Tokyo Medical Center

Despite multiple disparate prognostic risk analysis systems for evaluating clinical outcome for patients with myelodysplastic syndrome (MDS), imprecision persists with such analyses. To attempt to improve on these systems, an International MDS Risk Analysis Workshop combined cytogenetic, morphological, and clinical data from seven large previously reported risk-based studies that had generated prognostic systems. A global analysis was performed on these patients, and critical prognostic variables were re-evaluated to generate a consensus prognostic system, particularly using a more refined bone marrow (BM) cytogenetic classification. Univariate analysis indicated that the major variables having an impact on disease outcome for evolution to acute myeloid leukemia were cytogenetic abnormalities, percentage of BM myeloblasts, and number of cytopenias; for survival, in addition to the above, variables also included age and gender. Cytogenetic subgroups of outcome were as follows: "good" outcomes were normal, -Y alone, del(5q) alone, del(20q) alone; "poor" outcomes were complex (ie, > or = 3 abnormalities) or chromosome 7 anomalies; and "intermediate" outcomes were other abnormalities. Multivariate analysis combined these cytogenetic subgroups with percentage of BM blasts and number of cytopenias to generate a prognostic model. Weighting these variables by their statistical power separated patients into distinctive subgroups of risk for 25% of patients to undergo evolution to acute myeloid leukemia, with: low (31% of patients), 9.4 years; intermediate-1 (INT-1; 39%), 3.3 years; INT-2 (22%), 1.1 years; and high (8%), 0.2 year. These features also separated patients into similar distinctive risk groups for median survival: low, 5.7 years; INT-1, 3.5 years; INT-2, 1.2 years; and high, 0.4 year. Stratification for age further improved analysis of survival. Compared with prior risk-based classifications, this International Prognostic Scoring System provides an improved method for evaluating prognosis in MDS. This classification system should prove useful for more precise design and analysis of therapeutic trials in this disease.

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

Many clinical studies on narrow-band imaging (NBI) magnifying endoscopy classifications advocated so far in Japan (Sano, Hiroshima, Showa, and Jikei classifications) have reported the usefulness of NBI magnifying endoscopy for qualitative and quantitative diagnosis of colorectal lesions. However, discussions at professional meetings have raised issues such as: (i) the presence of multiple terms for the same or similar findings; (ii) the necessity of including surface patterns in magnifying endoscopic classifications; and (iii) differences in the NBI findings in elevated and superficial lesions. To resolve these problems, the Japan NBI Expert Team (JNET) was constituted with the aim of establishing a universal NBI magnifying endoscopic classification for colorectal tumors (JNET classification) in 2011. Consensus was reached on this classification using the modified Delphi method, and this classification was proposed in June 2014. The JNET classification consists of four categories of vessel and surface pattern (i.e. Types 1, 2A, 2B, and 3). Types 1, 2A, 2B, and 3 are correlated with the histopathological findings of hyperplastic polyp/sessile serrated polyp (SSP), low-grade intramucosal neoplasia, high-grade intramucosal neoplasia/shallow submucosal invasive cancer, and deep submucosal invasive cancer, respectively.

Due to the high genetic heterogeneity of hearing loss (HL), current clinical testing includes sequencing large numbers of genes, which often yields a significant number of novel variants. Therefore, the standardization of variant interpretation is crucial to provide consistent and accurate diagnoses. The Hearing Loss Variant Curation Expert Panel was created within the Clinical Genome Resource to provide expert guidance for standardized genomic interpretation in the context of HL. As one of its major tasks, our Expert Panel has adapted the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for the interpretation of sequence variants in HL genes. Here, we provide a comprehensive illustration of the newly specified ACMG/AMP HL rules. Three rules remained unchanged, four rules were removed, and the remaining 21 rules were specified. These rules were further validated and refined using a pilot set of 51 variants assessed by curators and disease experts. Of the 51 variants evaluated in the pilot, 37% (19/51) changed category based upon application of the expert panel specified rules and/or aggregation of evidence across laboratories. These HL-specific ACMG/AMP rules will help standardize variant interpretation, ultimately leading to better care for individuals with HL.

BACKGROUND: The Japanese Gastric Cancer Association (JGCA) started a new nationwide gastric cancer registration in 2008. METHODS: From 208 participating hospitals, 53 items including surgical procedures, pathological diagnosis, and survival outcomes of 13,626 patients with primary gastric cancer treated in 2002 were collected retrospectively. Data were entered into the JGCA database according to the JGCA classification (13th edition) and UICC TNM classification (5th edition) using an electronic data collecting system. Finally, data of 13,002 patients who underwent laparotomy were analyzed. RESULTS: The 5-year follow-up rate was 83.3 %. The direct death rate was 0.48 %. UICC 5-year survival rates (5YEARSs)/JGCA 5YEARSs were 92.2 %/92.3 % for stage IA, 85.3 %/84.7 % for stage IB, 72.1 %/70.0 % for stage II, 52.8 %/46.8 % for stage IIIA, 31.0 %/28.8 % for stage IIIB, and 14.9 %/15.3 % for stage IV, respectively. The proportion of patients more than 80 years old was 7.8 %, and their 5YEARS was 51.6 %. Postoperative outcome of the patients with primary gastric carcinoma in Japan have apparently improved in advanced cases and among the aged population when compared with the archival data. Further efforts to improve the follow-up rate are needed. CONCLUSIONS: Postoperative outcome of the patients with primary gastric carcinoma in Japan have apparently improved in advanced cases and among the aged population when compared with the archival data. Further efforts to improve the follow-up rate are needed.

Oxidative stress has long been linked to the pathogenesis of neurodegenerative diseases; however, whether it is a cause or merely a consequence of the degenerative process is still unknown. We show that mice deficient in Cu, Zn-superoxide dismutase (SOD1) have features typical of age-related macular degeneration in humans. Investigations of senescent Sod1(-/-) mice of different ages showed that the older animals had drusen, thickened Bruch's membrane, and choroidal neovascularization. The number of drusen increased with age, and exposure of young Sod1(-/-) mice to excess light induced drusen. The retinal pigment epithelial cells of Sod1(-/-) mice showed oxidative damage, and their beta-catenin-mediated cellular integrity was disrupted, suggesting that oxidative stress may affect the junctional proteins necessary for the barrier integrity of the retinal pigment epithelium. These observations strongly suggest that oxidative stress may play a causative role in age-related retinal degeneration, and our findings provide evidence for the free radical theory of aging. In addition, these results demonstrate that the Sod1(-/-) mouse is a valuable animal model to study human age-related macular degeneration.

Glia-activating factor (GAF) is a novel heparin-binding growth factor purified from the culture supernatant of a human glioma cell line. It shows a spectrum of activity slightly different from those of other known growth factors. We have isolated the cDNA which encodes human GAF. A homology search revealed that GAF would be the ninth member of the FGF family, and we therefore call it FGF-9. The human FGF-9 cDNA cloned by using oligonucleotide probes encoded a polypeptide consisting of 208 amino acids. Sequence similarity to other members of the FGF family was estimated to be around 30%. Two cysteine residues and other consensus sequences in family members were also well conserved in the FGF-9 sequence. FGF-9 was found to have no typical signal sequence in its N terminus like those in acidic FGF and basic FGF. Acidic FGF and basic FGF are known not to be secreted from cells in a conventional manner. However, FGF-9 was found to be secreted from cells after synthesis despite its lack of a typical signal sequence. It could be detected exclusively in the culture medium of cDNA-transfected COS cells. The amino acid sequence of proteins purified from culture supernatant of the CHO cell line, which was cDNA transfected and selected as a high producer of FGF-9, showed that no peptides were cleaved from the N terminus except the initiation methionine. The rat FGF-9 cDNA was also cloned, and the structural analysis indicated that the PGF-9 gene is highly conserved. Expression of the FGF-9 gene could be detected in the brain and kidney of the adult rat. Restricted gene expression in organs and the unique secretion nature of the protein suggest that FGF-9 plays a physiological role which differs from those of well-characterized acidic FGF and basic FGF.

A 4-kilobase complementary DNA (cDNA) encoding human macrophage-specific colony-stimulating factor (CSF-1) was isolated. When introduced into mammalian cells, this cDNA directs the expression of CSF-1 that is structurally and functionally indistinguishable from the natural human urinary CSF-1. Direct structural analysis of both the recombinant CSF-1 and the purified human urinary protein revealed that these species contain a sequence of at least 40 amino acids at their carboxyl termini which are not found in the coding region of a 1.6-kilobase CSF-1 cDNA that was previously described. These results demonstrate that the human CSF-1 gene can be expressed to yield at least two different messenger RNA species that encode distinct but related forms of CSF-1.

Stargardt disease (STGD1; MIM 248200) is the most prevalent inherited macular dystrophy and is associated with disease-causing sequence variants in the gene ABCA4 Significant advances have been made over the last 10 years in our understanding of both the clinical and molecular features of STGD1, and also the underlying pathophysiology, which has culminated in ongoing and planned human clinical trials of novel therapies. The aims of this review are to describe the detailed phenotypic and genotypic characteristics of the disease, conventional and novel imaging findings, current knowledge of animal models and pathogenesis, and the multiple avenues of intervention being explored.

The Japanese Gastric Cancer Association (JGCA) started a new nationwide gastric cancer registry in 2008. Approximately 50 data items, including surgical procedures, pathological diagnoses, and survival outcomes, for 12004 patients with primary gastric cancer treated in 2001 were collected retrospectively from 187 participating hospitals. Data were entered into the JGCA database according to the JGCA Classification of gastric carcinoma, 13th edition and the International Union Against Cancer (UICC) TNM Classification of malignant tumors, 5th edition by using an electronic data collecting system. Finally, data of 11261 patients with gastric resection were analyzed. The 5-year follow-up rate was 83.5%. The direct death rate was 0.6%. TNM 5-year survival rates (5YSRs)/JGCA 5YSRs were 91.8/91.9% for stage IA, 84.6/85.1% for stage IB, 70.5/73.1% for stage II, 46.6/51.0% for stage IIIA, 29.9/33.4% for stage IIIB, and 16.6/15.8% for stage IV. The proportion of patients more than 80 years old was 7.0%, and their 5YSR was 48.7%. Compared to the JGCA archived data, though the follow-up rate needs to be improved, these data suggest that the postoperative results of patients with primary gastric carcinoma have improved in those with advanced disease and in the aged population in Japan.

Of all of the epithelial ovarian cancers, clear cell carcinoma (CCC) of the ovary has the worst prognosis. We applied the oligonucleotide array technique to identify genes generally involved in CCC. Of the ∼12,600 genes that were analyzed, 28 were expressed significantly differently between four CCC and seven non-CCC cell lines. Among 16 up-regulated genes in CCC, we further investigated a transcription factor, hepatocyte nuclear factor-1β (HNF-1β). We validated up-regulation of HNF-1β in CCC in terms of both mRNA and protein level using real-time quantitative reverse transcriptase-polymerase chain reaction and immunoblotting. Immunohistochemical analysis of 83 surgically resected ovarian cancers showed that almost all CCC specimens (21 of 22 cases) had nuclear staining for HNF-1β, whereas most non-CCC specimens (60 of 61 cases) showed no immunostaining or only focal and faint staining in the nucleus. Furthermore, we investigated the significance of HNF-1β expression in CCC using RNA interference. The reduction of HNF-1β expression by RNA interference induced apoptotic cell death in ovarian CCC cells, which was confirmed by terminal dUTP nick-end labeling and fluorescence-activated cell-sorting analyses. Our results suggest that HNF-1β is not only an excellent CCC-specific molecular marker but also a molecular target for therapy of ovarian CCC. Of all of the epithelial ovarian cancers, clear cell carcinoma (CCC) of the ovary has the worst prognosis. We applied the oligonucleotide array technique to identify genes generally involved in CCC. Of the ∼12,600 genes that were analyzed, 28 were expressed significantly differently between four CCC and seven non-CCC cell lines. Among 16 up-regulated genes in CCC, we further investigated a transcription factor, hepatocyte nuclear factor-1β (HNF-1β). We validated up-regulation of HNF-1β in CCC in terms of both mRNA and protein level using real-time quantitative reverse transcriptase-polymerase chain reaction and immunoblotting. Immunohistochemical analysis of 83 surgically resected ovarian cancers showed that almost all CCC specimens (21 of 22 cases) had nuclear staining for HNF-1β, whereas most non-CCC specimens (60 of 61 cases) showed no immunostaining or only focal and faint staining in the nucleus. Furthermore, we investigated the significance of HNF-1β expression in CCC using RNA interference. The reduction of HNF-1β expression by RNA interference induced apoptotic cell death in ovarian CCC cells, which was confirmed by terminal dUTP nick-end labeling and fluorescence-activated cell-sorting analyses. Our results suggest that HNF-1β is not only an excellent CCC-specific molecular marker but also a molecular target for therapy of ovarian CCC. Epithelial ovarian cancer has the worst prognosis of all gynecological malignancies.1Scully RE Young RH Clement PB Rosai J Tumors of the Ovary, Maldeveloped Gonads, Fallopian Tube, and Broad Ligament. Armed Forces Institute of Pathology, Washington DC1999: 27-50Google Scholar Since the emergence of platinum-based chemotherapy, the survival rate of patients with epithelial ovarian cancer has improved dramatically.2Piver MS Ovarian carcinoma. A decade of progress.Cancer. 1984; 54: 2706-2715Crossref PubMed Scopus (90) Google Scholar Debulking surgery and adjuvant chemotherapy (such as a combination of paclitaxel and carboplatin) have now gained a position as the standard therapy for epithelial ovarian cancer.3Parmar MKB Adams M Balestrino M Bertelsen K Bonazzi C Calvert H Colombo N Delaloye JF Durando A Guthrie D Hagen B Harper P Mangioni C Perren T Poole C Qian W Rustin G Sandercock J Tumolo S Torri V Vecchione F Tinazzi A Uscinska B Collins S Flann M Buda A Taylor B Tannock I Souhami R Granzia-Valsecchi M Paclitaxel plus carboplatin versus standard chemotherapy with either single-agent carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer: the ICON3 randomised trial.Lancet. 2002; 360: 505-515Abstract Full Text Full Text PDF PubMed Scopus (512) Google Scholar However, we still face many problems in the therapy of epithelial ovarian cancer. One of the most difficult is the treatment of clear cell carcinoma (CCC). The incidence of CCC among epithelial ovarian cancers is not high (∼10%), but patients with CCC have a significantly worse prognosis than patients with serous carcinoma.4Tammela J Geisler JP Eskew Jr, PN Geisler HE Clear cell carcinoma of the ovary: poor prognosis compared to serous carcinoma.Eur J Gynaecol Oncol. 1998; 19: 438-440PubMed Google Scholar, 5O'Brien ME Schofield JB Tan S Fryatt I Fisher C Wiltshaw E Clear cell epithelial ovarian cancer (mesonephroid): bad prognosis only in early stages.Gynecol Oncol. 1993; 49: 250-254Abstract Full Text PDF PubMed Scopus (98) Google Scholar One of the reasons why CCC has such a poor prognosis is its low response to standard platinum-based chemotherapy.6Goff BA Sainz de la Cuesta R Muntz HG Fleischhacker D Ek M Rice LW Nikrui N Tamimi HK Cain JM Greer BE Fuller Jr, AF Clear cell carcinoma of the ovary: a distinct histologic type with poor prognosis and resistance to platinum-based chemotherapy in stage III disease.Gynecol Oncol. 1996; 60: 412-417Abstract Full Text PDF PubMed Scopus (317) Google Scholar From a pathogenetic viewpoint, CCC has a number of features distinguishing it from other epithelial ovarian cancers. The percentage of patients with stage I disease is significantly higher in patients with CCC (48.5%) than in those with serous adenocarcinoma (16.6%),7Sugiyama T Kamura T Kigawa J Terakawa N Kikuchi Y Kita T Suzuki M Sato I Taguchi K Clinical characteristics of clear cell carcinoma of the ovary: a distinct histologic type with poor prognosis and resistance to platinum-based chemotherapy.Cancer. 2000; 88: 2584-2589Crossref PubMed Scopus (698) Google Scholar which means the properties of invasion differ between CCC and non-CCCs. The incidence of p53 mutation differs between CCC (0%) and endometrioid adenocarcinoma (63%).8Okuda T Otsuka J Sekizawa A Saito H Makino R Kushima M Farina A Kuwano Y Okai T p53 mutations and overexpression affect prognosis of ovarian endometrioid cancer but not clear cell cancer.Gynecol Oncol. 2003; 88: 318-325Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar The loss of heterozygosity pattern differs between CCC and non-CCCs.9Okada S Tsuda H Takarabe T Yoshikawa H Taketani Y Hirohashi S Allelotype analysis of common epithelial ovarian cancers with special reference to comparison between clear cell adenocarcinoma with other histological types.Jpn J Cancer Res. 2002; 93: 798-806Crossref PubMed Scopus (27) Google Scholar Immunohistochemical analysis has revealed that CCC shows trends such as weak expression of both p53 and cyclin A and markedly increased expression of both p21 and cyclin E compared with the other histological subtypes.10Shimizu M Nikaido T Toki T Shiozawa T Fujii S Clear cell carcinoma has an expression pattern of cell cycle regulatory molecules that is unique among ovarian adenocarcinomas.Cancer. 1999; 85: 669-677Crossref PubMed Scopus (84) Google Scholar Glutathione peroxidase 3 (GPX3) is overexpressed in CCC, which may explain the cancer's chemoresistance.11Hough CD Cho KR Zonderman AB Schwartz DR Morin PJ Coordinately up-regulated genes in ovarian cancer.Cancer Res. 2001; 61: 3869-3876PubMed Google Scholar Considering these facts, it is evident that CCC is not just another type of epithelial ovarian cancer but a distinct entity, and there is a need to determine its molecular pathogenesis if we are to improve its prognosis. Until the establishment of the genome-wide expression-analyzing technique such as serial analysis of gene expression12Velculescu VE Zhang L Vogelstein B Kinzler KW Serial analysis of gene expression.Science. 1995; 270: 484-487Crossref PubMed Scopus (3633) Google Scholar or cDNA microarray13Schena M Shalon D Davis RW Brown PO Quantitative monitoring of gene expression patterns with a complementary DNA microarray.Science. 1995; 270: 467-470Crossref PubMed Scopus (7711) Google Scholar, 14Lockhart DJ Dong H Byrne MC Follettie MT Gallo MV Chee MS Mittmann M Wang C Kobayashi M Horton H Brown EL Expression monitoring by hybridization to high-density oligonucleotide arrays.Nat Biotechnol. 1996; 14: 1675-1680Crossref PubMed Scopus (2831) Google Scholar there was only fragmentary knowledge about the molecular pathogenesis of epithelial ovarian cancer. Since then, there have been extensive studies and rapid progress in our understanding of the molecular pathogenesis of various tumors15Golub TR Slonim DK Tamayo P Huard C Gaasenbeek M Mesirov JP Coller H Loh ML Downing JR Caligiuri MA Bloomfield CD Lander ES Molecular classification of cancer: class discovery and class prediction by gene expression monitoring.Science. 1999; 286: 531-537Crossref PubMed Scopus (9355) Google Scholar, 16Higgins JP Shinghal R Gill H Reese JH Terris M Cohen RJ Fero M Pollack JR van de Rijn M Brooks JD Gene expression patterns in renal cell carcinoma assessed by complementary DNA microarray.Am J Pathol. 2003; 162: 925-932Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar, 17Varambally S Dhanasekaran SM Zhou M Barrette TR Kumar-Sinha C Sanda MG Ghosh D Pienta KJ Sewalt RG Otte AP Rubin MA Chinnaiyan AM The polycomb group protein EZH2 is involved in progression of prostate cancer.Nature. 2002; 419: 624-629Crossref PubMed Scopus (2270) Google Scholar including epithelial ovarian cancer.18Wang K Gan L Jeffery E Gayle M Gown AM Skelly M Nelson PS Ng WV Schummer M Hood L Mulligan J Monitoring gene expression profile changes in ovarian carcinomas using cDNA microarray.Gene. 1999; 229: 101-108Crossref PubMed Scopus (286) Google Scholar, 19Hough CD Sherman-Baust CA Pizer ES Montz FJ Im DD Rosenshein NB Cho KR Riggins GJ Morin PJ Large-scale serial analysis of gene expression reveals genes differentially expressed in ovarian cancer.Cancer Res. 2000; 60: 6281-6287PubMed Google Scholar, 20Ono K Tanaka T Tsunoda T Kitahara O Kihara C Okamoto A Ochiai K Takagi T Nakamura Y Identification by cDNA microarray of genes involved in ovarian carcinogenesis.Cancer Res. 2000; 60: 5007-5011PubMed Google Scholar, 21Welsh JB Zarrinkar PP Sapinoso LM Kern SG Behling CA Monk BJ Lockhart DJ Burger RA Hampton GM Analysis of gene expression profiles in normal and neoplastic ovarian tissue samples identifies candidate molecular markers of epithelial ovarian cancer.Proc Natl Acad Sci USA. 2001; 98: 1176-1181Crossref PubMed Scopus Google Scholar, DR R G Taylor JM R Y H SM Cho KR Gene expression in ovarian cancer both and distinguishing clear cell from other ovarian Res. 2002; Google Scholar such studies the genome-wide expression analysis have many genes involved in ovarian the and significance of almost all of such genes still we that a between four CCC cell and seven non-CCC cell in terms of molecular We that hepatocyte nuclear factor-1β a transcription factor, is up-regulated both the mRNA and protein level in CCC, other epithelial ovarian cancers, using of ovarian cancer cell and of 83 surgically resected analysis revealed that HNF-1β expression was to CCC, we investigated the significance of HNF-1β expression in CCC using RNA interference a A S and interference by RNA in 1998; PubMed Scopus Google Scholar, JR RW of interference to that and in the 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, SM J W A K T of RNA interference in 2001; PubMed Scopus Google Scholar Ovarian CCC were with interference RNA the HNF-1β dUTP nick-end labeling and fluorescence-activated cell-sorting revealed that the reduction of HNF-1β induced apoptotic cell death in ovarian CCC Our that HNF-1β not only an excellent CCC-specific molecular marker but also a molecular target for the therapy of ovarian CCC. and cell were by and were by was by was from the Cancer and were from the for these cell and the cell are in cell were in with and in a of and Ovarian Cancer in a RNA was from cell using to the and with I The target was from of RNA from using a and the RNA to the of target to oligonucleotide to genes and expressed and of the were as by the analysis was with The hybridization were to for The were further and by From RNA cDNA was with an and quantitative was with a and a the cycle for for for and for of the of expression of in was The for of HNF-1β, and cDNA were as HNF-1β and and and Quantitative was including a as a were by the were with and The was and the was of were by and to the were by for with in of the were with for HNF-1β for and for as a in the The were and for with were using an We investigated a of 83 epithelial ovarian cancers surgically resected the Cancer between and The from to and of the patients had chemotherapy or other treatment features are in of ovarian and of normal ovarian from patients with other gynecological were also The were to the of the and the of and RE of ovarian of of cell stage in a of tissue were with with in in in a for and to for the were in normal in with for HNF-1β as the with and for with as the were for with using a and to the peroxidase reaction using as the and in by nuclear with was by and The results were the of the percentage of for HNF-1β no to to The and were to the significance of the between HNF-1β expression and the HNF-1β which was was from The HNF-1β was to the to to the of the to and SM J W A K T of RNA interference in 2001; 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Of the genes up-regulated in the CCC cell in HNF-1β and were also up-regulated in surgically resected CCC tissue to a microarray analysis of ovarian cancer tissue DR R G Taylor JM R Y H SM Cho KR Gene expression in ovarian cancer both and distinguishing clear cell from other ovarian Res. 2002; Google Scholar with such as is a in the microarray analysis of tissue whereas changes in cell including the expression the of a cell are in the analysis of cell lines. the between the results from surgically resected tissue and those from the cell that these genes are features of ovarian CCC. the most up-regulated gene in is a overexpression is to poor prognosis and in S Terris DJ B Identification of as a marker for and cell Cancer Res. 2003; Google Scholar, M P R Y Y Wang B carcinomas using gene expression and 2003; PubMed Scopus Google Scholar is up-regulated in epithelial ovarian cancer CCC and compared with normal JH T as a for ovarian 2002; PubMed Scopus Google Scholar but its overexpression in CCC in was that overexpression of to the poor prognosis of CCC. the of and other and its overexpression is with H V R N A of and in response to in J 2002; PubMed Scopus Google Scholar of may for the of CCC which an in in response to DNA induced by such as JB GM S of nuclear and from by and PubMed Scopus Google Scholar of a transcription M H D R a to a the of a and transcription from PubMed Scopus Google Scholar was confirmed by real-time quantitative and analysis and involved in the of CCC protein has been to expressed a high level in A H S A B A P D a and expression in and PubMed Google Scholar and is to of cell and in P The of 1993; PubMed Scopus Google Scholar using surgically resected specimens with we that up-regulated HNF-1β expression the protein level was to ovarian CCC, of stage or histological than (21 of 22 cases) of showed cancer cells, whereas of 61 cases) of showed cancer was that no of or normal ovary showed HNF-1β immunostaining is with S T S Kobayashi H T K Kamura T H Ovarian with ovarian a and Oncol. 2000; Full Text PDF PubMed Scopus Google Scholar and is to of M of ovarian epithelial 2001; PubMed Scopus Google Scholar results of analysis that HNF-1β is a molecular marker for ovarian CCC. in HNF-1β immunostaining an excellent of distinguishing ovarian CCC from other which to now has been difficult with the standard HNF-1β or is a transcription that the or of genes that are expressed in a such as and G S hepatocyte nuclear with a of Natl Acad Sci USA. 85: PubMed Scopus Google Scholar, S M M A for transcription differs between and PubMed Scopus Google Scholar, J T M S is a that transcription and with PubMed Scopus Google Scholar HNF-1β and protein to J T M S is a that transcription and with PubMed Scopus Google are also to of M nuclear a transcription the of 2000; Google Scholar HNF-1β mutations Y N M H Y T K M O H T Y in hepatocyte nuclear gene with PubMed Scopus Google Scholar HNF-1β is overexpressed in W Y T K H T H Expression of and in various histological of Pathol. 1998; PubMed Scopus Google Scholar but its up-regulation has not been in other cancers the significance of HNF-1β expression in CCC, we analysis and to and ovarian CCC cell lines. these cell reduction of HNF-1β expression by apoptotic cell we not to and ovarian CCC cell using such as and We that the why we not gene to these cell was these had or the using to than of and whereas than of and not We not in and cell not the results to we that the reduction of HNF-1β by in and cell that HNF-1β expression was for the survival of CCC Our is by that of cell H H D Wang H C Byrne JH of results in cell and increased to but not to high cell 2002; PubMed Scopus Google Scholar However, it is not clear why reduction of in CCC or HNF-1β may or target genes to cell to the between of and changes by the reduction of HNF-1β are in our our results suggest that HNF-1β a molecular target for therapy of ovarian CCC. 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Glia-activating factor (GAF) is a novel heparin-binding growth factor purified from the culture supernatant of a human glioma cell line. It shows a spectrum of activity slightly different from those of other known growth factors. We have isolated the cDNA which encodes human GAF. A homology search revealed that GAF would be the ninth member of the FGF family, and we therefore call it FGF-9. The human FGF-9 cDNA cloned by using oligonucleotide probes encoded a polypeptide consisting of 208 amino acids. Sequence similarity to other members of the FGF family was estimated to be around 30%. Two cysteine residues and other consensus sequences in family members were also well conserved in the FGF-9 sequence. FGF-9 was found to have no typical signal sequence in its N terminus like those in acidic FGF and basic FGF. Acidic FGF and basic FGF are known not to be secreted from cells in a conventional manner. However, FGF-9 was found to be secreted from cells after synthesis despite its lack of a typical signal sequence. It could be detected exclusively in the culture medium of cDNA-transfected COS cells. The amino acid sequence of proteins purified from culture supernatant of the CHO cell line, which was cDNA transfected and selected as a high producer of FGF-9, showed that no peptides were cleaved from the N terminus except the initiation methionine. The rat FGF-9 cDNA was also cloned, and the structural analysis indicated that the PGF-9 gene is highly conserved. Expression of the FGF-9 gene could be detected in the brain and kidney of the adult rat. Restricted gene expression in organs and the unique secretion nature of the protein suggest that FGF-9 plays a physiological role which differs from those of well-characterized acidic FGF and basic FGF.

The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 (J-SSCG 2020), a Japanese-specific set of clinical practice guidelines for sepsis and septic shock created as revised from J-SSCG 2016 jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in September 2020 and published in February 2021. An English-language version of these guidelines was created based on the contents of the original Japanese-language version. The purpose of this guideline is to assist medical staff in making appropriate decisions to improve the prognosis of patients undergoing treatment for sepsis and septic shock. We aimed to provide high-quality guidelines that are easy to use and understand for specialists, general clinicians, and multidisciplinary medical professionals. J-SSCG 2016 took up new subjects that were not present in SSCG 2016 (e.g., ICU-acquired weakness [ICU-AW], post-intensive care syndrome [PICS], and body temperature management). The J-SSCG 2020 covered a total of 22 areas with four additional new areas (patient- and family-centered care, sepsis treatment system, neuro-intensive treatment, and stress ulcers). A total of 118 important clinical issues (clinical questions, CQs) were extracted regardless of the presence or absence of evidence. These CQs also include those that have been given particular focus within Japan. This is a large-scale guideline covering multiple fields; thus, in addition to the 25 committee members, we had the participation and support of a total of 226 members who are professionals (physicians, nurses, physiotherapists, clinical engineers, and pharmacists) and medical workers with a history of sepsis or critical illness. The GRADE method was adopted for making recommendations, and the modified Delphi method was used to determine recommendations by voting from all committee members.As a result, 79 GRADE-based recommendations, 5 Good Practice Statements (GPS), 18 expert consensuses, 27 answers to background questions (BQs), and summaries of definitions and diagnosis of sepsis were created as responses to 118 CQs. We also incorporated visual information for each CQ according to the time course of treatment, and we will also distribute this as an app. The J-SSCG 2020 is expected to be widely used as a useful bedside guideline in the field of sepsis treatment both in Japan and overseas involving multiple disciplines.

Time spent walking and relaxing in a forest environment ("forest bathing" or "forest therapy") has well demonstrated anti-stress effects in healthy adults, but benefits for ill or at-risk populations have not been reported. The present study assessed the physiological and psychological effects of forest therapy (relaxation and stress management activity in the forest) on middle-aged males with high-normal blood pressure. Blood pressure and several physiological and psychological indices of stress were measured the day before and approximately 2 h following forest therapy. Both pre- and post-treatment measures were conducted at the same time of day to avoid circadian influences. Systolic and diastolic blood pressure (BP), urinary adrenaline, and serum cortisol were all significantly lower than baseline following forest therapy (p<0.05). Subjects reported feeling significantly more "relaxed" and "natural" according to the Semantic Differential (SD) method. Profile of Mood State (POMS) negative mood subscale scores for "tension-anxiety," "confusion," and "anger-hostility," as well as the Total Mood Disturbance (TMD) score were significantly lower following forest therapy. These results highlight that forest is a promising treatment strategy to reduce blood pressure into the optimal range and possibly prevent progression to clinical hypertension in middle-aged males with high-normal blood pressure.

We examined genetically determined oxidation polymorphisms of metoprolol and mephenytoin in 200 unrelated, healthy Japanese subjects and in 98 mainland Chinese subjects simultaneously. This examination was done according to the respective reported phenotyping criteria by use of the urinary metabolic ratio of metoprolol and of the percentage of excretion of 4-hydroxymephenytoin 8 hours after dose administration. The frequencies of occurrence of poor metabolizers (PMs) in the Japanese versus the Chinese subjects were 0.5% versus 0% for metoprolol and 22.5% versus 17.4% for mephenytoin, respectively. There were no statistically significant differences in these frequencies between the two Oriental populations. However, Chinese extensive metabolizers (EMs) showed a significantly lower excretion of alpha-hydroxymetoprolol (p less than 0.01) and 4-hydroxymephenytoin (p less than 0.001) than that of Japanese EMs, and the mode of the distribution histogram of the Chinese EMs for the two test probes was skewed compared with that of the Japanese EMs. The findings indicate that the two Far Eastern Oriental subject groups have a lower frequency of PM phenotype of debrisoquin/sparteine-type oxidation and a greater incidence of PM phenotype of mephenytoin oxidation compared with the respective frequencies reported from white subjects. However, the explanation for the observation that the metabolic capacities of the test drugs differed between the EMs of the two populations who had a similar ethnic origin and who resided in the same geographic area remains obscure.

Retinitis pigmentosa (RP) is the most common inherited human eye disease resulting in night blindness and visual defects. It is well known that the disease is caused by rod photoreceptor degeneration; however, it remains incurable, due to the unavailability of disease-specific human photoreceptor cells for use in mechanistic studies and drug screening. We obtained fibroblast cells from five RP patients with distinct mutations in the RP1, RP9, PRPH2 or RHO gene, and generated patient-specific induced pluripotent stem (iPS) cells by ectopic expression of four key reprogramming factors. We differentiated the iPS cells into rod photoreceptor cells, which had been lost in the patients, and found that they exhibited suitable immunocytochemical features and electrophysiological properties. Interestingly, the number of the patient-derived rod cells with distinct mutations decreased in vitro; cells derived from patients with a specific mutation expressed markers for oxidation or endoplasmic reticulum stress, and exhibited different responses to vitamin E than had been observed in clinical trials. Overall, patient-derived rod cells recapitulated the disease phenotype and expressed markers of cellular stresses. Our results demonstrate that the use of patient-derived iPS cells will help to elucidate the pathogenic mechanisms caused by genetic mutations in RP.

The stomach is a sensitive digestive organ that is susceptible and exposed to exogenous pathogens from the diet. In response to such pathogens, the stomach induces oxidative stress, which might be related to the development of gastric organic disorders such as gastritis, gastric ulcers, and gastric cancer, as well as functional disorders such as functional dyspepsia. In particular, the bacterium Helicobacter pylori plays a major role in eliciting and confronting oxidative stress in the stomach. The present paper summarizes the pathogenesis of oxidative stress in the stomach during the development of various stomach diseases.

Our objectives were to determine whether clinic-pathological markers and immune-related gene signatures in breast cancer exhibit any change upon brain metastasis and whether previously reported genes significantly associated with brain metastases and the epithelial-mesenchymal transition (EMT) were reproducible and consistent in our dataset. Sixteen pair-matched samples from primary breast cancers and brain metastases diagnosed were collected from the Japan Clinical Oncology Group Breast Cancer Study Group. Gene expression profiles for immune-, brain metastases-, and EMT-related genes were compared between primary breast cancers and brain metastases. Potential therapeutic target genes of 41 FDA-approved or under-investigation agents for brain metastases were explored. Immune-related signatures exhibited significantly lower gene expression in brain metastases than in primary breast cancers. No significant differences were detected for the majority of genes associated with brain metastases and EMT in the two groups. Among 41 therapeutic target candidates, VEGFA and DNMT3A demonstrated significantly higher gene expression in brain metastases. We found that distinct patterns of gene expression exist between primary breast cancers and brain metastases. Further studies are needed to explore whether these distinct expression profiles derive from or underlie disease status and compare these features between metastases to the brain and other sites.

BACKGROUND: Mycoplasma pneumoniae is a major pathogen causing community-acquired pneumonia in children and young adults. Outbreaks typically occur at intervals of several years. In 2011, a widespread outbreak was associated with macrolide-resistant M. pneumoniae (MRMP) in Japanese children, often those of school age. METHODS: Two hundred fifty-eight children were diagnosed with M. pneumoniae-associated pneumonia based on chest radiography, real-time polymerase chain reaction (PCR), and antibody titers between January and December 2011. Mycoplasma pneumoniae cultures obtained from nasopharyngeal samples using appropriate broth were subjected to real-time PCR, by which decreases in M. pneumoniae in patients treated with minocycline (MIN), doxycycline (DOX), or tosufloxacin (TFX) were calculated. Mutations of the 23S ribosomal RNA gene that confer high resistance to macrolides in M. pneumoniae were identified by DNA sequencing. RESULTS: Among 202 M. pneumoniae isolates from M. pneumoniae-associated pneumonia patients, 176 (87.1%) were MRMP. Macrolide-resistant M. pneumoniae infection was significantly related to school age (P < .01) and initial administration of macrolides (P < .01). Minocycline or DOX (n = 125) or TFX or levofloxacin (n = 15) was used for definitive treatment of MRMP patients. Minocycline or DOX was significantly more effective than TFX (P ≤ .05) in achieving defervescence within 24 hours and in decreasing numbers of M. pneumoniae DNA copies 3 days after initiation. CONCLUSIONS: Macrolides are inappropriate as first-choice agents against MRMP in terms of shortening the clinical course and decreasing M. pneumoniae. Control and prevention of MRMP outbreaks in children require early decreases in M. pneumoniae as well as improvement of clinical findings.

The natural environment is increasingly recognized as an effective counter to urban stress, and "Forest Therapy" has recently attracted attention as a relaxation and stress management activity with demonstrated clinical efficacy. The present study assessed the physiological and psychological effects of a forest therapy program on middle-aged females. Seventeen Japanese females (62.2 ± 9.4 years; mean ± standard deviation) participated in this experiment. Pulse rate, salivary cortisol level, and psychological indices were measured on the day before forest therapy and on the forest therapy day. Pulse rate and salivary cortisol were significantly lower than baseline following forest therapy, indicating that subjects were in a physiologically relaxed state. Subjects reported feeling significantly more "comfortable," "relaxed," and "natural" according to the semantic differential (SD) method. The Profile of Mood State (POMS) negative mood subscale score for "tension-anxiety" was significantly lower, while that for "vigor" was significantly higher following forest therapy. Our study revealed that forest therapy elicited a significant (1) decrease in pulse rate, (2) decrease in salivary cortisol levels, (3) increase in positive feelings, and (4) decrease in negative feelings. In conclusion, there are substantial physiological and psychological benefits of forest therapy on middle-aged females.