The complex TIE between macrophages and angiogenesis

Macrophages are primarily known as phagocytic immune cells, but they also play a role in diverse processes, such as morphogenesis, homeostasis and regeneration. In this review, we discuss the influence of macrophages on angiogenesis, the process of new blood vessel formation from the pre-existing vasculature. Macrophages play crucial roles at each step of the angiogenic cascade, starting from new blood vessel sprouting to the remodelling of the vascular plexus and vessel maturation. Macrophages form promising targets for both pro- and anti-angiogenic treatments. However, to target macrophages, we will first need to understand the mechanisms that control the functional plasticity of macrophages during each of the steps of the angiogenic cascade. Here, we review recent insights in this topic. Special attention will be given to the TIE2-expressing macrophage (TEM), which is a subtype of highly angiogenic macrophages that is able to influence angiogenesis via the angiopoietin-TIE pathway

Predictive Nomogram for Recurrence following Surgery for Nonmetastatic Renal Cell Cancer with Tumor Thrombus

Purpose Following surgery for nonmetastatic renal cell carcinoma with tumor thrombus the risk of recurrence is significant but variable among patients. The purpose of this study was to develop and validate a predictive nomogram for individual estimation of recurrence risk following surgery for renal cell carcinoma with venous tumor thrombus. Materials and Methods Comprehensive data were collected on patients with nonmetastatic renal cell carcinoma and thrombus treated at a total of 5 institutions from 2000 to 2013. Independent predictors of recurrent renal cell carcinoma from a competing risks analysis were developed into a nomogram. Predictive accuracy was compared between the development and validation cohorts, and between the nomogram and the UISS (UCLA Integrated Staging System, SSIGN (Stage, Size, Grade and Necrosis) and Sorbellini models. Results A total of 636 patients were analyzed, including the development cohort of 465 and the validation cohort of 171. Independent predictors, including tumor diameter, body mass index, preoperative hemoglobin less than the lower limit of normal, thrombus level, perinephric fat invasion and nonclear cell histology, were developed into a nomogram. Estimated 5-year recurrence-free survival was 49% overall. Five-year recurrence-free survival in patients with 0, 1, 2 and more than 2 risk factors was 77%, 53%, 47% and 20%, respectively. Predictive accuracy was similar in the development and validation cohorts (AUC 0.726 and 0.724, respectively). Predictive accuracy of the thrombus nomogram was higher than that of the UISS (AUC 0.726 vs 0.595, p = 0.001), SSIGN (AUC 0.713 vs 0.612, p = 0.04) and Sorbellini models (AUC 0.709 vs 0.638, p = 0.02). Conclusions We present a predictive nomogram for postoperative recurrence in patients with nonmetastatic renal cell carcinoma with venous thrombus. Improving individual postoperative risk assessment may allow for better design and analysis of future adjuvant clinical trials

RTOG/NRG 1115 Quality of Life of Phase III Dose Escalated Radiation Therapy (RT) and Standard Androgen Deprivation Therapy (ADT) with GnRH Agonist vs. Dose Escalated RT and ADT with GnRH Agonist and Orteronel (TAK-700) for Men with High-Risk Prostate

Purpose/Objective(s): Quality of life (QOL) was assessed with the hypothesis that QOL and fatigue scores would not differ significantly between the ADT + RT (Arm A) and the experimental group receiving ADT + RT + oreteronel (Arm B). Materials/Methods: In both arms, ADT with GnRH agonist was given for 24 mos, and dose escalated RT started 8-10 wks after initiation of ADT. In Arm B, oreteronel was given BID for 24 mos. QOL was measured with Expanded Prostate Cancer Index Composite (EPIC) and EQ-5D global QOL assessment. EPIC has 4 domains: bowel, urinary, sexual, and hormonal. EQ-5D index score was calculated using health states obtained from 5 dimensions, and a visual analog score (VAS). For EPIC, EQ-5D index and VAS, higher scores indicate better QOL. Fatigue was measured by the 7-item Patient-Reported Outcome Measurement Information System (PROMIS) short form. Total score is standardized into a T-score with mean of 50 and standard deviation of 10 with higher score representing more fatigue. Change scores, calculated as follow-up minus baseline, were compared between arms. Longitudinal analysis using repeated measures mixed effects models was conducted (prior to ADT [baseline], one wk prior to starting RT, last wk of RT, and 1 and 2.5 yrs after initiation of therapy). Results: Of 231 eligible patients, 196 consented to QOL, 102 on Arm A and 94 on Arm B. Compliance prior to start of RT and end of RT was 83%. At 1 and 2.5 yrs, 80% and 62% of pts, respectively, completed the EPIC. There were no differences between any EPIC domain between arms from the start of RT through the end of follow-up. Men on oreteronel had a significantly greater decline in bowel score prior to starting RT then control patients (-6.12, 95% confidence interval [CI]: -9.24, -3.01 vs. -1.93, 95% CI: -4.48, 0.63, respectively, p=0.038). Arm B patients also had a statistically significant and clinically meaningful worse change in urinary score vs control from baseline to pre-RT (-2.33, 95% CI: -5.02, 0.36 vs. 1.38, 95% CI: -1.07, 3.83, respectively, p=0.043). No other timepoints were significant. The only sig. between arm difference in EPIC sexual and hormonal scores was also at pre-RT in favor of Arm A over Arm B; p=0.024 and p=0.0024 respectively). Fatigue was also greater in the oreteronel patients prior to starting RT (3.81, 95% CI: 1.88, 5.74 vs. 1.18, 95% CI: -0.23, 2.60, p=0.028). Conclusion: The addition of oreteronel to RT and ADT resulted in greater declines in QOL prior to the start of RT but did not result in significant differences at any other time points. Although oreteronel development has been halted, the QOL results are encouraging for other drugs in this class that remain under investigation. In ongoing prospective trials, QOL impacts should be measured in conjunction with changes in clinical outcome and survival. This project was supported by grants UG1CA189867, U10CA180868, U10CA180822 from the National Cancer Institute and Takeda Pharmaceutical

Towards nanomedicines of the future: Remote magneto-mechanical actuation of nanomedicines by alternating magnetic fields

The paper describes the concept of magneto-mechanical actuation of single-domain magnetic nanoparticles (MNPs) in super-low and low frequency alternating magnetic fields (AMFs) and its possible use for remote control of nanomedicines and drug delivery systems. The applications of this approach for remote actuation of drug release as well as effects on biomacromolecules, biomembranes, subcellular structures and cells are discussed in comparison to conventional strategies employing magnetic hyperthermia in a radio frequency (RF) AMF. Several quantitative models describing interaction of functionalized MNPs with single macromolecules, lipid membranes, and proteins (e.g. cell membrane receptors, ion channels) are presented. The optimal characteristics of the MNPs and an AMF for effective magneto-mechanical actuation of single molecule responses in biological and bio-inspired systems are discussed. Altogether, the described studies and phenomena offer opportunities for the development of novel therapeutics both alone and in combination with magnetic hyperthermia

The immortalized UROtsa cell line as a potential cell culture model of human urothelium.

The UROtsa cell line was isolated from a primary culture of normal human urothelium through immortalization with a construct containing the SV40 large T antigen. It proliferates in serum-containing growth medium as a cell monolayer with little evidence of uroepithelial differentiation. The working hypothesis in the present study was that this cell line could be induced to differentiate and express known features of in situ urothelium if the original serum-containing growth medium was changed to a serum-free formulation. We demonstrated that the UROtsa cells could be successfully placed into a serum-free growth medium consisting of a 1:1 mixture of Dulbeco\u27s modified Eagle\u27s medium and Ham\u27s F-12 supplemented with selenium (5 ng/mL), insulin (5 microg/mL), transferrin (5 microg/mL), hydrocortisone (36 ng/mL), triiodothyronine (4 pg/mL), and epidermal growth factor (10 ng/mL). Under serum-free growth conditions, confluent UROtsa cells were shown by light microscopy to produce raised, three-dimensional structures. Routine ultrastructural examination disclosed these three-dimensional areas to consist of a stratified layer of cells that strongly resembled in situ urothelium. The cells displayed numerous desmosomal connections, complex interactions of the lateral membranes, and abundant intermediate filaments within the cytoplasm. Freeze fracture analysis demonstrated that the cells possessed tight-junction sealing strands and gap junctions. The overall morphology was most consistent with that found in the intermediate layers of in situ urothelium. The basal expression patterns of the metallothionein (MT) and heat shock proteins 27, 60, and 70 were determined in these cells, and expression was in agreement with that known to occur for in situ urothelium. The cells were also successfully tested for their ability to be stably transfected using expression vectors containing the MT-3 or MT-2A genes. The findings suggest that the UROtsa cells grown with a serum-free medium could be a valuable adjunct for studying environmental insult to the human urothelium in general and for the stress response in particular

Prodrug Strategy for PSMA-targeted Delivery of TGX-221 to Prostate Cancer Cells

TGX-221 is a potent, selective, and cell membrane permeable inhibitor of the PI3K p110β catalytic subunit. Recent studies showed that TGX-221 has anti-proliferative activity against PTEN-deficient tumor cell lines including prostate cancers. The objective of this study was to develop an encapsulation system for parenterally delivering TGX-221 to the target tissue through a prostate-specific membrane aptamer (PSMAa10) with little or no side effects. In this study, PEG-PCL micelles were formulated to encapsulate the drug, and a prodrug strategy was pursued to improve the stability of the carrier system. Fluorescence imaging studies demonstrated that the cellular uptake of both drug and nanoparticles were significantly improved by targeted micelles in a PSMA positive cell line. The area under the plasma concentration time curve of the micelle formulation in nude mice was 2.27-fold greater than the naked drug, and the drug clearance rate was 17.5-fold slower. These findings suggest a novel formulation approach for improving site-specific drug delivery of a molecular-targeted prostate cancer treatment

Driven to excess? Linking calling, character and the (mis)behaviour of marketers

We are presently at a point of unique circumstantial convergence where recession, an increased emphasis on business ethics, and marketer’s reluctance to accept shifting social agendas have combined to identify the need for a new approach to marketing. Using concepts from the human resources, marketing and psychology literatures, and especially Erich Fromm’s ideas concerning economic character, this paper posits that marketers – as a professional community – are driven to promote consumerist outcomes; victims of an automaton amalgam of calling and character. The analysis suggests the vulnerability of both marketer and consumer are mutually reinforcing and that we need, somehow, to break this damaging cycle of dependence. We know little, however, about how marketers think and feel about their discipline, so this paper also promotes an agenda for marketer behaviour research, as a countervailing balance to a currently disproportionate focus on the consumer

Delayed-type hypersensitivity in classic Kaposi sarcoma patients and controls

BACKGROUND: Immune perturbation likely affects the development of Kaposi sarcoma (KS) among people infected with the KS-associated herpesvirus (KSHV). We tested whether KSHV-seropositive individuals or cases of classic KS (cKS), which typically originates in the leg, had differing delayed-type hypersensitivity (DTH) in the forearm or leg. METHODS: Mantoux DTH with three antigens (Candida, tetanus, PPD) was performed on the forearm and leg of 15 cKS cases, 14 KSHV-positives without KS, and 15 KSHV-negative controls. The diameters of induration responses were compared by group and body site. RESULTS: Leg DTH was greater than forearm DTH among controls (mean difference 5.6 mm, P\ubc0.0004), whereas this was not observed in cKS cases ( 2.2 mm, P\ubc0.32) or KSHV-positives (0.5 mm, P\ubc0.56). Leg-minus-forearm DTH difference was greater in controls compared with cKS cases (P\ubc0.004) and KSHV-positives (P\ubc0.002). Leg-plus-forearm DTH was similar in controls (mean 28.2 mm) and cKS cases (24.5 mm, P\ubc0.60), but it was reduced in KSHV-positives (11.8 mm, P\ubc0.02), particularly in the leg (P\ubc0.004) and marginally in the forearm (P\ubc0.07). CONCLUSION: KS cases had weaker DTH only in the leg, whereas both body sites appeared weaker in KSHV-positives without KS. Both systemic and regional immune alterations may influence the development of this malignancy