PXR as the tipping point between innate immune response, microbial infections, and drug metabolism.

Pregnane X receptor (PXR) is a xenosensor that acts as a transcription factor in the cell nucleus to protect cells from toxic insults. In response to exposure to several chemical agents, PXR induces the expression of enzymes and drug transporters that biotransform xenobiotic and endobiotic and eliminate metabolites. Recently, PXR has been shown to have immunomodulatory effects that involve cross-communication with molecular pathways in innate immunity cells. Conversely, several inflammatory factors regulate PXR signaling. This review examines the crosstalk between PXR and nuclear factor kappa B (NFkB), Toll-like receptors (TLRs), and inflammasome components. Discussions of the consequences of these interactions on immune responses to infections caused by viruses, bacteria, fungi, and parasites are included together with a review of the effects of microorganisms on PXR-associated drug metabolism. This paper aims to encourage researchers to pursue studies that will better elucidate the relationship between PXR and the immune system and thus inform treatment development.

Detection and dynamics of circulating tumor cells in patients with high-risk prostate cancer treated with radiotherapy and hormones: a prospective phase II study.

BACKGROUND: Circulating tumor cells (CTCs) are an established prognostic marker in castration-resistant prostate cancer but have received little attention in localized high-risk disease. We studied the detection rate of CTCs in patients with high-risk prostate cancer before and after androgen deprivation therapy and radiotherapy to assess its value as a prognostic and monitoring marker. PATIENTS AND METHODS: We performed a prospective analysis of CTCs in the peripheral blood of 65 treatment-naïve patients with high-risk prostate cancer. EpCAM-positive CTCs were enumerated using the CELLSEARCH system at 4 timepoints. A cut off of 0 vs ≥ 1 CTC/7.5 ml blood was defined as a threshold for negative versus positive CTCs status. RESULTS: CTCs were detected in 5/65 patients (7.5%) at diagnosis, 8/62 (12.9%) following neoadjuvant androgen deprivation and 11/59 (18.6%) at the end of radiotherapy, with a median CTC count/7.5 ml of 1 (range, 1-136). Only 1 patient presented a positive CTC result 9 months after radiotherapy. Positive CTC status (at any timepoint) was not significantly associated with any clinical or pathologic factors. However, when we analyzed variations in CTC patterns following treatment, we observed a significant association between conversion of CTCs and stages T3 (P = 0.044) and N1 (P = 0.002). Detection of CTCs was not significantly associated with overall survival (P > 0.40). CONCLUSIONS: Our study showed a low detection rate for CTCs in patients with locally advanced high-risk prostate cancer. The finding of a de novo positive CTC count after androgen deprivation therapy is probably due to a passive mechanism associated with the destruction of the tumor. Further studies with larger samples and based on more accurate detection of CTCs are needed to determine the potential prognostic and therapeutic value of this approach in non-metastatic prostate cancer. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT01800058.

Sample preparation of serum to allow capillary electrophoresis analysis of prostate specific antigen isoforms.

Prostate cancer is the second most frequently diagnosed cancer in men worldwide. Currently prostate specific antigen (PSA) serum concentration is the most used prostate cancer marker, but it only shows limited specificity. Because PSA glycosylation is altered by prostate cancer, detecting glycosylation changes could increase PSA specificity as a prostate cancer marker. Changes in PSA glycosylation can modify its electrophoretic- behavior and techniques such as capillary zone electrophoresis (CZE) and two-dimensional electrophoresis (2-DE) could be applied to detect changes in PSA glycosylation. Most serum PSA is complexed with alpha-1 antichymotrypsin (ACT). To have access to most of the PSA, the complexed PSA has to be released as free PSA (fPSA); in addition, this total fPSA must be purified from the serum matrix so that it can be analyzed using CZE. In this work a methodology for isolating PSA from serum for its CZE analysis was established. By using PSA standard, the effect of this methodology, which combines conditions for dissociating complexed PSA and immunoaffinity chromatographic purification, was studied. It was seen that this highly repeatable sample treatment did not noticeably alter the circular dichroism (CD) spectrum or the CZE pattern of PSA standard. Therefore, as a proof-of-concept, the developed sample treatment was applied to serum from a cancer patient with a high PSA content. The following observations can be made from these experiments: first of all, the 2-DE pattern of serum PSA remained unchanged after sample treatment; second, as hypothesized, the established sample preparation methodology made it possible to obtain the CZE pattern of PSA from serum; and third, the CZE pattern of serum PSA and of PSA standard from seminal plasma of healthy individuals, both submitted to the sample treatment method, showed some differences regarding the proportion of CZE peaks of the glycoprotein. These differences could be related to possible changes in the linkages of peptide backbone, in glycosylation or in other post-translational modifications between samples from both origins.

Vardenafil improves penile erection in type 2 diabetes mellitus patients with erectile dysfunction: role of tropomyosin.

INTRODUCTION: Evidences have been suggested that phosphodiesterase type 5 (PDE5) inhibition promotes vasculoprotective benefits in patients with cardiovascular diseases. AIM: The aim of this study is to analyze the systemic effect of PDE5 inhibition in type 2 diabetes mellitus patients with erectile dysfunction (ED) determining changes in the expression levels of plasma proteins. METHODS: Seventeen patients with controlled type 2 diabetes mellitus and ED were included in the study. Patients received vardenafil hydrochloride 20 mg on demand during 12 weeks. At the beginning and 12 weeks after vardenafil administration, plasma samples were collected and analyzed using proteomics. MAIN OUTCOME MEASURES: International Index of Erectile Function-Erectile Function Domain (IIEF-EFD) and plasma protein expression before and after vardenafil administration. Nitrate/nitrite release, PDE5, and soluble guanylate cyclase (sGC) expression and cyclic guanosine monophosphate (cGMP) content in cultured bovine aortic endothelial cells (BAECs). RESULTS: The IIEF-EFD score was markedly improved after 12 weeks of vardenafil administration. Plasma levels of alpha 1-antitrypsin isotypes 4 and 6 and ß-tropomyosin were decreased, whereas apolipoprotein AI isoype 5 was increased 12 weeks after vardenafil administration. Only ß-tropomyosin plasma levels were inversely correlated with IIEF-EFD score. Tropomyosin has been added to cultured BAECs and after 24 hours reduced the protein expression level of sGC-ß1 subunit and decreased the cGMP content. Tropomyosin did not modify PDE5 expression and nitric oxide release in BAECs as compared with control BAECs. Vardenafil (10 µg/mL) did not modify sGC-ß1 subunit expression in tropomyosin + vardenafil-incubated BAECs; however, vardenafil significantly reversed the reduction of cGMP content induced by tropomyosin. CONCLUSION: Vardenafil administration improved erectile functionality in controlled type 2 diabetes mellitus patients with ED, which was associated with reduction of circulating plasma ß-tropomyosin levels. Tropomyosin affected by itself the cGMP generating system suggesting a possible new mechanism involved in ED. Vardenafil reversed the reduction effect of cGMP content elicited by tropomyosin in BAECs.

Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy.

OBJECTIVE: To report long-term outcomes of selective organ preservation for muscle-invasive bladder cancer (MIBC) using 2 bladder-sparing trimodality approaches. MATERIALS AND METHODS: From 1990 to 2010, 80 patients with T2-T4 bladder cancer were prospectively enrolled in 2 successive bladder-sparing protocols. Forty-one patients were treated with neoadjuvant methotrexate, cisplatin, and vinblastine (MCV) chemotherapy followed by radiotherapy (60 Gy) in complete responders (protocol 1 [P1]) and 39 patients were treated with weekly cisplatin concurrent with radiotherapy (64.8 Gy) (protocol 2 [P2]). RESULTS: The median follow-up was 72 months (range, 9-204 months). Five and 10-year cumulative overall survival for all series were 73% and 60% and the corresponding numbers for cancer-specific survival were 82% and 80%, respectively. Of all surviving patients, 83% maintained their own bladder. Although there were no significant differences in overall survival (P = .820), cancer-specific survival (P = .688) and distant metastasis (P = .417) between protocols, complete response rates (P = .003), and disease-free survival (P = .031) were significantly higher in P2 treatment. CONCLUSION: Trimodality therapy with bladder preservation represents a real alternative to radical cystectomy (RC) in selected patients. Overall survival and cancer-specific survival rates are encouraging with more than 80% of survivors retaining functional bladders.

Circulating tumor cells in solid tumor in metastatic and localized stages.

UNLABELLED: The aim of this study was the detection of circulating tumor cells (CTC) in three tumor types of epithelial origin. PATIENTS AND METHODS: Four hundred and thirty-eight patients with breast cancer (56.2% localized and 43.8% metastatic), 195 with colorectal tumors (84.1% localized and 15.9% metastatic) and 50 with prostate cancer (52% localized and 48% metastatic) took part in this study. CTC quantification was performed using the CellSpotter Analyzer (Veridex LLC). RESULTS: 31.5% of patients with cancer had > or =2 CTCs/7.5 mL but none of the healthy volunteers were above this level (p<0.001). Among patients with metastatic disease, 62.3% of them had > or =2 CTCs/7.5 mL but only 14.0% of those with localized disease were above this level (p<0.001). The presence of CTCs were correlated to stage in the three studied tumor types and no differences in the number of cells were found between them. CONCLUSION: The presence of more than 2 CTCs/7.5 ml is a frequent event in metastatic cases. In particular, patients with localized disease who have more than 2 CTCs/7.5 ml should be carefully studied to determine the possible prognostic and predictive value of this finding.

[Hereditary renal cancer]. / Cáncer de riñón hereditario.

Kidney cancer is the tenth most common cause of cancer death. There are a growing number of genes known to be associated with an increased risk of specific types of kidney cancer. People with Von Hippel-Lindau syndrome have about a 40% risk of developing multiple bilateral clear cell kidney cancers. They can also develop retinal and brain hemangioblastoma, kidneys or pancreas cysts, pheochromocytoma and endolymphatic sac tumor. Four phenotypes with different renal cancer and pheocromocitoma risk have been described depending on the germline mutation. Hereditary papillary renal cell carcinoma syndrome has type 1 papillary renal cell carcinomas associated with protooncogene c-MET germline mutations. Birt-Hogg-Dubé syndrome has FLCN gene mutations associated with fibrofolliculomas, lung cysts with a high risk for spontaneous pneumothorax, and a 15% to 30% risk of kidney cancer (most classified as chromophobe carcinoma, oncocytoma or oncocytic hybrid, but clear cell and papillary kidney cancers have also been reported). Histopathological findings such as oncocytosis and oncocytic hybrids are very unusual outside the syndrome. Hereditary leiomyomatosis and renal cell cancer syndrome shows mutations of Fumarate hydratase gene and cutaneous leiomyomata in 76% of affected individuals, uterine leiomyomata in 100% of females, and unilateral, solitary, and aggressive papillary renal cancer in 10 to 16% of patients. A specific histopathological change is eosinophilic prominent nucleoli with a perinucleolar halo. Tuberous sclerosis complex is one of the most prevalent (1/5.800) hereditary syndromes where renal disease is the second leading cause of death, associated with angiomyolipomas (70%), renal cysts, oncocytomas or clear cell cancer.

Cáncer de riñón hereditario / Hereditary renal cancer

El cáncer de riñón es la décima causa más común de muerte por cáncer. Esta revisión analiza las características de los síndromes hereditarios más frecuentes asociados a un subtipo histológico de tumor renal específico, su prevalencia y penetrancia, test genéticos disponibles y programas de cribado/detección precoz y tratamiento recomendados. En el síndrome de Von Hippel-Lindau un 40% de los pacientes desarrollan carcinoma renal de células claras bilateral y multifocal. También son frecuentes el hemangioblastoma del SNC o retina, feocromocitomas y tumores del saco endolinfático. Se han descrito cuatro fenotipos clásicos de VHL en función de la mutación y un diferente riesgo de feocromocitoma o carcinoma de células renales. Se puede realizar test genético de diagnóstico de confirmación, diagnóstico prenatal o preimplantación. El cáncer papilar renal hereditario tiene múltiples carcinomas papilares bilaterales de subtipo histológico 1. El gen asociado es el proto-oncogen c-met. El síndrome de Birt-Hogg-Dubé por mutaciones en el gen FLCN combina múltiples tumores renales bilaterales de tipo oncocitoma, carcinoma cromófobo, tumor híbrido oncocítico y una minoría carcinoma de células claras renales. Se asocia a fibrofoliculomas cutáneos, quistes de pulmón y neumotórax espontáneo. Histológicamente, hay lesiones iniciales de oncocitosis o híbridos oncocíticos excepcionales fuera del síndrome hereditario. La leiomiomatosis hereditaria y cáncer de células renales por mutaciones del gen fumarato hidratasa tiene en un 15%de los pacientes un agresivo carcinoma papilar tipo 2, en un 75% leiomiomas cutáneos múltiples y en 100% leiomiomas uterinos. En el estudio histopatológico se observan unos macronúcleolos eosinófilos característicos. La Esclerosis tuberosa es uno de los síndromes hereditarios más frecuentes asociado a angiomiolipoma (70% de afectados),quistes renales, oncocitoma o carcinoma renal de células claras (AU)

Kidney cancer is the tenth most common cause of cancer death. There are a growing number of genes known to be associated with an increased risk of specific types of kidney cancer. People with Von Hippel-Lindau syndrome have about a 40% risk of developing multiple bilateral clear cell kidney cancers. They can also develop retinal and brain hemangioblastoma, kidneys or pancreas cysts, pheochromocytoma and endolymphatic sac tumor. Four phenotypes with different renal cancer and pheocromocitoma risk have been described depending on the germline mutation. Hereditary papillary renal cell carcinoma syndrome has type 1 papillary renal cell carcinomas associated with protooncogenec-MET germline mutations. Birt-Hogg-Dubé syndrome has FLCN gene mutations associated with fibrofolliculomas, lung cysts with a high risk for spontaneous pneumothorax, and a 15% to 30% risk of kidney cancer (most classified as chromophobe carcinoma, oncocytoma or oncocytic hybrid, but clear cell and papillary kidney cancers have also been reported). Histopathological findings such as oncocytosis and oncocytic hybrids are very unusual outside the syndrome. Hereditary leiomyomatosis and renal cell cancer syndrome shows mutations of Fumarate hydratase gene and cutaneous leiomyomata in 76% of affected individuals, uterine leiomyomata in 100% of females, and unilateral, solitary, and aggressive papillary renal cancer in 10 to 16% of patients. A specific histopathological change is eosinophilic prominent nucleoli with a perinucleolar halo. Tuberous sclerosis complex is one of the most prevalent (1/5.800) hereditary syndromes where renal disease is the second leading cause of death, associated with angiomyolipomas (70%), renal cysts, oncocytomas or clear cell cancer (AU)