bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of Compounds Selectively Killing Multidrug-Resistant Cancer Cells
Authors: Türk Dóra , Hall Matthew D. , Chu Benjamin F. , Ludwig Joseph A. , Fales Henry M. , Gottesman Michael M. , Szakács Gergely 
Published: October 2009

AbstractThere is a great need for the development of novel chemotherapeutic agents that overcome the emergence of multidrug resistance (MDR) in cancer. We catalogued the National Cancer Institute's DTP drug repository in search of compounds showing increased toxicity in MDR cells. By comparing the sensitivity of parental cell lines with MDR derivatives, we identified 22 compounds possessing MDR-selective activity. Analysis of structural congeners led to the identification of 15 additional drugs showing increased toxicity in Pgp-expressing cells. Analysis of MDR-selective compounds led to the formulation of structure activity relationships and pharmacophore models. This data mining coupled with experimental data points to a possible mechanism of action linked to metal chelation. Taken together, the discovery of the MDR-selective compound set shows the robustness of the developing field of MDR-targeting therapy as a new strategy for resolving Pgp-mediated MDR. [Cancer Res 2009;69(21):8293–301]
The Mitogen-Activated Protein/Extracellular Signal-Regulated Kinase Kinase 1/2 Inhibitor AZD6244 (ARRY-142886) Enhances the Radiation Responsiveness of Lung and Colorectal Tumor Xenografts
Authors: Shannon Aoife M. , Telfer Brian A. , Smith Paul D. , Babur Muhammed , Logie Armelle , Wilkinson Robert W. , Debray Camille , Stratford Ian J. , Williams Kaye J. , Wedge Stephen R. 
Published: October 2009

Abstract
Purpose: Novel molecularly targeted agents, given in combination with radiotherapy, have the potential to increase tumor response rates and the survival of patients with lung cancer. AZD6244 is a potent and selective inhibitor of mitogen-activated protein kinase (MAPK) kinase 1/2 (MEK1/2), a critical enzyme within the MAPK/extracellular signal-regulated kinase (ERK) signaling pathway that regulates the proliferation and survival of tumor cells.
Experimental Design: This study examined the potential benefit of combining AZD6244 with fractionated radiotherapy using human lung and colon carcinoma xenograft models.
Results: AZD6244 reduced ERK phosphorylation in Calu-6 lung cancer cells in vitro. Administration of AZD6244 for 10 days (25 mg/kg twice daily p.o.) inhibited the tumor growth of Calu-6 xenografts, with regrowth occurring on cessation of drug treatment. When fractionated tumor-localized radiotherapy (5 × 2 Gy) was combined with AZD6244 treatment, the tumor growth delay was enhanced significantly when compared with either modality alone, and this effect was also seen in a colon tumor model. We examined the effect of inhibiting MEK1/2 on the molecular responses to hypoxia, a potential interaction that could contribute to radioresponsiveness. AZD6244 reduced hypoxia-inducible factor–specific transactivation in vivo, shown using Calu-6 dual clone cells that stably express a Firefly luciferase gene under the control of a hypoxia-driven promoter. Furthermore, hypoxia-inducible factor-1α, GLUT-1, and vascular endothelial growth factor levels were reduced by AZD6244, and there was a significant decrease in vascular perfusion in the tumors given combination treatment when compared with the other treatment groups.
Conclusions: These data provide support for the clinical development of AZD6244 in combination with radiotherapy and indicate a potential role for AZD6244 in inhibiting the tumor hypoxia response. (Clin Cancer Res 2009;15(21):6619–29)
Circulating Mesothelin Protein and Cellular Antimesothelin Immunity in Patients with Pancreatic Cancer
Authors: Johnston Fabian Mc. , Tan Marcus C.B. , Tan Benjamin R. , Porembka Matthew R. , Brunt Elizabeth M. , Linehan David C. , Simon Peter O. , Plambeck-Suess Stacey , Eberlein Timothy J. , Hellstrom Karl Erik , Hellstrom Ingegerd , Hawkins William G. , Goedegebuure Peter 
Published: October 2009

Abstract
Purpose: Mesothelin is a glycoprotein expressed on normal mesothelial cells and is overexpressed in several histologic types of tumors including pancreatic adenocarcinomas. A soluble form of mesothelin has been detected in patients with ovarian cancer and malignant mesothelioma, and has prognostic value. Mesothelin has also been considered as a target for immune-based therapies. We conducted a study on the potential clinical utility of mesothelin as a biomarker for pancreatic disease and therapeutic target pancreatic cancer.
Experimental Design: Tumor cell–bound and soluble mesothelin in patients was evaluated by immunohistochemistry and ELISA, respectively. The in vitro cellular immune response to mesothelin was evaluated by INFγ ELISA and intracellular cytokine staining for IFNγ in CD4+ and CD8+ T cells. The level of circulating antibodies to mesothelin was measured by ELISA.
Results: All tumor tissue from patients with pancreatic adenocarcinoma expressed mesothelin (n = 10). Circulating mesothelin protein was detected in patients with pancreatic adenocarcinoma (73 of 74 patients) and benign pancreatic disease (5 of 5) but not in healthy individuals. Mesothelin-specific CD4+ and CD8+ T cells were generated from peripheral blood lymphocytes of patients with pancreatic cancer in 50% of patients compared with only 20% of healthy individuals. Antibodies reactive to mesothelin were detected in &lt;3% of either patients or healthy individuals.
Conclusions: Circulating mesothelin is a useful biomarker for pancreatic disease. Furthermore, mesothelin-specific T cells can be induced in patients with pancreatic cancer. This suggests that mesothelin is a potential target for immune-based intervention strategies in pancreatic cancer. (Clin Cancer Res 2009;15(21):6511–8)
Repeated Treatment with Subtoxic Doses of TRAIL Induces Resistance to Apoptosis through Its Death Receptors in MDA-MB-231 Breast Cancer Cells
Authors: Yoshida Tatsushi , Zhang Yaqin , Rivera Rosado Leslie A. , Zhang Baolin 
Published: October 2009

Abstract
Recombinant human tumor necrosis factor–related apoptosis–inducing ligand (rhTRAIL) is being evaluated clinically in treating various malignancies. Previous studies have shown that repeated application of high doses of rhTRAIL results in a subpopulation of parental cells that is unresponsive to the death ligand. However, it is not clear whether TRAIL-sensitive cancer cells could acquire resistance to TRAIL treatment. Here, we found that MDA-MB-231 breast cancer cells, which are highly sensitive to TRAIL-induced apoptosis, became resistant to TRAIL killing after a prolonged exposure to subtoxic doses of rhTRAIL. The resulting TRAIL-resistant cells were cross-resistant to antibodies against its death receptors (DR4 and DR5); however, they retained sensitivity to several clinically relevant chemotherapies. Surface expression of DR4 and DR5 was significantly reduced in the selected cells, resulting in failure in death-inducing signaling complex formation and caspase activation. In addition, real-time PCR analysis revealed an upregulation in multiple apoptosis-regulator genes, including c-FLIP, Stat5a, and Stat5b. Inhibition of Janus-activated kinase, an upstream activator of signal transducer and activator of transcription 5 (Stat5), or knockdown of Stat5 itself partially restored cellular sensitivity to TRAIL-induced apoptosis, suggesting that Stat5 signaling is also involved in the development of TRAIL resistance. Furthermore, we showed that acquired TRAIL resistance was effectively eliminated by combination with etoposide, doxorubicin, or paclitaxel. These results suggest that tumor cells could acquire resistance to TRAIL therapy especially when they are repeatedly exposed to low levels of the death ligand, highlighting the necessity of combination with therapies that target the resistance mechanisms. (Mol Cancer Res 2009;7(11):1835–44)
Biogeography and variations in allopatric populations of Distolabrellus veechi Anderson, 1983 (Nematoda: Rhabditidae)
Authors: Tahseen Qudsia , Shah Ali Asghar , Khan Rahmat , Sultana Razia , Hussain Ather , Ahmad Irfan 
Published: October 2009

Abstract
A detailed description of Distolabrellus veechi (syn. nov. D. pakistanensis)
is given based on variations observed in different populations collected
from India and Korea, and comparisons made with those reported from Arizona
and Argentina. The populations, which showed a great degree of morphometric
overlap and a continuous range in variation, could not be differentiated
from the type population of D. veechi. The relationships of the populations
were studied using morphological data subjected to cluster analysis. The
characteristics of the species and its relationship with Teratorhabditis are
also discussed. Biogeographical information revealed an interesting trend of
distribution for the species, i.e., between 22-55° north and south of the
equator.
Reproductive Lesions in Female Harlan Sprague-Dawley Rats Following Two-Year Oral Treatment with Dioxin and Dioxin-like Compounds
Authors: Yoshizawa Katsuhiko , Brix Amy E. , Sells Donald M. , Jokinen Micheal P. , Wyde Michael , Orzech Denis P. , Kissling Grace E. , Walker Nigel J. , Nyska Abraham 
Published: October 2009

Results from previously published animal studies suggest that prenatal and postnatal exposure to dioxin and dioxin-like compounds (DLCs) may profoundly affect the reproductive system of both sexes via endocrine disruption. In the present work, we evaluate the toxicity and carcinogenicity of various DLCs, with an emphasis on their effect on the reproductive organs, induced by chronic exposure of female adult Harlan Sprague-Dawley rats. This investigation represents part of an initiative of the National Toxicology Program to determine the relative potency of chronic toxicity and carcinogenicity of polychlorinated dioxins, furans, and biphenyls. For fourteen, thirty-one, or fifty-three weeks or for two years, animals were administered by gavage 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD); 3,3′,4,4′,5-pentachlorobiphenyl (PCB126); 2,3,4,7,8-pentachlorodibenzofuran (PeCDF); 2,2′,4,4′,5,5′-hexachlorobiphenyl (PCB153); 2,3′,4,4′,5-pentachlorobiphenyl (PCB118); a tertiary mixture of TCDD, PCB126, and PeCDF; a binary mixture of PCB126 and 153; or a binary mixture of PCB126 and PCB118.The ranges of treatment-related changes in the reproductive system included chronic active inflammation in the ovary that occurred in the 1,000 and 3,000 μg/kg core groups (two-year exposure) of PCB153 and in the 300 ng/3,000 μg/kg core group of binary mixture of PCB126 and PCB153. Increases in the incidence of acute and/or chronic active inflammation of the uterus were observed in all dosed groups, including the stop-exposure group (withdrawal after thirty-week exposure) of PeCDF and the 1,000 μg/kg and/or higher group dosed with PCB153. The incidence of cystic endometrial hyperplasia was marginally increased in the 92 PeCDF ng/kg group at two years. The incidence of squamous metaplasia was significantly increased in the 44 ng/kg and higher dose group, including the stop-exposure group. The incidence of uterine squamous cell carcinoma was significantly or marginally increased in the 6 ng/kg core and 100 ng/kg stop-exposure groups of TCDD and in the 300 ng/300 μg/kg core group that received the binary mixture of PCB126 and 153. The incidence of uterine carcinoma was marginally increased in the 92 ng/kg PeCDF group at two years and clearly increased in the 1,000 and 4,600 μg/kg PCB118 core group and the 4,600 μg/kg stop group. In the studies of PCB 126, the tertiary mixture, and the binary mixture of PCB126 and PCB118, no increased incidence of any change occurred in the reproductive systems. The range of changes seen with the different compounds suggests that more than one mechanism may have been involved in promoting the female reproductive pathology.
Biochemical hypogonadism in men with type 2 diabetes in primary care practice
Authors: Hackett Geoffrey I , Cole Nigel S , Deshpande Arup A , Popple Mark D , Kennedy David , Wilkinson Peter 
Published: October 2009

Objective: This study explores the links between testosterone deficiency and Quality Outcomes Framework (QOF) parameters in three south Staffordshire practices prior to a major double-blind placebo-controlled intervention study. Research design and methods: Four hundred and eighty-eight consecutive type 2 diabetic patients, aged over 18, attending their general practitioner for routine diabetes visits were assessed for sex hormone binding globulin, total testosterone (TT), calculated free testosterone (FT) and bioavailable testosterone, glycated haemoglobin A1c (HbA1c), body mass index, waist circumference, blood pressure, lipid profile, Sexual Health Inventory for Men, and current and past prescriptions for erectile dysfunction (ED). Results: TT and FT were significantly inversely associated with raised body mass index, waist circumference and HbA1C. The prevalence of ED was 77%, which was associated with low levels of TT, FT and raised HbA1C. Only 10% were receiving treatment for ED. Conclusions: Patients with low testosterone were more likely to fall outside the QOF targets and new markers might be difficult to achieve unless low testosterone is addressed. There is a strong case for the inclusion of TT and FT estimation in routine diabetic care.
Phase 1/2 study of lumiliximab combined with fludarabine, cyclophosphamide, and rituximab in patients with relapsed or refractory chronic lymphocytic leukemia
Authors: Byrd John C. , Kipps Thomas J. , Flinn Ian W. , Castro Januaro , Lin Thomas S. , Wierda William , Heerema Nyla , Woodworth James , Hughes Steve , Tangri Shabnam , Harris Sarah , Wynne Dee , Molina Arturo , Leigh Bryan , O'Brien Susan 
Published: October 2009

AbstractPreclinical data demonstrate enhanced antitumor effect when lumiliximab, an anti-CD23 monoclonal antibody, is combined with fludarabine or rituximab. Clinical data from a phase 1 trial with lumiliximab demonstrated an acceptable toxicity profile in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). We therefore pursued a phase 1/2 dose-escalation study of lumiliximab added to fludarabine, cyclophosphamide, and rituximab (FCR) in previously treated CLL patients. Thirty-one patients received either 375 mg/m2 (n = 3) or 500 mg/m2 (n = 28) of lumiliximab in combination with FCR for 6 cycles. The toxicity profile was similar to that previously reported for FCR in treatment of relapsed CLL. The overall response rate was 65%, with 52% of patients achieving a complete response (CR), which compares favorably with the CR rate previously reported for the FCR regimen alone in relapsed CLL. The estimated median progression-free survival for all responders was 28.7 months. The addition of lumiliximab to FCR therapy is feasible, achieves a high CR rate, and does not appear to enhance toxicity in previously treated patients with CLL. A randomized trial comparing lumiliximab plus FCR with FCR alone is underway to define the benefit of this combination in relapsed CLL. This trial was registered at clinicaltrials.gov as NCT00103558.
Investigation of innate immunity genes CARD4, CARD8 and CARD15 as germline susceptibility factors for colorectal cancer
Authors: Möckelmann Nikolaus , von Schönfels Witigo , Buch Stephan , von Kampen Oliver , Sipos Bence , Egberts Jan Hendrik , Rosenstiel Philip , Franke Andre , Brosch Mario , Hinz Sebastian , Röder Christian , Kalthoff Holger , Fölsch Ulrich R , Krawczak Michael , Schreiber Stefan , Bröring Clemens Dieter , Tepel Jürgen , Schafmayer Clemens , Hampe Jochen 
Published: October 2009

AbstractBackgroundVariation in genes involved in the innate immune response may play a role in the predisposition to colorectal cancer (CRC). Several polymorphisms of theCARD15gene (caspase activating recruitment domain, member 15) have been reported to be associated with an increased susceptibility to Crohn disease. Since theCARD15gene product and other CARD proteins function in innate immunity, we investigated the impact of germline variation at theCARD4,CARD8andCARD15loci on the risk for sporadic CRC, using a large patient sample from Northern Germany.MethodsA total of 1044 patients who had been operated with sporadic colorectal carcinoma (median age at diagnosis: 59 years) were recruited and compared to 724 sex-matched, population-based control individuals (median age: 68 years). Genetic investigation was carried out following both a coding SNP and haplotype tagging approach. Subgroup analyses for N = 143 patients with early manifestation of CRC (≤50 age at diagnosis) were performed for allCARDloci and subgroup analyses for diverse age strata were carried out forCARD15mutations R702W, G908R and L1007fs. In addition, all SNPs were tested for association with disease presentation and family history of CRC.ResultsNo significant differences were observed between the patient and control allelic or haplotypic spectra of the three genes under study for the total cohort (N = 1044 patients). None of the analysed SNPs was significantly associated with either tumour location or yielded significant association in the familial or non-familial CRC patient subgroups. However, in a patient subgroup (≤45 age at diagnosis) with early disease manifestation the mutant allele ofCARD15R702W was found to be significantly associated with disease susceptibility (9.7% in casesvs4.6% in controls; Pallelic= 0.008, Pgenotypic= 0.0008, ORallelic= 2.22 (1.21-4.05) ORressessive= 21.9 (1.96-245.4).ConclusionVariation in the innate immunity genesCARD4,CARD8andCARD15is unlikely to play a major role in the susceptibility to CRC in the German population. But, we report a significant disease contribution ofCARD15for CRC patients with very early disease manifestation, mainly driven by variant R702W.
Chronic disease prevalence and care among the elderly in urban and rural Beijing, China - a 10/66 Dementia Research Group cross-sectional survey
Authors: Liu Zhaorui , Albanese Emiliano , Li Shuran , Huang Yueqin , Ferri Cleusa P , Yan Fang , Sousa Renata , Dang Weimin , Prince Martin 
Published: October 2009

Abstract

Background
Demographic ageing is occurring at an unprecedented rate in China. Chronic diseases and their disabling consequences will become much more common. Public policy has a strong urban bias, and older people living in rural areas may be especially vulnerable due to limited access to good quality healthcare, and low pension coverage. We aim to compare the sociodemographic and health characteristics, health service utilization, needs for care and informal care arrangements of representative samples of older people in two Beijing communities, urban Xicheng and rural Daxing.

Methods
A one-phase cross-sectional survey of all those aged 65 years and over was conducted in urban and rural catchment areas in Beijing, China. Assessments included questionnaires, a clinical interview, physical examination, and an informant interview. Prevalence of chronic diseases, self-reported impairments and risk behaviours was calculated adjusting for household clustering. Poisson working models were used to estimate the independent effect of rural versus urban residence, and to explore the predictors of health services utilization.

Results
We interviewed 1002 participants in rural Daxing, and 1160 in urban Xicheng. Those in Daxing were more likely to be younger, widowed, less educated, not receiving a pension, and reliant on family transfers. Chronic diseases were more common in Xicheng, when based on self-report rather than clinical assessment. Risk exposures were more common in Daxing. Rural older people were much less likely to access health services, controlling for age and health. Community health services were ineffective, particularly in Daxing, where fewer than 3% of those with hypertension were adequately controlled. In Daxing, care was provided by family, who had often given up work to do so. In Xicheng, 45% of those needing care were supported by paid caregivers. Caregiver strain was higher in Xicheng. Dementia was strongly associated with care needs and caregiver strain, but not with medical helpseeking.

Conclusion
Apparent better health in Daxing might be explained by under-diagnosis, under-reporting or selective mortality. Far-reaching structural reforms may be needed to improve access and strengthen rural healthcare. The impact of social and economic change is already apparent in Xicheng, with important implications for future long-term care.
Mitomycin C induces bystander killing in homogeneous and heterogeneous hepatoma cellular models
Authors: Kumari Ratna , Sharma Aanchal , Ajay Amrendra Kumar , Bhat Manoj Kumar 
Published: October 2009

Abstract

Background
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide that is particularly refractory to chemotherapy. Several studies have proposed combination chemotherapy regimen for HCC treatment. However, these therapies are not effective in regressing tumor and prolonging survival of patient's suffering from HCC. Therefore, the development of more effective therapeutic tools and new strategies for the treatment of HCC are urgently needed. Over the last decade much attention has been focused on "bystander effect" as a possible therapeutic strategy for the treatment of certain human tumors. Interest in this therapeutic approach originated from numerous reports describing the radiation induced bystander effect. However, the knowledge about chemotherapy induced bystander effect is still limited. Hence, chemotherapy induced bystander phenomenon in hepatoma cells was explored by utilizing Mitomycin C (MMC).

Results
MMC induced bystander killing was observed only in hepatoma cells and it did not occur in cervical cancer cells. MMC induced bystander killing was transferable via medium. It occurred in co-cultured cells indicating the involvement of secreted as well as membrane bound factors. FasL and TRAIL were detected in the conditioned medium from treated cells. In medium transfer experiment, pre-treatment with EDTA (a broad range protease inhibitor) diminished MMC induced bystander killing. Following drug exposure, expression of Fas and TRAIL receptors increased and treatment with neutralizing antibodies against FasL and TRAIL inhibited bystander killing.

Conclusion
Our results highlight the therapeutic importance of MMC in the treatment of HCC and implicate role of membrane bound and secreted forms of FasL and TRAIL in MMC induced bystander killing.