The Cumulative Incidence of Post-Traumatic Epilepsy After Mild Traumatic Brain Injury: A Systematic Review and Individual Participant Data Meta-Analysis Protocol.

A precise understanding of the latency to post-traumatic epilepsy (PTE) following a traumatic brain injury (TBI) is necessary for optimal patient care. This precision is currently lacking despite a surprising number of available data sources that could address this pressing need. Following guidance from the Cochrane Collaboration and Joanna Briggs Institute, we conduct a systematic review to address the research questions: What is the cumulative incidence of PTE following mild TBI (mTBI; concussion), and what is the distribution of the latency to onset? We designed a comprehensive search of medical databases and gray literature sources. Citations will be screened on both abstract and full-text levels, independently and in duplicate. Studies will be evaluated for risk of bias independently and in duplicate using published instruments specific to incidence/prevalence studies. Data will be abstracted independently and in duplicate using piloted extraction forms. Disagreements will be resolved by consensus or third-party adjudication. Evidence synthesis will involve pairwise and individual participant data meta-analysis with heterogeneity explored via a set of predetermined subgroups. The robustness of the findings will be subjected to sensitivity analyses based on the risk of bias, outlier studies, and mTBI definitional criteria. The overall certainty in the estimates will be reported using GRADE (Grading of Recommendations, Assessment, Development, and Evaluations). This protocol presents an innovative and impactful approach to build on the growing body of knowledge surrounding post-mTBI PTE. Through a precise understanding of the latency period, this study can contribute to early detection, tailored interventions, and improved outcomes, leading to a substantial impact on patient care and quality of life.

Prostate cancers with distinct transcriptional programs in Black and White men.

BACKGROUND: Black men are at a higher risk of prostate cancer (PC) diagnosis and present with more high-grade PC than White men in an equal access setting. This study aimed to identify differential transcriptional regulation between Black and White men with PC. METHODS: We performed microarray of radical prostatectomy tissue blocks from 305 Black and 238 White men treated at the Durham Veterans Affairs Medical Center. Differential expression, gene set enrichment analysis, master regulator analysis, and network modeling were conducted to compare gene expression by race. Findings were validated using external datasets that are available in the Gene Expression Omnibus (GEO) database. The first was a multi-institutional cohort of 1152 prostate cancer patients (596 Black, 556 White) with microarray data (GEO ID: GSE169038). The second was an Emory cohort of 106 patients (22 Black, 48 White, 36 men of unknown race) with RNA-seq data (GEO ID: GSE54460). Additionally, we analyzed androgen receptor (AR) chromatin binding profiles using paired AR ChIP-Seq datasets from Black and White men (GEO IDs: GSE18440 and GSE18441). RESULTS: We identified 871 differentially expressed genes between Black and White men. White men had higher activity of MYC-related pathways, while Black men showed increased activity of inflammation, steroid hormone responses, and cancer progression-related pathways. We further identified the top 10 transcription factors (TFs) in Black patients, which formed a transcriptional regulatory network centered on the AR. The activities of this network and the pathways were significantly different in Black vs. White men across multiple cohorts and PC molecular subtypes. CONCLUSIONS: These findings suggest PC in Black and White men have distinct tumor transcriptional profiles. Furthermore, a highly interactive TF network centered on AR drives differential gene expression in Black men. Additional study is needed to understand the degree to which these differences in transcriptional regulatory elements contribute to PC health disparities.

Profiling phagosome proteins identifies PD-L1 as a fungal-binding receptor.

Phagocytosis is the process by which myeloid phagocytes bind to and internalize potentially dangerous microorganisms1. During phagocytosis, innate immune receptors and associated signalling proteins are localized to the maturing phagosome compartment, forming an immune information processing hub brimming with microorganism-sensing features2-8. Here we developed proximity labelling of phagosomal contents (PhagoPL) to identify proteins localizing to phagosomes containing model yeast and bacteria. By comparing the protein composition of phagosomes containing evolutionarily and biochemically distinct microorganisms, we unexpectedly identified programmed death-ligand 1 (PD-L1) as a protein that specifically enriches in phagosomes containing yeast. We found that PD-L1 directly binds to yeast upon processing in phagosomes. By surface display library screening, we identified the ribosomal protein Rpl20b as a fungal protein ligand for PD-L1. Using an auxin-inducible depletion system, we found that detection of Rpl20b by macrophages cross-regulates production of distinct cytokines including interleukin-10 (IL-10) induced by the activation of other innate immune receptors. Thus, this study establishes PhagoPL as a useful approach to quantifying the collection of proteins enriched in phagosomes during host-microorganism interactions, exemplified by identifying PD-L1 as a receptor that binds to fungi.

ONECUT2 acts as a lineage plasticity driver in adenocarcinoma as well as neuroendocrine variants of prostate cancer.

Androgen receptor- (AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that ONECUT2 (OC2) activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. Direct OC2 gene targets include the glucocorticoid receptor (GR; NR3C1) and the NE splicing factor SRRM4, which are key drivers of lineage plasticity. Thus, OC2, despite its previously described NEPC driver function, can indirectly activate a portion of the AR cistrome through epigenetic activation of GR. Mechanisms by which OC2 regulates gene expression include promoter binding, enhancement of genome-wide chromatin accessibility, and super-enhancer reprogramming. Pharmacologic inhibition of OC2 suppresses lineage plasticity reprogramming induced by the AR signaling inhibitor enzalutamide. These results demonstrate that OC2 activation promotes a range of drug resistance mechanisms associated with treatment-emergent lineage variation in PC and support enhanced efforts to therapeutically target OC2 as a means of suppressing treatment-resistant disease.

Lumbar Drain Use during Middle Fossa Approaches for Nonneoplastic Pathology of the Skull Base.

Introduction The middle fossa craniotomy (MFCs) is commonly utilized for spontaneous cerebrospinal fluid (CSF) leaks, encephaloceles, and superior semicircular canal dehiscence (SSCD). This study compares postoperative outcomes of MFCs with and without LD use. Methods A retrospective cohort study of adults over the age of 18 years presenting for the repair of nonneoplastic CSF leak, encephalocele, or SSCD via MFC from 2009 to 2021 was conducted. The main exposure of interest was the placement of an LD. The primary outcome was the presence of postoperative complications (acute/delayed neurologic deficit, meningitis, intracranial hemorrhage, and stroke). Secondary outcomes included operating room (OR) time, length of stay, recurrence, and need for reoperation. Results In total, 172 patients were included, 96 of whom received an LD and 76 who did not. Patients not receiving an LD were more likely to receive intraoperative mannitol ( n = 24, 31.6% vs. n = 16, 16.7%, p = 0.02). On univariate logistic regression, LD placement did not influence overall postoperative complications (OR: 0.38, 95% confidence interval [CI]: 0.05-2.02, p = 0.28), CSF leak recurrence (OR: 0.75, 95% CI: 0.25-2.29, p = 0.61), or need for reoperation (OR: 1.47, 95% CI: 0.48-4.96, p = 0.51). While OR time was shorter for patients not receiving LD (349 ± 71 vs. 372 ± 85 minutes), this difference was not statistically significant ( p = 0.07). Conclusion No difference in postoperative outcomes was observed in patients who had an intraoperative LD placed compared to those without LD. Operative times were increased in the LD cohort, but this difference was not statistically significant. Given the similar outcomes, we conclude that LD is not necessary to facilitate safe MCF for nonneoplastic skull base pathologies.

Discovery of Borosin Catalytic Strategies and Function through Bioinformatic Profiling.

Borosins are ribosomally synthesized and post-translationally modified peptides (RiPPs) containing backbone α-N-methylations. These modifications confer favorable pharmacokinetic properties including increased membrane permeability and resistance to proteolytic degradation. Previous studies have biochemically and bioinformatically explored several borosins, revealing (1) numerous domain architectures and (2) diverse core regions lacking conserved sequence elements. Due to these characteristics, large-scale computational identification of borosin biosynthetic genes remains challenging and often requires additional, time-intensive manual inspection. This work builds upon previous findings and updates the genome-mining tool RODEO to automatically evaluate borosin biosynthetic gene clusters (BGCs) and identify putative precursor peptides. Using the new RODEO module, we provide an updated analysis of borosin BGCs identified in the NCBI database. From our data set, we bioinformatically predict and experimentally characterize a new fused borosin domain architecture, in which the modified natural product core is encoded N-terminal to the methyltransferase domain. Additionally, we demonstrate that a borosin precursor peptide is a native substrate of shewasin A, a reported aspartyl peptidase with no previously identified substrates. Shewasin A requires post-translational modification of the leader peptide for proteolytic maturation, a feature not previously observed in RiPPs. Overall, this work provides a user-friendly and open-access tool for the analysis of borosin BGCs and we demonstrate its utility to uncover additional biosynthetic strategies within the borosin class of RiPPs.

ONECUT2 is a druggable driver of luminal to basal breast cancer plasticity.

PURPOSE: Tumor heterogeneity complicates patient treatment and can be due to transitioning of cancer cells across phenotypic cell states. This process is associated with the acquisition of independence from an oncogenic driver, such as the estrogen receptor (ER) in breast cancer (BC), resulting in tumor progression, therapeutic failure and metastatic spread. The transcription factor ONECUT2 (OC2) has been shown to be a master regulator protein of metastatic castration-resistant prostate cancer (mCRPC) tumors that promotes lineage plasticity to a drug-resistant neuroendocrine (NEPC) phenotype. Here, we investigate the role of OC2 in the dynamic conversion between different molecular subtypes in BC. METHODS: We analyze OC2 expression and clinical significance in BC using public databases and immunohistochemical staining. In vitro, we perform RNA-Seq, RT-qPCR and western-blot after OC2 enforced expression. We also assess cellular effects of OC2 silencing and inhibition with a drug-like small molecule in vitro and in vivo. RESULTS: OC2 is highly expressed in a substantial subset of hormone receptor negative human BC tumors and tamoxifen-resistant models, and is associated with poor clinical outcome, lymph node metastasis and heightened clinical stage. OC2 inhibits ER expression and activity, suppresses a gene expression program associated with luminal differentiation and activates a basal-like state at the gene expression level. We also show that OC2 is required for cell growth and survival in metastatic BC models and that it can be targeted with a small molecule inhibitor providing a novel therapeutic strategy for patients with OC2 active tumors. CONCLUSIONS: The transcription factor OC2 is a driver of BC heterogeneity and a potential drug target in distinct cell states within the breast tumors.

Acute kidney injury in hospitalized children with proteinuria: A multicenter retrospective analysis.

BACKGROUND AND OBJECTIVE: Acute kidney injury (AKI) is a common complication in hospitalized pediatric patients. Previous studies focused on adults found that proteinuria detected during an admission urinalysis is fit to serve as an indicator for AKI and associated clinical outcomes. The objective of this study is to evaluate if proteinuria on the first day of hospital services in hospitalized children is associated with AKI, need for renal replacement therapy, shock and/or antibiotic use, critical care services, and all-cause mortality at 30 days, hypothesizing that it is associated with these outcomes. METHODS: This is a retrospective cohort study using TriNetX electronic health record data of patients 2 to 18 years of age who underwent urinalysis laboratory testing on hospital admission, had three subsequent days of hospital or critical care services billing codes and creatinine laboratory values, and no pre-existing renal-related complex chronic condition. This study evaluated for the frequency, odds, and severity of AKI as defined by Kidney Disease: Improving Global Outcomes modified criteria and assessed for associated clinical outcomes. RESULTS: This study included 971 pediatric subjects [435 (44.7%) with proteinuria]. Proteinuria on the first day of hospital services was associated with an increased odds for higher severity AKI on any day of hospitalization (odds ratio [OR] 2.41, CI 1.8-3.23, p<0.001), need for renal replacement therapy (OR 4.58, CI 1.69-12.4, p = 0.001), shock and/or antibiotic use (OR 1.34, CI 1.03-1.75, p = 0.033), and all-cause mortality at 30 days post-admission (OR 10.0, CI 1.25-80.5, p = 0.013). CONCLUSION: Children with proteinuria on the first day of hospital care services may have an increased odds of higher severity AKI, need for renal replacement therapy, shock and/or antibiotic use, and all-cause mortality at 30 days post-admission, with no significant association found for critical care services, mechanical intubation, or inotrope or vasopressor use.

Endoscopic Versus Microscopic Transcanal Resection of Glomus Tympanicum: A Retrospective Comparative Study.

OBJECTIVE: Comparison of outcomes of microscopic and endoscopic resection of glomus tympanicum (GT) tumors. STUDY DESIGN: Retrospective case review. SETTING: Single tertiary referral center. PATIENTS: All adult patients undergoing transcanal GT resection without mastoidectomy from 2007 to 2021. INTERVENTIONS: Surgical resection-endoscopic versus microscopic approach. MAIN OUTCOME MEASURES: Primary outcomes were tumor recurrence at 1 year and presence of residual tumor at conclusion of surgery. Secondary outcome measures included operative time, postoperative air-bone gap, postoperative symptom resolution, and surgical complications. RESULTS: Thirty-eight patients underwent resection of GT (74% female; mean age, 59 years). Twenty-nine cases were performed microscopically, and nine cases were performed endoscopically. Both endoscopic and microscopic approaches yielded high rates of complete tumor resection (27/29 microscopic cases, 7/9 endoscopic cases). There was no significant difference in mean operative time (2.3 hours for microscopic; 2.6 hours for endoscopic). On average, air-bone gaps (ABGs) decreased by 6.3 dB after endoscopic resection compared with 1.0 dB after microscopic resection ( p = 0.064). No patients were found to have tumor recurrence during an average follow-up interval of 21 months. CONCLUSIONS: These results suggest comparable outcomes with both endoscopic and microscopic approaches for GT resection, and decisions regarding preferred approach should be dictated by surgeon preference.

Improved Postoperative Speech Recognition and Processor Use With Early Cochlear Implant Activation.

OBJECTIVE: To report speech recognition outcomes and processor use based on timing of cochlear implant (CI) activation. STUDY DESIGN: Retrospective cohort. SETTING: Tertiary referral center. PATIENTS: A total of 604 adult CI recipients from October 2011 to March 2022, stratified by timing of CI activation (group 1: ≤10 d, n = 47; group 2: >10 d, n = 557). MAIN OUTCOME MEASURES: Average daily processor use; Consonant-Nucleus-Consonant (CNC) and Arizona Biomedical (AzBio) in quiet at 1-, 3-, 6-, and 12-month visits; time to peak performance. RESULTS: The groups did not differ in sex ( p = 0.887), age at CI ( p = 0.109), preoperative CNC ( p = 0.070), or preoperative AzBio in quiet ( p = 0.113). Group 1 had higher median daily processor use than group 2 at the 1-month visit (12.3 versus 10.7 h/d, p = 0.017), with no significant differences at 3, 6, and 12 months. The early activation group had superior median CNC performance at 3 months (56% versus 46%, p = 0.007) and 12 months (60% versus 52%, p = 0.044). Similarly, the early activation group had superior median AzBio in quiet performance at 3 months (72% versus 59%, p = 0.008) and 12 months (75% versus 68%, p = 0.049). Both groups were equivalent in time to peak performance for CNC and AzBio. Earlier CI activation was significantly correlated with higher average daily processor use at all follow-up intervals. CONCLUSION: CI activation within 10 days of surgery is associated with increased early device usage and superior speech recognition at both early and late follow-up visits. Timing of activation and device usage are modifiable factors that can help optimize postoperative outcomes in the CI population.

Association of Lipoprotein(a) with peri-coronary inflammation in persons with and without HIV infection.

BACKGROUND: Persons with human immunodeficiency virus (HIV) (PWH) have an increased risk of developing cardiovascular disease (CVD) compared to persons without HIV (PWoH). Lipoprotein(a) [Lp(a)] is a known atherosclerotic risk factor in PWoH, but there are no studies investigating Lp(a) and peri-coronary inflammation. OBJECTIVE: To investigate whether Lp(a) is associated with peri-coronary inflammation as assessed by the fat attenuation index (FAI) and activated monocytes and T lymphocytes in PWH and PWoH. METHODS: We measured plasma levels of Lp(a) at study entry in 58 PWH and 21 PWoH without CVD and who had FAI measurements. Associations of Lp(a) with FAI values of the right coronary artery (RCA) and left anterior descending artery were evaluated using multivariable regression models adjusted for potential confounders. Correlations between Lp(a) levels and systemic inflammatory markers and immune cell subsets were examined. RESULTS: Lp(a) was associated with greater peri-coronary inflammation among PWH compared to PWoH (ß=1.73, P=0.019) in the RCA, in adjusted models. Significant correlations were observed with certain inflammatory markers (tumor necrosis factor receptor [TNFR]-I, b=0.295, P<0.001; TNFR-II, b=0.270, P=0.002; high-sensitivity C-reactive protein, b=0.195, P=0.028). Significant correlations were found between Lp(a) levels and several markers of monocyte activation: CD16 -CD163+ (b= -0.199, P=0.024), and CD16 -DR+ MFI (b= -0.179, P=0.042) and T cell subset CD38+CD4+ TEMRA (b= 0.177, P= 0.044). CONCLUSIONS: Lp(a) was associated with greater peri-coronary inflammation in the RCA in PWH compared to PWoH, as well as with select systemic inflammatory markers and specific subsets of immune cells in peripheral circulation.

Computationally guided exploration of borosin biosynthetic strategies.

Borosins are ribosomally synthesized and post-translationally modified peptides containing backbone α- N -methylations. Identification of borosin precursor peptides is difficult because (1) there are no conserved sequence elements among borosin precursor peptides and (2) the biosynthetic gene clusters contain numerous domain architectures and peptide fusions. To tackle this problem, we updated the genome mining tool RODEO to automatically evaluate putative borosin BGCs and identify precursor peptides. Enabled by the new borosin module, we analyzed all borosin BGCs found in available sequence data and assigned precursor peptides to previously orphan borosin methyltransferases. Additionally, we bioinformatically predict and experimentally characterize a new fused borosin domain architecture, in which the modified core is N-terminal to the methyltransferase domain. Finally, we demonstrate that a borosin precursor peptide is the native substrate of shewasin A, a previously characterized pepsin-like aspartic peptidase whose native biological function was unknown.

A novel method for the percutaneous induction of myocardial infarction by occlusion of small coronary arteries in the rabbit.

Arrhythmic sudden cardiac death (SCD) is an important cause of mortality following myocardial infarction (MI). The rabbit has similar cardiac electrophysiology to humans and is therefore an important small animal model to study post-MI arrhythmias. The established approach of surgical coronary ligation results in thoracic adhesions that impede epicardial electrophysiological studies. Adhesions are absent following a percutaneously induced MI, which is also associated with reduced surgical morbidity and so represents a clear refinement of the approach. Percutaneous procedures have previously been described in large rabbits (3.5-5.5 kg). Here, we describe a novel method of percutaneous MI induction in smaller rabbits (2.5-3.5 kg) that are readily available commercially. New Zealand White rabbits (n = 51 males, 3.1 ± 0.3 kg) were anesthetized using isoflurane (1.5-3%) and underwent either a percutaneous MI procedure involving microcatheter tip deployment (≤1.5 Fr, 5 mm), coronary ligation surgery, or a sham procedure. Electrocardiography (ECG) recordings were used to confirm ST-segment elevation indicating coronary occlusion. Blood samples (1 and 24 h) were taken for cardiac troponin I (cTnI) levels. Ejection fraction (EF) was measured at 6-8 wk. Rabbits were then euthanized (Euthatal) and hearts were processed for magnetic resonance imaging and histology. Mortality rates were similar in both groups. Scar volume, cTnI, and EF were similar between both MI groups and significantly different from their respective sham controls. Thus, percutaneous coronary occlusion by microcatheter tip deployment is feasible in rabbits (2.5-3.5 kg) and produces an MI with similar characteristics to surgical ligation with lower procedural trauma and without epicardial adhesions.NEW & NOTEWORTHY Surgical coronary ligation is the standard technique to induce myocardial infarction (MI) in rabbits but is associated with procedural trauma and the generation of thoracic adhesions. Percutaneous coronary occlusion avoids these shortcomings and is established in pigs but has only been applicable to large rabbits because of a mismatch between the equipment used and target vessel size. Here, we describe a new scalable approach to percutaneous MI induction that is safe and effective in 2.5-3.5-kg rabbits.

Epigenetic disruption of the RARγ complex impairs its function to bookmark AR enhancer interactions required for enzalutamide sensitivity in prostate cancer.

The current study in prostate cancer (PCa) focused on the genomic mechanisms at the cross-roads of pro-differentiation signals and the emergence of lineage plasticity. We explored an understudied cistromic mechanism involving RARγ's ability to govern AR cistrome-transcriptome relationships, including those associated with more aggressive PCa features. The RARγ complex in PCa cell models was enriched for canonical cofactors, as well as proteins involved in RNA processing and bookmarking. Identifying the repertoire of miR-96 bound and regulated gene targets, including those recognition elements marked by m6A, revealed their significant enrichment in the RARγ complex. RARγ significantly enhanced the AR cistrome, particularly in active enhancers and super-enhancers, and overlapped with the binding of bookmarking factors. Furthermore, RARγ expression led to nucleosome-free chromatin enriched with H3K27ac, and significantly enhanced the AR cistrome in G2/M cells. RARγ functions also antagonized the transcriptional actions of the lineage master regulator ONECUT2. Similarly, gene programs regulated by either miR-96 or antagonized by RARγ were enriched in alternative lineages and more aggressive PCa phenotypes. Together these findings reveal an under-investigated role for RARγ, modulated by miR-96, to bookmark enhancer sites during mitosis. These sites are required by the AR to promote transcriptional competence, and emphasize luminal differentiation, while antagonizing ONECUT2.

27-hydroxycholesterol and DNA damage repair: implication in prostate cancer.

Introduction: We previously reported that cholesterol homeostasis in prostate cancer (PC) is regulated by 27-hydroxycholesterol (27HC) and that CYP27A1, the enzyme that converts cholesterol to 27HC, is frequently lost in PCs. We observed that restoring the CYP27A1/27HC axis inhibited PC growth. In this study, we investigated the mechanism of 27HC-mediated anti-PC effects. Methods: We employed in vitro models and human transcriptomics data to investigate 27HC mechanism of action in PC. LNCaP (AR+) and DU145 (AR-) cells were treated with 27HC or vehicle. Transcriptome profiling was performed using the Affymetrix GeneChip™ microarray system. Differential expression was determined, and gene set enrichment analysis was done using the GSEA software with hallmark gene sets from MSigDB. Key changes were validated at mRNA and protein levels. Human PC transcriptomes from six datasets were analyzed to determine the correlation between CYP27A1 and DNA repair gene expression signatures. DNA damage was assessed via comet assays. Results: Transcriptome analysis revealed 27HC treatment downregulated Hallmark pathways related to DNA damage repair, decreased expression of FEN1 and RAD51, and induced "BRCAness" by downregulating genes involved in homologous recombination regulation in LNCaP cells. Consistently, we found a correlation between higher CYP27A1 expression (i.e., higher intracellular 27HC) and decreased expression of DNA repair gene signatures in castration-sensitive PC (CSPC) in human PC datasets. However, such correlation was less clear in metastatic castration-resistant PC (mCRPC). 27HC increased expression of DNA damage repair markers in PC cells, notably in AR+ cells, but no consistent effects in AR- cells and decreased expression in non-neoplastic prostate epithelial cells. While testing the clinical implications of this, we noted that 27HC treatment increased DNA damage in LNCaP cells via comet assays. Effects were reversible by adding back cholesterol, but not androgens. Finally, in combination with olaparib, a PARP inhibitor, we showed additive DNA damage effects. Discussion: These results suggest 27HC induces "BRCAness", a functional state thought to increase sensitivity to PARP inhibitors, and leads to increased DNA damage, especially in CSPC. Given the emerging appreciation that defective DNA damage repair can drive PC growth, future studies are needed to test whether 27HC creates a synthetic lethality to PARP inhibitors and DNA damaging agents in CSPC.

Actionable Driver Events in Small Cell Lung Cancer.

Small cell lung cancer (SCLC) stands out as the most aggressive form of lung cancer, characterized by an extremely high proliferation rate and a very poor prognosis, with a 5-year survival rate that falls below 7%. Approximately two-thirds of patients receive their diagnosis when the disease has already reached a metastatic or extensive stage, leaving chemotherapy as the remaining first-line treatment option. Other than the recent advances in immunotherapy, which have shown moderate results, SCLC patients cannot yet benefit from any approved targeted therapy, meaning that this cancer remains treated as a uniform entity, disregarding intra- or inter-tumoral heterogeneity. Continuous efforts and technological improvements have enabled the identification of new potential targets that could be used to implement novel therapeutic strategies. In this review, we provide an overview of the most recent approaches for SCLC treatment, providing an extensive compilation of the targeted therapies that are currently under clinical evaluation and inhibitor molecules with promising results in vitro and in vivo.

Measurement of plasma levels of vascular endothelial growth factor in prostate cancer patients: relationship with clinical stage, Gleason score, prostate volume, and serum prostate-specific antigen

PURPOSE: This study focused on circulating levels of vascular endothelial growth factor in patients with prostate cancer compared to a normal population. METHODS: We analyzed 26 normal individuals and 80 patients with prostate cancer. Blood was drawn from all subjects, and plasma was extracted to determine the concentration of vascular endothelial growth factor using a quantitative immunoassay technique (ELISA-enzyme-linked immunosorbent assay). RESULTS: The median plasma level of vascular endothelial growth factor was significantly elevated in patients with metastatic disease compared to patients with localized disease and with healthy controls. Patients with serum prostate-specific antigen > 20 ng/mL had significantly higher levels of plasma vascular endothelial growth factor than patients with serum prostate-specific antigen < 20 ng/mL. There was a trend for patients with a Gleason score of 8 to 10 to have higher levels of plasma vascular endothelial growth factor when compared to patients with lower Gleason scores. No relationship was found between plasma vascular endothelial growth factor and clinical staging, or between plasma vascular endothelial growth factor and prostate volume, in patients with localized prostate cancer. CONCLUSION: This study indicates that patients with metastatic prostate cancer have higher plasma vascular endothelial growth factor levels than patients with localized disease or in healthy controls.

OBJETIVO: Analisar os níveis circulantes do fator de crescimento do endotélio vascular em pacientes com câncer prostático comparados com uma população de indivíduos eutróficos. MÉTODOS: Vinte e seis indivíduos eutróficos e oitenta pacientes com câncer de próstata foram analisados nesse estudo. A coleta sangüínea foi realizada da mesma maneira em todos os pacientes e o plasma foi extraído para a determinação dos níveis do fator de crescimento do endotélio vascular, utilizando-se o método quantitativo ELISA (enzyme-linked immunosorbent assay). RESULTADOS: Os níveis de fator de crescimento do endotélio vascular plasmático encontraram-se significativamente elevados nos pacientes com doença metastática quando comparados com pacientes com doença localizada e com indivíduos sadios. Pacientes com PSA sérico maior que 20 ng/ml apresentaram níveis maiores de fator de crescimento do endotélio vascular plasmático quando comparados com pacientes com PSA menor que 20 ng/ml. Houve uma tendência dos pacientes com escore de Gleason de 8 a 10 apresentarem níveis maiores do fator de crescimento do endotélio vascular plasmático em relação a pacientes com escores de Gleason menores que 8. Não houve relação entre fator de crescimento do endotélio vascular plasmático e estado clínico, ou entre fator de crescimento do endotélio vascular e volume prostático em pacientes com câncer de próstata localizado. CONCLUSÃO: Os dados indicam que pacientes com câncer de próstata metastático apresentam níveis significativamente mais elevados de fator de crescimento do endotélio vascular plasmático quando comparados com pacientes com câncer localizado e com indivíduos normais.

O suprimento sanguíneo da cabeça femoral artrósica: um estudo comparativo / The blood supply to the osteoarthritic femoral head: a comparative study

O suprimento sanguíneo à parte proximal do fêmur foi medido em dois grupos de pacientes. Foi usado um método que utiliza hemácias marcadas in vivo pelo tecnécio 99m. Doze pacientes submetidos à substituição total do quadril por artrose primária constituíram o grupo osteoartrósico (OA). O grupo controle foi formado por 11 pacientes sem artrose do quadril, operados por fraturas transtrocanterianas ou subtrocanterianas produzidas por impactos de baixa energia, sabidamente inócuas à irrigação da cabeça femoral. Os pacientes dos dois grupos pertenciam à mesma faixa etária. O suprimento sanguíneo da cabeça femoral, expresso por um quociente de atividade, não mostrou diferença significante entre os grupos OA e controle quando comparados por um modelo que levou em conta efeitos aleatórios individuais. Relevância clínica: ao programar o tratamento cirúrgico de um quadril artrósico, a cabeça femoral não deve ser considerada isquêmica.