Basal cytokines profile in metastatic renal cell carcinoma patients treated with subcutaneous IL-2-based therapy compared with that of healthy donors

<p>Abstract</p> <p>Background and purpose</p> <p>Metastatic renal cell carcinoma (MRCC) has a poor prognosis with a median overall survival of about one year. Since only a minority of patients experienced therapeutic benefit to current treatments, several studies have attempted to identify factors that may have an impact on response and survival. Cytokines play a crucial role in the host's immune response by regulating the development and function of a lot of biological compartments. Nevertheless, available data on basal cytokine levels in MRCC are very few and no clear profile of serum cytokines has been identified yet in these patients population. Thus, determining the levels of cytokines in MRCC could not only help in understanding the biological mechanisms of the tumor growth, but also in evaluating if different cytokine profiles are correlated with particular clinical behaviors.</p> <p>Materials and methods</p> <p>In 144 healthy donors and 55 MRCC treated with subcutaneous IL-2-based regimens, we analysed a panel of basal cytokines particularly involved in the neoplastic progression (IL-1beta, IL-6, IL-8, IL-10, IL-12, alpha-TNF) and C-reactive protein (CRP) in order to compare their levels in the two groups, and to verify their impact on patient response and survival.</p> <p>We first compared cytokines levels in patients population and healthy donors. Than, in definite patients group, univariate and multivariate analyses were performed to evaluate the correlation existing between each factor considered and clinical outcomes. For these analyses, baseline values were included as dichotomous variables using the median values (above and below) of control group.</p> <p>Results</p> <p>In general, higher levels of cytokines were found in patients with respect to those of healthy donors, both in term of percentage of undetectable levels or median values. The impact on response was insignificant, except for higher levels of CRP that were strongly correlated with a worse response (p < 0.001). Within the patients groups, a worse survival was associated with higher values of CRP (8 vs 31 months, p = 0.0000), IL-6 (9 vs 25 months, p = 0.0295), and IL-8 (9 vs 17 months, p = 0.0371). Conversely, higher levels of IL-12 were associated with a better survival (25 vs 15 months, months p = 0.0882). A correlation was found between CRP and IL-6 (p = 0.009) and between CRP and IL-10 (p = 0.038). After multivariate analysis only CRP (p = 0.0035) and IL-12 (p = 0.0371) maintained an independent impact on survival, while IL-6 showed a borderline value (p = 0.0792).</p> <p>Conclusion</p> <p>Higher cytokines levels characterize patients population with respect to healthy donors. Moreover, higher basal level of some immunosuppressive cytokines (CRP, IL-6, IL-8) result correlated with a poorer survival, whereas higher levels of IL-12, a cytokine with a potent antineoplastic activity, was associated with a better survival. A wider sample of patients is needed to better clarify if our findings are intrinsically related to patients population or if they are simply an epiphenomenon of disease progression.</p

A Multicenter Clinical Evaluation of Data Logging in Cochlear Implant Recipients Using Automated Scene Classification Technologies

Currently, there are no studies assessing everyday use of cochlear implant (CI) processors by recipients by means of objective tools. The Nucleus 6 sound processor features a data logging system capable of real-time recording of CI use in different acoustic environments and under various categories of loudness levels. In this study, we report data logged for the different scenes and different loudness levels of 1,366 CI patients, as recorded by SCAN. Monitoring device use in cochlear implant recipients of all ages provides important information about the listening conditions encountered in recipients' daily lives that may support counseling and assist in the further management of their device settings. The findings for this large cohort of active CI users confirm differences between age groups concerning device use and exposure to various noise environments, especially between the youngest and oldest age groups, while similar levels of loudness were observed

Detection of Central Visual Field Defects in Early Glaucomatous Eyes: comparison of Humphrey and Octopus perimetry

Purpose: To compare the detection rate of central visual field defect (CVFD) between the 30-degree Octopus G1 program (Dynamic strategy) and the HFA 10–2 SITA-Standard test in early glaucoma eyes not showing any CVFD on the HFA 24–2 SITA-Standard test. Methods: One eye of 41 early glaucoma patients without CVFD in the central 10 on HFA 24–2 test was tested with both the HFA 10–2 test and the Octopus G1 program 15 minutes apart, in random order. The primary outcome measure was the comparison of CVFD detection rates. Secondary outcome measures comprised the agreement in detecting CVFD, and the comparison of test durations and the numbers of depressed test points outside the central 10-degree area between the HFA 24–2 test and the Octopus G1 program. Results: The mean age of the population was 65.2±10.1 years, and the mean deviation with HFA 24–2 was -3.26±2.6 dB. The mean test duration was not significantly different between the tests (p = 0.13). A CVFD was present in 33 (80.4%) HFA 10–2 test and in 23 (56.0%) Octopus G1 tests (p = 0.002). The overall agreement between the HFA 10–2 and Octopus G1 examinations in classifying eyes as having or not having CVFD was moderate (Cohen’s kappa 0.47). The Octopus G1 program showed 69.6% sensitivity and 100% specificity to detect CVFD in eyes where the HFA 10–2 test revealed a CVFD. The number of depressed test points (p<5%) outside the central 10 area detected with the Octopus G1 program (19.68±10.6) was significantly higher than that detected with the HFA 24–2 program (11.95±5.5, p<0.001). Conclusion: Both HFA 10–2 and Octopus G1programs showed CVFD not present at HFA 24–2 test although the agreement was moderate. The use of a single Octopus G1 examination may represent a practical compromise for the assessment of both central and peripheral visual field up to 30 eccentricity without any additional testing and increasing the total investigation time

Why Amphibians Are More Sensitive than Mammals to Xenobiotics

Dramatic declines in amphibian populations have been described all over the world since the 1980s. The evidence that the sensitivity to environmental threats is greater in amphibians than in mammals has been generally linked to the observation that amphibians are characterized by a rather permeable skin. Nevertheless, a numerical comparison of data of percutaneous (through the skin) passage between amphibians and mammals is lacking. Therefore, in this investigation we have measured the percutaneous passage of two test molecules (mannitol and antipyrine) and three heavily used herbicides (atrazine, paraquat and glyphosate) in the skin of the frog Rana esculenta (amphibians) and of the pig ear (mammals), by using the same experimental protocol and a simple apparatus which minimizes the edge effect, occurring when the tissue is clamped in the usually used experimental device

Model for in vivo progression of tumors based on co-evolving cell population and vasculature

With countless biological details emerging from cancer experiments, there is a growing need for minimal mathematical models which simultaneously advance our understanding of single tumors and metastasis, provide patient-personalized predictions, whilst avoiding excessive hard-to-measure input parameters which complicate simulation, analysis and interpretation. Here we present a model built around a co-evolving resource network and cell population, yielding good agreement with primary tumors in a murine mammary cell line EMT6-HER2 model in BALB/c mice and with clinical metastasis data. Seeding data about the tumor and its vasculature from in vivo images, our model predicts corridors of future tumor growth behavior and intervention response. A scaling relation enables the estimation of a tumor's most likely evolution and pinpoints specific target sites to control growth. Our findings suggest that the clinically separate phenomena of individual tumor growth and metastasis can be viewed as mathematical copies of each other differentiated only by network structure

Twenty-four-hour intraocular pressure and ocular perfusion pressure characteristics in newly diagnosed patients with normal tension glaucoma

PurposeTo determine the mean 24-h intraocular pressure (IOP) and mean ocular perfusion pressure (MOPP) characteristics of newly diagnosed, previously untreated, Caucasian, normal tension glaucoma (NTG) patients and to identify relationships between these features and visual field (VF) loss at diagnosis.MethodsConsecutive newly diagnosed NTG patients underwent 24-h habitual IOP and blood pressure (BP) monitoring. Parameters from pooled measurements obtained in the sitting (0800-2200 hours) and supine (1200-0600 hours) positions were compared and associations were sought with VF mean deviation (MD) and pattern standard deviation (PSD).ResultsSixty-two Caucasian NTG patients (24 men and 38 women) successfully completed circadian IOP and BP monitoring. In habitual position, 8 subjects (12.9%) exhibited a diurnal acrophase, 42 subjects (67.7%) demonstrated a nocturnal acrophase, one subject (1.6%) showed a flat rhythm and 11 patients (17.7%) revealed a biphasic/polyphasic rhythm. Nighttime MOPP values (supine position) were significantly greater than diurnal values (sitting position); (P<0.001). No association could be demonstrated between glaucomatous damage, as indicated by VF parameters, and either mean habitual 24-h IOP (P=0.20 and P=0.12 for MD and PSD, respectively), or habitual 24-h MOPP (P=0.96 and 0.29, for MD and PSD, respectively).ConclusionsIn this cohort of Caucasian NTG patients, most patients exhibited a nocturnal IOP acrophase when evaluated in a habitual position. No association was found between 24-h IOP or MOPP and VF damage.Eye advance online publication, 29 July 2016; doi:10.1038/eye.2016.168

Evolutionary History of Tissue Kallikreins

The gene family of human kallikrein-related peptidases (KLKs) encodes proteins with diverse and pleiotropic functions in normal physiology as well as in disease states. Currently, the most widely known KLK is KLK3 or prostate-specific antigen (PSA) that has applications in clinical diagnosis and monitoring of prostate cancer. The KLK gene family encompasses the largest contiguous cluster of serine proteases in humans which is not interrupted by non-KLK genes. This exceptional and unique characteristic of KLKs makes them ideal for evolutionary studies aiming to infer the direction and timing of gene duplication events. Previous studies on the evolution of KLKs were restricted to mammals and the emergence of KLKs was suggested about 150 million years ago (mya). In order to elucidate the evolutionary history of KLKs, we performed comprehensive phylogenetic analyses of KLK homologous proteins in multiple genomes including those that have been completed recently. Interestingly, we were able to identify novel reptilian, avian and amphibian KLK members which allowed us to trace the emergence of KLKs 330 mya. We suggest that a series of duplication and mutation events gave rise to the KLK gene family. The prominent feature of the KLK family is that it consists of tandemly and uninterruptedly arrayed genes in all species under investigation. The chromosomal co-localization in a single cluster distinguishes KLKs from trypsin and other trypsin-like proteases which are spread in different genetic loci. All the defining features of the KLKs were further found to be conserved in the novel KLK protein sequences. The study of this unique family will further assist in selecting new model organisms for functional studies of proteolytic pathways involving KLKs

HIV interactions with monocytes and dendritic cells: viral latency and reservoirs

HIV is a devastating human pathogen that causes serious immunological diseases in humans around the world. The virus is able to remain latent in an infected host for many years, allowing for the long-term survival of the virus and inevitably prolonging the infection process. The location and mechanisms of HIV latency are under investigation and remain important topics in the study of viral pathogenesis. Given that HIV is a blood-borne pathogen, a number of cell types have been proposed to be the sites of latency, including resting memory CD4+ T cells, peripheral blood monocytes, dendritic cells and macrophages in the lymph nodes, and haematopoietic stem cells in the bone marrow. This review updates the latest advances in the study of HIV interactions with monocytes and dendritic cells, and highlights the potential role of these cells as viral reservoirs and the effects of the HIV-host-cell interactions on viral pathogenesis