bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pure pointer programs with iteration
Authors: Hofmann Martin , Schöpp Ulrich 
Published: July 2010

Many logspace algorithms are naturally described as programs that operate on a structured input (e.g., a graph), that store in memory only a constant number of pointers (e.g., to graph nodes) and that do not use pointer arithmetic. Such “pure pointer algorithms” thus are a useful abstraction for studying the nature of logspace-computation.
In this article, we introduce a formal class purple of pure pointer programs and study them on locally ordered graphs. Existing classes of pointer algorithms, such as Jumping Automata on Graphs (jags) or Deterministic Transitive Closure (dtc) logic, often exclude simple programs. purple subsumes these classes and allows for a natural representation of many graph algorithms that access the input graph using a constant number of pure pointers. It does so by providing a primitive for iterating an algorithm over all nodes of the input graph in an unspecified order.
Since pointers are given as an abstract data type rather than as binary digits we expect that logarithmic-size worktapes cannot be encoded using pointers as is done, for example, in totally ordered dtc-logic. We show that this is indeed the case by proving that the property “the number of nodes is a power of two,” which is in logspace, is not representable in purple.
6-Thioguanine Selectively Kills BRCA2-Defective Tumors and Overcomes PARP Inhibitor Resistance
Authors: Issaeva Natalia , Thomas Huw D. , Djurenovic Tatjana , Jaspers Janneke E. , Stoimenov Ivaylo , Kyle Suzanne , Pedley Nicholas , Gottipati Ponnari , Zur Rafal , Sleeth Kate , Chatzakos Vicky , Mulligan Evan A. , Lundin Cecilia , Gubanova Evgenia , Kersbergen Ariena , Harris Adrian L. , Sharma Ricky A. , Rottenberg Sven , Curtin Nicola J. , Helleday Thomas 
Published: July 2010

Abstract
Familial breast and ovarian cancers are often defective in homologous recombination (HR) due to mutations in the BRCA1 or BRCA2 genes. Cisplatin chemotherapy or poly(ADP-ribose) polymerase (PARP) inhibitors were tested for these tumors in clinical trials. In a screen for novel drugs that selectively kill BRCA2-defective cells, we identified 6-thioguanine (6TG), which induces DNA double-strand breaks (DSB) that are repaired by HR. Furthermore, we show that 6TG is as efficient as a PARP inhibitor in selectively killing BRCA2-defective tumors in a xenograft model. Spontaneous BRCA1-defective mammary tumors gain resistance to PARP inhibitors through increased P-glycoprotein expression. Here, we show that 6TG efficiently kills such BRCA1-defective PARP inhibitor–resistant tumors. We also show that 6TG could kill cells and tumors that have gained resistance to PARP inhibitors or cisplatin through genetic reversion of the BRCA2 gene. Although HR is reactivated in PARP inhibitor–resistant BRCA2-defective cells, it is not fully restored for the repair of 6TG-induced lesions. This is likely to be due to several recombinogenic lesions being formed after 6TG. We show that BRCA2 is also required for survival from mismatch repair–independent lesions formed by 6TG, which do not include DSBs. This suggests that HR is involved in the repair of 6TG-induced DSBs as well as mismatch repair–independent 6TG-induced DNA lesion. Altogether, our data show that 6TG efficiently kills BRCA2-defective tumors and suggest that 6TG may be effective in the treatment of advanced tumors that have developed resistance to PARP inhibitors or platinum-based chemotherapy. Cancer Res; 70(15); 6268–76. ©2010 AACR.
FOXO3 Encodes a Carcinogen-Activated Transcription Factor Frequently Deleted in Early-Stage Lung Adenocarcinoma
Authors: Mikse Oliver R. , Blake Daniel C. , Jones Nathan R. , Sun Yuan-Wan , Amin Shantu , Gallagher Carla J. , Lazarus Philip , Weisz Judith , Herzog Christopher R. 
Published: July 2010

Abstract
The FOXO family of transcription factors elicits cell cycle arrest, apoptosis, and resistance to various physiologic and pathologic stresses relevant to sporadic cancer, such as DNA damage and oxidative stress. Although implicated as tumor suppressors, FOXO genetic inactivation has not been observed in human cancer. In an investigation of the two major types of non–small cell lung cancer, here, we identify the FOXO3 gene as a novel target of deletion in human lung adenocarcinoma (LAC). Biallelic or homozygous deletion (HD) of FOXO3 was detected in 8 of 33 (24.2%) mostly early-stage LAC of smokers. Another 60.6% of these tumors had losses of FOXO3 not reaching the level of HD (hereafter referred to as sub-HD). In contrast, no HD of FOXO3 was observed in 19 lung squamous cell carcinoma. Consistent with the deletion of FOXO3 were corresponding decreases in its mRNA and protein levels in LAC. The potential role of FOXO3 loss in LAC was also investigated. The carcinogen (+)-anti-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) is strongly implicated as a cause of human lung cancer. Here, we show that FOXO3a is functionally activated and augments the level of caspase-dependent apoptosis in cells exposed to this DNA-damaging carcinogen. These results implicate FOXO3 as a suppressor of LAC carcinogenesis, a role frequently lost through gene deletion. Cancer Res; 70(15); 6205–15. ©2010 AACR.
Construction and Characterization of a Bispecific Anti-CD20 Antibody with Potent Antitumor Activity against B-Cell Lymphoma
Authors: Li Bohua , Zhang Xunming , Shi Shu , Zhao Lei , Zhang Dapeng , Qian Weizhu , Zheng Lei , Gao Jie , Wang Hao , Guo Yajun 
Published: July 2010

Abstract
To develop more effective anti-CD20 reagents for B-cell lymphoma, we designed and constructed a bispecific tetravalent anti-CD20 antibody, 11B8/2F2(ScFvHL)4-Fc, derived from two fully human monoclonal antibodies (mAb), 2F2 and 11B8. 2F2 is a type I CD20 mAb, which is potent in complement-dependent cytotoxicity (CDC) assays but poor at inducing apoptosis, whereas 11B8 is a type II CD20 mAb, which is effective in induction of apoptosis but ineffective in CDC. Our results showed that 11B8/2F2(ScFvHL)4-Fc possessed apoptosis-inducing activity markedly superior to that of 2F2, and even 11B8, 11B8 plus 2F2, and 2F2(ScFvHL)4-Fc, a 2F2-derived monospecific tetravalent antibody developed previously. Interestingly, 11B8/2F2(ScFvHL)4-Fc displayed a similar ability to mediate CDC as 2F2(ScFvHL)4-Fc, although two of its four antigen-binding arms originated from 11B8. To explore why 11B8/2F2(ScFvHL)4-Fc was so potent in both CDC and apoptotic activity, a bispecific divalent antibody composed of 2F2 and 11B8, denoted as 11B8/2F2-ScFvFc, was constructed and characterized. Our results partially explained the reason for the potent CDC and apoptosis-inducing activity of 11B8/2F2(ScFvHL)4-Fc. Further in vivo therapy studies showed that 11B8/2F2(ScFvHL)4-Fc had a significantly more potent antitumor activity compared with 2F2, 11B8, 2F2 plus 11B8, and 2F2(ScFvHL)4-Fc. These data suggest that 11B8/2F2(ScFvHL)4-Fc may serve as a potential therapeutic agent for B-cell lymphoma. Cancer Res; 70(15); 6293–302. ©2010 AACR.
HERC2 Is an E3 Ligase That Targets BRCA1 for Degradation
Authors: Wu Wenwen , Sato Ko , Koike Ayaka , Nishikawa Hiroyuki , Koizumi Hirotaka , Venkitaraman Ashok R. , Ohta Tomohiko 
Published: July 2010

Abstract
The breast cancer suppressor BRCA1 forms a stable heterodimeric E3 ubiquitin ligase with BARD1. Each protein controls the abundance and stability of the other, and loss of the interaction leads to BRCA1 degradation. Here, we show that HERC2, a protein recently implicated in DNA damage repair, targets BARD1-uncoupled BRCA1 for degradation. HERC2 shuttles between the nucleus and the cytoplasm. Its COOH-terminal HECT-containing domain interacts with an NH2-terminal degron domain in BRCA1. HERC2 ubiquitinates BRCA1; this reaction depends on Cys4762 of HERC2, the catalytic ubiquitin binding site, and the degron of BRCA1. The HERC2-BRCA1 interaction is maximal during the S phase of the cell cycle and rapidly diminishes as cells enter G2-M, inversely correlated with the steady-state level of BRCA1. Significantly, HERC2 depletion antagonizes the effects of BARD1 depletion by restoring BRCA1 expression and G2-M checkpoint activity. Conversely, BARD1 protects BRCA1 from HERC2-mediated ubiquitination. Collectively, our findings identify a function for HERC2 in regulating BRCA1 stability in opposition to BARD1. The HERC2 expression in breast epithelial cells and breast carcinomas suggests that this mechanism may play a role in breast carcinogenesis. Cancer Res; 70(15); 6384–92. ©2010 AACR.
PI(3)King Apart PTEN's Role in Cancer
Authors: Zhang Siyuan , Yu Dihua 
Published: July 2010

Abstract
The tumor suppressor phosphatase and tensin homolog (PTEN) is a nonredundant phosphatase, counteracting one of the most critical cancer-promoting pathways: the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. In addition to the canonical function of dephosphorylation of phosphatidylinositol-3,4,5-trisphosphate (PIP3), recent studies showed the intriguing roles of PTEN in regulating genomic instability, DNA repair, stem cell self-renewal, cellular senescence, and cell migration and/or metastasis. Clinically, PTEN mutations and deficiencies are prevalent in many types of human cancers. Severe PTEN deficiency is also associated with advanced tumor stage and therapeutic resistance, such as the resistance to trastuzumab, an anti-HER2 therapy. Currently, targeting the deregulated PI3K/PTEN-Akt signaling axis has emerged as one of the major tenets in anticancer drug development. In this review, we highlight our current knowledge of PTEN function and the recent discoveries in dissecting the PTEN signaling pathway. The deregulations of PTEN in cancers, clinical lessons, and new prospects of rationally designed PI3K/Akt-targeted therapy for effective cancer treatment are also discussed. Clin Cancer Res; 16(17); 4325–30. ©2010 AACR.
Arsenic Trioxide and the Phosphoinositide 3-Kinase/Akt Pathway in Chronic Lymphocytic Leukemia
Authors: Goussetis Dennis J. , Platanias Leonidas C. 
Published: July 2010

AbstractSimultaneous targeting of the phosphoinositide 3-kinase (PI3K)/Akt pathway increases arsenic trioxide (ATO)–dependent cytotoxicity of chronic lymphocytic leukemia (CLL) cells, whereas it has no significant effects on normal lymphocytes. Combinations of ATO with small molecules that target PI3K and/or Akt may provide a novel approach for the treatment of CLL. Clin Cancer Res; 16(17); 4311–2. ©2010 AACR.
The Timing and Impact of Follow-Up Studies After Normal Stress Single-Photon Emission Computed Tomography Sestamibi Studies
Authors: Carryer Damita Jo , Wells Askew J. , Hodge David O. , Miller Todd D. , Gibbons Raymond J. 
Published: July 2010

Background—
The purpose of this study was to determine the prevalence and timing of routine follow-up single-photon emission computed tomography (SPECT) studies after a normal stress SPECT scan compared with the patient's warranty period (ie, time to 1% risk of death or myocardial infarction).

Methods and Results—
We identified patients at Mayo Clinic Rochester who had normal stress SPECT scans in 2002. Of 2354 patients without prior coronary artery disease, 309 (13%) had routine follow-up scans. The time to routine follow-up was a median of 2.1 years (25th percentile, 1.2 years; 75th percentile, 3.6 years). This interval was a median of 45% of the warranty period. Of the 309 patients, only 9 (3%) underwent subsequent coronary angiography, without revascularization. Of 656 patients with prior coronary artery disease, 171 (26%) had routine follow-up scans. The time to routine follow-up was a median of 1.6 years (25th percentile, 1.0 years; 75th percentile, 2.7 years). This interval was a median of 164% of the warranty period. Of the 171 patients, only 7 (4%) underwent coronary angiography, without revascularization.

Conclusions—
In patients without prior coronary artery disease, routine follow-up SPECT scans are performed infrequently but well before the end of the patient's warranty period. Routine follow-up scans are performed more commonly in patients with prior coronary artery disease but generally after the end of the warranty period. Routine follow-up SPECT scans have minimal impact on referral to catheterization or revascularization.
First administration to man of Org 25435, an intravenous anaesthetic: A Phase 1 Clinical Trial
Authors: Rigby-Jones Ann E , Sneyd J Robert , Vijn Peter , Boen Patrick , Cross Maurice 
Published: July 2010

AbstractBackgroundOrg 25435 is a new water-soluble alpha-amino acid ester intravenous anaesthetic which proved satisfactory in animal studies. This study aimed to assess the safety, tolerability and efficacy of Org 25435 and to obtain preliminary pharmacodynamic and pharmacokinetic data.MethodsIn the Short Infusion study 8 healthy male volunteers received a 1 minute infusion of 0.25, 0.5, 1.0, or 2.0 mg/kg (n = 2 per group); a further 10 received 3.0 mg/kg (n = 5) or 4.0 mg/kg (n = 5). Following preliminary pharmacokinetic modelling 7 subjects received a titrated 30 minute Target Controlled Infusion (TCI), total dose 5.8-20 mg/kg.ResultsWithin the Short Infusion study, all subjects were successfully anaesthetised at 3 and 4 mg/kg. Within the TCI study 5 subjects were anaesthetised and 2 showed signs of sedation. Org 25435 caused hypotension and tachycardia at doses over 2 mg/kg. Recovery from anaesthesia after a 30 min administration of Org 25435 was slow (13.7 min). Pharmacokinetic modelling suggests that the context sensitive half-time of Org 25435 is slightly shorter than that of propofol in infusions up to 20 minutes but progressively longer thereafter.ConclusionsOrg 25435 is an effective intravenous anaesthetic in man at doses of 3 and 4 mg/kg given over 1 minute. Longer infusions can maintain anaesthesia but recovery is slow. Hypotension and tachycardia during anaesthesia and slow recovery of consciousness after cessation of drug administration suggest this compound has no advantages over currently available intravenous anaesthetics.
Effect of codon optimization and subcellular targeting on Toxoplasma gondii antigen SAG1 expression in tobacco leaves to use in subcutaneous and oral immunization in mice
Authors: Laguía-Becher Melina , Martín Valentina , Kraemer Mauricio , Corigliano Mariana , Yacono María L , Goldman Alejandra , Clemente Marina 
Published: July 2010

AbstractBackgroundCodon optimization and subcellular targeting were studied with the aim to increase the expression levels of the SAG178-322antigen ofToxoplasma gondiiin tobacco leaves. The expression of the tobacco-optimized and native versions of theSAG1gene was explored by transient expression from theAgrobacterium tumefaciensbinary expression vector, which allows targeting the recombinant protein to the endoplasmic reticulum (ER) and the apoplast. Finally, mice were subcutaneously and orally immunized with leaf extracts-SAG1 and the strategy of prime boost with rSAG1 expressed inEscherichia coliwas used to optimize the oral immunization with leaf extracts-SAG1.ResultsLeaves agroinfiltrated with an unmodifiedSAG1gene accumulated 5- to 10-fold more than leaves agroinfiltrated with a codon-optimizedSAG1gene. ER localization allowed the accumulation of higher levels of native SAG1. However, no significant differences were observed between the mRNA accumulations of the different versions of SAG1. Subcutaneous immunization with leaf extracts-SAG1 (SAG1) protected mice against an oral challenge with a non-lethal cyst dose, and this effect could be associated with the secretion of significant levels of IFN-γ. The protection was increased when mice were ID boosted with rSAG1 (SAG1+boost). This group elicited a significant Th1 humoral and cellular immune response characterized by high levels of IFN-γ. In an oral immunization assay, the SAG1+boost group showed a significantly lower brain cyst burden compared to the rest of the groups.ConclusionTransient agroinfiltration was useful for the expression of all of the recombinant proteins tested. Our results support the usefulness of endoplasmic reticulum signal peptides in enhancing the production of recombinant proteins meant for use as vaccines. The results showed that this plant-produced protein has potential for use as vaccine and provides a potential means for protecting humans and animals against toxoplasmosis.
Cloning, expression and transmission-blocking activity of anti-PvWARP, malaria vaccine candidate, in Anopheles stephensi mysorensis
Authors: Gholizadeh Saber , Basseri Hamid Reza , Zakeri Sedigheh , Ladoni Hossein , Djadid Navid Dinparast 
Published: July 2010

Abstract

Background
Notwithstanding progress in recent years, a safe, an effective and affordable malaria vaccine is not available yet. Ookinete-secreted protein, Plasmodium vivax von Willebrand factor A domain-related protein (PvWARP), is a candidate for malaria transmission-blocking vaccines (TBVs).

Methods
The PvWARP was expressed in Escherichia coli BL21 using the pET-23a vector and was purified using Ni-NTA affinity chromatography from a soluble fraction. Polyclonal antibody was raised against rPvWARP and transmission blocking activity was carried out in an Anopheles stephensi-P. vivax model.

Results
Expression of full length of PvWARP (minus signal peptide) expression showed a 35-kDa protein. The purified protein was recognized by mouse polyclonal antibody directed against rPvWARP. Sera from the animals displayed significantly a blocking activity in the membrane feeding assay of An. stephensi mysorensis.

Conclusions
This is the first report on P. vivax WARP expression in E. coli that provides an essential base for development of the malaria TBV against P. vivax. This may greatly assist in malaria elimination, especially in the oriental corner of WHO Eastern Mediterranean Regional Office (WHO/EMRO) including Afghanistan, Iran and Pakistan.
Complete genome sequence of a Megalocytivirus (family Iridoviridae) associated with turbot mortality in China
Authors: Shi Cheng-Yin , Jia Kun-Tong , Yang Bing , Huang Jie 
Published: July 2010

Abstract

Background
Turbot reddish body iridovirus (TRBIV) causes serious systemic diseases with high mortality in the cultured turbot, Scophthalmus maximus. We here sequenced and analyzed the complete genome of TRBIV, which was identified in Shandong province, China.

Results
The genome of TRBIV is a linear double-stranded DNA of 110,104 base pairs, comprising 55% G + C. Total 115 open reading frames were identified, encoding polypeptides ranging from 40 to 1168 amino acids. Amino acid sequences analysis revealed that 39 of the 115 potential gene products of TRBIV show significant homology to other iridovirus proteins. Phylogenetic analysis of conserved genes indicated that TRBIV is closely related to infectious spleen and kidney necrosis virus (ISKNV), rock bream iridovirus (RBIV), orange-spotted grouper iridovirus (OSGIV), and large yellow croaker iridovirus (LYCIV). The results indicated that TRBIV belongs to the genus Megalocytivirus (family Iridoviridae).

Conclusions
The determination of the genome of TRBIV will provide useful information for comparative study of Megalocytivirus and developing strategies to control outbreaks of TRBIV-induced disease.
Sporadic meningioangiomatosis-associated atypical meningioma mimicking parenchymal invasion of brain: a case report and review of the literature
Authors: Chen Yan-yang , Tiang Xiao-ying , Li Zhi , Luo Bo-ning , Huang Quan 
Published: July 2010

Abstract
Meningioangiomatosis is a rare hamartomatous lesion or meningiovascular malformation in brain. In extremely rare condition, meningioma may occur together with meningioangiomatosis, and only 19 cases have been described in English literature until now. We now report a case of meningioangiomatosis-associated meningioma with atypical and clear cell variant. A 34-year-old man presented a 3-month history of progressive numbness and weakness of his left lower extremity. He had no stigmata of neurofibromatosis type 2. Magnetic resonance imaging (MRI) revealed multifocal lesions in the right frontoparietal lobe. The lesions were totally removed. Microscopically, parts of lesions were atypical and clear cell meningioma corresponding to WHO grade II. The adjacent brain parenchyma showed the histological features of meningioangiomatosis. Neoplastic cells in atypical meningioma area were immunoreactive to epithelial membrane antigen (EMA) with high MIB-1 index of up to 20%. However, the spindle cells in meningioangiomatosis area were negative for EMA with low MIB-1 index of up to 1%. The diagnosis of atypical meningioma associated with sporadic meningioangiomatosis was made. To our knowledge, this is the first case of a meningioangiomatosis-associated meningioma with atypical and clear cell variant component to be described. The patient had been followed-up for 11 months without adjuvant radiotherapy or chemotherapy. No tumor recurrence was found during this period. Meningioangiomatosis-associated meningioma is more likely to occur in younger patients and histologically to mimic parenchymal invasion of brain. We suggest that postoperative radiotherapy or chemotherapy should be given careful consideration to avoid over-treatment due to erroneously interpret as malignant meningioma.
Computed tomography assessment of exogenous surfactant-induced lung reaeration in patients with acute lung injury
Authors: Lu Qin , Zhang Mao , Girardi Cassio , Bouhemad Belaïd , Kesecioglu Jozef , Rouby Jean-Jacques 
Published: July 2010

Abstract
Introduction
Previous randomized trials failed to demonstrate a decrease in mortality of patients with acute lung injury treated by exogenous surfactant. The aim of this prospective randomized study was to evaluate the effects of exogenous porcine-derived surfactant on pulmonary reaeration and lung tissue in patients with acute lung injury and acute respiratory distress syndrome (ALI/ARDS).

Methods
Twenty patients with ALI/ARDS were studied (10 treated by surfactant and 10 controls) in whom a spiral thoracic computed tomography scan was acquired before (baseline), 39 hours and 7 days after the first surfactant administration. In the surfactant group, 3 doses of porcine-derived lung surfactant (200 mg/kg/dose) were instilled in both lungs at 0, 12 and 36 hours. Each instillation was followed by recruitment maneuvers. Gas and tissue volumes were measured separately in poorly/nonaerated and normally aerated lung areas before and seven days after the first surfactant administration. Surfactant-induced lung reaeration was defined as an increase in gas volume in poorly/non-aerated lung areas between day seven and baseline compared to the control group.

Results
At day seven, surfactant induced a significant increase in volume of gas in poorly/non-aerated lung areas (320 ± 125 ml versus 135 ± 161 ml in controls, P = 0.01) and a significant increase in volume of tissue in normally aerated lung areas (189 ± 179 ml versus -15 ± 105 ml in controls, P < 0.01). PaO2/FiO2 ratio was not different between the surfactant treated group and control group after surfactant replacement.

Conclusions
Intratracheal surfactant replacement induces a significant and prolonged lung reaeration. It also induces a significant increase in lung tissue in normally aerated lung areas, whose mechanisms remain to be elucidated.

Trial registration
NCT00742482.