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MOTIVATION: The query for the number of reads overlapping a given region is a common step in the analysis of Illumina sequencing data. Sometimes, these queries are not conveniently precomputable. It seems beneficial to make this kind of arbitrary query as fast and convenient as possible. RESULTS: We present Bathometer, a tool that indexes BAM files in a space efficient way, which allows ad hoc queries for the number of reads overlapping any given genomic region to be answered much more quickly than by counting with common tools such as Samtools, while incurring much less disk I/O. AVAILABILITYAND IMPLEMENTATION: Bathometer is implemented in C, licensed under the GNU General Public License version 3+ and freely downloadable from Bitbucket (https://bitbucket.org/ustenzel/bathometer). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Genômica , Software , Genoma , Sequenciamento de Nucleotídeos em Larga EscalaRESUMO
BACKGROUND: GNAQ and GNA11 mutant nonuveal melanoma represent a poorly characterized rare subgroup of melanoma with a gene mutation profile similar to uveal melanoma. OBJECTIVES: To characterize these tumours in terms of clinical behaviour and genetic characteristics. METHODS: Patients with nonuveal GNAQ/11 mutated melanoma were identified from the prospective multicentre tumour tissue registry ADOREG, Tissue Registry in Melanoma (TRIM) and additional cooperating skin cancer centres. Extensive data on patient, tumour and treatment characteristics were collected retrospectively. Targeted sequencing was used to determine tumour mutational burden. Immunohistochemistry staining was performed for programmed death-ligand 1 and BRCA1-associated protein (BAP)1. Existing whole-exome cutaneous and uveal melanoma data were analysed for mutation type and burden. RESULTS: We identified 18 patients with metastatic GNAQ/11 mutant nonuveal melanoma. Tumours had a lower tumour mutational burden and fewer ultraviolet signature mutations than cutaneous melanomas. In addition to GNAQ and GNA11 mutations (nine each), six splicing factor 3b subunit 1 (SF3B1), three eukaryotic translation initiation factor 1A X-linked (EIF1AX) and four BAP1 mutations were detected. In contrast to uveal melanoma, GNAQ/11 mutant nonuveal melanomas frequently metastasized lymphatically and concurrent EIF1AX, SF3B1 and BAP1 mutations showed no apparent association with patient prognosis. Objective response to immunotherapy was poor with only one partial response observed in 10 treated patients (10%). CONCLUSIONS: Our findings suggest that GNAQ/11 mutant nonuveal melanomas are a subtype of melanoma that is both clinically and genetically distinct from cutaneous and uveal melanoma. As they respond poorly to available treatment regimens, novel effective therapeutic approaches for affected patients are urgently needed. What is already known about this topic? The rare occurrence of GNAQ/11 mutations in nonuveal melanoma has been documented. GNAQ/11 mutant nonuveal melanomas also harbour genetic alterations in EIF1AX, SF3B1 and BAP1 that are of prognostic relevance in uveal melanoma. What does this study add? GNAQ/11 mutant nonuveal melanomas show metastatic spread reminiscent of cutaneous melanoma, but not uveal melanoma. GNAQ/11 mutant nonuveal melanomas have a low tumour mutational burden that is higher than uveal melanoma, but lower than cutaneous melanoma. What is the translational message? Primary GNAQ/11 mutant nonuveal melanomas are a subtype of melanoma that is clinically and genetically distinct from both cutaneous and uveal melanoma. As metastatic GNAQ/11 mutant nonuveal melanomas respond poorly to available systemic therapies, including immune checkpoint inhibition, novel therapeutic approaches for these tumours are urgently needed. Linked Comment: Rafei-Shamsabadi. Br J Dermatol 2020; 183:806-807.
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Melanoma , Neoplasias Cutâneas , Neoplasias Uveais , Análise Mutacional de DNA , Subunidades alfa de Proteínas de Ligação ao GTP/genética , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Humanos , Melanoma/genética , Mutação/genética , Estudos Prospectivos , Estudos Retrospectivos , Neoplasias Cutâneas/genética , Proteínas Supressoras de Tumor , Ubiquitina Tiolesterase , Neoplasias Uveais/genética , Neoplasias Uveais/terapiaRESUMO
Constitutive activation of the PI3K/AKT signaling pathway is found in ~50-70% of AML patients. The SH2-containing inositol 5-phosphatase 1 (SHIP1) is a negative regulator of PI3K/AKT signaling in hematopoietic cells. SHIP1 knockout mice develop a myeloproliferative syndrome and concomitant deletion of SHIP1 and the tumor suppressor PTEN leads to the development of lethal B-cell lymphomas. In the study presented here, we investigated the role of SHIP1 as a tumor suppressor in myeloid leukemia cells in an in vivo xenograft transplantation model. NSG Mice transplanted with UKE-1 cells derived from a secondary AML showed a significantly extended lifespan after lentiviral-mediated overexpression of SHIP1 in comparison to the vector control cohort. In contrast, the AML-derived SHIP1Y643H mutant, which has a strongly reduced enzymatic activity showed a significant reversion of the SHIP1-induced prolongation of the survival time. In addition, the analysis of 290 AML patients revealed a correlation between expression of SHIP1 and overall survival of the AML patients. These results indicate that SHIP1 can act as a tumor suppressor in acute myeloid leukemia cells and that higher SHIP1 expression is associated with prolonged overall survival in AML patients. SHIP1 may be an interesting candidate for gene therapy.
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Leucemia Mieloide Aguda/terapia , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/genética , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Regulação Leucêmica da Expressão Gênica/genética , Humanos , Lentivirus/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Transplante Heterólogo/métodosRESUMO
The aim of this study was to evaluate the quality of the data provided from sheepdog trials in Norway, estimate heritabilities, repeatabilities and genetic correlations for the traits included in the trial and make recommendations on how sheepdog trials best can be utilized in the breeding of Border Collies in Norway. The analyses were based on test results from sheepdog trials carried out in Norway from 1993 to 2012. A total of 45 732 records from 3841 Border Collies were available, but after quality assurance only a third was left. The results demonstrated little information in the data. Heritabilities varied between 0.010 and 0.056 with standard errors ranging from 0.010 to 0.023, while repeatabilities ranged from 0.041 to 0.286. There is a need to assure the quality of data to improve the information in the test results. We recommend adding new traits based on the Herding Trait Characterization scheme evaluated in Sweden, and on traits from the predatory motor pattern, regarded as common for all dogs. These new traits may be scored across the elements that make up the current trial system, which should be kept in place to stimulate participation in the genetic evaluation scheme.
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Cruzamento , Cães/genética , Cães/fisiologia , Animais , Cães/classificação , Feminino , Masculino , Noruega , Linhagem , Comportamento Predatório , SuéciaRESUMO
Because of its antimicrobial properties, nonthermal plasma could serve as an alternative to chemical antisepsis in wound treatment. Therefore, this study investigated the inactivation of biofilm-embedded Pseudomonas aeruginosa SG81 by a surface barrier-discharged (SBD) plasma for 30, 60, 150 and 300 s. In order to optimize the efficacy of the plasma, different carrier gases (argon, argon admixed with 1% oxygen, and argon with increased humidity up to approx. 80%) were tested and compared against 0.1% chlorhexidine digluconate (CHG) exposure for 600 s. The antimicrobial efficacy was determined by calculating the difference between the numbers of colony-forming units (CFU) of treated and untreated biofilms. Living bacteria were distinguished from dead by fluorescent staining and confocal laser scanning microscopy. Both SBD plasmas and CHG showed significant antimicrobial effects compared to the untreated control. However, plasma treatment led to a higher antimicrobial reduction (argon plasma 4.9 log10 CFU/cm(2), argon with admixed oxygen 3 log10 CFU/cm(2), and with increased gas humidity 2.7 log10 CFU/cm(2) after 300 s) compared to CHG. In conclusion, SBD plasma is suitable as an alternative to CHG for inactivation of Pseudomonas aeruginosa embedded in biofilm. Further development of SBD plasma sources and research on the role of carrier gases and humidity may allow their clinical application for wound management in the future.
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Biofilmes/efeitos dos fármacos , Clorexidina/análogos & derivados , Gases em Plasma/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Anti-Infecciosos/farmacologia , Argônio/química , Clorexidina/farmacologia , Contagem de Colônia Microbiana , Fluorescência , Umidade , Microscopia Confocal , Oxigênio/química , Fatores de TempoRESUMO
BACKGROUND: The results of spondylodesis depend on various medical and non-medical factors. Prerequisites for a good functional result are a well-founded assessment of the indications and a technically successful execution of the intervention. Furthermore, non-medical factors also play an important role. APPRAISAL: Attention must be paid to personal context factors and environmental conditions. In addition to psychological disorders and social background conditions, the economic considerations of the patient and expected pension payments influence the desire and willingness to return to gainful employment. ASESSMENT: Based on the physical findings, the criteria for assessment of the suitability for old-age pension insurance, the reduction in earning capacity for the obligatory social insurance and establishment of the severity of the resulting impairment/handicap according to the Social Compensation Act and the Act for the Severely Handicapped (Social Act IX) in Germany are systematically presented.
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Avaliação da Deficiência , Imobilização/métodos , Avaliação de Resultados em Cuidados de Saúde/métodos , Recuperação de Função Fisiológica , Doenças da Coluna Vertebral/diagnóstico , Doenças da Coluna Vertebral/cirurgia , Fusão Vertebral/métodos , Alemanha , Humanos , Resultado do TratamentoRESUMO
PURPOSE: Erectile function preservation is an important quality of life factor in patients treated for prostate cancer. A dose-optimization approach on sexual structures was developed and evaluated to limit erectile dysfunction after radiotherapy. MATERIALS AND METHODS: Twenty-three men with localized prostate cancer and no erectile dysfunction were enrolled in the study. All patients received a prescription dose between 76 and 78Gy. Computed tomography/magnetic resonance image registration was used to delineate the prostatic volume and the sexual structures: internal pudendal arteries (IPA), penile bulb and corpus cavernosum. Erectile function was evaluated using the 5-items International Index of Erectile Function (IIEF-5) score every 6 months during the 2 years after radiotherapy and once a year afterwards. No erectile dysfunction, mild erectile dysfunction and severe erectile dysfunction were defined if the IIEF-5 scores were 20-25, 17-19 and < 17, respectively. RESULTS: The mean follow-up was 4.5 years. The mean age of the patients was 66.3 years. At 2 years, 67% of the patients had no erectile dysfunction, 11% had mild erectile dysfunction and 22% had severe erectile dysfunction. No significant difference was found between the patients with and without erectile dysfunction (IIEF-5≥20 and IIEF-5<20, respectively) for any of the parameters: dosimetric values (internal pudendal arteries, penile bulb, corpus cavernosum), age, comorbidity and smoking status. The biochemical-relapse free survival was 100% at 2 years. CONCLUSION: This approach with dose-optimization on sexual structures for localized prostate cancer found excellent results on erectile function preservation after radiotherapy, with 78% of the patients with no or mild erectile dysfunction at 2 years.
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Disfunção Erétil , Neoplasias da Próstata , Masculino , Humanos , Idoso , Disfunção Erétil/etiologia , Qualidade de Vida , Recidiva Local de Neoplasia , Ereção Peniana , Neoplasias da Próstata/radioterapiaRESUMO
Escalating wildfire frequency and severity, exacerbated by shifting climate patterns, pose significant ecological and economic challenges. Prescribed burns, a common forest management tool, aim to mitigate wildfire risks and protect biodiversity. Nevertheless, understanding the impact of prescribed burns on soil and microbial communities in temperate mixed forests, considering temporal dynamics and slash fuel types, remains crucial. Our study, conducted at the University of Tennessee Forest Resources AgResearch and Education Center in Oak Ridge, TN, employed controlled burns across various treatments, and the findings indicate that low-intensity prescribed burns have none or minimal short-term effects on soil parameters but may alter soil nutrient concentrations, as evidenced by significant changes in porewater acetate, formate, and nitrate concentrations. These burns also induce shifts in microbial community structure and diversity, with Proteobacteria and Acidobacteria increasing significantly post-fire, possibly aiding soil recovery. In contrast, Verrucomicrobia showed a notable decrease over time, and other specific microbial taxa correlated with soil pH, porewater nitrate, ammonium, and phosphate concentrations. Our research contributes to understanding the intricate relationships between prescribed fire, soil dynamics, and microbial responses in temperate mixed forests in the Southern Appalachian Region, which is valuable for informed land management practices in the face of evolving environmental challenges.
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PURPOSE: During prostatic radiotherapy, damage to several anatomical structures could be the cause of erectile dysfunction: corpora cavernosa, internal pudendal arteries, penile bulb, and neurovascular bundles. Numerous studies have analysed the correlations between the dose received by these structures and erectile function. The objective of this article is to make a systematic review on current knowledge. MATERIALS AND METHODS: A systematic review was performed in the Medline database using the search engine PubMed. Keywords for the search included: erectile dysfunction, penile bulb, corpora cavernosa, cavernosum, neurovascular bundles, radiation therapy, cancer, prostate cancer. The selected articles must study a correlation between erectile dysfunction and the dose received by anatomical structures. A total of 152 articles were identified. Of these 152 articles, 45 fulfilled the defined selection criteria. RESULTS: For corpora cavernosa, seven studies were identified, only two studies demonstrated a significant correlation between the dose received by corpora cavernosa and the occurrence of erectile dysfunction. For penile bulb, only 15 of 23 studies showed a correlation. A mean dose on the penile bulb greater than 20Gy was found to be predictive of erectile dysfunction. None of the eight trials concerning neurovascular bundles succeeded to show a correlation between dose and erectile dysfunction. Only one study evaluated the relationship between the dose received by internal pudendal arteries and erectile dysfunction but was found to be negative. However, vessels-sparing studies showed good results on erectile function preservation without compromising the target volume. CONCLUSION: We currently have little data to show a correlation between erectile dysfunction and sexual structures. It would be necessary to have additional prospective studies evaluating the impact of an optimization on these sexual structures on erectile dysfunction.
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Disfunção Erétil , Neoplasias da Próstata , Radioterapia (Especialidade) , Masculino , Humanos , Disfunção Erétil/etiologia , Estudos Prospectivos , Neoplasias da Próstata/radioterapia , Bases de Dados FactuaisRESUMO
AIM: Testing the ability of the alternative ethanol production yeast Dekkera bruxellensis to produce ethanol from lignocellulose hydrolysate and comparing it to Saccharomyces cerevisiae. METHODS AND RESULTS: Industrial isolates of D. bruxellensis and S. cerevisiae were cultivated in small-scale batch fermentations of enzymatically hydrolysed steam exploded aspen sawdust. Different dilutions of hydrolysate were tested. None of the yeasts grew in undiluted or 1:2 diluted hydrolysate [final glucose concentration always adjusted to 40 g l⻹ (0.22 mol l⻹)]. This was most likely due to the presence of inhibitors such as acetate or furfural. In 1:5 hydrolysate, S. cerevisiae grew, but not D. bruxellensis, and in 1:10 hydrolysate, both yeasts grew. An external vitamin source (e.g. yeast extract) was essential for growth of D. bruxellensis in this lignocellulosic hydrolysate and strongly stimulated S. cerevisiae growth and ethanol production. Ethanol yields of 0.42 ± 0.01 g ethanol (g glucose)⻹ were observed for both yeasts in 1:10 hydrolysate. In small-scale continuous cultures with cell recirculation, with a gradual increase in the hydrolysate concentration, D. bruxellensis was able to grow in 1:5 hydrolysate. In bioreactor experiments with cell recirculation, hydrolysate contents were increased up to 1:2 hydrolysate, without significant losses in ethanol yields for both yeasts and only slight differences in viable cell counts, indicating an ability of both yeasts to adapt to toxic compounds in the hydrolysate. CONCLUSIONS: Dekkera bruxellensis and S. cerevisiae have a similar potential to ferment lignocellulose hydrolysate to ethanol and to adapt to fermentation inhibitors in the hydrolysate. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first study investigating the potential of D. bruxellensis to ferment lignocellulosic hydrolysate. Its high competitiveness in industrial fermentations makes D. bruxellensis an interesting alternative for ethanol production from those substrates.
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Biocombustíveis , Dekkera/metabolismo , Etanol , Microbiologia Industrial , Lignina/metabolismo , Saccharomyces cerevisiae/metabolismo , Reatores Biológicos , Fermentação , Hidrólise , Saccharomyces cerevisiae/crescimento & desenvolvimentoRESUMO
BACKGROUND: Head shape and head volume of preterm infants give important information on short- and long-term development. Three-dimensional (3D) assessment of a preterm infant's head would therefore provide more information than currently used two-dimensional methods. AIMS: To evaluate a contactless 3D imaging system to assess head shape and volume in preterm infants. METHODS: A protocol for 3D imaging and reconstruction of an infant's head with a portable stereophotogrammetric camera system was developed. It was validated on a manikin by comparison to an established stationary stereophotogrammetric device. Feasibility for clinical routine and 3D data analysis were assessed in six preterm infants. RESULTS: Ten 3D reconstructions from a manikin were done with ten images each taken from different angles. The accuracy of the 3D reconstruction was measured at the overlapping areas between two images. Comparing the portable to the stationary system, a high concordance was found for the 3D manikin head-reconstructions (mean difference 0.21⯱â¯0.03â¯mm). In preterm infants, digital evaluation of the head was proven to be feasible for head circumference (HC), cranial index and asymmetry indices. There was good concordance between manual and digital measurement of the HC (95% CI -0.85 to 0.38â¯mm). CONCLUSIONS: The portable camera system allowed fast and contactless 3D image capture of a preterm infant's head without any risk or interference with neonatal care. Together with a new software, this technique would allow more precise evaluation of head growth even in very preterm infants and thereby may improve their care and long-term outcome.
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The human adenovirus E1B gene encodes a 55-kilodalton protein that inactivates the cellular tumor suppressor protein p53. Here it is shown that a mutant adenovirus that does not express this viral protein can replicate in and lyse p53-deficient human tumor cells but not cells with functional p53. Ectopic expression of the 55-kilodalton EIB protein in the latter cells rendered them sensitive to infection with the mutant virus. Injection of the mutant virus into p53-deficient human cervical carcinomas grown in nude mice caused a significant reduction in tumor size and caused complete regression of 60 percent of the tumors. These data raise the possibility that mutant adenoviruses can be used to treat certain human tumors.
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Proteínas E1B de Adenovirus/genética , Adenovírus Humanos/fisiologia , Genes p53 , Neoplasias de Cabeça e Pescoço/terapia , Neoplasias Experimentais/terapia , Proteínas E1B de Adenovirus/metabolismo , Adenovírus Humanos/genética , Animais , Efeito Citopatogênico Viral , Deleção de Genes , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Camundongos , Camundongos Nus , Mutação , Transplante de Neoplasias , Neoplasias Experimentais/patologia , Neoplasias Experimentais/virologia , Sigmodontinae , Transplante Heterólogo , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/metabolismo , Replicação ViralRESUMO
A dimensional crossover of superconducting fluctuations in an external magnetic field, applied parallel to the layers, has been found for superconductor/ferromagnet bilayers of Nb/Cu(41)Ni(59). By lowering the temperature, a reduction of the superconducting nuclei size occurs. As soon as the size of the nuclei becomes smaller than the thickness of the superconducting bilayer structure, the dimensionality changes. The temperature dependence of the fluctuation conductivity exhibits a 2D behaviour in zero and weak magnetic fields in the vicinity of the critical temperature, switching to a 3D behaviour in a strong magnetic field at low temperatures.
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Informational need assessment has become an important part of health care in order to provide information effectively in clinical settings. Literature on information needs in the West suggests that breast cancer (BC) patients needed more information than doctors had provided, and information that fully met their needs was associated with patients' long-term well-being. Since few studies on this issue have been conducted in Japan, where the general consultation style is less open and more indirect, compared with that in the West, the application of the findings in the West is questionable. The purpose of this qualitative study was to explore perceived information needs among female BC patients in Japan. Twelve Japanese women with BC participated in semi-structured face-to-face interviews. Grounded theory using verbatim transcripts extracted two main themes: information needed to minimize physical and psychological impacts of treatment and information needed for the resumption of normal life. These were closely related at two time points. Physical support after discharge was perceived as relatively insufficient, especially by women experiencing post-operative arm complications. More open and direct communication was preferred between patients and doctors/family members in the recovery phase. Unmet needs for information may lead to patients' distress.
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Adaptação Psicológica , Neoplasias da Mama/psicologia , Comunicação , Avaliação das Necessidades/normas , Educação de Pacientes como Assunto/normas , Relações Profissional-Paciente , Adulto , Feminino , Humanos , Japão , Pessoa de Meia-Idade , Pesquisa QualitativaRESUMO
The following guidelines were developed for the medical assessment services of the German pension fund. Starting from day-to-day practice, criteria and attributes to guide decisions for a systematisation of the sociomedical assessment of performance in diseases of the liver and the bile ducts were compiled. The guidelines aim at standardising the sociomedical assessment of performance and help to make the decision-making process more transparent, e. g., for the assessment of applications for decreased earning capacity benefits. The guidelines summarise the typical manifestations of diseases of the liver and the bile ducts and describe the necessary medical information for the sociomedical assessment of performance. Relevant assessment criteria for the medical history, clinical examination, and for diagnostic tests are illustrated. The assessment of the individual's capacity is outlined, taking occupational factors into account. Following the determination of dysfunctions, the remaining abilities and disabilities, respectively, are deduced and compared with occupational demands. Finally, inferences are drawn regarding the occupational capacity of the individual. The guidelines followed from an extended procedure to attain a wide consensus in the setting of the German Pension Fund and an upgraded evidence base.
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Doenças Biliares/diagnóstico , Doenças Biliares/terapia , Atenção à Saúde/normas , Hepatopatias/diagnóstico , Hepatopatias/terapia , Garantia da Qualidade dos Cuidados de Saúde/métodos , Garantia da Qualidade dos Cuidados de Saúde/normas , Doença Crônica , Alemanha , Humanos , Fatores SocioeconômicosRESUMO
For the last decade, stereotactic body radiotherapy has become a leading treatment for localized prostate cancer. It can be delivered using a wide array of radiotherapy machines. However, although numerous clinical studies, both prospective and retrospective, have been published, the different techniques have never been properly compared. This article aims at giving an overview of the published trials, and at pointing out the major differences between the machines, from a clinical (efficacy end toxicity), technical and radiobiological point of view.
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Aceleradores de Partículas , Neoplasias da Próstata/radioterapia , Radiocirurgia/instrumentação , Ensaios Clínicos como Assunto , Fracionamento da Dose de Radiação , Humanos , Masculino , Estudos Prospectivos , Radiocirurgia/efeitos adversos , Radiocirurgia/métodos , Radioterapia Conformacional/métodos , Radioterapia de Intensidade Modulada/métodos , Estudos Retrospectivos , Fatores de TempoRESUMO
INTRODUCTION: Treatment of patients with metastatic melanoma is hampered by drug-resistance and often requires combination with radiotherapy as last-resort option. However, also after radiotherapy, clinical relapses are common. METHODS & RESULTS: Our preclinical models indicated a higher rate of tumour relapse when melanoma cells were first treated with BRAFV600E inhibition (BRAFi) followed by radiotherapy as compared to the reverse sequence. Accordingly, retrospective follow-up data from 65 stage-IV melanoma patients with irradiated melanoma brain metastases confirmed a shortened duration of local response of mitogen-activated protein kinase (MAPK)-inhibitor-pretreated compared with MAPK-inhibitor-naïve intracranial metastases. On the molecular level, we identified JARID1B/KDM5B as a cellular marker for cross-resistance between BRAFi and radiotherapy. JARID1Bhigh cells appeared more frequently under upfront BRAFi as compared with upfront radiation. JARID1B favours cell survival by transcriptional regulation of genes controlling cell cycle, DNA repair and cell death. CONCLUSION: The level of cross-resistance between combined MAPK inhibition and radiotherapy is dependent on the treatment sequence. JARID1B may represent a novel therapy-overarching resistance marker.
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Neoplasias Encefálicas/terapia , Resistencia a Medicamentos Antineoplásicos , Melanoma/terapia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Tolerância a Radiação , Radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundário , Ciclo Celular , Movimento Celular , Proliferação de Células , Quimiorradioterapia , Feminino , Seguimentos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Melanoma/genética , Melanoma/patologia , Pessoa de Meia-Idade , Mutação , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , Estudos Retrospectivos , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Because polycythemia vera (PV) is a clonal hematopoietic stem cell disease with a trilineage hyperplasia, and interleukin-3 (IL-3) stimulates trilineage hematopoiesis, we have studied the response of highly purified PV blood burst-forming units-erythroid (BFU-E) to recombinant human IL-3 (rIL-3). Whereas the growth of normal blood BFU-E in vitro rapidly declined by 40 and 60% after 24 and 48 h of incubation without 50 U/ml of rIL-3, the growth of PV BFU-E declined by only 10 and 30% under the same conditions, demonstrating a reduced dependence on rIL-3. A reduced dependence of PV BFU-E on recombinant human erythropoietin (rEP) was also present. Dose-response experiments showed a 117-fold increase in PV BFU-E sensitivity to rIL-3, and a 6.5-fold increase in sensitivity to rEP, compared to normal BFU-E, whereas blood BFU-E from patients with secondary polycythemia responded like normal BFU-E. Endogenous erythroid colony (EEC) formation, which is independent of the addition of rEP, was reduced by 50% after erythroid colony-forming cells were generated from PV BFU-E in vitro without rIL-3 for 3 d, whereas rEP-stimulated erythroid colonies were unaffected. These studies demonstrate a striking hypersensitivity of PV blood BFU-E to rIL-3, which may be the major factor in the pathogenesis of increased erythropoiesis without increased EP concentrations.
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Células Precursoras Eritroides/efeitos dos fármacos , Interleucina-3/farmacologia , Policitemia Vera/sangue , Relação Dose-Resposta a Droga , Eritropoetina/farmacologia , Humanos , Técnicas In Vitro , Proteínas Recombinantes/farmacologiaRESUMO
Artery wall calcification associated with atherosclerosis frequently contains fully formed bone tissue including marrow. The cellular origin is not known. In this study, bone morphogenetic protein-2a, a potent factor for osteoblastic differentiation, was found to be expressed in calcified human atherosclerotic plaque. In addition, cells cultured from the aortic wall formed calcified nodules similar to those found in bone cell cultures and expressed bone morphogenetic protein-2a with prolonged culture. The predominant cells in these nodules had immunocytochemical features characteristic of microvascular pericytes that are capable of osteoblastic differentiation. Pericyte-like cells were also found by immunohistochemistry in the intima of bovine and human aorta. These findings suggest that arterial calcification is a regulated process similar to bone formation, possibly mediated by pericyte-like cells.
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Arteriosclerose/metabolismo , Proteínas/fisiologia , Animais , Aorta , Proteínas Morfogenéticas Ósseas , Bovinos , Imunofluorescência , Humanos , Imuno-Histoquímica , Hibridização In Situ , Microscopia Eletrônica , Músculo Liso Vascular/citologia , Sondas RNARESUMO
We used electron microscopy to determine the relative numbers of the three synaptic terminal types, RL (round vesicle, large terminal), RS (round vesicles, small terminal), and F (flattened vesicles), found in several representative thalamic nuclei in cats chosen as representative examples of first and higher order thalamic nuclei, where the first order nuclei relay subcortical information mainly to primary sensory cortex, and the higher order nuclei largely relay information from one cortical area to another. The nuclei sampled were the first order ventral posterior nucleus (somatosensory) and the ventral portion of the medial geniculate nucleus (auditory), and the higher order posterior nucleus (somatosensory) and the medial portion of the medial geniculate nucleus (auditory). We found that the relative percentage of synapses from RL terminals varied significantly among these nuclei, these values being higher for first order nuclei (12.6% for the ventral posterior nucleus and 8.2% for the ventral portion of the medial geniculate nucleus) than for the higher order nuclei (5.4% for the posterior nucleus, and 3.5% for the medial portion of the medial geniculate nucleus). This is consistent with a similar analysis of first and higher order nuclei for the visual system (the lateral geniculate nucleus and pulvinar, respectively). Since synapses from RL terminals represent the main information to be relayed, whereas synapses from F and RS terminals are modulatory in function, we conclude that there is relatively more modulation of the thalamic relay in the cortico-thalamo-cortical higher order pathway than in first order relays.