PSMA-Targeted Radiopharmaceuticals for Prostate Cancer Diagnosis and Therapy.

ABSTRACT: Prostate cancer (PCa) is the most common noncutaneous malignancy in men. Until recent years, accurate imaging of men with newly diagnosed PCa, or recurrent or low-volume metastatic disease, was limited. Further, therapeutic options for men with advanced, metastatic, castration-resistant disease were increasingly limited as a result of increasing numbers of systemic therapies being combined in the upfront metastatic setting. The advent of urea-based, small-molecule inhibitors of prostate-specific membrane antigen (PSMA) has partially addressed those shortcomings in diagnosis and therapy of PCa. On the diagnostic side, there are multiple pivotal phase III trials with several different agents having demonstrated utility in the initial staging setting, with generally modest sensitivity but very high specificity for determining otherwise-occult pelvic nodal involvement. That latter statistic drives the utility of the scan by allowing imaging interpreters to read with very high sensitivity while maintaining a robust specificity. Other pivotal phase III trials have demonstrated high detection efficiency in patients with biochemical failure, with high positive predictive value at the lesion level, opening up possible new avenues of therapy such as metastasis-directed therapy. Beyond the diagnostic aspects of PSMA-targeted radiotracers, the same urea-based chemical scaffolds can be altered to deliver therapeutic isotopes to PCa cells that express PSMA. To date, one such agent, when combined with best standard-of-care therapy, has demonstrated an ability to improve overall survival, progression-free survival, and freedom from skeletal events relative to best standard-of-care therapy alone in men with metastatic, castration-resistant PCa who are post chemotherapy. Within the current milieu, there are a number of important future directions including the use of artificial intelligence to better leverage diagnostic findings, further medicinal chemistry refinements to the urea-based structure that may allow improved tumor targeting and decreased toxicities, and the incorporation of new radionuclides that may better balance efficacy with toxicities than those nuclides that are available.

Dietary Omega-3 Polyunsaturated Fatty-Acid Supplementation Upregulates Protective Cellular Pathways in Patients with Type 2 Diabetes Exhibiting Improvement in Painful Diabetic Neuropathy.

BACKGROUND: Omega-3 polyunsaturated fatty acids (PUFAs) have been proposed to improve chronic neuroinflammatory diseases in peripheral and central nervous systems. For instance, docosahexaenoic acid (DHA) protects nerve cells from noxious stimuli in vitro and in vivo. Recent reports link PUFA supplementation to improving painful diabetic neuropathy (pDN) symptoms, but cellular mechanisms responsible for this therapeutic effect are not well understood. The objective of this study is to identify distinct cellular pathways elicited by dietary omega-3 PUFA supplementation in patients with type 2 diabetes mellitus (T2DM) affected by pDN. METHODS: Forty volunteers diagnosed with type 2 diabetes were enrolled in the "En Balance-PLUS" diabetes education study. The volunteers participated in weekly lifestyle/nutrition education and daily supplementation with 1000 mg DHA and 200 mg eicosapentaenoic acid. The Short-Form McGill Pain Questionnaire validated clinical determination of baseline and post-intervention pain complaints. Laboratory and untargeted metabolomics analyses were conducted using blood plasma collected at baseline and after three months of participation in the dietary regimen. The metabolomics data were analyzed using random forest, hierarchical clustering, ingenuity pathway analysis, and metabolic pathway mapping. RESULTS: The data show that metabolites involved in oxidative stress and glutathione production shifted significantly to a more anti-inflammatory state post supplementation. Example of these metabolites include cystathionine (+90%), S-methylmethionine (+9%), glycine cysteine-glutathione disulfide (+157%) cysteinylglycine (+19%), glutamate (-11%), glycine (+11%), and arginine (+13.4%). In addition, the levels of phospholipids associated with improved membrane fluidity such as linoleoyl-docosahexaenoyl-glycerol (18:2/22:6) (+253%) were significantly increased. Ingenuity pathway analysis suggested several key bio functions associated with omega-3 PUFA supplementation such as formation of reactive oxygen species (p = 4.38 × 10-4, z-score = -1.96), peroxidation of lipids (p = 2.24 × 10-5, z-score = -1.944), Ca2+ transport (p = 1.55 × 10-4, z-score = -1.969), excitation of neurons (p = 1.07 ×10-4, z-score = -1.091), and concentration of glutathione (p = 3.06 × 10-4, z-score = 1.974). CONCLUSION: The reduction of pro-inflammatory and oxidative stress pathways following dietary omega-3 PUFA supplementation is consistent with the promising role of these fatty acids in reducing adverse symptoms associated with neuroinflammatory diseases and painful neuropathy.

Detection of Antibodies to Lokern, Main Drain, St. Louis Encephalitis, and West Nile Viruses in Vertebrate Animals in Chihuahua, Guerrero, and Michoacán, Mexico.

We conducted serologic surveillance for flaviviruses and orthobunyaviruses in vertebrate animals in Mexico in 2018-2019. Sera were collected from 856 vertebrate animals, including 323 dogs, 223 horses, and 121 cows, from 16 species. The animals were from 3 states: Chihuahua in northwest Mexico (704 animals) and Guerrero and Michoacán on the Pacific Coast (27 and 125 animals, respectively). Sera were assayed by plaque reduction neutralization test using four flaviviruses (dengue type 2, St. Louis encephalitis, West Nile, and Zika viruses) and six orthobunyaviruses from the Bunyamwera (BUN) serogroup (Cache Valley, Lokern, Main Drain, Northway, Potosi, and Tensaw viruses). Antibodies to West Nile virus (WNV) were detected in 154 animals of 9 species, including 89 (39.9%) horses, 3 (21.4%) Indian peafowl, and 41 (12.7%) dogs. Antibodies to St. Louis encephalitis virus (SLEV) were detected in seven animals, including three (0.9%) dogs. Antibodies to Lokern virus (LOKV) were detected in 22 animals: 19 (8.5%) horses, 2 (1.7%) cows, and a dog (0.3%). Antibodies to Main Drain virus (MDV) were detected in three (1.3%) horses. WNV and LOKV activity was detected in all three states, SLEV activity was detected in Chihuahua and Michoacán, and MDV activity was detected in Chihuahua. None of the animals was seropositive for Cache Valley virus, the most common and widely distributed BUN serogroup virus in North America. In conclusion, we provide serologic evidence that select flaviviruses and BUN serogroup viruses infect vertebrate animals in Chihuahua, Guerrero, and Michoacán. We also provide the first evidence of LOKV and MDV activity in Mexico.

Effects of omega-3 polyunsaturated fatty-acid supplementation on neuropathic pain symptoms and sphingosine levels in Mexican-Americans with type 2 diabetes.

PURPOSE: To determine whether dietary supplementation with omega-3 polyunsaturated fatty acids (PUFAs) reduces neuropathic pain symptoms in Mexican-Americans with type 2 diabetes. METHODS: Forty volunteers with type 2 diabetes enrolled in the "En Balance-PLUS" program, which provided weekly nutrition-diabetes education and daily supplementation with 1,000 mg docosahexaenoic acid (DHA)-200 mg eicosapentaenoic acid over 3 months. The study assessed self-reported neuropathic pain symptoms pre/postintervention using the short-form McGill Pain Questionnaire (SF-MPQ), monitored clinical laboratory values at baseline and 3 months, and performed baseline and 3-month metabolomic analysis of plasma samples. RESULTS: A total of 26 participants self-reported neuropathic pain symptoms at baseline. After 3 months of omega-3 PUFA supplementation, participants reported significant improvement in SF-MPQ scores (sensory, affective, and visual analogue scale; P<0.001, P=0.012, and P<0.001, respectively). Untargeted metabolomic analysis revealed that participants in the moderate-high SF-MPQ group had the highest relative plasma sphingosine levels at baseline compared to the low SF-MPQ group (P=0.0127) and the nonpain group (P=0.0444). Omega-3 PUFA supplementation increased plasma DHA and reduced plasma sphingosine levels in participants reporting neuropathic pain symptoms (P<0.001 and P<0.001, respectively). Increased plasma DHA levels significantly correlated with improved SF-MPQ sensory scores (r=0.425, P=0.030). Improved SF-MPQ scores, however, did not correlate with clinical/laboratory parameters. CONCLUSION: The data suggest that omega-3 PUFAs dietary supplementation may reduce neuropathic pain symptoms in individuals with type 2 diabetes and correlates with sphingosine levels in the plasma.

Glucocorticoids Induce Stress Oncoproteins Associated with Therapy-Resistance in African American and European American Prostate Cancer Cells.

Glucocorticoid receptor (GR) is emerging as a key driver of prostate cancer (PCa) progression and therapy resistance in the absence of androgen receptor (AR) signaling. Acting as a bypass mechanism, GR activates AR-regulated genes, although GR-target genes contributing to PCa therapy resistance remain to be identified. Emerging evidence also shows that African American (AA) men, who disproportionately develop aggressive PCa, have hypersensitive GR signaling linked to cumulative stressful life events. Using racially diverse PCa cell lines (MDA-PCa-2b, 22Rv1, PC3, and DU145) we examined the effects of glucocorticoids on the expression of two stress oncoproteins associated with PCa therapy resistance, Clusterin (CLU) and Lens Epithelium-Derived Growth Factor p75 (LEDGF/p75). We observed that glucocorticoids upregulated LEDGF/p75 and CLU in PCa cells. Blockade of GR activation abolished this upregulation. We also detected increased GR transcript expression in AA PCa tissues, compared to European American (EA) tissues, using Oncomine microarray datasets. These results demonstrate that glucocorticoids upregulate the therapy resistance-associated oncoproteins LEDGF/p75 and CLU, and suggest that this effect may be enhanced in AA PCa. This study provides an initial framework for understanding the contribution of glucocorticoid signaling to PCa health disparities.

RNA sequencing reveals upregulation of a transcriptomic program associated with stemness in metastatic prostate cancer cells selected for taxane resistance.

Patients with metastatic castration-resistant prostate cancer (mCRPC) develop resistance to conventional therapies including docetaxel (DTX). Identifying molecular pathways underlying DTX resistance is critical for developing novel combinatorial therapies to prevent or reverse this resistance. To identify transcriptomic signatures associated with acquisition of chemoresistance we profiled gene expression in DTX-sensitive and -resistant mCRPC cells using RNA sequencing (RNA-seq). PC3 and DU145 cells were selected for DTX resistance and this phenotype was validated by immunoblotting using DTX resistance markers (e.g. clusterin, ABCB1/P-gp, and LEDGF/p75). Overlapping genes differentially regulated in the DTX-sensitive and -resistant cells were ranked by Gene Set Enrichment Analysis (GSEA) and validated to correlate transcript with protein expression. GSEA revealed that genes associated with cancer stem cells (CSC) (e.g., NES, TSPAN8, DPPP, DNAJC12, and MYC) were highly ranked and comprised 70% of the top 25 genes differentially upregulated in the DTX-resistant cells. Established markers of epithelial-to-mesenchymal transition (EMT) and CSCs were used to evaluate the stemness of adherent DTX-resistant cells (2D cultures) and tumorspheres (3D cultures). Increased formation and frequency of cells expressing CSC markers were detected in DTX-resistant cells. DU145-DR cells showed a 2-fold increase in tumorsphere formation and increased DTX resistance compared to DU145-DR 2D cultures. These results demonstrate the induction of a transcriptomic program associated with stemness in mCRPC cells selected for DTX resistance, and strengthen the emerging body of evidence implicating CSCs in this process. In addition, they provide additional candidate genes and molecular pathways for potential therapeutic targeting to overcome DTX resistance.

Physician Consultations, Prostate Cancer Knowledge, and PSA Screening of African American Men in the Era of Shared Decision-Making.

African American (AA)/Black men are more likely to develop aggressive prostate cancer (PCa), yet less likely to be screened despite guidelines espousing shared decision-making regarding PCa screening and prostate-specific antigen (PSA) testing. Given the documented racial disparities in PCa incidence and mortality, engaging interactions with physicians are especially important for AA/Black men. Thus, this study evaluated occurrence of physician-patient conversations among AA/Black men, and whether such conversations were associated with PCa knowledge. We also quantified the serum PSA values of participants who had, and had not, discussed testing with their physicians. Self-identified AA/Black men living in California and New York, ages 21-85, donated blood and completed a comprehensive sociodemographic and health survey ( n = 414). Less than half (45.2%) of participants had discussed PCa screening with their physicians. Multivariate analyses were used to assess whether physician-patient conversations predicted PCa knowledge after adjusting for key sociodemographic/economic and health-care variables. Increased PCa knowledge was correlated with younger age, higher income and education, and having discussed the pros and cons of PCa testing with a physician. Serum PSA values were measured by ELISA. Higher-than-normal PSA values were found in 38.5% of men who had discussed PCa screening with a physician and 29.1% who had not discussed PCa screening. Our results suggest that physician-AA/Black patient conversations regarding PCa risk need improvement. Encouraging more effective communication between physicians and AA/Black men concerning PCa screening and PSA testing has the potential to reduce PCa health disparities.

El fenómeno del envejecimiento y su relación con la clínica / Aging phenomenon and its relation with clinics

Hay una pregunta actual que no puede responder con precisión: mientras más desarrollo tiene la medicina, y se ha conseguido superar muchas enfermedades del paciente viejo ¿se puede realmente considerar que la vida se ha prolongado?. Se necesita deducir la razón por qué los ancianos son mayor número en las estadísticas en comparación con décadas anteriores. Se pretende que un estímulo intrínseco hace que se viva más largo que antes, sin que la medicina haya tenido óptimos logros al respecto. Otro punto a confirmar es que las ciencias de la salud consiguen que la mortalidad disminuye en jóvenes y adultos, ocasionando el número crecido de viejos

Miocardiopatatía diabetica / Diabetic miocardiopathy

Durante mucho tiempo no se sospechaba la existencia de esta entidad clínica, y en la última década se trata de confirmarla gracias a la tecnología recientemente desarrollada. Por eso es que resulta difícil encontrarla en muchos libros, incluso en los exclusivos de Cardiología y Endocrinología, y también con relativa frecuencia en las revistas especializadas

Manejo del paciente politraumatizado y emergencia masiva en el banco de sangre / Politraumatism patient management and mass emergency in the blood bank

Se presenta un programa establecido en el Banco de Sangre del Hospital Nacional de Niños de Costa Rica para situaciones de emergencia. Consiste en el envío de GRE o Rho (D) positivo reconstituidos con suero fisiológico tibio sin que aun se haya hecho la determinación del grupo sanguíneo y pruebas de compatibilidad. El procedimiento agiliza la transfusión de sangre pues se disminuye la viscosidad considerablemente, se evita la sensibilización innecesaria por otros antígenos sanguíneos y a la vez disminuye los errores clericales que ocurren en estas situaciones de emergencia. Se presenta la experiencia obtenida entre octubre de 1993 y abril de 1994.

Talasemia mayor en Costa Rica a propósito de un nuevo caso B supresor, con estudio genético-molecular / Mayor thalassemia in Costa Rica. A new case B suppresor, with genetic-molecular study

En una niña caucásica costarricense, oriunda como sus padres de la ciudad de Cartago, Costa Rica, se demostró que su severa anemia hemolítica era producida por una talasemia mayor (B tal) o enfermedad de Cooley. Los estudios moleculares efectuados posteriormente pusieron en evidencia la existencia de una mutación sin sentido en el segundo exon, codón 39 tipo C->T, la cual provoca interrupción de la traducción, y por lo tanto un fenotipo B tal supresor. Este informe constituye el primer caso costarricense de enfermedad de Cooley estudiado con técnicas de biología molecular