bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clostridium perfringens Enterotoxin as a Novel-Targeted Therapeutic for Brain Metastasis
Authors: Kominsky Scott L. , Tyler Betty , Sosnowski Jeffrey , Brady Kelly , Doucet Michele , Nell Delissa , Smedley James G. , McClane Bruce , Brem Henry , Sukumar Saraswati 
Published: September 2007

Abstract
Brain metastasis is the most commonly occurring intracranial tumor whose incidence seems to be increasing. With standard therapy, the average survival time of patients is ∼8 months, and treatment often leads to neurologic dysfunction in long-term survivors, emphasizing the need for novel therapeutics. Clostridium perfringens enterotoxin (CPE) has recently been shown to rapidly and specifically destroy cancer cells expressing CPE receptors claudin-3 and claudin-4. Unfortunately, the utility of CPE is precluded by systemic toxicity because its receptors are expressed in numerous organs. Here, we provide the first preclinical evidence that CPE may be uniquely suited to the local treatment of brain metastasis. By immunohistochemical analysis, claudin-3 and claudin-4 were expressed frequently in metastases from breast (15 of 18), lung (15 of 20), and colon (12 of 14) carcinoma, and infrequently in metastases from renal cell carcinoma (2 of 16) and melanoma (2 of 16). In contrast, expression of claudin-3 and claudin-4 was absent in adjacent normal brain tissue. Further examination of the central nervous system (CNS) revealed low or undetectable levels of claudin-3 and claudin-4 in all regions tested by Western and immunohistochemical analysis. Treatment of breast cancer cell lines (MCF-7, MDA-MB-468, NT2.5-luc) and normal human astrocytes with CPE in vitro resulted in rapid and dose-dependent cytolysis exclusively in breast cancer cells, correlating with claudin-3 and claudin-4 expression. Moreover, intracranial CPE treatment significantly inhibited tumor growth and increased survival in two murine models of breast cancer brain metastasis, without any apparent local or systemic toxicity. These data suggest that CPE therapy may have efficacy against a wide variety of brain metastases without CNS toxicity. [Cancer Res 2007;67(17):7977–82]
YM155, a Novel Small-Molecule Survivin Suppressant, Induces Regression of Established Human Hormone-Refractory Prostate Tumor Xenografts
Authors: Nakahara Takahito , Takeuchi Masahiro , Kinoyama Isao , Minematsu Tsuyoshi , Shirasuna Kenna , Matsuhisa Akira , Kita Aya , Tominaga Fumiko , Yamanaka Kentaro , Kudoh Masafumi , Sasamata Masao 
Published: September 2007

Abstract
Various accumulating evidence suggests that survivin, a member of the inhibitor of apoptosis (IAP) family, plays an important role in drug resistance and cancer cell survival in many types of cancer, including hormone-refractory prostate cancer (HRPC). Here, we characterized YM155, a novel small-molecule survivin suppressant, using a survivin gene promoter activity assay. YM155 suppressed expression of survivin and induced apoptosis in PC-3 and PPC-1 human HRPC cell lines at 10 nmol/L. In contrast, YM155 up to 100 nmol/L showed little effect on expression levels of other IAP- or Bcl-2–related proteins. In a s.c. xenografted PC-3 tumor model in mice, 3-day continuous infusions of YM155 at 3 to 10 mg/kg induced massive tumor regression accompanied by suppression of intratumoral survivin. YM155 also completely inhibited the growth of orthotopically xenografted PC-3 tumors. No significant decreases in body weight were observed in mice treated with YM155 during the experimental period. Pharmacokinetic analyses indicated that YM155 is highly distributed to tumors and at concentrations ∼20-fold higher than those in plasma. Our findings represent the first attempt to show tumor regression and suppression of survivin in p53-deficient human HRPC cells by a single small molecular compound treatment. Further extensive investigation of YM155 in many types of cancer, including HRPC, seems to be worthwhile to develop this novel therapeutic approach. [Cancer Res 2007;67(17):8014–21]
Expression of Interleukin-13 Receptor α2 in Glioblastoma Multiforme: Implications for Targeted Therapies
Authors: Jarboe John S. , Johnson Kory R. , Choi Yong , Lonser Russell R. , Park John K. 
Published: September 2007

Abstract
Glioblastoma multiforme is the most common primary malignant brain tumor and despite treatment with surgery, radiation, and chemotherapy, the median survival of patients with glioblastoma multiforme is ∼1 year. Glioblastoma multiforme explants and cell lines have been reported to overexpress the interleukin-13 receptor α2 subunit (IL13Rα2) relative to nonneoplastic brain. Based on this finding, a recombinant cytotoxin composed of IL13 ligand and a truncated form of Pseudomonas aeruginosa exotoxin A (IL13-PE38QQR) was developed for the targeted treatment of glioblastoma multiforme tumors. In a recently completed phase III clinical trial, however, IL13-PE38QQR was found to be no more effective than an existing therapy in prolonging survival. To determine possible explanations for this result, we analyzed the relative expression levels of IL13Rα2 in glioblastoma multiforme and nonneoplastic brain specimens using publicly available oligonucleotide microarray databases, quantitative real-time reverse transcription PCR, and immunohistochemical staining. Increased expression of the IL13Rα2 gene relative to nonneoplastic brain was observed in 36 of 81 (44%) and 8 of 17 (47%) tumor specimens by microarray and quantitative real-time reverse transcription PCR analyses, respectively. Immunohistochemical staining of tumor specimens showed highly variable expression of IL13Rα2 protein both within and across specimens. These data indicate that prescreening of subjects may be of benefit in future trials of IL13Rα2 targeting therapies. [Cancer Res 2007;67(17):7983–6]
Identification of an Integrated SV40 T/t-Antigen Cancer Signature in Aggressive Human Breast, Prostate, and Lung Carcinomas with Poor Prognosis
Authors: Deeb Kristin K. , Michalowska Aleksandra M. , Yoon Cheol-yong , Krummey Scott M. , Hoenerhoff Mark J. , Kavanaugh Claudine , Li Ming-chung , Demayo Francesco J. , Linnoila Ilona , Deng Chu-xia , Lee Eva Y-H.P. , Medina Daniel , Shih Joanna H. , Green Jeffrey E. 
Published: September 2007

Abstract
Understanding the genetic architecture of cancer pathways that distinguishes subsets of human cancer is critical to developing new therapies that better target tumors based on their molecular expression profiles. In this study, we identify an integrated gene signature from multiple transgenic models of epithelial cancers intrinsic to the functions of the Simian virus 40 T/t-antigens that is associated with the biological behavior and prognosis for several human epithelial tumors. This genetic signature, composed primarily of genes regulating cell replication, proliferation, DNA repair, and apoptosis, is not a general cancer signature. Rather, it is uniquely activated primarily in tumors with aberrant p53, Rb, or BRCA1 expression but not in tumors initiated through the overexpression of myc, ras, her2/neu, or polyoma middle T oncogenes. Importantly, human breast, lung, and prostate tumors expressing this set of genes represent subsets of tumors with the most aggressive phenotype and with poor prognosis. The T/t-antigen signature is highly predictive of human breast cancer prognosis. Because this class of epithelial tumors is generally intractable to currently existing standard therapies, this genetic signature identifies potential targets for novel therapies directed against these lethal forms of cancer. Because these genetic targets have been discovered using mammary, prostate, and lung T/t-antigen mouse cancer models, these models are rationale candidates for use in preclinical testing of therapies focused on these biologically important targets. [Cancer Res 2007;67(17):8065–80]
Toll-like Receptor Ligands Energize Peptide Vaccines through Multiple Paths
Authors: Celis Esteban 
Published: September 2007

Abstract
The potential of vaccines for cancer therapy or prevention has yet to be realized. Recently, we showed that using an immunologic adjuvant composed of a Toll-like receptor (TLR) ligand can increase the production of antitumor CTLs produced by a peptide vaccine in a mouse model of breast cancer. By increasing the cross talk between the innate and adaptive immune systems, TLR ligands can drive expansion and memory of CTLs that can destroy cancer cells. [Cancer Res 2007;67(17):7945–7]
Meriolins, a New Class of Cell Death–Inducing Kinase Inhibitors with Enhanced Selectivity for Cyclin-Dependent Kinases
Authors: Bettayeb Karima , Tirado Oscar M. , Marionneau-Lambot Séverine , Ferandin Yoan , Lozach Olivier , Morris Jonathan C. , Mateo-Lozano Silvia , Drueckes Peter , Schächtele Christoph , Kubbutat Michael H.G. , Liger François , Marquet Bernard , Joseph Benoît , Echalier Aude , Endicott Jane A. , Notario Vicente , Meijer Laurent 
Published: September 2007

Abstract
Protein kinases represent promising anticancer drug targets. We describe here the meriolins, a new family of inhibitors of cyclin-dependent kinases (CDK). Meriolins represent a chemical structural hybrid between meridianins and variolins, two families of kinase inhibitors extracted from various marine invertebrates. Variolin B is currently in preclinical evaluation as an antitumor agent. A selectivity study done on 32 kinases showed that, compared with variolin B, meriolins display enhanced specificity toward CDKs, with marked potency on CDK2 and CDK9. The structures of pCDK2/cyclin A/variolin B and pCDK2/cyclin A/meriolin 3 complexes reveal that the two inhibitors bind within the ATP binding site of the kinase, but in different orientations. Meriolins display better antiproliferative and proapoptotic properties in human tumor cell cultures than their parent molecules, meridianins and variolins. Phosphorylation at CDK1, CDK4, and CDK9 sites on, respectively, protein phosphatase 1α, retinoblastoma protein, and RNA polymerase II is inhibited in neuroblastoma SH-SY5Y cells exposed to meriolins. Apoptosis triggered by meriolins is accompanied by rapid Mcl-1 down-regulation, cytochrome c release, and activation of caspases. Meriolin 3 potently inhibits tumor growth in two mouse xenograft cancer models, namely, Ewing's sarcoma and LS174T colorectal carcinoma. Meriolins thus constitute a new CDK inhibitory scaffold, with promising antitumor activity, derived from molecules initially isolated from marine organisms. [Cancer Res 2007;67(17):8325–34]
Heterogeneity of TMPRSS2 Gene Rearrangements in Multifocal Prostate Adenocarcinoma: Molecular Evidence for an Independent Group of Diseases
Authors: Mehra Rohit , Han Bo , Tomlins Scott A. , Wang Lei , Menon Anjana , Wasco Matthew J. , Shen Ronglai , Montie James E. , Chinnaiyan Arul M. , Shah Rajal B. 
Published: September 2007

Abstract
Recurrent gene fusions between the androgen-regulated gene TMPRSS2 and the ETS family transcription factors ERG, ETV1, and ETV4 have been identified in the majority of prostate adenocarcinomas (PCA). PCA is often multifocal with histologic heterogeneity of different tumor foci. As TMPRSS2 is a common 5′ partner of ETS gene fusions, we monitored TMPRSS2 rearrangement by fluorescence in situ hybridization (FISH) to study the origin and molecular basis of multifocal PCA heterogeneity. TMPRSS2 rearrangement was evaluated by FISH on a tissue microarray representing 93 multifocal PCAs from 43 radical prostatectomy resections. Overall, 70% (30 of 43) of the cases showed TMPRSS2 rearrangement, including 63% through deletion (loss of the 3′ TMPRSS2 signal), 27% through translocation (split of 5′ and 3′ TMPRSS2 signals), and 10% through both mechanisms in different tumor foci. Of the 30 TMPRSS2 rearranged cases, 30% showed concordance in all tumor foci, whereas 70% were discordant in at least one focus. In TMPRSS2 rearranged cases, the largest (index) tumor was rearranged 83% of the time. Pathologic stage, size, or Gleason grade of the multifocal PCA did not correlate with overall TMPRSS2 rearrangement. Our results suggest that multifocal PCA is a heterogeneous group of diseases arising from multiple, independent clonal expansions. Understanding this molecular heterogeneity is critical to the future development and utility of diagnostic and prognostic PCA biomarkers. [Cancer Res 2007;67(17):7991–5]
Thyroid-Stimulating Hormone–Initiated Proliferative Signals Converge In vivo on the mTOR Kinase without Activating AKT
Authors: Brewer Charlene , Yeager Nicole , Di Cristofano Antonio 
Published: September 2007

Abstract
Thyroid-stimulating hormone (TSH) has long been recognized as the major proliferative and functional stimulus for thyroid follicular cells. TSH receptor (TSHR) engagement stimulates the production of cyclic AMP and the subsequent activation of downstream effector molecules, including protein kinase A, S6K1, and Rap1, whereas the role of the RAS and phosphatidylinositol-3-kinase signaling cascades downstream of TSHR is still controversial. Despite the abundance of candidates, it is still unclear which of these pathways represent(s) the key mitogenic output of TSH-initiated signaling. We have used an in vivo model of goitrogenesis to dissect the contribution of these pathways to TSH-induced thyrocyte proliferation and thyroid hyperplasia. We show that the in vivo proliferative response to chronic TSHR stimulation relies heavily on the activation of the mTOR/S6K1 axis, and that mTOR inhibition during goitrogenic stimulation abrogates the hyperplastic but not the hypertrophic thyrocyte responses to TSH, thus functionally uncoupling these two processes. Strikingly, goitrogenesis was not associated with an increase in AKT phosphorylation levels, underlining the existence of an AKT-independent pathway leading to mTOR activation upon TSH stimulation. [Cancer Res 2007;67(17):8002–6]
Dynamics of BCR-ABL kinase domain mutations in chronic myeloid leukemia after sequential treatment with multiple tyrosine kinase inhibitors
Authors: Cortes Jorge , Jabbour Elias , Kantarjian Hagop , Yin C. Cameron , Shan Jianqin , O'Brien Susan , Garcia-Manero Guillermo , Giles Francis , Breeden Megan , Reeves Nubia , Wierda William G. , Jones Dan 
Published: September 2007

AbstractDasatinib and nilotinib are potent tyrosine kinase inhibitors (TKIs) with activity against many imatinib-resistant chronic myeloid leukemia (CML) clones with BCR-ABL kinase domain (KD) mutations, except T315I. We assessed for changes in the BCR-ABL KD mutation status in 112 patients with persistent CML who received a second-generation TKI after imatinib failure. Sixty-seven different KD mutations were detected before the start of therapy with a second TKI, with T315I seen in 15%. Equal numbers of patients received nilotinib or dasatinib following imatinib, and 18 received 3 TKIs. Response rates were similar for patients with and without mutations, regardless of mutation site except for T315I. Overall, 29 patients (26%) developed new KD mutations after therapy with a second (n = 24) or third (n = 5) TKI, but only 4 (4%) developed T315I. In 73% of cases, the KD mutations that persisted or developed following switch to new TKI were at sites also found in prior in vitro TKI mutagenesis assays. Although there is only a mild increase in mutation frequency with sequential TKI treatment, novel mutations do occur and mutation regression/acquisition/persistence generally reflects the in vitro differential sensitivity predicted for each TKI. In this study, there was no marked increase in development of T315I.
Can family planning outreach bridge the urban-rural divide in Zambia?
Authors: White Justin S , Speizer Ilene S 
Published: September 2007

Abstract
Background
Zambia experienced declining aggregate fertility and increasing aggregate contraceptive use from 1990 to 2000. Yet, in rural Zambia, progress in family planning has lagged far behind the advances made in Zambia's urban areas. The contraceptive prevalence rate in Lusaka and other urban areas outstripped the rate in rural Zambia by nearly 25 percentage points (41.2 percent versus 16.6 percent) in 2001. The total fertility rate varied between urban and rural areas by 2.5 children (4.3 versus 6.9 children). This paper considers the urban-rural differentials in Zambia and assesses family planning outreach as a tool to narrow this divide.

Methods
This study uses the Zambia Demographic and Health Survey (DHS) data, collected between 2001 and 2002. Logistic regression techniques were employed to examine factors associated with contraceptive use. The first analysis tested modern contraceptive use versus traditional method use and no use. In addition, separate models were run for samples stratified by type of residence (rural or urban) to determine if different factors were associated with use by residence. A simulation determined the effect of all women receiving at least one household visit from a health worker if all other variables were held constant.

Results
Differences in modern contraceptive use between urban and rural areas persist (OR: 1.56, 95 percent CI: 1.24–1.96) even after adjusting for a number of demographic, socioeconomic, cognitive, and attitudinal factors. Household visits by a community health worker significantly increased the likelihood of modern contraceptive use among rural women (OR: 1.83; 95 percent CI: 1.29–2.58). If all rural women received at least one outreach visit per year, the prevalence rate for modern contraceptive methods would be expected to increase for this group by 5.9 percentage points, a marked increase but less than one-quarter of the total urban-rural differential.

Conclusion
Outreach in the form of health worker visits can improve access to family planning services, but it does not eliminate barriers to access or address continued high-fertility desires in Zambia. Until policymakers consider strategies that address both family planning demand creation and supply of services, progress in Zambia and the rest of sub-Saharan Africa will continue to lag behind the rest of the world.
Spontaneous ventral urethral fistula in a young diabetic man: a case report
Authors: Denzinger Stefan , Wieland Wolf F , Burger Maximilian , Otto Wolfgang 
Published: September 2007

Abstract
We present the first case reported in the medical literature of a patient with a spontaneous ventral urethral fistula accompanied by severe infection due to diabetes mellitus. A 34-year-old man with poor controlled adult-onset diabetes mellitus was admitted to our hospital with a large subcutaneous abscess involving the complete penis, scrotum and perineum. The patient did not report any history of any penile trauma or local infection but has experienced transient swelling of the perineal region following urination. Initial surgical treatment consisted of surgical debridement of necrotic tissue. At this time reconstructive surgery was impossible and a suprapubic cystostomy was performed. After 4 months of suprapubic urinary diversion the urethral fistula resolved and function of external genitalia was reestablished. In a follow-up period of 40 months no recurrence occurred. Spontaneous diabetes-associated ventral urethral fistulas are extremely rare and we are not aware of any other published case report.
Randomized Controlled Trial of Yoga Among a Multiethnic Sample of Breast Cancer Patients: Effects on Quality of Life
Authors: Moadel Alyson B. , Shah Chirag , Wylie-Rosett Judith , Harris Melanie S. , Patel Sapana R. , Hall Charles B. , Sparano Joseph A. 
Published: September 2007

Purpose This study examines the impact of yoga, including physical poses, breathing, and meditation exercises, on quality of life (QOL), fatigue, distressed mood, and spiritual well-being among a multiethnic sample of breast cancer patients. Patients and Methods One hundred twenty-eight patients (42% African American, 31% Hispanic) recruited from an urban cancer center were randomly assigned (2:1 ratio) to a 12-week yoga intervention (n = 84) or a 12-week waitlist control group (n = 44). Changes in QOL (eg, Functional Assessment of Cancer Therapy) from before random assignment (T1) to the 3-month follow-up (T3) were examined; predictors of adherence were also assessed. Nearly half of all patients were receiving medical treatment. Results Regression analyses indicated that the control group had a greater decrease in social well-being compared with the intervention group after controlling for baseline social well-being and covariates (P < .0001). Secondary analyses of 71 patients not receiving chemotherapy during the intervention period indicated favorable outcomes for the intervention group compared with the control group in overall QOL (P < .008), emotional well-being (P < .015), social well-being (P < .004), spiritual well-being (P < .009), and distressed mood (P < .031). Sixty-nine percent of intervention participants attended classes (mean number of classes attended by active class participants = 7.00 ± 3.80), with lower adherence associated with increased fatigue (P < .001), radiotherapy (P < .0001), younger age (P < .008), and no antiestrogen therapy (P < .02). Conclusion Despite limited adherence, this intent-to-treat analysis suggests that yoga is associated with beneficial effects on social functioning among a medically diverse sample of breast cancer survivors. Among patients not receiving chemotherapy, yoga appears to enhance emotional well-being and mood and may serve to buffer deterioration in both overall and specific domains of QOL.
Effects of Aerobic and Resistance Exercise in Breast Cancer Patients Receiving Adjuvant Chemotherapy: A Multicenter Randomized Controlled Trial
Authors: Courneya Kerry S. , Segal Roanne J. , Mackey John R. , Gelmon Karen , Reid Robert D. , Friedenreich Christine M. , Ladha Aliya B. , Proulx Caroline , Vallance Jeffrey K.H. , Lane Kirstin , Yasui Yutaka , McKenzie Donald C. 
Published: September 2007

PurposeBreast cancer chemotherapy may cause unfavorable changes in physical functioning, body composition, psychosocial functioning, and quality of life (QOL). We evaluated the relative merits of aerobic and resistance exercise in blunting these effects.Patients and MethodsWe conducted a multicenter randomized controlled trial in Canada between 2003 and 2005 that randomly assigned 242 breast cancer patients initiating adjuvant chemotherapy to usual care (n = 82), supervised resistance exercise (n = 82), or supervised aerobic exercise (n = 78) for the duration of their chemotherapy (median, 17 weeks; 95% CI, 9 to 24 weeks). Our primary end point was cancer-specific QOL assessed by the Functional Assessment of Cancer Therapy–Anemia scale. Secondary end points were fatigue, psychosocial functioning, physical fitness, body composition, chemotherapy completion rate, and lymphedema.ResultsThe follow-up assessment rate for our primary end point was 92.1%, and adherence to the supervised exercise was 70.2%. Unadjusted and adjusted mixed-model analyses indicated that aerobic exercise was superior to usual care for improving self-esteem (P = .015), aerobic fitness (P = .006), and percent body fat (adjusted P = .076). Resistance exercise was superior to usual care for improving self-esteem (P = .018), muscular strength (P < .001), lean body mass (P = .015), and chemotherapy completion rate (P = .033). Changes in cancer-specific QOL, fatigue, depression, and anxiety favored the exercise groups but did not reach statistical significance. Exercise did not cause lymphedema or adverse events.ConclusionNeither aerobic nor resistance exercise significantly improved cancer-specific QOL in breast cancer patients receiving chemotherapy, but they did improve self-esteem, physical fitness, body composition, and chemotherapy completion rate without causing lymphedema or significant adverse events.