Blood-based kinase activity profiling: A potential predictor of response to immune checkpoint inhibition in metastatic cancer

Background Many cancer patients do not obtain clinical benefit from immune checkpoint inhibition. Checkpoint blockade targets T cells, suggesting that tyrosine kinase activity profiling of baseline peripheral blood mononuclear cells may predict clinical outcome. Methods Here a total of 160 patients with advanced melanoma or non-small-cell lung cancer (NSCLC), treated with anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) or anti-programmed cell death 1 (anti-PD-1), were divided into five discovery and cross-validation cohorts. The kinase activity profile was generated by analyzing phosphorylation of peripheral blood mononuclear cell lysates in a microarray comprising of 144 peptides derived from sites that are substrates for protein tyrosine kinases. Binary grouping into patients with or without clinical benefit was based on Response Evaluation Criteria in Solid Tumors V.1.1. Predictive models were trained using partial least square discriminant analysis (PLS-DA), performance of the models was evaluated by estimating the correct classification rate (CCR) using cross-validation. Results The kinase phosphorylation signatures segregated responders from non-responders by differences in canonical pathways governing T-cell migration, infiltration and co-stimulation. PLS-DA resulted in a CCR of 100% and 93% in the anti-CTLA-4 and anti-PD1 melanoma discovery cohorts, respectively. Cross-validation cohorts to estimate the accuracy of the predictive models showed CCRs of 83% for anti-CTLA-

Nanotopography on implant biomaterials

No abstract

Initial cellular response to laser surface engineered biomaterials

Introducing micro- and nanoscale features on biomaterials in an engineered, controlled manner has been shown to positively affect medical implant integration into the human body. A key factor in this process is the initial cellular response toward the implant. Different techniques such as chemical treatment, plasma spraying, lithography, and coatings, among others, have been applied during the last decades to improve the implant integration. One of the methods that started to be recently exploited is laser surface engineering (LSE). LSE offers a wide range of new surface engineering methods, such as laser surface melting (LSM), laser engineered net shaping (LENS), and selective laser melting/sintering (SLM/S) that can generate complex micro- and nanoscale features with high resolution. This review provides an overview of the initial cellular response to medical implants and the different techniques used to modify the surface of different biomaterials. An emphasis is given to laser techniques that were recently developed for surface texturing, describing in vitro, pre-clinical, and clinical trials performed thus far

The influence of nanoscale grooved substrates on osteoblast behavior and extracellular matrix deposition

To fight bone diseases characterized by poor bone quality like osteoporosis and osteoarthritis, as well as in reconstructive surgery, there is a need for a new generation of implantable biomaterials. It is envisioned that implant surfaces can be improved by mimicking the natural extracellular matrix of bone tissue, which is highly a organized nano-composite. In this study we aimed to get a better understanding of osteoblast response to nanometric grooved substrates varying in height, width and spacing. A throughput screening biochip was created using electron beam lithography. Subsequently, uniform large-scale nanogrooved substrates were created using laser interference lithography and reactive ion etching. Results showed that osteoblasts were responsive to nanopatterns down to 75 nm in width and 33 nm in depth. SEM and TEM studies showed that an osteoblast-driven calcium phosphate (CaP) mineralization was observed to follow the surface pattern dimensions. Strikingly, aligned mineralization was found on even smaller nanopatterns of 50 nm in width and 17 nm in depth. A single cell based approach for real time PCR demonstrated that osteoblast-specific gene expression was increased on nanopatterns relative to a smooth control. The results indicate that nanogrooves can be a very promising tool to direct the bone response at the interface between an implant and the bone tissue