RESUMO
We present a numerical algorithm that allows the approximation of optimal controls for stochastic reaction-diffusion equations with additive noise by first reducing the problem to controls of feedback form and then approximating the feedback function using finitely based approximations. Using structural assumptions on the finitely based approximations, rates for the approximation error of the cost can be obtained. Our algorithm significantly reduces the computational complexity of finding controls with asymptotically optimal cost. Numerical experiments using artificial neural networks as well as radial basis function networks illustrate the performance of our algorithm. Our approach can also be applied to stochastic control problems for high dimensional stochastic differential equations and more general stochastic partial differential equations.
RESUMO
Since the introduction of cerebral bypass surgery by Professor Yasargil in 1967, a plethora of literature has been published on direct cerebral revascularization. Against this background, it is remarkable that at present, only three randomized controlled trials (RCTs) exist in the field, both dealing with extracranial to intracranial bypass surgery for flow augmentation in patients at risk to suffer ischemic or hemorrhagic stroke due to cerebrovascular disease. Next to flow augmentation, the other main indication for bypass surgery is to provide flow replacement following proximal vessel sacrifice for treatment of complex aneurysms or skull base tumors. The aim of this review was to provide a comprehensive overview of the literature regarding the indications and the techniques of cerebral bypass surgery for prevention of cerebral ischemia.
Assuntos
Isquemia Encefálica/prevenção & controle , Isquemia Encefálica/cirurgia , Revascularização Cerebral/métodos , Isquemia Encefálica/etiologia , Humanos , Procedimentos Neurocirúrgicos/métodosRESUMO
BACKGROUND: While next generation sequencing has enhanced our understanding of the biological basis of malignancy, current knowledge on global practices for sequencing cancer samples is limited. To address this deficiency, we developed a survey to provide a snapshot of current sequencing activities globally, identify barriers to data sharing and use this information to develop sustainable solutions for the cancer research community. METHODS: A multi-item survey was conducted assessing demographics, clinical data collection, genomic platforms, privacy/ethics concerns, funding sources and data sharing barriers for sequencing initiatives globally. Additionally, respondents were asked as to provide the primary intent of their initiative (clinical diagnostic, research or combination). RESULTS: Of 107 initiatives invited to participate, 59 responded (response rate = 55%). Whole exome sequencing (P = 0.03) and whole genome sequencing (P = 0.01) were utilized less frequently in clinical diagnostic than in research initiatives. Procedures to identify cancer-specific variants were heterogeneous, with bioinformatics pipelines employing different mutation calling/variant annotation algorithms. Measurement of treatment efficacy varied amongst initiatives, with time on treatment (57%) and RECIST (53%) being the most common; however, other parameters were also employed. Whilst 72% of initiatives indicated data sharing, its scope varied, with a number of restrictions in place (e.g. transfer of raw data). The largest perceived barriers to data harmonization were the lack of financial support (P < 0.01) and bioinformatics concerns (e.g. lack of interoperability) (P = 0.02). Capturing clinical data was more likely to be perceived as a barrier to data sharing by larger initiatives than by smaller initiatives (P = 0.01). CONCLUSIONS: These results identify the main barriers, as perceived by the cancer sequencing community, to effective sharing of cancer genomic and clinical data. They highlight the need for greater harmonization of technical, ethical and data capture processes in cancer sample sequencing worldwide, in order to support effective and responsible data sharing for the benefit of patients.
Assuntos
Estudos de Associação Genética , Neoplasias/genética , Análise Mutacional de DNA , Bases de Dados Genéticas , Predisposição Genética para Doença , Genoma Humano , Humanos , Anotação de Sequência Molecular , Inquéritos e Questionários , Sequenciamento do ExomaRESUMO
The genetics of renal cancer is dominated by inactivation of the VHL tumour suppressor gene in clear cell carcinoma (ccRCC), the commonest histological subtype. A recent large-scale screen of â¼3,500 genes by PCR-based exon re-sequencing identified several new cancer genes in ccRCC including UTX (also known as KDM6A), JARID1C (also known as KDM5C) and SETD2 (ref. 2). These genes encode enzymes that demethylate (UTX, JARID1C) or methylate (SETD2) key lysine residues of histone H3. Modification of the methylation state of these lysine residues of histone H3 regulates chromatin structure and is implicated in transcriptional control. However, together these mutations are present in fewer than 15% of ccRCC, suggesting the existence of additional, currently unidentified cancer genes. Here, we have sequenced the protein coding exome in a series of primary ccRCC and report the identification of the SWI/SNF chromatin remodelling complex gene PBRM1 (ref. 4) as a second major ccRCC cancer gene, with truncating mutations in 41% (92/227) of cases. These data further elucidate the somatic genetic architecture of ccRCC and emphasize the marked contribution of aberrant chromatin biology.
Assuntos
Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Mutação/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Animais , Linhagem Celular Tumoral , Proteínas de Ligação a DNA , Modelos Animais de Doenças , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Neoplasias Pancreáticas/genéticaRESUMO
Intrinsic subtypes are widely accepted for the classification of breast cancer. Lacking gene expression data, surrogate classifications based on immunohistochemistry (IHC) have been proposed. A recent St. Gallen consensus meeting recommends to use this "surrogate intrinsic subtypes" for predicting adjuvant chemotherapy resistance, implying that "Surrogate Luminal A" breast cancers should only receive endocrine therapy. In this study we assessed both gene expression based intrinsic subtypes as well as surrogate intrinsic subtypes regarding their power to predict neoadjuvant chemotherapy benefit. Single institution data of 560 breast cancer patients were reviewed. Gene expression data was available for 247 patients. Subtypes were determined on the basis of IHC, Ki67, histological grade, endocrine responsiveness, and gene expression, and were correlated with chemotherapy response and recurrence-free survival. In ER+/HER2- tumors, a high histological grade was the best predictor for chemotherapy benefit, both in terms of pCR (p = 0.004) and recurrence-free survival (p = 0.002). The gene expression based and surrogate intrinsic subtype based on Ki67 had no predictive or prognostic value in ER+/HER2- tumors. Histological grade, ER, PR, and HER2 were the best predictive factors for chemotherapy response in breast cancer. We propose to continue the conventional use of these markers.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Quimioterapia Adjuvante , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Terapia Neoadjuvante , Gradação de Tumores , Valor Preditivo dos Testes , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Análise de Sobrevida , Resultado do TratamentoRESUMO
The altered posterior question-mark incision for decompressive hemicraniectomy (DHC) was proposed to reduce the risk of intraoperative injury of the superficial temporal artery (STA) and demonstrated a reduced rate of wound-healing disorders after cranioplasty. However, decompression size during DHC is essential and it remains unclear if the new incision type allows for an equally effective decompression. Therefore, this study evaluated the efficacy of the altered posterior question-mark incision for craniectomy size and decompression of the temporal base and assessed intraoperative complications compared to a modified standard reversed question-mark incision. The authors retrospectively identified 69 patients who underwent DHC from 2019 to 2022. Decompression and preservation of the STA was assessed on postoperative CT scans and CT or MR angiography. Forty-two patients underwent DHC with the standard reversed and 27 patients with the altered posterior question-mark incision. The distance of the margin of the craniectomy to the temporal base was 6.9 mm in the modified standard reversed and 7.2 mm in the altered posterior question-mark group (p = 0.77). There was no difference between the craniectomy sizes of 158.8 mm and 158.2 mm, respectively (p = 0.45), and there was no difference in the rate of accidental opening of the mastoid air cells. In both groups, no transverse/sigmoid sinus was injured. Twenty-four out of 42 patients in the modified standard and 22/27 patients in the altered posterior question-mark group had a postoperative angiography, and the STA was preserved in all cases in both groups. Twelve (29%) and 5 (19%) patients underwent revision due to wound-healing disorders after DHC, respectively (p = 0.34). There was no difference in duration of surgery. Thus, the altered posterior question-mark incision demonstrated technically equivalent and allows for an equally effective craniectomy size and decompression of the temporal base without increasing risks of intraoperative complications. Previously described reduction in wound-healing complications and cranioplasty failures needs to be confirmed in prospective studies to demonstrate the superiority of the altered posterior question-mark incision.
Assuntos
Craniectomia Descompressiva , Ferida Cirúrgica , Humanos , Estudos Retrospectivos , Resultado do Tratamento , Crânio , DescompressãoRESUMO
The luminal composition of the auditory tube influences its function. The mechanisms involved in the monitoring are currently not known. For the lower respiratory epithelium, such a sentinel role is carried out by cholinergic brush cells. Here, using two different mouse strains expressing eGFP under the control of the promoter of choline acetyltransferase (ChAT), we show the presence of solitary cholinergic villin-positive brush cells also in the mouse auditory tube epithelium. They express the vesicular acetylcholine (ACh) transporter and proteins of the taste transduction pathway such as α-gustducin, phospholipase C beta 2 (PLC(ß2)) and transient receptor potential cation channel subfamily M member 5 (TRPM5). Immunoreactivity for TRPM5 and PLCß2 was found regularly, whereas α-gustducin was absent in approximately 15% of the brush cells. Messenger RNA for the umami taste receptors (TasR), Tas1R1 and 3, and for the bitter receptors, Tas2R105 and Tas2R108, involved in perception of cycloheximide and denatonium were detected in the auditory tube. Using a transgenic mouse that expresses eGFP under the promotor of the nicotinic ACh receptor α3-subunit, we identified cholinoceptive nerve fibers that establish direct contacts to brush cells in the auditory tube. A subpopulation of these fibers displayed also CGRP immunoreactivity. Collectively, we show for the first time the presence of brush cells in the auditory tube. These cells are equipped with all proteins essential for sensing the composition of the luminal microenvironment and for communication of the changes to the CNS via attached sensory nerve fibers.
Assuntos
Células Quimiorreceptoras/citologia , Neurônios Colinérgicos/citologia , Tuba Auditiva/citologia , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Língua/citologiaRESUMO
BACKGROUND: Breast cancer cells deficient for BRCA1 are hypersensitive to agents inducing DNA double-strand breaks (DSB), such as bifunctional alkylators and platinum agents. Earlier, we had developed a comparative genomic hybridisation (CGH) classifier based on BRCA1-mutated breast cancers. We hypothesised that this BRCA1-like(CGH) classifier could also detect loss of function of BRCA1 due to other causes besides mutations and, consequently, might predict sensitivity to DSB-inducing agents. PATIENTS AND METHODS: We evaluated this classifier in stage III breast cancer patients, who had been randomly assigned between adjuvant high-dose platinum-based (HD-PB) chemotherapy, a DSB-inducing regimen, and conventional anthracycline-based chemotherapy. Additionally, we assessed BRCA1 loss through mutation or promoter methylation and immunohistochemical basal-like status in the triple-negative subgroup (TN subgroup). RESULTS: We observed greater benefit from HD-PB chemotherapy versus conventional chemotherapy among patients with BRCA1-like(CGH) tumours [41/230 = 18%, multivariate hazard ratio (HR) = 0.12, 95% confidence interval (CI) 0.04-0.43] compared with patients with non-BRCA1-like(CGH) tumours (189/230 = 82%, HR = 0.78, 95% CI 0.50-1.20), with a significant difference (test for interaction P = 0.006). Similar results were obtained for overall survival (P interaction = 0.04) and when analyses were restricted to the TN subgroup. Sixty-three percent (20/32) of assessable BRCA1-like(CGH) tumours harboured either a BRCA1 mutation (n = 8) or BRCA1 methylation (n = 12). CONCLUSION: BRCA1 loss as assessed by CGH analysis can identify patients with substantially improved outcome after adjuvant DSB-inducing chemotherapy when compared with standard anthracycline-based chemotherapy in our series.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteína BRCA1/genética , Neoplasias da Mama/tratamento farmacológico , Carcinoma Basocelular/tratamento farmacológico , Hibridização Genômica Comparativa , Mutação/genética , Receptor ErbB-2/metabolismo , Adulto , Neoplasias da Mama/classificação , Neoplasias da Mama/genética , Carboplatina/administração & dosagem , Carcinoma Basocelular/classificação , Carcinoma Basocelular/genética , Ciclofosfamida/administração & dosagem , Metilação de DNA , Epirubicina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Hibridização in Situ Fluorescente , Regiões Promotoras Genéticas , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Taxa de Sobrevida , Tiotepa/administração & dosagem , Resultado do TratamentoRESUMO
Germline mutations in BRCA1 and BRCA2 explain approximately 25% of all familial breast cancers. Despite intense efforts to find additional high-risk breast cancer genes (BRCAx) using linkage analysis, none have been reported thus far. Here we explore the hypothesis that BRCAx breast tumors from genetically related patients share a somatic genetic etiology that might be revealed by array comparative genomic hybridization (aCGH) profiling. As BRCA1 and BRCA2 tumors can be identified on the basis of specific genomic profiles, the same may be true for a subset of BRCAx families. Analyses used aCGH to compare 58 non-BRCA1/2 familial breast tumors (designated BRCAx) to sporadic (non-familiar) controls, BRCA1 and BRCA2 tumors. The selection criteria for BRCAx families included at least three cases of breast cancer diagnosed before the age of 60 in the family, and the absence of ovarian or male breast cancer. Hierarchical cluster analysis was performed to determine sub-groups within the BRCAx tumor class and family heterogeneity. Analysis of aCGH profiles of BRCAx tumors indicated that they constitute a heterogeneous class, but are distinct from both sporadic and BRCA1/2 tumors. The BRCAx class could be divided into sub-groups. One subgroup was characterized by a gain of chromosome 22. Tumors from family members were classified within the same sub-group in agreement with the hypothesis that tumors from the same family would harbor a similar genetic background. This approach provides a method to target a sub-group of BRCAx families for further linkage analysis studies.
Assuntos
Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Carcinoma Lobular/genética , Hibridização Genômica Comparativa , Estudos de Casos e Controles , Duplicação Cromossômica , Cromossomos Humanos Par 22 , Análise por Conglomerados , Feminino , Genes BRCA1 , Genes BRCA2 , Genes Neoplásicos , Ligação Genética , Estudo de Associação Genômica Ampla , Genótipo , HumanosRESUMO
Muscle-invasive bladder cancer (MIBC) is a heterogeneous disease that often recurs despite aggressive treatment with neoadjuvant chemotherapy and (radical) cystectomy. Basal and luminal molecular subtypes have been identified that are linked to clinical characteristics and have differential sensitivities to chemotherapy. While it has been suggested that epigenetic mechanisms play a role in defining these subtypes, a thorough understanding of the biological mechanisms is lacking. This report details the first genome-wide analysis of histone methylation patterns of human primary bladder tumours by chromatin immunoprecipitations and next-generation sequencing (ChIP-seq). We profiled multiple histone marks: H3K27me3, a marker for repressed genes, and H3K4me1 and H3K4me3, which are indicators of active enhancers and active promoters. Integrated analysis of ChIP-seq data and RNA sequencing revealed that H3K4 mono-methylation demarcates MIBC subtypes, while no association was found for the other two histone modifications in relation to basal and luminal subtypes. Additionally, we identified differentially methylated H3K4me1 peaks in basal and luminal tumour samples, suggesting that active enhancers play a role in defining subtypes. Our study is the first analysis of histone modifications in primary bladder cancer tissue and provides an important resource for the bladder cancer community.
Assuntos
Biomarcadores Tumorais/genética , Cistectomia/métodos , Metilação de DNA , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Musculares/patologia , Neoplasias da Bexiga Urinária/patologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Musculares/classificação , Neoplasias Musculares/genética , Neoplasias Musculares/cirurgia , Invasividade Neoplásica , Prognóstico , Neoplasias da Bexiga Urinária/classificação , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/cirurgiaRESUMO
MOTIVATION: Cells receive a wide variety of environmental signals, which are often processed combinatorially to generate specific genetic responses. Changes in transcript levels, as observed across different environmental conditions, can, to a large extent, be attributed to changes in the activity of transcription factors (TFs). However, in unraveling these transcription regulation networks, the actual environmental signals are often not incorporated into the model, simply because they have not been measured. The unquantified heterogeneity of the environmental parameters across microarray experiments frustrates regulatory network inference. RESULTS: We propose an inference algorithm that models the influence of environmental parameters on gene expression. The approach is based on a yeast microarray compendium of chemostat steady-state experiments. Chemostat cultivation enables the accurate control and measurement of many of the key cultivation parameters, such as nutrient concentrations, growth rate and temperature. The observed transcript levels are explained by inferring the activity of TFs in response to combinations of cultivation parameters. The interplay between activated enhancers and repressors that bind a gene promoter determine the possible up- or downregulation of the gene. The model is translated into a linear integer optimization problem. The resulting regulatory network identifies the combinatorial effects of environmental parameters on TF activity and gene expression. AVAILABILITY: The Matlab code is available from the authors upon request. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Assuntos
Técnicas de Cultura de Células/métodos , Meio Ambiente , Perfilação da Expressão Gênica/métodos , Modelos Biológicos , Proteínas de Saccharomyces cerevisiae/fisiologia , Saccharomyces cerevisiae/fisiologia , Fatores de Transcrição/fisiologia , Simulação por Computador , Interpretação Estatística de Dados , Regulação Fúngica da Expressão Gênica/fisiologia , Análise de Sequência com Séries de Oligonucleotídeos/métodosRESUMO
Most invasive breast cancers are classified as invasive ductal carcinoma not otherwise specified (IDC NOS), whereas about 25% are defined as histological 'special types'. These special-type breast cancers are categorized into at least 17 discrete pathological entities; however, whether these also constitute discrete molecular entities remains to be determined. Current therapy decision-making is increasingly governed by the molecular classification of breast cancer (luminal, basal-like, HER2+). The molecular classification is derived from mainly IDC NOS and it is unknown whether this classification applies to all histological subtypes. We aimed to refine the breast cancer classification systems by analysing a series of 11 histological special types [invasive lobular carcinoma (ILC), tubular, mucinous A, mucinous B, neuroendocrine, apocrine, IDC with osteoclastic giant cells, micropapillary, adenoid cystic, metaplastic, and medullary carcinoma] using immunohistochemistry and genome-wide gene expression profiling. Hierarchical clustering analysis confirmed that some histological special types constitute discrete entities, such as micropapillary carcinoma, but also revealed that others, including tubular and lobular carcinoma, are very similar at the transcriptome level. When classified by expression profiling, IDC NOS and ILC contain all molecular breast cancer types (ie luminal, basal-like, HER2+), whereas histological special-type cancers, apart from apocrine carcinoma, are homogeneous and only belong to one molecular subtype. Our analysis also revealed that some special types associated with a good prognosis, such as medullary and adenoid cystic carcinomas, display a poor prognosis basal-like transcriptome, providing strong circumstantial evidence that basal-like cancers constitute a heterogeneous group. Taken together, our results imply that the correct classification of breast cancers of special histological type will allow a more accurate prognostication of breast cancer patients and facilitate the identification of optimal therapeutic strategies.
Assuntos
Neoplasias da Mama/classificação , Carcinoma Ductal de Mama/classificação , Regulação Neoplásica da Expressão Gênica , Biomarcadores Tumorais/análise , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patologia , Análise por Conglomerados , Feminino , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Análise de Sequência com Séries de Oligonucleotídeos , Transdução de Sinais/genética , Estatísticas não ParamétricasRESUMO
Early elimination of natural organic matter (NOM) by ion exchange (IEX) in water treatment is expected to improve subsequent water treatment processes and the final drinking water quality. Nine anionic exchange resins were investigated to remove NOM and specific NOM fractions determined by liquid chromatography in combination with organic carbon detection (LC-OCD) and fluorescence excitation-emission matrices (EEM). Breakthrough of NOM was predicted by model calculations using Freundlich isotherms and IEX rate experiments. The time to breakthrough varied from 4 to 38 days. Removal of specific NOM fractions proved to vary considerably for the different types of IEX resins, ranging from 1% to almost 60%. The removal of NOM fractions, specifically humic substances, increased with an increase in water content of the investigated IEX resins and with a decrease in resin size. The best-performing IEX resins consisted of the smallest resins and/or those with the highest water content. The worst-performing IEX resins reflected the highest exchanging capacities and the lowest water contents.
Assuntos
Resinas de Troca Aniônica/química , Benzopiranos/química , Substâncias Húmicas , Poluentes da Água/química , Adsorção , Países Baixos , Purificação da Água/métodosRESUMO
Cancer is a complex disease in which cells progressively accumulate mutations disrupting their cellular processes. A fraction of these mutations drive tumourigenesis by affecting oncogenes or tumour suppressor genes, but many mutations are passengers with no clear contribution to tumour development. The advancement of DNA and RNA sequencing technologies has enabled in-depth analysis of thousands of human tumours from various tissues to perform systematic characterization of their (epi)genomes and transcriptomes in order to identify (epi)genetic changes associated with cancer. Combined with considerable progress in algorithmic development, this expansion in scale has resulted in the identification of many cancer-associated mutations, genes and pathways that are considered to be potential drivers of tumour development. However, it remains challenging to systematically identify drivers affected by complex genomic rearrangements and drivers residing in non-coding regions of the genome or in complex amplicons or deletions of copy-number driven tumours. Furthermore, functional characterization is challenging in the human context due to the lack of genetically tractable experimental model systems in which the effects of mutations can be studied in the context of their tumour microenvironment. In this respect, mouse models of human cancer provide unique opportunities for pinpointing novel driver genes and their detailed characterization. In this review, we provide an overview of approaches for complementing human studies with data from mouse models. We also discuss state-of-the-art technological developments for cancer gene discovery and validation in mice.
Assuntos
Perfilação da Expressão Gênica/métodos , Neoplasias Experimentais/genética , Análise de Sequência de DNA/métodos , Animais , Progressão da Doença , Epigênese Genética , Redes Reguladoras de Genes , Predisposição Genética para Doença , Humanos , Camundongos , Neoplasias Experimentais/patologia , Análise de Sequência de RNA/métodosRESUMO
Androgen receptor (AR) is a key player in prostate cancer development and progression. Here we applied immunoprecipitation mass spectrometry of endogenous AR in LNCaP cells to identify components of the AR transcriptional complex. In total, 66 known and novel AR interactors were identified in the presence of synthetic androgen, most of which were critical for AR-driven prostate cancer cell proliferation. A subset of AR interactors required for LNCaP proliferation were profiled using chromatin immunoprecipitation assays followed by sequencing, identifying distinct genomic subcomplexes of AR interaction partners. Interestingly, three major subgroups of genomic subcomplexes were identified, where selective gain of function for AR genomic action in tumorigenesis was found, dictated by FOXA1 and HOXB13. In summary, by combining proteomic and genomic approaches we reveal subclasses of AR transcriptional complexes, differentiating normal AR behavior from the oncogenic state. In this process, the expression of AR interactors has key roles by reprogramming the AR cistrome and interactome in a genomic location-specific manner.
Assuntos
Carcinogênese/genética , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Proteínas de Homeodomínio/metabolismo , Neoplasias da Próstata/genética , Receptores Androgênicos/genética , Androgênios/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Epigênese Genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Genômica , Fator 3-alfa Nuclear de Hepatócito/genética , Proteínas de Homeodomínio/genética , Humanos , Masculino , Camundongos , Camundongos Nus , Próstata/citologia , Próstata/patologia , Neoplasias da Próstata/patologia , Proteômica , Receptores Androgênicos/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A new tool--the Membrane Fouling Simulator (MFS)--is developed to measure membrane fouling (pressure drop increase) in a small and simple system, representative for spiral wound membranes applied in water treatment. With the MFS, fouling development can be monitored systematically by (i) pressure drop, (ii) in situ and non-destructive (visual) observations using the sight glass and (iii) analysis of coupons sampled from the membrane sheet in the MFS. A comparison study of the MFS with spiral wound membrane elements (test rigs and a full scale installation) showed the same fouling. The MFS provided reproducible data. The small size and low water and chemical use of the MFS facilitate to perform systematic parallel studies. With the MFS, fouling of membranes applied in water treatment can be characterised.
Assuntos
Biofilmes/crescimento & desenvolvimento , Membranas Artificiais , Purificação da Água/instrumentação , Bactérias/crescimento & desenvolvimento , Filtração , Previsões , Pressão , Reprodutibilidade dos Testes , Purificação da Água/métodosRESUMO
Mutations of the retinoblastoma tumor-suppressor gene (RB1) or components regulating the CDK-RB-E2F pathway have been identified in nearly every human malignancy. Re-establishing cell cycle control through cyclin-dependent kinase (CDK) inhibition has therefore emerged as an attractive option in the development of targeted cancer therapy. The most successful example of this today is the use of the CDK4/6 inhibitor palbociclib combined with aromatase inhibitors for the treatment of estrogen receptor-positive breast cancers. Multiple studies have demonstrated that the CDK-RB-E2F pathway is critical for the control of cell proliferation. More recently, studies have highlighted additional roles of this pathway, especially E2F transcription factors themselves, in tumor progression, angiogenesis and metastasis. Specific E2Fs also have prognostic value in breast cancer, independent of clinical parameters. We discuss here recent advances in understanding of the RB-E2F pathway in breast cancer. We also discuss the application of genome-wide genetic screening efforts to gain insight into synthetic lethal interactions of CDK4/6 inhibitors in breast cancer for the development of more effective combination therapies.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Quinase 4 Dependente de Ciclina/genética , Quinase 6 Dependente de Ciclina/genética , Fatores de Transcrição E2F/genética , Proteínas de Ligação a Retinoblastoma/genética , Ubiquitina-Proteína Ligases/genética , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Feminino , Humanos , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêuticoRESUMO
Microarrays for gene expression profiling are rapidly becoming important research tools for the identification of novel markers, for example, for novel classification of leukemias and lymphomas. Here, we review the considerations and infrastructure for microarray experiments. These considerations are illustrated via a microarray-based comparison of gene expression profiles of paired diagnosis-relapse samples from patients with precursor-B acute lymphoblastic leukemia (ALL), who relapsed during therapy or after completion of treatment. Initial experiments showed that several seemingly differentially expressed genes were actually derived from contaminating non-leukemic cells, particularly myeloid cells and T-lymphocytes. Therefore, we purified the ALL cells of the diagnosis and relapse samples if their frequency was lower than 95%. Furthermore, we observed in earlier studies that extra RNA amplification leads to skewing of particular gene transcripts. Sufficient (non-amplified) RNA of purified and paired diagnosis-relapse samples was obtained from only seven cases. The gene expression profiles were evaluated with Affymetrix U95A chips containing 12 600 human genes. These diagnosis-relapse comparisons revealed only a small number of genes (n=6) that differed significantly in expression: mostly signaling molecules and transcription factors involved in cell proliferation and cell survival were highly upregulated at relapse, but we did not observe any increase in drug-resistance markers. This finding fits with the observation that tumors with a high proliferation index have a poor prognosis. The genes that changed between diagnosis and relapse are currently not in use as diagnostic or disease progression markers, but represent potential new markers for such applications. Leukemia (2003) 17, 1324-1332. doi:10.1038/sj.leu.2402974
Assuntos
Perfilação da Expressão Gênica/métodos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Biomarcadores , Divisão Celular/genética , Sobrevivência Celular/genética , Criança , Pré-Escolar , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/genética , Perfilação da Expressão Gênica/normas , Humanos , Lactente , Masculino , Análise de Sequência com Séries de Oligonucleotídeos/instrumentação , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , RecidivaRESUMO
The inference of genetic interactions from measured expression data is one of the most challenging tasks of modern functional genomics. When successful, the learned network of regulatory interactions yields a wealth of useful information. An inferred genetic network contains information about the pathway to which a gene belongs and which genes it interacts with. Furthermore, it explains the function of the gene in terms of how it influences other genes and indicates which genes are pathway initiators and therefore potential drug targets. Obviously, such wealth comes at a price and that of genetic network modeling is that it is an extremely complex task. Therefore, it is necessary to develop sophisticated computational tools that are able to extract relevant information from a limited set of microarray measurements and integrate this with different information sources, to come up with reliable hypotheses of a genetic regulatory network. Thus far, a multitude of modeling approaches have been proposed for discovering genetic networks. However, it is unclear what the advantages and disadvantages of each of the different approaches are and how their results can be compared. In this review, genetic network models are put in a historical perspective that explains why certain models were introduced. Various modeling assumptions and their consequences are also highlighted. In addition, an overview of the principal differences and similarities between the approaches is given by considering the qualitative properties of the chosen models and their learning strategies.