RESUMEN
Introduction: As sufficient nutrition helps alleviate catabolic stress and modulate the systemic inflammatory response of the body, it plays an indispensable role in the good prognosis of critically ill patients. Thus, this study aimed to investigate the malnutrition of patients with severe COVID-19 and its association with adverse treatment outcomes. Methods: We conducted a retrospective cross-sectional study in two provincial hospitals in Hanoi from February to April 2022. Participants were patients with severe COVID-19 admitted to the Intensive Care Unit (ICU). Malnutrition risk were evaluated by Nutritional Risk Screening-2002 (NRS), Global Leadership Initiative on Malnutrition (GLIM), Prognostic Nutritional Index (PNI), and the adverse prognosis was assessed by Acute Physiology and Chronic Health Evaluation II (APACHE II). The multivariate receiver-operating characteristic (ROC) curve was applied to estimate the predictive ability of those criteria regarding worse treatment results. Results: The percentages of malnutrition measured by NRS, GLIM, PNI, and BMI were 62.6, 51.5, 42.9, and 16.6%, respectively. Patients with more severe malnutrition assessed by GLIM, PNI, and having above target fasting blood glucose (FBG) (≥10.0 mmol/L) were more likely to have higher APACHE scores. PNI had a better diagnostic performance than NRS and BMI (AUC = 0.84, 0.81, and 0.82, respectively). In addition, FBG revealed a good prognostic implication (AUC = 0.84). Conclusion: A relatively high percentage of patients experienced moderate and severe malnutrition regardless of screening tools. Individuals at higher risk of malnutrition and high FBG were predicted to have more adverse treatment outcomes. It is recommended that nutritional screening should be conducted regularly, and personalizing nutritional care strategies is necessary to meet patients' nutrient demands and prevent other nutrition-related complications.
RESUMEN
BACKGROUND: Toy-related injuries have increased significantly in the past decade, in particular those related to ride-on toys. This increase has been attributed to movement related events such as falls and inertial impacts. Furthermore, children with disabilities have been reported to be at a greater risk of being injured, and are therefore more susceptible to toy-related injuries. Although, efforts are being made to modify ride-on toys as a method for increasing quality of life in children with disabilities, there are very limited pediatric safety studies regarding children with disabilities and modified ride-on toys. METHODS: This manuscript presents a systematic review of literature summarizing the current state of toy-related injuries including children with and without disabilities. Children exposed to inertial impacts in motor vehicle crashes have also been reviewed to present current pediatric safety testing methodologies and injury tolerance thresholds. Out of 2608 articles, 10 studies were included regarding current trends in toy-related injuries and safety testing methodologies. CONCLUSIONS: From this study, a gap in the literature was discovered concerning the susceptibility of children with disabilities to toy-related injuries, specifically in relation to ride-on toys and the repercussion surrounding such injuries. It is theorized that such lack of data is due to the difficulty and costs associated with experimental validation. Hence, it is recommended that computer simulations be used to provide preliminary data analysis.
RESUMEN
OBJECTIVE: To evaluate the therapeutic efficacy of bevacizumab and cetuximab, alone and in combination, in an orthotopic model of anaplastic thyroid carcinoma (ATC) in athymic nude mice. STUDY DESIGN AND SETTING: This was a randomized, controlled in vivo study. MATERIALS AND METHODS: The ATC cell line, ARO, was used to establish orthotopic xenografts of ATC in athymic nude mice. Mice were randomized to therapy for 4 weeks in one of four treatment groups: placebo, cetuximab, bevacizumab, or the combination of cetuximab and bevacizumab. A second study compared the antitumor efficacy of the cetuximab-bevacizumab combination with doxorubicin. In both studies, tumor volumes on completion were measured and compared. Immunohistochemical analysis was performed with antiCD31 and antiproliferating cell nuclear antigen (PCNA) antibodies to assess the in vivo mechanisms of action of these agents. RESULTS: Cetuximab decreased the production of vascular endothelial growth factor by ATC cell lines in vitro. Mean tumor volumes for the control, bevacizumab, cetuximab, and combination groups at the end of the in vivo study were 291, 213, 94, and 42 mm(3), respectively. The differences in mean tumor volume for the control versus treatment groups were statistically significant. Immunohistochemical analysis showed decreased microvessel density and PCNA positivity in the treatment groups. In the doxorubicin comparison study, mean tumor volumes for control, doxorubicin, and combination antibody treatment groups were 175, 162, and 22 mm(3), respectively. CONCLUSIONS: Cetuximab and bevacizumab alone and in combination inhibit tumor growth and angiogenesis in an in vivo model of ATC. Also, this therapy was superior to doxorubicin therapy.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma/tratamiento farmacológico , Neoplasias de la Tiroides/tratamiento farmacológico , Animales , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/uso terapéutico , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Bevacizumab , Western Blotting , Carcinoma/inmunología , Carcinoma/patología , Recuento de Células , Línea Celular Tumoral , Cetuximab , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Receptores ErbB/antagonistas & inhibidores , Inmunohistoquímica , Masculino , Ratones , Ratones Desnudos , Antígeno Nuclear de Célula en Proliferación/inmunología , Distribución Aleatoria , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Neoplasias de la Tiroides/inmunología , Neoplasias de la Tiroides/patologíaRESUMEN
Therapies that target signaling pathways critical to the pathogenesis and progression of squamous cell carcinoma of the head and neck (HNSCC) are needed. One such target, phosphatidylinositol 3-kinase, and its downstream target serine/threonine kinase, Akt, are up-regulated in HNSCC. Targeted therapy could consist of inhibitors of these kinases or, alternatively, of inhibitors of the pathways that they regulate. To explore the effect of Akt inhibition on the growth and survival of HNSCC tumors, we evaluated the effect of a novel Akt inhibitor, KP372-1, on the growth, survival, and sensitivity to anoikis of HNSCC cell lines in culture. Using Western blotting of head and neck cancer cell lines and squamous mucosa and carcinoma specimens, we found that Akt was highly phosphorylated in head and neck cancer cell lines and human head and neck squamous carcinoma specimens. Treatment of HNSCC cell lines with KP372-1 blocked the activation of Akt, inhibited head and neck cancer cell proliferation, and induced apoptosis and anoikis in several HNSCC cell lines. Furthermore, KP372-1 decreased the phosphorylation of the S6 ribosomal (Ser240/244) protein, which is a downstream target of Akt. Taken together, these findings indicate that KP372-1 may be a useful therapeutic agent for HNSCC and should be further evaluated in preclinical models of HNSCC.
Asunto(s)
Apoptosis/fisiología , Carcinoma de Células Escamosas/patología , Neoplasias de Cabeza y Cuello/patología , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Tetrazoles/farmacología , Western Blotting , Línea Celular Tumoral , Proliferación Celular , HumanosRESUMEN
Anaplastic thyroid carcinoma (ATC) is one of the most aggressive human malignancies with a mean survival of only 6 months. The poor prognosis of patients with ATC reflects the current lack of curative therapeutic options and the need for development of novel therapeutic strategies. In this study, we report the results of a preclinical study of AEE788, a dual inhibitor of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) tyrosine kinases, against ATC. AEE788 was able to inhibit the proliferation and induce apoptosis of ATC cell lines in vitro. Administration of AEE788, alone and in combination with paclitaxel, to athymic nude mice bearing s.c. ATC xenografts inhibited the growth of ATC xenografts by 44% and 69%, respectively, compared with the control group. Furthermore, tumors from mice treated with AEE788, alone and in combination with paclitaxel, showed increase in apoptosis of tumor cells by approximately 6- and 8-fold, respectively, compared with the control group. The microvessel density within the ATC xenografts was decreased by >80% in the mice treated with AEE788 alone and in combination with paclitaxel compared with the control group. Lastly, immunofluorescence microscopy showed the inhibition of EGFR autophosphorylation on the tumor cells as well as the inhibition of VEGFR-2 autophosphorylation on tumor endothelium. Considering the fact that curative options seldom exist for patients with ATC, concurrent inhibition of EGFR and VEGFR tyrosine kinases seems to be a valid and promising anticancer strategy for these patients.
Asunto(s)
Carcinoma/tratamiento farmacológico , Purinas/farmacología , Neoplasias de la Tiroides/tratamiento farmacológico , Animales , Antineoplásicos/farmacología , Apoptosis , Western Blotting , Muerte Celular , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Endotelio Vascular/metabolismo , Receptores ErbB/antagonistas & inhibidores , Humanos , Inmunohistoquímica , Masculino , Ratones , Ratones Desnudos , Microcirculación , Microscopía Fluorescente , Trasplante de Neoplasias , Paclitaxel/farmacología , Fosforilación , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factores de TiempoRESUMEN
PURPOSE: To develop an orthotopic model of anaplastic thyroid carcinoma (ATC) in athymic nude mice. EXPERIMENTAL DESIGN: Various thyroid carcinoma cell lines were injected into the thyroid gland of athymic nude mice to determine whether such injection was technically feasible. ATC cells were then injected into the thyroid gland or the subcutis of nude mice at various concentrations, and the mice were then followed for tumor development. The tumors were examined histopathologically for local invasion or regional or distant metastasis. RESULTS: Injection of tumor cells into the thyroid glands of nude mice was technically feasible and resulted in the formation of thyroid tumors. The ATC cell line DRO showed significantly higher tumorigenicity in the thyroid gland than in the subcutis. In contrast, oral squamous cell carcinoma cell line TU167 shows no significantly higher tumorigenicity in the thyroid gland than in the subcutis. ATC tumors established in the thyroid gland also produced symptomatic compression of the esophagus and the trachea. Local invasion of the larynx and trachea was as well as high rates of pulmonary metastasis were also observed. Immunohistochemical staining showed higher microvessel density as well as higher expression of vascular endothelial growth factor and interleukin-8 in the orthotopic thyroid tumors than in ectopic tumors. CONCLUSION: An orthotopic model of ATC in athymic nude mice was developed that closely recapitulates the clinical findings of human ATC. This model should facilitate the understanding of the pathogenesis of ATC and aid in the development of novel therapies against ATC.
Asunto(s)
Carcinoma/patología , Carcinoma/veterinaria , Modelos Animales de Enfermedad , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/veterinaria , Animales , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Masculino , Ratones , Ratones Desnudos , Invasividad Neoplásica , Metástasis de la Neoplasia , Trasplante Heterólogo , Células Tumorales CultivadasRESUMEN
PURPOSE: No effective treatment options currently are available to patients with anaplastic thyroid cancer (ATC), resulting in high mortality rates. Epidermal growth factor (EGF) has been shown to play a role in the pathogenesis of many types of cancer, and its receptor (EGFR) provides an attractive target for molecular therapy. EXPERIMENTAL DESIGN: The expression of EGFR was determined in ATC in vitro and in vivo and in human tissue arrays of ATC. We assessed the potential of the EGFR inhibitor gefitinib ("Iressa," ZD1839) to inhibit EGFR activation in vitro and in vivo, inhibit ATC cellular proliferation, induce apoptosis, and reduce the growth of ATC cells in vivo when administered alone and in combination with paclitaxel. RESULTS: EGFR was overexpressed in ATC cell lines in vitro and in vivo and in human ATC specimens. Activation of EGFR by EGF was blocked by the addition of gefitinib. In vitro studies showed that gefitinib greatly inhibited cellular proliferation and induced apoptosis in ATC cell lines and slowed tumor growth in a nude mouse model of thyroid carcinoma cells injected subcutaneously. CONCLUSIONS: ATC cells consistently overexpress EGFR, rendering this receptor a potential target for molecular therapy. Gefitinib effectively blocks activation of EGFR by EGF, inhibits ATC cellular proliferation, and induces apoptosis in vitro. Our in vivo results show that gefitinib has significant antitumor activity against ATC in a subcutaneous nude mouse tumor model and therefore is a potential candidate for human clinical trials.
Asunto(s)
Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Carcinoma/tratamiento farmacológico , Receptores ErbB/antagonistas & inhibidores , Quinazolinas/uso terapéutico , Neoplasias de la Tiroides/tratamiento farmacológico , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma/metabolismo , Carcinoma/prevención & control , Carcinoma Papilar/tratamiento farmacológico , Carcinoma Papilar/metabolismo , Carcinoma Papilar/prevención & control , Proliferación Celular/efectos de los fármacos , Factor de Crecimiento Epidérmico/metabolismo , Factor de Crecimiento Epidérmico/farmacología , Receptores ErbB/metabolismo , Gefitinib , Humanos , Ratones , Ratones Desnudos , Paclitaxel/administración & dosificación , Fosforilación/efectos de los fármacos , Neoplasias de la Tiroides/metabolismo , Neoplasias de la Tiroides/prevención & control , Factor de Crecimiento Transformador alfa/metabolismo , Factor de Crecimiento Transformador alfa/farmacología , Células Tumorales CultivadasRESUMEN
Expression of the epidermal growth factor (EGF) and activation of its receptor (EGFR), a tyrosine kinase, are associated with progressive growth of head and neck cancer. Expression of the vascular endothelial growth factor (VEGF) is associated with angiogenesis and progressive growth of tumor. The tyrosine kinase inhibitor NVP-AEE788 (AEE788) blocks the EGF and VEGF signaling pathways. We examined the effects of AEE788 administered alone, or with paclitaxel (Taxol), on the progression of human head and neck cancer implanted orthotopically into nude mice. Cells of two different human oral cancer lines, JMAR and MDA1986, were injected into the tongues of nude mice. Mice with established tumors were randomized to receive three times per week oral AEE788, once weekly injected paclitaxel, AEE788 plus paclitaxel, or placebo. Oral tumors were resected at necropsy. Kinase activity, cell proliferation, apoptosis, and mean vessel density were determined by immunohistochemical immunofluorescent staining. AEE788 inhibited cell growth, induced apoptosis, and reduced the phosphorylation of EGFR, VEGFR-2, AKT, and mitogen-activated protein kinase in both cell lines. Mice treated with AEE788 and AEE788 plus paclitaxel had decreased microvessel density, decreased proliferative index, and increased apoptosis. Hence, AEE788 inhibited tumor vascularization and growth and prolonged survival. Inhibition of EGFR and VEGFR phosphorylation by AEE788 effectively inhibits cellular proliferation of squamous cell carcinoma of the head and neck, induces apoptosis of tumor endothelial cells and tumor cells, and is well tolerated in mice. These data recommend the consideration of patients with head and neck cancer for inclusion in clinical trials of AEE788.
Asunto(s)
Carcinoma de Células Escamosas/tratamiento farmacológico , Receptores ErbB/antagonistas & inhibidores , Neoplasias de la Boca/tratamiento farmacológico , Purinas/uso terapéutico , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Línea Celular Tumoral , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Humanos , Inmunohistoquímica , Ratones , Ratones Desnudos , Paclitaxel/farmacología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiologíaRESUMEN
We hypothesized that acquisition of resistance to anoikis is a critical step in oral cancer progression. To test this hypothesis, we compared a panel of cell lines derived from human oral tissues across the spectrum of tumor progression from oral keratinocytes (HOK-16B), invasive oral squamous cell carcinoma (Tu167), and finally metastatic carcinoma (TxCS-1, MDA1986) for their sensitivity to detachment from the extracellular matrix. The relationship between stage of tumor progression and anoikis resistance was demonstrated by the apoptotic fractions after 48 h in suspension culture which were 93.33, 61.6, 34.5, and 3.71%, respectively. To further demonstrate that anoikis resistance is important for tumor progression, we selected a highly anoikis resistant cell line, JMAR, by serial passage of the Tu167 cell line in suspension culture. Initially, the JMAR line, and clones derived from it, were characterized for anoikis resistance in vitro, and after 72 h in suspension culture the rates of anoikis in the Tu167 and JMAR lines were found to be 73 and 26%, respectively. The degree of anoikis resistance was found to correlate with survival of nude mice orthotopically injected with 5x10(5) Tu167 or JMAR cells. The JMAR mice had a median survival of 17 days versus over 30 days in mice implanted with the Tu167 line. Finally, we found that in vivo selection in the orthotopic model for a regionally metastatic cell line by implantation of Tu167 into the tongues of nude mice and harvesting and culturing cervical lymph nodes led to production of a cell line, Tu167LN1, which was found to be anoikis-resistant. This cell line had an apoptotic cell fraction of 16.2% (+/-3.14%) after 48 h in suspension culture.
Asunto(s)
Anoicis , Carcinoma de Células Escamosas/patología , Neoplasias de la Lengua/patología , Animales , Apoptosis , División Celular , Progresión de la Enfermedad , Humanos , Metástasis Linfática , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Tasa de Supervivencia , Células Tumorales CultivadasRESUMEN
PURPOSE: Because survival for patients with oral cancer has not improved over the past 25 years, new approaches for treatment are needed. Targeted molecular therapy against epidermal growth factor receptor (EGFR) has shown promise as an adjuvant therapy in preliminary studies in several solid tumors, including head and neck cancer. The objective of this study was to determine the efficacy of paclitaxel and PKI166, a novel inhibitor of EGFR, against oral cavity cancer. EXPERIMENTAL DESIGN AND RESULTS: JMAR human oral cancer cells were pretreated for 1 h with PKI166 and then stimulated with epidermal growth factor. EGFR-specific tyrosine kinase autophosphorylation measured by Western immunoblotting was inhibited by PKI166 in a dose-dependent fashion at all doses tested (0.01-1 micro M). Next, the induction of apoptosis in JMAR cells treated with paclitaxel (0.001 to 0.1 micro M) with or without PKI166 (0, 1, or 2 micro M) was determined using a propidium iodide assay. The addition of 2.0 micro M PKI166 significantly increased tumor cell death, shifting the amount of paclitaxel needed to induce apoptosis in 50% of cells from 0.1 to 0.001 micro M. These in vitro findings were confirmed using an orthotopic model of oral cancer. JMAR oral cancer cells were implanted into the tongues of nude mice. After lingual tumors developed, mice were randomized into four groups (n = 10): (a) oral PKI166 (100 mg/kg); (b) i.p. paclitaxel (200 micro g/wk); (c) PKI166 and paclitaxel; or (d) placebo. Mice treated with PKI166/paclitaxel demonstrated a significant increase in survival (P = 0.028). After necropsy, all tongue tumors were evaluated for apoptosis by the terminal deoxynucleotidyl transferase-mediated nick end labeling assay. A greater apoptotic fraction of tumor cells was found in tumors of mice treated with paclitaxel and PKI166 as compared with the other treatment groups (136.4 versus 37.8; P = 0.016). CONCLUSIONS: Combination therapy with paclitaxel and PKI166 prolongs survival in an orthotopic preclinical model of tongue cancer by increasing programmed cell death of oral cancer.