[Prognostic value of skeletal muscle measured by CT at the T4 level in advanced EGFR-positive non-small cell lung cancer patients treated with ecotinib].

Objective: To investigate the prognostic value of skeletal muscle measured by CT at the level of the fourth thoracic vertebra (T4) in advanced epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC) patients treated with ecotinib. Methods: The study retrospectively reviewed clinical and pathological characteristics of 176 patients with advanced EGFR-positive NSCLC who received ecotinib and underwent chest CT scans at Wuhan Union Hospital between January 2017 and October 2020. Among them, 70 were male and 106 were female, with ages ranging from 27 to 80 (58.6±10.6) years. As of August 21, 2021, the median follow-up duration was 19.2 months (95%CI: 15.3 to 23.7 months). The optimal cut-off value of skeletal muscle density (T4-SMD) on CT images at the T4 level were determined using X-tile software. Kaplan-Meier analysis and log-rank test were used to plot progression-free survival curves. Cox proportional hazards regression models were employed to analyze factors influencing 1-year progression-free survival (PFS), and a nomogram prognostic model was constructed accordingly. Receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA) were utilized to evaluate the predictive value of the nomogram. Results: The T4-SMD [M (Q1,Q3)] of 176 patients was 42.56 (37.05, 45.93) HU. Patients were divided into low T4-SMD group (n=122) and high T4-SMD group (n=54) based on the cut-off value (The values for males and females were 49.44 and 41.41 HU, respectively) of T4-SMD. The median PFS time and 1-year PFS rate in the low T4-SMD group were significantly lower than those in the high T4-SMD group [10.4 (95%CI: 9.3-11.8) vs 13.7 (95%CI: 11.1-18.5) months, 36.1% vs 59.3%, respectively, P=0.034]. Eastern Cooperative Oncology Group performance status (HR=3.308, 95%CI: 1.183-9.247, P=0.023), lactate dehydrogenase level (HR=1.852, 95%CI: 1.037-3.307, P=0.037), systemic immune-inflammation index (HR=1.772, 95%CI: 1.019-3.080, P=0.043), and T4-SMD (HR=0.563, 95%CI: 0.325-0.974, P=0.040) were prognostic factors for 1-year PFS in advanced EGFR-positive NSCLC patients treated with ecotinib. A nomogram for predicting 1-year PFS of advanced EGFR-positive NSCLC patients treated with ecotinib was constructed based on the four indicators selected by multivariate Cox regression analysis. The area under the ROC curve of the nomogram was 0.775 (95%CI: 0.676-0.874). The calibration curve showed good consistency between the predicted and actual 1-year PFS. DCA demonstrated good clinical prediction effectiveness of the nomogram. Conclusion: Low T4-SMD is a prognostic risk factor for patients with advanced EGFR-positive NSCLC receiving icotinib therapy.

Radiological evaluation of temporal bone surgical landmarks for a transcanal transpromontorial approach to the internal auditory canal using three-dimensional computed tomography.

OBJECTIVE: This study aimed to analyse a three-dimensional transcanal transpromontorial approach to the internal auditory canal using three-dimensional computed tomography. METHOD: This study was a retrospective investigation of 48 ears of 24 patients using three-dimensional reconstruction data from normal temporal bone computed tomography. The inner structures of the temporal bone were three-dimensionally reconstructed. Eight points were marked in the three-dimensional object with reference to the axial, coronal and sagittal plane images of the computed tomography scans. Distances and angles to each point were measured from the oval and round windows. RESULTS: The point of the facial nerve from the internal auditory canal to the labyrinthine segment could be traced between the cochlear apex and the geniculate ganglion based on the oval window. CONCLUSION: This technique helps with identifying the locations of important surgical landmarks using three-dimensional reconstructions of pre-operative computed tomography scans and to identify the facial nerve from the internal auditory canal during surgery.

Associations between Hair Mineral Concentrations and Skeletal Muscle Mass in Korean Adults.

OBJECTIVES: Muscle health plays an important role in maintaining function and independence in the elderly, and some nutrients provide protection against the age-related decline of muscle strength and function. Minerals are important nutrients that may contribute to the prevention and treatment of sarcopenia, but they have not been well-studied. This study investigated whether hair mineral concentrations differ between subjects with low muscle mass (LMM) and subjects with normal muscle mass. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: A total of 232 adults ≥ 20 years of age who visited the Health Promotion Center of the University Hospital in Gyeonggi-do, Republic of Korea. MEASUREMENTS: The data from 232 subjects were analyzed and divided into LMM and normal groups based on the appendicular skeletal muscle mass index (ASMI) (LMM was defined as ASMI < 7.0 kg/m2 in men and < 5.7 kg/m2 in women). Skeletal muscle mass was estimated using a multi-frequency bioelectrical impedance analysis (BIA) device with a body composition analyzer. RESULTS: Overall mean age of participants was 50.4±11.6 years (29.7% women). Subjects with LMM showed significantly lower triglyceride levels, greater high-density lipoprotein cholesterol levels, and lower body mass index (BMI), compared with subjects who had normal muscle mass. No significant differences in hair mineral concentrations were observed between subjects with LMM and subjects with normal muscle mass, with the exception of copper. Hair copper concentrations were significantly greater in subjects with LMM than in subjects with normal muscle mass after adjustment for covariates and factors (65.7±14.2 vs 33.1±4.3 µg/g, P = 0.035). CONCLUSION: These results suggest that hair mineral status may play a role in the development of LMM. Therefore, further studies with larger numbers of subjects are required to identify the effects of mineral imbalances, their relationships with sarcopenia, and the differences between subjects with LMM and subjects with normal muscle mass.

Prevalence of Intracranial Aneurysms in Patients with Aortic Dissection.

BACKGROUND AND PURPOSE: There is an uncertainty about the association between intracranial aneurysms and aortic dissection. We aimed to determine the prevalence of intracranial aneurysms in patients with aortic dissection and evaluate the independent risk factors for the presence of intracranial aneurysms in these patients. MATERIALS AND METHODS: Seventy-one patients with a confirmed aortic dissection who underwent additional brain imaging were enrolled as the aortic dissection group, and 2118 healthy individuals with brain imaging, as controls. Demographic data were obtained from their medical records, including age, sex, comorbidities, and arch vessel involvement of aortic dissection. Two readers reviewed all brain images independently regarding the presence, morphology, size, and location of intracranial aneurysms. Baseline characteristics were compared between the aortic dissection group and controls by propensity score matching, and logistic regression analysis was performed for independent risk factors for the presence of intracranial aneurysms. RESULTS: The prevalence of intracranial aneurysms was 12.96% in the aortic dissection group and 1.85% in controls (P = .022). The mean diameter of intracranial aneurysms was significantly larger in the aortic dissection group (5.79 ± 3.26 mm in aortic dissection versus 3.04 ± 1.57 mm in controls; P = .008), and intracranial aneurysms of >7 mm were also more common in the aortic dissection group (28.6% in aortic dissection versus 5.3% in controls, P = .003). On multivariate analysis, arch vessel involvement of aortic dissection was an independent risk factor for the presence of intracranial aneurysms (odds ratio, 6.246; 95% confidence interval, 1.472-26.50; P = .013). CONCLUSIONS: Patients with aortic dissection have a high prevalence of intracranial aneurysms, and selective screening for brain vessels could be considered in these patients with arch vessel involvement. A further prospective study is needed to demonstrate a substantial prevalence of intracranial aneurysms.

Clinical features and radiological evaluation of otic capsule sparing temporal bone fractures.

OBJECTIVE: To evaluate the clinical and radiological aspects of otic capsule sparing temporal bone fractures. METHODS: Using medical records, 188 temporal bones of 173 patients with otic capsule sparing temporal bone fractures were evaluated. Otoscopic findings and symptoms, facial paralysis, and hearing loss were assessed. RESULTS: Using regional analysis, 7 fractures were classified as type I, 85 as type II, 169 as type III and 114 as type IV. Fourteen of the 17 facial paralysis cases improved to House-Brackmann grade II or lower at an average of 57.6 days after the initial evaluation. Thirty-one patients underwent initial and follow-up pure tone audiometry examinations. The air-bone gap closed significantly from 27.2 dB at an average of 21.8 days post-trauma to 19.6 dB at an average of 79.9 days post-trauma, without the need for surgical intervention. CONCLUSION: Initial conservative treatment for facial paralysis or conductive hearing loss is possible in otic capsule sparing fracture cases after careful evaluation of the patient.

Associations between osteoporosis and coronary artery disease in postmenopausal women.

OBJECTIVE: Coronary artery disease (CAD) and osteoporosis are major causes of mortality and morbidity in postmenopausal women. We aimed to investigate the association between osteoporosis and CAD in asymptomatic postmenopausal women at a single center. METHODS: This study included 863 postmenopausal women without histories of cardiovascular diseases who visited the Health Promotion Center from June 1, 2004 to May 31, 2015. All subjects were screened for bone mineral density (BMD) by dual-energy X-ray absorptiometry and for the degree of CAD by multidetector computed tomography. RESULTS: Low BMD including osteopenia and osteoporosis was found to be significantly associated with old age, low body mass index, and a higher prevalence of diabetes mellitus. The incidences of CAD including a high coronary artery calcium score (≥100), obstructive coronary artery disease, and multivessel disease were significantly higher in subjects with low BMD. After adjusting for age and cardiovascular risk factors, osteoporosis was associated with a high coronary artery calcium score (p = 0.015) and with obstructive coronary artery disease (p = 0.002). There was a trend toward significance with multivessel disease (p = 0.052). CONCLUSIONS: High coronary artery calcium score and obstructive coronary artery disease, as revealed by multidetector computed tomography, were associated with osteoporosis in asymptomatic postmenopausal women, independent of cardiovascular risk factors and age.

Clinical Feasibility of Multiplanar Reconstruction Images of Temporal Bone CT in the Diagnosis of Temporal Bone Fracture with Otic-Capsule-Sparing Facial Nerve Paralysis.

The aim of this study is to evaluate the feasibility of multiplanar reconstructive (MPR) imaging of temporal bone CT in the diagnosis of temporal bone fracture with oticcapsule-sparing facial nerve paralysis. Twelve patients with traumatic facial nerve paralysis with otic-capsule sparing and temporal bone fractures were selected. Multiplanar reconstruction images were obtained with the V-works 4.0 software program (Cybermed, Seoul, Korea) using axial scanning of high-resolution temporal bone CT of the fracture line. The clinical profiles of the patients displaying temporal bone fractures were examined in relation to the findings. Multiplanar images of the fracture line provided information regarding the direction of the external force that fractured the temporal bone. The fracture line was more continuous in the MPR images than in the axial view. All patients showed an imaginary extended fracture line directed toward the otic capsule. The direction of the fracture line toward the middle ear cavity is important, as it may suggest insult to the otic capsule. The MPR image parallel to the fracture line of the temporal bone provides a guideline for the vector of the force that induced the fracture. Thorough investigation of the critical organs during surgical exploration is recommended if the direction of the fracture in the MPR image points toward the otic capsule in the middle ear even if the fracture line relative to the otic capsule is not well defined in the axial or CT view.

The fate of patients on the waiting list for lung transplantation in Korea.

Lung transplantation for end-stage lung disease results in prolonged actuarial survival and improved pulmonary function. However, the shortage of donor lungs has been a major limiting factor in transplantation. The purpose of this study was to analyze the waiting time and mortality rate for each disease entity. The medical records of all patients listed in The Korean Network for Organ Sharing (KONOS) from May 1996 to May 2011 were analyzed to identify waiting times and causes of death. During the study period, 146 patients (86 males and 60 females) of mean age of 46.6 years (range; 5 to 73 years) showed idiopathic pulmonary fibrosis (IPF; n = 61), chronic obstructive pulmonary disease (COPD; n = 19) or bronchiectasis (n = 15). Sixty-five patients (44.5%) underwent lung or heart-lung transplantation. Sixty-two patients (42.5%) expired during the waiting period, and 19 patients are still on the waiting list. The mortality rate while waiting was highest among patients with primary pulmonary hypertension (62.5%) followed by IPF (57.4%), and acute respiratory distress syndrome (ARDS) (55.6%). The mean time from diagnosis to registration in KONOS was 15.5 months among the expired and 13.2 months in the transplanted group (P = .455). The mean time on waiting list was 8.2 months in the expired group and 3.7 months in the transplanted group (P = .012). In the expired group, the mean survival time was significantly shorter among patients with ARDS (2.2 months, P = .004) compared to IPF (7.9 months), COPD (10.7 months), and primary pulmonary hypertension (PPH) (30.0 months). The high mortality rate (42.5%) during the waiting period in Korea may result from the lack of donors and the delay in registration.

Donor evaluation for lung transplantation in Korea.

Lung transplantation for end-stage lung disease results in prolonged survival and improved pulmonary function. However, the shortage of donor lungs has been a major limiting factor in Korea. We sought to investigate the number and utilization of donor lungs by the five institutions performing LTx in Korea, retrospectively reviewing outcomes of organs registered in the Korean Network for Organ Sharing from January to December, 2010. Lungs were offered from 270 brain-dead patients (189 males and 81 females) of mean age of 45.2 ± 14.2 years (range, 12 to 77 years). The most common cause of brain death was hemorrhage (n = 219, 81%). Only 18 (6.7%) donor lungs were used, which was low compared with kidney (93.3%), liver (86.3%), heart (26.7%), and pancreas (11.1%) use. The mean age of donors of transplanted lungs was 35.7 years (range, 14 to 51 years) compared with 45.9 years for other organs (P = .003). The characteristics of utilized donor lungs were: mean partial pressure of oxygen (PaO(2)), 300.9 mm Hg; mean smoking history, as 2.7 pack-years; and mean body mass index, 21.2 kg/m(2). The causes of refusal were medical ineligibility (n = 129) including poor PaO(2), abnormal chest x-ray, long smoking history, older age (n = 46), no properly matched recipient (n = 46), unknown (n = 17), and family withdrawal (n = 14). Only 8 (33.3%) were transplanted from standard criteria and 10 from the lungs that did not satisfy these criteria. An efficient utilization system is needed to improve lung transplantations.

Elevated serum antibodies against insulin-like growth factor-binding protein-2 allow detecting early-stage cancers: evidences from glioma and colorectal carcinoma studies.

BACKGROUND: Tumor-specific immunity of insulin-like growth factor-binding protein-2 (IGFBP-2) has been reported in several cancers. We aimed to assess the role of serum IGFBP-2 antibodies (IGFBP-2 Abs) in early cancer detection. PATIENTS AND METHODS: Glioma and colorectal carcinoma (CRC) were used as models. Serum IGFBP-2 and IGFBP-2 Abs were measured in 260 tumor patients (145 gliomas, 45 colorectal polyps, and 70 CRCs) and 141 controls. Receiver operating characteristic curves were applied. RESULTS: Serum IGFBP-2 Ab levels were significantly elevated in tumors (mean: 82 ng/ml, median: 17 ng/ml, range: 0-1387 ng/ml) compared with controls (11, 0, 0-212 ng/ml) (P < 0.0001) and higher in early than advanced cancers opposite of serum IGFBP-2 levels. IGFBP-2 Abs effectively discriminated between controls and grade II and III gliomas [area under the curve (AUC): 0.821-0.864; 95% confidence interval (CI) = 0.762-0.936; P < 0.0001], and CRC I-II (AUC: 0.668; 95% CI = 0.566-0.770; P = 0.002) as well as indicative of advanced polyps at high risk of CRC (AUC: 0.72; 95% CI = 0.630-0.811; P < 0.0001). The sensitivity and specificity for diagnosing grade II-III gliomas reached 66%-84% and 81%. Combined serum IGFBP-2 and IGFBP-2 Abs augmented the discriminative power of all stage tumors (AUC: 0.823), gliomas (AUC: 0.800), and CRCs (AUC = 0.917). CONCLUSION: Our results first demonstrate IGFBP-2 Abs for early cancer detection and in combination of serum IGFBP-2 for improved cancer diagnosis.

Inhibition of gliomagenesis and attenuation of mitotic transition by MIIP.

The migration and invasion inhibitor protein (MIIP, also known as IIp45) was discovered as a negative regulator of cell migration and invasion in glioma. Our previous studies have shown that the MIIP protein was reduced or undetectable in some tissue samples obtained from patients with glioblastoma. The significance of MIIP in gliomagenesis is unknown. In this study, we report that MIIP has an important role in the inhibition of gliomagenesis and attenuation of mitotic transition. Increased MIIP expression levels inhibited colony formation and cell growth of glioma cell lines in vitro, whereas decreased expression by specific small interfering RNA for MIIP resulted in increased cell growth. Expression of MIIP in a glial-specific mouse model blocked glioma development and progression, thus showing that MIIP is an inhibitor of gliomagenesis. Furthermore, we show that MIIP attenuates mitotic transition and results in increased mitotic catastrophe. The biochemical mechanism of MIIP in this process is associated with its regulation of anaphase-promoting complex (APC/C) activity. MIIP interacts directly with Cdc20, and the interaction of MIIP with Cdc20 inhibits APC/C-mediated degradation of cyclin B1. Thus, MIIP attenuates mitotic transition and increases mitotic catastrophe, thereby inhibiting glioma development and progression.

Pretreatment with calcitonin gene-related peptide attenuates hepatic ischemia/reperfusion injury in rats.

OBJECTIVE: Oxygen free radicals and apoptosis play important roles in liver ischemia/reperfusion (I/R) injury. We sought to investigate the protective effect of calcitonin gene-related peptide (CGRP) to attenuate liver I/R injury due to oxygen free radicals and apoptosis. MATERIALS AND METHODS: Harvested rat livers were perfused via the portal vein with 60 mL of 4 degrees C histidine-tryptophan-ketoglutarate (HTK) solution alone in the control group, or with the same solution containing CGRP (3 microg/10 g body weight) in the experimental group. After 24 hours of cold storage, hepatic enzyme leakage, portal venous pressure, oxygen consumption, total adenine nucleotides (TAN), bile production, lipoperoxide (LPO) release, apoptosis, and histochemical changes were evaluated upon 45 minutes of isolated reperfusion. RESULTS: Compared with control livers, CGRP-treated organs showed significantly decreased alanine aminotransferase (ALT) and glutamate-lactate dehydrogenase (GLDH) leakage and portal venous pressure (2.0 +/- 0.3 vs 4.0 +/- 0.4 mmHg; P < .01), with significantly increased bile production (8.56 +/- 0.76 vs 3.34 +/- 0.68 microL/g/45 min; P < .01), oxygen consumption (5.14 +/- 0.4 vs 2.57 +/- 0.2 microL/g/min; P < .01), and total adenine nucleotides (TAN) (11.1 +/- 0.71 vs 7.02 +/- 0.53 micromol/g; P < .01) upon reperfusion as signs of recovered viability. We observed infrequent positive terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labeling (TUNEL) staining, especially in sinusoidal lining cells (SLC). The percentage of TUNEL-positive cells in the CGRP group was significantly decreased compared with the control group: (4.1 +/- 0.67 vs 8.0 +/- 1.27; P < .05). Perfusate levels of low molecular weight (LMW) histone-associated DNA fragments (0.36 +/- 0.04 vs 0.53 +/- 0.06 AU; P < .05) were also decreased, coupled with strong 5'-nucleotidase (5'-NT) and LDH activity staining concentrated on the endothelial cells. LPO release in the perfusate was largely decreased: (0.12 +/- 0.02 vs 0.36 +/- 0.04 nmoL/g, P < .01). CONCLUSION: CGRP ameliorated liver I/R injury due to reactive oxygen species and apoptosis.

Exogenous superoxide dismutase prevents peroxynitrite-induced apoptosis in non-heart-beating donor livers.

OBJECTIVE: To investigate the role of oxygen free radicals in the induction of apoptosis in non-heart-beating donor (NHBD) livers, and if superoxide dismutase (SOD) ameliorates these alterations. METHODS: Rat livers were perfused via the portal vein with histidine/tryptophan/alpha-ketoglutarate solution from heart-beating donors (HBD) or 60-min warm ischemia from NHBD, with or without the addition of SOD. After 24 h, cold storage livers were evaluated by isolated reperfusion. RESULTS: NHBD showed significantly higher enzyme leakage and elevated portal venous pressure (PVP) versus HBD. Bile and total adenine nucleotides (TAN) were significantly decreased. Apoptosis was prominent in sinusoidal lining cells, coupled with strong nitrotyrosine staining (NTR). The concentrations of nitric oxide and lipoperoxides were largely increased. SOD medication reduced hepatic enzyme release by 30% and lipoperoxides by nearly 50%. Apoptosis and NTR were significantly decreased, and PVP was strikingly reduced to normal values. A 3-fold enhancement in bile production and 1.5-fold increase in TAN of the liver tissue were also observed. CONCLUSION: NHBD livers are prone to severe reoxygenation injury promoted by oxygen free radicals, massive nitrite oxide production and peroxynitrite-induced apoptosis within the sinusoids. Antioxidant medication with SOD should be considered as a useful means of preserving NHBD livers.

Autoimmune dacryoadenitis and keratoconjunctivitis induced in rabbits by subcutaneous injection of autologous lymphocytes activated ex vivo against lacrimal antigens.

Autologous peripheral blood lymphocytes (PBL), activated in a mixed cell reaction when co-cultured with purified rabbit lacrimal epithelial cells, are known to induce a Sjögren's-like autoimmune dacryoadenitis and keratoconjunctivitis when injected directly back into the donor animal's inferior lacrimal gland (LG). This study shows that autoreactive lymphocytes injected subcutaneously in a site away from the LG is capable of inducing an autoimmune disease in a rabbit. Induced disease (ID) develops more slowly, taking 4weeks as compared to 2weeks in the direct injection model. Initially, both clinical symptoms and histopathology are less pronounced than in the direct injection ID model, but later the immunocytochemistry shows the same CD4+/CD8+ ratio of 4:1 for both injection methods. The finding that lymphocytes activated against lacrimal antigens can travel or home from the injection site back to the inferior and superior LG, as well as the conjunctiva, suggests that these anatomical sites may have common epitopes that induce pathogenic CD4+ T cells that produce a Sjögren's-like syndrome.

Fish oil supplementation improves large arterial elasticity in overweight hypertensive patients.

OBJECTIVES: To observe the effect of fish oil supplementation on arterial elasticity and blood pressure (BP) in overweight hypertensive patients. SUBJECTS AND METHODS: This was a double-blind, randomized and placebo-controlled clinical study, in which 52 overweight hypertensive patients from a community were selected and randomly allocated to two groups (26 in the fish oil group (3 g day(-1), fish oil capsules) and 26 in the placebo group (only capsules). All the subjects were follow-up for 8 weeks. The arterial elasticity was determined by CVProfilor DO-2020 and expressed as elasticity indexes (C(1)-large artery and C(2)-small artery). During the follow-up, totally nine cases were dropped out (three cases from the fish oil group and six cases from the placebo group). RESULTS: After 8 weeks follow-up, the large artery elasticity in the fish oil group, compared with its baseline, was significantly improved (C(1): 15.5+/-1.5 vs 12.8+/-3.7 ml mm Hg(-1) x 10), whereas no effects were found in the placebo group (C(1): 13.0+/-3.4 vs 13.4+/-3.8 ml mm Hg(-1) x 10), P=0.027, RM-ANOVA across the two groups. The small artery elasticity (C(2)), BP and pulse pressure were not found any changes, either in the fish oil group or in the placebo group. At same time, the serum soluble vascular cell adhesion molecule-1(sVCAM-1) and leptin levels, the lipid profile and insulin sensitivity index (ISI) as well, did not show significant differences between two groups. CONCLUSIONS: Fish oil supplementation certainly would improve large arterial elasticity but no effect on BP in overweight hypertensive patients. Further study is needed to confirm the benefits of fish oil supplementation on age-related increases in arterial stiffness.

pH-Controllable drug release using hydrogel encapsulated mesoporous silica.

Amine-functionalized mesoporous SBA-15 silica loaded with bovine serum albumin (BSA) has been successfully encapsulated with a thin layer coating of poly(acrylic acid) PAA, with the entrapped BSA being released from the PAA-encapsulated SBA-15 at the higher pH value of 7.4 rather than at the lower pH value of 1.2. This novel drug delivery system has a potential application in the release of protein drug to the site of higher pH value, such as small intestine or colon.

Effect of interleukin-4 on vascular endothelial growth factor production in rheumatoid synovial fibroblasts.

Interleukin (IL)-4 has been demonstrated to have anti-inflammatory and anti-tumour activity. Because aberrant angiogenesis is a significant pathogenic component of tumour growth and chronic inflammation, we investigated the effect of IL-4 on the production of vascular endothelial growth factor (VEGF) by synovial fibroblasts derived from patients with rheumatoid arthritis (RA). Fibroblast-like synoviocytes (FLS) were prepared from synovial tissues of RA and incubated with different concentrations of IL-4 in the presence or absence of transforming growth factor (TGF)-beta. VEGF level was measured by enzyme-linked immunosorbent assay and semiquantitative reverse transcription--polymerase chain reaction. Treatment of FLS with IL-4 alone caused a dose-dependent increase in VEGF levels. In contrast, IL-4 exhibited the inhibitory effect on VEGF production when FLS were stimulated with TGF-beta. Combined treatment of IL-4 and IL-10 inhibited TGF-beta-induced VEGF production in an additive fashion. TGF-beta increased the induction of cyclooxygenase-2 mRNA, which was inhibited significantly by the treatment of IL-4. NS-398, a COX-2 inhibitor, inhibited TGF-beta-induced VEGF production in a dose-dependent manner. Furthermore, exogenous addition of prostaglandin E2 (PGE2) restored IL-4 inhibition on TGF-beta induced VEGF production. Collectively, our results suggest that IL-4 have an anti-angiogenic effect, especially in the inflammatory milieu of RA by inhibiting the VEGF production in synovial fibroblasts.

Hydroxychloroquine potentiates Fas-mediated apoptosis of rheumatoid synoviocytes.

Inadequate apoptosis may contribute to the synovial hyperplasia associated with rheumatoid arthritis (RA). The Fas-associated death domain protein (FADD)-like interleukin (IL)-1beta-converting enzyme (FLICE)-inhibitory protein (FLIP), which is an apoptotic inhibitor, has been implicated in the resistance to Fas-mediated apoptosis of synoviocytes. This study investigated whether hydroxychloroquine (HCQ), an anti-rheumatic drug, induces the apoptosis of rheumatoid synoviocytes, and modulates the expression of FLIP. Fibroblast-like synoviocytes (FLS) were prepared from the synovial tissues of RA patients, and were cultured with various concentrations of HCQ in the presence or absence of the IgM anti-Fas monoclonal antibodies (mAb) (CH11). Treatment with HCQ, ranging from 1 to 100 microM, induced the apoptosis of FLS in a dose- and time-dependent manner. The increase in synoviocytes apoptosis by HCQ was associated with caspase-3 activation. A combined treatment of HCQ and anti-Fas mAb increased FLS apoptosis and caspase-3 activity synergistically, compared with either anti-Fas mAb or HCQ alone. The Fas expression level in the FLS was not increased by the HCQ treatment, while the FLIP mRNA and protein levels were decreased rapidly by the HCQ treatment. Moreover, time kinetics analysis revealed that the decreased expression of FLIP by HCQ preceded the apoptotic event that was triggered by HCQ plus anti-Fas mAb. Taken together, HCQ increases the apoptosis of rheumatoid synoviocytes by activating caspase-3, and also sensitizes rheumatoid synoviocytes to Fas-mediated apoptosis. Our data suggest that HCQ may exert its anti-rheumatic effect in rheumatoid joints through these mechanisms.

Functionalized SBA-15 materials as carriers for controlled drug delivery: influence of surface properties on matrix-drug interactions.

Mesoporous SBA-15 materials were functionalized with amine groups through postsynthesis and one-pot synthesis, and the resulting functionalized materials were investigated as matrixes for controlled drug delivery. The materials were characterized by FTIR, N(2) adsorption/desorption analysis, zeta potential measurement, XRD, XPS, and TEM. Ibuprofen (IBU) and bovine serum albumin (BSA) were selected as model drugs and loaded onto the unmodified and functionalized SBA-15. It was revealed that the adsorption capacities and release behaviors of these model drugs were highly dependent on the different surface properties of SBA-15 materials. The release rate of IBU from SBA-15 functionalized by postsynthesis is found to be effectively controlled as compared to that from pure SBA-15 and SBA-15 functionalized by one-pot synthesis due to the ionic interaction between carboxyl groups in IBU and amine groups on the surface of SBA-15. However, SBA-15 functionalized by one-pot synthesis is found to be more favorable for the adsorption and release of BSA due to the balance of electrostatic interaction and hydrophilic interaction between BSA and the functionalized SBA-15 matrix.