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INTRODUCTION: Haemophilia patients experience painful joint episodes which may or may not be associated with haemarthrosis. We sought to validate a questionnaire developed by the Canadian Haemophilia Society using point-of-care musculoskeletal ultrasound (POC MSKUS) to confirm haemarthrosis. METHODS: The questionnaire comprised of 20 questions (10 each associated with haemarthrosis and arthritis pain) and was administered to adult haemophilia patients reporting to the Haemophilia Treatment Centre (University of California San Diego). We confirmed the presence (or absence) of haemarthrosis using POC MSKUS [Joint Activity and Damage Exam (JADE)]. We fitted univariate and multivariate generalized estimating equations to identify symptoms associated with haemarthrosis. RESULTS: We evaluated 79 painful episodes in 32 patients [median age = 38 years (range 21-74)]. POC MSKUS detected haemarthrosis in 36 (46%) episodes. The strongest predictor for haemarthrosis pain was 'like a balloon swelling with water' (odds ratio [OR] 2.88 [CI .68;12.10]); 'no feeling of sponginess with movement' (OR .24[CI .07;.76]) was the strongest for arthritic pain. We identified four questions with the strongest OR for differentiating haemarthrosis pain from arthritic pain to develop an algorithm for haemarthrosis prediction. Answering these questions in "yes/no" fashion yielded estimates of the probability of haemarthrosis CONCLUSION: Objective diagnosis of haemarthrosis by MSKUS facilitated the development of a symptom-based prediction tool for diagnosis of haemarthrosis. The tool requires further validation and will be particularly helpful in situations where MSKUS is not readily available.
Assuntos
Hemofilia A , Comportamento de Utilização de Ferramentas , Adulto , Idoso , Artralgia , Canadá , Hemartrose/diagnóstico por imagem , Hemartrose/etiologia , Hemofilia A/complicações , Hemofilia A/diagnóstico , Humanos , Pessoa de Meia-Idade , Dor/complicações , Adulto JovemRESUMO
Sickle cell disease (SCD) is associated with significant morbidity and mortality, and limits both the quality and quantity of life. Transfusion therapy, specifically automated red cell exchange (aRCE), plays a key role in management of SCD and is beneficial for certain indications in the chronic, outpatient setting. The approach to maintain a successful chronic aRCE program for SCD is multifaceted. This review will highlight important considerations including indications for aRCE, patient selection, transfusion medicine pearls, vascular access needs, complications of therapy, aRCE prescription, and therapy optimization. Moreover, the importance of a multidisciplinary approach with frequent communication between the services involved cannot be overstated. Ultimately, the underlying goal of a chronic RCE program is to improve the quality of life and longevity of patients with SCD.
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Anemia Falciforme , Doença Enxerto-Hospedeiro , Anemia Falciforme/terapia , Transfusão de Eritrócitos , Humanos , Qualidade de VidaRESUMO
Protein disulfide isomerase (PDI), secreted from platelets and endothelial cells after injury, is required for thrombus formation. The effect of platelet and endothelial cell granule contents on PDI-mediated thrombus formation was studied by intravital microscopy using a mouse model of Hermansky-Pudlak syndrome in which platelet dense granules are absent. Platelet deposition and fibrin generation were nearly absent, and extracellular PDI was significantly reduced in HPS6(-/-) mice after vascular injury. HPS6(-/-) platelets displayed impaired PDI secretion and impaired exocytosis of α granules, lysosomes, and T granules due to decreased sensitivity to thrombin, but these defects could be corrected by addition of subthreshold amounts of adenosine 5'-diphosphate (ADP). Human Hermansky-Pudlak syndrome platelets demonstrated similar characteristics. Infusion of wild-type platelets rescued thrombus formation in HPS6(-/-) mice. Human umbilical vein endothelial cells in which the HPS6 gene was silenced displayed impaired PDI secretion and exocytosis of Weibel-Palade bodies. Defective thrombus formation in Hermansky-Pudlak syndrome, associated with impaired exocytosis of residual granules in endothelial cells and platelets, the latter due to deficiency of ADP, is characterized by a defect in T granule secretion, a deficiency in extracellular PDI secretion, and impaired fibrin generation and platelet aggregation. Hermansky-Pudlak syndrome is an example of a hereditary disease whereby impaired PDI secretion contributes to a bleeding phenotype.
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Plaquetas/enzimologia , Células Endoteliais/enzimologia , Síndrome de Hermanski-Pudlak/sangue , Síndrome de Hermanski-Pudlak/enzimologia , Isomerases de Dissulfetos de Proteínas/metabolismo , Trombose/sangue , Trombose/enzimologia , Difosfato de Adenosina/deficiência , Difosfato de Adenosina/metabolismo , Difosfato de Adenosina/farmacologia , Animais , Apirase/metabolismo , Apirase/farmacologia , Plaquetas/efeitos dos fármacos , Degranulação Celular , Modelos Animais de Doenças , Células Endoteliais/patologia , Exocitose/efeitos dos fármacos , Feminino , Fibrina/biossíntese , Síndrome de Hermanski-Pudlak/genética , Células Endoteliais da Veia Umbilical Humana , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/sangue , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Agregação Plaquetária , Isomerases de Dissulfetos de Proteínas/sangue , RNA Interferente Pequeno/genética , Trombina/metabolismo , Proteínas de Transporte Vesicular/deficiência , Proteínas de Transporte Vesicular/genéticaRESUMO
Protein disulfide isomerase (PDI) and endoplasmic reticulum protein 57 (ERp57) are emerging as important regulators of thrombus formation. Another thiol isomerase, endoplasmic reticulum protein 5 (ERp5), is involved in platelet activation. We show here the involvement of ERp5 in thrombus formation using the mouse laser-injury model of thrombosis and a specific antibody raised against recombinant ERp5. Anti-ERp5 antibody inhibited ERp5-dependent platelet and endothelial cell disulfide reductase activity in vitro. ERp5 release at the thrombus site was detected after infusion of Alexa Fluor 488-labeled anti-ERp5 antibody at 0.05 µg/g body weight, a dose that does not inhibit thrombus formation. Anti-ERp5 at 3 µg/g body weight inhibited laser-induced thrombus formation in vivo by causing a 70% decrease in the deposition of platelets and a 62% decrease in fibrin accumulation compared to infusion of control antibody (P < .01). ERp5 binds to ß3 integrin with an equilibrium dissociation constant (KD) of 21 µM, measured by surface plasmon resonance. The cysteine residues in the ERp5 active sites are not required for binding to ß3 integrin. These results provide evidence for a novel role of ERp5 in thrombus formation, a function that may be mediated through its association with αIIbß3.
Assuntos
Modelos Animais de Doenças , Integrina beta3/metabolismo , Lasers/efeitos adversos , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Isomerases de Dissulfetos de Proteínas/metabolismo , Trombose/patologia , Animais , Plaquetas/metabolismo , Plaquetas/patologia , Western Blotting , Células Cultivadas , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Ensaio de Imunoadsorção Enzimática , Fibrina/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ativação Plaquetária , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Ressonância de Plasmônio de Superfície , Trombose/enzimologia , Trombose/etiologiaRESUMO
Quercetin-3-rutinoside inhibits thrombus formation in a mouse model by inhibiting extracellular protein disulfide isomerase (PDI), an enzyme required for platelet thrombus formation and fibrin generation. Prior studies have identified PDI as a potential target for novel antithrombotic agents. Using a fluorescence enhancement-based assay and isothermal calorimetry, we show that quercetin-3-rutinoside directly binds to the b' domain of PDI with a 1:1 stoichiometry. The binding of quercetin-3-rutinoside to PDI induces a more compact conformation and restricts the conformational flexibility of PDI, as revealed by small angle x-ray scattering. The binding sites of quercetin-3-rutinoside to PDI were determined by studying its interaction with isolated fragments of PDI. Quercetin-3-rutinoside binds to the b'x domain of PDI. The infusion of the b'x fragment of PDI rescued thrombus formation that was inhibited by quercetin-3-rutinoside in a mouse thrombosis model. This b'x fragment does not possess reductase activity and, in the absence of quercetin-3-rutinoside, does not affect thrombus formation in vivo. The isolated b' domain of PDI has potential as an antidote to reverse the antithrombotic effect of quercetin-3-rutinoside by binding and neutralizing quercetin-3-rutinoside.
Assuntos
Isomerases de Dissulfetos de Proteínas/antagonistas & inibidores , Rutina/farmacologia , Animais , Sítios de Ligação , Calorimetria , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Endogâmicos C57BL , Isomerases de Dissulfetos de Proteínas/metabolismo , Rutina/metabolismo , Espalhamento a Baixo Ângulo , Trombose/prevenção & controle , Difração de Raios XRESUMO
Molecularly targeted anti-cancer therapies have revolutionized cancer treatment by improving both quality of life and survival in cancer patients. However, many of these drugs are associated with cardiovascular toxicities that are sometimes dose-limiting. Moreover, the long-term cardiovascular consequences of these drugs, some of which are used chronically, are not yet known. Although the scope and mechanisms of the cardiac toxicities are better defined, the mechanisms for vascular toxicities are only beginning to be elucidated. This review summarizes what is known about the vascular adverse events associated with three classes of novel anti-cancer therapies: vascular endothelial growth factor (VEGF) inhibitors, breakpoint cluster-Abelson (BCR-ABL) kinase inhibitors used to treat chronic myelogenous leukaemia (CML) and immunomodulatory agents (IMiDs) used in myeloma therapeutics. Three of the best described vascular toxicities are reviewed including hypertension, increased risk of acute cardiovascular ischaemic events and arteriovenous thrombosis. The available data regarding the mechanism by which each therapy causes vascular complication are summarized. When data are limited, potential mechanisms are inferred from the known effects of inhibiting each target on vascular cell function and disease. Enhanced understanding of the molecular mechanisms of vascular side effects of targeted cancer therapy is necessary to effectively manage cancer patients and to design safer targeted cancer therapies for the future.
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Antineoplásicos/efeitos adversos , Doenças Cardiovasculares/etiologia , Terapia de Alvo Molecular/efeitos adversos , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/uso terapêutico , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Humanos , Neoplasias/genética , Neoplasias/metabolismoRESUMO
BACKGROUND: Chronic kidney disease (CKD) is a significant complication in patients with sickle cell disease (SCD), leading to increased mortality. OBJECTIVE: This study aims to investigate the burden of CKD in Medicaid-enrolled adults with SCD in California, examine differences in disease burden between male and female individuals, and assess mortality rates and access to specialized care. METHODS: This retrospective cohort study used the California Sickle Cell Data Collection program to identify and monitor individuals with SCD. Medicaid claims, vital records, emergency department, and hospitalization data from 2011 to 2020 were analyzed. CKD prevalence was assessed based on ICD (International Classification of Diseases) codes, and mortality rates were calculated. Access to specialized care was examined through outpatient encounter rates with hematologists and nephrologists. RESULTS: Among the 2345 adults with SCD, 24.4% (n=572) met the case definition for CKD. The SCD-CKD group was older at the beginning of this study (average age 44, SD 14 vs 34, SD 12.6 years) than the group without CKD. CKD prevalence increased with age, revealing significant disparities by sex. While the youngest (18-29 years) and oldest (>65 years) groups showed similar CKD prevalences between sexes (female: 12/111, 10.8% and male: 12/101, 11.9%; female: 74/147, 50.3% and male: 34/66, 51.5%, respectively), male individuals in the aged 30-59 years bracket exhibited significantly higher rates than female individuals (30-39 years: 49/294, 16.7%, P=.01; 40-49 years: 52/182, 28.6%, P=.02; and 50-59 years: 76/157,48.4%, P<.001). During this study, of the 2345 adults, 435 (18.5%) deaths occurred, predominantly within the SCD-CKD cohort (226/435, 39.5%). The median age at death was 53 (IQR 61-44) years for the SCD-CKD group compared to 43 (IQR 33-56) years for the SCD group, with male individuals in the SCD-CKD group showing significantly higher mortality rates (111/242, 45.9%; P=.009) than female individuals (115/330, 34.9%). Access to specialist care was notably limited: approximately half (281/572, 49.1%) of the SCD-CKD cohort had no hematologist visits, and 61.9% (354/572) did not see a nephrologist during this study's period. CONCLUSIONS: This study provides robust estimates of CKD prevalence and mortality among Medicaid-enrolled adults with SCD in California. The findings highlight the need for improved access to specialized care for this population and increased awareness of the high mortality risk and progression associated with CKD.
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Anemia Falciforme , Acessibilidade aos Serviços de Saúde , Medicaid , Insuficiência Renal Crônica , Humanos , Masculino , Feminino , California/epidemiologia , Adulto , Estudos Retrospectivos , Medicaid/estatística & dados numéricos , Prevalência , Anemia Falciforme/complicações , Anemia Falciforme/epidemiologia , Anemia Falciforme/mortalidade , Pessoa de Meia-Idade , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/terapia , Insuficiência Renal Crônica/mortalidade , Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , Estados Unidos/epidemiologia , Estudos de Coortes , Adulto Jovem , AdolescenteRESUMO
Background: Crizanlizumab was approved by the United States Food and Drug Administration agency in 2019 for decreasing vaso-occlusive events (VOEs) in sickle cell disease (SCD). Data regarding the use of crizanlizumab in the real-world setting are limited. Our goal was to identify patterns of crizanlizumab prescriptions in our SCD program and evaluate the benefits and identify barriers to its use in our SCD clinic. Methods: We conducted a retrospective analysis of patients who received crizanlizumab at our institution between July 2020 and January 2022. We compared acute care usage patterns before and after initiation of crizanlizumab, adherence to treatment, discontinuation and reasons for discontinuation. High utilizers of hospital-based services were defined as those with more than one visit to the emergency department (ED) per month or more than three visits to the day infusion program per month. Results: Fifteen patients received at least one dose of crizanlizumab 5 mg/kg of actual body weight during the study period. The average number of acute care visits decreased following crizanlizumab initiation but was not statistically significant (20 visits vs. 10 visits, P = 0.07). Among high users of hospital-based services, the average number of acute care visits decreased after initiation of crizanlizumab (40 vs. 16, P = 0.005). Only five patients included in this study remained on crizanlizumab 6 months after initiation. Conclusion: Our study suggests that crizanlizumab use may be helpful in decreasing acute care visits in SCD, particularly among high utilizers of hospital-based acute care services. However, the discontinuation rate in our cohort was extremely high, and further evaluation of efficacy and causes contributing to discontinuation in larger cohorts is warranted.
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ß-thalassemia is a genetic hemoglobin (Hb) disorder that affects millions of people world-wide. It is characterized by ineffective erythropoiesis and anemia. The resultant chronic anemia can require life-long blood transfusion regimens, leading to secondary hemochromatosis. Moreover, the abnormal red blood cells (RBCs) from ß-thalassemia patients are prone to hemolytic events that release cell-free Hb and heme causing a series of events that result in oxidative organ and tissue damage. In this study, ß-thalassemic mice were treated with a protein scavenger for six weeks, apohemoglobin-haptoglobin (apoHb-Hp), this protein scavenges cell free Hb and heme. We hypothesize that scavenging cell-free Hb and heme will lead to a positive therapeutic event. After the apoHb-hp treatment it was observed to reduce the weight of the liver and spleen and show an improvement in liver function by a drop in ALT, AST, and ALP markers. ApoHb-hp treatment also hints at an improved RBC half-life as the number of reticulocytes decreased, the mean corpuscular volume (MCV) increased, mean corpuscular hemoglobin increase and the RBC distribution width decreased. Furthermore, apoHb-Hp treatment reduced circulating serum iron concentration and transferrin saturation concentration. Based on these outcomes, introducing a scavenger protein can benefit ß-thalassemic mice. This study demonstrated that apoHb-Hp treatment may be a viable strategy to mitigate toxicities associated with cell free Hb and heme, a driver of ß-thalassemic issues.
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Haptoglobinas , Talassemia beta , Camundongos , Animais , Haptoglobinas/metabolismo , Heme/metabolismo , Talassemia beta/tratamento farmacológico , Hemoglobinas/metabolismo , FerroRESUMO
INTRODUCTION: Interstitial, cartilage, and bone collagens have been proposed as biomarkers of joint deterioration in hemophilic arthropathy. The role of basement membrane (type IV and VIII) collagens as biomarkers of endothelial turnover in relation to acute joint bleeding is not understood. METHODS: Thirty-one adult patients with hemophilia were studied prospectively for 3 years with musculoskeletal ultrasound/power Doppler (MSKUS/PD) during pain-free intervals and painful events for joint bleed status, synovial vascular flow, and 10 plasma markers of collagen turnover. Joint health was determined using Hemophilia Joint Health Scores and Pettersson scores. In animal studies, bleeding was induced in factor VIII-/- mice by knee joint injury. Synovial vascular remodeling was assessed using MSKUS/PD and histology. Murine plasma samples were analyzed for type IV collagen turnover markers. RESULTS: Ninety-one patient visits were compiled. Twenty-five were due to acute painful episodes, with 16 confirmed hemarthroses. Type IV collagen turnover markers (PRO-C4 and C4M), and a type VIII collagen synthesis marker (PRO-C8), were transiently elevated during acute hemarthrosis. Hemarthrosis was accompanied by increased synovial microvascular flow (MSKUS/PD), and levels of type IV collagen markers correlated with PD signals in the joint. In factor VIII-deficient mice, plasma levels of type IV collagen turnover markers correlated negatively with synovial αSMA staining, indicating that reduced type IV collagen turnover was associated with thicker vessels. CONCLUSIONS: Our findings suggest that basement membrane turnover markers, closely linked to synovial vascular remodeling, may be systemic biomarkers of acute hemarthrosis. Vascular instability during neovascularization may be involved in the dynamics of hemarthrosis.
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Hemartrose , Hemofilia A , Adulto , Animais , Membrana Basal , Biomarcadores , Hemofilia A/complicações , Humanos , Camundongos , Remodelação VascularRESUMO
BACKGROUND & OBJECTIVE: Availability of clean water and adequate sanitation facilities are of prime importance for limiting diarrhoeal diseases. We examined the water and sanitation facilities of a village in southern India using geographic information system (GIS) tools. METHODS: Places of residence, water storage and distribution, sewage and places where people in the village defaecated were mapped and drinking water sources were tested for microbial contamination in Nelvoy village, Vellore district, Tamil Nadu. RESULTS: Water in the village was found to be microbiologically unfit for consumption. Analysis using direct observations supplemented by GIS maps revealed poor planning, poor engineering design and lack of policing of the water distribution system causing possible contamination of drinking water from sewage at multiple sites. INTERPRETATION & CONCLUSION: Until appropriate engineering designs for water supply and sewage disposal to suit individual village needs are made available, point-of-use water disinfection methods could serve as an interim solution.
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Diarreia/prevenção & controle , Sistemas de Informação Geográfica , Esgotos , Purificação da Água/métodos , Purificação da Água/normas , Abastecimento de Água/normas , Controle de Doenças Transmissíveis/métodos , Defecação , Diarreia/epidemiologia , Arquitetura de Instituições de Saúde , Habitação , Humanos , Índia/epidemiologia , Morbidade , Saúde Pública , População Rural/estatística & dados numéricos , Classe SocialRESUMO
BACKGROUND: Vascular remodeling associated with hemophilic arthropathy (HA) may contribute to bleed propagation, but the mechanisms remain poorly understood. OBJECTIVES: To explore molecular mechanisms of HA and the effects of hemostasis correction on synovial vascular remodeling after joint injury in hypocoagulable mice. METHODS: Factor VIII (FVIII)-deficient mice +/- FVIII treatment and hypocoagulable wild-type mice (Hypo BALB/c) were subjected to subpatellar puncture. Hypo BALB/c mice were treated with warfarin and anti-FVIII before injury, after which warfarin was continued for 2 weeks or reversed +/- continuous anti-FVIII until harvest. Synovial vascularity was analyzed at baseline and 2 to 4 weeks post injury by histology, musculoskeletal ultrasound with power Doppler (microvascular flow), and Evans blue extravasation (vascular permeability). Synovial gene expression and systemic markers of vascular collagen turnover were studied in FVIII-deficient mice by RNA sequencing and enzyme-linked immunosorbent assay. RESULTS: Vascular changes occurred in FVIII-deficient and Hypo BALB/c mice after injury with minimal effect of hemostasis correction. Increased vascular permeability was only significant in FVIII-deficient mice, who exhibited more pronounced vascular remodeling than Hypo BALB/c mice despite similar bleed volumes. FVIII-deficient mice exhibited a strong transcriptional response in synovium that was only partially affected by FVIII treatment and involved genes relating to angiogenesis and extracellular matrix remodeling, with vascular collagen turnover markers detected systemically. CONCLUSIONS: Intact hemostasis at the time of hemarthrosis and during healing are both critical to prevent vascular remodeling, which appears worse with severe and prolonged FVIII deficiency. Unbiased RNA sequencing revealed potential targets for intervention and biomarker development to improve management of HA.
Assuntos
Permeabilidade Capilar , Fator VIII/metabolismo , Hemartrose/metabolismo , Hemofilia A/metabolismo , Membrana Sinovial/irrigação sanguínea , Remodelação Vascular , Animais , Permeabilidade Capilar/efeitos dos fármacos , Modelos Animais de Doenças , Fator VIII/administração & dosagem , Fator VIII/genética , Feminino , Hemartrose/genética , Hemartrose/fisiopatologia , Hemartrose/prevenção & controle , Hemofilia A/tratamento farmacológico , Hemofilia A/genética , Hemofilia A/fisiopatologia , Hemostasia , Hemostáticos/administração & dosagem , Masculino , Camundongos Endogâmicos BALB C , Camundongos Knockout , Fatores de Tempo , Remodelação Vascular/efeitos dos fármacosRESUMO
Diarrhoea and water-borne diseases are leading causes of mortality in developing countries. To understand the socio-cultural factors impacting on water safety, we documented knowledge, attitudes and practices of water handling and usage, sanitation and defecation in rural Tamilnadu, India, using questionnaires and focus group discussions, in a village divided into an upper caste Main village and a lower caste Harijan colony. Our survey showed that all households stored drinking water in wide-mouthed containers. The quantity of water supplied was less in the Harijan colony, than in the Main village (P<0.001). Residents did not associate unsafe water with diarrhoea, attributing it to 'heat', spicy food, ingesting hair, mud or mosquitoes. Among 97 households interviewed, 30 (30.9%) had toilets but only 25 (83.3%) used them. Seventy-two (74.2%) of respondents defecated in fields, and there was no stigma associated with this traditional practice. Hand washing with soap after defecation and before meals was common only in children under 15 years (86.4%). After adjusting for other factors, perception of quantity of water received (P<0.001), stated causation of diarrhoea (P=0.02) and low socio-economic status (P<0.001) were significantly different between the Main village and the Harijan colony. Traditional practices may pose a significant challenge to programmes aimed at toilet usage and better sanitation.
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Defecação , Diarreia/prevenção & controle , Conhecimentos, Atitudes e Prática em Saúde , Saneamento/normas , Adolescente , Adulto , Criança , Diarreia/epidemiologia , Feminino , Desinfecção das Mãos , Humanos , Higiene , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Saúde da População Rural , Abastecimento de Água/normasAssuntos
Compostos de Anilina/efeitos adversos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Nitrilas/efeitos adversos , Fosfoproteínas/metabolismo , Inibidores de Proteínas Quinases/efeitos adversos , Proteômica , Quinolinas/efeitos adversos , Compostos de Anilina/farmacologia , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Nitrilas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/farmacologiaRESUMO
INTRODUCTION: Several chemotherapy agents and combinations have proven effective in the therapy of advanced enteropancreatic neuroendocrine tumors (EP-NETs). However, their toxicity can be significant. Recent understanding of the molecular mechanisms of these tumors, especially the central role of tumor angiogenesis, has led to the identification of new therapeutic targets and agents directed at the molecular level. AREAS COVERED: This paper gives a comprehensive evaluation of the existing therapeutic armamentarium for EP-NETs. Narrated in a historical perspective, this review analyzes the available information on traditional chemotherapy agents, interferon-α and somatostatin analogs, as well as newer therapies and experimental agents. EXPERT OPINION: Despite recent advances, a curative approach for metastatic EP-NETs is yet to be discovered. To date, sunitinib and everolimus have been shown to impact progression-free survival only in pancreatic NETs, and the duration of this benefit has not yet been established. Further research is necessary to determine whether a combination of these drugs, either together or with other therapies, may yield superior outcomes. Moreover, sequential use of these agents should be explored in an attempt to improve survival. Efficacy of a variety of experimental agents is also being tested in clinical trials.