Clinical diagnostic accuracy of acute colonic diverticulitis in patients admitted with acute abdominal pain, a receiver operating characteristic curve analysis.

PURPOSE: The study investigated the capability of clinical findings, temperature, C-reactive protein (CRP), and white blood cell (WBC) count to discern patients with acute colonic diverticulitis from all other patients admitted with acute abdominal pain. METHODS: The probability of acute diverticulitis was assessed by the examining doctor, using a scale from 0 (zero probability) to 10 (100 % probability). Receiver operating characteristic (ROC) curves were used to assess the clinical diagnostic accuracy of acute colonic diverticulitis in patients admitted with acute abdominal pain. RESULTS: Of 833 patients admitted with acute abdominal pain, 95 had acute colonic diverticulitis. ROC curve analysis gave an area under the ROC curve (AUC) of 0.95 (CI 0.92 to 0.97) for ages <65 years, AUC = 0.86 (CI 0.78 to 0.93) in older patients. Separate analysis showed an AUC = 0.83 (CI 0.80 to 0.86) of CRP alone. White blood cell count and temperature were almost useless to discriminate acute colonic diverticulitis from other types of acute abdominal pain, AUC = 0.59 (CI 0.53 to 0.65) for white blood cell count and AUC = 0.57 (0.50 to 0.63) for temperature, respectively. CONCLUSION: This prospective study demonstrates that standard clinical evaluation by non-specialist doctors based on history, physical examination, and initial blood tests on admission provides a high degree of diagnostic precision in patients with acute colonic diverticulitis.

Risk factors for requiring cholecystectomy for gallstone disease in a prospective population-based cohort study.

BACKGROUND: The relationship between different lifestyle factors and the risk of needing cholecystectomy for gallstone disease is not clear. This study aimed to assess the association between anthropometric, lifestyle and sociodemographic risk factors and the subsequent risk of requiring cholecystectomy for gallstone disease during long-term follow-up in a defined population cohort. METHODS: Data from a large population-based cohort study performed from 1995 to 1997 were used (the second Norwegian Nord-Trøndelag health study, HUNT2). Following HUNT2, from 1998 to 2011, all patients operated on for gallstone disease with cholecystectomy at the two hospitals in the county, Levanger Hospital and Namsos Hospital, were identified. A Cox proportional hazards model was used for multivariable risk analysis. RESULTS: The HUNT2 cohort included 65 237 individuals (69·5 per cent response rate), aged 20-99 years. During a median follow-up of 15·3 (range 0·6-16·4) years, 1162 cholecystectomies were performed. In multivariable analysis, overweight individuals (body mass index (BMI) 25·0-29·9 kg/m(2) ) had a 58 per cent increased risk of cholecystectomy compared with individuals with normal weight (BMI less than 25·0 kg/m(2) ). Obese individuals (BMI 30 kg/m(2) or above) had a twofold increased risk. Increasing waist circumference independently increased the risk of cholecystectomy. In women, current hormone replacement therapy (HRT) increased the risk, whereas hard physical activity and higher educational level were associated with reduced risk of cholecystectomy. CONCLUSION: High BMI and waist circumference increased the risk of having cholecystectomy for both sexes. In women, the risk was increased by HRT, and decreased by hard physical activity and higher educational level.

Prior statin use and 90-day mortality in Gram-negative and Gram-positive bloodstream infection: a prospective observational study.

In several studies on patients with bloodstream infection (BSI), prior use of statins has been associated with improved survival. Gram-positive and Gram-negative bacteria alert the innate immune system in different ways. We, therefore, studied whether the relation between prior statin use and 90-day total mortality differed between Gram-positive and Gram-negative BSI. We conducted a prospective observational cohort study of 1,408 adults with BSI admitted to Levanger Hospital between January 1, 2002, and December 31, 2011. Data on the use of statins and other medications at admission, comorbidities, functional status, treatment, and outcome were obtained from the patients' hospital records. The relation of statin use with 90-day mortality differed between Gram-negative and Gram-positive BSI (p-value for interaction 0.01). Among patients with Gram-negative BSI, statin users had significantly lower 90-day total mortality [odds ratio (OR) 0.42, 95 % confidence interval (CI) 0.23-0.75, p = 0.003]. The association remained essentially unchanged after adjusting for the effect of sex, age, functional status before the infection, and underlying diseases that were considered confounders (adjusted OR 0.38, 95 % CI 0.20-0.72, p = 0.003). A similar analysis of patients with Gram-positive BSI showed no association of statin use with mortality (adjusted OR 1.22, 95 % CI 0.69-2.17, p = 0.49). The present study suggests that prior statin use is associated with a lower 90-day total mortality in Gram-negative BSI, but not in Gram-positive BSI.

Acute Glomerulonephritis as a Paraneoplastic Syndrome Secondary to Urachal Adenocarcinoma: An Unknown Entity.

Urachal carcinoma is an uncommon malignancy with a peculiar biomolecular characterization and therefore a complex approach. It was incorporated by the World Health Organization in 2004 in the tumors of the urinary system classification. This neoplasm is generally diagnosed in advanced stages. The standard treatment is surgical, however, due to the rarity and relatively late clinical manifestation of urachal carcinomas, the survival data are mostly case reports, as well as information about medical-surgical treatment based on evidence. The data used were extracted from both the physical and electronic clinical records. Among atypical presentations reported in the literature, we report a case of urachal adenocarcinoma with simultaneous glomerulonephritis as a paraneoplastic syndrome of which there is no report to date. Surgery was carried out in our patient, unfortunately with lifetime morbidity from kidney function replacement secondary to kidney function damage by glomerulonephritis, despite previous immunosuppression treatment for rapidly progressive glomerulonephritis. It is worth mentioning that if the initial diagnosis represents a clinical challenge, treatment is even more complex, given the little information that currently exists about it. Urachal carcinoma is a diagnostic and treatment challenge. Up to now, surgery has been the treatment of choice in localized or locally advanced disease, however, with a high morbidity for the patient.

Revisiting the utility of identifying nuclear grooves as unique nuclear changes by an object detector model.

BACKGROUND: Among other structures, nuclear grooves are vastly found in papillary thyroid carcinoma (PTC). Considering that the application of artificial intelligence in thyroid cytology has potential for diagnostic routine, our goal was to develop a new supervised convolutional neural network capable of identifying nuclear grooves in Diff-Quik stained whole-slide images (WSI) obtained from thyroid fineneedle aspiration. METHODS: We selected 22 Diff-Quik stained cytological slides with cytological diagnosis of PTC and concordant histological diagnosis. Each of the slides was scanned, forming a WSI. Images that contained the region of interest were obtained, followed by pre-formatting, annotation of the nuclear grooves and data augmentation techniques. The final dataset was divided into training and validation groups in a 7:3 ratio. RESULTS: This is the first artificial intelligence model based on object detection applied to nuclear structures in thyroid cytopathology. A total of 7,255 images were obtained from 22 WSI, totaling 7,242 annotated nuclear grooves. The best model was obtained after it was submitted 15 times with the train dataset (14th epoch), with 67% true positives, 49.8% for sensitivity and 43.1% for predictive positive value. CONCLUSIONS: The model was able to develop a structure predictor rule, indicating that the application of an artificial intelligence model based on object detection in the identification of nuclear grooves is feasible. Associated with a reduction in interobserver variability and in time per slide, this demonstrates that nuclear evaluation constitutes one of the possibilities for refining the diagnosis through computational models.

Endogenous expression of Hras(G12V) induces developmental defects and neoplasms with copy number imbalances of the oncogene.

We developed mice with germline endogenous expression of oncogenic Hras to study effects on development and mechanisms of tumor initiation. They had high perinatal mortality, abnormal cranial dimensions, defective dental ameloblasts, and nasal septal deviation, consistent with some of the features of human Costello syndrome. These mice developed papillomas and angiosarcomas, which were associated with Hras(G12V) allelic imbalance and augmented Hras signaling. Endogenous expression of Hras(G12V) was also associated with a higher mutation rate in vivo. Tumor initiation by Hras(G12V) likely requires augmentation of signal output, which in papillomas and angiosarcomas is achieved via increased Hras-gene copy number, which may be favored by a higher mutation frequency in cells expressing the oncoprotein.

Muscle Stem Cell Function Is Impaired in ß2-Adrenoceptor Knockout Mice.

Knockout (ko) mice for the ß2 adrenoceptor (Adrß2) have impaired skeletal muscle regeneration, suggesting that this receptor is important for muscle stem cell (satellite cell) function. Here, we investigated the role of Adrß2 in the function of satellite cells from ß2ko mice in the context of muscle regeneration, through in vivo and in vitro experiments. Immunohistochemical analysis showed a significant reduction in the number of self-renewed Pax7+ satellite cells, proliferating Pax7+/MyoD+ myogenic precursor cells, and regenerating eMHC+ myofibers in regenerating muscle of ß2ko mice at 30, 3, and 10 days post-injury, respectively. Quiescent satellite cells were isolated by fluorescence-activated cell sorting, and cell cycle entry was assessed by EdU incorporation. The results demonstrated a lower number of proliferating Pax7+/EdU+ satellite cells from ß2ko mice. There was an increase in the gene expression of the cell cycle inhibitor Cdkn1a and Notch pathway components and the activation of Notch signaling in proliferating myoblasts from ß2ko mice. There was a decrease in the number of myogenin-positive nuclei in myofibers maintained in differentiation media, and a lower fusion index in differentiating myoblasts from ß2ko mice. Furthermore, the gene expression of Wnt/ß-catenin signaling components, the expression of nuclear ß-catenin and the activation of Wnt/ß-catenin signaling decreased in differentiating myoblasts from ß2ko mice. These results indicate that Adrß2 plays a crucial role in satellite cell self-renewal, as well as in myoblast proliferation and differentiation by regulating Notch and Wnt/ß-catenin signaling, respectively.

Thyroid and Breast Cancer in 2 Sisters With Monoallelic Mutations in the Ataxia Telangiectasia Mutated (ATM) Gene.

The presence of a bidirectional risk for metachronous carcinomas among women with thyroid and breast cancer is well established. However, the underlying risk factors remain poorly understood. Two sisters developed papillary thyroid cancer (PTC) at age 32 and 34 years, followed by ductal carcinoma of the breast at 44 and 42 years. The 2 children of the younger sister developed ataxia-telangiectasia; the son also developed lymphoblastic lymphoma and his sister died secondary to acute lymphoblastic leukemia (ALL). They were found to be compound heterozygous for ataxia telangiectasia mutated (ATM) gene mutations (c.3848T>C, p.L1283P; and c.802C>T, p.Q268X). Exome sequencing of the 2 sisters (mother and aunt of the children with ataxia-telangiectasia) led to the detection of the pathogenic monoallelic ATM mutation in both of them (c.3848T>C; minor allele frequency [MAF] < 0.01) but detected no other variants known to confer a risk for PTC or breast cancer. The findings suggest that monoallelic ATM mutations, presumably in conjunction with additional genetic and/or nongenetic factors, can confer a risk for developing PTC and breast cancer.

hnRNP A1 and hnRNP C associate with miR-17 and miR-18 in thyroid cancer cells.

Heterogeneous nuclear ribonucleoproteins (hnRNPs) are essential players in the regulation of gene expression. The majority of the twenty different hnRNP proteins act through the modulation of pre-mRNA splicing. Most have been shown to regulate the expression of critical genes for the progression of tumorigenic processes and were also observed to be overexpressed in several types of cancer. Moreover, these proteins were described as essential components for the maturation of some microRNAs (miRNAs). In the human genome, over 70% of miRNAs are transcribed from introns; therefore, we hypothesized that regulatory proteins involved with splicing could be important for their maturation. Increased expression of the miR-17-92 cluster has already been shown to be related to the development of many cancers, such as thyroid, lung, and lymphoma. In this article, we show that overexpression of hnRNP A1 and hnRNP C in BCPAP thyroid cancer cells directly affects the expression of miR-17-92 miRNAs. Both proteins associate with the 5'-end of this cluster, strongly precipitate miRNAs miR-17 and miR-18a and upregulate the expression of miR-92a. Upon overexpression of these hnRNPs, BCPAP cells also show increased proliferation, migration, and invasion rates, suggesting upregulation of these proteins and miRNAs is related to an enhanced tumorigenic phenotype.

Colon cancer incidence, presentation, treatment and outcomes over 25 years.

AIM: The aim of this study was to evaluate changes in the incidence, presentation, treatment and outcome of colon cancer in a complete cohort of patients treated at a single institution over a 25-year period. METHOD: All 869 patients at Levanger Hospital, Norway with colon cancer during 1980-2004 were included in the study. RESULTS: The incidence of colon cancer increased by 2.1% per year. During the later years, patients presented with less advanced stages, and fewer patients had emergency presentation with obstruction. The rate of operations performed by a colorectal specialist attending increased from 56 to 98%. Postoperative mortality after resection with curative intent decreased from 6.3 to 3.2%, and the presence of a colorectal specialist during the operation was an independent factor that reduced the risk of postoperative death. The local recurrence rate after curative surgery was 10.9% (19 of 174) in 1980-1989, 5.9% (14 of 239) in 1990-1999 and 0.6% (1 of 154) in 2000-2004 (P < 0.001). The 5-year relative survival after resection with curative intent was 71, 81 and 85% in the three periods 1980-1989, 1990-1999 and 2000-2004, respectively. CONCLUSION: The outcome of colon cancer improved from 1980 to 2004. Patients presented at earlier stages, and fewer had emergency presentation. The local recurrence and postoperative mortality rates were reduced, and relative survival improved.

Prostaglandins for adult liver transplanted patients.

BACKGROUND: Prostaglandins may reduce ischaemic injury after liver transplantation. Several small randomised trials have evaluated the effects of prostaglandins in patients undergoing liver transplantation. Results of these trials are inconsistent, and none has enough power to reliably exclude effects of prostaglandins. OBJECTIVES: To assess the benefits and harms of prostaglandin E1 or E2 in adult liver-transplanted patients. SEARCH METHODS: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, and LILACS (search on 20 April 2011). In addition, we perused the reference lists of the identified studies and contacted trials investigators, and national and international experts in order to identify more trials for the review. SELECTION CRITERIA: We included randomised clinical trials evaluating prostaglandin E1 or E2 initiated in the perioperative period versus placebo or standard treatment for adult patients undergoing liver transplantation. We did not apply any language or publication status restrictions. DATA COLLECTION AND ANALYSIS: Two authors independently evaluated methodological quality, ie, risk of bias of the included trials, and extracted data using standardised data extraction forms. We contacted trial investigators in attempt to retrieve information not available in the original manuscripts. We used random-effects model meta-analyses and fixed-effect model meta-analyses to estimate the odds ratio with 95% confidence interval (CI). MAIN RESULTS: We included ten trials in which 652 patients were randomised. The risk of bias was considered high in most trials. There was no significant effect of prostaglandins on all-cause mortality (37/298[12.4%] in prostaglandin group versus 47/312[15.1%] in control group; OR 0.84, 95% CI 0.53 to 1.37; I(2) = 0%), on primary non-function of the allograft (8/238 [3.4%] versus. 16/250[6.4%] ;OR 0.55, 95% CI 0.23 to 1.33; I(2) = 0%), and on liver re-transplantation (12/161[7.5%] versus 14/171[8.2%]; OR 0.99, 95% CI 0.44 to 2.25; I(2) = 0%). Prostaglandins seemed to significantly decrease the risk of acute kidney failure requiring dialysis (13/158[8.2%] versus 34/171[9.9%]; OR 0.37, 95% CI 0.18 to 0.75; I(2) = 0%). There was no significant increase in the risk of adverse events with prostaglandins. AUTHORS' CONCLUSIONS: We found no evidence that the administration of prostaglandins to liver transplanted patients reduces the risk of death, primary non-function of the allograft, or liver re-transplantation. Prostaglandins might reduce the risk of acute kidney failure requiring dialysis, but the quality of the evidence is considered only moderate due to high risk of bias in most of the included trials. Moreover, there are risks of outcome measure reporting bias and random errors. Therefore, further randomised, placebo-controlled trials are deemed necessary.

Safety and Photoprotective Efficacy of a Sunscreen System Based on Grape Pomace (Vitis vinifera L.) Phenolics from Winemaking.

In winemaking, a large amount of grape pomace is produced that is rich in polyphenolics and highly beneficial for human health, as phenols are useful for skin ultraviolet (UV) protection. In this investigation, we evaluated the safety and clinical efficacy of a sunscreen system containing a grape pomace extract from Vitis vinifera L. as a bioactive ingredient. The recovery of phenolics in the waste was performed by percolation. Nine emulsions were developed using a factorial design and two were evaluated clinically: Formulation E, containing only UV filters (butylmethoxydibenzoyl methane, ethylhexyl methoxycinnamate and ethylhexyl dimethyl PABA), and F, with the extract at 10.0% w/w + UV filters. The antioxidant activity was determined by the DPPH assay and the in vitro efficacy was established by sun protection factor (SPF) measurements (Labsphere UV-2000S). Clinical tests were performed to determine safety (human repeated insult patch test) and to confirm efficacy (photoprotective effectiveness in participants). The results showed a synergistic effect between the sunscreen system and the extract on UVB protection and antioxidant activity. Both samples were considered safe. Formulation F was 20.59% more efficient in protecting skin against UVB radiation, taking approximately 21% more time to induce erythema compared to the extract-free sample.

An orthotopic skull base model of malignant meningioma.

Meningioma tumor growth involves the subarachnoid space that contains the cerebrospinal fluid. Modeling tumor growth in this microenvironment has been associated with widespread leptomeningeal dissemination, which is uncharacteristic of human meningiomas. Consequently, survival times and tumor properties are varied, limiting their utility in testing experimental therapies. We report the development and characterization of a reproducible orthotopic skull-base meningioma model in athymic mice using the IOMM-Lee cell line. Localized tumor growth was obtained by using optimal cell densities and matrigel as the implantation medium. Survival times were within a narrow range of 17-21 days. The xenografts grew locally compressing surrounding brain tissue. These tumors had histopathologic characteristics of anaplastic meningiomas including high cellularity, nuclear pleomorphism, cellular pattern loss, necrosis and conspicuous mitosis. Similar to human meningiomas, considerable invasion of the dura and skull and some invasion of adjacent brain along perivascular tracts were observed. The pattern of hypoxia was also similar to human malignant meningiomas. We use bioluminescent imaging to non-invasively monitor the growth of the xenografts and determine the survival benefit from temozolomide treatment. Thus, we describe a malignant meningioma model system that will be useful for investigating the biology of meningiomas and for preclinical assessment of therapeutic agents.

Lack of effects of isoflavones on the lipid profile of Brazilian postmenopausal women.

OBJECTIVE: To evaluate the effects of soy isoflavone supplementation on profile lipid and endogenous hormone levels. METHODS: In this double-blind, placebo-controlled study, 47 postmenopausal women 47-66 y of age received 40 mg of isoflavone (n = 25) or 40 mg of casein placebo (n = 22). Cardiovascular risk factors were assessed by evaluating lipid profile at baseline and after 6 mo of treatment. To examine the effects of this regime on endogenous hormone levels, follicle-stimulating hormone and beta-estradiol were measured. Urinary isoflavone concentrations (genistein and daidzein) were measured as markers of both compliance and absorption using high performance liquid chromatography. Baseline characteristics were compared by the unpaired Student's t-test. Within-group changes were determined by paired Student's t-test and comparison between the isoflavone and casein placebo groups were determined by analysis of variance. RESULTS: Lipid levels (low-density lipoprotein and total cholesterol) similarly decreased in both groups. High-density lipoprotein increased significantly in both groups and cannot thus be attributable to treatment; the reason for such variation is unknown and can be attributed to chance or to bias (even that of a real placebo effect in both groups or perhaps in spontaneous changes in exercise and dietary habits of patients after their inclusion). Furthermore, in both groups very low-density lipoprotein and triacylglycerol levels increased in a non-significant manner. CONCLUSION: The results of the present study do not support any biologically significant estrogenic effects of isoflavone on the parameters assessed. Further research will be necessary to definitively assess the safety and efficacy of isoflavone.

Effects of isoflavones on the coagulation and fibrinolytic system of postmenopausal women.

OBJECTIVE: We evaluated the effects of soy isoflavone supplementation on hemostasis in healthy postmenopausal women. METHODS: In this double-blinded, placebo-controlled study, 47 postmenopausal women 47-66 y of age received 40 mg of soy isoflavone (n = 25) or 40 mg of casein placebo (n = 22) once a day for 6 mo. Levels of factors VII and X, fibrinogen, thrombin-antithrombin complex, prothrombin fragments 1 plus 2, antithrombin, protein C, total and free protein S, plasminogen, plasminogen activator inhibitor-1, and D-dimers were measured at baseline and 6 mo. Urinary isoflavone concentrations (genistein and daidzein) were measured as a marker of compliance and absorption using high-performance liquid chromatography. Baseline characteristics were compared by unpaired Student's t test. Within-group changes and comparison between the isoflavone and casein placebo groups were determined by a mixed effects model. RESULTS: The levels of hemostatic variables did not change significantly throughout the study in the isoflavone group; however, the isoflavone group showed a statistically significant reduction in plasma concentration of prothrombin fragments 1 plus 2; both groups showed a statistically significant reduction in antithrombin, protein C, and free protein S levels. A significant increase in D-dimers was observed only in the isoflavone group. Plasminogen activator inhibitor-1 levels increased significantly in the placebo group. However, these changes were not statistically different between groups. CONCLUSION: The results of the present study do not support a biologically significant estrogenic effect of soy isoflavone on coagulation and fibrinolysis in postmenopausal women. However, further research will be necessary to definitively assess the safety and efficacy of isoflavone.

Functional Toll-like Receptor 4 Overexpression in Papillary Thyroid Cancer by MAPK/ERK-Induced ETS1 Transcriptional Activity.

Emerging evidence suggests that unregulated Toll-like receptor (TLR) signaling promotes tumor survival signals, thus favoring tumor progression. Here, the mechanism underlying TLR4 overexpression in papillary thyroid carcinomas (PTC) mainly harboring the BRAFV600E mutation was studied. TLR4 was overexpressed in PTC compared with nonneoplastic thyroid tissue. Moreover, paired clinical specimens of primary PTC and its lymph node metastasis showed a significant upregulation of TLR4 levels in the metastatic tissues. In agreement, conditional BRAFV600E expression in normal rat thyroid cells and mouse thyroid tissue upregulated TLR4 expression levels. Furthermore, functional TLR4 expression was demonstrated in PTC cells by increased NF-κB transcriptional activity in response to the exogenous TLR4-agonist lipopolysaccharide. Of note, The Cancer Genome Atlas data analysis revealed that BRAFV600E-positive tumors with high TLR4 expression were associated with shorter disease-free survival. Transcriptomic data analysis indicated a positive correlation between TLR4 expression levels and MAPK/ERK signaling activation. Consistently, chemical blockade of MAPK/ERK signaling abrogated BRAFV600E-induced TLR4 expression. A detailed study of the TLR4 promoter revealed a critical MAPK/ERK-sensitive Ets-binding site involved in BRAFV600E responsiveness. Subsequent investigation revealed that the Ets-binding factor ETS1 is critical for BRAFV600E-induced MAPK/ERK signaling-dependent TLR4 gene expression. Together, these data indicate that functional TLR4 overexpression in PTCs is a consequence of thyroid tumor-oncogenic driver dysregulation of MAPK/ERK/ETS1 signaling.Implications: Considering the participation of aberrant NF-κB signaling activation in the promotion of thyroid tumor growth and the association of high TLR4 expression with more aggressive tumors, this study suggests a prooncogenic potential of TLR4 downstream signaling in thyroid tumorigenesis. Mol Cancer Res; 16(5); 833-45. ©2018 AACR.

Evaluation in vitro of the antagonistic substances produced by Lactobacillus spp. isolated from chickens.

To determine the inhibitory capacity of lactic acid bacteria due to the action of antagonistic substances, we tested 474 isolates of Lactobacillus from the crop and cecum of chickens against gram-positive and gram-negative indicator microorganisms by the spot-on-the-lawn and well-diffusion antagonism methods. Of the 474 isolates, 265 demonstrated antimicrobial activity against the indicator microorganisms. Isolates identified as L. reuteri, L. salivarius, or Lactobacillus spp. inhibited Enterococcus faecalis, E. faecium, Listeria monocytogenes, and Salmonella spp. but not L. casei, L. delbrueckii, L. fermentum, or L. helveticus by the well-diffusion simultaneous antagonism method under anaerobic incubation conditions. The antagonistic substances produced by some of the Lactobacillus isolates were inactivated after treatment by proteolytic enzymes, which suggested that the substances could be antimicrobial peptides or bacteriocins.

[TGFbeta, activin and SMAD signalling in thyroid cancer]. / TGFbeta, activina e sinalização SMAD em câncer de tiróide.

TGFbeta and activin are members of the TGFbeta superfamily and play a wide role in development, proliferation and apoptosis. These growth factors exert their biological effects by binding to the type I and II membrane receptors to transduce their signalling through the nucleus by phosphorylation of R-SMADs (SMAD 2/3) and co-SMADs (Smad 4). The proper control of TGFbeta/activin pathway is negatively regulated by inhibitory SMAD (SMAD7) and by E3 ubiquitination enzymes (Smurfs). Physiologically, TGFbeta and activin act as potent growth inhibitors in thyroid follicular cell. Thus, alterations in the receptors and components of SMAD signalling pathway are associated with several types of tumors. Since TGFbeta and activin generate their intracellular signalling through the same components of the SMAD pathway, the unbalance of this pathway impairs both of anti-mitogenic signals in the cell. This review addresses aspects of the molecular mechanisms in the understanding of resistance to the growth inhibitory effects of TGFbeta and activin due to the disequilibrium in the SMAD inhibitory pathway in thyroid neoplasia.

Large-scale transcriptome analyses reveal new genetic marker candidates of head, neck, and thyroid cancer.

A detailed genome mapping analysis of 213,636 expressed sequence tags (EST) derived from nontumor and tumor tissues of the oral cavity, larynx, pharynx, and thyroid was done. Transcripts matching known human genes were identified; potential new splice variants were flagged and subjected to manual curation, pointing to 788 putatively new alternative splicing isoforms, the majority (75%) being insertion events. A subset of 34 new splicing isoforms (5% of 788 events) was selected and 23 (68%) were confirmed by reverse transcription-PCR and DNA sequencing. Putative new genes were revealed, including six transcripts mapped to well-studied chromosomes such as 22, as well as transcripts that mapped to 253 intergenic regions. In addition, 2,251 noncoding intronic RNAs, eventually involved in transcriptional regulation, were found. A set of 250 candidate markers for loss of heterozygosis or gene amplification was selected by identifying transcripts that mapped to genomic regions previously known to be frequently amplified or deleted in head, neck, and thyroid tumors. Three of these markers were evaluated by quantitative reverse transcription-PCR in an independent set of individual samples. Along with detailed clinical data about tumor origin, the information reported here is now publicly available on a dedicated Web site as a resource for further biological investigation. This first in silico reconstruction of the head, neck, and thyroid transcriptomes points to a wealth of new candidate markers that can be used for future studies on the molecular basis of these tumors. Similar analysis is warranted for a number of other tumors for which large EST data sets are available.

miR18a and miR19a Recruit Specific Proteins for Splicing in Thyroid Cancer Cells.

BACKGROUND: Thyroid cancer is one of the most frequent types of endocrine cancers. In most cases, thyroid cancers are caused by deregulated miRNA expression, especially involving the miR17-92 cluster. miR17-92 transcription is altered in several different tumor types including lymphoma, leukemia, and of the breast and thyroid. As an intronic cluster, miR17-92 must be processed during splicing and therefore interaction between microprocessor and spliceosome machineries is of major importance in understanding its expression. MATERIALS AND METHODS: We investigated the protein composition of spliceosomes assembled on pre-RNAs containing intronic miR18a and miR19a, components of the miR17-92 cluster, using mass spectrometry. RESULTS: Interestingly, we observed that proteins associated with intronic miR18a and miR19a are cell-specific, and are similar for both miRNAs analyzed. The only exception is the group of heterogeneous nuclear proteins that are commonly recruited by different cells. CONCLUSION: miRNA processing depends on cell-specific proteins and heterogeneous nuclear proteins have a general role in miRNA processing from introns.