bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sculpting tumor microenvironment with immune system: from immunometabolism to immunoediting
Authors: Yu Y-R , Ho P-C 
Published: March 2019

Summary
Cancer immunotherapy unleashing the power of host immunity on eliminating cancer cells represents a critical advance in cancer treatment; however, effective anti-tumor responses are largely dampened by the immunosuppressive tumor microenvironment (TME). Emerging studies have revealed that physiological features in the TME, including glucose deprivation, hypoxia and low pH, established by the metabolically dysregulated cancer cells restrict anti-tumor immunity by impeding the metabolic fitness of tumor-infiltrating cytotoxic CD8+ T cells and natural killer (NK) cells. Furthermore, infiltrating immunomodulatory cells with different metabolic preferences also facilitate the establishment of the immunosuppressive TME. Therefore, deciphering the metabolic cross-talk between immune cells and cancer cells in the TME and elucidating the impact of this process during tumorigenesis are needed to harness anti-tumor immunity more effectively. Herein, we summarize the immunosuppressive features of TME and how these features impair anti-tumor immunity. Moreover, we postulate how immune cells may be involved in shaping the metabolic features of cancer cells and discuss how we might improve the anti-tumor functions of tumor-specific T cells by rewiring their metabolic regulations.
Management of dupilumab‐associated conjunctivitis in atopic dermatitis
Authors: Aszodi Nora , Thurau Stephan , Seegräber Marlene , de Bruin‐Weller Marjolein , Wollenberg Andreas 
Published: March 2019

SummarySince September 2017, the monoclonal antibody dupilumab (Dupixent®) has been approved in the EU for the treatment of moderate‐to‐severe atopic dermatitis. By blocking IL‐4 and IL‐13 signaling pathways, dupilumab improves both objective signs and subjective symptoms of the disease. Blocking of the IL‐4aRα subunit leads to improvement of the skin's barrier function and reduction in Th2‐mediated inflammation. While the rate of adverse events on dupilumab is generally low, mild‐to‐moderate conjunctivitis associated with redness as well as a burning and foreign body sensation has been reported in up to 28 % of patients. Treatment options include topical corticosteroids and topical calcineurin inhibitors. The present review highlights the clinical presentation of dupilumab‐associated conjunctivitis and addresses pharmacological and non‐pharmacological options available for the treatment of this clinically highly relevant condition.
Zinc and skin: an update
Authors: Glutsch Valerie , Hamm Henning , Goebeler Matthias 
Published: March 2019

SummaryThe essential trace element zinc (Zn) plays a key role in the development, differentiation and growth of various human tissues. Zinc homeostasis is primarily regulated by two zinc transporter families (solute‐linked carrier families, SLC). Disturbances in zinc metabolism may give rise to disorders that typically manifest themselves on the skin. An autosomal recessive zinc deficiency disorder, acrodermatitis enteropathica is caused by a mutation in the gene coding for the ZIP4 transporter. Due to intestinal malabsorption, affected infants develop clinical signs and symptoms shortly after weaning. Acquired zinc deficiency is a rare but underdiagnosed disorder associated with various etiologies and variable clinical manifestations. Depending on the patient's age, a multitude of causes have to be considered. Given the characteristic periorificial and acral lesions, the clinical diagnosis is usually made by dermatologists. Laboratory confirmation includes measurement of plasma zinc levels and – as a supplementary measure – zinc‐dependent enzymes such as alkaline phosphatase. Oral zinc replacement therapy frequently leads to clinical remission within a few days. Depending on the cause, disease management should include cooperation with pediatricians and gastroenterologists in order to guarantee optimal patient care.
A balance of winners and losers in the Anthropocene
Authors: Dornelas Maria , Gotelli Nicholas J. , Shimadzu Hideyasu , Moyes Faye , Magurran Anne E. , McGill Brian J. 
Published: March 2019

AbstractScientists disagree about the nature of biodiversity change. While there is evidence for widespread declines from population surveys, assemblage surveys reveal a mix of declines and increases. These conflicting conclusions may be caused by the use of different metrics: assemblage metrics may average out drastic changes in individual populations. Alternatively, differences may arise from data sources: populations monitored individually, versus whole‐assemblage monitoring. To test these hypotheses, we estimated population change metrics using assemblage data. For a set of 23 241 populations, 16 009 species, in 158 assemblages, we detected significantly accelerating extinction and colonisation rates, with both rates being approximately balanced. Most populations (85%) did not show significant trends in abundance, and those that did were balanced between winners (8%) and losers (7%). Thus, population metrics estimated with assemblage data are commensurate with assemblage metrics and reveal sustained and increasing species turnover.
Reduced exposure to darunavir and cobicistat in HIV‐1‐infected pregnant women receiving a darunavir/cobicistat‐based regimen
Authors: Crauwels HM , Osiyemi O , Zorrilla C , Bicer C , Brown K 
Published: March 2019

ObjectivesThe aim of the study was to evaluate darunavir and cobicistat pharmacokinetics in pregnant women with HIV‐1 infection.MethodsThis phase 3b, open‐label study enrolled HIV‐1‐infected pregnant women (18–26 weeks of gestation) receiving combination antiretroviral therapy with once‐daily darunavir/cobicistat 800/150 mg. The plasma pharmacokinetics of darunavir (total and unbound) and cobicistat were assessed over 24 h during the second and third trimesters (24–28 and 34–38 weeks of gestation, respectively) and 6–12 weeks postpartum. Pharmacokinetic parameters [area under the plasma concentration–time curve over 24 h (AUC24 h), maximum plasma concentration (Cmax) and minimum plasma concentration (Cmin)] were derived using noncompartmental analysis and compared using linear mixed effects modelling (pregnancy versus postpartum). Antiviral activity and safety were evaluated.ResultsSeven women were enrolled in the study; six completed it. Total darunavir exposure was lower during pregnancy than postpartum (AUC24 h, 50–56% lower; Cmax, 37–49% lower; Cmin, 89–92% lower); unbound darunavir exposure was also reduced (AUC24 h, 40–45% lower; Cmax, 32–41% lower; Cmin, 88–92% lower). Cobicistat exposure was also lower during pregnancy than postpartum (AUC24 h, 49–63% lower; Cmax, 27–50% lower; Cmin, 83% lower). At study completion, five of six (83%) women were virologically suppressed (HIV‐1 RNA < 50 copies/mL). There was one virological failure (the patient was nonadherent; no emerging genotypic resistance was observed and susceptibility to antiretrovirals was maintained). No mother‐to‐child transmission was detected among six infants born to the six women who completed the study. Overall, darunavir/cobicistat was well tolerated in women and infants.ConclusionsIn view of markedly reduced darunavir and cobicistat exposures during pregnancy, this combination is not recommended in HIV‐1‐infected pregnant women.
Germinal center B cell initiation, GC maturation, and the coevolution of its stromal cell niches
Authors: Haberman Ann M. , Gonzalez David G. , Wong Patrick , Zhang Ting‐ting , Kerfoot Steven M. 
Published: March 2019

SummaryThroughout the developing GC response, B cell survival and fate choices made at the single cell level are dependent on signals received largely through interactions with other cells, often with cognate T cells. The type of signals that a given B cell can encounter is dictated by its location within tissue microarchitecture. The focus of this review is on the initiation and evolution of the GC response at the earliest time points. Here, we review the key factors influencing the progression of GC B cell differentiation that are both stage and context dependent. Finally, we describe the coevolution of niches within and surrounding the GC that influence the outcome of the GC response.
T‐bet+ memory B cells: Generation, function, and fate
Authors: Knox James J. , Myles Arpita , Cancro Michael P. 
Published: March 2019

SummaryB cells expressing the transcription factor T‐bet have emerged as participants in a number of protective and pathogenic immune responses. T‐bet+ B cells characteristically differentiate in response to combined Toll‐like receptor and cytokine signaling, contribute to protective immunity against intracellular pathogens via IgG2a/c production and antibody‐independent mechanisms, and are prone to produce autoantibodies. Despite recent advances, a number of questions remain regarding the basic biology of T‐bet+ B cells and their functional niche within the immune system. Herein, we review the discovery and defining characteristics of the T‐bet+ B cell subset in both mice and humans. We further discuss their origins, the basis for their persistence, and their potential fate in vivo. Evidence indicates that T‐bet+ B cells represent a distinct, germinal center‐derived memory population that may serve as an important therapeutic target for the improvement of humoral immunity and prevention of autoimmunity.
T cell interactions with B cells during germinal center formation, a three‐step model
Authors: Biram Adi , Davidzohn Natalia , Shulman Ziv 
Published: March 2019

SummaryEstablishment of effective immunity against invading microbes depends on continuous generation of antibodies that facilitate pathogen clearance. Long‐lived plasma cells with the capacity to produce high affinity antibodies evolve in germinal centers (GCs), where B cells undergo somatic hypermutation and are subjected to affinity‐based selection. Here, we focus on the cellular interactions that take place early in the antibody immune response during GC colonization. Clones bearing B‐cell receptors with different affinities and specificities compete for entry to the GC, at the boundary between the B‐cell and T‐cell zones in lymphoid organs. During this process, B cells compete for interactions with T follicular helper cells, which provide selection signals required for differentiation into GC cells and antibody secreting cells. These cellular engagements are long‐lasting and depend on activation of adhesion molecules that support persistent interactions and promote transmission of signals between the cells. Here, we discuss how interactions between cognate T and B cells are primarily maintained by three types of molecular interactions: homophilic signaling lymphocytic activation molecule (SLAM) interactions, T‐cell receptor: peptide‐loaded major histocompatibility class II (pMHCII), and LFA‐1:ICAMs. These essential components support a three‐step process that controls clonal selection for entry into the antibody affinity maturation response in the GC, and establishment of long‐lasting antibody‐mediated immunity.
The B‐cell receptor in control of tumor B‐cell fitness: Biology and clinical relevance
Authors: Casola Stefano , Perucho Laura , Tripodo Claudio , Sindaco Paola , Ponzoni Maurilio , Facchetti Fabio 
Published: March 2019

SummarySurface expression of a functional B cell antigen receptor (BCR) is essential for the survival and proliferation of mature B cells. Most types of B‐cell lymphoproliferative disorders retain surface BCR expression, including B‐cell non‐Hodgkin lymphomas (B‐NHL) and chronic lymphocytic leukemia (CLL). Targeting BCR effectors in B‐NHL cell lines in vitro has indicated that this signaling axis is crucial for malignant B cell growth. This has led to the development of inhibitors of BCR signaling, which are currently used for the treatment of CLL and several B‐NHL subtypes. Recent studies based on conditional BCR inactivation in a MYC‐driven mouse B‐cell lymphoma model have revisited the role of the BCR in MYC‐expressing tumor B cells. Indeed, lymphoma cells losing BCR expression continue to grow unless subjected to competition with their BCR‐expressing counterparts, which causes their elimination. Here, we discuss the molecular nature of the fitness signal delivered by the BCR to MYC‐expressing malignant B cells, ensuring their preferential persistence within a rapidly expanding tumor population. We also review growing evidence of Ig‐negative cases belonging to several B‐NHL subtypes and CLL, and discuss the clinical implications of these findings in relation to an emerging picture of clinical resistances to anti‐BCR therapies.
T follicular regulatory (Tfr) cells: Dissecting the complexity of Tfr‐cell compartments
Authors: Fonseca Válter R. , Ribeiro Filipa , Graca Luis 
Published: March 2019

SummaryGerminal centers (GC) have been known as key anatomic structures in humoral immunity, where isotype switching and affinity maturation occur. As a consequence, elucidation of GC regulation has potential implications for the understanding of autoantibody‐mediated diseases. It is now accepted that different regulatory mechanisms coexist, including the action of a specialized population of Foxp3+ regulatory T cells with unique access to the B‐cell follicle: the T follicular regulatory (Tfr) cells. Tfr cells develop through a multistep process requiring migration through different compartments of lymphoid tissues. This review discusses the ontogeny and physiology of Tfr cells, their distribution within distinct anatomic compartments, and their function. A greater understanding of Tfr biology and GC regulation is likely to lead to better stratification of patients with autoantibody‐mediated diseases, and to the identification of novel therapeutic targets.
Extrafollicular responses in humans and SLE
Authors: Jenks Scott A. , Cashman Kevin S. , Woodruff Matthew C. , Lee F. Eun‐Hyung , Sanz Ignacio 
Published: March 2019

SummaryChronic autoimmune diseases, and in particular Systemic Lupus Erythematosus (SLE), are endowed with a long‐standing autoreactive B‐cell compartment that is presumed to reactivate periodically leading to the generation of new bursts of pathogenic antibody‐secreting cells (ASC). Moreover, pathogenic autoantibodies are typically characterized by a high load of somatic hypermutation and in some cases are highly stable even in the context of prolonged B‐cell depletion. Long‐lived, highly mutated antibodies are typically generated through T‐cell–dependent germinal center (GC) reactions. Accordingly, an important role for GC reactions in the generation of pathogenic autoreactivity has been postulated in SLE. Nevertheless, pathogenic autoantibodies and autoimmune disease can be generated through B‐cell extrafollicular (EF) reactions in multiple mouse models and human SLE flares are characterized by the expansion of naive‐derived activated effector B cells of extrafollicular phenotype. In this review, we will discuss the properties of the EF B‐cell pathway, its relationship to other effector B‐cell populations, its role in autoimmune diseases, and its contribution to human SLE. Furthermore, we discuss the relationship of EF B cells with Age‐Associated B cells (ABCs), a TLR‐7‐driven B‐cell population that mediates murine autoimmune and antiviral responses.
TFH cells in bystander and cognate interactions with B cells
Authors: Wan Zurong , Lin Yihan , Zhao Yongshan , Qi Hai 
Published: March 2019

SummaryFollicular T‐helper (TFH) cells play a crucial role in three aspects of the germinal center (GC) response. They promote GC formation, arbitrate competition among GC B cells to determine the outcome of affinity maturation, and regulate GC output of memory and plasma cells to shape the long‐lived humoral immune memory. Of fundamental importance are dynamic physical interactions between TFH and B cells, which are the main platform for TFH cells to deliver “help” factors to B cells and also for reciprocal signaling from B cells to maintain the helper state of TFH cells. Recent work has significantly expanded our understanding of how T‐B interactions are spatiotemporally regulated and molecularly orchestrated to fulfill those TFH functions. In this review, we elaborate two modes of T‐B interactions, the antigen‐specific or cognate mode in which TFH cells engage individual antigen‐presenting B cells and the antigen nonspecific bystander mode in which TFH cells are engaged with the ensemble of follicular B cells. We discuss findings that indicate how short‐lived cognate T‐B contacts coupled with an intercellular positive feedback drive affinity‐based selection and how bystander interactions between T and B cells regulate follicular T‐cell recruitment and maintenance of an appropriate helper state. We argue that this combination of bystander and cognate interactions with B cells constantly shapes the internal state of TFH cells and provides the platform to execute their helper functions.
Plasma cell differentiation during the germinal center reaction
Authors: Ise Wataru , Kurosaki Tomohiro 
Published: March 2019

SummaryGerminal centers (GCs) are formed in secondary lymphoid tissues upon immunization with T‐dependent antigens. In GCs, somatic hypermutation generates B cells with increased antibody affinity and these high‐affinity B cells preferentially differentiate into plasma cells, which home to bone marrow and confer long‐lived humoral immunity. Recent studies have shed new light on the cellular and molecular basis for initiating the transition from a GC B cell to a plasma cell. Here, we review recent progress in our understanding of how plasma cell generation during the GC reaction is regulated for inducing effective long‐term protective immunity and for preventing harmful autoimmunity.
The continuing story of T‐cell independent antibodies
Authors: Allman David , Wilmore Joel R. , Gaudette Brian T. 
Published: March 2019

SummaryThe purpose of this article is to review the role of extrafollicular and T‐cell independent antibody responses in humoral immunity. We consider two interrelated questions: (a) do T‐cell independent antibody responses dominated by IgM and/or IgA play unique functions in immunity and homeostasis; and (b) is it typical for these responses to result in lifelong protection? In addressing these questions, we consider the established advantages of T‐cell driven responses including the unique role played by germinal center reactions in these responses, and contrast the processes and outcomes of germinal center‐centric responses with germinal center‐ and T‐cell independent antibodies. We suggest that T‐independent and other extrafollicular responses contribute substantially to highly stable antibody repertoires in both the serum and the intestine, providing relatively constitutive humoral barriers with the collective dual function of protecting against invading pathogens and regulating the composition of non‐pathogenic microbial communities.
Immunity induced by recombinant attenuated IHNV (infectious hematopoietic necrosis virus)‐GN438A expresses VP2 gene‐encoded IPNV (infectious pancreatic necrosis virus) against both pathogens in rainbow trout
Authors: Chen Yaping , Guo Mengting , Wang Yanxue , Hua Xiaojing , Gao Shuai , Wang Yuting , Li Dechuan , Shi Wen , Tang Lijie , Li Yijing , Liu Min 
Published: March 2019

AbstractInfectious hematopoietic necrosis virus (IHNV) and infectious pancreatic necrosis virus (IPNV) are important pathogens in rainbow trout farming worldwide. Their co‐infection is also common, which causes great economic loss in juvenile salmon species. Development of a universal virus vaccine providing broadly cross‐protective immunity will be of great importance. In this study, we generated two recombinant (r) virus (rIHNV‐N438A‐ΔNV‐EGFP and rIHNV‐N438A‐ΔNV‐VP2) replacing the NV gene of the backbone of rIHNV at the single point mutation at residue 438 with an efficient green fluorescent protein (EGFP) reporter gene and antigenic VP2 gene of IPNV. Meanwhile, we tested their efficacy against the wild‐type (wt) IHNV HLJ‐09 virus and IPNV serotype Sp virus challenge. The relative per cent survival rates of two recombinant viruses against (wt) IHNV HLJ‐09 virus challenge were 84.6% and 81.5%, respectively. Simultaneously, the relative per cent survival rate of rIHNV‐N438A‐ΔNV‐VP2 against IPNV serotype Sp virus challenge was 88.9%. It showed the two recombinant viruses had high protection rates and induced a high level of antibodies against IHNV or IPNV. Taken together, these results suggest the VP2 gene of IPNV can act as candidate gene for vaccine and attenuated multivalent live vaccines and molecular marker vaccines have potential application for viral vaccine.
Indoles: metabolites produced by intestinal bacteria capable of controlling liver disease manifestation
Authors: Hendrikx T. , Schnabl B. 
Published: March 2019

AbstractAlterations in the bacteria that reside in our gastrointestinal tract play a role in the pathogenesis and progression of many disorders including liver and gastrointestinal diseases. Both qualitative (composition) and quantitative (amount) changes in gut microbes are associated with increased susceptibility to liver disease. Importantly, the intestinal microbiota is involved in the regulation of many host signalling pathways via the generation of different metabolites. Hence, dysbiosis influences disease development and progression by directly affecting the host–bacteria metabolic interaction. Microbe‐derived harmful metabolites can translocate to distant organs due to increased intestinal permeability as observed during dysbiosis. Contrary, certain bacterial metabolites such as tryptophan metabolites contribute to intestinal and systemic homeostasis. Here, we provide an overview of current evidence describing to what extent microbial metabolites modulate the development of chronic liver diseases such as alcoholic steatohepatitis and nonalcoholic fatty liver disease with a special emphasis on indoles.
Rethinking Violence Prevention in Rural and Underserved Communities: How Veteran Peer Support Groups Help Participants Deal with Sequelae from Violent Traumatic Experiences
Authors: Azevedo Kathryn J. , Ramirez Jeremy C. , Kumar Anusha , LeFevre Ann , Factor Adam , Hailu Elon , Lindley Steven E. , Jain Shaili 
Published: March 2019

AbstractPurposeAccess to mental health care and programs that address violence prevention can be a challenge for veterans residing in rural and underserved areas. A growing number of trauma‐affected veterans are now returning to rural areas upon completion of military service. The Palo Alto VA Health Care System has piloted a program known as the Peer Support Program (PSP) where certified peer support specialists hold group sessions for their fellow veterans in remote, community‐based outpatient clinics.MethodsA total of 29 peer‐support group participants and 1 certified peer specialist were interviewed. Semistructured interviews began with open‐ended questions regarding participant firsthand experiences with the support group setting. These were followed by direct questions that addressed the role of the PSP, expectations for the PSP, as well as benefits and limitations of the program. We performed a domain analysis using the Spradley ethnographic method on 325 pages of compiled narrative data focusing on violence‐related themes.FindingsFour key themes emerged, including: 1) Violence in Military Training Not Acceptable in Civilian Life, 2) Peer Support Creates the Trust to Speak Freely, 3) Skills Are Taught to Defuse Violence, and 4) The Veteran Peer Support Specialist Relationship Is Multi‐Dimensional.ConclusionsThese emergent themes illustrate how trauma‐focused assistance rendered by peer support specialists as part of an interdisciplinary mental health team can be implemented to benefit trauma‐affected individuals and their communities in the prevention of future violence.