Prognostic factors and selection for clinical studies of patients with kidney cancer

Over the past 2 decades, a greater understanding of the basic biology and genetics of kidney cancer has occurred. Surgical techniques have also evolved, and technological advances have made possible new methods of managing renal tumors. The most extensively used system to provide prognostic information for renal cell carcinoma (RCC) is currently the tumor, nodes, metastasis (TNM) staging system. Emerging data over the last few years has questioned whether further revisions are needed and if improvements can be made with the introduction of new, more accurate and predictive prognostic factors. The recent discovery of molecular tumor biomarkers are expected to revolutionize the staging of RCC and potentially lead to the development of new therapies based on molecular targeting. This review will examine the current staging modalities and prognostic factors associated with RCC as well as the selection of patients most likely to benefit from clinical trials.     

Concentrations of lysosomal cysteine proteases are decreased in renal cell carcinoma compared with normal kidney

Renal cell carcinoma contains significantly lower concentrations of the lysosomal cysteine proteases, cathepsins B, C, H, L and S, than does normal kidney, as shown by several methods, such as activity determination, enzyme-linked immunosorbent assay, immunoblotting and immunohistochemistry. The same low levels of enzyme activity and concentration have been determined in renal cell carcinoma metastases in the lung. Our results on the decreased concentration of cysteine peptidases at the protein level would seem to conflict with earlier results on an increased concentration of the cathepsin L mRNA in renal cell carcinoma.Abbreviations ELISA enzyme-linked immunosorbent assay - FCS fetal calf serum - NHMec 7-(4-methyl)coumarylamide - NHNap 2-naphthylamide - Z benzyloxycarbonyl     

Renal insufficiency and long-term mortality and incidence of myocardial infarction in patients undergoing coronary artery bypass grafting.

AIMS: To evaluate the impact of renal insufficiency (RI) on long-term mortality and incident myocardial infarction (MI) in patients undergoing coronary artery bypass grafting (CABG). METHODS AND RESULTS: All patients (n = 6575) without dialysis-dependent RI undergoing a first isolated CABG during 1980-1995 at the Karolinska hospital who survived 30 days post-operatively were included. Estimated glomerular filtration rate (eGFR) was related to the incidence of MI and all-cause mortality within 5 years. There were 628 deaths and 496 incident MIs during follow-up. After multivariable adjustment, patients with mild (eGFR 60-90 mL/min), moderate (eGFR 30-60 mL/min), and severe (eGFR <30 mL/min) RI had an increased mortality within 5 years post-CABG; hazard ratio (HR) 1.2 [95% confidence interval (CI) 1.0-1.6], HR 1.8 (95% CI 1.3-2.4), and HR 5.2 (95% CI 3.1-8.6), respectively, compared with patients with normal renal function (eGFR >90 mL/min). In patients with moderate and severe RI, there was an increased incidence of MI; HR 1.5 (95% CI 1.1-2.1) and HR 3.5 (95% CI 1.8-6.8), respectively. There were no gender differences. CONCLUSION: Already mild RI predicts late all-cause mortality after coronary artery bypass grafting (CABG), and moderate and severe RI is associated with an increased long-term incidence of MI post-CABG.     

Contact force and impedance decrease during ablation depends on catheter location and orientation: insights from pulmonary vein isolation using a contact force-sensing catheter

Journal of Interventional Cardiac Electrophysiology - Contact force (CF) sensing during radiofrequency (RF) ablation allows controlling lesion size. The aim of this study was to analyze the impact...     

Tyrphostin AG126 exerts neuroprotection in CNS inflammation by a dual mechanism

The putative protein tyrosine kinase (PTK) inhibitor tyrphostin AG126 has proven beneficial in various models of inflammatory disease. Yet molecular targets and cellular mechanisms remained enigmatic. We demonstrate here that AG126 treatment has beneficial effects in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. AG126 alleviates the clinical symptoms, diminishes encephalitogenic Th17 differentiation, reduces inflammatory CNS infiltration as well as microglia activation and attenuates myelin damage. We show that AG126 directly inhibits Bruton's tyrosine kinase (BTK), a PTK associated with B cell receptor and Toll‐like receptor (TLR) signaling. However, BTK inhibition cannot account for the entire activity spectrum. Effects on TLR‐induced proinflammatory cytokine expression in microglia involve AG126 hydrolysis and conversion of its dinitrile side chain to malononitrile (MN). Notably, while liberated MN can subsequently mediate critical AG126 features, full protection in EAE still requires delivery of intact AG126. Its anti‐inflammatory potential and especially interference with TLR signaling thus rely on a dual mechanism encompassing BTK and a novel MN‐sensitive target. Both principles bear great potential for the therapeutic management of disturbed innate and adaptive immune functions. GLIA 2015;63:1083–1099     

Transcranial direct current stimulation of the posterior parietal cortex modulates arithmetic learning

The successful acquisition of arithmetic skills is an essential step in the development of mathematical competencies and has been associated with neural activity in the left posterior parietal cortex (PPC). It is unclear, however, whether this brain region plays a causal role in arithmetic skill acquisition and whether arithmetic learning can be modulated by means of non‐invasive brain stimulation of this key region. In the present study we addressed these questions by applying transcranial direct current stimulation (tDCS) over the left PPC during a short‐term training that simulates the typical path of arithmetic skill acquisition (specifically the transition from effortful procedural to memory‐based problem‐solving strategies). Sixty participants received either anodal, cathodal or sham tDCS while practising complex multiplication and subtraction problems. The stability of the stimulation‐induced learning effects was assessed in a follow‐up test 24 h after the training. Learning progress was modulated by tDCS. Cathodal tDCS (compared with sham) decreased learning rates during training and resulted in poorer performance which lasted over 24 h after stimulation. Anodal tDCS showed an operation‐specific improvement for subtraction learning. Our findings extend previous studies by demonstrating that the left PPC is causally involved in arithmetic learning (and not only in arithmetic performance) and that even a short‐term tDCS application can modulate the success of arithmetic knowledge acquisition. Moreover, our finding of operation‐specific anodal stimulation effects suggests that the enhancing effects of tDCS on learning can selectively affect just one of several cognitive processes mediated by the stimulated area.