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1.
Cancers (Basel) ; 12(6)2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32560475

RESUMO

Reliable entity subtyping is paramount for therapy stratification in lung cancer. Morphological evaluation remains the basis for entity subtyping and directs the application of additional methods such as immunohistochemistry (IHC). The decision of whether to perform IHC for subtyping is subjective, and access to IHC is not available worldwide. Thus, the application of additional methods to support morphological entity subtyping is desirable. Therefore, the ability of convolutional neuronal networks (CNNs) to classify the most common lung cancer subtypes, pulmonary adenocarcinoma (ADC), pulmonary squamous cell carcinoma (SqCC), and small-cell lung cancer (SCLC), was evaluated. A cohort of 80 ADC, 80 SqCC, 80 SCLC, and 30 skeletal muscle specimens was assembled; slides were scanned; tumor areas were annotated; image patches were extracted; and cases were randomly assigned to a training, validation or test set. Multiple CNN architectures (VGG16, InceptionV3, and InceptionResNetV2) were trained and optimized to classify the four entities. A quality control (QC) metric was established. An optimized InceptionV3 CNN architecture yielded the highest classification accuracy and was used for the classification of the test set. Image patch and patient-based CNN classification results were 95% and 100% in the test set after the application of strict QC. Misclassified cases mainly included ADC and SqCC. The QC metric identified cases that needed further IHC for definite entity subtyping. The study highlights the potential and limitations of CNN image classification models for tumor differentiation.

2.
Accid Anal Prev ; 125: 138-151, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30754016

RESUMO

PURPOSE: Interaction is the process of behavior adaption between two or more participants primarily based on what they visually perceive. It is an important aspect of traffic participation and supports a safe and efficient flow of traffic. However, prior driving simulator studies investigating the effects of vision impairment have typically used pre-programmed pedestrians that did not interact with the human driver. In the current study we used a linked pedestrian and driving simulator setting to increase the ecological validity of the experimental paradigm. We evaluated the effects of mild vision loss on interactions between drivers and human-controlled, interactive pedestrians compared to preprogrammed, non-interactive pedestrians. METHOD: Young subjects (mean age 31 years) wore safety goggles with diffusing filters that reduced visual acuity to 20/50 Snellen and contrast sensitivity to 1.49 log units. Two types of crossings (zebra vs. free lane) and two types of pedestrians (non-interactive vs. interactive) were presented to the driver using a multiple simulator setting. Gaze, safety and time series measures were analyzed to quantify the behavior of the participants during the different crossing situations. RESULTS: Simulated vision impairment significantly increased the time taken to first fixate on the pedestrian, but only had mild adverse effects on safety measures and subsequent interactions. By comparison, pedestrian type and crossing type were found to significantly affect interaction measures. In crossings with the interactive pedestrians the behavior adaption between the driver and the pedestrian took longer and was less correlated in contrast to the situations with the non-interactive pedestrian. CONCLUSION: Mild vision impairment (slightly worse than the common 20/40 requirement for driving) had little effect on interactions with pedestrians once they were detected and only had mild adverse consequences on driving safety. Time series measures were sensitive to differences in behavior adaption between road users depending on the level of interaction and type of crossing situation.


Assuntos
Condução de Veículo , Pedestres , Baixa Visão , Acuidade Visual , Caminhada , Acidentes de Trânsito , Adulto , Sensibilidades de Contraste , Feminino , Humanos , Masculino , Reconhecimento Psicológico , Segurança , Adulto Jovem
3.
Gut ; 60(2): 225-37, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20876774

RESUMO

BACKGROUND: Evasion of apoptosis is a hallmark of pancreatic cancer. However, the underlying mechanisms are still only partly understood and may involve antiapoptotic proteins such as c-FLIP. Here, the role of c-FLIP in the regulation of death receptor-mediated apoptosis in pancreatic cancer was investigated. METHODS: Expression of c-FLIP(L) and c-FLIP(S) was analysed in primary pancreatic carcinoma samples, pancreatic carcinoma cell lines and primary tumour cells together with its function as a regulator of death receptor-induced apoptosis by knockdown and overexpression studies and through modulation by chemotherapeutics. RESULTS: c-FLIP is expressed in pancreatic intraepithelial neoplasm (PanIN) lesions and in pancreatic ductal adenocarcinomas, whereas normal pancreatic ducts were consistently negative for c-FLIP. Simultaneous downregulation of c-FLIP(L) and c-FLIP(S) as well as individual knockdown of either isoform by RNA interference significantly enhances TRAIL (tumour necrosis factor-related apoptosis-inducing ligand)- and CD95-induced caspase activation and caspase-dependent apoptosis. Also, pretreatment with chemotherapeutic drugs--that is, 5-fluorouracil (5-FU), cisplatin or gemcitabine--downregulates c-FLIP and renders cells sensitive to death receptor-triggered apoptosis. Similarly, primary cultured pancreatic cancer cells are primed for TRAIL-induced apoptosis by pre-exposure to 5-FU or cisplatin. Mechanistic studies revealed that 5-FU-mediated suppression of c-FLIP results in increased TRAIL-induced recruitment and activation of caspase-8 at the death-inducing signalling complex (DISC), leading to caspase-3 activation and caspase-dependent cell death. Overexpression of c-FLIP(L) rescues cells from 5-FU- or cisplatin-mediated sensitisation for TRAIL-induced apoptosis, indicating that c-FLIP suppression is a key event in this chemotherapy-mediated sensitisation to TRAIL. Further, concomitant neutralisation of c-FLIP and XIAP acts in concert to potentiate TRAIL-induced apoptosis. CONCLUSIONS: Both the long and the short isoform of the antiapoptotic protein c-FLIP are critical regulators of death receptor-induced apoptosis in pancreatic carcinoma cells and are suppressed by chemotherapeutics. Targeting either c-FLIP(L) or c-FLIP(S) is sufficient to promote death receptor-induced apoptosis in pancreatic carcinoma cells. These findings have important implications for the design of TRAIL-based combination protocols in pancreatic cancer.


Assuntos
Apoptose/fisiologia , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/fisiologia , Proteínas de Neoplasias/fisiologia , Neoplasias Pancreáticas/patologia , Receptores de Morte Celular/fisiologia , Antimetabólitos Antineoplásicos/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/genética , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/metabolismo , Cisplatino/farmacologia , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Fluoruracila/farmacologia , Técnicas de Silenciamento de Genes , Humanos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Pâncreas/metabolismo , Neoplasias Pancreáticas/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Isoformas de Proteínas/fisiologia , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Ligante Indutor de Apoptose Relacionado a TNF/fisiologia , Células Tumorais Cultivadas , Receptor fas/fisiologia
4.
Int J Cancer ; 124(6): 1301-11, 2009 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-19065652

RESUMO

The transcription factor nuclear factor-kappaB (NF-kappaB) plays a central role in stress-induced transcriptional activation and has been implicated in chemoresistance of cancers. In the present study, we investigated the role of NF-kappaB in inducible chemoresistance of neuroblastoma. Doxorubicin, VP16 and the cytotoxic ligand TRAIL trigger NF-kappaB activation, whereas cisplatin and taxol have no impact on NF-kappaB activity. Specific inhibition of NF-kappaB activation by overexpression of dominant-negative mutant IkappaBalpha-super-repressor does not alter cell death upon doxorubicin or VP16 treatment, although it prevents doxorubicin- or VP16-mediated NF-kappaB activation. By comparison, inhibition of TRAIL-stimulated NF-kappaB activation by IkappaBalpha-superrepressor or the small molecule NF-kappaB inhibitor BMS-345541 significantly enhances TRAIL-induced apoptosis, pointing to an antiapoptotic function of NF-kappaB in TRAIL-mediated apoptosis. Analysis of signaling pathways reveals that NF-kappaB inhibition prevents TRAIL-triggered up-regulation of Mcl-1, promoting TRAIL-induced cytochrome c release and activation of caspases. Accordingly, knockdown of Mcl-1 by RNA interference significantly enhances TRAIL-induced apoptosis and also increases sensitivity of neuroblastoma cells to CD95- or chemotherapy-induced apoptosis. In conclusion, NF-kappaB regulates apoptosis in a stimulus-specific manner in neuroblastoma cells and confers protection against TRAIL-induced apoptosis. By demonstrating that NF-kappaB inhibition sensitizes neuroblastoma cells for TRAIL-induced apoptosis, our findings have important implications. Thus, NF-kappaB inhibitors may open new perspectives to potentiate the efficacy of TRAIL-based protocols in the treatment of neuroblastoma.


Assuntos
Apoptose/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Neuroblastoma/patologia , Ligante Indutor de Apoptose Relacionado a TNF/fisiologia , Técnicas de Cultura de Células , Morte Celular , Citocromos c/análise , Humanos , Luciferases/análise , Interferência de RNA , RNA Catalítico/genética , Retroviridae/fisiologia
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