Oncofetal expression of glutathione S-transferase placental form in human stomach carcinomas

The content of glutathione S-transferase placental form (GST-pi) was immunohistochemically analyzed in 100 cases of human stomach carcinoma of various histological types and compared with the content in the stomach mucosa of the human fetus, infant and adult. High levels of GST-pi content were demonstrated in all stomach carcinomas except for signet ring cell carcinomas. High levels were also present in surface mucous cells and glandular cells of the stomach from a fetus aged 18 weeks, whereas only the parietal cells of fundic glands in the adult stomach showed slight staining for GST-pi. These results indicate that the phenotypic expression of GST-pi in human stomach carcinoma is oncofetal in character.     

A study of the antineoplastic activity of K18

K18 is a new drug produced by a combination of Melphalan and human immunoglobulin. K18 produced an inhibitory effect on the proliferation of human gastric and colon cancer transplanted in to nude mice. Also, combination effects of K18 with MMC and 5-FU were recognized in the same system. In a study of distribution after K18 administration, the accumulation and retention of this drug in the tumor region were observed. In the case of Melphalan administration, these phenomena were not observed. The antitumor activity of tumor homogenate was evaluated using a colony-forming assay with KB cells. As to the Melphalan-treated group, a four-hour homogenate reduced the number of colonies but a 48-h one did not. In the K18-treated group, the four-hour homogenate decreased the number slightly and the decrease became obvious with 48-h homogenate. In cell cycle analysis using K18 or Melphalan administration, gathering of S-phase cells was observed, but these changes appeared later with K18 than with Melphalan. This result showed that the effect of K18 was produced by the alkylating activity of Melphalan which was combined with immunoglobulin. For clinical application, K18 was administered to cancer patients at a dose of 60-90 mg every day. Two cases of good response were achieved. No side effect was observed. This remarkable efficacy and low degree of side effects in clinical application is probably due to the higher affinity and accumulation of K18 in the tumor region. K18 is a useful new drug for clinical application alone, or in combination with other chemotherapeutic drugs.     

GTP-cyclohydrolase I gene mutations in hereditary progressive and dopa-responsive dystonia

Recently, mutations of the GTP-cyclohydrolase I (GTP-CH I) gene, which catalyzes the first step in the tetrahydrobiopterin (BH₄) biosynthesis, were discovered in Japanese patients with hereditary progressive dystonial/dopa-responsive dystonia (HPD/DRD). However, it has not been confirmed that non-Japanese patients also contain mutations in the same gene, or whether these mutations are specific to HPD/DRD. In this study, two novel nonsense mutations in exon 1 of the GTP-CH I gene and a new mutation at the splice acceptor site of intron 1 were identified in an autopsied case of English-Irish descent and 2 Japanese patients with HPD/DRD. In the latter, cerebrospinal fluid (CSF) neopterin levels (which may reflect the GTP-CH I activity in the brain) were reduced to 18% and 37% of controls. A therapeutic trial of oral BH₄ was ineffective, however, in a genetically proven patient. In contrast, no mutations in any exons of the GTP-CH I gene were found in 2 patients with early-onset parkinsonism with dystonia (EOP-D) who developed dopa-responsive parkinsonism and dystonia at 6 and 8 years old, respectively. Neopterin levels in CSF were well preserved in 6 EOP-D patients. These data suggest that, among patients of different racial backgrounds, the pathogenesis of HPD/DRD, unlike EOP-D, involves partial reduction of the brain GTP-CH I activity consequent to mutations in the GTP-CH I gene. Measurement of CSF neopterin concentration may be useful for the differential diagnosis between HPD/DRD and EOP-D.     

Association of preoperative serum CRP with PD-L1 expression in 508 patients with non-small cell lung cancer: A comprehensive analysis of systemic inflammatory markers

Objectives

Programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors have been approved as a standard therapy for metastatic non-small cell lung cancer (NSCLC). Although PD-L1 expression serves as a predictive biomarker for the efficacy of immunotherapy, there are no established biomarkers to predict the expression of PD-L1. The inflammatory markers C-reactive protein (CRP) and neutrophil-lymphocyte ratio (NLR) were recently shown to predict the efficacy of nivolumab for NSCLC patients. Therefore, here we investigated the potential association of PD-L1 expression with systemic inflammatory markers, including CRP, NLR, lymphocyte-monocyte ratio and platelet-lymphocyte ratio.

Occurrence of hyaline droplets in renal biopsy specimens: an ultrastructural study

Hyaline droplets are apical cytoplasmic vesicles containing an accumulation of electron-dense amorphous materials surrounded by a unit membrane. Hyaline droplets may originate from apical vesicles after conversion to osmotic vesicles and loss of internally lined glycocalyx. They are found in the proximal tubular epithelium in biopsies from patients with renal diseases; however, their biological importance is not well understood. We reviewed ultrastructural pathology records of 140 renal biopsy patients to determine the occurrence and relevance of hyaline droplets. Of the cases, 14 (10%) showed the presence of hyaline droplets in proximal tubular epithelium. The distribution of cases were 8 of the 19 (42%) with minimal change nephritic syndrome, 2 of the 37 (5%) with IgA nephropathy, 2 of the 4 (50%) with membranous glomerulonephropathy, 1 of the 4 (25%) with tubulointerstitial nephritis, and 1 of the 1 (100%) with acute renal failure. The droplets were frequently found in male patients (86%), never in children, and were mostly associated with tubular necrosis (8 of 14 cases; 56%). Many hyaline droplets were observed in the cytoplasm of necrotic proximal tubular epithelial cells, and even when tubular necrosis was not evident, the proximal tubular epithelial cells containing hyaline droplets showed degenerated microvilli and decreased basal interdigitations. These results suggest that hyaline droplets could be one marker of renal tubular necrosis and a sign of functional disorder of protein reabsorption by degenerating proximal tubular epithelium.     

Feature of food allergy developed during infancy (1)--relationship between infantile atopic dermatitis and food allergy]

BACKGROUND: Most of food allergy (FA) cases during childhood start as infantile atopic dermatitis (AD) at the ages of a few months old. We tried to clarify the association between infantile AD and FA during infancy. METHODS: We analyzed relationship between AD and FA during infancy among patients with 208 cases, who had visited our outpatient clinic with chief complaint of "eczema" from 1998 to 2000. RESULTS: Among 208 cases, 148 cases (71%) were diagnosed as infantile AD, moreover 109 cases (74%) were diagnosed as FA among infantile AD. The most frequent food antigens among infantile AD were egg (72.3%), cow's milk (39.9%), wheat (12.2%) and soybean (7.4%), respectively, in addition to these food antigens, food allergy was widely recognized against peanuts, sesame, meats, buckwheat, fishes and potato. In terms of food antigen, 44 cases with single food allergy against egg were seen out of 46 single allergy cases, whereas 36 cases with double food allergy against both egg and cow's milk were seen in 63 multiple food allergy cases. Although the value of antigen specific IgE against egg and cow's milk was recognized for the diagnosis of food allergy during infancy, even cases with negative IgE against those foods were proved to be food allergy by food elimination and provocation tests. In contrast to egg and cow's milk, positive IgE against rice, soybean, and wheat did not always correlate with the results of the diagnosis of food allergy. Concerning risk factors of AD, family history of any allergy diseases and passive smoking were recognized in comparison with infantile eczema. Neither the nutrition method nor incomplete elimination of diet during pregnancy and lactation had anything to do with the development of AD. CONCLUSION: When infantile AD cases were not improved by environmental control, skin care and application of steroid ointment, it would be important for doctors to think of the possibility of FA.     

Immune responses in tuberculosis: antibodies and CD4-CD8 lymphocytes with vascular adhesion molecules and cytokines (chemokines) cause a rapid antigen-specific cell infiltration at sites of bacillus Calmette-Guérin reinfection

Rabbit primary dermal bacillus Calmette-Guérin (BCG) lesions were compared with reinfection BCG lesions in order to gain insight into how immune responses protect against clinical tuberculosis. As early as 3 hr, a marked infiltration of macrophages and lymphocytes occurred in the reinfection group, while very little cell infiltration occurred in the primary group. It seems that only an antigen-antibody reaction could produce such an immediate pronounced antigen-specific chemotactic effect, because very few lymphocytes are normally present in the skin. Therefore, antibodies hasten the accumulation of an expanded antigen-specific T-lymphocyte population (memory cells) at sites of bacillary lodgement. By 1-2 days, the primary and reinfection BCG lesions differed 400- to 500-fold in size. By 4-5 days, the size of the reinfection lesions had declined, while the size of the primary lesions had increased, so that, grossly, both types of lesion were similar. At 8 days in reinfection lesions and at 12 days in primary lesions, small secondary peaks in size occurred, which were probably caused by cell-mediated immune responses. In rabbits with primary BCG lesions, skin tests with Old Tuberculin were positive at 9 days, accompanied by a rise in the levels of antibodies to the secreted antigen, phosphate-specific transport protein 1, but the levels of antibodies to the constitutive antigens, purified protein derivative and heat-shock protein 65, did not increase appreciably until some time after 23 days. In tissue sections of reinfection BCG lesions, the percentage of mononuclear cells labelled, by in situ hybridization techniques, for the mRNA of monocyte chemoattractant protein 1 (MCP-1), a chemokine, peaked at 3 hr and then was down-regulated, whereas in primary lesions, this percentage was down-regulated only after 2 days. [The percentage in the tissue sections for the mRNAs of interleukins 1beta and 8, as well as the proteins of MCP-1 and tumor necrosis factor alpha (TNF-alpha), followed a somewhat similar time-course to that of MCP-1 mRNA.] A high percentage of mononuclear cells containing the MCP-1 mRNA 'factory' would favour enlargement of the lesions and a low percentage would favour their regression. At 5 days, the percentage of CD4 and CD8 lymphocytes, stained by immunohistochemical techniques, and the amount of microvasculature stained similarly for vascular cell adhesion molecule 1 were higher in the reinfection group, indicating that prior immunization caused a more rapid (antigen-dependent) up-regulation of these factors. Tuberculin reactions resembled early reinfection BCG lesions in almost every factor evaluated herein. In brief, the production of chemokines began soon after BCG reinfection, peaked within a few hours and was markedly down-regulated by 24 hr, a time at which the lesions of reinfection were of maximal size. Therefore, the amount of cell infiltration was tightly controlled, probably by the variety of mechanisms listed herein.