A novel Mutein of TNFα Containing the Arg-Gly-Asp Sequence Shows Reduced Toxicity in Intestine

The effects of human tumour necrosis factor-α (TNFα), or its mutein (F4168) having the cell adhesive Arg-Gly-Asp sequence at the N-terminus, on intestinal injury, were examined. Histopathological examination revealed that an intravenous injection of TNFα resulted in marked haemorrhage or oedema in the caecum of rats, whereas F4168 showed no such effects even at the same therapeutic dose. Moreover, the number of neutrophils that adhered to endothelial cells or infiltrated the mucosal tissue was much higher after TNFα injection compared with F4168 in vivo. The enhanced adhesion of neutrophils on to human umbilical vein endothelial cells also occurred when the latter were pre-stimulated with TNFα but not with F4168 in vitro. The expression of the cell adhesion molecules including endothelial leukocyte adhesion molecule-1 or intercellular adhesion molecule-1 on F4168- stimulated human umbilical vein endothelial ceils was significantly lower than that stimulated with TNFα. These results suggest that the Arg-Gly-Asp sequence introduced into the TNFα molecule abrogates the side effect of this cytokine such as tissue injury or shock, and that F4168 could be useful for systemic therapy

Effects of the anti-RANKL antibody denosumab on joint structural damage in patients with rheumatoid arthritis treated with conventional synthetic disease-modifying antirheumatic drugs (DESIRABLE study): a randomised, double-blind, placebo-controlled phase 3 trial.

ObjectiveTo evaluate the efficacy of denosumab in suppressing joint destruction when added to conventional synthetic disease-modifying antirheumatic drug (csDMARD) therapy in patients with rheumatoid arthritis (RA).MethodsThis was a multi-centre, randomised, double-blind, parallel-group, placebo-controlled phase 3 study in Japan. Patients with RA aged ≥20 years receiving csDMARDs were randomly assigned (1:1:1) to denosumab 60 mg every 3 months (Q3M), denosumab 60 mg every 6 months (Q6M) or placebo. The change in the modified total Sharp score (mTSS) and effect on bone mineral density (BMD) at 12 months was evaluated.ResultsIn total, 654 patients received the trial drugs. Denosumab groups showed significantly less progression of joint destruction. The mean changes in the mTSS at 12 months were 1.49 (95% CI 0.99 to 1.99) in the placebo group, 0.99 (95% CI 0.49 to 1.49) in the Q6M group (p=0.0235) and 0.72 (95% CI 0.41 to 1.03) in the Q3M group (p=0.0055). The mean changes in bone erosion score were 0.98 (95% CI 0.65 to 1.31) in the placebo group, 0.51 (95% CI 0.22 to 0.80) in the Q6M group (p=0.0104) and 0.22 (95% CI 0.09 to 0.34) in the Q3M group (p=0.0001). No significant between-group difference was observed in the joint space narrowing score. The per cent change in lumbar spine (L1-L4) BMD in the placebo, Q6M and Q3M groups were -1.03%, 3.99% (p<0.0001) and 4.88% (p<0.0001). No major differences were observed among safety profiles.ConclusionsDenosumab inhibits the progression of joint destruction, increases BMD and is well tolerated in patients with RA taking csDMARD

Neuropathologic basis of frontotemporal dementia in progressive supranuclear palsy.

BackgroundProgressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by neuronal loss in the extrapyramidal system with pathologic accumulation of tau in neurons and glia. The most common clinical presentation of PSP, referred to as Richardson syndrome, is that of atypical parkinsonism with vertical gaze palsy, axial rigidity, and frequent falls. Although cognitive deficits in PSP are often ascribed to subcortical dysfunction, a subset of patients has dementia with behavioral features similar to the behavioral variant of frontotemporal dementia. In this study we aimed to identify the clinical and pathological characteristics of PSP presenting with frontotemporal dementia.MethodsIn this study, we compared clinical and pathologic characteristics of 31 patients with PSP with Richardson syndrome with 15 patients with PSP with frontotemporal dementia. For pathological analysis, we used semiquantitative methods to assess neuronal and glial lesions with tau immunohistochemistry, as well image analysis of tau burden using digital microscopic methods.ResultsWe found greater frontal and temporal neocortical neuronal tau pathology in PSP with frontotemporal dementia compared with PSP with Richardson syndrome. White matter tau pathology was also greater in PSP with frontotemporal dementia than PSP with Richardson syndrome. Genetic and demographic factors were not associated with atypical distribution of tau pathology in PSP with frontotemporal dementia.ConclusionsThe results confirm the subset of cognitive-predominant PSP mimicking frontotemporal dementia in PSP. PSP with frontotemporal dementia has distinct clinical features that differ from PSP with Richardson syndrome, as well as differences in distribution and density of tau pathology. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society

Secondary-Structure Design of Proteins by a Backbone Torsion Energy

We propose a new backbone-torsion-energy term in the force field for protein systems. This torsion-energy term is represented by a double Fourier series in two variables, the backbone dihedral angles phi and psi. It gives a natural representation of the torsion energy in the Ramachandran space in the sense that any two-dimensional energy surface periodic in both phi and psi can be expanded by the double Fourier series. We can then easily control secondary-structure-forming tendencies by modifying the torsion-energy surface. For instance, we can increase/decrease the alpha-helix-forming-tendencies by lowering/raising the torsion-energy surface in the alpha-helix region and likewise increase/decrease the beta-sheet-forming tendencies by lowering/raising the surface in the beta-sheet region in the Ramachandran space. We applied our approach to AMBER parm94 and AMBER parm96 force fields and demonstrated that our modifications of the torsion-energy terms resulted in the expected changes of secondary-structure-forming-tendencies by performing folding simulations of alpha-helical and beta-hairpin peptides.Comment: 13 pages, (Revtex4), 5 figure

Impaired Development of Somatotropes, Lactotropes and Thyrotropes in Growth-Retarded (grt) Mice

Congenitally primary hypothyroid growth-retarded (grt) mice exhibit a characteristic growth pause followed by delayed onset of pubertal growth. We characterized the developmental pattern of somatotropes, lactotropes and thyrotropes in the anterior pituitary, as well as plasma levels of their secretory hormones, in grt mice. Compared with normal mice, the weight of grt pituitary gland was similar at 8 weeks of age but significantly heavier after 12 weeks of age. Compared with normal mice, there were significantly fewer somatotropes in the grt pituitary until 8 weeks of age, but the number gradually increased up to 48 weeks. The number of lactotropes in grt mice was consistently lower than that in normal mice from 2 through 48 weeks, whereas the number of thyrotropes in the grt pituitary was consistently higher than in the normal pituitary. Thyrotropes in the grt pituitary exhibited hypertrophy and hyperplasia with less intensive thyroid-stimulating hormone (TSH) immunoreactivity than normal thyrotropes. In normal mice, the sum of the relative proportions of these cells plateaued at 8 weeks, where it remained up to 48 weeks of age. In grt mice, these proportions almost reached normal levels at 12 weeks of age but gradually declined after 24 weeks. Plasma growth hormone concentrations did not differ between grt and normal mice until 24 weeks of age. Compared with normal mice, grt mice exhibited significantly lower plasma prolactin and thyroxine levels but higher TSH levels. These findings indicate that development of somatotropes, lactotropes and thyrotropes in grt mice is impaired, being followed by altered hormone secretion

A phase II study of cisplatin and 5-fluorouracil with concurrent hyperfractionated thoracic radiation for locally advanced non-small-cell lung cancer: a preliminary report from the Okayama Lung Cancer Study Group

A recent meta-analysis and randomized studies have demonstrated that combined chemoradiotherapy is associated with a survival advantage for selected patients with locally advanced unresectable non-small-cell lung cancer (NSCLC). We conducted a phase II study of combined chemoradiotherapy to find a more effective combination of drugs and radiation than those previously reported for such patients. Between January 1994 and November 1996, 50 previously untreated patients with locally advanced unresectable NSCLC (stage IIIA with N2 or IIIB disease) were entered in this study. Patients were required to have Eastern Cooperative Oncology Group performance status ≤ 2, age ≤ 75 years and adequate organ function. Treatment consisted of three cycles of cisplatin (20 mg m−2, days 1–5) and 5-fluorouracil (5-FU) (500 mg m−2, days 1–5) every 4 weeks, and concurrent hyperfractionated thoracic radiation (1.25 Gy twice daily, with a 6-h interfraction interval; total radiation dose, 62.5–70 Gy). Of the 50 patients entered, 37 (74%) responded to this chemoradiotherapy, including two (4%) with complete response. By a median follow-up time of 41.0 months, 35 patiennts had died and 15 were stil alive. The median time to progression for responding patients was 14.1 months (range, 2.6–51.3+ months). The median survival time was 18.7 months, with a survival rate of 66.0% at 1 year, 46.0% at 2 years and 27.6% at 3 years. Survival outcome was strongly affected by the extent of nodal involvement (median survival time, 27.4 months for N0–2 disease (n = 37) vs 10.7 months for N3 disease (n = 13);P = 0.007). The major toxicities of treatment were leukopenia and neutropenia (≥ Grade 3, 58% and 60% respectively). Other toxicities of ≥ Grade 3 included thrombocytopenia (26%), anaemia (26%), nausea/vomiting (16%) and radiation oesophagitis (6%). Treatment-related death occurred for one patient. Our findings suggest that cisplatin and 5-FU in combination with concurrent hyperfractionated thoracic radiation is effective and feasible for the treatment of locally advanced unresectable NSCLC. The short-term survival in this study appeared to be more encouraging than those of similar chemoradiation trials. A randomized trial will be needed to compare the combination of cisplatin and 5-FU with other platinum-based regimens together with concurrent hyperfractionated thoracic radiation. In addition, in future studies, inclusion criteria for N3 disease with or without supraclavicular involvement should be reconsidered to correctly evaluate the effect of combined chemoradiotherapy for locally advanced unresectable NSCLC. © 2000 Cancer Research Campaig

Alcohol drinking and risk of Parkinson's disease: a case-control study in Japan

<p>Abstract</p> <p>Background</p> <p>Although some epidemiologic studies found inverse associations between alcohol drinking and Parkinson's disease (PD), the majority of studies found no such significant associations. Additionally, there is only limited research into the possible interactions of alcohol intake with aldehyde dehydrogenase (ALDH) 2 activity with respect to PD risk. We examined the relationship between alcohol intake and PD among Japanese subjects using data from a case-control study.</p> <p>Methods</p> <p>From 214 cases within 6 years of PD onset and 327 controls without neurodegenerative disease, we collected information on "peak", as opposed to average, alcohol drinking frequency and peak drinking amounts during a subject's lifetime. Alcohol flushing status was evaluated via questions, as a means of detecting inactive ALHD2. The multivariate model included adjustments for sex, age, region of residence, smoking, years of education, body mass index, alcohol flushing status, presence of selected medication histories, and several dietary factors.</p> <p>Results</p> <p>Alcohol intake during peak drinking periods, regardless of frequency or amount, was not associated with PD. However, when we assessed daily ethanol intake separately for each type of alcohol, only Japanese sake (rice wine) was significantly associated with PD (adjusted odds ratio of ≥66.0 g ethanol per day: 3.39, 95% confidence interval: 1.10-11.0, <it>P </it>for trend = 0.001). There was no significant interaction of alcohol intake with flushing status in relation to PD risk.</p> <p>Conclusions</p> <p>We did not find significant associations between alcohol intake and PD, except for the daily amount of Japanese sake. Effect modifications by alcohol flushing status were not observed.</p

Development of multiple regions tracking system to reduce inter and intra-fractional error for proton therapy

PTCOG49 - 49th Annual Meeting of the Particle Therapy Co-Operative Group Scientific Meeting, 2010This is to certificate of the Outstanding Poster Award of the 49th Annual Meeting of the Particle Therapy Co-Operative Group, Scientific Meeting, 2010. (Category: Physics, 5/21/2010