Mechanism of action by which 5-NIdR acts as a therapeutic agent against brain cancer

Approximately 10,000 people in the United States are diagnosed annually with a brain tumor. In addition, the prognosis for brain cancer patients is poor as these cancers have low survival rates of less than 10%. One important chemotherapeutic agent used to treat brain cancer is temozolomide, an alkylating agent that causes cell death by damaging DNA. In this project, we tested the ability of a specific non-natural nucleoside developed in our lab, designated 5-NIdR, to increase the efficacy of temozolomide against brain cancer. Animal studies using xenograft mice were performed to evaluate the in vivo efficacy of this drug combination against brain cancer. Results indicate that treatment with 5-NIdR does not affect the rate of tumor growth compared to treatment with vehicle control. While treatment with temozolomide slows the rate of tumor growth by 2-fold, more striking results are obtained when 5-NIdR is combined with temozolomide as this drug combination causes complete tumor regression within two weeks of treatment. To better define the cellular mechanism for this effect, a series of cell-based studies were performed to compare the cytotoxic effects of temozolomide alone and in combination with 5-NIdR. Flow cytometry experiments measuring Annexin V staining as a marker for apoptosis demonstrate that cells treated with 5-NIdR and temozolomide accumulate show significantly higher levels of apoptosis compared to cells treated with 5-NIdR or temozolomide alone. Experiments measuring cell-cycle progression demonstrate that treatment with 5-NIdR and temozolomide causes cancer cells to accumulate at S-phase before undergoing apoptosis. The block at S-phase likely results from the ability of 5-NIdR to inhibit the replication of damaged DNA created by temozolomide. Consistent with this mechanism, significantly higher levels of single- and double-strand DNA breaks are detected in cancer cells treated with 5-NIdR and temozolomide compared to cells treated individually with either agent. Collectively, these studies provide additional pharmacological evidence for combining 5-NIdR and temozolomide as a possible treatment strategy to effectively treat brain cancers.https://engagedscholarship.csuohio.edu/u_poster_2015/1019/thumbnail.jp

Competitive Evolutionary Dynamics of Cloud Service Offerings in Korea: A Path-Dependency Perspective

Cloud service for personal users has become more popular world-wide since Apple Inc. launched iCloud storage service in October, 2011. However, such cloud storage service was not new because many global telecom companies, usually called telcos, as well as many portals had already offered similar Internet-based online storage services at that time. As of now, there can be seen hundreds of diverse cloud storage and computing services for both personal and enterprise users in the global market. During last several years, Korean cloud service market has been led by three major telcos, who have launched more advanced and more diversified services competing with each other. Some questions may arise: What makes that happen and what kind of market dynamics affects on the evolution of cloud service offerings? This paper tries to answer these questions by categorizing and analysing 84 cloud services offered by three major telcos in Korea during last three years. As a research framework, Pessemier’s new product classification scheme was employed and precedence relationships among differently positioned service categories were analyzed to figure out the competitive evolutionary dynamics of the market. From the empirical study, path dependency was observed and resource-based view of the market competition was validated. Also, it was found that a player’s next move in service offering to a better position in Pessemier’s product space is quite closely related with the competitive position as well as the company-owned competitive resources like technology competency and company-wide service scope

End-to-End Differentiable Learning to HDR Image Synthesis for Multi-exposure Images

Recently, high dynamic range (HDR) image reconstruction based on the multiple exposure stack from a given single exposure utilizes a deep learning framework to generate high-quality HDR images. These conventional networks focus on the exposure transfer task to reconstruct the multi-exposure stack. Therefore, they often fail to fuse the multi-exposure stack into a perceptually pleasant HDR image as the inversion artifacts occur. We tackle the problem in stack reconstruction-based methods by proposing a novel framework with a fully differentiable high dynamic range imaging (HDRI) process. By explicitly using the loss, which compares the network's output with the ground truth HDR image, our framework enables a neural network that generates the multiple exposure stack for HDRI to train stably. In other words, our differentiable HDR synthesis layer helps the deep neural network to train to create multi-exposure stacks while reflecting the precise correlations between multi-exposure images in the HDRI process. In addition, our network uses the image decomposition and the recursive process to facilitate the exposure transfer task and to adaptively respond to recursion frequency. The experimental results show that the proposed network outperforms the state-of-the-art quantitative and qualitative results in terms of both the exposure transfer tasks and the whole HDRI process

Pharmacological and Pre-Clinical Testing of 5-NIdR as a New Therapeutic Agent Against Brain Cancer

Approximately 4,000 children in the United States are diagnosed annually with a brain tumor. Brain cancers are the deadliest of all pediatric cancers as they have survival rates of less than 20%. Although surgery and radiation therapy are widely used to treat adult patients, chemotherapy is the primary therapeutic option for children. One important chemotherapeutic agent is temozolomide, an alkylating agent that causes cell death by damaging DNA. In this project, we tested the ability of a specific non-natural nucleoside developed in our lab, designated 5-NIdR, to increase the efficacy of temozolomide against brain cancer. Cell-based studies demonstrate that the combination of 5-NIdR and temozolomide kills more cells compared to treatment with either temozolomide or 5-NIdR used alone. Microscopy techniques demonstrate that the combination of 5-NIdR and temozolomide causes cell death via apoptosis rather than necrosis. Animal studies using xenograft (nude) mice were performed to evaluate the in vivo efficacy and safety of this drug combination against brain cancer. Preliminary results are provided which indicate that treatment with 5-NIdR does not inhibit the rate of tumor growth. In contrast, treatment with temozolomide reduces the rate of tumor growth but does not lead to the complete elimination of the tumor. Striking results are obtained using 5-NIdR and temozolomide together as this drug combination causes a significant reduction in tumor size. Finally, mice treated with the combination of 5-NIdR and temozolomide do not show overt signs of side effects such as weight loss, dehydration, or fatigue. Collectively, these studies provide pharmacological evidence for combining 5-NIdR and temozolomide as a new treatment strategy to effectively treat brain cancers.https://engagedscholarship.csuohio.edu/u_poster_2014/1018/thumbnail.jp

Surgical repair of descending thoracic and thoracoabdominal aortic aneurysm involving the distal arch: Open proximal anastomosis under deep hypothermia versus arch clamping technique

BackgroundSurgical repair of a descending thoracic and thoracoabdominal aortic aneurysm (DTA/TAAA) involving the distal arch is challenging and requires either deep hypothermic circulatory arrest (DHCA) or crossclamping of the distal arch. The aim of this study was to compare these 2 techniques in the treatment of DTA/TAAA involving the distal arch.MethodsFrom 1994 to 2012, 298 patients underwent open repair of DTA/TAAA through a left thoracotomy. One hundred seventy-four patients with distal arch involvement who were suitable for either DHCA (n = 81) or arch clamping (AC; n = 93), were analyzed. In-hospital outcomes were compared using propensity scores and inverse-probability-of-treatment weighting adjustment to reduce treatment selection bias.ResultsEarly mortality was 11.1% in the DHCA group and 8.6% in the AC group (P = .58). Major adverse outcomes included stroke in 16 patients (9.2%), low cardiac output syndrome in 15 (8.6%), paraplegia in 10 (5.7%), and multiorgan failure in 10 (5.7%). After adjustment, patients who underwent DHCA were at similar risk of death (odds ratio [OR], 1.14; P = .80) and permanent neurologic injury (OR, 0.95; P = .92) to those who underwent AC. Although prolonged ventilator support (>24 hours) was more frequent with DHCA than with AC (OR, 2.60; P = .003), DHCA showed a tendency to lower the risk of paraplegia (OR, 0.15; P = .057).ConclusionsCompared with AC, DHCA did not increase postoperative mortality and morbidity, except for prolonged ventilator support. However, DHCA may offer superior spinal cord protection to AC during repair of DTA/TAAA involving the distal arch

Inhibiting Translesion DNA Synthesis as an Approach to Combat Drug Resistance to DNA Damaging Agents

Anti-cancer agents exert therapeutic effects by damaging DNA. Unfortunately, DNA polymerases can effectively replicate the formed DNA lesions to cause drug resistance and create more aggressive cancers. To understand this process at the cellular level, we developed an artificial nucleoside that visualizes the replication of damaged DNA to identify cells that acquire drug resistance through this mechanism. Visualization is achieved using click chemistry to covalently attach azide-containing fluorophores to the ethynyl group present on the nucleoside analog after its incorporation opposite damaged DNA. Flow cytometry and microscopy techniques demonstrate that the extent of nucleotide incorporation into genomic DNA is enhanced by treatment with DNA damaging agents. In addition, this nucleoside analog inhibits translesion DNA synthesis and synergizes the therapeutic activity of certain anticancer agents such as temozolomide. The combined diagnostic and therapeutic activities of this synthetic nucleoside analog represent a new paradigm in personalized medicine

Interpreting positive signs of the supraspinatus test in screening for torn rotator cuff.

The purpose of this study was to investigate the validity of the supraspinatus test as a screening test for detecting torn rotator cuff and to determine what its valuable positive signs were. Both the empty-can test and full-can test were performed on 200 shoulders diagnosed by magnetic resonance imaging (MRI)-and in some cases, surgical findings-to have full-thickness or partial-thickness torn rotator cuff s, or no tear in the rotator cuff . During the maneuver, the presence of pain or weakness or both pain and weakness were recorded as positive signs, and the distribution of these signs were analyzed according to the degree of tear. The predictive values were calculated in 2 ways by considering (1) only full-thickness tears as tears and (2) both full- and partial-thickness tears as tears. The 2 tests and the 2 ways of considering partial-thickness tears were compared. Pain and weakness were severity-dependent, and the empty-can test had a higher incidence of pain. The sensitivities of the 2 supraspinatus tests in all positive signs were higher when including partial-thickness tears in the tear group ; however, their specificities were higher when excluding partial-thickness tears. Both pain and weakness were interpretive for the supraspinatus test, and both tests were sensitive to full- and partial- thickness tears and specific for full-thickness tears