bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cantharidin-induced mitotic arrest is associated with the formation of aberrant mitotic spindles and lagging chromosomes resulting, in part, from the suppression of PP2Aα
Authors: Bonness Kathy , Aragon Ileana V. , Rutland Beth , Ofori-Acquah Solomon , Dean Nicholas M. , Honkanen Richard E. 
Published: November 2006

Abstract
Cantharidin, a natural vesicant, inhibits the activity of several PPP family phosphatases, displays antitumor activity, and induces apoptosis in many types of tumor cells. However, the molecular mechanisms underlying the antitumor activity of cantharidin are not clear. Here, dose-response studies confirm a strong correlation between the suppression of phosphatase activity and cell death. Flow cytometry analysis indicates that before apoptosis, cantharidin delays cell cycle progression following DNA replication with no apparent effect on G1-S or S-G2 phase progression. In contrast, studies with double thymidine-synchronized populations of cells indicate that cantharidin can rapidly arrest growth when added during G2 or early M phase. Immunostaining indicates that cell cycle arrest occurs before the completion of mitosis and is associated with the appearance of aberrant mitotic spindles. Live cell imaging with time-lapse microscopy shows that cantharidin disrupts the metaphase alignment of chromosomes and produces a prolonged mitotic arrest, with the onset of apoptosis occurring before the onset of anaphase. To explore the contribution of individual phosphatases, antisense oligonucleotides and small interfering RNA were developed to suppress the expression of cantharidin-sensitive phosphatases. The suppression of PP2Aα, but not PP2Aβ, is sufficient to induce metaphase arrest, during which time lagging chromosomes are observed moving between the spindle poles and the metaphase plate. Immunostaining revealed slightly abnormal, yet predominately bipolar, mitotic spindles. Nonetheless, after a 10- to 15-hour delay, the cells enter anaphase, suggesting that an additional cantharidin-sensitive phosphatase is involved in the progression from metaphase into anaphase or to prevent the onset of apoptosis in cells arrested during mitosis. [Mol Cancer Ther 2006;5(11):2727–36]
Increase in Mrp1 expression and 4-hydroxy-2-nonenal adduction in heart tissue of Adriamycin-treated C57BL/6 mice
Authors: Jungsuwadee Paiboon , Cole Marsha P. , Sultana Rukhsana , Joshi Gurujaj , Tangpong Jitbanjong , Butterfield D. Allan , St. Clair Daret K. , Vore Mary 
Published: November 2006

AbstractMultidrug resistance-associated protein 1 (MRP1) mediates the ATP-dependent efflux of endobiotics and xenobiotics, including estradiol 17-(β-d-glucuronide), leukotriene C4, and the reduced glutathione conjugate of 4-hydroxy-2-nonenal (HNE), a highly reactive product of lipid peroxidation. Adriamycin is an effective cancer chemotherapeutic drug whose use is limited by cardiotoxicity. Adriamycin induces oxidative stress and production of HNE in cardiac tissue, which may contribute to cardiomyopathy. We investigated the role of Mrp1 in Adriamycin-induced oxidative stress in cardiac tissue. Mice were treated with Adriamycin (20 mg/kg, i.p.), and heart homogenate and sarcolemma membranes were assayed for Mrp1 expression and ATP-dependent transport activity. Expression of Mrp1 was increased at 6 and 24 hours after Adriamycin treatment compared with saline treatment. HNE-adducted proteins were significantly increased (P &lt; 0.001) in the homogenates at 6 hours after Adriamycin treatment and accumulated further with time; HNE adduction of a 190-kDa protein was evident 3 days after Adriamycin treatment. Mrp1 was localized predominately in sarcolemma as shown by confocal and Western blot analysis. Sarcolemma membrane vesicles transported leukotriene C4 with a Km and Vmax of 51.8 nmol/L and 94.1 pmol/min/mg, respectively, and MK571 (10 μmol/L) inhibited the transport activity by 65%. Exposure of HEKMrp1 membranes to HNE (10 μmol/L) significantly decreased the Vmax for estradiol 17-(β-d-glucuronide) transport by 50%. These results show that expression of Mrp1 in the mouse heart is localized predominantly in sarcolemma. Adriamycin treatment increased Mrp1 expression and HNE adduction of Mrp1. Cardiac Mrp1 may play a role in protecting the heart from Adriamycin-induced cardiomyopathy by effluxing HNE conjugates. [Mol Cancer Ther 2006;5(11):2851–60]
Ornithine decarboxylase activity in tumor cell lines correlates with sensitivity to cell death induced by histone deacetylase inhibitors
Authors: Saunders Laura R. , Verdin Eric 
Published: November 2006

AbstractInhibitors of histone deacetylases (HDAC) show significant promise as targeted anticancer agents against a variety of hematologic and solid tumors. HDAC inhibitors arrest the growth of primary cells, but they induce apoptosis or differentiation of tumor cells. Although the precise mechanism is unknown, differences in cell cycle checkpoints and chromatin structure may be responsible. Cellular polyamines regulate both cell cycle progression and chromatin structure. In tumors, polyamines are abundantly produced because of increased activity of the rate-limiting enzyme in polyamine synthesis, ornithine decarboxylase (ODC). To determine if polyamines contribute to the cellular response to HDAC inhibitors, we inhibited ODC activity with α-difluoromethylornithine. Polyamine depletion increased resistance to apoptosis induced by HDAC inhibitors. In addition, we found that ODC activity levels correlated with sensitivity to HDAC inhibitors in a panel of tumor cell lines. We conclude that polyamines participate in the cellular response to HDAC inhibitors and that ODC activity correlates with sensitivity to HDAC inhibitor–induced apoptosis. Thus, elevated polyamine levels might be a biomarker for tumor sensitivity to HDAC inhibitor–induced apoptosis. These findings warrant clinical evaluation of tumor samples to determine if high ODC activity levels predict sensitivity to HDAC inhibitors. [Mol Cancer Ther 2006;5(11):2777–85]
Clinical relevance of different dihydropyrimidine dehydrogenase gene single nucleotide polymorphisms on 5-fluorouracil tolerance
Authors: Morel Alain , Boisdron-Celle Michele , Fey Luc , Soulie Patrick , Craipeau Marie Claire , Traore Sori , Gamelin Erick 
Published: November 2006

Abstract
Purpose: Although single nucleotide polymorphisms (SNP) of the dihydropyrimidine dehydrogenase gene (DPYD) have been reported, which affect enzyme activity and the severity of 5-fluorouracil (5-FU) toxicity, no pretherapeutic detection has thus far been developed. We investigated 22 DPYD gene SNPs, their respective incidence, their link with grade 3 to 4 toxic side effects, and their management in practice: 9 were looked for in 487 patients, whereas 13 others were investigated in 171 patients. Patients and Methods: SNPs were detected before 5-FU-based treatment in WBC using a Pyrosequencing method. Close clinical and biological follow-up was done. Results: Five different SNPs were found in 187 patients (IVS14 + 1G&gt;A, 2846A&gt;T, 1679T&gt;G, 85T&gt;C, −1590T&gt;C). Three hundred patients had no SNP. Forty-four patients had grade 3 to 4 toxic side effects in either the first or second cycle. Sixty percent of patients with either IVS14 + 1G&gt;A or 2846A&gt;T SNPs and the only patient with 1679T&gt;G SNP experienced early grade 3 to 4 toxicity, compared with 0%, 5.5%, and 15% of those with either −1590T&gt;C, 85T&gt;C SNP, or no SNP, respectively. In cases with grade 3 to 4 toxicity, treatment either had to be quickly stopped, or could be safely continued with an individual dose adjustment. Sensitivity, specificity, and positive and negative predictive values of the detection of these three major SNPs as toxicity predictive factors were 0.31, 0.98, and 0.62 and 0.94, respectively. Conclusion: Pretreatment detection of three DPYD SNPs could help to avoid severe toxic side effects. This approach is suitable for clinical practice and should be compared or combined with pharmacologic approaches. In the case of dihydropyrimidine dehydrogenase deficiency, 5-FU administration often can be safely continued with an individual dose adjustment. [Mol Cancer Ther 2006;5(11):2895–904]
Note on J.A. Emerton: lines 25-6 of the Moabite Stone and a recently-discovered inscription
Authors: Kallai Zecharia 
Published: November 2006

AbstractThe term hmkrtt (plural with article) in 1.25 of the Moabite stone, compared to the singular form mkrt in 1.4 of the newly discovered Moabite royal inscription, was interpreted as referring to a water reservoir, similar ro 'šwvh mentioned in ll. 9 and 23. It is suggested that the two terms should be regarded as distinct features of such water installation, with the mkrt referring to an auxiliary element of the reservoir, namely a shaft, passage or conduit.
Protestantism, Anxiety and Orientations to the Environment: Sweden as a Test Case for the Ideas of Richard Sennett
Authors: Stanworth Hilary 
Published: November 2006

AbstractThis paper examines how Protestant beliefs can influence orientations to the natural and built environment. Sweden is taken as a test case for a critical evaluation of Richard Sennett's American-focused claims that Protestant-induced anxieties encourage moves to create bland, neutralised environments in which temptation and contact with distractingly different others can be minimised. The paper documents ways in which Swedish environmental orientations fail to fit with Sennett's account and elaborates how Protestantism has the potential to generate a wider range of outcomes than he recognises. It then suggests that variations in the impact the same religion may have produced in the Swedish and American context might be linked to cross-societal differences in the relation between the individual and the collective, and in the role of the state.
Fraud: From the Biblical Basis to General Commercial Law in Roman Palestine
Authors: Rosenfeld Ben-Zion , Menirav Joseph 
Published: November 2006

AbstractThe article deals with the understanding of the historical and legal components of the law prohibiting fraud (honayah) as appears from the Bible to Rabbinic literature. The first section reviews this law and its understanding from Biblical times until the destruction of the Second Temple. Then follows a discussion of the changes that arose after this period, based on the information gleaned from the rabbinic literature, on fraud, its development, and its structure. The law declares that every deviation of one sixth of an accepted price is called fraud. The article analyzes the main issues of the law such as: is this sixth of the gross price or of the net price? How can one set the legal definitions of profit and fraud for an object that was resold several times. The authors analyze cases in which it is difficult to set a price due to various reasons, or items that both the buyer and seller cannot complain of fraud. The rabbinic law is compared and contrasted to the contemporary Roman law.
Protecting Its Exclusive Jurisdiction: The Mox Plant-judgment of the ECJ
Authors: Lavranos Nikolaos 
Published: November 2006

AbstractIn the judgment in Case C-459/03, Commission v Ireland, the ECJ for the first time explicitly determined the scope of its exclusive jurisdiction based on Article 292 EC. The ECJ interpreted its jurisdiction very expansively in order to protect its exclusive jurisdiction to interpret and apply Community law. Accordingly, EU Member States involved in a dispute that potentially raises issues of Community law are not allowed to bring the case before a dispute settlement body other than the ECJ. Furthermore, Member States have the duty to inform and consult the Community institutions prior of bringing a case before another dispute settlement body. Otherwise, the ECJ claims, the danger arises that the autonomy of the Community legal order and its exclusive jurisdiction may adversely be affected by rulings of other international courts or tribunals in disputes that also touch on EC law. With this judgment the ECJ substantially restricted the right of the EU Member States to select a dispute settlement system of their choice. Moreover, this expansive interpretation by the ECJ of its exclusive jurisdiction limits the exercise of the jurisdiction of other international courts and tribunals that are called upon to adjudicate on a dispute that possibly involves Community law.It is submitted that with this extensive understanding of its exclusive jurisdiction, the ECJ is unduly restricting the sovereign right of the Member States to select the dispute settlement system of their choice as well as interfering in the exercise of the jurisdiction of the other international courts and tribunals.
Bearing the risk in pledging: Lysias VIII, 10
Authors: Schanbacher D. 
Published: November 2006

AbstractGiving a thing in pledge sometimes means the transfer of ownership to the creditor in case of default of payment. If it happens that the pledge is damaged or even destroyed before the payment is due, the question arises who has to bear the loss. Ancient as well as recent legal sources decide or tend to decide against the creditor.
Intracellular Protein Degradation: From a Vague Idea thru the Lysosome and the Ubiquitin-Proteasome System and onto Human Diseases and Drug Targeting
Authors: Ciechanover Aaron 
Published: November 2006

AbstractBetween the 1950s and 1980s, scientists were focusing mostly on how the genetic code is transcribed to RNA and translated to proteins, but how proteins are degraded has remained a neglected research area. With the discovery of the lysosome by Christian de Duve it was assumed that cellular proteins are degraded within this organelle. Yet, several independent lines of experimental evidence strongly suggested that intracellular proteolysis is largely non-lysosomal, but the mechanisms involved remained obscure. The discovery of the ubiquitin-proteasome system resolved the enigma. We now recognize that degradation of intracellular proteins is involved in regulation of a broad array of cellular processes, such as cell cycle and division, regulation of transcription factors, and assurance of the cellular quality control. Not surprisingly, aberrations in the system have been implicated in the pathogenesis of human disease, such as malignancies and neurodegenerative disorders, which led subsequently to an increasing effort to develop mechanism-based drugs.
Central Nervous System Disease in Acute Lymphoblastic Leukemia: Prophylaxis and Treatment
Authors: Pui Ching-Hon 
Published: November 2006

Abstract
Improved treatment for acute lymphoblastic leukemia (ALL) has virtually eliminated testicular relapse. However, the control of central nervous system (CNS) leukemia remains a therapeutic challenge in childhood ALL, partly because of the late complications arising from cranial irradiation. In most current pediatric protocols, cranial irradiation (12 to 18 Gy) is given to 5% to 25% of patients—those with T-cell ALL, overt CNS disease (CNS3 status) or high-risk cytogenetics. CNS control is a less urgent concern in adults with ALL, in whom systemic relapse remains the major problem. With current approaches, approximately 2% to 10% of patients can be expected to develop CNS relapse. Children with B-cell precursor ALL who have a late CNS relapse (after an initial remission of 18 months or more) and did not receive cranial irradiation have an excellent outcome after retrieval therapy, with a 5-year event-free survival (EFS) rate approaching that in newly diagnosed patients. Innovative treatment options are needed for children who develop CNS relapses after a short initial remission or after receiving cranial irradiation, and in any adults with CNS leukemia at diagnosis or relapse.
FLT3 Mutations: Biology and Treatment
Authors: Small Donald 
Published: November 2006

AbstractFLT3 is a receptor tyrosine kinase with important roles in hematopoietic stem/progenitor cell survival and proliferation. It is mutated in about 1/3 of acute myeloid leukemia (AML) patients, either by internal tandem duplications (ITD) of the juxtamembrane domain or by point mutations usually involving the kinase domain (KD). Both types of mutation constitutively activate FLT3. Many studies have shown that AML patients with FLT3/ITD mutations have poor cure rates due to relapse. This has led to the development of a number of small molecule tyrosine kinase inhibitors (TKI) with activity against FLT3. Many of these are still in preclinical development, but several have entered clinical phase I and II trials as monotherapy in patients with relapsed AML. Patients with FLT3 mutations in these trials have shown clinical responses, most often a clearing of peripheral blasts, but rarely major reductions of bone marrow blasts. Several studies have shown that FLT3 was successfully inhibited in most patients. However, complete remissions have rarely been achieved in these trials. The difference in responses of chronic myeloid leukemia (CML) patients to BCR-ABL inhibitors compared to FLT3 mutant AML patients to FLT3 inhibitors may be reflective of treating a single gene disease in CML versus multiply altered gene disease in AML. This has led to clinical testing of FLT3 TKI in combination with conventional chemotherapy, with trial designs based on preclinical testing showing synergistic effects between these agents in inducing cytotoxic responses. Several combination trials are ongoing or planned in both relapsed and newly diagnosed FLT3-mutant AML patients.
Defining and Managing Imatinib Resistance
Authors: Mauro Michael J. 
Published: November 2006

AbstractWhile imatinib is highly effective therapy, with improving prospects over time for sustained remission and potential to severely limit or eliminate disease progression and transformation, a minority of patients either fail or respond suboptimally to imatinib; as well, disease eradication may not be possible with imatinib. Distinct patterns of resistance have evolved with the use of imatinib, and Abl kinase mutations, which alter imatinib binding or favor kinase conformations inaccessible to imatinib, are a common finding associated with clinical resistance. Dasatinib and nilotinib, alternate Abl kinase inhibitors, restore hematologic and cytogenetic remission in the majority of patients with primary failure or acquired resistance in chronic phase disease; in advanced disease and Philadelphia chromosome (Ph)+ ALL, responses are more limited and relapse is common. Future studies with these agents will focus on further optimizing imatinib response, reduction of minimal residual disease, and prevention of resistance. Still newer inhibitors active against T315I mutant BCR-ABL may overcome primary and secondary resistance to dasatinib and nilotinib.
Managing the Patient with Chronic Myeloid Leukemia Through and After Allogeneic Stem Cell Transplantation
Authors: Apperley Jane F. 
Published: November 2006

Abstract
Although the only curative therapy for chronic myeloid leukemia remains allogeneic stem cell transplantation (allo-SCT), early to mid-term results of imatinib in newly diagnosed patients are sufficiently impressive to have displaced allo-SCT to second- or third-line treatment. Patients now arrive at a decision for transplantation in a variety of disease situations: failing to achieve certain hematological, cytogenetic and molecular milestones by some pre-determined timepoint, having lost a previous best response or by progression to advanced phase. The decision, therefore, is not simply whether to transplant or not, but also how to transplant. Evolving transplant technology requires that the individual circumstances of each patient should be considered when recommending the procedure. Attempts to improve the safety of transplant are generally associated with a reduction in long-term disease control and patient monitoring, and management is life-long. The treatment of recurrent disease is no longer straightforward, with the choices being donor lymphocytes or tyrosine kinase inhibitors alone or in combination. This section will review the evidence supporting some of these decisions and highlight current controversies.
The Management of Patients with Limited-Stage Classical Hodgkin Lymphoma
Authors: Gospodarowicz Mary K. , Meyer Ralph M. 
Published: November 2006

AbstractThe term limited-stage Hodgkin lymphoma refers to those patients with stage I–II disease and an absence of bulky disease. Among those patients with classical Hodgkin lymphoma, approximately one-third of patients will fall into this category. As long-term disease control can now be anticipated in more than 90% of these patients, management strategies must increasingly address the need to reduce the long-term treatment-related risks. Current treatment options include use of combined modality therapy that includes an abbreviated course of chemotherapy and involved-field radiation or treatment with chemotherapy, currently consisting of ABVD, as a single modality. The choice of treatment between these two options involves specific trade-offs that must balance issues of disease control against long-term risk of late effects.
Biology, Clinical Course and Management of Nodular Lymphocyte-Predominant Hodgkin Lymphoma
Authors: Nogová Lucia , Rudiger Thomas , Engert Andreas 
Published: November 2006

Abstract
Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) differs in histological and clinical presentation from classical Hodgkin lymphoma (cHL). The typical morphologic signs of NLPHL are atypical “lymphocytic and histiocytic” (L&H) cells, which are surrounded by a non-neoplastic nodular background of small lymphocytes of B-cell origin. The NLPHL cells are positive for CD45, CD19, CD20, CD22 and CD79a, but lack expression of CD15 and CD30, the typical markers for cHL. NLPHL patients are predominantly of male gender with a median age of 37 years. Patients often present in early stages (63%) and rarely have B-symptoms (9%). Treatment of NLPHL patients using standard Hodgkin lymphoma (HL) protocols leads to complete remission (CR) in more than 95% of patients. Survival and freedom from treatment failure (FFTF) are worse in advanced-stage patients than in early-stage patients. Thus, patients in advanced and in early stages with unfavorable risk factors are treated similarly to cHL patients. In contrast, patients with early-stage NLPHL without risk factors can be sufficiently treated with reduced intensity programs having less severe adverse effects. As a result, treatment of early NLPHL is less clearly defined, including radiotherapy in extended field (EF) or involved field (IF) technique, combined modality treatment, and, more recently, monoclonal antibody rituximab. Watch and wait strategy plays an important role in pediatric oncology to avoid adverse effects associated with therapy.