bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synergistic Activity of Sorafenib and Sulforaphane Abolishes Pancreatic Cancer Stem Cell Characteristics
Authors: Rausch Vanessa , Liu Li , Kallifatidis Georgios , Baumann Bernd , Mattern Jürgen , Gladkich Jury , Wirth Thomas , Schemmer Peter , Büchler Markus W. , Zöller Margot , Salnikov Alexei V. , Herr Ingrid 
Published: June 2010

Abstract
Recent evidence suggests that pancreatic cancer and other solid tumors contain a subset of tumorigenic cells capable of extensive self-renewal that contribute to metastasis and treatment resistance. Sorafenib (SO) is a promising new multikinase inhibitor for treatment of advanced kidney and liver cancers. We report here targeting of pancreatic cancer stem cells (CSC) by SO and the development of a strategy to enhance this effect. Although SO administration diminished clonogenicity, spheroid formation, aldehyde dehydrogenase 1 (ALDH1) activity, growth on immunodeficient mice, proliferation, and angiogenesis and induced apoptosis, we observed SO-induced activation of NF-κB associated with survival and regrowth of spheroids. For enhanced elimination of CSC characteristics by SO, we cotreated cells with sulforaphane (SF). This broccoli isothiocyanate was recently described to eliminate pancreatic CSCs by downregulation of NF-κB activity without inducing toxic side effects. On combination treatment, SF completely eradicated SO-induced NF-κB binding, which was associated with abrogated clonogenicity, spheroid formation, ALDH1 activity, migratory capacity, and induction of apoptosis. In vivo, combination therapy reduced the tumor size in a synergistic manner. This was due to induction of apoptosis, inhibition of proliferation and angiogenesis, and downregulation of SO-induced expression of proteins involved in epithelial-mesenchymal transition. Our data suggest that SF may be suited to increase targeting of CSCs by SO. Cancer Res; 70(12); 5004–13. ©2010 AACR.
Traf2- and Nck-Interacting Kinase Is Essential for Wnt Signaling and Colorectal Cancer Growth
Authors: Shitashige Miki , Satow Reiko , Jigami Takafumi , Aoki Kazunori , Honda Kazufumi , Shibata Tatsuhiro , Ono Masaya , Hirohashi Setsuo , Yamada Tesshi 
Published: June 2010

Abstract
T-cell factor-4 (TCF4) is a transcription factor essential for maintaining the undifferentiated status and self-renewal of intestinal epithelial cells. It has therefore been considered that constitutive activation of TCF4 by aberrant Wnt signaling is a major force driving colorectal carcinogenesis. We previously identified Traf2- and Nck-interacting kinase (TNIK) as one of the proteins that interact with TCF4 in colorectal cancer cells, but its functional significance has not been elucidated. Here, we report that TNIK is an activating kinase for TCF4 and essential for colorectal cancer growth. TNIK, but not its catalytically inactive mutant, phosphorylated the conserved serine 154 residue of TCF4. Small interfering RNA targeting TNIK inhibited the proliferation of colorectal cancer cells and the growth of tumors produced by injecting colorectal cancer cells s.c. into immunodeficient mice. The growth inhibition was abolished by restoring the catalytic domain of TNIK, thus confirming that its enzyme activity is essential for the maintenance of colorectal cancer growth. Several ATP-competing kinase inhibitors have been applied to cancer treatment and have shown significant activity. Our findings suggest TNIK as a feasible target for pharmacologic intervention to ablate aberrant Wnt signaling in colorectal cancer. Cancer Res; 70(12); 5024–33. ©2010 AACR.
How to Train Your Biomarker
Authors: Yee Douglas 
Published: June 2010

AbstractType I insulin-like growth factor (IGF) receptor (IGF1R) inhibitors are new cancer therapies. Pitts and colleagues used in vitro data to “train” a predictive biomarker for an IGF1R tyrosine kinase inhibitor. Given the complexity of IGF signaling, additional layers of biomarker analysis will likely be needed to develop predictive factors. Clin Cancer Res; 16(12); 3091–3. ©2010 AACR.
Sensitization to Radiation and Alkylating Agents by Inhibitors of Poly(ADP-ribose) Polymerase Is Enhanced in Cells Deficient in DNA Double-Strand Break Repair
Authors: Löser Dana A. , Shibata Atsushi , Shibata Akiko K. , Woodbine Lisa J. , Jeggo Penny A. , Chalmers Anthony J. 
Published: June 2010

Abstract
As single agents, chemical inhibitors of poly(ADP-ribose) polymerase (PARP) are nontoxic and have clinical efficacy against BRCA1- and BRCA2-deficient tumors. PARP inhibitors also enhance the cytotoxicity of ionizing radiation and alkylating agents but will only improve clinical outcomes if tumor sensitization exceeds effects on normal tissues. It is unclear how tumor DNA repair proficiency affects the degree of sensitization. We have previously shown that the radiosensitizing effect of PARP inhibition requires DNA replication and will therefore affect rapidly proliferating tumors more than normal tissues. Because many tumors exhibit defective DNA repair, we investigated the impact of double-strand break (DSB) repair integrity on the sensitizing effects of the PARP inhibitor olaparib. Sensitization to ionizing radiation and the alkylating agent methylmethane sulfonate was enhanced in DSB repair–deficient cells. In Artemis−/− and ATM−/− mouse embryo fibroblasts, sensitization was replication dependent and associated with defective repair of replication-associated damage. Radiosensitization of Ligase IV−/− mouse embryo fibroblasts was independent of DNA replication and is explained by inhibition of "alternative" end joining. After methylmethane sulfonate treatment, PARP inhibition promoted replication-independent accumulation of DSB, repair of which required Ligase IV. Our findings predict that the sensitizing effects of PARP inhibitors will be more pronounced in rapidly dividing and/or DNA repair defective tumors than normal tissues and show their potential to enhance the therapeutic ratio achieved by conventional DNA-damaging agents. Mol Cancer Ther; 9(6); 1775–87. ©2010 AACR.
Artemin-Stimulated Progression of Human Non–Small Cell Lung Carcinoma Is Mediated by BCL2
Authors: Tang Jian-Zhong , Kong Xiang-Jun , Kang Jian , Fielder Graeme C. , Steiner Michael , Perry Jo K. , Wu Zheng-Sheng , Yin Zhinan , Zhu Tao , Liu Dong-Xu , Lobie Peter E. 
Published: June 2010

AbstractWe herein show that Artemin (ARTN), one of the glial cell line–derived neurotrophic factor family of ligands, promotes progression of human non–small cell lung carcinoma (NSCLC). Oncomine data indicate that expression of components of the ARTN signaling pathway (ARTN, GFRA3, and RET) is increased in neoplastic compared with normal lung tissues; increased expression of ARTN in NSCLC also predicted metastasis to lymph nodes and a higher grade in certain NSCLC subtypes. Forced expression of ARTN stimulated survival, anchorage-independent, and three-dimensional Matrigel growth of NSCLC cell lines. ARTN increased BCL2 expression by transcriptional upregulation, and inhibition of BCL2 abrogated the oncogenic properties of ARTN in NSCLC cells. Forced expression of ARTN also enhanced migration and invasion of NSCLC cells. Forced expression of ARTN in H1299 cells additionally resulted in larger xenograft tumors, which were highly proliferative, invasive, and metastatic. Concordantly, either small interfering RNA–mediated depletion or functional inhibition of endogenous ARTN with antibodies reduced oncogenicity and invasiveness of NSCLC cells. ARTN therefore mediates progression of NSCLC and may be a potential therapeutic target for NSCLC. Mol Cancer Ther; 9(6); 1697–708. ©2010 AACR.
A Novel Plant Homeodomain Finger 10–Mediated Antiapoptotic Mechanism Involving Repression of Caspase-3 in Gastric Cancer Cells
Authors: Wei Min , Liu Bingya , Su Liping , Li Jianfang , Zhang Jun , Yu Yingyan , Yan Min , Yang Zhongyin , Chen Xuehua , Liu Jiayun , Lv Xin , Nie Hui , Zhang Qing , Zheng Zhong , Yu Beiqin , Ji Jun , Zhang Jianian , Zhu Zhenggang , Gu Qinlong 
Published: June 2010

Abstract
The mechanisms governing tumorigenesis of gastric cancer have been an area of intense investigation. Currently, plant homeodomain (PHD) finger (PHF) proteins have been implicated in both tumor suppression and progression. However, the function of PHF10 has not been well characterized. Here, we show that various levels of PHF10 protein were observed in gastric cancer cell lines. Alteration of PHF10 expression, which is associated with tumor cell growth, may result in apoptosis in gastric cancer cells both in vitro and in vivo. Knockdown of PHF10 expression in gastric cancer cells led to significant induction of caspase-3 expression at both the RNA and protein levels and thus induced alteration of caspase-3 substrates in a time-dependent manner. Moreover, results from luciferase assays indicated that PHF10 acted as a transcriptional repressor when the two PHD domains contained in PHF10 were intact. Combined with previous findings, our data suggest that PHF10 transcriptionally regulates the expression of caspase-3. Finally, by using systematic reporter deletion and chromatin immunoprecipitation assays, we localized a region between nucleotides −270 and −170 in the caspase-3 promoter that was required for the efficient inhibition of caspase-3 promoter activity by PHF10. Collectively, our findings show that PHF10 repressed caspase-3 expression and impaired the programmed cell death pathway in human gastric cancer at the transcriptional level. Mol Cancer Ther; 9(6); 1764–74. ©2010 AACR.
XPB Induces C1D Expression to Counteract UV-Induced Apoptosis
Authors: Li Guang , Liu Juhong , Abu-Asab Mones , Masabumi Shibuya , Maru Yoshiro 
Published: June 2010

Abstract
Although C1D has been shown to be involved in DNA double-strand break repair, how C1D expression was induced and the mechanism(s) by which C1D facilitates DNA repair in mammalian cells remain poorly understood. We and others have previously shown that expression of xeroderma pigmentosum B (XPB) protein efficiently compensated the UV irradiation–sensitive phenotype of 27-1 cells, which lack functional XPB. To further explore XPB-regulated genes that could be involved in UV-induced DNA repair, differential display analysis of mRNA levels from CHO-9, 27-1, and 27-1 complemented with wild-type XPB was done and C1D gene was identified as one of the major genes whose expression was significantly upregulated by restoring XPB function. We found that XPB is essential to induce C1D transcription after UV irradiation. The increase in C1D expression effectively compensates for the UV-induced proteolysis of C1D and thus maintains cellular C1D level to cope with DNA damage inflicted by UV irradiation. We further showed that although insufficient to rescue 27-1 cells from UV-induced apoptosis by itself, C1D facilitates XPB DNA repair through direct interaction with XPB. Our findings provided direct evidence that C1D is associated with DNA repair complex and may promote repair of UV-induced DNA damage. Mol Cancer Res; 8(6); 885–95. ©2010 AACR.
PRDM1 Is Required for Mantle Cell Lymphoma Response to Bortezomib
Authors: Desai Shruti , Maurin Michelle , Smith Matthew A. , Bolick Sophia C.E. , Dessureault Sophie , Tao Jianguo , Sotomayor Eduardo , Wright Kenneth L. 
Published: June 2010

Abstract
Mantle cell lymphoma (MCL) is an aggressive form of B-cell lymphoma with a poor disease-free survival rate. The proteasome inhibitor bortezomib is approved for the treatment of relapsed and refractory MCL and has efficacy in about 30% of patients. However, the precise mechanism of action of bortezomib is not well understood. This report establishes a requirement for the transcription repressor PR domain zinc finger protein 1 (PRDM1, Blimp1) in the response to bortezomib. Bortezomib rapidly induces transcription of PRDM1 as part of the apoptotic response in both cell lines and primary MCL tumor cells. Knockdown of PRDM1 blocks activation of NOXA and inhibits apoptosis, whereas ectopic expression of PRDM1 alone leads to apoptosis in MCL. Two novel direct targets of PRDM1 were identified in MCL cells: MKI67 (Ki67) and proliferating cell nuclear antigen (PCNA). Both MKI67 and PCNA are required for proliferation and survival. Chromatin immunoprecipitation and knockdown studies reveal that specific repression of MKI67 and PCNA is mediated by PRDM1 in response to bortezomib. Furthermore, promoter studies and mutation/deletion analysis show that PRDM1 functions through specific sites in the PCNA proximal promoter and an MKI67 distal upstream repression domain. Together, these findings establish PRDM1 as a key mediator of bortezomib activity in MCL. Mol Cancer Res; 8(6); 907–18. ©2010 AACR.
Cause-Specific Cardiovascular Risk Associated With Nonsteroidal Antiinflammatory Drugs Among Healthy Individuals
Authors: Fosbøl Emil Loldrup , Folke Fredrik , Jacobsen Søren , Rasmussen Jeppe N. , Sørensen Rikke , Schramm Tina Ken , Andersen Søren S. , Rasmussen Søren , Poulsen Henrik Enghusen , Køber Lars , Torp-Pedersen Christian , Gislason Gunnar H. 
Published: June 2010

Background—
Studies have raised concern on the cardiovascular safety of nonsteroidal antiinflammatory drugs (NSAIDs). We studied safety of NSAID therapy in a nationwide cohort of healthy individuals.

Methods and Results—
With the use of individual-level linkage of nationwide administrative registers, we identified a cohort of individuals without hospitalizations 5 years before first prescription claim of NSAIDs and without claimed drug prescriptions for selected concomitant medication 2 years previously. The risk of cardiovascular death, a composite of coronary death or nonfatal myocardial infarction, and fatal or nonfatal stroke associated with the use of NSAIDs was estimated by case-crossover and Cox proportional hazard analyses. The entire Danish population age 10 years or more consisted of 4 614 807 individuals on January 1, 1997, of which 2 663 706 (57.8%) claimed at least 1 prescription for NSAIDs during 1997 to 2005. Of these; 1 028 437 individuals were included in the study after applying selection criteria regarding comorbidity and concomitant pharmacotherapy. Use of the nonselective NSAID diclofenac and the selective cyclooxygenase-2 inhibitor rofecoxib was associated with an increased risk of cardiovascular death (odds ratio, 1.91; 95% confidence interval, 1.62 to 2.42; and odds ratio, 1.66; 95% confidence interval, 1.06 to 2.59, respectively), with a dose-dependent increase in risk. There was a trend for increased risk of fatal or nonfatal stroke associated with ibuprofen treatment (odds ratio, 1.29; 95% confidence interval, 1.02 to 1.63), but naproxen was not associated with increased cardiovascular risk (odds ratio for cardiovascular death, 0.84; 95% confidence interval, 0.50 to 1.42).

Conclusions—
Individual NSAIDs have different degrees of cardiovascular safety, which must be considered when choosing appropriate treatment. In particular, rofecoxib and diclofenac were associated with increased cardiovascular mortality and morbidity and should be used with caution in most individuals, whereas our results suggest that naproxen has a safer cardiovascular risk-profile.
Traditional Economy of the Herder-Horticulturists of South Iran
Authors: Amanolahi Sekandar 
Published: June 2010

AbstractThe traditional ecological adaptation of the herder-horticulturists of South Iran represents a distinct pattern of subsistence and a different type of adaptation. Being neither pastoral nomads nor sedentary agriculturists, their economy is maintained by a combination of herding (mainly goats) and cultivation of semi-wild orchards and rose bushes on the high altitudes, without the use of irrigation. This study is predominantly based on the field-work materials recorded during several years in the late 1980s.
Genetic Affinity between the Armenian Yezidis and the Iraqi Kurds
Authors: Harutyunian Ashot , Khudoyan Armine , Andonian Laris , Margarian Ashot , Yepiskoposian Levon 
Published: June 2010

AbstractThe Yezidi community in Armenia has been formed during last two-three centuries as a consequence of several waves of migration. Due to the esoteric character of the community, the Yezidis have been reproductively isolated from neighbouring populations for centuries, which has left significant traces in their genetic structure. Our results based on the analysis of patrilineal genetic lineages demonstrate that the long-term isolation of the Yezidis has resulted in notable reduction of male sex chromosome variability compared to other populations and significant difference from the Kurds living in Iraq. However, the analysis of specific lineages provides evidence on similar genetic traits between the Armenian Yezidis and the Iraqi Kurds.
Does eccentric endurance training improve walking capacity in patients with coronary artery disease? A randomized controlled pilot study
Authors: Gremeaux V. , Duclay J. , Deley G. , Philipp JL , Laroche D. , Pousson M , Casillas JM 
Published: June 2010

Objective: To examine the effect of eccentric endurance training on exercise capacities in patients with coronary artery disease. Design: Randomized parallel group controlled study. Setting: Cardiac rehabilitation unit, Dijon University Hospital. Participants: Fourteen patients with stable coronary artery disease after percutaneous coronary intervention. Intervention: Patients followed 15 sessions of training (1 session per day, 3 days a week), either in the concentric group, following a standard programme, or in the eccentric group, performing eccentric resistance exercises using both lower limbs on a specifically designed ergometer. Main outcomes measured: Symptom-limited Vo2, peak workload, isometric strength of leg extensor and ankle plantar flexors, distance covered during the 6-minute walk test and time to perform the 200-m fast walk test in both groups, before and after the training period. Results: Patients did not report any adverse effects and were highly compliant. All measured parameters improved in eccentric and concentric group, except for 200-m fast walk test: symptom-limited Vo2 (+14.2% versus +4.6%), peak workload (+30.8% versus +19.3%), 6-minute walk test distance walked (+12.6% versus +10.1%) and leg extensor strength (+7% versus +13%) improved to a similar degree in both groups (P<0.01); ankle plantar flexor strength improved in both groups with a significantly greater increase in the eccentric group (+17% versus +7%, P<0.05). Conclusion: Patients with stable coronary artery disease can safely engage in eccentric endurance training, which appears to be as efficient as usual concentric training, with reduced oxygen consumption.
Adapted version of constraint-induced movement therapy promotes functioning in children with cerebral palsy: a randomized controlled trial
Authors: de Brito Brandão Marina , Mancini Marisa Cotta , Vaz Daniela Virgínia , Pereira de Melo Ana Paula , Fonseca Sérgio Teixeira 
Published: June 2010

Objective: To evaluate the effects of constraint-induced movement therapy on the use of the affected arm and on daily functioning in children with hemiplegic cerebral palsy. Design: A single-blinded randomized clinical trial. Subjects: Sixteen children with cerebral palsy randomized to intervention (n = 8, 4 males, 4 females, mean age 5 years and 6 months) and control groups (n = 8, 4 males, 4 females, mean age 6 years and 7 months). Interventions: Non-affected arm of intervention group was restricted for 10 hours/ day and the affected arm intensively trained for 3 hours/day for two weeks. The intervention protocol included one week of bimanual functional training following constraint therapy. The control group maintained usual rehabilitation throughout the intervention period. Main measures: Pediatric Evaluation of Disability Inventory (self-care domain) and an adapted version of the Jebsen—Taylor test were administered before and after intervention, and at one month follow-up. General linear models tested differences in gain scores and the number needed to treat estimated relative effectiveness of intervention protocol for functional skills and independence in self-care. Results: Results are reported for 15 children who completed assessments and intervention. Higher gains were observed in the intervention group for functional skills and independence post intervention (dfunctional skills = 1.61, P =0.0134; dindependence=1.37; P =0.0001) and follow-up (dfunctional skills = 2.08, P =0.004; dindependence = 0.85; P =0.0016). No group difference in manual dexterity gains was observed. Low indices of number needed to treat (1.75 and 2.33) illustrate clinical relevance of intervention. Conclusions: The protocol associating constraint-induced movement therapy and bimanual functional training was effective in promoting daily living functioning among children with cerebral palsy.
The Effect of Medial Versus Lateral Meniscectomy on the Stability of the Anterior Cruciate Ligament-Deficient Knee
Authors: Musahl Volker , Citak Musa , O’Loughlin Padhraig F. , Choi Daniel , Bedi Asheesh , Pearle Andrew D. 
Published: June 2010

Background: The pivot shift is a dynamic test of knee stability that involves a pathologic, multiplanar motion path elicited by a combination of axial load and valgus force during a knee flexion from an extended position. Purpose: To assess the stabilizing effect of the medial and lateral meniscus on anterior cruciate ligament-deficient (ACL-D) knees during the pivot shift examination. Study Design: Controlled laboratory study. Methods: A Lachman and a mechanized pivot shift test were performed on 16 fresh-frozen cadaveric hip-to-toe lower extremity specimens. The knee was tested intact, ACL-D, and after sectioning the medial meniscus (ACL/MM-D; n = 8), lateral meniscus (ACL/LM-D; n = 8), and both (ACL/LM/MM-D; n = 16). A navigation system recorded the resultant anterior tibial translations (ATTs). For statistical analysis an analysis of variance was used; significance was set at P < .05. Results: The ATT significantly increased in the ACL-D knee after lateral meniscectomy (ACL/LM-D; P < .05) during the pivot shift maneuver. In the lateral compartment of the knee, ATT in the ACL-D knee increased by 6 mm after lateral meniscectomy during the pivot shift (16.6 ± 6.0 vs 10.5 ± 3.5 mm, P < .01 for ACL/LM out vs ACL out). Medial meniscectomy, conversely, had no significant effect on ATT in the ACL-D knee during pivot shift examination ( P > .05). With standardized Lachman examination, however, ATT significantly increased after medial but not lateral meniscectomy compared with the ACL-D knee ( P < .001). Conclusion: Although the medial meniscus functions as a critical secondary stabilizer to anteriorly directed forces on the tibia during a Lachman examination, the lateral meniscus appears to be a more important restraint to anterior tibial translation during combined valgus and rotatory loads applied during a pivoting maneuver. Clinical Relevance: This model may have implications in the evaluation of surgical reconstruction procedures in complex knee injuries.