RESUMEN
Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide. Therefore, the need for new therapeutic strategies is still a challenge. Surgery and chemotherapy represent the first-line interventions; nevertheless, the prognosis for metastatic CRC (mCRC) patients remains unacceptable. An important step towards targeted therapy came from the inhibition of the epidermal growth factor receptor (EGFR) pathway, by the anti-EGFR antibody, Cetuximab, or by specific tyrosine kinase inhibitors (TKI). Cetuximab, a mouse-human chimeric monoclonal antibody (mAb), binds to the extracellular domain of EGFR thus impairing EGFR-mediated signaling and reducing cell proliferation. TKI can affect the EGFR biochemical pathway at different steps along the signaling cascade. Apart from Cetuximab, other anti-EGFR mAbs have been developed, such as Panitumumab. Both antibodies have been approved for the treatment of KRAS-NRAS wild type mCRC, alone or in combination with chemotherapy. These antibodies display strong differences in activating the host immune system against CRC, due to their different immunoglobulin isotypes. Although anti-EGFR antibodies are efficient, drug resistance occurs with high frequency. Resistant tumor cell populations can either already be present before therapy or develop later by biochemical adaptations or new genomic mutations in the EGFR pathway. Numerous efforts have been made to improve the efficacy of the anti-EGFR mAbs or to find new agents that are able to block downstream EGFR signaling cascade molecules. Indeed, we examined the importance of analyzing the anti-EGFR antibody-drug conjugates (ADC) developed to overcome resistance and/or stimulate the tumor host's immunity against CRC growth. Also, patient-derived CRC organoid cultures represent a useful and feasible in vitro model to study tumor behavior and therapy response. Organoids can reflect tumor genetic heterogeneity found in the tissue of origin, representing a unique tool for personalized medicine. Thus, CRC-derived organoid cultures are a smart model for studying the tumor microenvironment and for the preclinical assay of anti-EGFR drugs.
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Neoplasias Colorrectales , Resistencia a Antineoplásicos , Receptores ErbB , Organoides , Humanos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Organoides/metabolismo , Organoides/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Animales , Cetuximab/farmacología , Cetuximab/uso terapéutico , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Terapia Molecular Dirigida/métodos , Panitumumab/farmacología , Panitumumab/uso terapéutico , Antineoplásicos Inmunológicos/farmacología , Antineoplásicos Inmunológicos/uso terapéutico , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND: The frequency of alarms from monitors and other electro-medical devices is of great utility but can increase the professional's workload and expose nurses in the intensive care unit to Alarm Fatigue. A recent study suggested that students in training can also experience the problem during their first clinical experiences in intensive care. Unfortunately, no data are available about the Italian panorama. To explore Alarm Fatigue among Bachelor of Science in Nursing students at the end of their internship experience in intensive care settings. METHODS: Multicenter cross-sectional design. A convenience sample of nurses from 3 Italian university hospitals was recruited. The students completed the revised version of the "Alarm Fatigue questionnaire-ita" at the end of the clinical internship in intensive care settings. RESULTS: 130 nursing students were enrolled (response rate 59.36%). The overall level of Alarm Fatigue was Me= 24.5 IQR [17.5, 30.5]. In addition, 9.23% of the sample reported errors or near misses related to Alarm Fatigue during the internship experience. The alarm fatigue level was higher in students who committed "errors/almost errors" (p=0.038) and in "student workers" (p=0.005). DISCUSSION: The extent of alarm fatigue experienced by nursing students requires developing a preventive strategy.
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Alarmas Clínicas , Estudiantes de Enfermería , Humanos , Estudios Transversales , Monitoreo Fisiológico , Unidades de Cuidados IntensivosRESUMEN
Shedding of ADAM10 substrates, like TNFa or CD30, can affect both anti-tumor immune response and antibody-drug-conjugate (ADC)-based immunotherapy. We have published two new ADAM10 inhibitors, LT4 and MN8 able to prevent such shedding in Hodgkin lymphoma (HL). Since tumor tissue architecture deeply influences the outcome of anti-cancer treatments, we set up a new threedimensional (3D) culture systems to verify whether ADAM10 inhibitors can contribute to, or enhance, the anti-lymphoma effects of the ADC brentuximab-vedotin (BtxVed). In order to recapitulate some aspects of lymphoma structure and architecture, we assembled two 3D culture models: mixed spheroids made of HL lymph node (LN) mesenchymal stromal cells (MSC) and Reed Sternberg/Hodgkin lymphoma cells (HL cells) or collagen scaffolds repopulated with LN-MSC and HL cells. In these 3D systems we found that: i) the ADAM10 inhibitors LT4 and MN8 reduce ATP content or glucose consumption, related to cell proliferation, increasing lactate dehydrogenase release as a cell damage hallmark; ii) these events are paralleled by mixed spheroids size reduction and inhibition of CD30 and TNFa shedding; iii) the effects observed can be reproduced in repopulated HL LN-derived matrix or collagen scaffolds; iv) ADAM10 inhibitors enhance the anti-lymphoma effect of the anti-CD30 ADC BtxVed both in conventional cultures and in repopulated scaffolds. Thus, we provide evidence for a direct and combined antilymphoma effect of ADAM10 inhibitors with BtxVed, leading to the improvement of ADC effects; this is documented in 3D models recapitulating features of the LN microenvironment, that can be proposed as a reliable tool for anti-lymphoma drug testing.
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Proteína ADAM10/antagonistas & inhibidores , Brentuximab Vedotina/uso terapéutico , Enfermedad de Hodgkin , Inmunoconjugados , Linfoma , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/patología , Humanos , Inmunoconjugados/uso terapéutico , Antígeno Ki-1 , Linfoma/tratamiento farmacológico , Proteínas de la Membrana , Microambiente TumoralRESUMEN
108 isolates of Staphylococcus aureus, belonging to six large ribogroups according to the automated Ribo-Printer® system, were studied with two highly used molecular methods for epidemiological studies, namely multi-locus sequence typing (MLST) and spa typing, followed by BURP and eBURST v3 analysis for clustering spa types and sequence (ST) types. The aim was to evaluate whether automated ribotyping could be considered a useful screening tool for identifying S. aureus genetic lineages with respect to spa typing and MLST. Clarifying the relationship of riboprinting with these typing methods and establishing whether ribogroups fit single clonal complexes were two main objectives. Further information on the genetic profile of the isolates was obtained from agr typing and the search for the mecA, tst genes, and the IS256 insertion sequence. Automated ribotyping has been shown to predict spa clonal complexes and MLST clonal complexes. The high cost and lower discriminatory power of automated ribotyping compared to spa and MSLT typing could be an obstacle to fine genotyping analyzes, especially when high discriminatory power is required. On the other hand, numerous advantages such as automation, ease and speed of execution, stability, typeability and reproducibility make ribotyping a reliable method to be juxtaposed to gold standard methods.
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Tipificación de Secuencias Multilocus , Ribotipificación , Infecciones Estafilocócicas/genética , Staphylococcus aureus , Humanos , Staphylococcus aureus/clasificación , Staphylococcus aureus/genética , Staphylococcus aureus/aislamiento & purificaciónRESUMEN
Enzymes, once considered static molecular machines acting in defined spatial patterns and sites of action, move to different intra- and extracellular locations, changing their function. This topological regulation revealed a close cross-talk between proteases and signaling events involving post-translational modifications, membrane tyrosine kinase receptors and G-protein coupled receptors, motor proteins shuttling cargos in intracellular vesicles, and small-molecule messengers. Here, we highlight recent advances in our knowledge of regulation and function of A Disintegrin And Metalloproteinase (ADAM) endopeptidases at specific subcellular sites, or in multimolecular complexes, with a special focus on ADAM10, and tumor necrosis factor-α convertase (TACE/ADAM17), since these two enzymes belong to the same family, share selected substrates and bioactivity. We will discuss some examples of ADAM10 activity modulated by changing partners and subcellular compartmentalization, with the underlying hypothesis that restraining protease activity by spatial segregation is a complex and powerful regulatory tool.
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Proteína ADAM10/metabolismo , Animales , Humanos , Modelos Biológicos , Procesamiento Proteico-Postraduccional , Transporte de Proteínas , Transducción de Señal , Especificidad por SustratoRESUMEN
BACKGROUND: Suicidal acts are a public health problem worldwide and require nurses to have appropriate skills to deal with it. It is important to study the level of knowledge, as well as the perception of nursing students towards suicidal ideation; a tool created for this purpose, the Suicide Behavior Attitude Questionnaire (SBAQ) has proven its validity and reliability in English. AIM: To assess the psychometric properties of the Italian version of the SBAQ (SBAQ-ita). METHODS: Multicentric study. The SBAQ-ita was administered to students of two Nursing schools in two universities in Italy. The CVI-I was calculated to evaluate the validity of the content of the SBAQ-ita. Construct validity was investigated through exploratory factor analysis. Cronbach's alpha coefficient (α) was used to examine the internal consistency of each scale factor. Spearman's rho coefficient was used to test stability. RESULTS: The SBAQ-ita was administered to 205 students from October to November 2019. The analysis showed a four-factor structure with Cronbach's α always ≥0.70. The CVI-I was 0.97. 25 students filled in the scale again after 7 days (test-retest rho=0.92). CONCLUSION: The SBAQ-ita is a valid and reliable tool for the study of the students' attitude in the Bachelor of Science in Nursing towards caring for the person with suicidal ideation. postoperative settings.
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Estudiantes de Enfermería , Suicidio , Actitud , Humanos , Italia , Reproducibilidad de los Resultados , Ideación Suicida , Encuestas y CuestionariosRESUMEN
BACKGROUND: Nursing students represent an important resource both for the patients and for the company organization; however, the impact of their presence on the quality of care is still underestimated. OBJECTIVE: To provide an objective assessment of the quality of care perceived by the patient admitted to hospital departments where internships are held for nursing students. METHOD: A descriptive observational study was conducted, recruiting a convenience sample made up of patients hospitalized in clinical departments where internships for nursing students of La Fe Hospital in Valencia (ES) are located. RESULTS: 75 patients out of 160 hospitalized partecipated to the survey, with a response rate equal to 46.87%. Most patients believe that nurses have careless attitudes towards them (42.9%) even though there is a noticeable emotional support from nurses perceived by patients (90.1%). The degree of relationship and information perceived by patients (96%) suggests that nurses in most cases guaranteed confidentiality and the assistance time employed (70.5%) was perceived as longer than usual, defining a high opinion of patients about the treatment received. CONCLUSIONS: The data showed that patients were very keen to be taken into consideration from a social and human point of view and not only from a clinical point of view, so much so that they claimed to perceive a careless attitude from nurses. Despite this, however, the perceived quality of nursing care by the patient was not affected. Regarding the presence of the trainee student, being the latter in the Spanish reality totally flanked by that of the nurse, almost in symbiosis, the degree of attention perceived by the patient in relation to the assistance provided does not vary.
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Internado y Residencia , Atención de Enfermería , Estudiantes de Enfermería , Actitud del Personal de Salud , Humanos , Encuestas y CuestionariosRESUMEN
Castration-resistant prostate cancer (CRPC) is an incurable stage of the disease. A multivariate principal component analysis on CRPC in vitro models identified aspartyl (asparaginyl) ß hydrolase (ASPH) as the most relevant molecule associated with the CRPC phenotype. ASPH is overexpressed in various malignant neoplasms and catalyzes the hydroxylation of aspartyl and asparaginyl residues in the epidermal growth factor (EGF)-like domains of proteins like NOTCH receptors and ligands, enhancing cell motility, invasion and metastatic spread. Bioinformatics analyses of ASPH in prostate cancer (PCa) and CRPC datasets indicate that ASPH gene alterations have prognostic value both in PCa and CRPC patients. In CRPC cells, inhibition of ASPH expression obtained through specific small interfering RNA or culturing cells in hypoxic conditions, reduced cell proliferation, invasion and cyclin D1 expression through modulation of the NOTCH signaling. ASPH and HIF1α crosstalk, within a hydroxylation-regulated signaling pathway, might be transiently driven by the oxidative stress evidenced inside CRPC cells. In addition, increased phosphorylation of GSK3ß by ASPH silencing demonstrates that ASPH regulates GSK3ß activity inhibiting its interactions with upstream kinases. These findings demonstrate the critical involvement of ASPH in CRPC development and may represent an attractive molecular target for therapy.
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Biomarcadores de Tumor/metabolismo , Proteínas de Unión al Calcio/antagonistas & inhibidores , Regulación Neoplásica de la Expresión Génica , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Proteínas de la Membrana/antagonistas & inhibidores , Oxigenasas de Función Mixta/antagonistas & inhibidores , Proteínas Musculares/antagonistas & inhibidores , Neoplasias de la Próstata Resistentes a la Castración/patología , Receptor Notch1/metabolismo , Apoptosis , Biomarcadores de Tumor/genética , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Proliferación Celular , Glucógeno Sintasa Quinasa 3 beta/genética , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Oxigenasas de Función Mixta/genética , Oxigenasas de Función Mixta/metabolismo , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Pronóstico , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , ARN Interferente Pequeño/genética , Receptor Notch1/genética , Tasa de Supervivencia , Células Tumorales CultivadasRESUMEN
The expression of the immune checkpoint molecule CTLA-4 has been almost exclusively studied in the T cell lineage, but increasing evidence has shown its expression on tumors with implications for immunotherapy. To date, the degree of expression of CTLA-4 on tumor cells as a predictive biomarker of response to immune checkpoint inhibitors has not been studied. In this report, we analyzed this issue in melanoma patients treated with CTLA-4 inhibitor Ipilimumab (IPI). We show that the level of CTLA-4 expression on melanoma cells is higher than that on tumor infiltrating lymphocytes (TIL) and it is associated with clinical response to IPI therapy supporting the idea of its possible role as a predictive biomarker.
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Antineoplásicos Inmunológicos/uso terapéutico , Antígeno CTLA-4/metabolismo , Ipilimumab/uso terapéutico , Melanoma/tratamiento farmacológico , Melanoma/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/metabolismo , Femenino , Humanos , Inmunoterapia/métodos , Masculino , Persona de Mediana EdadRESUMEN
Immune checkpoint inhibitors, including ipilimumab (IPI), achieve a clinical benefit in a small proportion of melanoma patients highlighting the need to investigate predictive biomarkers. In this study, we characterized tumor infiltrating lymphocytes (TILs), focusing on the CTLA-4+ subset, and evaluated their possible predictive significance. We characterized TIL density, cell type, and localization in 40 melanoma lesions from 17 patients treated with IPI. Associations of TILs with IPI timing, tissue localization, and response to IPI were estimated using a linear mixed-effects modelling approach. We found that most of TIL subsets increased in situ upon IPI therapy, with particular reference to FoxP3+ cells. TILs and TIL subsets, such as CD3+, CD45RO+, CTLA-4+, CD4+, CD8+ T cells, CD20+ B cells, and NKp46+ NK cells, showed significantly different spatial distributions in the tumor microenvironment being higher at the invasive margin (IM) as compared to the tumor center (TC) (P value < 0.001 for TIL score and P value < 0.05 for all subsets). Remarkably, high TIL score and density of CD3+, CD8+ T cells, and CTLA-4+ immune cells were significantly associated with a better response to IPI (P values = 0.002, 0.023, 0.007, and 0.001, respectively, for responders vs non-responders). In conclusion, we provide a detailed analysis of CTLA-4+ TIL distribution in melanoma tissues taking into account localization, relationship with CD3+/CD8+ TILs, and changes in response to IPI treatment. We identified that CTLA-4+ TILs may represent a marker of IPI response, alone or with CD3+/CD8+ subsets, although this requires confirmation in larger studies.
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Antígeno CTLA-4/antagonistas & inhibidores , Ipilimumab/uso terapéutico , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Melanoma/tratamiento farmacológico , Microambiente Tumoral/efectos de los fármacos , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/uso terapéutico , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Antígeno CTLA-4/inmunología , Antígeno CTLA-4/metabolismo , Femenino , Humanos , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Masculino , Melanoma/inmunología , Melanoma/metabolismo , Persona de Mediana Edad , Estudios Retrospectivos , Microambiente Tumoral/inmunologíaRESUMEN
BACKGROUND AND AIM: Systemic lupus erythematosus (SLE) is associated with accelerated atherogenesis. Traditional risk factors do not seem to fully explain this process in patients with SLE and no other imaging/serum biomarkers have so far improved risk stratification. Here, we focused on the role of adiponectin in women with SLE. METHODS AND RESULTS: This is a sub-analysis of a validated cohort enrolling eighty females (age 18-65 years) affected by SLE. Patient underwent a single blood sampling and carotid echography. Serum adipocytokines (i.e. leptin, resistin and adiponectin) were assessed by enzyme-linked immunosorbent assay (ELISA). Patients with a carotid plaque (n = 23) were older, with longer duration of the disease, chronic use of corticosteroids, and immunosuppressive therapies. As expected, patients with a carotid plaque had increased vascular risk and high serum levels of inflammatory biomarkers, total and LDL cholesterol and adiponectin. Significant positive correlation between serum adiponectin and presence of a carotid plaque was found independently of patient age, SCORE Risk Charts, duration of disease, and SLE treatments. CONCLUSIONS: These results indicate that high serum adiponectin is associated with accelerated carotid atherosclerosis in SLE young women and it might be useful to improve vascular risk stratification in this patient setting.
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Adiponectina/sangre , Enfermedades de las Arterias Carótidas/sangre , Lupus Eritematoso Sistémico/sangre , Placa Aterosclerótica , Adolescente , Corticoesteroides/uso terapéutico , Adulto , Anciano , Biomarcadores/sangre , Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Enfermedades de las Arterias Carótidas/epidemiología , Progresión de la Enfermedad , Femenino , Humanos , Inmunosupresores/uso terapéutico , Italia/epidemiología , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/epidemiología , Persona de Mediana Edad , Prevalencia , Pronóstico , Factores de Riesgo , Factores Sexuales , Factores de Tiempo , Regulación hacia Arriba , Adulto JovenRESUMEN
Preclinical models for the definition of anti-cancer drug safety and efficacy are constantly evolving [...].
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Técnicas de Cultivo de Célula , Evaluación Preclínica de Medicamentos , Inmunidad/efectos de los fármacos , Esferoides Celulares/efectos de los fármacos , Antineoplásicos/farmacología , Evaluación Preclínica de Medicamentos/métodos , Humanos , Células Tumorales CultivadasRESUMEN
Ovarian cancer (OvCA) accounts for one of the leading causes of death from gynecologic malignancy. Despite progress in therapy improvements in OvCA, most patients develop a recurrence after first-line treatments, dependent on the tumor and non-tumor complexity/heterogeneity of the neoplasm and its surrounding tumor microenvironment (TME). The TME has gained greater attention in the design of specific therapies within the new era of immunotherapy. It is now clear that the immune contexture in OvCA, here referred as tumor immune microenvironment (TIME), acts as a crucial orchestrator of OvCA progression, thus representing a necessary target for combined therapies. Currently, several advancements of antitumor immune responses in OvCA are based on the characterization of tumor-infiltrating lymphocytes, which have been shown to correlate with a significantly improved clinical outcome. Here, we reviewed the literature on selected TIME components of OvCA, such as macrophages, neutrophils, γδ T lymphocytes, and natural killer (NK) cells; these cells can have a role in either supporting or limiting OvCA, depending on the TIME stimuli. We also reviewed and discussed the major (immune)-therapeutic approaches currently employed to target and/or potentiate macrophages, neutrophils, γδ T lymphocytes, and NK cells in the OvCA context.
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Inmunidad Innata/efectos de los fármacos , Neoplasias Ováricas/terapia , Microambiente Tumoral/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Tratamiento Basado en Trasplante de Células y Tejidos , Progresión de la Enfermedad , Femenino , Humanos , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/metabolismo , Terapia Molecular Dirigida , Neoplasias Ováricas/inmunologíaRESUMEN
BACKGROUND: The COVID-19 pandemic had a relevant health impact in a large part of the planet and there are several studies aimed at understanding its diffusion; however, to date, the problem has not been explored in the correctional setting, with particular concern for the Italian context. AIM: To assess and investigate the risk of exposure to COVID-19 in nurses working in the Italian prison system. METHODS: A multicenter observational descriptive study was conducted, enrolling a convenience sample composed of nurses registered with SIMSPE onlus (Italian Society of Penitentiary Medicine and Health), working in any Italian prison facility at the time of the survey. RESULTS: 204 nurses participating in the survey (response rate 49.27%). Most nurses working in prisons (92.65%) were exposed to the risk of Covid-19 virus infection, since they came directly into contact with positive patients (90.69%) and in situations where they were exposed during care procedures in which aerosol was produced by the patient (56.21%). The number of nurses who "always" complied with safety rules for prevention of infection did not differ significantly (p >0.05 for each comparison) in situations involving or not involving aerosol exposure. CONCLUSIONS: The results highlight the relevance of these issues in the Italian prison context and the need for further investigation. The knowledge of the dimension of this phenomenon, unexplored before this study in this context, represents the first step to be able to identify organizational strategies to manage it effectively or, if possible, to prevent it.
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COVID-19/epidemiología , COVID-19/prevención & control , Personal de Salud , Exposición Profesional/prevención & control , Prisiones , Adulto , Anciano , Femenino , Humanos , Italia , Masculino , Persona de Mediana Edad , Medición de Riesgo , Gestión de RiesgosRESUMEN
BACKGROUND: Ultrasound evaluation of carotid intima-media thickness (cIMT) has been extensively used for potentially improving cardiovascular (CV) risk stratification in several patients' categories. Subjects with systemic lupus erythematosus (SLE) have been investigated by both imaging and molecular biomarker approaches with contrasting results. Here, we focused on the role of osteopontin (OPN) as biomarker of subclinical atherosclerosis associated with SLE. MATERIALS AND METHODS: Eighty females (age 18-65 years) affected by SLE and eighty age-matched healthy female controls without a clinical history of CV disease underwent ultrasound evaluation of cIMT and blood sample assay of high-sensitivity C-reactive protein (hs-CRP) and OPN. RESULTS: Healthy controls and SLE patients significantly differed for CV risk factors (ie, waist circumference, hypertension and dyslipidaemia) and the inflammatory status. Noteworthy, an opposite association between cIMT and OPN was observed in the two study groups. Whereas OPN was positively associated with mean cIMT (r = 0.364; P = 0.001) in SLE patients, a negative correlation was found in healthy controls. Furthermore, in SLE patients increased circulating levels of OPN were associated with the use of hydroxychloroquine and the positivity for the anti-dsDNA autoantibodies. At linear regression analysis, only OPN remained independently associated with cIMT also after adjustment for age, smoking pack-year, Heart SCORE, disease length and steroid therapy length. CONCLUSIONS: These results indicate that serum OPN levels were strongly associated with subclinical atherosclerosis in patients with LES and it might be a useful CV biomarker that requires additional validation in larger trials.
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Aterosclerosis/diagnóstico , Lupus Eritematoso Sistémico/complicaciones , Osteopontina/metabolismo , Adolescente , Adulto , Anciano , Aterosclerosis/sangre , Aterosclerosis/etiología , Biomarcadores/metabolismo , Proteína C-Reactiva/metabolismo , Arteria Carótida Común/diagnóstico por imagen , Grosor Intima-Media Carotídeo , Estudios de Casos y Controles , Femenino , Humanos , Inflamación/sangre , Lupus Eritematoso Sistémico/sangre , Persona de Mediana Edad , Factores de Riesgo , Adulto JovenRESUMEN
BACKGROUND: Prostate cancer (PCa) is a significant health concern throughout the world. Standard therapy for advanced disease consists of anti-androgens, however, almost all prostate tumors become castration resistant (CRPC). Progression from androgen-sensitive PCa to CRPC is promoted by inflammatory signaling through cyclooxygenase-2 (COX-2) expression and ErbB family receptors/AKT activation, compensating androgen receptor inactivity. METHODS: Making use of CRPC cell lines, we investigated the effects of the anti-inflammatory drug celecoxib. Biochemical data obtained using immunoblotting, enzyme-linked immunosorbent assay (ELISA), invasion, and xenografts were further integrated by bioinformatic analyses. RESULTS: Celecoxib reduced cell growth and induced apoptosis through AKT blockade, cleavage of poly (ADP-ribose) polymerase-1 (PARP-1), and proteasomal degradation of the anti-apoptotic protein Mcl-1. Epidermal growth factor receptor (EGFR), ErbB2, and ErbB3 degradation, and heterogeneous nuclear ribonucleoprotein K (hnRNP K) downregulation, further amplified the inhibition of androgen signaling. Celecoxib reduced the invasive phenotype of CRPC cells by modulating NF-κB activity and reduced tumor growth in mice xenografts when administered in association with the anti-EGFR receptor antibody cetuximab. Bioinformatic analyses on human prostate cancer datasets support the relevance of these pathways in PCa progression. CONCLUSIONS: Signaling nodes at the intersection of pathways implicated in PCa progression are simultaneously modulated by celecoxib treatment. In combination therapies with cetuximab, celecoxib could represent a novel therapeutic strategy to curb signal transduction during CRPC progression.
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Celecoxib/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Transducción de Señal , Anfirregulina/metabolismo , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis/efectos de los fármacos , Apoptosis/genética , Celecoxib/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Cetuximab/farmacología , Cetuximab/uso terapéutico , Regulación hacia Abajo/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Factor de Crecimiento Epidérmico/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ribonucleoproteína Heterogénea-Nuclear Grupo K/metabolismo , Humanos , Masculino , Ratones SCID , FN-kappa B/metabolismo , Invasividad Neoplásica , Fosforilación/efectos de los fármacos , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor ErbB-2/metabolismo , Receptores Androgénicos/metabolismo , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
INTRODUCTION AND AIM: Organ transplantation is considered a life-saving treatment for patients with end-stage pathologies. The knowledge and the attitude of nurses can positively influence the willingness of family members and patients to give consent to organ and conse- quently organ donation rates. To understand the critical capacity of nursing students to self- evaluate themselves on information on brain death, donation and transplantation, investi- gating scientific knowledge, predisposition and attitude related to these topics through a survey. METHOD: This work is a cross-sectional descriptive study carried out among conveniently selected undergraduate nursing students (n = 578) of three Universities respectively in northern, center and southern of Italy using a questionnaire formulated on the basis of the FAQs prepared by the National Transplant Center (CNT). RESULTS: Most of students show an adequate level of knowledge and attitudes favorable to organ and tissue donation even if very few students have signed the donor card. Students' knowledge and perceptions are still lacking in specific areas such as legislations (only 6%). CONCLUSIONS: The findings suggest the need for revising the nursing curricula to improve the future nurses' skills, increase the modality to sign the donor card and favor the rate of organ donation.
Asunto(s)
Conocimientos, Actitudes y Práctica en Salud , Estudiantes de Enfermería/psicología , Donantes de Tejidos/psicología , Obtención de Tejidos y Órganos , Actitud del Personal de Salud , Estudios Transversales , Curriculum , Bachillerato en Enfermería , Femenino , Humanos , Italia , Masculino , Encuestas y Cuestionarios , Adulto JovenRESUMEN
The fusion protein L19mTNF (mouse TNF and human antibody fragment L19 directed to fibronectin extra domain B) selectively targets the tumor vasculature, and in combination with melphalan induces a long-lasting T-cell therapeutic response and immune memory in murine models. Increasing evidence suggests that natural killer (NK) cells act to promote effective T-cell-based antitumor responses. We have analyzed the role of NK cells and dendritic cells (DCs) on two different murine tumor models: WEHI-164 fibrosarcoma and C51 colon carcinoma, in which the combined treatment induces high and low rejection rates, respectively. In vivo NK-cell depletion strongly reduced the rejection of WEHI-164 fibrosarcoma and correlated with a decrease in mature DCs, CD4+ , and CD8+ T cells in the tumor-draining LNs and mature DCs and CD4+ T cells in the tumor 40 h after initiation of the therapy. NK-cell depletion also resulted in the impairment of the stimulatory capability of DCs derived from tumor-draining LNs of WEHI-164-treated mice. Moreover, a significant reduction of M2-type infiltrating macrophages was detected in both tumors undergoing therapy. These results suggest that the efficacy of L19mTNF/melphalan therapy is strongly related to the early activation of NK cells and DCs, which are necessary for an effective T-cell response.
Asunto(s)
Antineoplásicos Alquilantes/uso terapéutico , Linfocitos T CD4-Positivos/inmunología , Neoplasias Colorrectales/tratamiento farmacológico , Células Dendríticas/inmunología , Quimioterapia Combinada , Fibrosarcoma/tratamiento farmacológico , Células Asesinas Naturales/inmunología , Melfalán/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Linfocitos T Citotóxicos/inmunología , Animales , Linfocitos T CD4-Positivos/efectos de los fármacos , Diferenciación Celular , Línea Celular Tumoral , Células Dendríticas/efectos de los fármacos , Modelos Animales de Enfermedad , Humanos , Células Asesinas Naturales/efectos de los fármacos , Activación de Linfocitos , Depleción Linfocítica , Ratones , Ratones Endogámicos BALB C , Linfocitos T Citotóxicos/efectos de los fármacos , Carga Tumoral/efectos de los fármacosRESUMEN
Several enzymes are involved in the energy production, becoming a possible target for new anti-cancer drugs. In this paper, we used biochemical and in silico studies to evaluate the effects of two guanidine molecules, (Boc)2 -creatine and metformin, on creatine kinase, an enzyme involved in the regulation of intracellular energy levels. Our results show that both drugs inhibit creatine kinase activity; however, (Boc)2 -creatine displays a competitive inhibition, while metformin acts with a non-competitive mechanism. Moreover, (Boc)2 -creatine is able to inhibit the activity of hexokinase with a non-competitive mechanism. Considering that creatine kinase and hexokinase are involved in energy metabolism, we evaluated the effects of (Boc)2 -creatine and metformin on the ATP/AMP ratio and on cellular proliferation in healthy fibroblasts, human breast cancer cells (MDA-MB-468), a human neuroblastoma cell line (SH-SY5Y), a human Hodgkin lymphoma cell line (KMH2). We found that healthy fibroblasts were only partially affected by (Boc)2 -creatine, while both ATP/AMP ratio and viability of the three cancer cell lines were significantly decreased. By inhibiting both creatine kinase and hexokinase, (Boc)2 -creatine appears as a promising new agent in anticancer treatment. Further research is needed to understand what types of cancer cells are most suitable to treatment by this new compound. J. Cell. Biochem. 118: 2700-2711, 2017. © 2017 Wiley Periodicals, Inc.
Asunto(s)
Creatina Quinasa/metabolismo , Creatina/farmacología , Metabolismo Energético/efectos de los fármacos , Hexoquinasa/metabolismo , Metformina/farmacología , Modelos Biológicos , Línea Celular Tumoral , Creatina/química , Humanos , Metformina/químicaRESUMEN
The NAD+-dependent deacetylase SIRT6 is an emerging cancer drug target, whose inhibition sensitizes cancer cells to chemo-radiotherapy and has pro-differentiating effects. Here we report on the identification of novel SIRT6 inhibitors with a salicylate-based structure. The new SIRT6 inhibitors show improved potency and specificity compared to the hit inhibitor identified in an in silico compound screen. As predicted based on SIRT6 biological roles, the new leads increase histone 3 lysine 9 acetylation and glucose uptake in cultured cells, while blocking TNF-α production and T lymphocyte proliferation. Notably, the new SIRT6 inhibitors effectively sensitize pancreatic cancer cells to gemcitabine. Finally, studies of compound fingerprinting and pharmacokinetics defined the drug-like properties of one of the new SIRT6 inhibitors, potentially allowing for subsequent in vivo proof-of-concept studies. In conclusion, new SIRT6 inhibitors with a salicylate-like structure were identified, which are active in cells and could potentially find applications in disease conditions, including cancer and immune-mediated disorders.