Understanding Sociodemographic Factors among Hispanics Through a Population-Based Study on Testicular Cancer in Mexico.

Testicular cancer (TCa) is a rare malignancy affecting young men worldwide. Sociodemographic factors, especially socioeconomic level (SEL) and healthcare access, seem to impact TCa incidence and outcomes, particularly among Hispanic populations. However, limited research has explored these variables in Hispanic groups. This study aimed to investigate sociodemographic and clinical factors in Mexico and their role in health disparities among Hispanic TCa patients. We retrospectively analyzed 244 Mexican TCa cases between 2007 and 2020 of a representative cohort with diverse social backgrounds from a national reference cancer center. Logistic regression identified risk factors for fatality: non-seminoma histology, advanced stage, and lower education levels. Age showed a significant trend as a risk factor. Patient delay and healthcare distance lacked significant associations. Inadequate treatment response and chemotherapy resistance were more likely in advanced stages, while higher education positively impacted treatment response. Cox regression highlighted non-seminoma histology, below-median SEL, higher education, and advanced-stage survival rates. Survival disparities emerged based on tumor histology and patient SEL. This research underscores the importance of comprehensive approaches that integrate sociodemographic, biological, and environmental factors to address health disparities improving outcomes through personalized interventions in Hispanic individuals with TCa.

High cell-free DNA is associated with disease progression, inflammasome activation and elevated levels of inflammasome-related cytokine IL-18 in patients with myelofibrosis.

Myelofibrosis (MF) is a clonal hematopoietic stem cell disorder classified among chronic myeloproliferative neoplasms, characterized by exacerbated myeloid and megakaryocytic proliferation and bone marrow fibrosis. It is induced by driver (JAK2/CALR/MPL) and high molecular risk mutations coupled to a sustained inflammatory state that contributes to disease pathogenesis. Patient outcome is determined by stratification into risk groups and refinement of current prognostic systems may help individualize treatment decisions. Circulating cell-free (cf)DNA comprises short fragments of double-stranded DNA, which promotes inflammation by stimulating several pathways, including inflammasome activation, which is responsible for IL-1ß and IL-18 maturation and release. In this work, we assessed the contribution of cfDNA as a marker of disease progression and mediator of inflammation in MF. cfDNA was increased in MF patients and higher levels were associated with adverse clinical outcome, a high-risk molecular profile, advanced disease stages and inferior overall survival, indicating its potential value as a prognostic marker. Cell-free DNA levels correlated with tumor burden parameters and markers of systemic inflammation. To mimic the effects of cfDNA, monocytes were stimulated with poly(dA:dT), a synthetic double-stranded DNA. Following stimulation, patient monocytes released higher amounts of inflammasome-processed cytokine, IL-18 to the culture supernatant, reflecting enhanced inflammasome function. Despite overexpression of cytosolic DNA inflammasome sensor AIM2, IL-18 release from MF monocytes was shown to rely mainly on the NLRP3 inflammasome, as it was prevented by NLRP3-specific inhibitor MCC950. Circulating IL-18 levels were increased in MF plasma, reflecting in vivo inflammasome activation, and highlighting the previously unrecognized involvement of this cytokine in MF cytokine network. Monocyte counts were higher in patients and showed a trend towards correlation with IL-18 levels, suggesting monocytes represent a source of circulating IL-18. The close correlation shown between IL-18 and cfDNA levels, together with the finding of enhanced DNA-triggered IL-18 release from monocytes, suggest that cfDNA promotes inflammation, at least in part, through inflammasome activation. This work highlights cfDNA, the inflammasome and IL-18 as additional players in the complex inflammatory circuit that fosters MF progression, potentially providing new therapeutic targets.

CT Rendering and Radiomic Analysis in Post-Chemotherapy Retroperitoneal Lymph Node Dissection for Testicular Cancer to Anticipate Difficulties for Young Surgeons.

Post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND) in non-seminomatous germ-cell tumor (NSTGCTs) is a complex procedure. We evaluated whether 3D computed tomography (CT) rendering and their radiomic analysis help predict resectability by junior surgeons. The ambispective analysis was performed between 2016-2021. A prospective group (A) of 30 patients undergoing CT was segmented using the 3D Slicer software while a retrospective group (B) of 30 patients was evaluated with conventional CT (without 3D reconstruction). CatFisher's exact test showed a p-value of 0.13 for group A and 1.0 for Group B. The difference between the proportion test showed a p-value of 0.009149 (IC 0.1-0.63). The proportion of the correct classification showed a p-value of 0.645 (IC 0.55-0.87) for A, and 0.275 (IC 0.11-0.43) for Group B. Furthermore, 13 shape features were extracted: elongation, flatness, volume, sphericity, and surface area, among others. Performing a logistic regression with the entire dataset, n = 60, the results were: Accuracy: 0.7 and Precision: 0.65. Using n = 30 randomly chosen, the best result obtained was Accuracy: 0.73 and Precision: 0.83, with a p-value: 0.025 for Fisher's exact test. In conclusion, the results showed a significant difference in the prediction of resectability with conventional CT versus 3D reconstruction by junior surgeons versus experienced surgeons. Radiomic features used to elaborate an artificial intelligence model improve the prediction of resectability. The proposed model could be of great support in a university hospital, allowing it to plan the surgery and to anticipate complications.

Mutational Landscape of Bladder Cancer in Mexican Patients: KMT2D Mutations and chr11q15.5 Amplifications Are Associated with Muscle Invasion.

Bladder cancer (BC) is the most common neoplasm of the urinary tract, which originates in the epithelium that covers the inner surface of the bladder. The molecular BC profile has led to the development of different classifications of non-muscle invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). However, the genomic BC landscape profile of the Mexican population, including NMIBC and MIBC, is unknown. In this study, we aimed to identify somatic single nucleotide variants (SNVs) and copy number variations (CNVs) in Mexican patients with BC and their associations with clinical and pathological characteristics. We retrospectively evaluated 37 patients treated between 2012 and 2021 at the National Cancer Institute-Mexico (INCan). DNA samples were obtained from paraffin-embedded tumor tissues and exome sequenced. Strelka2 and Lancet packages were used to identify SNVs and insertions or deletions. FACETS was used to determine CNVs. We found a high frequency of mutations in TP53 and KMT2D, gains in 11q15.5 and 19p13.11-q12, and losses in 7q11.23. STAG2 mutations and 1q11.23 deletions were also associated with NMIBC and low histologic grade.

Influence of luminal and basal subtype in prognosis of high-grade non muscle invasive urothelial carcinoma.

BACKGROUND: Recent studies have shown that the classification of high-grade urothelial carcinoma non-muscle invasive (HGBCNMI) based on molecular subtypes might be a valuable strategy to identify patients with a worse clinical prognosis. OBJECTIVE: Determine the effect of the luminal and basal molecular subtype determined by immunistochemical on prognosis in patients with HGBC in Mexican population. METHODS: Phenotypes were evaluated by immunohistochemical staining of luminal (GATA3, FOXA1) and basal (CK5/6, CK14) markers in paraffin-embedded tissue samples from 45 patients with a diagnosis of HGBCNMI treated at Instituto Nacional de Cancerología-México (INCan) between 2009 and 2019. The association with prognosis was evaluated using Kaplan-Meier curves and multivariable-adjusted Cox models. RESULTS: HGBCNMI patients showed mean age of 58.77 years (SD: ±12.08 years). We identified expression of the luminal molecular subtype in 35 cases (77.78 %), and 10 cases (22.22 %) with "combined" expression of the molecular subtype (basal and luminal expression). The combined phenotype was statistically more frequent in metastatic cases (p-value = 0.028). In Kaplan-Meier curves, combined expression of luminal and basal molecular markers was associated with disease progression (p-value = 0.002, log-rank test). Cox regression models confirmed this association, which was not influenced by age (p-value = 0.007) or gender (p-value = 0.007). No association of phenotypes with overall survival (p-value = 0.860) or relapse (p-value = 0.5) was observed. CONCLUSION: The combined expression of immunohistochemical markers of the luminal and basal subtype might be considered as predictor for disease progression in patients with HGBCNMI in Mexican population.

Negation detection in Dutch clinical texts: an evaluation of rule-based and machine learning methods.

When developing models for clinical information retrieval and decision support systems, the discrete outcomes required for training are often missing. These labels need to be extracted from free text in electronic health records. For this extraction process one of the most important contextual properties in clinical text is negation, which indicates the absence of findings. We aimed to improve large scale extraction of labels by comparing three methods for negation detection in Dutch clinical notes. We used the Erasmus Medical Center Dutch Clinical Corpus to compare a rule-based method based on ContextD, a biLSTM model using MedCAT and (finetuned) RoBERTa-based models. We found that both the biLSTM and RoBERTa models consistently outperform the rule-based model in terms of F1 score, precision and recall. In addition, we systematically categorized the classification errors for each model, which can be used to further improve model performance in particular applications. Combining the three models naively was not beneficial in terms of performance. We conclude that the biLSTM and RoBERTa-based models in particular are highly accurate accurate in detecting clinical negations, but that ultimately all three approaches can be viable depending on the use case at hand.

Genomic Profile in a Non-Seminoma Testicular Germ-Cell Tumor Cohort Reveals a Potential Biomarker of Sensitivity to Platinum-Based Therapy.

Despite having a favorable response to platinum-based chemotherapies, ~15% of Testicular Germ-Cell Tumor (TGCT) patients are platinum-resistant. Mortality rates among Latin American countries have remained constant over time, which makes the study of this population of particular interest. To gain insight into this phenomenon, we conducted whole-exome sequencing, microarray-based comparative genomic hybridization, and copy number analysis of 32 tumors from a Mexican cohort, of which 18 were platinum-sensitive and 14 were platinum-resistant. We incorporated analyses of mutational burden, driver mutations, and SNV and CNV signatures. DNA breakpoints in genes were also investigated and might represent an interesting research opportunity. We observed that sensitivity to chemotherapy does not seem to be explained by any of the mutations detected. Instead, we uncovered CNVs, particularly amplifications on segment 2q11.1 as a novel variant with chemosensitivity biomarker potential. Our data shed light into understanding platinum resistance in a Latin-origin population.

The promising role of new molecular biomarkers in prostate cancer: from coding and non-coding genes to artificial intelligence approaches.

BACKGROUND: Risk stratification or progression in prostate cancer is performed with the support of clinical-pathological data such as the sum of the Gleason score and serum levels PSA. For several decades, methods aimed at the early detection of prostate cancer have included the determination of PSA serum levels. The aim of this systematic review is to provide an overview about recent advances in the discovery of new molecular biomarkers through transcriptomics, genomics and artificial intelligence that are expected to improve clinical management of the prostate cancer patient. METHODS: An exhaustive search was conducted by Pubmed, Google Scholar and Connected Papers using keywords relating to the genetics, genomics and artificial intelligence in prostate cancer, it includes "biomarkers", "non-coding RNAs", "lncRNAs", "microRNAs", "repetitive sequence", "prognosis", "prediction", "whole-genome sequencing", "RNA-Seq", "transcriptome", "machine learning", and "deep learning". RESULTS: New advances, including the search for changes in novel biomarkers such as mRNAs, microRNAs, lncRNAs, and repetitive sequences, are expected to contribute to an earlier and accurate diagnosis for each patient in the context of precision medicine, thus improving the prognosis and quality of life of patients. We analyze several aspects that are relevant for prostate cancer including its new molecular markers associated with diagnosis, prognosis, and prediction to therapy and how bioinformatic approaches such as machine learning and deep learning can contribute to clinic. Furthermore, we also include current techniques that will allow an earlier diagnosis, such as Spatial Transcriptomics, Exome Sequencing, and Whole-Genome Sequencing. CONCLUSION: Transcriptomic and genomic analysis have contributed to generate knowledge in the field of prostate carcinogenesis, new information about coding and non-coding genes as biomarkers has emerged. Synergies created by the implementation of artificial intelligence to analyze and understand sequencing data have allowed the development of clinical strategies that facilitate decision-making and improve personalized management in prostate cancer.

Oncological outcomes of retroperitoneal node dissection for residual masses after chemotherapy in germ cell tumor. Retrospective analysis of 15 years.

OBJECTIVE: To report experience in a hospital in Mexico regarding oncological results in overall survival (OS) and specific cancer survival (SCS), the presence of recurrence in the management of residual masses after chemotherapy with lymphadenectomy retroperitoneal for 15 years. METHOD: Between 2004 and 2019, a retrospective study was carried out in a single centre with patients with a germ cell tumor diagnosis who have received first or second line of chemotherapy and who present retroperitoneal residual mass were included have performed RPLND. Sociodemographic characteristics were analyzed, overall and histological survival. RESULTS: 346 patients had inclusion criteria, mean age was 27.6 years, the most affected testis was the left, the most frequent testicular histology was mixed germline. The most frequent retroperitoneal location was paraortic, the most frequent type of RPLND was standard, the most frequent histology was necrosis. Recurrence occurred in 24.2%, mean of 17.1 months, when analyzing individual factors, the most significant was the type of RPLND. The clinical stage, histology of the retroperitoneal tumor and type of RPLND influence mortality. Global follow up of 141 months, OS was 85.5% and SCS was 86.1%, mean of 139.9 months and 141 months respectively. CONCLUSIONS: RPLND is effective in survival and recurrence in advanced disease in patients who present postchemotherapy retroperitoneal tumor and although there is a clear benefit in the resection of retroperitoneal tumors in teratoma, there are conditioning factors that must be analyzed individually.

OBJETIVO: Reportar nuestra experiencia en supervivencia y recurrencia en el manejo de masas residuales posquimioterapia con linfadenectomía retroperitoneal durante 15 años. MÉTODO: Estudio retrospectivo de 2004 a 2019. Se incluyeron pacientes con diagnóstico de tumor de células germinales que habían recibido quimioterapia y presentaron una masa residual retroperitoneal en un solo centro y se les realizó linfadenectomía retroperitoneal. Se analizaron las características sociodemográficas, de supervivencia global e histológicas. RESULTADOS: Cumplían los criterios de inclusión 346 pacientes, con una media de edad de 27.6 años. El testículo más afectado fue el izquierdo, y la histología testicular más frecuente fue germinal mixto. La localización retroperitoneal más frecuente fue paraaórtica, el tipo de linfadenectomía más frecuente fue la estándar y la histología más frecuente fue la necrosis. Se presentó recurrencia en el 24.2% de los pacientes, en una media de 17.1 meses; al analizar los factores individuales, el más significativo fue el tipo de linfadenectomía. El estadio clínico, la histología del tumor retroperitoneal y el tipo de linfadenectomía influyen en la mortalidad. El seguimiento global fue de 141 meses, la supervivencia global fue del 85.5% y la supervivencia específica del cáncer fue del 86.1%, con media de 139.9 y 141 meses, respectivamente. CONCLUSIONES: La linfadenectomía retroperitoneal es efectiva en cuanto a supervivencia y recurrencia en la enfermedad avanzada en pacientes que presentan tumor retroperitoneal posquimioterapia, y aunque existe un claro beneficio en la resección de los tumores retroperitoneales en teratoma, existen factores condicionantes que deben ser analizados de manera individual.

Propiedades psicométricas de la Escala de Evaluación Funcional para el Tratamiento del Cáncer, versión próstata (FACT-P), en pacientes mexicanos.

BACKGROUND: Prostate cancer is the most frequent neoplasm in Mexican men, the research literature contains few studies that address prostate cancer patients and quality of life in Mexico. OBJECTIVE: To validate the Functional Assessment Cancer therapy (FACT-P) scale. METHOD: 201 males 49 to 90 years of age, at any clinical stage of prostate cancer, under treatment or follow-up participated. It's a non-experimental cross-sectional study. Patients were evaluated through the FACT-P jointly with the European Organization for Research and Treatment of Cancer Quality of Life and Hospital Anxiety and Depression Scale. Exploratory analysis examined the factorial structure, and confirmatory analysis to evaluate the adjustment of the exploratory model to the data. RESULTS: A four-factor model that explained 64.65% of the variance, Cronbach's alpha 0.79, and correlations were statistically significant, Pearson's r of 0.146-0.716, p < 0.01 and p < 0.05. Analyses also distinguished metastatic patients from non-metastatic ones. The main indices of the confirmatory model were satisfactory for the adjustment of data and showed an estimate error close to zero. CONCLUSIONS: This Mexican version of FACT-P showed reliability and validity comparable to the original one.

ANTECEDENTES: El cáncer de próstata es la neoplasia más frecuente en los varones mexicanos, pero pocos estudios han abordado la calidad de vida en los pacientes con cáncer de próstata en México. OBJETIVO: Validar la Escala de Evaluación Funcional para el Tratamiento del Cáncer, versión próstata (FACT-P). MÉTODO: 201 pacientes de 49 a 90 años en cualquier etapa clínica, en tratamiento o seguimiento. Diseño de estudio: transversal no experimental. Se usaron el FACT-P, el Inventario de la Organización Europea para la Investigación y Tratamiento del cáncer y Calidad de Vida, y la Escala de Ansiedad y Depresión Hospitalaria. Se realizaron análisis factorial exploratorio y análisis factorial confirmatorio para evaluar el ajuste del modelo de los datos, mediante el método de máxima verosimilitud. RESULTADOS: Se obtuvo un modelo de dos factores y dos indicadores que explicaron el 64.65% de la varianza, alfa de Cronbach 0.79, correlaciones estadísticamente significativas, r de Pearson de 0.146-0.716, p < 0.01 y p < 0.05. La escala discrimina los pacientes sin y con metástasis. Los principales índices del modelo confirmatorio sugieren un modelo estable y parsimonioso, con error próximo a cero, que se ajusta aceptablemente a los datos analizados. CONCLUSIONES: La versión mexicana del FACT-P posee una confiabilidad y una validez adecuadas, similares a las de la original.

Platelet Toll-Like Receptors Mediate Thromboinflammatory Responses in Patients With Essential Thrombocythemia.

Essential thrombocythemia (ET) is comprised among chronic myeloproliferative neoplasms (MPN) and is caused by driver mutations in JAK2, CALR, and MPL, which lead to megakaryocyte proliferation and prominent thrombocytosis. Thrombosis remains the main cause of morbidity in ET and is driven by the interplay between blood cells, the endothelium, the clotting cascade, and host-derived inflammatory mediators. Platelet activation plays a key role in the thrombotic predisposition, although the underlying mechanisms remain poorly defined. In addition to their role in hemostasis, platelets participate in innate immunity and inflammation owing to the expression of toll-like receptors (TLR), which recognize inflammatory signals, triggering platelet functional responses. Considering the impact of inflammation on ET procoagulant state, we assessed the contribution of TLR2 and TLR4 to platelet hemostatic and inflammatory properties in ET patients, by using Pam3CSK4 and lipopolysaccharide (LPS) as specific TLR2 and TLR4 ligands, respectively. TLR2 ligation induced increased surface translocation of α-granule-derived P-selectin and CD40L, which mediate platelet interaction with leukocytes and endothelial cells, respectively, and higher levels of dense granule-derived CD63 in patients, whereas PAC-1 binding was not increased and LPS had no effect on these platelet responses. Platelet-neutrophil aggregate formation was elevated in ET at baseline and after stimulation of both TLR2 and TLR4. In addition, ET patients displayed higher TLR2- and TLR4-triggered platelet secretion of the chemokine RANTES (CCL5), whereas von Willebrand factor release was not enhanced, revealing a differential releasate pattern for α-granule-stored inflammatory molecules. TLR-mediated hyperresponsiveness contrasted with impaired or preserved responses to classic platelet hemostatic agonists, such as TRAP-6 and thrombin. TLR2 and TLR4 expression on the platelet surface was normal, whereas phosphorylation of downstream effector ERK1/2 was higher in patients at baseline and after incubation with Pam3CSK4, which may partly explain the enhanced TLR2 response. In conclusion, exacerbated response to TLR stimulation may promote platelet activation in ET, boosting platelet/leukocyte/endothelial interactions and secretion of inflammatory mediators, overall reinforcing the thromboinflammatory state. These findings highlight the role of platelets as inflammatory sentinels in MPN prothrombotic scenario and provide additional evidence for the close intertwining between thrombosis and inflammation in this setting.

The Secret Life of Translation Initiation in Prostate Cancer.

Prostate cancer (PCa) is the second most prevalent cancer in men worldwide. Despite the advances understanding the molecular processes driving the onset and progression of this disease, as well as the continued implementation of screening programs, PCa still remains a significant cause of morbidity and mortality, in particular in low-income countries. It is only recently that defects of the translation process, i.e., the synthesis of proteins by the ribosome using a messenger (m)RNA as a template, have begun to gain attention as an important cause of cancer development in different human tissues, including prostate. In particular, the initiation step of translation has been established to play a key role in tumorigenesis. In this review, we discuss the state-of-the-art of three key aspects of protein synthesis in PCa, namely, misexpression of translation initiation factors, dysregulation of the major signaling cascades regulating translation, and the therapeutic strategies based on pharmacological compounds targeting translation as a novel alternative to those based on hormones controlling the androgen receptor pathway.

Head to head comparison performance of 99mTc-EDDA/HYNIC-iPSMA SPECT/CT and 68Ga-PSMA-11 PET/CT a prospective study in biochemical recurrence prostate cancer patients.

Positron emission tomography (PET) with prostate-specific membrane antigen (PSMA) has found widespread use for the diagnosis of biochemical recurrence of prostate cancer (PCa). Unfortunately, PET/CT is not as widely available; thus a PSMA-targeting compound for scintigraphy is of special interest. The aim of this study was to compare 99mTc-EDDA/HYNIC-iPSMA and 68Ga-PSMA-11 PET/CT qualitatively and semi-quantitatively. Twenty-three patients with metastatic PCa were underwent 99mTc-EDDA/HYNIC-iPSMA SPECT/CT followed by 68Ga-PSMA-11 PET/CT. Gleason score in all patients was obtained. Maximal standardized uptake value (SUVmax) and counts per organ, including the primary and metastatic tumor, were normalized and compared using Pearson's correlation test. Sites considered as positive have increased SUVmax and tumor-to-background ratio (TBR) in comparison with non-diseased organs/tissues (SUVmax =25.2±4.7, 18.4±1.6, 11.4±1.2 (P=0.037) from prostate, bone and lymph nodes versus TBR =35.9±45.2, 15.4±18.9, 19.1±51.7 (P=0.035) for prostate, bone and lymph nodes. 99mTc-HYNIC-iPSMA and 68Ga-PSMA-11 uptake values in the evaluation of the affected nodes were very similar, although their ranges ranged from 5-21 mm (12±7.6). Correlation coefficient was normalized between SUVmax and TBR, demonstrating r values for prostate of r2=0.731; for bone of r2=0.720; and lymph nodes of r2=0.864 (P<0.05 in all cases). Values and confidence interval at the 95% are supporting the equivalency of both parameters in primary tumor and metastases (prostate 95% CI=4.61, 4.38; bone tissue 95% CI=-2.21, 3.41 and lymph node 95% CI=4.67). We conclude that 68Ga-PSMA-11 PET/CT and 99mTc-EDDA/HYNIC-iPSMA SPECT/CT were comparable, supporting the use of 99mTc-EDDA/HYNIC-iPSMA in patients with progressive metastatic castration-resistant PCa.

Neutrophil extracellular trap formation and circulating nucleosomes in patients with chronic myeloproliferative neoplasms.

The mechanisms underlying increased thrombotic risk in chronic myeloproliferative neoplasms (MPN) are incompletely understood. We assessed whether neutrophil extracellular traps (NETs), which promote thrombosis, contribute to the procoagulant state in essential thrombocythemia, polycythemia vera and myelofibrosis (MF) patients. Although MPN neutrophils showed increased basal reactive oxygen species (ROS), enhanced NETosis by unstimulated neutrophils was an infrequent finding, whereas PMA-triggered NETosis was impaired, particularly in MF, due to decreased PMA-triggered ROS production. Elevated circulating nucleosomes were a prominent finding and were higher in patients with advanced disease, which may have potential prognostic implication. Histone-MPO complexes, proposed as specific NET biomarker, were seldomly detected, suggesting NETs may not be the main source of nucleosomes in most patients, whereas their correlation with high LDH points to increased cell turn-over as a plausible origin. Lack of association of nucleosomes or NETs with thrombosis or activation markers does not support their use as predictors of thrombosis although prospective studies in a larger cohort may help define their potential contribution to MPN thrombosis. These results do not provide evidence for relevant in vivo NETosis in MPN patients under steady state conditions, although availability of standardized NET biomarkers may contribute to further research in this field.

The PXR rs7643645 polymorphism is associated with the risk of higher prostate-specific antigen levels in prostate cancer patients.

Levels of enzymes that determine testosterone catabolism such as CYP3A4 have been associated with prostate cancer (PCa) risk. Although some studies have related CYP3A4*1B allele, a gene polymorphism that modifies CYP3A4 expression level, with PCa risk, others have failed, suggesting that additional genetic variants may be involved. Expression of CYP3A4 is largely due to the activation of Pregnane X Receptor (PXR). Particularly, rs2472677 and rs7643645 PXR polymorphisms modify CYP3A4 expression levels. To evaluate whether PXR-HNF3ß/T (rs2472677), PXR-HNF4/G (rs7643645), and CYP3A4*1B (rs2740574) polymorphisms are associated with PCa a case control-study was performed. The multiple testing analysis showed that the PXR-HNF4/G polymorphism was associated with higher levels of prostate-specific antigen (PSA) in patients with PCa (OR = 3.99, p = 0.03). This association was stronger in patients diagnosed at the age of 65 years or older (OR = 10.8, p = 0.006). Although the CYP3A4*1B/*1B genotype was overrepresented in PCa patients, no differences were observed in the frequency of this and PXR-HNF3ß/T alleles between controls and cases. Moreover, no significant association was found between these polymorphisms and PSA, Gleason grade, or tumor lymph node metastasis.

Prostate cancer risk prediction in a urology clinic in Mexico.

OBJECTIVES: To evaluate factors affecting the risk of prostate cancer (CaP) and high-grade disease (HGCaP, Gleason score ≥ 7) in a Mexican referral population, with comparison to the Prostate Cancer Prevention Trial Prostate Cancer Risk Calculator (PCPTRC). METHODS AND MATERIALS: From a retrospective study of 826 patients who underwent prostate biopsy between January 2005 and December 2009 at the Instituto Nacional de Cancerología, Mexico, logistic regression was used to assess the effects of age, prostate-specific antigen (PSA), digital rectal exam (DRE), first-degree family history of CaP, and history of a prior prostate biopsy on CaP and HGCaP, separately. Internal discrimination, goodness-of-fit, and clinical utility of the resulting models were assessed with comparison to the PCPTRC. RESULTS: Rates of both CaP (73.2%) and HGCaP (33.3%) were high among referral patients in this Mexican urology clinic. The PCPTRC generally underestimated the risk of CaP but overestimated the risk of HGCaP. Four factors influencing CaP on biopsy were logPSA, DRE, family history and a prior biopsy history (all P < 0.001). The internal AUC of the logistic model was 0.823 compared with 0.785 of the PCPTRC for CaP (P < 0.001). The same 4 factors were significantly associated with HGCaP as well and the AUC was 0.779 compared with 0.766 of the PCPTRC for HGCaP (P = 0.13). CONCLUSIONS: Lack of screening programs or regular urologic checkups in Mexico imply that men typically first reach specialized clinics with a high cancer risk. This renders diagnostic tools developed on comparatively healthy populations, such as the PCPTRC, of lesser utility. Continued efforts are needed to develop and externally validate new clinical diagnostic tools specific to high-risk referral populations incorporating new biomarkers and more clinical characteristics.

The use of the finasteride-adjusted Prostate Cancer Prevention Trial Prostate Cancer Risk Calculator in a Mexican referral population: a validation study.

OBJECTIVES: To perform the first validation study of the finasteride-adjusted Prostate Cancer Prevention Trial Prostate Cancer Risk Calculator (finPCPTRC) in a contemporary referral population in Mexico. METHODS: 837 patients referred to the Instituto Nacional de Cancerología, Mexico City, Mexico, between 2005 and 2009 were used to validate the finPCPTRC by examining various measures of discrimination and calibration. Net benefit curve analysis was used to gain insight into the use of the finPCPTRC for clinical decisions. RESULTS: Prostate cancer (PCa) incidence (72.8%) was high in this Mexican referral cohort and 45.7% of men who were diagnosed with PCa had high-grade lesions (HGPCa, Gleason score >6). 1.3% of the patients were taking finasteride. The finPCPTRC was a superior diagnostic tool compared to prostate-specific antigen alone when discriminating patients with PCa from those without PCa (AUC = 0.784 vs. AUC = 0.687, p < 0.001) and when discriminating patients with HGPCa from those without HGPCa (AUC = 0.768 vs. AUC = 0.739, p < 0.001). The finPCPTRC underestimated the risk of PCa but overestimated the risk of HGPCa (both p < 0.001). Compared with other strategies to opt for biopsy, the net benefit would be larger with utilization of the finPCPTRC for patients accepting higher risks of HGPCa. CONCLUSIONS: Rates of biopsy-detectable PCa and HGPCa were high and 1.3% of this referral cohort in Mexico was taking finasteride. The risks of PCa or HGPCa calculated by the finPCPTRC were not well calibrated for this referral Mexican population and new clinical diagnostic tools are needed.

Nitric oxide is not involved in Neisseria gonorrhoeae-induced cellular damage of human Fallopian tubes in vitro.

In the present study, we investigated whether cellular damage, as demonstrated by lactate dehydrogenase (LDH) release in the human fallopian tube (FT) infected by Neisseria gonorrhoeae (Ngo), correlated with high levels of nitric oxide synthase (NOS) mRNA and enzyme activity. Infection with Ngo induced a significant increase (~35-fold) in mRNA transcripts of the inducible isoform of NOS. Paradoxically, a reduction in NOS enzyme activity was observed in infected cultures, suggesting that gonococcal infection possibly influences translation of iNOS mRNA to the enzyme. In addition, treatment with the NOS inhibitor TRIM did not prevent gonococcal-induced cellular damage. In contrast, the addition of the inhibitor L-NAME induced a 40% reduction in LDH release, which correlated with a ~50% reduction in gonococcal numbers. Moreover, treatment of normal FT explants with an exogenous NO donor, SNAP, did not induce significant cellular damage. Taken together, our data suggest that NO does not contribute to cellular damage during infection of the human FT with Neisseria gonorrhoeae.

Nitric oxide is not involved in Neisseria gonorrhoeae-induced cellular damage of human Fallopian tubes in vitro

In the present study, we investigated whether cellular damage, as demonstrated by lactate dehydrogenase (LDH) release in the human fallopian tube (FT) infected by Neisseria gonorrhoeae (Ngo), correlated with high levels of nitric oxide synthase (NOS) mRNA and enzyme activity. Infection with Ngo induced a significant increase (~35-fold) in mRNA transcripts of the inducible isoform of NOS. Paradoxically, a reduction in NOS enzyme activity was observed in infected cultures, suggesting that gonococcal infection possibly influences translation of iNOS mRNA to the enzyme. In addition, treatment with the NOS inhibitor TRIM did not prevent gonococcal-induced cellular damage. In contrast, the addition of the inhibitor L-NAME induced a 40 percent reduction in LDH release, which correlated with a ~50 percent reduction in gonococcal numbers. Moreover, treatment of normal FT explants with an exogenous NO donor, SNAP, did not induce significant cellular damage. Taken together, our data suggest that NO does not contribute to cellular damage during infection of the human FT with Neisseria gonorrhoeae.

Solvent-modulated ground-state rotamerism and tautomerism and excited-state proton-transfer processes in o-hydroxynaphthylbenzimidazoles.

The ground-state rotamerism and tautomerism and the excited-state proton-transfer processes of 2-(1'-hydroxy-2'-naphthyl)benzimidazole (1) and 2-(3'-hydroxy-2'-naphthyl)benzimidazole (2) have been investigated in various solvents by means of UV-vis absorption spectroscopy, steady-state and time-resolved fluorescence spectroscopy, and quantum-mechanical ab initio calculations. For both compounds, a solvent-modulated rotameric equilibrium, and also tautomeric for 1, was observed in the ground state. In apolar solvents, both 1 and 2 exist as planar syn normal forms, with the hydroxyl group hydrogen bonded to the benzimidazole N3. In acetonitrile and ethanol, a rotameric equilibrium is established between the syn form and its planar anti rotamer, with the phenyl ring rotated 180 degrees about the C2-C2' bond. In ethylene glycol, glycerol, and aqueous solution with 40% ethanol, a tautomeric equilibrium was detected for 1 between the syn and anti normal forms and the tautomer form, with the hydroxyl proton transferred to the benzimidazole N3. In all of the solvents studied, the syn normal form of 1 and 2 undergoes an ultrafast excited-state intramolecular proton transfer (ESIPT) to yield the excited tautomer. The anti normal forms of 1 and 2, unable to experience ESIPT, give normal form fluorescence. In addition, the anti normal conformer of 2 partly deprotonates at the hydroxyl group in aqueous solution with 40% ethanol, giving the excited anion. The monocations of 1 and 2, protonated at the benzimidazole N3, are strong photoacids that deprotonate completely in aqueous solution with 40% ethanol and to a great extent in ethanol, giving the excited tautomer.