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1.
Am J Crit Care ; 31(1): 42-50, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34972856

RESUMO

BACKGROUND: Accurately measuring the risk of pressure injury remains the most important step for effective prevention and intervention. Relative contributions of risk factors for the incidence of pressure injury in adult critical care patients are not well understood. OBJECTIVE: To develop and validate a model to identify risk factors associated with hospital-acquired pressure injuries among adult critical care patients. METHODS: This retrospective cohort study included 23 806 adult patients (28 480 encounters) with an intensive care unit stay at an academic quaternary care center. Patient encounters were randomly split (7:3) into training and validation sets. The training set was used to develop a multivariable logistic regression model using the least absolute shrinkage and selection operator method. The model's performance was evaluated with the validation set. RESULTS: Independent risk factors identified by logistic regression were length of hospital stay, preexisting diabetes, preexisting renal failure, maximum arterial carbon dioxide pressure, minimum arterial oxygen pressure, hypotension, gastrointestinal bleeding, cellulitis, and minimum Braden Scale score of 14 or less. On validation, the model differentiated between patients with and without pressure injury, with area under the receiver operating characteristic curve of 0.85, and performed better than a model with Braden Scale score alone (P < .001). CONCLUSIONS: A model that identified risk factors for hospital-acquired pressure injury among adult critical care patients was developed and validated using a large data set of clinical variables. This model may aid in selecting high-risk patients for focused interventions to prevent formation of hospital-acquired pressure injuries.

2.
Crit Care Explor ; 3(11): e0580, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34841251

RESUMO

Accurately measuring the risk of pressure injury remains the most important step for effective prevention and intervention. Time-dependent risk factors for pressure injury development in the adult intensive care unit setting are not well understood. OBJECTIVES: To develop and validate a dynamic risk prediction model to estimate the risk of developing a hospital-acquired pressure injury among adult ICU patients. DESIGN: ICU admission data were split into training and validation sets. With death as a competing event, both static and dynamic Fine-Gray models were developed to predict hospital-acquired pressure injury development less than 24, 72, and 168 hours postadmission. Model performance was evaluated using Wolbers' concordance index, Brier score, net reclassification improvement, and integrated discrimination improvement. SETTING AND PARTICIPANTS: We performed a retrospective cohort study of ICU patients in a tertiary care hospital located in San Francisco, CA, from November 2013 to August 2017. MAIN OUTCOMES AND MEASURES: Data were extracted from electronic medical records of 18,019 ICU patients (age ≥ 18 yr; 21,220 encounters). Record of hospital-acquired pressure injury data was captured in our institution's incident reporting system. The information is periodically reviewed by our wound care team. Presence of hospital-acquired pressure injury during an encounter and hospital-acquired pressure injury diagnosis date were provided. RESULTS: The dynamic model predicting hospital-acquired pressure injury more than 24 hours postadmission, including predictors age, body mass index, lactate serum, Braden scale score, and use of vasopressor and antifungal medications, had adequate discrimination ability within 6 days from time of prediction (c = 0.73). All dynamic models produced more accurate risk estimates than static models within 26 days postadmission. There were no significant differences in Brier scores between dynamic and static models. CONCLUSIONS AND RELEVANCE: A dynamic risk prediction model predicting hospital-acquired pressure injury development less than 24 hours postadmission in ICU patients for up to 7 days postadmission was developed and validated using a large dataset of clinical variables readily available in the electronic medical record.

3.
Org Biomol Chem ; 19(36): 7792-7809, 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34549230

RESUMO

Nearly all FDA approved drugs and bioactive small molecules exert their effects by binding to and modulating proteins. Consequently, understanding how small molecules interact with proteins at an molecular level is a central challenge of modern chemical biology and drug development. Complementary to structure-guided approaches, chemoproteomics has emerged as a method capable of high-throughput identification of proteins covalently bound by small molecules. To profile noncovalent interactions, established chemoproteomic workflows typically incorporate photoreactive moieties into small molecule probes, which enable trapping of small molecule-protein interactions (SMPIs). This strategy, termed photoaffinity labelling (PAL), has been utilized to profile an array of small molecule interactions, including for drugs, lipids, metabolites, and cofactors. Herein we describe the discovery of photocrosslinking chemistries, including a comparison of the strengths and limitations of implementation of each chemotype in chemoproteomic workflows. In addition, we highlight key examples where photoaffinity labelling has enabled target deconvolution and interaction site mapping.

5.
J Med Internet Res ; 22(12): e22420, 2020 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-33325836

RESUMO

Historically, medical trainees were educated in the hospital on real patients. Over the last decade, there has been a shift to practicing skills through simulations with mannequins or patient actors. Virtual reality (VR), and in particular, the use of 360-degree video and audio (cineVR), is the next-generation advancement in medical simulation that has novel applications to augment clinical skill practice, empathy building, and team training. In this paper, we describe methods to design and develop a cineVR medical education curriculum for trauma care training using real patient care scenarios at an urban, safety-net hospital and Level 1 trauma center. The purpose of this publication is to detail the process of finding a cineVR production partner; choosing the camera perspectives; maintaining patient, provider, and staff privacy; ensuring data security; executing the cineVR production process; and building the curriculum.


Assuntos
Simulação por Computador/normas , Educação Médica/métodos , Treinamento por Simulação/métodos , Realidade Virtual , Humanos , Ferimentos e Lesões
7.
Urol Oncol ; 2020 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-32859462

RESUMO

BACKGROUND: With an increase in the number of cancer survivors each year, male sexual dysfunction becomes an important topic for discussion between patients and providers who treat cancer. The aim of this article is to review types and mechanisms of sexual dysfunction after cancer therapy and discuss treatment options. METHODS: Contemporary concepts regarding male sexual dysfunction after cancer treatment are reviewed and translated for clinical utility. FINDINGS: To optimize recovery of erectile capacity after erectile dysfunction causing cancer treatments, a penile rehabilitation protocol involving phosphodiesterase inhibitors, vacuum erection device, intra corporal injections, or a combination is likely to provide some degree of clinically significant benefit. Treating hypogonadism post cancer treatment depends on the type of cancer that has been treated and patient comorbidities. Anejaculation after cancer treatments is typically not successfully or reliably treated due to the mechanism and severity of sympathetic nerve injury. Semen cryopreservation prior to cancer treatments that may injure nerve fibers essential for the ejaculatory response is highly recommended. CONCLUSION: Management of post cancer treatment sexual dysfunction requires identification of this problem and referral to a specialist if necessary. There are several management options available that can greatly enhance quality of life in this often overlooked aspect of post cancer treatment care.

8.
Curr Pain Headache Rep ; 24(10): 64, 2020 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-32845365

RESUMO

PURPOSE OF REVIEW: The purpose of this review is to evaluate and explain our current understanding of the clinical use of low-dose naltrexone in the treatment of chronic pain. RECENT FINDINGS: Recent pre-clinical uses and clinical studies further elucidate the use of low-dose naltrexone in the treatment of chronic pain. Low-dose naltrexone (LDN) has shown promise to reduce symptoms related to chronic pain conditions such as fibromyalgia, inflammatory bowel conditions, and multiple sclerosis. The mechanism of LDN appears to be modulation of neuro-inflammation, specifically, the modulation of the glial cells and release of inflammatory chemicals in the central nervous system. These effects appear to unique at low dosage compared to dosage for food and drug administration approved use for alcohol and opioid dependence. We review the evidence that LDN has shown more than promise and should be further investigated in clinical practice.


Assuntos
Dor Crônica/tratamento farmacológico , Fibromialgia/tratamento farmacológico , Esclerose Múltipla/tratamento farmacológico , Naltrexona/uso terapêutico , Humanos , Naltrexona/administração & dosagem , Antagonistas de Entorpecentes/uso terapêutico , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico
11.
Curr Pain Headache Rep ; 22(12): 83, 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30291571

RESUMO

PURPOSE OF REVIEW: The purpose of this review is to evaluate and explain our current understanding of the clinical use of buprenorphine in the treatment of chronic pain. RECENT FINDINGS: There has been few high-quality, unbiased studies performed on the use of buprenorphine in the treatment of chronic pain. Buprenorphine is an effective and safe analgesic that is tolerated at least as well, if not better, than other opioids. Given its safety and mechanistic advantages, the authors believe there is an important role for buprenorphine in the treatment of chronic pain severe enough to warrant the use of an opioid analgesic. Though data is lacking for superiority in chronic pain states, the other advantages of the molecule make it the preferential first-line opioid for around-the-clock pain in our practice.


Assuntos
Analgésicos Opioides/uso terapêutico , Buprenorfina/uso terapêutico , Dor Crônica/tratamento farmacológico , Analgésicos Opioides/farmacologia , Buprenorfina/farmacologia , Humanos
12.
Oncotarget ; 8(15): 24250-24261, 2017 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-28445954

RESUMO

To date, targeted therapy for pancreatic ductal adenocarcinoma (PDAC) remains largely unsuccessful in the clinic. Current genomics-based technologies are unable to reflect the quantitative, dynamic signaling changes in the tumor, and require larger tumor samples that are difficult to obtain in PDAC patients. Therefore, a highly sensitive functional tool that can reliably and comprehensively inform intra-tumoral signaling events is direly needed to guide treatment decision. We tested the utility of a highly sensitive proteomics-based functional diagnostic platform, Collaborative Enzyme Enhanced Reactive-immunoassay (CEERTM), on fine-needle aspiration (FNA) samples obtained from 102 patients with radiographically-evident pancreatic tumors. Two FNA passes were collected from each patient, hybridized to customized chips coated with an array of capture antibodies, and detected using two enzyme-conjugated antibodies which emit quantifiable signals. We demonstrate that this technique is highly sensitive in detecting total and phosphorylated forms of multiple signaling molecules in FNA specimens, with reasonable correlation of marker intensities between two different FNA passes. Notably, signals of several markers were significantly higher in PDAC compared to non-cancerous samples. In PDAC samples, we found high total c-Met signal to be associated with poor survival, and confirmed this finding using an independent PDAC tissue microarray.


Assuntos
Biomarcadores Tumorais , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/metabolismo , Imunoensaio , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/metabolismo , Proteômica , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia por Agulha Fina , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/terapia , Endossonografia/métodos , Feminino , Humanos , Imunoensaio/métodos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/terapia , Prognóstico , Proteômica/métodos , Reprodutibilidade dos Testes
13.
Clin Cancer Res ; 23(15): 4323-4334, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-28381415

RESUMO

Purpose: Dual blockade of HER2 with trastuzumab and lapatinib or pertuzumab has been shown to be superior to single-agent trastuzumab. However, a significant fraction of HER2-overexpressing (HER2+) breast cancers escape from these drug combinations. In this study, we sought to discover the mechanisms of acquired resistance to the combination of lapatinib + trastuzumab.Experimental Design: HER2+ BT474 xenografts were treated with lapatinib + trastuzumab long-term until resistance developed. Potential mechanisms of acquired resistance were evaluated in lapatinib + trastuzumab-resistant (LTR) tumors by targeted capture next-generation sequencing. In vitro experiments were performed to corroborate these findings, and a novel drug combination was tested against LTR xenografts. Gene expression and copy-number analyses were performed to corroborate our findings in clinical samples.Results: LTR tumors exhibited an increase in FGF3/4/19 copy number, together with an increase in FGFR phosphorylation, marked stromal changes in the tumor microenvironment, and reduced tumor uptake of lapatinib. Stimulation of BT474 cells with FGF4 promoted resistance to lapatinib + trastuzumab in vitro Treatment with FGFR tyrosine kinase inhibitors reversed these changes and overcame resistance to lapatinib + trastuzumab. High expression of FGFR1 correlated with a statistically shorter progression-free survival in patients with HER2+ early breast cancer treated with adjuvant trastuzumab. Finally, FGFR1 and/or FGF3 gene amplification correlated with a lower pathologic complete response in patients with HER2+ early breast cancer treated with neoadjuvant anti-HER2 therapy.Conclusions: Amplification of FGFR signaling promotes resistance to HER2 inhibition, which can be diminished by the combination of HER2 and FGFR inhibitors. Clin Cancer Res; 23(15); 4323-34. ©2017 AACR.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Fator 3 de Crescimento de Fibroblastos/genética , Receptor ErbB-2/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Animais , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Fator 3 de Crescimento de Fibroblastos/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Lapatinib , Camundongos , Terapia Neoadjuvante/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Quinazolinas/administração & dosagem , Receptor ErbB-2/antagonistas & inibidores , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Trastuzumab/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Eur Radiol ; 27(7): 2784-2793, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27885414

RESUMO

OBJECTIVES: To evaluate the efficiency and safety of emergency department (ED) coronary computed tomography angiography (CTA) during a 3-year clinical experience. METHODS: Single-center registry of coronary CTA in consecutive ED patients with suspicion of acute coronary syndrome (ACS). The primary outcome was efficiency of coronary CTA defined as the length of hospitalization. Secondary endpoints of safety were defined as the rate of downstream testing, normalcy rates of invasive coronary angiography (ICA), absence of missed ACS, and major adverse cardiac events (MACE) during follow-up, and index radiation exposure. RESULTS: One thousand twenty two consecutive patients were referred for clinical coronary CTA with suspicion of ACS. Overall, median time to discharge home was 10.5 (5.7-24.1) hours. Patient disposition was 42.7 % direct discharge from the ED, 43.2 % discharge from emergency unit, and 14.1 % hospital admission. ACS rate during index hospitalization was 9.1 %. One hundred ninety two patients underwent additional diagnostic imaging and 77 underwent ICA. The positive predictive value of CTA compared to ICA was 78.9 % (95 %-CI 68.1-87.5 %). Median CT radiation exposure was 4.0 (2.5-5.8) mSv. No ACS was missed; MACE at follow-up after negative CTA was 0.2 %. CONCLUSIONS: Coronary CTA in an experienced tertiary care setting allows for efficient and safe management of patients with suspicion for ACS. KEY POINTS: • ED Coronary CTA using advanced systems is associated with low radiation exposure. • Negative coronary CTA is associated with low rates of MACE. • CTA in ED patients enables short median time to discharge home. • CTA strategy is characterized by few downstream tests including unnecessary ICA.


Assuntos
Síndrome Coronariana Aguda/diagnóstico , Angiografia por Tomografia Computadorizada/métodos , Angiografia Coronária/métodos , Unidades de Cuidados Coronarianos , Vasos Coronários/diagnóstico por imagem , Triagem/métodos , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes
15.
Oncotarget ; 8(3): 4277-4288, 2017 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-28032592

RESUMO

The EGFR inhibitor cetuximab is approved for the treatment of colorectal cancer. However, both innate and acquired resistance mechanisms, including compensatory feedback loops, limit its efficacy. Nevertheless, the emergence of these feedback loops has remained largely unexplored to date. Here, we showed feedback upregulation of HER3 and induction of HER3 phosphorylation after cetuximab treatment in colon cancer cells. We also showed that this upregulation occurs, at least partly, through AKT inhibition. Together with this, we observed increased HER2:HER3 dimerization upon cetuximab treatment. Interestingly, lapatinib, a dual EGFR and HER2 tyrosine kinase inhibitor, blocked the increase of cetuximab-induced HER3 phosphorylation. Additionally, we showed that upon HER3 knockdown, cetuximab combined with lapatinib was able to decrease cell viability compared to HER3 expressing cells. These results suggest the existence of a cetuximab-induced feedback HER3 activation that could potentially result in reduced cetuximab efficacy in colorectal cancer patients. Taken together, we provide evidence of the limited effectiveness of cetuximab monotherapy compared to rational combinations.


Assuntos
Cetuximab/farmacologia , Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Receptor ErbB-2/metabolismo , Receptor ErbB-3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo , Resistencia a Medicamentos Antineoplásicos , Retroalimentação Fisiológica , Humanos , Lapatinib , Fosforilação , Multimerização Proteica , Receptor ErbB-3/genética , Regulação para Cima
16.
J Thorac Imaging ; 31(6): 380-390, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27768631

RESUMO

PURPOSE: Coronary-pulmonary arterial fistulas (CPAFs) are rare coronary artery anomalies that have been described only in limited case reports. This study aims to evaluate the clinical presentation and imaging findings of CPAFs collected from 6 participating medical centers along with CPAFs reported in the literature, to discern any general trends present in CPAFs. MATERIALS AND METHODS: A total of 25 cases of CPAF diagnosed by coronary computed tomography angiography were collected across 6 participating institutions. In addition, utilizing a PubMed literature search, 78 additional CPAF cases were obtained. The imaging findings and relevant clinical history were reviewed. RESULTS: Of the 103 CPAF patients, 60 (63% of patients with sex known) were male, with ages ranging from newborn to 88 years (mean=46.1 y). The most common symptoms reported were chest pain (n=40, 39%) and dyspnea (n=26, 25%), with a murmur as the most common physical examination finding (n=38, 37%). The most common coronary artery of origin for a CPAF was the left main/left anterior descending (n=87, 84%), followed by the right coronary artery (n=39, 38%). The fistula most commonly terminated in the main pulmonary artery (n=92, 89%). Multiple CPAFs were present in 46 cases (45%). Coronary artery aneurysms were identified in 20 cases (19%). Pediatric CPAF cases were usually associated with pulmonary atresia with ventricular septal defect. CONCLUSIONS: CPAFs are seen in a variety of clinical settings, from infants with advanced congenital heart disease to elderly patients who have undergone revascularization surgery. Although coronary artery fistulas have previously been described as rarely involving multiple coronary arteries, with the right coronary artery being most often involved, our series demonstrates that multiple fistulas are commonly present, with the most common pattern being between the left main/left anterior descending and the main pulmonary trunk.


Assuntos
Fístula Artério-Arterial/diagnóstico por imagem , Anomalias dos Vasos Coronários/diagnóstico por imagem , Artéria Pulmonar/anormalidades , Artéria Pulmonar/diagnóstico por imagem , Angiografia por Tomografia Computadorizada , Angiografia Coronária , Vasos Coronários/diagnóstico por imagem , Humanos
17.
J Med Internet Res ; 18(6): e141, 2016 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-27277523

RESUMO

BACKGROUND: Electronic medical records and electronic data capture (EDC) have changed data collection in clinical and translational research. However, spreadsheet programs, such as Microsoft Excel, are still used as data repository to record and organize patient data for research. OBJECTIVE: The objective of this study is to assess the efficiency of EDC as against a standard spreadsheet in regards to time to collect data and data accuracy, measured in number of errors after adjudication. METHODS: This was a crossover study comparing the time to collect data in minutes between EDC and a spreadsheet. The EDC tool used was Research Electronic Data Capture (REDCap), whereas the spreadsheet was Microsoft Excel. The data collected was part of a registry of patients who underwent coronary computed tomography angiography in the emergency setting. Two data collectors with the same experience went over the same patients and collected relevant data on a case report form identical to the one used in our Emergency Department (ED) registry. Data collection tool was switched after the patient that represented half the cohort. For this, the patient cohort was exactly 30 days of our ED coronary Computed Tomography Angiography registry and the point of crossover was determined beforehand to be 15 days. We measured the number of patients admitted, and time to collect data. Accuracy was defined as absence of blank fields and errors, and was assessed by comparing data between data collectors and counting every time the data differed. Statistical analysis was made using paired t -test. RESULTS: The study included 61 patients (122 observations) and 55 variables. The crossover occurred after the 30th patient. Mean time to collect data using EDC in minutes was 6.2±2.3, whereas using Excel was 8.0±2.0 (P <.001), a difference of 1.8 minutes between both means (22%). The cohort was evenly distributed with 3 admissions in the first half of the crossover and 4 in the second half. We saw 2 (<0.1%) continuous variable typos in the spreadsheet that a single data collector made. There were no blank fields. The data collection tools showed no differences in accuracy of data on comparison. CONCLUSIONS: Data collection for our registry with an EDC tool was faster than using a spreadsheet, which in turn allowed more efficient follow-up of cases.


Assuntos
Coleta de Dados/métodos , Registros Eletrônicos de Saúde , Internet , Sistema de Registros , Estudos Cross-Over , Confiabilidade dos Dados , Humanos
18.
Oncotarget ; 6(31): 30929-38, 2015 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-26439803

RESUMO

PURPOSE: Although activating mutations in the epidermal growth factor receptor (EGFR) gene are predictive markers for response to EGFR inhibitors, 30-40% of EGFR-mutant non-small cell lung cancer (NSCLC) patients are de novo non-responders. Hence, we sought to explore additional biomarkers of response. METHODS: We conducted a prospective pilot study to characterize the expression and/or activation of key receptor tyrosine kinases (RTKs) in stage IIIB-IV NSCLC tumors. A total of 37 patients were enrolled and 34 underwent EGFR inhibitor treatment. RESULTS: As expected, patients bearing activating EGFR mutations showed increased progression free survival (PFS) compared to patients with wild-type EGFR status (9.3 vs 1.4 months, p = 0.0629). Analysis of baseline tumor RTK profiles revealed that, regardless of EGFR mutation status, higher levels of EGFR relative to MET correlated with longer PFS. At multiple EGFR/MET ratio cut-offs, including 1, 2 and 3, median PFS according to below vs. above cut-offs were 0.4 vs. 6.1 (p = 0.0001), 0.5 vs. 9.3 (p = 0.0006) and 1.0 vs. 11.2 months (p = 0.0008), respectively. CONCLUSION: The EGFR/MET ratio measured in tumors at baseline may help identify NSCLC patients most likely to benefit from prolonged PFS when treated with EGFR inhibitors.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Mutação/genética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Adulto , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Projetos Piloto , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida
19.
PLoS One ; 9(8): e103551, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25090459

RESUMO

BACKGROUND: Oncogenic mutational analysis provides predictive guidance for therapeutics such as anti-EGFR antibodies, but it is successful only for a subset of colorectal cancer (CRC) patients. METHOD: A comprehensive molecular profiling of 120 CRC patients, including 116 primary, 15 liver metastasis, and 1 peritoneal seeding tissue samples was performed to identify the relationship between v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) WT and mutant CRC tumors and clinical outcomes. This included determination of the protein activation patterns of human epidermal receptor 1 (HER1), HER2, HER3, c-MET, insulin-like growth factor 1 receptor (IGF1R), phosphatidylinositide 3-kinase (PI3K), Src homology 2 domain containing (Shc), protein kinase B (AKT), and extracellular signal-regulated kinase (ERK) kinases using multiplexed collaborative enzyme enhanced reactive (CEER) immunoassay. RESULTS: KRAS WT and mutated CRCs were not different with respect to the expression of the various signaling molecules. Poor prognosis in terms of early relapse (<2 years) and shorter disease-free survival (DFS) correlated with enhanced activation of PI3K signaling relative to the HER kinase pathway signaling, but not with the KRAS mutational status. KRAS WT CRCs were identified as a mixed prognosis population depending on their level of PI3K signaling. KRAS WT CRCs with high HER1/c-MET index ratio demonstrated a better DFS post-surgery. c-MET and IGF1R activities relative to HER axis activity were considerably higher in early relapse CRCs, suggesting a role for these alternative receptor tyrosine kinases (RTKs) in driving high PI3K signaling. CONCLUSIONS: The presented data subclassified CRCs based on their activated signaling pathways and identify a role for c-MET and IGF1R-driven PI3K signaling in CRCs, which is superior to KRAS mutational tests alone. The results from this study can be utilized to identify aggressive CRCs, explain failure of currently approved therapeutics in specific CRC subsets, and, most importantly, generate hypotheses for pathway-guided therapeutic strategies that can be tested clinically.


Assuntos
Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/genética , Mutação/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Proteínas Proto-Oncogênicas/genética , Receptor IGF Tipo 1/metabolismo , Proteínas ras/genética , Idoso , Neoplasias Colorretais/patologia , Receptores ErbB/metabolismo , Feminino , Heterogeneidade Genética , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/enzimologia , Recidiva Local de Neoplasia/patologia , Prognóstico , Proteínas Proto-Oncogênicas p21(ras) , Transdução de Sinais , Análise de Sobrevida
20.
JAMA Neurol ; 71(10): 1228-36, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25111166

RESUMO

IMPORTANCE: The identification of a patient with a rare form of severe dysbetalipoproteinemia allowed the study of the consequences of total absence of apolipoprotein E (apoE). OBJECTIVES: To discover the molecular basis of this rare disorder and to determine the effects of complete absence of apoE on neurocognitive and visual function and on lipoprotein metabolism. DESIGN, SETTING, AND PARTICIPANTS: Whole-exome sequencing was performed on the patient's DNA. He underwent detailed neurological and visual function testing and lipoprotein analysis. Lipoprotein analysis was also performed in the Cardiovascular Research Institute, University of California, San Francisco, on blood samples from the proband's mother, wife, 2 daughters, and normolipidemic control participants. MAIN OUTCOME MEASURES: Whole-exome sequencing, lipoprotein analysis, and neurocognitive function. RESULTS: The patient was homozygous for an ablative APOE frameshift mutation (c.291del, p.E97fs). No other mutations likely to contribute to the phenotype were discovered, with the possible exception of two, in ABCC2 (p.I670T) and LIPC (p.G137R). Despite complete absence of apoE, he had normal vision, exhibited normal cognitive, neurological, and retinal function, had normal findings on brain magnetic resonance imaging, and had normal cerebrospinal fluid levels of ß-amyloid and tau proteins. He had no significant symptoms of cardiovascular disease except a suggestion of myocardial ischemia on treadmill testing and mild atherosclerosis noted on carotid ultrasonography. He had exceptionally high cholesterol content (760 mg/dL; to convert to millimoles per liter, multiply by 0.0259) and a high cholesterol to triglycerides ratio (1.52) in very low-density lipoproteins with elevated levels of small-diameter high-density lipoproteins, including high levels of prebeta-1 high-density lipoprotein. Intermediate-density lipoproteins, low-density lipoproteins, and very low-density lipoproteins contained elevated apoA-I and apoA-IV levels. The patient's apoC-III and apoC-IV levels were decreased in very low-density lipoproteins. Electron microscopy revealed large lamellar particles having electron-opaque cores attached to electron-lucent zones in intermediate-density and low-density lipoproteins. Low-density lipoprotein particle diameters were distributed bimodally. CONCLUSIONS AND RELEVANCE: Despite a profound effect on lipoprotein metabolism, detailed neurocognitive and retinal studies failed to demonstrate any defects. This suggests that functions of apoE in the brain and eye are not essential or that redundant mechanisms exist whereby its role can be fulfilled. Targeted knockdown of apoE in the central nervous system might be a therapeutic modality in neurodegenerative disorders.


Assuntos
Apolipoproteínas E/genética , Hiperlipoproteinemia Tipo III/genética , Lipase/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Adulto , Apolipoproteínas A/sangue , Apolipoproteínas C/sangue , Apolipoproteínas E/deficiência , Doenças das Artérias Carótidas/diagnóstico por imagem , Teste de Esforço , Exoma , Mutação da Fase de Leitura , Genótipo , Lipoproteínas de Alta Densidade Pré-beta/sangue , Humanos , Hiperlipoproteinemia Tipo III/fisiopatologia , Hiperlipoproteinemia Tipo III/psicologia , Metabolismo dos Lipídeos/genética , Lipoproteínas HDL/sangue , Lipoproteínas LDL/sangue , Lipoproteínas VLDL/sangue , Masculino , Fenótipo , Retina , Análise de Sequência de DNA , Índice de Gravidade de Doença , Dermatopatias/genética , Triglicerídeos/sangue , Ultrassonografia , Xantomatose/genética
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