bluuebunny/crossref_metadata_2025_split huggingface dataset:
PALB2/FANCN: Recombining Cancer and Fanconi Anemia
Authors: Tischkowitz Marc , Xia Bing 
Published: September 2010

Abstract
Partner and localizer of BRCA2 (PALB2) was originally identified as a BRCA2-interacting protein that is crucial for key BRCA2 genome caretaker functions. It subsequently became clear that PALB2 was another Fanconi anemia (FA) gene (FANCN), and that monoallelic PALB2 mutations are associated with increased risk of breast and pancreatic cancer. Mutations in PALB2 have been identified in breast cancer families worldwide, and recent studies have shown that PALB2 also interacts with BRCA1. Here, we summarize the molecular functions and clinical phenotypes of this key DNA repair pathway component and discuss how its discovery has advanced our knowledge of both FA and adult cancer predisposition. Cancer Res; 70(19); 7353–9. ©2010 AACR.
Epidermal Growth Factor Receptor Expression Identifies Functionally and Molecularly Distinct Tumor-Initiating Cells in Human Glioblastoma Multiforme and Is Required for Gliomagenesis
Authors: Mazzoleni Stefania , Politi Letterio S. , Pala Mauro , Cominelli Manuela , Franzin Alberto , Sergi Sergi Lucia , Falini Andrea , De Palma Michele , Bulfone Alessandro , Poliani Pietro L. , Galli Rossella 
Published: September 2010

Abstract
Epidermal growth factor receptor (EGFR) is a known diagnostic and, although controversial, prognostic marker of human glioblastoma multiforme (GBM). However, its functional role and biological significance in GBM remain elusive. Here, we show that multiple GBM cell subpopulations could be purified from the specimens of patients with GBM and from cancer stem cell (CSC) lines based on the expression of EGFR and of other putative CSC markers. All these subpopulations are molecularly and functionally distinct, are tumorigenic, and need to express EGFR to promote experimental tumorigenesis. Among them, EGFR-expressing tumor-initiating cells (TIC) display the most malignant functional and molecular phenotype. Accordingly, modulation of EGFR expression by gain-of-function and loss-of-function strategies in GBM CSC lines enhances and reduces their tumorigenic ability, respectively, suggesting that EGFR plays a fundamental role in gliomagenesis. These findings open up the possibility of new therapeutically relevant scenarios, as the presence of functionally heterogeneous EGFRpos and EGFRneg TIC subpopulations within the same tumor might affect clinical response to treatment. Cancer Res; 70(19); 7500–13. ©2010 AACR.
Sequential Cytarabine and α-Particle Immunotherapy with Bismuth-213–Lintuzumab (HuM195) for Acute Myeloid Leukemia
Authors: Rosenblat Todd L. , McDevitt Michael R. , Mulford Deborah A. , Pandit-Taskar Neeta , Divgi Chaitanya R. , Panageas Katherine S. , Heaney Mark L. , Chanel Suzanne , Morgenstern Alfred , Sgouros George , Larson Steven M. , Scheinberg David A. , Jurcic Joseph G. 
Published: September 2010

Abstract
Purpose: Lintuzumab (HuM195), a humanized anti-CD33 antibody, targets myeloid leukemia cells and has modest single-agent activity against acute myeloid leukemia (AML). To increase the potency of the antibody without the nonspecific cytotoxicity associated with β-emitters, the α-particle–emitting radionuclide bismuth-213 (213Bi) was conjugated to lintuzumab. This phase I/II trial was conducted to determine the maximum tolerated dose (MTD) and antileukemic effects of 213Bi-lintuzumab, the first targeted α-emitter, after partially cytoreductive chemotherapy.
Experimental Design: Thirty-one patients with newly diagnosed (n = 13) or relapsed/refractory (n = 18) AML (median age, 67 years; range, 37-80) were treated with cytarabine (200 mg/m2/d) for 5 days followed by 213Bi-lintuzumab (18.5-46.25 MBq/kg).
Results: The MTD of 213Bi-lintuzumab was 37 MB/kg; myelosuppression lasting &gt;35 days was dose limiting. Extramedullary toxicities were primarily limited to grade ≤2 events, including infusion-related reactions. Transient grade 3/4 liver function abnormalities were seen in five patients (16%). Treatment-related deaths occurred in 2 of 21 (10%) patients who received the MTD. Significant reductions in marrow blasts were seen at all dose levels. The median response duration was 6 months (range, 2-12). Biodistribution and pharmacokinetic studies suggested that saturation of available CD33 sites by 213Bi-lintuzumab was achieved after partial cytoreduction with cytarabine.
Conclusions: Sequential administration of cytarabine and 213Bi-lintuzumab is tolerable and can produce remissions in patients with AML. Clin Cancer Res; 16(21); 5303–11. ©2010 AACR.
Involvement of Human Herpesvirus-6 Variant B in Classic Hodgkin's Lymphoma via DR7 Oncoprotein
Authors: Lacroix Aurélie , Collot-Teixeira Sophie , Mardivirin Laurent , Jaccard Arnaud , Petit Barbara , Piguet Christophe , Sturtz Franck , Preux Pierre-Marie , Bordessoule Dominique , Ranger-Rogez Sylvie 
Published: September 2010

Abstract
Purpose: Hodgkin's lymphoma (HL) is associated with the presence of EBV in Reed-Sternberg (RS) cells in ∼40% of cases. Here, we studied the presence of human herpesvirus type 6 (HHV-6) variant B in RS cells of HL patients and correlated results with clinical parameters. We then examined the implication of HHV-6 DR7B protein in cell deregulation.
Experimental Design: HHV-6 DR7B protein was produced in a Semliki Forest virus system. Polyclonal antibodies were then generated and used for immunochemical HHV-6 localization in HL biopsies. Binding between DR7B and p53 was studied using a double-hybrid system. Transactivation of NFκB was observed after transient transfection using reporter gene assays. We looked for Id2 factor expression after stable transfection of the BJAB cell line by reverse transcription-PCR and Western blot analysis.
Results: HHV-6 was more common in nodular sclerosis subtype HL, and DR7B oncoprotein was detected in RS cells for 73.7% of EBV-negative patients. Colocalization of EBV and HHV-6 was observed in RS cells of doubly infected patients. DR7B protein bound to human p53 protein. p105-p50/p65 mRNA expression and activation of the NFκB complex were increased when DR7B was expressed. Stable expression of DR7B exhibited a strong and uniform expression of Id2. A slightly higher percentage of remission was observed in patients with RS cells testing positive for DR7B than in those testing negative.
Conclusions: Collectively, these data provide evidence for the implication of a novel agent, HHV-6, in cases of nodular sclerosis HL. Clin Cancer Res; 16(19); 4711–21. ©2010 AACR.
Poly(ADP-Ribose) Polymerase Inhibition: “Targeted” Therapy for Triple-Negative Breast Cancer
Authors: Anders Carey K. , Winer Eric P. , Ford James M. , Dent Rebecca , Silver Daniel P. , Sledge George W. , Carey Lisa A. 
Published: September 2010

AbstractIn contrast to endocrine-sensitive and human epidermal growth factor receptor 2 (HER2)–positive breast cancer, novel agents capable of treating advanced triple-negative breast cancer (TNBC) are lacking. Poly(ADP-ribose) polymerase (PARP) inhibitors are emerging as one of the most promising “targeted” therapeutics to treat TNBC, with the intended “target” being DNA repair. PARPs are a family of enzymes involved in multiple cellular processes, including DNA repair. TNBC shares multiple clinico-pathologic features with BRCA-mutated breast cancers, which harbor dysfunctional DNA repair mechanisms. Investigators hypothesized that PARP inhibition, in conjunction with the loss of DNA repair via BRCA-dependent mechanisms, would result in synthetic lethality and augmented cell death. This hypothesis has borne out in both preclinical models and in clinical trials testing PARP inhibitors in both BRCA-deficient and triple-negative breast cancer. The focus of this review includes an overview of the preclinical rationale for evaluating PARP inhibitors in TNBC, the presumed mechanism of action of this novel therapeutic class, promising results from several influential clinical trials of PARP inhibition in advanced breast cancer (both TNBC and BRCA deficient), proposed mechanisms of acquired resistance to PARP inhibitors, and, finally, concludes with current challenges and future directions for the development of PARP inhibitors in the treatment of breast cancer. Clin Cancer Res; 16(19); 4702–10. ©2010 AACR.
Cisplatin-Induced Downregulation of OCTN2 Affects Carnitine Wasting
Authors: Lancaster Cynthia S. , Hu Chaoxin , Franke Ryan M. , Filipski Kelly K. , Orwick Shelley J. , Chen Zhaoyuan , Zuo Zhili , Loos Walter J. , Sparreboom Alex 
Published: September 2010

AbstractPurpose: Carnitine is an essential cofactor for mitochondrial fatty acid oxidation that is actively reabsorbed by the luminal transporter Octn2 (Slc22a5). Because the nephrotoxic agent cisplatin causes urinary loss of carnitine in humans, we hypothesized that cisplatin may affect Octn2 function.Experimental Design: Excretion of carnitine and acetylcarnitine was measured in urine collected from mice with or without cisplatin administration. The transport of carnitine was assessed in cells that were transfected with OCT1 or OCT2. The effect of cisplatin treatment on gene expression was analyzed using a mouse GeneChip array and validated using quantitative reverse transcriptase-PCR.Results: In wild-type mice, urinary carnitine excretion at baseline was ∼3-fold higher than in mice lacking the basolateral cisplatin transporters Oct1 and Oct2 [Oct1/2(−/−) mice], indicating that carnitine itself undergoes basolateral uptake into the kidney. Transport of carnitine by OCT2, but not OCT1, was confirmed in transfected cells. We also found that cisplatin caused an increase in the urinary excretion of carnitine and acetylcarnitine in wild-type mice but not in Oct1/2(−/−) mice, suggesting that tubular transport of cisplatin is a prerequisite for this phenomenon. Cisplatin did not directly inhibit the transport of carnitine by Octn2 but downregulated multiple target genes of the transcription factor peroxisome proliferator activated receptor α, including Slc22a5, in the kidney of wild-type mice that were absent in Oct1/2(−/−) mice.Conclusion: Our study shows a pivotal role of Oct1 and Oct2 in cisplatin-related disturbances in carnitine homeostasis. We postulate that this phenomenon is triggered by deactivation of peroxisome proliferator activated receptor α and leads to deregulation of carnitine-shuttle genes. Clin Cancer Res; 16(19); 4789–99. ©2010 AACR.
The Use of One-Bead One-Compound Combinatorial Library Technology to Discover High-Affinity αvβ3 Integrin and Cancer Targeting Arginine-Glycine-Aspartic Acid Ligands with a Built-in Handle
Authors: Xiao Wenwu , Wang Yan , Lau Edmond Y. , Luo Juntao , Yao Nianhuan , Shi Changying , Meza Leah , Tseng Harry , Maeda Yoshiko , Kumaresan Pappanaicken , Liu Ruiwu , Lightstone Felice C. , Takada Yoshikazu , Lam Kit S. 
Published: September 2010

Abstract
The αvβ3 integrin, expressed on the surface of various normal and cancer cells, is involved in numerous physiologic processes such as angiogenesis, apoptosis, and bone resorption. Because this integrin plays a key role in angiogenesis and metastasis of human tumors, αvβ3 integrin ligands are of great interest to advances in targeted therapy and cancer imaging. In this report, one-bead one-compound (OBOC) combinatorial libraries containing the arginine-glycine-aspartic acid (RGD) motif were designed and screened against K562 myeloid leukemia cells that had been transfected with the human αvβ3 integrin gene. Cyclic peptide LXW7 was identified as a leading ligand with a built-in handle that binds specifically to αvβ3 and showed comparable binding affinity (IC50 = 0.68 ± 0.08 μmol/L) to some of the well-known RGD “head-to-tail” cyclic pentapeptide ligands reported in the literature. The biotinylated form of LXW7 ligand showed similar binding strength as LXW7 against αvβ3 integrin, whereas biotinylated RGD cyclopentapeptide ligands revealed a 2- to 8-fold weaker binding affinity than their free forms. LXW7 was able to bind to both U-87MG glioblastoma and A375M melanoma cell lines, both of which express high levels of αvβ3 integrin. In vivo and ex vivo optical imaging studies with the biotinylated ligand/streptavidin-Cy5.5 complex in nude mice bearing U-87MG or A375M xenografts revealed preferential uptake of biotinylated LXW7 in tumor. When compared with biotinylated RGD cyclopentapeptide ligands, biotinylated LXW7 showed higher tumor uptake but lower liver uptake. Mol Cancer Ther; 9(10); 2714–23. ©2010 AACR.
Antitumor Effect of Temsirolimus against Oral Squamous Cell Carcinoma Associated with Bone Destruction
Authors: Okui Tatsuo , Shimo Tsuyoshi , Fukazawa Takuya , Kurio Naito , Hassan Nur Mohammad Monsur , Honami Tatsuki , Takaoka Munenori , Naomoto Yoshio , Sasaki Akira 
Published: September 2010

Abstract
The mammalian target of rapamycin (mTOR) is engaged in the molecular pathogenesis of oral squamous cell carcinoma, which frequently invades the maxilla or the mandible. However, the effects of a mTOR inhibitor on bone destruction associated with oral squamous cell carcinoma are still unclear. In this study, we investigated the antitumor effect of temsirolimus-mediated mTOR inhibition against advanced oral squamous cell carcinoma. Temsirolimus inhibited the proliferation and migration of HSC-2 oral squamous cell carcinoma cells in vitro and suppressed the growth of oral squamous cell carcinoma xenografts in vivo. Significantly, we clearly show that temsirolimus inhibited osteoclast formation both in vitro and in vivo. Reverse transcriptase-PCR analysis showed that temsirolimus decreased the mRNA expression of receptor activator for nuclear factor-κB ligand, known as an osteoclast differentiation factor in bone stromal ST2 cells. Moreover, temsirolimus normalized blood-free calcium concentration in mouse models for humoral hypercalcemia. These findings suggest that mTOR signaling is a potential target of oral squamous cell carcinoma associated with bone destruction, and hence we describe the efficacy of temsirolimus for the treatment of advanced oral squamous carcinoma. Mol Cancer Ther; 9(11); 2960–9. ©2010 AACR.
Genetic Variations in the Sonic Hedgehog Pathway Affect Clinical Outcomes in Non–Muscle-Invasive Bladder Cancer
Authors: Chen Meng , Hildebrandt Michelle A.T. , Clague Jessica , Kamat Ashish M. , Picornell Antoni , Chang Joshua , Zhang Xiaofan , Izzo Julie , Yang Hushan , Lin Jie , Gu Jian , Chanock Stephen , Kogevinas Manolis , Rothman Nathaniel , Silverman Debra T. , Garcia-Closas Montserrat , Grossman H. Barton , Dinney Colin P. , Malats Núria , Wu Xifeng 
Published: September 2010

Abstract
Sonic hedgehog (Shh) pathway genetic variations may affect bladder cancer risk and clinical outcomes. Therefore, we genotyped 177 single-nucleotide polymorphisms (SNP) in 11 Shh pathway genes in a study including 803 bladder cancer cases and 803 controls. We assessed SNP associations with cancer risk and clinical outcomes in 419 cases of non–muscle-invasive bladder cancer (NMIBC) and 318 cases of muscle-invasive and metastatic bladder cancer (MiMBC). Only three SNPs (GLI3 rs3823720, rs3735361, and rs10951671) reached nominal significance in association with risk (P ≤ 0.05), which became nonsignificant after adjusting for multiple comparisons. Nine SNPs reached a nominally significant individual association with recurrence of NMIBC in patients who received transurethral resection (TUR) only (P ≤ 0.05), of which two (SHH rs1233560 and GLI2 rs11685068) were replicated independently in 356 TUR-only NMIBC patients, with P values of 1.0 × 10−3 (SHH rs1233560) and 1.3 × 10−3 (GLI2 rs11685068). Nine SNPs also reached a nominally significant individual association with clinical outcome of NMIBC patients who received Bacillus Calmette-Guérin (BCG; P ≤ 0.05), of which two, the independent GLI3 variants rs6463089 and rs3801192, remained significant after adjusting for multiple comparisons (P = 2 × 10−4 and 9 × 10−4, respectively). The wild-type genotype of either of these SNPs was associated with a lower recurrence rate and longer recurrence-free survival (versus the variants). Although three SNPs (GLI2 rs735557, GLI2 rs4848632, and SHH rs208684) showed nominal significance in association with overall survival in MiMBC patients (P ≤ 0.05), none remained significant after multiple-comparison adjustments. Germ-line genetic variations in the Shh pathway predicted clinical outcomes of TUR and BCG for NMIBC patients. Cancer Prev Res; 3(10); 1235–45. ©2010 AACR.
Association between C-Peptide Concentration and Prostate Cancer Incidence in the CLUE II Cohort Study
Authors: Lai Gabriel Y. , Helzlsouer Kathy J. , Clipp Sandra L. , Rifai Nader , Platz Elizabeth A. 
Published: September 2010

Abstract
Diabetes, characterized by perturbations in insulin production and signaling, is inversely associated with prostate cancer risk irrespective of stage. Obesity, a diabetes risk factor, is inversely associated with localized disease but positively associated with advanced disease. To understand the complex association between hyperinsulinemia and prostate cancer, we evaluated the association of plasma C-peptide, an insulin secretion marker, with prostate cancer risk in a case-control study nested in a prospective community cohort. Prostate cancer cases (n = 264) and matched controls (n = 264) were identified in the CLUE II cohort between 1989 (baseline) and 2002. C-peptide concentration was measured in baseline plasma by ELISA. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using conditional logistic regression, adjusting for being overweight or obese and family history. Median C-peptide concentration was lower in cases (1,180 pmol/L) than in controls (1,365 pmol/L; P = 0.03). Men in the highest (versus lowest) fourth of C-peptide had a lower risk for prostate cancer (OR, 0.65; 95% CI, 0.37-1.14; P-trend = 0.08), primarily localized disease (OR, 0.44; 95% CI, 0.19-1.03; P-trend = 0.04). Associations were similar to overall, when excluding cases diagnosed during the first 5 years of follow-up, men with diabetes, or men who had not had a prostate-specific antigen test. C-peptide concentration was inversely associated with subsequent diagnosis of prostate cancer, primarily localized disease, similar to the association for obesity. However, we cannot rule out detection bias that might result if men with higher C-peptide have lower prostate-specific antigen irrespective of whether prostate cancer is present or not. Cancer Prev Res; 3(10); 1334–41. ©2010 AACR.
The Association of Patent Foramen Ovale Morphology and Stroke Size in Patients With Paradoxical Embolism
Authors: Akhondi Andre , Gevorgyan Rubine , Tseng Chi-Hong , Slavin Leo , Dao Catherine , Liebeskind David S. , Tobis Jonathan M. 
Published: September 2010

Background—
Patent foramen ovale (PFO) has been implicated in the pathogenesis of cryptogenic stroke through paradoxical embolization to the cerebral circulation. This study evaluated the relationship between the morphological and functional size of the PFO by echocardiography compared with cerebral infarct volume identified on MRI.

Methods and Results—

Patients who were referred to interventional cardiology with the diagnosis of cryptogenic stroke were included and had either a transesophageal echocardiogram or an intracardiac echo and a brain MRI at the time of stroke. Transesophageal echocardiogram or intracardiac echo was used to obtain PFO measurements. MRI of the brain with 3 sequences (T2, diffusion-weighted imaging, and fluid-attenuated inversion recovery) was used to diagnose acute stroke and measure the infarct volume. In the 72 patients studied, the median measured stroke volume was 4.3 cm
3
on diffusion-weighted imaging, 4.1 cm
3
on T2, and 3.5 cm
3
on fluid-attenuated inversion recovery. There was no significant correlation between the PFO height, length, septum secundum thickness, or echo bubble grade and the infarct volume measured from the 3 MRI sequences. There was a significant correlation between septal excursion distance and infarct volume (
r
=0.35;
P
=0.005), but the 12 patients with atrial septal aneurysm did not have the largest strokes.

Conclusions—
This analysis revealed that septal excursion distance correlates with stroke size by MRI. However, smaller PFO size without the presence of atrial septal aneurysm may still be associated with significant strokes. There was no significant association between PFO height, length by echo, or shunt grade by transcranial Doppler study and brain infarct volume. Therefore, PFO size or morphology should not be the only criteria to decide whether a PFO should be closed.
A Model for Predicting Mortality in Acute ST-Segment Elevation Myocardial Infarction Treated With Primary Percutaneous Coronary Intervention
Authors: Stebbins Amanda , Mehta Rajendra H. , Armstrong Paul W. , Lee Kerry L. , Hamm Christian , Van de Werf Frans , James Stefan , Toftegaard-Nielsen Torsten , Seabra-Gomes Ricardo , White Harvey D. , Granger Christopher B. ,   for the Assessment of Pexelizumab in Acute Myocardial Infarction (APEX AMI Investigators)
Published: September 2010

Background—
Accurate models to predict mortality are needed for risk stratification in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI).

Methods and Results—
We examined 5745 patients with STEMI undergoing primary PCI in the Assessment of Pexelizumab in Acute Myocardial Infarction Trial within 6 hours of symptom onset. A Cox proportional hazards model incorporating regression splines to accommodate nonlinearity in the log hazard ratio (HR) scale was used to determine baseline independent predictors of 90-day mortality. At 90 days, 271 (4.7%) of 5745 patients died. Independent correlates of 90-day mortality were (in descending order of statistical significance) age (HR, 2.03/10-y increments; 95% CI, 1.80 to 2.29), systolic blood pressure (HR, 0.86/10-mm Hg increments; 95% CI, 0.82 to 0.90), Killip class (class 3 or 4 versus 1 or 2) (HR, 4.24; 95% CI, 2.97 to 6.08), heart rate (>70 beats per minute) (HR, 1.45/10-beat increments; 95% CI, 1.31 to 1.59), creatinine (HR, 1.23/10-μmol/L increments >90 μmol/L; 95% CI, 1.13 to 1.34), sum of ST-segment deviations (HR, 1.25/10-mm increments; 95% CI, 1.11 to 1.40), and anterior STEMI location (HR, 1.47; 95% CI, 1.12 to 1.93) (c-index, 0.82). Internal validation with bootstrapping confirmed minimal overoptimism (c-index, 0.81).

Conclusions—
Our study provides a practical method to assess intermediate-term prognosis of patients with STEMI undergoing primary PCI, using baseline clinical and ECG variables. This model identifies key factors affecting prognosis and enables quantitative risk stratification that may be helpful in guiding clinical care and for risk adjustment for observational analyses.