Promising developments in targeted therapies for non-small-cell lung cancer

Despite advances in chemotherapy, radiation therapy, and surgery, the overall survival for patients with lung cancer remains poor. Thus, novel therapeutic approaches are warranted. As knowledge of the molecular abnormalities and dysregulated cellular processes contributing to the pathogenesis and progression of lung cancer has been acquired, intense interest has been directed at developing agents that target these abnormalities. New agents targeting aberrant receptor tyrosine kinases, the Ras oncoprotein, mediators of metastases and angiogenesis, and the tumor suppressor gene p53 have, among other agents, shown promise in preclinical studies. Early clinical trials with these agents in patients with advanced malignancies suggest preliminary evidence of clinical activity and possible applications in non-small-cell lung cancer (NSCLC). Ongoing clinical trials will help clarify the settings in which these agents are of greatest therapeutic value, the optimal schedule of administration, toxicities associated with chronic administration, and hopefully, provide additional insight into the biology of lung cancer. Selected clinical trials will be presented to highlight the use of rationally designed, targeted therapies for patients with NSCLC.     

Isolation and characterization of species-specific microsatellite loci in African penguin (Spheniscus demersus)

Eight microsatellite markers were developed via pyrosequencing of a microsatellite-enriched library for the African Penguin (Spheniscus demersus). These microsatellite loci displayed 2–6 alleles with expected heterozygosity values ranging between 0.316 and 0.782 and observed heterozygosity between 0.381 and 0.84. These loci may be suitable for assessing patterns of genetic variability in African penguin. This is the first development of species-specific markers for the African penguin.     

Virtual reality for the enhancement of emotion regulation

In recent decades, a growing body of literature has focused on emotion regulation (ER), which refers to the ability to implement strategies in order to modulate emotional responses and reach desirable goals. To date, impaired ER (i.e., emotion dysregulation) has been identified as a transdiagnostic factor across a wide range of psychopathological conditions, which shows the importance of improving patients' ability to regulate negative and positive emotions in clinical practice. In addition to the increasing evidence showing its efficacy in the treatment of several clinical conditions, virtual reality (VR) has recently emerged as a potentially powerful tool for enhancing ER, thus breaking new ground in the development of cutting-edge transdiagnostic interventions. In the present narrative review, we will provide an overview of the existing evidence about VR-based interventions in the field of ER, emphasizing the promising findings and the barriers that still have to be addressed. To this aim, the available VR-based literature will be analysed in relation to four categories of ER strategies: situational strategies, attentional strategies, cognitive strategies, and response modulation strategies. Furthermore, new emerging fields of research targeting innovative aspects of ER will be highlighted, including the use of VR to promote positive emotions and interpersonal ER skills. Besides, its cost-effectiveness will be discussed, taking into account the costs for both developers (e.g., clinicians and researchers) and end-users. Finally, future directions in this promising field of research will be outlined.     

Discrete-Trial SCP and GSR Training and the Interrelationship Between Central and Peripheral Arousal

Introduction. Slow Cortical Potential (SCP) neurofeedback and Galvanic Skin Response (GSR) biofeedback training were used to investigate self-regulatory control over central and peripheral arousal processes in two groups of healthy participants.

Method. One group completed the SCP neurofeedback training procedure; the other group performed the GSR biofeedback procedure. Both groups underwent treatment while the other variable was passively recorded. The participants were instructed to either increase (Up trials) or decrease (Down trials) arousal. Twenty sessions were completed by each of the 18 participants over an 8-week period.

Results. Participants in each group performed better on the variable they were trained on. In the GSR group, a significant increase in performance over blocks was obtained for both trial types (Up and Down). In the SCP group a better performance on the Down trials was obtained. When comparing performance of both trial types, the SCP-trained participants showed a marginal increase and the GSR-trained participants a significant increase over time preliminary-training.

Conclusion. Overall, the results showed that GSR regulation is easier to learn than SCP training with neurofeedback, that both variables can be trained in a bidirectional design, and that the SCP training subjects were predominantly able to learn performance at the Down trials. Preliminary results from the cross-correlations are inconsistent over trial types, trained parameters, and participants. However, the general trend shows a more positive correlation at the end of training compared to the start of training. Cross-correlation analysis suggests that this training encourages positive correlation between the SCP and GSR. Future research directions should be aimed at improving motivational conditions, implementing contingent reward principles, and controlling confounding variables.     

Renalase Prevents AKI Independent of Amine Oxidase Activity

AKI is characterized by increased catecholamine levels and hypertension. Renalase, a secretory flavoprotein that oxidizes catecholamines, attenuates ischemic injury and the associated increase in catecholamine levels in mice. However, whether the amine oxidase activity of renalase is involved in preventing ischemic injury is debated. In this study, recombinant renalase protected human proximal tubular (HK-2) cells against cisplatin- and hydrogen peroxide–induced necrosis. Similarly, genetic depletion of renalase in mice (renalase knockout) exacerbated kidney injury in animals subjected to cisplatin-induced AKI. Interestingly, compared with the intact renalase protein, a 20–amino acid peptide (RP-220), which is conserved in all known renalase isoforms, but lacks detectable oxidase activity, was equally effective at protecting HK-2 cells against toxic injury and preventing ischemic injury in wild-type mice. Furthermore, in vitro treatment with RP-220 or recombinant renalase rapidly activated Akt, extracellular signal-regulated kinase, and p38 mitogen-activated protein kinases and downregulated c-Jun N-terminal kinase. In summary, renalase promotes cell survival and protects against renal injury in mice through the activation of intracellular signaling cascades, independent of its ability to metabolize catecholamines, and we have identified the region of renalase required for these effects. Renalase and related peptides show potential as therapeutic agents for the prevention and treatment of AKI.AKI is a common clinical condition affecting up to 20% of hospitalized patients and is frequently associated with sepsis, surgery, and certain drugs. Epidemiologic data indicate a positive association between the severity of AKI and in-hospital and long-term mortality.^1,2 Unfortunately, the development of effective therapy for AKI has been hampered by (1) an inherent delay in diagnosis, a consequence of relying on serum creatinine, which only increases 48–72 hours after the original insult, and (2) the paucity of validated targets of therapy. There is an urgent need to identify novel therapeutic modalities.Renalase is a novel secretory flavoprotein with amine oxidase activity.^3–5 In vitro, renalase metabolizes epinephrine, norepinephrine, and dopamine and also possesses significant intrinsic nicotinamide adenine dinucleotide (NADH) oxidase activity.^6,7 Other investigators have questioned the amine oxidase activity of renalase.^8,9 We had proposed that, in contrast to the classic amine oxidases, renalase reacts with oxygen to generate superoxide anions and hydrogen peroxide, with subsequent oxidation of catecholamines to their respective aminochromes. Recent results indicate that renalase functions as an oxidase/anomerase, using molecular oxygen to convert α-NAD(P)H to β-NAD⁺, with hydrogen peroxide as reaction byproduct.¹⁰ Because it was also shown to bind epinephrine, the authors pointed out that the hydrogen peroxide (H₂O₂) generated from the anomerase reaction will drive the oxidation of epinephrine to adrenochrome, albeit at a slower rate. Single-nucleotide polymorphisms present in the gene are associated with hypertension, cardiac disease, and diabetes.^6,11–14 The administration of renalase in wild-type (WT) mice lowers plasma catecholamines and systemic BP. In contrast, the deficiency of renalase in renalase knockout (KO) mice raises catecholamine levels and BP.¹⁵ Renalase also modulates the severity of renal ischemia and reperfusion injury.¹⁶ In WT mice, the administration of recombinant human renalase before induction of renal ischemia significantly blunts the severity of renal injury, with less renal tubular necrosis, inflammation, and apoptosis. In contrast, the lack of renalase in renalase KO mice exacerbates the renal damage after similar ischemic injury.AKI is characterized by an elevation in plasma catecholamine levels. It has been postulated that, in addition to causing hypertension, excess catecholamines in AKI may produce an inflammatory response, aggravating tissue damage and contributing to multiorgan dysfunction.¹⁷ Interestingly, renalase levels in the blood and kidneys of WT mice are reduced following acute renal ischemia. Because the renalase in blood is secreted from the kidneys and is thought to metabolize circulating catecholamines, the excess catecholamines in AKI may be a direct consequence of the concurrent renalase deficiency. Notably, the administration of renalase to WT mice before induction of ischemia, which greatly attenuates ischemic renal injury, dampens the rise in blood catecholamine levels. On the basis of these findings, it is inviting to speculate that the renal protective effect in ischemic injury of renalase and its hemodynamic effect stem from its amine oxidase activity.The role of amine oxidase activity of renalase in mediating its hemodynamic effect has been questioned. First, measurement of the amine oxidase activity of renalase relies on the production of H₂O₂ as an indirect measure of oxidase activity. Because the measured rate of H₂O₂ synthesis is low, the putative oxidase activity of renalase has been deemed unlikely to have physiologic significance.⁹ Second, the recombinant renalase synthesized in Escherichia coli with a histidine-tag possesses no detectable oxidase activity, and yet it markedly lowers BP when injected into rats.^8,18In this study, we sought to clarify the role of amine oxidase activity in the renal protective effects of renalase and to explore an additional mechanism of action of renalase that is independent of its oxidase activity.     

Full-Thickness Closure in Breast-Conserving Surgery: The Impact on Radiotherapy Target Definition for Boost and Partial Breast Irradiation. A Multimodality Image Evaluation

Background

During breast-conserving surgery (BCS), surgeons increasingly perform full-thickness closure (FTC) to prevent seroma formation. This could potentially impair precision of target definition for boost and accelerated partial breast irradiation (APBI). The purpose of this study was to investigate the precision of target volume definition following BCS with FTC among radiation oncologists, using various imaging modalities.

Methods

Twenty clinical T1–2N0 patients, scheduled for BCS involving clip placement and FTC, were included in the study. Seven experienced breast radiation oncologists contoured the tumor bed on computed tomography (CT), magnetic resonance imaging (MRI) and fused CT–MRI datasets. A total of 361 observer pairs per image modality were analyzed. A pairwise conformity among the generated contours of the observers and the distance between their centers of mass (dCOM) were calculated.

Results

On CT, median conformity was 44 % [interquartile range (IQR) 28–58 %] and median dCOM was 6 mm (IQR 3–9 mm). None of the outcome measures improved when MRI or fused CT–MRI were used. In two patients, superficial closure was performed instead of FTC. In these 14 image sets and 42 observer pairs, median conformity increased to 70 %.

Conclusions

Localization of the radiotherapy target after FTC is imprecise, on both CT and MRI. This could potentially lead to a geographical miss in patients at increased risk of local recurrence receiving a radiation boost, or for those receiving APBI. These findings highlight the importance for breast surgeons to clearly demarcate the tumor bed when performing FTC.     

A novel nano-structured porous polycaprolactone scaffold improves hyaline cartilage repair in a rabbit model compared to a collagen type I/III scaffold: in vitro and in vivo studies

Purpose

To develop a nano-structured porous polycaprolactone (NSP-PCL) scaffold and compare the articular cartilage repair potential with that of a commercially available collagen type I/III (Chondro-Gide^®) scaffold.

Methods

By combining rapid prototyping and thermally induced phase separation, the NSP-PCL scaffold was produced for matrix-assisted autologous chondrocyte implantation. Lyophilizing a water–dioxane–PCL solution created micro and nano-pores. In vitro: The scaffolds were seeded with rabbit chondrocytes and cultured in hypoxia for 6 days. qRT–PCR was performed using primers for sox9, aggrecan, collagen type 1 and 2. In vivo: 15 New Zealand White Rabbits received bilateral osteochondral defects in the femoral intercondylar grooves. Autologous chondrocytes were harvested 4 weeks prior to surgery. There were 3 treatment groups: (1) NSP-PCL scaffold without cells. (2) The Chondro-Gide^® scaffold with autologous chondrocytes and (3) NSP-PCL scaffold with autologous chondrocytes. Observation period was 13 weeks. Histological evaluation was made using the O’Driscoll score.

Results

In vitro: The expressions of sox9 and aggrecan were higher in the NSP-PCL scaffold, while expression of collagen 1 was lower compared to the Chondro-Gide^® scaffold. In vivo: Both NSP-PCL scaffolds with and without cells scored significantly higher than the Chondro-Gide^® scaffold when looking at the structural integrity and the surface regularity of the repair tissue. No differences were found between the NSP-PCL scaffold with and without cells.

Conclusion

The NSP-PCL scaffold demonstrated higher in vitro expression of chondrogenic markers and had higher in vivo histological scores compared to the Chondro-Gide^® scaffold. The improved chondrocytic differentiation can potentially produce more hyaline cartilage during clinical cartilage repair. It appears to be a suitable cell-free implant for hyaline cartilage repair and could provide a less costly and more effective treatment option than the Chondro-Gide^® scaffold with cells.     

Molecular physiology of renal potassium channels.

The application of patch-clamp technique to the study of ion channels showed the enormous diversity of K channels. In the kidney, K channels play an major role in transepithelial K transport, in the regulation of vascular tone, and in cellular proliferation. In the last 5 years, the use of powerful genetic and molecular biological techniques has provided an understanding of the molecular structure of some types of K channels. Although much work remains to be done in this area, the greater challenge will be to integrate the molecular information with the extensive physiological data already available. Finally, the rapidly accumulating knowledge of K channel structure, and the recent appreciation of their possible role in important disease states, such as hypertension, make the study of K channels very exciting.     

Effects of exercise in breast cancer patients: implications of the trials within cohorts (TwiCs) design in the UMBRELLA Fit trial

Breast Cancer Research and Treatment - The Trials within Cohorts (TwiCs) design aims to overcome problems faced in conventional RCTs. We evaluated the TwiCs design when estimating the effect of...