bluuebunny/crossref_metadata_2025 huggingface dataset:
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

Multidrug 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 < 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

Inhibitors 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

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>A, 2846A>T, 1679T>G, 85T>C, −1590T>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>A or 2846A>T SNPs and the only patient with 1679T>G SNP experienced early grade 3 to 4 toxicity, compared with 0%, 5.5%, and 15% of those with either −1590T>C, 85T>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

The 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

This 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

The 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

In 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

Giving 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.
Understanding of Psychiatry & Psychiatrists in England and China
Authors: Higgins Louise T.
Published: November 2006

This descriptive study aimed to test the findings of Williams, Cheyne, and Macdonald (2001) on the accuracy of people's knowledge of psychiatry and psychiatrists and extends the findings to another culture, namely, the People's Republic of China. The questions asked by Williams et al. were repeated with people on the streets in England and China and also with groups of students who had been educated in mental health issues. The results showed that there were some shared misperceptions about psychiatry in both countries. For example, a lack of awareness about psychiatrists’ medical qualifications. There were also some cultural differences, which reflected the different social systems involved. Education was found to increase awareness of problems treated and treatments used, to improve the image of psychiatrists, and to emphasise the role of the criminal justice system in dealing with the mentally ill.
If Special Issues of Journals Are Not So Special, Why Has Their Use Proliferated?
Authors: Mowday Richard T.
Published: November 2006

In the context of the increasing publication of special issues in scholarly journals, this commentary critically examines the arguments in favor and against special issues. Both arguments are found to be wanting. Possible reasons for the proliferation of special issues are offered, as are thoughts on when special issues may be more useful.
Competitive Positioning, Deracialization, and Attack Speech
Authors: Krebs Timothy B. , Holian David B.
Published: November 2006

Previous research on negative campaigning has focused on the influence of competitive circumstances and the timing of attacks. Here, we focus on whether campaign issues or character are more likely to be the focus of attacks and whether, as part of a deracialized campaign, minority candidates attack less than do nonminorities. Data are derived from content analyses of newspaper coverage and candidates’ TV ads in the 2001 Los Angeles mayoral election. Contrary to expectations, one’s position in the horse race is not a significant predictor of attacks in the primary campaign. More important are conditions in the campaign environment that maximize the benefits of attack speech. When candidates attack, they are likely to do so on salient issues and character. We also find that minority candidates attack significantly less than do nonminorities, in support of our expectations regarding deracialized campaigns. In a concluding section, we discuss the implications of our findings.
Campaign Finance Reform as Institutional Choice
Authors: Moscardelli Vincent G. , Haspel Moshe
Published: November 2006

If the Bipartisan Campaign Reform Act (BCRA) of 2002 banned the use of soft money—the only source of funds in which Democrats approached parity with Republicans—why did the Republican congressional leadership revile the bill and the Democratic congressional leadership embrace it? We address this puzzle by modeling competing electoral, partisan, and policy motives that guided members’ decision making on the vote for final passage of this bill. Our solution lies in the fact that members believed that BCRA would reduce the role of the national parties in congressional elections. Although the parties may behave similarly under a fixed electoral regime, we find that the BCRA vote is consistent with two parties that prefer different sets of electoral rules. Specifically, Democrats appear more sympathetic to changes that enhance the role of candidates and outside groups, whereas Republicans appear to prefer stronger national parties.
Candidate Divergence, Ideology, and Vote Choice in U.S. Senate Elections
Authors: Ensley Michael J.
Published: November 2006

Although it has been long established that ideology influences the decisions of American voters, scholars have begun more recently to delineate which voters under what conditions will vote ideologically. Although these studies have been illuminating, most analyses have failed to account for one critical contextual factor: candidate ideological divergence. Using a random-effects probit model and data from the 1988 to 1992 American Senate Election Studies, I show that the ideological divergence among Senate candidates conditions the influence of ideology on vote choice, at least among the more politically knowledgeable segment of the population. This reinforces and extends the findings of Wright and Berkman that ideologically polarized candidates produce ideological voters.
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

Between 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

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

FLT3 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

While 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

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

The 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

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.
Hepcidin and Its Role in Regulating Systemic Iron Metabolism
Authors: Ganz Tomas
Published: November 2006

Maintenance of stable extracellular iron concentrations requires the coordinate regulation of iron transport into plasma from dietary sources in the duodenum, from recycled senescent red cells in macrophages and from storage in hepatocytes. Moreover, during fetal development, the iron requirements of the fetus must be matched by the transport of maternal iron across the placenta. Hepcidin is a 25–amino acid disulfide-rich peptide synthesized in the liver that acts as a systemic iron-regulatory hormone by regulating iron transport from iron-exporting tissues into plasma. Hepcidin inhibits the cellular efflux of iron by binding to, and inducing the degradation of, ferroportin, the sole iron exporter in iron-transporting cells. In turn, hepcidin synthesis is increased by iron loading and decreased by anemia and hypoxia. Additionally, hepcidin synthesis is greatly increased during inflammation, trapping iron in macrophages, decreasing plasma iron concentrations and causing iron-restricted erythropoiesis characteristic of anemia of inflammation (anemia of chronic disease). Recent studies indicate that hepcidin deficiency underlies most known forms of hereditary hemochromatosis. This implies that, with the exception of very rare mutations that affect the hepcidin gene itself or modify ferroportin to make it less responsive to hepcidin, hemochromatosis genes encode molecules that regulate hepcidin synthesis. The central involvement of hepcidin in iron regulation and its pathologies should make the eventual hepcidin assay useful for the diagnosis of iron disorders and the monitoring of their treatments. The development of hepcidin agonists and antagonists may provide useful therapeutics for the treatment of iron disorders.
Therapy of Peripheral T/NK Neoplasms
Authors: Greer John P.
Published: November 2006

The mature T/natural killer (NK) lymphoma/leukemias represent 5–15% of all non-Hodgkin lymphoma. These diseases have a geographic variation, with more nodal disease in North America and Europe, including peripheral T cell lymphomas, unspecified, anaplastic large cell lymphoma, and angioimmunoblastic T cell lymphoma; and more extranodal disease in Asia due to Epstein-Barr virus–related nasal NK/T lymphoma and human T-cell leukemia virus (HTLV)-1–associated adult T cell leukemia/lymphoma. The prognosis in most peripheral T/NK neoplasms is poor, with 5-year survival less than 30%. Progress has been slow due to the rarity of the diseases, geographic variation, relative chemoresistance, and lack of randomized trials. There is no consensus about optimal therapy in T/NK neoplasms, and recommendations are based on anecdotal reports, small series, and phase II trials. In this review, topics include the question of CHOP as standard therapy, prognostic factors, disease-adapted therapy, novel approaches, monoclonal antibody therapy, and stem cell transplantation.
Bisphosphonate Complications Including Osteonecrosis of the Jaw
Authors: Mehrotra Bhoomi , Ruggiero Salvatore
Published: November 2006

Bisphosphonate therapy has been incorporated in the standard management of patients with multiple myeloma–related bony disease. Although their efficacy in reducing skeletal related events is important in the supportive management of the myeloma patient, post-marketing experience with this class of agents, particularly the more potent intravenous agents pamidronate and zoledronic acid, have raised cautionary notes regarding the potential side effects of these agents. The focus of this session is to review the risk factors, incidence, prevention strategies and management of bisphosphonate-related osteonecrosis of the jaw. In addition, pathophysiology, incidence and monitoring for renal dysfunction during chronic therapy with these agents are reviewed.
Viral Infections in Patients with Hematological Malignancies
Authors: Wade James C.
Published: November 2006

Viral infections are important causes of morbidity and mortality for patients with a hematological malignancy. However, the true incidence and consequences of viral infections for these patients who undergo conventional nontransplant therapy are poorly defined. The difference in incidence and outcome of viral infections among patient groups is wide, but dependent upon the intensity and duration of T-cell–mediated immune suppression. Infections caused by cytomegalovirus (CMV), herpes simplex virus (HSV), varicella-zoster virus (VZV), respiratory syncytial virus (RSV), parainfluenza viruses and influenza viruses have been intensely studied, yet newly recognized aspects of these viral infections including late CMV infection; the emergence of new viral pathogens (human herpesvirus-6, BK virus, adenovirus, and human metapneumovirus); the development of molecular diagnostic techniques, and the potential of new agents for viral prophylaxis (maribavir), or preemptive therapy (valganciclovir) form the basis of this review. Well-designed prospective studies are needed to better clarify the spectrum of these viral infections and develop effective prevention and treatment strategies. Yet the increased use of agents like alemtuzumab that induce profound T-cell depletion demands that we develop a better understanding of viral infections that occur in patients with hematological malignancy who receive nontransplant therapy.
Acquired Factor VIII Inhibitors: Pathophysiology and Treatment
Authors: Ma Alice D. , Carrizosa Daniel
Published: November 2006

Hemophilia A is classically caused by a congenital deficiency of factor VIII, but an acquired form due to inhibitors to factor VIII (FVIII) typically presents later in life. Patients who develop such acquired factor VIII inhibitors may present with catastrophic bleeding episodes, despite having no prior history of a bleeding disorder. Though the disorder is rare, it is known to cause significant morbidity and mortality. This review will focus on what is currently known about acquired hemophilia A, its pathogenesis, its associated etiologies, and its treatment.
Thrombosis and Cancer: The Role of Screening for Occult Cancer and Recognizing the Underlying Biological Mechanisms
Authors: Lee Agnes Y. Y.
Published: November 2006

The association between cancer and thrombosis is well recognized. What is not known, however, is the exact relationship between these two common medical conditions. Although the development of venous thromboembolism (VTE) in a patient with known cancer is the most common presentation, in some patients, VTE may precede the diagnosis of malignancy by many months. The variation in clinical presentation is likely due to the heterogeneous biology of different tumor types and also reflects the limitations of detection or available diagnostic methods. Accumulating evidence now suggests that critical oncogenic events may also trigger activation of the coagulation cascade, leading to a prothrombotic environment that not only manifests as venous thromboembolic disease but also promotes the growth and progression of the malignancy. This chapter will review the evidence for screening for occult malignancy in patients presenting with unprovoked or idiopathic thrombosis, briefly outline the known biological relationships between malignancy and thrombosis, and summarize the clinical data on the potential anticancer effects of low molecular weight heparins (LMWHs).
Vaccine-Enhanced Donor Lymphocyte Infusion (veDLI)
Authors: Roback John D.
Published: November 2006

Hematopoietic stem cell or bone marrow transplantation (HSCT/BMT) is curative in many cases of hemato-logical malignancy, but the post-transplant course is often complicated by delayed immune reconstitution that predisposes to opportunistic infections and disease recurrence. Furthermore, since HLA-matched donors cannot be found for almost half of all patients that would benefit from HSCT, donors mismatched at 2-3 HLA loci are increasingly being used, which is associated with elevated rates of opportunistic infections. Donor lymphocyte infusion (DLI) is a powerful and direct approach to improve post-transplant immune function. For example, DLI using enriched antiviral cytolytic effectors (CTLs) has been shown to reconstitute cellular immunity to cytomega-lovirus (CMV) and Epstein-Barr virus (EBV) and prevent viral disease following HSCT.1 However, because in vitro expansion and purification of CTLs is lengthy, labor-intensive, and costly, it is rarely used clinically to prevent and treat viral infections following HSCT. Active vaccination after allogeneic transplantation to stimulate in vivo expansion of donor and/or recipient CTLs has been proposed as an alternative method to rapidly reconstitute antiviral immunity, prevent viral disease, and reduce adverse sequelae of antiviral drugs.2 Fortunately, recent progress has been made in developing vaccines and methodologies that are both safe and effective when administered to immunocompromised HSCT recipients.
RhoH is important for positive thymocyte selection and T-cell receptor signaling
Authors: Dorn Tatjana , Kuhn Ursula , Bungartz Gerd , Stiller Sebastian , Bauer Martina , Ellwart Joachim , Peters Thorsten , Scharffetter-Kochanek Karin , Semmrich Monika , Laschinger Melanie , Holzmann Bernhard , Klinkert Wolfgang E. F. , Straten Per Thor , Køllgaard Tania , Sixt Michael , Brakebusch Cord
Published: November 2006

RhoH is a small GTPase expressed only in the hematopoietic system. With the use of mice with targeted disruption of the RhoH gene, we demonstrated that RhoH is crucial for thymocyte maturation during DN3 to DN4 transition and during positive selection. Furthermore, the differentiation and expansion of DN3 and DN4 thymocytes in vitro were severely impaired. These defects corresponded to defective TCR signaling. Although RhoH is not required for TCR-induced activation of ZAP70 and ZAP70-mediated activation of p38, it is crucial for the tyrosine phosphorylation of LAT, PLCγ1, and Vav1 and for the activation of Erk and calcium influx. These data suggest that RhoH is important for pre–TCR and TCR signaling because it allows the efficient interaction of ZAP70 with the LAT signalosome, thus regulating thymocyte development.
Naive recirculating B cells mature simultaneously in the spleen and bone marrow
Authors: Cariappa Annaiah , Chase Catharine , Liu Haoyuan , Russell Paul , Pillai Shiv
Published: November 2006

We have recently demonstrated that IgDhi B cells can occupy an extravascular perisinusoidal niche in the bone marrow in addition to the well-established follicular niche in conventional secondary lymphoid organs. The spleen has long been considered to be the site at which newly formed B lymphocytes mature into IgDhi naive recirculating B cells, but the existence of mutant mice that have selectively lost mature B cells in the bone marrow prompted an examination of B-cell maturation at this latter site. Following a single pulse of BrdU in intact mice, sequential labeling of more mature B-cell populations in the bone marrow suggested ongoing maturation at this site. Further evidence for B-cell maturation in the bone marrow was obtained from analyses of transitional B cells in splenectomized lymphotoxin α-deficient mice that lack all secondary lymphoid organs. In these mice, antibody-secreting cells recognizing multivalent antigens were also observed in the bone marrow following an intravenous microbial challenge. These data suggest that newly formed B cells mature into IgDhi B cells simultaneously in the spleen and the bone marrow and establish in a stringent manner that humoral immune responses can be initiated in situ in the bone marrow.
Aberrant NF-κB signaling in lymphoma: mechanisms, consequences, and therapeutic implications
Authors: Jost Philipp J. , Ruland Jürgen
Published: November 2006

The transcription factor NF-κB is a tightly regulated positive mediator of T- and B-cell development, proliferation, and survival. The controlled activity of NF-κB is required for the coordination of physiologic immune responses. However, constitutive NF-κB activation can promote continuous lymphocyte proliferation and survival and has recently been recognized as a critical pathogenetic factor in lymphoma. Various molecular events lead to deregulation of NF-κB signaling in Hodgkin disease and a variety of T- and B-cell non-Hodgkin lymphomas either upstream or downstream of the central IκB kinase. These alterations are prerequisites for lymphoma cell cycling and blockage of apoptosis. This review provides an overview of the NF-κB pathway and discusses the mechanisms of NF-κB deregulation in distinct lymphoma entities with defined aberrant pathways: Hodgkin lymphoma (HL), diffuse large B-cell lymphoma (DLBCL), mucosa-associated lymphoid tissue (MALT) lymphoma, primary effusion lymphoma (PEL), and adult T-cell lymphoma/leukemia (ATL). In addition, we summarize recent data that validates the NF-κB signaling pathway as an attractive therapeutic target in T- and B-cell malignancies.
A neoepitope generated by an FLT3 internal tandem duplication (FLT3-ITD) is recognized by leukemia-reactive autologous CD8+ T cells
Authors: Graf Claudine , Heidel Florian , Tenzer Stefan , Radsak Markus P. , Solem Fian K. , Britten Cedrik M. , Huber Christoph , Fischer Thomas , Wölfel Thomas
Published: November 2006

The FLT3 receptor tyrosine kinase is expressed in more than 90% of acute myelogeneous leukemias (AMLs), up to 30% of which carry an internal tandem duplication (ITD) within the FLT3 gene. Although varying duplication sites exist, most FLT3-ITDs affect a single protein domain. We analyzed the FLT3-ITD of an AML patient for encoding HLA class I–restricted immunogenic peptides. One of the tested peptides (YVDFREYEYY) induced in vitro autologous T-cell responses restricted by HLA-A*0101 that were also detectable ex vivo. These peptide-reactive T cells recognized targets transfected with the patient's FLT3-ITD, but not wild-type FLT3, and recognized the patient's AML cells. Our results demonstrate that AML leukemic blasts can in principle process and present immunogenic FLT3-ITD neoepitopes. Therefore, FLT3-ITD represents a potential candidate target antigen for the immunotherapy of AML.
Development of a secondary autoimmune disorder after hematopoietic stem cell transplantation for autoimmune diseases: role of conditioning regimen used
Authors: Loh Yvonne , Oyama Yu , Statkute Laisvyde , Quigley Kathleen , Yaung Kimberly , Gonda Elizabeth , Barr Walter , Jovanovic Borko , Craig Robert , Stefoski Dusan , Cohen Bruce , Burt Richard K.
Published: November 2006

Patients undergoing autologous hematopoietic stem cell transplantation (auto-HSCT) for autoimmune disease may have an added propensity to develop a second autoimmune disorder, given the genetic predisposition to autoimmunity. Therefore, we undertook a retrospective analysis of all patients who have undergone auto-HSCT for an autoimmune disease in our institution to determine the occurrence of a second autoimmune disorder and possible risk factors. In all, 155 patients underwent auto-HSCT for various autoimmune diseases; of those patients, 6 manifested a distinct secondary autoimmune disease at a median of 8.5 months (range, 2-30 months) after auto-HSCT. There were 2 patients with systemic lupus erythematosus, conditioned with a regimen containing antithymocyte globulin (ATG), who developed factor VIII inhibitors with severe bleeding. There were 4 patients (2 with multiple sclerosis, one each with lupus and systemic sclerosis) who received an alemtuzumab-containing conditioning regimen who developed autoimmune cytopenias. Among the 155 patients, the frequency of secondary autoimmune complications was 16.0% with alemtuzumab (4/25), 1.9% for ATG (2/102), and 0% for conditioning regimens without lympho-depleting antibodies (0/28)—a difference that was found to be significantly higher with alemtuzumab exposure (P = .011). In contrast, sex, type of ATG used, and CD34-selection of peripheral blood stem cells were not found to be significantly associated with development of a secondary autoimmune disorder.
Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)–dependent migration and homing in multiple myeloma
Authors: Alsayed Yazan , Ngo Hai , Runnels Judith , Leleu Xavier , Singha Ujjal K. , Pitsillides Costas M. , Spencer Joel A. , Kimlinger Teresa , Ghobrial Joanna M. , Jia Xiaoying , Lu Ganwei , Timm Michael , Kumar Ashok , Côté Daniel , Veilleux Israel , Hedin Karen E. , Roodman G. David , Witzig Thomas E. , Kung Andrew L. , Hideshima Teru , Anderson Kenneth C. , Lin Charles P. , Ghobrial Irene M.
Published: November 2006

The mechanisms by which multiple myeloma (MM) cells migrate and home to the bone marrow are not well understood. In this study, we sought to determine the effect of the chemokine SDF-1 (CXCL12) and its receptor CXCR4 on the migration and homing of MM cells. We demonstrated that CXCR4 is differentially expressed at high levels in the peripheral blood and is down-regulated in the bone marrow in response to high levels of SDF-1. SDF-1 induced motility, internalization, and cytoskeletal rearrangement in MM cells evidenced by confocal microscopy. The specific CXCR4 inhibitor AMD3100 and the anti-CXCR4 antibody MAB171 inhibited the migration of MM cells in vitro. CXCR4 knockdown experiments demonstrated that SDF-1–dependent migration was regulated by the PI3K and ERK/MAPK pathways but not by p38 MAPK. In addition, we demonstrated that AMD3100 inhibited the homing of MM cells to the bone marrow niches using in vivo flow cytometry, in vivo confocal microscopy, and whole body bioluminescence imaging. This study, therefore, demonstrates that SDF-1/CXCR4 is a critical regulator of MM homing and that it provides the framework for inhibitors of this pathway to be used in future clinical trials to abrogate MM trafficking.
Physiologic and aberrant regulation of memory T-cell trafficking by the costimulatory molecule CD28
Authors: Mirenda Vincenzo , Jarmin Sarah J. , David Rachel , Dyson Julian , Scott Diane , Gu Yan , Lechler Robert I. , Okkenhaug Klaus , Marelli-Berg Federica M.
Published: November 2006

Productive T-cell immunity requires both the activation and the migration of specific T cells to the antigenic tissue. The costimulatory molecule CD28 plays an essential role in the initiation of T-cell–mediated immunity. We investigated the possibility that CD28 may also regulate migration of primed T cells to target tissue. In vitro, CD28-mediated signals enhanced T-cell transendothelial migration, integrin clustering, and integrin-mediated migration. In vivo, T cells bearing a mutation in the CD28 cytoplasmic domain, which abrogates PI3K activation, displayed normal clonal expansion but defective localization to antigenic sites following antigenic rechallenge. Importantly, antibody-mediated CD28 stimulation led to unregulated memory T-cell migration to extra-lymphoid tissue, which occurred independently of T-cell receptor (TCR)–derived signals and homing-receptor expression. Finally, we provide evidence that CD28- and CTLA-4–mediated signals exert opposite effects on T-cell trafficking in vivo. These findings highlight a novel physiologic function of CD28 that has crucial implications for the therapeutic manipulation of this and other costimulatory molecules.
Predictors of gallstone composition in 1025 symptomatic gallstones from Northern Germany
Authors: Schafmayer Clemens , Hartleb Jürgen , Tepel Jürgen , Albers Stefan , Freitag Sandra , Völzke Henry , Buch Stephan , Seeger Markus , Timm Birgit , Kremer Bernd , Fölsch Ulrich R , Fändrich Fred , Krawczak Michael , Schreiber Stefan , Hampe Jochen
Published: November 2006

Background

Gallstones represent a prevalent and costly health problem. The changing epidemiology and the emerging non-surgical interventions for gallstone disease necessitate the definition of target populations for future therapies. This study aimed to define patterns of gallstone composition and identify demographic predictors of gallstone composition in a large sample of symptomatic gallstones from Northern Germany.

Methods

One thousand and seventy-four post-cholecystectomy gallstone specimens were obtained. Demographic and clinical information was provided by questionnaire (N = 1025 independent individuals with complete information). Two samples from each gallstone were analyzed using Fourier transformed infrared spectrometry.

Results

The most prevalent substance was cholesterol, which was detected in 95.0% of gallstone specimens. Bilirubin and bilirubinate were present in 30.0% and calcium was detected in 10.0% of the spectra. Ninety-two percent of measurements from the same stone yielded the same "main" substances, indicating a homogenous stone composition in most cases. Female sex and higher body mass index (BMI) were associated with the presence of cholesterol as a main substance in the gallstones (p < 0.001).

Conclusion

The changing epidemiology of gallstone disease is reflected by a marked shift in stone composition: Only two percent of stones in this study were pigment stones as compared to 91% percent of stones containing cholesterol as a main substance. Obese individuals from Germany with a BMI > 30 kg/m2 have in 95% cholesterol-dominant gallstones and represent a potential target population for non-surgical interventions for the prevention or treatment of cholesterol stones.
Hypergravity as a Crystallization Tool
Authors: CHRISTO N. NANEV , DIMITROV I. , HODJAOGLU F.
Published: November 2006

Abstract:  The centrifugal increase of concentration is nondestructive, rapid, and simple technology. Therefore it is used to create a higher supersaturation that is required for crystal nucleation, as the one that is appropriate for the subsequent growth. Crystal nucleation is evoked in glass capillary tubes filled with protein solutions. The couple ferritin/ apoferritin is used as model proteins in the present article. Although differing in their masses the two (quasi) spherical molecules have exactly the same size and surface properties. Together with the temperature‐independent solubility this makes them very convenient for our investigations. Decoupling nucleation and growth, for example, by means of hypergravity makes it possible to grow quasi‐equidimensional crystals. The use of monodisperse crystalline forms of therapeutic agents can ensure constant time‐release of protein‐based medications.