191 research outputs found
Ectopic Noggin Blocks Sensory and Nonsensory Organ Morphogenesis in the Chicken Inner Ear
AbstractBone morphogenetic protein 4 (Bmp4) is expressed during multiple stages of development of the chicken inner ear. At the otocyst stage, Bmp4 is expressed in each presumptive sensory organ, as well as in the mesenchymal cells surrounding the region of the otocyst that is destined to form the semicircular canals. After the formation of the gross anatomy of the inner ear, Bmp4 expression persists in some sensory organs and restricted domains of the semicircular canals. To address the role of this gene in inner ear development, we blocked BMP4 function(s) by delivering one of its antagonists, Noggin, to the developing inner ear in ovo. Exogenous Noggin was delivered to the developing otocyst by using a replication-competent avian retrovirus encoding the Noggin cDNA (RCAS-N) or implanting beads coated with Noggin protein. Noggin treatment resulted in a variety of phenotypes involving both sensory and nonsensory components of the inner ear. Among the nonsensory structures, the semicircular canals were the most sensitive and the endolymphatic duct and sac most resistant to exogenous Noggin. Noggin affected the proliferation of the primordial canal outpouch, as well as the continual outgrowth of the canal after its formation. In addition, Noggin affected the structural patterning of the cristae, possibly via a decrease of Msx1 and p75NGFR expression. These results suggest that BMP4 and possibly other BMPs are required for multiple phases of inner ear development
Evidence of a noncoding transcript of the RIPK2 gene overexpressed in head and neck tumor
Receptor-interacting proteins are a family of serine/threonine kinases, which integrate extra and intracellular stress signals caused by different factors, including infections, inflammation and DNA damage. Receptor-interacting serine/threonine-protein kinase 2 (RIP-2) is a member of this family and an important component of the nuclear factor NF-kappa-B signaling pathway. The corresponding human gene RIPK2 generates two transcripts by alternative splicing, the full-length and a short transcript. The short transcript has a truncated 5? sequence, which results in a predicted isoform with a partial kinase domain but able to transduce signals through its caspase recruitment domain. In this study, the expression of RIPK2 was investigated in human tissue samples and, in order to determine if both transcripts are similarly regulated at the transcriptional level, cancer cell lines were submitted to temperature and acid stresses. We observed that both transcripts are expressed in all tissues analyzed, with higher expression of the short one in tumor samples, and they are differentially regulated following temperature stress. Despite transcription, no corresponding protein for the short transcript was detected in tissues and cell lines analyzed. We propose that the shorter transcript is a noncoding RNA and that its presence in the cell may play regulatory roles and affect inflammation and other biological processes related to the kinase activity of RIP-2.Fil: Mancini Villagra, Ulises Maximiliano. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - La Plata. Instituto de BiotecnologĂa y BiologĂa Molecular. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de BiotecnologĂa y BiologĂa Molecular; ArgentinaFil: da Cunha, Bianca R.. Universidade de Sao Paulo; BrasilFil: Polachini, Giovana M.. No especifĂca;Fil: Tiago, Tiago Henrique. No especifĂca;Fil: Carlos H. T. P. da Silva. Universidade de Sao Paulo; BrasilFil: Feitosa, Olavo A.. Universidade de Sao Paulo; BrasilFil: Fukuyama, Erica E.. Arnaldo Vieira de Carvalho Cancer Institute; BrasilFil: LĂłpez, Rossana V. M.. No especifĂca;Fil: Dias Neto, Emmanuel. Universidade de Sao Paulo; BrasilFil: Nunes, Fabio D.. Universidade de Sao Paulo; BrasilFil: Severino, Patricia. Hospital Israelita Albert Einstein; BrasilFil: Tajara, Eloiza Helena Tajara. Universidade de Sao Paulo; Brasi
Structural basis of GC-1 selectivity for thyroid hormone receptor isoforms
Background: Thyroid receptors, TRα and TRÎČ, are involved in important physiological functions such as metabolism, cholesterol level and heart activities. Whereas metabolism increase and cholesterol level lowering could be achieved by TRÎČ isoform activation, TRα activation affects heart rates. Therefore, ÎČ-selective thyromimetics have been developed as promising drug-candidates for treatment of obesity and elevated cholesterol level. GC-1 [3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)-phenoxy acetic acid] has ability to lower LDL cholesterol with 600- to 1400-fold more potency and approximately two- to threefold more efficacy than atorvastatin (Lipitor©) in studies in rats, mice and monkeys.
Results: To investigate GC-1 specificity, we solved crystal structures and performed molecular dynamics simulations of both isoforms complexed with GC-1. Crystal structures reveal that, in TRα Arg228 is observed in multiple conformations, an effect triggered by the differences in the interactions between GC-1 and Ser277 or the corresponding asparagine (Asn331) of TRÎČ. The corresponding Arg282 of TRÎČ is observed in only one single stable conformation, interacting effectively with the ligand. Molecular dynamics support this model: our simulations show that the multiple conformations can be observed for the Arg228 in TRα, in which the ligand interacts either strongly with the ligand or with the Ser277 residue. In contrast, a single stable Arg282 conformation is observed for TRÎČ, in which it strongly interacts with both GC-1 and the Asn331.
Conclusion: Our analysis suggests that the key factors for GC-1 selectivity are the presence of an oxyacetic acid ester oxygen and the absence of the amino group relative to T3. These results shed light into the ÎČ-selectivity of GC-1 and may assist the development of new compounds with potential as drug candidates to the treatment of hypercholesterolemia and obesity
Global gene expression profiling of oral cavity cancers suggests molecular heterogeneity within anatomic subsites
<p>Abstract</p> <p>Background</p> <p>Oral squamous cell carcinoma (OSCC) is a frequent neoplasm, which is usually aggressive and has unpredictable biological behavior and unfavorable prognosis. The comprehension of the molecular basis of this variability should lead to the development of targeted therapies as well as to improvements in specificity and sensitivity of diagnosis.</p> <p>Results</p> <p>Samples of primary OSCCs and their corresponding surgical margins were obtained from male patients during surgery and their gene expression profiles were screened using whole-genome microarray technology. Hierarchical clustering and Principal Components Analysis were used for data visualization and One-way Analysis of Variance was used to identify differentially expressed genes. Samples clustered mostly according to disease subsite, suggesting molecular heterogeneity within tumor stages. In order to corroborate our results, two publicly available datasets of microarray experiments were assessed. We found significant molecular differences between OSCC anatomic subsites concerning groups of genes presently or potentially important for drug development, including mRNA processing, cytoskeleton organization and biogenesis, metabolic process, cell cycle and apoptosis.</p> <p>Conclusion</p> <p>Our results corroborate literature data on molecular heterogeneity of OSCCs. Differences between disease subsites and among samples belonging to the same TNM class highlight the importance of gene expression-based classification and challenge the development of targeted therapies.</p
Recommended from our members
Current status and recommendations for biomarkers and biobanking in neurofibromatosis
Objective: Clinically validated biomarkers for neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2),
and schwannomatosis (SWN) have not been identified to date. The biomarker working groupâs goals
are to (1) define biomarker needs in NF1, NF2, and SWN; (2) summarize existing data on biomarkers
in NF1, NF2, and SWN; (3) outline recommendations for sample collection and biomarker development;
and (4) standardize sample collection and methodology protocols where possible to promote
comparison between studies by publishing standard operating procedures (SOPs).
Methods: The biomarker group reviewed published data on biomarkers in NF1, NF2, and SWN and
on biobanking efforts outside these diseases via literature search, defined the need for biomarkers
in NF, and developed recommendations in a series of consensus meetings.
Results: We describe existing biomarkers in NF and report consensus recommendations for SOP
and a minimal clinical dataset to accompany samples derived from patients with NF1, NF2, and
SWN in decentralized biobanks.
Conclusions: These recommendations are intended to provide clinicians and researchers with
a common set of guidelines to collect and store biospecimens and for establishment of biobanks
for NF1, NF2, and SWN
Enxaqueca em 746 pacientes com esclerose mĂșltipla
Enxaqueca piora o sofrimento do paciente que tem esclerose mĂșltipla (EM). ID-migraine Ă© uma ferramenta Ăștil para seleção de pacientes com enxaqueca e Migraine Disability Assessment (MIDAS) Ă© um questionĂĄrio que avalia o impacto da doença. O objetivo do presente estudo foi avaliar a presença e impacto de enxaqueca em pacientes com EM. MĂ©todos: Pacientes diagnosticados com EM e tratados em clĂnicas especializadas foram convidados a responder um questionĂĄrio online se tambĂ©m apresentassem cefaleia. Resultados: O estudo incluiu 746 participantes com cefaleia e EM que preencheram completamente as respostas. Foram 625 mulheres e 121 homens, sendo 69% dos pacientes com idade entre 20 e 40 anos. Enxaqueca foi identificada em 404 pacientes (54,1%) e moderado a grave impacto da doença foi observado em 68,3% dos casos. ConclusĂŁo: Enxaqueca Ă© uma cefaleia primĂĄria frequente e incapacitante relatada por pacientes com EM.Migraine adds to the burden of patients suffering from multiple sclerosis (MS). The ID-migraine is a useful tool for screening migraine, and the Migraine Disability Assessment questionnaire can evaluate disease burden. The aim of the present study was to assess the presence and burden of migraine in patients with MS. Methods: Patients diagnosed with MS attending specialized MS units were invited to answer an online survey if they also experienced headache. Results: The study included 746 complete responses from patients with MS and headache. There were 625 women and 121 men, and 69% of all the patients were aged between 20 and 40 years. Migraine was identified in 404 patients (54.1%) and a moderate-to-high burden of disease was observed in 68.3% of the patients. Conclusion: Migraine is a frequent and disabling type of primary headache reported by patients with MS
Genome-wide association analyses identify new susceptibility loci for oral cavity and pharyngeal cancer
We conducted a genome-wide association study of oral cavity and pharyngeal cancer in 6,034 cases and 6,585 controls from Europe, North America and South America. We detected eight significantly associated loci (P < 5 x 10(-8)), seven of which are new for these cancer sites. Oral and pharyngeal cancers combined were associated with loci at 6p21.32 (rs3828805, HLA-DQB1), 10q26.13 (rs201982221, LHPP) and 11p15.4 (rs1453414, OR52N2-TRIM5). Oral cancer was associated with two new regions, 2p23.3 (rs6547741, GPN1) and 9q34.12 (rs928674, LAMC3), and with known cancer-related loci-9p21.3 (rs8181047, CDKN2B-AS1) and 5p15.33 (rs10462706, CLPTM1L). Oropharyngeal cancer associations were limited to the human leukocyte antigen (HLA) region, and classical HLA allele imputation showed a protective association with the class II haplotype HLA-DRB1*1301-HLA-DQA1*0103-HLA-DQB1*0603 (odds ratio (OR) = 0.59, P = 2.7 x 10(-9)). Stratified analyses on a subgroup of oropharyngeal cases with information available on human papillomavirus (HPV) status indicated that this association was considerably stronger in HPV-positive (OR = 0.23, P = 1.6 x 10(-6)) than in HPV-negative (OR = 0.75, P = 0.16) cancers
- âŠ