The ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family consists of 19 proteases. These enzymes are known to play important roles in development, angiogenesis and coagulation; dysregulation and mutation of these enzymes have been implicated in many disease processes, such as inflammation, cancer, arthritis and atherosclerosis. This review briefly summarizes the structural organization and functional roles of ADAMTSs in normal and pathological conditions, focusing on members that are known to be involved in the degradation of extracellular matrix and loss of cartilage in arthritis, including the aggrecanases (ADAMTS-4 and ADAMTS-5), ADAMTS-7 and ADAMTS-12, the latter two are associated with cartilage oligomeric matrix protein (COMP), a component of the cartilage extracellular matrix (ECM). We will discuss the expression pattern and the regulation of these metalloproteinases at multiple levels, including their interaction with substrates, induction by pro-inflammatory cytokines, protein processing, inhibition (e.g., TIMP-3, alpha-2-macroglobulin, GEP), and activation (e.g., syndecan-4, PACE-4).
ADAM Proteins ; antagonists & inhibitors ; chemistry ; genetics ; physiology ; Aggrecans ; metabolism ; Alternative Splicing ; Arthritis ; enzymology ; genetics ; Cartilage ; enzymology ; Endopeptidases ; genetics ; physiology ; Extracellular Matrix ; enzymology ; Humans ; Protein Structure, Tertiary

BACKGROUND AND OBJECTIVECD133-positive colon cancer stem like cells (CSLCs) are resistant to the conventional cytotoxic drug 5-fluorouracil (5-FU). Wnt signaling pathway plays important roles in colon cancer carcinogenesis and metastasis, and regulates the self-renewal capacity of CSLCs. In the present study, we explored the impact of 5-FU on Wnt signaling pathway of CD133-positive colon CSLCs, and the relation between Wnt signaling pathway and drug resistance of CD133-positive colon CSLCs.

METHODSMagnetic activation cell separation was used to collect CD133-positive cells from colon cancer cell line DLD1, which was transfected with luciferase reporter for Wnt signaling activity. The activity of Wnt signaling pathway was compared between CD133-positive and CD133-negative cells. After the treatment with 1 μg/mL of 5-FU, the cell proliferation rates of DLD1 cells, CD133-positive cells, and CD133-negative cells were compared. After the treatment with 1 μg/mL and 10 μg/mL of 5-FU for 48 h, Wnt activity was compared between CD133-positive and CD133-negative cells. The expression of CD133 and cell apoptosis of CD133-positive cells was detected after exposure to 50 ng/mL of dickkopf (DKK)-1, a Wnt pathway inhibitor.

RESULTSAfter the treatment with 5-FU, the cell proliferation rate of CD133-positive cells was higher than that of CD133-negative cells and the sensitivity of CD133-positive cells to 5-FU decreased. Wnt activity was higher in CD133-positive cells than in CD133-negative cells [(46.3 ± 0.3)% vs. (33.9 ± 2.7)%, P = 0.009]. After the treatment with 1 μg/mL and 10 μg/mL of 5-FU, Wnt activity of CD133-positive cells was (90.1 ± 10.0)% (P = 0.012) and (52.9 ± 2.5)% (P = 0.047), respectively, whereas that of CD133-negative cells was (35.5 ± 3.3)% (P = 0.434) and (26.5 ± 0.4)% (P = 0.046), respectively. CD133 expression in CD133-positive cells decreased from (87.2 ± 5.3)% to (60.6 ± 3.1)% (P = 0.022) after treatment with DKK-1, whereas the cell apoptosis rate increased from (11.8 ± 0.2)% to (28.3 ± 0.6)% (P = 0.013).

CONCLUSIONSWnt activity is higher in CD133-positive DLD1 cells than in CD133-negative DLD1 cells. 5-FU can upregulate Wnt activity of CD133-positive colon CSLCs. Blocking Wnt activity may reverse drug sensitivity of CD133-positive cells to 5-FU.

AC133 Antigen ; Antigens, CD ; metabolism ; Antimetabolites, Antineoplastic ; pharmacology ; Apoptosis ; drug effects ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Colonic Neoplasms ; metabolism ; pathology ; Drug Resistance, Neoplasm ; Fluorouracil ; pharmacology ; Glycoproteins ; metabolism ; Humans ; Intercellular Signaling Peptides and Proteins ; pharmacology ; Neoplastic Stem Cells ; metabolism ; pathology ; Peptides ; metabolism ; Wnt Signaling Pathway ; drug effects

OBJECTIVETo compare the efficacy and safety of gefitinib or docetaxel in Chinese patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who had failed previous platinum-based first-line chemotherapy.

METHODSWe retrospectively reviewed 222 Chinese NSCLC patients in the subgroup of INTEREST (gefitinib versus docetaxel in previously treated non-small cell lung cancer) study. Survival analysis was evaluated by Kaplan-Meier method, and Functional Assessment of Cancer Therapy-Lung (FACT-L) was used to compare the quality of life between gefitinib group and docetaxel group.

RESULTSA total of 222 patients were analyzed in this subgroup study. 107 patients were treated with gefitinib, and 115 patients treated with docetaxel. There were all balanced between the two groups in terms of sex, age, staging and pathology in patient characteristics. The median overall survival in the two groups was similar (11 months in the gefitinib group vs. 14.0 months in the docetaxel group, P = 0.783). The progression-free survival (PFS) was also similar between the two groups (median PFS: 3.4 months in gefitinib group vs. 3.8 months in docetaxel group, P = 0.214). The response rate in gefitinib group was significantly higher than that in the docetaxel group (21.9% vs. 9.1%, P = 0.016).

CONCLUSIONThe efficacy of gefitinib is similar with that of docetaxel in pretreated patients with locally advanced or metastatic NSCLC, however, gefitinib is more favorable in the tolerance and quality of life improvement.

Adult ; Antineoplastic Agents ; adverse effects ; therapeutic use ; Carcinoma, Non-Small-Cell Lung ; drug therapy ; pathology ; Diarrhea ; chemically induced ; Disease-Free Survival ; Exanthema ; chemically induced ; Female ; Humans ; Lung Neoplasms ; drug therapy ; pathology ; Male ; Neoplasm Staging ; Neutropenia ; chemically induced ; Platinum ; therapeutic use ; Quality of Life ; Quinazolines ; adverse effects ; therapeutic use ; Randomized Controlled Trials as Topic ; Remission Induction ; Retrospective Studies ; Survival Rate ; Taxoids ; adverse effects ; therapeutic use

Background: To compare risk of diabetic retinopathy (DR) between patients taking sodium-glucose cotransporter-2 inhibitors (SGLT2is) and those taking glucagon-like peptide-1 receptor agonists (GLP1-RAs) in routine care. Methods: This retrospective cohort study emulating a target trial included patient data from the multi-institutional Chang Gung Research Database in Taiwan. Totally, 33,021 patients with type 2 diabetes mellitus using SGLT2is and GLP1-RAs between 2016 and 2019 were identified. 3,249 patients were excluded due to missing demographics, age <40 years, prior use of any study drug, a diagnosis of retinal disorders, a history of receiving vitreoretinal procedure, no baseline glycosylated hemoglobin, or no follow-up data. Baseline characteristics were balanced using inverse probability of treatment weighting with propensity scores. DR diagnoses and vitreoretinal interventions served as the primary outcomes. Occurrence of proliferative DR and DR receiving vitreoretinal interventions were regarded as vision-threatening DR. Results: There were 21,491 SGLT2i and 1,887 GLP1-RA users included for the analysis. Patients receiving SGLT2is and GLP-1 RAs exhibited comparable rate of any DR (subdistribution hazard ratio [SHR], 0.90; 95% confidence interval [CI], 0.79 to 1.03), whereas the rate of proliferative DR (SHR, 0.53; 95% CI, 0.42 to 0.68) was significantly lower in the SGLT2i group. Also, SGLT2i users showed significantly reduced risk of composite surgical outcome (SHR, 0.58; 95% CI, 0.48 to 0.70). Conclusion Compared to those taking GLP1-RAs, patients receiving SGLT2is had a lower risk of proliferative DR and vitreoretinal interventions, although the rate of any DR was comparable between the SGLT2i and GLP1-RA groups. Thus, SGLT2is may be associated with a lower risk of vision-threatening DR but not DR development.

Humans ; Edema ; Leg

OBJECTIVETo study the early effects of coal dust on lung function in new underground coal miners.

METHODSTwo hundred and eighty-seven male miners were selected from new employees at the Xuzhou Mining Group Company as study group, and 132 male students at a mining technical school were selected as control. Data collection included: individual demographic parameters, family medical history, occupational history, and smoking history, measurement of dust concentrations in work areas, and lung function tests. This prospective cohort study took place over 3 years during which time total dust and respirable dust concentrations in the new coal miners' work areas were measured twice each month. For both miner and student groups, FVC and FEV(1) were tested initially before dust exposure, and then 15 times over the 3 years.

RESULTSThe average total dust and respirable dust concentrations in the miners' work areas were 23.8 mg/m(3) and 8.9 mg/m(3) respectively, which greatly exceeded national health criteria. During the first year of dust exposure, the miners's average FVC was higher than that of the controls (5.19 L vs 4.92 L, P < 0.01). During the 2nd and 3rd year the difference in average FVC between miners and control group was not significant (5.14 L vs 5.12 L, P > 0.05). Before dust exposure, the miners' FEV(1) was significantly higher than that of the control group (4.48 L vs 4.28 L). In the miners group, FEV(1) declined rapidly during the first year following dust exposure (from 4.48 L to 4.25 L), and in the 2nd and the 3rd year the average FEV(1) of the miners was significantly lower than that of controls (4.34 L vs 4.56 L, P < 0.01), although there were some fluctuations during the follow-up period. Overall, the average FEV(1) of miners group showed a significant decline during the study. There were significant correlations between FVC or FEV(1) and age, height, weight, and smoking. The three-year total loss of FVC and FEV(1) in smoking miners (154 ml, 184 ml) were greater than in non-smoking miners (83 ml, 91 ml).

CONCLUSIONThere are apparent effects of coal dust on lung function in new underground coal miners, with FEV(1) being more impacted than FVC. Smoking may aggravate the effect of dust exposure on reducing lung function.

Adolescent ; Adult ; Coal Mining ; Cohort Studies ; Dust ; analysis ; Forced Expiratory Volume ; Humans ; Inhalation Exposure ; adverse effects ; Male ; Occupational Exposure ; adverse effects ; Prospective Studies ; Pulmonary Ventilation ; physiology ; Smoking ; physiopathology

INTRODUCTIONSchwannomas that arise within the muscle plane are called intramuscular schwannomas. The low incidence of these tumours and the lack of specific clinical features make preoperative diagnosis difficult. Herein, we report our experience with intramuscular schwannomas. We present details of the clinical presentation, radiological diagnosis and management of these tumours.

METHODSBetween January 2011 and December 2013, 29 patients were diagnosed and treated for histologically proven schwannoma at the National University Hospital, Singapore. Among these 29 patients, eight (five male, three female) had intramuscular schwannomas.

RESULTSThe mean age of the eight patients was 40 (range 27-57) years. The most common presenting feature was a palpable mass. The mean interval between surgical treatment and the onset of clinical symptoms was 17.1 (range 4-72) months. Six of the eight tumours (75.0%) were located in the lower limb, while 2 (25.0%) were located in the upper limb. None of the patients had any preoperative neurological deficits. Tinel's sign was present in one patient. Magnetic resonance (MR) imaging showed that the findings of split-fat sign, low signal margin and fascicular sign were present in all patients. The entry and exit sign was observed in 4 (50.0%) patients, a hyperintense rim was observed in 7 (87.5%) patients and the target sign was observed in 5 (62.5%) patients. All patients underwent microsurgical excision of the tumour and none developed any postoperative neurological deficits.

CONCLUSIONIntramuscular schwannomas demonstrate the findings of split-fat sign, low signal margin and fascicular sign on MR imaging. These findings are useful for the radiological diagnosis of intramuscular schwannoma.

Adult ; Female ; Humans ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Muscle Neoplasms ; diagnostic imaging ; Neurilemmoma ; diagnostic imaging ; Postoperative Period ; Retrospective Studies ; Singapore

Objective: To evaluate predictors of difficult intubation in patients with obstructive sleep apnoea (OSA). Methodology: Prospective series of 405 OSA patients (350 males/55 females) who had upper airway surgery. Procedures included functional endoscopic sinus surgery, septoplasty, turbinate reduction, palate/tonsil surgery, and/or tongue base surgery. Intubation difficulty (ID) was assessed using Mallampati grade, Laryngoscopic grade (Cormack and Lehane), and clinical parameters including BMI, neck circumference, thyromental distance, jaw adequacy, neck movements and glidescope grading. Results: Mean age was 41.6 years old; mean BMI 26.6; mean neck circumference 44.5cm; mean Apnea Hypopnea Index (AHI) was 25.0; and mean LSAT 82%. The various laryngeal grades (based on Cormack and Lehane), grade 1 - 53 patients (12.9%), grade 2A - 127 patients (31.0%), grade 2B - 125 patients (30.5%), grade 3 - 93 patients (22.7%) and grade 4 - seven patients (1.7%); hence, 24.4% had difficulties in intubation. Parameters that adversely affected intubation were, age of the patient, opening of mouth, retrognathia, overbite, overjet, limited neck extension, thyromental distance, Mallampati grade, and macroglossia (p<0.001). Body mass index (BMI) (p=0.087), neck circumference (p=0.645), neck aches (p=0.728), jaw aches (p=0.417), tonsil size (p=0.048), and AHI (p=0.047) had poor correlation with intubation. BMI-adjusted for Asians and Caucasians, showed that Asians were more likely to have difficulties in intubation (adjusted OR = 4.6 (95%Confidence Interval: 1.05 to 20.06) (p=0.043), compared to the Caucasian group.

Acorus macrospadiceus is a common medicinal and food plant used different ethnic groups in Guizhou and surrounding areas. In this paper, the leaf and rhizome tissues of A. macrospadiceus were hydro-distilled to extract the volatile oils. The chemical constituents of these oils were analyzed by GC-MS and identified using the NIST 14.0 & NIST 14.0s mass spectral libraries. The relative contents of chemical constituents from the different plant parts were determined by area normalization. The analysis of A. macrospadiceus volatile oils resulted in the identification of 25 compounds from the leaf and 36 compounds from the rhizome. The identified compounds accounted for 97.85% of the leaf essential oil content and 97.18% of the rhizome essential oil content. The main volatile constituent of A. macrospadiceus was identified as estragole (93.56% of total oil content in leaf and 71.62% of total oil content in rhizome). Fourteen compounds were found to be common to essential oils of both leaf and rhizome. However, the relative amounts of these compounds were significantly different between the plant parts; the remaining identified compounds were unique to each part. This comparison of volatile oils from the different parts of A. macrospadiceus can serve as a reference for future development. Because of the higher estragole content and better harvesting sustainability of the leaves compared to rhizomes, the leaves of A. macrospadiceus deserve consideration for sustainable development. However, when we use it as a medical plant, we should draw a distinction between it with A. tatarinowii.