RESUMO
Class III malocclusion for individuals with cleft lip and palate has historically been managed with surgery. Orthodontic protraction is a noninvasive alternative that may be associated with lower costs. This analysis investigated the budget impact of protraction versus surgery from an institutional perspective. Using a decision tree, analysis was conducted using costs derived from Medicaid reimbursement codes and using actual institutional reimbursement. Probabilities of success, failure, and complications were based on a clinical trial comparing the 2 treatment modalities. One-way and probabilistic sensitivity analyses tested the robustness of results to model parameters. Based on Medicaid fee schedules and failure rates requiring additional surgery, the total cost of protraction was $79,506 versus $172,807 for surgery, resulting in $93,302 cost-savings per patient. The cost and probability of surgery success, as well as the cost of surgery failure and repeat surgery, had the largest impact on these cost-savings. Probabilistic sensitivity analysis showed cost-savings of nearly $92,000 or higher in >50% of simulations. This study showed that protraction is associated with lower costs than surgery and may present a cost-effective alternative to surgery in eligible, appropriate patients.
Assuntos
Fenda Labial , Fissura Palatina , Má Oclusão Classe III de Angle , Humanos , Fenda Labial/cirurgia , Fissura Palatina/cirurgiaRESUMO
Studies of inherited platelet disorders have provided many insights into platelet development and function. Loss of function of neurobeachin-like 2 (NBEAL2) causes gray platelet syndrome (GPS), where the absence of platelet α-granules indicates NBEAL2 is required for their production by precursor megakaryocytes. The endoplasmic reticulum is a dynamic network that interacts with numerous intracellular vesicles and organelles and plays key roles in their development. The megakaryocyte endoplasmic reticulum is extensive, and in this study we investigated its role in the biogenesis of α-granules by focusing on the membrane-resident trafficking protein SEC22B. Coimmunoprecipitation (co-IP) experiments using tagged proteins expressed in human HEK293 and megakaryocytic immortalized megakaryocyte progenitor (imMKCL) cells established binding of NBEAL2 with SEC22B, and demonstrated that NBEAL2 can simultaneously bind SEC22B and P-selectin. NBEAL2-SEC22B binding was also observed for endogenous proteins in human megakaryocytes using co-IP, and immunofluorescence microscopy detected substantial overlap. SEC22B binding was localized to a region of NBEAL2 spanning amino acids 1798 to 1903, where 2 GPS-associated missense variants have been reported: E1833K and R1839C. NBEAL2 containing either variant did not bind SEC22B coexpressed in HEK293 cells. CRISPR/Cas9-mediated knockout of SEC22B in imMKCL cells resulted in decreased NBEAL2, but not vice versa. Loss of either SEC22B or NBEAL2 expression resulted in failure of α-granule production and reduced granule proteins in imMKCL cells. We conclude that SEC22B is required for α-granule biogenesis in megakaryocytes, and that interactions with SEC22B and P-selectin facilitate the essential role of NBEAL2 in granule development and cargo stability.
Assuntos
Proteínas Sanguíneas/fisiologia , Grânulos Citoplasmáticos/fisiologia , Retículo Endoplasmático/fisiologia , Megacariócitos/ultraestrutura , Biogênese de Organelas , Proteínas R-SNARE/fisiologia , Sítios de Ligação , Proteínas Sanguíneas/deficiência , Proteínas Sanguíneas/genética , Células Cultivadas , Técnicas de Inativação de Genes , Síndrome da Plaqueta Cinza/genética , Células HEK293 , Humanos , Imunoprecipitação , Células Progenitoras de Megacariócitos , Megacariócitos/metabolismo , Microscopia Confocal , Microscopia de Fluorescência , Mutação de Sentido Incorreto , Selectina-P/fisiologia , Mapeamento de Interação de Proteínas , Proteínas Recombinantes/metabolismoRESUMO
Cushing's syndrome (CS) during pregnancy is rare. It causes the clinical disorder by overproduction of cortisol. Hypercortisolemia in pregnancy can lead to severe complications, both for the mother and the fetus, including spontaneous abortion, perinatal death, prematurity, maternal hypertension, heart failure, diabetes and opportunistic infections. The most common cause of hypercortisolemia in pregnancy is a cortisol-secreting adrenal tumor. Herein we present a 31 year-old female patient, at 20 weeks' gestation, with CS secondary to a left adrenal tumor. A brief review of reported similar cases is included.
Assuntos
Neoplasias do Córtex Suprarrenal/cirurgia , Adenoma Adrenocortical/cirurgia , Síndrome de Cushing/cirurgia , Laparoscopia , Complicações na Gravidez/cirurgia , Neoplasias do Córtex Suprarrenal/complicações , Adenoma Adrenocortical/complicações , Adulto , Síndrome de Cushing/etiologia , Feminino , Humanos , Gravidez , Complicações na Gravidez/etiologia , Espaço Retroperitoneal/cirurgiaRESUMO
OBJECTIVES: Yttrium-90 (Y90)-radioembolisation (RE) significantly regresses locally advanced hepatocellular carcinoma and delays disease progression. The current study is designed to deeply interrogate the immunological impact of Y90-RE, which elicits a sustained therapeutic response. DESIGN: Time-of-flight mass cytometry and next-generation sequencing (NGS) were used to analyse the immune landscapes of tumour-infiltrating leucocytes (TILs), tumour tissues and peripheral blood mononuclear cells (PBMCs) at different time points before and after Y90-RE. RESULTS: TILs isolated after Y90-RE exhibited signs of local immune activation: higher expression of granzyme B (GB) and infiltration of CD8+ T cells, CD56+ NK cells and CD8+ CD56+ NKT cells. NGS confirmed the upregulation of genes involved in innate and adaptive immune activation in Y90-RE-treated tumours. Chemotactic pathways involving CCL5 and CXCL16 correlated with the recruitment of activated GB+CD8+ T cells to the Y90-RE-treated tumours. When comparing PBMCs before and after Y90-RE, we observed an increase in tumour necrosis factor-α on both the CD8+ and CD4+ T cells as well as an increase in percentage of antigen-presenting cells after Y90-RE, implying a systemic immune activation. Interestingly, a high percentage of PD-1+/Tim-3+CD8+ T cells coexpressing the homing receptors CCR5 and CXCR6 denoted Y90-RE responders. A prediction model was also built to identify sustained responders to Y90-RE based on the immune profiles from pretreatment PBMCs. CONCLUSION: High-dimensional analysis of tumour and systemic immune landscapes identified local and systemic immune activation that corresponded to the sustained response to Y90-RE. Potential biomarkers associated with a positive clinical response were identified and a prediction model was built to identify sustained responders prior to treatment.
Assuntos
Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/radioterapia , Leucócitos Mononucleares/imunologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/radioterapia , Radioisótopos de Ítrio , Células Apresentadoras de Antígenos/imunologia , Biomarcadores Tumorais/imunologia , Quimiocina CCL5/imunologia , Quimiocina CXCL16/imunologia , Progressão da Doença , Feminino , Citometria de Fluxo/métodos , Granzimas/imunologia , Humanos , Linfócitos do Interstício Tumoral/imunologia , Masculino , Singapura , Resultado do Tratamento , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Objective- Human and mouse megakaryocytes lacking NBEAL2 (neurobeachin-like 2) produce platelets where α-granules lack protein cargo. This cargo is mostly megakaryocyte-synthesized, but some proteins, including FGN (fibrinogen), are endocytosed. In this study, we examined the trafficking of both types of cargo within primary megakaryocytes cultured from normal and NBEAL2-null mice, to determine the role of NBEAL2 in α-granule maturation. We also examined the interaction of NBEAL2 with the granule-associated protein P-selectin in human megakaryocytes and platelets. Approach and Results- Fluorescence microscopy was used to compare uptake of labeled FGN by normal and NBEAL2-null mouse megakaryocytes, which was similar in both. NBEAL2-null cells, however, showed decreased FGN retention, and studies with biotinylated protein showed rapid loss rather than increased degradation. Intracellular tracking via fluorescence microscopy revealed that in normal megakaryocytes, endocytosed FGN sequentially associated with compartments expressing RAB5 (Ras-related protein in brain 5), RAB7 (Ras-related protein in brain 7), and P-selectin, where it was retained. A similar initial pattern was observed in NBEAL2-null megakaryocytes, but then FGN passed from the P-selectin compartment to RAB11 (Ras-related protein in brain 11)-associated endosomes before release. Megakaryocyte-synthesized VWF (Von Willebrand factor) was observed to follow the same route out of NBEAL2-null cells. Immunofluorescence microscopy revealed intracellular colocalization of NBEAL2 with P-selectin in human megakaryocytes, proplatelets, and platelets. Native NBEAL2 and P-selectin were coimmunoprecipitated from platelets and megakaryocytes. Conclusions- NBEAL2 is not required for FGN uptake by megakaryocytes. NBEAL2 is required for the retention of both endocytosed and megakaryocyte-synthesized proteins by maturing α-granules, and possibly by platelet-borne granules. This function may involve interaction of NBEAL2 with P-selectin.
Assuntos
Proteínas Sanguíneas/metabolismo , Grânulos Citoplasmáticos/metabolismo , Endocitose , Fibrinogênio/metabolismo , Megacariócitos/metabolismo , Animais , Proteínas Sanguíneas/deficiência , Proteínas Sanguíneas/genética , Células Cultivadas , Endossomos/metabolismo , Feminino , Masculino , Camundongos Knockout , Selectina-P/metabolismo , Transporte Proteico , Via Secretória , Proteínas rab de Ligação ao GTP/metabolismo , Proteínas rab5 de Ligação ao GTP/metabolismo , proteínas de unión al GTP Rab7 , Fator de von Willebrand/metabolismoRESUMO
Purpose To compare lesion primary patency and restenosis rates between drug-eluting balloon (DEB) percutaneous transluminal angioplasty (PTA) and conventional balloon PTA (cPTA) in the treatment of arteriovenous fistula (AVF) and arteriovenous graft (AVG) stenosis. Materials and Methods In this prospective study, 119 participants (mean age, 59.2 years; 79 men, 40 women) with failing AVFs (n = 98) or AVGs (n = 21) were randomly assigned to undergo either DEB PTA (n = 59) or cPTA (n = 60) from January 2012 to May 2013. Primary end points were lesion primary patency and restenosis rates at 6 months; secondary outcomes were anatomic and clinical success after PTA, circuit primary patency at 6 months and 1 year, and lesion primary patency at 1 year. Statistical analysis was performed by using the Kaplan-Meier product limit estimator, and hazard ratio was calculated by using Cox proportional hazards regression. Complication rates were assessed in both groups. Results Estimated lesion primary patency in the DEB PTA and cPTA arms was 0.81 and 0.61, respectively, at 6 months (P = .03) and 0.51 and 0.34, respectively, at 1 year (P = .04). Estimated circuit primary patency in the DEB PTA and cPTA arms was 0.76 and 0.56, respectively, at 6 months (P = .048) and 0.45 and 0.32, respectively, at 1 year (P = .16). Restenosis rate was 34.0% (16 of 47) for DEB PTA and 62.9% (22 of 35) for cPTA at 6 months (P = .01). No major complications were noted. Conclusion Drug-eluting balloon angioplasty was effective in prolonging lesion primary patency of dialysis access stenoses at 6 months and 1 year. © RSNA, 2018.
Assuntos
Angioplastia , Fístula Arteriovenosa/cirurgia , Stents Farmacológicos , Oclusão de Enxerto Vascular/cirurgia , Idoso , Angioplastia/efeitos adversos , Angioplastia/métodos , Angioplastia/estatística & dados numéricos , Angioplastia com Balão/efeitos adversos , Angioplastia com Balão/métodos , Angioplastia com Balão/estatística & dados numéricos , Fístula Arteriovenosa/diagnóstico por imagem , Angiografia por Tomografia Computadorizada , Stents Farmacológicos/efeitos adversos , Stents Farmacológicos/estatística & dados numéricos , Feminino , Oclusão de Enxerto Vascular/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Diálise Renal , Grau de Desobstrução VascularRESUMO
BACKGROUND: Atopic diseases, including asthma, exacerbate type 2 immune responses and involve a number of immune cell types, including regulatory T (Treg) cells and the emerging type 2 innate lymphoid cells (ILC2s). Although ILC2s are potent producers of type 2 cytokines, the regulation of ILC2 activation and function is not well understood. OBJECTIVE: In the present study, for the first time, we evaluate how Treg cells interact with pulmonary ILC2s and control their function. METHODS: ILC2s and Treg cells were evaluated by using in vitro suppression assays, cell-contact assays, and gene expression panels. Also, human ILC2s and Treg cells were adoptively transferred into NOD SCID γC-deficient mice, which were given isotype or anti-inducible T-cell costimulator ligand (ICOSL) antibodies and then challenged with IL-33 and assessed for airway hyperreactivity. RESULTS: We show that induced Treg cells, but not natural Treg cells, effectively suppress the production of the ILC2-driven proinflammatory cytokines IL-5 and IL-13 both in vitro and in vivo. Mechanistically, our data reveal the necessity of inducible T-cell costimulator (ICOS)-ICOS ligand cell contact for Treg cell-mediated ILC2 suppression alongside the suppressive cytokines TGF-ß and IL-10. Using a translational approach, we then demonstrate that human induced Treg cells suppress syngeneic human ILC2s through ICOSL to control airway inflammation in a humanized ILC2 mouse model. CONCLUSION: These findings suggest that peripheral expansion of induced Treg cells can serve as a promising therapeutic target against ILC2-dependent asthma.
Assuntos
Asma/imunologia , Citocinas/imunologia , Linfócitos/imunologia , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Células Cultivadas , Técnicas de Cocultura , Modelos Animais de Doenças , Humanos , Imunidade Inata , Camundongos Endogâmicos NOD , Camundongos SCID , Camundongos TransgênicosRESUMO
Bin-Amphiphysin-Rvs (BAR) and Fes-CIP4 homology BAR (F-BAR) proteins generate tubular membrane invaginations reminiscent of the megakaryocyte (MK) demarcation membrane system (DMS), which provides membranes necessary for future platelets. The F-BAR protein PACSIN2 is one of the most abundant BAR/F-BAR proteins in platelets and the only one reported to interact with the cytoskeletal and scaffold protein filamin A (FlnA), an essential regulator of platelet formation and function. The FlnA-PACSIN2 interaction was therefore investigated in MKs and platelets. PACSIN2 associated with FlnA in human platelets. The interaction required FlnA immunoglobulin-like repeat 20 and the tip of PACSIN2 F-BAR domain and enhanced PACSIN2 F-BAR domain membrane tubulation in vitro. Most human and wild-type mouse platelets had 1 to 2 distinct PACSIN2 foci associated with cell membrane GPIbα, whereas Flna-null platelets had 0 to 4 or more foci. Endogenous PACSIN2 and transfected enhanced green fluorescent protein-PACSIN2 were concentrated in midstage wild-type mouse MKs in a well-defined invagination of the plasma membrane reminiscent of the initiating DMS and dispersed in the absence of FlnA binding. The DMS appeared less well defined, and platelet territories were not readily visualized in Flna-null MKs. We conclude that the FlnA-PACSIN2 interaction regulates membrane tubulation in MKs and platelets and likely contributes to DMS formation.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Plaquetas , Membrana Celular/ultraestrutura , Filaminas/metabolismo , Megacariócitos , Proteínas Adaptadoras de Transdução de Sinal/química , Animais , Plaquetas/metabolismo , Plaquetas/ultraestrutura , Membrana Celular/metabolismo , Células Cultivadas , Filaminas/fisiologia , Células HEK293 , Humanos , Megacariócitos/metabolismo , Megacariócitos/ultraestrutura , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Ligação Proteica/fisiologia , Domínios e Motivos de Interação entre Proteínas/fisiologia , Pseudópodes/metabolismoRESUMO
OBJECTIVE: Thiol isomerases facilitate protein folding in the endoplasmic reticulum, and several of these enzymes, including protein disulfide isomerase and ERp57, are mobilized to the surface of activated platelets, where they influence platelet aggregation, blood coagulation, and thrombus formation. In this study, we examined the synthesis and trafficking of thiol isomerases in megakaryocytes, determined their subcellular localization in platelets, and identified the cellular events responsible for their movement to the platelet surface on activation. APPROACH AND RESULTS: Immunofluorescence microscopy imaging was used to localize protein disulfide isomerase and ERp57 in murine and human megakaryocytes at various developmental stages. Immunofluorescence microscopy and subcellular fractionation analysis were used to localize these proteins in platelets to a compartment distinct from known secretory vesicles that overlaps with an inner cell-surface membrane region defined by the endoplasmic/sarcoplasmic reticulum proteins calnexin and sarco/endoplasmic reticulum calcium ATPase 3. Immunofluorescence microscopy and flow cytometry were used to monitor thiol isomerase mobilization in activated platelets in the presence and absence of actin polymerization (inhibited by latrunculin) and in the presence or absence of membrane fusion mediated by Munc13-4 (absent in platelets from Unc13d(Jinx) mice). CONCLUSIONS: Platelet-borne thiol isomerases are trafficked independently of secretory granule contents in megakaryocytes and become concentrated in a subcellular compartment near the inner surface of the platelet outer membrane corresponding to the sarco/endoplasmic reticulum of these cells. Thiol isomerases are mobilized to the surface of activated platelets via a process that requires actin polymerization but not soluble N-ethylmaleimide-sensitive fusion protein attachment receptor/Munc13-4-dependent vesicular-plasma membrane fusion.
Assuntos
Plaquetas/enzimologia , Membrana Celular/enzimologia , Megacariócitos/enzimologia , Ativação Plaquetária , Isomerases de Dissulfetos de Proteínas/sangue , Actinas/sangue , Animais , Plaquetas/efeitos dos fármacos , Proteínas Sanguíneas/deficiência , Proteínas Sanguíneas/genética , Calnexina/sangue , Membrana Celular/efeitos dos fármacos , Genótipo , Humanos , Megacariócitos/efeitos dos fármacos , Fusão de Membrana , Proteínas de Membrana/sangue , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Ativação Plaquetária/efeitos dos fármacos , Isomerases de Dissulfetos de Proteínas/biossíntese , Transporte Proteico , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/sangueRESUMO
Complications related to percutaneous biliary tract interventions (PBTIs) can range from access site discomfort to life-threatening vascular complications. These complications are relatively uncommon, and most of them are self-limiting. However, major complications for which an increased level of patient care and/or a prolonged hospital stay are required and that may lead to death-albeit rarely-can occur. Some of the most common complications related to PBTI include pain, infection, bile leakage, and catheter blockage. These conditions can be easily recognized by using the patient's clinical history and laboratory examination results. However, the more uncommon complications, such as life-threatening hemobilia, acute pancreatitis, and catheter and stent fractures, may have nonspecific clinical manifestations, and the underlying pathologic condition may be found only when it is being sought specifically. It is important that diagnostic and interventional radiologists be aware of the wide spectrum of PBTI-related complications, as early recognition and treatment may prevent catastrophic situations. In addition, knowledge of the different treatment options is essential for guidance in interventional radiology procedures such as transarterial control of hemobilia, imaging-guided direct percutaneous embolization of pseudoaneurysms, and percutaneous treatment of catheter- and stent-related complications such as fractures. The authors review a wide spectrum of complications associated with PBTI and the percutaneous management of these conditions. They also highlight valuable lessons learned from morbidity and mortality rounds at a high-volume tertiary care center. ©RSNA, 2017.
Assuntos
Doenças Biliares/cirurgia , Complicações Pós-Operatórias/diagnóstico por imagem , Complicações Pós-Operatórias/terapia , Radiologia Intervencionista/métodos , HumanosRESUMO
Platelets are critical to hemostasis and thrombosis. Upon detecting injury, platelets show a range of responses including the release of protein cargo from α-granules. This cargo is synthesized by platelet precursor megakaryocytes or endocytosed by megakaryocytes and/or platelets. Insights into α-granule biogenesis have come from studies of hereditary conditions where these granules are immature, deficient or absent. Studies of Arthrogryposis, Renal dysfunction, and Cholestasis (ARC) syndrome identified the first proteins essential to α-granule biogenesis: VPS33B and VPS16B. VPS33B and VPS16B form a complex, and in the absence of either, platelets lack α-granules and the granule-specific membrane protein P-selectin. Gray Platelet Syndrome (GPS) platelets also lack conventionally recognizable α-granules, although P-selectin containing structures are present. GPS arises from mutations affecting NBEAL2. The GPS phenotype is more benign than ARC syndrome, but it can cause life-threatening bleeding, progressive thrombocytopenia, and myelofibrosis. We review the essential roles of VPS33B, VPS16B, and NBEAL2 in α-granule development. We also examine the existing data on their mechanisms of action, where many details remain poorly understood. VPS33B and VPS16B are ubiquitously expressed and ARC syndrome is a multisystem disorder that causes lethality early in life. Thus, VPS33B and VPS16B are clearly involved in other processes besides α-granule biogenesis. Studies of their involvement in vesicular trafficking and protein interactions are reviewed to gain insights into their roles in α-granule formation. NBEAL2 mutations primarily affect megakaryocytes and platelets, and while little is known about NBEAL2 function some insights can be gained from studies of related proteins, such as LYST.
Assuntos
Plaquetas/metabolismo , Grânulos Citoplasmáticos/metabolismo , Animais , Artrogripose/diagnóstico , Artrogripose/etiologia , Artrogripose/metabolismo , Transporte Biológico , Plaquetas/ultraestrutura , Colestase/diagnóstico , Colestase/etiologia , Colestase/metabolismo , Grânulos Citoplasmáticos/ultraestrutura , Síndrome da Plaqueta Cinza/diagnóstico , Síndrome da Plaqueta Cinza/etiologia , Síndrome da Plaqueta Cinza/metabolismo , Humanos , Megacariócitos/metabolismo , Mutação , Fenótipo , Insuficiência Renal/diagnóstico , Insuficiência Renal/etiologia , Insuficiência Renal/metabolismo , Vesículas Secretórias/metabolismo , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismoRESUMO
BACKGROUND: Approximately 20 % of hepatocellular carcinoma (HCC) patients diagnosed in the early stages may benefit from potentially curative ablative therapies such as surgical resection, transplantation or radiofrequency ablation. For patients not eligible for such options, prognosis is poor. Sorafenib and Selective Internal Radiation Therapy (SIRT) are clinically proven treatment options in patients with unresectable HCC, and this study aims to assess overall survival following either SIRT or Sorafenib therapy for locally advanced HCC patients. METHODS: This investigator-initiated, multi-centre, open-label, randomized, controlled trial will enrol 360 patients with locally advanced HCC, as defined by Barcelona Clinic Liver Cancer stage B or stage C, without distant metastases, and which is not amenable to immediate curative treatment. Exclusion criteria include previous systemic therapy, metastatic disease, complete occlusion of the main portal vein, or a Child-Pugh score of >7. Eligible patients will be randomised 1:1 and stratified by centre and presence or absence of portal vein thrombosis to receive either a single administration of SIRT using yttrium-90 resin microspheres (SIR-Spheres®, Sirtex Medical Limited, Sydney, Australia) targeted at HCC in the liver by the trans-arterial route or continuous oral Sorafenib (Nexavar®, Bayer Pharma AG, Berlin, Germany) at a dose of 400 mg twice daily until disease progression, no further response, complete regression or unacceptable toxicity. Patients for both the Sorafenib and SIRT arms will be followed-up every 4 weeks for the first 3 months and 12 weekly thereafter. Overall survival is the primary endpoint, assessed for the intention-to-treat population. Secondary endpoints are tumour response rate, time-to-tumour progression, progression free survival, quality of life and down-staging to receive potentially curative therapy. DISCUSSION: Definitive data comparing these two therapies will help to determine clinical practice in the large group of patients with locally advanced HCC and improve outcomes for such patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01135056 , first received 24, May 2010.
Assuntos
Antineoplásicos/uso terapêutico , Braquiterapia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Protocolos Clínicos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Braquiterapia/métodos , Terapia Combinada , Feminino , Humanos , Estadiamento de Neoplasias , Niacinamida/uso terapêutico , Projetos de Pesquisa , SorafenibeRESUMO
An expert panel met to review the evidence for selective internal radiation therapy (SIRT) using yttrium-90 microspheres in hepatocellular carcinoma and metastases from colorectal cancer and neuroendocrine tumors. There is now convincing evidence for the safety and efficacy of SIRT in these situations albeit mostly from retrospective cohort studies. There are a number of ongoing prospective randomized controlled clinical trials investigating the role of SIRT in liver tumors; however, data from these trials are still several years away (although the SIRFLOX study has been recently published). In this evolving environment, published evidence and the authors' experience were used to summarize the current and potential role of SIRT in the management of hepatocellular carcinoma of intermediate or advanced stage and in liver-dominant metastatic colorectal cancer and metastatic neuroendocrine tumors.
Assuntos
Neoplasias Hepáticas/radioterapia , Compostos Radiofarmacêuticos/uso terapêutico , Radioisótopos de Ítrio/uso terapêutico , Carcinoma Hepatocelular/radioterapia , Humanos , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos RetrospectivosRESUMO
Gray platelet syndrome (GPS) is an inherited bleeding disorder associated with macrothrombocytopenia and α-granule-deficient platelets. GPS has been linked to loss of function mutations in NEABL2 (neurobeachin-like 2), and we describe here a murine GPS model, the Nbeal2(-/-) mouse. As in GPS, Nbeal2(-/-) mice exhibit splenomegaly, macrothrombocytopenia, and a deficiency of platelet α-granules and their cargo, including von Willebrand factor (VWF), thrombospondin-1, and platelet factor 4. The platelet α-granule membrane protein P-selectin is expressed at 48% of wild-type levels and externalized upon platelet activation. The presence of P-selectin and normal levels of VPS33B and VPS16B in Nbeal2(-/-) platelets suggests that NBEAL2 acts independently of VPS33B/VPS16B at a later stage of α-granule biogenesis. Impaired Nbeal2(-/-) platelet function was shown by flow cytometry, platelet aggregometry, bleeding assays, and intravital imaging of laser-induced arterial thrombus formation. Microscopic analysis detected marked abnormalities in Nbeal2(-/-) bone marrow megakaryocytes, which when cultured showed delayed maturation, decreased survival, decreased ploidy, and developmental abnormalities, including abnormal extracellular distribution of VWF. Our results confirm that α-granule secretion plays a significant role in platelet function, and they also indicate that abnormal α-granule formation in Nbeal2(-/-) mice has deleterious effects on megakaryocyte survival, development, and platelet production.
Assuntos
Plaquetas/patologia , Proteínas Sanguíneas/genética , Medula Óssea/patologia , Grânulos Citoplasmáticos/patologia , Síndrome da Plaqueta Cinza/patologia , Megacariócitos/patologia , Animais , Plaquetas/metabolismo , Proteínas Sanguíneas/deficiência , Medula Óssea/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Diferenciação Celular , Grânulos Citoplasmáticos/metabolismo , Modelos Animais de Doenças , Feminino , Expressão Gênica , Síndrome da Plaqueta Cinza/genética , Síndrome da Plaqueta Cinza/metabolismo , Masculino , Megacariócitos/metabolismo , Camundongos , Camundongos Knockout , Selectina-P/genética , Selectina-P/metabolismo , Agregação Plaquetária , Fator Plaquetário 4/genética , Fator Plaquetário 4/metabolismo , Isoformas de Proteínas/deficiência , Isoformas de Proteínas/genética , Trombospondina 1/genética , Trombospondina 1/metabolismo , Fator de von Willebrand/genética , Fator de von Willebrand/metabolismoRESUMO
PURPOSE: To compare the efficacy and safety of cutting balloon angioplasty (CBA) versus high-pressure balloon angioplasty (HPBA) for the treatment of hemodialysis autogenous fistula stenoses resistant to conventional percutaneous transluminal angioplasty (PTA). MATERIALS AND METHODS: In a prospective, randomized clinical trial involving patients with dysfunctional, stenotic hemodialysis arteriovenous fistulas (AVFs), patients were randomized to receive CBA or HPBA if conventional PTA had suboptimal results (ie, residual stenosis > 30%). A total of 516 patients consented to participate in the study from October 2008 to September 2011, 85% of whom (n = 439) had technically successful conventional PTA. The remaining 71 patients (mean age, 60 y; 49 men) with suboptimal PTA results were eventually randomized: 36 to the CBA arm and 35 to the HPBA arm. Primary and secondary target lesion patencies were determined by Kaplan-Meier analysis. RESULTS: Clinical success rates were 100% in both arms. Primary target lesion patency rates at 6 months were 66.4% and 39.9% for CBA and HPBA, respectively (P = .01). Secondary target lesion patency rates at 6 months were 96.5% for CBA and 80.0% for HPBA (P = .03). There was a single major complication of venous perforation following CBA. The 30-day mortality rate was 1.4%, with one non-procedure-related death in the HPBA group. CONCLUSIONS: Primary and secondary target lesion patency rates of CBA were statistically superior to those of HPBA following suboptimal conventional PTA. For AVF stenoses resistant to conventional PTA, CBA may be a better second-line treatment given its superior patency rates.
Assuntos
Angioplastia com Balão/métodos , Derivação Arteriovenosa Cirúrgica/efeitos adversos , Implante de Prótese Vascular/efeitos adversos , Oclusão de Enxerto Vascular/terapia , Diálise Renal , Adolescente , Adulto , Idoso , Angioplastia com Balão/efeitos adversos , Angioplastia com Balão/mortalidade , Derivação Arteriovenosa Cirúrgica/mortalidade , Implante de Prótese Vascular/mortalidade , Criança , Pré-Escolar , Constrição Patológica , Feminino , Oclusão de Enxerto Vascular/diagnóstico , Oclusão de Enxerto Vascular/etiologia , Oclusão de Enxerto Vascular/mortalidade , Oclusão de Enxerto Vascular/fisiopatologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Pressão , Estudos Prospectivos , Recidiva , Singapura , Fatores de Tempo , Resultado do Tratamento , Grau de Desobstrução Vascular , Adulto JovemRESUMO
PURPOSE: To evaluate the feasibility and safety of yttrium-90 ((90)Y) radioembolization through the inferior phrenic arteries (IPAs). MATERIALS AND METHODS: Retrospective analysis of 108 patients referred for radioembolization to treat primary (n = 103) or secondary (n = 5) liver malignancy was performed. Five patients had malignant hepatic tumors supplied by the IPA and met criteria for infusion of (90)Y spheres into the IPA. Digital subtraction angiography (DSA), catheter-directed computed tomographic (CT) angiography, and technetium-99m ((99m)Tc) macroaggregated albumin (MAA) single photon emission CT (SPECT)/CT were used to plan treatment. Bremsstrahlung SPECT/CT was performed 1 day after radioembolization. Follow-up included clinical and biochemical tests and cross-sectional CT or magnetic resonance imaging. RESULTS: Parasitized extrahepatic arteries were detected in 37% of patients (n = 40). Of these, 62.5% (n = 25) had tumor supply through an IPA. Of the patients with IPA supply, 20% (n = 5) underwent infusion of (90)Y into the right IPA. Reasons for disqualifying patients from infusion into the IPA were less than 10% tumor supply (n = 11), failed catheterization of IPA (n = 3), arterioportovenous shunt (n = 2), failed identification of IPA on pretreatment angiography (n = 1), and gastric or esophageal enhancement on catheter-directed CT angiography (n = 3). In all five patients, technical success was demonstrated on (90)Y imaging, with no significant extrahepatic radionuclide activity. No adverse events related to IPA radioembolization occurred at mean follow-up of 4.5 months (range, 2.2-10.1 mo). CONCLUSIONS: Delivery of (90)Y microspheres through the right IPA is feasible and safe with the use of catheter-directed CT angiography in addition to DSA and (99m)Tc MAA SPECT/CT in patients with tumors with greater than 10% IPA supply.
Assuntos
Carcinoma Hepatocelular/radioterapia , Embolização Terapêutica/métodos , Neoplasias Hepáticas/radioterapia , Compostos Radiofarmacêuticos/administração & dosagem , Radioisótopos de Ítrio/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Angiografia Digital , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/diagnóstico , Embolização Terapêutica/efeitos adversos , Estudos de Viabilidade , Feminino , Humanos , Infusões Intra-Arteriais , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/diagnóstico , Imageamento por Ressonância Magnética , Masculino , Microesferas , Pessoa de Meia-Idade , Imagem Multimodal , Tomografia por Emissão de Pósitrons , Valor Preditivo dos Testes , Radiografia Intervencionista , Compostos Radiofarmacêuticos/efeitos adversos , Estudos Retrospectivos , Agregado de Albumina Marcado com Tecnécio Tc 99m , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Radioisótopos de Ítrio/efeitos adversosRESUMO
Objective: To investigate the effects of miRNA-145-5p on the tumor development and progression of prostate cancer (Pca) bone metastasis. Methods: Levels of miRNA-145-5p were assessed by real-time quantitative PCR in PC3 (bone metastatic Pca cells), 22RV1 (non-metastatic Pca cells), RWPE-1 (non-cancerous prostate epithelial cells) and Pca tissues collected from patients with and without bone metastases. The impact of miRNA-145-5p on cell proliferation was tested by CCK8 assay, colony formation assay and flow cytometric cell cycle analysis. Effects on invasion and migration of PC3 cells were determined by Transwell and wound healing assays. Western blotting, enzyme-linked immunosorbent assay, and flow cytometry apoptosis analyses were also performed to assess roles in metastasis. Results: Levels of miRNA-145-5p were decreased in Pca bone metastases and miRNA-145-5p inhibited cell proliferation, migration and invasion. miRNA-145-5p inhibited the expression of basic fibroblast growth factor (bFGF), insulin-like growth factor (IGF) and transforming growth factor-ß (TGF-ß) in PC3 cells. miR-145-5p increased the expression of the epithelial marker E-cadherin and reduced the expression of matrix metalloproteinase 2 and 9 (MMP-2 and MMP-9). It was found that miRNA-145-5p mediated the epithelial-mesenchymal transition (EMT) and induced apoptosis. Conclusions: miRNA-145-5p negatively regulated the EMT, inhibited Pca bone metastasis and promoted apoptosis in Pca bone metastasis. Mimicry of miRNA-145-5p action raises the possibility of a novel target for treating Pca with bone metastases.
RESUMO
Purpose: The purpose of this study was to identify the potential exosome-derived microRNAs (miRNAs) related to prostate cancer (Pca) bone metastasis. Methods: Two datasets were collected. One dataset was from the authors' institute, for which two groups of 10 patients each were designed: in the first one, the patients had early-stage localised Pca without bone metastasis, and in the other, the patients presented with Pca with bone metastasis. Then, the miRNA expression profiles of the blood exosomes were obtained and analysed. The other dataset was a public dataset of the miRNA expression transcriptome (GSE26964), which was downloaded from Gene Expression Omnibus (GEO). The results of both datasets were jointly analysed and the most bone-metastatic-related differentially expressed miRNAs (diff-miRNAs) were identified and further validated. Finally, a series of bioinformatics analyses were performed and the relationship between target genes of the diff-miRNAs and the pathogenesis and progression of bone metastasis of Pca were studied. Results: From the authors' dataset, in all, 313 diff-miRNAs were identified, of which 205 were up-regulated while 108 were down-regulated. From the GSE26964 dataset, 107 diff-miRNAs were found, of which 44 were up-regulated and 63 were down-regulated. Taking the intersection of the results of both datasets, four diff-miRNAs were identified: hsa-miR-125a-3p, hsa-miR-330-3p, hsa-miR-339-5p and hsa-miR-613. In all, 94 target genes of the four diff-miRNAs were predicted. After considering the intersection of the results from the GSE32269 dataset, we obtained 25 target genes. Although either positive or negative correlations were found among the diff-miRNAs with some of the target genes, there is a lack of evidence on how such correlations regulate the development and promotion of Pca bone metastasis. Conclusion: Hsa-miR-125a-3p, hsa-miR-330-3p, hsa-miR-339-5p and hsa-miR-613 are potential biomarkers for Pca bone metastasis.