Influence of Concomitant Treatments under Anticoagulants and Statins in Detecting Signals of Adverse Drug Reactions.

The aim of the present study was to evaluate the risk of adverse drug reactions (ADRs) of concomitant treatments in patients treated with anticoagulants and statins. The authors performed an observational cross-sectional study in two cohorts of surveyed patients treated with vitamin K antagonists (VKAs) or non-vitamin K antagonist oral anticoagulants (NOACs). Different groups were analyzed based on the drug that each patient was taking, that is, VKAs or NOACs, as well as on the use of HMG CoA reductase inhibitors (statins) versus nonuse of these drugs; they also took into account the potential exposure to other common medications. Descriptive, clinical, and ADR data were reported and analyzed through an adaptation of Bayesian methodology (false discovery rate < 0.05) to detect new signals. Eleven different ADRs in patients on VKAs and statins and 12 in patients on VKAs without statins were found. In evaluating the concomitant therapies, the authors found that analgesics and nonsteroidal anti-inflammatory drugs were the most common therapeutic options, followed by proton pump inhibitors (PPIs). Seven ADRs were observed in patients concomitantly treated with NOACs and statins, whereas NOACs without concomitant statins were associated with a significantly lower risk of bleeding. The risk of observing an ADR among the patients who are concomitantly treated with VKAs and statins is lower than with analgesics or PPI, while the concomitant use of NOACs and statins is associated with both an increment in the number of observed ADRs and increased risk of bleeding.

New Anticoagulant Agents: Incidence of Adverse Drug Reactions and New Signals Thereof.

The aim of this study was to evaluate the adverse drug reaction (ADR) incidence rate and new signals thereof for classic compared with new anticoagulants in real-life ambulatory settings. The authors performed an observational cross-sectional study in two cohorts of surveyed patients treated with vitamin K antagonists (VKAs; acenocoumarol or warfarin) or nonvitamin K antagonist oral anticoagulants (NOACs; apixaban, edoxaban, rivaroxaban, dabigatran etexilate). Descriptive, clinical, and ADRs data were reported and analyzed through a bivariate analysis (odds ratio [OR]) to compare the ADRs incidence rate and an adaptation of Bayesian methodology (false discovery rate [FDR] < 0.05) to detect new signals. A total of 334 patients were surveyed-average international normalized ratio (INR) of 2.6-and 45.4% taking new anticoagulants. Note that 835 ADRs were reported; 2.5 per patient (2.8 in the VKA cohort, 2.1 in the NOAC cohort). The authors obtained higher risk of epistaxis (OR, 2.18; 95% confidence interval [CI], 1.01-4.74) and hematoma (OR, 2.43; 95% CI, 1.39-4.25) with VKAs and lower risk of global bleeding symptoms with NOACs (OR, 0.45; 95% CI, 0.28-0.71). After standardizing the data, a significant risk of diarrhea with VKAs was observed (OR, 3.37; 95% CI, 1.09-10.41). They also detected an intense positive signal regarding the use of VKAs and osteoporosis (FDR < 0.001), specifically acenocoumarol (FDR < 0.002). NOACs presented lower risk of bleeding, especially dabigatran (FDR < 0.031), and of dermatological pathologies with apixaban being the safest (FDR = 0.050). The lower risk of global bleeding and a potential protective effect against osteoporosis in patients treated with NOACs postulate them as safer than VKAs.

Genetic polymorphisms in key hypoxia-regulated downstream molecules and phenotypic correlation in prostate cancer.

BACKGROUND: In this study we sought if, in their quest to handle hypoxia, prostate tumors express target hypoxia-associated molecules and their correlation with putative functional genetic polymorphisms. METHODS: Representative areas of prostate carcinoma (n = 51) and of nodular prostate hyperplasia (n = 20) were analysed for hypoxia-inducible factor 1 alpha (HIF-1α), carbonic anhydrase IX (CAIX), lysyl oxidase (LOX) and vascular endothelial growth factor (VEGFR2) immunohistochemistry expression using a tissue microarray. DNA was isolated from peripheral blood and used to genotype functional polymorphisms at the corresponding genes (HIF1A +1772 C > T, rs11549465; CA9 + 201 A > G; rs2071676; LOX +473 G > A, rs1800449; KDR - 604 T > C, rs2071559). RESULTS: Immunohistochemistry analyses disclosed predominance of positive CAIX and VEGFR2 expression in epithelial cells of prostate carcinomas compared to nodular prostate hyperplasia (P = 0.043 and P = 0.035, respectively). In addition, the VEGFR2 expression score in prostate epithelial cells was higher in organ-confined and extra prostatic carcinoma compared to nodular prostate hyperplasia (P = 0.031 and P = 0.004, respectively). Notably, for LOX protein the immunoreactivity score was significantly higher in organ-confined carcinomas compared to nodular prostate hyperplasia (P = 0.015). The genotype-phenotype analyses showed higher LOX staining intensity for carriers of the homozygous LOX +473 G-allele (P = 0.011). Still, carriers of the KDR-604 T-allele were more prone to have higher VEGFR2 expression in prostate epithelial cells (P < 0.006). CONCLUSIONS: Protein expression of hypoxia markers (VEGFR2, CAIX and LOX) on prostate epithelial cells was different between malignant and benign prostate disease. Two genetic polymorphisms (LOX +473 G > A and KDR-604 T > C) were correlated with protein level, accounting for a potential gene-environment effect in the activation of hypoxia-driven pathways in prostate carcinoma. Further research in larger series is warranted to validate present findings.

Tuning Oxide Properties by Oxygen Vacancy Control During Growth and Annealing.

Electrical, optical, and magnetic properties of oxide materials can often be controlled by varying the oxygen content. Here we outline two approaches for varying the oxygen content and provide concrete examples for tuning the electrical properties of SrTiO3-based heterostructures. In the first approach, the oxygen content is controlled by varying the deposition parameters during a pulsed laser deposition. In the second approach, the oxygen content is tuned by subjecting the samples to annealing in oxygen at elevated temperatures after the film growth. The approaches can be used for a wide range of oxides and nonoxide materials where the properties are sensitive to a change in the oxidation state. The approaches differ significantly from electrostatic gating, which is often used to change the electronic properties of confined electronic systems such as those observed in SrTiO3-based heterostructures. By controlling the oxygen vacancy concentration, we are able to control the carrier density over many orders of magnitude, even in nonconfined electronic systems. Moreover, properties can be controlled, which are not sensitive to the density of itinerant electrons.

Tumor cell-educated periprostatic adipose tissue acquires an aggressive cancer-promoting secretory profile.

BACKGROUND/AIMS: The microenvironment produces important factors that are crucial to prostate cancer (PCa) progression. However, the extent to which the cancer cells stimulate periprostatic adipose tissue (PPAT) to produce these proteins is largely unknown. Our purpose was to determine whether PCa cell-derived factors influence PPAT metabolic activity. METHODS: Primary cultures of human PPAT samples from PCa patients (adipose tissue organotypic explants and primary stromal vascular fraction, SVF) were stimulated with conditioned medium (CM) collected from prostate carcinoma (PC3) cells. Cultures without CM were used as control. We used multiplex analysis and ELISA for protein quantification, qPCR to determine mitochondrial DNA (mtDNA) copy number and zymography for matrix metalloproteinase activity, in order to evaluate the response of adipose tissue explants and SVFs to PC3 CM. RESULTS: Stimulation of PPAT explants with PCa PC3 CM induced adipokines associated with cancer progression (osteopontin, tumoral necrosis factor alpha and interleukin-6) and reduced the expression of the protective adipokine adiponectin. Notably, osteopontin protein expression was 13-fold upregulated. Matrix metalloproteinase 9 activity and mitochondrial DNA copy number were higher after stimulation with cancer CM. Stromovascular cells from PPAT in culture were not influenced by tumor-derived factors. CONCLUSION: The modulation of adipokine expression by tumor CM indicates the pervasive extent to which tumor cells command PPAT to produce factors favorable to their aggressiveness.

Obesity and prostate cancer: gene expression signature of human periprostatic adipose tissue.

BACKGROUND: Periprostatic (PP) adipose tissue surrounds the prostate, an organ with a high predisposition to become malignant. Frequently, growing prostatic tumor cells extend beyond the prostatic organ towards this fat depot. This study aimed to determine the genome-wide expression of genes in PP adipose tissue in obesity/overweight (OB/OW) and prostate cancer patients. METHODS: Differentially expressed genes in human PP adipose tissue were identified using microarrays. Analyses were conducted according to the donors' body mass index characteristics (OB/OW versus lean) and prostate disease (extra prostatic cancer versus organ confined prostate cancer versus benign prostatic hyperplasia). Selected genes with altered expression were validated by real-time PCR. Ingenuity Pathway Analysis (IPA) was used to investigate gene ontology, canonical pathways and functional networks. RESULTS: In the PP adipose tissue of OB/OW subjects, we found altered expression of genes encoding molecules involved in adipogenic/anti-lipolytic, proliferative/anti-apoptotic, and mild immunoinflammatory processes (for example, FADS1, down-regulated, and LEP and ANGPT1, both up-regulated). Conversely, in the PP adipose tissue of subjects with prostate cancer, altered genes were related to adipose tissue cellular activity (increased cell proliferation/differentiation, cell cycle activation and anti-apoptosis), whereas a downward impact on immunity and inflammation was also observed, mostly related to the complement (down-regulation of CFH). Interestingly, we found that the microRNA MIRLET7A2 was overexpressed in the PP adipose tissue of prostate cancer patients. CONCLUSIONS: Obesity and excess adiposity modified the expression of PP adipose tissue genes to ultimately foster fat mass growth. In patients with prostate cancer the expression profile of PP adipose tissue accounted for hypercellularity and reduced immunosurveillance. Both findings may be liable to promote a favorable environment for prostate cancer progression.

On-Demand Generation of Entangled Photon Pairs in the Telecom C-Band with InAs Quantum Dots.

Entangled photons are an integral part in quantum optics experiments and a key resource in quantum imaging, quantum communication, and photonic quantum information processing. Making this resource available on-demand has been an ongoing scientific challenge with enormous progress in recent years. Of particular interest is the potential to transmit quantum information over long distances, making photons the only reliable flying qubit. Entangled photons at the telecom C-band could be directly launched into single-mode optical fibers, enabling worldwide quantum communication via existing telecommunication infrastructure. However, the on-demand generation of entangled photons at this desired wavelength window has been elusive. Here, we show a photon pair generation efficiency of 69.9 ± 3.6% in the telecom C-band by an InAs/GaAs semiconductor quantum dot on a metamorphic buffer layer. Using a robust phonon-assisted two-photon excitation scheme we measure a maximum concurrence of 91.4 ± 3.8% and a peak fidelity to the Φ+ state of 95.2 ± 1.1%, verifying on-demand generation of strongly entangled photon pairs and marking an important milestone for interfacing quantum light sources with our classical fiber networks.

Trends in the consumption of antidepressants in Castilla y León (Spain). Association between suicide rates and antidepressant drug consumption.

OBJECTIVE: To learn the evolution of antidepressant and lithium use in Castilla y León (Central Spain) and its relationship with suicide rates. METHODS: A search in the ECOM (Especialidades Consumo de Medicamentos) database of the Spanish Ministry of Health for antidepressants and lithium was carried out for the period 1992-2005. Defined daily doses (DDD) per 1000 inhabitants per day were obtained as consumption data. Population and suicide rates data come from the Spanish National Statistics Institute. RESULTS: Antidepressant consumption increased 7-fold, from 6.9 DDD per 1000 inhabitants per day in 1992 to 47.3 in 2005; the corresponding increase in cost was more than 10-fold. Selective serotonin reuptake inhibitors (SSRIs) comprised 77% of the total consumption. Venlafaxine consumption multiplied by 2.2. The consumption of monoamine oxidase inhibitors (MAOIs) decreased after venlafaxine and mirtazapine were marketed. Lithium consumption increased by 76% during the period studied, but it plateaued in 2000. CONCLUSIONS: The consumption of antidepressants in Castilla y León has increased remarkably and the pattern has changed; there is an increase in the consumption of the new and more expensive antidepressants such as venlafaxine and escitalopram. No association was observed between suicide rates and antidepressant consumption.

Hypotensive and vasorelaxant effects of the procyanidin fraction from Guazuma ulmifolia bark in normotensive and hypertensive rats.

THE AIM OF THE STUDY: was to investigate the in vivo and in vitro cardiovascular activity of a procyanidin fraction (PCF) obtained from acetone extract of Guazuma ulmifolia bark which has traditionally been used as an antihypertensive agent. RESULTS: 10 mg/kg PCF doses orally administered to sugar-fed hypertensive rats decreased both the systolic arterial pressure and the heart rate, whereas the same doses intravenously administered induced arterial hypotension which was attenuated by NG-nitro-L-arginine methylester (L-NAME 31 mg/kg) pretreatment. In these experiments we employed carbachol as a positive control test. The PCF reduced the contraction induced by norepinephrine (1x10(-7) M) in isolated aortic rings of normotensive (IC50=35.3+/-12.4 ng/mL) and sugar-fed hypertensive (IC50=101.3+/-57.2 ng/mL) rats. This relaxant activity was inhibited by either vascular endothelium removal or L-NAME (30 microM) pretreatment, while indomethacin (10 microM) or atropine (10 microM) had no effect. Preliminary analysis of the PCF by HPLC-DAD-MS and FAB+ mass spectrometry allowed the detection of the main components such as the complex of procyanidin oligomers consisting mainly of tetramers and trimers. CONCLUSIONS: Guazuma ulmifolia bark possesses long-lasting antihypertensive and vasorelaxing properties linked to the endothelium related factors, where nitric oxide is involved.

Primary mesenchymal chondrosarcoma of the kidney: A case report and review of literature.

Primary mesenchymal chondrosarcoma of the kidney is extremely rare, with only nine cases reported in the English literature. We report a new case of this disease. A 35-year-old man, presented with flank pain, episodic gross hematuria and a painless palpable mass in left abdominal quadrant. Computed tomography scan identified a left renal tumor with 20 cm, with no evidence of regional or metastatic spread disease. The patient underwent radical nephrectomy. The immunohistopathological diagnosis was mesenchymal chondrosarcoma of the kidney. At 18 months of follow-up, there was no evidence of recurrence or distant metastasis. Primary renal chondrosarcoma is so rare that its prognosis is unknown. Disease recurrence is unpredictable and when it is detected, the prognosis is poor. The radical nephrectomy with complete resection of the tumor with wide resection free margins is recommended, and the patients need long-term and close surveillance, with particular attention to local recurrence and uncommon sites of metastization.

Antipsychotics and cardiovascular risk: A case/non-case study.

Severe mental disorders have been reported to be associated with an increased cardiovascular risk. To measure the potential risk excess as compared, not with the baseline cardiovascular risk for the general population, but with the cardiovascular risk associated with drug iatrogenia. 197 reported cases of cardiovascular adverse reaction to antipsychotic drugs as compared to the reported cases of this type of adverse reactions to drugs other than antipsychotics entered in the Spanish Pharmacovigilance System database (FEDRA) (1995-2018) in an observational case/non-case study. Risk estimates of association were reporting odds ratio (ROR), and, chi-square test (χ2). Overall disproportionality for the whole drug class was found [ROR 2.3 (95% CI 2.0-2.7)], χ2 = 127.07]. When the two types of antipsychotics (typical and atypical) were analysed separately, we also found statistically significant disproportionality, and this disproportionality is similar between both groups, with disproportionality measures around 2.30, with the confidence intervals not including the 1. The disproportionality observed suggests a risk excess that might be greater than expected, which holds particularly true for torsade de pointes, sudden death and cardiac arrhythmias in patients treated with any of the two types of antipsychotics. There was no significant risk for ischaemic heart disease.

Atypical Fracture of the Sternum After Long-Term Alendronate Plus Cholecalciferol Treatment: A Case Report.

A 55-year-old woman developed an atraumatic sternum fracture during treatment with alendronate for osteoporosis. The woman received alendronate 70 mg in combination with cholecalciferol 5600 IU once weekly, as well as nonsteroidal anti-inflammatory drugs. After 4 years of treatment, following a dorsal flexion with no direct thoracic trauma, the patient suffered a fracture of the sternum, with an X-ray revealing sternal body fracture. This fracture was seen to be transverse, noncomminuted and without displacement. Magnetic resonance imaging was carried out to rule out the presence of either a pathological fracture or a fracture resulting from osteoporotic fragility, and showed a triple sternal fracture involving the body, as well as the upper and lower manubrium of the sternum. This fracture presented the features of an atypical femur fracture, except for the location. The alendronate and cholecalciferol combination was discontinued and denosumab was prescribed. After the withdrawal of alendronate, the patient showed clinical improvement, with a decrease in pain, and is currently having routine checkups. The causality algorithm of the Spanish Pharmacovigilance System shows a score of 5, indicating a possible relationship between the patient's sternum fracture and her use of the suspect drug (Naranjo scale 6 = probable).

Risk excess of mortality and use of antipsychotics: a case-noncase study.

Severe mental disorders are associated with an increased mortality risk and the use of antipsychotic drugs may be one of the causes. In this study, we addressed the potential association of the reported mortality among patients on antipsychotics compared to other drugs from a pharmacovigilance database with the aim of evaluating the drug-induced mortality risk. A database containing 189 441 entries of suspected adverse reactions reported from 1 January 1995 to 31 December 2012 was explored for fatal outcomes. Potential disproportionality was estimated using the reporting odds ratio, proportional reporting ratio, and the χ-test. Two-hundred fatal outcomes were reported in patients on antipsychotics, which indicated the occurrence of disproportionality for this pharmacological class compared with any other drugs. When data were analysed by antipsychotic subclass, disproportionality was found only for atypical but not for typical antipsychotics. When individually analysed by active substances and routes, only a few substances were found to show disproportionality. The disproportionality encountered in this study compared with the mortality associated with other drugs suggests that the active substances under study may be associated with a mortality risk higher than what is assumed currently. Also, it suggests that atypical antipsychotics are likely to have a mortality risk higher than the risk of typical antipsychotics. The disproportionality found for zuclopentixol, in both oral and depot formulations, can be considered to be a drug surveillance signal.

Elucidation of the defence mechanism in microalgae Chlorella sorokiniana under mercury exposure. Identification of Hg-phytochelatins.

Algae and aquatic macrophytes are capable of accumulating heavy metals up to concentrations several orders of magnitude higher than those existing in their surrounding environment. Investigation of mercury toxicology in microalgae is of great interest from ecological point of view, since they could be used as bioindicator to evaluate aquatic ecosystems affected by Hg pollution. In this study, we have performed an exposure experiment focused on the biological response of microalgae Chlorella sorokiniana, a unicellular model organism, to Hg-induced toxicity. The culture was exposed to different concentrations of this element for nine days, namely 0.5, 1, 5 and 10mg L(-1) of HgCl2 (as Hg). To achieve a better understanding of the biological mechanisms triggered by Hg-induced toxicity in this alga a metallomic approach based on SEC-ICP-ORS-MS was applied to survey biomarkers of biological response to mercury contamination in surface water. In addition, the combination of RP-HPLC-ICP-ORS-MS and RP-HPLC-ESI-QqQ-TOF-MS was applied to identify, for the first time, two Hg-binding phytochelatins in this aquatic organism, using cell extracts from microalgae exposed to inorganic mercury.

The HIF1A functional genetic polymorphism at locus +1772 associates with progression to metastatic prostate cancer and refractoriness to hormonal castration.

The hypoxia inducible factor 1 alpha (HIF1a) is a key regulator of tumour cell response to hypoxia, orchestrating mechanisms known to be involved in cancer aggressiveness and metastatic behaviour. In this study we sought to evaluate the association of a functional genetic polymorphism in HIF1A with overall and metastatic prostate cancer (PCa) risk and with response to androgen deprivation therapy (ADT). The HIF1A +1772 C>T (rs11549465) polymorphism was genotyped, using DNA isolated from peripheral blood, in 1490 male subjects (754 with prostate cancer and 736 controls cancer-free) through Real-Time PCR. A nested group of cancer patients who were eligible for androgen deprivation therapy was followed up. Univariate and multivariate models were used to analyse the response to hormonal treatment and the risk for developing distant metastasis. Age-adjusted odds ratios were calculated to evaluate prostate cancer risk. Our results showed that patients under ADT carrying the HIF1A +1772 T-allele have increased risk for developing distant metastasis (OR, 2.0; 95%CI, 1.1-3.9) and an independent 6-fold increased risk for resistance to ADT after multivariate analysis (OR, 6.0; 95%CI, 2.2-16.8). This polymorphism was not associated with increased risk for being diagnosed with prostate cancer (OR, 0.9; 95%CI, 0.7-1.2). The HIF1A +1772 genetic polymorphism predicts a more aggressive prostate cancer behaviour, supporting the involvement of HIF1a in prostate cancer biological progression and ADT resistance. Molecular profiles using hypoxia markers may help predict clinically relevant prostate cancer and response to ADT.

Antagonistic interaction of selenomethionine enantiomers on methylmercury toxicity in the microalgae Chlorella sorokiniana.

The protective effect of selenium against mercury toxicity is well known especially between selenomethionine and methylmercury and it has been studied in several living organisms, however information is lacking about the interaction of these species in Chlorella. Investigation into which chiral form of selenomethionine effectively acts against the toxic effects of methylmercury has not previously been carried out. In the present work, two control cultures and two cultures of C. sorokiniana were grown in standard medium with D,L-SeMet, L-SeMet or D-SeMet. After the experiment was started up MeHg(+) was added periodically to the cultures containing D,L-SeMet, L-SeMet, D-SeMet and to one of the control batches. The results show that both SeMet enantiomers counteract the toxicity of MeHg(+), by markedly increasing the total content of chlorophyll, carotenoids, as well as the dry weight and light dependent oxygen production, compared to the culture which is non pre-treated with SeMet and is only exposed to MeHg(+). The levels of MeHg(+) measured in cells are lower in the cultures pre-treated with SeMet indicating that the passage of MeHg(+) into the cells is negligible when carried out in the presence of SeMet, or that SeMet enhances the release of MeHg(+). On the other hand, L-SeMet is directly involved in the detoxification of MeHg(+), but the involvement of D-SeMet occurs only indirectly since it has been neither identified in the medium nor in C. sorokiniana after supplementation with this enantiomer. It may be that D-SeMet is transformed into SeMeSec and L-SeMet. Moreover, SeMeSec is almost totally released from the cells after 72 hours. No mercury-selenium complex was detected but, since the summation of the different species identified accounted only for 77% of the total selenium and mercury measured directly after sample digestion, it is possible that they are present in the form of an undetected Se-Hg complex. This hypothesis is supported by the decrease of inorganic selenium during the experiment. The present paper reports new data about the relationship between the mechanism of detoxification of methylmercury and selenomethionine enantiomers through the study of the metabolic intermediates by means of speciation analysis.

Performance of Chlorella sorokiniana under simulated extreme winter conditions.

High annual microalgae productivities can only be achieved if solar light is efficiently used through the different seasons. During winter the productivity is low because of the light and temperature conditions. The productivity and photosynthetic efficiency of Chlorella sorokiniana were assessed under the worst-case scenario found during winter time in Huelva, south of Spain. The maximum light intensity (800 µmol photons m(-2) s(-1)) and temperature (20°C) during winter were simulated in a lab-scale photobioreactor with a short light-path of 14 mm. Chemostat conditions were applied and the results were compared with a temperature-controlled situation at 38°C (optimal growth temperature for C. sorokiniana). When temperature was optimal the highest productivity was found at a dilution rate of 0.18 h(-1) (P(v) = 0.28 g Kg(-1) h(-1)), and the biomass yield on light energy was high (Y(x,E) = 1.2 g mol(-1) photons supplied). However, at suboptimal temperature, the specific growth rate of C. sorokiniana was surprisingly low, not being able to support continuous operation at a dilution rate higher than 0.02 h(-1). The slow metabolism under suboptimal temperature resulted in a decline of the light energy requirements of the cells. Consequently, the maximum winter irradiance was experienced as excessive, leading to a low photosynthetic efficiency and productivity (Y(x,E) = 0.5 g mol(-1) photons supplied, P(v) = 0.1 g Kg(-1) h(-1)). At suboptimal temperature a higher carotenoid-to-chlorophyll ratio was observed indicating the activation of light-dissipating processes. We conclude that temperature control and/or light dilution during winter time will enhance the productivity.

Posterior scleritis resembling acute retinal necrosis syndrome.

PURPOSE: To report a challenging diagnosis of posterior scleritis in a patient with features of retinal necrosis. METHODS: Single observational case report. RESULTS: A 74-year-old man presented with atypical anterior scleritis in the left eye. Funduscopy showed subretinal inflammatory infiltration resembling acute retinal necrosis. The patient was treated with indomethacin, with resolution of the process. CONCLUSION: Typical signs of posterior scleritis include serous retinal detachment and choroidal folds in the posterior pole. Nonetheless, an atypical presentation can also occur, with peripheral whitish or subretinal inflammatory infiltrate, serous retinal detachment, and hemorrhages, resembling an acute retinal necrosis syndrome.

Human periprostatic white adipose tissue is rich in stromal progenitor cells and a potential source of prostate tumor stroma.

A body of growing evidence now implicates white adipose tissue as a relevant source of stromal progenitor cells recruited to the tumor microenvironment to form supportive tumor stroma. While the role of periprostatic (PP) adipose tissue in prostate cancer progression has been barely appreciated, we sought to determine the progenitor cell population in PP adipose tissue and the association with prostate cancer. We isolated and characterized CD31(-)CD34(+)CD45(-)CD146(-) progenitor cells (adipose-derived stem cells [ASC]) in paired samples of PP and preperitoneal visceral adipose tissue from prostate tissue and peripheral blood mononuclear cells of prostate cancer and nodular prostatic hyperplasia patients. ASC were quantified by flow cytometry and confirmed through target gene expression. Here we show a significantly higher amount of ASC in PP than in visceral adipose tissue, independent of body mass index and prostatic disease. In the prostate, ASC are increased in cancer compared with prostatic nodular hyperplasia patients. Concordantly, adipsin gene (CFD) expression, which is known to be up-regulated in adipose stem cells, was overexpressed in PP adipose tissue, in the prostate of cancer patients and in prostate CD31(-)CD34(+)CD45(-)CD146(-) sorted cells. ASC were found at higher levels in the blood of prostate cancer patients simultaneously overweight/obese. Present findings indicate that PP adipose tissue is a reservoir of progenitor cells with the potential to migrate towards prostate tumors, although its clinical significance merits further evaluation.

Human periprostatic adipose tissue promotes prostate cancer aggressiveness in vitro.

BACKGROUND: Obesity is associated with prostate cancer aggressiveness and mortality. The contribution of periprostatic adipose tissue, which is often infiltrated by malignant cells, to cancer progression is largely unknown. Thus, this study aimed to determine if periprostatic adipose tissue is linked with aggressive tumor biology in prostate cancer. METHODS: Supernatants of whole adipose tissue (explants) or stromal vascular fraction (SVF) from paired fat samples of periprostatic (PP) and pre-peritoneal visceral (VIS) anatomic origin from different donors were prepared and analyzed for matrix metalloproteinases (MMPs) 2 and 9 activity. The effects of those conditioned media (CM) on growth and migration of hormone-refractory (PC-3) and hormone-sensitive (LNCaP) prostate cancer cells were measured. RESULTS: We show here that PP adipose tissue of overweight men has higher MMP9 activity in comparison with normal subjects. The observed increased activities of both MMP2 and MMP9 in PP whole adipose tissue explants, likely reveal the contribution of adipocytes plus stromal-vascular fraction (SVF) as opposed to SVF alone. MMP2 activity was higher for PP when compared to VIS adipose tissue. When PC-3 cells were stimulated with CM from PP adipose tissue explants, increased proliferative and migratory capacities were observed, but not in the presence of SVF. Conversely, when LNCaP cells were stimulated with PP explants CM, we found enhanced motility despite the inhibition of proliferation, whereas CM derived from SVF increased both cell proliferation and motility. Explants culture and using adipose tissue of PP origin are most effective in promoting proliferation and migration of PC-3 cells, as respectively compared with SVF culture and using adipose tissue of VIS origin. In LNCaP cells, while explants CM cause increased migration compared to SVF, the use of PP adipose tissue to generate CM result in the increase of both cellular proliferation and migration. CONCLUSIONS: Our findings suggest that the PP depot has the potential to modulate extra-prostatic tumor cells' microenvironment through increased MMPs activity and to promote prostate cancer cell survival and migration. Adipocyte-derived factors likely have a relevant proliferative and motile role.