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Showing papers on "Transplantation published in 2015"


Journal ArticleDOI
TL;DR: Nivolumab had substantial therapeutic activity and an acceptable safety profile in patients with previously heavily treated relapsed or refractory Hodgkin's lymphoma.
Abstract: BACKGROUND Preclinical studies suggest that Reed–Sternberg cells exploit the programmed death 1 (PD-1) pathway to evade immune detection. In classic Hodgkin’s lymphoma, alterations in chromosome 9p24.1 increase the abundance of the PD-1 ligands, PD-L1 and PD-L2, and promote their induction through Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signaling. We hypothesized that nivolumab, a PD-1–blocking antibody, could inhibit tumor immune evasion in patients with relapsed or refractory Hodgkin’s lymphoma. METHODS In this ongoing study, 23 patients with relapsed or refractory Hodgkin’s lymphoma that had already been heavily treated received nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks until they had a complete response, tumor progression, or excessive toxic effects. Study objectives were measurement of safety and efficacy and assessment of the PDL1 and PDL2 (also called CD274 and PDCD1LG2, respectively) loci and PD-L1 and PD-L2 protein expression. RESULTS Of the 23 study patients, 78% were enrolled in the study after a relapse following autologous stem-cell transplantation and 78% after a relapse following the receipt of brentuximab vedotin. Drug-related adverse events of any grade and of grade 3 occurred in 78% and 22% of patients, respectively. An objective response was reported in 20 patients (87%), including 17% with a complete response and 70% with a partial response; the remaining 3 patients (13%) had stable disease. The rate of progression-free survival at 24 weeks was 86%; 11 patients were continuing to participate in the study. Reasons for discontinuation included stem-cell transplantation (in 6 patients), disease progression (in 4 patients), and drug toxicity (in 2 patients). Analyses of pretreatment tumor specimens from 10 patients revealed copy-number gains in PDL1 and PDL2 and increased expression of these ligands. Reed–Sternberg cells showed nuclear positivity of phosphorylated STAT3, indicative of active JAK-STAT signaling. CONCLUSIONS Nivolumab had substantial therapeutic activity and an acceptable safety profile in patients with previously heavily treated relapsed or refractory Hodgkin’s lymphoma. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT01592370.)

3,008 citations



Journal ArticleDOI
27 Nov 2015-Science
TL;DR: A key role is revealed for Bacteroidales in the immunostimulatory effects of CTLA-4 blockade, which is found to depend on distinct Bacteroides species in mice and patients.
Abstract: Antibodies targeting CTLA-4 have been successfully used as cancer immunotherapy. We find that the antitumor effects of CTLA-4 blockade depend on distinct Bacteroides species. In mice and patients, T cell responses specific for B. thetaiotaomicron or B. fragilis were associated with the efficacy of CTLA-4 blockade. Tumors in antibiotic-treated or germ-free mice did not respond to CTLA blockade. This defect was overcome by gavage with B. fragilis, by immunization with B. fragilis polysaccharides, or by adoptive transfer of B. fragilis–specific T cells. Fecal microbial transplantation from humans to mice confirmed that treatment of melanoma patients with antibodies against CTLA-4 favored the outgrowth of B. fragilis with anticancer properties. This study reveals a key role for Bacteroidales in the immunostimulatory effects of CTLA-4 blockade.

2,360 citations


Journal ArticleDOI
09 Jun 2015-JAMA
TL;DR: How to identify patients with nonalcoholic fatty liver disease at greatest risk of non Alcoholic steatohepatitis and cirrhosis is illustrated and the role and limitations of current diagnostics and liver biopsy are discussed to provide an outline for the management of patients across the spectrum of non alcoholic fatty Liver disease.
Abstract: Importance Nonalcoholic fatty liver disease and its subtype nonalcoholic steatohepatitis affect approximately 30% and 5%, respectively, of the US population. In patients with nonalcoholic steatohepatitis, half of deaths are due to cardiovascular disease and malignancy, yet awareness of this remains low. Cirrhosis, the third leading cause of death in patients with nonalcoholic fatty liver disease, is predicted to become the most common indication for liver transplantation. Objectives To illustrate how to identify patients with nonalcoholic fatty liver disease at greatest risk of nonalcoholic steatohepatitis and cirrhosis; to discuss the role and limitations of current diagnostics and liver biopsy to diagnose nonalcoholic steatohepatitis; and to provide an outline for the management of patients across the spectrum of nonalcoholic fatty liver disease. Evidence Review PubMed was queried for published articles through February 28, 2015, using the search termsNAFLD and cirrhosis, mortality, biomarkers,andtreatment. A total of 88 references were selected, including 14 randomized clinical trials, 19 cohort or case-control studies, 1 population-based study, 2 practice guidelines, 7 meta-analyses, 43 classified as other, and 2 webpages. Findings Sixty-six percent of patients older than 50 years with diabetes or obesity are thought to have nonalcoholic steatohepatitis with advanced fibrosis. Even though the ability to identify the nonalcoholic steatohepatitis subtype within those with nonalcoholic fatty liver disease still requires liver biopsy, biomarkers to detect advanced fibrosis are increasingly reliable. Lifestyle modification is the foundation of treatment for patients with nonalcoholic steatosis. Available treatments with proven benefit include vitamin E, pioglitazone, and obeticholic acid; however, the effect size is modest ( Conclusions and Relevance Between 75 million and 100 million individuals in the United States are estimated to have nonalcoholic fatty liver disease and its potential morbidity extends beyond the liver. It is important that primary care physicians, endocrinologists, and other specialists be aware of the scope and long-term effects of the disease. Early identification of patients with nonalcoholic steatohepatitis may help improve patient outcomes through treatment intervention, including transplantation for those with decompensated cirrhosis.

1,743 citations


Journal ArticleDOI
TL;DR: Patients with NASH are less likely to undergo liver transplantation (LT) andLess likely to survive for 90 days on the waitlist than patients with HCV, ALD, or HCV and ALD.

1,444 citations


Journal ArticleDOI
15 Jan 2015-Cell
TL;DR: Conditions allowing long-term expansion of adult bile duct-derived bipotent progenitor cells from human liver opens up experimental avenues for disease modeling, toxicology studies, regenerative medicine, and gene therapy.

1,081 citations


Journal ArticleDOI
TL;DR: Recommendations include discussions not present in previous ISHLT guidelines, including lung allocation scores, bridging to transplant with mechanical circulatory and ventilator support, and expanded indications for lung transplantation.
Abstract: The appropriate selection of lung transplant recipients is an important determinant of outcomes. This consensus document is an update of the recipient selection guidelines published in 2006. The Pulmonary Council of the International Society for Heart and Lung Transplantation (ISHLT) organized a Writing Committee of international experts to provide consensus opinion regarding the appropriate timing of referral and listing of candidates for lung transplantation. A comprehensive search of the medical literature was conducted with the assistance of a medical librarian. Writing Committee members were assigned specific topics to research and discuss. The Chairs of the Writing Committee were responsible for evaluating the completeness of the literature search, providing editorial support for the manuscript, and organizing group discussions regarding its content. The consensus document makes specific recommendations regarding the timing of referral and of listing for lung transplantation. These recommendations include discussions not present in previous ISHLT guidelines, including lung allocation scores, bridging to transplant with mechanical circulatory and ventilator support, and expanded indications for lung transplantation. In the absence of high-grade evidence to support decision making, these consensus guidelines remain part of a continuum of expert opinion based on available studies and personal experience. Some positions are immutable. Although transplant is rightly a treatment of last resort for end-stage lung disease, early referral allows proper evaluation and thorough patient education. Subsequent waiting list activation implies a tacit agreement that transplant offers a significant individual survival advantage. It is both the challenge and the responsibility of the transplant community globally to ensure organ allocation maximizes the potential benefits of a scarce resource, thereby achieving that advantage.

1,063 citations



Journal ArticleDOI
TL;DR: Single-agent blinatumomab showed antileukaemia activity in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia characterised by negative prognostic factors.
Abstract: Summary Background Adults with relapsed or refractory B-precursor acute lymphoblastic leukaemia have an unfavourable prognosis. Blinatumomab is a bispecific T-cell engager antibody construct targeting CD19, an antigen consistently expressed on B-lineage acute lymphoblastic leukaemia cells. We aimed to confirm the activity and safety profile of blinatumomab for acute lymphoblastic leukaemia. Methods In a multicentre, single-arm, open-label phase 2 study, we enrolled adult patients with Philadelphia-chromosome-negative, primary refractory or relapsed (first relapse within 12 months of first remission, relapse within 12 months after allogeneic haemopoietic stem-cell transplantation [HSCT], or no response to or relapse after first salvage therapy or beyond) leukaemia. Patients received blinatumomab (9 μg/day for the first 7 days and 28 μg/day thereafter) by continuous intravenous infusion over 4 weeks every 6 weeks (up to five cycles), per protocol. The primary endpoint was complete remission (CR) or CR with partial haematological recovery of peripheral blood counts (CRh) within the first two cycles. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT01466179. Findings Between Jan 13, 2012, and Oct 10, 2013, 189 patients were enrolled and treated with blinatumomab. After two cycles, 81 (43%, 95% CI 36–50) patients had achieved a CR or CRh: 63 (33%) patients had a CR and 18 (10%) patients had a CRh. 32 (40%) of patients who achieved CR/CRh underwent subsequent allogeneic HSCT. The most frequent grade 3 or worse adverse events were febrile neutropenia (48 patients, 25%), neutropenia (30 patients, 16%), and anaemia (27 patients, 14%). Three (2%) patients had grade 3 cytokine release syndrome. Neurologic events of worst grade 3 or 4 occurred in 20 (11%) and four (2%) patients, respectively. Three deaths (due to sepsis, Escherichia coli sepsis, and Candida infection) were thought to be treatment-related by the investigators. Interpretation Single-agent blinatumomab showed antileukaemia activity in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia characterised by negative prognostic factors. Further assessment of blinatumomab treatment earlier in the course of the disease and in combination with other treatment approaches is warranted. Funding Amgen.

986 citations


Journal ArticleDOI
12 Nov 2015-Nature
TL;DR: Oxidative stress limits distant metastasis by melanoma cells in vivo, particularly among inefficiently metastasizing melanomas, which underwent reversible metabolic changes during metastasis that increased their capacity to withstand oxidative stress.
Abstract: Solid cancer cells commonly enter the blood and disseminate systemically, but are highly inefficient at forming distant metastases for poorly understood reasons. Here we studied human melanomas that differed in their metastasis histories in patients and in their capacity to metastasize in NOD-SCID-Il2rg(-/-) (NSG) mice. We show that melanomas had high frequencies of cells that formed subcutaneous tumours, but much lower percentages of cells that formed tumours after intravenous or intrasplenic transplantation, particularly among inefficiently metastasizing melanomas. Melanoma cells in the blood and visceral organs experienced oxidative stress not observed in established subcutaneous tumours. Successfully metastasizing melanomas underwent reversible metabolic changes during metastasis that increased their capacity to withstand oxidative stress, including increased dependence on NADPH-generating enzymes in the folate pathway. Antioxidants promoted distant metastasis in NSG mice. Folate pathway inhibition using low-dose methotrexate, ALDH1L2 knockdown, or MTHFD1 knockdown inhibited distant metastasis without significantly affecting the growth of subcutaneous tumours in the same mice. Oxidative stress thus limits distant metastasis by melanoma cells in vivo.

910 citations


Journal ArticleDOI
17 Dec 2015-Cell
TL;DR: This work comprehensively map myeloid progenitor subpopulations by transcriptional sorting of single cells from the bone marrow, showing unexpected transcriptional priming toward seven differentiation fates but no progenitors with a mixed state.

Book
01 Nov 2015
TL;DR: Hematopoietic cell transplantation is the IV infusion of hematopoetic stem and progenitor cells designed to establish marrow and immune function in patients with a variety of acquired and inherited malignant and nonmalignant disorders.
Abstract: Hematopoietic cell transplantation (HCT) is the IV infusion of hematopoietic stem and progenitor cells designed to establish marrow and immune function in patients with a variety of acquired and inherited malignant and nonmalignant disorders.

Journal ArticleDOI
TL;DR: In those patients at high risk for the development of ONJ, including cancer patients receiving high‐dose BP or Dmab therapy, consideration should be given to withholding antiresorptive therapy following extensive oral surgery until the surgical site heals with mature mucosal coverage.
Abstract: This work provides a systematic review of the literature from January 2003 to April 2014 pertaining to the incidence, pathophysiology, diagnosis, and treatment of osteonecrosis of the jaw (ONJ), and offers recommendations for its management based on multidisciplinary international consensus. ONJ is associated with oncology-dose parenteral antiresorptive therapy of bisphosphonates (BP) and denosumab (Dmab). The incidence of ONJ is greatest in the oncology patient population (1% to 15%), where high doses of these medications are used at frequent intervals. In the osteoporosis patient population, the incidence of ONJ is estimated at 0.001% to 0.01%, marginally higher than the incidence in the general population (<0.001%). New insights into the pathophysiology of ONJ include antiresorptive effects of BPs and Dmab, effects of BPs on gamma delta T-cells and on monocyte and macrophage function, as well as the role of local bacterial infection, inflammation, and necrosis. Advances in imaging include the use of cone beam computerized tomography assessing cortical and cancellous architecture with lower radiation exposure, magnetic resonance imaging, bone scanning, and positron emission tomography, although plain films often suffice. Other risk factors for ONJ include glucocorticoid use, maxillary or mandibular bone surgery, poor oral hygiene, chronic inflammation, diabetes mellitus, ill-fitting dentures, as well as other drugs, including antiangiogenic agents. Prevention strategies for ONJ include elimination or stabilization of oral disease prior to initiation of antiresorptive agents, as well as maintenance of good oral hygiene. In those patients at high risk for the development of ONJ, including cancer patients receiving high-dose BP or Dmab therapy, consideration should be given to withholding antiresorptive therapy following extensive oral surgery until the surgical site heals with mature mucosal coverage. Management of ONJ is based on the stage of the disease, size of the lesions, and the presence of contributing drug therapy and comorbidity. Conservative therapy includes topical antibiotic oral rinses and systemic antibiotic therapy. Localized surgical debridement is indicated in advanced nonresponsive disease and has been successful. Early data have suggested enhanced osseous wound healing with teriparatide in those without contraindications for its use. Experimental therapy includes bone marrow stem cell intralesional transplantation, low-level laser therapy, local platelet-derived growth factor application, hyperbaric oxygen, and tissue grafting.

Journal ArticleDOI
TL;DR: In this article, the European League against Rheumatism (EULAR) developed a set of recommendations for the treatment of systemic sclerosis (SSc) with attention to new therapeutic questions.
Abstract: The aim was to update the 2009 European League against Rheumatism (EULAR) recommendations for the treatment of systemic sclerosis (SSc), with attention to new therapeutic questions. Update of the previous treatment recommendations was performed according to EULAR standard operating procedures. The task force consisted of 32 SSc clinical experts from Europe and the USA, 2 patients nominated by the pan-European patient association for SSc (Federation of European Scleroderma Associations (FESCA)), a clinical epidemiologist and 2 research fellows. All centres from the EULAR Scleroderma Trials and Research group were invited to submit and select clinical questions concerning SSc treatment using a Delphi approach. Accordingly, 46 clinical questions addressing 26 different interventions were selected for systematic literature review. The new recommendations were based on the available evidence and developed in a consensus meeting with clinical experts and patients. The procedure resulted in 16 recommendations being developed (instead of 14 in 2009) that address treatment of several SSc-related organ complications: Raynaud's phenomenon (RP), digital ulcers (DUs), pulmonary arterial hypertension (PAH), skin and lung disease, scleroderma renal crisis and gastrointestinal involvement. Compared with the 2009 recommendations, the 2016 recommendations include phosphodiesterase type 5 (PDE-5) inhibitors for the treatment of SSc-related RP and DUs, riociguat, new aspects for endothelin receptor antagonists, prostacyclin analogues and PDE-5 inhibitors for SSc-related PAH. New recommendations regarding the use of fluoxetine for SSc-related RP and haematopoietic stem cell transplantation for selected patients with rapidly progressive SSc were also added. In addition, several comments regarding other treatments addressed in clinical questions and suggestions for the SSc research agenda were formulated. These updated data-derived and consensus-derived recommendations will help rheumatologists to manage patients with SSc in an evidence-based way. These recommendations also give directions for future clinical research in SSc.

Journal ArticleDOI
TL;DR: The criteria for printing viable and functional scaffolds, scaffolding materials, and 3DP technologies used to print scaffolds for tissue engineering are discussed and could potentially help to meet the demand by patients for tissues and organs without having to wait or rely on donors for transplantation.
Abstract: The current need for organ and tissue replacement, repair, and regeneration for patients is continually growing such that supply is not meeting demand primarily due to a paucity of donors as well as biocompatibility issues leading to immune rejection of the transplant. In order to overcome these drawbacks, scientists have investigated the use of scaffolds as an alternative to transplantation. These scaffolds are designed to mimic the extracellular matrix (ECM) by providing structural support as well as promoting attachment, proliferation, and differentiation with the ultimate goal of yielding functional tissues or organs. Initial attempts at developing scaffolds were problematic and subsequently inspired an interest in 3D printing as a mode for generating scaffolds. Utilizing three-dimensional printing (3DP) technologies, ECM-like scaffolds can be produced with a high degree of complexity, where fine details can be included at a micrometer level. In this Review, the criteria for printing viable and functional scaffolds, scaffolding materials, and 3DP technologies used to print scaffolds for tissue engineering are discussed. Creating biofunctional scaffolds could potentially help to meet the demand by patients for tissues and organs without having to wait or rely on donors for transplantation.

Journal ArticleDOI
26 Feb 2015-Nature
TL;DR: A mouse model allowing inducible genetic labelling of the most primitive Tie2+ HSCs in bone marrow is devised, and label progression along haematopoietic development is quantified by limiting dilution analysis and data-driven modelling, which uncovers fundamental differences between the normal maintenance of the haematography system, its regulation by challenge, and its re-establishment after transplantation.
Abstract: Haematopoietic stem cells (HSCs) are widely studied by HSC transplantation into immune- and blood-cell-depleted recipients. Single HSCs can rebuild the system after transplantation. Chromosomal marking, viral integration and barcoding of transplanted HSCs suggest that very low numbers of HSCs perpetuate a continuous stream of differentiating cells. However, the numbers of productive HSCs during normal haematopoiesis, and the flux of differentiating progeny remain unknown. Here we devise a mouse model allowing inducible genetic labelling of the most primitive Tie2(+) HSCs in bone marrow, and quantify label progression along haematopoietic development by limiting dilution analysis and data-driven modelling. During maintenance of the haematopoietic system, at least 30% or ∼5,000 HSCs are productive in the adult mouse after label induction. However, the time to approach equilibrium between labelled HSCs and their progeny is surprisingly long, a time scale that would exceed the mouse's life. Indeed, we find that adult haematopoiesis is largely sustained by previously designated 'short-term' stem cells downstream of HSCs that nearly fully self-renew, and receive rare but polyclonal HSC input. By contrast, in fetal and early postnatal life, HSCs are rapidly used to establish the immune and blood system. In the adult mouse, 5-fluoruracil-induced leukopenia enhances the output of HSCs and of downstream compartments, thus accelerating haematopoietic flux. Label tracing also identifies a strong lineage bias in adult mice, with several-hundred-fold larger myeloid than lymphoid output, which is only marginally accentuated with age. Finally, we show that transplantation imposes severe constraints on HSC engraftment, consistent with the previously observed oligoclonal HSC activity under these conditions. Thus, we uncover fundamental differences between the normal maintenance of the haematopoietic system, its regulation by challenge, and its re-establishment after transplantation. HSC fate mapping and its linked modelling provide a quantitative framework for studying in situ the regulation of haematopoiesis in health and disease.

Journal ArticleDOI
TL;DR: This report is a proof-of-concept for uterus transplantation as a treatment for uterine factor infertility and shows the feasibility of live uterus donation, even from a postmenopausal donor.


Journal ArticleDOI
19 Feb 2015-Nature
TL;DR: The results show that measurement of genomically defined clonal population dynamics will be highly informative for functional studies using patient-derived breast cancer xenoengraftment, and indicates that genomic aberrations can be reproducible determinants of evolutionary trajectories.
Abstract: Deep-genome and single-cell sequencing analyses of patient-derived breast cancer xenografts reveal extensive, dynamic and reproducible changes in intra-tumoral mutational clonal composition on engraftment and serial propagation. Xenograft transplantation of primary human cancer cells into mice provides valuable models in which to study mechanisms underlying tumorigenesis, drug response and resistance. This study demonstrates that clonal evolution resembling that seen in human tumours also occurs on engraftment and during subsequent passaging of breast tumours in immunodeficient mice. In addition, similar clonal expansion patterns emerge in independent grafts of the same starting tumour population, indicating that genomic aberrations can be reproducible determinants of evolutionary trajectories. These findings suggest that patient-derived xenografts may be useful for studying patient-specific tumour characteristics such as the response to drugs tailored to specific genomic alterations. Human cancers, including breast cancers, comprise clones differing in mutation content. Clones evolve dynamically in space and time following principles of Darwinian evolution1,2, underpinning important emergent features such as drug resistance and metastasis3,4,5,6,7. Human breast cancer xenoengraftment is used as a means of capturing and studying tumour biology, and breast tumour xenografts are generally assumed to be reasonable models of the originating tumours8,9,10. However, the consequences and reproducibility of engraftment and propagation on the genomic clonal architecture of tumours have not been systematically examined at single-cell resolution. Here we show, using deep-genome and single-cell sequencing methods, the clonal dynamics of initial engraftment and subsequent serial propagation of primary and metastatic human breast cancers in immunodeficient mice. In all 15 cases examined, clonal selection on engraftment was observed in both primary and metastatic breast tumours, varying in degree from extreme selective engraftment of minor (<5% of starting population) clones to moderate, polyclonal engraftment. Furthermore, ongoing clonal dynamics during serial passaging is a feature of tumours experiencing modest initial selection. Through single-cell sequencing, we show that major mutation clusters estimated from tumour population sequencing relate predictably to the most abundant clonal genotypes, even in clonally complex and rapidly evolving cases. Finally, we show that similar clonal expansion patterns can emerge in independent grafts of the same starting tumour population, indicating that genomic aberrations can be reproducible determinants of evolutionary trajectories. Our results show that measurement of genomically defined clonal population dynamics will be highly informative for functional studies using patient-derived breast cancer xenoengraftment.

Journal ArticleDOI
TL;DR: A general approach for studying the major tissue contributors to the circulating DNA pool using genome-wide bisulfite sequencing of plasma DNA and deconvolution of the sequencing data with reference to methylation profiles of different tissues is developed.
Abstract: Plasma consists of DNA released from multiple tissues within the body. Using genome-wide bisulfite sequencing of plasma DNA and deconvolution of the sequencing data with reference to methylation profiles of different tissues, we developed a general approach for studying the major tissue contributors to the circulating DNA pool. We tested this method in pregnant women, patients with hepatocellular carcinoma, and subjects following bone marrow and liver transplantation. In most subjects, white blood cells were the predominant contributors to the circulating DNA pool. The placental contributions in the plasma of pregnant women correlated with the proportional contributions as revealed by fetal-specific genetic markers. The graft-derived contributions to the plasma in the transplant recipients correlated with those determined using donor-specific genetic markers. Patients with hepatocellular carcinoma showed elevated plasma DNA contributions from the liver, which correlated with measurements made using tumor-associated copy number aberrations. In hepatocellular carcinoma patients and in pregnant women exhibiting copy number aberrations in plasma, comparison of methylation deconvolution results using genomic regions with different copy number status pinpointed the tissue type responsible for the aberrations. In a pregnant woman diagnosed as having follicular lymphoma during pregnancy, methylation deconvolution indicated a grossly elevated contribution from B cells into the plasma DNA pool and localized B cells as the origin of the copy number aberrations observed in plasma. This method may serve as a powerful tool for assessing a wide range of physiological and pathological conditions based on the identification of perturbed proportional contributions of different tissues into plasma.


Journal ArticleDOI
TL;DR: Attention is paid to problems in wound healing understanding and treatment, such as lack of specific epithelial stem cell markers, reliable identification of stem cells, efficient prevention of haze and stromal scar formation, lack of data on wound regulating microRNAs in keratocytes and endothelial cells, as well as virtual lack of targeted systems for drug and gene delivery to select corneal cells.

Book ChapterDOI
01 Jan 2015
TL;DR: In this article, five key terms identify the fields or activities that relate to the care and use of animals in research, education, and testing, including Animal experimentation refers to the scientific study of animals, usually in a laboratory, for the purpose of gaining new biological knowledge or solving specific medical, veterinary medical, dental, or biological problems.
Abstract: Five key terms identify the fields or activities that relate to the care and use of animals in research, education, and testing Animal experimentation refers to the scientific study of animals, usually in a laboratory, for the purpose of gaining new biological knowledge or solving specific medical, veterinary medical, dental, or biological problems Most commonly, such experimentation is carried out by or under the direction of persons holding research or professional degrees Laboratory animal care is the application of veterinary medicine and animal science to the acquisition of laboratory animals and to their management, nutrition, breeding, and diseases The term also relates to the care that is provided to animals as an aid in managing pain and distress Laboratory animal care is usually provided in scientific institutions under veterinary supervision or guidance Laboratory animal medicine is recognized by the American Veterinary Medical Association as the specialty field within veterinary medicine that is concerned with the diagnosis, treatment, and prevention of diseases in animals used as subjects in biomedical activities Laboratory animal medicine also encompasses the methods of minimizing and preventing pain or distress in research animals and identifying of complicating factors in animal research Comparative medicine is “the study of the nature, cause and cure of abnormal structure and function in people, animals and plants for the eventual application to and benefit of all living things” (Bustad et al, 1976) Laboratory animal science is the body of scientific and technical information, knowledge, and skills that bears on both laboratory animal care and laboratory animal medicine and that is roughly analogous to animal science in the agricultural sector

Journal ArticleDOI
03 Dec 2015-Cell
TL;DR: The results demonstrate the microbiota as a key factor orchestrating the overall energy homeostasis during increased demand, leading to altered intestinal gene expression promoting tissue remodeling and suppression of apoptosis.

Journal ArticleDOI
27 Nov 2015-Science
TL;DR: This study shows that CRISPR-Cas9 multiplexability can be as high as 62 and demonstrates the possibility that PERVs can be inactivated for clinical application of porcine-to-human xenotransplantation and demonstrated a >1000-fold reduction in PERV transmission to human cells, using engineered cells.
Abstract: The shortage of organs for transplantation is a major barrier to the treatment of organ failure. Although porcine organs are considered promising, their use has been checked by concerns about the transmission of porcine endogenous retroviruses (PERVs) to humans. Here we describe the eradication of all PERVs in a porcine kidney epithelial cell line (PK15). We first determined the PK15 PERV copy number to be 62. Using CRISPR-Cas9, we disrupted all copies of the PERV pol gene and demonstrated a >1000-fold reduction in PERV transmission to human cells, using our engineered cells. Our study shows that CRISPR-Cas9 multiplexability can be as high as 62 and demonstrates the possibility that PERVs can be inactivated for clinical application of porcine-to-human xenotransplantation.

Journal ArticleDOI
17 Apr 2015-Science
TL;DR: In this article, the authors reveal the presence of at least two fibroblast lineages in murine dorsal skin and identify CD26/DPP4 as a surface marker that allows isolation of this lineage.
Abstract: Dermal fibroblasts represent a heterogeneous population of cells with diverse features that remain largely undefined. We reveal the presence of at least two fibroblast lineages in murine dorsal skin. Lineage tracing and transplantation assays demonstrate that a single fibroblast lineage is responsible for the bulk of connective tissue deposition during embryonic development, cutaneous wound healing, radiation fibrosis, and cancer stroma formation. Lineage-specific cell ablation leads to diminished connective tissue deposition in wounds and reduces melanoma growth. Using flow cytometry, we identify CD26/DPP4 as a surface marker that allows isolation of this lineage. Small molecule-based inhibition of CD26/DPP4 enzymatic activity during wound healing results in diminished cutaneous scarring. Identification and isolation of these lineages hold promise for translational medicine aimed at in vivo modulation of fibrogenic behavior.

Journal ArticleDOI
TL;DR: A patient with refractory multiple myeloma received an infusion of CTL019 cells, a cellular therapy consisting of autologous T cells transduced with an anti-CD19 chimeric antigen receptor, after myeloablative chemotherapy and autOLOGous stem-cell transplantation, which led to a complete response.
Abstract: A patient with refractory multiple myeloma received an infusion of CTL019 cells, a cellular therapy consisting of autologous T cells transduced with an anti-CD19 chimeric antigen receptor, after myeloablative chemotherapy (melphalan, 140 mg per square meter of body-surface area) and autologous stem-cell transplantation Four years earlier, autologous transplantation with a higher melphalan dose (200 mg per square meter) had induced only a partial, transient response Autologous transplantation followed by treatment with CTL019 cells led to a complete response with no evidence of progression and no measurable serum or urine monoclonal protein at the most recent evaluation, 12 months after treatment This response was achieved despite the absence of CD19 expression in 9995% of the patient's neoplastic plasma cells (Funded by Novartis and others; ClinicalTrialsgov number, NCT02135406)

Journal ArticleDOI
TL;DR: The guidelines strongly recommend systematic testing and treatment of LTBI in people living with HIV, adult and child contacts of pulmonary TB cases, patients initiating anti-tumour necrosis factor treatment, patients receiving dialysis, patients preparing for organ or haematological transplantation and patients with silicosis.
Abstract: Latent tuberculosis infection (LTBI) is characterised by the presence of immune responses to previously acquired Mycobacterium tuberculosis infection without clinical evidence of active tuberculosis (TB). Here we report evidence-based guidelines from the World Health Organization for a public health approach to the management of LTBI in high risk individuals in countries with high or middle upper income and TB incidence of <100 per 100 000 per year. The guidelines strongly recommend systematic testing and treatment of LTBI in people living with HIV, adult and child contacts of pulmonary TB cases, patients initiating anti-tumour necrosis factor treatment, patients receiving dialysis, patients preparing for organ or haematological transplantation, and patients with silicosis. In prisoners, healthcare workers, immigrants from high TB burden countries, homeless persons and illicit drug users, systematic testing and treatment of LTBI is conditionally recommended, according to TB epidemiology and resource availability. Either commercial interferon-gamma release assays or Mantoux tuberculin skin testing could be used to test for LTBI. Chest radiography should be performed before LTBI treatment to rule out active TB disease. Recommended treatment regimens for LTBI include: 6 or 9 month isoniazid; 12 week rifapentine plus isoniazid; 3-4 month isoniazid plus rifampicin; or 3-4 month rifampicin alone.

Journal ArticleDOI
31 Jul 2015-Leukemia
TL;DR: Ruxolitinib may constitute a promising new treatment option for SR-aGVHD and SR-cGVHD that should be validated in a prospective trial.
Abstract: Despite major improvements in allogeneic hematopoietic cell transplantation over the past decades, corticosteroid-refractory (SR) acute (a) and chronic (c) graft-versus-host disease (GVHD) cause high mortality. Preclinical evidence indicates the potent anti-inflammatory properties of the JAK1/2 inhibitor ruxolitinib. In this retrospective survey, 19 stem cell transplant centers in Europe and the United States reported outcome data from 95 patients who had received ruxolitinib as salvage therapy for SR-GVHD. Patients were classified as having SR-aGVHD (n=54, all grades III or IV) or SR-cGVHD (n=41, all moderate or severe). The median number of previous GVHD-therapies was 3 for both SR-aGVHD (1-7) and SR-cGVHD (1-10). The overall response rate was 81.5% (44/54) in SR-aGVHD including 25 complete responses (46.3%), while for SR-cGVHD the ORR was 85.4% (35/41). Of those patients responding to ruxolitinib, the rate of GVHD-relapse was 6.8% (3/44) and 5.7% (2/35) for SR-aGVHD and SR-cGVHD, respectively. The 6-month-survival was 79% (67.3-90.7%, 95% confidence interval (CI)) and 97.4% (92.3-100%, 95% CI) for SR-aGVHD and SR-cGVHD, respectively. Cytopenia and cytomegalovirus-reactivation were observed during ruxolitinib treatment in both SR-aGVHD (30/54, 55.6% and 18/54, 33.3%) and SR-cGVHD (7/41, 17.1% and 6/41, 14.6%) patients. Ruxolitinib may constitute a promising new treatment option for SR-aGVHD and SR-cGVHD that should be validated in a prospective trial.

Journal ArticleDOI
TL;DR: It is demonstrated that high-aspect-ratio, mesoporous silica rods (MSRs) injected with a needle spontaneously assemble in vivo to form macroporous structures that provide a 3D cellular microenvironment for host immune cells.
Abstract: Materials implanted in the body to program host immune cells are a promising alternative to transplantation of ex vivo–manipulated cells to direct an immune response, but required a surgical procedure. Here we demonstrate that high-aspectratio, mesoporous silica rods (MSRs) injected with a needle spontaneously assemble in vivo to form macroporous structures that provide a 3D cellular microenvironment for host immune cells. In mice, substantial numbers of DCs are recruited to the pores between the scaffold rods. The recruitment of DCs and their subsequent homing to lymph nodes can be modulated by sustained release of inflammatory signals and adjuvants from the scaffold. Moreover, injection of an MSR-based vaccine formulation enhances systemic TH1 and TH2 serum antibody and cytotoxic T cell levels compared to bolus controls. These findings suggest that injectable MSRs may serve as a multifunctional vaccine platform to modulate host immune cell function and provoke adaptive immune responses.