bluuebunny/crossref_metadata_2025 huggingface dataset:
Breast Cancer Risk 55+ Years After Irradiation for an Enlarged Thymus and Its Implications for Early Childhood Medical Irradiation Today
Authors: Adams M. Jacob , Dozier Ann , Shore Roy E. , Lipshultz Steven E. , Schwartz Ronald G. , Constine Louis S. , Pearson Thomas A. , Stovall Marilyn , Winters Paul , Fisher Susan G.
Published: January 2010

Background: Radiotherapy during childhood increases long-term cancer risk, but the risk from radiation as a result of relatively higher dose diagnostic procedures remains less well known. This study, which evaluates breast cancer incidence in a cohort treated with “lower dose” chest radiotherapy over 50 years ago, can assist with estimating lifetime breast cancer risk in young children exposed to radiation from procedures such as chest computed tomography (CT) or treatment with recent “lower dose” chest radiotherapy protocols.

Methods: A population-based, longitudinal cohort of subjects exposed to thymic irradiation during infancy from 1926 to 1957 and of their unexposed siblings was re-established. Previously followed until 1987, we resurveyed cohort members from 2004 to 2008. Poisson regression models compared breast cancer incidence rates between women in the cohort by treatment and dose category groups.

Results: Breast cancer occurred in 96 treated (mean breast dose, 0.71 Gy) and 57 untreated women during 159,459 person-years of follow-up. After adjusting for attained age and treatment/birth cohort, the rate ratio was 3.01 (2.18-4.21). The adjusted excess relative risk per Gy was 1.10 (95% confidence interval, 0.61-1.86). Traditional breast cancer risk factors did not contribute significantly to multivariate model fit.

Conclusion: Our results show that at radiation doses between those received by the breast from chest CT and cancer therapy during early childhood, breast cancer incidence rates remain elevated >50 years after exposure. This implies that increased breast cancer risk will remain a lifelong concern in females treated during childhood with currently reduced radiotherapy doses and for infants receiving multiple chest CTs. Cancer Epidemiol Biomarkers Prev; 19(1); 48–58
Association of Mitotic Regulation Pathway Polymorphisms with Pancreatic Cancer Risk and Outcome
Authors: Couch Fergus J. , Wang Xianshu , Bamlet William R. , de Andrade Mariza , Petersen Gloria M. , McWilliams Robert R.
Published: January 2010

Background: Mitosis is a highly regulated process that serves to ensure the fidelity of cell division. The disruption of mitotic regulators leading to aneuploidy and polyploidy is commonly observed in cancer cells. Single nucleotide polymorphisms (SNP) in regulators of mitosis may promote chromosome missegregation and influence pancreatic cancer and/or survival.

Methods: Thirty-four SNPs, previously associated with breast cancer risk, from 33 genes involved in the regulation of mitosis, were investigated for associations with pancreatic cancer risk in 1,143 Caucasian patients with pancreatic adenocarcinoma and 1,097 unaffected controls from the Mayo Clinic. Associations with survival from pancreatic cancer were also assessed using 1,030 pancreatic cancer cases with known outcome.

Results: Two SNPs in the APC (rs2431238) and NIN (rs10145182) loci, of 34 examined, were significantly associated with pancreatic cancer risk (P = 0.035 and P = 0.038, respectively). Further analyses of individuals categorized by smoking and body mass index identified several SNPs displaying significant associations (P < 0.05) with pancreatic cancer risk, including APC rs2431238 in individuals with high body mass index (≥30; P = 0.031) and NIN rs10145182 in ever smokers (P = 0.01). In addition, survival analyses detected significant associations between SNPs in EIF3S10 and overall survival (P = 0.009), SNPs from five genes and survival in resected cancer cases (P < 0.05), and SNPs from two other genes (P < 0.05) and survival of locally advanced cancer cases.

Conclusion: Common variation in genes encoding regulators of mitosis may independently influence pancreatic cancer susceptibility and survival. Cancer Epidemiol Biomarkers Prev; 19(1); 251–7
Variation in the FGFR2 Gene and the Effect of a Low-Fat Dietary Pattern on Invasive Breast Cancer
Authors: Prentice Ross L. , Huang Ying , Hinds David A. , Peters Ulrike , Cox David R. , Beilharz Erica , Chlebowski Rowan T. , Rossouw Jacques E. , Caan Bette , Ballinger Dennis G.
Published: January 2010

Background: The Women's Health Initiative dietary modification (DM) trial provided suggestive evidence of a benefit of a low-fat dietary pattern on breast cancer risk, with stronger evidence among women whose baseline diet was high in fat. Single nucleotide polymorphisms (SNP) in the FGFR2 gene relate strongly to breast cancer risk and could influence intervention effects.

Methods: All 48,835 trial participants were postmenopausal and ages 50 to 79 years at enrollment (1993-1998). We interrogated eight SNPs in intron 2 of the FGFR2 gene for 1,676 women who developed breast cancer during trial follow-up (1993-2005). Case-only analyses were used to estimate odds ratios for the DM intervention in relation to SNP genotype.

Results: Odds ratios for the DM intervention did not vary significantly with the genotype for any of the eight FGFR2 SNPs (P ≥ 0.18). However, odds ratios varied (P < 0.05) with the genotype of six of these SNPs, among women having baseline percent of energy from fat in the upper quartile (≥36.8%). This variation is most evident for SNP rs3750817, with odds ratios for the DM intervention at 0, 1, and 2 minor SNP alleles of 1.06 [95% confidence intervals (95% CI), 0.80-1.41], 0.53 (95% CI, 0.38-0.74), and 0.62 (95% CI, 0.33-1.15). The nominal significance level for this interaction is P = 0.005, and P = 0.03 following multiple testing adjustment, with most evidence deriving from hormone receptor–positive tumors.

Conclusion: Invasive breast cancer odds ratios for a low-fat dietary pattern, among women whose usual diets are high in fat, seem to vary with SNP rs3750817 in the FGFR2 gene. Cancer Epidemiol Biomarkers Prev; 19(1); 74–9
Feasibility Study for Collection of HER2 Data by National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) Program Central Cancer Registries
Authors: Reichman Marsha E. , Altekruse Sean , Li Christopher I. , Chen Vivien W. , Deapen Dennis , Potts Mary , Wu Xiao-Cheng , Morrell Donna , Hafterson Jennifer , Phipps Amanda I. , Harlan Linda C. , Ries Lynn G. , Edwards Brenda K.
Published: January 2010

The clinical importance of human epidermal growth factor receptor-2 (HER2) in breast cancer is now clearly established, given that expression of this tumor marker is used to guide therapy and as a prognostic indicator. Despite its now routine evaluation in breast cancer patients, population-based data are lacking because information on HER2 status is not routinely collected in the majority of population-based cancer registries. We assessed the feasibility of collecting HER2 data and its completeness in three registries in the Surveillance Epidemiology and End Results (SEER) Program. Among a sample of invasive first primary breast cancer patients diagnosed between June and December 2007, HER2 tests had been done on 96.5% (n = 522), and test results were available for 95.2% (n = 515) of patients. The majority of HER2 tests were performed by immunohistochemistry alone (50.9%), 35.3% by both immunohistochemistry and fluorescence in situ hybridization (FISH), and 11.8% of tests by FISH alone. As a result of these findings, SEER registries will collect HER2 data on all invasive breast cancer patients as an optional data element for those diagnosed in 2009 and HER2 will likely be a required data element for these patients in 2010. Cancer Epidemiol Biomarkers Prev; 19(1); 144–7
Genetic Variation of Genes Involved in Dihydrotestosterone Metabolism and the Risk of Prostate Cancer
Authors: Setlur Sunita R. , Chen Chen X. , Hossain Ruhella R. , Ha Jung Sook , Van Doren Vanessa E. , Stenzel Birgit , Steiner Eberhard , Oldridge Derek , Kitabayashi Naoki , Banerjee Samprit , Chen Jin Yun , Schäfer Georg , Horninger Wolfgang , Lee Charles , Rubin Mark A. , Klocker Helmut , Demichelis Francesca
Published: January 2010

Purpose: Dihydrotestosterone (DHT) is an important factor in prostate cancer (PCA) genesis and disease progression. Given PCA's strong genetic component, we evaluated the possibility that variation in genes involved in DHT metabolism influence PCA risk.

Experimental Design: We investigated copy number variants (CNV) and single nucleotide polymorphisms (SNP). We explored associations between CNV of uridine diphospho-glucuronosyltransferase (UGT) genes from the 2B subclass, given their prostate specificity and/or involvement in steroid metabolism and PCA risk. We also investigated associations between SNPs in genes (HSD3B1, SRD5A1/2, and AKR1C2) involved in the conversion of testosterone to DHT, and in DHT metabolism and PCA risk. The population consisted of 426 men (205 controls and 221 cases) who underwent prostate-specific antigen screening as part of a PCA early detection program in Tyrol, Austria.

Results: No association between CNV in UGT2B17 and UGT2B28 and PCA risk was identified. Men carrying the AA genotype at SNP rs6428830 (HSD3B1) had an odds ratio (OR) of 2.0 [95% confidence intervals (95% CI), 1.1-4.1] compared with men with GG, and men with AG or GG versus AA in rs1691053 (SRD5A1) had an OR of 1.8 (95% CI, 1.04-3.13). Individuals carrying both risk alleles had an OR of 3.1 (95% CI, 1.4-6.7) when compared with men carrying neither (P = 0.005). Controls with the AA genotype on rs7594951 (SRD5A2) tended toward higher serum DHT levels (P = 0.03).

Conclusions: This is the first study to implicate the 5α-reductase isoform 1 (SRD5A1) and PCA risk, supporting the rationale of blocking enzymatic activity of both isoforms of 5α-reductase for PCA chemoprevention. Cancer Epidemiol Biomarkers Prev; 19(1); 229–39
The Antitumor Activity of Homoharringtonine against Human Mast Cells Harboring the KIT D816V Mutation
Authors: Jin Yanli , Lu Zhongzheng , Cao Kaiyuan , Zhu Yunhui , Chen Qi , Zhu Feng , Qian Chenchen , Pan Jingxuan
Published: January 2010

Gain-of-function mutations of the receptor tyrosine kinase KIT play a critical role in the pathogenesis of systemic mastocytosis (SM) and gastrointestinal stromal tumors. The various juxtamembrane type of KIT mutations, including V560G, are found in 60% to 70% of patients with gastrointestinal stromal tumors; loop mutant D816V, which exists in ∼80% of SM patients, is completely resistant to imatinib. In the present study, we hypothesized that homoharringtonine (HHT), a protein synthesis inhibitor, would decrease the level of KIT protein by inhibiting translation, resulting in a decreased level of phospho-KIT and abrogating its constitutive downstream signaling. Imatinib-sensitive HMC-1.1 cells harboring the mutation V560G in the juxtamembrane domain of KIT, imatinib-resistant HMC-1.2 cells harboring both V560G and D816V mutations, and murine P815 cells were treated with HHT and analyzed in terms of growth, apoptosis, and signal transduction. The in vivo antitumor activity was evaluated by using the murine mast cell leukemia model. Our results indicated that HHT effectively inhibited the growth and induced apoptosis in cells bearing both V560G and D816V or D814Y KIT. Additionally, HHT inhibited the KIT-dependent phosphorylation of downstream signaling molecules Akt, signal transducer and activator of transcription 3 and 5, and extracellular signal-regulated kinase 1/2. Furthermore, HHT significantly prolonged the survival duration of mice with aggressive SM or mast cell leukemia by inhibiting the expansion and infiltration of imatinib-resistant mast tumor cells harboring imatinib-resistant D814Y KIT. Collectively, we show that HHT circumvents D816V KIT-elicited imatinib resistance. Our findings warrant a clinical trial of HHT in patients with SM harboring D816V or D814Y KIT. Mol Cancer Ther; 9(1); 211–23
Human Sodium/Iodide Symporter–Mediated Radioiodine Gene Therapy Enhances the Killing Activities of CTLs in a Mouse Tumor Model
Authors: Jeon Yong Hyun , Choi Yun , Kim Chul Woo , Kim Young-Hwa , Youn Hyewon , Lee Jaetae , Chung June-Key
Published: January 2010

We examined whether human sodium/iodide symporter (hNIS) radioiodine gene therapy can modulate the phenotype of cancer cells and enhance the killing activities of CTLs in a mouse tumor model. Various doses of I-131 (75, 300, 600, 1,200, and 2,400 μCi/5 mL) were incubated with hNIS-expressing colon cancer (CT26/hNIS) and parental cells (CT26), and numbers of MHC class I and Fas-expressing cells were determined by fluorescence-activated cell sorting (FACS). In addition, CT26/hNIS or CT26 tumor-bearing mice were treated with 1,200 μCi of I-131, and percentages of MHC class I and Fas-expressing tumor cells were determined by FACS. The levels of tumor-infiltrating CD8+IFNγ+ and CD11c+CD86+ cells and CTL killing activities were measured in CT26/hNIS tumor-bearing mice (treated with PBS or 1,200 μCi of I-131) by FACS and lactate dehydrogenase assay, respectively. MHC class I and Fas gene expressions were markedly upregulated in CT26/hNIS cells, but not in CT26 cells, in an I-131 dose-dependent manner. The level of MHC class I and Fas-expressing cancer cell were 4.5-fold and 2.1-fold higher in CT26/hNIS tumors than in CT26 tumors, respectively (P < 0.01). Interestingly, numbers of tumor-infiltrating CD8+IFNγ+ cells and CD11c+CD86+ cells were 5-fold and 2.5-fold higher in I-131–treated tumors than in PBS tumors, respectively (P < 0.001). Furthermore, CTL assays showed significantly more specific tumor cell lysis in I-131 tumors than in PBS tumors (P < 0.01). Our findings suggest that hNIS radioiodine gene therapy can generate tumor-associated immunity in tumor microenvironments and enhance the killing activities of CTLs. Mol Cancer Ther; 9(1); 126–33
Disablingc-Mycin Childhood Medulloblastoma and Atypical Teratoid/Rhabdoid Tumor Cells by the Potent G-Quadruplex Interactive Agent S2T1-6OTD
Authors: Shalaby Tarek , von Bueren André O. , Hürlimann Marie-Louise , Fiaschetti Giulio , Castelletti Deborah , Masayuki Tera , Nagasawa Kazuo , Arcaro Alexandre , Jelesarov Ilian , Shin-ya Kazuo , Grotzer Michael
Published: January 2010

We investigated here the effects of S2T1-6OTD, a novel telomestatin derivative that is synthesized to target G-quadruplex–forming DNA sequences, on a representative panel of human medulloblastoma (MB) and atypical teratoid/rhabdoid (AT/RT) childhood brain cancer cell lines. S2T1-6OTD proved to be a potent c-Myc inhibitor through its high-affinity physical interaction with the G-quadruplex structure in the c-Myc promoter. Treatment with S2T1-6OTD reduced the mRNA and protein expressions of c-Myc and hTERT, which is transcriptionally regulated by c-Myc, and decreased the activities of both genes. In remarkable contrast to control cells, short-term (72-hour) treatment with S2T1-6OTD resulted in a dose- and time-dependent antiproliferative effect in all MB and AT/RT brain tumor cell lines tested (IC50, 0.25–0.39 μmol/L). Under conditions where inhibition of both proliferation and c-Myc activity was observed, S2T1-6OTD treatment decreased the protein expression of the cell cycle activator cyclin-dependent kinase 2 and induced cell cycle arrest. Long-term treatment (5 weeks) with nontoxic concentrations of S2T1-6OTD resulted in a time-dependent (mainly c-Myc–dependent) telomere shortening. This was accompanied by cell growth arrest starting on day 28 followed by cell senescence and induction of apoptosis on day 35 in all of the five cell lines investigated. On in vivo animal testing, S2T1-6OTD may well represent a novel therapeutic strategy for childhood brain tumors. Mol Cancer Ther; 9(1); 167–79
MK-5108, a Highly Selective Aurora-A Kinase Inhibitor, Shows Antitumor Activity Alone and in Combination with Docetaxel
Authors: Shimomura Toshiyasu , Hasako Shinichi , Nakatsuru Yoko , Mita Takashi , Ichikawa Koji , Kodera Tsutomu , Sakai Takumi , Nambu Tadahiro , Miyamoto Mayu , Takahashi Ikuko , Miki Satomi , Kawanishi Nobuhiko , Ohkubo Mitsuru , Kotani Hidehito , Iwasawa Yoshikazu
Published: January 2010

Aurora-A kinase is a one of the key regulators during mitosis progression. Aurora-A kinase is a potential target for anticancer therapies because overexpression of Aurora-A, which is frequently observed in some human cancers, results in aberrant mitosis leading to chromosomal instability and possibly tumorigenesis. MK-5108 is a novel small molecule with potent inhibitory activity against Aurora-A kinase. Although most of the Aurora-kinase inhibitors target both Aurora-A and Aurora-B, MK-5108 specifically inhibited Aurora-A kinase in a panel of protein kinase assays. Inhibition of Aurora-A by MK-5108 in cultured cells induced cell cycle arrest at the G2-M phase in flow cytometry analysis. The effect was confirmed by the accumulation of cells with expression of phosphorylated Histone H3 and inhibition of Aurora-A autophosphorylation by immunostaining assays. MK-5108 also induced phosphorylated Histone H3 in skin and xenograft tumor tissues in a nude rat xenograft model. MK-5108 inhibited growth of human tumor cell lines in culture and in different xenograft models. Furthermore, the combination of MK-5108 and docetaxel showed enhanced antitumor activities compared with control and docetaxel alone–treated animals without exacerbating the adverse effects of docetaxel. MK-5108 is currently tested in clinical trials and offers a new therapeutic approach to combat human cancers as a single agent or in combination with existing taxane therapies. Mol Cancer Ther; 9(1); 157–66
Overexpression of EpCAM in Uterine Serous Papillary Carcinoma: Implications for EpCAM-Specific Immunotherapy With Human Monoclonal Antibody Adecatumumab (MT201)
Authors: El-Sahwi Karim , Bellone Stefania , Cocco Emiliano , Casagrande Francesca , Bellone Marta , Abu-Khalaf Maysa , Buza Natalia , Tavassoli Fattaneh A. , Hui Pei , Rüttinger Dominik , Silasi Dan-Arin , Azodi Masoud , Schwartz Peter E. , Rutherford Thomas J. , Pecorelli Sergio , Santin Alessandro D.
Published: January 2010

We evaluated the expression of epithelial cell adhesion molecule (EpCAM) and the potential of MT201 (adecatumumab), a human monoclonal antibody against EpCAM, in uterine serous papillary carcinoma (USPC). EpCAM expression was evaluated by real-time PCR and immunohistochemistry in a total of 56 USPC fresh-frozen biopsies and paraffin-embedded tissues. EpCAM surface expression was also evaluated by flow cytometry and immunohistochemistry in six USPC cell lines. Sensitivity to MT201 antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity was tested against a panel of primary USPC cell lines expressing different levels of EpCAM in standard 5-h 51Cr release assays. EpCAM transcript was significantly overexpressed in fresh-frozen USPC when compared with normal endometrial cells (NEC). Median (minimum–maximum) copy number was 943.8 (31.5–1568.3) in tumor samples versus 12.9 (1.0–37.0) in NEC (P < 0.001). By immunohistochemistry, EpCAM expression was found in 96% (26 out of 27) of USPC samples with significantly higher expression compared with NECs (P < 0.001). High surface expression of EpCAM was found in 83% (five out of six) of the USPC cell lines tested by flow cytometry. EpCAM-positive cell lines were found highly sensitive to MT201-mediated antibody-dependent cellular cytotoxicity in vitro, whereas primary USPC cell lines were resistant to natural killer cell–dependent cytotoxicity. Human plasma IgG did not significantly inhibit MT201-mediated cytotoxicity against USPC. EpCAM is highly expressed in uterine serous carcinoma at mRNA and protein levels, and primary USPC are highly sensitivity to MT201-mediated cytotoxicity. MT201 might represent a novel therapeutic strategy in patients harboring advanced/recurrent or metastatic USPC refractory to standard treatment modalities. Mol Cancer Ther; 9(1); 57–66
Sensitivity to the Aromatase Inhibitor Letrozole Is Prolonged After a “Break” in Treatment
Authors: Sabnis Gauri , Goloubeva Olga , Gilani Rabia , Macedo Luciana , Brodie Angela
Published: January 2010

Using a hormone-dependent xenograft model, we established that loss of response to letrozole was accompanied by upregulation of the Her-2/mitogen-activated protein kinase (MAPK) pathway and downregulation of estrogen receptor α (ERα) and aromatase activity. In our previous study, we showed that stopping letrozole treatment or adding trastuzumab could reverse acquired resistance. In this study, we compared the effects of intermittent letrozole treatment and switching treatment between letrozole and trastuzumab on tumor growth in an attempt to optimize discontinuous letrozole treatment. The mice were treated with letrozole until the tumors developed resistance and then were divided into three groups: (a) letrozole, (b) trastuzumab, and (c) “off” (Δ4A supplement only); tumors were collected every week to examine changes in tumor protein expression and activity. In off group tumors, Her-2/p-MAPK activation gradually decreased and ERα and aromatase protein (and activity) increased. Within the first week of trastuzumab treatment, Her-2 and MAPK were downregulated and ERα was upregulated. When letrozole-resistant MCF-7Ca tumors were taken off treatment for 4 weeks, the second course of letrozole treatment provided a much longer duration of response (P = 0.02). However, switching treatment to trastuzumab for 4 weeks did not provide any inhibition of tumor growth. Our studies revealed that the adaptation of cells to a low-estrogen environment by upregulation of Her-2/MAPK and downregulation of ERα/aromatase was reversed on letrozole withdrawal. The tumors once again became responsive to letrozole for a significant period. These results suggest that response to letrozole can be prolonged by a short “break” in the treatment. Mol Cancer Ther; 9(1); 46–56
Glioblastoma Cancer-Initiating Cells Inhibit T-Cell Proliferation and Effector Responses by the Signal Transducers and Activators of Transcription 3 Pathway
Authors: Wei Jun , Barr Jason , Kong Ling-Yuan , Wang Yongtao , Wu Adam , Sharma Amit K. , Gumin Joy , Henry Verlene , Colman Howard , Priebe Waldemar , Sawaya Raymond , Lang Frederick F. , Heimberger Amy B.
Published: January 2010

Glioblastoma multiforme (GBM) is a lethal cancer that responds poorly to radiotherapy and chemotherapy. Glioma cancer-initiating cells have been shown to recapitulate the characteristic features of GBM and mediate chemotherapy and radiation resistance. However, it is unknown whether the cancer-initiating cells contribute to the profound immune suppression in GBM patients. Recent studies have found that the activated form of signal transducer and activator of transcription 3 (STAT3) is a key mediator in GBM immunosuppression. We isolated and generated CD133+ cancer-initiating single colonies from GBM patients and investigated their immune-suppressive properties. We found that the cancer-initiating cells inhibited T-cell proliferation and activation, induced regulatory T cells, and triggered T-cell apoptosis. The STAT3 pathway is constitutively active in these clones and the immunosuppressive properties were markedly diminished when the STAT3 pathway was blocked in the cancer-initiating cells. These findings indicate that cancer-initiating cells contribute to the immune evasion of GBM and that blockade of the STAT3 pathway has therapeutic potential. Mol Cancer Ther; 9(1); 67–78
PHF10 Is Required for Cell Proliferation in Normal and SV40-Immortalized Human Fibroblast Cells
Authors: Banga S.S. , Peng L. , Dasgupta T. , Palejwala V. , Ozer H.L.
Published: January 2010

Normal human diploid fibroblasts have limited life span in culture and undergo replicative senescence after 50–60 population doublings. On the contrary, cancer cells typically divide indefinitely and are immortal. Expression of SV40 large T and small t antigens in human fibroblasts transiently extends their life span by 20–30 population doublings and facilitates immortalization. We have identified a rearrangement in chromosome 6 shared by SV40-transformed human fibroblasts. Rearrangements involving chromosome 6 are among the most frequent in human carcinogenesis. In this paper, we extend analysis of the 6q26–q27 region, a putative site for a growth suppressor gene designated SEN6 involved in immortalization of SV40-transformed cells. Detailed molecular characterization of the rearranged chromosomes (6q*, normal appearing; and 6qt, translocated) in the SV40-immortalized cell line HALneo by isolating each of these 2 chromosomes in mouse/HAL somatic cell hybrids is presented. Analysis of these mouse/HAL somatic cell hybrids with polymorphic and nonpolymorphic markers revealed that the 6q* has undergone a chromosomal break in the MLLT4 gene (alias AF6). This result in conjunction with previous published observations leads us to conclude that SEN6 lies between MLLT4 and TBP at chromosomal region 6q27. Examination of different genes (MLLT4, DLL1, FAM120B, PHF10) located within this interval that are expressed in HS74 normal fibroblast cells reveals that overexpression of epitope-tagged truncated PHF10 cDNAs resulted in reduced cell proliferation in multiple cell lines. Paradoxically, down-regulation of PHF10 by RNAi also resulted in loss of cell proliferation in normal fibroblast cells, indicating PHF10 function is required for cell growth. Taken together, these observations suggest that decreased cell proliferation with epitope-tagged truncated PHF10 proteins may be due to dominant negative effects or due to unregulated expression of these mutant proteins. Hence we conclude that PHF10 is not SEN6 but is required for cell growth.
Increasing Incidence of Hepatitis A in Korean Adults
Authors: Kim Yoon Jun , Lee Hyo-Suk
Published: January 2010

Hepatitis A infection is caused by the hepatitis A virus (HAV), which is transmitted through the fecal-oral route. Lifelong protective antibodies are present after infection. The number of cases of adult hepatitis A has progressively been increasing during the last several decades in Korea. In addition, the pattern of age-specific seroprevalence of anti-HAV has changed with economic growth. The prevalence of anti-HAV in the 10–50-year age range has declined rapidly during the last 3 decades. As a result, this age group has a high risk for HAV infection and clinically overt hepatitis A is increasing in adolescents and adults. It is well established that the severity of the disease is related to the age of the patients. The development of more cases of adult hepatitis A with severe presentation is expected in the near future. The clinical features and the epidemiological shift of HAV underscore the importance in Korea, as well as in other countries with similar issues, of childhood vaccination and consideration of catch-up vaccination for adolescents and adults as well as of targeted vaccination for individuals at increased risk for infection or its complications. There is a need to extensively evaluate the nationwide epidemiology of HAV infection, make cost-benefit analyses of HAV vaccination, and establish guidelines for HAV vaccination.
How to Overcome Antiviral-Resistant Hepatitis B Virus?
Authors: Song Byung-Cheol
Published: January 2010

The goal of antiviral therapy in patients with chronic hepatitis B is long-lasting suppression of hepatitis B virus (HBV) DNA, normalization of serum alanine aminotransferase and prevention of progression of chronic liver disease to liver cirrhosis, hepatocellular carcinoma and death. Even though substantial advances have been made in the treatment of chronic hepatitis B in the past decade with the use of oral nucleoside/nucleotide analogs, emergence of antiviral resistance is the most important factor in treatment failure for chronic hepatitis B. Herein, we will discuss how to prevent antiviral resistance.
HCV Genetic Elements Determining the Early Response to Peginterferon and Ribavirin Therapy
Authors: Enomoto Nobuyuki , Maekawa Shinya
Published: January 2010

The aim of this study was to search hepatitis C virus (HCV) genetic elements determining the early response to peginterferon/ribavirin therapy using HCV genome-wide analysis. From a total of 88 chronic hepatitis C patients with HCV-1b treated with peginterferon/ribavirin, the whole HCV amino acid sequence was determined and analyzed according to the viral response during the treatment. Mutations in NS5A-ISDR (interferon sensitivity-determining region) are associated with rapid viral response at week 4, and the core arginine70glutamine (R70Q) mutation is associated with no early viral response at week 12, revealing that core 70 and NS5A are the most important factors determining the virological kinetics during peginterferon and ribavirin therapy.
Non-Invasive Evaluation of Hepatic Fibrosis for Type C Chronic Hepatitis
Authors: Tatsumi Chie , Kudo Masatoshi , Ueshima Kazuomi , Kitai Satoshi , Ishikawa Emi , Yada Norihisa , Hagiwara Satoru , Inoue Tatsuo , Minami Yasunori , Chung Hobyung , Maekawa Kiyoshi , Fujimoto Kenji , Kato Michio , Tonomura Akiko , Mitake Tsuyoshi , Shiina Tsuyoshi
Published: January 2010

Objective: The aim of this study was to investigate liver fibrosis using non-invasive Real-time Tissue Elastography® (RTE) and transient elastography (FibroScan®) methods. Methods: RTE, FibroScan and percutaneous liver biopsy were all performed on patients with chronic liver disease, particularly hepatitis C, to investigate liver fibrosis. Results: FibroScan and RTE were compared for fibrous liver staging (F stage), which was pathologically classified using liver biopsy. In FibroScan, significant differences were observed between F1/F3 and F2/F4, but no such differences were observed between F1/F2, F2/F3 and F3/F4. In RTE, significant differences were observed between F1/F2, F2/F3 and F2/F4. But for F3/F4, no significant differences were observed. Conclusion: FibroScan and RTE correlated well with F staging of the liver. In particular RTE was more successful than FibroScan in diagnosing the degree of liver fibrosis.
The Reversed Clock Drawing Test Phenomenon in Alzheimer’s Disease: A Perfusion SPECT Study
Authors: Brugnolo A. , Morbelli S. , Dessi B. , Girtler N. , Mazzei D. , Famà F. , Barbieri P. , Cabassi G. , Koulibaly P.M. , Sambuceti G. , Rodriguez G. , Nobili F.
Published: January 2010

Aim: To unveil a brain single photon emission computed tomography (SPECT) pattern in Alzheimer’s disease (AD) patients, showing a reversed clock drawing test (CDT) phenomenon. Patients and Methods: Among 1,005 consecutive subjects, 9 AD patients who drew a reversed CDT (AD-R) underwent SPECT, which was analysed (SPM2) versus a group of 10 AD patients performing the CDT correctly (AD+) and versus 15 controls (CTR). Brain SPECT in 11 AD patients who mistook the CDT in a common way (AD–) was compared with AD+ and CTR groups. Results: Relative hypoperfusion was found in AD-R versus CTR in right medial frontal, parahippocampal and subcallosal gyri, and in left insula and superior temporal gyrus. Hypoperfusion was found in AD-R versus AD+ in the right uncus, superior temporal and parahippocampal gyri. In the AD– versus CTR comparison, hypoperfusion was found in left hippocampus, parahippocampal gyrus and superior parietal lobule. In AD-R versus AD+ and CTR merged together, the analysis showed hypoperfusion in the right parahippocampus, medial frontal gyrus, superior temporal gyrus and uncus, in the left insula and superior temporal gyrus. Conclusion: Fronto-temporal dysfunction, especially in the right hemisphere, plays a role in the reversed CDT phenomenon in AD patients, whereas matched AD patients mistaking the CDT in a common way show left posterior temporo-parietal hypoperfusion.
Primary Pituitary Lymphoma: Idiopathic Anasarca with Relapse in Bone Marrow Only
Authors: Bayraktar Soley , Bassini Wilfredo , Goodman Mark
Published: January 2010

We report a case of primary large B cell-type pituitary lymphoma in a 47-year-old immunocompetent female who presented with headache and cranial nerve palsy. She was treated with the DeAngelis chemotherapy protocol and achieved a complete remission. At 1 and 6 months after completion of chemotherapy, she presented with anasarca and was diagnosed with relapse exclusively in the bone marrow twice. She received 8 cycles of R-CHOP chemotherapy and had complete resolution of anasarca. Consequently, we proceeded with salvage chemotherapy followed by autologous stem cell transplantation. To our knowledge, this is the first reported case of primary pituitary lymphoma that relapsed exclusively in the bone marrow and presented with clinical findings of idiopathic anasarca.
Effect of Work-Related Ultraviolet Exposure and Ophthalmic Changes in Austrian Farmers: The SVB-UV Study
Authors: Schmid-Kubista Katharina E. , Kellner Lukas , Maier Harald , Felke Stefan , Wanka Alexandra , El Modeir Adel , Schmidt Jolanta B. , Cabaj Alexander , Schmalwieser Alois , Rohn Herbert , Stadelmann Heinrich , Spiess Johannes , Fischer Wolfgang , Hönigsmann Herbert , Binder Susanne
Published: January 2010

Background: Epidemiological screening to examine possible ultraviolet-induced ocular changes and pathologies in Austrian farmers. Methods: The study was performed on behalf of the Austrian farmer insurance (Sozialversicherungsanstalt der Bauern). Randomly selected farmers and office workers as controls, both at the age of 35–55 years, underwent ophthalmic screening examinations. All subjects underwent complete ophthalmic examinations by slit lamp examination and Schirmer’s test 1. A survey, regarding per- sonal habits in the sun, was also conducted. Results: Three hundred and ninety-two subjects underwent ophthalmic examinations of whom 297 were farmers and 95 were controls. Due to the survey, 89.7% of the farmers claimed to protect themselves from the sun during work. From these subjects, 83.7% wear a head protection, 71.0% wear sunglasses, and 54.4% usually work in the shade. There were significant differences in lid (p = 0.021) and conjunctival pathologies (p < 0.0001) between farmers and controls. Conclusion: Austrian farmers are at a higher risk for developing lid and conjunctival tumours which require treatment at some point. We believe that the study group was too young to show significant differences within the lens and the posterior pole. A 5-year follow-up is planned.
Concurrent Weekly Nedaplatin, External Beam Radiotherapy and High-Dose-Rate Brachytherapy in Patients with FIGO Stage IIIb Cervical Cancer: A Comparison with a Cohort Treated by Radiotherapy Alone
Authors: Mabuchi Seiji , Ugaki Hiromi , Isohashi Fumiaki , Yoshioka Yasuo , Temma Kumiko , Yada-Hashimoto Namiko , Takeda Takashi , Yamamoto Toshiya , Yoshino Kiyoshi , Nakajima Ryuichi , Kuragaki Chie , Morishige Kenichirou , Enomoto Takayuki , Inoue Takehiro , Kimura Tadashi
Published: January 2010

Objectives: The aim of this study was to evaluate whether nedaplatin-based concurrent chemoradiotherapy (CCRT) using high-dose-rate intracavitary brachytherapy (HDR-ICBT) is superior to radiotherapy (RT) alone in patients with FIGO stage IIIb cervical cancer. Methods: The records of 41 consecutive women treated either with nedaplatin-based CCRT using HDR-ICBT (n = 20) or RT alone (nonrandomized control group, n = 21) for stage IIIb cervical cancer were retrospectively reviewed. The activity and toxicity were compared between the two treatment groups. Progression-free survival (PFS) and overall survival (OS) were the main endpoints. Results: The 5-year overall survival rates in the CCRT and RT groups were 65 and 33.3%, respectively. The median OS of the CCRT and RT groups were 60 and 29 months, respectively. CCRT was significantly superior to RT alone with regard to PFS (p = 0.0015) and OS (p = 0.0364). The frequency of acute grade 3–4 toxicity was significantly higher in the CCRT group than in the RT group. However, no statistically significant difference was observed with regard to severe late toxicity. Conclusions: Nedaplatin-based concurrent chemoradiotherapy was safely performed and significantly improved the prognosis of patients with FIGO stage IIIb cervical cancer. This treatment can be considered as an alternative to cisplatin-based chemoradiotherapy in this patient population.
Impact of a Rehabilitation Program on Dyspnea Intensity and Quality in Patients with Chronic Obstructive Pulmonary Disease
Authors: Bianchi Roberto , Gigliotti Francesco , Romagnoli Isabella , Lanini Barbara , Castellani Carla , Binazzi Barbara , Stendardi Loredana , Bruni Giulia Innocenti , Scano Giorgio
Published: January 2010

Background: It has yet to be determined whether the language of dyspnea responds to pulmonary rehabilitation programs (PRP). Objective: We tested the hypothesis that PRP affect both the intensity and quality of exercise-induced dyspnea in patients with chronic obstructive pulmonary disease (COPD). Methods: We studied 49 patients equipped with a portable telemetric spiroergometry device during the 6-min walking test before and 4 weeks after PRP. In a first screening visit, appropriate verbal descriptors of dyspnea were chosen that patients were familiar with during daily living activities. Tidal volume, respiratory frequency, inspiratory capacity, inspiratory reserve volume (IRV) and dyspnea intensity were evaluated by a modified Borg scale every minute during the test. Results: Qualitative descriptors of dyspnea were defined by three different sets of cluster descriptors (a–c) at the end of the exercise test, before and after PRP: a – work/effort (W/E); b – inspiratory difficulty (ID) and chest tightness (CT), and c – W/E, ID and/or CT. The three language subgroups exhibited similar lung function at baseline, and similar rating of dyspnea and ventilatory changes during exercise. The rehabilitation program shifted the Borg-IRV relationship (less Borg at any given IRV) towards the right without modifying the set of descriptors in most patients. Conclusions: Rehabilitation programs allowed patients to tolerate a greater amount of restrictive dynamic ventilatory defect by modifying the intensity, but not necessarily the quality of dyspnea.
Discoidin Domain of Chitosanase Is Required for Binding to the Fungal Cell Wall
Authors: Kimoto Hisashi , Akamatsu Miho , Fujii Yutaka , Tatsumi Hirosuke , Kusaoke Hideo , Taketo Akira
Published: January 2010

Previously, we reported properties of a glycosylase belonging to GH-8 glycosyl hydrolase (GH) and having both chitosanase and glucanase activities. This enzyme (D2), whose molecular mass (86 kDa) was the largest among the GH-8 group, has its catalytic domain at the N-terminal region, and discoidin domain (DD) at the C-terminal region. Although various chitosanases, chitinases and glucanases have been known, DD is unique to the D2 enzyme. Glucanase and chitinase, but not chitosanase, are known to have functional domain such as carbohydrate-binding module, besides catalytic domain. Accordingly, function of the DD of D2 chitosanase was analyzed, using zygomycete cell wall containing chitosan, glucan and chitin as the basic constituents. The DD specifically and tightly bound to chitosan, but did not participate in affinity for glucan and chitin. Deletion of the DD caused marked reduction in absorbability to cell wall and in hydrolytic activity toward chitosan and glucan. These results suggest that the DD is concerned in binding of the enzyme to cell wall and in effective digestion of the insoluble substrate, through hydrolysis of not only chitosan but also coexisting glucan. Thus, this is the first example of chitosan-binding domain among various carbohydrate-binding modules reported thus far.
Gap Junction Channel Modulates Pulmonary Vascular Permeability through Calcium in Acute Lung Injury: An Experimental Study
Authors: Zhang Jinzhou , Wang Wen , Sun Jing , Li Qiang , Liu Jincheng , Zhu Hailong , Chen Tao , Wang Hongbing , Yu Shiqiang , Sun Guocheng , Chen Wensheng , Yi Dinghua
Published: January 2010

Background: Increased pulmonary vascular permeability is a hallmark of acute lung injury (ALI). Gap junction channels (GJCs) connect adjacent cells and facilitate ion exchange. It remained unclear whether GJCs modulate pulmonary permeability in ALI through intracellular calcium. Objectives: This study aimed to verify if GJCs in pulmonary microvessel endothelial cells (PMVECs) modulate pulmonary vascular permeability in ALI via intracellular calcium. Methods: Firstly, an animal model of ALI was studied using connexin 40 (Cx40) inmunohistochemistry in the lung with Evans’ blue (EB) leakage. Then cultured PMVECs were divided into three groups: Gcontrol, Gserum and Gblocker. Serum was obtained from animals with ALI following gunshot injury (injured serum). Initially, Gblocker was treated with the blocker of GJCs, and then Gserum and Gblocker were stimulated with the injured serum, respectively. GJCs, the permeability of cell monolayers and intracellular Ca2+ were assessed. Results: Cx40 time-dependently decreased, whereas EB leakage increased. Cx40 and EB leakage exhibited a strong inverse correlation (ρ = –0.934, p < 0.05). Injured serum decreased GJCs and expression of Cx40, whereas the blocker aggravated this effect. Similarly, when PMVEC monolayer was treated with injured serum, both permeability and intracellular Ca2+ increased. These effects were also aggravated with the blocker. Conclusions: Depression of GJCs of PMVECs increased pulmonary vascular permeability in ALI; this effect may be mediated by the overload of intracellular calcium.
Tracheoesophageal Fistula with Chronic Bronchitis
Authors: Hentzer E.
Published: January 2010

A man of 48 was admitted to hospital because of chronic bronchitis and difficulty in swallowing. X-ray films of the esophagus showed contrast material in the trachea but no fistula. During esophagoscopy and bronchoscopy a small opening was found on the front wall of the esophagus 22 cm from the upper incisors and 4 cm above the carina. Thoracotomy was performed with resection of the fistula. No sign of malignancy was found. According to etiology tracheoesophageal fistulas can be divided into 3 groups: 1. those caused by malignant diseases or specific infectious diseases of the esophagus; 2. those caused by trauma, and 3. congenital fistulas. In the reported case the fistula was probably congenital since no sign of malignancy was found and since the patient’s chronic bronchitis stopped entirely after the operation.
Auditory Responses in Tay-Sachs Disease
Authors: Tanaka Y. , Taguchi K. , Arayama T.
Published: January 2010

It is demonstrated that local diagnosis of the hearing impairment and evaluating of the degenerating process in the central nervous system in Tay-Sachs disease may be possible by means of various kinds of audiometric methods applicable to young children, such as cerebral evoked response audiometry using a computer as well as startle response, auropalpebral reflex (APR) and cochleopupillary reflex (CPR) audiometries. Thresholds of startle response, APR, CPR during sleep and cerebral evoked potentials in response to sound stimuli were measured in three patients with Tay-Sachs disease. The thresholds of the startle response, APR and CPR were found to be comparable to those in normal newborn infants and normal young children, whereas no auditory cerebral evoked responses were detected by an average response computer even at the maximum intensity except for a case with the threshold of 80 dB. Since the startle response as well as APR and CPR may be integrated at the level of the brain stem and the cerebral evoked response may arise from the cerebral cortex over a wide area, it is suggested that the lack of the auditory cerebral evoked response probably reflects a predominant degeneration of the higher supranuclear auditory pathways.
Histological Studies on the Human Endolymphatic Duct and Sac
Authors: Zechner G. , Altmann F.
Published: January 2010

The endolymphatic duct and sac was histologically studied in 190 normal and diseased temporal bones coming from 100 individuals of all age groups. A number of hitherto unknown morphological details was reported, particularly in the physiologically most active portion, the pars rugosa of the sac. The histological findings in man are in good agreement with the results of experimental studies and indicate an intensive resorptive function of this area. A marked fibrosis of the tunica propria in Menière’s disease evidently interferes with the resorption of the endolymph in this area and could therefore act as predisposing factor for the development of the attacks. The fact that in the great majority of the cases the pars rugosa is located within the bony capsule makes the chances for a successful treatment of Menière’s disease through decompression of the pars intraduralis dubious.
Anatomic Relationship between Limbus spiralis and Tectorial Membrane
Authors: Borghesan C.
Published: January 2010

In the limbus of human foetus at term the following anatomic data can be pointed out: (1) the fibrils constituting Huscke’s teeth seem to continue into those of the tectorial membrane over the limbus; (2) between the limbus and the tectorial membrane there is a formation, planum limbi, constituted by the cytoplasm of the most superficial interdental cells separated by the above-mentioned fibrils. An important function in the metabolism of the endolymph may be attributed to the planum limbi.
Zur Geschichte der konservativen Radikaloperation des Ohres
Authors: Jansen C.
Published: January 2010

In most of all cases of tympanoplasty a radical mastoidectomy is needed. In addition to the destruction which is caused by the chronic discharged process the radical procedure involves more destruction. Prevention of those destructions is the aim of the so-called conservative radical mastoidectomy. History of this procedure including the authors technique of ‘Posterior Tympanotomy’ is described.
Etude expérimentale des modifications du nystagmus diencéphalique en relation avec la position de la tête dans l’espace
Authors: Montandon A. , Huguenin S. , Luyet M.
Published: January 2010

Our experiments on 8 rabbits, with 96 trials per animal, consist of a DNA stereotaxic stimulation with a variation of the position of the animal in space. We base our findings on the augmentation or diminution of the nystagmic frequential plateau in different positions, and we find an optimal response in a position that corresponds with a traction on the otoliths and a minimal response in a position that corresponds with a pressure on them, as well in the frontal plane as in the sagittal plane. These results cannot be explained without a saccular and utricular otolith action.
Studies on the Ototoxicity of Kanamycin
Authors: Ouchi J. , Ohtani I.
Published: January 2010

The serial observations of the onset and progression of kanamycin-induced cochlear functional damage and the histopathological examinations were carried out by the use of the rabbits with electrodes permanently implanted on the round windows. There are wide variations of cochlea on the response to drug administration both electrophysiologically and histopathologically. But we can find out that there is a certain interesting correlation between them. That is, group A which showed a reduction of maximum CM amplitude soon after the start of drug schedule and was followed by a gentle slope until the CM came to low voltage, revealed histopathologically the damage of the outer hair cells and the supporting cells. On the other hand, group B showed a reduction of maximum CM amplitude at the later stage and thereafter showed the rapid disappearance of CM without any gentle slope, revealed selectively the damage of the outer hair cells. As to three animals which showed the curves of CM lying between group A and group B (group C), two of them were similar in histopathological change to group A, and the third similar to group B. The above-mentioned fact suggests that the functional changes and the morphological damages vary with the individual susceptibility of cochlea to the drug, having a close correlation with each other, even under the same experimental conditions. It fells us that the individual variation of cochlea in functional or morphological susceptibility to the drug should not be neglected in the course of an animal experiment designed to examine the ototoxic effect of drug.