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1.
J Perinatol ; 44(7): 1069-1072, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38499755

RESUMO

Emotional disorders in parents of infants admitted to the neonatal intensive care unit (NICU) carry the potential for serious ramifications in neonatal and childhood outcomes. Despite this, current NICU mental health supports are less than optimum; postpartum mental health screening is limited, often missed in parents of inpatient infants, and may not be applicable to all family structures. Current evidence demonstrates improved outcomes in neonates and family members with early identification and multidisciplinary approaches to managing mental health problems. Physician Associates/Assistants (PAs) are a skilled group of advanced practice providers who are often a point of first contact for parents in the NICU, helping maintain continuity of care. In this perspective, we underscore leveraging the skills of PAs to promote the emotional wellbeing of parents in the NICU by way of practice and policy involvement. We also included a generic set of recommendations to equip PAs in this role.


Assuntos
Unidades de Terapia Intensiva Neonatal , Saúde Mental , Pais , Humanos , Recém-Nascido , Pais/psicologia , Feminino
2.
Vet Comp Oncol ; 21(3): 541-550, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37337253

RESUMO

Enumeration of circulating tumour cells (CTC) has shown promise for prognostication and guidance of therapeutic decisions in human cancers. The objective of this study was to enumerate CTC over time in dogs with naturally occurring osteosarcoma (OSA), and to determine correlation with patient outcome. Twenty-six dogs with OSA and no evidence of metastatic disease at the time of amputation were enrolled. Dogs were assessed for lung metastases and CTC prior to and following amputation, and at each chemotherapy visit. Twenty-one dogs completed the study. Nineteen dogs were euthanized and two were alive and free of metastases. Overall survival time ranged from 88 to 1058 days (median survival time (MST) 374 days). Increased serum alkaline phosphatase activity, advanced age, and higher body weight were significantly associated with lower MST. Dogs with OSA had a mean of 356 (0 to 4443) CTC/106 leukocytes. In 12 of 15 dogs that developed radiographic evidence of metastasis, a pre-metastatic CTC spike was retrospectively detectable on average 36.5 (1-100 days) days prior to metastasis and was associated with significantly shorter MST (301 ± 64 vs. 626 ± 55 days; p = .0107). In a multivariable analysis, dogs with a CTC spike were 10× more likely to die compared with those without. These results suggest that a spike in CTC frequency precedes detection of metastasis in dogs with OSA and is associated with shorter survival. More frequent enumeration of CTC in a larger cohort of dogs with OSA may be warranted.


Assuntos
Neoplasias Ósseas , Doenças do Cão , Células Neoplásicas Circulantes , Osteossarcoma , Cães , Humanos , Animais , Estudos Retrospectivos , Neoplasias Ósseas/veterinária , Neoplasias Ósseas/tratamento farmacológico , Doenças do Cão/patologia , Osteossarcoma/tratamento farmacológico , Osteossarcoma/veterinária
3.
BMC Vet Res ; 15(1): 453, 2019 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-31842875

RESUMO

BACKGROUND: Assessment of the efficacy of a multi-agent chemotherapy protocol in which cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) are administered in canine lymphoma is generally performed by physical measurement of lymph node diameter. However, no consistent correlation has been made with prognostic indicators and the length or absence of clinical remission based on lymph node size. RNA disruption measured mid-therapy has been correlated with increased disease-free survival in recent studies of human cancer and was assessed in this study of canine lymphoma patients. Fine needle aspirate samples were taken before treatment and at weeks 3, 6, and 11 of CHOP therapy. RNA was isolated from these samples and assessed using an Agilent Bioanalyzer. RNA disruption assay (RDA) analysis was performed on the data from the resulting electropherograms. RESULTS: An increased RNA disruption index (RDI) score was significantly associated with improved progression-free survival. CONCLUSIONS: Predicting the risk of early relapse during chemotherapy could benefit veterinary patients by reducing ineffective treatment and could allow veterinary oncologists to switch earlier to a more effective drug regimen.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doenças do Cão/tratamento farmacológico , Linfoma não Hodgkin/veterinária , RNA Neoplásico/análise , Animais , Ciclofosfamida/uso terapêutico , Cães , Doxorrubicina/uso terapêutico , Linfoma não Hodgkin/tratamento farmacológico , Prednisona/uso terapêutico , Intervalo Livre de Progressão , Vincristina/uso terapêutico
4.
Cytometry A ; 95(9): 997-1007, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31282052

RESUMO

Osteosarcoma (OSA) is a malignant tumor of middle-aged dogs and adolescent humans. The clinical outcome of OSA has not improved over more than three decades, and dogs typically succumb to metastatic disease within 6 months despite tumor resection through limb amputation and adjuvant chemotherapy. Therefore, undetectable tumor cells with potential to form metastases are present at diagnosis. An assay to identify canine immortalized and primary OSA cells through flow cytometric detection of intracellular collagen 1 (Col I) and osteocalcin was optimized, and applied to blood samples from tumor-bearing dogs for detection of circulating tumor cells (CTCs). Spiking variable number of OSA cells into normal dog blood recovered 50-60% of Col I positive cells with high forward and variable side light scatter. An algorithm to exclude nonviable, doublet, and autofluorescent cells was applied to sequential blood samples from three dogs obtained prior to and after limb amputation, and at approximately, triweekly intervals over 121, 142, and 183 days of chemotherapy, respectively. Dogs had >100 CTC/106 leukocytes prior to amputation, variably frequent CTC during chemotherapy, and an increase up to 4,000 CTC/106 leukocytes within 4 weeks before overt metastases or death. Sorted CTCs were morphologically similar to direct tumor aspirates and positive for Col I. Although preliminary, findings suggest that CTCs are frequent in canine OSA, more numerous than carcinoma CTC in humans, and that an increase in CTC frequency may herald clinical deterioration. This assay may enable enumeration and isolation of OSA CTC for prognostic and functional studies, respectively. © 2019 International Society for Advancement of Cytometry.


Assuntos
Neoplasias Ósseas/veterinária , Doenças do Cão/diagnóstico por imagem , Citometria de Fluxo/métodos , Células Neoplásicas Circulantes/metabolismo , Osteossarcoma/veterinária , Amputação Cirúrgica , Animais , Neoplasias Ósseas/sangue , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/tratamento farmacológico , Linhagem Celular Tumoral , Colágeno/metabolismo , Doenças do Cão/sangue , Doenças do Cão/tratamento farmacológico , Cães , Processamento de Imagem Assistida por Computador , Leucócitos/metabolismo , Células Neoplásicas Circulantes/efeitos dos fármacos , Células Neoplásicas Circulantes/patologia , Osteocalcina/metabolismo , Osteossarcoma/sangue , Osteossarcoma/diagnóstico por imagem , Osteossarcoma/tratamento farmacológico , Prognóstico
5.
PLoS One ; 9(7): e103243, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25079072

RESUMO

DNA hypomethylation is an important epigenetic modification found to occur in many different cancer types, leading to the upregulation of previously silenced genes and loss of genomic stability. We previously demonstrated that hypoxia and hypoglycaemia (ischemia), two common micro-environmental changes in solid tumours, decrease DNA methylation through the downregulation of DNMTs in human colorectal cancer cells. Here, we utilized a genome-wide cross-platform approach to identify genes hypomethylated and upregulated by ischemia. Following exposure to hypoxia or hypoglycaemia, methylated DNA from human colorectal cancer cells (HCT116) was immunoprecipitated and analysed with an Affymetrix promoter array. Additionally, RNA was isolated and analysed in parallel with an Affymetrix expression array. Ingenuity pathway analysis software revealed that a significant proportion of the genes hypomethylated and upregulated were involved in cellular movement, including PLAUR and CYR61. A Matrigel invasion assay revealed that indeed HCT116 cells grown in hypoxic or hypoglycaemic conditions have increased mobility capabilities. Confirmation of upregulated expression of cellular movement genes was performed with qPCR. The correlation between ischemia and metastasis is well established in cancer progression, but the molecular mechanisms responsible for this common observation have not been clearly identified. Our novel data suggests that hypoxia and hypoglycaemia may be driving changes in DNA methylation through downregulation of DNMTs. This is the first report to our knowledge that provides an explanation for the increased metastatic potential seen in ischemic cells; i.e. that ischemia could be driving DNA hypomethylation and increasing expression of cellular movement genes.


Assuntos
Neoplasias Colorretais/genética , Metilação de DNA , Estudo de Associação Genômica Ampla , Isquemia/genética , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Humanos , Regiões Promotoras Genéticas
6.
Neoplasia ; 14(7): 612-23, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22904678

RESUMO

Receptors for the angiogenic factor VEGF are expressed by tumor cancer cells including melanoma, although their functionality remains unclear. Paired human melanoma cell lines WM115 and WM239 were used to investigate differences in expression and functionality of VEGF and VEGFR2 in vitro and in vivo with the anti-VEGF antibody bevacizumab. Both WM115 and WM239 cells expressed VEGF and VEGFR2, the levels of which were modulated by hypoxia. Detection of native and phosphorylated VEGFR2 in subcellular fractions under serum-free conditions showed the presence of a functional autocrine as well as intracrine VEGF/VEGFR2 signaling loops. Interestingly, treatment of WM115 and WM239 cells with increasing doses of bevacizumab (0-300 µg/ml) in vitro did not show any significant inhibition of VEGFR2 phosphorylation. Small-molecule tyrosine kinase inhibitor, sunitinib, caused an inhibition of VEGFR2 phosphorylation in WM239 but not in WM115 cells. An increase in cell proliferation was observed in WM115 cells treated with bevacizumab, whereas sunitinib inhibited proliferation. When xenografted to immune-deficient mice, we found bevacizumab to be an effective antiangiogenic but not antitumorigenic agent for both cell lines. Because bevacizumab is unable to neutralize murine VEGF, this supports a paracrine angiogenic response. We propose that the failure of bevacizumab to generate an antitumorigenic effect may be related to its generation of enhanced autocrine/intracrine signaling in the cancer cells themselves. Collectively, these results suggest that, for cancers with intracrine VEGF/ VEGFR2 signaling loops, small-molecule inhibitors of VEGFR2 may be more effective than neutralizing antibodies at disease control.


Assuntos
Inibidores da Angiogênese/farmacologia , Anticorpos Monoclonais Humanizados/farmacologia , Comunicação Autócrina/efeitos dos fármacos , Melanoma/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Bevacizumab , Hipóxia Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Melanoma/genética , Melanoma/patologia , Camundongos , Camundongos Nus , Fosforilação/efeitos dos fármacos , Carga Tumoral/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Ensaios Antitumorais Modelo de Xenoenxerto
7.
BMC Cancer ; 10: 683, 2010 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-21159176

RESUMO

BACKGROUND: Targeting tumor vasculature is a strategy with great promise in the treatment of many cancers. However, anti-angiogenic reagents that target VEGF/VEGFR2 signaling have met with variable results clinically. Among the possible reasons for this may be heterogeneous expression of the target protein. METHODS: Double immunofluorescent staining was performed on formalin-fixed paraffin embedded sections of treated and control SW480 (colorectal) and WM239 (melanoma) xenografts, and tissue microarrays of human colorectal carcinoma and melanoma. Xenografts were developed using RAG1-/- mice by injection with WM239 or SW480 cells and mice were treated with 20 mg/kg/day of cyclophosphamide in their drinking water for up to 18 days. Treated and control tissues were characterized by double immunofluorescence using the mural cell marker α-SMA and CD31, while the ratio of desmin/CD31 was also determined by western blot. Hypoxia in treated and control tissues were quantified using both western blotting for HIF-1α and immunohistochemistry of CA-IX. RESULTS: VEGFR2 is heterogeneously expressed in tumor vasculature in both malignant melanoma and colorectal carcinoma. We observed a significant decrease in microvascular density (MVD) in response to low dose metronomic cyclophosphamide chemotherapy in both malignant melanoma (with higher proportion VEGFR2 positive blood vessels; 93%) and colorectal carcinoma (with lower proportion VEGFR2 positive blood vessels; 60%) xenografts. This reduction in MVD occurred in the absence of a significant anti-tumor effect. We also observed less hypoxia in treated melanoma xenografts, despite successful anti-angiogenic blockade, but no change in hypoxia of colorectal xenografts, suggesting that decreases in tumor hypoxia reflect a complex relationship with vascular density. Based on α-SMA staining and the ratio of desmin to CD31 expression as markers of tumor blood vessel functionality, we found evidence for increased stabilization of colorectal microvessels, but no such change in melanoma vessels. CONCLUSIONS: Overall, our study suggests that while heterogeneous expression of VEGFR2 is a feature of human tumors, it may not affect response to low dose metronomic cyclophosphamide treatment and possibly other anti-angiogenic approaches. It remains to be seen whether this heterogeneity is partly responsible for the variable clinical success seen to date with targeted anti-VEGFR2 therapy.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Ciclofosfamida/administração & dosagem , Melanoma/tratamento farmacológico , Microvasos/efeitos dos fármacos , Neovascularização Patológica/prevenção & controle , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Actinas/metabolismo , Animais , Antígenos de Neoplasias/metabolismo , Anidrase Carbônica IX , Anidrases Carbônicas/metabolismo , Hipóxia Celular , Linhagem Celular Tumoral , Neoplasias Colorretais/irrigação sanguínea , Neoplasias Colorretais/metabolismo , Desmina/metabolismo , Feminino , Imunofluorescência , Proteínas de Homeodomínio/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Imuno-Histoquímica , Masculino , Melanoma/irrigação sanguínea , Melanoma/metabolismo , Camundongos , Camundongos Knockout , Microvasos/metabolismo , Neovascularização Patológica/metabolismo , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Fatores de Tempo , Análise Serial de Tecidos , Carga Tumoral , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Epigenetics ; 5(6): 547-56, 2010 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-20543577

RESUMO

Epigenetic modifications are involved in the initiation and progression of cancer. Expression patterns and activity of DNA methyltransferases (DNMTs) are strictly controlled in normal cells, however, regulation of these enzymes is lost in cancer cells due to unknown reasons. Cancer therapies which target DNMTs are promising treatments of hematologic cancers, but they lack effectiveness in solid tumors. Solid tumors exhibit areas of hypoxia and hypoglycaemia due to their irregular and dysfunctional vasculature, and we previously showed that hypoxia reduces global DNA methylation. Colorectal carcinoma (CRC) cells (HCT116 and 379.2; p53+/+ and p53-/-, respectively) were subjected to ischemia (hypoxia and hypoglycaemia) in vitro, and levels of DNMTs were assessed. We found a significant decrease in mRNA for DNMT1, DNMT3a and DNMT3b, and similar reductions in DNMT1 and DNMT3a protein levels were detected by western blotting. In addition, total activity levels of DNMTs (as measured by an ELISA-based DNMT activity assay) were reduced in cells exposed to hypoxic and hypoglycaemic conditions. Immunofluorescence of HCT116 tumor xenografts demonstrated an inverse relationship between ischemia (as revealed by carbonic anhydrase IX staining) and DNMT1 protein. Bisulfite sequencing of the proximal promoter region of p16INK4a showed a decrease in 5-methylcytosine following in vitro exposure to ischemia. These studies provide evidence for the down-regulation of DNMTs and modulation of methylation patterns by hypoxia and hypoglycaemia in human CRC cells, both in vitro and in vivo. Our findings suggest that ischemia, either intrinsic or induced through the use of anti-angiogenic drugs, may influence epigenetic patterning and hence tumor progression.


Assuntos
Carcinoma/genética , Neoplasias Colorretais/genética , DNA (Citosina-5-)-Metiltransferases/genética , Metilação de DNA , Genes p16 , Isquemia/genética , Carcinoma/metabolismo , Carcinoma/patologia , Hipóxia Celular/genética , Hipóxia Celular/fisiologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , DNA (Citosina-5-)-Metiltransferases/metabolismo , Metilação de DNA/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Genes p16/efeitos dos fármacos , Genes p53 , Glucose/farmacologia , Células HCT116 , Humanos , Isquemia/metabolismo , Isquemia/patologia , Oxigênio/farmacologia
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