A new pseudo-peptide of Arg-Gly-Asp (RGD) with inhibitory effect on tumor metastasis and enzymatic degradation of extracellular matrix

A series of pseudo-peptide analogs of the Arg-Gly-Asp (RGD) sequence of fibronectin have been synthe-sized, and their anti-metastatic effects in mice and inhibitory effects on tumor cell invasion in vitro have been examined. The partially modified retro pseudo-peptide of RGD, R_rev-COCH₂CO-D (FC-63), was more effective in inhibiting tumor metastasis than the original RGDS peptide. Replacement of the malonyl moiety of FC-63 with a carboxyethylene linkage (R_rev-COCH₂CH₂-D, FC-303 ) achieved more potent inhibition of lung metastasis of melanoma cells than FC-63. Among the analogs, FC-336, a p-xylylendiamine derivative having two FC-303 moieties, showed the most potent inhibitory effect on experimental lung metastasis produced by i.v. co-injection with B16-BL6 melanoma or colon 26 M3.1 cells in a dose-dependent manner. Multiple administrations of FC-336 after tumor inoculation also showed efficient therapeutic potency against spontaneous lung metastasis of B16-BL6 melanoma in mice. Furthermore, FC-336 effectively inhibited the invasion, migration and adhesion of tumor cells in vitro, but its inhibitory effects were not more than those of RGDS peptide. Zymography analysis revealed that FC-336 inhibited the degradation of gelatin substrate by matrix metalloproteinases (MMPs) produced by tumor cells, while the RGDS peptide did not affect the enzymatic degradation. These findings indicate that the pseudo-peptides of the RGD sequence, possessing the inhibitory property of the degradation by MMPs differently from original RGD-containing peptides, may be advantageous and useful in preventing tumor metastasis. © Rapid Science 1998     

Venodilator effects of adenosine triphosphate and sodium nitroprusside; Comparisons during controlled hypotension

Adenosine triphosphate as well as sodium nitroprusside has been used for hypotensive anesthesia. The purpose of this study was to examine the possibility that two hypotensive drugs may exert different effects on venous capacitance during controlled hypotension. In rats anesthetized with ketamine, mean arterial pressure was lowered to 50mmHg by intravenous infusion of adenosine triphosphate or sodium nitroprusside. Venous capacitance was assessed before and during induced hypotension by measuring the mean circulatory filling pressure (MCFP). MCFP was measured after briefly arresting the circulation by inflating an indwelling balloon in the right atrium. MCFP was lower during adenosine triphosphate-induced as well as sodium nitroprusside-induced hypotension as compared with the respective value at control (P < 0.01 for adenosine triphosphate and sodium nitroprusside). However, the decrease in MCFP by adenosine triphosphate (0.8 ± 0.1mmHg) was less (P < 0.01) than that by sodium nitroprusside (2.3 ± 0.3mmHg). These results suggest that at a comparable level of arterial hypotension venodilator effect of adenosine triphosphate was less than that of sodium nitroprusside. Less venodilatation during adenosine triphosphate-induced hypotension may contribute to the maintenance of cardiac output during hypotensive anesthesia.(Hoka S, Takeshita A, Aishima K et al.: Venodilator effects of adenosine triphosphate and sodium nitroprusside; comparisons during controlled hypotension. J Anesth 1: 144–147, 1987)     

Comparison of Single and Dual Monitoring during Carotid Endarterectomy

We compared the rate of selective shunt and pattern of monitoring change between single and dual monitoring in patients undergoing carotid endarterectomy (CEA). A total of 121 patients underwent 128 consecutive CEA procedures. Excluding five procedures using internal shunts in a premeditated manner, we classified patients according to the monitoring: Group A (n = 72), patients with single somatosensory evoked potential (SSEP) monitoring; and Group B (n = 51), patients with dual SSEP and motor evoked potential (MEP). Among the 123 CEAs, an internal shunt was inserted in 12 procedures (9.8%) due to significant changes in monitoring (Group A 5.6%, Group B 15.7%, p = 0.07). The rate of shunt use was significantly higher in patients with the absence of contralateral proximal anterior cerebral artery (A1) on magnetic resonance angiography (MRA) than in patients with other types of MRA (p <0.001). Significant monitor changes were seen in 16 (12.5%) in both groups. In four of nine patients in Group B, SSEP and MEP changes were synchronized, and in the remaining five patients, a time lag was evident between SSEP and MEP changes. In conclusion, the rate of internal shunt use tended to be more frequent in patients with dual monitoring than in patients with single SSEP monitoring, but the difference was not significant. Contralateral A1 absence may predict the need for a shunt and care should be taken to monitor changes throughout the entire CEA procedure. Use of dual monitoring can capture ischemic changes due to the complementary relationship, and may reduce the rate of false-negative monitor changes during CEA.     

Peliosis Hepatis in a Child with X-Linked Myotubular Myopathy Treated with Living-Donor Liver Transplant: A Case Report

BackgroundMyotubular myopathy is a rare disease sometimes accompanied by peliosis hepatis, a leading cause of fatal liver hemorrhage.Case ReportWe present a case of a 2-year-old boy with myotubular myopathy who developed liver hemorrhage because of peliosis hepatis and was successfully treated with living-donor liver transplant. The patient initially presented with fever, anemia, and liver dysfunction. A computed tomographic scan revealed hemorrhages in the liver, and the patient underwent hepatic artery embolization twice. After the second embolization, multiple peliosis hepatis cavities appeared in the left lobe of the liver that had increased in size. Therefore, the patient underwent ABO-incompatible living-donor liver transplant using a lateral segment graft from his father. The patient developed severe septic shock with an unknown focus on postoperative day 18, which resolved with antibiotic therapy. On postoperative day 62, he was discharged. Fourteen months after undergoing living-donor liver transplant, the patient showed no recurrence of peliosis hepatis.ConclusionsAlthough the long-term prognosis of peliosis hepatis due to myotubular myopathy after living-donor liver transplant remains unclear, liver transplant may be a curative treatment for patients with myotubular myopathy who have uncontrollable peliosis hepatis.     

Effects of prior osteoporosis treatment on 12-month treatment response of romosozumab in patients with postmenopausal osteoporosis

ObjectivesTo investigate the effects of prior treatment and determine the predictors of a 12-month treatment response of romosozumab (ROMO) in 148 patients with postmenopausal osteoporosis.MethodsIn this prospective, observational, and multicenter study, treatment naïve patients (Naïve; n = 50) or patients previously treated with bisphosphonates (BP; n = 37) or denosumab (DMAb; n = 45) or teriparatide (TPTD; n = 16) (mean age, 75.0 years; T-scores of the lumbar spine [LS] ?3.2 and total hip [TH] ?2.6) were switched to ROMO due to insufficient effects of prior treatment. Bone mineral density (BMD) and serum bone turnover markers were evaluated for 12 months.ResultsAt 12 months, changes in LS BMD were Naïve (18.2%), BP (10.2%), DMAb (6.4%), and TPTD (11.2%) (P < 0.001 between groups) and changes in TH BMD were Naïve (5.6%), BP (3.3%), DMAb (0.6%), and TPTD (4.4%) (P < 0.01 between groups), respectively. In all groups, the LS BMD significantly increased from baseline at 6 and 12 months, although only the DMAb group failed to obtain a significant increase in TH BMD during 12-month treatment. Mean values of N-terminal type I procollagen propeptide (PINP; μg/L) from baseline → 1 month → 12 months were Naïve (67.9 → 134.1 → 51.0), BP (32. 2 → 81.7 → 40.9), DMAb (30.4 → 56.2 → 75.3), and TPTD (97.4 → 105.1 → 37.1), and those of isoform 5b of tartrate-resistant acid phosphatase (TRACP-5b; mU/dL) were Naïve (500.4 → 283.8 → 267.1), BP (273.4 → 203.1 → 242.0), DMAb (220.3 → 246.1 → 304.8), and TPTD (446.6 → 305.1 → 235.7), respectively. Multiple regression analysis revealed that the significant predictors of BMD change at 12 months were difference of prior treatment (r = ?2.8, P < 0.001) and value of PINP at 1 month (r = 0.04, P < 0.01) for LS, and difference of prior treatment (r = ?1.3, P < 0.05) and percentage change of TRACP-5b at 1 month (r = ?0.06, P < 0.05) for TH.ConclusionsThe early effects of ROMO on LS and TH BMD increase at 12 months were significantly affected by the difference of prior treatment and are predicted by the early change in bone turnover markers.     

Outcome of advanced renal cell carcinoma arising in end-stage renal disease: comparison with sporadic renal cell carcinoma

Clinical and Experimental Nephrology - The data regarding oncological outcome in advanced renal cell carcinoma (RCC) arising in end-stage renal disease (ESRD) are limited. Patients diagnosed with...     

TLR-MyD88 signaling blockades inhibit refractory B-1b cell immune responses to transplant-related glycan antigens

Refractory B cell responses to T cell–independent (TI) carbohydrate antigens (Ags) are critical drivers of rejection reactions to ABO-incompatible allogeneic grafts and xenogeneic grafts from other species. To explore the biological significance of crosstalk between Toll-like receptors (TLRs) and B cell receptors (BCRs) in the TI B cell immunity, we here used MyD88-, TRIF-, and α-galactosyltransferase-deficient mice to study B cell phenotypes and functional properties during TI transplant–related glycan Ag exposure. BCR stimulation alone induced differentiation into CD5^high (B-1a) cells, which were highly sensitive to a calcineurin inhibitor (CNI), while co-stimulation of TLRs and BCRs induced differentiation into CD5^dim (B-1b) cells in MyD88-dependent and CNI-resistant manner. MyD88-dependent TLR stimulation in B-1b cells enhanced downstream factors in the BCR-calcineurin pathway, including a nuclear factor of activated T cells, cytoplasmic 1 (NFATc1). TLR inhibitor together with CNI abrogated refractory B-1b cell immune responses against the ABO-blood group Ags, while blocking both BCRs and TLR-MyD88 by using Bruton's tyrosine kinase inhibitor and histone deacetylase inhibitor abrogated refractory B-1b cell immune responses against Gal-glycan Ags. Thus, this study provides a rationale for a novel therapeutic approach to overcome refractory transplant-related anti-glycan Ab production by blocking both BCR and TLR-MyD88 signals.     

Analysis of acute-phase toxicities of intensity-modulated proton therapy using a model-based approach in pharyngeal cancer patients

Pharyngeal cancer patients treated with intensity-modulated proton therapy (IMPT) using a model-based approach were retrospectively reviewed, and acute toxicities were analyzed. From June 2016 to March 2019, 15 pharyngeal (7 naso-, 5 oro- and 3 hypo-pharyngeal) cancer patients received IMPT with robust optimization. Simulation plans for IMPT and intensity-modulated X-ray therapy (IMXT) were generated before treatment. We also reviewed 127 pharyngeal cancer patients with IMXT in the same treatment period. In the simulation planning comparison, all of the normal-tissue complication probability values for dysphagia, dysgeusia, tube-feeding dependence and xerostomia were lower for IMPT than for IMXT in the 15 patients. After completing IMPT, 13 patients completed the evaluation, and 12 of these patients had a complete response. The proportions of patients who experienced grade 2 or worse acute toxicities in the IMPT and IMXT cohorts were 21.4 and 56.5% for dysphagia (P < 0.05), 46.7 and 76.3% for dysgeusia (P < 0.05), 73.3 and 62.8% for xerostomia (P = 0.43), 73.3 and 90.6% for mucositis (P = 0.08) and 66.7 and 76.4% for dermatitis (P = 0.42), respectively. Multivariate analysis revealed that IMPT was independently associated with a lower rate of grade 2 or worse dysphagia and dysgeusia. After propensity score matching, 12 pairs of IMPT and IMXT patients were selected. Dysphagia was also statistically lower in IMPT than in IMXT (P < 0.05). IMPT using a model-based approach may have clinical benefits for acute dysphagia.     

Effect of negative air ions on computer operation, anxiety and salivary chromogranin A-like immunoreactivity.

The effects of negative air ions on computer operation were examined using a biochemical index of the activity of the sympathetic/adrenomedullary system (i.e. salivary chromogranin A-like immunoreactivity (CgA-like IR)) and a self-report questionnaire (State-Trait Anxiety Inventory, Anxiety State--STAI-S). Twelve female students carried out a word processing task for 40 min. The salivary CgA-like IR increased more than three times on the task, but the salivary cortisol did not change. The increase in the CgA-like IR level was attenuated by the exposure to negative air ions during the task. The exposure to the ions during the recovery period following the task was effective for rapidly decreasing the CgA-like IR level that had increased after the task. These effects by negative air ions were also observed using STAI-S. Task performance was slightly but significantly improved by the presence of negative air ions. These results suggest that negative air ions are effective for the reduction of and the prompt recovery from stress caused by computer operation.