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1.
Nature ; 544(7651): 493-497, 2017 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-28424516

RESUMO

Cancer cells elude anti-tumour immunity through multiple mechanisms, including upregulated expression of ligands for inhibitory immune checkpoint receptors. Phagocytosis by macrophages plays a critical role in cancer control. Therapeutic blockade of signal regulatory protein (SIRP)-α, an inhibitory receptor on macrophages, or of its ligand CD47 expressed on tumour cells, improves tumour cell elimination in vitro and in vivo, suggesting that blockade of the SIRPα-CD47 checkpoint could be useful in treating human cancer. However, the pro-phagocytic receptor(s) responsible for tumour cell phagocytosis is(are) largely unknown. Here we find that macrophages are much more efficient at phagocytosis of haematopoietic tumour cells, compared with non-haematopoietic tumour cells, in response to SIRPα-CD47 blockade. Using a mouse lacking the signalling lymphocytic activation molecule (SLAM) family of homotypic haematopoietic cell-specific receptors, we determined that phagocytosis of haematopoietic tumour cells during SIRPα-CD47 blockade was strictly dependent on SLAM family receptors in vitro and in vivo. In both mouse and human cells, this function required a single SLAM family member, SLAMF7 (also known as CRACC, CS1, CD319), expressed on macrophages and tumour cell targets. In contrast to most SLAM receptor functions, SLAMF7-mediated phagocytosis was independent of signalling lymphocyte activation molecule-associated protein (SAP) adaptors. Instead, it depended on the ability of SLAMF7 to interact with integrin Mac-1 (refs 18, 19, 20) and utilize signals involving immunoreceptor tyrosine-based activation motifs. These findings elucidate the mechanism by which macrophages engulf and destroy haematopoietic tumour cells. They also reveal a novel SAP adaptor-independent function for a SLAM receptor. Lastly, they suggest that patients with tumours expressing SLAMF7 are more likely to respond to SIRPα-CD47 blockade therapy.


Assuntos
Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/patologia , Antígeno de Macrófago 1/metabolismo , Macrófagos/imunologia , Fagocitose/imunologia , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo , Actinas/metabolismo , Animais , Antígenos de Diferenciação/imunologia , Antígenos de Diferenciação/metabolismo , Antígeno CD47/imunologia , Antígeno CD47/metabolismo , Feminino , Neoplasias Hematológicas/tratamento farmacológico , Humanos , Macrófagos/citologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/imunologia , Receptores Imunológicos/metabolismo , Família de Moléculas de Sinalização da Ativação Linfocitária/deficiência
2.
J Wound Ostomy Continence Nurs ; 49(6): 529-539, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36417375

RESUMO

PURPOSE: The purpose of this study was to examine patient characteristics, length of stay (LOS), hospital revisits, and complications of patients undergoing abdominal ostomy surgery. DESIGN: Retrospective cohort study. SUBJECTS AND SETTING: Data were extracted from the PINC AI Healthcare Database (PHD), a large archive that stores data from 25% of all US inpatient hospital discharges. Patients were admitted to 658 hospitals in the United States between December 1, 2017, and November 30, 2018. The sample comprised 27,658 adult patients; 15,512 underwent creation of a colostomy, 10,207 underwent ileostomy construction, and 1930 had a urostomy procedure. Their median age was 64 years (interquartile range [IQR] = 19 years). Emergent admission type was 71.2% for patients who underwent a colostomy procedure, 49.4% for ileostomy, and 9.9% for urostomy. The majority of patients underwent open surgery (77.7%); 22.3% of procedures used an endoscopic approach. METHODS: Patients were identified as having undergone abdominal ostomy surgery via ICD-10-PCS (International Classification of Diseases, Tenth Revision, Procedure Coding System) procedure codes. Demographic, visit, hospital and clinical characteristics, LOS, and hospital revisits (ie, readmissions and emergency department [ED]) were captured for qualifying patients. Data were evaluated using unadjusted descriptive analyses. RESULTS: The median LOS of 9 days (IQR = 9 days) varied by ostomy surgery; the cumulative postsurgical LOS was 7 days (IQR = 5 days). The most frequent underlying diagnoses resulting in ostomy surgery were diverticulitis of the large bowel (19.6%) managed by colostomy, colorectal cancer managed by ileostomy (22.5%), or urothelial cancer managed by urostomy (78.1%). Slightly less than a quarter (23.7%) of patients were discharged home without home care, 43.0% went home with home healthcare, and 29.6% were discharged to a non-acute care facility. Hospital readmission within 120 days of discharge was 36.3% for patients with a colostomy, 52.3% for those with an ileostomy, and 34.6% for patients with a urostomy. Ostomy complications were identified as the reason for readmission in 62.4% of patients. Slightly more than 1 in 5 patients (20.7%) had a subsequent ED visit within 120 days, 39.7% of which involved ostomy complication. CONCLUSIONS: Characteristics of patients undergoing abdominal stoma surgery varied based on underlying diagnosis and ostomy type. The median hospital LOS was more than 1 week. Patients experienced high rates of healthcare utilization (hospital admission or ED visits) during the 120 days following surgery.


Assuntos
Estomia , Readmissão do Paciente , Adulto , Humanos , Adulto Jovem , Tempo de Internação , Estudos Retrospectivos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Estomia/efeitos adversos , Hospitais , Atenção à Saúde
3.
Biol Blood Marrow Transplant ; 26(3): 600-605, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31678539

RESUMO

Acute graft-versus-host disease (GVHD) contributes to poor outcomes following allogeneic hematopoietic cell transplantation (HCT). Data are limited regarding the economic burden of acute GVHD, particularly steroid-refractory or high-risk (SR/HR) disease. This retrospective analysis of the Premier Healthcare Database reports inpatient healthcare resource utilization (HCRU), costs, and mortality during initial hospitalization for allogeneic HCT and through 100 days post-HCT among patients who developed acute GVHD, including a subgroup with SR/HR disease, compared with patients without GVHD. The analysis included adults discharged for first HCT between January 1, 2011, and June 30, 2016 (acute GVHD, n = 906; SR/HR acute GVHD, n = 158; no GVHD, n = 1529). During the initial hospitalization for HCT, patients with acute GVHD and SR/HR acute GVHD (n = 455 and 125, respectively) had significantly longer median lengths of stay (31 and 46 days versus 24 days) and higher median total costs ($153,849 and $205,880 versus $97,417) versus patients with no GVHD (n = 1529; P < .0001 for all). During the 100-day post-HCT period, patients with acute GVHD and SR/HR acute GVHD had higher readmission rates (78.3% and 77.2% versus 28.3%; P < .0001) and inpatient mortality rates (20.2% and 35.4% versus 8.9%; P < .0001) versus patients with no GVHD. In summary, acute GVHD, especially SR/HR disease, is associated with longer inpatient stays, higher readmission rates, and higher inpatient mortality compared with no GVHD.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Adulto , Humanos , Pacientes Internados , Aceitação pelo Paciente de Cuidados de Saúde , Estudos Retrospectivos , Esteroides/uso terapêutico , Transplante Homólogo
4.
Crit Care Med ; 46(12): 1889-1897, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30048332

RESUMO

OBJECTIVES: To characterize the current burden, outcomes, and costs of managing sepsis patients in U.S. hospitals. DESIGN: A retrospective observational study was conducted using the Premier Healthcare Database, which represents ~20% of U.S. inpatient discharges among private and academic hospitals. Hospital costs were obtained from billing records per the cost accounting method used by each hospital. Descriptive statistics were performed on patient demographics, characteristics, and clinical and economic outcomes for the index hospitalization and 30-day readmissions. SETTING: Sepsis patient hospitalizations, including inpatient, general ward, and ICU (intermediate and/or step-down). PATIENTS: Adults over 18 years old with a hospital discharge diagnosis code of sepsis from January 1, 2010, to September 30, 2016. INTERVENTIONS: None. This was a retrospective observational study of deidentified data. MEASUREMENTS AND MAIN RESULTS: The final study cohort consisted of 2,566,689 sepsis cases, representing patients with a mean age of 65 years (50.8% female). Overall mortality was 12.5% but varied greatly by severity (5.6%, 14.9%, and 34.2%) for sepsis without organ dysfunction, severe sepsis, and septic shock, respectively. Costs followed a similar pattern increasing by severity level: $16,324, $24,638, and $38,298 and varied widely by sepsis present at admission ($18,023) and not present at admission ($51,022). CONCLUSIONS: The highest burden of incidence and total costs occurred in the lowest severity sepsis cohort population. Sepsis cases not diagnosed until after admission, and those with increasing severity had a higher economic burden and mortality on a case-by-case basis. Methods to improve early identification of sepsis may provide opportunities for reducing the severity and economic burden of sepsis in the United States.


Assuntos
Preços Hospitalares/estatística & dados numéricos , Sepse/economia , Sepse/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Feminino , Mortalidade Hospitalar , Humanos , Incidência , Unidades de Terapia Intensiva/economia , Unidades de Terapia Intensiva/estatística & dados numéricos , Tempo de Internação/economia , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Escores de Disfunção Orgânica , Readmissão do Paciente , Estudos Retrospectivos , Sepse/mortalidade , Índice de Gravidade de Doença , Choque Séptico/economia , Choque Séptico/epidemiologia , Fatores Socioeconômicos , Tempo para o Tratamento , Estados Unidos
5.
PLoS Pathog ; 12(4): e1005555, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27058347

RESUMO

The immune mechanisms that recognize inhaled Aspergillus fumigatus conidia to promote their elimination from the lungs are incompletely understood. FleA is a lectin expressed by Aspergillus fumigatus that has twelve binding sites for fucosylated structures that are abundant in the glycan coats of multiple plant and animal proteins. The role of FleA is unknown: it could bind fucose in decomposed plant matter to allow Aspergillus fumigatus to thrive in soil, or it may be a virulence factor that binds fucose in lung glycoproteins to cause Aspergillus fumigatus pneumonia. Our studies show that FleA protein and Aspergillus fumigatus conidia bind avidly to purified lung mucin glycoproteins in a fucose-dependent manner. In addition, FleA binds strongly to macrophage cell surface proteins, and macrophages bind and phagocytose fleA-deficient (∆fleA) conidia much less efficiently than wild type (WT) conidia. Furthermore, a potent fucopyranoside glycomimetic inhibitor of FleA inhibits binding and phagocytosis of WT conidia by macrophages, confirming the specific role of fucose binding in macrophage recognition of WT conidia. Finally, mice infected with ΔfleA conidia had more severe pneumonia and invasive aspergillosis than mice infected with WT conidia. These findings demonstrate that FleA is not a virulence factor for Aspergillus fumigatus. Instead, host recognition of FleA is a critical step in mechanisms of mucin binding, mucociliary clearance, and macrophage killing that prevent Aspergillus fumigatus pneumonia.


Assuntos
Aspergillus fumigatus/imunologia , Lectinas/imunologia , Macrófagos/imunologia , Mucinas/imunologia , Aspergilose Pulmonar/imunologia , Adulto , Animais , Aspergillus fumigatus/patogenicidade , Western Blotting , Modelos Animais de Doenças , Feminino , Citometria de Fluxo , Imunofluorescência , Fucose/metabolismo , Proteínas Fúngicas/imunologia , Proteínas Fúngicas/metabolismo , Humanos , Imunidade nas Mucosas/imunologia , Lectinas/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Mucinas/metabolismo , Aspergilose Pulmonar/metabolismo , Esporos Fúngicos/imunologia
6.
PLoS Pathog ; 12(8): e1005787, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27542117

RESUMO

Soaring rates of systemic fungal infections worldwide underscore the need for vaccine prevention. An understanding of the elements that promote vaccine immunity is essential. We previously reported that Th17 cells are required for vaccine immunity to the systemic dimorphic fungi of North America, and that Card9 and MyD88 signaling are required for the development of protective Th17 cells. Herein, we investigated where, when and how MyD88 regulates T cell development. We uncovered a novel mechanism in which MyD88 extrinsically regulates the survival of activated T cells during the contraction phase and in the absence of inflammation, but is dispensable for the expansion and differentiation of the cells. The poor survival of activated T cells in Myd88-/- mice is linked to increased caspase3-mediated apoptosis, but not to Fas- or Bim-dependent apoptotic pathways, nor to reduced expression of the anti-apoptotic molecules Bcl-2 or Bcl-xL. Moreover, TLR3, 7, and/or 9, but not TLR2 or 4, also were required extrinsically for MyD88-dependent Th17 cell responses and vaccine immunity. Similar MyD88 requirements governed the survival of virus primed T cells. Our data identify unappreciated new requirements for eliciting adaptive immunity and have implications for designing vaccines.


Assuntos
Vacinas Fúngicas/imunologia , Ativação Linfocitária , Micoses/imunologia , Fator 88 de Diferenciação Mieloide/imunologia , Células Th17/imunologia , Animais , Proteína 11 Semelhante a Bcl-2/genética , Proteína 11 Semelhante a Bcl-2/imunologia , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/imunologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Camundongos , Camundongos Knockout , Micoses/genética , Micoses/prevenção & controle , Fator 88 de Diferenciação Mieloide/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/imunologia , Receptores Toll-Like/genética , Receptores Toll-Like/imunologia , Proteína bcl-X/genética , Proteína bcl-X/imunologia , Receptor fas/genética , Receptor fas/imunologia
7.
Am J Respir Cell Mol Biol ; 57(2): 248-257, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28287822

RESUMO

The transgenic mouse strains surfactant protein C-reverse tetracycline transactivator (SP-C-rtTA), club cell secretory protein (CCSP)-rtTA, and tetracycline operator (TetO)-Cre have been invaluable for spatiotemporally regulating gene deletion in the pulmonary epithelium. In this study, we measured the efficiency and specificity of gene deletion that can be achieved in these mice using the Rosa26-eYFP reporter. Triple-transgenic mice (tTg or rtTA/TetO-Cre/Rosa-eYFP) were bred and treated with various doxycycline (dox) regimens to induce gene deletion, which was then quantified in various cell populations by flow cytometry. In these crosses, we found that the TetO-Cre transgene must be transmitted through the female parent to avoid germline gene deletion. With dox exposure during lung development, SP-C-tTg mice deleted in ∼65-75% of alveolar epithelial type II (ATII) cells, but in only ∼45-50% of the integrin ß4+ population, which consisted of club cells and distal lung progenitor cells. In contrast, CCSP-tTg mice deleted in ∼50% of ATII cells and ∼80% of integrin ß4+ cells. Upon dox treatment of adults, deletion in ATII cells and integrin ß4+ cells in SP-C-tTg mice dropped significantly to ∼20% and ∼6%, respectively, whereas CCSP-tTg mice deleted in ∼57% of ATII and ∼40% of integrin ß4+ cells. Interestingly, untreated CCSP-tTg mice also deleted in ∼40% of integrin ß4+ cells, indicating significant leakiness of CCSP-tTg in ß4+ cells. In all mouse groups, minimal deletion occurred in mouse tracheal epithelial cells or in mesenchymal or hematopoietic cells. These data provide the first quantitative, side-by-side comparison of the deletion efficiency for these widely used transgenic mouse strains.


Assuntos
Células Epiteliais Alveolares/metabolismo , Deleção de Genes , Técnicas de Inativação de Genes , Integrases/genética , Pulmão/citologia , Camundongos Transgênicos/genética , Traqueia/citologia , Transgenes , Animais , Proteínas de Bactérias/genética , Proteínas de Transporte/genética , Doxiciclina/farmacologia , Feminino , Citometria de Fluxo , Genes Reporter , Integrina beta4/análise , Peptídeos e Proteínas de Sinalização Intercelular , Proteínas Luminescentes/genética , Pulmão/embriologia , Masculino , Herança Materna , Camundongos , Camundongos Endogâmicos C57BL , Especificidade de Órgãos , Peptídeos/genética , Proteína C Associada a Surfactante Pulmonar , Uteroglobina/genética
8.
Am J Respir Cell Mol Biol ; 54(6): 802-13, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26574781

RESUMO

Lung epithelial cells play critical roles in initiating and modulating immune responses during pulmonary infection or injury. To better understand the spectrum of immune response-related proteins present in lung epithelial cells, we developed an improved method of isolating highly pure primary murine alveolar type (AT) II cells and murine tracheal epithelial cells (mTECs) using negative selection for a variety of lineage markers and positive selection for epithelial cell adhesion molecule (EpCAM), a pan-epithelial cell marker. This method yielded 2-3 × 10(6) ATII cells/mouse lung and 1-2 × 10(4) mTECs/trachea that were highly pure (>98%) and viable (>98%). Using these preparations, we found that both ATII cells and mTECs expressed the Lyn tyrosine kinase, which is best studied as an inhibitory kinase in hematopoietic cells. However, we found little or no expression of Syk in either ATII cells or mTECs, which is in contrast to earlier published reports. Both cell types expressed C-type lectin receptors, anaphylatoxin receptors, and various Toll-like receptors (TLRs). In addition, stimulation of ATII cells with TLR ligands led to secretion of various cytokines and chemokines. Interestingly, lyn(-/-) ATII cells were hyperresponsive to TLR3 stimulation, suggesting that, as in hematopoietic cells, Lyn might be playing an inhibitory role in ATII cells. In conclusion, the improved isolation method reported here, along with expression profiles of various immune defense proteins, will help refocus investigations of immune-related signaling events in pulmonary epithelium.


Assuntos
Células Epiteliais Alveolares/citologia , Células Epiteliais Alveolares/imunologia , Separação Celular/métodos , Proteínas/metabolismo , Animais , Quimiocinas/metabolismo , Citometria de Fluxo , Lectinas Tipo C/metabolismo , Camundongos Endogâmicos C57BL , Quinase Syk/metabolismo , Receptores Toll-Like/metabolismo , Traqueia/citologia , Quinases da Família src/metabolismo
9.
Cancer Immunol Res ; 12(4): 453-461, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38276989

RESUMO

Denosumab is a fully human mAb that binds receptor activator of NFκB ligand (RANKL). It is routinely administered to patients with cancer to reduce the incidence of new bone metastasis. RANK-RANKL interactions regulate bone turnover by controlling osteoclast recruitment, development, and activity. However, these interactions also can regulate immune cells including dendritic cells and medullary thymic epithelial cells. Inhibition of the latter results in reduced thymic negative selection of T cells and could enhance the generation of tumor-specific T cells. We examined whether administering denosumab could modify modulate circulating immune cells in patients with cancer. Blood was collected from 23 patients with prostate cancer and 3 patients with renal cell carcinoma, all of whom had advanced disease and were receiving denosumab, prior to and during denosumab treatment. Using high-dimensional mass cytometry, we found that denosumab treatment by itself induced modest effects on circulating immune cell frequency and activation. We also found minimal changes in the circulating T-cell repertoire and the frequency of new thymic emigrants with denosumab treatment. However, when we stratified patients by whether they were receiving chemotherapy and/or steroids, patients receiving these concomitant treatments showed significantly greater immune modulation, including an increase in the frequency of natural killer cells early and classical monocytes later. We also saw broad induction of CTLA-4 and TIM3 expression in circulating lymphocytes and some monocyte populations. These findings suggest that denosumab treatment by itself has modest immunomodulatory effects, but when combined with conventional cancer treatments, can lead to the induction of immunologic checkpoints. See related Spotlight by Nasrollahi and Davar, p. 383.


Assuntos
Neoplasias Ósseas , Denosumab , Humanos , Masculino , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/prevenção & controle , Neoplasias Ósseas/secundário , Denosumab/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Ligante RANK/antagonistas & inibidores , Neoplasias da Próstata/tratamento farmacológico
10.
J Immunother Cancer ; 11(1)2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36593070

RESUMO

BACKGROUND: In preclinical studies of pancreatic ductal adenocarcinoma (PDAC), ibrutinib improved the antitumor efficacy of the standard of care chemotherapy. This led to a phase 1b clinical trial to determine the safety, tolerability, and immunologic effects of ibrutinib treatment in patients with advanced PDAC. METHODS: Previously untreated patients with PDAC were enrolled in a phase 1b clinical trial (ClinicalTrials.gov) to determine the safety, toxicity, and maximal tolerated dose of ibrutinib when administered with the standard regimen of gemcitabine and nab-paclitaxel. To study the immune response to ibrutinib alone, the trial included an immune response arm where patients were administered with ibrutinib daily for a week followed by ibrutinib combined with gemcitabine and nab-paclitaxel. Endoscopic ultrasonography-guided primary PDAC tumor biopsies and blood were collected before and after ibrutinib monotherapy. Changes in abundance and functional state of immune cells in the blood was evaluated by mass cytometry by time of flight and statistical scaffold analysis, while that in the local tumor microenvironment (TME) were assessed by multiplex immunohistochemistry. Changes in B-cell receptor and T-cell receptor repertoire were assessed by sequencing and analysis of clonality. RESULTS: In the blood, ibrutinib monotherapy significantly increased the frequencies of activated inducible T cell costimulator+(ICOS+) CD4+ T cells and monocytes. Within the TME, ibrutinib monotherapy led to a trend in decreased B-cell abundance but increased interleukin-10+ B-cell frequency. Monotherapy also led to a trend in increased mature CD208+dendritic cell density, increased late effector (programmed cell death protein 1 (PD-1-) eomesodermin (EOMES+)) CD8+ T-cell frequency, with a concomitantly decreased dysfunctional (PD-1+ EOMES+) CD8+ T-cell frequency. When ibrutinib was combined with chemotherapy, most of these immune changes were not observed. Patients with partial clinical responses had more diverse T and B cell receptor repertoires prior to therapy initiation. CONCLUSION: Ibrutinib monotherapy skewed the immune landscape both in the circulation and TME towards activated T cells, monocytes and DCs. These effects were not observed when combining ibrutinib with standard of care chemotherapy. Future studies may focus on other therapeutic combinations that augment the immunomodulatory effects of ibrutinib in solid tumors. TRIAL REGISTRATION NUMBER: NCT02562898.


Assuntos
Adenocarcinoma , Antineoplásicos , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Adenocarcinoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Carcinoma Ductal Pancreático/patologia , Gencitabina , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Receptor de Morte Celular Programada 1/uso terapêutico , Microambiente Tumoral , Neoplasias Pancreáticas
11.
Am J Cardiovasc Drugs ; 21(4): 443-452, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33313988

RESUMO

BACKGROUND: Venous thromboembolism (VTE) is a serious complication in medically ill inpatients. Enoxaparin or unfractionated heparin (UFH) thromboprophylaxis has been shown to reduce VTE in clinical trials; however, comparative effectiveness and differences in hospital costs are unknown in US hospital practice. OBJECTIVE: This study compared clinical and economic outcomes between enoxaparin and UFH thromboprophylaxis in medically ill inpatients. METHODS: A retrospective cohort study was conducted using the Premier Healthcare Database between 1 January 2010 and 30 September 2016. Inpatients aged ≥ 18 years with a ≥ 6-day hospital stay for serious medical conditions were included. Two patient groups receiving thromboprophylaxis were identified during hospitalization: one receiving enoxaparin and other receiving UFH. Regression models were constructed to compare VTE events, in-hospital mortality, pulmonary embolism (PE)-related mortality, major bleeding, and total hospital costs during both the index hospitalization and the 90-day readmission period between the two groups. RESULTS: A total of 242,474 and 134,384 inpatients received enoxaparin or UFH for thromboprophylaxis, respectively. Compared with UFH prophylaxis, enoxaparin was significantly associated with 15%, 9%, 33%, and 41% reduced odds of VTE, in-hospital mortality, PE-related mortality, and major bleeding, respectively, during index hospitalization, and 10% and 19% reduced odds of VTE and bleeding, respectively, during the readmission period. Mean total hospital costs were significantly lower in patients receiving enoxaparin prophylaxis than in those given UFH. CONCLUSIONS: Thromboprophylaxis with enoxaparin was associated with significantly reduced in-hospital VTE events, death, and major bleeding and lower hospital costs compared with UFH in hospitalized medically ill patients.


Assuntos
Anticoagulantes/administração & dosagem , Enoxaparina/administração & dosagem , Heparina/administração & dosagem , Tromboembolia Venosa/prevenção & controle , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/economia , Custos e Análise de Custo , Enoxaparina/economia , Feminino , Hemorragia/induzido quimicamente , Heparina/economia , Mortalidade Hospitalar , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores Sexuais , Fatores Socioeconômicos , Estados Unidos
12.
J Immunother Cancer ; 9(5)2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33986125

RESUMO

BACKGROUND: Sipuleucel-T is a US Food and Drug Administration-approved autologous cellular immunotherapy that improves survival in patients with metastatic castration-resistant prostate cancer (mCRPC). We examined whether administering ipilimumab after sipuleucel-T could modify immune and/or clinical responses to this treatment. METHODS: A total of 50 patients with mCRPC were enrolled into a clinical trial (NCT01804465, ClinicalTrials.gov) where they received ipilimumab either immediately or delayed 3 weeks following completion of sipuleucel-T treatment. Blood was collected at various timepoints of the study. Luminex assay for anti-prostatic acid phosphatase (PAP) and anti-PA2024-specific serum immunoglobulin G (IgG) and ELISpot for interferon-γ (IFN-γ) production against PAP and PA2024 were used to assess antigen-specific B and T cell responses, respectively. Clinical response was defined as >30% reduction in serum prostate-specific antigen levels compared with pretreatment levels. The frequency and state of circulating immune cells were determined by mass cytometry by time-of-flight and statistical scaffold analysis. RESULTS: We found the combination to be well tolerated with no unexpected adverse events occurring. The timing of ipilimumab did not significantly alter the rates of antigen-specific B and T cell responses, the primary endpoint of the clinical trial. Clinical responses were observed in 6 of 50 patients, with 3 having responses lasting longer than 3 months. The timing of ipilimumab did not significantly associate with clinical response or toxicity. The combination treatment did induce CD4 and CD8 T cell activation that was most pronounced with the immediate schedule. Lower frequencies of CTLA-4 positive circulating T cells, even prior to treatment, were associated with better clinical outcomes. Interestingly, these differences in CTLA-4 expression were associated with prior localized radiation therapy (RT) to the prostate or prostatic fossa. Prior radiation treatment was also associated with improved radiographic progression-free survival. CONCLUSION: Combining CTLA-4 blockade with sipuleucel-T resulted in modest clinical activity. The timing of CTLA-4 blockade following sipuleucel-T did not alter antigen-specific responses. Clinical responses were associated with both lower baseline frequencies of CTLA-4 expressing T cells and a history of RT. Prior cancer therapy may therefore result in long-lasting immune changes that influence responsiveness to immunotherapy with sipuleucel-T and anti-CTLA-4.


Assuntos
Biomarcadores Tumorais/sangue , Vacinas Anticâncer/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Ipilimumab/uso terapêutico , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Neoplasias de Próstata Resistentes à Castração/terapia , Células Th1/efeitos dos fármacos , Extratos de Tecidos/uso terapêutico , Microambiente Tumoral/imunologia , Idoso , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Vacinas Anticâncer/efeitos adversos , Células Cultivadas , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Ipilimumab/efeitos adversos , Ativação Linfocitária/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Neoplasias de Próstata Resistentes à Castração/imunologia , Células Th1/imunologia , Células Th1/metabolismo , Fatores de Tempo , Extratos de Tecidos/efeitos adversos , Resultado do Tratamento
13.
J Immunother Cancer ; 9(6)2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34083417

RESUMO

BACKGROUND: Glioblastoma (GBM) is refractory to immune checkpoint inhibitor (ICI) therapy. We sought to determine to what extent this immune evasion is due to intrinsic properties of the tumor cells versus the specialized immune context of the brain, and if it can be reversed. METHODS: We used CyTOF mass cytometry to compare the tumor immune microenvironments (TIME) of human tumors that are generally ICI-refractory (GBM and sarcoma) or ICI-responsive (renal cell carcinoma), as well as mouse models of GBM that are ICI-responsive (GL261) or ICI-refractory (SB28). We further compared SB28 tumors grown intracerebrally versus subcutaneously to determine how tumor site affects TIME and responsiveness to dual CTLA-4/PD-1 blockade. Informed by these data, we explored rational immunotherapeutic combinations. RESULTS: ICI-sensitivity in human and mouse tumors was associated with increased T cells and dendritic cells (DCs), and fewer myeloid cells, in particular PD-L1+ tumor-associated macrophages. The SB28 mouse model of GBM responded to ICI when grown subcutaneously but not intracerebrally, providing a system to explore mechanisms underlying ICI resistance in GBM. The response to ICI in the subcutaneous SB28 model required CD4 T cells and NK cells, but not CD8 T cells. Recombinant FLT3L expanded DCs, improved antigen-specific T cell priming, and prolonged survival of mice with intracerebral SB28 tumors, but at the cost of increased Tregs. Targeting PD-L1 also prolonged survival, especially when combined with stereotactic radiation. CONCLUSIONS: Our data suggest that a major obstacle for effective immunotherapy of GBM is poor antigen presentation in the brain, rather than intrinsic immunosuppressive properties of GBM tumor cells. Deep immune profiling identified DCs and PD-L1+ tumor-associated macrophages as promising targetable cell populations, which was confirmed using therapeutic interventions in vivo.


Assuntos
Neoplasias Encefálicas/terapia , Antígeno CTLA-4/metabolismo , Glioblastoma/terapia , Inibidores de Checkpoint Imunológico/administração & dosagem , Proteínas de Membrana/administração & dosagem , Receptor de Morte Celular Programada 1/metabolismo , Animais , Neoplasias Encefálicas/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Linhagem Celular Tumoral , Glioblastoma/imunologia , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Proteínas de Membrana/farmacologia , Camundongos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linfócitos T Reguladores/metabolismo , Evasão Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
14.
J Leukoc Biol ; 81(1): 212-20, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16997854

RESUMO

Complement C5a anaphylatoxin is a potent activator of macrophages, neutrophils, and dendritic cells (DC) and binds the C5a receptor (C5a-R; CD88). Although C5a is chemotactic for T cells, expression of C5a-R on murine T cells has been disputed. We report here that naïve, Con A-activated, and cytokine (IL-12, IL-18)-stimulated murine CD3+ T cells from three strains of mice [C57Bl/6, B10.nSn (C5+/+), B10.on (C5-/-)] lacked C5a-R, as evaluated by immunophenotyping with an anti-C5a-R mAb. Ligation of CD3 induced a modest up-regulation with 3% of CD3+ T cells expressing cell surface C5a-R. T cells primed by APC differentiate into effector T cells. Activation of mycobacteria [bacillus Calmette-Guerin (BCG)]-sensitized T cells through MHC II and TCR interactions via BCG-infected macrophages enhanced the expression of C5a-R with approximately 14% of CD3+ T cells positive for C5a-R. Comparable expression was found in C5+/+ as well as C5-/- strains of mice (14% and 15%, respectively). Furthermore, anti-CD3-activated T cells were primed by BCG-infected DC, and a larger proportion of the primed T cells expressed C5a-R (30-40%). Finally, mice infected with BCG showed significant numbers of CD3+ T cells expressing C5a-R in the spleens during infection. As APC, such as macrophages and DC, can secrete C5 and cleave C5 to C5a and C5b through a peptidase, we suggest that macrophage and DC-T cell interactions can up-regulate C5a-R on T cells through MHC II-TCR and provide a C5a peptide for additional local activation of T cells via C5a-R.


Assuntos
Complexo CD3/metabolismo , Células Dendríticas/fisiologia , Macrófagos/fisiologia , Mycobacterium/fisiologia , Receptor da Anafilatoxina C5a/metabolismo , Linfócitos T/metabolismo , Regulação para Cima , Animais , Apresentação de Antígeno , Células Cultivadas , Feminino , Ativação Linfocitária , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptor da Anafilatoxina C5a/genética , Sefarose/análogos & derivados , Sefarose/farmacologia
15.
J Pain Res ; 11: 1017-1025, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29881304

RESUMO

PURPOSE: Constipation is a well-known complication of surgery that can be exacerbated by opioid analgesics. This study evaluated resource utilization and costs associated with opioid-induced constipation (OIC). PATIENTS AND METHODS: This retrospective, observational, and propensity-matched cohort study utilized the Premier Healthcare Database. The study included adults ≥18 years of age undergoing total hip or total knee replacement as inpatients who received an opioid analgesic and were discharged between January 1, 2012, and June 30, 2015. Diagnosis codes identified patients with OIC who were then matched 1:1 to patients without OIC. Generalized linear and logistic regression models were used to compare inpatient resource utilization, total hospital costs, inpatient mortality, and 30-day all-cause readmissions and emergency department visits. RESULTS: Of 788,448 eligible patients, 40,891 (5.2%) had OIC. Covariates were well balanced between matched patients with and without OIC (n=40,890 each). In adjusted analyses, patients with OIC had longer hospital lengths of stay (3.6 versus 3.3 days; p<0.001), higher total hospital costs (US$17,479 versus US$16,265; p<0.001), greater risk of intensive care unit admission (odds ratio [OR]=1.12, 95% CI: 1.01-1.24), and increased likelihood of 30-day hospital read-missions (OR=1.16, 95% CI: 1.11-1.22) and emergency department visits (OR=1.38, 95% CI: 1.07-1.79) than patients without OIC. No statistically significant difference was found with inpatient mortality (OR=0.89, 95% CI: 0.59-1.35). CONCLUSION: OIC was associated with greater resource utilization and hospital costs for patients undergoing primarily elective total hip or total knee replacement surgery. These results support OIC screening and management strategies as part of perioperative care management.

16.
Bio Protoc ; 6(22)2016 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-28180137

RESUMO

In this protocol, we describe the method for isolating highly pure primary alveolar epithelial type II (ATII) cells from lungs of naïve mice. The method combines negative selection for a variety of lineage markers along with positive selection for EpCAM, a pan-epithelial cell marker. This method yields 2-3 × 106 ATII cells per mouse lung. The cell preps are highly pure and viable and can be used for genomic or proteomic analyses or cultured ex vivo to understand their roles in various biological processes.

17.
PLoS One ; 11(12): e0167693, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27977701

RESUMO

Excessive type 2 helper T cell responses to environmental antigens can cause immunopathology such as asthma and allergy, but how such immune responses are induced remains unclear. We studied this process in the airways by immunizing mice intranasally with the antigen ovalbumin together with either of two Toll-like receptor (TLR) ligands. We found the TLR5 ligand flagellin promoted a type 2 helper T cell response, whereas, a TLR9 ligand CpG oligodeoxyribonucleotide (ODN) promoted a type 1 helper T cell response. CpG ODN induced mRNA encoding interleukin (IL)-12 p40, whereas, flagellin caused IL-33 secretion and induced mRNAs encoding IL-1 and thymic stromal lymphopoietin (TSLP). By using mice deficient in the TLR and IL-1R signaling molecule, myeloid differentiation primary response 88 (MyD88), in conventional dendritic cells (cDCs) and alveolar macrophages (AMs), and by cell sorting different lung populations after 2 hours of in vivo stimulation, we characterized the cell types that rapidly produced inflammatory cytokines in response to TLR stimulation. CpG ODN was likely recognized by TLR9 on cDCs and AMs, which made mRNA encoding IL-12. IL-12 was necessary for the subsequent innate and adaptive interferon-γ production. In contrast, flagellin stimulated multiple cells of hematopoietic and non-hematopoietic origin, including AMs, DCs, monocytes, and lung epithelial cells. AMs were largely responsible for IL-1α, whereas lung epithelial cells made TSLP. Multiple hematopoietic cells, including AMs, DCs, and monocytes contributed to other cytokines, including IL-1ß and TNFα. MyD88-dependent signals, likely through IL-1R and IL-33R, and MyD88-independent signals, likely from TSLP, were necessary in cDCs for promotion of the early IL-4 response by CD4 T cells in the draining lymph node. Thus, the cell types that responded to TLR ligands were a critical determinant of the innate cytokines produced and the character of the resulting adaptive immune response in the airways.


Assuntos
Imunidade Adaptativa/efeitos dos fármacos , Flagelina/farmacologia , Oligonucleotídeos/farmacologia , Receptor 5 Toll-Like/metabolismo , Receptor Toll-Like 9/metabolismo , Animais , Citocinas/metabolismo , Feminino , Interleucina-1/metabolismo , Interleucina-33/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Fator 88 de Diferenciação Mieloide/metabolismo , Receptor 5 Toll-Like/agonistas , Receptor Toll-Like 9/agonistas , Linfopoietina do Estroma do Timo
18.
FASEB J ; 17(2): 136-43, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12554692

RESUMO

Autoantibodies to the recombinant extracellular domain of epidermal growth factor receptor (exEGFR) were detected by ELISA in the serum of Fas-defective old MRL/MpJ/lpr and C3H/HeJ/gld mice, but not young mice from these strains, or nonautoimmune young and old BALB/c, MRL/MpJ/++, and C3H/HeJ/MMTV mice. Compared with control human subjects without autoimmune disease, the frequency of exEGFR-binding autoantibodies was increased in scleroderma (systemic sclerosis) patients and to a lesser extent in lupus patients. Phage autoantibodies (Fv fragments) isolated from a lupus library by selection on a linear epitope of EGFR (residues 294-310) displayed the ability to bind exEGFR. Treatment of EGFR-expressing A431 cells with autoantibodies purified by affinity chromatography on immobilized exEGFR resulted in specific staining of the cells. Short-lived but strong inhibition of cellular DNA synthesis was observed in the presence of the autoantibodies. We concluded that autoantibody responses to EGFR hold the potential of fulfilling a pathogenic role in autoimmune disease.


Assuntos
Autoanticorpos/imunologia , Doenças Autoimunes/imunologia , Receptores ErbB/imunologia , Lúpus Vulgar/imunologia , Escleroderma Sistêmico/imunologia , Animais , Autoanticorpos/metabolismo , Autoanticorpos/farmacologia , DNA/biossíntese , DNA/efeitos dos fármacos , Receptores ErbB/metabolismo , Humanos , Fragmentos de Imunoglobulinas/imunologia , Fragmentos de Imunoglobulinas/metabolismo , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Imunoglobulina G/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Ligação Proteica , Células Tumorais Cultivadas
19.
Am J Respir Crit Care Med ; 173(8): 852-7, 2006 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-16439722

RESUMO

RATIONALE: Reports from our laboratory, as well as those from others, have documented the importance of complement activation, the C3a anaphylatoxin, and its receptor, C3aR, in promoting Th2 effector functions in a mouse model of bronchopulmonary allergy. Although deficiency in the fifth complement component (C5) has been linked to enhanced airway hyperresponsiveness in mice, the contribution of C5 to other major biological hallmarks of asthma has not been evaluated. OBJECTIVE: Accordingly, congenic C5-sufficient and C5-deficient mice were subjected to a mouse model of bronchopulmonary allergy to assess the impact of C5 on pulmonary inflammation and Th2 effector functions in experimental asthma. METHODS AND MAIN RESULTS: In contrast to observations reported for C3- and C3aR-deficient animals, C5-deficient mice exhibited significantly increased airway hyperresponsiveness relative to wild-type congenic control mice after antigen challenge. Moreover, challenged C5-deficient mice had a 3.4-fold and 2.7-fold increase in the levels of airway eosinophils and lung interleukin (IL)-4-producing cells, respectively, compared with challenged wild-type mice. Consistent with the numbers of IL-4-producing cells, C5-deficient mice also had increased bronchoalveolar lavage levels of the Th2 cytokines IL-5 and IL-13 and elevated serum levels of total and antigen-specific IgE. CONCLUSIONS: These data indicate that C5 plays an important protective role in allergic lung disease by suppressing inflammatory responses and Th2 effector functions observed in this experimental model. The protection provided by the presence of C5 is likely mediated by C5a, suggesting that C5a may play a significant role in tempering inflammation in Th2-driven diseases such as asthma.


Assuntos
Complemento C5/uso terapêutico , Fatores Imunológicos/uso terapêutico , Hipersensibilidade Respiratória/prevenção & controle , Animais , Biomarcadores/metabolismo , Ativação do Complemento/fisiologia , Complemento C3/deficiência , Complemento C5/deficiência , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Interferon gama/metabolismo , Interleucina-4/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/metabolismo , Células Th2/imunologia , Resultado do Tratamento
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