Stimuli-Responsive Microtools for Biomedical and Defense Applications

We live in a 3D world which has embraced ever shrinking technologies, yet the techniques used to create these micro- and nanoscale technologies are inherently 2D. Self-assembly of 2D templates into 3D devices enables the creation of complex tools cheaply, efficiently, and in mass quantity. I utilize this technique to create stimuli-responsive microgrippers, which are shaped like hands with flexible joints and rigid phalanges and range in size from 10 µm to 4 mm. Intrinsic stress within the hinges provides all the energy necessary for gripping, and thus they require no wires or batteries for operation. Here, I demonstrate their use for both biomedical and defense applications. These microgrippers can be used as microsurgical tools, gripping onto tissue in response to body temperature and excising tissue from the gastrointestinal tract in both in vivo and ex vivo porcine models. A Monte Carlo model confirmed that these tiny tools has a higher probability of sampling tissue from a lesion as compared to the traditional biopsy foreceps. These grippers were scaled down to 10 µm and used to capture single cells for in vitro isolation, imaging, and assays. All-polymeric, porous, stimuli-responsive therapeutic grippers or “theragrippers” which swell and de-swell around body temperature were created for drug delivery applications. These theragrippers can be loaded with commercial drugs for biphasic, site-specific controlled release and were successfully demonstrated in an in vitro and an in vivo model. For defense applications, integrating microelectronics like RFID’s onto the microgrippers creates tagging, tracking, and locating (TTL) devices capable of latching onto clothing, hair, and moving animal targets. This integrated design is enabled using high throughput solder-based self-assembly. This defense application, particularly reliant on covert, wireless technology, benefits from our novel photothermal actuation mechanism using low power, handheld lasers. In addition to triggering microgripper closing, this actuation scheme also enables complex sequential folding pathways, a step towards programmable matter

36. A prospective, randomized study to compare the value of two fractionation schemes of palliative radiotherapy for inoperable non-small cell lung cancer

A prospective, randomized study was conducted in eight Polish institutions to compare the value of two fractionation schemes of palliative radiotherapy for inoperable non-small cell lung cancer. Assessed was the impact of either treatment on the degree and duration of relief of tumor-related symptoms and on patient's performance status. Secondary endpoints included treatment side-effects, objective response and overall survival. One hundred patients were randomly assigned to the dose of 20 Gy/5×/5 days (Arm A) or 16 Gy/2×/8 days (Arm B). There were 90 men and 10 women aged between 47 and 79 (mean 66). Eighty four patients had locally advanced tumor and 16 patients had metastatic disease. Squamous cell carcinoma was diagnosed in 65 patients, adenocarcinoma – in 9 patients, large cell carcinoma – in 1 patient and unspecified non-small cell carcinoma – in 25 patients. Fifty five patients were assigned to Arm A and 45 – to Arm B. Ninety eight patients received assigned treatment whereas two patients died before the end of treatment. The final results of the study will be presented at the conference

A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma

<p>Abstract</p> <p>Background</p> <p>Ipilimumab, a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4, has demonstrated an improvement in overall survival in two phase III trials of patients with advanced melanoma. The primary objective of the current trial was to prospectively explore candidate biomarkers from the tumor microenvironment for associations with clinical response to ipilimumab.</p> <p>Methods</p> <p>In this randomized, double-blind, phase II biomarker study (ClinicalTrials.gov NCT00261365), 82 pretreated or treatment-naïve patients with unresectable stage III/IV melanoma were induced with 3 or 10 mg/kg ipilimumab every 3 weeks for 4 doses; at Week 24, patients could receive maintenance doses every 12 weeks. Efficacy was evaluated per modified World Health Organization response criteria and safety was assessed continuously. Candidate biomarkers were evaluated in tumor biopsies collected pretreatment and 24 to 72 hours after the second ipilimumab dose. Polymorphisms in immune-related genes were also evaluated.</p> <p>Results</p> <p>Objective response rate, response patterns, and safety were consistent with previous trials of ipilimumab in melanoma. No associations between genetic polymorphisms and clinical activity were observed. Immunohistochemistry and histology on tumor biopsies revealed significant associations between clinical activity and high baseline expression of FoxP3 (p = 0.014) and indoleamine 2,3-dioxygenase (p = 0.012), and between clinical activity and increase in tumor-infiltrating lymphocytes (TILs) between baseline and 3 weeks after start of treatment (p = 0.005). Microarray analysis of mRNA from tumor samples taken pretreatment and post-treatment demonstrated significant increases in expression of several immune-related genes, and decreases in expression of genes implicated in cancer and melanoma.</p> <p>Conclusions</p> <p>Baseline expression of immune-related tumor biomarkers and a post-treatment increase in TILs may be positively associated with ipilimumab clinical activity. The observed pharmacodynamic changes in gene expression warrant further analysis to determine whether treatment-emergent changes in gene expression may be associated with clinical efficacy. Further studies are required to determine the predictive value of these and other potential biomarkers associated with clinical response to ipilimumab.</p

The Tumor-Selective Cytotoxic Agent β-Lapachone is a Potent Inhibitor of IDO1

β-lapachone is a naturally occurring 1,2-naphthoquinone-based compound that has been advanced into clinical trials based on its tumor-selective cytotoxic properties. Previously, we focused on the related 1,4-naphthoquinone pharmacophore as a basic core structure for developing a series of potent indoleamine 2,3-dioxygenase 1 (IDO1) enzyme inhibitors. In this study, we identified IDO1 inhibitory activity as a previously unrecognized attribute of the clinical candidate β-lapachone. Enzyme kinetics-based analysis of β-lapachone indicated an uncompetitive mode of inhibition, while computational modeling predicted binding within the IDO1 active site consistent with other naphthoquinone derivatives. Inhibition of IDO1 has previously been shown to breach the pathogenic tolerization that constrains the immune system from being able to mount an effective anti-tumor response. Thus, the finding that β-lapachone has IDO1 inhibitory activity adds a new dimension to its potential utility as an anti-cancer agent distinct from its cytotoxic properties, and suggests that a synergistic benefit can be achieved from its combined cytotoxic and immunologic effects