Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 18 de 18
Filtrar
2.
Sci Rep ; 10(1): 19168, 2020 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-33154441

RESUMO

Antibody phage display is a powerful platform for discovery of clinically applicable high affinity monoclonal antibodies against a broad range of targets. Libraries generated from immunized animals offer the advantage of in vivo affinity-maturation of V regions prior to library generation. Despite advantages, few studies have described isolation of antibodies from rats using immune phage display. In our study, we describe a novel primer set, covering the full rat heavy chain variable and kappa light chain variable regions repertoire for the generation of an unbiased immune libraries. Since the immune repertoire of rats is poorly understood, we first performed a deep sequencing analysis of the V(D)J regions of VH and VLK genes, demonstrating the high abundance of IGVH2 and IGVH5 families for VH and IGVLK12 and IGVLK22 for VLK. The comparison of gene's family usage in naïve rats have been used to validate the frequency's distribution of the primer set, confirming the absence of PCR-based biases. The primers were used to generate and assemble a phage display library from human CD160-vaccinated rats. CD160 represents a valid therapeutic target as it has been shown to be expressed on chronic lymphocytic leukaemia cells and on the surface of newly formed vessels. We utilised a novel phage display panning strategy to isolate a high affinity pool (KD range: 0.399-233 nM) of CD160 targeting monoclonal antibodies. Subsequently, identified binders were tested for function as third generation Chimeric Antigen Receptors (CAR) T cells demonstrating specific cytolytic activity. Our novel primer set coupled with a streamlined strategy for phage display panning enable the rapid isolation and identification of high affinity antibodies from immunised rats. The therapeutic utility of these antibodies was demonstrated in CAR format.

4.
Biol Blood Marrow Transplant ; 26(12): 2211-2216, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32966880

RESUMO

Chimeric antigen receptor (CAR) T cell therapy is approved in the United States for the treatment of acute lymphocytic leukemia and aggressive B cell lymphomas. Multiple cardiovascular adverse events (CVEs) associated with CAR-Ts have been observed in small studies, but no large-scale studies exist. Leveraging the Food and Drug Administration (FDA) Adverse Events Reporting System (FAERS), we identified all reported adverse events (AEs) associated with CAR-T therapy (tisagenlecleucel and axicabtagene ciloleucel) from 2017 to 2019. Reports with missing age and sex were excluded. CVEs were classified into arrhythmias, heart failure (HF), myocardial infarction (MI), and other CVEs. Logistic regression and hierarchical clustering were used to identify factors associated with CVEs. A total of 996 reported AEs were observed (39.1% associated with tisagenlecleucel and 60% with axicabtagene ciloleucel). Of all patients experiencing AEs, the median age was 54 (interquartile range, 21 to 65) years; 38.9% were females. In total, 19.7% (196) of all AEs reported to the FDA were CVEs. The most common CVEs were arrhythmia (77.6%), followed by HF (14.3%) and MI (0.5%). In adjusted analysis a positive association was observed between those presenting with CVE with neurotoxicity (odds ratio, 1.76; 95% confidence interval, 1.20 to 2.60; P = .004). Additionally, when both CVE and cytokine release syndrome (CRS) are present, neurotoxicity is the most common noncardiac AE, which clusters with them (Jaccard similarity: 73.1). The mortality rate was 21.1% overall but 30.1% for those reporting CVEs. In FAERS, reported CVEs with CAR-T are associated with high reported mortality. The development of either CRS or neurotoxicity should prompt vigilance for cardiovascular events.

5.
Front Immunol ; 11: 1694, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32849591

RESUMO

Cytomegalovirus (CMV) infection is common following allogeneic hematopoietic stem cell transplant (HSCT) and is a major cause of morbidity and increased mortality. Whilst pharmacotherapy can be effective in the prevention and treatment of CMV, these agents are often expensive, toxic and in some cases ineffective due to viral resistance mechanisms. Immunotherapeutic approaches are compelling and early clinical trials of adoptively transferred donor-derived virus-specific T (VST) cells against CMV have demonstrated efficacy. However, significant logistical challenges limit their broad application. Strategies to optimize VST manufacture and cell banking alongside scientific developments to enhance efficacy whilst minimizing toxicity are ongoing. This review will discuss the development of CMV-specific T-cell therapies, the challenges of widespread delivery of VSTs for CMV and explore how VST therapy can change outcomes in CMV infection following HSCT.

6.
Br J Haematol ; 191(2): 194-206, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32678948

RESUMO

Haematology patients receiving chemo- or immunotherapy are considered to be at greater risk of COVID-19-related morbidity and mortality. We aimed to identify risk factors for COVID-19 severity and assess outcomes in patients where COVID-19 complicated the treatment of their haematological disorder. A retrospective cohort study was conducted in 55 patients with haematological disorders and COVID-19, including 52 with malignancy, two with bone marrow failure and one immune-mediated thrombotic thrombocytopenic purpura (TTP). COVID-19 diagnosis coincided with a new diagnosis of a haematological malignancy in four patients. Among patients, 82% were on systemic anti-cancer therapy (SACT) at the time of COVID-19 diagnosis. Of hospitalised patients, 37% (19/51) died while all four outpatients recovered. Risk factors for severe disease or mortality were similar to those in other published cohorts. Raised C-reactive protein at diagnosis predicted an aggressive clinical course. The majority of patients recovered from COVID-19, despite receiving recent SACT. This suggests that SACT, where urgent, should be administered despite intercurrent COVID-19 infection, which should be managed according to standard pathways. Delay or modification of therapy should be considered on an individual basis. Long-term follow-up studies in larger patient cohorts are required to assess the efficacy of treatment strategies employed during the pandemic.

7.
Pract Neurol ; 20(4): 285-293, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32503897

RESUMO

Chimeric antigen receptor (CAR) T-cell therapy is one of the most innovative therapies for haematological malignancies to emerge in a generation. Clinical studies have shown that a single dose of CAR T-cells can deliver durable clinical remissions for some patients with B-cell cancers where conventional therapies have failed.A significant complication of CAR therapy is the immune effector cell-associated neurotoxicity syndrome (ICANS). This syndrome presents a continuum from mild tremor to cerebral oedema and in a minority of cases, death. Management of ICANS is mainly supportive, with a focus on seizure prevention and attenuation of the immune system, often using corticosteroids. Parallel investigation to exclude other central nervous system pathologies (infection, disease progression) is critical. In this review, we discuss current paradigms around CAR T-cell therapy, with a focus on appropriate investigation and management of ICANS.

10.
Cytotherapy ; 21(3): 327-340, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30685216

RESUMO

Clinical trials of adoptively transferred CD19 chimeric antigen receptor (CAR) T cells have delivered unprecedented responses in patients with relapsed refractory B-cell malignancy. These results have prompted Food and Drug Administration (FDA) approval of two CAR T-cell products in this high-risk patient population. The widening range of indications for CAR T-cell therapy and increasing patient numbers present a significant logistical challenge to manufacturers aiming for reproducible delivery systems for high-quality clinical CAR T-cell products. This review discusses current and novel CAR T-cell processing methodologies and the quality control systems needed to meet the increasing clinical demand for these exciting new therapies.


Assuntos
Imunoterapia Adotiva/métodos , Instalações Industriais e de Manufatura/normas , Neoplasias/terapia , Controle de Qualidade , Receptores de Antígenos Quiméricos , Antígenos CD19/imunologia , Remoção de Componentes Sanguíneos/métodos , Sobrevivência Celular , Criopreservação/métodos , Endotoxinas/análise , Humanos , Imunoterapia Adotiva/efeitos adversos , Ativação Linfocitária , Mycoplasma , Linfócitos T/imunologia , Transdução Genética/métodos
11.
Blood ; 132(20): 2154-2165, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30181174

RESUMO

Improving outcomes in multiple myeloma will involve not only development of new therapies but also better use of existing treatments. We performed RNA sequencing on samples from newly diagnosed patients enrolled in the phase 2 PADIMAC (Bortezomib, Adriamycin, and Dexamethasone Therapy for Previously Untreated Patients with Multiple Myeloma: Impact of Minimal Residual Disease in Patients with Deferred ASCT) study. Using synthetic annealing and the large margin nearest neighbor algorithm, we developed and trained a 7-gene signature to predict treatment outcome. We tested the signature in independent cohorts treated with bortezomib- and lenalidomide-based therapies. The signature was capable of distinguishing which patients would respond better to which regimen. In the CoMMpass data set, patients who were treated correctly according to the signature had a better progression-free survival (median, 20.1 months vs not reached; hazard ratio [HR], 0.40; confidence interval [CI], 0.23-0.72; P = .0012) and overall survival (median, 30.7 months vs not reached; HR, 0.41; CI, 0.21-0.80; P = .0049) than those who were not. Indeed, the outcome for these correctly treated patients was noninferior to that for those treated with combined bortezomib, lenalidomide, and dexamethasone, arguably the standard of care in the United States but not widely available elsewhere. The small size of the signature will facilitate clinical translation, thus enabling more targeted drug regimens to be delivered in myeloma.


Assuntos
Antineoplásicos/uso terapêutico , Bortezomib/uso terapêutico , Lenalidomida/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dexametasona/uso terapêutico , Doxorrubicina/uso terapêutico , Humanos , Estimativa de Kaplan-Meier , Aprendizado de Máquina , Mutação , Modelos de Riscos Proporcionais , Análise de Sequência de RNA , Transcriptoma , Resultado do Tratamento , Estados Unidos
12.
Cancer Cell ; 33(4): 649-663.e4, 2018 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-29576375

RESUMO

With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8+ to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Melanoma/tratamento farmacológico , Polimorfismo de Nucleotídeo Único , Receptores de IgG/genética , Linfócitos T Reguladores/imunologia , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Antineoplásicos Imunológicos/farmacologia , Antígeno CTLA-4/antagonistas & inibidores , Linhagem Celular Tumoral , Feminino , Humanos , Ipilimumab/administração & dosagem , Ipilimumab/farmacologia , Melanoma/genética , Melanoma/imunologia , Camundongos , Receptores de IgG/metabolismo , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
13.
J Clin Invest ; 127(7): 2513-2522, 2017 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-28628043

RESUMO

Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections following allogeneic hematopoietic stem cell transplantation (HSCT) are a major cause of morbidity and mortality. Early clinical trials demonstrate that adoptive transfer of donor-derived virus-specific T cells to restore virus-specific immunity is an effective strategy to control CMV and EBV infection after HSCT, conferring protection in 70%-90% of patients. The field has evolved rapidly to develop solutions to some of the manufacturing challenges identified in early clinical studies, such as prolonged in vitro culture, optimization of the purity of the virus-specific T cell product, the potential limitations of targeting a single viral antigen, and how to manage the patient with a virus-naive donor. This Review both discusses the seminal early studies and explores cutting-edge novel technologies that broaden the feasibility of and the scope for delivering virus-specific T cells to patients after HSCT.


Assuntos
Transferência Adotiva , Infecções por Citomegalovirus/terapia , Citomegalovirus/imunologia , Infecções por Vírus Epstein-Barr/terapia , Transplante de Células-Tronco Hematopoéticas , Herpesvirus Humano 4/imunologia , Aloenxertos , Infecções por Citomegalovirus/imunologia , Infecções por Vírus Epstein-Barr/imunologia , Humanos
14.
Immunotargets Ther ; 3: 67-78, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-27482517

RESUMO

Ipilimumab is a fully human immunoglobulin subclass G1 anticytotoxic-T-lymphocyte-antigen-4 monoclonal antibody. It has been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency for use in advanced melanoma following clear evidence of survival benefit in randomized Phase III studies. It is also under investigation as a treatment for other solid tumors such as renal cell, lung, and prostate cancers. The purported mechanism of antitumor activity of ipilimumab is through T-cell activation, and the side effect profile reflects this. Immune-related adverse events (irAEs) affect 60% of treated patients and 15% are defined as severe. Fortunately, most irAEs are reversible with early diagnosis and correct management. FDA approval of ipilimumab is dependent on the careful execution of a risk evaluation and mitigation strategy, with the aim of increasing awareness amongst patients and clinicians of the immunological risks of treatment, and providing algorithms for management of irAEs as they develop. Ipilimumab is one of the first immunotherapies to become widely available in the setting of solid tumors, and ongoing research aims to elucidate optimal dosing, optimal scheduling, and expanded access to ipilimumab as an adjuvant or maintenance therapy where appropriate. The identification of clinical correlates or biomarkers to identify those likely to benefit from this high-cost therapy is a top priority.

15.
J Exp Med ; 210(9): 1695-710, 2013 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-23897981

RESUMO

Treatment with monoclonal antibody specific for cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), an inhibitory receptor expressed by T lymphocytes, has emerged as an effective therapy for the treatment of metastatic melanoma. Although subject to debate, current models favor a mechanism of activity involving blockade of the inhibitory activity of CTLA-4 on both effector (T eff) and regulatory (T reg) T cells, resulting in enhanced antitumor effector T cell activity capable of inducing tumor regression. We demonstrate, however, that the activity of anti-CTLA-4 antibody on the T reg cell compartment is mediated via selective depletion of T reg cells within tumor lesions. Importantly, T reg cell depletion is dependent on the presence of Fcγ receptor-expressing macrophages within the tumor microenvironment, indicating that T reg cells are depleted in trans in a context-dependent manner. Our results reveal further mechanistic insight into the activity of anti-CTLA-4-based cancer immunotherapy, and illustrate the importance of specific features of the local tumor environment on the final outcome of antibody-based immunomodulatory therapies.


Assuntos
Antígeno CTLA-4/antagonistas & inibidores , Depleção Linfocítica , Linfócitos do Interstício Tumoral/imunologia , Melanoma/imunologia , Melanoma/terapia , Receptores de IgG/metabolismo , Linfócitos T Reguladores/imunologia , Animais , Anticorpos Bloqueadores/farmacologia , Anticorpos Bloqueadores/uso terapêutico , Antígeno CD11b/metabolismo , Antígenos CD4/metabolismo , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Células Clonais , Proteína Ligante Fas/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Linfonodos/patologia , Contagem de Linfócitos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/patologia , Melanoma/patologia , Melanoma/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , Fagócitos/efeitos dos fármacos , Fagócitos/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
16.
Expert Opin Biol Ther ; 11(4): 473-87, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21269237

RESUMO

INTRODUCTION: Allogeneic hematopoietic stem cell transplantation (SCT) is the treatment of choice for many malignant hematological disorders. Following recent improvements in non-relapse-related mortality rates, relapse has become the commonest cause of treatment failure. Infusion of donor lymphocytes can potentially enhance immune-mediated antitumor activity and offers a salvage option for some patients. This paper reviews the current literature on the efficacy of this therapeutic strategy. AREAS COVERED: The biology of adoptive cellular therapy with allogeneic immune cells to treat relapse across a spectrum of diseases in both the full intensity and reduced intensity hematopoietic SCT settings is explored. The review discusses the current limitations of the approach and reviews several new experimental strategies which aim to segregate the desired graft-versus-tumor effect from the deleterious effects of more widespread graft-versus-host reactivity. EXPERT OPINION: Durable responses to DLI have been noted in chronic myeloid leukemia and responses have also been described in acute leukemia, multiple myeloma and chronic lymphoproliferative disorders. The new challenge in transplantation is to optimize DLI therapy in order to further improve patient outcomes.


Assuntos
Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Transfusão de Linfócitos , Doadores de Tecidos , Adulto , Animais , Criança , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Efeito Enxerto vs Tumor , Neoplasias Hematológicas/história , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/cirurgia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/história , História do Século XX , Humanos , Transfusão de Linfócitos/efeitos adversos , Transfusão de Linfócitos/história , Neoplasia Residual , Prevenção Secundária , Linfócitos T Reguladores/imunologia , Doadores de Tecidos/história , Transplante Homólogo , Resultado do Tratamento
17.
Biol Blood Marrow Transplant ; 12(12): 1310-7, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17162213

RESUMO

Relapsed acute myeloid leukemia (AML) in adults has a poor prognosis if treated with chemotherapy alone. Case series have previously supported the role of myeloablation and autologous transplantation as a potentially curative treatment. This study aimed to use the large numbers and extended follow-up data in the British Society of Blood and Marrow Transplantation (BSBMT) registry database to establish long-term outcomes and relate these to biological and procedural factors. The BSBMT registry database was used to retrospectively identify 152 adult patients (age, 16-69 years) with AML in second remission treated with autologous transplantation in 1982-2003. Cytogenetic data were available for 68% of the patients; of these, at diagnosis, 42% had good risk features, 57% had standard risk features, and 1% had poor risk features. Conditioning regimens varied; autologous rescue was provided with bone marrow (BM) (71%), peripheral blood stem cells (PBSCs) (18%), or both (11%), which were harvested during first complete remission (CR1) and/or second CR (CR2). Median follow-up was 84 months (range, 2-200 months). At 10 years, actuarial overall survival (OS) was 32%, progression-free survival (PFS) was 28%, and relapse rate (RR) was 57%. The 100-day nonrelapse mortality (NRM) was 7%, rising to 11% at 1 year and to 14% at 10 years. OS was significantly related to M3 subtype (5-year OS, 66%; P = .005), patient age at diagnosis (P = .005) and transplantation (P = .026), and length of CR1, with greatest significance if the patient was dichotomized at CR1 duration of < 8 months or > or = 8 months (P = .0001). There was no difference in OS between regimens containing total body irradiation (TBI) and chemotherapy alone (P = .7). In relation to the nature of autologous graft material, there was improved OS (P = .025) and PFS (P = .009) with the use of cells harvested entirely in CR1 compared with cells harvested in CR2 or in both CR1 and CR2. Engraftment times were significantly shortened with the use of PBSCs alone or in combination with BM compared with BM alone (P = .0001), but there was no significant long-term impact on OS, PFS, RR, or NRM. This study provides long-term follow-up data in one of the largest series of patients with standard-risk and good-risk AML in CR2 treated with autologous transplantation and supports earlier observations that long-term survival is achievable in about 1/3 of patients overall and in about 2/3 of patients with M3 with a relatively low NRM. Outcomes are better in patients with CR1 > or = 8 months by use of grafts obtained entirely in CR1 and use of PBSCs. TBI conditioning did not confer an advantage. Randomized studies against unrelated donor transplantation are warranted.


Assuntos
Transplante de Medula Óssea/estatística & dados numéricos , Leucemia Mieloide/cirurgia , Transplante de Células-Tronco de Sangue Periférico/estatística & dados numéricos , Terapia de Salvação , Condicionamento Pré-Transplante/estatística & dados numéricos , Transplante Autólogo/estatística & dados numéricos , Doença Aguda , Adolescente , Adulto , Fatores Etários , Idoso , Bussulfano/administração & dosagem , Bussulfano/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Pessoa de Meia-Idade , Sistema de Registros/estatística & dados numéricos , Indução de Remissão , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida , Condicionamento Pré-Transplante/métodos , Reino Unido/epidemiologia , Irradiação Corporal Total/estatística & dados numéricos
18.
Bone ; 39(2): 369-76, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16644301

RESUMO

Fibroblast growth factor 23 (FGF23) is now recognized as a key regulator of phosphate metabolism. Numerous reports have found elevated serum FGF23 concentrations in oncogenic osteomalacia associated with mesenchymal tumors. Hypophosphatemic osteomalacia more rarely occurs in non-mesenchymal tumors. We identified elevated serum FGF23 levels in one patient with chronic lymphatic leukemia (CLL) and hypophosphatemia, prompting us to examine FGF23 concentrations in other patients with B-cell neoplasms. FGF23 levels were elevated in several patients with myeloma and monoclonal gammopathy of undetermined significance (MGUS), and were significantly associated with serum paraprotein and beta-2 microglobulin concentrations in these patients. Hypophosphatemia was not observed even in those patients with elevated FGF23, and a weak positive correlation was noted between serum FGF23 and phosphate concentrations. Malignant plasma cells in bone marrow trephines from patients with myeloma showed cytoplasmic expression of FGF23, similar to the cytoplasmic localization of FGF23 already described in mesenchymal tumors associated with oncogenic osteomalacia. Our findings contribute to an expanding literature regarding abnormal FGF/FGF receptor-signaling in myeloma. The absence of hypophosphatemia in these cases suggests either that FGF23 produced by clonal B-cells lacks systemic bioactivity or that other factors contribute to maintain serum phosphate. We suggest that the relationship between FGF23 and skeletal disease associated with plasma cell dyscrasias deserves further study.


Assuntos
Fatores de Crescimento de Fibroblastos/sangue , Plasmócitos/patologia , Idoso , Cálcio/sangue , Evolução Fatal , Feminino , Humanos , Hipofosfatemia/sangue , Imuno-Histoquímica , Leucemia Linfocítica Crônica de Células B/diagnóstico , Osteomalacia/sangue , Fosfatos/sangue , Microglobulina beta-2/sangue
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...