bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic Significance of TRAIL Signaling Molecules in Stage II and III Colorectal Cancer
Authors: McLornan Donal P. , Barrett Helen L. , Cummins Robert , McDermott Ultan , McDowell Cliona , Conlon Susie J. , Coyle Victoria M. , Van Schaeybroeck Sandra , Wilson Richard , Kay Elaine W. , Longley Daniel B. , Johnston Patrick G. 
Published: June 2010

AbstractPurpose: We previously found that cellular FLICE-inhibitory protein (c-FLIP), caspase 8, and tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) receptor 2 (DR5) are major regulators of cell viability and chemotherapy-induced apoptosis in colorectal cancer. In this study, we determined the prognostic significance of c-FLIP, caspase 8, TRAIL and DR5 expression in tissues from patients with stage II and III colorectal cancer.Experimental Design: Tissue microarrays were constructed from matched normal and tumor tissue derived from patients (n = 253) enrolled in a phase III trial of adjuvant 5-fluorouracil–based chemotherapy versus postoperative observation alone. TRAIL, DR5, caspase 8, and c-FLIP expression levels were determined by immunohistochemistry.Results: Colorectal tumors displayed significantly higher expression levels of c-FLIP (P &lt; 0.001), caspase 8 (P = 0.01), and DR5 (P &lt; 0.001), but lower levels of TRAIL (P &lt; 0.001) compared with matched normal tissue. In univariate analysis, higher TRAIL expression in the tumor was associated with worse overall survival (P = 0.026), with a trend to decreased relapse-free survival (RFS; P = 0.06), and higher tumor c-FLIP expression was associated with a significantly decreased RFS (P = 0.015). Using multivariate predictive modeling for RFS in all patients and including all biomarkers, age, treatment, and stage, we found that the model was significant when the mean tumor c-FLIP expression score and disease stage were included (P &lt; 0.001). As regards overall survival, the overall model was predictive when both TRAIL expression and disease stage were included (P &lt; 0.001).Conclusions: High c-FLIP and TRAIL expression may be independent adverse prognostic markers in stage II and III colorectal cancer and might identify patients most at risk of relapse. Clin Cancer Res; 16(13); 3442–51. ©2010 AACR.
Immunohistochemical Detection of EGFR Mutation Using Mutation-Specific Antibodies in Lung Cancer
Authors: Kitamura Atsuko , Hosoda Waki , Sasaki Eiichi , Mitsudomi Tetsuya , Yatabe Yasushi 
Published: June 2010

Abstract
Purpose: Patients with mutations of epidermal growth factor receptor (EGFR) receive more benefit from EGFR-tyrosine kinase inhibitor treatment. However, usually such treatment is used to treat advanced lung cancer and only small biopsy samples are available for mutational analysis. We used immunohistochemistry to examine recently developed antibodies specific to major hotspot mutations of L858R and DEL E746-A750.
Experimental Design: We used five series of lung cancers: 47 non–small cell lung cancers (NSCLC) to evaluate various types of EGFR mutations, a consecutive series of 238 NSCLCs to study the sensitivity and specificity, 11 NSCLCs with both EGFR mutation and amplification to examine the spatial distribution, 32 patients treated with gefitinib to compare clinical responses, and 15 NSCLCs to explore changes associated with acquired T790M mutation.
Results: Each antibody specifically recognized the corresponding mutation but also recognized other types of mutations. Overall specificity and sensitivity were 96% and 47%, respectively. The positive reaction showed heterogeneous distribution that agreed with the expression of the total EGFR molecule, part of which was associated with gene amplification. A clinical response to gefitinib treatment correlated with the reaction, although one of the two patients with a positive reaction responded well despite having the wild-type EGFR. Acquired T790M mutation did not change the reaction to the antibodies.
Conclusions: On some characteristics, the positive reaction to mutation-specific antibodies differs from the molecular EGFR mutation. Therefore, this study revealed that not all patients with EGFR mutations can be selected using these mutation-specific antibodies. Clin Cancer Res; 16(13); 3349–55. ©2010 AACR.
Sorafenib, a Multikinase Inhibitor, Enhances the Response of Melanoma to Regional Chemotherapy
Authors: Augustine Christina K. , Toshimitsu Hiroaki , Jung Sin-Ho , Zipfel Patricia A. , Yoo Jin S. , Yoshimoto Yasunori , Selim M. Angelica , Burchette James , Beasley Georgia M. , McMahon Nicole , Padussis James , Pruitt Scott K. , Ali-Osman Francis , Tyler Douglas S. 
Published: June 2010

Abstract
Melanoma responds poorly to standard chemotherapy due to its intrinsic chemoresistance. Multiple genetic and molecular defects, including an activating mutation in the BRaf kinase gene, are associated with melanoma, and the resulting alterations in signal transduction pathways regulating proliferation and apoptosis are thought to contribute to its chemoresistance. Sorafenib, a multikinase inhibitor that targets BRaf kinase, is Food and Drug Administration approved for use in advanced renal cell and hepatocellular carcinomas. Although sorafenib has shown little promise as a single agent in melanoma patients, recent clinical trials suggest that, when combined with chemotherapy, it may have more benefit. We evaluated the ability of sorafenib to augment the cytotoxic effects of melphalan, a regional chemotherapeutic agent, and temozolomide, used in systemic and regional treatment of melanoma, on a panel of 24 human melanoma-derived cell lines and in an animal model of melanoma. Marked differences in response to 10 μmol/L sorafenib alone were observed in vitro across cell lines. Response to sorafenib significantly correlated with extracellular signal-regulated kinase (ERK) downregulation and loss of Mcl-1 expression (P &lt; 0.05). Experiments with the mitogen-activated protein kinase/ERK kinase inhibitor U0126 suggest a unique role for ERK downregulation in the observed effects. Sorafenib in combination with melphalan or temozolomide led to significantly improved responses in vitro (P &lt; 0.05). In the animal model of melanoma, sorafenib in combination with regional melphalan or regional temozolomide was more effective than either treatment alone in slowing tumor growth. These results show that sorafenib in combination with chemotherapy provides a novel approach to enhance chemotherapeutic efficacy in the regional treatment of in-transit melanoma. Mol Cancer Ther; 9(7); 2090–101. ©2010 AACR.
A Genetically Encoded Multifunctional TRAIL Trimer Facilitates Cell-Specific Targeting and Tumor Cell Killing
Authors: Spitzer Dirk , McDunn Jonathan E. , Plambeck-Suess Stacey , Goedegebuure Peter S. , Hotchkiss Richard S. , Hawkins William G. 
Published: June 2010

Abstract
Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL, Apo2L) has been shown to exhibit potent and specific apoptotic activity against tumor cells. Several TRAIL constructs have been tried in patients, and the molecule remains under active clinical investigation. Native and recombinant TRAIL must form a homotrimer to become biologically active. However, noncovalently associated TRAIL displays a high degree of sensitivity to degradation, which limits its therapeutic potential. To enforce trimerization of the recombinant protein, we developed a covalently linked TRAIL trimer (TR3) by genetic fusion. This molecular drug design conferred improved stability without altering the native killing ability of TRAIL. Target specificity was shown by blocking TR3 activity with soluble death receptor 5 (DR5-Fc). In addition, we have shown that TR3 is amenable to further, genetic modifications. The incorporation of additional functional domains to TR3, such as antibody fragments (scFvs) that allow for a more cell-specific delivery of the agent, is stoichiometrically controlled and inconsequential with regard to the bioactivity of TRAIL. As proof of this concept, TR3 activity was targeted to the mouse RBC membrane. TR3-decorated RBCs were effectively capable of target cell killing in a model of pancreatic cancer. TR3 represents a generally applicable platform tool to study basic mechanisms along the death receptor pathway. More importantly, the ability to target TR3 to a cell surface presents the opportunity to create a cancer-selective drug with fewer off-target toxicities and enhanced killing capacities. Mol Cancer Ther; 9(7); 2142–51. ©2010 AACR.
Combining the FLT3 Inhibitor PKC412 and the Triterpenoid CDDO-Me Synergistically Induces Apoptosis in Acute Myeloid Leukemia with the Internal Tandem Duplication Mutation
Authors: Ahmad Rehan , Liu Suiyang , Weisberg Ellen , Nelson Erik , Galinsky Ilene , Meyer Colin , Kufe Donald , Kharbanda Surender , Stone Richard 
Published: June 2010

Abstract
Mutations of the FLT3 receptor tyrosine kinase consisting of internal tandem duplications (ITD) have been detected in blasts from 20% to 30% of patients with acute myeloid leukemia (AML) and are associated with a poor prognosis. FLT3/ITD results in constitutive autophosphorylation of the receptor and factor-independent survival in leukemia cell lines. The C-28 methyl ester of the oleane triterpenoid (CDDO-Me) is a multifunctional molecule that induces apoptosis of human myeloid leukemia cells. Here, we report that CDDO-Me blocks targeting of NFκB to the nucleus by inhibiting IκB kinase β–mediated phosphorylation of IκBα. Moreover, CDDO-Me blocked constitutive activation of the signal transducer and activator of transcription 3. We report the potent and selective antiproliferative effects of CDDO-Me on FLT3/ITD-positive myeloid leukemia cell lines and primary AML cells. The present studies show that CDDO-Me treatment results in caspase-3–mediated induction of apoptosis of FLT3/ITD-expressing cells and its antiproliferative effects are synergistic with PKC412, a FLT3-tyrosine kinase inhibitor currently in clinical trials. Taken together, our studies indicate that CDDO-Me greatly enhanced the efficacy of the FLT3 inhibitor PKC412, suggesting that combining two separate pathway inhibitors might be a viable therapeutic strategy for AML associated with a FLT3/ITD mutation. Mol Cancer Res; 8(7); 986–93. ©2010 AACR.
Optical Measurement of Rectal Microvasculature as an Adjunct to Flexible Sigmoidosocopy: Gender-Specific Implications
Authors: Roy Hemant K. , Gomes Andrew J. , Ruderman Sarah , Bianchi Laura K. , Goldberg Michael J. , Stoyneva Valentina , Rogers Jeremy D. , Turzhitsky Vladimir , Kim Young , Yen Eugene , Jameel Mohammed , Bogojevic Andrej , Backman Vadim 
Published: June 2010

Abstract
Flexible sigmoidoscopy is a robust, clinically validated, and widely available colorectal cancer screening technique that is currently sanctioned by major guideline organizations. Given that endoscopic visualization is generally limited to the distal third of the colon and women tend to have a proclivity for proximal lesions, the flexible sigmoidoscopy performance is markedly inferior in women than in men. Our group has shown that by using a novel light-scattering approach, we were able to detect an early increase in blood supply (EIBS) in the distal colonic mucosa, which served as a marker of field carcinogenesis and, hence, proximal neoplasia. Therefore, we sought to ascertain whether rectal EIBS would improve flexible sigmoidoscopy, especially in women. A polarization-gated spectroscopy fiber-optic probe was used to assess EIBS in the endoscopically normal rectum (n = 366). When compared with gender-matched neoplasia-free controls, females with advanced proximal neoplasia (n = 10) had a robust (60%; P = 0.002) increase in rectal mucosal oxyhemoglobin content whereas the effect size in males was less marked (33%; P = 0.052). In women, addition of rectal oxyhemoglobin tripled the sensitivity for advanced neoplasia over flexible sigmoidoscopy alone. Indeed, the performance characteristics seemed to be excellent (sensitivity, 100%; specificity, 76.8%; positive predictive value, 32.6%; and negative predictive value, 100%). A variety of nonneoplastic factors were assessed and did not confound the relationship between rectal EIBS and advanced neoplasia. Therefore, using rectal EIBS in combination with flexible sigmoidoscopy mitigated the gender gap and may allow flexible sigmoidoscopy to be considered as a viable colorectal cancer screening test in women. Cancer Prev Res; 3(7); 844–51. ©2010 AACR.
One Year Recurrence of Aberrant Crypt Foci
Authors: Pinsky Paul F. , Fleshman James , Mutch Matt , Rall Christopher , Charabaty Aline , Seligson David , Dry Sarah , Umar Asad , Schoen Robert E. 
Published: June 2010

Abstract
Aberrant crypt foci (ACF) are putative precursors of colorectal adenomas and have been postulated as a potential biomarker for colorectal cancer. Few studies have followed subjects after ACF removal to monitor recurrence. Subjects enrolled in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial were recruited for a study of ACF. A standardized protocol using magnified endoscopy and mucosal staining with methylene blue was implemented to detect rectal ACF. After removal of all baseline ACF, subjects returned 1 year later and recurrent ACF were observed and biopsied. A total of 434 of 505 (86%) subjects observed at baseline returned for the year 1 exam. The mean number of ACF at year 1 was strongly correlated with the number at baseline; subjects with 0, 1, 2 to 3, 4 to 6, and 7+ ACF at baseline had a mean of 1.2, 1.4, 1.7, 3.0, and 5.5 ACF, respectively, at year 1. ACF prevalence and mean count at year 1 (61% and 1.93, respectively), were only slightly lower than the corresponding values at year 0 (69% and 2.25, respectively). The locations of ACF at year 1 and baseline were significantly correlated. Of 96 ACF assessed for histology, 70 (73%) were hyperplastic and none were dysplastic. After removal of ACF at baseline, ACF counts 1 year later were only slightly reduced and were significantly correlated with the baseline ACF count. The results of this study do not support a role for ACF in clinical practice. Cancer Prev Res; 3(7); 839–43. ©2010 AACR.
Genetic Determinants of Major Blood Lipids in Pakistanis Compared With Europeans
Authors: Saleheen Danish , Soranzo Nicole , Rasheed Asif , Scharnagl Hubert , Gwilliam Rhian , Alexander Myriam , Inouye Michael , Zaidi Moazzam , Potter Simon , Haycock Philip , Bumpstead Suzanna , Kaptoge Stephen , Di Angelantonio Emanuele , Sarwar Nadeem , Hunt Sarah E. , Sheikh Nasir , Shah Nabi , Samuel Maria , Haider Shajjia Razi , Murtaza Muhammed , Thompson Alexander , Gobin Reeta , Butterworth Adam , Ahmad Usman , Hakeem Abdul , Zaman Khan Shah , Kundi Assadullah , Yaqoob Zia , Cheema Liaquat Ali , Qamar Nadeem , Faruqui Azhar , Mallick Nadeem Hayat , Azhar Muhammad , Samad Abdus , Ishaq Muhammad , Rasheed Syed Zahed , Jooma Rashid , Niazi Jawaid Hassan , Gardezi Ali Raza , Memon Nazir Ahmed , Ghaffar Abdul , Rehman Fazal-ur , Hoffmann Michael Marcus , Renner Wilfried , Kleber Marcus E. , Grammer Tanja B. , Stephens Jonathon , Attwood Anthony , Koch Kerstin , Hussain Mustafa , Kumar Kishore , Saleem Asim , Kumar Kishwar , Daood Muhammad Salman , Gul Aftab Alam , Abbas Shahid , Zafar Junaid , Shahid Faisal , Bhatti Shahzad Majeed , Ali Syed Saadat , Muhammad Fahim , Sagoo Gurdeep , Bray Sarah , McGinnis Ralph , Dudbridge Frank , Winkelmann Bernhard R. , Böehm Bernhard , Thompson Simon , Ouwehand Willem , März Winfried , Frossard Philippe , Danesh John , Deloukas Panos 
Published: June 2010

Background—
Evidence is sparse about the genetic determinants of major lipids in Pakistanis.

Methods and Results—

Variants (n=45 000) across 2000 genes were assessed in 3200 Pakistanis and compared with 2450 Germans using the same gene array and similar lipid assays. We also did a meta-analysis of selected lipid-related variants in Europeans. Pakistani genetic architecture was distinct from that of several ethnic groups represented in international reference samples. Forty-one variants at 14 loci were significantly associated with levels of HDL-C, triglyceride, or LDL-C. The most significant lipid-related variants identified among Pakistanis corresponded to genes previously shown to be relevant to Europeans, such as
CETP
associated with HDL-C levels (rs711752;
P
<10
−13
),
APOA5/ZNF259
(rs651821;
P
<10
−13
) and
GCKR
(rs1260326;
P
<10
−13
) with triglyceride levels; and
CELSR2
variants with LDL-C levels (rs646776;
P
<10
−9
). For Pakistanis, these 41 variants explained 6.2%, 7.1%, and 0.9% of the variation in HDL-C, triglyceride, and LDL-C, respectively. Compared with Europeans, the allele frequency of rs662799 in
APOA5
among Pakistanis was higher and its impact on triglyceride concentration was greater (
P
-value for difference <10
−4
).

Conclusions—
Several lipid-related genetic variants are common to Pakistanis and Europeans, though they explain only a modest proportion of population variation in lipid concentration. Allelic frequencies and effect sizes of lipid-related variants can differ between Pakistanis and Europeans.
Circadian Rhythms in Patients With ST-Elevation Myocardial Infarction
Authors: Holmes David R. , Aguirre Frank V. , Aplin Richard , Lennon Ryan J. , Nestler David M. , Bell Malcolm R. , Rihal Charanjit S. , Ting Henry H. 
Published: June 2010

Background—
Circadian rhythms with regard to time of symptom onset for patients with acute myocardial infarction have been observed, although their relationship to outcomes has been debated. We evaluated these rhythms in patients with ST-elevation myocardial infarction as a function of the 24-hour circadian cycle.

Methods and Results—

The relationship between onset of symptoms during the 24-hour circadian cycle and prehospital delays from symptom onset to hospital arrival, timeliness of reperfusion, and in-hospital death was assessed in 2143 patients with ST-elevation myocardial infarction presenting from 2004–2008 at 1 of 3 tertiary-care healthcare ST-elevation myocardial infarction systems. There was a significant association between time of onset and the circadian cycle, with the greatest percentage (39%) of patients experiencing onset between 8
am
and 3
pm
(
P
<0.001). Time of onset was associated with prehospital delay and timeliness of reperfusion. Patients with onset from 12
am
to 5:59
am
had median prehospital delays of 121 minutes versus 70 minutes from 12
pm
to 5:59
pm
(
P
<0.001). Patients with onset time from 12
am
to 5:59
am
had median door-to-balloon times of 75 minutes versus 60 minutes from 6
am
to 11:59
am
(
P
<0.001). Using multivariable modeling to control for baseline patient characteristics, prehospital delay, and timeliness of reperfusion, there was no significant association between time of symptom onset with in-hospital death.

Conclusions—

Patients with ST-elevation myocardial infarction exhibit significant circadian patterns in symptom onset, prehospital delay, and timeliness of reperfusion. Patients who develop symptoms from 12
am
to 5:59
am
present with longer prehospital delays and have longer door-to-balloon times. After multivariable adjustment, there was no significant association between circadian patterns of time of onset and in-hospital death.
Perception of Weight-Bearing Distribution During Sit-to-Stand Tasks in Hemiparetic and Healthy Individuals
Authors: Brière Anabèle , Lauzière Séléna , Gravel Denis , Nadeau Sylvie 
Published: June 2010

Background and Purpose—It is unknown whether hemiparetic individuals are aware of their weight-bearing asymmetry during sit-to-stand tasks. This study compared the error between hemiparetic and healthy individuals’ perception of weight-bearing and their actual weight-bearing distribution during the sit-to-stand task and analyzed the association between the knee extensor muscle strength and the weight-bearing distribution and perception.Methods—Nineteen unilateral hemiparetic subjects and 15 healthy individuals participated in the study. They performed the sit-to-stand transfer on force platforms under different foot placements (spontaneous and symmetrical) and had to rate their perceived weight-bearing distribution at the lower limbs on a visual analog scale. The strength of the knee extensors was assessed with a Biodex dynamometer.Results—The hemiparetic individuals presented greater weight-bearing asymmetry and errors of perception than the healthy individuals. Although no significant association was found between strength and weight-bearing perception, moderate associations were found between strength and weight-bearing distribution for both the spontaneous (r=0.75,P<0.01) and symmetrical (r=0.71,P<0.01) foot position conditions.Conclusions—This study revealed that individuals with hemiparesis after a stroke do not perceive themselves as asymmetrical when executing the sit-to-stand transfer and that the knee extensor strength is a factor linked to their weight-bearing asymmetry, not to their perception.
Description of an Academic Community Partnership Lifestyle Program for Lower Income Minority Adults at Risk for Diabetes
Authors: Delgadillo Adriana T. , Grossman Melanie , Santoyo-Olsson Jasmine , Gallegos-Jackson Elisa , Kanaya Alka M. , Stewart Anita L. 
Published: June 2010

Purpose Translating strategies and approaches from the successful clinically based Diabetes Prevention Program’s lifestyle intervention to community settings is a key next step. This article describes a lifestyle program developed in partnership by researchers at a major university and public health professionals at a local health department. Methods The Live Well, Be Well (LWBW) program was designed to meet the needs of lower income, minority, and low-literacy adults at risk for diabetes. It was adapted from interventions with demonstrated efficacy and delivered in Spanish and English by health department staff. The program consisted of a 6-month active phase and a 6-month maintenance phase and was primarily telephone based, with one in-person planning session and several group workshops. In-person and group sessions were held in convenient community-based settings. Counselors provided education and skills training to modify diet and increase physical activity. Self-selected and attainable goal-setting and action plans were emphasized to enhance self-efficacy. LWBW is the intervention component of a randomized trial with primary outcomes of fasting glucose, weight, and other clinical measures. Conclusions The program provides a unique translational model for implementing diabetes risk reduction programs for underserved populations. Individually tailored and non-prescriptive, it utilized existing health department infrastructure, focused on telephone counseling, used culturally appropriate, low-literacy materials, and was delivered in local, community-based facilities.
Trade union interventions in work-life balance
Authors: Rigby Mike , O'Brien-Smith Fiona 
Published: June 2010

Work-life balance has received increasing attention during the last decade but successful action to help employees to manage their work and non-work lives has been slow to develop and there has been a failure to translate policies into take-up. Trade union intervention might be expected to help resolve these problems but evidence on their role has been limited. The current research, based on empirical data derived from interviews with union representatives, considers the union role in the retailing and media sectors, examining their definition of and engagement with work-life balance issues and intervention strategies. It locates their approach against current discussions of the national discourse on work-life balance and trade union strategy. Although in both sectors trade union engagement with work-life balance was evident, differences could be traced to the impact of structural variables. In neither case did work-life balance, as defined by respondents, represent a common interest area with employers.