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The recruitment of cells with effector functions into the tumor microenvironment holds potential for delaying cancer progression. We show that subsets of human CD28-effector CD8 T cells, CCR7- CD45RO+ effector memory, and CCR7- CD45RO- effector memory RA phenotypes, express the chemerin receptor CMKLR1 and bind chemerin via the receptor. CMKLR1-expressing human CD8 effector memory T cells present gene, protein, and cytotoxic features of NK cells. Active chemerin promotes chemotaxis of CMKLR1-expressing CD8 effector memory cells and triggers activation of the α4ß1 integrin. In an experimental prostate tumor mouse model, chemerin expression is downregulated in the tumor microenvironment, which is associated with few tumor-infiltrating CD8+ T cells, while forced overexpression of chemerin by mouse prostate cancer cells leads to an accumulation of intra-tumor CD8+ T cells. Furthermore, α4 integrin blockade abrogated the chemerin-dependent recruitment of CD8+ T effector memory cells into implanted prostate tumors in vivo. The results identify a role for chemerin:CMKLR1 in defining a specialized NK-like CD8 T cell, and suggest the use of chemerin-dependent modalities to target effector CMKLR1-expressing T cells to the tumor microenvironment for immunotherapeutic purposes.
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Linfócitos T CD8-Positivos , Neoplasias , Humanos , Animais , Camundongos , Linfócitos T CD8-Positivos/metabolismo , Receptores CCR7/metabolismo , Subpopulações de Linfócitos T/metabolismo , Células Matadoras Naturais/metabolismo , Neoplasias/metabolismo , Quimiocinas/genética , Quimiocinas/metabolismo , Microambiente Tumoral , Peptídeos e Proteínas de Sinalização Intercelular/metabolismoRESUMO
BACKGROUND: Approximately 1% of all breast cancers occur in men. With an annual incidence of 130 cases in the Netherlands, the occurrence of male breast cancer is rare. CASE DESCRIPTION: We report the case of a 72-year-old male who was referred to a breast outpatient clinic for the evaluation of a multinodular skin lesion of the nipple. The nipple lesion was found to be an invasive carcinoma of the breast with neuroendocrine differentiation. Retrospectively, a breast abnormality could be detected on radiologic imaging 2 years prior to cancer diagnosis. CONCLUSION: Breast cancer in men is associated with an increased diagnostic delay compared to women and is subsequently diagnosed at a later stage. Studies on the survival of breast cancer report worse survival in men compared to women. Health care professionals should be alerted to the presence of a malignancy when dealing with abnormalities of the male breast.
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Neoplasias da Mama Masculina , Neoplasias da Mama , Neoplasias , Masculino , Humanos , Feminino , Idoso , Neoplasias da Mama Masculina/diagnóstico , Neoplasias da Mama Masculina/patologia , Estudos Retrospectivos , Diagnóstico Tardio , Neoplasias da Mama/diagnóstico , Neoplasias/epidemiologia , Mama/patologiaRESUMO
CD27 is a tumor necrosis factor (TNF) receptor, which stimulates lymphocytes and promotes their differentiation upon activation by TNF ligand CD70. Activation of the CD27 receptor provides a costimulatory signal to promote T cell, B cell, and NK cell activity to facilitate antitumor and anti-infection immunity. Aberrant increased and focused expression of CD70 on many tumor cells renders CD70 an attractive therapeutic target for direct tumor killing. However, despite their use as drug targets to treat cancers, the molecular basis and atomic details of CD27 and CD70 interaction remain elusive. Here we report the crystal structure of human CD27 in complex with human CD70. Analysis of our structure shows that CD70 adopts a classical TNF ligand homotrimeric assembly to engage CD27 receptors in a 3:3 stoichiometry. By combining structural and rational mutagenesis data with reported disease-correlated mutations, we identified the key amino acid residues of CD27 and CD70 that control this interaction. We also report increased potency for plate-bound CD70 constructs compared with solution-phase ligand in a functional activity to stimulate T-cells in vitro. These findings offer new mechanistic insight into this critical costimulatory interaction.
Assuntos
Ligante CD27/química , Complexos Multiproteicos/química , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/química , Ligante CD27/genética , Ligante CD27/imunologia , Cristalografia por Raios X , Humanos , Complexos Multiproteicos/genética , Complexos Multiproteicos/imunologia , Estrutura Quaternária de Proteína , Linfócitos T/imunologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologiaRESUMO
There is a well-described need to increase the competence of the primary care workforce in the principles of geriatrics and palliative care, and as value-based payment models proliferate, there is increased incentive for the acquisition of these skills. Through a Geriatric Workforce Enhancement Program grant, we developed an adaptable curriculum around commonly encountered topics in palliative care and geriatrics that can be delivered to multidisciplinary clinicians in primary care settings. All participants in this training were part of an Accountable Care Organization (ACO) and were motivated to improve to care for complex older adults. A needs assessment was performed on each practice or group of learners and the curriculum was adapted accordingly. With the use of patient education and screening tools with strong validity evidence, the participants were trained in the principals of geriatrics and palliative care with a focus on advance care planning and assessing for frailty and functional decline. Comparison of pre- and post-test scores demonstrated increased confidence and knowledge in goals of care and basic geriatric assessment. Participants described feeling more able to address needs, have conversations around goals of care, and more able to recognize patients who would benefit from collaboration with geriatrics and palliative care.
Assuntos
Geriatria/educação , Relações Interprofissionais , Cuidados Paliativos/organização & administração , Equipe de Assistência ao Paciente/organização & administração , Atenção Primária à Saúde/organização & administração , Organizações de Assistência Responsáveis/organização & administração , Idoso , Idoso de 80 Anos ou mais , Comportamento Cooperativo , Currículo , Avaliação Geriátrica , Humanos , Planejamento de Assistência ao Paciente , Educação de Pacientes como Assunto/organização & administração , Avaliação de Programas e Projetos de Saúde , Melhoria de Qualidade/organização & administraçãoRESUMO
Non-invasive imaging using radiolabels is a common technique used to study the biodistribution of biologics. Due to the limited shelf-life of radiolabels and the requirements of specialized labs, non-invasive optical imaging is an attractive alternative for preclinical studies. Previously, we demonstrated the utility of fluorescence molecular tomography (FMT) an optical imaging modality in evaluating the biodistribution of antibody-drug conjugates. As FMT is a relatively new technology, few fluorophores have been validated for in vivo imaging. The goal of this study was to characterize and determine the utility of near-infrared (NIR) fluorophores for biodistribution studies using interleukin-13 receptor subunit alpha-2 antibody (IL13Rα2-Ab). Eight fluorophores (ex/em: 630/800 nm) with an N-hydroxysuccinimide (NHS) linker were evaluated for Ab conjugation. The resulting antibody-fluorophore (Ab-F) conjugates were evaluated in vitro for degree of conjugation, stability and target-binding, followed by in vivo/ex vivo FMT imaging to determine biodistribution in a xenograft model. The Ab-F conjugates (except Ab-DyLight800) showed good in vitro stability and antigen binding. All Ab-F conjugates (except for Ab-BOD630) resulted in a quantifiable signal in vivo and had similar biodistribution profiles, with peak tumor accumulation between 6 and 24 h post-injection. In vivo/ex vivo FMT imaging showed 17-34% ID/g Ab uptake by the tumor at 96 h. Overall, this is the first study to characterize the biodistribution of an Ab using eight NIR fluorophores. Our results show that 3-dimensional optical imaging is a valuable technology to understand biodistribution and targeting, but a careful selection of the fluorophore for each Ab is warranted.
RESUMO
PURPOSE: To determine the optimal radiation dose for treatment of primary cutaneous anaplastic large cell lymphoma (C-ALCL) with solitary or localized, multifocal or recurrent skin lesions. METHODS AND MATERIALS: In this multicenter study, patients with C-ALCL who had been treated with radiation therapy (RT) between 1984 and 2016 were retrieved from the Dutch registry of cutaneous lymphomas. Distinction was made between patients first presenting with solitary or localized lesions (n=63), with multifocal skin lesions (n=6), and patients with a skin relapse (n=22). Radiation doses, treatment response, and follow-up were evaluated. Radiation doses were categorized as low-dose (≤20 Gy), intermediate-dose (21-39 Gy), and high-dose (≥40 Gy) RT. RESULTS: Of 63 patients presenting with solitary or localized skin lesions, 61 (97%) showed a complete response (CR). There were no differences in CR between low-dose (16 of 17), intermediate-dose (15 of 15), and high-dose RT (30 of 31). After a median follow-up of 46 months, 30 of 63 patients (48%) had a relapse, but in-field relapses were never observed. Six of 6 patients (100%) initially presenting with multifocal skin lesions showed a CR (3 of 3 low-dose, 2 of 2 intermediate-dose, 1 of 1 high-dose RT). After a median follow-up of 27 months, 3 of 6 patients had a relapse. Treatment of 33 skin relapses in 22 patients showed no differences in CR between low-dose (18 of 19), intermediate-dose (6 of 6), and high-dose RT (8 of 8). In the last 10 years there has been a decrease in radiation dose used in the treatment of C-ALCL. Treatment of multifocal and recurrent lesions with a dose of 8 Gy (2 × 4 Gy) resulted in CR of 17 of 18 lesions. CONCLUSIONS: Our results show that a radiation dose of 20 Gy (8 × 2.5 Gy) is effective in patients presenting with solitary or localized skin lesions. For patients with multifocal skin lesions and patients with a skin relapse, a dose of 8 Gy (2 × 4 Gy) may be sufficient.
Assuntos
Linfoma Anaplásico Cutâneo Primário de Células Grandes/radioterapia , Recidiva Local de Neoplasia/radioterapia , Neoplasias Primárias Múltiplas/radioterapia , Dosagem Radioterapêutica/normas , Neoplasias Cutâneas/radioterapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Linfoma Anaplásico Cutâneo Primário de Células Grandes/mortalidade , Linfoma Anaplásico Cutâneo Primário de Células Grandes/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Neoplasias Primárias Múltiplas/mortalidade , Neoplasias Primárias Múltiplas/patologia , Países Baixos , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Resultado do TratamentoRESUMO
Fibroblast growth factor 23 (FGF23) is the causative factor of X-linked hypophosphatemia (XLH), a genetic disorder effecting 1:20,000 that is characterized by excessive phosphate excretion, elevated FGF23 levels and a rickets/osteomalacia phenotype. FGF23 inhibits phosphate reabsorption and suppresses 1α,25-dihydroxyvitamin D (1,25D) biosynthesis, analytes that differentially contribute to bone integrity and deleterious soft-tissue mineralization. As inhibition of ligand broadly modulates downstream targets, balancing efficacy and unwanted toxicity is difficult when targeting the FGF23 pathway. We demonstrate that a FGF23 c-tail-Fc fusion molecule selectively modulates the phosphate pathway in vivo by competitive antagonism of FGF23 binding to the FGFR/α klotho receptor complex. Repeated injection of FGF23 c-tail Fc in Hyp mice, a preclinical model of XLH, increases cell surface abundance of kidney NaPi transporters, normalizes phosphate excretion, and significantly improves bone architecture in the absence of soft-tissue mineralization. Repeated injection does not modulate either 1,25D or calcium in a physiologically relevant manner in either a wild-type or disease setting. These data suggest that bone integrity can be improved in models of XLH via the exclusive modulation of phosphate. We posit that the selective modulation of the phosphate pathway will increase the window between efficacy and safety risks, allowing increased efficacy to be achieved in the treatment of this chronic disease. © 2017 American Society for Bone and Mineral Research.
Assuntos
Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Fatores de Crescimento de Fibroblastos/uso terapêutico , Animais , Densidade Óssea/efeitos dos fármacos , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/patologia , Calcificação Fisiológica/efeitos dos fármacos , Calcitriol/sangue , Calcitriol/farmacologia , Cálcio/sangue , Osso Esponjoso/patologia , Modelos Animais de Doenças , Raquitismo Hipofosfatêmico Familiar/sangue , Raquitismo Hipofosfatêmico Familiar/diagnóstico por imagem , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/química , Células HEK293 , Humanos , Camundongos , Peptídeos/farmacologia , Fosfatos/sangue , Ratos Wistar , Proteínas Recombinantes/farmacologia , Reabsorção Renal/efeitos dos fármacosRESUMO
IMPORTANCE: Large case series suggest that patients with folliculotropic mycosis fungoides (FMF) have a worse prognosis than patients with classic mycosis fungoides (MF). However, recent studies described a subgroup of patients with FMF with a more favorable prognosis. Distinction between indolent and aggressive FMF may have important therapeutic consequences but is hampered by the inability of the current tumor-node-metastasis-blood (TNMB) staging system to classify patients with FMF in a clinically meaningful way. OBJECTIVE: To differentiate between indolent and aggressive FMF using clinicopathological criteria and to define prognostic factors in patients with FMF. DESIGN, SETTING, AND PARTICIPANTS: In this prospective cohort study, we followed 203 patients with FMF, included in the Dutch Cutaneous Lymphoma Registry between October 1985 and May 2014 at a tertiary referral center hosting the Dutch Cutaneous Lymphoma Registry. Overall, 220 patients with FMF had been registered, but 17 patients with incomplete follow-up data or a history of classic MF were excluded. MAIN OUTCOMES AND MEASURES: Main outcomes included clinical and histological characteristics, disease progression, and survival. Prognostic factors were investigated using Cox proportional hazard regression analysis. Distinction between early plaque-stage FMF and advanced plaque-stage FMF was made by a blinded review of skin biopsy specimens from patients presenting with plaques. RESULTS: In a cohort of 147 men and 56 women (median [range] age, 59 [15-93] years), patients with histologically early plaque-stage FMF had a very similar overall survival (OS) rate to patients with only patches and/or follicular papules (10-year OS, 71% vs 80%), while the survival rate of patients with histologically advanced plaque-stage FMF was almost identical to that of patients presenting with tumors (10-year OS, 25% vs 27%). Subsequently, 3 clinical subgroups with significantly different survival data were distinguished: early skin-limited FMF (group A; n = 84; 5-year and 10-year OS, 92% and 72%); advanced skin-limited FMF (group B; n = 102; 5-year and 10-year OS, 55% and 28%); and FMF presenting with extracutaneous disease (group C; n = 17; 5-year and 10-year OS, 23% and 2%). Age at diagnosis, large cell transformation and secondary bacterial infection were independent risk factors for disease progression and/or poor survival. CONCLUSIONS AND RELEVANCE: The results of this study provide useful criteria to differentiate between indolent and aggressive FMF and confirm the existence of a subgroup of FMF with a favorable prognosis.
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Neoplasias de Cabeça e Pescoço/patologia , Micose Fungoide/patologia , Couro Cabeludo , Neoplasias Cutâneas/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Infecções Bacterianas/complicações , Progressão da Doença , Feminino , Folículo Piloso/patologia , Neoplasias de Cabeça e Pescoço/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Micose Fungoide/complicações , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Fatores de Risco , Neoplasias Cutâneas/complicações , Taxa de Sobrevida , Adulto JovemRESUMO
BACKGROUND: Combined oral contraceptives (COCs) have been associated with an increased risk of arterial thrombosis, i.e. myocardial infarction or ischemic stroke. However, as these diseases are rare in young women and as many types of combined oral contraception exist, the magnitude of the risk and the effect of different hormonal contents of COC preparations remain unclear. OBJECTIVES: To estimate the risk of myocardial infarction or ischemic stroke in users compared with non-users of different types, doses and generations of combined oral contraception. SEARCH METHODS: We searched electronic databases (MEDLINE (1966 to July 08, 2015), EMBASE (1980 to July 08, 2015), Popline (1970 to July 08, 2015) and LILACS (1985 to July 08, 2015) for eligible studies, without language restrictions. SELECTION CRITERIA: We included observational studies that recruited women in the reproductive age group (18 to 50 years) and compared the risk of myocardial infarction or ischemic stroke between users and non-users of COCs. DATA COLLECTION AND ANALYSIS: Two review authors independently selected relevant studies and extracted data. We pooled relative risks ()(combined odds ratios and one incidence rate ratio) and 95% confidence intervals (CIs) for myocardial infarction or ischemic stroke in users versus non-users of COCs.We combined the outcomes of myocardial infarction and ischemic stroke and also analysed these outcomes separately. Analyses were stratified according to estrogen dose and progestagen type. MAIN RESULTS: In total, we identified 1298 publications through the search strategy. We included 28 publications reporting on 24 studies. COC users were at increased risk of myocardial infarction or ischemic stroke compared with non-users: relative risk (RR) 1.6 (95% CI 1.3-1.9).These RRs were similar for myocardial infarction (1.6, 95% CI 1.2 to 2.1) and ischemic stroke (1.7, 95% CI 1.5 to 1.9). The risks did not vary clearly according to the generation of progestagen or according to progestagen type. When we stratified preparations according to estrogen dose, the risk of myocardial infarction or ischemic stroke seemed to increase with higher doses of estrogen. AUTHORS' CONCLUSIONS: This meta-analysis showed that the risk of myocardial infarction or ischemic stroke was 1.6-fold increased in women using COCs . The risk was highest for pills with > 50 microgram estrogen. When combined with the results of studies on the risk of venous thrombosis in COC users, it seems that the COC pill containing levonorgestrel and 30 µg of estrogen is the safest oral form of hormonal contraception.
Assuntos
Anticoncepcionais Orais Combinados/efeitos adversos , Estrogênios/efeitos adversos , Infarto do Miocárdio/induzido quimicamente , Progestinas/efeitos adversos , Acidente Vascular Cerebral/induzido quimicamente , Estudos de Casos e Controles , Estudos de Coortes , Estrogênios/administração & dosagem , Feminino , Humanos , Estudos Observacionais como Assunto , Progestinas/administração & dosagem , Medição de RiscoRESUMO
BACKGROUND: The risk of recurrent venous thrombosis is 2-fold higher in men than in women. In contrast, no such sex difference in the risk of first venous thrombosis has been reported. We hypothesized that, for a first event, a risk difference between the sexes is masked by female exposure to reproductive factors (oral contraception, pregnancy/puerperium, and postmenopausal hormone therapy). METHODS AND RESULTS: From the Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis (MEGA) study, a population-based case-control study on risk factors for venous thrombosis, 2915 patients with a first venous thrombosis and their partners as control subjects were included. Odds ratios and 95% confidence intervals for first venous thrombosis were assessed in men compared with women without reproductive risk factors by use of conditional logistic regression. Analyses were stratified in 10-year age categories to account for the variation in exposure to reproductive risk factors over different age groups and adjusted for body mass index and smoking. Overall, men had a 2.1-fold (95% confidence interval, 1.9-2.4) increased risk of first venous thrombosis compared with women without reproductive risk factors. Similar results were found when 10-year age categories were viewed separately. Adjustment for body mass index and smoking and exclusion of cancer patients did not materially affect the results. CONCLUSIONS: When female reproductive risk factors are taken into account, the risk of a first venous thrombosis is twice as high in men as in women. These findings are in line with previous studies on recurrent venous thrombosis and may have implications for future treatment and prevention strategies.
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Anticoncepcionais Orais/uso terapêutico , Terapia de Reposição de Estrogênios/estatística & dados numéricos , Caracteres Sexuais , Trombose Venosa/epidemiologia , Adolescente , Adulto , Distribuição por Idade , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Gravidez , Recidiva , Fatores de Risco , Distribuição por Sexo , Adulto JovemRESUMO
Superficial vein thrombosis (SVT) increases the risk of venous thrombosis fourfold to sixfold. As most individuals with SVT do not develop venous thrombosis, additional risk factors may explain the risk of developing a venous thrombosis. In the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis study, we assessed the risk of venous thrombosis in individuals with previous SVT and a mild thrombotic risk factor (smoking or overweight/obesity), a strong risk factor (surgery, hospitalization, plaster cast immobilization, or malignancy), or a reproductive factor in women (oral contraception, postmenopausal hormone therapy, or pregnancy/puerperium). Individuals with previous SVT alone had a 5.5-fold (95% confidence interval [CI], 4.4-6.8) increased risk of venous thrombosis. This was 9.3 (95% CI, 7.2-12.1) combined with a mild thrombotic risk factor, 31.4 (95% CI, 14.6-67.5) with a strong risk factor, and 34.9 (95% CI, 19.1-63.8) in women with a reproductive risk factor. The highest separate risk estimates were found for SVT with surgery (42.5; 95% CI, 10.2-177.6), hospitalization (49.8; 95% CI, 11.9-209.2), or oral contraception (43.0; 95% CI, 15.5-119.3 in women). In conclusion, the risk of venous thrombosis is markedly increased in individuals with previous SVT who have an acquired thrombotic risk factor.
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Vasculite/sangue , Vasculite/epidemiologia , Veias , Trombose Venosa/sangue , Trombose Venosa/epidemiologia , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Anticoncepcionais Orais , Terapia de Reposição de Estrogênios , Feminino , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Obesidade/epidemiologia , Fatores de Risco , Fumar/epidemiologia , Adulto JovemRESUMO
Patients with venous thrombosis (VT) have an increased risk of subsequent CVD (CVD), but the underlying pathophysiology is unclear. Using data from the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis follow-up study, 4480 patients with VT, 2926 partner control participants, and 2638 random digit dialing (RDD) control participants were followed-up between 1999 and 2008. Incidence rates and hazard ratios with 95% confidence intervals (95% CIs) of CVD (defined as myocardial infarction or ischemic stroke) were calculated for patients vs controls. Measurable confounders (age, sex, body mass index, smoking, chronic disease, malignancy, genetic thrombophilia, and procoagulant markers) were adjusted for when comparing patients with RDD controls. Unmeasured lifestyle-related factors were also considered by comparing patients with their partners. During a median follow-up time of 5 years, 124 CVD events occurred. Incidence of CVD per 1000 person-years was 3.2 (95% CI, 2.5-4.0) in patients, 2.2 (95% CI, 1.5-3.0) in partners, and 1.6 (95% CI, 0.9-2.6) in RDD controls. Crude hazard ratio was 2.2 (95% CI, 1.2-3.8) in patients compared with RDD controls and 1.5 (95% CI, 1.0-2.3) in patients compared with partners. After adjustment for all confounders, these risks attenuated to 1.8 (95% CI, 0.8-4.2) and 1.3 (95% CI, 0.7-2.5) for patients compared with RDD control participants and partners, respectively. In conclusion, individuals with VT had an increased risk of CVD. This could be explained by common etiologic factors.