A quantitative microfluidic angiogenesis screen for studying anti-angiogenic therapeutic drugs

Anti-angiogenic therapy, which suppresses tumor growth by disrupting oxygen and nutrient supply from blood to the tumor, is now widely accepted as a treatment for cancer. To investigate the mechanisms of action of these anti-angiogenesis drugs, new three dimensional (3D) cell culture-based drug screening models are increasingly employed. However, there is no in vitro high-throughput screening (HTS) angiogenesis assay that can provide uniform culture conditions for the quantitative assessment of physiological responses to chemoattractant reagents under various concentrations of anti-angiogenesis drugs. Here we describe a method for screening and quantifying the vascular endothelial growth factor (VEGF)-induced chemotactic response on human umbilical vein endothelial cells (HUVECs) cultured with different concentrations of bortezomib, a selective 26S proteasome inhibitor. With this quantitative microfluidic angiogenesis screen (QMAS), we demonstrate that bortezomib-induced endothelial cell death is preceded by a series of morphological changes that develop over several days. We also explore the mechanisms by which bortezomib can inhibit angiogenesis.National Institutes of Health (U.S.) (R33 CA174550)National Science Foundation (U.S.) (CBET-0939511)National Research Foundation of Korea (Pioneer Research Center Program 2012-0009565 and 2014M3A7B4052193)Korea (South). Sanggong Chawŏnbu (No. 2012401020325

Sonodegradation of amitriptyline and ibuprofen in the presence of Ti3C2Tx MXene

This study, which investigated the sonodegradation of selected pharmaceutical active compounds (PhACs) (amitriptyline (AMT) and ibuprofen (IBP)) with MXene, was carried out in an aqueous solution. To investigate the practicality of the degradation process, the experiments were conducted in various water quality conditions, including pH, temperature, natural organic matter, and ionic strength. Based on the experimental results, the produced hydrogen peroxide, which could be a representative of the produced OH radicals, was a vital factor that affected the degradation performance of both PhACs. To confirm the importance of OH radicals, the effect of a OH radical promoter (H2O2) and scavenger (t-BuOH) was also studied. In addition, the synergism between ultrasonication (US) and MXene was evaluated with the rate constants of US only, MXene only, and a US/MXene combined system. Mineralization of the PhACs was also investigated, and removal of AMT was higher than that of IBP, which could be attributed to the physicochemical properties of the compounds and enhanced adsorption by the well-dispersed MXene. Overall, utilization of MXene by means of ultrasonication could enhance the removal performance of PhACs in water

Pure red-cell aplasia and autoimmune hemolytic anemia in a patient with acute hepatitis A

Pure red cell aplasia (PRCA) and autoimmune hemolytic anemia (AIHA) have rarely been reported as an extrahepatic manifestation of acute hepatitis A (AHA). We report herein a case of AHA complicated by both PRCA and AIHA. A 49-year-old female with a diagnosis of AHA presented with severe anemia (hemoglobin level, 6.9 g/dL) during her clinical course. A diagnostic workup revealed AIHA and PRCA as the cause of the anemia. The patient was treated with an initial transfusion and corticosteroid therapy. Her anemia and liver function test were completely recovered by 9 months after the initial presentation. We review the clinical features and therapeutic strategies for this rare case of extrahepatic manifestation of AHA

Acute Pyelonephritis: Clinical Characteristics and the Role of the Surgical Treatment

The epidemiology of acute pyelonephritis (APN) has changed with time. Therefore we investigated the current clinical characteristics of APN and the significance of proper surgical management for treatment of 1,026 APN patients in South Korea for the past 5 yr. The male-to-female ratio was about 1:8. The peak ages of female patients were 20s (21.3%) and over 60s (23.7%), while that of male was over 60s (38.1%). The occurrence of sepsis was 10.1%. Complicated APN patients were 35.4%. Ninety-four patients (9.2%) needed urological procedures. The duration of the flank pain and of the costovertebral angle tenderness in complicated APN patients was statistically significantly longer than that with simple APN patients (4.3 vs. 3.4 days, 4.4 vs. 4.0 days). If flank pain and costovertebral angle tenderness sustain over 4 days, proper radiologic studies should be performed immediately with the consideration of surgical procedure. Also the resistance to antibiotics was increasing. As the sensitivities to ampicillin (27.2%) and trimethoprim/sulfamethoxazole (44.7%) of Escherichia coli and Klebsiella pneumoniae were very low, it is necessary to take the careful choice of antibiotics into consideration

Influence of Lamina Terminalis Fenestration on the Occurrence of the Shunt-Dependent Hydrocephalus in Anterior Communicating Artery Aneurysmal Subarachnoid Hemorrhage

Recently, it was reported that fenestration of the lamina terminalis (LT) may reduce the incidence of shunt-dependent hydrocephalus in aneurysmal subarachnoid hemorrhage (SAH). The authors investigated the efficacy of the LT opening on the incidence of shunt-dependent hydrocephalus in the ruptured anterior communicating artery (ACoA) aneurysms. The data of 71-ruptured ACoA aneurysm patients who underwent aneurysmal clipping in acute stage were reviewed retrospectively. Group I (n=36) included the patients with microsurgical fenestration of LT during surgery, Group II (n=35) consisted of patients in whom fenestration of LT was not feasible. The rate of shunt-dependent hydrocephalus was compared between two groups by logistic regression to control for confounding factors. Ventriculo-peritoneal shunts were performed after aneurysmal obliteration in 18 patients (25.4%). The conversion rates from acute hydrocephalus on admission to chronic hydrocephalus in each group were 29.6% (Group I) and 58.8% (Group II), respectively. However, there was no significant correlation between the microsurgical fenestration and the rate of occurrence of shunt-dependent hydrocephalus (p>0.05). Surgeons should carefully decide the concomitant use of LT fenestration during surgery for the ruptured ACoA aneurysms because of the microsurgical fenestration of LT can play a negative role in reducing the incidence of chronic hydrocephalus

Enhanced Immunogenicity of Engineered HER2 Antigens Potentiates Antitumor Immune Responses

For cancer vaccines, the selection of optimal tumor-associated antigens (TAAs) that can maximize the immunogenicity of the vaccine without causing unwanted adverse effects is challenging. In this study, we developed two engineered Human epidermal growth factor receptor 2 (HER2) antigens, K965 and K1117, and compared their immunogenicity to a previously reported truncated HER2 antigen, K684, within a B cell and monocyte-based vaccine (BVAC). We found that BVAC-K965 and BVAC-K1117 induced comparable antigen-specific antibody responses and antigen-specific T cell responses to BVAC-K684. Interestingly, BVAC-K1117 induced more potent antitumor activity than the other vaccines in murine CT26-HER2 tumor models. In addition, BVAC-K1117 showed enhanced antitumor effects against truncated p95HER2-expressing CT26 tumors compared to BVAC-K965 and BVAC-K684 based on the survival analysis by inducing T cell responses against intracellular domain (ICD) epitopes. The increased ICD epitope-specific T cell responses induced by BVAC-K1117 compared to BVAC-K965 and BVAC-K684 were recapitulated in human leukocyte antigen (HLA)-untyped human PBMCs and HLA-A*0201 PBMCs. Furthermore, we also observed synergistic antitumor effects between BVAC-K1117 and anti-PD-L1 antibody treatment against CT26-HER2 tumors. Collectively, our findings demonstrate that inclusion of a sufficient number of ICD epitopes of HER2 in cellular vaccines can improve the antitumor activity of the vaccine and provide a way to optimize the efficacy of anticancer cellular vaccines targeting HER2.Y