Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.7.49 (reverse transcriptase)
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Recent development of tuberculosis in Japan tends to converge on a specific high risk group. The proportion of tuberculosis developing particularly from the compromised hosts in the high risk group is especially high. At this symposium, therefore, we took up diabetes mellitus, gastrectomy, dialysis, AIDS and the elderly for discussion. Many new findings and useful reports for practical medical treatment are submitted; why these compromised hosts are predisposed to tuberculosis, tuberculosis diagnostic and remedial notes of those compromised hosts etc. It is an important question for the future to study how to prevent tuberculosis from these compromised hosts. 1. Tuberculosis in diabetes mellitus: aggravation and its immunological mechanism: Kazuyoshi KAWAKAMI (Department of Internal Medicine, Division of Infectious Diseases, Graduate School and Faculty of Medicine, University of the Ryukyus). It has been well documented that diabetes mellitus (DM) is a major aggravating factor in tuberculosis. The onset of this disease is more frequent in DM patients than in individuals with any underlying diseases. However, the precise mechanism of this finding remains to be fully understood. Earlier studies reported that the migration, phagocytosis and bactericidal activity of neutrophils are all impaired in DM patients, which is related to their reduced host defense to infection with extracellular bacteria, such as S. aureus and E. colli. Host defense to mycobacterial infection is largely mediated by cellular immunity, and Th1-related cytokines, such as IFN-gamma and IL-12, play a central role in this response. It is reported that serum level of these cytokines and their production by peripheral blood mononuclear cells (PBMC) are reduced in tuberculosis patients with DM, and this is supposed to be involved in the high incidence of tuberculosis in DM. Our study observed similar findings and furthermore indicated that IFN-gamma and IL-12 production by BCG-stimulated PBMC was lower in poorly-controlled DM patients than that in well-controlled DM patients and healthy subjects. Thus, these clinical data suggest that the high incidence of tuberculosis in DM patients is due to the impaired production of Th1-related cytokines. However, direct evidences to prove this possibility remain to be obtained. In 1980, Saiki and co-workers reported that host defense and delayed-type hypersensitivity response to M. tuberculosis was hampered in a mouse DM model established by injecting streptozotocin (Infect Immun. 1980; 28: 127-131). We followed their investigation with the similar observations. Interestingly, levels of IFN-gamma and IL-12 in serum, lung, liver and spleen after infection were significantly reduced in DM mice when compared with those in control mice. Considered collectively, these results strongly suggest that the reduced production of Th1-related cytokines leads to the susceptibility of DM to mycobacterial infection. However, it remains to be understood how DM hampers the synthesis of Th1-related cytokines. In our preliminary study, the production of these cytokines by PBMC from DM patients and healthy subjects was not affected under a high glucose condition. Thus, it is not likely that the increased level of glucose directly suppresses the cell-mediated immune responses. Further investigations are needed to make these points clear. 2. A study of gastrectomy cases in pulmonary tuberculosis patients: Takenori YAGI (Division of Thoracic Disease, National Chiba-Higashi Hospital). Patients who have undergone gastric resection are considered at increased risk of developing pulmonary tuberculosis. I have investigated the role played by gastrectomy in giving rise to pulmonary tuberculosis. Of 654 pulmonary tuberculosis patients admitted to National Chiba-Higashi Hospital from January 1999 to December 2001, 55 patients (31-84 years old, mean 63.5 +/- 12.5 years, 48 males and 7 females) had the history of gastric resection. The incidence of gastrectomy among patients with pulmonary tuberculosis was 8.4 percent. The mean age of gastric resection was 50.2 +/- 16.6 years, and the mean interval from gastrectomy to pulmonary tuberculosis was 13.6 +/- 11.0 years. On admission to our hospital, 34 out of 55 cases were smear positive by sputum examination for acid-fast bacilli and 39 cases had cavitary lesions on chest X-ray. Gastrectomy was done due to carcinoma of the stomach in 31 cases, gastric and/or duodenal ulcer in 21 cases, adenomatous polyp in two cases, and accidental injury in one case. 52 patients improved, but three cases died due to pulmonary tuberculosis. No one had recurrence of carcinoma of the stomach. Body weight, Body Mass Index, Prognostic Nutritional Index (PNI; 10x serum albumin concentration +0.005 x peripheral lymphocyte count) which was proposed by Onodera, serum albumin level and serum total cholesterol level were lower in the gastrectomy group than in the non-gastrectomy group. I calculated the odds of tuberculosis among gastrectomy patients to be 3.8 times that of appropriate controls. This study confirms that gastrectomy is one of the risk factor(s) of tuberculosis. However, whether gastrectomy in itself is a risk factor or whether it is secondarily associated with another risk factor such as underweight status and/or inadequate nutrition following surgery remains unclear. 3. Immunodefficiency and tuberculosis in dialysis patients: Hajime INAMOTO (Division of Dialysis, Keio University School of Medicine). The patients who have renal insufficiency is fatal, but they can live much longer by dialysis. The number of lymphocytes of the patients whose serum creatinine was 10 mg/dl or more has decreased to about 50% of the people who have normal kidney. When the lymphocyte was cultured after it was stimulated with PHA, the DNA synthesis of the patients' lymphocyte was much lower than that of the modest people's. In the dialysis food, the nutrient such as vitamins, minerals, etc. were lacked. The density of the serum albumin of the dialysis patient has decreased. Many of them were thin when their BMI was examined. The size of the patients' erythema by the tuberculin test has become small. There were many patients receiving dialysis with erythema but no induration. It means that the delayed skin reaction specific to Mycobacterium tuberculosis has decreased among the dialysis patients. The morbidity rate, the mortality rate and the prevalence of tuberculosis was much higher than the general population. The anamnesis of tuberculosis was also high. Most of those tuberculosis patients appear the disease from the period immediately before the beginning of dialysis to one year after that. That is also the period that patients' number of peripheral blood lymphocyte decreased and the tuberculin reaction positivity rate fell sharply. During the dialysis patients, pulmonary tuberculosis with cavities was minority and extrapulmonary tuberculosis and miliary tuberculosis were remarkably many. People with large reaction against the tuberculin test were better prognosis than those with smaller reaction. It was thought that anorexia, weakening, and a weight decrease were seen when the immunity decreased. At the end stage of renal failure, kidney shrink, vitamin D activation becomes difficult, and the low calcium blood syndrome appears. The calcification of tuberculoma is absorbed, soft tuberculoma becomes baring, the caseation abscess melts, and the endogenous infection occurs. The cell immunity has decreased, and tuberculosis attacks. It might be such circumstances that tuberculosis happen frequently at the dialysis introduction period. There are a lot of cases that the caseation necrosis is a little, and the formation of tuberculoma is bad in the pathology opinion. Due to the decrease in the cell immunity, cavities are not formed easily. It is easy to stay in the leaching lesion so that anti-tuberculosis drugs are much effective, and the patients recover easily. However, if the treatment is delayed, it is fatally because hematogenous metastasis are easy to occur and become miliary tuberculosis. 4. AIDS and tuberculosis: Hideaki NAGAI (Department of Respiratory Diseases, National Tokyo Hospital). With AIDS patients with tuberculosis, there are the following problems on the treatment. (1) The adverse reactions by antituberculosis drugs tend to occur in AIDS patients. Eleven of 33 AIDS patients with tuberculosis had the adverse reactions (skin rash, fever, liver dysfunction) considered to be due to antituberculosis drugs. It is a very large burden for the HIV infected persons to take simultaneously antituberculosis drugs, medicines for opportunistic infections, and anti-HIV medicines. Since many medicines are taken, it is difficult to determine which drug is the cause once an adverse reaction occurs and all medicines should be often stopped. (2) The combined use with rifampicin (RFP) is difficult for the protease inhibitors and nonnuclear acid reverse transcriptase inhibitors. RFP induces cytochrome P-450 in liver, accelerates the metabolism of some concomitant drug agents, and reduces blood concentration them remarkably. When starting the two above-mentioned medicines during tuberculosis treatment, RFP should be changed to rifabutin (RFB) which has less induction of P-450 than RFP. However, some procedures are required for acquisition of RFB and it is a little complicated in Japan. CDC mentioned the combined use with RFP and efavirenz (EFV) is possible. So, the treatment with EFV and RFP is recently chosen. However, the monitor of the blood concentration of EFV is required, and the dose of EFV should be increased if it is a low value. (3) When a highly active antiretroviral therapy (HAART) is given to AIDS patients with tuberculosis, transient worsening of tuberculosis may develop after about two weeks. (ABSTRACT TRUNCATED)
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PMID:[Tuberculosis in compromised hosts]. 1467 50

A 57-year-old Japanese man had type II c gastric cancer with marked lymph node metastases associated with leukocytosis and elevated granulocyte colony-stimulating factor (G-CSF). Total gastrectomy and distal pancreatectomy with lymph node dissection were performed. Although the primary lesion was negative for G-CSF by histopathological immunostaining, a highly increased G-CSF m-RNA level, measured using reverse transcriptase-polymerase chain reaction in frozen sections, led to a diagnosis of G-CSF-producing gastric cancer. The leukocytes and G-CSF decreased immediately after surgery. He then had an intraabdominal recurrence, and was diagnosed with multiple tumors in his lung and brain, with abnormally elevated leukocytes and greatly increased G-CSF; he died 4 months after the surgery. Autopsy showed intraabdominal recurrence of cancer, with no metastases to the lung or brain, but with multiple brain and lung abscesses. We speculate that the excessively increased neutrophils induced by G-CSF infiltrated the lung and brain and formed abscesses, mimicking metastases.
Gastric Cancer 2005
PMID:Aggressive G-CSF-producing gastric cancer complicated by lung and brain abscesses, mimicking metastases. 1608 24

Although the biologic function of Reg IV is poorly understood, it has been reported that Reg IV is a potent activator of the epidermal growth factor receptor/Akt/AP-1 signaling pathway in colon cancer cells and closely linked with the inhibition of apoptosis. To clarify the role of Reg IV in gastric carcinogenesis and subsequent progression, we examined its expression by immunohistochemistry and in situ hybridization on tissue microarray containing gastric carcinoma, adjacent nonneoplastic mucosa, adenoma, intestinal metaplasia, or gastritis. Gastric carcinoma cell lines (MKN28, AGS, MKN45, KATO-III, and HGC-27) were studied for Reg IV expression by Western blot and reverse transcriptase-polymerase chain reaction followed by sequencing. Frozen samples of gastric carcinoma and adjacent nonneoplastic mucosa were subjected to Western blot, and patient serum, to enzyme-linked immunosorbent assay for Reg IV. Gastric carcinoma cell lines showed different levels of Reg IV mRNA and its encoding protein. The Reg IV protein expression was gradually decreased from intestinal metaplasia, adenoma, and carcinoma to gastritis (P < .05). The positive rate of its mRNA was higher in intestinal metaplasia than carcinoma or nonneoplastic mucosa (P < .05). Elevated serum Reg IV level in gastric carcinoma patients was detected in comparison with that in health individuals (P < .05). Reg IV expression was significantly correlated with the MUC-2 and MUC-5AC expression (P < .05). Among histologic subtypes of the World Health Organization, signet ring cell carcinoma more frequently expressed Reg IV than the others (P < .05), whereas it is the converse for the poorly differentiated group (P < .05). Our study indicated that Reg IV expression experienced up-regulation in gastric intestinal metaplasia and adenoma and then down-regulation with malignant transformation of gastric epithelial cells. It was suggested that Reg IV expression should be considered as a good biomarker for gastric precancerous lesions and was especially related to the histogenic pathway of signet ring cell carcinoma.
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PMID:The role of Reg IV gene and its encoding product in gastric carcinogenesis. 1974 May 14

Bag-1 is an antiapoptotic protein with its altered expression and localization in malignancies. To clarify the role of Bag-1 in gastric carcinogenesis, its expression was examined by immunohistochemistry and in situ hybridization on a tissue microarray containing gastric carcinomas, adjacent nonneoplastic mucosa (NNM), adenomas, intestinal metaplasia (IM), or gastritis. Gastric carcinoma tissue and cell lines were studied for Bag-1 expression by Western blot and reverse transcriptase-polymerase chain reaction (RT-PCR). The results demonstrated that Bag-1 proteins were differentially expressed in the nucleus or cytosol of MKN28, AGS, MKN45, KATO-III, or HGC-27 cell lines, despite similar levels of messenger RNA (mRNA) expression. The Bag-1 mRNA overexpression was detectable in 73.3% of 15 gastric carcinomas without significant difference in its encoding products' levels. The nuclear Bag-1 expression gradually decreased from gastritis, IM, adenoma to carcinoma (P < .05), and negatively correlated with lymphatic invasion or lymph node metastasis, cytoplasmic Bag-1 expression, negative parafibromin expression, and poor prognosis (P < .05). Cytoplasmic Bag-1 was weakly immunoreactive in carcinomas, compared with gastritis (P < .05), and positively associated with invasive depth and poor prognosis of the carcinoma (P < .05). The positive rate of Bag-1 mRNA expression was higher in adjacent IMs than carcinomas or adjacent NNM (P < .05). Bag-1 mRNA was expressed more in carcinomas from female patients than the male counterparts (P < .05). There was a positive correlation of Bag-1 mRNA expression with invasive depth and venous invasion (P < .05). Our study indicated that aberrant expression and subcellular distribution of Bag-1 might play an important role in the malignant transformation of gastric epithelial cells and should be considered as a biomarker for gastric carcinogenesis, subsequent progression, and prognosis.
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PMID:Nuclear or cytoplasmic localization of Bag-1 distinctly correlates with pathologic behavior and outcome of gastric carcinomas. 2009 20

Gastric carcinoma is the most common neoplasm in Southeast Asian populations and is the second leading cause of cancer death worldwide. Annexins are a family of cytosolic calcium and membrane binding proteins that have been implicated in a wide variety of cell functions. Recent studies have suggested that Annexin A10 (ANXA10), a member of the Annexin protein family, is down-regulated in specific types of cancer. However, the underlying molecular mechanisms of the dysregulation of ANXA10 remain to be elucidated. In the present study, to investigate the biological effects of ANXA10 on gastric carcinoma, aberrant expression of ANXA10 was evaluated by Western blot analysis, reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC), in gastric cancer tissues and cell lines. Decreased expression of ANXA10 was observed in five selected gastric cancer tissues compared to the normal surrounding mucosa. In the cancer cell lines, seven out of nine selected gastric cancer cell lines had no detectable ANXA10 by RT-PCR. Among these, when an ANXA10 expressing plasmid was introduced into MKN-1 cells, cell growth was suppressed and apoptosis augmented. The results of this study demonstrated that ANXA10 was aberrantly regulated in gastric carcinoma and suggests that down-regulation of ANXA10 might be involved in gastric carcinogenesis. In addition, ANXA10 may play a role, as a tumor suppressor, in the development and progression of gastric cancer.
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PMID:Decreased expression of annexin A10 in gastric cancer and its overexpression in tumor cell growth suppression. 2066 64