Abstract,32-Microglobulin (jB2M) is a major constituent of amyloid fibrils in hemodialysis-associated amyloidosis (HAA), a complication of long-term hemodialysis. However, the pathological role of 62M in HAA remains to be determined. Recently, we demonstrated that ,62M in the amyloid deposits ofHAA is modified with advanced glycation end products (AGEs) of the Maillard reaction. Since AGEs have been implicated in tissue damage associated with diabetic complications and aging, we investigated the possible involvement of AGE-modified j82M (AGE-Ii2M) in the pathogenesis of HAA. AGE-and normalf32M were purified from urine of long-term hemodialysis patients. AGE-,2M enhanced directed migration (chemotaxis) and random cell migration (chemokinesis) of human monocytes in a dose-dependent manner. However, normal-,62M did not enhance any migratory activity. AGE-lB2M, but not normal-#2M, increased the secretion of TNF-a and IL-1,B from macrophages. Similar effects were also induced by in vitro prepared AGE-,32M (normal-B62M incubated with glucose in vitro for 30 d). When TNF-a or IL-1,6 was added to cultured human synovial cells in an amount equivalent to that secreted from macrophages in the presence of AGE-,02M, a significant increase in the synthesis of collagenase and morphological changes in cell shape were observed. These findings suggested that AGE-182M, a major component in amyloid deposits, participates in the pathogenesis of HAA as foci where monocyte /macrophage accumulate and initiate an inflammatory response that leads to bone/joint destruction. (J. Clin. Invest. 1994. 93:521-528.)

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Aging is associated with decreased skeletal muscle function. Increased levels of advanced glycation end products (AGEs) in skeletal muscle tissue are observed with advancing age and in diabetes. Although serum AGE level is negatively associated with grip strength in elderly people, it is unknown whether this association is present in adult males. To determine the relationship between AGE accumulation in tissue and muscle strength and power among Japanese adult men. Skin autofluorescence (AF) (a noninvasive method for measuring tissue AGEs), grip strength (n = 232), and leg extension power (n = 138) were measured in Japanese adult men [median (interquartile range) age, 46.0 (37.0, 56.0) years]. After adjustment for potential confounders, the adjusted means [95% confidence interval (CI)] for grip strength across the tertiles of skin AF were 44.5 (43.2, 45.9) kg for the lowest tertile, 42.0 (40.6, 43.3) kg for the middle tertile, and 41.7 (40.3, 43.1) kg for the highest tertile (P for trend < 0.01). Moreover, the adjusted geometric means (95% CI) of leg extension power across the tertiles of skin AF were 17.8 (16.6, 19.1) W/kg for the lowest tertile, 17.5 (16.4, 18.7) W/kg for the middle tertile, and 16.0 (14.9, 17.1) W/kg for the highest tertile (P for trend = 0.04). Among Japanese adult men, participants with higher skin AF had lower muscle strength and power, indicating a relationship between AGE accumulation and muscle strength and power. A long-term prospective study is required to clarify the causality.

1. Alectinib is a highly selective, central nervous system-active small molecule anaplastic lymphoma kinase inhibitor. 2. The absolute bioavailability, metabolism, excretion and pharmacokinetics of alectinib were studied in a two-period single-sequence crossover study. A 50 μg radiolabelled intravenous microdose of alectinib was co-administered with a single 600 mg oral dose of alectinib in the first period, and a single 600 mg/67 μCi oral dose of radiolabelled alectinib was administered in the second period to six healthy male subjects. 3. The absolute bioavailability of alectinib was moderate at 36.9%. Geometric mean clearance was 34.5 L/h, volume of distribution was 475 L and the hepatic extraction ratio was low (0.14). 4. Near-complete recovery of administered radioactivity was achieved within 168 h post-dose (98.2%) with excretion predominantly in faeces (97.8%) and negligible excretion in urine (0.456%). Alectinib and its major active metabolite, M4, were the main components in plasma, accounting for 76% of total plasma radioactivity. In faeces, 84% of dose was excreted as unchanged alectinib with metabolites M4, M1a/b and M6 contributing to 5.8%, 7.2% and 0.2% of dose, respectively. 5. This novel study design characterised the full absorption, distribution, metabolism and excretion properties in each subject, providing insight into alectinib absorption and disposition in humans.

There is no standard treatment modality for advanced gastric cancer (GC) at the present time. To develop a new treatment modality, we investigated the immunological responses of advanced GC patients (n = = = =13, 9 non-scirrhous and 4 scirrhous types) vaccinated with peptides to a regimen under which pre-vaccination peripheral blood mononuclear cells (PBMCs) were screened for their reactivity in vitro to each of 14 peptides on HLA-A24 or 16 peptides on -A2 allele, then only the reactive peptides (maximum: 4) were administered in vivo. This regimen was generally well tolerated, although grade I levels of fever and local skin reactions were observed in several patients. astric cancer (GC), a leading cause of cancer-related death worldwide throughout the past century, now ranks second only to lung cancer, with an estimated 750,000 new cases diagnosed annually around the world. 1) Except in Japan and a few East Asian countries, the prognosis of GC remains poor, and the overall 5-year survival rate ranges from 5 to 15% despite many clinical trials of chemotherapy and other new therapies. In particular, there is no current treatment modality for disseminated GC histologically of the scirrhous type.2) Therefore, development of a new treatment modality is needed, and one such modality could be specific immunotherapy, given that recent advances in tumor immunology have resulted in identification of many tumor antigens and epitopes recognized by HLA-class-I-restricted cytotoxic T lymphocytes (CTLs) from various cancers, including GC.3-6) However, clinical trials with these peptides have rarely obtained major clinical responses.7-9) This failure could have been due to an insufficient induction of antitumor responses by these vaccine regimens, since peptide-specific memory T cells were not measured in pre-vaccination peripheral blood mononuclear cells (PBMCs). We speculated that vaccination based on pre-vaccination measurement of peptidespecific CTLs in the circulation might be able to induce potent anti-tumor immune responses in cancer patients. [8][9][10][11][12][13] In this report, we describe the safety of such a regimen and the immune responses to peptides and tumor cells in advanced GC patients vaccinated with peptides based on pre-existing cellular response.

Peri-implantitis is an inflammatory disease with a relevant focus on the long-term success of dental implants and implant-supported prostheses. The present study focuses on the antibacterial effect of the silver nanoparticle and investigated the suppression of dental plaque adhesion on implant abutment and/or superstructure by micro-wave assistant nanosilver coating in vivo and in vitro. Nanosilver coating on pure titanium was prepared by microwave-assisted synthesis, and characterized by scanning electron microscopy and energy-dispersive X-ray spectroscopy. In vitro studies were conducted to analyze biocompatibility using MTS assay and fluorescence microscopy with human gingival fibroblasts to evaluate antibacterial activity. During the in vivo study, nanosilver coating was applied to the healing abutments, and the prevention of plaque accumulation on nanosilver coating was confirmed by a split-mouth randomized clinical trial. The aggregation of nano-sized particles was found on the titanium surface with an antibacterial effect. The coating had no cytotoxic effect on human gingival fibroblasts. The result of the clinical trial showed that the coating suppressed the dental plaque adhesion on the healing abutments. Nanosilver coating is a promising material with antibacterial properties and can be used for implant abutments and prostheses for preventing peri-implantitis.

Structure 6:571-586, 1998), we developed a three-dimensional model of KF707 BphA1 of Pseudomonas pseudoalcaligenes KF707. Based on structural information about the amino acids which coordinate the catalytic nonheme iron center, we constructed 12 site-directed BphA1 mutants with changes at positions 227, 332, 335, 376, 377, and 383 and expressed these enzymes in Escherichia coli. The Ile335Phe, Thr376Asn, and Phe377Leu Bph Dox mutants exhibited altered regiospecificities for various PCBs compared with wild-type Bph Dox. In particular, the Ile335Phe mutant acquired the ability to degrade 2,5,2,5-tetrachlorobiphenyl by 3,4-dioxygenation and showed bifunctional 2,3-dioxygenase and 3,4-dioxygenase activities for 2,5,2-trichlorobiphenyl and 2,5,4-trichlorobiphenyl. Furthermore, two mutants, the Phe227Val and Phe377Ala mutants, introduced molecular oxygen at the 2,3 position, forming 3-chloro-2,3-dihydroxy biphenyl with concomitant dechlorination.