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2.
Cancer Res ; 2020 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-32580961

RESUMO

KRAS is mutated in most pancreatic ductal adenocarcinomas (PDAC) and yet remains undruggable. Here we report that p38gamma MAPK, which promotes PDAC tumorigenesis by linking KRAS signaling and aerobic glycolysis (also called the Warburg effect), is a novel therapeutic target. p38gamma interacted with a glycolytic activator PFKFB3 that was dependent on mutated KRAS. KRAS transformation and overexpression of p38gamma increased expression of PFKFB3 and glucose transporter GLUT2; conversely, silencing mutant KRAS and p38gamma decreased PFKFB3 and GLUT2 expression. p38gamma phosphorylated PFKFB3 at S467, stabilized PFKFB3, and promoted their interaction with GLUT2. Pancreatic knockout (KO) of p38gamma decreased p-PFKFB3/PFKFB3/GLUT2 protein levels, reduced aerobic glycolysis, and inhibited PDAC tumorigenesis in KPC mice. PFKFB3 and GLUT2 depended on p38gamma to stimulate glycolysis and PDAC growth and p38gamma required PFKFB3/S467 to promote these activities. A p38gamma inhibitor cooperated with a PFKFB3 inhibitor to blunt aerobic glycolysis and PDAC growth, which was dependent on p38gamma. Moreover, overexpression of p38gamma, p-PFKFB3, PFKFB3, and GLUT2 in PDAC predicted poor clinical prognosis. These results indicate that p38gamma links KRAS oncogene signaling and aerobic glycolysis to promote pancreatic tumorigenesis through PFKFB3 and GLUT2, and that p38gamma and PFKFB3 may be targeted for therapeutic intervention in PDAC.

3.
Mass Spectrom Rev ; 2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-32588492

RESUMO

Since 2016, eight new oligonucleotide therapies have been approved which has led to increased interest in oligonucleotide analysis. There is a particular need for powerful bioanalytical tools to study the metabolism and biotransformation of these molecules. This review provides the background on the biological basis of these molecules as currently used in therapies. The article also reviews the current state of analytical methodology including state of the art sample preparation techniques, liquid chromatography-mass spectrometry methods, and the current limits of detection/quantitation. Finally, the article summarizes the challenges in oligonucleotide bioanalysis and provides future perspectives for this emerging field. © 2020 John Wiley & Sons Ltd. Mass Spec Rev 1-25, 2020.

4.
Stroke ; 51(7): 2153-2160, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32517581

RESUMO

BACKGROUND AND PURPOSE: For survivors of oral anticoagulation therapy (OAT)-associated intracerebral hemorrhage (OAT-ICH) who are at high risk for thromboembolism, the benefits of OAT resumption must be weighed against increased risk of recurrent hemorrhagic stroke. The ε2/ε4 alleles of the apolipoprotein E (APOE) gene, MRI-defined cortical superficial siderosis, and cerebral microbleeds are the most potent risk factors for recurrent ICH. We sought to determine whether combining MRI markers and APOE genotype could have clinical impact by identifying ICH survivors in whom the risks of OAT resumption are highest. METHODS: Joint analysis of data from 2 longitudinal cohort studies of OAT-ICH survivors: (1) MGH-ICH study (Massachusetts General Hospital ICH) and (2) longitudinal component of the ERICH study (Ethnic/Racial Variations of Intracerebral Hemorrhage). We evaluated whether MRI markers and APOE genotype predict ICH recurrence. We then developed and validated a combined APOE-MRI classification scheme to predict ICH recurrence, using Classification and Regression Tree analysis. RESULTS: Cortical superficial siderosis, cerebral microbleed, and APOE ε2/ε4 variants were independently associated with ICH recurrence after OAT-ICH (all P<0.05). Combining APOE genotype and MRI data resulted in improved prediction of ICH recurrence (Harrell C: 0.79 versus 0.55 for clinical data alone, P=0.033). In the MGH (training) data set, CSS, cerebral microbleed, and APOE ε2/ε4 stratified likelihood of ICH recurrence into high-, medium-, and low-risk categories. In the ERICH (validation) data set, yearly ICH recurrence rates for high-, medium-, and low-risk individuals were 6.6%, 2.5%, and 0.9%, respectively, with overall area under the curve of 0.91 for prediction of recurrent ICH. CONCLUSIONS: Combining MRI and APOE genotype stratifies likelihood of ICH recurrence into high, medium, and low risk. If confirmed in prospective studies, this combined APOE-MRI classification scheme may prove useful for selecting individuals for OAT resumption after ICH.

5.
Physiol Meas ; 2020 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-32498055

RESUMO

Heart rate variability has been largely used for the assessment of cardiac autonomic activity, due to the direct relationship between cardiac rhythm and the activity of the sympathetic and parasympathetic nervous system. In recent years, another technique, pulse rate variability , has been used for assessing heart rate variability information from pulse wave signals, especially from photoplethysmography, a non-invasive, non-intrusive, optical technique that measures the blood volume in tissue. The relationship, however, between pulse rate variability and heart rate variability is not entirely understood, and the effects of cardiovascular changes in pulse rate variability have not been thoroughly dilucidated. In this review, a comprehensive summary of the applications in which pulse rate variability has been used, with a special focus on cardiovascular health, and of the studies that have compared heart rate variability and pulse rate variability is presented. It was found that the relationship between heart rate variability and pulse rate variability is not entirely understood yet, and that pulse rate variability might be influenced not only due to technical aspects but also by physiological factors that might affect the measurements obtained from pulse-to-pulse time series extracted from pulse waves. Hence, pulse rate variability must not be considered as a valid surrogate of heart rate variability in all scenarios, and care must be taken when using pulse rate variability instead of heart rate variability. Specifically, the way pulse rate variability is affected by cardiovascular changes does not necessarily reflect the same information as heart rate variability, and might contain further valuable information. More research regarding the relationship between cardiovascular changes and pulse rate variability should be performed to evaluate if pulse rate variability might be useful for the assessment of not only cardiac autonomic activity but also for the analysis of mechanical and vascular autonomic responses to these changes.

6.
Nat Commun ; 11(1): 2739, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32483165

RESUMO

Synthetic biology is a powerful tool to create therapeutics which can be rationally designed to enable unique and combinatorial functionalities. Here we utilize non-pathogenic E coli Nissle as a versatile platform for the development of a living biotherapeutic for the treatment of cancer. The engineered bacterial strain, referred to as SYNB1891, targets STING-activation to phagocytic antigen-presenting cells (APCs) in the tumor and activates complementary innate immune pathways. SYNB1891 treatment results in efficacious antitumor immunity with the formation of immunological memory in murine tumor models and robust activation of human APCs. SYNB1891 is designed to meet manufacturability and regulatory requirements with built in biocontainment features which do not compromise its efficacy. This work provides a roadmap for the development of future therapeutics and demonstrates the transformative potential of synthetic biology for the treatment of human disease when drug development criteria are incorporated into the design process for a living medicine.

7.
Neurocrit Care ; 2020 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-32524527

RESUMO

BACKGROUND: Early systolic blood pressure (SBP) reduction is believed to improve outcome after spontaneous intracerebral hemorrhage (ICH), but there has been a limited assessment of SBP trajectories in individual patients. We aimed to determine the prognostic significance of SBP trajectories in ICH. METHODS: We collected routine data on spontaneous ICH patients from two healthcare systems over 10 years. Unsupervised functional principal components analysis (FPCA) was used to characterize SBP trajectories over first 24 h and their relationship to the primary outcome of unfavorable shift on modified Rankin scale (mRS) at hospital discharge, categorized as an ordinal trichotomous variable (mRS 0-2, 3-4, and 5-6 defined as good, poor, and severe, respectively). Ordinal logistic regression models adjusted for baseline SBP and ICH volume were used to determine the prognostic significance of SBP trajectories. RESULTS: The 757 patients included in the study were 65 ± 23 years old, 56% were men, with a median (IQR) Glasgow come scale of 14 (8). FPCA revealed that mean SBP over 24 h and SBP reduction within the first 6 h accounted for 76.8% of the variation in SBP trajectories. An increase in SBP reduction (per 10 mmHg) was significantly associated with unfavorable outcomes defined as mRS > 2 (adjusted-OR = 1.134; 95% CI 1.044-1.233, P = 0.003). Compared with SBP reduction < 20 mmHg, worse outcomes were observed for SBP reduction = 40-60 mmHg (adjusted-OR = 1.940, 95% CI 1.129-3.353, P = 0.017) and > 60 mmHg, (adjusted-OR = 1.965, 95% CI 1.011, 3.846, P = 0.047). Furthermore, the association of SBP reduction and outcome varied according to initial hematoma volume. Smaller SBP reduction was associated with good outcome (mRS 0-2) in small (< 7.42 mL) and medium-size (≥ 7.42 and < 30.47 mL) hematomas. Furthermore, while the likelihood of good outcome was low in those with large hematomas (≥ 30.47 mL), smaller SBP reduction was associated with decreasing probability of severe outcome (mRS 5-6). CONCLUSION: Our analyses suggest that in the first 6 h SBP reduction is significantly associated with the in-hospital outcome that varies with initial hematoma volume, and early SBP reduction > 40 mmHg may be harmful in ICH patients. For early SBP reduction to have an effective therapeutic effect, both target levels and optimum SBP reduction goals vis-à-vis hematoma volume should be considered.

8.
PLoS One ; 15(5): e0232628, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32407338

RESUMO

Leatherback sea turtles (Dermochelys coriacea) migrate to temperate Canadian Atlantic waters to feed on gelatinous zooplankton ('jellyfish') every summer. However, the spatio-temporal connection between predator foraging and prey-field dynamics has not been studied at the large scales over which these migratory animals occur. We use 8903 tows of groundfish survey jellyfish bycatch data between 2006-2017 to reveal spatial jellyfish hot spots, and matched these data to satellite-telemetry leatherback data over time and space. We found highly significant overlap of jellyfish and leatherback distribution on the Scotian Shelf (r = 0.89), moderately strong correlations of jellyfish and leatherback spatial hot spots in the Gulf of St. Lawrence (r = 0.59), and strong correlations in the Bay of Fundy (r = 0.74), which supports much lower jellyfish density. Over time, jellyfish bycatch data revealed a slight northward range shift in the Gulf of St. Lawrence, consistent with gradual warming of these waters. Two-stage generalized linear modelling corroborated that sea surface temperature, year, and region were significant predictors of jellyfish biomass, suggesting a climate signal on jellyfish distribution, which may shift leatherback critical feeding habitat over time. These findings are useful in predicting dynamic habitat use for endangered leatherback turtles, and can help to anticipate large-scale changes in their distribution in response to climate-related changes in prey availability.

9.
ACR Open Rheumatol ; 2020 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-32453505

RESUMO

OBJECTIVE: We aimed to evaluate the associations between response to algorithm-directed treat-to-target conventional synthetic disease-modifying antirheumatic drug therapy and potentially modifiable lifestyle factors, including dietary fish oil supplementation, body mass index (BMI), and smoking history in a rheumatoid arthritis (RA) inception cohort. METHODS: Patients with RA with a duration of less than 12 months were reviewed every 3 to 6 weeks to adjust therapy according to disease response. All patients received advice to take fish oil supplements, and omega-3 status was measured as plasma levels of eicosapentaenoic acid (EPA). Lifestyle factors and other variables potentially prognostic for 28-joint Disease Activity Score (DAS28) remission and DAS28 low disease activity (LDA) at the 12-month visit were included in multivariable logistic regression models. RESULTS: Of 300 participants, 57.7% reached DAS28 LDA, and 43.7% were in DAS28 remission at 1 year. Increase in plasma EPA was associated with an increase in the odds of being in LDA (adjusted odds ratio [OR] = 1.27; P < 0.0001) and remission (adjusted OR = 1.21; P < 0.001). There was some evidence that the effect of BMI on LDA might be modified by smoking history. An increase in BMI was associated with a decrease in the odds of being in LDA in current and former smokers but had no impact on LDA in patients who had never smoked. There were no meaningful associations between BMI or smoking history and remission. CONCLUSION: Omega-3 status, BMI, and smoking history are potential predictors of outcome in early RA. The possibility of an effect modification by smoking on the predictive value of BMI merits further investigation.

10.
J Arthroplasty ; 2020 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-32389404

RESUMO

BACKGROUND: The association between surgeon prescribing practices and new persistent postoperative opioid use is not well understood. We examined the association between surgeon prescribing and new persistent use among total hip arthroplasty (THA) patients. METHODS: A retrospective analysis of Medicare claims in Michigan was performed. The study cohort consisted of orthopedic surgeons performing THAs from 2013 to 2016 and their opioid-naïve patients, aged >65 years. High-risk prescribing included high daily doses, overlapping benzodiazepine prescriptions, concurrent opioid prescriptions, prescriptions from multiple providers, or long-acting opioid prescriptions. The occurrence of a preoperative prescription, initial prescription size, and 30-day prescription dosage were examined as individual exposures. Surgeons were categorized into quartiles by prescribing practices, and multilevel hierarchical logistic regression was used to examine associations with postoperative new persistent opioid use. RESULTS: Surgeons exhibited high-risk prescribing for 66% of encounters. Patients of surgeons with the highest rates of high-risk prescribing were more likely to develop persistent use compared with patients of surgeons with the lowest rates (adjusted rates: 9.7% vs 4.6%, P = .011). Patients of surgeons with initial prescription sizes in the "high" (third) quartile (adjusted odds ratio, 2.91; 95% confidence interval, 1.53-5.51), and of surgeons in the "highest" (fourth) quartile of 30-day prescription dosage (adjusted odds ratio, 1.93; 95% confidence interval, 1.03-3.61), were more likely to develop persistent opioid use compared with patients of surgeons with low initial and 30-day prescription sizes, respectively. CONCLUSION: The development of persistent opioid use after surgery is multifactorial, and surgeon prescribing patterns play an important role. Reducing prescribing and encouraging opioid alternatives could minimize postoperative persistent opioid use.

12.
Neurotherapeutics ; 17(2): 475-483, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32318912

RESUMO

Over the last few decades, increasing evidence demonstrates that the neuroinflammatory response is a double-edged sword. Although overly robust inflammatory responses may exacerbate secondary tissue injury, inflammatory processes are ultimately necessary for recovery. Traditional drug discovery often relies on reductionist approaches to isolate and modulate specific intracellular pathways believed to be involved in disease pathology. However, endogenous brain proteins are often pleiotropic in order to regulate neuroinflammation and recovery mechanisms. Thus, a process of "backward translation" aims to harness the adaptive properties of endogenous proteins to promote earlier and greater recovery after acute brain injury. One such endogenous protein is apolipoprotein E (apoE), the primary apolipoprotein produced in the brain. Robust preclinical and clinical evidence demonstrates that endogenous apoE produced within the brain modulates the neuroinflammatory response of the acutely injured brain. Thus, one innovative approach to improve outcomes following acute brain injury is administration of exogenous apoE-mimetic drugs optimized to cross the blood-brain barrier. In particular, one promising apoE mimetic peptide, CN-105, has demonstrated efficacy across a wide variety of preclinical models of brain injury and safety and feasibility in early-phase clinical trials. Preclinical and clinical evidence for apoE's neuroprotective effects and downregulation of neuroinflammatory and the resulting translational therapeutic development strategy for an apoE-based therapeutic are reviewed.

14.
Stroke ; 51(4): 1135-1141, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32126942

RESUMO

Background and Purpose- Selective serotonin reuptake inhibitors (SSRIs) have a well-established association with bleeding complications and conflicting reports on outcome after stroke. We sought to evaluate whether pre-intracerebral hemorrhage (ICH) SSRI use increased ICH risk and post-ICH SSRI use improved ICH outcome. Methods- Through post hoc analysis of the ERICH study (Ethnic/Racial Variations of Intracerebral Hemorrhage), SSRI use was categorized into no use, pre-ICH only, pre- and post-ICH use (termed "continuous"), and post-ICH only (termed "new"). Using multivariable modeling, associations were sought between pre-ICH SSRI use and ICH risk in the case-control set, and associations between post-ICH SSRI use and 3-month outcome were analyzed in the ICH case set. Exploratory analyses sought to assess influence of race/ethnicity in models. Results- The final study cohort consisted of 2287 ICH cases and 2895 controls. Pre-ICH SSRI use was not associated with ICH risk (odds ratio, 0.824 [95% CI, 0.632-1.074]) nor potentiation of ICH risk with anticoagulant or antiplatelet use. New post-ICH SSRI use was associated with unfavorable modified Rankin Scale score at 3 months after ICH (odds ratio, 1.673 [95% CI, 1.162-2.408]; P=0.006) in multivariable analyses. Additional propensity score analysis indicated a similar trend but did not reach statistical significance (P=0.107). When stratified by race/ethnicity, multivariable modeling demonstrated reduced ICH risk with pre-ICH SSRI use in Hispanics (odds ratio, 0.513 [95% CI, 0.301-0.875]; P=0.014), but not non-Hispanic whites or blacks, and no associations between post-ICH SSRI use and 3-month outcome in any racial/ethnic group. Conclusions- In a large multiethnic cohort, pre-ICH SSRI use was not associated with increased ICH risk, but post-ICH SSRI use was associated with unfavorable 3-month neurological outcome after ICH. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT01202864.

15.
Genes (Basel) ; 11(2)2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32085454

RESUMO

Cas3 has essential functions in CRISPR immunity but its other activities and roles, in vitro and in cells, are less widely known. We offer a concise review of the latest understanding and questions arising from studies of Cas3 mechanism during CRISPR immunity, and highlight recent attempts at using Cas3 for genetic editing. We then spotlight involvement of Cas3 in other aspects of cell biology, for which understanding is lacking-these focus on CRISPR systems as regulators of cellular processes in addition to defense against mobile genetic elements.

16.
Sci Total Environ ; 714: 136444, 2020 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-31986381

RESUMO

Boreal peatlands provide critical global and regional ecosystem functions including climate regulation and nutrient and water retention. Wildfire represents the largest disturbance to these ecosystems. Peatland resilience depends greatly on the extent of post-fire peat soil hydrophobicity. Climate change is altering wildfire intensity and severity and consequently impacting post-fire peat soil chemistry and structure. However, research on fire-impacted peatlands has rarely considered the influence of peat soil chemistry and structure on peatland resilience. Here we characterized the geochemical and physical properties of natural peat soils under laboratory heating conditions. The general trend observed is that hydrophilic peat soils become hydrophobic under moderate heating and then become hydrophilic again after heating for longer, or at higher, temperatures. The loss of peat soil hydrophilicity initially occurs due to evaporative water loss (250 °C and 300 °C for <5 min). Gently but thoroughly dried peat soils (105 °C for 24 h) also show mass losses after heating, indicating the loss of organic compounds through thermal degradation. Gas chromatography-mass spectrometry (GC-MS) and Fourier transform infrared (FTIR) spectroscopy were used to characterize the chemistry of unburned and 300 °C burned peat soils, and various fatty acids, polycyclic compounds, saccharides, aromatic acids, short-chain molecules, lignin and carbohydrates were identified. We determined that the heat-induced degradation of polycyclic compounds and aliphatic hydrocarbons, especially fatty acids, caused dried, hydrophobic peat soils to become hydrophilic after only 20 min of heating at 300 °C. Furthermore, peat soils became hydrophilic more quickly (20 min vs 6 h) with an increase in heat from 250 °C to 300 °C. Minimal structural changes occurred, as characterized by BET and SEM analyses, confirming that surface chemistry, in particular fatty acid content, rather than structure govern changes in peat soil hydrophobicity.

18.
IEEE Trans Biomed Eng ; 67(3): 697-705, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31150332

RESUMO

When using a statistical test for automatically detecting evoked potentials, the number of stimuli presented to the subject (the sample size for the statistical test) should be specified at the outset. For evoked response detection, this may be inefficient, i.e., because the signal-to-noise ratio (SNR) of the response is not known in advance, the user would usually err on the cautious side and use a relatively high number of stimuli to ensure adequate statistical power. A more efficient approach is to apply the statistical test repeatedly to the accumulating data over time, as this allows the test to be stopped early for the high SNR responses (thus reducing test time), or later for the low SNR responses. The caveat is that the critical decision boundaries for rejecting the null hypothesis need to be adjusted if the intended type-I error rate is to be obtained. This study presents an intuitive and flexible method for controlling the type-I error rate for sequentially applied statistical tests. The method is built around the discrete convolution of truncated probability density functions, which allows the null distribution for the test statistic to be constructed at each stage of the sequential analysis. Because the null distribution remains tractable, the procedure for finding the stage-wise critical decision boundaries is greatly simplified. The method also permits data-driven adaptations (using data from previous stages) to both the sample size and the statistical test, which offers new opportunities to speed up testing for evoked response detection.

19.
Neurobiol Dis ; 136: 104712, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31837422

RESUMO

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are progressive neurodegenerative diseases for which there is no disease-modifying treatment. PD and DLB are characterized by aggregation of the synaptic protein α-synuclein, and there is compelling evidence to suggest that progression of these diseases is associated with the trans-cellular spread of pathogenic α-synuclein through the brains of afflicted individuals. Therapies targeting extracellular, pathogenic α-synuclein may therefore hold promise for slowing or halting disease progression. In this regard, it has been suggested that highly-selective antibodies can be administered as therapeutic agents targeting pathogenic proteins. In the current study, we screened a series of antibodies using multiple selection criterion to identify those that selectively bind pathogenic α-synuclein and show potent inhibition of pathology seeding in a neuronal model of α-synucleinopathy. A lead antibody was tested in a mouse model of PD, and it was able to reduce the spread of α-synuclein pathology in the brain and attenuate dopamine reductions in the striatum. This study highlights the therapeutic potential of α-synuclein immunotherapy for the treatment of PD and DLB, and provides a framework for screening of α-synuclein antibodies to identify those with preferred properties.

20.
Mol Carcinog ; 59(1): 45-55, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31659808

RESUMO

A prostate cancer risk single-nucleotide polymorphism (SNP), rs13426236, is significantly associated with melanophilin (MLPH) expression. To functionally characterize role of the rs13426236 in prostate cancer, we first performed splicing-specific expression quantitative trait loci analysis and refined the significant association of rs13426236 allele G with an increased expression of MLPH splicing transcript variant 4 (V4) (P = 7.61E-5) but not other protein-coding variants (V1-V3) (P > .05). We then performed an allele-specific reporter assay to determine if SNP-containing sequences functioned as an active enhancer. Compared to allele A, allele G of rs13426236 showed significantly higher luciferase activity on the promoter of the splicing transcript V4 (P < .03) but not on the promoter of transcript V1 (P > .05) in two prostate cancer cell lines (DU145 and 22Rv1). Cell transfection assays showed stronger effect of transcript V4 than V1 on promoting cell proliferation, invasion, and antiapoptotic activities. RNA profiling analysis demonstrated that transcript V4 overexpression caused significant expression changes in glycosylation/glycoprotein and metal-binding gene ontology pathways (FDR < 0.01). We also found that both transcripts V4 and V1 were significantly upregulated in prostate adenocarcinoma (P ≤ 2.49E-6) but only transcript V4 upregulation was associated with poor recurrence-free survival (P = .028, hazard ratio = 1.63, 95% confidence interval = 1.05-2.42) in The Cancer Genome Atlas data. This study provides strong evidence showing that prostate cancer risk SNP rs13426236 upregulates expression of MLPH transcript V4, which may function as a candidate oncogene in prostate cancer.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Processamento Alternativo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Humanos , Masculino , Invasividade Neoplásica/genética , Isoformas de Proteínas/genética , Locos de Características Quantitativas , Regulação para Cima
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