Keratin 1 as a Cell-Surface Receptor in Cancer

Keratins are fibrous proteins that take part in several important cellular functions, including the formation of intermediate filaments. In addition, keratins serve as epithelial cell markers, which has made their role in cancer progression, diagnosis, and treatment an important focus of research. Keratin 1 (K1) is a type II keratin whose structure is comprised of a coiled-coil central domain flanked by flexible, glycine-rich loops in the N- and C-termini. While the structure of cytoplasmic K1 is established, the structure of cell-surface K1 is not known. Several transformed cells, such as cancerous cells and cells that have undergone oxidative stress, display increased levels of overall and/or cell-surface K1 expression. Cell-surface keratins (CSKs) may be modified or truncated, and their role is yet to be fully elucidated. Current studies suggest that CSKs are involved in receptor-mediated endocytosis and immune evasion. In this Review, we discuss findings relating to K1 structure, overexpression, and cell-surface expression in the context of utilizing CSK1 as a receptor for targeted drug delivery to cancer cells, and other strategies to develop novel treatments for cancer

As vantagens do planejamento tributário : um estudo simulado Lucro Real X Lucro Presumido X Simples Nacional

Orientador : MSc. Luiz Carlos de SouzaMonografia (especialização) - Universidade Federal do Paraná, Curso de Especialização em Contabilidade e FinançasInclui referênciasResumo : As vantagens do planejamento tributário: Um estudo simulado entre o planejamento tributário na modalidade "Lucro Real", "Lucro Presumido" e "Simples Nacional". Para garantir a sobrevivência de uma empresa e torná-la mais eficiente e competitiva no mercado, inúmeras decisões devem ser tomadas. Uma das decisões mais importantes é o planejamento tributário, que deve estar de acordo com a legislação brasileira vigente. Com o objetivo de identificar o regime tributário mais vantajoso economicamente para uma clínica odontológica, foram efetuadas consultas bibliográficas através de pesquisa em livros, revistas e artigos científicos, legislações vigentes, portais e sítios governamentais oficiais na internet. Também foram efetuados cálculos tributários e gráficos comparativos, simulando o regime tributário mais vantajoso para a clínica Sorriso Ltda. Este trabalho se baseou em abordagem qualitativa, não utilizando estatística. O procedimento adotado é o estudo de caso de uma clínica odontológica localizada na cidade de Curitiba, estado do Paraná. Atualmente a empresa esta enquadrada no regime tributário "Lucro Presumido" e conforme o estudo do caso verificou-se que atualmente é a modalidade indicada para a empresa em questão

Análise dosimétrica em pediatria neonatal

Chest radiographic examinations are frequently requested for newborn patients hospitalized in a Intensive Care Unit (ICU) Neonatal. However, children are more radiosensitive the younger they are and due to the higher number of cells in replication process. This feature arises greater concern in the scientific community to know the dose of radiation that these pediatric patients are exposed. This paper describes the methodology used for the implementation of a dosimetric analysis in neonatal pediatrics at the Children's Hospital Pequeno Príncipe, in Curitiba. Initially, the work proposes the construction of a phantom of a newborn to subsequent measurement of the radiation dose received by the neonate patient, through the use of TLDs (Thermoluminescent Dosimeters) for measures ESAK (Entrance Surface Air-Kerma) in the thoracic region and measure kerma-air in the deep lung, in water, with the use of an ionization chamber. The scattered radiation dose received by another patient near the patient under examination was also evaluated. The results showed, in general, dose levels below the reference values for the measures ESAK. For the kerma- air in the deep lung, and the values obtained compared to organ dose calculations through software is shown to be below the values obtained with TLDs. The measurements showed that the scattered radiation near the patient examined receive a small contribution of dose during examinations.Exames radiográficos do tórax são frequentemente solicitados para pacientes recém-nascidos internados na Unidade de Terapia Intensiva (UTI) Neonatal. Entretanto, as crianças são mais radiossensíveis quanto menor a idade que possuem e devido ao maior número de células em processo de replicação. Essa característica acaba despertando uma maior preocupação da comunidade científica em conhecer a dose de radiação a que são expostos esses pacientes pediátricos. Este trabalho descreve a metodologia aplicada para a execução de uma análise dosimétrica em pediatria neonatal no Hospital Infantil Pequeno Príncipe, em Curitiba. Inicialmente, o trabalho propõe a construção de um objeto simulador de um recém-nascido para consequentes medidas de dose de radiação recebida pelo paciente neonato, através do uso de TLDs (Dosímetros Termoluminescentes) para medidas de ESAK (Kerma-ar na Superfície de Entrada) sob a região torácica e medida de kerma-ar na profundidade do pulmão, na água, com o uso de uma câmara de ionização. Também foi avaliada a dose de radiação espalhada recebida pelo paciente internado próximo ao paciente examinado. Os resultados da pesquisa mostraram, em geral, níveis de dose abaixo dos valores de referência para as medidas de ESAK. Para as medidas de kerma-ar na profundidade do pulmão, os valores encontrados e comparados com cálculos de dose-órgão por meio de um software mostraram-se abaixo dos valores obtidos com os TLDs. As medidas de radiação espalhada mostraram que os pacientes próximos ao paciente examinado recebem uma pequena faixa de contribuição de dose durante os exames

Large numbers of random point and cluster mutations within the adenovirus VA I gene allow characterization of sequences required for efficient transcription

We have isolated clones with well over 100 randomly dispersed point mutations distributed throughout the 5' half of chemically synthesized adenovirus type 2 VA I genes. In addition, we have isolated clusters of mutations targeted to the regions corresponding to the A and B block consensus sequences of eukaryotic tRNA and adenovirus VA genes

Update of the keratin gene family: evolution, tissue-specific expression patterns, and relevance to clinical disorders.

Intermediate filament (IntFil) genes arose during early metazoan evolution, to provide mechanical support for plasma membranes contacting/interacting with other cells and the extracellular matrix. Keratin genes comprise the largest subset of IntFil genes. Whereas the first keratin gene appeared in sponge, and three genes in arthropods, more rapid increases in keratin genes occurred in lungfish and amphibian genomes, concomitant with land animal-sea animal divergence (~ 440 to 410 million years ago). Human, mouse and zebrafish genomes contain 18, 17 and 24 non-keratin IntFil genes, respectively. Human has 27 of 28 type I "acidic" keratin genes clustered at chromosome (Chr) 17q21.2, and all 26 type II "basic" keratin genes clustered at Chr 12q13.13. Mouse has 27 of 28 type I keratin genes clustered on Chr 11, and all 26 type II clustered on Chr 15. Zebrafish has 18 type I keratin genes scattered on five chromosomes, and 3 type II keratin genes on two chromosomes. Types I and II keratin clusters-reflecting evolutionary blooms of keratin genes along one chromosomal segment-are found in all land animal genomes examined, but not fishes; such rapid gene expansions likely reflect sudden requirements for many novel paralogous proteins having divergent functions to enhance species survival following sea-to-land transition. Using data from the Genotype-Tissue Expression (GTEx) project, tissue-specific keratin expression throughout the human body was reconstructed. Clustering of gene expression patterns revealed similarities in tissue-specific expression patterns for previously described "keratin pairs" (i.e., KRT1/KRT10, KRT8/KRT18, KRT5/KRT14, KRT6/KRT16 and KRT6/KRT17 proteins). The ClinVar database currently lists 26 human disease-causing variants within the various domains of keratin proteins

Community awareness of stroke, hypertension and modifiable risk factors for cardiovascular disease in Nkonya-Wurupong, Ghana

Hypertension and other non-communicable diseases are growing risk factors for cardiovascular disease and stroke in lowand middle-income countries like Ghana who are experiencing the effects of rapid urbanization and globalization. Awareness and education may help reduce the population’s exposure to modifiable risk-factors. A survey from a central clinic outside the city of Ho, in the Volta region investigates participants’ level of awareness and education surrounding hypertension and stroke. It provides important information about the approach to education and preventing modifiable risk factors. A central clinic in Nkonya-Wurupong, Ghana, evaluated 1671 patients in July 2016, and a group of 302 adults over the age of 18 provided a convenience sampling. The survey examined three main areas: demographics, medical history, and evaluation of knowledge with respect to stroke and cardiovascular risk factors. 18.5% of participants demonstrated hypertension (BP ³ 140/90). 30% of those with hypertension were female. Thirty-five percent believed hypertension was a risk factor for stroke, and only 26% were currently medicated for hypertension. Poor diet, obesity and alcohol were the most frequently identified risk factors for stroke and 86% of participants felt that it was preventable. However, diet, heart disease, smoking, obesity, diabetes, sedentary lifestyle or alcohol were not uniformly identified as stroke risk factors. One-sided weakness was the only symptom the group associated with stroke. Other symptoms included in the survey were headache, slurred speech, visual changes, dizziness, and facial droop. Educational resources included TV, school, internet, radio, medical books and health professionals and 7% responded that they had never been educated about stroke and its risk-factors. Knowledge of hypertensive consequences including cardiovascular disease and stroke varies significantly along with stroke identification and educational sources. However, many indicated that stroke is due to lifestyle and can be prevented. It is unclear what respondents believe these lifestyle choices are. This data suggests there are major areas where healthcare education is needed. Discerning baseline health in developing countries will become increasingly important when evaluating an area for health resource allocation including patient health education program

Extremozymes for bioprocessing

For many years, people have been seeking to employ enzymes, proteins that act as biocatalysts, as environmentally friendly replacements for many currently used industrial processes, as well as for the production of fuels and chemicals from biomass sources such as waste paper and agricultural residues. Current applications of enzymes include enzyme-assisted bleaching of wood pulp, preparation of textiles, design of biosensors, enzyme diagnostic kits, and bioremediation of toxic metals and chlorinated chemicals. However, until fairly recently, most of these enzymes came from mesophilic sources--organisms that grow at moderate temperatures (20--50 C) and pH 5 to 8. Frequently, these enzymes are not robust enough to perform well in industrial processes, have little tolerance for organic solvents or toxic chemicals, lose activity rapidly during catalysis, and cannot be used at high temperatures and alkaline or acidic conditions. But there are microorganisms that are known to grow under extreme conditions such as high temperature (thermophiles), low temperature (psychrophiles), acidic pH (acidophiles), and alkaline pH (alkalinophiles). The enzymes, extremozymes, from such microorganisms are active under the extreme conditions of temperature and pH at which the extremophiles grow. Use of extremozymes extends the potential temperature range for efficient enzymatic reactions to between 40 C and 100 C

Early and Sustained Improvements in Symptoms and Quality of Life with Upadacitinib in Adults and Adolescents with Moderate-to-Severe Atopic Dermatitis:52-Week Results from Two Phase III Randomized Clinical Trials (Measure Up 1 and Measure Up 2)

Background: Atopic dermatitis is a chronic inflammatory disease characterized by increased itch, skin pain, poor sleep quality, and other symptoms that negatively affect patient quality of life. Upadacitinib, an oral selective Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, or tyrosine kinase 2, is approved to treat moderate-to-severe atopic dermatitis. Objective: We aimed to evaluate the effect of upadacitinib on patient-reported outcomes over 52 weeks in adults and adolescents with moderate-to-severe atopic dermatitis. Methods: Data from two phase III monotherapy trials of upadacitinib (Measure Up 1, NCT03569293; Measure Up 2, NCT03607422) were integrated. Changes in pruritus, pain, other skin symptoms, sleep, quality of life, mental health, and patient impression were evaluated. Patient-reported outcome assessments included the Worst Pruritus Numerical Rating Scale, Patient-Oriented Eczema Measure, Dermatology Life Quality Index, Atopic Dermatitis Symptom Scale, Atopic Dermatitis Impact Scale, Hospital Anxiety and Depression Scale, SCORing Atopic Dermatitis index, Patient Global Impression of Severity, Patient Global Impression of Change, and Patient Global Impression of Treatment. Minimal clinically important differences, achievement of scores representing minimal disease burden, and the change from baseline were evaluated in patients who received upadacitinib through week 52 and in patients who received placebo through week 16. Results: This analysis included 1609 patients (upadacitinib 15 mg, N = 557; upadacitinib 30 mg, N = 567; placebo, N = 485). Baseline demographics and disease characteristics were generally similar across all arms. The proportion of patients treated with upadacitinib reporting improvements in itch increased rapidly by week 1, increased steadily through week 8, and was sustained through week 52. Patients receiving upadacitinib also experienced improvements in pain and other skin symptoms by week 1, which continued through week 16; improvements were maintained through week 52. Patient reports of improved sleep increased rapidly from baseline to week 1, increased steadily through week 32, and were sustained through week 52. Patients experienced quality-of-life improvements through week 8, which were maintained through week 52. By week 1, patients in both upadacitinib groups experienced rapid improvements in emotional state, and by week 12, patients also achieved meaningful improvements in anxiety and depression. Improvements in mental health continued steadily through week 32 and were maintained through week 52. Patients treated with upadacitinib 30 mg generally experienced improvements in patient-reported outcomes earlier than those treated with upadacitinib 15 mg. Through week 16, patients receiving upadacitinib experienced greater improvements versus those receiving placebo in all assessed patient-reported outcomes. Conclusions: Adults and adolescents with moderate-to-severe atopic dermatitis treated with once-daily upadacitinib 15 or 30 mg experienced early improvements in itch, pain, other skin symptoms, sleep, quality of life, and mental health that were sustained through week 52. Clinical Trial Registration: ClinicalTrials.gov identifiers NCT03569293 (13 August 2018) and NCT03607422 (27 July 2018).</p

A keratin scaffold regulates epidermal barrier formation, mitochondrial lipid composition, and activity.

Keratin intermediate filaments (KIFs) protect the epidermis against mechanical force, support strong adhesion, help barrier formation, and regulate growth. The mechanisms by which type I and II keratins contribute to these functions remain incompletely understood. Here, we report that mice lacking all type I or type II keratins display severe barrier defects and fragile skin, leading to perinatal mortality with full penetrance. Comparative proteomics of cornified envelopes (CEs) from prenatal KtyI(-/-) and KtyII(-/-)(K8) mice demonstrates that absence of KIF causes dysregulation of many CE constituents, including downregulation of desmoglein 1. Despite persistence of loricrin expression and upregulation of many Nrf2 targets, including CE components Sprr2d and Sprr2h, extensive barrier defects persist, identifying keratins as essential CE scaffolds. Furthermore, we show that KIFs control mitochondrial lipid composition and activity in a cell-intrinsic manner. Therefore, our study explains the complexity of keratinopathies accompanied by barrier disorders by linking keratin scaffolds to mitochondria, adhesion, and CE formation