bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular Alterations at 9q33.1 and Polyploidy in Asbestos-Related Lung Cancer
Authors: Nymark Penny , Kettunen Eeva , Aavikko Mervi , Ruosaari Salla , Kuosma Eeva , Vanhala Esa , Salmenkivi Kaisa , Pirinen Risto , Karjalainen Antti , Knuutila Sakari , Wikman Harriet , Anttila Sisko 
Published: January 2009

Abstract
Purpose: Asbestos causes DNA damage and the fibers, together with tobacco smoke, have a synergistic effect on lung cancer risk. We recently identified 18 chromosomal regions that showed differences in DNA copy number between the lung tumors of asbestos-exposed and nonexposed patients. One of the previously identified asbestos-associated chromosomal regions at 9q was further analyzed for allelic imbalance and DNA copy number alterations (CNA) in the lung tumors of asbestos-exposed and nonexposed patients. In addition, the ploidy level of the tumors was studied.
Experimental Design: Allelic imbalance was analyzed at 9q31.3-34.3 with 15 microsatellite markers in 52 lung tumor samples from asbestos-exposed and nonexposed patients. CNA at 9q32-34.3 were characterized by fluorescent in situ hybridization (FISH) with six bacterial artificial chromosome probes in 95 lung tumors. The ploidy level was analyzed in 100 lung tumors with FISH using three to five centromere probes.
Results: Allelic imbalance at 9q31.3-q34.3 was found in all asbestos-exposed patient tumors (100%, 17 of 17) compared with 64% (14 of 22) in the nonexposed cases (P = 0.005). The most significant difference was detected at 9q33.1 (P = 0.002). FISH results showed that also CNA were more frequent at 9q33.1 in the three major histologic types of non–small-cell lung tumors of exposed patients, and the association showed a dose-dependent trend (P = 0.03). Furthermore, we detected more frequent polyploidy among the exposed (48%, 28 of 58) than among the nonexposed (29%, 12 of 42) patient tumors (P &lt; 0.05).
Conclusions: These results provide a basis for the development of a method to identify asbestos-related lung cancer on a molecular level.
Sp-1 and c-Myc Mediate Lysophosphatidic Acid–Induced Expression of Vascular Endothelial Growth Factor in Ovarian Cancer Cells via a Hypoxia-Inducible Factor-1–Independent Mechanism
Authors: Song Yuanda , Wu Jinhua , Oyesanya Regina A. , Lee Zendra , Mukherjee Abir , Fang Xianjun 
Published: January 2009

Abstract
Purpose: Lysophosphatidic acid (LPA), which is present in ascites of ovarian cancer patients, stimulates expression of vascular endothelial growth factor (VEGF). VEGF is essential for the development and abdominal dissemination of ovarian cancer. We examined how LPA drives VEGF expression to gain a better understanding of tumor angiogenesis under normoxic conditions.
Experimental Design: ELISA, Northern blotting, immunoblotting, quantitative PCR, and promoter reporter analysis in combination with small interfering RNA and pharmacologic inhibitors were used to examine LPA-induced VEGF expression and the underlying mechanisms.
Results: LPA stimulated expression of multiple VEGF variants. A 123-bp fragment proximal to the transcriptional initiation site was identified to be functional promoter region responsible for the response to LPA. The fragment harbors consensus sites for several transcription factors including c-Myc and Sp-1 but not hypoxia-inducible factor-1. Blockade of Rho, ROCK, or c-Myc reduced LPA-dependent VEGF production and promoter activation, suggesting that the G12/13-Rho-ROCK-c-Myc cascade partially contributes to VEGF induction by LPA. More significantly, the multiple Sp-1 sites within the responsive region of the VEGF promoter were essential for LPA-mediated transcription. LPA induced Sp-1 phosphorylation and DNA-binding and transcriptional activities. The silencing of Sp-1 expression with small interfering RNA or inhibition of Sp-1 with pharmacologic inhibitors blocked VEGF production induced by LPA.
Conclusions: LPA stimulates hypoxia-inducible factor-1-independent VEGF expression to promote tumor angiogenesis through activation of the c-Myc and Sp-1 transcription factors.
In vitro and In vivo Radiosensitization of Glioblastoma Cells by the Poly (ADP-Ribose) Polymerase Inhibitor E7016
Authors: Russo Andrea L. , Kwon Hyuk-Chan , Burgan William E. , Carter Donna , Beam Katie , Weizheng Xu , Zhang Jie , Slusher Barbara S. , Chakravarti Arnab , Tofilon Philip J. , Camphausen Kevin 
Published: January 2009

Abstract
Purpose: Poly (ADP-ribose) polymerase (PARP) inhibitors are undergoing clinical evaluation for cancer therapy. Because PARP inhibition has been shown to enhance tumor cell sensitivity to radiation, we investigated the in vitro and in vivo effects of the novel PARP inhibitor E7016.
Experimental Design: The effect of E7016 on the in vitro radiosensitivity of tumor cell lines was evaluated using clonogenic survival. DNA damage and repair were measured using γH2AX foci and neutral comet assay. Mitotic catastrophe was determined by immunostaining. Tumor growth delay was evaluated in mice for the effect of E7016 on in vivo (U251) tumor radiosensitivity.
Results: Cell lines exposed to E7016 preirradiation yielded an increase in radiosensitivity with dose enhancement factors at a surviving fraction of 0.1 from 1.4 to 1.7. To assess DNA double-strand breaks repair, γH2AX measured at 24 hours postirradiation had significantly more foci per cell in the E7016/irradiation group versus irradiation alone. Neutral comet assay further suggested unrepaired double-strand breaks with significantly greater DNA damage at 6 hours postirradiation in the combination group versus irradiation alone. Mitotic catastrophe staining revealed a significantly greater number of cells staining positive at 24 hours postirradiation in the combination group. In vivo, mice treated with E7016/irradiation/temozolomide had an additional growth delay of six days compared with the combination of temozolomide and irradiation.
Conclusions: These results indicate that E7016 can enhance tumor cell radiosensitivity in vitro and in vivo through the inhibition of DNA repair. Moreover, enhanced growth delay with the addition of E7016 to temozolomide and radiotherapy in a glioma mouse model suggests a potential role for this drug in the treatment of glioblastoma multiforme.
Suppression of Anoikis by SKP2 Amplification and Overexpression Promotes Metastasis of Esophageal Squamous Cell Carcinoma
Authors: Wang Xiao-Chun , Wu Yu-Peng , Ye Bo , Lin De-Chen , Feng Yan-Bin , Zhang Zi-Qiang , Xu Xin , Han Ya-Ling , Cai Yan , Dong Jin-Tang , Zhan Qi-Min , Wu Min , Wang Ming-Rong 
Published: January 2009

Abstract
The gene of SKP2, located on chromosome 5p13, plays a critical role in cell cycle progression, especially at the G1-S transition, putatively through its control of several cell cycle regulator proteins including p27kip1, p21cip1, p57kip2, p130, cyclin E, and c-Myc. Previous studies in this laboratory revealed that gain of chromosome 5p was often seen in esophageal squamous cell carcinoma (ESCC). In the present study, we examined the amplification status and expression level of SKP2 in ESCC and investigated its clinicopathologic significance. Amplification and elevated expression of SKP2 correlated significantly with tumor stage and positive lymph node metastasis (P &lt; 0.05). The SKP2 protein expression level as determined by immunohistochemical staining showed a significant inverse correlation with p27 protein. In vivo assay showed that inhibition of SKP2 expression also decreased tumor growth and lung metastasis of ESCC cells. At the molecular level, knockdown of SKP2 by RNA interference inhibited cell migration and invasion ability. Knockdown of SKP2 expression sensitized cancer cells to anoikis, and a wobble mutant of SKP2 that is resistant to SKP2 small interfering RNA can rescue this effect. Expression level of pAkt decreased after SKP2 knockdown. Treatment of cells with phosphoinositidyl 3-kinase inhibitor (LY294002) and constitutively activator (insulin-like growth factor I) had significant effects on the anoikis of SKP2 RNA interference cells. These results show for the first time that SKP2 is amplified and overexpressed in ESCC. Elevated expression of SKP2 protected cancer cells from anoikis, and this effect was mediated, at least in part, by the phosphoinositidyl 3-kinase-Akt pathway. (Mol Cancer Res 2009;7(1):12–22)
Two Tumor Suppressors, p27Kip1 and Patched-1, Collaborate to Prevent Medulloblastoma
Authors: Ayrault Olivier , Zindy Frederique , Rehg Jerold , Sherr Charles J. , Roussel Martine F. 
Published: January 2009

Abstract
Two cyclin-dependent kinase inhibitors, p18Ink4c and p27Kip1, are required for proper cerebellar development. Loss of either of these proteins conferred a proliferative advantage to granule neuron progenitors, although inactivation of Kip1 exerted a greater effect. Mice heterozygous for Patched-1 (Ptc1+/−) that are either heterozygous or nullizygous for Kip1 developed medulloblastoma rapidly and with high penetrance. All tumors from Ptc1+/−;Kip1+/− or Ptc1+/−;Kip1−/− mice failed to express the wild-type Ptc1 allele, consistent with its role as a canonical “two-hit” tumor suppressor. In contrast, expression of the wild-type p27Kip1 protein was invariably maintained in medulloblastomas arising in Ptc1+/−;Kip1+/− mice, indicating that Kip1 is haploinsufficient for tumor suppression. Although medulloblastomas occurring in Ptc1+/− mice were histopathologically heterogeneous and contained intermixed regions of both rapidly proliferating and nondividing more differentiated cells, tumors that also lacked Kip1 were uniformly less differentiated, more highly proliferative, and invasive. Molecular analysis showed that the latter medulloblastomas exhibited constitutive activation of the Sonic hedgehog signaling pathway without loss of functional p53. Apart from gains or losses of single chromosomes, with gain of chromosome 6 being the most frequent, no other chromosomal anomalies were identified by spectral karyotyping, and half of the medulloblastomas so examined retained a normal karyotype. In this respect, this mouse medulloblastoma model recapitulates the vast majority of human medulloblastomas that do not sustain TP53 mutations and are not aneuploid. (Mol Cancer Res 2009;7(1):33–40)
Association Between Previous Concussion History and Symptom Endorsement During Preseason Baseline Testing in High School and Collegiate Athletes
Authors: Register-Mihalik Johna K. , Mihalik Jason P. , Guskiewicz Kevin M. 
Published: January 2009

Background: A graded symptom checklist is a commonly used concussion evaluation measure. Little is known about pre-season baseline symptomatology of high school and college athletes with and without a previous concussion history. Hypothesis: The primary hypothesis investigated was that those individuals with a concussion history would report more symptoms at baseline testing. The effects of sex and age on symptoms were also examined. Study Design: Cross-sectional study. Methods: Subjects included 8930 high school and collegiate athletes (height, 177.79 ± 9.97 cm; mass, 75.20 ± 19.21 kg; age, 16.60 ± 1.64 years). Subjects completed a self-report graded symptom checklist and concussion history questionnaire during a preseason clinical testing session. Symptoms reported (yes or no) on the 18-item graded symptom checklist served as the dependent variables. Results: A significant association was observed between symptoms on the graded symptom checklist and previous concussion history ( P ≤ .001). No differences were observed between high school and college athletes regarding symptom endorsement (t8928 = 0.620; P = .535). A statistical but not clinically meaningful difference was observed between the means for males and females symptom endorsement (t8928 = −3.03; P = .002): men endorsed 1.88 ± 2.81 symptoms, and women endorsed 2.09 ± 2.90 symptoms. Headache, sleeping more than usual, difficulty concentrating, drowsiness, difficulty remembering, fatigue, difficulty sleeping, and irritability were reported by more than 10% of athletes. Conclusion: High school and college athletes with a history of multiple concussions may be at risk for experiencing concussion-linked symptoms well beyond the acute stage of injury. Clinicians should be mindful of previous concussion history in athletes with increased presence of base-rate symptoms as they may be predisposed to future injury.
Factors Associated With Function After Anterior Cruciate Ligament Reconstruction
Authors: Lentz Trevor A. , Tillman Susan M. , Indelicato Peter A. , Moser Michael W. , George Steven Z. , Chmielewski Terese L. 
Published: January 2009

Background: Many individuals do not resume unrestricted, preinjury sports participation after anterior cruciate ligament reconstruction, thus a better understanding of factors associated with function is needed. The purpose of this study was to investigate the association of knee impairment and psychological variables with function in subjects with anterior cruciate ligament reconstruction. Hypothesis: After controlling for demographic variables, knee impairment and psychological variables contribute to function in subjects with anterior cruciate ligament reconstruction. Study Design: Cross-sectional study; Level of evidence, 4a. Methods: Fifty-eight subjects with a unilateral anterior cruciate ligament reconstruction completed a standardized testing battery for knee impairments (range of motion, effusion, quadriceps strength, anterior knee joint laxity, and pain intensity), kinesiophobia (shortened Tampa Scale for Kinesiophobia), and function (International Knee Documentation Committee subjective form and single-legged hop test). Separate 2-step regression analyses were conducted with International Knee Documentation Committee subjective form score and single-legged hop index as dependent variables. Demographic variables were entered into the model first, followed by knee impairment measures and Tampa Scale for Kinesiophobia score. Results: A combination of pain intensity, quadriceps index, Tampa Scale for Kinesiophobia score, and flexion motion deficit contributed to the International Knee Documentation Committee subjective form score (adjusted r2 = 0.67; P < .001). Only effusion contributed to the single-legged hop index (adjusted r2 = 0.346; P = .002). Conclusion: Knee impairment and psychological variables in this study were associated with self-report of function, not a performance test. Clinical Relevance: The results support focusing anterior cruciate ligament reconstruction rehabilitation on pain, knee motion deficits, and quadriceps strength, as well as indicate that kinesiophobia should be addressed. Further research is needed to reveal which clinical tests are associated with performance testing.
The Relationship Between Lower Extremity Alignment Characteristics and Anterior Knee Joint Laxity
Authors: Shultz Sandra J. , Nguyen Anh-Dung , Levine Beverly J. 
Published: January 2009

Background: Lower extremity alignment may influence the load distribution at the knee, potentially predisposing the anterior cruciate ligament to greater stress. We examined whether lower extremity alignment predicted the magnitude of anterior knee laxity in men and women. Hypothesis: Greater anterior pelvic angle, hip anteversion, tibiofemoral angle, genu recurvatum, and navicular drop will predict greater anterior knee laxity. Study Design: Descriptive laboratory study. Methods: Women (n = 122) and men (n = 97) were measured for anterior knee laxity and 7 lower extremity alignment variables on their dominant stance leg. Linear regression determined the extent to which the alignment variables predicted anterior knee laxity for each sex. Results: Lower anterior pelvic tilt and tibiofemoral angle, and greater genu recurvatum and navicular drop were related to greater anterior knee laxity in women, explaining 28.1% of the variance ( P < .001). Lower anterior pelvic tilt and greater hip anteversion, genu recurvatum and navicular drop were predictors of greater anterior knee laxity in men, explaining 26.5% of the variance ( P < .001). Conclusion: Lower anterior pelvic tilt, greater knee hyperextension, and foot pronation predicted greater anterior knee laxity in both men and women, with genu recurvatum and navicular drop having the greatest impact on anterior knee laxity. Greater hip anteversion was also a strong predictor in men, while a lower tibiofemoral angle was a significant predictor in women. Clinical Relevance: The associations between lower extremity alignment and anterior knee laxity suggest that alignment of the hip, knee, and ankle may be linked to or contribute to abnormal loading patterns at the knee, potentially stressing the capsuloligamentous structures and promoting greater joint laxity.
The Function of the Human Anterior Cruciate Ligament and Analysis of Single- and Double-Bundle Graft Reconstructions
Authors: Noyes Frank R. 
Published: January 2009

Context: There exists controversy on the ability of a single or double anterior cruciate ligament graft technique to restore anterior cruciate ligament function. This article examines the published experimental and clinical data supporting these surgical procedures in the ability to restore knee stability. Evidence Acquisition: An analysis of anterior cruciate ligament function and single- and double-graft reconstructions defined by selected biomechanical, robotic, kinematic, anatomical, and clinical studies. Results: The anterior cruciate ligament resists the combined motions of anterior tibial translation and internal tibial rotation, which defines the concept of rotational stability. This function prevents anterior tibial subluxation of the lateral and medial tibiofemoral compartments that accounts for the pivot-shift phenomena. The placement of single anterior cruciate ligament grafts high and proximal at the femoral attachment and posterior at the tibial attachment results in a vertical graft orientation. This graft placement results in a limited ability to provide rotational stability and is inferior when compared to a double-bundle graft procedure. Studies show that a more oblique single-graft orientation, in the sagittal and coronal plane, achieved from a central anatomic femoral and tibial location provides rotational stability similar to a double-bundle anterior cruciate ligament graft. Conclusion: There exists insufficient experimental and clinical data to recommend the more complex double- bundle anterior cruciate ligament graft technique over a well-placed central anatomic single graft in terms of restoring knee rotational stability. Meticulous surgical technique for anterior cruciate ligament graft placement is necessary to avoid failure.
The MLL recombinome of adult CD10-negative B-cell precursor acute lymphoblastic leukemia: results from the GMALL study group
Authors: Burmeister Thomas , Meyer Claus , Schwartz Stefan , Hofmann Julia , Molkentin Mara , Kowarz Eric , Schneider Björn , Raff Thorsten , Reinhardt Richard , Gökbuget Nicola , Hoelzer Dieter , Thiel Eckhard , Marschalek Rolf 
Published: January 2009

Abstract
MLL translocations in adult B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) are largely restricted to the immature CD10− immunophenotypes. MLL-AF4 is known to be the most frequent fusion transcript, but the exact frequencies of MLL aberrations in CD10− adult BCP-ALL are unknown. We present a genetic characterization of 184 BCR-ABL− CD10− adult ALL cases (156 cyIg−, 28 cyIg+) diagnosed between 2001 and 2007 at the central diagnostic laboratory of the GMALL study group. Patient samples were investigated by RT-PCR for MLL-AF4, MLL-ENL, and MLL-AF9 and by long-distance inverse polymerase chain reaction, thus also allowing the identification of unknown MLL fusion partners at the genomic level. MLL-AF4 was detected in 101 (54.9%) and MLL-ENL in 11 (6.0%) cases. In addition, rare MLL fusion genes were found: 2 MLL-TET1 cases, not previously reported in ALL, 1 MLL-AF9, 1 MLL-PTD, a novel MLL-ACTN4, and an MLL-11q23 fusion. Chromosomal breakpoints were determined in all 118 positive cases, revealing 2 major breakpoint cluster regions in the MLL gene. Characteristic features of MLL+ patients were significantly lower CD10 expression, expression of the NG2 antigen, a higher white blood count at diagnosis, and female sex. Proposals are made for diagnostic assessment. The clinical studies are registered at http://www.clinicaltrials.gov as NCT00199056 and NCT00198991.
Mapping of five candidate sex-determining loci in rainbow trout (Oncorhynchus mykiss)
Authors: Alfaqih Mahmoud A , Brunelli Joseph P , Drew Robert E , Thorgaard Gary H 
Published: January 2009

Abstract

Background
Rainbow trout have an XX/XY genetic mechanism of sex determination where males are the heterogametic sex. The homology of the sex-determining gene (SDG) in medaka to Dmrt1 suggested that SDGs evolve from downstream genes by gene duplication. Orthologous sequences of the major genes of the mammalian sex determination pathway have been reported in the rainbow trout but the map position for the majority of these genes has not been assigned.

Results
Five loci of four candidate genes (Amh, Dax1, Dmrt1 and Sox6) were tested for linkage to the Y chromosome of rainbow trout. We exclude the role of all these loci as candidates for the primary SDG in this species. Sox6i and Sox6ii, duplicated copies of Sox6, mapped to homeologous linkage groups 10 and 18 respectively. Genotyping fishes of the OSU × Arlee mapping family for Sox6i and Sox6ii alleles indicated that Sox6i locus might be deleted in the Arlee lineage.

Conclusion
Additional candidate genes should be tested for their linkage to the Y chromosome. Mapping data of duplicated Sox6 loci supports previously suggested homeology between linkage groups 10 and 18. Enrichment of the rainbow trout genomic map with known gene markers allows map comparisons with other salmonids. Mapping of candidate sex-determining loci is important for analyses of potential autosomal modifiers of sex-determination in rainbow trout.
Optical mapping of the Mycobacterium avium subspecies paratuberculosis genome
Authors: Wu Chia-wei , Schramm Timothy M , Zhou Shiguo , Schwartz David C , Talaat Adel M 
Published: January 2009

Abstract

Background
Infection of cattle with Mycobacterium avium subspecies paratuberculosis (M. ap) causes severe economic losses to the dairy industry in the USA and worldwide. In an effort to better examine diversity among M. ap strains, we used optical mapping to profile genomic variations between strains of M. ap K-10 (sequenced strain) and M. ap ATCC 19698 (type strain).

Results
The assembled physical restriction map of M. ap ATCC 19698 showed a genome size of 4,839 kb compared to the sequenced K-10 genome of 4,830 kb. Interestingly, alignment of the optical map of the M. ap ATCC 19698 genome to the complete M. ap K-10 genome sequence revealed a 648-kb inversion around the origin of replication. However, Southern blotting, PCR amplification and sequencing analyses of the inverted region revealed that the genome of M. ap K-10 differs from the published sequence in the region starting from 4,197,080 bp to 11,150 bp, spanning the origin of replication. Additionally, two new copies of the coding sequences > 99.8% were identified, identical to the MAP0849c and MAP0850c genes located immediately downstream of the MAP3758c gene.

Conclusion
The optical map of M. ap ATCC 19698 clearly indicated the miss-assembly of the sequenced genome of M. ap K-10. Moreover, it identified 2 new genes in M. ap K-10 genome. This analysis strongly advocates for the utility of physical mapping protocols to complement genome sequencing projects.