Targeted therapies for treatment of non-small cell lung cancer--Recent advances and future perspectives.

Non-small cell lung cancer (NSCLC) is one of the most deadly cancers worldwide, with poor prognosis once the disease has progressed past the point at which surgery is a viable option. Whilst chemotherapy has improved survival over recent decades, there is still great need for improvements in treatments for patients with advanced disease. Over the last decade, a variety of such drugs have received market approval for treating NSCLC, with a variety of others in the pipeline. Here, we review the development of targeted therapies for the treatment of advanced or metastatic NSCLC, including those already in clinical practice and those in early trials. The epidermal growth factor receptor (EGFR) inhibitors, gefitinib, erlotinib and afatinib; the anaplastic lymphoma kinase (ALK) inhibitor, crizotinib; and the anti-vascular endothelial growth factor receptor monoclonal antibody, bevacizumab, are already providing improved survival for patients with NSCLC. Moreover, the discovery of EGFR mutations and ALK rearrangements has enabled the identification of patients who are more likely to benefit from a specific drug. The recent approval of the immune checkpoint inhibitor nivolumab, along with the designation of alectinib and MPDL3280A as breakthrough therapies by the FDA, demonstrates how rapidly this area of research is expanding. Over the last decade there has been significant progress made in the treatment of advanced NSCLC, and the large and varied selection of drugs currently undergoing trials provide great promise for improving the prognosis of this highly prevalent and deadly form of cancer.

Integrating top-down and self-assembly in the fabrication of peptide and protein-based biomedical materials.

The capacity to create an increasing variety of bioactive molecules that are designed to assemble in specific configurations has opened up tremendous possibilities in the design of materials with an unprecedented level of control and functionality. A particular challenge involves guiding such self-assembling interactions across scales, thus precisely positioning individual molecules within well-organized, highly-ordered structures. Such hierarchical control is essential if peptides and proteins are to serve as both structural and functional building blocks of biomedical materials. To achieve this goal, top-down techniques are increasingly being used in combination with self-assembling systems to reproducibly manipulate, localize, orient and assemble peptides and proteins to form organized structures. In this tutorial review we provide insight into how both standard and novel top-down techniques are being used in combination with peptide or protein self-assembly to create a new generation of functional materials.

Results of the British Society of Gastroenterology supporting women in gastroenterology mentoring scheme pilot.

INTRODUCTION: Mentorship has long been recognised as beneficial in the business world and has more recently been endorsed by medical and academic professional bodies. Recruitment of women into gastroenterology and leadership roles has traditionally been difficult. The Supporting Women in Gastroenterology network developed this pilot scheme for female gastroenterologists 5 years either side of the Completion Certificate of Specialist Training (CCST) to examine the role that mentorship could play in improving this discrepancy. METHOD: Female gastroenterology trainees and consultant gastroenterologists within 5 years either side of CCST were invited to participate as mentees. Consultant gastroenterologists of both genders were invited to become mentors. 35 pairs of mentor:mentees were matched and completed the scheme over 1 year. Training was provided. RESULTS: The majority of the mentees found the sessions useful (82%) and enjoyable (77%), with the benefit of having time and space to discuss professional or personal challenges with a gastroenterologist who is not a colleague. In the longitudinal study of job satisfaction, work engagement, burnout, resilience, self-efficacy, self-compassion and work-life balance, burnout scale showed a small but non significant improvement over the year (probably an effect of small sample size). Personal accomplishment improved significantly. The main challenges were geography, available time to meet and pair matching. The majority of mentors surveyed found the scheme effective, satisfying, mutually beneficial (70%) and enjoyable (78%). CONCLUSION: Mentorship is shown to be beneficial despite the challenges and is likely to improve the recruitment and retention of women into gastroenterology and leadership roles, but is likely to benefit gastroenterologists of both genders.

Nitroglycerin application and coronary arteriogenesis.

BACKGROUND: In the presence of a coronary occlusion, pre-existing small collateral vessels (arterioles) develop into much larger arteries (biological bypasses) that have the potential to allow a certain level of perfusion distal to the blockage. Termed arteriogenesis, this phenomenon proceeds via a complex combination of events, with nitric oxide (NO) playing an essential role. The aim of this study was to investigate the effects of supplemental administration of NO donors, i.e., short-acting nitroglycerin (NTG) or slow-release pelleted isosorbide dinitrate (ISDN), on collateral development in a repetitive coronary artery occlusion model in rats. METHODS: Coronary collateral growth was induced via a repetitive occlusion protocol (ROP) of the left anterior descending coronary artery (LAD) in rats. The primary endpoints were the histological evaluation of rat heart infarct size and ST-segment elevation (ECG-analysis) upon final permanent occlusion of the LAD (experimentally induced myocardial infarction). The effects of NTG or ISDN were also evaluated by administration during 5 days of ROP. We additionally investigated whether concomitant application of NTG can compensate for the anti-arteriogenic effect of acetylsalicylic acid (ASA). RESULTS: After 5 days of ROP, the mean infarct size and degree of ST-elevation were only slightly lower than those of the SHAM group; however, after 10 days of the protocol, the ROP group displayed significantly less severe infarct damage, indicating enhanced arteriogenesis. Intermittent NTG application greatly decreased the ST-elevation and infarct size. The ISDN also had a positive effect on arteriogenesis, but not to the same extent as the NTG. Administration of ASA increased the infarct severity; however, concomitant dosing with NTG somewhat attenuated this effect. CONCLUSION: Intermittent treatment with the short-acting NTG decreased the size of an experimentally induced myocardial infarct by promoting coronary collateral development. These new insights are of great relevance for future clinical strategies for the treatment of occlusive vascular diseases.

Transapical transcatheter aortic valve implantation in patients with a low ejection fraction.

OBJECTIVES: It may be expected that patients with left ventricular dysfunction may be at greater risk of complications after transcatheter aortic valve implantation (TAVI) via transapical (TA) access compared with via transfemoral (TF) access. There is a lack of data comparing the outcomes of TAVI using TA and TF access in patients with a reduced left ventricular ejection fraction (EF). METHODS: This is a retrospective analysis of data from a high-volume heart centre in Germany. TAVI access route assignment was based on a 'best for TF' approach, where only patients who met a strict set of criteria underwent TF-TAVI, with the remainder receiving TA-TAVI. For this analysis, patients were included if they had a pre-TAVI EF of ≤ 40%. Early mortality and late (1-year) mortality were compared through multivariate logistic regression. RESULTS: A total of 342 patients in the registry had an EF of ≤ 40%, of which 74.9% underwent TA-TAVI and 25.1% underwent TF-TAVI. Higher proportions of the TA group presented with certain comorbidities, and their logistic EuroSCORE and Society of Thoracic Surgeons (STS) risk scores were higher than in the TF group. At 1 year, TA access was associated with greater mortality in the univariate analysis (odd ratio 2.43; 95% confidence interval 1.04-5.69). However, after multivariate adjustment, no significant differences were found in either 30-day or 1-year mortality rates. CONCLUSIONS: The data suggest that, for patients with a reduced EF, TA-TAVI is not associated with a poorer outcome compared with TF-TAVI. Therefore, TA access should not be discounted based on the presence of left ventricular dysfunction alone.

Induction of extracranial arteriogenesis by an arteriovenous fistula in a pig model.

BACKGROUND AND AIMS: Arteriogenesis, the positive outward remodeling and growth of pre-existent collateral vessels, holds potential as a novel treatment for ischemic vascular disease. An extracranial arteriogenesis model in a pig will allow us to study molecular changes in a complex arteriolar network in a more clinically relevant large-animal model. To increase fluid shear stress in the brain, an experimental carotid arteriovenous fistula (AVF model) in minipigs was established, providing high flow through the extracranial rete mirabile. The aim of the study was to examine whether creation of a carotid AVF can induce extracranial arteriogenesis in the pig. METHODS: Angiography was performed to demonstrate blood flow diversion. Animals were sacrificed after 0, 3 and 14 days post-surgery and both retia mirabilia were removed. Immunohistochemical analysis was performed to analyze cell proliferation and accumulation of mononuclear cells in the vessel wall. RESULTS: After 3 days of high-flow conditions, increases in vascular cell proliferation (approximately 1.5-fold; p = 0.143) and monocyte invasion (approximately 6-fold; p = 0.057) were observed when compared to animals sacrificed immediately after AVF formation. Quantitative PCR (RT-qPCR) analysis from rete mirabile tissue samples 3 days post-surgery revealed that monocyte chemoattractant protein (MCP)-1 and tissue inhibitor of metalloproteinases (TIMP)-1 were highly upregulated. Expression of the pro-arteriogenic marker, CD44, reached maximum expression level 14 days post-surgery. CONCLUSIONS: In response to high levels of shear stress produced in the pig AVF model, the onset of the arteriogenic process can be induced. This was demonstrated by enhanced cell proliferation, monocyte invasion and vascular remodeling.

The factor xa inhibitor edoxaban for the prevention of stroke and systemic embolism in patients with atrial fibrillation.

INTRODUCTION: With the rising prevalence of nonvalvular atrial fibrillation (NVAF) in the general population, the development of new drugs for prevention of thromboembolic events is essential. Non-vitamin K antagonist oral anticoagulants (NOACs) have been shown to present a number of advantages over conventionally used agents, such as predictable pharmacokinetics and no requirement for continuous anticoagulant monitoring. The most recently approved NOAC for the NVAF indication is edoxaban. Several subgroup analyses from the edoxaban phase III ENGAGE AF-TIMI 48 trial have now been published, alongside meta-analysis data comparing the four currently approved NOACs. Consequently, an updated review of the literature is merited. Areas covered: A PubMed search using the terms 'edoxaban', 'non-vitamin K antagonist oral anticoagulant', 'ENGAGE AF-TIMI 48', and 'atrial fibrillation' was performed and results screened for the most relevant English language publications. The market position, pharmacological profile, clinical efficacy, safety and tolerability of edoxaban are presented and discussed. Expert commentary: Edoxaban has been shown to have an efficacy similar or superior to that of warfarin, with a potentially lower risk of major bleeding and predictable, dose-dependent pharmacology. In order to clarify its position within the NOAC market, head-to-head comparative studies are required.

Targeted therapies for treatment of renal cell carcinoma: recent advances and future perspectives.

PURPOSE: A wide variety of targeted therapies are available for the treatment of renal cancer that has progressed beyond the point at which surgery is a viable option. In addition, there are many more that are in the different stages of clinical trials. Here, we provide a methodical discussion of the efficacy and safety of targeted therapies for the treatment of advanced renal cell carcinoma. METHODS: We conducted a systematic literature employing the search terms: renal cell carcinoma targets, tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, and each of the drugs discussed within these papers. RESULTS: The identified targeted therapies work by disrupting specific signalling pathways involved in tumour progression, such as those responsible for angiogenesis and cell proliferation. Tyrosine kinase inhibitors and mammalian target of rapamycin inhibitors are now established classes of drugs used in the treatment of renal cancer, with a total of six having received regulatory approval to date (sorafenib, sunitinib, pazopanib, axitinib, temsirolimus, and everolimus). Ongoing trials are likely to result in addition to these in the near future, for example, tivozanib, dovitinib, and cediranib. Furthermore, in addition to these small molecule drugs, immunotherapies involving monoclonal antibodies against signalling molecules such as vascular endothelial growth factor (bevacizumab) or programmed death-1 (nivolumab) are receiving increasing attention. CONCLUSIONS: Targeted therapies have great potential for disrupting tumour progression by inhibiting certain signalling pathways. As our understanding of the biochemical pathways involved in cancer progresses, additional targets are certain to become apparent, expanding treatment options even further.

Co-assembly, spatiotemporal control and morphogenesis of a hybrid protein-peptide system.

Controlling molecular interactions between bioinspired molecules can enable the development of new materials with higher complexity and innovative properties. Here we report on a dynamic system that emerges from the conformational modification of an elastin-like protein by peptide amphiphiles and with the capacity to access, and be maintained in, non-equilibrium for substantial periods of time. The system enables the formation of a robust membrane that displays controlled assembly and disassembly capabilities, adhesion and sealing to surfaces, self-healing and the capability to undergo morphogenesis into tubular structures with high spatiotemporal control. We use advanced microscopy along with turbidity and spectroscopic measurements to investigate the mechanism of assembly and its relation to the distinctive membrane architecture and the resulting dynamic properties. Using cell-culture experiments with endothelial and adipose-derived stem cells, we demonstrate the potential of this system to generate complex bioactive scaffolds for applications such as tissue engineering.

Bioactive membranes for bone regeneration applications: effect of physical and biomolecular signals on mesenchymal stem cell behavior.

This study focuses on the in vitro characterization of bioactive elastin-like recombinamer (ELR) membranes for bone regeneration applications. Four bioactive ELRs exhibiting epitopes designed to promote mesenchymal stem cell adhesion (RGDS), endothelial cell adhesion (REDV), mineralization (HAP), and both cell adhesion and mineralization (HAP-RGDS) were synthesized using standard recombinant protein techniques. The materials were then used to fabricate ELR membranes incorporating a variety of topographical micropatterns including channels, holes and posts. Primary rat mesenchymal stem cells (rMSCs) were cultured on the different membranes and the effects of biomolecular and physical signals on cell adhesion, morphology, proliferation, and differentiation were evaluated. All results were analyzed using a custom-made MATLAB program for high throughput image analysis. Effects on cell morphology were mostly dependent on surface topography, while cell proliferation and cell differentiation were largely dependent on the biomolecular signaling from the ELR membranes. In particular, osteogenic differentiation (evaluated by staining for the osteoblastic marker osterix) was significantly enhanced on cells cultured on HAP membranes. Remarkably, cells growing on membranes containing the HAP sequence in non-osteogenic differentiation media exhibited significant up-regulation of the osteogenic marker as early as day 5, while those growing on fibronectin-coated glass in osteogenic differentiation media did not. These results are part of our ongoing effort to develop an optimized molecularly designed periosteal graft.

Engineering membrane scaffolds with both physical and biomolecular signaling.

We report on the combination of a top-down and bottom-up approach to develop thin bioactive membrane scaffolds based on functional elastin-like polymers (ELPs). Our strategy combines ELP cross-linking and assembly, and a variety of standard and novel micro/nanofabrication techniques to create self-supporting membranes down to ∼500 nm thick that incorporate both physical and biomolecular signals, which can be easily tailored for a specific application. In this study we used an ELP that included the cell-binding motif arginine-glycine-aspartic acid-serine (RGDS). Furthermore, fabrication processes were developed to create membranes that exhibited topographical patterns with features down to 200 nm in lateral dimensions and up to 10 µm in height on either one or both sides, uniform and well-defined pores, or multiple ELP layers. A variety of processing parameters were tested in order to optimize membrane fabrication, including ELP and cross-linker concentration, temperature, reaction time and ambient humidity. Membrane micro/nanopatterning, swelling and stiffness were characterized by atomic force microscopy, nanoindentation tests and scanning electron microscopy. Upon immersion in phosphate-buffered saline and an increase in temperature from 25 to 40°C, membranes exhibited a significant increase in surface stiffness, with the reduced Young's modulus increasing with temperature. Finally, rat mesenchymal stem cells were cultured on thin RGDS-containing membranes, which allowed cell adhesion, qualitatively enhanced spreading compared to membranes without RGDS epitopes and permitted proliferation. Furthermore, cell morphology was drastically affected by topographical patterns on the surface of the membranes.

Reduced parenteral nutrition requirements following anastomosis of a short residual colonic segment to a short jejunum.

A 22-year-old man suffered an acute small bowel infarct leading to extensive bowel resection, resulting in only 20 cm of jejunum to a jejunostomy, although he also had 50 cm of residual colon with a mucous fistula. The patient was out on long-term home parenteral nutrition (PN) but endured high stomal losses of 5-6 L per day and, despite all conventional measures, required 6.1 L of fluid (including PN) and 555 mmol sodium per day. Although body mass index was maintained, he suffered debilitating malaise and recurrent episodes of catheter-related sepsis and also developed persistently abnormal liver function tests. He was considered a potential intestinal transplant patient, but before taking that step, he opted for reanastomosis of his residual colon to his jejunum, ending in a colostomy. At surgery, only 30 cm of additional bowel lengthening could be achieved, but despite this, the patient's stomal losses reduced to 2.5 L per day, intravenous fluid requirements reduced to 4.1 L per day, and liver function normalized. The patient also gained 7.5 kg despite no change in PN caloric prescription, and his quality of life was dramatically enhanced. The case illustrates that even a small length of colon can grant significant improvements, probably via improvements in small bowel transit and adaptive changes, better sodium and water resorption with decreased hyperaldosteronism, and enhanced energy and nitrogen recovery. Reanastomosis of defunctioned colon should therefore always be considered a management option in short bowel syndrome.