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Making CAR T cells in vivo Cardiac fibrosis is the stiffening and scarring of heart tissue and can be fatal. Rurik et al . designed an immunotherapy strategy to generate transient chimeric antigen receptor (CAR) T cells that can recognize the fibrotic cells in the heart (see the Perspective by Gao and Chen). By injecting CD5-targeted lipid nanoparticles containing the messenger RNA (mRNA) instructions needed to reprogram T lymphocytes, the researchers were able to generate therapeutic CAR T cells entirely inside the body. Analysis of a mouse model of heart disease revealed that the approach was successful in reducing fibrosis and restoring cardiac function. The ability to produce CAR T cells in vivo using modified mRNA may have a number of therapeutic applications. —PNK

Spermatid production is a complex regulatory process in which coordination between hormonal control and apoptosis plays a pivotal role in maintaining a balanced number of sperm cells. Apoptosis in spermatogenesis is controlled by pro-apoptotic and anti-apoptotic molecules. Hormones involved in the apoptotic process during spermatogenesis include gonadotrophins, sex hormones, and glucocorticoid (GC). GC acts broadly as an apoptosis inducer by binding to its receptor (glucocorticoid receptor: GR) during organ development processes, such as spermatogenesis. However, the downstream pathway induced in GC-GR signaling and the apoptotic process during spermatogenesis remains poorly understood. We reported previously that GC induces full-length glucocorticoid-induced transcript 1 (GLCCI1-long), which functions as an anti-apoptotic mediator in thymic T cell development. Here, we demonstrate that mature murine testis expresses a novel isoform of GLCCI1 protein (GLCCI1-short) in addition to GLCCI1-long. We demonstrate that GLCCI1-long is expressed in spermatocytes along with GR. In contrast, GLCCI1-short is primarily expressed in spermatids where GR is absent; instead, the estrogen receptor is expressed. GLCCI1-short also binds to LC8, which is a known mediator of the anti-apoptotic effect of GLCCI1-long. A luciferase reporter assay revealed that β-estradiol treatment synergistically increased Glcci1-short promotor-driven luciferase activity in Erα-overexpressing cells. Together with the evidence that the conversion of testosterone to estrogen is preceded by aromatase expression in spermatids, we hypothesize that estrogen induces GLCCI1-short, which, in turn, may function as a novel anti-apoptotic mediator in mature murine testis.

Whether pT3 urothelial carcinoma of the renal pelvis (UCRP) and urothelial carcinoma of the ureter (UCU) have the same prognosis is controversial, this study compared the prognosis of pT3 UCRP with that of pT3 UCU. We retrospectively evaluated 954 patients who underwent nephroureterectomy at our institutions between January 1983 and December 2017. All surgical specimens were reviewed by a single genitourinary pathologist. Cases of pT3 UCRP were subclassified as pT3a (urothelial carcinomas extending only to the renal medulla) and pT3b (urothelial carcinomas extending into the renal cortex and/or peripelvic adipose tissue). Fine and Gray's model was used to predict recurrence-free survival (RFS) and cancer-specific survival (CSS). A total of 493 (51.7%) had UCRP and 461 (48.3%) had UCU. Within this group, 202 patients had pT3 UCRP and 146 had pT3 UCU. The pT3 subclassification of UCRP resulted in 79 cases of pT3a and 120 of pT3b. The difference in 5-year CSS among the pT3a UCRP, pT2 UCRP, and pT2 UCU subgroups was not statistically significant (pT3a UCRP vs pT2 UCRP, HR = 0.69, p = 0.56; pT3a UCRP vs pT2 UCU, HR = 0.66, p = 0.31) However, RFS and CSS were significantly higher in the pT3a UCRP group than in the pT3b group (pT3a vs pT3b, HR = 2.59, p = 0.0038 and pT3a vs pT3b, HR = 3.10, p = 0.001). The results suggest that our proposed pT3 subclassification better predicts the prognosis of UCRP patients than does the pT3 of the current AJCC/UICC classification.

Aim: We aimed to improve the success rate of NGS (next-generation sequencing) analysis through improved strategies of lung cancer sampling. Materials & methods: The improvement strategies are as follows. Surgically resected specimens were preferentially submitted in cooperation with pathologists and surgeons. In bronchoscopic samples, the size of the sample collection device and the number of samples collected was increased. Results: The strategies increased the success rate of NGS analysis of DNA from 69.3 to 91.1%, and that of RNA from 64.6 to 90.0%. Discussion: The introduction of strategies aimed at improving the success of NGS analysis resulted in an improvement in the success rate and brought us closer to the delivery of effective precision medicine in cancer therapy.

Introduction Next-generation sequencing (NGS) of multiple metastases in an advanced cancer patient reveals the evolutional history of the tumor. The evolutionary model is clinically valuable because it reflects the future course of the tumorigenic process and prognosis of the patient. Materials and Methods We experienced two lung cancer patients whose clinical courses were abruptly deteriorating resulting in very poor prognosis. To investigate the evolutionary model of these patients, we performed targeted sequencing covering whole exons of 53 significantly mutated genes associated with lung cancer of multiple metastases by autopsy. We conducted PyClone analysis to infer subclonal archtecture of multi-lesional samples. Results The NGS analysis revealed both patients harboring multiple clonal driver mutations. In Case.1, KRAS Q61H, KEAP1 G333C, STK11 K312*, RBM10 Q320* and MGA I1429V and in Case.2, TP53 R337L, TP53 Q192*, PTEN W274C, RB1 P29fs and CREBBP P696L with high allele fraction were detected in all lesions. These mutations were clustered and occupied major population across multi-lesional tumor samples. Our data suggested their lung cancers progressed with punctuated and big bang evolutional model. Conclusion We should pay attention to clinical course of lung cancer patients harboring multiple clonal driver mutations in their primary lesions. Their punctuated and big bang evolutionary process could develop systemic clinically undetectable metastases with an unexpected speed.

Background AminoIndex™ Cancer Screening (AICS (lung)) was developed as a screening test for lung cancer using a multivariate analysis of plasma-free amino acid (PFAA) profiles. According to the developed index composed of PFAA, the probability of lung cancer was categorized into AICS (lung) ranks A, B, and C in order of increasing risk. The aim of the present study was to investigate the relationship between the preoperative AICS (lung) rank and surgical outcomes in patients who underwent curative resection for non-small cell lung cancer (NSCLC). Methods Preoperative blood samples were collected from 297 patients who underwent curative resection for NSCLC between 2006 and 2015. PFAA concentrations were measured. The relationship between the preoperative AICS (lung) rank and clinicopathological factors was examined. The effects of the preoperative AICS (lung) rank on postoperative outcomes were also analyzed. Results The AICS (lung) rank was A in 93 patients (31.3%), B in 82 (27.6%), and C in 122 (41.1%). The AICS (lung) rank did not correlate with any clinicopathological factors, except for age. Based on follow-up data (median follow-up period of 6 years), postoperative recurrence was observed in 22 rank A patients (23.7%), 15 rank B (18.3%) and 49 rank C (40.2%). In the univariate analysis, preoperative AICS (lung) rank C was a worse factor of recurrence-free survival (p = 0.0002). The multivariate analysis identified preoperative AICS (lung) rank C (HR: 2.17, p = 0.0005) as a significant predictor of postoperative recurrence, particularly in patients with early-stage disease or adenocarcinoma. Conclusion Preoperative AICS (lung) rank C is a high-risk predictor of postoperative recurrence in patients undergoing curative resection for NSCLC.

OBJECTIVES Characterizing pathological nodes (pNs) by location alone is sometimes inadequate as patients with pN1 or pN2 non-small-cell lung cancer (NSCLC) show prognostic heterogeneity. We aimed to assess the relationship of the number of metastatic lymph nodes (LNs) and zones with prognosis in NSCLC patients. METHODS We analysed 1393 patients who underwent lobectomy with mediastinal LN dissection for NSCLC at the Osaka International Cancer Institute between January 2006 and December 2015. Patients were classified into 3 groups according to the number of LNs: n1–3, n4–6 and n7–. We investigated the relationship of prognosis with the number of metastatic LNs and metastatic zones. RESULTS In the multivariable analyses, the number of metastatic LNs and zones were not independent factors for overall survival or recurrence-free survival in patients with pN1 disease after adjustment for age, sex, tumour histology and tumour diameter. However, n4–6 (ref. n1–3) was an independent prognostic factor for overall survival [hazard ratio (HR) 4.148, P CONCLUSIONS The number of metastatic LNs and metastatic zones were useful prognostic factors in NSCLC patients. The findings could help in establishing a new pN classification.

Progression of cardiac rehabilitation after cardiovascular surgery can be affected by frailty. The nutritional status of the patient has been proposed as an indicator of frailty. In this study, we aimed to evaluate the influence of preoperative nutritional status on the progress of postoperative cardiac rehabilitation. This study included 146 patients (82 males, 64 females, average age 71.9 ± 12.0 years) who underwent elective cardiovascular surgery. In-hospital mortality cases were excluded to focus on postoperative cardiac rehabilitation. We classified patients with a Geriatric Nutritional Risk Index of 92 or higher as the good nutrition group and those with a Geriatric Nutritional Risk Index less than 92 as the malnutrition group. Preoperative patient characteristics and postoperative cardiac rehabilitation progress were compared between the good nutrition (n = 93) and malnutrition (n = 53) groups. The patients in the good nutrition group had an earlier progression to walking after postoperative rehabilitation (p = 0.002), a shorter postoperative hospital stay (p = 0.004), and a higher rate of discharge home (p = 0.028) than those in the malnutrition group. Multivariable analysis demonstrated preoperative malnutrition to be an independent predictor for the day to 100 m walking (p = 0.010). Preoperative nutritional status was associated with progression of postoperative cardiac rehabilitation.

We conducted a prospective clinical study to individualize adjuvant chemotherapy after complete resection of non-small-cell lung cancer (NSCLC), based on the drug sensitivity test. Patients with resectable c-stage IB–IIIA NSCLC were registered between 2005 and 2010. We performed the collagen gel droplet-embedded culture drug sensitivity test (CD-DST) on a fresh surgical specimen to assess in vitro chemosensitivity and evaluated the prognostic outcome after adjuvant chemotherapy with carboplatin/paclitaxel based on the CD-DST. Among 92 registered patients, 87 were eligible for inclusion in the analysis. The success rate of CD-DST was 86% and chemosensitivity to carboplatin and/or paclitaxel was evident in 57 (76%) of the 75 patients. Adjuvant chemotherapy was completed in 22 (73%) of 30 patients. The 5-year overall survival rates were 71, 73, and 75% for all, CD-DST success, and chemosensitive patients, respectively. The 5-year disease-free survival and overall survival rates of the chemosensitive patients who completed adjuvant chemotherapy using carboplatin/paclitaxel were 68 and 82%, respectively. The 5-year disease-free survival and overall survival rates of the patients with stage II–IIIA chemosensitive NSCLC were 58 and 75%, respectively. Comparative analyses of the chemosensitive and non-chemosensitive/CD-DST failure groups showed no significant survival difference. CD-DST can be used to evaluate chemosensitivity after lung cancer surgery; however, its clinical efficacy for assessing individualized treatment remains uncertain.

Iodide transport and storage in the thyroid follicles is crucial for thyroid hormone synthesis. Pendrin, the iodide exporter that transports iodide to thyroid follicles, is responsible for Pendred syndrome, a disorder characterized by congenital hypothyroidism and hearing loss. However, thyroid hormone levels are basically normal in patients with Pendred syndrome, indicating the presence of another unknown iodide transporter. Here, we show that SLC26A7 is a novel iodide transporter in the thyroid. We observe that SLC26A7 is specifically expressed in normal thyroid tissues and demonstrate its function in iodide transport. Using whole-exome sequencing, we also find a homozygous nonsense mutation in SLC26A7 (c.1498 C > T; p.Gln500Ter) in two siblings with congenital goitrous hypothyroidism. The mutated SLC26A7 protein shows an abnormal cytoplasmic localisation and lacks the iodide transport function. These results reveal that SLC26A7 functions as a novel iodide transporter in the thyroid and its dysfunction affects thyroid hormonogenesis in humans and causes congenital goitrous hypothyroidism., Jun Ishii and Atsushi Suzuki et al. report the identification of SLC26A7 as a novel iodide transporter expressed in the thyroid. They identify a nonsense mutation in SLC26A7 in siblings with congenital hypothyroidism and goitre using whole-exome sequencing, implicating this transporter in disease.

Glucocorticoids (GCs) potently induce T-cell apoptosis in a GC receptor (GR)-dependent manner and are used to control lymphocyte function in clinical practice. However, its downstream pathways remain controversial. Here, we showed that GC-induced transcript 1 (GLCCI1) is a novel downstream molecule of the GC-GR cascade that acts as an antiapoptotic mediator in thymic T cells. GLCCI1 was highly phosphorylated and colocalized with microtubules in GLCCI1-transfected human embryonic kidney QBI293A cells. GR-dependent up-regulation of GLCCI1 was associated with GC-induced proapoptotic events in a cultured thymocyte cell line. However, GLCCI1 knockdown in a thymocyte cell line led to apoptosis. Consistently, transgenic mice overexpressing human GLCCI1 displayed enlarged thymi that consisted of larger numbers of thymocytes. Further molecular characterization showed that GLCCI1 bound to both dynein light chain LC8-type 1 (LC8) and its functional kinase, p21-protein activated kinase 1 (PAK1), thereby inhibiting the kinase activity of PAK1 toward LC8 phosphorylation, a crucial event in apoptotic signaling. GLCCI1 induction facilitated LC8 dimer formation and reduced Bim expression. Thus, GLCCI1 is a candidate factor involved in apoptosis regulation of thymic T cells.-Kiuchi, Z., Nishibori, Y., Kutsuna, S., Kotani, M., Hada, I., Kimura, T., Fukutomi, T., Fukuhara, D., Ito-Nitta, N., Kudo, A., Takata, T., Ishigaki, Y., Tomosugi, N., Tanaka, H., Matsushima, S., Ogasawara, S., Hirayama, Y., Takematsu, H., Yan, K. GLCCI1 is a novel protector against glucocorticoid-induced apoptosis in T cells.

To investigate the surgical outcomes of surgery for non-small cell lung cancer (NSCLC) in patients with atrial fibrillation (AF) as a preoperative comorbidity. Among 805 patients who underwent surgery for NSCLC, 27 (3.4%) had a history of AF. We analyzed the perioperative and long-term outcomes of these 27 patients. Fourteen patients (52%) had chronic AF and 13 (48%) had paroxysmal AF; being high rates of a comorbid illness. Nineteen patients (70%) underwent lobectomy, and 8 (30%) underwent sublobar resection. Ten patients (37%) received perioperative heparinization. There was no mortality. Other non-AF postoperative complications developed in 8 patients (30%), this incidence being higher than among the patients without AF (16%, 127 out of 778, p = 0.09). A thromboembolic event occurred in one patient (4%). With respect to the long-term outcomes, the 5-year overall survival and disease-free survival rates among the patients with AF were 70.3 and 60.8%, respectively, which were similar to those in the patients without AF (79.8 and 72.6%, p = 0.30 and 0.31). Lung cancer surgery in patients with AF is safe and provides favorable long-term outcomes; however, thoracic surgeons should monitor these patients carefully for postoperative thromboembolic events.

Cases of thymoma with pleural dissemination are occasionally encountered, and their management is difficult. Some reports have noted that surgical treatment for dissemination is effective, although the long-term results and clinical course details remain unclear. The current study investigated the short- and long-term outcomes of surgical resection of pleural dissemination. A retrospective review examined the medical records for 38 patients who underwent surgical resection for pleural dissemination occurring synchronously with a primary thymoma or metachronously after complete surgical resection of a primary thymoma between 1996 and 2017 at the authors’ institution. Clinical characteristics and prognostic factors were analyzed. The patients were classified into synchronous (n = 21) and metachronous (n = 17) groups. The 10-year overall survival rate was 59% for the synchronous group and 88% for the metachronous group. The median follow-up period for all the patients was 61 months (range 4–225 months). No perioperative deaths occurred. For all the patients, the 5- and 10-year overall survival rates were respectively 91% and 82%, and the 5- and 10-year relapse-free survival rates were respectively 29% and 19%. A significantly worse prognosis was observed for patients 50 years of age or older than for those younger than 50 years (p = 0.02). For 13 patients who underwent repeat resection for pleural dissemination, the prognosis was better than for those without repeat resection (p

Fibrosis is observed in nearly every form of myocardial disease1. Upon injury, cardiac fibroblasts in the heart begin to remodel the myocardium by depositing excess extracellular matrix, resulting in increased stiffness and reduced compliance of the tissue. Excessive cardiac fibrosis is an important factor in the progression of various forms of cardiac disease and heart failure2. However, clinical interventions and therapies that target fibrosis remain limited3. Here we demonstrate the efficacy of redirected T cell immunotherapy to specifically target pathological cardiac fibrosis in mice. We find that cardiac fibroblasts that express a xenogeneic antigen can be effectively targeted and ablated by adoptive transfer of antigen-specific CD8+ T cells. Through expression analysis of the gene signatures of cardiac fibroblasts obtained from healthy and diseased human hearts, we identify an endogenous target of cardiac fibroblasts-fibroblast activation protein. Adoptive transfer of T cells that express a chimeric antigen receptor against fibroblast activation protein results in a significant reduction in cardiac fibrosis and restoration of function after injury in mice. These results provide proof-of-principle for the development of immunotherapeutic drugs for the treatment of cardiac disease.

Preoperative frailty affects the progression of cardiac rehabilitation (CR) after cardiovascular surgery. Different frailty assessment measures are available. However, it remains unclear which tool most likely predicts the progress of CR. Our aim was to evaluate preoperative frailty using different methods and to identify the predictors in the progress of postoperative CR.Eighty-nine patients underwent elective cardiovascular surgery at our institution between May 2016 and April 2018. Mortality cases and patients without evaluation of preoperative frailty were excluded. This study included the remaining 78 patients. We divided the patients into two groups: 47 patients who achieved 100 m walking within 7 days after surgery (successful CR group) and 31 patients who achieved 100 m walking later than 8 days after surgery (delayed CR group). Preoperative frailty was assessed using the Kaigo-Yobo Check-List, Cardiovascular Health Study, Short Physical Performance Battery, and Clinical Frailty Scale.The prevalence of frailty defined by these four measures was higher in the delayed CR group. The delayed CR group had lower nutritional status, serum hemoglobin level, serum albumin level, and psoas muscle index. Multivariable analysis demonstrated the Kaigo-Yobo Check-List score as an independent predictor for delayed CR (odds ratio 1.53, 95% confidence interval 1.18-1.98, p = 0.001) and Clinical Frailty Scale as an independent predictor for discharge to a health care facility (odds ratio 3.70, 95% confidence interval 1.30-10.51, p = 0.014).Among the various tools for assessing frailty, the Kaigo-Yobo Check-List was most likely to predict the progress of postoperative CR after elective cardiovascular surgery.

The intestinal microbiota was revealed with the recent advances in molecular techniques, such as high-throughput sequencing analysis. As a result, the microbial changes are thought to influence the health of humans and animals and such changes are affected by several factors including diet, genetics, age, sex, and diseases. Similar studies are being conducted in dogs, and the knowledge of intestinal microbiota in dogs is expanding. Nonetheless, basic information on intestinal microbiota in dogs is less than that of humans. Our aim was to study toy poodles (n=21), a popular companion dog, in terms of basic characteristics of the faecal microbiota by 16S rRNA gene barcoding analysis. In the faecal microbiota, Firmicutes, Bacteroidetes, Proteobacteria, and Fusobacteria were the dominant phyla (over 93.4% of faecal microbiota) regardless of the attributes of the dogs. In family level, Enterobacteriaceae, Bacteroidaceae, and Lachnospiraceae were most prevalent. In case of a dog with protein-losing enteropathy, the diversity of faecal microbiota was different between before and after treatment. This study provides basic information for studying on faecal microbiota in toy poodles.

Rhabdomyosarcoma (RMS) is a malignant mesenchymal tumor and the most common soft tissue sarcoma in children. Because of several complications associated with intensive multimodal therapies, including growth disturbance and secondary cancer, novel therapies with less toxicity are urgently needed. C‐type natriuretic peptide (CNP), an endogenous peptide secreted by endothelial cells, exerts antiproliferative effects in multiple types of mesenchymal cells. Therefore, we investigated whether CNP attenuates proliferation of RMS cells. We examined RMS patient samples and RMS cell lines. All RMS clinical samples expressed higher levels of guanylyl cyclase B (GC‐B), the specific receptor for CNP, than RMS cell lines. GC‐B expression in RMS cells decreased with the number of passages in vitro. Therefore, GC‐B stable expression lines were established to mimic clinical samples. CNP increased cyclic guanosine monophosphate (cGMP) levels in RMS cells in a dose‐dependent manner, demonstrating the biological activity of CNP. However, because cGMP is quickly degraded by phosphodiesterases (PDEs), the selective PDE5 inhibitor sildenafil was added to inhibit its degradation. In vitro, CNP, and sildenafil synergistically inhibited proliferation of RMS cells stably expressing GC‐B and decreased Raf‐1, Mitogen‐activated protein kinase kinase (MEK), and extracellular signal‐regulated kinase (ERK) phosphorylation. These results suggested that CNP in combination with sildenafil exerts antiproliferative effects on RMS cells by inhibiting the Raf/MEK/ERK pathway. This regimen exerted synergistic effects on tumor growth inhibition without severe adverse effects in vivo such as body weight loss. Thus, CNP in combination with sildenafil represents a promising new therapeutic approach against RMS.

OBJECT The present study aimed to investigate aneurysm locations and treatments for ruptured cerebral aneurysms associated with secondary normal-pressure hydrocephalus (sNPH) after subarachnoid hemorrhage (SAH) by using comprehensive data from the Japanese Stroke DataBank. METHODS Among 101,165 patients with acute stroke registered between 2000 and 2013, 4693 patients (1482 men, 3211 women) were registered as having had an SAH caused by a ruptured saccular aneurysm. Of them, 1448 patients (438 men and 1010 women; mean age 61.9 ± 13.4 years) who were confirmed to have or not have coexisting acute hydrocephalus and sNPH were included for statistical analyses. Locations of the ruptured aneurysms were subcategorized into 1 of the following 4 groups: middle cerebral artery (MCA; n = 354), anterior communicating artery and anterior cerebral artery (ACA; n = 496), internal carotid artery (ICA; n = 402), and posterior circulation (n = 130). Locations of 66 of the ruptured aneurysms were unknown/unrecorded. Treatments included craniotomy and clipping alone in 1073 patients, endovascular coil embolization alone in 285 patients, and a combination of coiling and clipping in 17 patients. The age-adjusted and multivariate odds ratios from logistic regression analyses were calculated after stratification using the Fisher CT scale to investigate the effects of the hematoma volume of SAH. RESULTS Acute hydrocephalus was confirmed in 593 patients, and 521 patients developed sNPH. Patients with a ruptured ACA aneurysm had twice the risk for sNPH over those with a ruptured MCA aneurysm. Those with an ACA aneurysm with Fisher Grade 3 SAH had a 9-fold-higher risk for sNPH than those with an MCA aneurysm with Fisher Grade 1 or 2 SAH. Patients with a ruptured posterior circulation aneurysm did not have any significant risk for sNPH. Clipping of the ruptured aneurysm resulted in twice the risk for sNPH over coil embolization alone. CONCLUSIONS Patients with low-grade SAH caused by a ruptured MCA aneurysm had a low risk for the development of sNPH. In contrast, patients with high-grade SAH caused by a ruptured ACA aneurysm had a higher risk for sNPH. Endovascular coiling might confer a lower risk of developing sNPH than microsurgical clipping.

The significance of gastric xanthelasma in relation to gastric cancer still remains unclear. We investigated whether gastric xanthelasma would be a useful marker for predicting the development of early gastric cancer. A total of 1823 patients who underwent a medical health checkup were enrolled. We examined the relationship between gastric xanthelasma and various clinical features, and in an endoscopic follow-up study investigated whether the presence of gastric xanthelasma was predictive of the development of early gastric cancer. In the initial endoscopic examination, gastric xanthelasma was detected in 107 (5.9 %) of the 1823 patients. The presence of gastric xanthelasma was significantly associated with age ≥65 years, male gender, open-type atrophy, and the presence of diabetes mellitus (DM) (p

The present study examined the prognostic ability of our proposed performance status combined Japan Integrated Staging (PS-JIS) system in hepatocellular carcinoma (HCC) patients with liver cirrhosis (LC) comparing with other four prognostic systems including original JIS system, the Barcelona Clinic Liver Cancer classification system, TNM classification system and the Cancer of the Liver Italian Program (CLIP) scoring system. A total of 1,170 HCC patients complicated with LC were analysed. The disease was staged for all analysed patients by means of the five staging systems. The cumulative overall survival (OS) rate was calculated by Kaplan-Meier method and tested by log-rank test. We also examined prognostic factors associated with OS using univariate and multivariate analyses and compared the prognostic ability in each prognostic system using concordance index (c-index) at 1-, 3- and 5-year time-points. Overall significance in each prognostic system was P

Hypertension is considered as one of the cancer progressive factors, and often found comorbidity in cancer patients. Renin-angiotensin system (RAS) plays an important role in the regulation of blood pressure, and angiotensin II (Ang II) is well known pressor peptide associated with RAS. Ang II has been reported to accelerate progression and metastasis of cancer cells. However, its precise mechanisms have not been fully understood. In this study, we sought to elucidate the mechanisms by which Ang II exacerbates hematogenous metastasis in mouse melanoma cells, focusing the adhesion pathway in vascular endothelial cells. For this purpose, B16/F10 mouse melanoma cells, which do not express the Ang II type 1 receptor (AT1R), were intravenously injected into C57BL/6 mice. Two weeks after cell injection, the number of lung metastatic colonies was significantly higher in the Ang II-treated group (1 μg/kg/min) than in the vehicle-treated group. The AT1R blocker valsartan (40 mg/kg/day), but not the calcium channel blocker amlodipine (5 or 10 mg/kg/day), significantly suppressed the effect of Ang II. In endothelium-specific Agtr1a knockout mice, Ang II-mediated acceleration of lung metastases of melanoma cells was significantly diminished. Ang II treatment significantly increased E-selectin mRNA expression in vascular endothelial cells collected from lung tissues, and thus promoted adherence of melanoma cells to the vascular endothelium. Ang II-accelerated lung metastases of melanoma cells were also suppressed by treatment with anti-E-selectin antibody (20 mg/kg). Taken together, Ang II-treatment exacerbates hematogenous cancer metastasis by promoting E-selectin-mediated adhesion of cancer cells to vascular endothelial cells.

The aims of the present study were to examine the relationship between the preoperative FIB-4 index and background liver fibrosis in non-tumor parts obtained from surgical specimens and to investigate whether the FIB-4 index can be a useful predictor for non-B non-C hepatocellular carcinoma (NBNC-HCC) patients treated with surgical resection (SR). A total of 118 patients with NBNC-HCC treated with SR with curative intent were analyzed. Receiver operating characteristic (ROC) curve analysis was performed for calculating the area under the ROC (AUROC) for the FIB-4 index, aspartate aminotransferase (AST) to platelet ratio index, AST to alanine aminotransferase ratio, serum albumin, total bilirubin and platelet count for cirrhosis. We also examined predictors linked to overall survival (OS) and recurrence-free survival (RFS) after SR. The mean patient age was 68.9±9.0 years (93 males and 25 females) with a median observation period of 3.2 years. In extracted surgical specimens, background liver cirrhosis (F4) was observed in 39 patients (33.1%). The mean maximum tumor size was 5.7±3.2 cm. The mean body mass index was 24.3±3.9 kg/m2. The FIB-4 index yielded the highest AUROC for cirrhosis with a level of 0.887 at an optimal cut-off value of 2.97 (sensitivity, 92.3; specificity, 69.6%). In the multivariate analysis, serum α-fetoprotein >40 ng/ml (P=0.026) was the only significant independent predictor linked to OS, while tumor number (P=0.002) and FIB-4 index >2.97 (P=0.044) were significant factors linked to RFS. In conclusion, preoperative FIB-4 index can be a useful predictor for NBNC-HCC patients who undergo SR.

We examined whether supplementation of branched-chain amino acid (BCAA) granules in an early stage of underlying liver disease (pretreatment serum albumin levels ≥ 3.6 g/dl) can improve overall survival (OS) after therapy for hepatocellular carcinoma (HCC) using propensity score matching analysis. We compared OS between patients treated with BCAA granules and control group patients in two propensity score matched cohorts (cohort 1: pretreatment serum albumin levels ≥ 3.6 g/dl and

Claudin-16 (CLDN16) regulates the paracellular reabsorption of Mg(2+) in the thick ascending limb of Henle's loop. However, the mechanism regulating the tight junctional localization of CLDN16 remains unknown. In yeast two-hybrid systems, we found that CLDN16 bound to syntaxin 8 (STX8), a target soluble N-ethylmaleimide-sensitive factor attachment protein receptor. We have examined the effect of STX8 on the localization and function of CLDN16 using Madin-Darby canine kidney cells expressing FLAG-tagged CLDN16. A pulldown assay showed that the carboxyl cytoplasmic region of human CLDN16 bound to STX8. CLDN16 was localized in the thick ascending limb, whereas STX8 was widely distributed throughout the rat kidney. An association between CLDN16 and STX8 was observed in rat renal homogenates and Madin-Darby canine kidney cells. STX8 siRNA decreased the cell surface localization of CLDN16 and transepithelial electrical resistance and permeability to Mg(2+) but increased the co-localization of CLDN16 with early endosome and lysosome markers. Dephosphorylation of CLDN16 by protein kinase A inhibitors and S217A mutant, a dephosphorylated form, decreased the association with STX8 and the cell surface localization of CLDN16. Recycling assays indicated that STX8 siRNA decreased the trafficking of CLDN16 to the plasma membrane without affecting endocytosis. Dominant negative Rab11 and recycling inhibitor primaquine decreased the cell surface localization of CLDN16, which was similar to that in STX8 siRNA-transfected cells. These results suggest that STX8 mediates the recycling of CLDN16 and constitutes an important component of the CLDN16 trafficking machinery in the kidney.

The aim of the present study was to compare clinical outcomes in patients with intermediate-stage hepatocellular carcinoma (HCC) who underwent the following treatments: transcatheter arterial chemoembolization (TACE) using an epirubicin-mitomycin-lipiodol (EML) emulsion at initial therapy (TACE group; n=145), and transcatheter chemotherapy infusion (TACI) using an EML emulsion at initial therapy (TACI group; n=81). Overall survival (OS) and treatment efficacy in the TACE and TACI groups were retrospectively compared. Prognostic factors associated with OS were examined using univariate and multivariate analyses. Treatment-related mortality was also calculated. The median observation periods were 1.8 years (range, 0.2-9.0 years) in the TACE group and 2.0 years (range, 0.2-8.7 years) in the TACI group. The median survival time and the 1-, 2-, 3- and 5-year cumulative OS rates were 2.68 years and 81.5, 63.4, 43.9 and 32.7%, respectively, in the TACE group, and 2.64 years and 85.0, 60.0, 43.2 and 26.0%, respectively, in the TACI group (P=0.691). The objective response rate was significantly higher in the TACE group compared to the TACI group (80.0 vs. 66.7%; P=0.009). Using multivariate analysis, the Child-Pugh classification (P=0.017), tumor number ≤5 (P=0.045) and des-γ-carboxy prothrombin level >100 mAU/ml (P=0.002) were found to be significant predictors linked to OS. In all subgroup analyses involving Child-Pugh classification, maximum tumor size and tumor distribution, the differences in the two groups did not reach statistical significance in terms of OS. Treatment mortality was 0% in the two groups. In conclusion, patients with intermediate-stage HCC had a comparable prognosis when treated with TACI or TACE.

The aim of this study was to compare the clinical outcomes and safety of surgical resection for hepatocellular carcinoma between patients older than 75 years of age (elderly group) and those younger than 75 years (control group).A total of 92 patients were included in the elderly group and 206 patients were included in the control group. Clinical outcomes including overall survival, recurrence-free survival, and safety were compared between these two groups after initial surgery.The mean (±SD) observation periods were 2.5 ± 1.8 years in the elderly group and 3.1 ± 2.2 years in the control group. The 1, 3, and 5-year overall survival rates after surgery were 90.0, 73.3, and 43.0%, respectively, in the elderly group and 91.0, 77.5, and 64.4%, respectively, in the control group (P=0.188). The corresponding recurrence-free survival rates were 66.3, 38.8, and 26.2%, respectively, in the elderly group and 66.3, 38.8, and 22.2%, respectively, in the control group (P=0.634). Multivariate analysis identified a total bilirubin level greater than 1.0 mg/dl (P=0.003), a serum albumin level greater than 4.0 g/dl (P=0.005), an α-fetoprotein level greater than 100 ng/ml (P0.001), and microvascular invasion (P0.001) as significant factors linked to overall survival, and tumor number (P=0.014) and microvascular invasion (P=0.008) were significant factors associated with recurrence-free survival. There was no significant difference between the two groups in terms of surgery-related serious adverse events (P0.999).Surgical resection appears to be a safe and feasible procedure for the treatment of hepatocellular carcinoma in elderly patients.

Objectives A new pathological classification for pre- and minimally invasive adenocarcinoma has been established, with distinction prior to surgery crucial because of the extremely good prognosis. Methods Of 412 patients who underwent surgery for lung cancer from 2008 to 2011, 110 classified as c-stage I had each of the following four parameters assessed for predictive power for pre- or minimally invasive adenocarcinoma and relapse-free survival (RFS): (i) whole tumour size (WS) shown by computed tomography (CT) , (ii) size of the solid (SS) component in CT findings, (iii) maximum standard uptake value in fluorodeoxyglucose positron emission tomography (FDG-PET)/CT scan images (SUVmax) and (iv) serum level of carcinoembryonic antigen. Results For prediction of pre- or minimally invasive adenocarcinoma, the area under the receiver-operating curve was >0.7 for all the four parameters, while only SS was found to be an independent factor in multivariate logistic regression analysis. In Cox proportional hazard model analysis, SS and SUVmax were statistically significant, and SS was exclusively independent in multivariate analysis. Differences in RFS between T1a and T1b were more pronounced when using SS compared with WS. In the sub-classification of T1a, we used a breakpoint of 1.0 cm in SS (T1a-α and T1a-β), which resulted in a 2-year RFS rate of 1.00 for T1a-α (n=21), 0.89 for T1a-β (n=27) and 0.68 for T1b (n=26) (P=0.002 between T1a-β and T1b). Conclusions The SS parameter was useful to distinguish pre- and minimally invasive adenocarcinoma from other types of lung cancer, and set a T1a sub-classification.

The impact of antibodies to hepatitis B core antigen (anti-HBc) on survival after curative surgical resection (SR) for hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) remains unclear. The aim of the present study was to examine the relationship between anti-HBc positivity and survival of HCV-related HCC patients who underwent curative SR. A total of 222 patients with HCV-related, hepatitis B surface antigen (HBsAg)-negative HCC who underwent curative SR were analyzed. They included 119 anti-HBc-positive patients (53.6%) and 103 anti-HBc-negative patients (46.4%). Overall survival (OS) and recurrence-free survival (RFS) rates were compared between the two groups. The median follow-up periods in the anti-HBc-positive and anti-HBc-negative groups were 3.4 years (range, 0.3-10.9 years) and 3.2 years (range, 0.5-10.9 years), respectively. The 1-, 3- and 5-year cumulative OS rates were 88.8, 70.2 and 50.0%, respectively, in the anti-HBc-positive group and 95.8, 77.1 and 61.7% in the anti-HBc-negative group (P=0.300). The corresponding RFS rates were 68.7, 33.0 and 20.0%, respectively, in the anti-HBc-positive group and 74.4, 38.5 and 16.5% in the anti-HBc-negative group (P=0.482). Multivariate analyses identified serum albumin ≥3.8 g/dl (P=0.005) and the presence of microvascular invasion (P

Background The relationship between the thickness of subepithelial collagen bands (CB) and the development of linear ulcerations (LU) in collagenous colitis (CC) remains unclear. The aim of the present study was to compare the clinical and pathological features, including the thickness of CB, in CC patients with and without LU. Patients and Methods Twenty-five patients with CC diagnosed by pathological examination of biopsy specimens were analyzed. Eleven patients with LU (LU group) and 14 patients without LU (non-LU group) were compared. Results Ten patients in the LU group and seven in the non-LU group were taking lansoprazole (P = 0.038). Seven patients in the LU group and one in the non-LU group were taking non-steroidal anti-inflammatory drugs (NSAIDs) (P = 0.004). All LU were locatedin the transverse or left colon. Patients in the LU group were older than those in the non-LU group (P = 0.015). CB were significantly thicker in the LU group than in the non-LU group (mean ± SD, 40 ± 21 μm vs 20 ± 11 μm, P = 0.004). Multivariate analysis showed that NSAIDs use (odds ratio, 19.236; 95% confidence interval, 1.341–275.869) and CB thickness (odds ratio, 0.893; 95% confidence interval, 0.804–0.999) were independently associated with the development of LU. Conclusion Use of lansoprazole and NSAIDs, thick CB, and advanced age are associated with the development of LU in CC patients.

To clarify the role of pulmonary metastasectomy in colorectal cancer in the era of modern multidisciplinary therapy. The characteristics and outcomes of the patients who underwent pulmonary metastasectomy for colorectal cancer through 2002 (n = 26) and from 2003 (n = 68) were compared. The patients treated from 2003 had a smaller tumor size and more frequently had a history of extra-pulmonary relapses than did those treated through 2002. There was a significant improvement in the 5-year overall survival (42.0% vs. 73.1%, p = 0.03) but not the 5-year relapse-free survival (41.4% vs. 37.5%, p = 0.85) after pulmonary metastasectomy from 2003. The rate of patients who received local therapy with curative intent after the first pulmonary metastasectomy was significantly higher in patients treated from 2003 than in those treated through 2002 [4/13, (31%) vs. 25/39 (64%), p = 0.04]. The survival after relapse after the first pulmonary metastasectomy was significantly longer in patients treated from 2003 than in those treated through 2002 (median survival time: 14 vs. 47 months). Pulmonary metastasectomy for colorectal cancer remains an important treatment option in the sense that it can achieve a good relapse-free survival.

To propose a treatment strategy for simultaneously discovered non-small cell lung cancer (NSCLC) and cardiovascular disease (CVD). Of 1302 patients who underwent surgery for NSCLC, CVD requiring invasive treatment was simultaneously discovered in 33 (3 %). The details of the treatments as well as the short- and long-term outcomes of pulmonary resection were analyzed. CVD included coronary artery disease in 20 patients, valvular disease in 6, abdominal aortic aneurysm in 5, and congenital heart disease in 2. Twenty-six patients underwent two-stage treatment, while seven received simultaneous surgery. In 23 patients whose treatment for CVD preceded that for lung cancer, the median interval between those treatments was 78 days (range 18–197 days). Postoperative complications occurred in 8 (31 %) of 26 patients who underwent 2-stage treatment and in 3 (43 %) of 7 who underwent simultaneous surgery. Notably, of 3 patients who underwent lobectomy or bilobectomy, 2 (67 %) experienced respiratory dysfunction that required intubation. The 5-year overall survival rate of all 33 patients was 84.5 %. The outcomes of two-stage treatment in the present cohort were favorable. Given our experience, simultaneous surgery for lung cancer and CVD should, therefore, be selected only for patients who may benefit from that strategy.

Pulmonary fibrosis has high rates of mortality and morbidity; however, no effective pharmacological therapy has been established. C-type natriuretic peptide (CNP), a member of the natriuretic peptide family, selectively binds to the transmembrane guanylyl cyclase (GC)-B receptor and exerts anti-inflammatory and anti-fibrotic effects in various organs through vascular endothelial cells and fibroblasts that have a cell-surface GC-B receptor. Given the pathophysiological importance of fibroblast activation in pulmonary fibrosis, we hypothesized that the anti-fibrotic and anti-inflammatory effects of exogenous CNP against bleomycin (BLM)-induced pulmonary fibrosis were exerted in part by the effect of CNP on pulmonary fibroblasts.C57BL/6 mice were divided into two groups, CNP-treated (2.5 μg/kg/min) and vehicle, to evaluate BLM-induced (1 mg/kg) pulmonary fibrosis and inflammation. A periostin-CNP transgenic mouse model exhibiting CNP overexpression in fibroblasts was generated and examined for the anti-inflammatory and anti-fibrotic effects of CNP via fibroblasts in vivo. Additionally, we assessed CNP attenuation of TGF-β-induced differentiation into myofibroblasts by using immortalized human lung fibroblasts stably expressing GC-B receptors. Furthermore, to investigate whether CNP acts on human lung fibroblasts in a clinical setting, we obtained primary-cultured fibroblasts from surgically resected lungs of patients with lung cancer and analyzed levels of GC-B mRNA transcription.CNP reduced mRNA levels of the profibrotic cytokines interleukin (IL)-1β and IL-6, as well as collagen deposition and the fibrotic area in lungs of mice with bleomycin-induced pulmonary fibrosis. Furthermore, similar CNP effects were observed in transgenic mice exhibiting fibroblast-specific CNP overexpression. In cultured-lung fibroblasts, CNP treatment attenuated TGF-β-induced phosphorylation of Smad2 and increased mRNA and protein expression of α-smooth muscle actin and SM22α, indicating that CNP suppresses fibroblast differentiation into myofibroblasts. Furthermore, human lung fibroblasts from patients with or without interstitial lung disease substantially expressed GC-B receptor mRNA.These data suggest that CNP ameliorates bleomycin-induced pulmonary fibrosis by suppressing TGF-β signaling and myofibroblastic differentiation in lung fibroblasts. Therefore, we propose consideration of CNP for clinical application to pulmonary fibrosis treatment.

Leucine stimulates cancer cell proliferation through the mTOR pathway, therefore, inhibiting leucine transporters may be a novel therapeutic target for cancer. L-type amino acid transporter (LAT) 1, a NaLNCaP and DU145 and PC-3 cell lines were used as a model of androgen dependent, and metastatic prostate cancer. A new "LN-cr" cell line was established after culturing LNCaP cells for 6 months under androgen-free conditions, which is considered a model of castration resistant prostate cancer (CRPC) with androgen AR expression. The expression of leucine transporters was investigated with quantitative PCR and immunofluorescence. Uptake ofCell viability showed a 90% decrease in the absence of leucine in all four cell lines. LNCaP cells principally expressed LAT3, and their leucine uptake was more than 90% NaNew CRPC cell line with increased expression of y

The aim of the present study was to evaluate the influence of preoperative transcatheter arterial chemoembolization (TACE) on survival after surgical resection (SR) for hepatocellular carcinoma (HCC). Two hundred and thirty-five HCC patients who underwent SR with curative intent were analyzed. Overall survival (OS), recurrence-free survival (RFS) and complication rates were compared between the TACE (n=110) and control groups (n=125). Moreover, TACE subjects were classified into TACE responders (n=85) and TACE non-responders (n=25), according to the therapeutic efficacy of pretreatment TACE, and the factors contributing to OS and RFS after SR were analyzed using univariate and multivariate analyses. The 1-, 3- and 5-year OS rates were 87.4, 76.0 and 62.5%, respectively, in the TACE group and 94.9, 79.0 and 57.8%, respectively, in the control group (P=0.674). The corresponding RFS rates at 1, 3 and 5 years were 73.3, 48.9 and 33.2%, respectively, in the TACE group and 73.3, 29.4 and 16.3%, respectively, in the control group (P=0.062). No TACE-related serious adverse events (SAEs) were observed. There were no significant differences between the groups in terms of surgery-related SAEs (P=0.714), operation time (P=0.881), blood loss during surgery (P=0.334) and hospitalization period (P=0.447). Multivariate analyses identified TACE responder, TACE non-responder, total bilirubin ≥1 mg/dl, serum albumin ≥4 g/dl, pretreatment α-fetoprotein (AFP) level ≥100 ng/ml and microscopic vascular invasion as significant prognostic factors linked to OS. TACE non-responder, tumor number (multiple) and pretreatment AFP level ≥100 ng/ml were significant adverse prognostic factors linked to RFS. In conclusion, TACE is a safe procedure in patients with HCC, and the efficacy of TACE prior to surgery may be associated with clinical outcomes after SR.

Phospholipid accumulation manifests as an adverse effect of cationic amphiphilic drugs in particular. Detection, however, by histopathology examination is time-consuming and may require repeated administration of compounds for several weeks. To eliminate compounds with potential for inducing phospholipidosis from the discovery pipeline, we have identified and validated a set of biomarkers for predicting the phospholipidosis-inducing potential utilizing a comprehensive rat transcriptome microarray database created by the Japanese Toxicogenomics and Toxicogenomics Informatics Projects (TGP/TGP2) together with in-house data. The set of biomarkers comprising 25 Affymetrix GeneChip probe sets was identified using genetic algorithm optimization on 24-h time-point microarray data from rats treated with single doses of hepatotoxic compounds including amiodarone, clomipramine, haloperidol, hydroxyzine, imipramine, and perhexiline. The set of novel biomarkers represents an early time-point gene-expression pattern characteristic for a condition eventually leading to phospholipidosis. This implies significant advantages in terms of time and resources over currently published biomarkers derived using repeated-dosing late time-point data. The biomarker set was validated by 11 independent compounds. Accuracy, sensitivity, and specificity values were 82%, 67%, and 100%, respectively and the area under the receiver operating characteristic curve was 0.97. These results show that the biomarker set possesses a high classification accuracy for novel compounds. Pathway analysis was carried out for the biomarkers and the detection of pathways related to lipid-metabolism was statistically significant. These pathways most probably reflect lipid metabolism changes associated with phospholipidosis supporting the validity of our novel biomarkers.

Patients with pathologic N2 non-small cell lung cancer comprise a heterogeneous group. The objective of this study was to evaluate which subgroup of patients with pathologic N2 benefit from surgery in terms of survival probability.This retrospective study included 141 patients who had undergone major resection with pathologically proven N2 from 1990 to 2006 (103 with adenocarcinoma, 38 with squamous cell carcinoma). Patients undergoing preoperative induction therapy were excluded. Records were examined for age, gender, tumor size, surgical procedure, surgical side, clinical N status, primary tumor lobe, curative resection, and metastatic N2 stations.In patients with adenocarcinoma, surgical procedure, clinical N status, curative resection, and metastatic N2 stations were significant prognostic factors in univariate analysis. Age and curative resection were significant factors in patients with squamous cell carcinoma. In multivariate analysis, clinical N2 (P = 0.003), incomplete resection (P = 0.04), and multi-station N2 (P = 0.004) were significant adverse prognostic factors in patients with adenocarcinoma, whereas only incomplete resection (P = 0.002) was significant in patients with squamous cell carcinoma. For adenocarcinoma patients with pathologic N2, the 5-year survival rates were 58.8% for clinical N0-1 and single-station N2, 50% for clinical N2 and single-station N2, 23.9% for clinical N0-1 and multi-station N2, and 0% for clinical N2 and multi-station N2.Prognosis of patients with pathologic N2 can be grouped according to clinical N status and metastatic N2 stations in adenocarcinoma, but not in squamous cell carcinoma. Only adenocarcinoma patients with pathologic N2 appear to have heterogeneous subgroups with different prognoses.

Surgical excision is an option to diagnose small-sized lung cancer, although this procedure has potential to disseminate tumor cells from the surgical margin. This retrospective study enrolled 252 patients with clinical stage IA non-small cell lung carcinoma who had undergone lobectomy during the period 1998-2004. Except for 25 patients with ground-glass attenuation (GGA) lesions on computed tomography, all underwent preoperative biopsy using flexible fiberoptic bronchoscopy (FFB). A total of 148 patients were diagnosed by FFB, and 86 were diagnosed by surgical excision. In the surgical excision cases, 67 tumors were negative for malignancy at the surgical margins and 19 were positive. Diagnosis by surgical excision was associated significantly more often with smaller tumor size (P

Two powerful genome-wide association studies have recently reported significant association between sporadic late-onset Alzheimer's disease (AD) and markers at the CLU locus in chromosome 8p. In this study, we have stratified our previously analyzed 109 Swedish AD families according to range in age at onset and performed whole-genome linkage analysis and subsequent fine-mapping in 8p21. The subgroup analyzed in the fine-mapping consisted of 28 families with AD, having a within-family onset-range not exceeding 8 years and an age at onset between 49 ≤ 70 years. A maximum non-parametric linkage peak (LOD = 3.5) was found between markers D8S1809 and 236c6-1. Intriguingly this linked 9.5cM region contains clusterin (CLU), which is one of the two top susceptibility genes for AD. Our finding may be a reflection of linkage to the CLU susceptibility gene, in the same way as familial AD has previously been linked to the APOE locus.

Although behavioral studies have suggested that there are gender differences regarding facial recognition, the neural substrates of these differences have not been fully examined. In order to clarify them, we performed a functional magnetic resonance imaging (fMRI) experiment in which participants encoded and recognized male and female faces. Behaviorally, the facial recognition ability of men and women was similar, and was superior for female faces compared to male faces. At the neural level, widespread areas showed greater responses for men vs. women during the encoding and recognition phase, and several areas, including the hippocampal region, showed greater responses to female vs. male faces during recognition. The reduced activation of women's brains during encoding and recognition suggests that the relevant neural systems were more efficiently recruited in women than in men.

It has been proposed that different brain regions are recruited for processing two Japanese writing systems, namely, kanji (morphograms) and kana (syllabograms). However, this difference may depend upon what type of word was used and also on what type of task was performed. Using fMRI, we investigated brain activation for processing kanji and kana words with similar high familiarity in two tasks: word recognition and reading aloud. During both tasks, words and non-words were presented side by side, and the subjects were required to press a button corresponding to the real word in the word recognition task and were required to read aloud the real word in the reading aloud task. Brain activations were similar between kanji and kana during reading aloud task, whereas during word recognition task in which accurate identification and selection were required, kanji relative to kana activated regions of bilateral frontal, parietal and occipitotemporal cortices, all of which were related mainly to visual word-form analysis and visuospatial attention. Concerning the difference of brain activity between two tasks, differential activation was found only in the regions associated with task-specific sensorimotor processing for kana, whereas visuospatial attention network also showed greater activation during word recognition task than during reading aloud task for kanji. We conclude that the differences in brain activation between kanji and kana depend on the interaction between the script characteristics and the task demands.

We report a case of a 35-year-old man with histologically confirmed neurosarcoidosis who developed recurrent episodes of right-hemispheric dysfunction with diffuse cortical lesions of the right hemisphere on magnetic resonance imaging (MRI). A brain biopsy revealed granulomatous inflammatory cells in both the subarachnoid space and Virchow-Robin space, which might relate to the recurrent neurological dysfunction and MRI findings.

Background/Aims We evaluated the prognostic value of the pretreatment elevation of tumor markers for hepatocellular carcinoma (HCC) in patients who underwent curative treatment. Methods We studied 801 patients who had been diagnosed as initial HCC and fulfilled the following criteria: maximum tumor size, ⩽3cm; number of tumors, ⩽3; remnant liver function, Child-Pugh class A or B; treated by hepatectomy or locoregional thermal ablation (LTA); and alpha-fetoprotein (AFP), Lens culinaris agglutinin A-reactive fraction of AFP (AFP-L3), and des-gamma carboxy prothrombin (DCP) were measured at diagnosis. We analyzed the effects of elevated tumor markers on patient survival in these 2 distinct groups with different types of treatment, i.e. hepatectomy and LTA. Results By multivariate analysis in 345 patients who underwent hepatectomy, no tumor marker significantly affected decreased survival rate. In the 456 patients who underwent LTA, the elevation of AFP-L3 ( p =0.0171) and DCP ( p =0.0004) significantly affected decreased survival rate; DCP elevation had the strongest effect on patient survival. Conclusions The prognostic value of pretreatment tumor marker elevation was different in patients who underwent the curative treatment according to the type of treatment. Pretreatment elevation of AFP-L3 and DCP had prognostic values only in patients treated with LTA.

Large-scale clinical studies have shown that the biguanide drug metformin, widely used for type 2 diabetes, to be very safe. By contrast, another biguanide, phenformin, has been withdrawn from major markets because of a high incidence of serious adverse effects. The difference in mode of action between the two biguanides remains unclear. To gain insight into the different modes of action of the two drugs, we performed global gene expression profiling using the livers of obese diabetic db/db mice after a single administration of phenformin or metformin at levels sufficient to cause a significant reduction in blood glucose level. Metformin induced modest expression changes, including G6pc in the liver as previously reported. By contrast, phenformin caused changes in expression level of many additional genes. We used a knowledge-based bioinformatic analysis to study the effects of phenformin. Differentially expressed genes identified in this study constitute a large gene network, which may be related to cell death, inflammation or wound response. Our results suggest that the two biguanides show a similar hypoglycemic effect in db/db mice, but phenformin induces a greater stress on the liver even a short time after a single administration. These findings provide a novel insight into the cause of the relatively high occurrence of serious adverse effect after phenformin treatment.

The authors describe 2 patients who presented with transient directional disorientation (TDD) as a manifestation of cerebral ischemia. The patients suddenly lost sense of direction in a familiar environment despite preserved ability to recognize landmarks, and recovered within a short time. Brain MRI revealed an ischemic lesion in the right medial occipital lobe and the corpus callosum in case 1 and in the right parieto-occipital sulcus (POS) in case 2. After ictus, fMRI study of a navigation task was performed, which demonstrated the activation of the POS unilaterally in case 1 and bilaterally in case 2. We propose that TDD of our patients is related to temporary dysfunction of bilateral POS.

We report a 55-year-old right-handed man who presented with topographical disorientation following left retrosplenial hemorrhage. His directional information about familiar places, encoded by previous navigation, was severely impaired, and he could not learn the direction to new places in large-scale spaces beyond the range of visual surveillance. By contrast, he had no difficulties with directional information encoded in a tabletop manner: he could locate major cities or countries on a map, and he also could memorize the spatial relationship of objects in a room. Six months after the ictus, when he had recovered from his directional disorientation, a functional magnetic resonance imaging (fMRI) study of mental navigation demonstrated prominent activation in the retrosplenial area along the right parieto-occipital sulcus and the circumference of the injured area on the left side. The present study, together with previous investigations including clinical case reports, functional neuroimaging, and anatomical and physiological studies on monkeys, suggests that the 'sense of direction' in a large-scale locomotor environment is subserved by the visual area along the parieto-occipital sulcus, and that bilateral deterioration of this function causes directional disorientation.

Cancer cells require massive amounts of amino acids for survival. LAT1 (L-type amino acid transporter 1) transports essential amino acids, including leucine, which trigger the downstream mTOR (mammalian target of rapamycin) pathway. We examined the association between androgen receptor and LAT1, and the association between LAT1 expression and the acquisition of castration resistance.Western blot and real-time polymerase chain reaction were performed to study protein and mRNA expression. siRNA was used to knock down target genes. A total of 92 prostate biopsy specimens of patients who underwent androgen deprivation therapy were used for immunohistochemical analyses. Cox hazard proportional models and the Kaplan-Meier method were used for statistical analyses.LAT1 was highly expressed in hormone resistant prostate cancer cell lines. Knockdown of LAT1 in LNCaP and C4-2 cells significantly suppressed cell proliferation, migration and invasion. Androgen receptor siRNA or androgen receptor blocking through bicalutamide (10 μM) or MDV3100 (10 μM) significantly increased LAT1 expression (p0.01). Treatment with dihydrotestosterone (0.1 to 10 nM) reduced LAT1 expression in a dose dependent manner (p 0.01). Bicalutamide/MDV3100 plus siLAT1 synergistically suppressed prostate cancer cell proliferation compared to single inhibition by androgen receptor or LAT1 (p 0.01). High LAT1 expression correlated with significantly shorter prostate specific antigen recurrence-free survival in patients receiving androgen deprivation therapy (p0.0001). LAT1 expression was an independent predictor of castration resistance on multivariate analysis (HR 3.56, p = 0.0133).The current data may indicate a novel mechanism to acquire castration resistance through activation of the amino acid transporter LAT1.

Recent imaging studies demonstrated the usefulness of quantitative computed tomographic (CT) analysis assessing pulmonary hypertension (PH) in patients with chronic obstructive lung disease (COPD–PH). The aim of this study was to investigate whether it would be also valuable for predicting and evaluating the effect of pulmonary vasodilators in patients with COPD–PH. We analyzed a correlation between the extent of cystic destruction (LAA%) and total cross-sectional areas of small pulmonary vessels less than 5 mm2 (%CSA

Bezafibrate is a commonly used medicine for hyperlipidemia, and recently several reports have suggested the efficacy of bezafibrate for the treatment of primary biliary cirrhosis (PBC). To assess its efficacy for other liver diseases, we administered bezafibrate to patients with various categories of hepatobiliary impairment.Bezafibrate (400 mg/day) was orally administered to 67 patients with chronic liver disease [22 with PBC, six with primary sclerosing cholangitis (PSC), 20 with chronic liver disease associated with hepatitis C virus (HCV) infection (CLD-C), seven with auto immune hepatitis (AIH), ten with alcoholic liver injury, and two with drug-induced liver injury].The levels of biliary enzymes, such as alkaline phosphatase and gamma-glutamyltranspeptidase, decreased promptly and dramatically. The abnormally high level of alanine aminotransferase also showed a gradual decrease over 6 months in five of the eight PBC patients, all three PSC patients, eight of the 17 CLD-C patients, and all seven alcoholic liver injury patients. The level of immunoglobulin M showed a gradual decrease in 17 of the 22 PBC patients.Bezafibrate significantly reduced the level of biliary enzymes in various chronic liver diseases and may be useful for the treatment of certain liver disease subsets.

A 28-year-old man developed severe infundibular pulmonary stenosis (PS), coronary artery stenosis with sustained ventricular tachycardia (VT) 24 years after mediastinal irradiation (total amount of 40 Gray) for non-Hodgkin's lymphoma. Repair of right ventricular outflow tract and coronary artery bypass graft procedure were performed. Infundibular PS was successfully relieved after operation and VT was also controlled by medication. Mediastinal irradiation often causes various cardiac complications after a latent period. Therefore, continuous careful observation is mandatory in patients with the history of mediastinal irradiation.

We studied the neural correlates for the performance of auditory verbal memory using fMRI in 28 normal right-handed volunteers who had to encode and retrieve 50 related word-pair associates. Since the effectiveness of encoding and retrieval processes contribute to memory performance, we combined them in one analysis in addition to examining each condition. Between-subjects analyses were performed by a two-sample t-test in which brain activation in the good-performance group was compared with that of the poor-performance group. Regression analysis was also carried out to find the regions whose activations were linearly correlated to the number of correct recalls by all subjects. In addition to the positive correlates of memory performance, the areas whose activations have a negative effect were also examined. The results indicate that the brain networks of positive correlates including the parahippocampal gyrus and negative correlates including the right prefrontal cortex constitute neural substrates for the performance of auditory verbal memory.