bluuebunny/crossref_metadata_2025_split huggingface dataset:
Detection of KRAS Oncogene in Peripheral Blood as a Predictor of the Response to Cetuximab Plus Chemotherapy in Patients with Metastatic Colorectal Cancer
Authors: Yen Li-Chen , Yeh Yung-Sung , Chen Chao-Wen , Wang Hwei-Ming , Tsai Hsiang-Lin , Lu Chien-Yu , Chang Yu-Tang , Chu Koung-Shing , Lin Shiu-Ru , Wang Jaw-Yuan 
Published: June 2009

Abstract
Purpose: Previously we developed membrane-arrays as a promising tool to detect circulating tumor cells (CTC) with KRAS oncogene in patients with malignancies. This study was conducted to determinate the predictive values of CTCs with KARS mutation by membrane-arrays for metastatic colorectal cancer patients treated with cetuximab plus chemotherapy.
Experimental Design: Seventy-six metastatic colorectal cancer patients receiving cetuximab plus FOLFIRI or FOLFOX-4 chemotherapy were enrolled. KRAS mutation status in the peripheral blood of these patients was analyzed using membrane-arrays, and KRAS mutation status in tumors was analyzed by DNA sequencing.
Results: Among 76 metastatic colorectal cancer patients, KRAS mutations in tumors and in peripheral blood were identified in 33 (43.4%) and 30 (39.5%) patients, respectively. The detection sensitivity, specificity, and accuracy of membrane-arrays for CTCs with KRAS oncogene were 84.4%, 95.3%, and 90.8%, respectively, and indeed a highly significant correlation to KRAS mutations in tumors (P &lt; 0.0001) was observed. Forty-five (59.2%) patients responded to cetuximab plus chemotherapy, and 41 and 40 were wild-type KRAS in tumors and peripheral blood, respectively (both P &lt; 0.0001). Patients with tumors that harbor wild-type KRAS are more likely to have a better progression-free survival and overall survival when treated with cetuximab plus chemotherapy (P &lt; 0.0001). Likewise, patients with CTCs of wild-type KRAS in peripheral blood express a better progression-free survival and overall survival when treated with cetuximab plus chemotherapy (P &lt; 0.0001).
Conclusions: These findings provide evidence that detection of KRAS mutational status in CTCs, by gene expression array, has potential for clinical application in selecting metastatic colorectal cancer patients most likely to benefit from cetuximab therapy.
A Cohort Study of Cyclin D1 Expression and Prognosis in 602 Colon Cancer Cases
Authors: Ogino Shuji , Nosho Katsuhiko , Irahara Natsumi , Kure Shoko , Shima Kaori , Baba Yoshifumi , Toyoda Saori , Chen Li , Giovannucci Edward L. , Meyerhardt Jeffrey A. , Fuchs Charles S. 
Published: June 2009

Abstract
Purpose: Cyclin D1 and cyclin-dependent kinases (CDK) are commonly activated in colorectal cancer. The activity of cyclin D1 can be blocked by CDK inhibitors, including p27 (CDKN1B) and p21 (CDKN1A, which is induced by p53). However, prognostic significance of tumoral cyclin D1 remains uncertain, and no previous study has considered potential confounding effect of p53, p21, p27, and related molecular events [microsatellite instability (MSI), CpG island methylator phenotype, and LINE-1 hypomethylation].
Experimental Design: Among 602 colon cancer patients (stage I-IV) in two prospective cohort studies, cyclin D1 overexpression was detected in 330 (55%) tumors by immunohistochemistry. Cox proportional hazard models computed hazard ratios (HR) of colon cancer–specific and overall mortalities, adjusted for patient characteristics and tumoral molecular features, including p53, p21, p27, cyclooxygenase-2, fatty acid synthase, LINE-1 methylation, CpG island methylator phenotype, MSI, BMI, KRAS, and BRAF.
Results: Cyclin D1 overexpression was associated with a low cancer-specific mortality in Kaplan-Meier analysis (P = 0.006), and in both univariate Cox regression [unadjusted HR, 0.64; 95% confidence interval (CI), 0.47-0.88; P = 0.0063] and multivariate analyses (adjusted HR, 0.57; 95% CI, 0.39-0.84; P = 0.0048). Similar findings were observed for an overall mortality (adjusted HR, 0.74; 95% CI, 0.57-0.98; P = 0.036). Notably, the effect of cyclin D1 on survival might differ by MSI status (Pinteraction = 0.008). Compared with tumors that were both cyclin D1–negative and MSI-low/microsatellite stable, the presence of either cyclin D1 or MSI-high or both seemed to confer better clinical outcome (adjusted HR point estimates, 0.10-0.65).
Conclusions: Cyclin D1 overexpression is associated with longer survival in colon cancer.
A Phase I Trial of Radioimmunotherapy with 131I-A5B7 Anti-CEA Antibody in Combination with Combretastatin-A4-Phosphate in Advanced Gastrointestinal Carcinomas
Authors: Meyer Tim , Gaya Andrew M. , Dancey Gairin , Stratford Michael R.L. , Othman Shokri , Sharma Surinder K. , Wellsted David , Taylor N. Jane , Stirling J. James , Poupard Linda , Folkes Lisa K. , Chan Pei-san , Pedley R. Barbara , Chester Kerry A. , Owen Karen , Violet John A. , Malaroda Alessandra , Green Alan J. , Buscombe John , Padhani Anwar R. , Rustin Gordon J. , Begent Richard H. 
Published: June 2009

Abstract
Purpose: In preclinical models, radioimmunotherapy with 131I-A5B7 anti–carcinoembryonic antigen (CEA) antibody (131I-A5B7) combined with the vascular disruptive agent combretastatin-A4-phosphate (CA4P) produced cures unlike either agent alone. We conducted a phase I trial determining the dose-limiting toxicity (DLT), maximum tolerated dose, efficacy, and mechanism of this combination in patients with gastrointestinal adenocarcinomas.
Experimental Design: Patients had CEA of 10 to 1,000 μg/L, QTc ≤450 ms, no cardiac arrhythmia/ischaemia, and adequate hematology/biochemistry. Tumor was suitable for blood flow analysis by dynamic contrast enhanced-magnetic resonance imaging (MRI). The starting dose was 1,800 MBq/m2 of 131I-A5B7 on day 1 and 45 mg/m2 CA4P given 48 and 72 hours post-131I-A5B7, then weekly for up to seven weeks.
Results: Twelve patients were treated, with mean age of 63 years (range, 32-77). Two of six patients at the first dose level had DLTs (grade 4 neutropenia). The dose was reduced to 1,600 MBq/m2, and CA4P escalated to 54 mg/m2. Again, two of six patients had DLTs (neutropenia). Of ten assessable patients, three had stable disease and seven had progressive disease. Single-photon emission computed tomography confirmed tumor antibody uptake in all 10 patients. DCE-MRI confirmed falls in kinetic parameters (Ktrans/IAUGC60) in 9 of 12 patients. The change of both pharmacokinetic parameters reached a level expected to produce efficacy in one patient who had a minor response on computed tomography and a reduced serum tumor marker level.
Conclusions: This is believed to be the first trial reporting the combination of radioimmunotherapy and vascular disruptive agent; each component was shown to function, and myelosuppression was dose-limiting. Optimal dose and timing of CA4P, and moderate improvements in the performance of radioimmunotherapy seem necessary for efficacy.
Enhanced Systemic Immune Reactivity to a Basal Cell Carcinoma Associated Antigen Following Photodynamic Therapy
Authors: Kabingu Edith , Oseroff Allan R. , Wilding Gregory E. , Gollnick Sandra O. 
Published: June 2009

AbstractPurpose: Numerous preclinical studies have shown that local photodynamic therapy (PDT) of tumors enhances systemic antitumor immunity. However, other than single-case and anecdotal reports, this phenomenon has not been examined following clinical PDT. To determine whether PDT in a clinical setting enhances systemic recognition of tumor cells, we examined whether PDT of basal cell carcinoma resulted in an increased systemic immune response to Hip1, a tumor antigen associated with basal cell carcinoma.Experimental Design: Basal cell carcinoma lesions were either treated with PDT or surgically removed. Blood was collected from patients immediately before or 7 to 10 days following treatment. Peripheral blood leukocytes were isolated from HLA-A2–expressing patients and reactivity to a HLA-A2–restricted Hip1 peptide was measured by INF-γ ELISpot assay.Results: Immune recognition of Hip1 increased in patients whose basal cell carcinoma lesions were treated with PDT. This increase in reactivity was significantly greater than reactivity observed in patients whose lesions were surgically removed. Patients with superficial lesions exhibited greater enhancement of reactivity compared with patients with nodular lesions. Immune reactivity following PDT was inversely correlated with treatment area and light dose.Conclusions: These findings show for the first time that local tumor PDT can enhance systemic immune responses to tumors in patients, and validate previous preclinical findings.
Collapse of the CD27+ B-Cell Compartment Associated with Systemic Plasmacytosis in Patients with Advanced Melanoma and Other Cancers
Authors: Carpenter Erica L. , Mick Rosemarie , Rech Andrew J. , Beatty Gregory L. , Colligon Theresa A. , Rosenfeld Myrna R. , Kaplan David E. , Chang Kyong-Mi , Domchek Susan M. , Kanetsky Peter A. , Fecher Leslie A. , Flaherty Keith T. , Schuchter Lynn M. , Vonderheide Robert H. 
Published: June 2009

Abstract
Purpose: Disturbed peripheral blood B-cell homeostasis complicates certain infections and autoimmune diseases, such as HIV and systemic lupus erythematosus, but has not been reported in cancer. This study aimed to investigate whether B-cell physiology was altered in the presence of melanoma and other cancers.
Experimental Design: Flow cytometry was used to identify phenotypic differences in B cells from patients with melanoma and normal donors. In vitro stimulated B cells were assessed for responsiveness and also used as stimulators of allogeneic T cells in mixed lymphocyte reactions.
Results: We show B-cell dysregulation in patients with advanced melanoma (n = 26) and other solid tumors (n = 13), marked by a relative and absolute loss of CD27+ (memory) B cells and associated with an aberrant systemic plasmacytosis. Functionally, B cells from patients with melanoma inefficiently up-regulated immunoregulatory molecules and weakly secreted cytokines in response to CD40 and toll-like receptor 9 agonists. Stimulated B cells from patients induced proliferation of alloreactive CD4+ T cells, but these T cells poorly secreted IFNγ and interleukin-2. These effects were recapitulated by using purified normal donor CD27neg B cells in these same assays, linking the predominance of CD27neg B cells in patients with the observed functional hyporesponsiveness. Indeed, B-cell dysfunction in patients strongly correlated with the extent of loss of CD27+ B cells in peripheral blood.
Conclusions: Disturbed B-cell homeostasis is a previously unrecognized feature of patients with advanced melanoma and other cancers and may represent an unanticipated mechanism of immune incompetence in cancer.
Anti-inflammatory Action of Pterostilbene Is Mediated through the p38 Mitogen-Activated Protein Kinase Pathway in Colon Cancer Cells
Authors: Paul Shiby , Rimando Agnes M. , Lee Hong Jin , Ji Yan , Reddy Bandaru S. , Suh Nanjoo 
Published: June 2009

AbstractOxidative/nitrosative stress and generation of proinflammatory cytokines are hallmarks of inflammation. Because chronic inflammation is implicated in several pathologic conditions in humans, including cancers of the colon, anti-inflammatory compounds may be useful chemopreventive agents against colon cancer. Stilbenes, such as resveratrol, have diverse pharmacologic activities, which include anti-inflammation, cancer prevention, a cholesterol-lowering effect, enhanced insulin sensitivity, and increased life span. We previously showed that pterostilbene (trans-3,5-dimethoxy-4′-hydroxystilbene), a structural analogue of resveratrol, is present in blueberries and that pterostilbene inhibited expression of certain inflammation-related genes in the colon and suppressed aberrant crypt foci formation in rats. Here, we examined molecular mechanisms of the action of pterostilbene in colon cancer. Pterostilbene reduced cell proliferation, down-regulated the expression of c-Myc and cyclin D1, and increased the level of cleaved poly(ADP-ribose) polymerase. A combination of cytokines (tumor necrosis factor-α, IFN-γ, and bacterial endotoxin lipopolysaccharide) induced inflammation-related genes such as inducible nitric oxide synthase and cyclooxygenase-2, which was significantly suppressed by treatment with pterostilbene. We further identified upstream signaling pathways contributing to the anti-inflammatory activity of pterostilbene by investigating multiple signaling pathways, including nuclear factor-κB, Janus-activated kinase-signal transducer and activator of transcription, extracellular signal-regulated kinase, p38, c-Jun NH2-terminal kinase, and phosphatidylinositol 3-kinase. Cytokine induction of the p38-activating transcription factor 2 pathway was markedly inhibited by pterostilbene among the different mediators of signaling evaluated. By silencing the expression of the p38α isoform, there was significant reduction in cytokine induction of inducible nitric oxide synthase and cyclooxygenase-2. Our data suggest that the p38 mitogen-activated protein kinase cascade is a key signal transduction pathway for eliciting the anti-inflammatory action of pterostilbene in cultured HT-29 colon cancer cells.
The Interaction of a High-Fat Diet and Regular Moderate Intensity Exercise on Intestinal Polyp Development in ApcMin/+ Mice
Authors: Baltgalvis Kristen A. , Berger Franklin G. , Peña Maria Marjorette O. , Davis J. Mark , Carson James A. 
Published: June 2009

Abstract
Diet and exercise are two environmental factors that can alter colon cancer risk. The purpose of this study was to determine if regular moderate-intensity treadmill exercise training could attenuate polyp formation in ApcMin/+ mice fed the Western-style diet. Four-week-old male ApcMin/+ mice (n = 12 per group) were assigned to AIN-76A Control, AIN-76A Exercise, Western Control, or Western Exercise treatment groups. Mice were weaned to these diets and either subjected to regular moderate-intensity treadmill exercise (18 m/min, 60 min/d, 6 d/wk) or remained sedentary for 6 weeks. Mice fed the Western-style diet consumed ∼14% more calories and had 42% more epididymal fat compared with mice fed the AIN-76A diet. Exercise had no effect on fat pad mass with either diet treatment. Exercise reduced total intestinal polyp number by 50% and the number of large polyps (&gt;1 mm diameter) by 67% in AIN-76A–fed mice. The Western-style diet increased polyp number by 75% when compared with AIN-76A–fed mice, but exercise did not decrease polyp number or alter polyp size in mice fed the Western-style diet. Markers of systemic inflammation and immune system function were improved with exercise in mice fed the AIN-76A diet. Mice fed the Western-style diet showed more inflammation and immunosuppression, which were not completely ameliorated by exercise. These data suggest that the induction of adiposity, inflammation, and immunosuppression by the Western-style diet may compromise the beneficial effect of moderate-intensity exercise on the intestinal polyp burden in ApcMin/+ mice.
Wind Effects on Drogued and Undrogued Drifters in the Eastern Mediterranean
Authors: Poulain Pierre-Marie , Gerin Riccardo , Mauri Elena , Pennel Romain 
Published: June 2009

AbstractThe wind effects on drogued and undrogued drifters are assessed using Coastal Ocean Dynamics Experiment (CODE) and Surface Velocity Program (SVP) drifter datasets and ECMWF wind products in the eastern Mediterranean. Complex and real linear regression models are used to estimate the relative slip of undrogued SVP drifters and to extract the wind-driven currents from the drifter velocities. The frequency response of the wind-driven currents is studied using cross-spectral analysis. By comparing the velocities of cotemporal and nearly collocated undrogued and drogued SVP drifters, it appears that undrogued SVP drifters have a general downwind slippage of about 1% of the wind speed. Time-lagged complex correlations and cross-spectral results show that the wind response is almost simultaneous. The velocities of SVP drifters drogued to 15 m are poorly correlated with the winds (R2 ≈ 3%): wind-driven currents have a magnitude of 0.7% of the wind speed and are 27°–42° to the right of the wind. For undrogued SVP drifters, the correlation with the winds increases to R2 ≈ 22% and the angle between winds and currents decreases to 17°–20°. The magnitude of the wind-driven currents is about 2% of the wind speed. For CODE designs, wind-driven currents are 1% of the wind speed at an angle of about 28° to the right of the wind (R2 ≈ 8%). Spectral and cospectral analyses reveal that the drifters sampled more anticyclonic than cyclonic motions. The inner coherence spectra show that wind and currents are more correlated at temporal scales spanning 3–10 days. They also confirm that the wind response is quasi-simultaneous and that currents are generally to the right of the wind.
Social Relationships as a Decisive Factor in Recovering From Severe Mental Illness
Authors: Schön Ulla-Karin , Denhov Anne , Topor Alain 
Published: June 2009

Background: Recovery research often describes recovery from mental illness as a complex individual process. In this article a social perspective on recovery is developed. Aims: To ascertain which factors people regard as decisive to their own recovery and what makes them beneficial. Methods: In-depth interviews were conducted with 58 persons in Sweden who had recovered from severe mental illness. Interviews were qualitatively analyzed using grounded theory. Results: Three dimensions of contributing recovery factors were identified. Social relationships emerged as the core category throughout these dimensions. Conclusions: The results show that recovery processes are social processes in which social relationships play a key role.
Psychological Help-Seeking in Homeless Adolescents
Authors: Collins Pádraig , Barker Chris 
Published: June 2009

Background: Homeless young people in the UK are a vulnerable group: their levels of psychological problems, physical ill health and violent victimisation exceed those of their housed counterparts. Aims: This qualitative study aimed to examine homeless young people's views about seeking psychological help for their problems. Method: Semi-structured interviews were undertaken with 16 homeless young people at an emergency hostel. A thematic analysis and an analysis of the participants' narratives were undertaken. Results: A sense of hurt and anger at the perceived betrayal by their families and society made many participants reluctant to seek help and to trust help offered by others, and accordingly they placed a high value on self-sufficiency. Many said that they would, however, seek help from people whom they perceived to be genuine, caring, trustworthy, empathic and capable of containing their distress. Conclusion: Mental health professionals providing clinical services for this underserved population need to be aware of the importance of rejection and abandonment issues, along with the consequent hurt, anger and mistrust.
Compeer Friends: a Qualitative Study of a Volunteer Friendship Programme for People with Serious Mental Illness
Authors: Mccorkle Brian H. , Dunn Erin C. , Yu Mui Wan  , Gagne Cheryl 
Published: June 2009

Background: People with serious mental illness (SMI) experience numerous barriers to developing and maintaining friendships. Aims: To explore the benefits and drawbacks of an intentional friendship programme (Compeer, Inc), which develops new social relationships for people with SMI by matching them in one-to-one relationships with community volunteers for weekly social activities. Methods: Twenty clients and volunteers, in Compeer friendships for different lengths of time, participated in individual semi-structured qualitative interviews. Several volunteers were themselves current or former consumers of mental health services. Results: Participants reported numerous benefits to participating in Compeer. Clients and volunteers spoke enthusiastically about the benefits of gaining a friend. Many intentional relationships deepened over several years into mutually beneficial friendships. Most clients became more outgoing, sociable and active, with increased self-esteem, self-worth and self-confidence. Volunteers who had experienced mental illness themselves provided unique added benefits to the relationship. Drawbacks were minimal and financial and other costs to volunteers were low. Conclusions: Intentional friendships can be a potent yet cost-effective way to help people with SMI develop social skills, expand their social networks, and improve their quality of life. However, because relationships take several years to develop, quantitative evaluations using short follow-up periods may underestimate programme effectiveness.
Solo travel: Explorative insights from a mature market (Switzerland)
Authors: Laesser Christian , Beritelli Pietro , Bieger Thomas 
Published: June 2009

This study examines solo travel, and offers (1) a conceptual framework of solo travelers, (2) a profile of these types of travelers (by socio-demographic characteristics), and (3) a profile of travels (by specific descriptors). The data for this study stem from a comprehensive survey of Swiss travel behavior conducted in 2004 by the University of St. Gallen (Switzerland). The conceptual model is derived from transportation research. It proposes an a priori segmentation of four types of solo travel, delineated on the combination of the (1) departure status (a single, one-person household, compared to a collective, multi-persons household) and (2) arrival status (solo travel, compared to group travel), thus creating a two-by-two matrix with four segments overall. Solo travelers basically either tend to foster an existing social network or try to nurse their curiosity and at the same time look for new social contacts. The results of the profiling further reveal significant differences between the solo travel groups, as well as towards a control group incorporating all other travel. They include income, profession, and age, as well as familiarity with the destination, choice of type of accommodation, expenditures and various types of trips. However, no significant differences can be reported with regard to the choice of destination.
Lineages of human T-cell clones, including T helper 17/T helper 1 cells, isolated at different stages of anti–factor VIII immune responses
Authors: Ettinger Ruth A. , James Eddie A. , Kwok William W. , Thompson Arthur R. , Pratt Kathleen P. 
Published: June 2009

AbstractThe development of neutralizing antibodies (inhibitors) after factor VIII (FVIII) infusions is a serious complication that affects approximately one-quarter of hemophilia A patients who have access to replacement therapy. To investigate the differentiation of naive T cells into FVIII-specific helper T cells that promote B-cell activation and antibody secretion, HLA-DRA-DRB1*0101-restricted T-cell clones that respond to a specific epitope in FVIII were isolated from a mild hemophilia A subject (the proband) 19 weeks and 21 months after his development of a high-titer inhibitor. Clones responding to the same epitope were also isolated from his multiply infused brother, who has not developed a clinically significant inhibitor. The 19-week proband clones were T helper (TH)17/TH1- or TH1/TH2-polarized, whereas all 8 clones isolated 21 months postinhibitor development were TH2-polarized cells. In contrast, all 6 clones from the brother who did not develop an inhibitor were TH1-polarized, indicating that tolerance to FVIII can be maintained even with circulating TH1-polarized cells that respond vigorously to in vitro FVIII stimulation. This is the first evidence that TH17/TH1-polarized cells play a role in hemophilic immune responses to FVIII. Furthermore, this is the first report of successful isolation and expansion of antigen-specific human TH17/TH1 clones using standard culture conditions.