Quantitative Proteomics Reveals ß2 Integrin-mediated Cytoskeletal Rearrangement in Vascular Endothelial Growth Factor (VEGF)-induced Retinal Vascular Hyperpermeability.

Retinal vascular hyperpermeability causes macular edema, leading to visual deterioration in retinal diseases such as diabetic retinopathy and retinal vascular occlusion. Dysregulation of junction integrity between endothelial cells by vascular endothelial growth factor (VEGF) was shown to cause retinal vascular hyperpermeability. Accordingly, anti-VEGF agents have been used to treat retinal vascular hyperpermeability. However, they can confer potential toxicity through their deleterious effects on maintenance and survival of neuronal and endothelial cells in the retina. Thus, it is important to identify novel therapeutic targets for retinal vascular hyperpermeability other than VEGF. Here, we prepared murine retinas showing VEGF-induced vascular leakage from superficial retinal vascular plexus and prevention of VEGF-induced leakage by anti-VEGF antibody treatment. We then performed comprehensive proteome profiling of these samples and identified retinal proteins for which abundances were differentially expressed by VEGF, but such alterations were inhibited by anti-VEGF antibody. Functional enrichment and network analyses of these proteins revealed the ß2 integrin pathway, which can prevent dysregulation of junction integrity between endothelial cells through cytoskeletal rearrangement, as a potential therapeutic target for retinal vascular hyperpermeability. Finally, we experimentally demonstrated that inhibition of the ß2 integrin pathway salvaged VEGF-induced retinal vascular hyperpermeability, supporting its validity as an alternative therapeutic target to anti-VEGF agents.

Childhood abuse and cortical gray matter volume in patients with major depressive disorder.

Childhood abuse is associated with brain structural alterations; however, few studies have investigated the association between specific types of childhood abuse and cortical volume in patients with major depressive disorder (MDD). We aimed to investigate the association between specific types of childhood abuse and gray matter volumes in patients with MDD. Seventy-five participants with MDD and 97 healthy controls (HCs) aged 19-64 years were included. Cortical gray matter volumes were compared between MDD and HC groups, and also compared according to exposure to each type of specific childhood abuse. Emotional, sexual, and physical childhood abuse were assessed using the 28-item Childhood Trauma Questionnaire. Patients with MDD showed a significantly decreased gray matter volume in the right anterior cingulate gyrus (ACG). Childhood sexual abuse (CSA) was associated with significantly decreased gray matter volume in the right middle occipital gyrus (MOG). In the post-hoc comparison of volumes of the right ACG and MOG, MDD patients with CSA had significantly smaller volumes in the right MOG than did MDD patients without CSA or HCs. The right MOG volume decrease could be a neuroimaging marker associated with CSA and morphological changes in the brain may be involved in the pathophysiology of MDD.

DNA repair gene polymorphisms and benefit from gefitinib in never-smokers with lung adenocarcinoma.

BACKGROUND: The objective of this study was to investigate whether polymorphisms in DNA repair genes affect clinical outcome of never-smokers with lung adenocarcinoma (NSLA). METHOD: Common polymorphisms in the DNA repair genes ribonucleotide reductase M1 (RRM1), excision repair cross-complementation group 1 (ERCC1), and x-ray repair cross-complementing group 1 (XRCC1) were genotyped in DNA samples from 158 patients among 313 NSLA who were randomized to receive either gefitinib or gemcitabine plus cisplatin (GP) as first-line therapy. Immunohistochemistry for ERCC1 (n = 38) and direct sequencing of the epidermal growth factor gene (EGFR) (n = 42) were performed using tumor samples. RESULTS: Patients who had the XRCC1 arginine (Arg)/Arg polymorphism at codon 399 (399Arg/Arg) had a higher response rate to gefitinib (71% vs 36%; P = .002) and had more EGFR-mutant tumors (82% vs 29%; P = .001) than patients who had the glutamine (Gln) allele. Patients who had the ERCC1 adenine-adenine (AA) polymorphism at codon 8092 (8092AA) had a higher response to GP than patients who had the cytosine-cytosine (CC) or the CA genotype (100% vs 44%; P = .043).When gefitinib was compared with GP, significantly longer progression-free survival (PFS) was observed with gefitinib among patients who had the XRCC1 399Arg/Arg genotype (7.5 months vs 6.6 months; P = .013), the RRM1 2464 guanine-guanine (GG) genotype (11.5 months vs 6.0 months; P = .004), and the ERCC1 8092CA genotype (7.5 months vs 6.4 months; P = .024). When the 3 genotypes were analyzed jointly, significantly longer PFS was observed with gefitinib among patients who had ≥2 genotypes (8.1 months vs 6.4 months; P = .009), whereas a trend for longer PFS was observed with GP among patients without the 3 genotypes (6.3 months vs 2.0 months; P = .06). In a multivariate Cox regression model, the greater number of specific genotypes independently predicted improved overall survival (hazard ratio, 0.5; 95% confidence interval, 0.3-0.8; P = .006). CONCLUSIONS: Patients with the XRCC1 399Arg/Arg, RRM1 2464GG, and ERCC1 8092CA genotypes did benefit from gefitinib. Having more of these genotypes may predict favorable prognosis for NSLA.

The First Case Series of Cryopyrin-Associated Periodic Syndrome in Korea.

Cryopyrin-associated periodic syndrome (CAPS) is a hereditary autoinflammatory syndrome caused by mutations in NLRP3 (encoding cryopyrin), which presents with fever, fatigue and arthralgia. Thus far, however there have been no reports of CAPS in Korea. Herein, we report 3 cases of CAPS for the first time in Korea. The first case, a 28-year-old man with recurrent urticaria, arthralgia and fever induced by cold, all of which were observed in his father, showed elevated erythrocyte sedimentation rate and C-reactive protein. He exhibited a p.Gly303Asp variant of the NLPR3 gene. The second case, a 2-year-old girl who had recurrent urticaria, arthritis and oral and genital ulcers, was positive for HLA B51 and a p.Glu569Lys mutation in exon 3 of the NLRP3 gene. Administration of anakinra greatly improved her symptoms. The third case, a 4-year-old boy who presented with recurrent urticaria, arthralgia, and fever, exhibited a p.Val72Met mutation in exon 1 of the NLRP3 gene. Administration of tocilizumab improved all of his symptoms. This small case series suggests that clinicians consider CAPS and conduct genetic studies when arthralgia and fever are accompanied by urticaria in Korea.

Effect of knee positions on cardiac compression variables in cardiopulmonary resuscitation of rescuer; Manikin study.

The aim of the study was to analyze the effect of knee positions on cardiac compression variables in cardiopulmonary resuscitation (CPR) using the manikin. Adult with career of CPR instructor (n=9; mean age, 27.11±6.60 years; mean heights, 177.39±4.40 cm; mean weights, 69.45±14.85 kg) participated in the experiment, and each participant performed cardiac compression from two different knee positions. Cardiac compression was 30 times per minute for each position with order of position randomized. The results obtained from variables of cardiac compression force were composed of compression velocity, elapsed time, decay rate, and loading rate in maximum and minimum medial-lateral, anterior-posterior (AP), vertical direction respectively. The above variables in 20.3 cm of knee position showed effective result than that of 50 cm of knee position, while maximum AP compression force increased. Given the often predictable setting of sports and exercise rehabilitation related with cardiac arrest, CPR relative to change of knee position were significantly associated with more efficient cardiac compression variables. These data have significant implications for health services program in fields of sports and exercise rehabilitation.

A phase II study of sunitinib in patients with relapsed or refractory small cell lung cancer.

PURPOSE: This study was conducted to evaluate the efficacy and safety of sunitinib in patients with relapsed or refractory small cell lung cancer (SCLC). PATIENTS AND METHODS: Eligibility included histologic or cytologic diagnosis of SCLC, ECOG PS of 0-2, cancer progression following one or two prior chemotherapy or chemo-radiotherapy (CRT) and adequate organ functions. Treatment regimen consisted of a 6-week cycle of sunitinib given as 50mg p.o. daily for 4 weeks followed by 2 weeks off. The primary end point was objective response rate (ORR). RESULTS: From March 2008 to October 2010, 25 patients were enrolled and 24 received treatment. The median age was 64.5 years; 22 patients (92%) were male. Eight patients (33%) displayed sensitive relapse. Seven patients (29%) received CRT and fifteen patients (63%) had received one prior chemotherapy. A median of 1 cycle (range 1-4) of sunitinib was administered, and 23 patients were evaluable for response. Two patients displayed partial response, and seven patients presented stable disease with a ORR of 9% (95% CI, 1-28%). The median progression-free (PFS) and overall survivals were 1.4 months (95% CI, 1.1-1.7) and 5.6 months (95% CI, 3.5-7.7), respectively. The common grade 3 or 4 toxicities included thrombocytopenia (63%), asthenia (29%) and neutropenia (25%). CONCLUSIONS: Although tumor response was noted in 2 patients, the median PFS was short and most patients were unable to tolerate the treatment. At the current dose schedule, sunitinib does not appear to warrant further evaluation.

A new method for the evaluation of dental implant stability using an inductive sensor.

We developed a new method for the measurement of dental implant stability by analyzing the impulse response of the implant. The movement of the implant was measured by an inductive sensor with a dedicated adaptor. The large inductance of the adapter amplified the small displacement signal of the implant. The Periotest (Siemens, Bensheim, Germany) was used as a source of excitation force to acquire the impact response of the implant. Power spectrum analysis was applied to the impact response of the implant. The peak frequency of the spectrum was used as a measure of the implant stability. The performance of the system was tested and verified through simulation of the implant-bone interface in an in vitro model. Various implant-bone interfacial conditions were assessed. Holes of varying depth and diameter were drilled into a dental implantation model. Two types of impression materials (EXAMIXFINE, Regisil Rigid) with different degrees of hardness were used to fix the implant into the hole. The implant stability was also measured using the ISQ (implant stability quotient) by resonance frequency analysis on the Osstell Mentor (Integration Diagnostics AB, Goteborgsvagen, Sweden) for comparison. Linear regression analysis of the peak frequency as a stability parameter showed a linear relationship with both the depth and the diameter of the hole (p<0.05). When EXAMIXFINE was used, the peak frequency was linearly associated with the depth (R(2)=0.443) and diameter (R(2)=0.396) of the hole. When Regisil Rigid was used, the peak frequency also showed a linear relationship with the depth (R(2)=0.555) and diameter (R(2)=0.350) of the hole. The peak frequency also increased as the hardness of the impression material increased. Differentiability of the system was evaluated by an ANOVA test. A statistically significant difference (p<0.01) was found between all implantation conditions, except in one case using the Regisil Rigid material. In contrast, the ISQ value did not consistently differentiate under several implantation conditions. The developed method could differentiate the stability changes in simulated implantation conditions with a wider dynamic range and with higher resolution than the ISQ value.

First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung.

PURPOSE: Gefitinib has shown high response rate and improved progression-free survival (PFS) in never-smokers with lung adenocarcinoma (NSLAs). We compared efficacy of gefitinib with gemcitabine and cisplatin (GP) chemotherapy in this group of patients as first-line therapy. PATIENTS AND METHODS: In this randomized phase III trial, a total of 313 Korean never-smokers with stage IIIB or IV lung adenocarcinoma, Eastern Cooperative Oncology Group performance status 0 to 2, and adequate organ function were randomly assigned to receive either gefitinib (250 mg daily) or GP chemotherapy (gemcitabine 1,250 mg/m(2) on days 1 and 8; cisplatin 80 mg/m(2) on day 1 every 3 weeks, for up to nine courses). The primary objective was to demonstrate better overall survival (OS) for gefitinib compared with GP in chemotherapy-naive NSLAs. RESULTS: Three hundred nine patients were analyzed per protocol (gefitinib arm, n = 159; GP arm, n = 150). Gefitinib did not show better OS compared with GP (hazard ratio [HR], 0.932; 95% CI, 0.716 to 1.213; P = .604; median OS, 22.3 v 22.9 months, respectively). The 1-year PFS rates were 16.7% with gefitinib and 2.8% with GP (HR, 1.198; 95% CI, 0.944 to 1.520). Response rates were 55% with gefitinib and 46% with GP (P = .101). Myelosuppression, renal insufficiency, and fatigue were more common in the GP arm, but skin toxicities and liver dysfunction were more common in the gefitinib arm. Two patients (1.3%) in the gefitinib arm developed interstitial lung disease and died. CONCLUSION: Gefitinib failed to demonstrate superior OS compared with GP as first-line therapy for NSLAs.

Multiple central endobronchial chondroid hamartoma.

Benign neoplasm of the lung is rare, and pulmonary hamartoma is the most common form of benign neoplasm of the lung. Most pulmonary hamartomas are parenchymal hamartomas, and endobronchial hamartomas are very rare and usually occur as a single mass. We report a case of a 55-year-old man presenting with multiple endobronchial chondroid hamartomas that had not been confirmed preoperatively. The patient received bilobectomy, and the postoperative course was uneventful. There was no evidence of recurrence or complications during the 6-month follow-up period. Reports of multiple endobronchial chondroid hamartomas are rare in the literature, and the awareness of this form of benign disease is important in the differential diagnosis of pulmonary neoplasms.