EXPLORING THE EFFECT OF CHRONIC INFLAMMATION ON RESPONSE TO IMMUNE CHECKPOINT INHIBITORS IN CANCER

Precision medicine has allowed for the development of monoclonal antibodies that unmask the anti-tumor immune response. These agents have provided some patients durable clinical benefit. However, PD-1 and PD-L1 inhibitor therapies are effective in a small group (10-20%) of non-small cell lung cancer (NSCLC) patients when used as single-agent therapy. The approved companion diagnostic is expression of the immune cell surface molecule, programmed death ligand 1 (PD-L1), on tumors measured by immunohistochemistry (IHC). Studies in tumor biology and immune surveillance dictate that PD-1 inhibitor efficacy should depend on the level of PD-L1 expression; however, the literature has not followed with convincing evidence. The limitations of this test include timing of tissue acquisition, tumor heterogeneity, and timing of therapy relative to the expression of PD-L1. In addition, the requirement of analyzing tumor tissue biopsy samples from a patient is cumbersome. Thus, a peripheral blood biomarker that predicts efficacy of PD-1/PD-L1 inhibition would be optimal for precise and cost-effective treatment. A history of chronic inflammatory diseases may be advantageous for a cancer patient who is treated with PD-1/PD-L1 inhibitors and may allow them to then mobilize a swift immune response to tumor cells. Specific biological components of this persistent inflammation may predict PD-1 inhibitor response. We have taken a novel approach to leverage national healthcare claims data that couples patient history with response to therapy. We have identified potential peripheral blood biomarkers of response to PD-1/PD-L1 inhibitors using a combination of healthcare outcomes and molecular markers that correlate with therapeutic efficacy

Immune Checkpoint Inhibition and the Prevalence of Autoimmune Disorders Among Patients with Lung and Renal Cancer

PURPOSE: Immune checkpoint inhibition reactivates the immune response against cancer cells in multiple tissue types and has been shown to induce durable responses. However, for patients with autoimmune disorders, their conditions can worsen with this reactivation. We sought to identify, among patients with lung and renal cancer, how many harbor a comorbid autoimmune condition and may be at risk of worsening their condition while on immune checkpoint inhibitors such as nivolumab and pembrolizumab. METHODS: An administrative health care claims database, Truven MarketScan, was used to identify patients diagnosed with lung and renal cancer from 2010 to 2013. We assessed patients for diagnosis of autoimmune diseases 1 year prior to or after diagnosis of cancer using International Classification of Diseases, Ninth Revision codes for 41 autoimmune diseases. Baseline characteristics and other comorbid conditions were recorded. RESULTS: More than 25% of patients with both lung and renal cancer had a comorbid autoimmune condition between 2010 and 2013 and were more likely to be women, older, and have more baseline comorbidities. CONCLUSIONS: This population presents a dilemma to physicians when deciding to treat with immune checkpoint inhibitors and risk immune-related adverse events. Future evaluation of real-world use of immune checkpoint inhibitors in patients with cancer with autoimmune diseases will be needed

Diffraction Plane Dependence of Micro Residual Stresses in Uniaxially Extended Carbon Steels

In the stress measurement using X-ray or neutron diffraction, an elastic anisotropy as well as a plastic anisotropy of crystal must be carefully considered. In the X-ray and neutron diffraction stress measurement for polycrystalline materials, a particular {hkl} plane is used in measuring lattice strains. The dependence of an X-ray elastic constant on a diffraction plane is a typical example caused by an elastic anisotropy of the crystal. The yield strength and the work hardening rate of a single crystal depend on a crystallographic direction of the crystal. The difference in the yield strength and the work hardening rate relating to the crystallographic direction develops different residual stresses measured on each {hkl} diffraction after plastic deformation of a polycrystalline material. The present paper describes the result of the neutron stress measurement on uniaxially extended low and middle carbon steels. A tri-axial residual stress state developed in the extended specimens was measured on different kind of {hkl} diffraction plane. The measurement on the {110}, {200} and {211} diffraction showed that residual stresses increased with increasing the plastic elongation and the residual stresses on {110} were compressive, {200} were tensile and those on {211} were the middle of the former two planes. Received: 30 September 2010; Revised: 28 October 2010; Accepted: 1 November 201

Supporting inheritance hierarchy changes in model-based regression test selection

Models can be used to ease and manage the development, evolution, and runtime adaptation of a software system. When models are adapted, the resulting models must be rigorously tested. Apart from adding new test cases, it is also important to perform regression testing to ensure that the evolution or adaptation did not break existing functionality. Since regression testing is performed with limited resources and under time constraints, regression test selection (RTS) techniques are needed to reduce the cost of regression testing. Applying model-level RTS for model-based evolution and adaptation is more convenient than using code-level RTS because the test selection process happens at the same level of abstraction as that of evolution and adaptation. In earlier work, we proposed a model-based RTS approach called MaRTS to be used with a fine-grained model-based adaptation framework that targets applications implemented in Java. MaRTS uses UML models consisting of class and activity diagrams. It classifies test cases as obsolete, reusable, or retestable based on changes made to UML class and activity diagrams of the system being adapted. However, MaRTS did not take into account the changes made to the inheritance hierarchy in the class diagram and the impact of these changes on the selection of test cases. This paper extends MaRTS to support such changes, and demonstrates that the extended approach performs as well as or better than code-based RTS approaches in safely selecting regression test cases. While MaRTS can generally be used during any model-driven development or model-based evolution activity, we have developed it in the context of runtime adaptation. We evaluated the extended MaRTS on a set of applications, and compared the results with code-based RTS approaches that also support changes to the inheritance hierarchy. The results showed that the extended MaRTS selected all the test cases relevant to the inheritance hierarchy changes, and that the fault detection ability of the selected test cases was never lower than that of the baseline test cases. The extended MaRTS achieved comparable results to a graph-walk code-based RTS approach (DejaVu), and showed a higher reduction in the number of selected test cases when compared with a static analysis code-based RTS approach (ChEOPSJ)

Diffraction Plane Dependence of Micro Residual Stresses in Uniaxially Extended Carbon Steels

In the stress measurement using X-ray or neutron diffraction, an elastic anisotropy as well as a plastic anisotropy of crystal must be carefully considered. In the X-ray and neutron diffraction stress measurement for polycrystalline materials, a particular {hkl} plane is used in measuring lattice strains. The dependence of an X-ray elastic constant on a diffraction plane is a typical example caused by an elastic anisotropy of the crystal. The yield strength and the work hardening rate of a single crystal depend on a crystallographic direction of the crystal. The difference in the yield strength and the work hardening rate relating to the crystallographic direction develops different residual stresses measured on each {hkl} diffraction after plastic deformation of a polycrystalline material. The present paper describes the result of the neutron stress measurement on uniaxially extended low and middle carbon steels. A tri-axial residual stress state developed in the extended specimens was measured on different kind of {hkl} diffraction plane. The measurement on the {110}, {200} and {211} diffraction showed that residual stresses increased with increasing the plastic elongation and the residual stresses on {110} were compressive, {200} were tensile and those on {211} were the middle of the former two planes. Received: 30 September 2010; Revised: 28 October 2010; Accepted: 1 November 201

Supporting opportunities for female entrepreneurs in Jordan

Female entrepreneurship in developing countries is a growing body of research that tries to address the main challenges faced in such a context. The aim of this paper is to shed some light on the real opportunities for female entrepreneurs in terms of support for their start-ups. A lack of studies with this specific focus may detach the pertinent literature from real business practice and the true conditions faced by women during the start-up process. We grounded our analysis in Jordan, a country that has received little attention, despite the fact that it has one of the liveliest entrepreneurial contexts in the Middle East. A sample of 28 institutions operating in Jordan that offer support for entrepreneurial activities were examined. This is followed by a discussion of the main implications of the initiatives dedicated to female entrepreneurs

NANOEMULSION AS A NOVEL OPHTHALMIC DELIVERY SYSTEM FOR ACETAZOLAMIDE

Objective: The aim of this work was to formulate the antiglaucoma drug acetazolamide as ocular nanoemulsion of high therapeutic efficacy and prolonged effect. Methods: Eighteen nanoemulsion formulaions consisting of different oils, surfactants and cosurfactants at various ratios and constant water content (39%) were prepared based on their constructed pseudoternary-phase diagrams. According to the In vitro release studies, three nanoemulsions which exhibited fast drug release were used to prepare acetazolamide nanoemulsions with higher water content (59%). The six nanoemulsions at either water content (39 or 59%) were evaluated for their physicochemical properties and ex- vivo corneal permeability. In addition, Draize rabbit eye irritation test was performed. Moreover, biological evaluation of acetazolamide nanoemulsions for their intraocular pressure lowering activity on glaucomatous albino rabbits was carried out. Results: Isopropyl myristate nanoemulsion prepared with cremophor EL and transcutol P exhibited the fastest drug release among all isopropyl myristate nanoemulsions. Oleic acid nanoemulsion prepared with mixture of tween 80 and cremophor EL as surfactants together with transcutol P showed the fastest drug release among other oleic acid nanoemulsion formulae. Similar results were also observed for peanut oil nanoemulsions. The above mentioned formulations either at 39% or 59% water content showed acceptable physicochemical properties and higher acetazolamide permeability coefficient through goat corneas than that reported for the free drug. They also were non irritant to rabbit eye. Therapeutic efficacy testing revealed that peanut oil nanoemulsion at 39% water content showed better and prolonged intraocular pressure lowering effect relative to either commercial brinzolamide eye drops (Azopt®) or the commercial oral acetazolamide tablet (Cidamex®). Conclusion: Acetazolamide was successfully formulated in nanoemulsion form which revealed high therapeutic efficacy in treatment of glaucoma together with a prolonged effect