CST6 suppresses osteolytic bone disease in multiple myeloma by blocking osteoclast differentiation

Osteolytic bone disease is a hallmark of multiple myeloma (MM). A significant fraction (~20%) of MM patients do not develop osteolytic lesions (OLs). The molecular basis for the absence of bone disease in MM is not understood. We combined PET-CT and gene expression profiling (GEP) of purified BM CD138⁺ MM cells from 512 newly diagnosed MM patients to reveal that elevated expression of cystatin M/E (CST6) was significantly associated with the absence of OL in MM. An enzyme-linked immunosorbent assay revealed a strong correlation between CST6 levels in BM serum/plasma and CST6 mRNA expression. Both recombinant CST6 protein and BM serum from patients with high CST6 significantly inhibited the activity of the osteoclast-specific protease cathepsin K and blocked osteoclast differentiation and function. Recombinant CST6 inhibited bone destruction in ex vivo and in vivo myeloma models. Single-cell RNA-Seq showed that CST6 attenuates polarization of monocytes to osteoclast precursors. Furthermore, CST6 protein blocks osteoclast differentiation by suppressing cathepsin-mediated cleavage of NF-κB/p100 and TRAF3 following RANKL stimulation. Secretion by MM cells of CST6, an inhibitor of osteoclast differentiation and function, suppresses osteolytic bone disease in MM and probably other diseases associated with osteoclast-mediated bone loss.     

Effects of [Met5]enkephalin on regional blood flow and vascular resistance in rabbits

Methionine enkephalin [( Met5]enkephalin) has different cardiovascular effects, depending on species and routes of peptide administration. In anesthetized animals [Met5]enkephalin decreases blood pressure and heart rate. The site(s) and the mechanism of the hypotensive effects of the peptide are not known. The main purpose of this study was to test the hypothesis that [Met5]enkephalin dilates specifically a certain vascular bed which may account for the hypotensive effect of the peptide. Anesthetized male rabbits were instrumented for the measurement of blood pressure, heart rate, electrocardiogram and renal nerve activity. Four different microspheres (15 microns) were infused into the left ventricle in 10-15 s in either saline or with [Met5]enkephalin (1 mg/kg). Upon completion of the last microsphere injection the animals were killed and 35 tissues samples were taken for the determination of blood flow. Blood flows to many organs such as brain, glandular and cardiac tissues were not altered significantly by [Met5]enkephalin. However, [Met5]enkephalin increased blood flow to skeletal muscular bed. The increase in muscle blood flow was antagonized by naloxone, a specific opioid antagonist. These results suggest that the hypotensive action of [Met5]enkephalin in anesthetized rabbit is in part due to its vasodilatory effect in skeletal muscle.     

Synovial Osteochondromatosis: Clinical Characteristics Unique to the Shoulder

BackgroundSynovial osteochondromatosis (SOC) of the shoulder is a rare condition with unclear characteristics. This study evaluated the clinical features and postoperative functional outcomes of SOC of the shoulder that are distinct from SOC of other joints.MethodsThe characteristics of 28 shoulders with SOC that underwent arthroscopy were retrospectively assessed. Ten shoulders (35.7%) had rotator cuff tears (RCTs) and underwent concomitant arthroscopic rotator cuff repair. The mean follow-up period was 83.6 months (range, 24–154 months). Demographic characteristics and loose bodies localized under arthroscopy were compared between cases with and without concomitant RCTs. Radiography, ultrasonography, or magnetic resonance imaging were performed preoperatively and postoperatively. Visual analog scale (VAS) scores for pain and satisfaction were evaluated for all cases, and functional scores were assessed in shoulders with concomitant RCTs.ResultsThe average age was 36.2 ± 15.6 years among patients without RCTs and 58.3 ± 7.2 years among patients with RCTs. Seven shoulders (7%) had osteoarthritis. Arthroscopy revealed loose bodies in multiple spaces, including the glenohumeral joint, subacromial (SA) space, and biceps tendon sheath. Overall, loose bodies were found in multiple spaces in 12 shoulders (42.9%). Loose bodies were found in the SA space only in 4 shoulders (22.2%) without RCTs and in 7 shoulders (70.0%) with RCTs. VAS for pain decreased significantly from 3.9 ± 2.3 to 1.1 ± 1.3 (p < 0.001). The functional scores increased significantly after arthroscopic management for patients with concurrent RCTs (all p < 0.05). Recurrence of SOC occurred in 3 of the 22 shoulders (13.6%) who underwent postoperative imaging, but no patient had a recurrent RCT.ConclusionsPain relief and patient satisfaction were achieved via arthroscopic management. Unlike in other joints, loose bodies can occur simultaneously in several spaces in the shoulder, including the glenohumeral joint, SA space, and biceps tendon sheath. Early diagnosis of SOC of the SA space can help prevent osteoarthritis and RCT progression.     

The effects of oral steroid duration on stricture prevention after extensive endoscopic submucosal dissection for superficial esophageal cancer

BackgroundEsophageal stricture is a major complication of endoscopic submucosal dissection (ESD) in patients with superficial esophageal cancer (SEC). Oral steroids have been used to prevent esophageal stricture in patients with more than 75% of the esophageal circumference resected. However, there are no established guidelines regarding the optimal duration of steroid use. This retrospective observational study aimed to compare the incidence of esophageal stricture according to the period of prophylactic oral steroid use and to identify the risk factors for esophageal stricture.MethodsEighty-one patients who were prescribed prophylactic steroid after undergoing ESD for SEC with more than 75% of esophageal circumference resected were enrolled. Patients were classified into the four-week steroid group (n=72) or eight-week steroid group (n=9) to compare the incidence of esophageal stricture. In addition, the patients were subdivided into those who developed esophageal stricture (n=24) and those who did not (n=57) to identify the risk factors for esophageal stricture.ResultsTwenty patients (27.8%) in the four-week oral steroid group and four patients (44.4%) in the eight-week oral steroid group developed esophageal stricture (P=0.44). The univariable analysis identified tumor size, longitudinal length of semi-circumferential resection, and proportion of circumferential resection as risk factors of esophageal stricture. The multivariable analysis identified the proportion of circumferential resection as an independent risk factor. After adjusting for the proportion of circumferential resection, the incidence of stricture was marginally higher in the eight-week steroid group [P=0.05; odds ratio (OR): 5.69; 95% confidence interval (CI): 1.01–32.15].ConclusionsEight weeks of oral steroid prophylaxis does not reduce the risk of stricture after extensive ESD more than four weeks of oral steroid prophylaxis. The proportion of circumferential resection is the strongest risk factor for stricture in patients with SEC undergoing ESD.     

Phenotype of Asthma-COPD Overlap in COPD and Severe Asthma Cohorts

BackgroundAsthma and chronic obstructive pulmonary disease (COPD) are airway diseases with similar clinical manifestations, despite differences in pathophysiology. Asthma-COPD overlap (ACO) is a condition characterized by overlapping clinical features of both diseases. There have been few reports regarding the prevalence of ACO in COPD and severe asthma cohorts. ACO is heterogeneous; patients can be classified on the basis of phenotype differences. This study was performed to analyze the prevalence of ACO in COPD and severe asthma cohorts. In addition, this study compared baseline characteristics among ACO patients according to phenotype.MethodsPatients with COPD were prospectively enrolled into the Korean COPD subgroup study (KOCOSS) cohort. Patients with severe asthma were prospectively enrolled into the Korean Severe Asthma Registry (KoSAR). ACO was defined in accordance with the updated Spanish criteria. In the COPD cohort, ACO was defined as bronchodilator response (BDR) ≥ 15% and ≥ 400 mL from baseline or blood eosinophil count (BEC) ≥ 300 cells/μL. In the severe asthma cohort, ACO was defined as age ≥ 35 years, smoking ≥ 10 pack-years, and post-bronchodilator forced expiratory volume in 1 s/forced vital capacity < 0.7. Patients with ACO were divided into four groups according to smoking history (threshold: 20 pack-years) and BEC (threshold: 300 cells/μL).ResultsThe prevalence of ACO significantly differed between the COPD and severe asthma cohorts (19.8% [365/1,839] vs. 12.5% [104/832], respectively; P < 0.001). The percentage of patients in each group was as follows: group A (light smoker with high BEC) – 9.1%; group B (light smoker with low BEC) – 3.7%; group C (moderate to heavy smoker with high BEC) – 73.8%; and group D (moderate to heavy smoker with low BEC) – 13.4%. Moderate to heavy smoker with high BEC group was oldest, and showed weak BDR response. Age, sex, BDR, comorbidities, and medications significantly differed among the four groups.ConclusionThe prevalence of ACO differed between COPD and severe asthma cohorts. ACO patients can be classified into four phenotype groups, such that each phenotype exhibits distinct characteristics.     

Synthesis of a 35S‐labeled dinucleoside phosphorothioate prodrug,an orally bioavailable anti‐HBV agent

The ³⁵S‐labeled, dinucleoside phosphorothioate 1, an orally available agent against hepatitis B virus, was prepared in eight steps with high specific activity and radiochemical purity. Radiolabeled 3H‐benzodithiole‐3‐one‐1,1‐dioxide was synthesized in four steps from ³⁵S₈ and was used as the sulfurizing reagent. Copyright © 2012 John Wiley & Sons, Ltd.     

Inhibition of STAT3 signaling and induction of SHP1 mediate antiangiogenic and antitumor activities of ergosterol peroxide in U266 multiple myeloma cells

Background  

Ergosterol peroxide (EP) derived from edible mushroom has been shown to exert anti-tumor activity in several cancer cells. In the present study, anti-angiogenic activity of EP was investigated with the underlying molecular mechanisms in human multiple myeloma U266 cells.     

Yoga Training Improves Metabolic Parameters in Obese Boys

Yoga has been known to have stimulatory or inhibitory effects on the metabolic parameters and to be uncomplicated therapy for obesity. The purpose of the present study was to test the effect of an 8-week of yoga-asana training on body composition, lipid profile, and insulin resistance (IR) in obese adolescent boys. Twenty volunteers with body mass index (BMI) greater than the 95th percentile were randomly assigned to yoga (age 14.7±0.5 years, n=10) and control groups (age 14.6±1.0 years, n=10). The yoga group performed exercises three times per week at 40~60% of heart-rate reserve (HRR) for 8 weeks. IR was determined with the homeostasis model assessment of insulin resistance (HOMA-IR). After yoga training, body weight, BMI, fat mass (FM), and body fat % (BF %) were significantly decreased, and fat-free mass and basal metabolic rate were significantly increased than baseline values. FM and BF % were significantly improved in the yoga group compared with the control group (p<0.05). Total cholesterol (TC) was significantly decreased in the yoga group (p<0.01). HDL-cholesterol was decreased in both groups (p<0.05). No significant changes were observed between or within groups for triglycerides, LDL-cholesterol, glucose, insulin, and HOMA-IR. Our findings show that an 8-week of yoga training improves body composition and TC levels in obese adolescent boys, suggesting that yoga training may be effective in controlling some metabolic syndrome factors in obese adolescent boys.