bluuebunny/crossref_metadata_2025 huggingface dataset:
Hematopoietic Stem Cell Transplantation for Sickle Cell Disease: Current Practice and Emerging Trends
Authors: Shenoy Shalini
Published: December 2011

Allogeneic HSCT controls sickle cell disease (SCD)–related organ damage and is currently the only curative therapy available. Over the last 2 decades, HSCT has been limited largely to myeloablative matched sibling donor (MSD) procedures that are feasible only in a minority of patients. As the natural history of the disease has evolved, it is clear that subsets of patients with severe disease are at risk for sudden death, devastating CNS and pulmonary complications, and debilitating vasoocclusive crises. For these patients, the benefits of transplantation can outweigh the risks if HSCT can be safely and successfully performed with low early and late toxicities. This review describes advances and ongoing investigation of HSCT for SCD from the perspectives of recipient age and presentation, donor stem cell source, intensity of conditioning, family and medical perspectives, and other variables that influence outcome. Ultimately, HSCT should be viewed as a viable treatment option for SCD on par with other therapies for select patients who can benefit from the procedure.
Stem Cell Transplantation in Inherited Metabolic Disorders
Authors: Wynn Robert
Published: December 2011

Allogeneic HSCT is performed for a small number of inborn errors of metabolism (IEM). Over the last years, transplantation outcomes have improved in this group of patients as the factors that predicted for poor transplantation outcomes were understood and addressed. The role of transplantation and its potential benefit for an individual patient with a certain IEM is therefore now much better defined. In parallel with improvements in transplantation techniques, other therapies such as pharmacological enzyme replacement therapy (ERT), substrate inhibition, and gene therapy have been developed and are increasingly available to clinicians and their patients. This review covers the following areas: (1) the scientific principles that underpin transplantation in IEM; (2) the variables of the transplantation process itself that predict for successful outcome in terms of engrafted survival after HSCT; (3) the reasons that some apparently phenotypically similar disorders might respond very differently to transplantation therapy; (4) the factors that currently influence the response of a particular patient with a particular disease to allogeneic transplantation, and how these factors might be manipulated in the future to further improve transplantation outcomes in different metabolic illnesses; and (5) how other therapeutic modalities, including ERT, gene therapy, and substrate reduction therapy, might complement and compete with HSCT in the coming years.
Complications, Diagnosis, Management, and Prevention of CMV Infections: Current and Future
Authors: Boeckh Michael
Published: December 2011

Although major progress has been made in the prevention of CMV disease after hematopoietic cell transplantation (HCT), specific problems remain and available antiviral agents are associated with major toxicities. This article reviews current aspects of CMV diagnosis, prevention, and treatment in HCT recipients and defines areas of unmet medical need.
Optimal Therapy of Advanced Hodgkin Lymphoma
Authors: Advani Ranjana
Published: December 2011

Advanced-stage Hodgkin lymphoma (HL) has become a curable disease in the majority of patients. Research during the last decade has challenged chemotherapy with Adriamycin, bleomycin, vinblastine, dacarbazine (ABVD) as the standard of care and debates continue regarding the role of radiation therapy (RT) in this patient population. The incorporation of interim positron emission tomography (PET) imaging and, recently, further characterization of HL on cellular and molecular levels are emerging as tools for treatment stratification and predictors of disease status. Newer targeted therapies have emerged that are very effective in the relapsed setting and are actively being explored as frontline therapy. Lastly, the expanding population of survivors cured of HL outnumbers patients with the disease and needs to be monitored for therapy-related late effects.
Late Effects in the Era of Modern Therapy for Hodgkin Lymphoma
Authors: Hodgson David C.
Published: December 2011

Extended-field and subtotal nodal radiation therapy (RT), developed in the 1960s, was the first reliably curative treatment for early-stage Hodgkin lymphoma (HL). However, the large volume of normal tissue irradiated resulted in significant delayed toxicity, including cardiac disease and second cancers (SCs). The 30-year cumulative incidence of heart disease among adult survivors receiving 40-45 Gy of extended-field or mantle RT is approximately 30%; the incidence of SCs is similar. Improving disease control while reducing the toxicity of treatment has been a major objective of HL trials for more than 2 decades. Contemporary involved-field RT (IFRT) reduces irradiated volumes and produces significant reductions in normal tissue dose compared with historic treatments. Recent data indicate that, compared with mantle RT, IFRT reduces the relative risk of breast cancer among young females receiving mediastinal RT by approximately 60% and also reduces cardiac dose. The recent transition to involved-node RT allows further reductions in normal tissue dose. Response-adapted therapy is being evaluated in clinical trials as a means of identifying those patients most likely to benefit from treatment reduction or intensification, enhanced screening will facilitate early intervention to reduce the clinical burden of late effects, and there is increasing interest in elucidating the genetic correlates of treatment toxicity.
B Cells Behaving Badly: A Better Basis to Behold Belligerence in B-Cell Lymphomas
Authors: Bagg Adam
Published: December 2011

A plethora of genetic abnormalities has been described in B-cell lymphomas, some of which arise when physiologic mechanisms involved in the generation of immunologic diversity go awry. Several different lymphoma types, such as follicular lymphoma (FL), mantle cell lymphoma (MCL), and Burkitt lymphoma (BL), are associated with hallmark translocations that occur as a consequence of these errors (t(14;18)(q32;q21), t(11;14)(q13;q32), and t(8;14)(q24;q32), respectively); however, none of these associations is absolute and none is completely diagnostically specific or sensitive. The advantages and limitations of a variety of different testing strategies in the 2 most common lymphomas, FL and diffuse large B-cell lymphoma (DLBCL), are reviewed herein, including an evaluation of the role of PCR-based approaches, FISH, and more nascent genomic technologies. The use of immunophenotypic strategies that may potentially provide, albeit imperfectly, more user-friendly surrogates for underlying genetic aberrations and cell-of-origin designations derived from gene-expression profiling analyses are also discussed. Finally, a newly designated category of lymphoma with features intermediate between DLBCL and BL is appraised, highlighting the central role of genetic analysis in this diagnostic gray zone.
Many Multiple Myelomas: Making More of the Molecular Mayhem
Authors: Chesi Marta , Bergsagel P. Leif
Published: December 2011

Multiple myeloma (MM) is malignancy of isotype-switched, BM-localized plasma cells that frequently results in bone destruction, BM failure, and death. Important molecular subgroups are identified by three classes of recurrent immunoglobulin gene translocations and hyperdiploidy, both of which affect disease course. From a clinical standpoint, it is critical to identify MM patients carrying the t(4;14) translocation, which is present in 15% of myelomas and is associated with dysregulation of WHSC1/MMSET and often FGFR3. These patients should all receive bortezomib as part of their initial induction treatment because this has been shown to significantly prolong survival. In contrast, patients with translocations affecting the MAF family of transcription factors, del17p, or gene-expression profiling (GEP)–defined high-risk disease appear to have a worse prognosis that is not dramatically improved by any intervention. These patients should be enrolled in innovative clinical trials. The remaining patients with cyclin D translocations or hyperdiploidy do well with most therapies, and the goal should be to control disease while minimizing toxicity.
Impact of Genetic Features on Treatment Decisions in AML
Authors: Döhner Hartmut , Gaidzik Verena I.
Published: December 2011

In recent years, research in molecular genetics has been instrumental in deciphering the molecular pathogenesis of acute myeloid leukemia (AML). With the advent of the novel genomics technologies such as next-generation sequencing, it is expected that virtually all genetic lesions in AML will soon be identified. Gene mutations or deregulated expression of genes or sets of genes now allow us to explore the enormous diversity among cytogenetically defined subsets of AML, in particular the large subset of cytogenetically normal AML. Nonetheless, there are several challenges, such as discriminating driver from passenger mutations, evaluating the prognostic and predictive value of a specific mutation in the concert of the various concurrent mutations, or translating findings from molecular disease pathogenesis into novel therapies. Progress is unlikely to be fast in developing molecular targeted therapies. Contrary to the initial assumption, the development of molecular targeted therapies is slow and the various reports of promising new compounds will need to be put into perspective because many of these drugs did not show the expected effects.
Biological Rationale for New Drugs in the Bleeding Disorders Pipeline
Authors: Fogarty Patrick F.
Published: December 2011

Since the introduction of replacement coagulation factor infusions for the treatment of hemophilia in the 1970s and subsequent improvements in the safety profile of available factor VIII (FVIII) and factor IX (FIX) concentrates, mortality among patients with hemophilia has improved considerably and now parallels that of the noncoagulopathic population in developed countries. Substantial morbidity, however, continues from the development of inhibitory antibodies, a recognized complication of clotting factor replacement; from infections and thrombosis complicating placement of central venous catheters, which are required in children with hemophilia due to frequent prophylactic infusions of coagulation factors with defined half-lives; and from disabling joint disease in individuals without access to costly prophylaxis regimens. In response to the need for long-acting, more potent, less immunogenic, and more easily administered therapies, an impressive array of novel agents is nearly ready for use in the clinical setting. These therapeutics derive from rational bioengineering of recombinant coagulation factors or from the discovery of nonpeptide molecules that have the potential to support hemostasis through alternative pathways. The number of novel agents in clinical trials is increasing, and many of the initial results are promising. In addition to advancing treatment of bleeding episodes or enabling adherence to prophylactic infusions of clotting factor concentrate, newer therapeutics may also lead to improvements in joint health, quality of life, and tolerability of iatrogenic or comorbidity-associated bleeding challenges.
Current Controversies in the Formation and Treatment of Alloantibodies to Factor VIII in Congenital Hemophilia A
Authors: Kruse-Jarres Rebecca
Published: December 2011

Hemophilia A is a rare bleeding disorder treated with numerous factor VIII (FVIII)–containing replacement concentrates. This treatment approach has led to the formation of alloantibodies that neutralize the FVIII activity (inhibitors) conveyed by these commercially available concentrates in ∼ 25% of patients with severe hemophilia A (FVIII activity < 1% of normal). This phenomenon significantly complicates the treatment of these patients and compromises the effectiveness and efficiency of these products to reverse or prevent bleeding complications. Studying the population with alloantibody inhibitors is imperative but difficult due to the overall small number of individuals affected and the heterogeneity within this limited group. Furthermore, few randomized clinical trials have been conducted to answer pertinent questions so many controversies persist. This article focuses on the conflicting data on the variables associated with alloantibody FVIII inhibitor development with a particular emphasis on age and intensity of first treatment, the role of primary prophylaxis regimens in modulating this phenomenon, and the degree of purity of FVIII product as a potential contributing risk factor. The optimal dosing regimen and type of FVIII replacement product that should be used to achieve the highest success rate in immune tolerance induction (ITI) protocols are also discussed, as well as whether the addition of immunomodulatory agents, especially rituximab, to ITI regimens enhances the durability of ITI and the eradication of alloantibody FVIII inhibitors.
Impact of Iron Assessment by MRI
Authors: Wood John C.
Published: December 2011

The use of magnetic resonance imaging (MRI) to estimate tissue iron was conceived in the 1980s, but has only become a practical reality in the last decade. The technique is most often used to estimate hepatic and cardiac iron in patients with transfusional siderosis and has largely replaced liver biopsy for liver iron quantification. However, the ability of MRI to quantify extrahepatic iron has had a greater impact on patient care and on our understanding of iron overload pathophysiology. Iron cardiomyopathy used to be the leading cause of death in thalassemia major, but is now relatively rare in centers with regular MRI screening of cardiac iron, through earlier recognition of cardiac iron loading. Longitudinal MRI studies have demonstrated differential kinetics of uptake and clearance among the difference organs of the body. Although elevated serum ferritin and liver iron concentration (LIC) increase the risk of cardiac and endocrine toxicities, some patients unequivocally develop extrahepatic iron deposition and toxicity despite having low total body iron stores. These observations, coupled with the advent of increasing options for iron chelation therapy, are allowing clinicians to more appropriately tailor chelation therapy to individual patient needs, producing greater efficacy with fewer toxicities. Future frontiers in MRI monitoring include improved prevention of endocrine toxicities, particularly hypogonadotropic hypogonadism and diabetes.
Real-World Use of Iron Chelators
Authors: Kwiatkowski Janet L.
Published: December 2011

Whereas RBC transfusion therapy is lifesaving in thalassemia, obligatory iron loading accompanies such treatment and chelation therapy to remove and detoxify iron resulting from these chronic transfusions must therefore be administered. Morbidity and mortality in thalassemia is linked closely to the adequacy of chelation. Three chelators are currently available worldwide—deferoxamine, deferasirox, and deferiprone, although the latter is available in North America only in research protocols and compassionate use programs. These chelators can be used as monotherapy or in combination, although only the combination of deferiprone and deferoxamine has been extensively studied to date. Several factors, including chelator availability and its properties, drug tolerability, degree of organ-specific iron loading, ongoing transfusional iron burden, and patient preference, must be considered in the design of optimal, individualized chelation regimens, and these factors must periodically be reviewed and chelation adjusted accordingly. Ultimately, comparative effectiveness trials may help to determine the ideal strategy (eg, intensification of monotherapy or combined therapy including agents and doses) for treating various scenarios of organ-specific iron loading.
Immunomodulatory Mediators in Platelet Transfusion Reactions
Authors: Morrell Craig N.
Published: December 2011

Our appreciation of the roles that platelets play in vascular biology is constantly expanding. One of the major roles of platelets is in initiating and accelerating immune responses. Platelet transfusion may be associated with adverse inflammatory outcomes manifested as fever, discomfort, tachycardia, and respiratory issues. This may in part be due to immune mediators either expressed by activated platelets or released into the platelet media during platelet storage. This review will highlight some more recent knowledge gained regarding the platelet storage lesion and potential mediators of platelet transfusion reactions.
Fanconi Anemia
Authors: Soulier Jean
Published: December 2011

Fanconi anemia (FA) is the most frequent inherited cause of BM failure (BMF). Fifteen FANC genes have been identified to date, the most prevalent being FANCA, FANCC, FANCG, and FANCD2. In addition to classical presentations with progressive BMF during childhood and a positive chromosome breakage test in the blood, atypical clinical and/or biological situations can be seen in which a FA diagnosis has to be confirmed or eliminated. For this, a range of biological tools have been developed, including analysis of skin fibroblasts. FA patients experience a strong selective pressure in the BM that predisposes to clonal evolution and to the emergence in their teens or young adulthood of myelodysplasia syndrome (MDS) and/or acute myeloid leukemia (AML) with a specific pattern of somatic chromosomal lesions. The cellular mechanisms underlying (1) the hematopoietic defect which leads to progressive BMF and (2) somatic clonal evolutions in this background, are still largely elusive. Elucidation of these mechanisms at the molecular and cellular levels should be useful to understand the physiopathology of the disease and to adapt the follow-up and treatment of FA patients. This may also ultimately benefit older, non-FA patients with aplastic anemia, MDS/AML for whom FA represents a model genetic condition.
Relapsed/Refractory Diffuse Large B-Cell Lymphoma
Authors: Friedberg Jonathan W.
Published: December 2011

Despite overall improvements in outcomes of diffuse large B-cell lymphoma (DLBCL), approximately one-third of patients will develop relapsed/refractory disease that remains a major cause of morbidity and mortality. Novel insights from gene-expression analyses have increased our understanding of chemotherapy resistance and yielded rational targets for therapeutic intervention to both prevent and treat relapsed/refractory DLBCL. The clinical approach to relapsed/refractory DLBCL should include high-dose therapy and autologous stem cell transplantation (HD-ASCT) with curative intent in patients without comorbidities. Results from the recently reported CORAL study suggest that patients refractory to rituximab-containing regimens have inferior outcomes with HD-ASCT. Ongoing efforts to improve ASCT include novel conditioning regimens and evaluation of maintenance approaches after ASCT. Unfortunately, because the majority of patients are not eligible for ASCT due to refractory disease or age/comorbidities, these approaches have limited impact. The large group of patients not eligible for ASCT have incurable disease and should be referred for clinical trials of rationally targeted agents.
The Role of Platelets in Atherothrombosis
Authors: Kaplan Zane S. , Jackson Shaun P.
Published: December 2011

Platelets have evolved highly specialized adhesion mechanisms that enable cell-matrix and cell-cell interactions throughout the entire vasculature irrespective of the prevailing hemodynamic conditions. This unique property of platelets is critical for their ability to arrest bleeding and promote vessel repair. Platelet adhesion under conditions of high shear stress, as occurs in stenotic atherosclerotic arteries, is central to the development of arterial thrombosis; therefore, precise control of platelet adhesion must occur to maintain blood fluidity and to prevent thrombotic or hemorrhagic complications. Whereas the central role of platelets in hemostasis and thrombosis has long been recognized and well defined, there is now a major body of evidence supporting an important proinflammatory function for platelets that is linked to host defense and a variety of autoimmune and inflammatory diseases. In the context of the vasculature, experimental evidence indicates that the proinflammatory function of platelets can regulate various aspects of the atherosclerotic process, including its initiation and propagation. The mechanisms underlying the proatherogenic function of platelets are increasingly well defined and involve specific adhesive interactions between platelets and endothelial cells at atherosclerotic-prone sites, leading to the enhanced recruitment and activation of leukocytes. Through the release of chemokines, proinflammatory molecules, and other biological response modulators, the interaction among platelets, endothelial cells, and leukocytes establishes a localized inflammatory response that accelerates atherosclerosis. These inflammatory processes typically occur in regions of the vasculature experiencing low shear and perturbed blood flow, a permissive environment for leukocyte-platelet and leukocyte-endothelial interactions. Therefore, the concept has emerged that platelets are a central element of the atherothrombotic process and that future therapeutic strategies to combat this disease need to take into consideration both the prothrombotic and proinflammatory function of platelets.
The Hepcidin-Ferroportin System as a Therapeutic Target in Anemias and Iron Overload Disorders
Authors: Ganz Tomas , Nemeth Elizabeta
Published: December 2011

The review summarizes the current understanding of the role of hepcidin and ferroportin in normal iron homeostasis and its disorders. The various approaches to therapeutic targeting of hepcidin and ferroportin in iron-overload disorders (mainly hereditary hemochromatosis and β-thalassemia) and iron-restrictive anemias (anemias associated with infections, inflammatory disorders, and certain malignancies, anemia of chronic kidney diseases, and iron-refractory iron-deficiency anemia) are also discussed.
New Ways to Use DNA Methyltransferase Inhibitors for the Treatment of Myelodysplastic Syndrome
Authors: Gore Steven D.
Published: December 2011

Ongoing analysis of the seminal AZA-001 study has taught many important lessons in the use of DNA methyltransferase (DNMT) inhibitors. The data emphasize the importance of patience in the use of these drugs, with several cycles required for the manifestations of hematologic responses. Improved survival in patients with high-risk myelodysplastic syndrome (MDS) treated with azacitidine extends to patients with any International Working Group–defined hematologic response; however, the benefit to patients with stable disease is less clear. A great deal remains to be learned about the optimal dosing and scheduling of the DNMT inhibitors, alone and in combination. New information on the impact of DNMT inhibitors on the immune system and on stem cells will likely lead to novel uses of these drugs in MDS and other hematologic and nonhematologic malignancies.
Classification of Childhood Aplastic Anemia and Myelodysplastic Syndrome
Authors: Niemeyer Charlotte M. , Baumann Irith
Published: December 2011

Hypoplastic BM disorders in children and adolescents comprise a broad spectrum of disorders. Acquired severe aplastic anemia (SAA), refractory cytopenia of childhood (RCC), a subtype of myelodysplastic syndrome (MDS), and inherited BM failure (IBMF) disorders are the main and most difficult hematological differential diagnoses. Whereas IBMF disorders can often be diagnosed by their clinical features and/or underlying genetic aberrations, the morphological distinction between SAA and hypocellular RCC has been controversial. The histopathological pattern of RCC consists of islands of immature erythroid precursors accompanied by sparsely distributed granulocytic cells. Megakaryocytes are significantly decreased or absent and, rarely, micromegakaryocytes are detected on immunohistochemistry. Because fatty tissue between areas of hematopoiesis can mimic SAA, 2 biopsies are recommended to facilitate the detection of representative BM spaces. Recent data indicate that the response to immunosuppressive therapy is inferior in RCC compared with SAA. Furthermore, approaches to allogeneic hematopoietic transplantation differ. Controlled prospective clinical studies in patients with hypoplastic BM failure disorders will require comprehensive guidelines for diagnosing SAA, RCC, and the different IBMF disorders.
Erythrocyte plasma membrane–bound ERK1/2 activation promotes ICAM-4–mediated sickle red cell adhesion to endothelium
Authors: Zennadi Rahima , Whalen Erin J. , Soderblom Erik J. , Alexander Susan C. , Thompson J. Will , Dubois Laura G. , Moseley M. Arthur , Telen Marilyn J.
Published: December 2011

The core pathology of sickle cell disease (SCD) starts with the erythrocyte (RBC). Aberration in MAPK/ERK1/2 signaling, which can regulate cell adhesion, occurs in diverse pathologies. Because RBCs contain abundant ERK1/2, we predicted that ERK1/2 is functional in sickle (SS) RBCs and promotes adherence, a hallmark of SCD. ERK1/2 remained active in SS but not normal RBCs. β2-adrenergic receptor stimulation by epinephrine can enhance ERK1/2 activity only in SS RBCs via PKA- and tyrosine kinase p72syk-dependent pathways. ERK signaling is implicated in RBC ICAM-4 phosphorylation, promoting SS RBC adhesion to the endothelium. SS RBC adhesion and phosphorylation of both ERK and ICAM-4 all decreased with continued cell exposure to epinephrine, implying that activation of ICAM-4–mediated SS RBC adhesion is temporally associated with ERK1/2 activation. Furthermore, recombinant ERK2 phosphorylated α- and β-adducins and dematin at the ERK consensus motif. Cytoskeletal protein 4.1 also showed dynamic phosphorylation but not at the ERK consensus motif. These results demonstrate that ERK activation induces phosphorylation of cytoskeletal proteins and the adhesion molecule ICAM-4, promoting SS RBC adhesion to the endothelium. Thus, blocking RBC ERK1/2 activation, such as that promoted by catecholamine stress hormones, could ameliorate SCD pathophysiology.
An intrinsic BM hematopoietic niche occupancy defect of HSC in scid mice facilitates exogenous HSC engraftment
Authors: Qing Yulan , Lin Yuan , Gerson Stanton L.
Published: December 2011

Although scid mice have been widely used for human HSC engraftment studies, the function of HSCs of scid mice has not been characterized. We hypothesized that the DNA repair defect of scid mice results in a stem cell defect that facilitates HSC engraftment. scid BM cells showed severely impaired repopulation potentials in the competitive repopulation assay. To assess the BM hematopoietic niche occupancy ability of scid HSC, WT BM cells were transplanted into scid mice without any conditioning and observed to achieve long-term engraftment. Furthermore, the defects of scid HSCs are independent of their inability to perform lymphopoiesis because a similar defect in hematopoietic niche occupancy was not observed with Rag1−/− recipients. These results demonstrate that scid HSCs are impaired in maintenance within the niche, which may explain the nature of the conducive marrow niche environment of scid mice for xenotransplantation.
TLR3 essentially promotes protective class I–restricted memory CD8+ T-cell responses to Aspergillus fumigatus in hematopoietic transplanted patients
Authors: Carvalho Agostinho , De Luca Antonella , Bozza Silvia , Cunha Cristina , D'Angelo Carmen , Moretti Silvia , Perruccio Katia , Iannitti Rossana G. , Fallarino Francesca , Pierini Antonio , Latgé Jean-Paul , Velardi Andrea , Aversa Franco , Romani Luigina
Published: December 2011

Aspergillus fumigatus is a model fungal pathogen and a common cause of severe infections and diseases. CD8+ T cells are present in the human and murine T-cell repertoire to the fungus. However, CD8+ T-cell function in infection and the molecular mechanisms that control their priming and differentiation into effector and memory cells in vivo remain elusive. In the present study, we report that both CD4+ and CD8+ T cells mediate protective memory responses to the fungus contingent on the nature of the fungal vaccine. Mechanistically, class I MHC-restricted, CD8+ memory T cells were activated through TLR3 sensing of fungal RNA by cross-presenting dendritic cells. Genetic deficiency of TLR3 was associated with susceptibility to aspergillosis and concomitant failure to activate memory-protective CD8+ T cells both in mice and in patients receiving stem-cell transplantations. Therefore, TLR3 essentially promotes antifungal memory CD8+ T-cell responses and its deficiency is a novel susceptibility factor for aspergillosis in high-risk patients.
Loss-of-function germline GATA2 mutations in patients with MDS/AML or MonoMAC syndrome and primary lymphedema reveal a key role for GATA2 in the lymphatic vasculature
Authors: Kazenwadel Jan , Secker Genevieve A. , Liu Yajuan J. , Rosenfeld Jill A. , Wildin Robert S. , Cuellar-Rodriguez Jennifer , Hsu Amy P. , Dyack Sarah , Fernandez Conrad V. , Chong Chan-Eng , Babic Milena , Bardy Peter G. , Shimamura Akiko , Zhang Michael Y. , Walsh Tom , Holland Steven M. , Hickstein Dennis D. , Horwitz Marshall S. , Hahn Christopher N. , Scott Hamish S. , Harvey Natasha L.
Published: December 2011

Recent work has established that heterozygous germline GATA2 mutations predispose carriers to familial myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), “MonoMAC” syndrome, and DCML deficiency. Here, we describe a previously unreported MDS family carrying a missense GATA2 mutation (p.Thr354Met), one patient with MDS/AML carrying a frameshift GATA2 mutation (p.Leu332Thrfs*53), another with MDS harboring a GATA2 splice site mutation, and 3 patients exhibiting MDS or MDS/AML who have large deletions encompassing the GATA2 locus. Intriguingly, 2 MDS/AML or “MonoMAC” syndrome patients with GATA2 deletions and one with a frameshift mutation also have primary lymphedema. Primary lymphedema occurs as a result of aberrations in the development and/or function of lymphatic vessels, spurring us to investigate whether GATA2 plays a role in the lymphatic vasculature. We demonstrate here that GATA2 protein is present at high levels in lymphatic vessel valves and that GATA2 controls the expression of genes important for programming lymphatic valve development. Our data expand the phenotypes associated with germline GATA2 mutations to include predisposition to primary lymphedema and suggest that complete haploinsufficiency or loss of function of GATA2, rather than missense mutations, is the key predisposing factor for lymphedema onset. Moreover, we reveal a crucial role for GATA2 in lymphatic vascular development.
Genotype-informed estimation of risk of coronary heart disease based on genome-wide association data linked to the electronic medical record
Authors: Ding Keyue , Bailey Kent R , Kullo Iftikhar J
Published: December 2011

Background

Susceptibility variants identified by genome-wide association studies (GWAS) have modest effect sizes. Whether such variants provide incremental information in assessing risk for common 'complex' diseases is unclear. We investigated whether measured and imputed genotypes from a GWAS dataset linked to the electronic medical record alter estimates of coronary heart disease (CHD) risk.

Methods

Study participants (n = 1243) had no known cardiovascular disease and were considered to be at high, intermediate, or low 10-year risk of CHD based on the Framingham risk score (FRS) which includes age, sex, total and HDL cholesterol, blood pressure, diabetes, and smoking status. Of twelve SNPs identified in prior GWAS to be associated with CHD, four were genotyped in the participants as part of a GWAS. Genotypes for seven SNPs were imputed from HapMap CEU population using the program MACH. We calculated a multiplex genetic risk score for each patient based on the odds ratios of the susceptibility SNPs and incorporated this into the FRS.

Results

The mean (SD) number of risk alleles was 12.31 (1.95), range 6-18. The mean (SD) of the weighted genetic risk score was 12.64 (2.05), range 5.75-18.20. The CHD genetic risk score was not correlated with the FRS (P = 0.78). After incorporating the genetic risk score into the FRS, a total of 380 individuals (30.6%) were reclassified into higher-(188) or lower-risk groups (192).

Conclusion

A genetic risk score based on measured/imputed genotypes at 11 susceptibility SNPs, led to significant reclassification in the 10-y CHD risk categories. Additional prospective studies are needed to assess accuracy and clinical utility of such reclassification.
Identification of α(1,6)fucosylated proteins differentially expressed in human colorectal cancer
Authors: Muinelo-Romay Laura , Villar-Portela Susana , Cuevas Elisa , Gil-Martín Emilio , Fernández-Briera Almudena
Published: December 2011

Background

A universal hallmark of cancer cells is the change in their glycosylation phenotype. One of the most frequent alterations in the normal glycosylation pattern observed during carcinogenesis is the enhancement of α(1,6)linked fucose residues of glycoproteins, due to the up-regulation of the α(1,6)fucosyltransferase activity. Our previous results demonstrated the specific alteration of this enzyme activity and expression in colorectal cancer, suggesting its implication in tumour development and progression.

Methods

In the current work we combined a LCA-affinity chromatography with SDS-PAGE and mass spectrometry in order to identify α(1,6)fucosylated proteins differentially expressed in colorectal cancer. This strategy allowed the identification of a group of α(1,6)fucosylated proteins candidates to be involved in CRC malignancy.

Results

The majority of the identified proteins take part in cell signaling and interaction processes as well as in modulation of the immunological response. Likewise, we confirmed the increased expression of GRP94 in colorectal cancer tissue and the significant down-regulation of the IgGFcBP expression in tumour cells.

Conclusion

All these results validate the importance of core-fucosylated proteins profile analysis to understand the mechanisms which promote cancer onset and progression and to discover new tumour markers or therapeutic targets.
Definition of the viral targets of protective HIV-1-specific T cell responses
Authors: Mothe Beatriz , Llano Anuska , Ibarrondo Javier , Daniels Marcus , Miranda Cristina , Zamarreño Jennifer , Bach Vanessa , Zuniga Rosario , Pérez-Álvarez Susana , Berger Christoph T , Puertas Maria C , Martinez-Picado Javier , Rolland Morgane , Farfan Marilu , Szinger James J , Hildebrand William H , Yang Otto O , Sanchez-Merino Victor , Brumme Chanson J , Brumme Zabrina L , Heckerman David , Allen Todd M , Mullins James I , Gómez Guadalupe , Goulder Philip J , Walker Bruce D , Gatell Jose M , Clotet Bonaventura , Korber Bette T , Sanchez Jorge , Brander Christian
Published: December 2011

Background

The efficacy of the CTL component of a future HIV-1 vaccine will depend on the induction of responses with the most potent antiviral activity and broad HLA class I restriction. However, current HIV vaccine designs are largely based on viral sequence alignments only, not incorporating experimental data on T cell function and specificity.

Methods

Here, 950 untreated HIV-1 clade B or -C infected individuals were tested for responses to sets of 410 overlapping peptides (OLP) spanning the entire HIV-1 proteome. For each OLP, a "protective ratio" (PR) was calculated as the ratio of median viral loads (VL) between OLP non-responders and responders.

Results

For both clades, there was a negative relationship between the PR and the entropy of the OLP sequence. There was also a significant additive effect of multiple responses to beneficial OLP. Responses to beneficial OLP were of significantly higher functional avidity than responses to non-beneficial OLP. They also had superior in-vitro antiviral activities and, importantly, were at least as predictive of individuals' viral loads than their HLA class I genotypes.

Conclusions

The data thus identify immunogen sequence candidates for HIV and provide an approach for T cell immunogen design applicable to other viral infections.
Subcortical processing of speech regularities underlies reading and music aptitude in children
Authors: Strait Dana L , Hornickel Jane , Kraus Nina
Published: December 2011

Background

Neural sensitivity to acoustic regularities supports fundamental human behaviors such as hearing in noise and reading. Although the failure to encode acoustic regularities in ongoing speech has been associated with language and literacy deficits, how auditory expertise, such as the expertise that is associated with musical skill, relates to the brainstem processing of speech regularities is unknown. An association between musical skill and neural sensitivity to acoustic regularities would not be surprising given the importance of repetition and regularity in music. Here, we aimed to define relationships between the subcortical processing of speech regularities, music aptitude, and reading abilities in children with and without reading impairment. We hypothesized that, in combination with auditory cognitive abilities, neural sensitivity to regularities in ongoing speech provides a common biological mechanism underlying the development of music and reading abilities.

Methods

We assessed auditory working memory and attention, music aptitude, reading ability, and neural sensitivity to acoustic regularities in 42 school-aged children with a wide range of reading ability. Neural sensitivity to acoustic regularities was assessed by recording brainstem responses to the same speech sound presented in predictable and variable speech streams.

Results

Through correlation analyses and structural equation modeling, we reveal that music aptitude and literacy both relate to the extent of subcortical adaptation to regularities in ongoing speech as well as with auditory working memory and attention. Relationships between music and speech processing are specifically driven by performance on a musical rhythm task, underscoring the importance of rhythmic regularity for both language and music.

Conclusions

These data indicate common brain mechanisms underlying reading and music abilities that relate to how the nervous system responds to regularities in auditory input. Definition of common biological underpinnings for music and reading supports the usefulness of music for promoting child literacy, with the potential to improve reading remediation.
Tissue expression of squamous cellular carcinoma antigen and Ki67 in hepatocellular carcinoma-correlation with prognosis: A historical prospective study
Authors: Schmilovitz-Weiss Hemda , Tobar Ana , Halpern Marisa , Levy Izhar , Shabtai Esther , Ben-Ari Ziv
Published: December 2011

Background

Squamous cellular carcinoma antigen (SCCA) is overexpressed in hepatocellular carcinoma (HCC) tissue and in sera of HCC patients. Our aim was to assess hepatic SCCA immunostaining in a series of HCCs and to correlate its presence with cell proliferation, apoptosis and clinical outcome.

Methods

Sixty-one HCC patients were included. Liver specimens were obtained either by biopsy (n = 17) or surgically (resection 27, transplantation 17). Immunostaining for AFP, Ki-67, SCCA and TUNEL assay were performed.

Results

SCCA staining was detected in 83.6% of specimens. A statistical significant correlation was found between negative SCCA staining and mortality (p = 0.026) and a higher immunostaining score for Ki67 (p = 0.017). Positive SCCA staining was associated with well and moderate differentiated tumors (p = 0.022). Using multiple logistic regression analysis, Ki67 and TUNEL assay were found to be significant independent predictors of negative SCCA immunostaining. The area under the receiver operator characteristic curve was 0.87. Kaplan-Meier survival analysis revealed a significant difference between the patient group with positive versus negative SCCA immunostaining relating to survival time (p = 0.0106). Cox proportional hazard regression analysis demonstrated that Ki67 immunostaining and liver transplantation or resection were independently associated with mortality.

Conclusions

SCCA is overexpressed in HCC. SCCA status is associated with cell proliferation, apoptosis and survival. SCCA and Ki67 staining can predict survival. Our study results support a potential association of negative SCCA expression with other markers of poor outcome in HCC. More studies are needed to clarify the role of SCCA in HCC and expand the knowledge of the SCCA antigen in HCC patients.
Microtubules are organized independently of the centrosome in Drosophilaneurons
Authors: Nguyen Michelle M , Stone Michelle C , Rolls Melissa M
Published: December 2011

Background

The best-studied arrangement of microtubules is that organized by the centrosome, a cloud of microtubule nucleating and anchoring proteins is clustered around centrioles. However, noncentrosomal microtubule arrays are common in many differentiated cells, including neurons. Although microtubules are not anchored at neuronal centrosomes, it remains unclear whether the centrosome plays a role in organizing neuronal microtubules. We use Drosophila as a model system to determine whether centrosomal microtubule nucleation is important in mature neurons.

Results

In developing and mature neurons, centrioles were not surrounded by the core nucleation protein γ-tubulin. This suggests that the centrioles do not organize functional centrosomes in Drosophila neurons in vivo. Consistent with this idea, centriole position was not correlated with a specific region of the cell body in neurons, and growing microtubules did not cluster around the centriole, even after axon severing when the number of growing plus ends is dramatically increased. To determine whether the centrosome was required for microtubule organization in mature neurons, we used two approaches. First, we used DSas-4 centriole duplication mutants. In these mutants, centrioles were present in many larval sensory neurons, but they were not fully functional. Despite reduced centriole function, microtubule orientation was normal in axons and dendrites. Second, we used laser ablation to eliminate the centriole, and again found that microtubule polarity in axons and dendrites was normal, even 3 days after treatment.

Conclusion

We conclude that the centrosome is not a major site of microtubule nucleation in Drosophila neurons, and is not required for maintenance of neuronal microtubule organization in these cells.
Direct production of biodiesel from high-acid value Jatrophaoil with solid acid catalyst derived from lignin
Authors: Pua Fei-ling , Fang Zhen , Zakaria Sarani , Guo Feng , Chia Chin-hua
Published: December 2011

Background

Solid acid catalyst was prepared from Kraft lignin by chemical activation with phosphoric acid, pyrolysis and sulfuric acid. This catalyst had high acid density as characterized by scanning electron microscope (SEM), energy-dispersive x-ray spectrometry (EDX) and Brunauer, Emmett, and Teller (BET) method analyses. It was further used to catalyze the esterification of oleic acid and one-step conversion of non-pretreated Jatropha oil to biodiesel. The effects of catalyst loading, reaction temperature and oil-to-methanol molar ratio, on the catalytic activity of the esterification were investigated.

Results

The highest catalytic activity was achieved with a 96.1% esterification rate, and the catalyst can be reused three times with little deactivation under optimized conditions. Biodiesel production from Jatropha oil was studied under such conditions. It was found that 96.3% biodiesel yield from non-pretreated Jatropha oil with high-acid value (12.7 mg KOH/g) could be achieved.

Conclusions

The catalyst can be easily separated for reuse. This single-step process could be a potential route for biodiesel production from high-acid value oil by simplifying the procedure and reducing costs.
Characteristics, practice patterns, and outcomes in patients with acute hypertension: European registry for Studying the Treatment of Acute hyperTension (Euro-STAT)
Authors: Vuylsteke Alain , Vincent Jean-Louis , Payen de La Garanderie Didier , Anderson Frederick A , Emery Leigh , Wyman Allison , Rushton-Smith Sophie , Gore Joel M ,   the Euro-STAT Investigators
Published: December 2011

Introduction

Although effective strategies are available for the management of chronic hypertension, less is known about treating patients with acute, severe elevations in blood pressure. Using data from the European registry for Studying the Treatment of Acute hyperTension (Euro-STAT), we sought to evaluate 'real-life' management practices and outcomes in patients who received intravenous antihypertensive therapy to treat an episode of acute hypertension.

Methods

Euro-STAT is a European, hospital-based, observational study of consecutive adult patients treated with intravenous antihypertensive therapy while in the emergency department, perioperative unit or ICU. Enrolment took place between 1 July and 15 October 2009 in 11 hospitals in 7 European countries (Austria, Belgium, Germany, Italy, Spain, Sweden and the United Kingdom).

Results

The study population was composed of 791 consecutive patients (median age 69 years, 37% women). Median arterial blood pressure before treatment was 166 mmHg systolic blood pressure (IQR 141 to 190 mmHg) and 80 mmHg diastolic blood pressure (IQR 68 to 95). Nitroglycerine was the most commonly used antihypertensive treatment overall (40% of patients), followed by urapidil (21%), clonidine (16%) and furosemide (8%). Treatment was associated with hypotension in almost 10% of patients. Overall 30-day mortality was 4%, and new or worsening end-organ damage occurred in 19% of patients.

Conclusions

High blood pressure requiring intravenous therapy is currently managed with a variety of agents in Europe, with those most commonly used being nitroglycerine, urapidil and clonidine. Patients with acute hypertension have substantial concomitant morbidity and mortality, and intravenous antihypertensive treatment is associated with hypotension in almost 10% of cases.