bluuebunny/crossref_metadata_2025_split huggingface dataset:
The shadowlands of MDS: idiopathic cytopenias of undetermined significance (ICUS) and clonal hematopoiesis of indeterminate potential (CHIP)
Authors: Malcovati Luca , Cazzola Mario 
Published: September 2016

AbstractThe WHO classification provides the best diagnostic approach to myelodysplastic syndromes (MDS). However, biologic and analytic limitations have emerged in the criteria currently adopted to establish the diagnosis and to classify MDS. The provisional category of idiopathic cytopenia of undetermined significance (ICUS) has been proposed to describe patients in whom MDS is possible but not proven. To formulate a diagnosis of ICUS, a thorough diagnostic work-up is required and repeated tests should be performed to reach a conclusive diagnosis. Recent studies provided consistent evidence of age-related hematopoietic clones (clonal hematopoiesis of indeterminate potential; CHIP), driven by mutations of genes that are recurrently mutated in myeloid neoplasms and associated with increase in the risk of hematologic cancer. A subset of mutated genes, mainly involved in epigenetic regulation, are likely initiating lesions driving the expansion of a premalignant clone. However, in a fraction of subjects the detected clone may be a small malignant clone expanding under the drive of the detected and additional undetected mutations. In addition, several experimental evidences suggest the potential relevance of an abnormal bone marrow environment in the selection and evolution of hematopoietic clones in MDS. The spreading of massively parallel sequencing techniques is offering translational opportunities in the clinical approach to myeloid neoplasms. Although several issues remain to be clarified, targeted gene sequencing may be of potential value in the dissection between clonal myelodysplasia, nonclonal cytopenia, and clonal hematopoiesis arising upon aging or in the context of acquired marrow failure.
Nine years without a new FDA-approved therapy for MDS: how can we break through the impasse?
Authors: DeZern Amy E. 
Published: September 2016

Abstract
The myelodysplastic syndromes (MDSs) are a heterogeneous collection of clonal hematopoietic malignancies that compromise a large subgroup of the myeloid neoplasms and collectively are the most common acquired adult bone marrow failure syndromes. Currently, only 3 agents are approved for the treatment of MDS by the US Food and Drug Administration (FDA): azacitidine, decitabine, and lenalidomide. The latter drug, approved in 2006, is the most recent agent approved by the FDA for MDS and there has been mediocre success with novel agents for the past 9 years. The heterogeneity of MDS as a disease group is likely to be a strong contributor to this slow progress but recent developments in molecular characterization of MDS are improving diagnostic accuracy, providing insights into pathogenesis and refining our prognostic ability in the field. With the advent of these developments, appropriately chosen therapeutics or even targeted agents may be able to improve patient outcomes in the future.
Looking forward: novel therapeutic approaches in chronic and advanced phases of myelofibrosis
Authors: Mascarenhas John 
Published: September 2016

AbstractMyelofibrosis (MF) is complex at the pathobiologic level and heterogeneous at the clinical level. The advances in molecular characterization of MF provide important insight into the mechanisms driving this chronic myeloid malignancy, refine risk stratification, offer novel therapeutic targets, and serve to measure therapeutic response. Although JAK2 inhibition has been the focus of laboratory and clinical efforts over the last decade, current experimental therapeutic approaches have broadened to include inhibitors of key alternative signaling pathways, epigenetic modulators, anti-fibrotics, and immunotherapies. Based on compelling preclinical rationale, a number of JAK2 inhibitor based combination therapies are now actively being evaluated in the clinic with the goal of disease course modification. The role and timing of hematopoietic stem cell transplant (HSCT) for MF has been challenged with the availability of commercial ruxolitinib and the plethora of experimental treatment options that exist. Integration of preconditioning JAK2 inhibition, reduced intensity conditioning regimens, and alternative donor sources are all being explored in an attempt to optimize this potentially curative modality. This review will summarize modern MF risk stratification, current clinical research approaches to chronic and advance phase MF focusing on novel agents alone and in combination, and update the reader on new directions in HSCT.
Emerging genetic and pharmacologic therapies for controlling hemostasis: beyond recombinant clotting factors
Authors: Monahan Paul E. 
Published: September 2016

Abstract
For more than 3 decades, the scientific community has pursued gene correction of hemophilia, with the goal that an individual with congenitally deficient factor VIII or factor IX might synthesize adequate endogenous clotting factor to be relieved of burdensome repeated clotting factor infusions, as well as the emotional weight of continuous hemorrhage risk. Recent reports of successful factor IX gene therapy and partial correction of the bleeding phenotype have raised the bar for success for a robust crop of new clinical gene therapy efforts for both hemophilia A and B. At the same time that gene therapy is gaining momentum, suggesting the possibility of relief from regular intravenous coagulation protein replacement, a number of innovative technologies that enhance hemostatic potential independently of replacement factor administration are demonstrating success in human clinical application. Human clinical trial progress is reviewed regarding a recombinant bispecific IgG antibody to factors IXa and X that mimics factor VIII cofactor activity, as well as monoclonal antibody and short interfering RNA strategies that demonstrate hemostatic efficacy via opposing inhibitors of coagulation. These strategies, associated with prolonged hemostatic potential following subcutaneous (ACE910, ALN-AT3, Concizumab) or single administration (eg, gene therapy) make it possible to imagine a day when recombinant clotting factor administration, rather than being a daily preoccupation, is relegated to an adjunctive role in supporting more novel standard of care therapies.
Management of symptoms in polycythemia vera and essential thrombocythemia patients
Authors: Radia Deepti , Geyer Holly L. 
Published: September 2016

Abstract
The BCR-ABL-negative myeloproliferative neoplasms (MPNs) are clonal stem cell derived malignancies, which include polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). The MPNs are characterized by dysregulated JAK-STAT signaling pathways. PV and ET are associated with an increased risk of thrombo-hemorrhagic complications, risk of progression to MF and leukemia. Presentation of patients with PV and ET is variable and usually as a result of abnormal full blood count indices (raised hemoglobin and hematocrit, leukocytosis, and thrombocytosis). Presentation with thrombosis or splenomegaly occurs in ∼30% of patients. Historically thought of as indolent compared with MF, patients with PV and ET have significant disease symptom burden which does not directly correlate to the current clinical prognostic classifications. The mainstay of therapy is reserved for patients with high-risk disease and thus excludes a population of patients with significant symptom related morbidity impacting their quality-of-life and survival. Recent treatment strategies have aimed to incorporate disease burden assessment into the selection of therapeutic interventions such as JAK2 inhibitors and HDAC inhibitors. We will review the advances in the field of MPN symptom assessment and symptom burden experienced by ET and PV patients. We will also discuss the risk-stratified management of ET and PV patients alongside symptom assessment and the impact of potential novel therapies, for patients who fail to respond to conventional treatment.
Management of prolymphocytic leukemia
Authors: Dearden Claire 
Published: September 2016

Abstract
B-cell (B-PLL) and T-cell (T-PLL) prolymphocytic leukemias are rare, poor-prognosis lymphoid neoplasms with similar presentation characterized by symptomatic splenomegaly and lymphocytosis. They can be distinguished from each other and from other T- and B-cell leukemias by careful evaluation of morphology, immunophenotyping, and molecular genetics. The clinical behavior is typically aggressive, although a subset of patients may have an indolent phase of variable length. First-line therapy for T-PLL is with intravenous alemtuzumab and for B-PLL is with combination purine analog-based chemo-immunotherapy. New B-cell receptor inhibitors, such as ibrutinib and idelalisib, may have a role in the management of B-PLL, especially for the patients harboring abnormalities of TP53. Allogenic stem cell transplantation should still be considered for eligible patients and may be the only current therapy capable of delivering a cure. In the past few years, many of the molecular mechanisms underlying disease pathogenesis and progression have been revealed and are likely to lead to the development of novel targeted approaches.
Diagnosis and management of rare congenital nonimmune hemolytic disease
Authors: Gallagher Patrick G. 
Published: September 2016

AbstractRare, congenital nonimmune hemolytic disorders of the erythrocyte, although uncommon, are important causes of anemia in the child and adult. These are a heterogeneous group of diseases that disrupt normal erythrocyte structure and function in varying ways. Predominant are abnormalities of hemoglobin stability, defects of erythrocyte metabolism, and disorders of erythrocyte hydration. Unstable hemoglobinopathies may lead to chronic or episodic hemolysis. Perturbation of critical enzymes of the Embden–Meyerhof pathway lead to altered erythrocyte metabolism and chronic hemolysis. Disorders of erythrocyte hydration are an under-recognized cause of hemolytic anemia. Beyond pathophysiologic mechanisms of disease, clinical, laboratory, and genetic heterogeneity characterize this group of disorders. Often, they are underdiagnosed or misdiagnosed. This review discusses pathophysiology, inheritance, clinical findings, laboratory manifestations, and management considerations in several rare nonimmune hemolytic diseases including the unstable hemoglobins, disorders of erythrocyte metabolism, and abnormalities of erythrocyte hydration.
The use of novel monoclonal antibodies in the treatment of acute lymphoblastic leukemia
Authors: DeAngelo Daniel J. 
Published: September 2016

Abstract
Regardless of age, patients with relapsed or refractory acute lymphoblastic leukemia (ALL) have extremely poor outcomes. The success of reinduction chemotherapy remains dismal, because complete remission rates are low and seldom durable. Clearly, new and novel strategies are needed to improve the outcome of patients with relapsed or refractory ALL. Patients with early relapse, especially those still receiving chemotherapy, tend to have a much poorer outcome and are often chemotherapy resistant. Although high-dose approaches may overcome chemotherapy resistance, long-term disease-free and overall survival remains limited. Several approaches have been used to target antigens, including cluster of differentiation (CD) 19, CD20, CD22, and CD52, on the surface of the malignant lymphoblast with striking efficacy. This review will focus on the clinical application of the major classes of antibodies, including naked antibodies, drug–antibody conjugates, immunotoxins, and T cell–engaging bispecific antibodies. Hopefully, these novel monoclonal antibodies will result in a significant improvement in the outcome of patients with relapsed or refractory ALL.
Can selectin and iNKT cell therapies meet the needs of people with sickle cell disease?
Authors: Field Joshua J. 
Published: September 2016

AbstractRecent insights into the pathogenesis of microvascular occlusion downstream of the sickled red cell have revealed new therapeutic targets for sickle cell disease (SCD). After the formation of sickle cells, tissue injury spurs inflammation, which leads to receptor-mediated contacts between sickle cells, leukocytes, and vascular endothelium. Specifically, selectins decelerate sickled red cells and leukocytes in the circulation to facilitate endothelial adhesion and other cell–cell interactions, ultimately leading to vascular occlusion. Invariant NKT (iNKT) cells, activated during reperfusion, generate a broad inflammatory response, which further increases cellular adhesion and vascular occlusion. Novel therapies are in development that target selectins and iNKT cells to prevent or interrupt the vicious cycle of adhesion and inflammation. Although the therapies hold promise for the treatment of SCD, an underappreciated threat to their development is poor access to care for people with SCD. Unless the majority of people with SCD have access to consistent, high-quality care, they will not have the opportunity to participate in a clinical trial or receive any new therapy, regardless of its efficacy.
Palliative care in pediatric patients with hematologic malignancies
Authors: Humphrey Lisa , Kang Tammy I. 
Published: September 2016

Abstract
Children with advanced cancer, including those with hematologic malignancies, can benefit from interdisciplinary palliative care services. Palliative care includes management of distressing symptoms, attention to psychosocial and spiritual needs, and assistance with navigating complex medical decisions with the ultimate goal of maximizing the quality-of-life of the child and family. Palliative care is distinct from hospice care and can assist with the care of patients throughout the cancer continuum, irrespective of prognosis. While key healthcare organizations, including the Institute of Medicine, the American Academy of Pediatrics and the American Society of Clinical Oncology among many others endorse palliative care for children with advanced illness, barriers to integration of palliative care into cancer care still exist. Providing assistance with advance care planning, guiding patients and families through prognostic uncertainty, and managing transitions of care are also included in goals of palliative care involvement. For patients with advanced malignancy, legislation, included in the Patient Protection and Affordable Health Care Act allows patients and families more options as they make the difficult transition from disease directed therapy to care focused on comfort and quality-of-life.
Patient-reported outcomes in drug development for hematology
Authors: Acquadro Catherine , Regnault Antoine 
Published: September 2016

AbstractPatient-reported outcomes (PROs) are any outcome evaluated directly by the patient himself and based on the patient's perception of a disease and its treatment(s). PROs are direct outcome measures that can be used as clinical meaningful endpoints to characterize treatment benefit. They provide unique and important information about the effect of treatment from a patient's view. However, PROs will only be considered adequate if the assessment is well-defined and reliable. In 2009, the FDA has issued a guidance, which defines good measurement principles to consider for PRO measures intended to give evidence of treatment benefit in drug development. In hematologic clinical trials, when applied rigorously, they may be used to evaluate overall treatment effectiveness, treatment toxicity, and quality of patient's well-being at short-term and long-term after treatment from a patient's perspective. In situations in which multiple treatment options exist with similar survival outcome or if a new therapeutic strategy needs to be evaluated, the inclusion of PROs as an endpoint can provide additional data and help in clinical decision making. Given the diversity of the hematological field, the approach to measurement needs to be tailored for each specific situation. The importance of PROs in hematologic diseases has been highlighted in a number of international recommendations. In addition, new perspectives in the regulatory field will enhance the inclusion of PRO endpoints in clinical trials in hematology, allowing the voice of the patients with hematologic diseases to be taken into greater consideration in the development of new drugs.
Acute myeloid leukemia in children and adolescents: identification of new molecular targets brings promise of new therapies
Authors: Kolb E. Anders , Meshinchi Soheil 
Published: September 2016

Abstract
Recent reports of recurrent mutations in childhood acute myeloid leukemia (AML) have identified potential targets for new therapeutic strategies. Acute promyelocytic leukemia (APL) is characterized commonly by a fusion between the PML gene and the RARA gene, genes targetable by arsenic (ATO) and retinoic acid (ATRA), respectively. A mutation in GATA1, common in AML of Down syndrome (ML-DS), renders cells more susceptible to cytarabine and anthracyclines, thus permitting targeted dose reductions to preserve high survival rates while reducing toxicity. In all other patients, Ras pathway mutations, KMT2A and other methyltransferase mutations, FLT3 mutations, and KIT mutations are all relatively common in childhood AML and all are potentially “druggable”. The focus of this review is on those therapies likely to be clinically available in the near future. The preclinical and clinical data providing a rationale for testing in children of specific agents in children is discussed. Whether the expression of a potential target is sufficient to predict response to a targeted therapy is an open question in childhood AML. Development of clinical trials to evaluate targeted therapies in small molecularly defined subsets of AML will be the next great challenge for all cooperative groups in North America and Europe.
Molecularly targeted therapies for acute myeloid leukemia
Authors: Stein Eytan M. 
Published: September 2016

Abstract
The past 15 years have seen major leaps in our understanding of the molecular genetic mutations that act as drivers of acute myeloid leukemia (AML). Clinical trials of agents against specific mutant proteins, such as FLT3-internal tandem duplications (ITDs) and isocitrate dehydrogenase mutations (IDHs) are ongoing. This review discusses agents in clinical trials that target specific gene mutations and/or epigenetic targets.
Antigen-specific immunotherapies for acute myeloid leukemia
Authors: Buckley Sarah A. , Walter Roland B. 
Published: September 2016

Abstract
Antigen-specific immunotherapies have emerged as important components of curative treatment algorithms for many cancers. In acute myeloid leukemia (AML), success has been less obvious. Nonetheless, among the few drugs shown to improve survival in recent randomized trials is the CD33 antibody–drug conjugate gemtuzumab ozogamicin. Significant antileukemic activity is also well documented for radioimmunoconjugates targeting CD33, CD45, or CD66. These therapeutics can intensify conditioning before hematopoietic cell transplantation, but their effect on patient outcomes needs clarification. Emerging data now suggest clinical antileukemic activity of several novel antibodies and perhaps some adoptive T-cell immunotherapies and vaccines. In parallel, numerous other agents targeting a wider variety of antigens are currently being explored. However, the antigenic heterogeneity characteristic of AML is a considerable limitation for all these therapeutics, and many important questions related to the ideal target antigen(s), disease situation in which to use these therapies, most suitable patient populations, exact treatment modalities, and details of supportive care needs remain open. Addressing such questions in upcoming studies will be required to ensure that antigen-directed therapies become an effective tool in AML, a disease for which outcomes with standard “3 + 7”-based chemotherapy have remained unsatisfactory in many patients.
New approaches to transplantation in acute myelogenous leukemia
Authors: de Lima Marcos 
Published: September 2016

Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapeutic option for acute myelogenous leukemia (AML). This is due to the combined effect of chemo/radiation therapy and the immunologic graft-versus-leukemia effect. The field of HSCT has benefited from advances in a variety of “fronts,” including our increasing ability to break the human leukocyte antigen barrier, which has led to greater access to transplantation. Furthermore, progress in the biologic, genetic, and pharmacologic arenas is creating a scenario where traditional borders between transplant and non-transplant therapies are less clear. This overlap is exemplified by new approaches to pharmacologic maintenance of remission strategies after HSCT. In addition, cellular adoptive immunotherapy has the potential to exploit narrowly targeted anti-tumor effects within or outside the allogeneic HSCT “frame,” holding the promise of avoiding off target side effects, such as graft-versus-host disease. Here we discuss these and other lines of active investigation designed to improve outcomes of HSCT for AML.
Treatment of patients with transformed lymphoma
Authors: Montoto Silvia 
Published: September 2016

Abstract
Histologic transformation (HT) is a frequent event in the clinical course of patients with indolent lymphoma. Most of the available data in the literature comes from studies on transformation of follicular lymphoma (FL), as this is the most common indolent lymphoma; however, HT is also well documented following small lymphocytic lymphoma/chronic lymphocytic leukaemia (SLL/CLL), lymphoplasmacytic lymphoma (LPL), or marginal zone lymphoma (MZL), amongst other types of lymphoma, albeit most of the studies on transformation in these subtypes are case reports or short series. The outcome of patients with HT has traditionally been considered dismal with a median overall survival (OS) of around 1 year in most of the published studies. This prompted many authors to include stem cell transplant (SCT) as part of the treatment strategy for young and fit patients with HT. However, recent articles suggest that the outcome of patients with transformed lymphoma might be improving, questioning the need for such intensive therapies. The management of patients with HT is challenged by the heterogeneity of the population in terms of previous number and type of therapy lines and from their exclusion from prospective clinical trials. This review will examine whether the advent of new therapies has impacted on the prognosis of HT and on current treatment strategies.
Development of a prediction system for tail-anchored proteins
Authors: Shigemitsu Shunsuke , Cao Wei , Terada Tohru , Shimizu Kentaro 
Published: September 2016

Abstract
Background
“Tail-anchored (TA) proteins” is a collective term for transmembrane proteins with a C-terminal transmembrane domain (TMD) and without an N-terminal signal sequence. TA proteins account for approximately 3–5 % of all transmembrane proteins that mediate membrane fusion, regulation of apoptosis, and vesicular transport. The combined use of TMD and signal sequence prediction tools is typically required to predict TA proteins.

Results
Here we developed a prediction system named TAPPM that predicted TA proteins solely from target amino acid sequences according to the knowledge of the sequence features of TMDs and the peripheral regions of TA proteins. Manually curated TA proteins were collected from published literature. We constructed hidden markov models of TA proteins as well as three different types of transmembrane proteins with similar structures and compared their likelihoods as TA proteins.

Conclusions
Using the HMM models, we achieved high prediction accuracy; area under the receiver operator curve values reaching 0.963. A command line tool written in Python is available at https://github.com/davecao/tappm_cli.