two mutations in BRCA1 were found repeatedly in the material and accounted for seven of the 24 (29%) mutation carriers. The mutation frequency was about equal in patients with bilateral (22%) and multifocal breast cancer (18%). The incidence of breast and ovarian cancer was greatly increased in first degree relatives of BRCA1 and BRCA2 mutation carriers, but to a much lesser degree in relatives of non-carriers. An increased risk of cancer was also noted in brothers of non-carriers.
CONCLUSIONS—A relatively broad spectrum of germline mutations was observed in BRCA1 and BRCA2 and most of the mutations are present in other populations. Our results indicate that a diagnosis of bilateral and multifocal breast

  19. ERCC1 Induction after Oxaliplatin Exposure May Depend on KRAS Mutational Status in Colorectal Cancer Cell Line: In Vitro Veritas

    PubMed Central

    Orlandi, A.; Di Salvatore, M.; Bagalà, C.; Basso, M.; Strippoli, A.; Plastino, F.; Calegari, M.A.; Cassano, A.; Astone, A.; Barone, C.

    2015-01-01

    Introduction: Oxaliplatin (Oxa) is widely used in metastatic colorectal cancer (mCRC), but currently there are not valid predictors of response to this drug. In the control arms both of OPUS and PRIME studies Oxa seems more active in patients with mCRC with mutated (mt) KRAS than in those with wild type (wt) KRAS. Recently we have retrospectively confirmed this suggestion, therefore we have hypothesized that the mutational status of KRAS could influence the expression of ERCC1, one of the main mechanisms of Oxa resistance. Material and Methods: We used four cell lines of colorectal cancer: two KRAS wild type (wt) (HCT-8 and HT-29) and two KRAS mt (SW620 and SW480). We evaluated the sensitivity of these cell lines to Oxa by MTT-test as well the ERCC1 levels before and after 24 h exposure to Oxa by Real-Time PCR. We silenced KRAS in a KRAS mt cell line (SW620LV) to evaluate the impact on Oxa sensitivity and ERCC1 levels. Lastly, ERCC1 was also silenced in order to confirm the importance of this protein as an Oxa resistance factor. Results: The KRAS mt cell lines resulted more sensitive to Oxa (OR 2.68; IC 95% 1.511-4.757 p<0.001). The basal levels of ERCC1 did not show significant differences between KRAS mt and wt cell lines, however, after 24 h exposure to Oxa, only the wt KRAS lines showed the ability to induce ERCC1, with a statistically significant difference (OR 42.9 IC 95% 17.260-106.972 p<0.0005). By silencing KRAS, sensitivity to Oxa was reduced in mt KRAS cell lines and this effect was associated with the acquisition of ability to induce ERCC1. Silencing of ERCC1, in turn, enhanced the sensitivity to Oxa in wt KRAS cell lines and restored sensitivity to Oxa in SW620LV cell line. Conclusion: KRAS mutated cell lines were more sensitive to Oxa. This feature seems secondary to the inability of these cells to induce ERCC1 after exposure to Oxa. Thus, KRAS mutational status might be a predictor of response to Oxa in CRC surrogating the cell ability to induce ERCC

  20. Pooled Analysis of the Prognostic and Predictive Effects of KRAS Mutation Status and KRAS Mutation Subtype in Early-Stage Resected Non–Small-Cell Lung Cancer in Four Trials of Adjuvant Chemotherapy

    PubMed Central

    Shepherd, Frances A.; Domerg, Caroline; Hainaut, Pierre; Jänne, Pasi A.; Pignon, Jean-Pierre; Graziano, Stephen; Douillard, Jean-Yves; Brambilla, Elizabeth; Le Chevalier, Thierry; Seymour, Lesley; Bourredjem, Abderrahmane; Teuff, Gwénaël Le; Pirker, Robert; Filipits, Martin; Rosell, Rafael; Kratzke, Robert; Bandarchi, Bizhan; Ma, Xiaoli; Capelletti, Marzia; Soria, Jean-Charles; Tsao, Ming-Sound

    2013-01-01

    Purpose We undertook this analysis of KRAS mutation in four trials of adjuvant chemotherapy (ACT) versus observation (OBS) to clarify the prognostic/predictive roles of KRAS in non–small-cell lung cancer (NSCLC). Methods KRAS mutation was determined in blinded fashion. Exploratory analyses were performed to characterize relationships between mutation status and subtype and survival outcomes using a multivariable Cox model. Results Among 1,543 patients (763 OBS, 780 ACT), 300 had KRAS mutations (codon 12, n = 275; codon 13, n = 24; codon 14, n = 1). In OBS patients, there was no prognostic difference for overall survival for codon-12 (mutation v wild type [WT] hazard ratio [HR] = 1.04; 95% CI, 0.77 to 1.40) or codon-13 (HR = 1.01; 95% CI, 0.47 to 2.17) mutations. No significant benefit from ACT was observed for WT-KRAS (ACT v OBS HR = 0.89; 95% CI, 0.76 to 1.04; P = .15) or codon-12 mutations (HR = 0.95; 95% CI, 0.67 to 1.35; P = .77); with codon-13 mutations, ACT was deleterious (HR = 5.78; 95% CI, 2.06 to 16.2; P < .001; interaction P = .002). There was no prognostic effect for specific codon-12 amino acid substitution. The effect of ACT was variable among patients with codon-12 mutations: G12A or G12R (HR = 0.66; P = .48), G12C or G12V (HR = 0.94; P = .77) and G12D or G12S (HR = 1.39; P = .48; comparison of four HRs, including WT, interaction P = .76). OBS patients with KRAS-mutated tumors were more likely to develop second primary cancers (HR = 2.76, 95% CI, 1.34 to 5.70; P = .005) but not ACT patients (HR = 0.66; 95% CI, 0.25 to 1.75; P = .40; interaction, P = .02). Conclusion KRAS mutation status is not significantly prognostic. The potential interaction in patients with codon-13 mutations requires validation. At this time, KRAS status cannot be recommended to select patients with NSCLC for ACT. PMID:23630215

  1. Associations of anthropometric factors with KRAS and BRAF mutation status of primary colorectal cancer in men and women: a cohort study.

    PubMed

    Brändstedt, Jenny; Wangefjord, Sakarias; Nodin, Björn; Eberhard, Jakob; Sundström, Magnus; Manjer, Jonas; Jirström, Karin

    2014-01-01

    Obesity is a well-established risk factor for colorectal cancer (CRC), and accumulating evidence suggests a differential influence of sex and anthropometric factors on the molecular carcinogenesis of the disease. The aim of the present study was to investigate the relationship between height, weight, bodyfat percentage, waist- and hip circumference, waist-hip ratio (WHR), body mass index (BMI) and CRC risk according to KRAS and BRAF mutation status of the tumours, with particular reference to potential sex differences. KRAS and BRAF mutations were analysed by pyrosequencing in tumours from 494 incident CRC cases in the Malmö Diet and Cancer Study. Hazard ratios of CRC risk according to anthropometric factors and mutation status were calculated using multivariate Cox regression models. While all anthropometric measures except height were associated with an increased risk of KRAS-mutated tumours, only BMI was associated with an increased risk of KRAS wild type tumours overall. High weight, hip, waist, WHR and BMI were associated with an increased risk of BRAF wild type tumours, but none of the anthropometric factors were associated with risk of BRAF-mutated CRC, neither in the overall nor in the sex-stratified analysis. In men, several anthropometric measures were associated with both KRAS-mutated and KRAS wild type tumours. In women, only a high WHR was significantly associated with an increased risk of KRAS-mutated CRC. A significant interaction was found between sex and BMI with respect to risk of KRAS-mutated tumours. In men, all anthropometric factors except height were associated with an increased risk of BRAF wild type tumours, whereas in women, only bodyfat percentage was associated with an increased risk of BRAF wild type tumours. The results from this prospective cohort study further support an influence of sex and lifestyle factors on different pathways of colorectal carcinogenesis, defined by KRAS and BRAF mutation status of the tumours.

  2. Impact of the epidermal growth factor receptor mutation status on the post-recurrence survival of patients with surgically resected non-small-cell lung cancer.

    PubMed

    Takenaka, Tomoyoshi; Takenoyama, Mitsuhiro; Yamaguchi, Masafumi; Toyozawa, Ryo; Inamasu, Eiko; Kojo, Miyako; Toyokawa, Gouji; Yoshida, Tsukihisa; Shiraishi, Yoshimasa; Morodomi, Yosuke; Hirai, Fumihiko; Taguchi, Kenichi; Shimokawa, Mototsugu; Seto, Takashi; Ichinose, Yukito

    2015-03-01

    The impact of epidermal growth factor receptor (EGFR) status and the use of EGFR-tyrosine kinase inhibitor (EGFR-TKI) therapy have not been well discussed only in recurrent non-small-cell lung cancer (NSCLC). The purpose of this study was to identify the prognostic factors associated with post-recurrence survival after surgical resection of NSCLC in terms of the EGFR mutation status and the use of EGFR-TKI therapy. From 2000 through 2011, 1237 consecutive patients with NSCLC underwent pulmonary resection at our institution. Of these patients, 280 experienced postoperative recurrence by the end of 2012. We reviewed the cases of recurrence and analysed the predictors and length of post-recurrence survival. The median post-recurrence survival time and the 5-year survival rate of all patients were 25 months and 20.8%, respectively. A multivariate analysis identified the Eastern Cooperative Oncology Group (ECOG) performance status (PS), brain metastasis, number of sites of recurrence and EGFR mutation status to be independent prognostic factors for post-recurrence survival. Among all cases, the median post-recurrence survival time according to the use of EGFR-TKI therapy was as follows: 49 months in the EGFR mutation-positive patients treated with EGFR-TKI therapy, 20 months in the EGFR wild or unknown cases treated with EGFR-TKI therapy and 17 months in the patients not treated with EGFR-TKI therapy. As to EGFR mutation-positive cases, the patients treated with EGFR-TKIs exhibited significantly longer post-recurrence survival time than the patients treated without EGFR-TKIs (49 vs 12 months). It is essential for recurrent NSCLC patients to be examined for the EGFR mutation status. Patients with a positive EGFR mutation status receive significant benefits from EGFR-TKI therapy. © The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

  3. Multi-Center Evaluation of the Fully Automated PCR-Based Idylla™ KRAS Mutation Assay for Rapid KRAS Mutation Status Determination on Formalin-Fixed Paraffin-Embedded Tissue of Human Colorectal Cancer

    PubMed Central

    Solassol, Jérôme; Vendrell, Julie; Märkl, Bruno; Haas, Christian; Bellosillo, Beatriz; Montagut, Clara; Smith, Matthew; O’Sullivan, Brendan; D’Haene, Nicky; Le Mercier, Marie; Grauslund, Morten; Melchior, Linea Cecilie; Burt, Emma; Cotter, Finbarr; Stieber, Daniel; Schmitt, Fernando de Lander; Motta, Valentina; Lauricella, Calogero; Colling, Richard; Soilleux, Elizabeth; Fassan, Matteo; Mescoli, Claudia; Collin, Christine; Pagès, Jean-Christophe; Sillekens, Peter

    2016-01-01

    Since the advent of monoclonal antibodies against epidermal growth factor receptor (EGFR) in colorectal cancer therapy, the determination of RAS mutational status is needed for therapeutic decision-making. Most prevalent in colorectal cancer are KRAS exon 2 mutations (40% prevalence); lower prevalence is observed for KRAS exon 3 and 4 mutations (6%) and NRAS exon 2, 3, and 4 mutations (5%). The Idylla™ KRAS Mutation Test on the molecular diagnostics Idylla™ platform is a simple (<2 minutes hands-on time), highly reliable, and rapid (approximately 2 hours turnaround time) in vitro diagnostic sample-to-result solution. This test enables qualitative detection of 21 mutations in codons 12, 13, 59, 61, 117, and 146 of the KRAS oncogene being clinically relevant according to the latest clinical guidelines. Here, the performance of the Idylla™ KRAS Mutation Assay, for Research Use Only, was assessed on archived formalin-fixed paraffin-embedded (FFPE) tissue sections by comparing its results with the results previously obtained by routine reference approaches for KRAS genotyping. In case of discordance, samples were assessed further by additional methods. Among the 374 colorectal cancer FFPE samples tested, the overall concordance between the Idylla™ KRAS Mutation Assay and the confirmed reference routine test results was found to be 98.9%. The Idylla™ KRAS Mutation Assay enabled detection of 5 additional KRAS-mutated samples not detected previously with reference methods. As conclusion the Idylla™ KRAS Mutation Test can be applied as routine tool in any clinical setting, without needing molecular infrastructure or expertise, to guide the personalized treatment of colorectal cancer patients. PMID:27685259

  4. A comparative study of fluoride ingestion levels, serum thyroid hormone & TSH level derangements, dental fluorosis status among school children from endemic and non-endemic fluorosis areas.

    PubMed

    Singh, Navneet; Verma, Kanika Gupta; Verma, Pradhuman; Sidhu, Gagandeep Kaur; Sachdeva, Suresh

    2014-01-03

    The study was undertaken to determine serum/urinary fluoride status and comparison of free T4, free T3 and thyroid stimulating hormone levels of 8 to 15 years old children with and without dental fluorosis living in an endemic and non-endemic fluorosis area. A sample group of 60 male and female school children, with or without dental fluorosis, consuming fluoride-contaminated water in endemic fluoride area of Udaipur district, Rajasthan were selected through a school dental fluorosis survey. The sample of 10 children of same age and socio-economic status residing in non endemic areas who did not have dental fluorosis form controls. Fluoride determination in drinking water, urine and blood was done with Ion 85 Ion Analyzer Radiometer with Hall et al. method. The thyroid gland functional test was done by Immonu Chemiluminiscence Micropartical Assay with Bayer Centaur Autoanalyzer. The significantly altered FT3, FT4 and TSH hormones level in both group1A and 1B school children were noted. The serum and urine fluoride levels were found to be increased in both the groups. A significant relationship of water fluoride to urine and serum fluoride concentration was seen. The serum fluoride concentration also had significant relationship with thyroid hormone (FT3/FT4) and TSH concentrations. The testing of drinking water and body fluids for fluoride content, along with FT3, FT4, and TSH in children with dental fluorosis is desirable for recognizing underlying thyroid derangements and its impact on fluorosis.

  5. Association between lifetime exposure to passive smoking and risk of breast cancer subtypes defined by hormone receptor status among non-smoking Caucasian women

    PubMed Central

    Strumylaite, Loreta; Kregzdyte, Rima; Poskiene, Lina; Bogusevicius, Algirdas; Pranys, Darius; Norkute, Roberta

    2017-01-01

    Tobacco smoking is inconsistently associated with breast cancer. Although some studies suggest that breast cancer risk is related to passive smoking, little is known about the association with breast cancer by tumor hormone receptor status. We aimed to explore the association between lifetime passive smoking and risk of breast cancer subtypes defined by estrogen receptor and progesterone receptor status among non-smoking Caucasian women. A hospital-based case-control study was performed in 585 cases and 1170 controls aged 28–90 years. Information on lifetime passive smoking and other factors was collected via a self-administered questionnaire. Logistic regression was used for analyses restricted to the 449 cases and 930 controls who had never smoked actively. All statistical tests were two-sided. Adjusted odds ratio of breast cancer was 1.01 (95% confidence interval (CI): 0.72–1.41) in women who experienced exposure to passive smoking at work, 1.88 (95% CI: 1.38–2.55) in women who had exposure at home, and 2.80 (95% CI: 1.84–4.25) in women who were exposed at home and at work, all compared with never exposed regularly. Increased risk was associated with longer exposure: women exposed ≤ 20 years and > 20 years had 1.27 (95% CI: 0.97–1.66) and 2.64 (95% CI: 1.87–3.74) times higher risk of breast cancer compared with never exposed (Ptrend < 0.001). The association of passive smoking with hormone receptor-positive breast cancer did not differ from that with hormone receptor-negative breast cancer (Pheterogeneity > 0.05). There was evidence of interaction between passive smoking intensity and menopausal status in both overall group (P = 0.02) and hormone receptor-positive breast cancer group (P < 0.05). In Caucasian women, lifetime exposure to passive smoking is associated with the risk of breast cancer independent of tumor hormone receptor status with the strongest association in postmenopausal women. PMID:28151962

  6. Mild Lung Tuberculosis in a Patient Suffering from Status Epilepticus Caused by the Syndrome of Inappropriate Secretion of Antidiuretic Hormone (SIADH)

    PubMed Central

    Hashimoto, Mitsuo; Kuriiwa, Saki; Kojima, Ayako; Shinhuku, Kyota; Sato, Akihito; Sasaki, Ryoko; Hasegawa, Tsukasa; Ito, Akihiko; Utsumi, Hirofumi; Yanagisawa, Haruhiko; Wakui, Hiroshi; Minagawa, Shunsuke; Kojima, Jun; Numata, Takanori; Hara, Hiromichi; Araya, Jun; Kaneko, Yumi; Nakayama, Katsutoshi; Kuwano, Kazuyoshi

    2017-01-01

    A 76-year-old woman was diagnosed with lung tuberculosis. On the second day of anti-tuberculosis treatment, she became unconscious and developed status epilepticus accompanied by hyponatremia. The hyponatremia was caused by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Detailed examinations revealed that the patient's status epilepticus had occurred due to hyponatremia, which was caused by lung tuberculosis-associated SIADH. Previous case reports noted that patients with tuberculosis-associated SIADH showed mild clinical manifestations. They also reported that extensive lung involvement was associated with SIADH development. We herein report a rare case of SIADH complicated with status epilepticus that was caused by tuberculosis with mild lung involvement. PMID:28202866

  7. Mild Lung Tuberculosis in a Patient Suffering from Status Epilepticus Caused by the Syndrome of Inappropriate Secretion of Antidiuretic Hormone (SIADH).

    PubMed

    Hashimoto, Mitsuo; Kuriiwa, Saki; Kojima, Ayako; Shinhuku, Kyota; Sato, Akihito; Sasaki, Ryoko; Hasegawa, Tsukasa; Ito, Akihiko; Utsumi, Hirofumi; Yanagisawa, Haruhiko; Wakui, Hiroshi; Minagawa, Shunsuke; Kojima, Jun; Numata, Takanori; Hara, Hiromichi; Araya, Jun; Kaneko, Yumi; Nakayama, Katsutoshi; Kuwano, Kazuyoshi

    2017-01-01

    A 76-year-old woman was diagnosed with lung tuberculosis. On the second day of anti-tuberculosis treatment, she became unconscious and developed status epilepticus accompanied by hyponatremia. The hyponatremia was caused by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Detailed examinations revealed that the patient's status epilepticus had occurred due to hyponatremia, which was caused by lung tuberculosis-associated SIADH. Previous case reports noted that patients with tuberculosis-associated SIADH showed mild clinical manifestations. They also reported that extensive lung involvement was associated with SIADH development. We herein report a rare case of SIADH complicated with status epilepticus that was caused by tuberculosis with mild lung involvement.

  8. A randomized, controlled clinical trial comparing the effects of aromatase inhibitor (letrozole) and gonadotropin-releasing hormone agonist (triptorelin) on uterine leiomyoma volume and hormonal status.

    PubMed

    Parsanezhad, Mohammad Ebrahim; Azmoon, Mina; Alborzi, Saeed; Rajaeefard, Abdoreza; Zarei, Afsun; Kazerooni, Talieh; Frank, Vivian; Schmidt, Ernst Hienrich

    2010-01-01

    To examine and compare the efficacy and safety of GnRH agonist (GnRHa) vs. aromatase inhibitor in premenopausal women with leiomyomas. Multicenter, randomized, controlled clinical trial. University hospitals. A total of 70 subjects with a single uterine myoma measuring >or=5 cm. Subjects were randomized into two groups with use of a random table. They were treated with aromatase inhibitor (group A) or GnRHa (group B). Group A received letrozole (2.5 mg/d) for 12 weeks. Group B received triptorelin (3.75 mg/mo) for 12 weeks. Measurement of myoma volume and E(2), FSH, LH, and T levels. Total myoma volume decreased by 45.6% in group A and 33.2% in group B. Reductions in myoma volume in the two groups were statistically significant. There was no significant change in hormonal milieu in group A. The serum level of hormones significantly decreased in group B by the 12th week of treatment. Uterine myoma volume was successfully reduced by use of an aromatase inhibitor. Rapid onset of action and avoidance of initial gonadotropin flare with an aromatase inhibitor may be advantageous for short-term management of women with myomas of any size who are to be managed transiently and who wish to avoid surgical intervention, specifically women with unexplained infertility having uterine myoma. Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  9. Diagnostic Value of SLC26A4 Mutation Status in Hereditary Hearing Loss With EVA

    PubMed Central

    Lu, Ya-Jie; Yao, Jun; Wei, Qin-Jun; Xing, Guang-Qian; Cao, Xin

    2015-01-01

    Abstract Many SLC26A4 mutations have been identified in patients with nonsyndromic enlarged vestibular aqueduct (EVA). However, the roles of SLC26A4 genotypes and phenotypes in hereditary deafness remain unexplained. This study aims to perform a meta-analysis based on the PRISMA statement to evaluate the diagnostic value of SLC26A4 mutant alleles and their correlations with multiethnic hearing phenotypes in EVA patients. The systematic literature search of the PubMed, Wiley Online Library, EMBASE, Web of Science, and Science Direct databases was conducted in English for articles published before July 15, 2015. Two investigators independently reviewed retrieved literature and evaluated eligibility. Discrepancy was resolved by discussion and a third investigator. Quality of included studies was evaluated using Newcastle-Ottawa Quality Assessment Scale. Data were synthesized using random-effect or fixed-effect models. The effect sizes were estimated by measuring odds ratios (ORs) with 95% confidence interval (CI). Twenty-five eligible studies involved 2294 cases with EVA data. A total of 272 SLC26A4 variations were found in deafness with EVA and 26 mutations of SCL26A4 had higher frequency. The overall OR was 646.71 (95% CI: 383.30–1091.15, P = 0.000). A total of 22 mutants were considered statistically significant in all ethnicities (ORs >1, P < 0.05). In particular, 8 mutants were specificity of EVA phenotypes in mutations of SLC26A4 for Asia deafness populations (ORs >1, P < 0.05), 4 mutants for Europe and North America (ORs >1, P < 0.05), and the IVS7-2A>G mutations in SLC26A4 were found to have the highest frequency in deafness individuals with EVA phenotype (62.42%). Moreover, subgroups for studies limited to cases with EVA phenotype, 11 mutants relevant risks (RRs) were P < 0.05, especially for IVS7-2A>G bi-allelic mutants assayed in a deafness population (RR = 0.880, P = 0.000). Diagnostic accuracy of SLC26A4 mutation results also

  10. Radiosensitization of EGFR/HER2 positive pancreatic cancer is mediated by inhibition of Akt independent of Ras mutational status

    PubMed Central

    Kimple, Randall J.; Vaseva, Angelina V.; Cox, Adrienne D.; Baerman, Kathryn M.; Calvo, Benjamin F.; Tepper, Joel E.; Shields, Janiel M.; Sartor, Carolyn I.

    2009-01-01

    Purpose Epidermal growth factor receptor family members (e.g., EGFR, HER2, HER3, and HER4) are commonly overexpressed in pancreatic cancer. We investigated the effects of inhibition of EGFR/HER2 signaling on pancreatic cancer to elucidate the role(s) of EGFR/HER2 in radiosensitization and to provide evidence in support of further clinical investigations. Experimental Design Expression of EGFR family members in pancreatic cancer lines was assessed by qRT-PCR. Cell growth inhibition was determined by MTS assay. The effects of inhibition of EGFR family receptors and downstream signaling pathways on in vitro radiosensitivity were evaluated using clonogenic assays. Growth delay was used to evaluate the effects of nelfinavir on in vivo tumor radiosensitivity. Results Lapatinib inhibited cell growth in four pancreatic cancer cell lines, but radiosensitized only wild-type K-ras-expressing T3M4 cells. Akt activation was blocked in a wild-type K-ras cell line, whereas constitutive phosphorylation of Akt and ERK was seen in lines expressing mutant K-ras. Overexpression of constitutively-active K-ras(G12V) abrogated lapatinib-mediated inhibition of both Akt phosphorylation and radiosensitization. Inhibition of MEK/ERK signaling with U0126 had no effect on radiosensitization, whereas inhibition of activated Akt with LY294002 (enhancement ratio 1.2–1.8) or nelfinavir (enhancement ratio 1.2–1.4) radiosensitized cells regardless of K-ras mutation status. Oral nelfinavir administration to mice bearing mutant K-ras-containing Capan-2 xenografts resulted in a greater than additive increase in radiation-mediated tumor growth delay (synergy assessment ratio of 1.5). Conclusions Inhibition of EGFR/HER2 enhances radiosensitivity in wild-type K-ras pancreatic cancer. Nelfinavir, and other PI3K/Akt inhibitors, are effective pancreatic radiosensitizers regardless of K-ras mutation status. PMID:20103665

  11. [Effect of combined hormonal oral contraception on the somatic and psychic status of women of reproductive age].

    PubMed

    Vertkin, A L; Nosova, A V

    2012-01-01

    The paper is devoted to the topical problem of maintaining somatic and psychic health of the women of reproductive age by rational pregnancy planning and prevention of abortions by modern methods of contraception including combined oral hormonal contraception. Unfortunately, this approach is rarely employed in this country (5-6%). Results of retrospective analysis of medical documentation, clinical efficacy and safety of modern combined oral hormonal contraception are presented.

  12. Effects of acute and chronic heat stress on plasma metabolites, hormones and oxidant status in restrictedly fed broiler breeders.

    PubMed

    Xie, Jingjing; Tang, Li; Lu, Lin; Zhang, Liyang; Lin, Xi; Liu, Hsiao-Ching; Odle, Jack; Luo, Xugang

    2015-07-01

    Heat tolerance can be improved by feed restriction in broiler chickens. It is unknown whether the same is true for broiler breeders, which are restrictedly fed. Therefore, the current study was conducted to study the effects of heat stress on plasma metabolites, hormones, and oxidative status of restricted fed broiler breeders with special emphases on the temperature and latency of heat exposure. In trial 1, 12 broiler breeders were kept either in a thermoneutral chamber (21°C, control, n = 6) or in a chamber with a step-wise increased environmental temperature from 21 to 33°C (21, 25, 29, 33°C, heat-stressed, n = 6). Changes in plasma total cholesterol, glucose, and triiodothyronine (T3) were closely related to the environmental temperature. When the temperature reached 29°C, plasma T3 (P < 0.05) was significantly decreased in acute heat-stressed birds, whereas plasma glucose (P < 0.001) and cholesterol (P = 0.002) increased only when the temperature reached 33°C. Plasma triglyceride (P = 0.026) and creatine kinase (CK, P = 0.018) were lower in heat-stressed birds than controls regardless of the temperatures applied. In Trial 2, 24 broiler breeders were divided into 2 groups and raised under 21°C and 32°C for 8 weeks, respectively. Total cholesterol was increased in chronic heat-stressed broiler breeders after 4 weeks. Plasma lactate dehydrogenase (LDH, P = 0.047) and glutamic-oxaloacetic transaminase (GOT, P = 0.036) was up-regulated after 6 weeks of thermal treatment, whereas plasma CK (P = 0.009) was increased at the end of thermal treatment. Plasma malonaldehyde, protein carbonyl content, activity of total superoxide dismutase (SOD), and corticosterone content were not altered after acute and prolonged heat challenges. Taken together, acute heat stress primarily resulted in disturbance of plasma metabolites, whereas chronic heat stress caused tissue damage reflected by increased plasma LDA, GOT, and CK. During acute heat stress, plasma metabolites were

  13. Putative relationship between hormonal status and serum pyrrolidone carboxypeptidase activity in pre- and post- menopausal women with breast cancer.

    PubMed

    Carrera-González, María del Pilar; Ramírez-Expósito, María Jesús; Dueñas, Basilio; Martínez-Ferrol, Julia; Mayas, María Dolores; Martínez-Martos, José Manuel

    2012-12-01

    In breast cancer, hormonal changes are rather constant in post-menopausal women since they tend to vary only over long time spans. However, in pre-menopausal women, the development of breast cancer is associated with hormonal physiological variations. The aim of the present work was to analyse the changes in circulating levels of gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in pre- and post-menopausal women that were healthy or with breast cancer, and their connection to serum pyrrolidone carboxypeptidase (Pcp) activity. We observed significant changes in the hormonal profile in post-menopausal women with breast cancer compared to the control group. In pre-menopausal women, we found significant changes in circulating GnRH levels with respect to the healthy group. Our present results support the existence of neuroendocrine misregulation that could be involved in tumour progression, with Pcp being a potentially new pharmacological target in breast cancer treatments. Copyright © 2012 Elsevier Ltd. All rights reserved.

  14. High BRAF Mutation Frequency and Marked Survival Differences in Subgroups According to KRAS/BRAF Mutation Status and Tumor Tissue Availability in a Prospective Population-Based Metastatic Colorectal Cancer Cohort.

    PubMed

    Sorbye, Halfdan; Dragomir, Anca; Sundström, Magnus; Pfeiffer, Per; Thunberg, Ulf; Bergfors, Monica; Aasebø, Kristine; Eide, Geir Egil; Ponten, Fredrik; Qvortrup, Camilla; Glimelius, Bengt

    2015-01-01

    RAS and BRAF mutations impact treatment and prognosis of metastatic colorectal cancer patients (mCRC), but the knowledge is based on trial patients usually not representative for the general cancer population. Patient characteristics, treatment and efficacy according to KRAS, BRAF and MSI status were analyzed in a prospectively collected unselected population-based cohort of 798 non-resectable mCRC patients. The cohort contained many patients with poor performance status (39% PS 2-4) and elderly (37% age>75), groups usually not included in clinical trials. Patients without available tissue micro array (TMA) (42%) had worse prognostic factors and inferior survival (all patients; 7m vs 11m, chemotherapy-treated;12m vs 17m). The 92 patients (21%) with BRAF mutation had a poor prognosis regardless of microsatellite instability, but receipt of 1-2nd chemotherapy was similar to wildtype BRAF patients. Median survival in this cohort varied from 1 month in BRAF mutated patients not given chemotherapy to 26 months in wildtype KRAS/BRAF patients <75 years in good PS. TMA availability, BRAF mutation and KRAS mutation were all independent prognostic factors for survival. The observed 21% BRAF mutation incidence is higher than the previously and repeatedly reported incidence of 5-12% in mCRC. Screening for BRAF mutations before selection of treatment is relevant for many patients, especially outside clinical trials. A BRAF mutation only partly explained the very poor prognosis of many mCRC patients. Survival in unselected metastatic colorectal cancer patients is extremely variable and subgroups have an extremely short survival compared to trial patients. Patients without available TMA had worse prognostic factors and shorter survival, which questions the total generalizability of present TMA studies and implies that we lack information on the biologically worst mCRC cases. Lack of available tissue is an important underexposed issue which introduces sample bias, and this should

  15. Contribution of mammography to MRI screening in BRCA mutation carriers by BRCA status and age: individual patient data meta-analysis.

    PubMed

    Phi, Xuan-Anh; Saadatmand, Sepideh; De Bock, Geertruida H; Warner, Ellen; Sardanelli, Francesco; Leach, Martin O; Riedl, Christopher C; Trop, Isabelle; Hooning, Maartje J; Mandel, Rodica; Santoro, Filippo; Kwan-Lim, Gek; Helbich, Thomas H; Tilanus-Linthorst, Madeleine M A; van den Heuvel, Edwin R; Houssami, Nehmat

    2016-03-15

    We investigated the additional contribution of mammography to screening accuracy in BRCA1/2 mutation carriers screened with MRI at different ages using individual patient data from six high-risk screening trials. Sensitivity and specificity of MRI, mammography and the combination of these tests were compared stratified for BRCA mutation and age using generalised linear mixed models with random effect for studies. Number of screens needed (NSN) for additional mammography-only detected cancer was estimated. In BRCA1/2 mutation carriers of all ages (BRCA1 = 1,219 and BRCA2 = 732), adding mammography to MRI did not significantly increase screening sensitivity (increased by 3.9% in BRCA1 and 12.6% in BRCA2 mutation carriers, P > 0.05). However, in women with BRCA2 mutation younger than 40 years, one-third of breast cancers were detected by mammography only. Number of screens needed for mammography to detect one breast cancer not detected by MRI was much higher for BRCA1 compared with BRCA2 mutation carriers at initial and repeat screening. Additional screening sensitivity from mammography above that from MRI is limited in BRCA1 mutation carriers, whereas mammography contributes to screening sensitivity in BRCA2 mutation carriers, especially those ⩽ 40 years. The evidence from our work highlights that a differential screening schedule by BRCA status is worth considering.

  16. Divergent effects of the 677C>T mutation of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene on ovarian responsiveness and anti-Müllerian hormone concentrations.

    PubMed

    Pavlik, Roman; Hecht, Stephanie; Ochsenkühn, Robert; Noss, Ulrich; Lohse, Peter; Thaler, Christian J

    2011-06-01

    To investigate the influence of the 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C>T mutation on serum anti-Müllerian hormone (AMH) concentrations and on the numbers of oocytes retrieved (NOR) following controlled ovarian hyperstimulation (COH). Prospective cohort study. University-based infertility clinic. Two hundred and seventy women undergoing COH for IVF with or without intracytoplasmic sperm injection. None. AMH levels were determined from blood samples collected after 10 days of GnRH superagonist treatment and before COH. The MTHFR 677C>T genotype was characterized by a TaqMan 5' nuclease assay. AMH serum concentrations correlated significantly with the NOR in all individuals studied. Average (±SD) AMH levels of TT carriers (2.85±2.23 ng/mL) were significantly higher than those of homozygous CC (1.91±1.59 ng/mL) or heterozygous CT individuals (2.23±1.74 ng/mL). When evaluated by multiple regression analysis, AMH had a significant positive effect on NOR, whereas age and MTHFR 677TT genotype had significant negative effects. The MTHFR 677TT genotype is associated with higher serum AMH concentrations and has a negative effect on NOR. This apparent paradox might be resolved in light of recent findings describing a negative feedback function of AMH in the coordination of follicle development. Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  17. IDH mutation status impact on in vivo hypoxia biomarkers expression: new insights from a clinical, nuclear imaging and immunohistochemical study in 33 glioma patients.

    PubMed

    Metellus, Philippe; Colin, Carole; Taieb, David; Guedj, Eric; Nanni-Metellus, Isabelle; de Paula, Andre Maues; Colavolpe, Cécile; Fuentes, Stephane; Dufour, Henry; Barrie, Marylin; Chinot, Olivier; Ouafik, L'houcine; Figarella-Branger, Dominique

    2011-12-01

    Mutations in the gene encoding isocitrate dehydrogenase enzyme isoforms 1 (IDH1) and 2 (IDH2) have recently been identified in a large proportion of glial tumors of the CNS, but their mechanistic role in tumor development remains unclear. Here, we assessed the actual impact of IDH1 and IDH2 mutations in patients harboring WHO grade II and III gliomas. We sequenced IDH1 at codon 132 and IDH2 at codon 172 in 33 patients with WHO grade II and III gliomas who benefited from a preoperative (18)F-FDG positron emission tomography (PET). Immunohistochemical expression of Hypoxia Inducible Factor-1alpha (HIF-1α), Carbonic Anhydrase IX (CAIX), Glucose Transporter 1 (GLUT1) and Caspase 3 active form (CASP3) along with the R132HIDH1 mutation was assessed in all cases as well as 1p/19q deletion status and p53 expression. HIF-1α expression was found in 15% of IDH-mutated compared to 7.7% of IDH-nonmutated tumors (P = 0.954). Also, GLUT-1 positive staining was found in 5% of IDH-mutated and in 7.1% of IDH-nonmutated tumors (P = 0.794). Finally, CA-IX expression was found in 15% of IDH-mutated and in 7.7% of IDH-nonmutated tumors (P = 0.484). The combined expression of these three hypoxic markers was found in two WHO grade III tumors, one of which was IDH-mutated whereas the other was IDH-nonmutated (P = 0.794). In IDH-mutated tumors, the median SUVmax ratio was 2.24 versus 2.15 in IDH-nonmutated tumors (P = 0.775). Together, these data question the actual relationship between IDH mutation status and in vivo hypoxic biomarkers expression in WHO grade II and III gliomas.

  18. Hormone levels

    MedlinePlus

    Blood or urine tests can determine the levels of various hormones in the body. This includes reproductive hormones, thyroid hormones, adrenal hormones, pituitary hormones, and many others. For more information, see: ...

  19. Prognostic Factors for Survival After Recurrence in Patients With Completely Resected Lung Adenocarcinoma: Important Roles of Epidermal Growth Factor Receptor Mutation Status and the Current Staging System.

    PubMed

    Kudo, Yujin; Shimada, Yoshihisa; Saji, Hisashi; Kato, Yasufumi; Yoshida, Koichi; Matsubayashi, Jun; Nagase, Seisuke; Kakihana, Masatoshi; Kajiwara, Naohiro; Ohira, Tatsuo; Nagao, Toshitaka; Ikeda, Norihiko

    2015-11-01

    Epidermal growth factor receptor (EGFR) status and pathological stage (p-stage) were shown to be essential prognostic factors for estimating survival after recurrence of lung adenocarcinoma. In patients with EGFR mutations, those with early p-stage tumors showed better survival after disease recurrence than those with advanced p-stage tumors. The EGFR mutation status and p-stage could also prompt the design of clinical trials on adjuvant therapy for patients after complete surgical resection. The current staging system and epidermal growth factor receptor (EGFR) mutation status are key factors for predicting survival. However, the significance of these factors as predictors of survival after disease recurrence (PRS) has not been sufficiently elucidated. The objective of this study was to investigate the clinicopathological factors, particularly the EGFR mutation status and pathological stage (p-stage), which affect PRS in patients with completely resected lung adenocarcinoma. We retrospectively reviewed the data of 198 consecutive lung adenocarcinoma patients with disease recurrence who previously underwent complete surgical resection in our hospital. Of the 198 patients, 117 were examined for EGFR mutations (mutants). Mutants were detected in 57 patients (28.7%). The patients with mutants had a significantly better 3-year PRS (3y-PRS) rate (68.6%) than those with an EGFR wild type (WT) status (51.7%) or an unknown (UN) status (27.0%). The 3y-PRS rates for p-stage I to II (p-I-II) and p-stage III (p-III) were 52.5% and 29.3%, respectively. Multivariate survival analysis showed that the EGFR mutation status and p-stage had significant associations with favorable PRS. The 3y-PRS rate for mutants/p-I-II (81.4%) was significantly better than that for mutants/p-III (48.0%). Conversely, there was no significant difference between mutants/p-III and WT/UN/p-I-II (3y-PRS: 40.7%) or between mutants/p-III and WT/UN/p-III (3y-PRS: 24.4%). EGFR status and p-stage were shown to

  20. Assessment of MAGE-A expression in resected non-small cell lung cancer in relation to clinicopathologic features and mutational status of EGFR and KRAS.

    PubMed

    Ayyoub, Maha; Memeo, Lorenzo; Alvarez-Fernández, Emilio; Colarossi, Cristina; Costanzo, Rosario; Aiello, Eleonora; Martinetti, Daniela; Valmori, Danila

    2014-10-01

    Non-small cell lung cancer (NSCLC) is a major public health problem, accounting for more cancer-related deaths than any other cancer. Both immunotherapy, based on the expression of tumor-specific antigens, and targeted therapy, based on the presence of oncogenic mutations, are under development for NSCLC. In this study, we analyzed the expression of MAGE-A, a cancer-testis antigen, in tumors from a cohort of patients with resected NSCLC with respect to their clinicopathologic characteristics and their mutational status for the EGFR and KRAS genes. We found MAGE-A expression by IHC in 43% of the tumors. MAGE-A expression was significantly more frequent in squamous tumors than in adenocarcinomas, did not correlate with disease stage, but was correlated significantly with high tumor grade and worse survival. EGFR and KRAS mutations were present in adenocarcinomas, but not in squamous tumors. Whereas the presence of EGFR mutations did not seem to affect survival, the presence of KRAS mutations was associated with early-stage disease and better survival. MAGE-A expression was absent from adenocarcinomas with KRAS mutations, but not significantly different in tumors with or without EGFR mutations. Together, the reported results provide guidance for the design of combination therapies in patients with NSCLC.

  1. [Combined effect of insolation and drinking mineral waters on hormonal and immune status in medium-height mountains.(Experimental study)].

    PubMed

    Polushina, N D; Vasin, V A; Kozhevnikov, S A; Demeshko, N I

    2001-01-01

    80 Wistar male rats were kept for 24 days in moderate altitude conditions of mountain resort Teberda. Before the experiment and after it their blood was examined with enzyme immunoassay for hydrocortisone, T3, T4, TSH, with radioimmunoassay for insulin; glucose levels, dynamics of peripheral blood count, immune status were also measured. It was found that UV radiation has a negative effect on hormonal and immune status of healthy rats in medium-high mountains (hydrocortisone levels fell by 50%, insulin rose 5-6-fold, CIC rose by 24.2%, eosinophils count rose 3-fold, T-cell immunity and lymphocyte phagocyting activity got suppressed, lymphocyte/neutrophil proportion reduced by 35%. Intake of mineral water corrected all the negative effects of insolation but hyperinsulinemia decreased insignificantly.

  2. Hyperpolarized [1-13C] glutamate: a metabolic imaging biomarker of IDH1 mutational status in glioma.

    PubMed

    Chaumeil, Myriam M; Larson, Peder E Z; Woods, Sarah M; Cai, Larry; Eriksson, Pia; Robinson, Aaron E; Lupo, Janine M; Vigneron, Daniel B; Nelson, Sarah J; Pieper, Russell O; Phillips, Joanna J; Ronen, Sabrina M

    2014-08-15

    Mutations of the isocitrate dehydrogenase 1 (IDH1) gene are among the most prevalent in low-grade glioma and secondary glioblastoma, represent an early pathogenic event, and are associated with epigenetically driven modulations of metabolism. Of particular interest is the recently uncovered relationship between the IDH1 mutation and decreased activity of the branched-chain amino acid transaminase 1 (BCAT1) enzyme. Noninvasive imaging methods that can assess BCAT1 activity could therefore improve detection of mutant IDH1 tumors and aid in developing and monitoring new targeted therapies. BCAT1 catalyzes the transamination of branched-chain amino acids while converting α-ketoglutarate (α-KG) to glutamate. Our goal was to use (13)C magnetic resonance spectroscopy to probe the conversion of hyperpolarized [1-(13)C] α-KG to hyperpolarized [1-(13)C] glutamate as a readout of BCAT1 activity. We investigated two isogenic glioblastoma lines that differed only in their IDH1 status and performed experiments in live cells and in vivo in rat orthotopic tumors. Following injection of hyperpolarized [1-(13)C] α-KG, hyperpolarized [1-(13)C] glutamate production was detected both in cells and in vivo, and the level of hyperpolarized [1-(13)C] glutamate was significantly lower in mutant IDH1 cells and tumors compared with their IDH1-wild-type counterparts. Importantly however, in our cells the observed drop in hyperpolarized [1-(13)C] glutamate was likely mediated not only by a drop in BCAT1 activity, but also by reductions in aspartate transaminase and glutamate dehydrogenase activities, suggesting additional metabolic reprogramming at least in our model. Hyperpolarized [1-(13)C] glutamate could thus inform on multiple mutant IDH1-associated metabolic events that mediate reduced glutamate production. ©2014 American Association for Cancer Research.

  3. Nutritional Status Improved in Cystic Fibrosis Patients with the G551D Mutation After Treatment with Ivacaftor.

    PubMed

    Borowitz, Drucy; Lubarsky, Barry; Wilschanski, Michael; Munck, Anne; Gelfond, Daniel; Bodewes, Frank; Schwarzenberg, Sarah Jane

    2016-01-01

    The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gating mutation G551D prevents sufficient ion transport due to reduced channel-open probability. Ivacaftor, an oral CFTR potentiator, increases the channel-open probability. To further analyze improvements in weight and body mass index (BMI) in two studies of ivacaftor in patients aged ≥6 years with CF and the G551D mutation. Patients were randomized 1:1 to ivacaftor 150 mg or placebo every 12 h for 48 weeks. Primary end point (lung function) was reported previously. Other outcomes included weight and height measurements and CF Questionnaire-Revised (CFQ-R). Studies included 213 patients (aged ≤ 20 years, n = 105; aged > 20 years, n = 108). In patients ≤20 years, adjusted mean change from baseline to week 48 in body weight was 4.9 versus 2.2 kg (ivacaftor vs. placebo, p = 0.0008). At week 48, change from baseline in mean weight-for-age z-score was 0.29 versus -0.06 (p < 0.0001); change in mean BMI-for-age z-score was 0.26 versus -0.13 (p < 0.0001). In patients >20 years, adjusted mean change from baseline to week 48 in body weight was 2.7 versus -0.2 kg (p = 0.0003). Mean BMI change at week 48 was 0.9 versus -0.1 kg/m(2) (p = 0.0003). There was no linear correlation evident between changes in body weight and improvements in lung function or sweat chloride. Significant CFQ-R improvements were seen in perception of eating, body image, and sense of ability to gain weight. Nutritional status improved following treatment with ivacaftor for 48 weeks.

  4. Hyperpolarized [1-13C] glutamate: a metabolic imaging biomarker of IDH1 mutational status in glioma

    PubMed Central

    Chaumeil, Myriam M.; Larson, Peder E.Z.; Woods, Sarah M.; Cai, Larry; Eriksson, Pia; Robinson, Aaron E.; Lupo, Janine M.; Vigneron, Daniel B.; Nelson, Sarah J.; Pieper, Russell O.; Phillips, Joanna J.; Ronen, Sabrina M.

    2014-01-01

    Mutations of the isocitrate dehydrogenase 1 (IDH1) gene are among the most prevalent in low-grade glioma and secondary glioblastoma, represent an early pathogenic event, and are associated with epigenetically-driven modulations of metabolism. Of particular interest is the recently uncovered relationship between the IDH1 mutation and decreased activity of the branched-chain amino acid transaminase 1 (BCAT1) enzyme. Non-invasive imaging methods that can assess BCAT1 activity could therefore improve detection of mutant IDH1 tumors and aid in developing and monitoring new targeted therapies. BCAT1 catalyzes the transamination of branched-chain amino acids while converting α-ketoglutarate (α-KG) to glutamate. Our goal was to use 13C magnetic resonance spectroscopy to probe the conversion of hyperpolarized [1-13C] α-KG to hyperpolarized [1-13C] glutamate as a readout of BCAT1 activity. We investigated two isogenic glioblastoma lines that differed only in their IDH1 status, and performed experiments in live cells and in vivo in rat orthotopic tumors. Following injection of hyperpolarized [1-13C] α-KG, hyperpolarized [1-13C] glutamate production was detected both in cells and in vivo, and the level of hyperpolarized [1-13C] glutamate was significantly lower in mutant IDH1 cells and tumors compared to their IDH1-wild-type counterparts. Importantly however, in our cells the observed drop in hyperpolarized [1-13C] glutamate was likely mediated not only by a drop in BCAT1 activity, but also by reductions in aspartate transaminase and glutamate dehydrogenase activities, suggesting additional metabolic reprogramming at least in our model. Hyperpolarized [1-13C] glutamate could thus inform on multiple mutant IDH1-associated metabolic events that mediate reduced glutamate production. PMID:24876103

  5. [The changes in hormonal status of the cardiovascular and the thyroid systems in rats with 18-month type 2 diabetes mellitus].

    PubMed

    Derkach, K V; Ignatieva, P A; Bogush, I V; Balluzek, M F; Shpakov, A O

    2016-01-01

    Among the most common complications of type 2 diabetes mellitus (DM2) are disorders of the cardiovascular and the thyroid systems. The functions of these systems may be weakened with increasing age. However, the mechanisms of these disorders, including the role of alterations in the adenylyl cyclase signaling system (ACSS), are not fully elucidated. Objective was to study thyroid status and ACSS activity of the myocardium and the thyroid gland (TG) of rats with 8- and 18-month DM2 (DM-8 and DM-18) as compared to control animals of the same age (C-8 and C-18). In the myocardium of rats with DM2 an imbalance of β-adrenergic regulation of ACSS was detected, and these disturbances were amplified with increasing age. In the myocardium of rats of the C-18 group the disturbances of ACSS hormonal regulation were also identified, but they were less pronounced. In diabetic rats, the levels of free thyroxine and total triiodothyronine decreased, the level of thyroid stimulating hormone (TSH) increased, and the stimulatory effect of TSH on the ACSS in TG was attenuated, which indicates the hypothyroid state in long-term DM2. In the C-18 group, these changes were absent. Thus, in the myocardium and TG of rats with 18-month DM2 the hormonal regulation of ACSS was violated, which may be one of the causes of cardiovascular pathology and hypothyroid states in long-term DM2.

  6. Interaction of mammographic breast density with menopausal status and postmenopausal hormone use in relation to the risk of aggressive breast cancer subtypes.

    PubMed

    Yaghjyan, Lusine; Tamimi, Rulla M; Bertrand, Kimberly A; Scott, Christopher G; Jensen, Matthew R; Pankratz, V Shane; Brandt, Kathy; Visscher, Daniel; Norman, Aaron; Couch, Fergus; Shepherd, John; Fan, Bo; Chen, Yunn-Yi; Ma, Lin; Beck, Andrew H; Cummings, Steven R; Kerlikowske, Karla; Vachon, Celine M

    2017-09-01

    We examined the associations of mammographic breast density with breast cancer risk by tumor aggressiveness and by menopausal status and current postmenopausal hormone therapy. This study included 2596 invasive breast cancer cases and 4059 controls selected from participants of four nested case-control studies within four established cohorts: the Mayo Mammography Health Study, the Nurses' Health Study, Nurses' Health Study II, and San Francisco Mammography Registry. Percent breast density (PD), absolute dense (DA), and non-dense areas (NDA) were assessed from digitized film-screen mammograms using a computer-assisted threshold technique and standardized across studies. We used polytomous logistic regression to quantify the associations of breast density with breast cancer risk by tumor aggressiveness (defined as presence of at least two of the following tumor characteristics: size ≥2 cm, grade 2/3, ER-negative status, or positive nodes), stratified by menopausal status and current hormone therapy. Overall, the positive association of PD and borderline inverse association of NDA with breast cancer risk was stronger in aggressive vs. non-aggressive tumors (≥51 vs. 11-25% OR 2.50, 95% CI 1.94-3.22 vs. OR 2.03, 95% CI 1.70-2.43, p-heterogeneity = 0.03; NDA 4th vs. 2nd quartile OR 0.54, 95% CI 0.41-0.70 vs. OR 0.71, 95% CI 0.59-0.85, p-heterogeneity = 0.07). However, there were no differences in the association of DA with breast cancer by aggressive status. In the stratified analysis, there was also evidence of a stronger association of PD and NDA with aggressive tumors among postmenopausal women and, in particular, current estrogen+progesterone users (≥51 vs. 11-25% OR 3.24, 95% CI 1.75-6.00 vs. OR 1.93, 95% CI 1.25-2.98, p-heterogeneity = 0.01; NDA 4th vs. 2nd quartile OR 0.43, 95% CI 0.21-0.85 vs. OR 0.56, 95% CI 0.35-0.89, p-heterogeneity = 0.01), even though the interaction was not significant. Our findings suggest that associations of mammographic

  7. Correlations Between the EGFR Mutation Status and Clinicopathological Features of Clinical Stage I Lung Adenocarcinoma

    PubMed Central

    Isaka, Tetsuya; Yokose, Tomoyuki; Ito, Hiroyuki; Nagata, Masashi; Furumoto, Hideyuki; Nishii, Teppei; Katayama, Kayoko; Yamada, Kouzo; Nakayama, Haruhiko; Masuda, Munetaka

    2015-01-01

    Abstract Advanced lung cancers with epidermal growth factor receptor (EGFR) exon 19 deletions (Ex19s) and EGFR exon 21 L858R point mutations (Ex21s) exhibit different clinical behavior. However, these differences are unclear in resectable primary lung tumors. The clinicopathological features of 88 (20.9%) Ex19, 124 (29.4%) Ex21, and 198 (46.9%) EGFR wild-type (Wt) clinical stage I primary adenocarcinomas resected between January 1, 2012 and October 31, 2014 were compared by using Chi-square tests, residual error analysis, analysis of variance, and Tukey tests. Ex21 lesions occurred more frequently in women and never-smokers and had a higher tumor disappearance rate (TDR: 59.6% vs 43.9%; P < 0.001) and lower maximum standardized uptake value (maxSUV: 2.0 vs 3.5; P < 0.01) than Wt lesions; Ex19 lesions had intermediate values (52.8% and 2.6). There was a low frequency of vascular invasion in Ex21 lesions (12.1%; P < 0.05) and a high frequency in Wt lesions (22.7%; P < 0.05). Most Ex19 lesions were intermediate-grade adenocarcinoma (lepidic, acinar, and papillary predominant: 73.9%; P < 0.05). Wt and Ex21 lesions were predominately high-grade (micropapillary or solid predominant, mucinous variant) and low-grade (adenocarcinoma in situ and minimally invasive adenocarcinoma) adenocarcinoma, respectively. Wt lesions had smaller lepidic components (42.1% vs 56.3%; P < 0.001) and larger papillary and solid components (papillary: 15.5% vs 9.0%; P < 0.05; solid: 13.2% vs 3.2%; P < 0.001) than Ex21 lesions. Most Ex19 lesions had intermediate component rates. Most Ex21 lesions were low-grade adenocarcinoma with lepidic growth patterns. Wt high-grade adenocarcinomas included solid and papillary components with vascular invasion. Ex19 lesions were intermediate grade between Ex21 and Wt. PMID:26496308

  8. The effect of mislabeled phenotypic status on the identification of mutation-carriers from SNP genotypes in dairy cattle.

    PubMed

    Biffani, Stefano; Pausch, Hubert; Schwarzenbacher, Hermann; Biscarini, Filippo

    2017-06-26

    Statistical and machine learning applications are increasingly popular in animal breeding and genetics, especially to compute genomic predictions for phenotypes of interest. Noise (errors) in the data may have a negative impact on the accuracy of predictions. The effects of noisy data have been investigated in genome-wide association studies for case-control experiments, and in genomic predictions for binary traits in plants. No studies have been published yet on the impact of noisy data in animal genomics. In this work, the susceptibility to noise of five classification models (Lasso-penalised logistic regression-Lasso, K-nearest neighbours-KNN, random forest-RF, support vector machines with linear-SVML-or radial-SVMR-kernel) was tested. As illustration, the identification of carriers of a recessive mutation in cattle (Bos taurus) was used. A population of 3116 Fleckvieh animals with SNP genotypes on the same chromosome as the mutation locus (BTA 19) was available. The carrier status (0/1 phenotype) was randomly sampled to generate noise. Increasing proportions of noise-up to 20%- were introduced in the data. SVMR and Lasso were relatively more robust to noise in the data, with total accuracy still above 0.975 and TPR (true positive rate; accuracy in the minority class) in the range 0.5-0.80 also with 17.5-20% mislabeled observations. The performance of SVML and RF decreased monotonically with increasing noise in the data, while KNN constantly failed to identify mutation carriers (observations in the minority class). The computation time increased with noise in the data, especially for the two support vector machines classifiers. This work was the first to assess the impact of phenotyping errors on the accuracy of genomic predictions in animal genetics. The choice of the classification method can influence results in terms of higher or lower susceptibility to noise. In the presented problem, SVM with radial kernel performed relatively well even when the proportion

  9. Customized chemotherapy based on epidermal growth factor receptor mutation status for elderly patients with advanced non-small-cell lung cancer: a phase II trial

    PubMed Central

    2012-01-01

    Background Elderly patients are more vulnerable to toxicity from chemotherapy. Activating epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer (NSCLC) are associated with enhanced response to EGFR tyrosine-kinase inhibitors. We studied patients with advanced NSCLC for whom treatment was customized based on EGFR mutation status. Methods We screened 57 chemotherapy-naïve patients with histologically or cytologically confirmed NSCLC, stage IIIB or IV, aged 70 years or older, and with an Eastern Cooperative Oncology Group performance status 0 or 1, for EGFR exon 19 codon 746–750 deletion and exon 21 L858R mutation. Twenty-two patients with EGFR mutations received gefitinib; 32 patients without mutations received vinorelbine or gemcitabine. The primary endpoint was the response rate. Results The response rate was 45.5% (95% confidence interval [CI]: 24.4%, 67.8%) in patients with EGFR mutations and 18.8% (95% CI: 7.2%, 36.4%) in patients without EGFR mutations. The median overall survival was 27.9 months (95%CI: 24.4 months, undeterminable months) in patients with EGFR mutations and 14.9 months (95%CI: 11.0 months, 22.4 months) in patients without EGFR mutations. In the gefitinib group, grade 3/4 hepatic dysfunction and dermatitis occurred in 23% and 5% of patients, respectively. In patients treated with vinorelbine or gemcitabine, the most common grade 3 or 4 adverse events were neutropenia (47%; four had febrile neutropenia), anemia (13%), and anorexia (9%). No treatment-related deaths occurred. Conclusions Treatment customization based on EGFR mutation status deserves consideration, particularly for elderly patients who often cannot receive second-line chemotherapy due to poor organ function or comorbidities. Trial registration This trial is registered at University hospital Medical Information Network-clinical trial registration (http://www.umin.ac.jp/ctr/index/htm) with the registration identification number C000000436

  10. Severe Acute Malnutrition in Childhood: Hormonal and Metabolic Status at Presentation, Response to Treatment, and Predictors of Mortality

    PubMed Central

    Bartz, Sarah; Mody, Aaloke; Hornik, Christoph; Bain, James; Muehlbauer, Michael; Kiyimba, Tonny; Kiboneka, Elizabeth; Stevens, Robert; Bartlett, John; St Peter, John V.; Newgard, Christopher B.

    2014-01-01

    Objective: Malnutrition is a major cause of childhood morbidity and mortality. To identify and target those at highest risk, there is a critical need to characterize biomarkers that predict complications prior to and during treatment. Methods: We used targeted and nontargeted metabolomic analysis to characterize changes in a broad array of hormones, cytokines, growth factors, and metabolites during treatment of severe childhood malnutrition. Children aged 6 months to 5 years were studied at presentation to Mulago Hospital and during inpatient therapy with milk-based formulas and outpatient supplementation with ready-to-use food. We assessed the relationship between baseline hormone and metabolite levels and subsequent mortality. Results: Seventy-seven patients were enrolled in the study; a subset was followed up from inpatient treatment to the outpatient clinic. Inpatient and outpatient therapies increased weight/height z scores and induced striking changes in the levels of fatty acids, amino acids, acylcarnitines, inflammatory cytokines, and various hormones including leptin, insulin, GH, ghrelin, cortisol, IGF-I, glucagon-like peptide-1, and peptide YY. A total of 12.2% of the patients died during hospitalization; the major biochemical factor predicting mortality was a low level of leptin (P = .0002), a marker of adipose tissue reserve and a critical modulator of immune function. Conclusions: We have used metabolomic analysis to provide a comprehensive hormonal and metabolic profile of severely malnourished children at presentation and during nutritional rehabilitation. Our findings suggest that fatty acid metabolism plays a central role in the adaptation to acute malnutrition and that low levels of the adipose tissue hormone leptin associate with, and may predict, mortality prior to and during treatment. PMID:24606092

  11. Effects of nutritional status on hormone concentrations of the somatotropin axis and metabolites in plasma and colostrum of Japanese Black cows.

    PubMed

    Phomvisith, Ouanh; Takahashi, Hideyuki; Mai, Ha Thi; Shiotsuka, Yuji; Matsubara, Atsuko; Sugino, Toshihisa; Mcmahon, Christopher D; Etoh, Tetsuji; Fujino, Ryoichi; Furuse, Mitsuhiro; Gotoh, Takafumi

    2017-04-01

    We aimed to determine the effects of nutritional status on concentrations of somatotropic axis hormones (growth hormone (GH) and insulin-like growth factor 1 (IGF-1)), insulin and metabolites (glucose, total protein and nonesterified fatty acids (NEFA)) in the plasma and colostrum in late antepartum cows. Eight pregnant Japanese Black cows were randomly assigned to two experimental groups (n = 4 per group). Control cows (CON) received 100% of their nutritional requirements until parturition, whereas restricted group cows (RES) received 60% of their nutritional requirements. Blood samples were taken during the antepartum period, and blood and colostrum samples were collected on days 0, 1, and 3 after calving. Compared to the CON group, the RES group had higher concentrations of GH and NEFA in plasma, but significantly lower concentrations of glucose and insulin in plasma. The concentrations of GH in plasma after calving were significantly higher, but total plasma protein was significantly lower in RES than in CON cows. Compared to the CON group, the RES group had significantly higher concentrations of GH in colostrum, but significantly lower total concentrations of protein in colostrum. Concentrations of IGF-1 were not different between the two groups. These findings suggest that maternal nutritional status during late gestation influences concentrations of GH and total protein in the blood and colostrum of Japanese Black cows.

  12. Maternal diabetes mellitus, a rat model for nonthyroidal illness: correction of hypothyroxinemia with thyroxine treatment does not improve fetal thyroid hormone status.

    PubMed

    Calvo, R; Morreale de Escobar, G; Escobar del Rey, F; Obregón, M J

    1997-02-01

    Maintenance of normal maternal thyroxinemia prevents severe triiodothyronine (T3) deficiency of the fetus with primary thyroid failure (1). We have studied whether thyroxine (T4) would also protect the fetal brain when maternal hypothyroxinemia is caused by nonthyroidal illnesses. We have used the streptozotocin-induced diabetes mellitus pregnant rat as a model of maternal nonthyroidal illness. We measured the effects of diabetes mellitus, and of correction of the ensuing maternal hypothyroxinemia with T4 as compared to insulin, on maternal body weight, the outcome of pregnancy, glucose, insulin, T4, T3, reverse T3, and thyrotropin levels in the maternal and fetal circulation, as well as T4 and T3 concentrations in tissues, and iodothyronine deiodinases in liver, lung, and brain. The diabetic mothers showed changes in thyroid hormone status typical of nonthyroidal illnesses. Thyroid hormone status of the fetuses was severely affected: the total T4 and T3 pools decreased to one-third of normal values. T4 and T3 concentrations in the fetal brain were lower than normal and the expected increase in 5'-deiodinase activity was not observed. Although insulin treatment avoided or mitigated these changes, the low cerebral T3 did not improve with T4 treatment of the maternal hypothyroxinemia. Several findings indicated that treatment of the severely ill dams with T4 was actually harmful for the outcome of pregnancy. These negative effects were observed without the expected increase in the maternal or fetal T3 pools.

  13. COBLL1, LPL and ZAP70 expression defines prognostic subgroups of chronic lymphocytic leukemia patients with high accuracy and correlates with IGHV mutational status.

    PubMed

    Plesingerova, Hana; Librova, Zuzana; Plevova, Karla; Libra, Antonin; Tichy, Boris; Skuhrova Francova, Hana; Vrbacky, Filip; Smolej, Lukas; Mayer, Jiri; Bryja, Vitezslav; Doubek, Michael; Pospisilova, Sarka

    2017-01-01

    The clinical course of chronic lymphocytic leukemia (CLL) is highly variable. Patients with unmutated IGHV (U-CLL) usually progress rapidly, whereas patients with mutated IGHV (M-CLL) have a more indolent disease. The expression of several genes correlates closely with the IGHV mutational status and could be used to assess prognosis in CLL. We analyzed the prognostic relevance of COBLL1, LPL, and ZAP70 gene expression, which correlated with IGHV mutational status (p < 0.0001), in 117 CLL patients and established a prognostic parameter dividing the tested cohort according to the disease aggressiveness. Our prognostic parameter was validated on an independent cohort of 161 CLL patients and achieved a high accuracy (94%). Patients divided according to the prognostic parameter differ in overall survival and time to first treatment (p < 0.0001, HR  = 2.300/5.970, 95% CI: 1.587-3.450/4.621-15.86). Our approach provides a reliable alternative method to prognosis assessment via IGHV mutational status analysis.

  14. TH1/TH2 cytokine profile, metalloprotease-9 activity and hormonal status in pregnant rheumatoid arthritis and systemic lupus erythematosus patients

    PubMed Central

    MUÑOZ-VALLE, J F; VÁZQUEZ-DEL MERCADO, M; GARCÍA-IGLESIAS, T; OROZCO-BAROCIO, G; BERNARD-MEDINA, G; MARTÍNEZ-BONILLA, G; BASTIDAS-RAMÍREZ, B E; NAVARRO, A D; BUENO, M; MARTÍNEZ-LÓPEZ, E; BEST-AGUILERA, C R; KAMACHI, M; ARMENDÁRIZ-BORUNDA, J

    2003-01-01

    During the course of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), several immune and neuroendocrine changes associated with pregnancy may exert positive (amelioration) or negative (exacerbation) effects on the clinical outcome. In order to shed light on the mechanisms underlying these responses, we performed a prospective longitudinal study in RA and SLE pregnant women, including healthy pregnant women as a control group. Cytokine messenger RNA (mRNA) expression assessed by quantitative competitive polymerase chain reaction (PCR) in peripheral blood mononuclear cells (PBMC), cytokine levels and lymphocyte proliferation responses (LPR) following phytohaemagglutinin (PHA) stimulation of PBMC, plasma metalloprotease-9 activity (MMP-9) and hormonal status during pregnancy were determined. TNFa was the most abundant cytokine mRNA expressed in PBMC in all groups studied (healthy pregnant women, RA and SLE pregnant patients). However, a general TH2 response reflected by high IL-10 levels was found in RA, as well as SLE, patients. A significant change in IFN-γ was observed in RA patients but only during the first trimester of pregnancy. This compared with a major TH1 response in healthy pregnant women. Interestingly, our study showed a homogeneous hormonal pattern in RA and SLE patients. Although decreased cortisol levels were observed in all patients studied, this is possibly related to the remission of disease activity status brought about by steroid treatment before and during pregnancy. In summary, we suggest that complex immune and hormonal networks are involved in pregnancy and that rheumatic diseases are very dynamic immune processes that cannot be described with a clear-cut cytokine profile. Furthermore, the observations in this study may reflect treatment-related immune effects more than those associated with disease. PMID:12562402

  15. Evidence for a dualistic model of high-grade serous carcinoma: BRCA mutation status, histology, and tubal intraepithelial carcinoma.

    PubMed

    Howitt, Brooke E; Hanamornroongruang, Suchanan; Lin, Douglas I; Conner, James E; Schulte, Stephanie; Horowitz, Neil; Crum, Christopher P; Meserve, Emily E

    2015-03-01

    Most early adnexal carcinomas detected in asymptomatic women with germline BRCA mutations (BRCA) present as serous tubal intraepithelial carcinomas (STIC). However, STICs are found in only ∼40% of symptomatic high-grade serous carcinomas (HGSCs) and less frequently in pseudoendometrioid variants of HGSC. Consecutive cases of untreated HGSC from BRCA and BRCA women with detailed fallopian tube examination (SEE-FIM protocol) were compared. STIC status (+/-) was determined, and tumors were classified morphologically as SET ("SET", >50% solid, pseudoendometrioid, or transitional) or classic predominate ("Classic"). SET tumors trended toward a higher frequency in BRCA versus BRCA women (50% vs. 28%, P=0.11), had a significantly younger mean age than those with classic HGSC in BRCA women (mean 56.2 vs. 64.8 y, P=0.04), and displayed a better clinical outcome in both groups combined (P=0.024). STIC was significantly more frequent in tumors from the BRCA cohort (66% vs. 31%, P=0.017) and specifically the BRCA tumors with classic morphology (83%) versus those with SET morphology (22%, P=0.003). Overall, several covariables-histology, BRCA status, age, coexisting STIC, and response to therapy-define 2 categories of HGSC with differences in precursor (STIC) frequency, morphology, and outcome. We introduce a dualistic HGSC model that could shed light on the differences in frequency of STIC between symptomatic and asymptomatic women with HGSC. This model emphasizes the need for further study of HGSC precursors to determine their relevance to the prevention of this lethal malignancy.

  16. Dominant negative effect of mutated thyroid stimulating hormone receptor (P556L) causes hypothyroidism in C.RF-Tshr(hyt/wild) mice.

    PubMed

    Endo, Toyoshi; Kobayashi, Tetsuro

    2012-01-01

    C.RF-Tshr(hyt/hyt) mice have a mutated thyroid stimulating hormone receptor (P556L-TSHR) and these mice develop severe hypothyroidism. We found that C.RF-Tshr(hyt/wild) heterozygous mice are also in a hypothyroid state. Thyroid glands from C.RF-Tshr(hyt/wild) mice are smaller than those from wild-type mice, and (125)I uptake activities of the former are significantly lower than those in the latter. When TSHR (TSHR(W)) and P556L-TSHR (TSHR(M)) cDNAs were cloned and co-transfected into HEK 293 cells, the cells retained (125)I-TSH binding activity, but cAMP response to TSH was decreased to about 20% of HEK 293 cells transfected with TSHR(W) cDNA. When TSHR(W) and TSHR(M) were tagged with eCFP or eYFP, we observed fluorescence resonance energy transfer (FRET) in HEK 293 cells expressing TSHR(W)-eCFP and TSHR(W)-eYFP in the absence of TSH, but not in the presence of TSH. In contrast, we obtained FRET in HEK 293 cells expressing TSHR(W)-eCFP and TSHR (M)-eYFP, regardless of the presence or absence of TSH. These results suggest that P556L TSHR has a dominant negative effect on TSHR(W) by impairing polymer to monomer dissociation, which decreases TSH responsiveness and induces hypothyroidism in C.RF-Tshr(hyt/wild) mice.

  17. Mutational status of NRAS, KRAS, and PTPN11 genes is associated with genetic/cytogenetic features in children with B-precursor acute lymphoblastic leukemia.

    PubMed

    Liang, Der-Cherng; Chen, Shih-Hsiang; Liu, Hsi-Che; Yang, Chao-Ping; Yeh, Ting-Chi; Jaing, Tang-Her; Hung, Iou-Jih; Hou, Jen-Yin; Lin, Tung-Huei; Lin, Chun-Hui; Shih, Lee-Yung

    2017-08-29

    We aimed to investigate the frequencies and the association with genetic/cytogenetic abnormalities as well as prognostic relevance of RAS pathway mutations in Taiwanese children with B-precursor acute lymphoblastic leukemia (ALL), the largest cohort in Asians. Between 1995 and 2012, marrow samples at diagnosis from 535 children were studied for NRAS, KRAS, and PTPN11 mutations. The mutational status of each gene was correlated with the clinico-hematological features, recurrent genetic abnormalities, and outcomes for those treated with TPOG-ALL-2002 protocol (n = 346). The frequencies of NRAS, KRAS, and PTPN11 mutations were 10.8% (57/530), 10.2% (54/530), and 3.0% (16/526), respectively. NRAS mutations were associated with a higher frequency of hyperdiploidy (P = 0.01) and lower frequency of ETV6-RUNX1 (P < 0.01), whereas KRAS mutations were associated with younger age (P < 0.01), a higher frequency of KMT2A rearranged (P < 0.01) but no significant difference if infants with ALL were excluded, and inferior event-free survival (66.6% vs. 80.5%, P = 0.04). None of patients with TCF3-PBX1 had KRAS mutation (P = 0.02). Our study showed that the frequency of KRAS mutations in Taiwan was significantly higher than that reported in Caucasians. The occurrence of RAS pathway mutations was associated with recurrent genetic/cytogenetic abnormalities in pediatric B-precursor ALL. © 2017 Wiley Periodicals, Inc.

  18. Distinct patterns of KRAS mutations in colorectal carcinomas according to germline mismatch repair defects and hMLH1 methylation status.

    PubMed

    Oliveira, Carla; Westra, Jantine L; Arango, Diego; Ollikainen, Miina; Domingo, Enric; Ferreira, Ana; Velho, Sérgia; Niessen, Renee; Lagerstedt, Kristina; Alhopuro, Pia; Laiho, Paivi; Veiga, Isabel; Teixeira, Manuel R; Ligtenberg, Marjolijn; Kleibeuker, Jan H; Sijmons, Rolf H; Plukker, John T; Imai, Kohzoh; Lage, Pedro; Hamelin, Richard; Albuquerque, Cristina; Schwartz, Simo; Lindblom, Annika; Peltomaki, Päivi; Yamamoto, Hiroyuki; Aaltonen, Lauri A; Seruca, Raquel; Hofstra, Robert M W

    2004-10-01

    In sporadic colorectal tumours the BRAFV600E is associated with microsatellite instability (MSI-H) and inversely associated to KRAS mutations. Tumours from hereditary non-polyposis colorectal cancer (HNPCC) patients carrying germline mutations in hMSH2 or hMLH1 do not show BRAFV600E, however no consistent data exist regarding KRAS mutation frequency and spectrum in HNPCC tumours. We investigated KRAS in 158 HNPCC tumours from patients with germline hMLH1, hMSH2 or hMSH6 mutations, 166 MSI-H and 688 microsatellite stable (MSS) sporadic carcinomas. All tumours were characterized for MSI and 81 of 166 sporadic MSI-H colorectal cancer (CRCs) were analysed for hMLH1 promoter hypermethylation. KRAS mutations were observed in 40% of HNPCC tumours, and the mutation frequency varied upon the mismatch repair gene affected: 48% (29/61) in hMSH2, 32% (29/91) in hMLH1 and 83% (5/6) in hMSH6 (P = 0.01). KRAS mutation frequency was different between HNPCC, MSS and MSI-H CRCs (P = 0.002), and MSI-H with hMLH1 hypermethylation (P = 0.005). Furthermore, HNPCC CRCs had more G13D mutations than MSS (P < 0.0001), MSI-H (P = 0.02) or MSI-H tumours with hMLH1 hypermethylation (P = 0.03). HNPCC colorectal and sporadic MSI-H tumours without hMLH1 hypermethylation shared similar KRAS mutation frequency, in particular G13D. In conclusion, we show that depending on the genetic/epigenetic mechanism leading to MSI-H, the outcome in terms of oncogenic activation may be different, reinforcing the idea that HNPCC, sporadic MSI-H (depending on the hMLH1 status) and MSS CRCs, may target distinct kinases within the RAS/RAF/MAPK pathway.

  19. Correlation of KIT and PDGFRA mutational status with clinical benefit in patients with gastrointestinal stromal tumor treated with sunitinib in a worldwide treatment-use trial.

    PubMed

    Reichardt, Peter; Demetri, George D; Gelderblom, Hans; Rutkowski, Piotr; Im, Seock-Ah; Gupta, Sudeep; Kang, Yoon-Koo; Schöffski, Patrick; Schuette, Jochen; Soulières, Denis; Blay, Jean-Yves; Goldstein, David; Fly, Kolette; Huang, Xin; Corsaro, Massimo; Lechuga, Maria Jose; Martini, Jean-Francois; Heinrich, Michael C

    2016-01-15

    Several small studies indicated that the genotype of KIT or platelet-derived growth factor receptor-α (PDGFRA) contributes in part to the level of clinical effectiveness of sunitinib in gastrointestinal stromal tumor (GIST) patients. This study aimed to correlate KIT and PDGFRA mutational status with clinical outcome metrics (progression-free survival [PFS], overall survival [OS], objective response rate [ORR]) in a larger international patient population. This is a non-interventional, retrospective analysis in patients with imatinib-resistant or intolerant GIST who were treated in a worldwide, open-label treatment-use study (Study 1036; NCT00094029) in which sunitinib was administered at a starting dose of 50 mg/day on a 4-week-on, 2-week-off schedule. Molecular status was obtained in local laboratories with tumor samples obtained either pre-imatinib, post-imatinib/pre-sunitinib, or post-sunitinib treatment, and all available data were used in the analyses regardless of collection time. The primary analysis compared PFS in patients with primary KIT exon 11 versus exon 9 mutations (using a 2-sided log-rank test) and secondary analyses compared OS (using the same test) and ORR (using a 2-sided Pearson χ(2) test) in the same molecular subgroups. Of the 1124 sunitinib-treated patients in the treatment-use study, 230 (20%) were included in this analysis, and baseline characteristics were similar between the two study populations. Median PFS was 7.1 months. A significantly better PFS was observed in patients with a primary mutation in KIT exon 9 (n = 42) compared to those with a primary mutation in exon 11 (n = 143; hazard ratio = 0.59; 95 % confidence interval, 0.39-0.89; P = 0.011), with median PFS times of 12.3 and 7.0 months, respectively. Similarly, longer OS and higher ORR were observed in patients with a primary KIT mutation in exon 9 versus exon 11. The data available were limited to investigate the effects of additional KIT or PDGFRA mutations on the efficacy

  20. BRAF mutations and phosphorylation status of mitogen-activated protein kinases in the development of flat and depressed-type colorectal neoplasias.

    PubMed

    Konishi, K; Takimoto, M; Kaneko, K; Makino, R; Hirayama, Y; Nozawa, H; Kurahashi, T; Kumekawa, Y; Yamamoto, T; Ito, H; Yoshikawa, N; Kusano, M; Nakayama, K; Rembacken, B J; Ota, H; Imawari, M

    2006-01-30

    Although some molecular differences between flat-depressed neoplasias (FDNs) and protruding neoplasias (PNs) have been reported, it is uncertain if the BRAF mutations or the status of phosphorylated mitogen-activated protein kinase (p-MAPK) are different between theses two groups. We evaluated the incidence of BRAF and KRAS mutations, high-frequency microsatellite instability (MSI-H), and the immunohistochemical status of p-MAPK in the nonserrated neoplasias (46 FDNs and 57 PNs). BRAF mutations were detected in four FDNs (9%) and none of PNs (P=0.0369 by Fisher's exact test). KRAS mutations were observed in none of FDNs and in 14 PNs (25%; P=0.0002 by Fisher's exact test). MSI-H was detected in seven out of 44 FDNs (16%) and in one out of 52 of PNs (2%) (P=0.022 by Fisher's exact test). Type B and C immunostaining for p-MAPK was observed in 34 out of 46 FDNs (72%), compared with 24 out of 55 PNs (44%; P=0.0022 by chi(2) test). There was no significant difference in the type B and C immunostaining of p-MAPK between FDNs with and without BRAF mutations. BRAF and KRAS mutations are mutually exclusive in the morphological characteristics of