Secondary immunoglobulin A nephropathy with gross hematuria leading to rapidly progressive glomerulonephritis following severe acute respiratory syndrome coronavirus 2 vaccination: a case report.

BACKGROUND: The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been followed by many reports of the development and relapse of autoimmune diseases associated with SARS-CoV-2 vaccination. Some of these reports have involved relapse or onset of immunoglobulin A (IgA) nephropathy following SARS-CoV-2 vaccination. Here, we report on a patient with IgA nephropathy who presented with gross hematuria and rapidly progressive glomerulonephritis following SARS-CoV-2 vaccination. CASE PRESENTATION: A 63-year-old male patient with a history of habitual tonsillitis underwent bilateral tonsillectomy. He had a history of alcoholic cirrhosis of the liver and microscopic hematuria and proteinuria were indicated during a health checkup 2 years before hospital admission. He developed hematuria after the SARS-CoV-2 vaccination, which led to rapidly progressive glomerulonephritis, for which he was hospitalized. A renal biopsy led to the diagnosis of IgA nephropathy. Although pulse steroid therapy during his condition resulted in hepatic encephalopathy, three courses combined with mizoribine improved his renal function. CONCLUSION: SARS-CoV-2 mRNA vaccines activate T cells, which are involved in the pathophysiology of IgA nephropathy. Therefore, this case suggests that the exacerbation of IgA nephropathy by the vaccine favors the vasculitis aspect of the disease.

Ameliorating effects of compounds derived from Salvia miltiorrhiza root extract on microcirculatory disturbance and target organ injury by ischemia and reperfusion.

Ischemia and reperfusion (I/R) exerts multiple insults in microcirculation, frequently accompanied by endothelial cell injury, enhanced adhesion of leukocytes, macromolecular efflux, production of oxygen free radicals, and mast cell degranulation. Since the microcirculatory disturbance results in injury of organ involved, protection of organ after I/R is of great importance in clinic. Salvia miltiorrhiza root has long been used in Asian countries for clinical treatment of various microcirculatory disturbance-related diseases. This herbal drug contains many active water-soluble compounds, including protocatechuic aldehyde (PAl), 3,4-dihydroxyphenyl lactic acid (DLA) and salvianolic acid B (SalB). These compounds, as well as water-soluble fraction of S. miltiorrhiza root extract (SMRE), have an ability to scavenge peroxides and are able to inhibit the expression of adhesion molecules in vascular endothelium and leukocytes. Moreover, lipophilic compounds of SMRE also prevent the development of vascular damage; NADPH oxidase and platelet aggregation are inhibited by tanshinone IIA and tanshinone IIB, respectively, and the mast cell degranulation is blunted by cryptotanshinone and 15,16-dihydrotanshinone I. Thus, the water-soluble and lipophilic compounds of SMRE appear to improve the I/R-induced vascular damage multifactorially and synergically. This review will summarize the ameliorating effect of compounds derived from SMRE on microcirculatory disturbance and target organ injury after I/R and will provide a new perspective on remedy with multiple drugs.

[Influence of habitual drinking and viral hepatitis type C in the progression of liver cirrhosis].

Recently prevalence of alcoholic liver disease has been increasing in Japan associated with an increase in alcoholic beverage consumption. In the present study, we addressed the recent trend in the etiology of liver cirrhosis (LC) in Japan, and investigated the influence of habitual drinking and viral hepatitis type C in the progression of LC. We carried out nation-wide survey by asking for the hospitals that are approved by the Japanese Society of Gastroenterology for the etiology of in-patients with LC, and compared to that in our hospital. Regarding the cases in nation-wide survey, 1274 cases (14%) of 9126 patients with LC were pure (without any markers of hepatitis virus) heavy drinkers, and 580 cases (6%) were heavy drinkers with any markers of hepatitis virus. However, in our general hospital, 24 cases of 101 patients with LC (24%) were pure heavy drinker, and 31 cases (30%) were heavy drinkers with any markers of hepatitis virus. In conclusion, although influence of hepatitis virus infection in alcoholic LC has been decreasing, it still plays an important role in the progression of alcoholic LC, especially in the general hospitals. Education of abstinence or low risk drinking is important not only heavy drinkers but also habitual drinkers with hepatitis virus infection.

Effect of a herbal medicine on fatty liver in rats fed ethanol chronically.

AIM: The objective of this study was to determine whether Cardiotopic Pills (CP) affects fatty liver in rats fed ethanol chronically. MATERIALS AND METHODS: Male Wistar rats were treated with liquid diet that contained ethanol (36% of total calories) or an isocaloric carbohydrate instead of ethanol for 6 weeks. CP, an oral herbal medicine including Danshen (Salviae Miltiorrhiza), Panax notoginseny and Dyroblanops aromatica gaertn, have been clinically used for vascular diseases such as coronary diseases and cerebral infarction. CP was administered orally with the liquid diets for 2 weeks 0.4 mg/kg body weight/day with the liquid diet thereafter. Serum triglyceride and total cholesterol levels, total protein, albumin, and AST and ALT activities are measured. Histological examination was also carried out. In another set of experiments, autofluorescence of NAD(P)H, an indicator of mitochondrial O2 consumption and redox status, was measured by an intravital microscopy, and peroxisome proliferators-activated receptor-(PPAR)-alpha and gamma mRNA levels were evaluated by real time quantitative PCR methods. RESULTS: Chronic ethanol consumption elevated serum triglyceride level, and caused fatty degeneration of liver. After administration of CP, fatty degeneration was not observed in rats fed ethanol chronically. Elevation of serum triglyceride level was not noted after treatment with CP (Ethanol: 79.4 +/- 9.3 mg/dl, Ethanol+CP: 48.0 +/- 4.4, respectively, p<0.05). CP did not affect any other laboratory data or NAD(P)H levels. Chronic ethanol consumption did not affect PPAR-gamma mRNA levels, while it decreased PPAR-alpha mRNA levels in the liver. CP prevented the ethanol-induced decrease in PPAR-alpha mRNA levels. CP and its components could enhance expression of PPAR-alpha mRNA levels. CONCLUSION: These results suggest that CP may be useful to prevent alcoholic fatty liver via enhanced expression of PPAR-alpha.

p53 Protein accumulation, cancer multiplicity, and aldehyde dehydrogenase-2 genotype in Japanese alcoholic men with early esophageal squamous cell carcinoma.

Synchronous multiple intra-esophageal squamous cell carcinomas (SCCs) or oropharyngolaryngeal SCCs are common in alcoholics with esophageal SCC, and more frequently found in those with inactive heterozygous aldehyde dehydrogenase-2 (ALDH2). p53 alterations have been suspected as key molecular events in such multifocal esophageal carcinogenesis. We studied 95 Japanese alcoholic men with Tis and mucosal invasive esophageal SCC and found very high levels of p53 protein accumulation occurring in early esophageal SCC. Synchronous cancer multiplicity in the upper aerodigestive tract was found in 40 patients. p53 expression was not correlated with either cancer multiplicity or ALDH2 genotype. The risk for cancer multiplicity was associated with inactive heterozygous ALDH2 alone (OR=4.22) among the risk factors investigated, which also included smoking, less-active alcohol dehydrogenase-1B, and macrocytosis, enhancing the validity of the link between acetaldehyde exposure and cancer multiplicity.

Risk of squamous cell carcinoma of the upper aerodigestive tract in cancer-free alcoholic Japanese men: an endoscopic follow-up study.

Asian case-control studies have shown a strong relationship between the development of squamous cell carcinoma (SCC) of the esophagus and alcohol consumption combined with inactive aldehyde dehydrogenase-2 (ALDH2*1/*2), less-active alcohol dehydrogenase-1B (ADH1B*1/*1), high mean corpuscular volume (MCV), and self-reported facial flushing in response to alcohol. However, little is known about whether these risk factors prospectively influence cancer development in cancer-free alcoholics. Between 1993 and 2005, 808 Japanese alcoholic men diagnosed as cancer-free by an initial endoscopic screening examination received follow-up examinations ranging from 1 to 148 months (median, 31 months) later, and SCC of the upper aerodigestive tract was diagnosed in 53 of them (esophagus in 33 and oropharyngolarynx in 30). Cox proportional hazards analysis showed that the age-adjusted relative hazard for SCC was 11.55 [95% confidence interval (95% CI), 5.73-23.3] in ALDH2*1/*2 heterozygotes compared with ALDH2*1/*1 homozygotes, 2.02 (95% CI, 1.02-4.02) in ADH1B*1/*1 homozygotes compared with ADH1B*1/*2 heterozygotes or *2/*2 homozygotes, 2.64 (95% CI, 1.49-4.67) in patients with flushing compared with those who had never experienced flushing, 2.91 (95% CI, 1.63-5.20) in those with an MCV >or= 106 compared with those with an MCV < 106, 2.52 (95% CI, 1.22-5.22) in those who smoked >or=30 cigarettes per day compared with those who smoked 0 to 19 cigarettes per day, 7.26 (95% CI, 3.99-13.23) in those with esophageal dysplasia compared with those without distinct iodine-unstained lesions >or=5 mm, and 0.28 (95% CI, 0.09-0.85) in those with body mass index >or= 23.2 (highest quartile) compared with those with body mass index < 19.0 (lowest quartile). These predictors are useful for selecting appropriately patients for careful follow-up examinations.

Induction therapy with twice-daily interferon-beta does not improve the therapeutic efficacy of consensus interferon monotherapy for chronic hepatitis C.

We examined therapeutic superiority of induction therapy with twice-daily IFN-beta (3X2=6 million units/day) onto 6-months consensus interferon monotherapy for chronic hepatitis C. Patients were randomly assigned to monotherapy without (group I, n=16) and with induction therapy (group II, n=12). The mean age of group II was older than that of group I, and other baseline condition was not statistically significant. Sustained virological response (SVR) rates of group I and II were 81.3% (13/16) and 58.3% (7/12), respectively (p=0.365). SVR rates in patients with genotype 1b were 66.7% (4/6) and 0% (0/2, because of drop-out), and those with high viral load were 70% (7/10) and 75% (6/8) in group I and II, respectively (p=1.000). Drop-out rates during therapy were 6.3% (1/16) and 33.3% (4/12) in group I and II, respectively (p=0.176). Age less than 50 years was the only independent factor that was shown by multivariate logistic model analysis to be associated with a sustained virological response. Although randomization failed to produce and equal age distribution in the two groups in this study, our results suggest that induction therapy with twice-daily IFN-beta has no beneficial effect on the efficacy of monotherapy with consensus interferon, probably because of the higher drop-out rates and incidence of adverse reactions with induction therapy.

Efficacy of natural BALL-1 interferon-alpha treatment for patients with chronic hepatitis C and a possible enhancing effect of a twice-daily starting regimen with interferon-beta.

BACKGROUND/AIMS: Two distinct natural interferon-alpha (BALL-1 and Namalwa) are available for patients with chronic hepatitis C in Japan, but the efficacy has not been well documented. We investigated two studies using a natural BALL-1 interferon-alpha treatment for chronic hepatitis C and assessed its efficacy. METHODOLOGY: In interferon-alpha monotherapy (Study I), 42 patients with chronic hepatitis C received 10 mega units of BALL-1 interferon-alpha intramuscularly consecutively for an initial 2 weeks followed by three times a week for 6 months totally. In a combination therapy of natural interferon-alpha and interferon-beta (Study II), 24 patients received intravenous 3 mega units of interferon-beta twice daily for the initial 2 weeks followed by 10 mega units of natural BALL-1 interferon-alpha consecutively for 2 weeks and three times a week for 6 months totally. Efficacy and predictive factors for sustained viral response was investigated. RESULTS: Study II included significant younger patients than study I. Sustained virological response was obtained in 31.0% in Study I and 56.5% in Study II by intention-to-treat analysis. Sustained viral response in the group of genotype 1b and viral load more than 100 KIU/mL was 3/23 (13.0%) and 8/18 (44.4%) in Study I and II, respectively. The response rate in Study II was higher than that of Study I especially among the patients with high pretreatment viral load or genotype 1b (p<0.05). Multivariate analysis showed that pre-treatment HCV-RNA levels, HCV-genotype, and histological staging before the interferon treatment were significant predictive factors of sustained viral response. CONCLUSIONS: These studies suggest that natural BALL-1 interferon-alpha is useful for inducing sustained viral response in patients with chronic hepatitis C, even in those possessing genotype 1b and high viral load. In addition, the combination therapy with a starting regimen with twice-daily interferon-beta administration for 2 weeks may be more effective than monotherapy.

Attenuating effect of Myakuryu on mesenteric microcirculatory disorders induced by ischemia and reperfusion.

Myakuryu (MR) is a newly developed herbal medicine composing Crataegue oinnatifida bge (COB), Panax notoginseng (PN) and Ginkyo biloba (GB). To examine the effectiveness of MR, we investigated its effects on rat mesenteric microcirculatory injury induced by ischemia/reperfusion (I/R). The mesenteric microcirculation of ileocecal portion of a male Wistar rat was observed through an inverted-type intravital microscope assisted with a charge-coupled devise (CCD) camera. Mesenteric I/R was conducted by a ligation of the mesenteric artery and vein (10 min) and subsequent release of the occlusion. We measured venular diameter, the number of adherent leukocytes, dihydrorhodamine 123 (DHR) fluorescence as an indicator of oxidative stress and mast cell degranulation, with or without MR extract (0.4 g/kg b.w.) via an orogastric tube 1 hr before I/R. The diameters of the observed mesenteric venules were not changed after the mesenteric I/R. MR had no effect on venular diameter. The leukocytes adhering to the post-capillary venular walls started just after reperfusion, and increased thereafter. The increased number of adherent leukocytes was significantly reduced by treatment with MR. DHR fluorescence ratio was significantly increased along the venular wall. MR attenuated the increased oxidation. The mesenteric I/R induced mast cell degranulation. The increase in mast cell degranulation was inhibited by MR. In conclusion, oral administration of MR attenuates I/R-induced microvascular damages in rat mesentery. MR has a therapeutic potential for prevention of I/R-related microvascular injury.

[Alcoholic liver diseases and hepatitis virus C in Japan].

Recently incidence of alcoholic liver disease (ALD) has been increasing in Japan associated with an increase in alcoholic beverage consumption. There have been a large number of reports about the relationship between alcohol and hepatocarcinogenesis, but it remains controversial. In the present study, we addressed the recent trend in incidence of ALD including liver cirrhosis (LC), and hepatocellular carcinoma (HCC) in heavy drinkers in Japan. We carried out nation-wide survey by asking for the hospitals that are approved by the Japanese Society of Gastroenterology for recent aspects of in-patients with ALD. Except for HCC, percentage of ALD without viral hepatitis is more than 70%, which is increased when compared to the national survey carried out in 1992. In alcoholic LC patients, those who did not have viral hepatitis were 81%. However, the percentage of HCC without viral hepatitis was 34% of all of the heavy drinkers with HCC. Regarding the case in our university hospital, 138 cases (32%) of 432 patients with HCC were heavy drinkers. However, regarding in our general hospital, 15 cases of 23 patients with HCC (61%) were heavy drinkers. In conclusion, since the consumption of alcohol is increasing in Japan, the frequency and number of cases of alcoholic liver cirrhosis are increasing. Viral hepatitis infection, however, still plays an important role in hepatocarcinogenesis in heavy drinkers.

Limited capability of regional lymph nodes to eradicate metastatic cancer cells.

The capacity of lymph nodes to eradicate cancer is a controversial issue. The purpose of this study was to determine the interplay between tumor growth and host resistance at early stages of lymph node metastasis. A metastasis model was made in the rat mesenteric lymph node, and migration of cancer cells was visualized in vivo. The lymph node was removed for histologic analysis and cytokine measurement. Migrant cancer cells were initially arrested in the marginal sinus. After an initial increase, the number of cancer cells in the marginal sinus declined until 48 hours after inoculation. Germinal centers and lymphoid cells in the medulla proliferated before 48 hours. ED3(+) macrophages incorporated apoptotic cancer cells, but significant cancer proliferation occurred after 4 days. Lymph nodes depleted of macrophages were massively invaded by cancer cells. Tumor necrosis factor alpha and interleukin (IL)-1beta in the nodes transiently increased after 1 hour and 3 hours, respectively, and were expressed in ED3(+) and ED2(+) macrophages, respectively. These changes were followed by a transient increase in IL-2. Interferon-gamma and IL-12 did not increase during the early stages of metastasis, but they decreased after 48 hours. In conclusion, the marginal sinus constitutes a mechanical barrier against cancer cell passage. Early pathological manifestations in the regional lymph node are consistent with those in cancer patients with improved survival. Parasinus macrophages play a role in the transient antimetastatic capability of the node, and cytokines secreted by these cells increased at the early stages of metastasis. Deterioration of cytokine induction may be responsible for subsequent cancer proliferation.

A specific genetic alteration on chromosome 6 in ulcerative colitis-associated colorectal cancers.

Various genetic alterations in ulcerative colitis (UC)-associated colorectal cancers (CRCs) have been reported. However, almost all studies have shown abnormalities of the known genes that have been demonstrated in sporadic CRCs. To identify novel genetic alterations, we selected unintentionally 35 microsatellite markers, and performed allelotype study in CRCs or dysplastic lesions from UC. High frequency of loss of heterozygosity (LOH; 62.5%) was detected on chromosome 6 (D6S468) but not on other chromosomes. With four additional microsatellite markers around the D6S468 locus, we determined the commonly deleted region between two loci, D6S1543 and D6S1580, in UC-associated CRCs and dysplasia. Interestingly, there was no LOH in this region in sporadic CRCs and severely inflamed lesions of longstanding and extensive UC without cancers. These results indicated the presence of novel tumor suppressor genes on chromosome 6 related to the carcinogenesis of UC but not to sporadic CRCs.

[Current trends of NASH/NAFLD in Asia-Pacific region].

In Japan, much attention has been paid to NASH and NAFLD for the past several years and the prevalence of this disease entity has been estimated, and NASH is thought to be present in 10% of those who have fatty liver diseases. Other points out the prevalence of NASH in Japan as 6 to 8 hundred thousand patients. The last two or three decades have seen the evolution of Western-style life of near complete inactivity, energy-dense food choices and liberal fiscal resources to obtain them and other means to avoid physical activity. Moreover, what is increasingly apparent is that NASH and NAFLD is not a Western disease and many population groups in the Asia-Pacific region are particularly prone to type 2 diabetes. Thus, it is not surprising that NASH has increasingly been diagnosed in several regions in Asia including Indonesia, Malaysia, Philippines, Thailand and India.

[Nonalcoholic steatohepatitis: a brief review on its concept].

Since the first report by Ludwig, considerable progress has been made in the understanding of NASH and it is not currently considered as a merely benign clinical entity, but is rather thought as a common disease with a variety of clinical sequelae including liver cirrhosis and even hepatocellular carcinoma. Thus, NASH is considered as a type of a larger spectrum of nonalcoholic fatty liver disease (NAFLD) that is a consequence of insulin resistance and other underlining factors with histological findings ranging from fatty change alone to fat plus inflammation, to fat plus ballooning degeneration, and to fat plus alcoholic hepatitis-like lesions including Mallory body and fibrosis, the latter two categories being considered as NASH. In this brief review article, particular emphasis has been paid to the clinical entity, namely cryptogenic cirrhosis in relation to the pathogenesis of NASH.

Identification and characterization of novel gut-associated lymphoid tissues in rat small intestine.

BACKGROUND: The crypt lamina propria of the mouse small intestine has been shown to harbor multiple tiny clusters filled with c-kit- and interleukin 7 receptor (IL-7R)-positive lympho-hemopoietic cells (cryptopatches; CPs). However, it has remained an open question whether similar lymphoid tissue are present in the gastrointesitinal tract in other animals. In the present study, we investigated whether the small intestine of rats harbored lymphoid tissues similar to mouse CPs. METHODS: Immunohistochemical and flow cytometric analyses were carried out using various antibodies, including those to c-kit and IL-7R molecules. RESULTS: Lymphocyte-filled villi (LFVs), populated predominantly with c-kit- and IL-7 receptor (IL-7R)-positive cells and less with T cell receptor (TCR)-alphabeta T cells were found throughout the small intestine of young adult rats. Although LFVs were absent from fetal rat intestine, they were first detected at around 2 weeks after birth. Notably, in most LFVs that settled in the antimesenteric wall of the small intestine in young adult rats, immunoglobulin M-positive B cells were also detectable at the bottom of the LFVs. In aged rats, lymphocytes in some LFVs displayed a different phenotype, comprising a large B-cell area that included a germinal center. Thus, these clusters represent the first description of isolated lymphoid follicles (ILFs) in the rat small intestine. CONCLUSIONS: The present study provides the first evidence for c-kit- and IL-7R-positive lymphocyte clusters in the rat small intestine. Our data also indicating that LFVs and ILFs may constitute novel organized gut-associated lymphoid tissues in lamina propria of the rat small intestine.

Association of pseudomembranous colitis with Henoch-Schönlein purpura.

A 79-year-old man was admitted because of cholecystitis that occurred about 40 days after sigmoidectomy had been performed for colonic cancer. Though antibiotics improved his condition, the patient had hematochezia, diarrhea, and left lower abdominal pain. Colonoscopic findings showed multiple ring-like areas of redness and petechiae in the rectosigmoid colon and marked edema from the descending to the transverse colon. The patient then developed purpura on the extensor surfaces of the legs and bilateral gonalgia, and exacerbation of the hematochezia. A second colonoscopy (CS) showed multiple ring-like areas of redness and ecchymosis throughout the colon. The patient was diagnosed with Henoch-Schönlein purpura (HSP), and the symptoms were attenuated after the administration of prednisolone. However, diarrhea recurred in about a week; stool culture confirmed Clostridium difficile, and a third CS revealed pseudomembranes throughout the colon. The patient was diagnosed with pseudomembranous colitis (PMC), and the administration of vancomycin attenuated the symptoms. In conclusion, we have reported a rare adult case of PMC that occurred during prednisolone treatment for HSP. The PMC may have been caused by changes in the intestinal bacterial flora after the sigmoidectomy and by the intestinal lesions of HSP, as well as by the administration of antibiotics after the sigmoidectomy and for the treatment of cholecystitis, and by the use of prednisolone for the treatment of the HSP.

Esophageal melanosis, an endoscopic finding associated with squamous cell neoplasms of the upper aerodigestive tract, and inactive aldehyde dehydrogenase-2 in alcoholic Japanese men.

BACKGROUND: Esophageal melanosis is often observed in alcoholic Japanese men, in whom the prevalence of squamous cell dysplasia and carcinoma (SCC) in the upper aerodigestive tract are high. This study evaluated the associations of esophageal melanosis with these neoplasms, and the factors contributing to the development of esophageal melanosis in this population. METHODS: Endoscopic screening was combined with esophageal iodine staining in 1535 alcoholic Japanese men (aged 40-79 years), of whom 1007 underwent aldehyde dehydrogenase-2 (ALDH2) genotyping. RESULTS: Fifty patients (3.3%) were diagnosed with esophageal melanosis, which had a higher incidence in those with noncancerous distinct iodine-unstained lesions (DIULs; 16/268; 6.0%), esophageal SCC (9/66; 13.6%), and oropharyngolaryngeal SCC (4/19; 21.1%) than in cancer- and DIUL-free controls (24/1182; 2.0%). The presence of esophageal melanosis was associated with higher risks for noncancerous DIULs, esophageal SCC, and oropharyngolaryngeal SCC (odds ratios, 2.81, 6.54, and 14.77, respectively). Men with the inactive ALDH2*1/2*2 genotype had a higher risk for esophageal melanosis (2.66-fold), as well as for DIULs and SCCs. CONCLUSIONS: The presence of esophageal melanosis in alcoholic Japanese men could indicate a high risk for DIULs and SCCs in the upper aerodigestive tract. The high incidence of esophageal melanosis may be partially linked to high acetaldehyde exposure, a consequence of drinking alcohol in persons with inactive ALDH2.

A novel apoptosis-inducing monoclonal antibody (anti-LHK) against a cell surface antigen on colon cancer cells.

BACKGROUND: Apoptosis is a crucial element in the behavior of mammalian cells in many different situations. We here report the establishment of a novel monoclonal antibody (anti-LHK mAb) that has apoptosis-inducing activity against colon cancer Colo205 cells. METHODS: The mechanism of anti-LHK mAb-induced cell death was assessed by microscopic morphology, Annexin V/Hoechst 33528 staining, and detection of DNA fragmentation. The molecular weight of LHK antigen was determined by Western blotting. Growth inhibition of Colo205 cells induced by anti-LHK mAb was determined by in vitro and in vivo studies. RESULTS: Anti-LHK reacted with a 70-kDa antigen and completely blocked the proliferation of Colo205 cells bearing LHK in vitro in a manner characteristic of apoptosis. Strikingly, anti-LHK mAb suppressed tumor growth in a murine peritoneal dissemination model. CONCLUSIONS: LHK antigen, which is restricted to epithelial cells, may be a novel death receptor that plays a critical role in controlling the growth, invasion, and metastasis of human colon cancer cells.

Contribution of Irf-1 promoter polymorphisms to the Th1-type cell response and interferon-beta monotherapy for chronic hepatitis C.

We recently reported promoter polymorphisms in the IRF-1 gene, an interferon-inducible gene that plays an important role in host antiviral function. The promoter activity was shown to be different between different polymorphisms. In this study, we investigated the relationship between IRF-1 promoter polymorphisms and the response to interferon monotherapy for chronic hepatitis C. Eighteen patients with a low initial viral load or hepatitis C virus (HCV) genotype non-1b received 6-months course of interferon-beta monotherapy. IRF-1 gene mutations and the treatment response were investigated. The IRF-1 promoter type possessing a higher promoter activity (-415C/-410A/-300A) was found in only three patients, all of which had a lower viral load than those with other promoter types and were able to obtain a sustained viral response. Flow cytometric analysis of peripheral blood mononuclear cells showed that the patients with a higher promoter activity of the IRF-1 had a significantly higher proportion of T helper 1-type CD4(+) cells after interferon administration than those of other promoter types. These results suggest that IRF-1 promoter polymorphisms may contribute, at least partially, to host antiviral activity for chronic hepatitis C.