bluuebunny/crossref_metadata_2025 huggingface dataset:
Can we make a better match or mismatch with KIR genotyping?
Authors: Mehta Rohtesh S. , Rezvani Katayoun
Published: December 2016

Natural killer (NK) cell function is regulated by a fine balance between numerous activating and inhibitory receptors, of which killer-cell immunoglobulin-like receptors (KIRs) are among the most polymorphic and comprehensively studied. KIRs allow NK cells to recognize downregulation or the absence of HLA class I molecules on target cells (known as missing-self), a phenomenon that is commonly observed in virally infected cells or cancer cells. Because KIR and HLA genes are located on different chromosomes, in an allogeneic environment such as after hematopoietic stem cell transplantation, donor NK cells that express an inhibitory KIR for an HLA class I molecule that is absent on recipient targets (KIR/KIR-ligand mismatch), can recognize and react to this missing self and mediate cytotoxicity. Accumulating data indicate that epistatic interactions between KIR and HLA influence outcomes in several clinical conditions. Herein, we discuss the genetic and functional features of KIR/KIR-ligand interactions in hematopoietic stem cell transplantation and how these data can guide donor selection. We will also review clinical studies of adoptive NK cell therapy in leukemia and emerging data on the use of genetically modified NK cells that could broaden the scope of cancer immunotherapy.
Role of the intestinal mucosa in acute gastrointestinal GVHD
Authors: Peled Jonathan U. , Hanash Alan M. , Jenq Robert R.
Published: December 2016

Intestinal graft-versus-host disease (GVHD) remains a significant obstacle to the success of allogeneic hematopoietic cell transplantation. The intestinal mucosa comprises the inner lining of the intestinal tract and maintains close proximity with commensal microbes that reside within the intestinal lumen. Recent advances have significantly improved our understanding of the interactions between the intestinal mucosa and the enteric microbiota. Changes in host mucosal tissue and commensals posttransplant have been actively investigated, and provocative insights into mucosal immunity and the enteric microbiota are now being translated into clinical trials of novel approaches for preventing and treating acute GVHD. In this review, we summarize recent findings related to aspects of the intestinal mucosa during acute GVHD.
Novel agents in chronic lymphocytic leukemia
Authors: Lamanna Nicole , O’Brien Susan
Published: December 2016

The advent of novel small-molecule inhibitors has transformed the treatment approaches for patients with chronic lymphocytic leukemia (CLL). These therapies are becoming increasingly used in patients with relapsed disease, patients with 17p deletion, and, as of recently, also in the frontline setting for previously untreated patients with CLL. Moreover, many of these are oral therapies that are significantly less myelosuppressive than chemoimmunotherapy. However, these agents have their own set of unique toxicities with which providers must gain familiarity. There is also ongoing development of second-generation agents which have the promise of less toxicity than the US Food and Drug Administration (FDA)–approved compounds. In addition, immunotherapy and the role of the microenvironment are becoming increasingly important and have therapeutic implications in the treatment of patients with CLL. Ultimately, investigators need to evaluate how to position these and other new exciting therapies and decide on the ultimate role for chemoimmunotherapy in modern times.
First-line therapy for young patients with CLL
Authors: Jain Nitin , O’Brien Susan
Published: December 2016

A 61-year-old man with a history of chronic lymphocytic leukemia (CLL) presents with complaints of worsening fatigue and night sweats. He was diagnosed with CLL 3 years ago on routine blood count testing. He has no major medical comorbidities. On examination, he has several 2- to 3-cm lymph nodes in the cervical and axillary area. Spleen is palpable 5 cm below the costal margin. Blood counts show lymphocytosis with thrombocytopenia and anemia. Prognostic markers include deletion 13q by fluorescence in situ hybridization analysis and mutated IGHV. You are asked by the hematology fellow you are supervising about the best treatment of this patient.
Chronic myeloid leukemia: sequencing of TKI therapies
Authors: Cortes Jorge , Kantarjian Hagop
Published: December 2016

Multiple tyrosine kinase inhibitors (TKIs) are available for managing patients with chronic myeloid leukemia. Although most patients have a favorable outcome with their initial therapy, whether imatinib or a second-generation TKI was used, some will require subsequent use of one or more different TKIs. Such sequencing might be indicated in a reactive way (ie, for patients who have experienced resistance or intolerance to their initial therapy) or in a proactive way (ie, for patients with a somewhat favorable outcome who have not reached an “optimal” outcome). Sequencing of TKIs has become standard practice, and the proper use of sequenced TKIs is likely to optimize outcomes and resource utilization.
Thrombosis in the setting of cancer
Authors: Streiff Michael B.
Published: December 2016

Venous thromboembolism (VTE) is a common cause of adverse outcomes in patients with cancer. The risk of VTE varies with cancer type, stage and grade, cancer therapy, and supportive care, as well as patient characteristics including age, ethnicity, and inherited and acquired comorbid conditions. VTE prophylaxis should be provided to all hospitalized cancer patients and high-risk outpatients. Low-molecular-weight heparin (LMWH) remains the first-line therapy for VTE in patients with active cancer. Anticoagulation should be continued as long as there is evidence of active disease or patients are receiving cancer treatment. The efficacy of direct oral anticoagulants in the treatment of cancer-associated thrombosis remains incompletely defined. Central venous catheter (CVC)–associated VTE should be treated with anticoagulation alone, unless the CVC is no longer required. Recent studies indicate that anticoagulation may be appropriate for patients with persistent thrombocytopenia or solid tumor brain metastases. Management of recurrent VTE includes the identification of the cause(s) of the recurrence and solutions targeted at addressing the potential precipitants.
Anti-Xa monitoring of low-molecular-weight heparin in adult patients with cancer
Authors: Kreuziger Lisa Baumann , Streiff Michael
Published: December 2016

A 68-year-old man developed a right femoral vein deep vein thrombosis and bilateral pulmonary embolism while receiving chemotherapy for stage IV prostate cancer. His creatinine at diagnosis is 1.4 mg/dL, with an estimated clearance of 63 mL/min. In patients with cancer, should low-molecular-weight heparin treatment be dosed according to weight, or adjusted using anti-Xa levels?
Update on the diagnosis and management of paroxysmal nocturnal hemoglobinuria
Authors: Parker Charles J.
Published: December 2016

Once suspected, the diagnosis of paroxysmal nocturnal hemoglobinuria (PNH) is straightforward when flow cytometric analysis of the peripheral blood reveals a population of glycosyl phosphatidylinositol anchor protein-deficient cells. But PNH is clinically heterogeneous, with some patients having a disease process characterized by florid intravascular, complement-mediated hemolysis, whereas in others, bone marrow failure dominates the clinical picture with modest or even no evidence of hemolysis observed. The clinical heterogeneity is due to the close, though incompletely understood, relationship between PNH and immune-mediated bone marrow failure, and that PNH is an acquired, nonmalignant clonal disease of the hematopoietic stem cells. Bone marrow failure complicates management of PNH because compromised erythropoiesis contributes, to a greater or lesser degree, to the anemia; in addition, the extent to which the mutant stem cell clone expands in an individual patient determines the magnitude of the hemolytic component of the disease. An understanding of the unique pathobiology of PNH in relationship both to complement physiology and immune-mediated bone marrow failure provides the basis for a systematic approach to management.
Cold agglutinin disease
Authors: Berentsen Sigbjørn
Published: December 2016

Primary chronic cold agglutinin disease (CAD) is a well-defined clinicopathologic entity in which a specific, clonal lymphoproliferative B-cell bone marrow disorder results in autoimmune hemolytic anemia. The immune hemolysis is entirely complement-dependent, predominantly mediated by activation of the classical pathway and phagocytosis of erythrocytes opsonized with complement protein C3b. Typical clinical features in CAD have diagnostic and therapeutic implications. Pharmacologic treatment should be offered to patients with symptom-producing anemia or disabling circulatory symptoms. CAD should not be treated with corticosteroids. Based on an individualized approach, rituximab monotherapy or rituximab-fludarabine in combination is recommended as first-line therapy. Rituximab-bendamustine is still an investigational therapy. Although complement-modulating agents are still to be considered experimental in CAD, therapy with the anti-C1s monoclonal antibody TNT009 seems promising.
Congenital and acquired bleeding disorders in pregnancy
Authors: Gernsheimer Terry B.
Published: December 2016

Obstetrical hematology represents challenges not only for the patient, but also for her progeny. In particular, bleeding disorders, both congenital and acquired, not only present problems both for delivery and in the immediate postpartum period, but also may have significant implications for the fetus and neonate. Women with congenital bleeding disorders or who are carriers of X-linked or autosomal disorders should be counseled prior to conception so that pregnancy can be safely undertaken with careful preparation. A treatment plan should be set up by a specialized care team that includes the hematologist, obstetrician, and anesthesiologist; the patient should be followed closely during pregnancy, through delivery, and in the immediate postpartum period. Acquired disorders of hemostasis that occur with pregnancy may present particular diagnostic difficulties and require rapid diagnosis and management.
Platelets in infectious disease
Authors: Middleton Elizabeth , Rondina Matthew T.
Published: December 2016

Sepsis is a dynamic, acute, infectious disease syndrome characterized by dysregulated thrombo-inflammatory responses. The high mortality associated with sepsis has been recognized since the earliest clinicians’ writings. Despite this, advances in the treatment of sepsis have been more modest. This is limited, in part, by the heterogeneity in the definition, population, presentation, and causal factors of infectious syndromes. Given the persistently high morbidity and mortality associated with sepsis, a better understanding of the dysregulated cellular biology underpinning sepsis is needed. Platelets are small, anucleate cells that have hemostatic, inflammatory, and immune-mediating properties. Platelets are the second most common circulating blood cell, and emerging evidence suggests that platelets serve as sentinel and effector cells during infectious syndromes. Nevertheless, the molecular and functional changes that occur in platelets during sepsis, and their impact on the clinical course of infected patients, remain incompletely understood. In this review, we first highlight the complex and dynamic pathophysiology characteristics of acute, systemic infections and we then discuss established and emerging evidence of the roles of platelets in sepsis.
Frontline strategy for follicular lymphoma: are we ready to abandon chemotherapy?
Authors: Fowler Nathan
Published: December 2016

Chemotherapy combinations have been the backbone of therapy for follicular lymphoma, and are associated with high initial response rates. Unfortunately, toxicity and secondary malignancies remain concerns, and most advanced-stage patients still relapse within 5 years, regardless of the regimen. Advances in the understanding of lymphoma biology have resulted in a new generation of noncytotoxic therapeutics with significant activity in follicular lymphoma. Recent studies exploring biological and targeted combinations in the frontline have shown promise, with response rates similar to chemotherapy. However, these regimens are also associated with significant cost as well as a unique toxicity profile. Large randomized studies are underway to compare noncytotoxic regimens with chemotherapy in the frontline, and several new combinations are being tested in the phase 2 setting. Ongoing work to identify predictive biomarkers and investment in mechanistic studies will ultimately lead to the personalization of therapy in the frontline setting for follicular lymphoma.
Diffuse large B-cell lymphoma: R-CHOP failure—what to do?
Authors: Coiffier Bertrand , Sarkozy Clémentine
Published: December 2016

Although rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the standard treatment for patients with diffuse large B-cell lymphoma (DLBCL), ∼30% to 50% of patients are not cured by this treatment, depending on disease stage or prognostic index. Among patients for whom R-CHOP therapy fails, 20% suffer from primary refractory disease (progress during or right after treatment) whereas 30% relapse after achieving complete remission (CR). Currently, there is no good definition enabling us to identify these 2 groups upon diagnosis. Most of the refractory patients exhibit double-hit lymphoma (MYC-BCL2 rearrangement) or double-protein-expression lymphoma (MYC-BCL2 hyperexpression) which have a more aggressive clinical picture. New strategies are currently being explored to obtain better CR rates and fewer relapses. Although young relapsing patients are treated with high-dose therapy followed by autologous transplant, there is an unmet need for better salvage regimens in this setting. To prevent relapse, maintenance therapy with immunomodulatory agents such as lenalidomide is currently undergoing investigation. New drugs will most likely be introduced over the next few years and will probably be different for relapsing and refractory patients.
Checkpoint inhibition and cellular immunotherapy in lymphoma
Authors: Lulla Premal , Heslop Helen E.
Published: December 2016

Hodgkin and non-Hodgkin lymphoma are both good targets for immunotherapy, as they are accessible to antibodies and cell-based immunotherapy, express costimulatory molecules, and express lineage-restricted, viral, and unique tumor antigens. Blockade of the programmed-death 1 (PD-1) immune checkpoint has produced very encouraging response rates in patients with Hodgkin lymphoma, whereas adoptive transfer of Epstein-Barr Virus (EBV)-specific T cells has shown clinical activity in patients with posttransplant lymphoma and other EBV-associated lymphomas. T cells can also be genetically modified with chimeric antigen receptors (CARs) to confer specificity for surface antigens, and studies of CD19 CARs in lymphoma also have had encouraging response rates. Future directions include combination of checkpoint blockade and adoptive T-cell studies.
The post-thrombotic syndrome
Authors: Kahn Susan R.
Published: December 2016

The post-thrombotic syndrome (PTS) is a frequent, sometimes disabling complication of deep vein thrombosis (DVT) that reduces quality of life and is costly. This article discusses risk factors for PTS after DVT and available means to prevent and treat PTS, with a focus on new information in the field. After DVT, PTS will develop in 20% to 50% of patients, and severe PTS, including venous ulcers, will develop in 5% to 10%. The principal risk factors for PTS are anatomically extensive DVT, recurrent ipsilateral DVT, persistent leg symptoms 1 month after acute DVT, obesity, and older age. By preventing the initial DVT and ipsilateral DVT recurrence, primary and secondary prophylaxes of DVT will prevent cases of PTS. Based on recent evidence from a large multicenter trial, routine use of elastic compression stockings (ECS) after DVT to prevent PTS is not advocated, but in patients with DVT-related leg swelling that is bothersome, a trial of ECS is reasonable. Selecting DVT patients for catheter-directed thrombolytic treatment as a means of preventing PTS should be done on a case-by-case basis, with a focus on patients with extensive thrombosis, recent symptoms onset, and low bleeding risk. For patients with established PTS, daily use of ECS may help to relieve symptoms and edema. Intermittent compression devices can be tried in patients with moderate-to-severe PTS whose symptoms are inadequately controlled with ECS alone. A supervised exercise training program may improve PTS symptoms. Management of post-thrombotic ulcers should ideally involve a multidisciplinary approach. Important areas for future research are summarized.
Understanding red blood cell alloimmunization triggers
Authors: Hendrickson Jeanne E. , Tormey Christopher A.
Published: December 2016

Blood group alloimmunization is “triggered” when a person lacking a particular antigen is exposed to this antigen during transfusion or pregnancy. Although exposure to an antigen is necessary for alloimmunization to occur, it is not alone sufficient. Blood group antigens are diverse in structure, function, and immunogenicity. In addition to red blood cells (RBCs), a recipient of an RBC transfusion is exposed to donor plasma, white blood cells, and platelets; the potential contribution of these elements to RBC alloimmunization remains unclear. Much attention in recent years has been placed on recipient factors that influence RBC alloantibody responses. Danger signals, identified in murine and human studies alike as being risk factors for alloimmunization, may be quite diverse in nature. In addition to exogenous or condition-associated inflammation, autoimmunity is also a risk factor for alloantibody formation. Triggers for alloimmunization in pregnancy are not well-understood beyond the presence of a fetal/maternal bleed. Studies using animal models of pregnancy-induced RBC alloimmunization may provide insight in this regard. A better understanding of alloimmunization triggers and signatures of “responders” and “nonresponders” is needed for prevention strategies to be optimized. A common goal of such strategies is increased transfusion safety and improved pregnancy outcomes.
Treatment options for patients with myelodysplastic syndromes after hypomethylating agent failure
Authors: Carraway Hetty E.
Published: December 2016

The treatment of patients with myelodysplastic syndromes (MDSs) has hinged primarily on supportive care (ie, blood transfusions, colony stimulating agents, iron chelation, etc.) and the US Food and Drug Administration-approved agents, including 5-azacytidine, deoxyazacytidine, and lenalidomide. For patients no longer benefitting from these agents, there is a paucity of effective therapies. The challenges at this time include our limited understanding of the mechanisms of resistance to these therapies and the variables employed to select next best therapies for patients based on: (1) their performance status and medical comorbidities; (2) the molecular feature(s) of their MDS; (3) the prior treatments they have received; and (4) the long-term goal(s)/possibilities for their future treatment (ie, transplant vs no transplant).
Transplantation for myelodysplastic syndromes: who, when, and which conditioning regimens
Authors: Saber Wael , Horowitz Mary M.
Published: December 2016

Allogeneic hematopoietic stem cell transplantation (HCT) is the only curative therapy for myelodysplastic syndrome (MDS). Broad application is hindered by high risks of transplant-related morbidity and mortality, especially in the older age range represented by the MDS population. However, recent advances in strategies to minimize regimen-related toxicity make HCT a viable option for many more patients. Appropriate selection of patients involves consideration of patient factors, including use of geriatric assessment tools and comorbidity scales, that predict risks of regimen-related toxicity as well as disease factors, including genetic markers, which predict survival with both non-HCT and HCT therapy. Optimal timing of HCT for fit patients must consider MDS risk scores and life-years to be gained, with earlier transplantation indicated for patients with intermediate-2 and high-risk disease but judicious delay for lower risk patients. Selection of suitable conditioning regimens must balance risks of toxicity with opportunity for maximum disease control.
Sequencing of nontransplant treatments in multiple myeloma patients with active disease
Authors: Yee Andrew J. , Raje Noopur S.
Published: December 2016

The approval of several different classes of drugs in recent years has resulted in a dramatic expansion of treatment options for multiple myeloma patients, improving both survival and quality of life. Lenalidomide and bortezomib are now core components of treatment both at time of diagnosis and at relapse. Next-generation immunomodulatory drugs, like pomalidomide, and newer proteasome inhibitors like carfilzomib and ixazomib are available for use at relapse. Drugs with novel mechanisms of action such as the histone deacetylase inhibitor panobinostat and the monoclonal antibodies targeting SLAMF7 (elotuzumab) and CD38 (daratumumab) are significant steps forward. Recent clinical trials describing novel combinations of these drugs have demonstrated unprecedented improvements in efficacy while maintaining tolerability. All of these options provide not only a challenge for choice of therapy, but also the opportunity to aim for increasing depth of response. This chapter will describe an approach on how to sequence and incorporate these therapies, focusing on patients where high-dose melphalan and autologous stem cell transplant are deferred or not applicable.
Advances and practical use of monoclonal antibodies in multiple myeloma therapy
Authors: Lee Hans C. , Weber Donna M.
Published: December 2016

The use of proteasome inhibitors and immunomodulatory agents in the treatment of myeloma have resulted in significant improvements in patient outcomes over the last decade. Although these agents now form the backbone of current myeloma treatment regimens both in the frontline and in a relapsed setting, drug resistance remains an inevitable challenge that most patients will encounter during their disease course. Hence, new treatment strategies continue to be explored, and the recent regulatory approvals of the monoclonal antibodies (mAbs) daratumumab (DARA) and elotuzumab (ELO), which target the plasma cell surface proteins CD38 and signaling lymphocytic activation molecule F7 (SLAMF7), respectively, have heralded the long-awaited era of antibody-based approaches in the treatment of myeloma. Hoping to build on these advances, a number of other mAbs are in various stages of clinical development, including those targeting myeloma cell surface antigens, the bone marrow microenvironment, and immune effector T cells such as anti-programmed cell death protein 1 antibodies. In this review, the current landscape and practical use of mAb-based therapy in myeloma will be discussed.
Single-dose intravenous iron for iron deficiency: a new paradigm
Authors: Auerbach Michael , Deloughery Thomas
Published: December 2016

Iron-deficiency anemia is the most common hematologic problem in the world. Although oral iron is often viewed as front-line therapy, extensive published evidence has accumulated that IV iron is superior, in both efficacy and safety, to oral iron in many clinical situations and should be introduced much sooner in the treatment paradigm of iron-deficient patients. In this chapter, we will review the formulations of IV iron that allow total complete replacement doses in 1 or 2 sessions including practical tips for administration. We realize safety concerns abound and therefore will analyze evidence based overstated concerns regarding serious adverse events highlighting unnecessary interventions for minor, self-limiting infusion reactions, which infrequently occur with intravenous iron administration. Recent data for the use of IV iron in a variety of clinic situations will be reviewed including women with heavy uterine bleeding, pregnancy, bariatric surgery, inflammatory bowel disease, and restless legs syndrome. Briefly discussed is the new frontier of IV iron’s use in the prevention of acute (high altitude) mountain sickness. It is clear that in many clinical situations IV iron is a new and improved standard of care offering advantages over oral iron in efficacy, toxicity, and convenience to patients and health care providers.
Treatment of older patients with acute lymphoblastic leukemia
Authors: Gökbuget Nicola
Published: December 2016

The treatment of older patients with acute lymphoblastic leukemia (ALL) is an unmet medical need. With increasing age, ALL patients have a significantly lower clinical remission rate, higher early mortality, higher relapse rate, and poorer survival compared with younger patients. This is only partly explained by a higher incidence of poor prognostic factors in the older age group. Most importantly, intensive chemotherapy with or without stem cell transplantation (SCT) is less well tolerated in older patients. Some progress has been made with delivering age-adapted, moderately intensive chemotherapy protocols for Ph/BCR–ABL-negative ALL and combinations of tyrosine kinase inhibitors with chemotherapy in Ph/BCR–ABL-positive ALL. For the future, optimizing supportive care, introducing targeted therapies, novel immunotherapies, moderately intensified consolidation strategies, and reduced intensity SCT are promising approaches. Prospective clinical trials for older patients are urgently needed to test these approaches.
Hemophilia and inhibitors: current treatment options and potential new therapeutic approaches
Authors: Meeks Shannon L. , Batsuli Glaivy
Published: December 2016

The immune response to infused factor concentrates remains a major source of morbidity and mortality in the treatment of patients with hemophilia A and B. This review focuses on current treatment options and novel therapies currently in clinical trials. After a brief review of immune tolerance regimens, the focus of the discussion is on preventing bleeding in patients with hemophilia and inhibitors. Recombinant factor VIIa and activated prothrombin complex concentrates are the mainstays in treating bleeds in patients with inhibitors. Both agents have been shown to reduce bleeding episodes to a similar degree when infused prophylactically; however, individual patients may respond better to one agent over the other at any given time. The international immune tolerance trial revealed that a high-dose factor VIII regimen provided significantly better bleeding protection than the low-dose regimen. Given the high cost of treatment and the potential for a high-dose immune tolerance regimen to prevent bleeding in some patients, we discuss how we treat patients to maximize the prevention of bleeds while minimizing cost. Novel approaches to treatment of these patients are in development. These include agents that mimic factor VIII or augment thrombin generation by bypassing the inhibitor, as well as agents that inhibit the natural anticoagulants.
Treatment of rare factor deficiencies in 2016
Authors: Peyvandi Flora , Menegatti Marzia
Published: December 2016

Rare bleeding disorders (RBDs) are a heterogeneous group of coagulation disorders characterized by fibrinogen, prothrombin, factors V, VII, X, XI, or XIII (FV, FVII, FX, FXI, or FXIII, respectively), and the combined factor V + VIII and vitamin K–dependent proteins deficiencies, representing roughly 5% of all bleeding disorders. They are usually transmitted as autosomal, recessive disorders, and the prevalence of the severe forms could range from 1 case in 500 000 for FVII up to 1 in 2-3 million for FXIII in the general population. Patients affected with RBDs may present a wide range of clinical symptoms, varying from mucocutaneous bleeding, common to all types of RBDs to the most life-threatening symptoms such as central nervous system and gastrointestinal bleeding. Treatment of these disorders is mainly based on the replacement of the deficient factor, using specific plasma-derived or recombinant products. In countries where these facilities are not available, bleedings could be managed using cryoprecipitate, fresh frozen plasma (FFP), or virus-inactivated plasma. Minor bleedings could be managed using antifibrinolytic agents. Recently, 2 novel drugs, recombinant FXIIIA and a plasma-derived FX, have been added to the list of available specific hemostatic factors; only prothrombin and FV deficiencies still remain without a specific product. Novel no-replacement therapies, such as monoclonal antibody anti–tissue factor pathway inhibitor, RNA interference, and a bispecific antibody that is an FVIIIa mimetic, enhancing thrombin generation through different mechanisms, were developed for patients with hemophilia and may in the future be a good therapeutic option also in RBDs.
Diagnosing von Willebrand disease: genetic analysis
Authors: Goodeve Anne
Published: December 2016

Investigation of a patient with possible von Willebrand disease (VWD) includes a range of phenotypic analyses. Often, this is sufficient to discern disease type, and this will suggest relevant treatment. However, for some patients, phenotypic analysis does not sufficiently explain the patient’s disorder, and for this group, genetic analysis can aid diagnosis of disease type. Polymerase chain reaction and Sanger sequencing have been mainstays of genetic analysis for several years. More recently, next-generation sequencing has become available, with the advantage that several genes can be simultaneously analyzed where necessary, eg, for discrimination of possible type 2N VWD or mild hemophilia A. Additionally, several techniques can now identify deletions/duplications of an exon or more that result in VWD including multiplex ligation-dependent probe amplification and microarray analysis. Algorithms based on next-generation sequencing data can also identify missing or duplicated regions. These newer techniques enable causative von Willebrand factor defects to be identified in more patients than previously, aiding in a specific VWD diagnosis. Genetic analysis can also be helpful in the discrimination between type 2B and platelet-type VWD and in prenatal diagnosis for families with type 3.
Teaching about Water Relations in Plant Cells: An Uneasy Struggle
Authors: Malińska Lilianna , Rybska Eliza , Sobieszczuk-Nowicka Ewa , Adamiec Małgorzata
Published: December 2016

University students often struggle to understand the role of water in plant cells. In particular, osmosis and plasmolysis appear to be challenging topics. This study attempted to identify student difficulties (including misconceptions) concerning osmosis and plasmolysis and examined to what extent the difficulties could be revised during a plant physiology course. A questionnaire was developed to monitor university students’ conceptual knowledge before and after a course, and both qualitative and quantitative data were obtained. The data were analyzed using the constant comparison technique and descriptive statistics. Students were found to come to university with many misconceptions that had accumulated during their education. These misconceptions are extremely difficult to change during the traditional course, which comprises lectures and practical exercises. Students’ misconceptions originate from commonly used sources such as textbooks, which are perceived as being reliable. Effective teaching of water relations in plant cells could include such didactic methods as “questioning the author,” which allow teachers to monitor students’ knowledge and help students acquire a more scientific understanding of key concepts.
Early Environmental Field Research Career Exploration: An Analysis of Impacts on Precollege Apprentices
Authors: Flowers Susan K. , Beyer Katherine M. , Pérez Maria , Jeffe Donna B.
Published: December 2016

Research apprenticeships offer opportunities for deep understanding of scientific practice, transparency about research careers, and possible transformational effects on precollege youth. We examined two consecutive field-based environmental biology apprenticeship programs designed to deliver realistic career exploration and connections to research scientists. The Shaw Institute for Field Training (SIFT) program combines introductory field-skills training with research assistance opportunities, and the subsequent Tyson Environmental Research Fellowships (TERF) program provides immersive internships on university field station–based research teams. In a longitudinal mixed-methods study grounded in social cognitive career theory, changes in youth perspectives were measured during program progression from 10th grade through college, evaluating the efficacy of encouraging career path entry. Results indicate SIFT provided self-knowledge and career perspectives more aligned with reality. During SIFT, differences were found between SIFT-only participants compared with those who progressed to TERF. Transition from educational activities to fieldwork with scientists was a pivotal moment at which data showed decreased or increased interest and confidence. Continuation to TERF provided deeper relationships with role models who gave essential early-career support. Our study indicates the two-stage apprenticeship structure influenced persistence in pursuit of an environmental research career pathway. Recommendations for other precollege environmental career–exploration programs are presented.
Step by Step: Biology Undergraduates’ Problem-Solving Procedures during Multiple-Choice Assessment
Authors: Prevost Luanna B. , Lemons Paula P.
Published: December 2016

This study uses the theoretical framework of domain-specific problem solving to explore the procedures students use to solve multiple-choice problems about biology concepts. We designed several multiple-choice problems and administered them on four exams. We trained students to produce written descriptions of how they solved the problem, and this allowed us to systematically investigate their problem-solving procedures. We identified a range of procedures and organized them as domain general, domain specific, or hybrid. We also identified domain-general and domain-specific errors made by students during problem solving. We found that students use domain-general and hybrid procedures more frequently when solving lower-order problems than higher-order problems, while they use domain-specific procedures more frequently when solving higher-order problems. Additionally, the more domain-specific procedures students used, the higher the likelihood that they would answer the problem correctly, up to five procedures. However, if students used just one domain-general procedure, they were as likely to answer the problem correctly as if they had used two to five domain-general procedures. Our findings provide a categorization scheme and framework for additional research on biology problem solving and suggest several important implications for researchers and instructors.
Collaborative Learning in Higher Education: Evoking Positive Interdependence
Authors: Scager Karin , Boonstra Johannes , Peeters Ton , Vulperhorst Jonne , Wiegant Fred
Published: December 2016

Collaborative learning is a widely used instructional method, but the learning potential of this instructional method is often underused in practice. Therefore, the importance of various factors underlying effective collaborative learning should be determined. In the current study, five different life sciences undergraduate courses with successful collaborative-learning results were selected. This study focuses on factors that increased the effectiveness of collaboration in these courses, according to the students. Nine focus group interviews were conducted and analyzed. Results show that factors evoking effective collaboration were student autonomy and self-regulatory behavior, combined with a challenging, open, and complex group task that required the students to create something new and original. The design factors of these courses fostered a sense of responsibility and of shared ownership of both the collaborative process and the end product of the group assignment. In addition, students reported the absence of any free riders in these group assignments. Interestingly, it was observed that students seemed to value their sense of achievement, their learning processes, and the products they were working on more than their grades. It is concluded that collaborative learning in higher education should be designed using challenging and relevant tasks that build shared ownership with students.
CD4 downregulation by the HIV-1 protein Nef reveals distinct roles for the γ1 and γ2 subunits of the AP-1 complex in protein trafficking
Authors: Tavares Lucas A. , da Silva Eulália M. L. , da Silva-Januário Mara E. , Januário Yunan C. , de Cavalho Julianne V. , Czernisz Érika S. , Mardones Gonzalo A. , daSilva Luis L. P.
Published: December 2016

The HIV accessory protein Nef is a major determinant of viral pathogenesis that facilitates viral particle release, prevents viral antigen presentation and increases infectivity of new virus particles. These functions of Nef involve its ability to remove specific host proteins from the surface of infected cells, including the CD4 receptor. Nef binds to the adaptor protein 2 (AP-2) and CD4 in clathrin-coated pits, forcing CD4 internalization and its subsequent targeting to lysosomes. Herein, we report that this lysosomal targeting requires a variant of AP-1 containing isoform 2 of γ-adaptin (AP1G2, hereafter γ2). Depletion of the γ2 or μ1A (AP1M1) subunits of AP-1, but not of γ1 (AP1G1), precludes Nef-mediated lysosomal degradation of CD4. In γ2-depleted cells, CD4 internalized by Nef accumulates in early endosomes and this alleviates CD4 removal from the cell surface. Depletion of γ2 also hinders EGFR–EGF-complex targeting to lysosomes, an effect that is not observed upon γ1 depletion. Taken together, our data provide evidence that the presence of γ1 or γ2 subunits delineates two distinct variants of AP-1 complexes, with different functions in protein sorting.
Integration of transmembrane domains is regulated by their downstream sequences
Authors: Junne Tina , Spiess Martin
Published: December 2016

The Sec61 translocon catalyzes translocation of proteins into the endoplasmic reticulum and the lateral integration of transmembrane segments into the lipid bilayer. Integration is mediated by the hydrophobicity of a polypeptide segment consistent with thermodynamic equilibration between the translocon and the lipid membrane. Integration efficiency of a generic series of increasingly hydrophobic sequences (H-segments) was found to diverge significantly in different reporter constructs as a function of the ∼100 residues that are C-terminal to the H-segments. The hydrophobicity threshold of integration was considerably lowered through insertion of generic ∼20-residue peptides either made of flexible glycine–serine repeats, containing multiple negative charges, or consisting of an oligoproline stretch. A highly flexible, 100-residue glycine–serine stretch maximally enhanced this effect. The apparent free energy of integration was found to be changed by more than 3 kcal/mol with the downstream sequences tested. The C-terminal sequences could also be shown to affect integration of natural mildly hydrophobic sequences. The results suggest that the conformation of the nascent polypeptide in the protected cavity between the ribosome and translocon considerably influences the release of the H-segment into the bilayer.
Mortalin-mediated and ERK-controlled targeting of HIF-1α to mitochondria confers resistance to apoptosis under hypoxia
Authors: Mylonis Ilias , Kourti Maria , Samiotaki Martina , Panayotou George , Simos George
Published: December 2016

Hypoxia inducible factor-1 (HIF-1) is the main transcriptional activator of the cellular response to hypoxia and an important target of anticancer therapy. Phosphorylation by ERK1 and/or ERK2 (MAPK3 and MAPK1, respectively; hereafter ERK) stimulates the transcriptional activity of HIF-1α by inhibiting its CRM1 (XPO1)-dependent nuclear export. Here, we demonstrate that phosphorylation by ERK also regulates the association of HIF-1α with a so-far-unknown interaction partner identified as mortalin (also known as GRP75 and HSPA9), which mediates non-genomic involvement of HIF-1α in apoptosis. Mortalin binds specifically to HIF-1α that lacks modification by ERK, and the HIF-1α–mortalin complex is localized outside the nucleus. Under hypoxia, mortalin mediates targeting of unmodified HIF-1α to the outer mitochondrial membrane, as well as association with VDAC1 and hexokinase II, which promotes production of a C-terminally truncated active form of VDAC1, denoted VDAC1-ΔC, and protection from apoptosis when ERK is inactivated. Under normoxia, transcriptionally inactive forms of unmodified HIF-1α or its C-terminal domain alone are also targeted to mitochondria, stimulate production of VDAC1-ΔC and increase resistance to etoposide- or doxorubicin-induced apoptosis. These findings reveal an ERK-controlled, unconventional and anti-apoptotic function of HIF-1α that might serve as an early protective mechanism upon oxygen limitation and promote cancer cell resistance to chemotherapy.
Heterochromatin aggregation during DNA elimination in Tetrahymena is facilitated by a prion-like protein
Authors: Kataoka Kensuke , Mochizuki Kazufumi
Published: December 2016

Regulated aggregations of prion and prion-like proteins play physiological roles in various biological processes. However, their structural roles in the nucleus are poorly understood. Here, we show that the prion-like protein Jub6p is involved in the regulation of chromatin structure in the ciliated protozoan Tetrahymena thermophila. Jub6p forms sodium dodecyl sulfate (SDS)-resistant aggregates when it is ectopically expressed in vegetative cells and binds to RNA in vitro. Jub6p is a heterochromatin component and is important for the formation of heterochromatin bodies during the process of programmed DNA elimination. We suggest that RNA–protein aggregates formed by Jub6p are an essential architectural component for the assembly of heterochromatin bodies.
Beneficial effects of rapamycin in a Drosophila model for hereditary spastic paraplegia
Authors: Xu Shiyu , Stern Michael , McNew James A.
Published: December 2016

The locomotor deficits in the group of diseases referred to as hereditary spastic paraplegia (HSP) reflect degeneration of upper motor neurons, but the mechanisms underlying this neurodegeneration are unknown. We established a Drosophila model for HSP, atlastin (atl), which encodes an ER fusion protein. Here, we show that neuronal atl loss causes degeneration of specific thoracic muscles that is preceded by other pathologies, including accumulation of aggregates containing polyubiquitin, increased generation of reactive oxygen species and activation of the JNK–Foxo stress response pathway. We show that inhibiting the Tor kinase, either genetically or by administering rapamycin, at least partially reversed many of these pathologies. atl loss from muscle also triggered muscle degeneration and rapamycin-sensitive locomotor deficits, as well as polyubiquitin aggregate accumulation. These results indicate that atl loss triggers muscle degeneration both cell autonomously and nonautonomously.
3D culture models of tissues under tension
Authors: Eyckmans Jeroen , Chen Christopher S.
Published: December 2016

Cells dynamically assemble and organize into complex tissues during development, and the resulting three-dimensional (3D) arrangement of cells and their surrounding extracellular matrix in turn feeds back to regulate cell and tissue function. Recent advances in engineered cultures of cells to model 3D tissues or organoids have begun to capture this dynamic reciprocity between form and function. Here, we describe the underlying principles that have advanced the field, focusing in particular on recent progress in using mechanical constraints to recapitulate the structure and function of musculoskeletal tissues.
Physostomous channel catfish, Ictalurus punctatus, modify swimming mode and buoyancy based on flow conditions
Authors: Yoshida Makoto A. , Yamamoto Daisuke , Sato Katsufumi
Published: December 2016

The employment of gliding in aquatic animals as a means of conserving energy has been theoretically predicted and discussed for decades. Several studies have shown that some species glide, whereas others do not. Freshwater fish species that widely inhabit both lentic and lotic environments are thought to be able to adapt to fluctuating flow conditions in terms of locomotion. In adapting to the different functional demands of lentic and lotic environments on fish energetics, physostomous (open swim bladder) fish may optimise their locomotion and activity by controlling their net buoyancy; few buoyancy studies have however been conducted on physostomous fish in the wild. We deployed accelerometers on free-ranging channel catfish, Ictalurus punctatus, in both lentic and lotic environments, to quantify their swimming activity, and to determine their buoyancy condition preferences, and whether gliding conserves energy. Individual comparisons of swimming efforts between ascent and descent phases revealed that all fish in the lentic environment had negative buoyancy. However, all individuals showed many descents without gliding phases, which was contrary to the behaviour predicted to minimise the cost of transport. The fact that significantly fewer gliding phases were observed in the lotic environment, together with the existence of neutrally buoyant fish, indicated that channel catfish seem to optimise their locomotion through buoyancy control based on flow conditions. The buoyancy optimisation of channel catfish relative to the flow conditions that they inhabit not only reflects differences in swimming behaviour but also provides new insights into the adaptation of physostome fish species to various freshwater environments.
On translation surfaces in 4-dimensional Euclidean space
Authors: Arslan Kadri , Bayram Bengü , Bulca Betül , Öztürk Günay
Published: December 2016

We consider translation surfaces in Euclidean spaces. Firstly, we give some results of translation surfaces in the 3-dimensional Euclidean space E3. Further, we consider translation surfaces in the 4-dimensional Euclidean space E4. We prove that a translation surface is flat in E4 if and only if it is either a hyperplane or a hypercylinder. Finally we give necessary and sufficient condition for a quadratic triangular Bézier surface in E4 to become a translation surface.
Discourse genres as determiners of discursive regularities: A case of semiotic predictability?
Authors: Gaspard Jeoffrey
Published: December 2016

This article focuses on discursive regularities that can generally be observed in text corpora produced in similar communication situations (medical interviews, political debates, teaching classes, etc.). One type of such regularities is related to the so-called ‘discourse genres’, considered as a set of tacit instructions broadly constraining the forms of utterances in a given discursive practice. Those regularities highlight the relatively regulated, non-random nature of most of our discursive practices and epitomize the necessary constrained creativity of meaning making in discourse. In this perspective, we suggest that the concepts of Thirdness and Habit, as theorized by Charles S. Peirce, can be fruitful in describing the role and importance of such regularities in our sociodiscursive life. More specifically, we believe that discourse regularities are ideal case studies if one wishes to investigate instances of predictability in semiotic (discursive) processes. Overall, we suggest that their study can be one of many research orientations through which a prediction-based scientific conception of semiotics could be applied.
Juri Lotman in Arabic: A bibliography
Authors: Elkouch Hassib
Published: December 2016

Juri Lotman in Arabic: A bibliography