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The metabolism in tumors is reprogrammed to meet its energetic and substrate demands. However, this metabolic reprogramming creates metabolic vulnerabilities, providing new opportunities for cancer therapy. Metabolic vulnerability as a therapeutic target in esophageal squamous cell carcinoma (ESCC) has not been adequately clarified. Here, we identified pyruvate dehydrogenase (PDH) component X (PDHX) as a metabolically essential gene for the cell growth of ESCC. PDHX expression was required for the maintenance of PDH activity and the production of ATP, and its knockdown inhibited the proliferation of cancer stem cells (CSCs) and in vivo tumor growth. PDHX was concurrently upregulated with the CD44 gene, a marker of CSCs, by co‐amplification at 11p13 in ESCC tumors and these genes coordinately functioned in cancer stemness. Furthermore, CPI‐613, a PDH inhibitor, inhibited the proliferation of CSCs in vitro and the growth of ESCC xenograft tumors in vivo. Thus, our study provides new insights related to the development of novel therapeutic strategies for ESCC by targeting the PDH complex‐associated metabolic vulnerability., Inoue et al. found that pyruvate dehydrogenase (PDH) component X expression is necessary for PDH activity and is involved in the cancer stemness of esophageal squamous cell carcinoma (ESCC) cells, thereby being metabolically essential for the tumor growth of ESCC. This study provides new insights related to the development of novel therapeutic strategies for ESCC by targeting the PDH complex‐associated metabolic vulnerability.

We examined long-term charcoal records spanning the glacial-interglacial cycles that are evident in two cores collected from Lake Biwa in central Japan. We found that the records of the two cores have a similar long-term variation pattern of charcoal concentrations and abundant large charcoal fragments in postglacial sediments, which indicates that frequent fires occurred near the shores of Lake Biwa during the postglacial period. ...

To investigate CO2 sink capacity in the western Arctic Ocean (north of 65°N), we conducted underway, ship-based observations of partial pressures of CO2

Aim Hepatitis B virus genotype B (HBV/B) has been reported to have less risk of liver cirrhosis and hepatocellular carcinoma (HCC), but long-term observation has rarely been reported. We aimed to clarify the characteristics of HBV/B in nucleos(t)ide analog-treated patients in an area where HBV/B is more prevalent than in other areas of Japan. Methods A total of 498 chronically HBV-infected patients treated with nucleos(t)ide analog (lamivudine, entecavir, tenofovir disoproxil fumarate, or tenofovir alafenamide fumarate) for >6 months (mean 70.6 months) were included from nine hospitals in northeast Japan. The frequencies of hepatitis B surface antigen loss and HCC occurrence were analyzed. Results Among 427 patients whose genotype could be determined, 34.0% and 64.4% were infected with HBV/B and genotype C (HBV/C), respectively. The age of patients with HBV/B was significantly older than those with HBV/C (57.7 vs. 48.1). The cumulative rate of hepatitis B surface antigen loss was significantly higher in HBV/B than in HBV/C (3.6% vs. 0.7% at 10 years). Among 480 patients without HCC history, HCC occurrence was found in 40 patients (13.4% at 10 years). There was no cumulative rate difference of HCC occurrence among the genotypes, but after propensity score matching for age/sex, it was significantly lower in HBV/B than in HBV/C (5.3% vs. 18.5% at 10 years). Conclusions Although a lower rate of HCC occurrence in HBV/B was shown by an age/sex-matched analysis than that in HBV/C, patients with HBV/B were significantly older and had a comparative risk of HCC occurrence in nucleos(t)ide analog-treated patients.

Aim Macrovesicular steatosis around the central vein (zone 3) is one of the pathological features of non-alcoholic fatty liver disease or steatohepatitis (NAFLD/NASH). The aim of this study is to elucidate precisely the association between the area of lipid droplets (LDs) and the plasma metabolic parameters in patients with NAFLD/NASH. Methods Eighty patients with NAFLD/NASH diagnosed by needle biopsy were enrolled. The LDs around zone 3 were counted automatically by image processing software, the total area of LDs (TLDs), the maximum area of LDs (MAXLDs), the average area of LDs (AVELDs) and the heterogeneity by the coefficient of variation (CV [%]) were quantified. The correlations between these values and plasma metabolic parameters were analyzed. We evaluated the association between branched chain amino acids (BCAAs) and the heterogeneity of LDs in hepatocytes in vitro and in vivo. Results The MAXLDs was significantly correlated with more metabolic parameters than AVELDs and TLDs. The level of BCAAs was independently associated with the CV among the metabolic parameters. In early stage NAFLD, aspartate and alanine aminotransferase were significantly higher in the high CV group than in the low CV group. The high concentration of BCAAs increased the CV of LDs in hepatocytes accompanied by the expression of phosphor-p70 S6 kinase and sterol regulatory element-binding protein 1 in vitro. A high BCAA diet induced high heterogeneity of LDs around zone 3 in ob/ob mice. Conclusions The levels of BCAAs were associated with the LD heterogeneity of hepatocytes around zone 3 in patients with NAFLD/NASH.

Full-length genomic sequences of hepatitis E virus (HEV) obtained from two consecutive cases of acute self-limiting hepatitis E in a city in northeast Japan were determined. Interestingly, two HEV isolates from each patient shared nucleotide identity of 99.97% in 7 225 nucleotides, and a phylogenetic analysis showed that they formed a cluster of Japanese isolates that is considered as a new HEV subtype 3k. The high similarity of HEV sequences of two isolates from these patients in this study suggested that a subtype 3k HEV strain had spread via a commonly distributed food in the city, possibly pig liver.

Activated microglia release pro-inflammatory factors and calpain into the extracellular milieu, damaging surrounding neurons. However, mechanistic links to progressive neurodegeneration in disease such as multiple sclerosis (MS) remain obscure. We hypothesize that persistent damaged/dying neurons may also release cytotoxic factors and calpain into the media, which then activate microglia again. Thus, inflammation, neuronal damage, and microglia activation, i.e., bi-directional interaction between neurons and microglia, may be involved in the progressive neurodegeneration. We tested this hypothesis using two in vitro models: (i) the effects of soluble factors from damaged primary cortical neurons upon primary rat neurons and microglia and (ii) soluble factors released from CD3/CD28 activated peripheral blood mononuclear cells of MS patients on primary human neurons and microglia. The first model indicated that neurons due to injury with pro-inflammatory agents (IFN-γ) release soluble neurotoxic factors, including COX-2, reactive oxygen species, and calpain, thus activating microglia, which in turn released neurotoxic factors as well. This repeated microglial activation leads to persistent inflammation and neurodegeneration. The released calpain from neurons and microglia was confirmed by the use of calpain inhibitor calpeptin or SNJ-1945 as well as μ- and m-calpain knock down using the small interfering RNA (siRNA) technology. Our second model using activated peripheral blood mononuclear cells, a source of pro-inflammatory Th1/Th17 cytokines and calpain released from auto-reactive T cells, corroborated similar results in human primary cell cultures and confirmed calpain to be involved in progressive MS. These insights into reciprocal paracrine regulation of cell injury and calpain activation in the progressive phase of MS, Parkinson's disease, and other neurodegenerative diseases suggest potentially beneficial preventive and therapeutic strategies, including calpain inhibition.

It has been reported that acute hepatitis B (AHB) patients with genotype A HBV (HBV/A) have been increasing since the 1990s in metropolitan areas in Japan. However, little is known about the trends of HBV genotypes in AHB patients in northeast Japan where genotype B HBV (HBV/B) prevails more than in other areas. In this study, we aimed to clarify the changes in the HBV genotypes and clinical characteristics of AHB patients in this area. HBV genotypes were determined by direct sequencing (n = 125) or enzyme immunoassay (n = 9) using serum samples from AHB patients including fulminant hepatitis in 1987-2014. Among 134 patients, 26 (19%), 33 (25%), and 75 (56%) patients were infected with HBV of genotypes A, B, and C, respectively. HBV/A emerged from 2001 and the percentage was increased gradually up to 48% in 2010-2014, whereas HBV/B was reduced from 40% in 1987-1994 to 10% in 2010-2014. Phylogenetic analysis showed that three major subgenotype A2 strains had come into this area serially. The levels of HBV DNA and prothrombin time were higher in HBV/A patients than other genotypes. This study could not show significant difference in the HBsAg-positive period among genotypes nor the effect of nucleoside analogues to shorten the HBsAg-positive period. A higher level of initial HBV DNA was associated with late disappearance of HBsAg. In conclusion, the percentage of HBV/A in AHB patients has been increasing in northeast Japan since 2001, which is later than metropolitan areas, whereas that of HBV/B is decreasing.

Background Depression is a frequent comorbid condition in patients with Alzheimer's disease (AD). In the present study, we reported the effect of additional donepezil treatment for patients with geriatric depression who exhibited cognitive deficit and were diagnosed with AD during treatment for depression. Methods The present retrospective study investigated 14 AD outpatients who were diagnosed with geriatric depression at first and received antidepressant treatment. When apparent cognitive decline was observed, all of them were diagnosed with AD and received donepezil (5 mg/day) for at least 1 year. All patients underwent periodic examination of cognitive function (Mini-Mental State Examination, Rorschach Cognitive Index) and clinical evaluation (Clinical Dementia Rating). The 14 patients were classified into three groups according to their treatment course: (i) ‘A’ group, patients who showed cognitive impairment during a long course of treatment for depression; (ii) ‘B’ group, patients who showed cognitive impairment at an early stage of treatment for depression and started to take additional donepezil at least 20 months after the first examination; and (iii) ‘C’ group, patients who showed cognitive impairment at an early stage of treatment for depression and began taking additional donepezil within 10 months of the first examination. The clinical feature and treatment effects were examined for each group. Results At 1 and 2 years after the start of treatment, the proportion of patients who had improved or maintained their Clinical Dementia Rating score was higher in ‘A’ and ‘C’ groups than in ‘B’ group. In ‘B’ group, additional donepezil treatment commenced later than in the other groups. Therefore, donepezil had an insufficient curative effect. Conclusion The results of this study suggested that early induction of donepezil treatment was necessary when apparent cognitive decline was identified during the treatment of geriatric depression.

AIM The extracellular hepatitis C virus (HCV)-antigen, including HCV-Core protein, can suppress immune cells. Recently, the efficacy of double filtration plasmapheresis (DFPP) for chronic hepatitis C (CHC) was reported. However, the mechanism of efficacy of DFPP might not be only the reduction of HCV but also the effect of immune cells via direct and/or indirect mechanisms. The aim of this study is to analyze the virological and immunological parameters of difficult-to-treat HCV patients treated with DFPP combined with Peg-interferon and RBV (DFPP/Peg-IFN/RBV) therapy. METHODS Twelve CHC patients were enrolled and treated with DFPP/Peg-IFN/RBV therapy. The immunological, virological and genetic parameters were studied. RESULTS All patients (4/4) treated with the major IL28B allele (T/T) could achieve complete early virological response (EVR). The amounts of HCV-Core antigen in the peripheral blood of EVR patients treated with DFPP/Peg-IFN/RBV rapidly declined in comparison to those of late virological response (LVR) patients treated with DFPP/Peg-IFN/RBV and EVR patients treated with Peg-IFN and RBV (Peg-IFN/RBV). The amount of IFN-γ produced from peripheral blood gradually increased. On the other hand, the amount of IL10 gradually decreased in the EVR patients. The frequencies of HCV-Core binding on CD3+ T cells rapidly declined in EVR patients treated with DFPP/Peg-IFN/RBV therapy. Moreover, the distributions of activated CD4(+) and CD8(+) T cells and CD16-CD56 high natural killer cells were significantly changed between before and after DFPP. CONCLUSIONS The rapid reduction of HCV-Core antigens and changes in the distribution of lymphoid cells could contribute to the favorable immunological response during DFPP/Peg-IFN/RBV therapy.

Here we show that the larger the amount of glutamine added to the medium, the more the expression of genes related to lipid homeostasis is promoted by the activation of sterol regulatory element binding proteins (SREBPs) at the transcriptional and post-translational levels in human hepatoma HepG2 cells. Glutamine increases the mRNA levels of several SREBP targets, including SREBP-2. The gene expression of SREBP-1a, a predominant form of SREBP-1 in most cultured cells and a target of the general transcription factor Sp1, is significantly augmented by glutamine via an increased binding of Sp1 to the SREBP-1a promoter. In contrast, the increased expression of SREBP targets including SREBP-2 is due to stimulation of the processing of SREBP proteins by glutamine. It is also shown that glutamine accelerates SREBP processing through increased transport of the SREBP/SREBP cleavage-activating protein complex from the endoplasmic reticulum to the Golgi apparatus. The processing of activating transcription factor 6 is activated by the same proteases as SREBPs in the Golgi in response to endoplasmic reticulum stress and is not induced by glutamine. Taken together, these results clearly demonstrate that glutamine brings about not only the induction of SREBP-1a transcription but also the stimulation of SREBP processing, thereby facilitating the gene expression of SREBP targets in cultured cells.

Aim: In the 2007–2008 guidelines of the study group (Ministry of Health, Labor and Welfare of Japan), lamivudine (LAM)-continuous treatment was recommended in patients treated with LAM for more than 3 years who maintained hepatitis B virus (HBV) DNA less than 2.6 log copies/mL, because in these patients LAM resistance might exist and switching treatment to entecavir (ETV) might cause ETV resistance. However, there was no evidence on whether switching treatment to ETV- or LAM-continuous treatment was better in those patients. In the present study, we performed a randomized controlled trial of LAM-to-ETV switching treatment. Methods: Twenty-seven patients treated with LAM for more than 3 years whose HBV DNA levels were less than 2.6 log copies/mL were enrolled and randomly divided into two groups, LAM-continued group or switching to ETV group. Then, we examined incidence of virological breakthrough (VBT) and breakthrough hepatitis (BTH) in each group. Results: There was no BTH in any of the patients. VBT was observed in six patients of the LAM group (6/15, 40%), and no patient of the ETV group (0/11, 0%) (P = 0.02). The differences of the proportion of cumulated VBT using a log–rank test with Kaplan–Meier analysis were significant between the LAM and ETV groups (P = 0.025). Conclusion: In patients treated with LAM for more than 3 years maintaining HBV DNA less than 2.6 log copies/mL, switching treatment to ETV is recommended at least during the 2 years' follow-up period.

Summary. To investigate the efficacy of long-term lamivudine (3TC) and adefovir dipivoxil (ADV) combination therapy in 3TC-resistant chronic hepatitis B virus (HBV) infected patients, we analysed 28 3TC-resistant patients treated with the combination therapy during 47 months (range, 9–75). At 12, 24, 36, and 48 months, the rates of virological response with undetectable HBV DNA (≤2.6 log copies/mL) were 56, 80, 86, and 92%, respectively. Among 17 hepatitis B e antigen (HBeAg)-positive patients, HBeAg disappeared in 24% at 12 months, 25% at 24 months, 62% at 36 months, and 88% at 48 months. When HBV genotypes were compared, patients with genotype B achieved virological response significantly more rapidly than those with genotype C (P = 0.0496). One patient developed virological breakthrough after 54 months, and sequence analysis of HBV obtained from the patient was performed. An rtA200V mutation was present in the majority of HBV clones, in addition to the 3TC-resistant mutations of rtL180M+M204V. The rtN236T ADV-resistant mutation was observed in only 25% clones. In vitro analysis showed that the rtA200V mutation recovered the impaired replication capacity of the clone with the rtL180M+M204V mutations and induced resistance to ADV. Moreover, rtT184S and rtS202C, which are known entecavir-resistant mutations, emerged in some rtL180M+M204V clones without rtA200V or rtN236T. In conclusion, 3TC+ADV combination therapy was effective for most 3TC-resistant patients, especially with genotype B HBV, but the risk of emergence of multiple drug-resistant strains with long-term therapy should be considered. The mutation rtA200V with rtL180M+M204V may be sufficient for failure of 3TC+ADV therapy.

The options for treating stroke are limited, but stem cells hold promise as a therapy because of their multipotency. Neuronal cells derived from mesenchymal stem cells (MSC) were reported to have more therapeutic effect than MSCs. For elucidating the therapeutic mechanism of neuronal cells, here we generated a model of focal cerebral infarction by performing left common carotid artery occlusion in adult gerbils. We transfected human trabecular bone-derived MSCs (hMSCs) with the Notch intracellular domain to induce their differentiation into neuronal cells (hN-MSCs). These cells were stereotaxically transplanted into the local ischemic hemisphere 4 days after the occlusion. Behavioral analyses were conducted 28 days after transplantation, and then fluorescence in situ hybridization (FISH) and a histological evaluation were performed. Histologically, transplanted cells were distributed around the periinfarct region, and approximately 8.5% and 4.2% of hN-MSCs and hMSCs survived, respectively; 53.2% ± 9.6% of hN-MSCs were microtubule-associated protein 2(+) (MAP-2(+) ) and extended neurites, whereas only 0.9% ± 0.3% of hMSCs were MAP-2(+) . In FISH, human nucleus-specific signals were detected in both hN-MSCs and hMSCs grafted brains, but no transplanted cell had a merged gerbil-specific nuclear signals. hN-MSC-transplanted animals showed significantly better recovery than animals given control vehicle in the T-maze, bilateral asymmetry, and open field tests. These findings suggested that hN-MSCs have greater therapeutic potential than hMSCs for stroke and that cell fusion does not primarily contribute to the therapeutic mechanism of MSC transplantation.

Background: Donepezil is effective in maintaining the cognitive function of patients with mild to moderate Alzheimer's disease (AD). However, not all patients respond to donepezil. In the present study, we examined the clinical features of responders and non-responders to long-term donepezil treatment. Methods: The present retrospective study was performed on 95 AD outpatients who had been taking donepezil for ≥2 years. All subjects underwent periodic examinations of cognitive function, namely Mini-Mental State Examination (MMSE) and Rorschach Cognitive Index (RCI), as well as clinical evaluations using the Clinical Dementia Rating (CDR) scale. Patients were divided into three groups as follows: (i) the ‘maintained’ group (MG), in which the global CDR score was maintained over the ≥2 years of treatment; (ii) the ‘declined’ group (DeG), in which the global CDR score increased one rank over the treatment period; and (iii) the ‘obvious and rapid decline’ group (ORDeG), in which the global CDR score increased two ranks early during the treatment period. Clinical features, treatment outcome, the time lag between a caregiver's recognition of the onset of dementia and the start of treatment, behavioral and psychological symptoms of dementia (BPSD), and cognitive functions were compared between the three groups. Results: Patients in the ORDeG (i.e. non-responders) were significantly younger and had a longer time lag between the onset of dementia and the start of treatment than patients in the MG (P

Accumulating evidence suggests that cancer stem cells (CSC) play an important role in tumorigenicity. Epithelial cell adhesion molecule (EpCAM) is one of the markers that identifies tumor cells with high tumorigenicity. The expression of EpCAM in liver progenitor cells prompted us to investigate whether CSC could be identified in hepatocellular carcinoma (HCC) cell lines. The sorted EpCAM(+) subpopulation from HCC cell lines showed a greater colony formation rate than the sorted EpCAM(-) subpopulation from the same cell lines, although cell proliferation was comparable between the two subpopulations. The in vivo evaluation of tumorigenicity, using supra-immunodeficient NOD/scid/γc(null) (NOG) mice, revealed that a smaller number of EpCAM(+) cells (minimum 100) than EpCAM(-) cells was necessary for tumor formation. The bifurcated differentiation of EpCAM(+) cell clones into both EpCAM(+) and EpCAM(-) cells was obvious both in vitro and in vivo, but EpCAM(-) clones sustained their phenotype. These clonal analyses suggested that EpCAM(+) cells may contain a multipotent cell population. Interestingly, the introduction of exogenous EpCAM into EpCAM(+) clones, but not into EpCAM(-) clones, markedly enhanced their tumor-forming ability, even though both transfectants expressed a similar level of EpCAM. Therefore, the difference in the tumor-forming ability between EpCAM(+) and EpCAM(-) cells is probably due to the intrinsic biological differences between them. Collectively, our results suggest that the EpCAM(+) population is biologically quite different from the EpCAM(-) population in HCC cell lines, and preferentially contains a highly tumorigenic cell population with the characteristics of CSC.

Radical vulvectomy is often complicated by problems associated with insufficient closure of large skin defects involving postoperative necrosis of the suture line over the mons pubis and the inguinal areas. To resolve these problems, the present study compared radical vulvectomy (RV, 7 cases) with radical vulvectomy followed by reconstructive operation using the gluteus maximus myocutaneous flap (RVR, 5 cases). There was no significant difference in operation time and blood loss between the two groups. Three of the 7 RV patients had wound separations requiring reoperation, while only 1 patient in the RVR group did. The average hospital stay was 86 days in the RV group and 38 days in the RVR. Risks of postoperative infection and wound breakdown were reduced with the flap technique, and ambulation and rehabilitation could begin earlier in this group. Surgical wounds were stable and the quality of life after operation was improved dramatically using the flap technique.

Multiple sclerosis (MS) is a T-cell mediated autoimmune disease of the CNS, possessing both immune and neurodegenerative events that lead to disability. Adoptive transfer (AT) of myelin basic protein (MBP)-specific T cells into naïve female SJL/J mice results in a relapsing-remitting (RR) form of experimental autoimmune encephalomyelitis (EAE). Blocking the mechanisms by which MBP-specific T cells are activated before AT may help characterize the immune arm of MS and offer novel targets for therapy. One such target is calpain, which is involved in activation of T cells, migration of immune cells into the CNS, degradation of axonal and myelin proteins, and neuronal apoptosis. Thus, the hypothesis that inhibiting calpain in MBP-specific T cells would diminish their encephalitogenicity in RR-EAE mice was tested. Incubating MBP-specific T cells with the calpain inhibitor SJA6017 before AT markedly suppressed the ability of these T cells to induce clinical symptoms of RR-EAE. These reductions correlated with decreases in demyelination, inflammation, axonal damage, and loss of oligodendrocytes and neurons. Also, calpain : calpastatin ratio, production of truncated Bid, and Bax : Bcl-2 ratio, and activities of calpain and caspases, and internucleosomal DNA fragmentation were attenuated. Thus, these data suggest calpain as a promising target for treating EAE and MS.

Background: Donepezil is effective in maintaining cognitive function in patients with mild to moderate Alzheimer's disease (AD). However, not all patients respond to donepezil. In the present study, we examined the short- and long-term effects of donepezil on cognitive function after 2 years treatment. Methods: The present retrospective study was performed on 122 AD outpatients who had been taking donepezil for ≥1 year. All subjects underwent periodic examination of cognitive function (Mini-Mental State Examination (MMSE), Rorschach Cognitive Index (RCI)) and clinical evaluation on the Clinical Dementia Rating (CDR); first before starting treatment and then at 4-month intervals after initiation of donepezil. Patients were divided into three groups: (i) MG, the ‘maintained’ group, in which the global CDR score was maintained during treatment; (ii) DeG, the ‘declined’ group, in which the global CDR score increased; and (iii) DrG, the drop out group, who discontinued the treatment. Changes in scores on the MMSE and RCI were compared before treatment and at 4-month intervals within each group. In addition, over each 4-month period, MMSE and RCI scores were compared between the three groups. Furthermore, to investigate the condition of effective treatment, the reasons why donepezil treatment was discontinued in the DrG were examined. Results: The most frequent reason for discontinuation was the appearance of behavioral and psychiatric symptoms of dementia (BPSD), which were more frequently observed in the DrG. Although depression and/or disinclination were more frequent in the MG, hyperactivity was more frequent in the DeG and DrG. Before treatment, patients in the DrG exhibited significantly lower scores on the MMSE than did patients in the MG and DeG. Upon examination 4 months after starting treatment, patients in the MG showed cognitive improvement on the MMSE and RCI, whereas those in the DeG showed cognitive deterioration on the MMSE. Conclusion: The results of the present study suggest that when a short-term beneficial effect of the donepezil on cognitive functions is seen, long-term effect may also be expected at 2 years. Periodic clinical evaluation and examination of cognitive function is indispensable for effective donepezil treatment.

We examined the absorption saturation properties in the 1.5 µm band of novel highly stacked InAs quantum dot layers. The transmission change at vertical incidence based on the saturable absorption of the quantum dots was more than 1%. This value is as large as the reflection changes of previously reported 1-µm-band quantum dot saturable absorber with interference enhancement. (© 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

Climate models use a variety of snow/ice albedo parameterizations for the ice covered ocean. In this study, we applied in situ measurements (surface temperature, snow depth and ice thickness) obtained from the Surface Heat Budget of the Arctic Ocean (SHEBA) as input values to four different snow/ice albedo parameterizations (representing the spectrum of parameterizations used in stand-alone sea ice models, numerical weather prediction and regional climate models of the Arctic Basin, and coupled global climate models), and evaluated the parameterized albedos against the SHEBA observed albedo. Results show that these parameterizations give very different representations of surface albedo. The impacts of systematic biases in the input values on the parameterized albedos were also assessed. To further understand how sea ice processes are influenced by differences in the albedo parameterizations, we examined baseline sea ice characteristics and responses of sea ice to an external perturbation for the simulations of the albedo parameterizations using a stand-alone basin-scale dynamic/thermodynamic sea ice model. Results show that an albedo treatment of sufficient complexity can produce more realistic basin-scale ice distributions, and likely more realistic ice responses as climate warms. Copyright © 2006 Royal Meteorological Society

Comparative genomic hybridization (CGH) has already made a significant impact on cancer cytogenetics. However, CGH to metaphase chromosomes can provide only limited resolution at the 5-10 Mb level. To circumvent this limitation, array-based CGH has been devised. Since spotted DNAs in a CGH-array contain sequence information directly connected with the genome database, we can easily note particular biological aspects of genes that lie within regions involved in copy-number aberrations. High-density, sub-megabase arrays can reveal nonrandom chromosome copy-number aberrations responsible for neoplastic transformation that have been masked under complex karyotypes in epithelial solid tumors. High-density CGH-array therefore paves the way for identification of disease-related genetic aberrations that have not yet been detected by existing technologies, and array-based CGH technology should soon be practical for diagnosis of cancer or genetic diseases in the clinical setting.

We report the first case of a hyalinizing spindle cell tumor with giant rosettes of the omentum. The mesenchymal tumor arises from a multiplication of fibroblastic cells containing large rosette-like structures composed of a central collagen core surrounded by plump oval to spindle tumor cells. A 38-year-old woman exhibited the symptom of abdominal pain in the right side, with a correlated sensation of a mass in the same area. A tumor consisting of both solid and cystic cytologic features was subsequently diagnosed, on the right side of the uterus. Her serum level of CA-125 was only slightly elevated. Surgical intervention indicated that the tumor originated from lower pole of the omentum and the histological diagnosis was hyalinizing spindle cell tumor with giant rosettes. The metastatic potential of this type of tumor is considered similar to that of the metastatic low-grade fibromyxoid sarcoma, which indicated the need for careful clinical follow up of this case.

Many tumor-suppressor genes are involved in the development and progression of cellular malignancy. To understand the functional role of tumor-suppressor genes in melanoma and to identify the human chromosome that carries these genes, we transferred individually each normal human chromosome, except for the Y chromosome, into the mouse melanoma cell line B16-F10, by microcell fusion. We examined the tumorigenicity of hybrid cells in nude mice and their in vitro growth properties. The introduction of human chromosomes 1 and 2 elicited a remarkable change in cell morphologic features, and cellular senescence was induced at seven to 10 population doublings. The growth rates of tumors derived from microcell hybrid clones containing introduced human chromosome 5, 7, 9, 10, 11, 13, 14, 15, 16, 19, 20, 21, 22, or X were significantly slower than that of the parental B16-F10 cells, whereas the introduction of other human chromosomes had no effect on the tumorigenicity of these cells. The majority of microcell hybrid clones that exhibited suppressed tumorigenicity also showed a moderate reduction in doubling time compared with B16-F10 cells. Microcell hybrid clones with an introduced human chromosome 5 showed complete suppression of in vitro-transformed phenotypes, including cell growth, saturation density, and colony-forming efficiency in soft agar. Thus, these results indicated the presence of many cell senescence-related genes and putative tumor-suppressor genes for the mouse melanoma cell line B16-F10 and showed in vitro that many tumor-suppressor genes control the phenotypes of transformed cells in the multistep process of neoplastic development.

A transgenic mouse containing the first exon of the human Huntington's disease (HD) gene has revealed a variety of behavioral and pathophysiological anomalies reminiscent of certain aspects of human Huntington's disease (HD). The present study has found that expression of the extracellular matrix glycoprotein tenascin-C appears to be unaffected in astroglial cells in wild-type and R6/2 transgenic mice that express the mutant huntingtin protein but that it is conspicuously absent in two neuronal populations within the cerebral cortex and thalamus of the R6/2 mice. Loss of tenascin-C expression begins between the fourth and eighth postnatal weeks, coincidental with the onset of abnormal behavioral phenotype and the appearance of intranuclear inclusion bodies and neuropil aggregates. By 12 weeks, R6/2 mice exhibit a complete absence of tenascin-C neuronal immunolabeling, a disappearance of cRNA probe-positive neurons across discrete cytoarchitectonic regions of the dorsal thalamus (e.g., the ventromedial, parafascicular, lateral posterior, and posterior thalamic groups) and frontal cortex, and an accompanying thalamic astrogliosis. The loss of neuronal tenascin-C expression includes structures that are known to send converging excitatory axonal projections to the caudate-putamen, the structure that is most at risk for neurodegeneration in HD. Altered neuronal expression of tenascin-C in R6/2 mice implicates altered transcriptional activities of the mutant huntingtin protein. The abnormal biochemistry and possibly abnormal activity of thalamostriate and corticostriate projection neurons may also affect abnormal neuronal activities in their primary connectional target, the neostriatum, which is severely compromised in HD. J. Comp. Neurol. 430:485–500, 2001. © 2001 Wiley-Liss, Inc.

A primary ovarian leiomyosarcoma is extremely rare. Moreover, there is no established treatment modality other than surgery, and the prognosis is extremely poor. We report a case of a primary ovarian leiomyosarcoma. The patient was a gravida 4, para 2, 73-year-old female. She first presented with chief complaints of constipation and a pelvic mass. A physical examination revealed a solid tumor in the pelvic cavity. Which was about the size of an infant's head and had an irregular shape. The patient was suspected of having a subserosal myoma of the uterus or an ovarian tumor, and she was subjected to a laparotomy. A solid tumor about the size of an infant's head was found in the left uterine adnexa, and an intraoperative rapid pathological diagnosis of an ovarian leiomyosarcoma was made. A total abdominal hysterectomy, a bilateral salpingo-oophorectomy, a pelvic lymphadenectomy, and an omentectomy were then performed. The final pathological diagnosis confirmed a left primary ovarian leiomyosarcoma. After a series of discussions with the patient's family about her therapeutic plan, we decided to let the patient be followed-up without adjuvant therapy. Forty-two months after the surgery, the patient accumulated massive amounts of pleural effusion and ascites, with extensive organ metastasis. She received terminal care and soon died.

The previously evaluated prototype, methyl 6-acetyl-2-[(4,6-dimethoxypyrimidin-2-yl)oxy]benzoate, was modified by the introduction of an oximino group. Further extensive synthetic modifications were then made to the 6-alkyl moiety (R1), the ester moiety (R2), the alkoxyimino moiety (R3), the bridge-atom (X) and the 4,6-disubstituted-pyrimidine moiety (A, B, Z). Structure–activity relationships of the synthesized compounds were studied by examining their herbicidal activity against Barnyard grass (Echinochloa oryzicola) in paddy rice at various growth stages, including pre-emergence. The novel herbicide methyl 2-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-[1-(methoxyimino)ethyl]benzoate, (KIH-6127) was found to be the most effective compound. The commercial development of this compound is currently in progress. © 1997 SCI.

Phenyl substituted α- (PhC(O)C(O)R) and β-diketones (PhC(O)CHRC(O)R′) are reduced by carbon monoxide and water in the presence of elemental selenium to give the corresponding aromatic ketones in moderate to good yields.

A series of peptidyl hydrazones was synthesized, and their inhibitory activity against mu-calpain and water-solubility were measured. Among these compounds, N,N-dimethyl glycyl hydrazone 6, which inhibited mu-calpain with IC(50) of 0.37 microM, possessed the appropriate water-solubility. Furthermore, hydrazone 6 was found to possess the excellent in vitro metabolic stability.

A 100-member combinatorial library of α-ketoamides, which was designed to search potent cysteine protease inhibitors, was generated by a parallel solution-phase synthesis. A two-step one-pot synthesis, in which the Ugi reaction followed by pyridinium dichromate (PDC) oxidation was employed in the same reaction vessel, easily afforded the α-ketoamides in a short time.

The uptake by barley roots from nutrient solution and subsequent transport to shoots of two series of amine bases were measured over 6 to 72 h. The compounds were chosen to span systematically ranges of lipophilicity (assessed using 1-octanol/water partition coefficients, K-ow) and pKa that would include commercial pesticide amines. In a series of six substituted phenethylamines, strong bases with pKa similar to 9.5, all the compounds were strongly taken up by roots from solutions of pH 8.0; uptake declined substantially as the pH was lowered to 5.0, especially for the compounds of intermediate lipophilicity (log k(ow) 2 to 3). This uptake could be ascribed to three processes: (i) accumulation of the cation inside the root cells due to the negative charge on the plasmalemma, as given by the Nernst equation and important only for the polar compounds which have low permeation rates through membranes; (ii) accumulation into the vacuole by ion-trapping, which was the dominant process at high pH for all compounds and at all pH values for the compounds of intermediate lipophilicity; (iii) partitioning on to the root solids, substantial only for the most lipophilic compounds. Translocation to shoots was proportional to uptake by roots, this ratio being independent of external pH for each compound and being optimal for the compounds of intermediate lipophilicity. Such proportionality was also observed in a series of three weaker bases of intermediate lipophilicity, in which compounds of pKa 7.4 to 8.0 were also well taken up and translocated whereas the very weak base 4-ethylaniline (pKa 5.03) was much less so. Tests with quaternised pyridines confirmed that organic cations move only slowly through membranes. The observed behaviour of the amines could be modelled reasonably well assuming that transport within the plant was dominated by movement across membranes of the non-ionised species, and this appeared to be true even for the most lipophilic phenethylamine (log K-ow 4.67) studied, though its long-distance movement would be as the protonated species. (C) 1998 Society of Chemical Industry.

Rontgenographisch und durch DTA wird ein groserer Teil des Ga-reichen Gebietes des Zustandsdiagramms Ga-GaAs-GaP ermittelt.