bluuebunny/crossref_metadata_2025 huggingface dataset:
NEDD9 Promotes Oncogenic Signaling in Mammary Tumor Development
Authors: Izumchenko Eugene , Singh Mahendra K. , Plotnikova Olga V. , Tikhmyanova Nadezhda , Little Joy L. , Serebriiskii Ilya G. , Seo Sachiko , Kurokawa Mineo , Egleston Brian L. , Klein-Szanto Andres , Pugacheva Elena N. , Hardy Richard R. , Wolfson Marina , Connolly Denise C. , Golemis Erica A.
Published: September 2009

In the past 3 years, altered expression of the HEF1/CAS-L/NEDD9 scaffolding protein has emerged as contributing to cancer metastasis in multiple cancer types. However, whereas some studies have identified elevated NEDD9 expression as prometastatic, other work has suggested a negative role in tumor progression. We here show that the Nedd9-null genetic background significantly limits mammary tumor initiation in the MMTV-polyoma virus middle T genetic model. Action of NEDD9 is tumor cell intrinsic, with immune cell infiltration, stroma, and angiogenesis unaffected. The majority of the late-appearing mammary tumors of MMTV-polyoma virus middle T;Nedd9−/− mice are characterized by depressed activation of proteins including AKT, Src, FAK, and extracellular signal-regulated kinase, emphasizing an important role of NEDD9 as a scaffolding protein for these prooncogenic proteins. Analysis of cells derived from primary Nedd9+/+ and Nedd9−/− tumors showed persistently reduced FAK activation, attachment, and migration, consistent with a role for NEDD9 activation of FAK in promoting tumor aggressiveness. This study provides the first in vivo evidence of a role for NEDD9 in breast cancer progression and suggests that NEDD9 expression may provide a biomarker for tumor aggressiveness. [Cancer Res 2009;69(18):7198–206]
Anticancer Activity of CX-3543: A Direct Inhibitor of rRNA Biogenesis
Authors: Drygin Denis , Siddiqui-Jain Adam , O'Brien Sean , Schwaebe Michael , Lin Amy , Bliesath Josh , Ho Caroline B. , Proffitt Chris , Trent Katy , Whitten Jeffrey P. , Lim John K. C. , Von Hoff Daniel , Anderes Kenna , Rice William G.
Published: September 2009

Hallmark deregulated signaling in cancer cells drives excessive ribosome biogenesis within the nucleolus, which elicits unbridled cell growth and proliferation. The rate-limiting step of ribosome biogenesis is synthesis of rRNA (building blocks of ribosomes) by RNA Polymerase I (Pol I). Numerous kinase pathways and products of proto-oncogenes can up-regulate Pol I, whereas tumor suppressor proteins can inhibit rRNA synthesis. In tumorigenesis, activating mutations in certain cancer-associated kinases and loss-of-function mutations in tumor suppressors lead to deregulated signaling that stimulates Pol I transcription with resultant increases in ribosome biogenesis, protein synthesis, cell growth, and proliferation. Certain anticancer therapeutics, such as cisplatin and 5-fluorouracil, reportedly exert, at least partially, their activity through disruption of ribosome biogenesis, yet many prime targets for anticancer drugs within the ribosome synthetic machinery of the nucleolus remain largely unexploited. Herein, we describe CX-3543, a small molecule nucleolus-targeting agent that selectively disrupts nucleolin/rDNA G-quadruplex complexes in the nucleolus, thereby inhibiting Pol I transcription and inducing apoptosis in cancer cells. CX-3543 is the first G-quadruplex interactive agent to enter human clinical trials, and it is currently under evaluation against carcinoid/neuroendocrine tumors in a phase II clinical trial. [Cancer Res 2009;69(19):7653–61]
miR-21: An Androgen Receptor–Regulated MicroRNA that Promotes Hormone-Dependent and Hormone-Independent Prostate Cancer Growth
Authors: Ribas Judit , Ni Xiaohua , Haffner Michael , Wentzel Erik A. , Salmasi Amirali Hassanzadeh , Chowdhury Wasim H. , Kudrolli Tarana A. , Yegnasubramanian Srinivasan , Luo Jun , Rodriguez Ron , Mendell Joshua T. , Lupold Shawn E.
Published: September 2009

Androgen receptor (AR)–mediated oncogenic pathways have not been fully elucidated. In this study, we used high-throughput microarray analysis on two AR-positive prostate cancer (CaP) cell lines to identify 16 AR-responsive microRNAs (miRNA). We focused on miR-21 because of its previously reported oncogenic activity in other cancers. We show androgen-induced AR binding to the defined miR-21 promoter, miPPR-21, suggesting direct transcriptional regulation. Inhibition of miR-21 diminished androgen-induced CaP cell proliferation, providing new evidence that miRNAs can contribute to androgen-driven cell growth. Elevated expression of miR-21 enhanced CaP tumor growth in vivo and, surprisingly, was sufficient for androgen-dependent tumors to overcome castration-mediated growth arrest. Thus, elevated miR-21 expression alone is sufficient to impart castration resistance. Moreover, quantitative reverse transcription-PCR analysis revealed elevated miR-21 expression in CaP when compared with adjacent normal tissue. These results suggest that miR-21 may contribute to CaP pathogenesis. [Cancer Res 2009;69(18):7165–9]
Antitumor Immunity Can Be Uncoupled from Autoimmunity following Heat Shock Protein 70–Mediated Inflammatory Killing of Normal Pancreas
Authors: Kottke Timothy , Pulido Jose , Thompson Jill , Sanchez-Perez Luis , Chong Heung , Calderwood Stuart K. , Selby Peter , Harrington Kevin , Strome Scott E. , Melcher Alan , Vile Richard G.
Published: September 2009

We have a long-term interest in the connectivity between autoimmunity and tumor rejection. However, outside of the melanocyte/melanoma paradigm, little is known about whether autoimmune responses to normal tissue can induce rejection of tumors of the same histologic type. Here, we induced direct, pathogen-like cytotoxicity to the normal pancreas in association with the immune adjuvant heat shock protein 70. In sharp contrast to our studies with a similar approach for the treatment of prostate cancer, inflammatory killing of the normal pancreas induced a Th1-like, anti-self-response to pancreatic antigens, which was rapidly suppressed by a concomitant suppressive regulatory T cell (Treg) response. Interestingly, even when Treg cells were depleted, the Th1-like response was insufficient to induce significant ongoing autoimmunity. However, the Th1-like response to antigens expressed in the pancreas at the time of damage was sufficient to induce rejection of tumors expressing either a foreign (ova) antigen or fully syngeneic tumor antigens (on Panc02 tumor cells), provided that Treg were depleted before inflammatory killing of the normal pancreas. Taken together, these data indicate that profound differences exist between the immunoprotective mechanisms in place between different tissues (pancreas and prostate) in their response to pathogen-like damage. Moreover, they also show that, although multiple layers of immunologic safeguards are in place to prevent the development of severe autoimmune consequences in the pancreas (in contrast to the prostate), tumor rejection responses can still be decoupled from pathologic autoimmune responses in vivo, which may provide novel insights into the immunotherapeutic treatment of pancreatic cancer. [Cancer Res 2009;69(19):7767–74]
Epithelial-Mesenchymal Transition and Cell Cooperativity in Metastasis
Authors: Tsuji Takanori , Ibaragi Soichiro , Hu Guo-fu
Published: September 2009

The role of epithelial-mesenchymal transition (EMT) in metastasis remains controversial. EMT has been postulated as an absolute requirement for tumor invasion and metastasis. Three different models including incomplete EMT, mesenchymal-epithelial transition (MET), and collective migration have been proposed for the role of EMT in cancer invasion and metastasis. However, skepticism remains about whether EMT truly occurs during cancer progression, and if it does, whether it plays an indispensible role in metastasis. Our recent findings suggest that EMT cells are responsible for degrading the surrounding matrix to enable invasion and intravasation of both EMT and non-EMT cells. Only non-EMT cells that have entered the blood stream are able to re-establish colonies in the secondary sites. Here, we discuss an alternative model for the role of EMT in cancer metastasis in which EMT and non-EMT cells cooperate to complete the entire process of spontaneous metastasis. [Cancer Res 2009;69(18):7135–9]
Glomus Tumors in Neurofibromatosis Type 1: Genetic, Functional, and Clinical Evidence of a Novel Association
Authors: Brems Hilde , Park Caroline , Maertens Ophélia , Pemov Alexander , Messiaen Ludwine , Upadhyaya Meena , Claes Kathleen , Beert Eline , Peeters Kristel , Mautner Victor , Sloan Jennifer L. , Yao Lawrence , Lee Chyi-Chia Richard , Sciot Raf , De Smet Luc , Legius Eric , Stewart Douglas R.
Published: September 2009

Neurofibromatosis type 1 (NF1) is a common disorder that arises secondary to mutations in the tumor suppressor gene NF1. Glomus tumors are small, benign but painful tumors that originate from the glomus body, a thermoregulatory shunt concentrated in the fingers and toes. We report 11 individuals with NF1 who harbored 20 glomus tumors of the fingers and 1 in the toe; 5 individuals had multiple glomus tumors. We hypothesized that biallelic inactivation of NF1 underlies the pathogenesis of these tumors. In 12 NF1-associated glomus tumors, we used cell culture and laser capture microdissection to isolate DNA. We also analyzed two sporadic (not NF1-associated) glomus tumors. Genetic analysis showed germ line and somatic NF1 mutations in seven tumors. RAS mitogen-activated protein kinase hyperactivation was observed in cultured NF1−/− glomus cells, reflecting a lack of inhibition of the pathway by functional neurofibromin, the protein product of NF1. No abnormalities in NF1 or RAS mitogen-activated protein kinase activation were found in sporadic glomus tumors. By comparative genomic hybridization, we observed amplification of the 3′-end of CRTAC1 and a deletion of the 5′-end of WASF1 in two NF1-associated glomus tumors. For the first time, we show that loss of neurofibromin function is crucial in the pathogenesis of glomus tumors in NF1. Glomus tumors of the fingers or toes should be considered as part of the tumor spectrum of NF1. [Cancer Res 2009;69(18):7393–401]
Platelet-Derived Transforming Growth Factor-β Down-Regulates NKG2D Thereby Inhibiting Natural Killer Cell Antitumor Reactivity
Authors: Kopp Hans-Georg , Placke Theresa , Salih Helmut Rainer
Published: September 2009

Natural killer (NK) cells play an important role in cancer immunosurveillance and may prevent tumor progression and metastasis due to their ability to mediate direct cellular cytotoxicity and by releasing immunoregulatory cytokines, which shape adaptive immune responses. Their reactivity is governed by various activating and inhibitory molecules expressed on target cells and reciprocal interactions with other hematopoietic cells such as dendritic cells. In mice, thrombocytopenia inhibits metastasis, and this is reversed by NK cell depletion, suggesting that platelets are an important additional player in NK cell-tumor interaction. Moreover, it has been shown that metastasizing tumor cells do not travel through the blood alone but are rapidly coated by platelets. However, the knowledge about the molecular mechanisms by which platelets influence NK cells is fragmentary at best. Here we show that platelet-derived soluble factors, secreted on coating of tumor cells or after stimulation with classic platelet agonists, impair NK cell antitumor reactivity resulting in diminished granule mobilization, cytotoxicity, and IFN-γ production. The impaired NK cell reactivity was not due to induction of apoptosis but mediated by down-regulation of the activating immunoreceptor natural killer group 2, member D (NKG2D) on NK cells by platelet-derived transforming growth factor β (TGF-β). Neutralization of TGF-β in platelet releasate not only prevented NKG2D down-regulation but also restored NK cell antitumor reactivity. Thus, our data elucidate the molecular basis of the previously described influence of platelets on NK cell antitumor reactivity and suggest that therapeutic intervention in tumor cell-platelet interaction and the resulting TGF-β release by platelets may serve to enhance antitumor immunity. [Cancer Res 2009;69(19):7775–83]
Inhibition of ALK Signaling for Cancer Therapy
Authors: Mossé Yael P. , Wood Andrew , Maris John M.
Published: September 2009

Paradigm shifting advances in cancer can occur after discovering the key oncogenic drivers of the malignant process, understanding their detailed molecular mechanisms, and exploiting this transdisciplinary knowledge therapeutically. A variety of human malignancies have anaplastic lymphoma kinase (ALK) translocations, amplifications, or oncogenic mutations, including anaplastic large cell lymphoma, inflammatory myofibroblastic tumors, non–small cell lung cancer, and neuroblastoma. This finding has focused intense interest in inhibiting ALK signaling as an effective molecular therapy against diseases with ALK-driven pathways. Recent progress in the elucidation of the major canonical signaling pathways postulated to be activated by NPM-ALK signaling has provided insight into which pathways may present a rational therapeutic approach. The identification of the downstream effector pathways controlled by ALK should pave the way for the rational design of ALK-inhibition therapies for the treatment of a subset of human cancers that harbor ALK aberrations. (Clin Cancer Res 2009;15(18):5609–14)
Immunotherapy of Metastatic Melanoma Using Genetically Engineered GD2-Specific T cells
Authors: Yvon Eric , Del Vecchio Michele , Savoldo Barbara , Hoyos Valentina , Dutour Aurélie , Anichini Andrea , Dotti Gianpietro , Brenner Malcolm K.
Published: September 2009

Purpose: Genetic engineering of human T lymphocytes to express tumor-directed chimeric antigen receptors (CAR) can produce antitumor effector cells that bypass tumor immune escape mechanisms that are due to abnormalities in protein-antigen processing and presentation. Moreover, these transgenic receptors can be directed to tumor-associated antigens that are not protein-derived, such as the ganglioside GD2, which is expressed in a high proportion of melanoma cells.

Experimental Design: We generated chimeric T cells specific for the ganglioside GD2 by joining an extracellular antigen-binding domain derived from the GD2-specific antibody sc14.G2a to cytoplasmic signaling domains derived from the T-cell receptor ζ-chain, with the endodomains of the costimulatory molecules CD28 and OX40. We expressed this CAR in human T cells and assessed the targeting of GD2-positive melanoma tumors in vitro and in a murine xenograft.

Results: Upon coincubation with GD2-expressing melanoma cells, CAR-GD2 T lymphocytes incorporating the CD28 and OX40 endodomains secreted significant levels of cytokines in a pattern comparable with the cytokine response obtained by engagement of the native CD3 receptor. These CAR-T cells had antimelanoma activity in vitro and in our xenograft model, increasing the survival of tumor-bearing animals.

Conclusion: Redirecting human T lymphocytes to the tumor-associated ganglioside GD2 generates effector cells with antimelanoma activity that should be testable in subjects with disease. (Clin Cancer Res 2009;15(18):5852–60)
Clinical and Biological Significance of CDK4 Amplification in Well-Differentiated and Dedifferentiated Liposarcomas
Authors: Italiano Antoine , Bianchini Laurence , Gjernes Elisabet , Keslair Frédérique , Ranchere-Vince Dominique , Dumollard Jean-Marc , Haudebourg Juliette , Leroux Agnès , Mainguené Claire , Terrier Philippe , Chibon Frédéric , Coindre Jean-Michel , Pedeutour Florence
Published: September 2009

Purpose: The MDM2 and HMGA2 genes are consistently amplified in well-differentiated/dedifferentiated liposarcomas (WDLPS/DDLPS) whereas CDK4 is frequently but not always amplified in these tumors. Our goal was to determine whether the absence of CDK4 amplification was (a) correlated to a specific clinico-histopathologic profile; and (b) compensated by another genomic anomaly involving the CCND1/CDK4/P16INK4a/RB1/E2F pathway.

Experimental Design: We compared the clinical characteristics of a series of 143 WDLPS/DDLPS with amplification of both MDM2 and CDK4 (MDM2+/CDK4+) to a series of 45 WDLPS/DDLPS with MDM2 amplification and no CDK4 amplification (MDM2+/CDK4-). We used fluorescence in situ hybridization, real time quantitative reverse transcription PCR, and immunohistochemistry to explore the status of CCND1, P16INK4a, P14ARF, and RB1.

Results: We found that MDM2+/CDK4- WDLPS/DDLPS represent a distinct clinical subgroup with favorable prognostic features, including low-grade lipoma-like histology, peripheral location, and lower rate of recurrence. By using fluorescence in situ hybridization, we found that genomic aberrations expected to be alternative mechanisms for compensating the lack of CDK4 amplification, such as RB1 and CDKN2A deletions or CCND1 amplification, were very uncommon. In contrast, by using real time quantitative reverse transcription PCR and immunohistochemistry, we observed that overexpression of P16INK4a (and P14ARF) and CCND1 and reduced expression of RB1 were very frequent, independently of the CDK4 status.

Conclusions: Our results underscore the complex coordinated regulation of the RB and p53 growth-control pathways in WDLPS/DDLPS. Because the absence of CDK4 amplification is not specifically counterbalanced by a genomic alteration of the CCND1/CDK4/P16INK4a/RB1/E2F pathway, CDK4 amplification may only represent a “MDM2-HMGA2-helper” in WDLPS/DDLPS tumorigenesis. (Clin Cancer Res 2009;15(18):5696–703)
A Multi-Institutional Phase II Study of the Efficacy and Tolerability of Lapatinib in Patients with Advanced Hepatocellular Carcinomas
Authors: Bekaii-Saab Tanios , Markowitz Joseph , Prescott Nichole , Sadee Wolfgang , Heerema Nyla , Wei Lai , Dai Zunyan , Papp Audrey , Campbell Angela , Culler Kristy , Balint Catherine , O'Neil Bert , Lee Ruey-min , Zalupski Mark , Dancey Janet , Chen Helen , Grever Michael , Eng Charis , Villalona-Calero Miguel
Published: September 2009

Background: Hepatocellular carcinoma (HCC) is on the rise worldwide. HCC responds poorly to chemotherapy. Lapatinib is an inhibitor of epidermal growth factor receptor and HER2/NEU both implicated in hepatocarcinogenesis. This trial was designed to determine the safety and efficacy of lapatinib in HCC.

Methods: A Fleming phase II design with a single stage of 25 patients with a 90% power to exclude a true response rate of <10% and detect a true response rate of ≥30% was used. The dose of lapatinib was 1,500 mg/day administered orally in 28-day cycles. Tumor and blood specimens were analyzed for expression of HER2/NEU/CEP17 and status of downstream signal pathway proteins.

Results: Twenty-six patients with HCC enrolled on this study. Nineteen percent had one prior therapy. Most common toxicities were diarrhea (73%), nausea (54%), and rash (42%). No objective responses were observed. Ten (40%) patients had stable disease as their best response including six (23%) with stable disease lasting >120 days. Median progression-free survival was 1.9 months and median overall survival was 12.6 months. Patients who developed a rash had a borderline statistically significant longer survival. Tissue and blood specimens were available on >90% of patients. No somatic mutations in EGFR (exons 18-21) were found. In contrast to our previous findings, we did not find evidence of HER2/NEU somatic mutations. PTEN, P-AKT, and P70S6K expression did not correlate with survival.

Conclusions: Lapatinib is well-tolerated but seems to benefit only a subgroup of patients for whom predictive molecular or clinical characteristics are not yet fully defined. (Clin Cancer Res 2009;15(18):5895–901)
Progesterone Inhibition of Wnt/β-Catenin Signaling in Normal Endometrium and Endometrial Cancer
Authors: Wang Yongyi , Hanifi-Moghaddam Payman , Hanekamp Eline E. , Kloosterboer Helenius J. , Franken Patrick , Veldscholte Jos , van Doorn Helena C. , Ewing Patricia C. , Kim J. Julie , Grootegoed J. Anton , Burger Curt W. , Fodde Riccardo , Blok Leen J.
Published: September 2009

Purpose. Wnt signaling regulates the fine balance between stemness and differentiation. Here, the role of Wnt signaling to maintain the balance between estrogen-induced proliferation and progesterone-induced differentiation during the menstrual cycle, as well as during the induction of hyperplasia and carcinogenesis of the endometrium, was investigated.

Experimental Design: Endometrial gene expression profiles from estradiol (E2) and E2 + medroxyprogesterone acetate–treated postmenopausal patients were combined with profiles obtained during the menstrual cycle (PubMed; GEO DataSets). Ishikawa cells were transfected with progesterone receptors and Wnt inhibitors dickkopf homologue 1 (DKK1) and forkhead box O1 (FOXO1), measuring Wnt activation. Expression of DKK1 and FOXO1 was inhibited by use of sequence-specific short hairpins. Furthermore, patient samples (hormone-treated endometria, hyperplasia, and endometrial cancer) were stained for Wnt activation using nuclear β-catenin and CD44.

Results: In vivo, targets and components of the Wnt signaling pathway (among them DKK1 and FOXO1) are regulated by E2 and progesterone. In Wnt-activated Ishikawa cells, progesterone inhibits Wnt signaling by induction of DKK1 and FOXO1. Furthermore, using siRNA-mediated knockdown of both DKK1 and FOXO1, progesterone inhibition of Wnt signaling was partly circumvented. Subsequently, immunohistochemical analysis of the Wnt target gene CD44 showed that progesterone acted as an inhibitor of Wnt signaling in hyperplasia and in well-differentiated endometrial cancer.

Conclusion: Progesterone induction of DKK1 and FOXO1 results in inhibition of Wnt signaling in the human endometrium. This Wnt inhibitory effect of progesterone is likely to play a rate-limiting role in the maintenance of endometrial homeostasis and, on its loss, in tumor onset and progression toward malignancy. (Clin Cancer Res 2009;15(18):5784–93)
Serine Protease Inhibitor Kazal Type 1 Promotes Proliferation of Pancreatic Cancer Cells through the Epidermal Growth Factor Receptor
Authors: Ozaki Nobuyuki , Ohmuraya Masaki , Hirota Masahiko , Ida Satoshi , Wang Jun , Takamori Hiroshi , Higashiyama Shigeki , Baba Hideo , Yamamura Ken-ichi
Published: September 2009

Serine protease inhibitor, Kazal type 1 (SPINK1) is expressed not only in normal human pancreatic acinar cells but also in a variety of pancreatic ductal neoplasms. There are structural similarities between SPINK1 and epidermal growth factor (EGF). Hence, we hypothesized that SPINK1 binds to EGF receptor (EGFR) to activate its downstream signaling. We first showed that SPINK1 induced proliferation of NIH 3T3 cells and pancreatic cancer cell lines. We showed that SPINK1 coprecipitated with EGFR in an immunoprecipitation experiment and that the binding affinity of SPINK1 to EGFR was about half of that of EGF using quartz-crystal microbalance (QCM) technique. As expected, EGFR and its downstream molecules, signal transducer and activator of transcription 3, v-Akt murine thymoma viral oncogene homologue, and extracellular signal-regulated kinase 1/2, were phosphorylated by SPINK1 as well as EGF. To determine which pathway is the most important for cell growth, we further analyzed the effect of inhibitors. Growth stimulation by EGF or SPINK1 was completely inhibited by EGFR and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase inhibitor but not by Janus-activated kinase and phosphoinositide 3-kinase inhibitors. To further analyze the clinical importance of SPINK1 in the development of pancreatic cancer, we examined the expression of SPINK1 and EGFR in pancreatic tubular adenocarcinomas and pancreatic intraepithelial neoplasm. Both SPNK1 and EGFR were coexpressed not only in the early stage of cancer, PanIN-1A, but also in advanced stages. Taken together, these results suggest that SPINK1 stimulates the proliferation of pancreatic cancer cells through the EGFR/mitogen-activated protein kinase cascade. (Mol Cancer Res 2009;7(9):1572–81)
Bcl-2 Modulation to Activate Apoptosis in Prostate Cancer
Authors: Bray Kevin , Chen Hsin-Yi , Karp Cristina M. , May Michael , Ganesan Shridar , Karantza-Wadsworth Vassiliki , DiPaola Robert S. , White Eileen
Published: September 2009

Apoptosis resistance is a hallmark of cancer linked to disease progression and treatment resistance, which has led to the development of anticancer therapeutics that restore apoptotic function. Antiapoptotic Bcl-2 is frequently overexpressed in refractory prostate cancer and increased following standard hormonal therapy and chemotherapy; however, the rationally designed Bcl-2 antagonist, ABT-737, has not shown single agent apoptosis-promoting activity against human prostate cancer cell lines. This is likely due to the coordinate expression of antiapoptotic, Bcl-2–related Mcl-1 that is not targeted by ABT-737. We developed a mouse model for prostate cancer in which apoptosis resistance and tumorigenesis were conferred by Bcl-2 expression. Combining ABT-737 with agents that target Mcl-1 sensitized prostate cancer cell lines with an apoptotic block to cell death in vitro. In mice in vivo, ABT-737 showed single agent efficacy in prostate tumor allografts in which tumor cells are under hypoxic stress. In human prostate cancer tissue, examined using a novel tumor explant system designated Tumor Tissue Assessment for Response to Chemotherapy, combination chemotherapy promoted efficient apoptosis. Thus, rational targeting of both the Bcl-2 and Mcl-1 mechanisms of apoptosis resistance may be therapeutically advantageous for advanced prostate cancer. (Mol Cancer Res 2009;7(9):1487–96)
Effects of Oral Contraceptives or a Gonadotropin-Releasing Hormone Agonist on Ovarian Carcinogenesis in Genetically Engineered Mice
Authors: Romero Iris L. , Gordon Ilyssa O. , Jagadeeswaran Sujatha , Mui Keeley L. , Lee Woo Seok , Dinulescu Daniela M. , Krausz Thomas N. , Kim Helen H. , Gilliam Melissa L. , Lengyel Ernst
Published: September 2009

Although epidemiologic evidence for the ability of combined oral contraception (OC) to reduce the risk of ovarian cancer (OvCa) is convincing, the biological mechanisms underlying this effect are largely unknown. We conducted the present study to determine if OC also influences ovarian carcinogenesis in a genetic mouse model and, if so, to investigate the mechanism underlying the protective effect. LSL-K-rasG12D/+PtenloxP/loxP mice were treated with ethinyl estradiol plus norethindrone, contraceptive hormones commonly used in combined OC, or norethindrone alone, or a gonadotropin-releasing hormone agonist. The combined OC had a 29% reduction in mean total tumor weight compared with placebo (epithelial tumor weight, −80%). Norethindrone alone reduced mean total tumor weight by 42% (epithelial tumor weight, −46%), and the gonadotropin-releasing hormone agonist increased mean total tumor weight by 71% (epithelial tumor weight, +150%). Large variations in tumor size affected the P values for these changes, which were not statistically significant. Nonetheless, the OC reductions are consistent with the epidemiologic data indicating a protective effect of OC. Matrix metalloproteinase-2 activity was decreased in association with OC, indicating that OC may affect ovarian carcinogenesis by decreasing proteolytic activity, an important early event in the pathogenesis of OvCa. In contrast, OC increased invasion in a K-ras/Pten OvCa cell line established from the mouse tumors, suggesting that OC hormones, particularly estrogen, may have a detrimental effect after the disease process is under way. Our study results support further investigation of OC effects and mechanisms for OvCa prevention.
Role of Cyclooxygenase-2 in Tumor Progression and Survival of Head and Neck Squamous Cell Carcinoma
Authors: Saba Nabil F. , Choi Misun , Muller Susan , Shin Hyung Ju C. , Tighiouart Mourad , Papadimitrakopoulou Vassiliki A. , El-Naggar Adel K. , Khuri Fadlo R. , Chen Zhuo Georgia , Shin Dong M.
Published: September 2009

Inhibition of cyclooxygenase-2 (COX-2) pathways may have significant implications for the prevention and treatment of head and neck squamous cell carcinoma (HNSCC). COX-2 is overexpressed in both premalignant lesions and invasive HNSCC. We examined COX-2 expression by immunohistochemistry in normal tissues, different stages of premalignant lesions, and carcinoma in situ (CIS). We also evaluated the correlation between COX-2 expression and clinical characteristics of HNSCC patients. Tissue specimens were obtained from the following: premalignant lesions from 25 subjects enrolled in a biochemoprevention trial, tumor samples collected at diagnosis from 38 HNSCC patients enrolled in an induction chemotherapy trial, and normal control tissues from 10 noncancer, nonsmoking subjects. COX-2 was expressed in early and intermediate stages of premalignant lesions, increasing first in the basal and parabasal layers, then lower spinous, and upper spinous layers. This correlation was noted in normal epithelium (P < 0.0001), histologically normal in-field samples (P < 0.0001), low-grade dysplasia (P = 0.024), and moderate-grade dysplasia (P = 0.009), but was lost in the majority of high-grade dysplasia/CIS (P = 0.896). COX-2 expression was also noted to increase progressively through the early stages of premalignancy, and to decrease in severe/CIS stage and invasive carcinoma. COX-2 expression in tumors from patients treated with induction chemotherapy was correlated with overall survival after controlling for clinical variables. These findings elucidate the differential expression pattern of COX-2 in stages of head and neck premalignant lesions and invasive carcinoma, supporting the rationale for COX-2 inhibition as an important strategy for cancer chemoprevention. Further validation of COX-2 expression is needed in prospective ongoing chemoprevention trials.
The Number of Stroke Physicians Is the Key to Preparing IV rt-PA
Authors: Iguchi Yasuyuki , Kimura Kazumi , Shibazaki Kensaku , Aoki Junya
Published: September 2009

Background: Our aim was to investigate the relationship between the number of stroke physicians (SPs) and management of intravenous thrombolysis using recombinant tissue plasminogen activator (IV rt-PA) in Japan. Methods: Questionnaires about the infrastructure of acute-stroke care were sent to 1,466 hospitals that treated acute-stroke patients in September 2007. The responses were categorized as follows: (1) established or ineligible for IV rt-PA before September 2007, and discontinued or starting IV rt-PA from October 2007 to September 2008; (2) total number of SPs in those hospitals; (3) infrastructures according to acute-stroke treatment. Components related to discontinuing or starting IV rt-PA were analyzed. Results: Responses were received from 1,025 hospitals. Of these, 950 hospitals were continuing administration to acute-stroke patients, but 75 had discontinued administration. Before September 2007, 466 hospitals had already established administration of IV rt-PA (rt-PA hospitals) after government approval of IV rt-PA (non-rt-PA hospitals). From October 2007 to September 2008, 45 of 466 rt-PA hospitals (9.7%) discontinued IV rt-PA, while 29 of 479 (6.1%) non-rt-PA hospitals started. Less than 3 SPs were present in 73.9% of the 45 discontinued IV rt-PA hospitals and 37.9% of the 29 starting hospitals. In multivariate analysis, discontinuing IV rt-PA was inversely associated with ≥3 SPs (odds ratio = 0.37; 95% confidence interval = 0.15–0.87; p = 0.023). Factors associated with starting IV rt-PA were ≥3 SPs (OR = 6.19; 95% CI = 2.01–19.08; p = 0.002). Conclusions: The number of SPs available may contribute to the management of rt-PA hospitals.
Effects of Simvastatin on Plasma Lipoproteins and Hearing Loss in Apolipoprotein E Gene-Deficient Mice
Authors: Cai Qing , Du Xiaoping , Zhou Bin , Cai Chun , Kermany Mohammand Habiby , Zhang Chunxiang , Yoo Taijune
Published: September 2009

Apolipoprotein E (ApoE) gene knockout (KO) mice develop hearing loss, as well as hair cell damage in the inner ear. Furthermore, the hearing loss and hair cell damage may be caused and exacerbated by hyperlipidemia and atherosclerosis. We are therefore seeking an effective treatment to protect the inner ear in ApoE-KO mice. ApoE-KO mice fed with an atherosclerotic diet were treated with simvastatin or with Strauss Heartdrops. The auditory brainstem responses were recorded, and plasma lipid levels and inner ear histology were examined. ApoE-KO and wild-type C57BL/6J mice fed with a normal chow diet served as controls. Compared to ApoE-KO mice fed only the atherosclerotic diet, ApoE-KO mice treated with simvastatin had no significant hearing loss and less severe atherosclerosis and hair cell damage in the inner ear. However, ApoE-KO mice treated with Strauss Heartdrops developed significant hearing loss and severe atherosclerosis and hair cell damage in the inner ear. These results demonstrate that statins may prevent hearing loss and inner ear damage in ApoE-KO mice by reducing the atherosclerotic lesions and levels of glucose, cholesterol, low-density lipoprotein, and triglyceride. Statins could be used to treat hearing loss associated with hyperlipidemia.
Current Treatments of Alzheimer Disease: Are Main Caregivers Satisfied with the Drug Treatments Received by Their Patients?
Authors: Sevilla C. , Jiménez Caballero P.E. , Alfonso V. , González-Adalid M.
Published: September 2009

Background/Aims: A full comparison of the satisfaction with treatment using the current Alzheimer’s disease (AD) therapies from the perspective of caregivers has not yet been done. The aim of this study was thus to find out the degree of satisfaction with the main available drug treatments in monotherapy for AD from this point of view. Methods: A cross-sectional, multicentre study of patients with possible/probable AD according to DSM-IV/NINCDS-ADRDA criteria, on monotherapy with donepezil, galantamine, rivastigmine or memantine, was carried out. Treatment satisfaction was measured by a caregiver proxy-administration of the generic SATMED-Q questionnaire [range: 0 (not satisfied at all) to 100 (totally satisfied)], overall and in 6 domains: tolerability, efficacy, medical care, ease and convenience, impact on daily activities and overall satisfaction. Results: A total of 829 patients were included: 63.3% women, aged 78.2 ± 6.8 years; 546 (67.3%) on donepezil, 106 (13.1%) on rivastigmine, 99 (12.2%) on galantamine and 60 (7.4%) on memantine. SATMED-Q scores p values were adjusted by MMSE and treatment duration. Caregivers of patients on donepezil showed significantly higher SATMED-Q total (71.8 ± 12.3; p < 0.05) and overall satisfaction domain scores (81.6 ± 18.4; p < 0.01) than those of patients on any other drugs, as well as significantly higher ease and convenience of use domain (81.5 ± 17.4; p < 0.01) and undesirable effects domain (96.0 ± 12.9; p < 0.05) scores than those of rivastigmine- and galantamine-treated patients. Of the caregivers of donepezil-treated patients, 76.7% were satisfied with treatment versus 68.7, 61.4 and 46.7% of those caregivers whose patients were treated with galantamine, rivastigmine and memantine, respectively (p = 0.0002). Conclusion: Caregivers of AD patients undergoing donepezil monotherapy seem to be more satisfied with treatment than those of patients receiving the other usual AD treatments in this study, particularly due to the ease and convenience of use of this drug. The higher level of satisfaction of these caregivers could be explained by the fact that, within the donepezil group, a high percentage of patients were treated with orally disintegrating tablets, which are easier for the patient to swallow.
Efficacy and Tolerability of Nonpenetrating Filtering Surgery in the Treatment of Open-Angle Glaucoma: A Meta-Analysis
Authors: Cheng Jin-Wei , Xi Gui-Lin , Wei Rui-Li , Cai Ji-Ping , Li You
Published: September 2009

Aims:To evaluate the efficacy and tolerability of nonpenetrating filtering surgery in the treatment of patients with open-angle glaucoma. Methods: Pertinent studies were selected by extensive searches. A total of 17 randomized controlled trials were included in the present meta-analysis. The main outcome measures were risk differences (RDs) of complete success for efficacy and postoperative complications for tolerability. Pooled estimates were computed according to a random-effects model. Results:Viscocanalostomy and deep sclerectomy were significantly less effective than tra- beculectomy, and pooled RDs of complete success were –0.16 (95% confidence interval, CI, –0.30 to –0.02) and –0.10 (–0.19 to 0.00). Deep sclerectomy plus mitomycin C (MMC) was also less effective than trabeculectomy plus MMC, with pooled RD of complete success being –0.16 (95% CI –0.32 to –0.01). Viscocanalostomy and deep sclerectomy caused main complications in fewer patients than trabeculectomy. Conclusions:Viscocanalostomy and deep sclerectomy were less effective than trabeculectomy in the treatment of open-angle glaucoma, and deep sclerectomy plus MMC was also less effective than trabeculectomy plus MMC. However, viscocanalostomy and deep sclerectomy were associated with fewer complications than trabeculectomy.
Clinical Features of Polypoidal Choroidal Vasculopathy and Visual Outcomes in the Absence of Classic Choroidal Neovascularization
Authors: Yamaoka Seijo , Okada Annabelle A. , Sugahara Michitaka , Hida Tetsuo
Published: September 2009

Background/Aims: To report on the clinical features of polypoidal choroidal vasculopathy (PCV) and to delineate visual outcomes in the absence of classic choroidal neovascularization (CNV). Methods: Records were retrospectively reviewed of 233 eyes of 215 patients diagnosed with ‘definite’ PCV using Japanese criteria. Results: Of patients with definite PCV, 72.1% were men and 91.6% had unilateral disease. A history of systemic hypertension was elicited in 18.1% of patients, and blood pressure measurement revealed possible hypertension in 27.4% of patients. At the initial evaluation, 28.3% of eyes had classic CNV as assessed by fluorescein angiography and were treated by photodynamic therapy or other means. Of 112 eyes with active exudation but no classic CNV and no recent decreased vision, best-corrected visual acuity (BCVA) at 3 months improved by ≧0.2 logarithm of the minimum angle of resolution (logMAR) in 17%, was unchanged in 72% and worsened by ≧0.2 logMAR in 11%. In 67 eyes of which 1-year data were available, BCVA improved in 19%, was unchanged in 64% and worsened in 16%. Conclusions: The majority of PCV patients were men, with a high rate of diagnosed or suspected hypertension. More than two thirds of eyes had no evidence of classic CNV, of which 89% had stable or improved vision at 3 months without specific treatment. Of eyes followed for 12 months, 83% had stable or improved vision.
A Critical Period in Cortical Interneuron Neurogenesis in Down Syndrome Revealed by Human Neural Progenitor Cells
Authors: Bhattacharyya Anita , McMillan Erin , Chen Serene I. , Wallace Kyle , Svendsen Clive N.
Published: September 2009

Down syndrome (DS) is a developmental disorder whose mental impairment is due to defective cortical development. Human neural progenitor cells (hNPCs) derived from fetal DS cortex initially produce normal numbers of neurons, but generate fewer neurons with time in culture, similar to the pattern of neurogenesis that occurs in DS in vivo. Microarray analysis of DS hNPCs at this critical time reveals gene changes indicative of defects in interneuron progenitor development. In addition, dysregulated expression of many genes involved in neural progenitor cell biology points to changes in the progenitor population and subsequent reduction in interneuron neurogenesis. Delineation of a critical period in interneuron development in DS provides a foundation for investigation of the basis of reduced neurogenesis in DS and defines a time when these progenitor cells may be amenable to therapeutic treatment.
Sleep Disorders in the Older Adult – A Mini-Review
Authors: Neikrug Ariel B. , Ancoli-Israel Sonia
Published: September 2009

Approximately 50% of older adults complain of difficulty sleeping. Poor sleep results in increased risk of significant morbidity and mortality. The decrements seen in the sleep of the older adult are often due to a decrease in the ability to get needed sleep. However, the decreased ability is less a function of age and more a function of other factors that accompany aging, such as medical and psychiatric illness, increased medication use, advances in the endogenous circadian clock and a higher prevalence of specific sleep disorders. Given the large number of older adults with sleep complaints and sleep disorders, there is a need for health care professionals to have an increased awareness of these sleep disturbances to better enable them to assess and treat these patients. A thorough sleep history (preferably in the presence of their bed partner) is required for a proper diagnosis, and when appropriate, an overnight sleep recording should be done. Treatment of primary sleep problems can improve the quality of life and daytime functioning of older adults. This paper reviews the diagnoses and characteristics of sleep disorders generally found in the older adult. While aimed at the practicing geriatrician, this paper is also of importance for any gerontologist interested in sleep.
A Reevaluation of Tetraploidy in the Alzheimer’s Disease Brain
Authors: Westra Jurjen W. , Barral Serena , Chun Jerold
Published: September 2009

Alzheimer’s disease (AD) is characterized by extensive neuronal death in distinct brain regions, including the frontal cortex and hippocampus, although the specific mechanisms of neuronal degeneration in AD remain a topic of intense scientific pursuit. One model for cell death in AD postulates that abortive cell cycle events in neurons, including tetraploidy, precede neuronal death, and novel therapeutics based on suppressing cell cycle re-entry are being pursued. Using DNA content fluorescence-activated cell sorting combined with fluorescence in situ hybridization and immunostaining, we analyzed neuronal nuclei from postmortem human brain samples from the frontal cortex and hippocampus of nondiseased and AD patients for evidence of tetraploidy. Here, we show that tetraploid nuclei are similarly prevalent in AD and control brains and are exclusively non-neuronal, contrasting with an absence of tetraploid neurons. Our findings demonstrate that neuronal tetraploidy is nonexistent in the AD brain and intimate a reevaluation of neuronal cell cycle re-entry as a therapeutic target for AD.
Antiarrhythmics After Ablation of Atrial Fibrillation (5A Study)
Authors: Roux Jean-François , Zado Erica , Callans David J. , Garcia Fermin , Lin David , Marchlinski Francis E. , Bala Rupa , Dixit Sanjay , Riley Michael , Russo Andrea M. , Hutchinson Mathew D. , Cooper Joshua , Verdino Ralph , Patel Vickas , Joy Parijat S. , Gerstenfeld Edward P.
Published: September 2009

Background—

Atrial arrhythmias are common early after atrial fibrillation (AF) ablation. We hypothesized that empirical antiarrhythmic drug (AAD) therapy for 6 weeks after AF ablation would reduce the occurrence of atrial arrhythmias.

Methods and Results—

We randomized consecutive patients with paroxysmal AF undergoing ablation to empirical antiarrhythmic therapy (AAD group) or no antiarrhythmic therapy (no-AAD group) for the first 6 weeks after ablation. In the no-AAD group, only atrioventricular nodal blocking agents were prescribed. All patients wore a transtelephonic monitor for 4 weeks after discharge and were reevaluated at 6 weeks. The primary end point of the study was a composite of (1) atrial arrhythmias lasting more than 24 hours; (2) atrial arrhythmias associated with severe symptoms requiring hospital admission, cardioversion, or initiation/change of antiarrhythmic drug therapy; and (3) intolerance to antiarrhythmic agent requiring drug cessation. Of 110 enrolled patients (age 55±9 years, 71% male), 53 were randomized to AAD and 57 to no-AAD. There was no difference in baseline characteristics between groups. During the 6 weeks after ablation, fewer patients reached the primary end point in the AAD compared with the no-AAD group (19% versus 42%;
P
=0.005). There remained fewer events in the AAD group (13% versus 28%;
P
=0.05) when only end points of AF >24 hours, arrhythmia-related hospitalization, or electrical cardioversion were compared.

Conclusions—

AAD treatment during the first 6 weeks after AF ablation is well tolerated and reduces the incidence of clinically significant atrial arrhythmias and need for cardioversion/hospitalization for arrhythmia management.
Improved Oral Anticoagulation After a Dietary Vitamin K–Guided Strategy
Authors: de Assis Michelli C. , Rabelo Eneida R. , Ávila Christiane W. , Polanczyk Carisi Anne , Rohde Luis E.
Published: September 2009

Background—

Dietary vitamin K is thought to be an important factor that interferes with anticoagulation stability, but the clinical applicability of this interaction has not been evaluated adequately in prospective studies.

Methods and Results—

In a randomized controlled trial that enrolled outpatients with a recent international normalized ratio (INR) outside the therapeutic target, we compared 2 strategies to optimize long-term oral anticoagulation: (1) a conventional approach based on changes in anticoagulant prescription and (2) a dietary vitamin K–guided strategy based on simple modifications of the amount of vitamin K–rich foods ingested per week. The primary efficacy end point was the percentage of patients who achieved a prespecified INR target at 90 days after randomization. Study population (n=132) predominantly included men with mechanical heart prostheses (58%) or atrial fibrillation (35%). Over time, patients allocated to the vitamin K–guided strategy reached the prespecified INR more frequently so that after 90 days of follow-up, 74% were on target compared with 58% of patients managed conventionally (
P
=0.04). Patients allocated to the dietary vitamin K–guided strategy had the same magnitude and direction of INR variation as those observed with the conventional approach in the short term (15 days) for both underanticaogulated and overanticoagulated patients. Minor bleeding or use of parenteral vitamin K were also marginally less frequent in patients managed according to the dietary intervention (1 [1.5%] versus 7 [11%];
P
=0.06).

Conclusions—

A vitamin K–guided management strategy to adjust long-term oral anticoagulation is feasible and safe and may result in an increased chance of reaching target levels of INR.