bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prevention of Progression in Monoclonal Gammopathy of Undetermined Significance
Authors: Rajkumar S. Vincent 
Published: September 2009

Abstract
Monoclonal gammopathy of undetermined significance (MGUS) is a common premalignant plasma cell proliferative disorder with a lifelong risk of progression to multiple myeloma. Because myeloma is an incurable malignancy, strategies to delay or prevent progression in high-risk patients are of considerable importance. (Clin Cancer Res 2009;15(18):5606–8)
Suberoylanilide hydroxamic acid sensitizes human oral cancer cells to TRAIL-induced apoptosis through increase DR5 expression
Authors: Yeh Cheng-Chang , Deng Yi-Ting , Sha De-Yuan , Hsiao Michael , Kuo Mark Yen-Ping 
Published: September 2009

Abstract
Suberoylanilide hydroxamic acid has been shown to selectively induce tumor apoptosis in cell cultures and animal models in several types of cancers and is about as a promising new class of chemotherapeutic agents. In addition, suberoylanilide hydroxamic acid showed synergistic anticancer activity with radiation, cisplatin, and tumor necrosis factor–related apoptosis–inducing ligand (TRAIL) in some cancers. Here, we report suberoylanilide hydroxamic acid also induced apoptosis in human oral cancer cells. Western blotting showed suberoylanilide hydroxamic acid increased Fas, Fas ligand, DR4, and DR5 protein expression and activated caspase-8 and caspase-9. The apoptosis was almost completely inhibited by caspase-8 inhibitor Z-IETD-FMK and attenuated by caspase-9 inhibitor Z-LEHD-FMK. Human recombinant DR5/Fc chimera protein but not Fas/Fc or DR4/Fc significantly inhibited apoptosis induced by suberoylanilide hydroxamic acid. These results suggest that suberoylanilide hydroxamic acid induces apoptosis mainly through activation of DR5/TRAIL death pathway. Furthermore, subtoxic concentrations of suberoylanilide hydroxamic acid sensitize two TRAIL resistant human oral cancer cells, SAS and Ca9-22, to exogenous recombinant TRAIL-induced apoptosis in a p53-independent manner. Combined treatment of suberoylanilide hydroxamic acid and TRAIL may be used as a new promising therapy for oral cancer. [Mol Cancer Ther 2009;8(9):2718–25]
Prx1 Enhances Androgen Receptor Function in Prostate Cancer Cells by Increasing Receptor Affinity to Dihydrotestosterone
Authors: Chhipa Rishi Raj , Lee Kwang-Soon , Onate Sergio , Wu Yue , Ip Clement 
Published: September 2009

Abstract
Androgen receptor (AR) signaling plays a critical role in the development and progression of prostate cancer. It has been reported previously that peroxiredoxin-1 (Prx1), a member of a novel family of peroxidases, interacts physically with AR to enhance AR transactivation of target genes. In the present study, we evaluated the biological significance of Prx1 in modulating dihydrotestosterone (DHT)-stimulated growth and AR target gene expression of prostate cancer cells. We also investigated the mechanism by which Prx1 might potentiate AR signaling. The contribution of Prx1 was assessed mainly by using the approach of stable Prx1 knockdown. The major observations are as follows: (a) A low level of Prx1 desensitizes cells to growth stimulation and AR target gene induction by DHT, such that exposure to a higher level of DHT is required to reach the same magnitude of response when Prx1 is depressed; (b) Prx1 increases the affinity of AR to DHT and decreases the rate of DHT dissociation from the occupied receptor; (c) Prx1 enhances the NH2 terminus and COOH terminus interaction of AR; a stronger N-C interaction is consistent with a more robust AR activation signal by keeping DHT tight in the ligand-binding pocket; (d) the stimulatory effects of Prx1 on AR ligand binding affinity and AR N-C interaction are manifested regardless of a wild-type or mutant AR. The above findings led us to believe that Prx1 may be a therapeutic target in blocking the transition of prostate cancer from an androgen-dependent to an androgen-refractory phenotype. (Mol Cancer Res 2009;7(9):1543–52)
Prevalence and Functional Analysis of Sequence Variants in the ATR Checkpoint Mediator Claspin
Authors: Zhang Jianmin , Song Young-Han , Brannigan Brian W. , Wahrer Doke C.R. , Schiripo Taryn A. , Harris Patricia L. , Haserlat Sara M. , Ulkus Lindsey E. , Shannon Kristen M. , Garber Judy E. , Freedman Matthew L. , Henderson Brian E. , Zou Lee , Sgroi Dennis C. , Haber Daniel A. , Bell Daphne W. 
Published: September 2009

Abstract
Mutational inactivation of genes controlling the DNA-damage response contributes to cancer susceptibility within families and within the general population as well as to sporadic tumorigenesis. Claspin (CLSPN) encodes a recently recognized mediator protein essential for the ATR and CHK1-dependent checkpoint elicited by replicative stress or the presence of ssDNA. Here, we describe a study to determine whether mutational disruption of CLSPN contributes to cancer susceptibility and sporadic tumorigenesis. We resequenced CLSPN from the germline of selected cancer families with a history of breast cancer (n = 25) or a multicancer phenotype (n = 46) as well as from a panel of sporadic cancer cell lines (n = 52) derived from a variety of tumor types. Eight nonsynonymous variants, including a recurrent mutation, were identified from the germline of two cancer-prone individuals and five cancer cell lines of breast, ovarian, and hematopoietic origin. None of the variants was present within population controls. In contrast, mutations were rare within genes encoding the CLSPN-interacting protein ATR and its binding partner ATRIP. One variant of CLSPN, encoding the I783S missense mutation, was defective in its ability to mediate CHK1 phosphorylation following DNA damage and was unable to rescue sensitivity to replicative stress in CLSPN-depleted cells. Taken together, these observations raise the possibility that CLSPN may encode a component of the DNA-damage response pathway that is targeted by mutations in human cancers, suggesting the need for larger population-based studies to investigate whether CLSPN variants contribute to cancer susceptibility. (Mol Cancer Res 2009;7(9):1510–16)
Functional Analysis of Secreted Caveolin-1 in Mouse Models of Prostate Cancer Progression
Authors: Watanabe Masami , Yang Guang , Cao Guangwen , Tahir Salahaldin A. , Naruishi Koji , Tabata Ken-ichi , Fattah Elmoataz Abdel , Rajagopalan Kartik , Timme Terry L. , Park Sanghee , Kurosaka Shinji , Edamura Kohei , Tanimoto Ryuta , Demayo Francesco J. , Goltsov Alexei A. , Thompson Timothy C. 
Published: September 2009

Abstract
Previously, we reported that caveolin-1 (cav-1) is overexpressed in metastatic prostate cancer and that virulent prostate cancer cells secrete biologically active cav-1. We also showed that cav-1 expression leads to prosurvival activities through maintenance of activated Akt and that cav-1 is taken up by other cav-1–negative tumor cells and/or endothelial cells, leading to stimulation of angiogenic activities through PI-3-K-Akt-eNOS signaling. To analyze the functional consequences of cav-1 overexpression on the development and progression of prostate cancer in vivo, we generated PBcav-1 transgenic mice. Adult male PBcav-1 mice showed significantly increased prostatic wet weight and higher incidence of epithelial hyperplasia compared with nontransgenic littermates. Increased immunostaining for cav-1, proliferative cell nuclear antigen, P-Akt, and reduced nuclear p27Kip1 staining occurred in PBcav-1 hyperplastic prostatic lesions. PBcav-1 mice showed increased resistance to castration-induced prostatic regression and elevated serum cav-1 levels compared with nontransgenic littermates. Intraprostatic injection of androgen-sensitive, cav-1–secreting RM-9 mouse prostate cancer cells resulted in tumors that were larger in PBcav-1 mice than in nontransgenic littermates (P = 0.04). Tail vein inoculation of RM-9 cells produced significantly more experimental lung metastases in PBcav-1 males than in nontransgenic male littermates (P = 0.001), and in cav-1+/+ mice than in cav-1−/− mice (P = 0.041). Combination treatment with surgical castration and systemic cav-1 antibody dramatically reduced the number of experimental metastases. These experimental data suggest a causal association of secreted cav-1 and prostate cancer growth and progression. (Mol Cancer Res 2009;7(9):1446–55)
Modulation of HER3 Is a Marker of Dynamic Cell Signaling in Ovarian Cancer: Implications for Pertuzumab Sensitivity
Authors: Nagumo Yoko , Faratian Dana , Mullen Peter , Harrison David J. , Hasmann Max , Langdon Simon P. 
Published: September 2009

Abstract
This study was designed to evaluate the expression of HER receptors as a marker of sensitivity to the humanized anti-HER2 monoclonal antibody pertuzumab in ovarian cancer cells. In a recent clinical trial, low levels of HER3 mRNA have been shown to associate with pertuzumab response when combined with gemcitabine. We sought to define how pertuzumab modulated HER expression levels in ovarian cancer using cell line models to better understand differential and dynamic receptor expression in therapeutic response. Changes in HER3 mRNA expression were also assessed in pertuzumab-treated xenografts. HER3 mRNA and, to a lesser extent, HER2, were down-regulated after stimulation both with heregulin-β1 and epidermal growth factor in a range of ovarian cancer cell lines either growth sensitive or growth resistant to pertuzumab. Pertuzumab reversed this down-regulation and the magnitude of the reversal correlated with pertuzumab sensitivity. The change in HER3 mRNA expression correlated inversely to how much the extracellular signal-regulated kinase and phosphoinositide 3-kinase pathways were dynamically activated with stimulation. Finally, up-regulation of HER3 mRNA was found in cancer xenografts treated with pertuzumab. We conclude that HER3 mRNA is down-regulated by both heregulin-β1 and epidermal growth factor activation. This suggests that in some tumors, low HER3 mRNA expression is driven by, or dependent on, growth factor. HER3 mRNA expression is effectively reversed in pertuzumab-sensitive tumors. These data are consistent with low HER3 mRNA identifying a pertuzumab-sensitive phenotype. (Mol Cancer Res 2009;7(9):1563–71)
The Aberrant Localization of Oncogenic Kit Tyrosine Kinase Receptor Mutants Is Reversed on Specific Inhibitory Treatment
Authors: Bougherara Houcine , Subra Frédéric , Crépin Ronan , Tauc Patrick , Auclair Christian , Poul Marie-Alix 
Published: September 2009

Abstract
Kit is a cell surface type III tyrosine kinase (TK) receptor implicated in cell transformation through overexpression or oncogenic mutation. Two categories of Kit mutants displaying mutations either in the juxtamembrane intracellular domain (regulatory mutants) or in the catalytic domain (catalytic mutants) have been described. To explore the effect of Kit oncogenic mutations on its subcellular localization, we constructed enhanced green fluorescent protein (EGFP)–tagged human Kit chimeras harboring mutations either in the regulatory (V560G) or in the catalytic (D816V) domain. When expressed in Chinese hamster ovary cells, EGFP-tagged wild-type Kit was activated on stem cell factor stimulation, whereas both EGFP-tagged Kit mutants displayed a constitutive TK activity. Constitutively activated mutants exhibited a high-mannose–type N-glycosylation pattern and an intracellular localization, suggesting that these mutants induce downstream oncogenic signaling without the need to reach the cell surface. Inhibition of constitutive Kit TK activity with dasatinib induced a complex, mature N-glycosylation pattern identical to unstimulated wild-type Kit and resulted in the redistribution of the mutants to the plasma membrane. This relocalization was clearly correlated to the inhibition of TK activity because imatinib, a specific inhibitor of the V560G mutant, inactive on the catalytic D816V mutant, induced only the relocalization of the V560G mutant. These data show that on TK inhibition, the aberrant localization of Kit mutants can be fully reversed. Kit mutants are then exported and/or stabilized at the cell surface as inactive and fully N-glycosylated isoforms. (Mol Cancer Res 2009;7(9):1525–33)
Concordant DNA Methylation in Synchronous Colorectal Carcinomas
Authors: Konishi Kazuo , Shen Lanlan , Jelinek Jaroslav , Watanabe Yoshiyuki , Ahmed Saira , Kaneko Kazuhiro , Kogo Mari , Takano Toshihumi , Imawari Michio , Hamilton Stanley R. , Issa Jean-Pierre J. 
Published: September 2009

AbstractEpigenetic changes have been proposed as mediators of the field defect in colorectal carcinogenesis, which has implications for risk assessment and cancer prevention. As a test of this hypothesis, we evaluated the methylation status of eight genes (MINT1, 2, 31, MLH1, p16, p14, MGMT, and ESR1), as well as BRAF and KRAS mutations, in 57 multiple colorectal neoplasias (M-CRN) and compared these to 69 solitary colorectal cancers (S-CRC). There were no significant differences in methylation between M-CRNs and S-CRCs except for p14 and MGMT that was significantly higher in M-CRNs than S-CRCs (16.1% versus 9.3%; 26.5% versus 17.3%, respectively; P &lt; 0.05). We found significant (P &lt; 0.05) correlations for MINT1 (r = 0.8), p16 (r = 0.8), MLH1 (r = 0.9), and MGMT (r = 0.6) methylation between tumors pairs of the same site (proximal/proximal and distal/distal). KRAS showed no concordance in mutations. BRAF mutation showed concordance in proximal site pairs but was discordant in different site pairs. Histologically, eight of 10 paired cancers with similar locations were concordant for a cribriform glandular configuration. We conclude that synchronous colorectal tumors of the same site are highly concordant for methylation of multiple genes, BRAF mutations, and a cribriform glandular configuration, all consistent with a patient-specific predisposition to particular subtypes of colorectal cancers. Screening for and secondary prevention of colon cancer should take this fact into account.
The Chemopreventive Bioflavonoid Apigenin Inhibits Prostate Cancer Cell Motility through the Focal Adhesion Kinase/Src Signaling Mechanism
Authors: Franzen Carrie A. , Amargo Evangeline , Todorović Viktor , Desai Bhushan V. , Huda Sabil , Mirzoeva Salida , Chiu Karen , Grzybowski Bartosz A. , Chew Teng-Leong , Green Kathleen J. , Pelling Jill C. 
Published: September 2009

Abstract
Prostate cancer mortality is primarily attributed to metastatic rather than primary, organ-confined disease. Acquiring a motile and invasive phenotype is an important step in development of tumors and ultimately metastasis. This step involves remodeling of the extracellular matrix and of cell-matrix interactions, cell movement mediated by the actin cytoskeleton, and activation of focal adhesion kinase (FAK)/Src signaling. Epidemiologic studies suggest that the metastatic behavior of prostate cancer may be an ideal target for chemoprevention. The natural flavone apigenin is known to have chemopreventive properties against many cancers, including prostate cancer. Here, we study the effect of apigenin on motility, invasion, and its mechanism of action in metastatic prostate carcinoma cells (PC3-M). We found that apigenin inhibits PC3-M cell motility in a scratch-wound assay. Live cell imaging studies show that apigenin diminishes the speed and affects directionality of cell motion. Alterations in the cytoskeleton are consistent with impaired cell movement in apigenin-treated cells. Apigenin treatment leads to formation of “exaggerated filopodia,” which show accumulation of focal adhesion proteins at their tips. Furthermore, apigenin-treated cells adhere more strongly to the extracellular matrix. Additionally, apigenin decreases activation of FAK and Src, and phosphorylation of Src substrates FAK Y576/577 and Y925. Expression of constitutively active Src blunts the effect of apigenin on cell motility and cytoskeleton remodeling. These results show that apigenin inhibits motility and invasion of prostate carcinoma cells, disrupts actin cytoskeleton organization, and inhibits FAK/Src signaling. These studies provide mechanistic insight into developing novel strategies for inhibiting prostate cancer cell motility and invasiveness.
Matched-Pair Analysis of Race or Ethnicity in Outcomes of Head and Neck Cancer Patients Receiving Similar Multidisciplinary Care
Authors: Chen Leon M. , Li Guojun , Reitzel Lorraine R. , Pytynia Kristen B. , Zafereo Mark E. , Wei Qingyi , Sturgis Erich M. 
Published: September 2009

Abstract
It is unknown whether population-level racial or ethnic disparities in mortality from squamous cell carcinoma of the head and neck (SCCHN) also occur in the setting of standardized multidisciplinary-team directed care. Therefore, we conducted a matched-pair study that controlled for several potentially confounding prognostic variables to assess whether a difference in survival exists for African American or Hispanic American compared with non-Hispanic white American SCCHN patients receiving similar care. Matched pairs were 81 African American case and 81 non-Hispanic white control patients and 100 Hispanic American cases and 100 matched non-Hispanic white controls selected from 1,833 patients of a prospective epidemiologic study of incident SCCHN within a single, large multidisciplinary cancer center. Matching variables included age (±10 years), sex, smoking status (never versus ever), site, tumor stage (T1-2 versus T3-4), nodal status (negative versus positive), and treatment. Cases and controls were not significantly different in proportions of comorbidity score, alcohol use, subsite distribution, overall stage, or tumor grade. Matched-pair and log-rank analyses showed no significant differences between cases and controls in recurrence-free, disease-specific, or overall survival. Site-specific analyses suggested that more aggressive oropharyngeal cancers occurred more frequently in minority than in non-Hispanic white patients. We conclude that minority and non-Hispanic white SCCHN patients receiving similar multidisciplinary-team directed care at a tertiary cancer center have similar survival results overall. These results encourage reducing health disparities in SCCHN through public-health efforts to improve access to multidisciplinary oncologic care (and to preventive measures) and through individual clinician efforts to make the best multidisciplinary cancer treatment choices available for their minority patients. The subgroup finding suggests a biologically based racial/ethnic disparity among oropharyngeal patients and that prevention and treatment strategies should be tailored to different populations of these patients.
The Monkey, the Hen, and the Mouse: Models to Advance Ovarian Cancer Chemoprevention
Authors: Lu Karen H. , Yates Melinda S. , Mok Samuel C. 
Published: September 2009

Abstract
This perspective on Romero et al. (beginning on p. 792 in this issue of the journal) discusses the available animal models of ovarian cancer, including the laying hen, non-human primate, and transgenic rodent models, and their relevance to ovarian cancer chemoprevention studies.
The Relationship between Posterior Tibial Slope and Anterior Cruciate Ligament Injuries
Authors: Todd Michael S. , Lalliss Steve , Garcia E'Stephan , DeBerardino Thomas M. , Cameron Kenneth L. 
Published: September 2009

Background Two previous studies have examined the association between an increased posterior tibial slope and anterior cruciate ligament (ACL) injuries as measured on plain radiographs. The study results were contradictory, with 1 reporting a statistical difference and the other showing no association. Purpose To determine if there is a difference in posterior tibial slope angle between patients with a history of noncontact ACL injury and a control group with no history of ACL injury. A secondary objective was to examine differences in tibial slope angle between male and female subjects within each group. Study Design Case-control study; Level of evidence, 3. Methods We identified all noncontact ACL injuries that were treated operatively at the United States Military Academy, West Point, New York, from 2004 to 2007. We digitally measured the posterior tibial slope from plain film radiographs of 140 noncontact ACL injuries, stratified them by sex, and compared them with a control cohort of 179 patients and radiographs. Results Subjects in the noncontact ACL group had significantly greater slope angles (9.39° ± 2.58°) than did control subjects (8.50° ± 2.67°) (P = .003). The trend toward greater tibial slope angles in the noncontact ACL group was also observed when each sex was examined independently; however, the difference was only statistically significant for the female subjects between the injury and control groups (9.8° ± 2.6° vs 8.20° ± 2.4°) (P = .002). Conclusion Despite the identification of an increased posterior tibial slope as a possible risk factor for women, more research that combines the multifactorial nature of an ACL injury must be performed.
Histologic Findings and Possible Causes of Osteochondritis Dissecans of the Knee
Authors: Uozumi Hiroaki , Sugita Takehiko , Aizawa Toshimi , Takahashi Atsushi , Ohnuma Masahiro , Itoi Eiji 
Published: September 2009

Background The histologic findings of osteochondritis dissecans of the knee vary widely, leading to differences in the interpretation of its origins. Hypothesis The differences in the histologic findings of osteochondritis dissecans might represent a course of pathologic progression. Study Design Descriptive laboratory study. Methods Twelve knees in 11 patients (average age, 16 years) with osteochondritis dissecans of the medial femoral condyle were treated by biological internal fixation. During the surgery, cylinder osteochondral plugs were taken from the center of the osteochondritis dissecans lesion and examined with light microscopy. Results A complete or partial cleft separated the specimens into 2 parts: basal and fragment sides. The surface of the basal side was covered with dense fibrous or cartilaginous tissue and active bone remodeling was found beneath the surface. In the fragment side, the deep surface was also covered with dense fibrous or cartilaginous tissue and the articular surface consisted of normal articular cartilage. The area between these 2 surfaces could be classified into 3 types: (1) necrotic subchondral trabeculae, (2) viable subchondral trabeculae, and (3) cartilage without bone trabeculae. Conclusion Based on the histologic findings of this study, the following origins and the pathologic progression of osteochondritis dissecans might be assumed: the initial change in the subchondral area is bone necrosis or subchondral fracture; the necrotic bone is then absorbed and replaced either by viable subchondral trabeculae or cartilage without bone trabeculae. Clinical Relevance The results of this histologic study provide readers with several insights about the causes and treatment options of osteochondritis dissecans.