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PURPOSE: Mesenchymal stromal cells (MSCs) within the glioblastoma microenvironment have been shown to promote tumor progression. Tumor Treating Fields (TTFields) are alternating electric fields with low intensity and intermediate frequency that exhibit anti-tumorigenic effects. While the effects of TTFields on glioblastoma cells have been studied previously, nothing is known about the influence of TTFields on MSCs. METHODS: Single-cell RNA sequencing and immunofluorescence staining were employed to identify glioblastoma-associated MSCs in patient samples. Proliferation and clonogenic survival of human bone marrow-derived MSCs were assessed after TTFields in vitro. MSC' characteristic surface marker expression was determined using flow cytometry, while multi-lineage differentiation potential was examined with immunohistochemistry. Apoptosis was quantified based on caspase-3 and annexin-V/7-AAD levels in flow cytometry, and senescence was assessed with ß-galactosidase staining. MSCs' migratory potential was evaluated with Boyden chamber assays. RESULTS: Single-cell RNA sequencing and immunofluorescence showed the presence of glioblastoma-associated MSCs in patient samples. TTFields significantly reduced proliferation and clonogenic survival of human bone marrow-derived MSCs by up to 60% and 90%, respectively. While the characteristic surface marker expression and differentiation capacity were intact after TTFields, treatment resulted in increased apoptosis and senescence. Furthermore, TTFields significantly reduced MSCs' migratory capacity. CONCLUSION: We could demonstrate the presence of tumor-associated MSCs in glioblastoma patients, providing a rationale to study the impact of TTFields on MSCs. TTFields considerably increase apoptosis and senescence in MSCs, resulting in impaired survival and migration. The results provide a basis for further analyses on the role of MSCs in glioblastoma patients receiving TTFields.
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Apoptosis , Neoplasias Encefálicas , Diferenciación Celular , Proliferación Celular , Glioblastoma , Células Madre Mesenquimatosas , Humanos , Células Madre Mesenquimatosas/fisiología , Glioblastoma/terapia , Glioblastoma/patología , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/patología , Terapia por Estimulación Eléctrica/métodos , Microambiente Tumoral , Movimiento CelularRESUMEN
Radiotherapy of head-and-neck squamous cell carcinoma (HNSCC) can cause considerable normal tissue injuries, and mesenchymal stromal cells (MSCs) have been shown to aid regeneration of irradiation-damaged normal tissues. However, utilization of MSC-based treatments for HNSCC patients undergoing radiotherapy is hampered by concerns regarding potential radioprotective effects. We therefore investigated the influence of MSCs on the radiosensitivity of HNSCCs. Several human papillomavirus (HPV)-negative and HPV-positive HNSCCs were co-cultured with human bone marrow-derived MSCs using two-dimensional and three-dimensional assays. Clonogenic survival, proliferation, and viability of HNSCCs after radiotherapy were assessed depending on MSC co-culture. Flow cytometry analyses were conducted to examine the influence of MSCs on irradiation-induced cell cycle distribution and apoptosis induction in HNSCCs. Immunofluorescence stainings of γH2AX were conducted to determine the levels of residual irradiation-induced DNA double-strand breaks. Levels of connective tissue growth factor (CTGF), a multifunctional pro-tumorigenic cytokine, were analyzed using enzyme-linked immunosorbent assays. Neither direct MSC co-culture nor MSC-conditioned medium exerted radioprotective effects on HNSCCs as determined by clonogenic survival, proliferation, and viability assays. Consistently, three-dimensional microwell arrays revealed no radioprotective effects of MSCs. Irradiation resulted in a G2/M arrest of HNSCCs at 96 h independently of MSC co-culture. HNSCCs' apoptosis rates were increased by irradiation irrespective of MSCs. Numbers of residual γH2AX foci after irradiation with 2 or 8 Gy were comparable between mono- and co-cultures. MSC mono-cultures and HNSCC-MSC co-cultures exhibited comparable CTGF levels. We did not detect radioprotective effects of human MSCs on HNSCCs. Our results suggest that the usage of MSC-based therapies for radiotherapy-related toxicities in HNSCC patients may be safe in the context of absent radioprotection.
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Neoplasias de Cabeza y Cuello , Células Madre Mesenquimatosas , Infecciones por Papillomavirus , Apoptosis , Línea Celular Tumoral , Puntos de Control de la Fase G2 del Ciclo Celular , Neoplasias de Cabeza y Cuello/patología , Humanos , Células Madre Mesenquimatosas/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/patologíaRESUMEN
BACKGROUND: Transthyretin amyloid cardiomyopathy is caused by the deposition of transthyretin amyloid fibrils in the myocardium. The deposition occurs when wild-type or variant transthyretin becomes unstable and misfolds. Tafamidis binds to transthyretin, preventing tetramer dissociation and amyloidogenesis. METHODS: In a multicenter, international, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 441 patients with transthyretin amyloid cardiomyopathy in a 2:1:2 ratio to receive 80 mg of tafamidis, 20 mg of tafamidis, or placebo for 30 months. In the primary analysis, we hierarchically assessed all-cause mortality, followed by frequency of cardiovascular-related hospitalizations according to the Finkelstein-Schoenfeld method. Key secondary end points were the change from baseline to month 30 for the 6-minute walk test and the score on the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS), in which higher scores indicate better health status. RESULTS: In the primary analysis, all-cause mortality and rates of cardiovascular-related hospitalizations were lower among the 264 patients who received tafamidis than among the 177 patients who received placebo (P<0.001). Tafamidis was associated with lower all-cause mortality than placebo (78 of 264 [29.5%] vs. 76 of 177 [42.9%]; hazard ratio, 0.70; 95% confidence interval [CI], 0.51 to 0.96) and a lower rate of cardiovascular-related hospitalizations, with a relative risk ratio of 0.68 (0.48 per year vs. 0.70 per year; 95% CI, 0.56 to 0.81). At month 30, tafamidis was also associated with a lower rate of decline in distance for the 6-minute walk test (P<0.001) and a lower rate of decline in KCCQ-OS score (P<0.001). The incidence and types of adverse events were similar in the two groups. CONCLUSIONS: In patients with transthyretin amyloid cardiomyopathy, tafamidis was associated with reductions in all-cause mortality and cardiovascular-related hospitalizations and reduced the decline in functional capacity and quality of life as compared with placebo. (Funded by Pfizer; ATTR-ACT ClinicalTrials.gov number, NCT01994889 .).
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Neuropatías Amiloides Familiares/tratamiento farmacológico , Benzoxazoles/uso terapéutico , Cardiomiopatías/tratamiento farmacológico , Prealbúmina/antagonistas & inhibidores , Administración Oral , Anciano , Anciano de 80 o más Años , Neuropatías Amiloides Familiares/complicaciones , Benzoxazoles/efectos adversos , Cardiomiopatías/complicaciones , Progresión de la Enfermedad , Método Doble Ciego , Femenino , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/mortalidad , Hospitalización/estadística & datos numéricos , Humanos , Masculino , Persona de Mediana Edad , Calidad de Vida , Análisis de Supervivencia , Prueba de PasoRESUMEN
PURPOSE: Painful osteoarthritis is common in elderly patients, and low-dose radiotherapy has been demonstrated to provide effective symptomatic treatment. We examined the analgesic effects of low-dose radiotherapy for osteoarthritis in the elderly aiming to reveal potential differences in the response rates relating to increasing age. METHODS: A retrospective analysis was performed at two university hospitals including elderly patients (≥â¯65 years) undergoing radiotherapy for osteoarthritis between 2008 and 2020. Pain intensity and response were quantified using the numerical rating scale (NRS) and the Pannewitz score. Age groups were defined for young old (65-74 years), older old (75-84 years), and oldest old patients (≥â¯85 years). RESULTS: In all, 970 patients with 1185 treated sites and a median age of 76 years were analyzed. Mean NRS was 66â¯at baseline (t0), 53 after radiotherapy (t1), and 44â¯at first follow-up (t2) (pâ¯< 0.001 for t0-t1, t1-t2, and t0-t2). At t1, 1.5% exhibited a Pannewitz score of 0 (no pain), 58.5% of 1-2 (less pain), 36.1% of 3 (equal pain), and 3.9% of 4 (worse pain), while at t2, pain response shifted towards 6.9% (0), 58.6% (1-2), 28.1% (3), and 6.3% (4). Pain response did not differ between age groups at t1 (pâ¯= 0.172) or t2 (pâ¯= 0.684). In addition, pain response after re-irradiation (nâ¯= 384 sites) was 61.0% and was comparable between age groups (pâ¯= 0.535). CONCLUSION: Low-dose radiotherapy results in pain reduction in about two-thirds of treated sites with no difference relating to increasing age, showing that radiotherapy is an effective analgesic treatment for osteoarthritis even at advanced ages.
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Osteoartritis , Anciano , Anciano de 80 o más Años , Estudios de Seguimiento , Humanos , Osteoartritis/radioterapia , Dolor , Dimensión del Dolor , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: COVID-19 has a direct impact on the employment of older people. This adds to the challenge of ageism. The World Health Organization has started a worldwide campaign to combat ageism and has called for more research and evidence-based strategies that have the potential to be scaled up. This study specifically aims to identify solutions to combat the adverse effects of COVID-19 on the global ageing workforce. METHODS: We present 15 case studies from different countries and report on what those countries are doing or not doing to address the impact of COVID-19 on ageing workers. RESULTS: We provide examples of how COVID-19 influences older people's ability to work and stay healthy, and offer case studies of what governments, organizations or individuals can do to help ensure older people can obtain, maintain and, potentially, expand their current work. Case studies come from Australia, Austria, Canada, China, Germany, Israel, Japan, Nigeria, Romania, Singapore, Sweden, South Korea, Thailand, United Kingdom (UK), and the United States (US). Across the countries, the impact of COVID-19 on older workers is shown as widening inequalities. A particular challenge has arisen because of a large proportion of older people, often with limited education and working in the informal sector within rural areas, e.g. in Nigeria, Thailand and China. Remedies to the particular disadvantage experienced by older workers in the context of COVID are presented. These range from funding support to encouraging business continuity, innovative product and service developments, community action, new business models and localized, national and international actions. The case studies can be seen as frequently fitting within strategies that have been proven to work in reducing ageism within the workplace. They include policy and laws that have increased benefits to workers during lockdowns (most countries); educational activities such as coaching seniorpreneurship (e,g, Australia); intergenerational contact interventions such as younger Thai people who moved back to rural areas and sharing their digital knowledge with older people and where older people reciprocate by teaching the younger people farming knowledge. CONCLUSION: Global sharing of this knowledge among international, national and local governments and organizations, businesses, policy makers and health and human resources experts will further understanding of the issues that are faced by older workers. This will facilitate the replication or scalability of solutions as called for in the WHO call to combat ageism in 2021. We suggest that policy makers, business owners, researchers and international organisations build on the case studies by investing in evidence-based strategies to create inclusive workplaces. Such action will thus help to challenge ageism, reduce inequity, improve business continuity and add to the quality of life of older workers.
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COVID-19 , Anciano , Envejecimiento , Control de Enfermedades Transmisibles , Humanos , Calidad de Vida , SARS-CoV-2 , Estados Unidos , Recursos HumanosRESUMEN
Astrocytic brain tumours, including glioblastomas, are incurable neoplasms characterized by diffusely infiltrative growth. Here we show that many tumour cells in astrocytomas extend ultra-long membrane protrusions, and use these distinct tumour microtubes as routes for brain invasion, proliferation, and to interconnect over long distances. The resulting network allows multicellular communication through microtube-associated gap junctions. When damage to the network occurred, tumour microtubes were used for repair. Moreover, the microtube-connected astrocytoma cells, but not those remaining unconnected throughout tumour progression, were protected from cell death inflicted by radiotherapy. The neuronal growth-associated protein 43 was important for microtube formation and function, and drove microtube-dependent tumour cell invasion, proliferation, interconnection, and radioresistance. Oligodendroglial brain tumours were deficient in this mechanism. In summary, astrocytomas can develop functional multicellular network structures. Disconnection of astrocytoma cells by targeting their tumour microtubes emerges as a new principle to reduce the treatment resistance of this disease.
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Astrocitoma/patología , Neoplasias Encefálicas/patología , Uniones Comunicantes/metabolismo , Animales , Astrocitoma/metabolismo , Astrocitoma/radioterapia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/radioterapia , Comunicación Celular/efectos de la radiación , Muerte Celular/efectos de la radiación , Proliferación Celular/efectos de la radiación , Extensiones de la Superficie Celular/metabolismo , Extensiones de la Superficie Celular/efectos de la radiación , Supervivencia Celular/efectos de la radiación , Conexina 43/metabolismo , Progresión de la Enfermedad , Proteína GAP-43/metabolismo , Uniones Comunicantes/efectos de la radiación , Glioma/metabolismo , Glioma/patología , Glioma/radioterapia , Humanos , Masculino , Ratones , Ratones Desnudos , Invasividad Neoplásica , Tolerancia a Radiación/efectos de los fármacosRESUMEN
Progress in the systemic control of osteosarcoma has been limited over the past decades thus indicating the urgent clinical need for the development of novel treatment strategies. Therefore, we have recently developed new preclinical models to study promising novel agents for the treatment of pediatric osteosarcoma. The checkpoint kinase (chk) inhibitor prexasertib (LY2606368) and its salt form (LSN2940930) have recently been shown to be active in adult and pediatric malignancies, including sarcoma. We have now tested the potency of prexasertib in clonogenic survival assays in two new lines of primary patient-derived osteosarcoma cells and in two established osteosarcoma cell lines as a single agent and in combination with cisplatin and the poly ADP-ribose polymerase (PARP) inhibitor talazoparib. Prexasertib alone results in strongly reduced clonogenic survival at low nanomolar concentrations and acts by affecting cell cycle progression, induction of apoptosis and induction of double-stranded DNA breakage at concentrations that are well below clinically tolerable and safe plasma concentrations. In combination with cisplatin and talazoparib, prexasertib acts in a synergistic fashion. Chk1 inhibition by prexasertib and its combination with the DNA damaging agent cisplatin and the PARP-inhibitor talazoparib thus emerges as a potential new treatment option for pediatric osteosarcoma which will now have to be tested in preclinical primary patient derived in vivo models and clinical studies.
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Apoptosis/efectos de los fármacos , Cisplatino/farmacología , Osteosarcoma/tratamiento farmacológico , Ftalazinas/farmacología , Pirazinas/farmacología , Pirazoles/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Células Clonales/efectos de los fármacos , Sinergismo Farmacológico , Humanos , Ratones , Osteosarcoma/patología , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
Purpose: Hyperthermia demonstrated clinical efficacy in multimodal cancer treatment. Multipotent mesenchymal stromal cells (MSCs) as part of the tumor-supporting stroma modulate tumor response and tissue regeneration after hyperthermia. We aimed to investigate the effects of hyperthermia on the survival, stem cell characteristics and heat shock expression of human MSCs.Materials and methods: Human MSCs and normal human dermal fibroblasts (NHDFs) were exposed to temperatures between 37 °C and 44 °C for 60 min, and hyperthermic sensitivity was examined by clonogenicity, proliferation and viability assays. The influence of 42 °C hyperthermia on the MSCs' adhesion potential, migratory capacity, surface marker expression and multi-lineage differentiation capability was investigated. Cell cycle distribution, apoptosis and senescence after 42 °C hyperthermia were determined by flow cytometry and ß-galactosidase staining. Heat shock protein expression was determined by Western Blots.Results: MSCs exhibited decreased clonogenic survival after 40 °C and 42 °C hyperthermia compared to NHDFs, while proliferative activity and viability were comparable after hyperthermia up to 44 °C. MSC adhesion was reduced after 42 °C hyperthermia, while the characteristic surface marker expression and the migratory ability remained unaffected in 42 °C hyperthermia-exposed MSCs. 42 °C hyperthermia diminished the adipogenic differential potential of all tested MSC samples. A pronounced G2/M arrest was found after 42 °C hyperthermia and was associated with increased apoptosis and senescence levels in MSCs. MSCs exhibited slightly lower heat shock protein levels compared to NHDFs.Conclusion: Human MSCs exhibit a thermosensitive phenotype which reduced the multipotent cells' regenerative abilities, resulting in impaired tissue regeneration after hyperthermia treatment or thermal injuries. On the other hand, tumor-associated MSCs may be efficiently targeted by hyperthermia treatment.
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Hipertermia Inducida/métodos , Células Madre Mesenquimatosas/metabolismo , Movimiento Celular , Voluntarios Sanos , HumanosRESUMEN
PURPOSE: Targeting fibroblast activation protein (FAP) is a new diagnostic approach allowing the visualization of tumor stroma. Here, we applied FAP-specific PET imaging to gliomas. We analyzed the target affinity and specificity of two FAP ligands (FAPI-02 and FAPI-04) in vitro, and the pharmacokinetics and biodistribution in mice in vivo. Clinically, we used 68Ga-labeled FAPI-02/04 for PET imaging in 18 glioma patients (five IDH-mutant gliomas, 13 IDH-wildtype glioblastomas). METHODS: For binding studies with 177Lu-radiolabeled FAPI-02/04, we used the glioblastoma cell line U87MG, FAP-transfected fibrosarcoma cells, and CD26-transfected human embryonic kidney cells. For pharmacokinetic and biodistribution studies, U87MG-xenografted mice were injected with 68Ga-labeled compounds followed by small-animal PET imaging and 177Lu-labeled FAPI-02/04, respectively. Clinical PET/CT scans were performed 30 min post intravenous administration of 68Ga-FAPI-02/04. PET and MRI scans were co-registrated. Immunohistochemistry was done on 14 gliomas using a FAP-specific antibody. RESULTS: FAPI-02 and FAPI-04 showed high binding specificity to FAP. FAPI-04 demonstrated higher tumor accumulation and delayed elimination compared with FAPI-02 in preclinical studies. IDH-wildtype glioblastomas and grade III/IV, but not grade II, IDH-mutant gliomas showed elevated tracer uptake. In glioblastomas, we observed spots with increased uptake in projection on contrast-enhancing areas. Immunohistochemistry showed FAP-positive cells with mainly elongated cell bodies and perivascular FAP-positive cells in glioblastomas and an anaplastic IDH-mutant astrocytoma. CONCLUSIONS: Using FAP-specific PET imaging, increased tracer uptake in IDH-wildtype glioblastomas and high-grade IDH-mutant astrocytomas, but not in diffuse astrocytomas, may allow non-invasive distinction between low-grade IDH-mutant and high-grade gliomas. Therefore, FAP-specific imaging in gliomas may be useful for follow-up studies although further clinical evaluation is required.
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Gelatinasas/metabolismo , Glioblastoma/genética , Glioblastoma/patología , Isocitrato Deshidrogenasa/genética , Proteínas de la Membrana/metabolismo , Tomografía Computarizada por Tomografía de Emisión de Positrones , Serina Endopeptidasas/metabolismo , Acebutolol , Adulto , Animales , Transporte Biológico , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Endopeptidasas , Femenino , Glioblastoma/diagnóstico por imagen , Glioblastoma/metabolismo , Humanos , Ligandos , Ratones , Persona de Mediana Edad , Mutación , Naftoles , Clasificación del Tumor , Trazadores Radiactivos , Triazinas , Adulto JovenRESUMEN
BACKGROUND: Hypofractionated palliative radiotherapy for metastatic lung cancer patients is frequently used in order to ease pain, to increase bone stability, to treat local mass effects, or to prolong progression-free survival at critical sites. Recently introduced, immunotherapy for patients with non-squamous non-small cell lung carcinoma (NSCLC) has significantly improved outcome in this cohort. Preclinical and early clinical data suggest that the combination of photon radiation with programmed death-1 (PD-1) targeting immunotherapies may promote a strong and durable immune response against tumor manifestations both within and beyond radiation targets. METHODS/DESIGN: In the present prospective, two-group, non-randomized, open-label phase II trial, 130 patients with stage IV non-squamous NSCLC in 2nd-line or 3rd-line treatment will be included. 65 patients with a clinical indication for palliative radiotherapy to non-cerebral/non-pulmonary metastatic sites will receive 240 mg nivolumab followed by palliative radiotherapy with 5 × 4 Gray (Gy) = 20 Gy photon radiation, which will be initiated within 72 h after first nivolumab administration (Group A). 65 patients without an indication for radiotherapy will only receive nivolumab (Group B). Nivolumab will be further administered every two weeks in both groups and will be continued until progression and loss of clinical benefit or until occurrence of limiting toxicities. The primary endpoint will be the objective response rate (ORR) according to response evaluation criteria in solid tumors (RECIST) 1.1. Secondary endpoints will be progression-free survival (PFS) according to RECIST 1.1, overall survival, descriptive subgroup analyses according to PD-L1 expression, toxicity and quality of life. Since response patterns following immunotherapies differ from those after conventional cytostatic agents, both objective response rate and progression-free survival will additionally be assessed according to immune-related RECIST (irRECIST) criteria. DISCUSSION: The FORCE study will prospectively investigate response rates, progression-free and overall survival (OS), and toxicity of nivolumab with and without hypofractionated palliative radiotherapy in a group of 130 patients with metastatic non-small cell lung cancer (non-squamous histology) in 2nd-line or 3rd-line treatment. This trial will contribute prospective data to the repeatedly published observation that the combination of hypofractionated photon radiotherapy and medical immunotherapy is not only safe but will also promote antitumoral immune responses. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03044626 (Date of initial registration: 05 January 2017). Eudra-CT Number: 2015-005741-31 (Date of initial registration: 18 December 2015).
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Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Carcinoma de Pulmón de Células no Pequeñas/terapia , Inmunoterapia , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/terapia , Nivolumab/uso terapéutico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/farmacología , Antígeno B7-H1/análisis , Biomarcadores de Tumor/análisis , Estudios de Cohortes , Terapia Combinada/métodos , Estudios de Seguimiento , Humanos , Nivolumab/administración & dosificación , Nivolumab/efectos adversos , Nivolumab/farmacología , Supervivencia sin Progresión , Estudios Prospectivos , Calidad de Vida , Hipofraccionamiento de la Dosis de Radiación , Criterios de Evaluación de Respuesta en Tumores SólidosRESUMEN
Dimethyl sulfoxide (DMSO) is an effective radical scavenger and, when added to cells, reduces the initial number of radiation-induced DNA double-strand breaks (DSB). The aim of this study was to investigate modification by DMSO of both DSB induction and DSB repair by means of pulsed-field gel electrophoresis (PFGE) as well as gamma-H2AX immunofluorescence staining. WiDr cells (human colon carcinoma provided by DKFZ) were incubated with 2% DMSO for 2 h (or mock-treated) prior to irradiation with varying X-ray doses and subsequent incubation for repair. Sample processing for PFGE analysis or counting of γ-H2AX foci was performed according to standard protocols. Effects on apoptosis induction and cell survival were investigated additionally by standard protocols. DMSO reduced DSB yield after 20-80 Gy measured by PFGE. A qualitatively similar result was found after low-dose irradiation (1 Gy) using γ-H2AX immunofluorescence staining. During incubation for repair, both DNA fragment rejoining (PFGE) as well as γ-H2AX foci removal occurred at a reduced rate when cells had been pre-treated with DMSO. But this effect was clearly more pronounced for the PFGE-analyzed double-strand breakage, particularly at early repair times. WiDr cells treated with DMSO (2%) showed a significantly increased clonogenic survival after irradiation doses above 8 Gy. Apoptosis rates were not changed by DMSO. The radio-protective effect of DMSO, well known from other PFGE studies, could be confirmed for the formation of γ-H2AX foci. DSB generated in the presence of DMSO were less rapidly repaired. DMSO showed radio-protective effects on clonogenic survival but not on apoptosis.
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Dimetilsulfóxido/química , Relación Dosis-Respuesta en la Radiación , Depuradores de Radicales Libres/química , Apoptosis , Línea Celular Tumoral , Supervivencia Celular/efectos de la radiación , ADN/efectos de la radiación , Roturas del ADN de Doble Cadena/efectos de los fármacos , Daño del ADN , Reparación del ADN/efectos de los fármacos , Electroforesis en Gel de Campo Pulsado , Humanos , Protectores contra Radiación/químicaRESUMEN
AIM: This study investigated whether generation Y nurses (1981-1995) adopt a different attitude about work than generation X caregivers (1966-1980) and baby boomers (1956-1965). BACKGROUND: Employees' positive attitude to work engagement is a competitive factor for clinics. In age-diverse team structures, possible different attitudes can lead to conflicts. METHODS: As part of a quantitative, descriptive, cross-sectional study with the survey instrument AVEM-44, health and nursing staff, as well as nursing directors and ward administrators, were interviewed. RESULTS: A total of N = 992 individuals (n = 312 nursing directors, n = 259 ward administrators and n = 421 nurses) were included in the study. Nurses and executives viewed generation Y as being less willing to give oneself out and as attaching less importance to work than generation X and the baby boomers. On the other hand, professional ambition was more important to generation Y than the older generations. CONCLUSIONS: Transformational leadership behaviour represents an approach to guide employees of different generations individually and to harmonize different attitudes. IMPLICATIONS FOR NURSE MANAGEMENT: To lead employees transformationally, it is necessary to know generation-specific differences concerning attitudes towards work.
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Relaciones Intergeneracionales , Enfermeras Administradoras/psicología , Enfermeras y Enfermeros/psicología , Compromiso Laboral , Adulto , Factores de Edad , Anciano , Actitud del Personal de Salud , Estudios Transversales , Femenino , Humanos , Relaciones Interprofesionales , Satisfacción en el Trabajo , Masculino , Persona de Mediana Edad , Enfermeras Administradoras/estadística & datos numéricos , Enfermeras y Enfermeros/estadística & datos numéricos , Encuestas y Cuestionarios , Lugar de Trabajo/psicologíaRESUMEN
Early and progressive colonization of the healthy brain is one hallmark of diffuse gliomas, including glioblastomas. We recently discovered ultralong (>10 to hundreds of microns) membrane protrusions [tumor microtubes (TMs)] extended by glioma cells. TMs have been associated with the capacity of glioma cells to effectively invade the brain and proliferate. Moreover, TMs are also used by some tumor cells to interconnect to one large, resistant multicellular network. Here, we performed a correlative gene-expression microarray and in vivo imaging analysis, and identified novel molecular candidates for TM formation and function. Interestingly, these genes were previously linked to normal CNS development. One of the genes scoring highest in tests related to the outgrowth of TMs was tweety-homolog 1 (TTYH1), which was highly expressed in a fraction of TMs in mice and patients. Ttyh1 was confirmed to be a potent regulator of normal TM morphology and of TM-mediated tumor-cell invasion and proliferation. Glioma cells with one or two TMs were mainly responsible for effective brain colonization, and Ttyh1 downregulation particularly affected this cellular subtype, resulting in reduced tumor progression and prolonged survival of mice. The remaining Ttyh1-deficient tumor cells, however, had more interconnecting TMs, which were associated with increased radioresistance in those small tumors. These findings imply a cellular and molecular heterogeneity in gliomas regarding formation and function of distinct TM subtypes, with multiple parallels to neuronal development, and suggest that Ttyh1 might be a promising target to specifically reduce TM-associated brain colonization by glioma cells in patients.SIGNIFICANCE STATEMENT In this report, we identify tweety-homolog 1 (Ttyh1), a membrane protein linked to neuronal development, as a potent driver of tumor microtube (TM)-mediated brain colonization by glioma cells. Targeting of Ttyh1 effectively inhibited the formation of invasive TMs and glioma growth, but increased network formation by intercellular TMs, suggesting a functional and molecular heterogeneity of the recently discovered TMs with potential implications for future TM-targeting strategies.
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Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Glioblastoma/metabolismo , Glioblastoma/patología , Proteínas de la Membrana/metabolismo , Animales , Línea Celular Tumoral , Proliferación Celular , Humanos , Masculino , Ratones , Ratones Desnudos , Invasividad NeoplásicaRESUMEN
Chemotherapeutic agents are part of the standard treatment algorithms for many malignancies; however, their application and dosage are limited by their toxic effects to normal tissues. Chemotherapy-induced toxicities can be long-lasting and may be incompletely reversible; therefore, causative therapies for chemotherapy-dependent side effects are needed, especially considering the increasing survival rates of treated cancer patients. Mesenchymal stem cells (MSCs) have been shown to exhibit regenerative abilities for various forms of tissue damage. Preclinical data suggest that MSCs may also help to alleviate tissue lesions caused by chemotherapeutic agents, mainly by establishing a protective microenvironment for functional cells. Due to the systemic administration of most anticancer agents, the effects of these drugs on the MSCs themselves are of crucial importance to use stem cell-based approaches for the treatment of chemotherapy-induced tissue toxicities. Here, we present a concise review of the published data regarding the influence of various classes of chemotherapeutic agents on the survival, stem cell characteristics and physiological functions of MSCs. Molecular mechanisms underlying the effects are outlined, and resulting challenges of MSC-based treatments for chemotherapy-induced tissue injuries are discussed.
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Antineoplásicos/efectos adversos , Células Madre Mesenquimatosas/citología , Algoritmos , Animales , Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Humanos , Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/efectos de los fármacosRESUMEN
BACKGROUND: The present work aimed to analyze the feasibility of a shuttle-based MRI-guided radiation therapy (MRgRT) in the treatment of pelvic malignancies. PATIENTS AND METHODS: 20 patients with pelvic malignancies were included in this prospective feasibility analysis. Patients underwent daily MRI in treatment position prior to radiotherapy at the German Cancer Research Center. Positional inaccuracies, time and patient compliance were assessed for the application of off-line MRgRT. RESULTS: In 78% of applied radiation fractions, MR imaging for position verification could be performed without problems. Additionally, treatment-related side effects and reduced patient compliance were only responsible for omission of MRI in 9% of radiation fractions. The study workflow took a median time of 61â¯min (range 47-99â¯min); duration for radiotherapy alone was 13â¯min (range 7-26â¯min). Patient positioning, MR imaging and CT imaging including patient repositioning and the shuttle transfer required median times of 10â¯min (range 7-14â¯min), 26â¯min (range 15-60â¯min), 5â¯min (range 3-8â¯min) and 8â¯min (range 2-36â¯min), respectively. To assess feasibility of shuttle-based MRgRT, the reference point coordinates for the x, y and z axis were determined for the MR images and CT obtained prior to the first treatment fraction and correlated with the coordinates of the planning CT. In our dataset, the median positional difference between MR imaging and CT-based imaging based on fiducial matching between MR and CT imaging was equal to or less than 2â¯mm in all spatial directions. The limited space in the MR scanner influenced patient selection, as the bore of the scanner had to accommodate the immobilization device and the constructed stereotactic frame. Therefore, obese, extremely muscular or very tall patients could not be included in this trial in addition to patients for whom exposure to MRI was generally judged inappropriate. CONCLUSION: This trial demonstrated for the first time the feasibility and patient compliance of a shuttle-based off-line approach to MRgRT of pelvic malignancies.
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Imagen por Resonancia Magnética/métodos , Neoplasias Pélvicas/radioterapia , Radioterapia Guiada por Imagen/métodos , Adulto , Anciano , Tomografía Computarizada de Haz Cónico , Estudios de Factibilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Evaluación de Procesos y Resultados en Atención de Salud , Posicionamiento del Paciente , Neoplasias Pélvicas/diagnóstico por imagen , Neoplasias Pélvicas/patología , Estudios ProspectivosRESUMEN
BACKGROUND: Fibrosis is a delayed side effect of radiation therapy (RT). Connective tissue growth factor (CTGF) promotes the development of fibrosis in multiple settings, including pulmonary radiation injury. METHODS: To better understand the cellular interactions involved in RT-induced lung injury and the role of CTGF in these responses, microarray expression profiling was performed on lungs of irradiated and non-irradiated mice, including mice treated with the anti-CTGF antibody pamrevlumab (FG-3019). Between group comparisons (Welch's t-tests) and principal components analyses were performed in Genespring. RESULTS: At the mRNA level, the ability of pamrevlumab to prolong survival and ameliorate RT-induced radiologic, histologic and functional lung deficits was correlated with the reversal of a clear enrichment in mast cell, macrophage, dendritic cell and mesenchymal gene signatures. Cytokine, growth factor and matrix remodeling genes that are likely to contribute to RT pneumonitis and fibrosis were elevated by RT and attenuated by pamrevlumab, and likely contribute to the cross-talk between enriched cell-types in injured lung. CONCLUSIONS: CTGF inhibition had a normalizing effect on select cell-types, including immune cells not typically regarded as being regulated by CTGF. These results suggest that interactions between RT-recruited cell-types are critical to maintaining the injured state; that CTGF plays a key role in this process; and that pamrevlumab can ameliorate RT-induced lung injury in mice and may provide therapeutic benefit in other immune and fibrotic disorders.
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Anticuerpos Monoclonales/farmacología , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Pulmón/metabolismo , Pulmón/efectos de la radiación , Fibrosis Pulmonar/metabolismo , Traumatismos Experimentales por Radiación/metabolismo , Animales , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Factor de Crecimiento del Tejido Conjuntivo/antagonistas & inhibidores , Femenino , Expresión Génica , Pulmón/efectos de los fármacos , Mastocitos/efectos de los fármacos , Mastocitos/metabolismo , Mastocitos/efectos de la radiación , Ratones , Ratones Endogámicos C57BL , Fibrosis Pulmonar/tratamiento farmacológico , Fibrosis Pulmonar/etiología , Traumatismos Experimentales por Radiación/tratamiento farmacológicoRESUMEN
Values of generation Y nurses compared to generation X and baby boomers - A cross-sectional study Abstract. BACKGROUND: Several studies point to special behaviours of generation Y employees. RESEARCH QUESTION: Starting from the assumption that there is an effect on the attitudes and behaviour of values, the study deals with the question of differences in the values between generation Y (1981 - 1995) and generations X (1966 - 1980) and the baby boomers (1956 - 1965). METHOD: Values are identified by nurses (n = 421) in the self-assessment as well as by stranger estimations of station leads (n = 259) and nursing directors (n = 312) in a quantitative cross-sectional study based on the PVQ-21 questionnaire was laid. RESULTS: While the values of self-centredness, stimulation, and hedonism are of high importance to generation Y in both self-assessment and outside consideration, tradition, conformity, and safety are considered less important. Likewise, for some values of generation Y, differences in self and other views can be determined. CONCLUSIONS: In the sense of a transformational understanding of leadership, operative and strategic nursing management must consider generation-specific differences in dealing with nursing staff.
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Envejecimiento/psicología , Relaciones Intergeneracionales , Personal de Enfermería en Hospital/psicología , Valores Sociales , Adulto , Estudios Transversales , Femenino , Alemania , Humanos , Liderazgo , Masculino , Persona de Mediana Edad , Filosofía , Crecimiento Demográfico , Autoimagen , Autoevaluación (Psicología) , Teoría Social , Encuestas y CuestionariosRESUMEN
Carbon ion radiation is a promising new form of radiotherapy for cancer, but the central question about the biologic effects of charged particle radiation is yet incompletely understood. Key to this question is the understanding of the interaction of ions with DNA in the cell's nucleus. Induction and repair of DNA lesions including double-strand breaks (DSBs) are decisive for the cell. Several DSB repair markers have been used to investigate these processes microscopically, but the limited resolution of conventional microscopy is insufficient to provide structural insights. We have applied superresolution microscopy to overcome these limitations and analyze the fine structure of DSB repair foci. We found that the conventionally detected foci of the widely used DSB marker γH2AX (Ø 700-1000 nm) were composed of elongated subfoci with a size of â¼100 nm consisting of even smaller subfocus elements (Ø 40-60 nm). The structural organization of the subfoci suggests that they could represent the local chromatin structure of elementary DSB repair units at the DSB damage sites. Subfocus clusters may indicate induction of densely spaced DSBs, which are thought to be associated with the high biologic effectiveness of carbon ions. Superresolution microscopy might emerge as a powerful tool to improve our knowledge of interactions of ionizing radiation with cells.-Lopez Perez, R., Best, G., Nicolay, N. H., Greubel, C., Rossberger, S., Reindl, J., Dollinger, G., Weber, K.-J., Cremer, C., Huber, P. E. Superresolution light microscopy shows nanostructure of carbon ion radiation-induced DNA double-strand break repair foci.
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Roturas del ADN de Doble Cadena , Reparación del ADN/fisiología , Radioterapia de Iones Pesados , Microscopía/métodos , Línea Celular Tumoral , Regulación de la Expresión Génica , Histonas/genética , Histonas/metabolismo , HumanosRESUMEN
PURPOSE: The aim of this work was to evaluate outcomes and toxicities of high dose-rate (HDR) endoluminal brachytherapy in a cohort of esophageal cancer patients. PATIENTS AND METHODS: We analyzed the records of 36 patients treated with HDR brachytherapy for histologically confirmed esophageal cancer. Brachytherapy was either applied as a boost treatment for definitive treatment regimens or as salvage therapy for recurrent tumors with single doses between 4 and 6 Gy. Survival and toxicities were retrospectively analyzed. RESULTS: Brachytherapy was performed as initially planned in all but one patient; 18 patients had a complete endoscopic response at the first follow-up examination. Locoregional recurrence was observed in 24 patients after a median time of 3 months; 1 and 2year recurrence-free survival rates were 51 and 51 % for the patients treated for primary tumors and 11 and 6 % for patients treated for tumor recurrence, respectively. Median overall survival was 18 months; estimated overall survival rates at 1, 2, and 3 years were 63, 50, and 30 % after primary brachytherapy, and 60, 25, and 6 % after recurrence therapy. Adenocarcinoma histology, non-complete remission after treatment, and treatment for recurrent cancers were associated with significantly reduced prognoses. Mild dysphagia was the most common side effect in 17 patients; 8 patients suffered from locoregional grade 3 toxicities, and no grade 4 or 5 toxicities were observed. CONCLUSIONS: Endoluminal brachytherapy during the course of esophageal cancer treatment can be safely applied and results in good functional outcomes regarding dysphagia with low rates of severe toxicities.
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Braquiterapia/mortalidad , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/radioterapia , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/radioterapia , Hipofraccionamiento de la Dosis de Radiación , Adulto , Anciano , Anciano de 80 o más Años , Braquiterapia/métodos , Braquiterapia/estadística & datos numéricos , Estudios de Cohortes , Supervivencia sin Enfermedad , Neoplasias Esofágicas/patología , Alemania/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Prevalencia , Estudios Retrospectivos , Factores de Riesgo , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Local control in patients with adenoid cystic carcinoma (ACC) of the head and neck remains a challenge because of the relative radioresistance of these tumors. This prospective carbon ion pilot project was designed to evaluate the efficacy and toxicity of intensity-modulated radiotherapy (IMRT) plus carbon ion (C12) boost (C12 therapy). The authors present the first analysis of long-term outcomes of raster-scanned C12 therapy compared with modern photon techniques. METHODS: Patients with inoperable or subtotally resected ACC received C12 therapy within the pilot project. Whenever C12 was not available, patients were offered IMRT or fractionated stereotactic radiotherapy (FSRT). Patients received either C12 therapy at a C12 dose of 3 Gray equivalents (GyE) per fraction up to 18 GyE followed by 54 Gray (Gy) of IMRT or IMRT up to a median total dose of 66 Gy. Toxicity was evaluated according to version 3 of the Common Toxicity Terminology for Adverse Events. Locoregional control (LC), progression-free survival (PFS), and overall survival (OS) were analyzed using the Kaplan-Meier method. RESULTS: Fifty-eight patients received C12 therapy, and 37 received photons (IMRT or FSRT). The median follow-up was 74 months in the C12 group and 63 months in the photon group. Overall, 90% of patients in the C12 group and 94% of those in the photon group had T4 tumors; and the most common disease sites were paranasal sinus, parotid with skull base invasion, and nasopharynx. LC, PFS, and OS at 5 years were significantly higher in the C12 group (59.6%, 48.4%, 76.5%, respectively) compared with the photon group (39.9%, 27%, and 58.7%, respectively). There was no significant difference between patients who had subtotally resected and inoperable ACC. CONCLUSIONS: C12 therapy resulted in superior LC, PFS, and OS without a significant difference between patients with inoperable and partially resected ACC. Extensive and morbid resections in patients with advanced ACC may need to be reconsidered. The most common site of locoregional recurrence remains in field, and further C12 dose escalation should be evaluated.