The Link of mRNA and rRNA Transcription by PUF60/FIR through TFIIH/P62 as a Novel Therapeutic Target for Cancer.

The interaction between mRNA and ribosomal RNA (rRNA) transcription in cancer remains unclear. RNAP I and II possess a common N-terminal tail (NTT), RNA polymerase subunit RPB6, which interacts with P62 of transcription factor (TF) IIH, and is a common target for the link between mRNA and rRNA transcription. The mRNAs and rRNAs affected by FUBP1-interacting repressor (FIR) were assessed via RNA sequencing and qRT-PCR analysis. An FIR, a c-myc transcriptional repressor, and its splicing form FIRΔexon2 were examined to interact with P62. Protein interaction was investigated via isothermal titration calorimetry measurements. FIR was found to contain a highly conserved region homologous to RPB6 that interacts with P62. FIRΔexon2 competed with FIR for P62 binding and coactivated transcription of mRNAs and rRNAs. Low-molecular-weight chemical compounds that bind to FIR and FIRΔexon2 were screened for cancer treatment. A low-molecular-weight chemical, BK697, which interacts with FIRΔexon2, inhibited tumor cell growth with rRNA suppression. In this study, a novel coactivation pathway for cancer-related mRNA and rRNA transcription through TFIIH/P62 by FIRΔexon2 was proposed. Direct evidence in X-ray crystallography is required in further studies to show the conformational difference between FIR and FIRΔexon2 that affects the P62-RBP6 interaction.

Phosphorylated mTOR expression as a predictor of survival after liver resection for colorectal liver metastases.

BACKGROUND: Phosphorylated mammalian target of rapamycin (p-mTOR) plays a crucial role in the process of cancer progression. Common gene mutations of colorectal cancer lead to the activation of the PI3k/Akt/mTOR pathway. In this study, we determined whether p-mTOR expression in colorectal liver metastases is a predictive marker of prognosis following liver resection. METHODS: Eighty-one patients with colorectal liver metastases who had undergone curative resection were evaluated using immunohistochemistry of p-mTOR. Data regarding clinicopathological features and patient survival were analyzed. RESULTS: The p-mTOR expression in colorectal liver metastases was detected in 55 (67.9%) patients. Patients whose metastases had high p-mTOR expression showed a significantly lower overall survival rate after resection as compared to patients with low p-mTOR expression (p = 0.016), while there was no significant difference in the disease-free survival between the two groups. Repeat resection for recurrence was performed more frequently in patients with p-mTOR positive than others (p = 0.024). Multivariate analysis showed that p-mTOR expression was an independent prognostic factor of overall survival after liver resection (p = 0.019). CONCLUSIONS: mTOR was frequently activated in colorectal liver metastases, and the p-mTOR expression was a biological marker for predicting the overall survival of patients with colorectal liver metastases following liver resection.

Helicobacter pylori protein that binds to and activates platelet specifically reacts with sera of H. pylori-associated chronic immune thrombocytopenia.

Immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by antiplatelet antibodies and/or CD8 + T cells, resulting in the destruction of platelets and decreased platelet counts. Helicobacter pylori that persistently colonizes the stomach causes various disorders, including extragastric diseases such as chronic ITP (cITP). Several studies have reported increased platelet counts in H. pylori-infected cITP patients with eradication treatment and also the pathophysiological pathways involving cross-reaction of antibodies against H. pylori with platelets, the modulation of Fcrγ receptors balance and others. We previously reported an immunocomplex pathway comprising H. pylori low-molecular-weight (LMW) antigens, their antibodies, and platelets, involved in the development of H. pylori-associated cITP; however, the LMW antigens were not identified. In the present study, we demonstrated that the H. pylori LMW antigen of the immunocomplex was identified as Lpp20 of outer membrane proteins. Lpp20 could bind to platelets and specifically react with sera of H. pylori-associated cITP patients.

Clinical and anthropometric characteristics of non-obese non-alcoholic fatty liver disease subjects in Japan.

AIM: The underlying mechanism of non-obese non-alcoholic fatty liver disease (NAFLD) has not been fully elucidated. We classified patients with NAFLD by sex and body mass index and compared their clinical features to clarify the background pathophysiology of non-obese NAFLD. METHODS: A total of 404 patients with NAFLD were divided according to their body mass index (<25 [non-obese], 25 to <30 [obese], and ≥30 [severe obese]), and were further compared with 253 patients without obesity and NAFLD (non-NAFLD). RESULTS: The proportion of the individuals with non-obese NAFLD was 25.7% in men and 27.6% in women. The male and female non-obese NAFLD groups had lower skeletal muscle mass and muscle strength than the obese NAFLD groups. The visceral fat area, although low, was ≥100 cm2 in 59.3% of men and 43.8% of women. An increase in liver fat accumulation, hepatic fibrosis, homeostasis model assessment of insulin resistance, and leptin levels was modest in the non-obese NAFLD group compared with a marked increase in the obese NAFLD groups. The muscle mass of the non-obese NAFLD group was similar to that of the non-NAFLD group, but muscle steatosis was particularly common among women. Multivariate analysis revealed that the factors contributing to increased liver fat accumulation in the non-obese NAFLD group were visceral fat area, HbA1c, myostatin, and leptin. CONCLUSIONS: In patients with non-obese NAFLD, a sex difference was observed in the clinical features. In addition to increased visceral fat, decreased muscle mass and muscle strength, muscle atrophy (presarcopenia), and impaired glucose tolerance were considered to be important pathophysiological factors.

Influence of Living Environment during Childhood on Helicobacter pylori Infection in Japanese Young Adults.

INTRODUCTION: Helicobacter pylori infection is usually established during childhood, for which certain responsible environmental factors have been identified. However, the details of the infection routes remain unclear. OBJECTIVE: To determine the relation between H. pylori infection statuses and living environment of Japanese young adult. METHODS: The subjects were 449 healthy young adult medical students of Tsukuba University (299 men and 150 women, mean age: 22.8 years). The H. pylori infection statuses were investigated using the rapid urease test or urine antibody. Questionnaires regarding sanitary conditions including usage of pit toilet or well water and experience of living with one's grandparents during childhood were surveyed. Each item was compared between the H. pylori-positive and -negative groups. RESULTS: Among all participants, 33 (7.3%) were H. pylori-positive. The usage rates of pit toilets were 12.1 and 3.1% for the H. pylori-positive and -negative groups respectively (p = 0.03; OR 4.35, 95% CI 1.33-14.22). The usage rates of well water were 24.2 and 13.7% for the H. pylori-positive and -negative groups respectively (p = 0.07; OR 2.12, 95% CI 0.91-4.98). The proportion of participants with a history of living with their grandparents was significantly greater in the H. pylori-positive group (46.7%) than in the -negative group (20.9%; p = 0.03; OR 3.28, 95% CI 1.13-9.54). Only a history of living with one's grandparents during childhood showed statistical significance in the multivariate regression analysis (p = 0.04; OR 3.20, 95% CI 1.08-9.49). CONCLUSIONS: These results suggest that H. pylori infection is more strongly related to living with one's grandparents than living in a hygienic environment.

Moderate to vigorous physical activity volume is an important factor for managing nonalcoholic fatty liver disease: a retrospective study.

UNLABELLED: Recently, the beneficial effects of increased physical activity (PA) on nonalcoholic fatty liver disease (NAFLD) in obese subjects were reported. However, the optimal strength and volume of PA in lifestyle modification to improve NAFLD pathophysiology and be recommended as an appropriate management of this condition are unclear. The primary goal of this retrospective study was to estimate the beneficial effects of a varying volume of moderate to vigorous intensity PA (MVPA) on the improvement of NAFLD. A total of 169 obese, middle-aged men were enrolled in a 12-week weight reduction program through lifestyle modification consisting of dietary restrictions plus aerobic exercise. Among these obese subjects, 40 performed MVPA for <150 min·wk(-1) , 42 performed MVPA for 150-250 min·wk(-1) , and 87 performed MVPA for >250 min·wk(-1) . The subjects in the MVPA ≥250 min·wk(-1) group, in comparison with those in the MVPA <250 min·wk(-1) group, showed significantly attenuated levels of hepatic steatosis (-31.8% versus -23.2%). This attenuation was likely independent of the detectable weight reduction. MVPA for ≥250 min·wk(-1) in comparison with that for <150 min·wk(-1) led to a significant decrease in the abdominal visceral adipose tissue severity (-40.6% versus -12.9%), levels of ferritin (-13.6% versus +1.5%), and lipid peroxidation (-15.1% versus -2.8%), and a significant increase in the adiponectin levels (+17.1% versus +5.6%). In association with these changes, the gene expression levels of sterol regulatory element-binding protein-1c and carnitine palmitoyltransferase-1 in peripheral blood mononuclear cells also significantly decreased and increased, respectively. CONCLUSION: MVPA for ≥250 min·wk(-1) as part of lifestyle management improves NAFLD pathophysiology in obese men. The benefits seem to be acquired through reducing inflammation and oxidative stress levels and altering fatty acid metabolism.

[A Case Report of Clinical Complete Response with Chemotherapy for Descending Colon Cancer Complicated with Severe Pulmonary Dysfunction].

A 76-year-old male patient was diagnosed with progressive descending colon cancer. Since the patient had severe respiratoryfunction impairment after right pneumonectomy, the anesthesiologydepartment of our hospital determined that general anesthesia induction was too difficult. He was thus started on capecitabine plus oxaliplatin(XELOX)therapy. Three months after starting this treatment, colonoscopyshowed that the site had become scarred, and tissue examination revealed no indication of malignancy. Accordingly, the patient achieved clinical complete response. The patient had no findings of recurrence 1 year and 11 months after the start of chemotherapy. Chemotherapy for unresectable progressive recurrent colorectal cancer is based on the 5-FU anticancer agent, which exerts its antitumor effect byinhibiting DNA synthesis. The antitumor effect is reportedly high when the expression of thymidylate synthase(TS), a target agent, is low. In this patient, TS expression was low based on tissue examination. TS expression maybe an effective useful predictive factor for the efficacyof chemotherapyadministered to patients with unresectable progressive recurrent colorectal cancer.

[A Case of Multiple Liver Metastases and Peritoneal Dissemination after Resection of a Gastrointestinal Stromal Tumor of the Stomach Successfully Treated with Imatinib Mesylate].

A 71-year-old man was diagnosed with a gastric tumor approximately 50mm in diameter on computed tomography (CT). In January 2000, he underwent a proximal gastrectomy. Pathological examination showed 5 mitoses per 50 high-power fields, while immunohistochemical analysis showed positive staining for KIT. Accordingly, the tumor was diagnosed as an intermediate- risk malignant gastrointestinal stromal tumor (GIST) for which the patient was followed. In January 2002, an abdominal CT scan revealed multiple hepatic tumors and a lower abdominal tumor, and the patient was diagnosed with liver metastases and peritoneal disseminations from GIST. After informed consent was provided, chemotherapy with 400 mg/day imatinib was initiated. The patient demonstrated a partial response 2 months after treatment. At 12 years 8 months after the diagnosis of liver metastasis and peritoneal disseminations, the patient shows no sign of recurrence.

[A Case of Idiopathic Thrombocytopenic Purpura during Adjuvant Chemotherapy for Colon Cancer].

A 76-year-old man underwent surgery for sigmoid colon cancer. The pathological finding was stage Ⅱ with a high-risk of recurrence (SI [bladder], l y0, v2, pN0, H0, P0, M0). He was treated with TS-1 as adjuvant chemotherapy. After the 1 course of chemotherapy, his platelet count was 4,000/mL. The high index of platelet associated IgG (PA-IgG) and bone marrow examination suggested that thrombocytopenia was caused by idiopathic thrombocytopenic purpura. The platelet count improved by prednisolone administration and Helicobacter pylori eradication treatment. After 6 months with no administration of adjuvant chemotherapy, the colon cancer recurred locally, and we performed a Hartmann's operation.

[Two Cases of Pancreatic Neuroendocrine Tumor with Liver Metastases Successfully Treated with Multidisciplinary Therapy including Multiple Surgical Resections].

UNLABELLED: We report 2 cases of pancreatic neuroendocrine tumor with liver metastases successfully treated with multidisciplinary therapy, including multiple surgical resections. Case 1: A 63-year-old man underwent distal pancreatectomy and portal vein resection for a pancreatic body tumor. Histological analysis revealed the tumor was a pancreatic neuroendocrine tumor (p-NET), classified as NET G2. His metachronous liver metastases were treated with lateral sectionectomy and 2 rounds of transcatheter arterial chemoembolization (TACE). He is being treated with everolimus for para-aortic lymph node metastases and is alive 90 months after the primary operation. Case 2: A 64-year-old man underwent distal gastrectomy for a duodenal ulcer and distal pancreatectomy for a pancreatic tumor. The histological diagnosis was gastrinoma classified as NET G2. Hepatectomy (segmentectomy of segment 8 and partial hepatectomy) was performed twice for metachronous liver metastases. Everolimus has been administered for liver and para-aortic lymph node metastases, and the patient is alive 108 months after the primary operation. CONCLUSION: Multidisciplinary treatment should be considered for patients with p-NETs with multiple metastases.

[A successful case with TS-1+CDDP chemotherapy for recurrent gastric cancer].

A 64-year-old woman underwent cholecystectomy for treatment of cholecystolithiasis in January 2005. Pathological examination rendered a diagnosis of gallbladder carcinoma. Wedge resection of the liver and dissection of the lymph nodes was performed. No tumor cells in either the liver nodule or lymph nodes were found during pathological examination. At 4 years after surgery, paraaortic lymph node recurrence was confirmed by computed tomography (CT). Gemcitabine was administered once weekly for the first 3 weeks in a monthly cycle, but the tumor continued to increase in size. Gemcitabine was then switched to TS-1, after which it was changed to cisplatin because of continued tumor growth. After 35 courses of chemotherapy, CT showed the disappearance of the paraaortic lymph node, and the patient achieved a complete response. She is currently free of disease at 9 years after surgery.

[A case of recurrent gastric cancer successfully treated with TS-1+CDDP chemotherapy].

A 74-year-old woman underwent distal gastrectomy and D1+ α dissection for the treatment of gastric cancer (pT2a, pN2, H0, P0, M0, Stage IIIA) in February 2008. She was treated with adjuvant postoperative chemotherapy consisting of TS-1. However, 32 months after the operation, paraaortic lymph node recurrence was confirmed by computed tomography (CT). She was treated with combined TS-1 and cisplatin chemotherapy. After 14 courses, CT revealed that the paraaortic lymph node metastasis had disappeared, and a complete response was attained. The patient is currently disease-free, 6 years after the operation.

Identification of a novel biomarker for sarcopenia diagnosis using serum metabolomic analysis: a pilot study.

PURPOSE: This pilot study compared serum metabolites in participants with and without sarcopenia. METHODS: Metabolomic techniques were applied to identify serum metabolites and novel biomarkers specific to patients with sarcopenia. In accordance with AWGS2019 criteria, sarcopenia was defined as low muscle mass plus either low muscle strength/low physical function, and severe sarcopenia was defined as low muscle mass, low muscle strength, and low physical function all together. RESULTS: The sarcopenia group had higher hypoxanthine, galactose, and mannose levels but lower triethanolamine and homogentisic acid levels than the non-sarcopenia group. The severe sarcopenia group had lower levels of alpha-tocopherol than the mild and moderate sarcopenia groups. CONCLUSION: This study is the first to identify hypoxanthine as a potential biomarker for sarcopenia in humans and provides new insights into the pathophysiology of sarcopenia. Furthermore, the identified metabolites may be useful for the early detection of sarcopenia.

Effect of acute moderate-intensity cycling on cfDNA levels considering menstrual cycle phases.

Introduction: We aimed to determine the effects of exercise on cell-free DNA (cfDNA) levels and concentration changes during the menstrual cycle in participants with regular menstrual cycles and no exercise habits. Methods: Eleven sedentary female students with regular menstrual cycles and ovulation performed bicycle exercises at 60% VO2max for 30 min during the menstrual, ovulatory, and luteal phases. Blood samples were collected before (Pre), immediately after (Post 0), 30 min after (Post 30), and 60 min after (Post 60) exercise. Blood concentrations of ovarian hormones, cfDNA, prostaglandin F2a (PGF2α), interleukin-6 (IL-6), and aromatase were evaluated. Results: Based on the concentration of ovarian hormones, seven individuals were finally analyzed. No significant phase difference was observed in cfDNA across all time points. cfDNA (menstrual phase: p = 0.028, ovulatory phase: p = 0.018, and luteal phase: p = 0.048) and aromatase concentrations (menstrual phase: p = 0.040, ovulatory phase: p = 0.039, and luteal phase: p = 0.045) significantly increased from Pre to Post 0 in all phases. Serum estradiol (E2) levels were significantly higher in the luteal phase at all time points than in the menstrual phase (Pre: p < 0.001, Post 0: p < 0.001, Post 30: p = 0.005, and Post 60: p = 0.011); however, serum progesterone (P4) levels were significantly higher in the luteal phase at all time points than in the menstrual (Pre: p < 0.001, Post 0: p < 0.001, Post 30: p < 0.001, and Post 60: p < 0.001) and ovulatory phases (Pre: p = 0.005, Post 0: p = 0.005, Post 30: p = 0.003, and Post 60: p = 0.003). E2 levels significantly increased from Pre to Post 0 in the ovulatory and luteal phases, whereas P4 levels increased in the luteal phase. Progesterone to estradiol level ratio (P4/E2) changes from Pre to Post 0 (%baseline) during the luteal phase were significantly negatively correlated (r = -0.82, p = 0.046) with the changes in cfDNA from Pre to Post 0. Furthermore, the repeated measures correlation between P4/E2 and cfDNA level showed a significant negative correlation in ovulatory and luteal phases. Discussion: The results indicate that while resting cfDNA levels are unlikely to be affected by a woman's menstrual cycle, the increase in cfDNA after exercise is higher in the ovulatory phase (when only E2 increases) and lower in the luteal phase (when E2 and P4 increase with exercise) compared to that in the menstrual phase (when E2 and P4 are in low levels), suggesting the contribution of increased ovarian hormone levels after exercise.

Proposal and validation of an equation to identify sarcopenia using bioelectrical impedance analysis-derived parameters.

OBJECTIVE: This study aimed to develop a simpler approach for diagnosing sarcopenia by using only bioelectrical impedance vector analysis parameters. METHODS: The study design was a cross-sectional study. The research was conducted based on the Itabashi Longitudinal Study on Aging, a community-based cohort study, with data collected from the 2022 and 2023 surveys in Itabashi Ward, Tokyo, Japan. The development cohort consisted of 1146 participants from the 2022 survey, and the validation cohort included 656 participants from the 2023 survey. Both cohorts were comprised of community-dwelling older adults with similar inclusion criteria. Sarcopenia was defined according to the Asian Working Group for Sarcopenia 2019 criteria. The logistic model utilized height divided by impedance at 50 kHz and phase angle to establish a new regression equation to identify sarcopenia. Regression equations were generated for the development cohort and validated for the validation cohort. Discriminatory ability was assessed using the area under the receiver operating characteristic curve (AUC) for men and women. RESULTS: The prevalence of sarcopenia was 20.7% and 14.8% in the development and validation cohort, respectively. The AUC (95% confidence interval) of the logistic model in discriminating sarcopenia was 0.92 (0.88, 0.95) for men and 0.82 (0.78, 0.86) for women in the development cohort and 0.85 (0.78, 0.91) for men and 0.90 (0.86, 0.95) for women in the validation cohort. CONCLUSION: The study demonstrated that a simple formula using bioelectrical parameters at 50 kHz proved useful in identifying sarcopenia in the older adult population.

Feasibility, Acceptability, and Potential Efficacy of a Mobile Health Application for Community-Dwelling Older Adults with Frailty and Pre-Frailty: A Pilot Study.

Smartphone applications aimed at enhancing physical, cognitive, and social activities through mobile health (mHealth) technology are of increasing interest. Their feasibility and acceptability, alongside impacts on frailty phenotype scores and step counts among older adults with frailty, remain to be fully validated. This study presents a 13-week preliminary intervention trial assessing an mHealth app's feasibility in a cohort of 34 eligible older adults, including 5 frail and 29 pre-frail participants. The intervention entailed a 6-week course on app usage, followed by 7 weeks of observation, with four participants withdrawing early. Feasibility was determined by login and active use rates, with a target login rate of 60% or higher. Post-intervention, 100% session attendance and a median login rate of 88.4% were observed. Acceptability was high, with 73% affirming the app's health benefits. Notably, frailty scores and step counts improved post-intervention, underscoring the app's potential for supporting older adults with frailty.

Association between dynapenia and cognitive decline in community-dwelling older Japanese adults: The IRIDE Cohort Study.

AIM: Muscle mass and strength correlate with cognitive function; however, it remains unclear whether dynapenia (i.e., muscle weakness with preserved muscle mass) is relevant. This study aimed to explore whether dynapenia is associated with global cognitive function in community-dwelling older Japanese adults. METHODS: This cross-sectional study used data from the Integrated Research Initiative for Living Well with Dementia Cohort Study, which pooled data from five community-based geriatric cohorts. Dynapenia was defined as muscle weakness without muscle mass loss according to the Asian Working Group for Sarcopenia criteria. Cognitive function was assessed using the Mini-Mental State Examination (MMSE). An ordered logistic regression analysis was conducted with dynapenia as the exposure and with cognitive decline stages, defined as an MMSE score of 27-30 for normal cognition, 24-26 for possible cognitive decline, and <24 for cognitive decline, as the outcome, stratified by sex and adjusted for age, muscle mass, education, alcohol consumption, smoking habits, living alone, and non-communicable diseases. RESULTS: We analyzed data for 3338 participants (2162 female) with preserved muscle mass. Of these, 449 (13.5%) had dynapenia, and 79 (2.4%) exhibited cognitive decline. Multivariate odds ratios (95% confidence interval) for cognitive decline among those with dynapenia, compared with those without dynapenia, were 1.51 (1.02-2.24) for males and 2.08 (1.51-2.86) for females. CONCLUSIONS: Muscle weakness is associated with cognitive decline, even in individuals with preserved muscle mass. Further studies are needed to better understand the association between muscle weakness and cognitive decline over time in order to develop dementia prevention strategies for those with dynapenia. Geriatr Gerontol Int 2024; 24: 123-129.

Factors Associated with Low Inter-Session Reliability of Conditioned Pain Modulation in Older People with or Without Chronic Musculoskeletal Pain.

Purpose: Conditioned pain modulation (CPM) is a measurement of the descending pain pathways that inhibit or facilitate afferent noxious stimuli. The reliability of CPM in older individuals with or without chronic musculoskeletal pain has not been sufficiently reported. This study aimed to examine the inter-session reliability of CPM in these cohorts and the factors in CPM reliability. Patients and Methods: Individuals aged 65 or older were recruited in Narita, Japan. The measurements were performed on separate days 2 weeks apart (sessions 1 and 2). Each participant's hand was immersed in cold water, and we measured pressure pain threshold (PPT) before and after the immersion. The ratio before and after PPT measurements was presented as CPM index. The autonomic activities (heart rate variability, heart rate, and blood pressure) were simultaneously measured. An absolute reliability of CPM index was analyzed by the adjusted two-way analysis of variance (ANOVA) and the Bland Altman plot, and relative reliability was analyzed by intraclass correlation coefficient (ICC). Spearman's rho correlation and the adjusted multivariate regression analysis were utilized for examining the CPM reliability factors. Results: Thirty-two participants were divided into two groups: chronic pain (n=19) and non-chronic pain (n=13) groups. The mean difference between session 1 and 2 in CPM index showed a systematic error in the chronic pain group at 17.3 (confidence interval, CI: 15.0 to 19.7), but none in the non-chronic pain group at 3.7 (CI: -0.02 to 7.4). The adjusted two-way ANOVA for CPM index did not identify any differences. ICC was not significant at p=-0.247 in the non-chronic and 0.167 in chronic pain. Multivariate regression analysis revealed total power and low/high frequencies as significant factors for CPM index. Conclusion: This study identified low inter-session reliability in older adults with chronic musculoskeletal pain and autonomic nervous system activities as factors in CPM reliability.

Fibroblast growth factor 19 expression correlates with tumor progression and poorer prognosis of hepatocellular carcinoma.

BACKGROUND: Although fibroblast growth factor 19 (FGF19) can promote liver carcinogenesis in mice, its involvement in human hepatocellular carcinoma (HCC) has not been well investigated. FGF19, a member of the FGF family, has unique specificity for its receptor FGFR4. This study aimed to clarify the involvement of FGF19 in the development of HCC. METHODS: We investigated human FGF19 and FGFR4 expression in 40 hepatocellular carcinoma specimens using quantitative real-time reverse transcription polymerase chain reaction (RT-PCR) analysis and immunohistochemistry. Moreover, we examined the expression and the distribution of FGF19 and FGFR4 in 5 hepatocellular carcinoma cell lines (HepG2, HuH7, HLE, HLF, and JHH7) using RT-PCR and immunohistochemistry. To test the role of the FGF19/FGFR4 system in tumor progression, we used recombinant FGF19 protein and small interfering RNA (siRNA) of FGF19 and FGFR4 to regulate their concentrations. RESULTS: We found that FGF19 was significantly overexpressed in HCCs as compared with corresponding noncancerous liver tissue (P < 0.05). Univariate and multivariate analyses revealed that the tumor FGF19 mRNA expression was an independent prognostic factor for overall and disease-free survival. Moreover, we found that the FGF19 recombinant protein could increase the proliferation (P < 0.01, n = 12) and invasion (P < 0.01, n = 6) capabilities of human hepatocellular carcinoma cell lines and inhibited their apoptosis (P < 0.01, n = 12). Inversely, decreasing FGF19 and FGFR4 expression by siRNA significantly inhibited proliferation and increased apoptosis in JHH7 cells (P < 0.01, n = 12). The postoperative serum FGF19 levels in HCC patients was significantly lower than the preoperative levels (P < 0.01, n = 29). CONCLUSIONS: FGF19 is critically involved in the development of HCCs. Targeting FGF19 inhibition is an attractive potential therapeutic strategy for HCC.

[A case of hepatoid adenocarcinoma of the stomach].

The patient was a 76-year-old man with no chief complaint. He presented to an internist of our hospital for an evaluation of anemia. An upper gastrointestinal endoscopy revealed a type 2 tumor at the lesser curvature of the gastric body. Although the blood analysis showed a high amount of AFP(2, 328 ng/mL), there was no abnormality found in the liver with a CT scan. The tumor was presumed to be an AFP-producing gastric cancer on the basis of the tumor biopsy. We performed total gastrectomy, splenectomy and cholecystectomy. The tumor cells were positive for AFP by immunohistochemistry. The final diagnosis was hepatoid adenocarcinoma, pT3(SS), INF b, ly1, v2, pN1(3/42), pStage II B. Tumor cells were negative for antihepatocyte antibody and anti-HER2 antibody. The amount of AFP normalized postoperatively. After discharge, he was treated with S-1(80mg/day)orally. He is relapse-free now, 14 months after the operation. Hepatoid adenocarcinoma is an extremely aggressive tumor with a poor prognosis, and effective chemotherapy has still not been established. A larger number of analyses, along with a molecular biological approach, is sure to be helpful for the establishment of an effective treatment for hepatoid adenocarcinoma.