PET scanning evaluation of response to imatinib mesylate therapy in gastrointestinal stromal tumor (GIST) patients

Background: Unresectable or metastatic gastrointestinal stromal tumors (GISTs) exhibit a dynamic clinical course, with no evidence of benefit from any standard cytotoxic chemotherapy and an inevitably fatal outcome. With the introduction of Imatinib, an oral drug able to inhibit the KIT receptor tyrosine kinase, new questions arise regarding our ability to monitor treatment response with conventional methods and optimally manage such patients on treatment with new agents. Materials and methods: Herein we report two cases of patients with a history of GIST in treatment with Imatinib. Results: After 4 weeks from treatment start, CT scan evaluation demonstrated a massive increase in the size of metastatic lesions, but a confirmatory PET excluded, in both patients, the presence of any metabolic activity in the previously known metastatic sites. Imatinib therapy was continued with subjective clinical benefit for 12 further months before a PET scan-confirmed disease progression had occurred in one patient and is still ongoing after 15 months in the other. Conclusion: These cases open the obvious question of whether conventional imaging techniques are adequate to assess the response to Imatinib treatment in GIST patients

Impact of gefitinib ('Iressa') treatment on the quality of life of patients with advanced non-small-cell lung cancer

Purpose: Patients with advanced non-small-cell lung cancer (NSCLC) have a short life expectancy; therefore, in addition to increasing their survival, improving their quality of life (QoL) is also an important treatment goal. Methods: We evaluated the QoL of patients with advanced NSCLC who were unfit to receive chemotherapy, failed to respond or progress following prior chemotherapy, who received subsequent treatment with gefitinib ('Iressa') on a compassionate use basis, using a standard QoL questionnaire, (EORTC) QLQ-C30 and the related lung cancer-specific module QLQ-LC13. Results: Analysis of the functional scales showed a trend towards improvement for role, emotional and cognitive scales, while a substantial stability was seen for general QoL scale. Analysis of the symptoms scales of QLQ-C30, showed a trend towards improvement for fatigue, dyspnoea, insomnia, and constipation, after one month of therapy. Fifty-six of the 57 patients were considered evaluable for response. One patient evidenced a partial response (patient is still on response), 29 patients had stable disease for a median duration of 5 months (range 4-7 months), and 26 patients progressed. Conclusions: After treatment with Gefitinib, we observed maintenance of QoL in a group of patients with poor prognosis that would be expected to have a worsening QoL. Furthermore important symptoms like dyspnoea fatigue and pain in other parts, that usually afflict patients with NSCLC, showed a trend toward improvement after only one month of therapy

Sequential chemotherapy in nonsmall-cell lung cancer: cisplatin and gemcitabine followed by docetaxel

Background: Improving results in nonsmall-cell lung cancer (NSCLC) will require the development of new drugs and strategies to combine available agents. On the basis of data indicating the activity of docetaxel as second-line therapy, a Phase II study was conducted to evaluate the efficacy and toxicity of the sequential combination of chemotherapy consisting of cisplatin (P) and gemcitabine (G) followed by docetaxel (DOC) in patients with advanced NSCLC. Methods: Patients with 1997 TNM stage IIIB (pleural effusion)/stage IV NSCLC, performance status (PS) of 0-1, and normal organ function were eligible. Therapy consisted of P at 75 mg/m(2) on Day 1 and G 1200 mg/m(2) on Days 1 and 8 every 3 weeks for 3 cycles followed, in nonprogressive patients, by DOC 30 mg/m(2) every week for 6 consecutive weeks every 8 weeks for 2 cycles. Results: Fifty-two eligible patients were enrolled (M/F, 39/13; stage IIIB/IV, 8/44; PS 0, 73%, PS 1, 27%; median age, 58 years; range, 36-73). The overall response rate was 36.5% (95% confidence interval [CI]: 23-49). The median overall survival was 11 months (95% CI: 9-13); the median progression-free survival was 6 months (95% CI: 5-7); and the 1- and 2-year survivals were 48% and 25%, respectively. One- and 2-year progression-free survivals were 12% and 8%, respectively. Both phases of the treatment protocol were well tolerated. Conclusions: P/G followed by weekly DOC is well tolerated and active as first-line therapy for NSCLC patients and provides a feasible chemotherapeutic option in this clinical setting

The THAP–zinc finger protein THAP1 regulates endothelial cell proliferation through modulation of pRB/E2F cell-cycle target genes

AbstractWe recently cloned a novel human nuclear factor (designated THAP1) from postcapillary venule endothelial cells (ECs) that contains a DNA-binding THAP domain, shared with zebrafish E2F6 and several Caenorhabditis elegans proteins interacting genetically with retinoblastoma gene product (pRB). Here, we show that THAP1 is a physiologic regulator of EC proliferation and cell-cycle progression, 2 essential processes for angiogenesis. Retroviral-mediated gene transfer of THAP1 into primary human ECs inhibited proliferation, and large-scale expression profiling with microarrays revealed that THAP1-mediated growth inhibition is due to coordinated repression of pRB/E2F cell-cycle target genes. Silencing of endogenous THAP1 through RNA interference similarly inhibited EC proliferation and G1/S cell-cycle progression, and resulted in down-regulation of several pRB/E2F cell-cycle target genes, including RRM1, a gene required for S-phase DNA synthesis. Chromatin immunoprecipitation assays in proliferating ECs showed that endogenous THAP1 associates in vivo with a consensus THAP1-binding site found in the RRM1 promoter, indicating that RRM1 is a direct transcriptional target of THAP1. The similar phenotypes observed after THAP1 overexpression and silencing suggest that an optimal range of THAP1 expression is essential for EC proliferation. Together, these data provide the first links in mammals among THAP proteins, cell proliferation, and pRB/E2F cell-cycle pathways

A 17-Gene Expression Signature for Early Identification of Poor Prognosis in Clear Cell Renal Cell Carcinoma

: The Identification of reliable Biomarkers able to predict the outcome after nephrectomy of patients with clear cell renal cell carcinoma (ccRCC) is an unmet need. The gene expression analysis in tumor tissues represents a promising tool for better stratification of ccRCC subtypes and patients' evaluation. Methods: In our study we retrospectively analyzed using Next-Generation expression analysis (NanoString), the expression of a gene panel in tumor tissue from 46 consecutive patients treated with nephrectomy for non-metastatic ccRCC at two Italian Oncological Centres. Significant differences in expression levels of selected genes was sought. Additionally, we performed a univariate and a multivariate analysis on overall survival according to Cox regression model. Results: A 17-gene expression signature of patients with a recurrence-free survival (RFS) < 1 year (unfavorable genomic signature (UGS)) and of patients with a RFS > 5 years (favorable genomic signature (FGS)) was identified and resulted in being significantly correlated with overall survival of the patients included in this analysis (HR 51.37, p < 0.0001). Conclusions: The identified Genomic Signatures may serve as potential biomarkers for prognosis prediction of non-metastatic RCC and could drive both follow-up and treatment personalization in RCC management

Curriculum directions and strategies for the implementation of a new pedagogic proposal

This study is aimed at contributing to the transformation movement to be developed in the Nursing Courses/Schools. The contribution refers to the formation of nurses with autonomy and discernment, to ensure the construction of the model of health attention, to the production of new knowledge and to the delivery of quality services directed to the health needs of the population. This study brings some conceptual and methodological reflections that may direct the change in the nurse formation process, as well as pointing strategies to implement the new pedagogic proposal from the challenge posed by the implementation of the National Curriculum Directions for Under-graduate Nursing Courses.O presente estudo busca contribuir com o movimento de transformação a ser desenvolvido nas Escolas/Cursos de Enfermagem. Essa contribuição se refere à formação de enfermeiras(os) com autonomia e discernimento, para assegurar a construção do modelo de atenção à saúde, à produção de novos conhecimentos e à prestação de serviços de qualidade voltados para as necessidades de saúde da população, com resolutividade. Traz algumas reflexões conceituais e metodológicas que possam direcionar a mudança no processo de formação de enfermeiras(os), além de apontar estratégias para a implantação da nova proposta pedagógica, baseando-se no desafio da implementação das Diretrizes Curriculares Nacionais do Curso de Graduação em Enfermagem.El presente estudio busca contribuir con el movimiento de transformación a desarrollarse en las Escuelas/Cursos de Enfermería. Esa contribución se refiere a la formación de enfermeras(os) con autonomía y discernimiento, para asegurar la construcción del modelo de atención a la salud, la producción de nuevos conocimientos y la prestación de servicios de calidad volcados hacia las necesidades de salud de la población, con resolutividad. Considera algunas reflexiones conceptuales y metodológicas que puedan orientar el cambio en el proceso de formación de enfermeras(os), además de señalar estrategias para la implantación de la nueva propuesta pedagógica, a partir del desafío de la implementación de las Directrices Curriculares Nacionales del Pre Grado en Enfermería.44344

Diretrizes curriculares e estratégias para implantação de uma nova proposta pedagógica

O presente estudo busca contribuir com o movimento de transformação a ser desenvolvido nas Escolas/Cursos de Enfermagem. Essa contribuição se refere à formação de enfermeiras(os) com autonomia e discernimento, para assegurar a construção do modelo de atenção à saúde, à produção de novos conhecimentos e à prestação de serviços de qualidade voltados para as necessidades de saúde da população, com resolutividade. Traz algumas reflexões conceituais e metodológicas que possam direcionar a mudança no processo de formação de enfermeiras(os), além de apontar estratégias para a implantação da nova proposta pedagógica, baseando-se no desafio da implementação das Diretrizes Curriculares Nacionais do Curso de Graduação em Enfermagem.El presente estudio busca contribuir con el movimiento de transformación a desarrollarse en las Escuelas/Cursos de Enfermería. Esa contribución se refiere a la formación de enfermeras(os) con autonomía y discernimiento, para asegurar la construcción del modelo de atención a la salud, la producción de nuevos conocimientos y la prestación de servicios de calidad volcados hacia las necesidades de salud de la población, con resolutividad. Considera algunas reflexiones conceptuales y metodológicas que puedan orientar el cambio en el proceso de formación de enfermeras(os), además de señalar estrategias para la implantación de la nueva propuesta pedagógica, a partir del desafío de la implementación de las Directrices Curriculares Nacionales del Pre Grado en Enfermería.This study is aimed at contributing to the transformation movement to be developed in the Nursing Courses/Schools. The contribution refers to the formation of nurses with autonomy and discernment, to ensure the construction of the model of health attention, to the production of new knowledge and to the delivery of quality services directed to the health needs of the population. This study brings some conceptual and methodological reflections that may direct the change in the nurse formation process, as well as pointing strategies to implement the new pedagogic proposal from the challenge posed by the implementation of the National Curriculum Directions for Under-graduate Nursing Courses

High-throughput chemogenetic drug screening reveals PKC-RhoA/PKN as a targetable signaling vulnerability in GNAQ-driven uveal melanoma

Uveal melanoma (UM) is the most prevalent cancer of the eye in adults, driven by activating mutation of GNAQ/GNA11; however, there are limited therapies against UM and metastatic UM (mUM). Here, we perform a high-throughput chemogenetic drug screen in GNAQ-mutant UM contrasted with BRAF-mutant cutaneous melanoma, defining the druggable landscape of these distinct melanoma subtypes. Across all compounds, darovasertib demonstrates the highest preferential activity against UM. Our investigation reveals that darovasertib potently inhibits PKC as well as PKN/PRK, an AGC kinase family that is part of the "dark kinome." We find that downstream of the Gαq-RhoA signaling axis, PKN converges with ROCK to control FAK, a mediator of non-canonical Gαq-driven signaling. Strikingly, darovasertib synergizes with FAK inhibitors to halt UM growth and promote cytotoxic cell death in vitro and in preclinical metastatic mouse models, thus exposing a signaling vulnerability that can be exploited as a multimodal precision therapy against mUM.</p

An NF-Y-Dependent Switch of Positive and Negative Histone Methyl Marks on CCAAT Promoters

Background: Histone tails have a plethora of different post-translational modifications, which are located differently in ‘‘open’ ’ and ‘‘closed’ ’ parts of genomes. H3K4me3/H3K79me2 and H4K20me3 are among the histone marks associated with the early establishment of active and inactive chromatin, respectively. One of the most widespread promoter elements is the CCAAT box, bound by the NF-Y trimer. Two of NF-Y subunits have an H2A-H2B-like structure. Principal findings: We established the causal relationship between NF-Y binding and positioning of methyl marks, by ChIP analysis of mouse and human cells infected with a dominant negative NF-YA: a parallel decrease in NF-Y binding, H3K4me3, H3K79me2 and transcription was observed in promoters that are dependent upon NF-Y. On the contrary, changes in the levels of H3K9-14ac were more subtle. Components of the H3K4 methylating MLL complex are not recruited in the absence of NF-Y. As for repressed promoters, NF-Y removal leads to a decrease in the H4K20me3 mark and deposition of H3K4me3. Conclusions: Two relevant findings are reported: (i) NF-Y gains access to its genomic locations independently from the presence of methyl histone marks, either positive or negative; (ii) NF-Y binding has profound positive or negative consequences on the deposition of histone methyl marks. Therefore NF-Y is a fundamental switch at the heart of decisio