A Practical Approach for Uncertainty Management in Rubber Manufacturing Processes Using Physics-Informed Real-Time Models.

Industrial manufacturing management can benefit from the use of modeling. For a correct representation of the manufacturing process and the subsequent management, the models must incorporate the effect of the uncertainty propagation throughout the stages considered. In this paper, the proposed methodology for uncertainty management uses a nonintrusive method that is based on building a deterministic physics-informed real-time model for the a posteriori computation of output uncertainties. This model is built using tensor factorization as the Model Order Reduction technique. It includes as model parameters: material properties, process operations, and those random and epistemic uncertainties of known variables. The resulting model is used off-line to identify sensitivities and therefore to unify uncertainty management across the material transformation process. This method is presented by its direct application to an automotive door seal manufactured by continuous co-extrusion of several rubbers and reinforcement (metal strip and glass fiber thread).

Circulating miR-181a-5p as a new biomarker for acute cellular rejection in heart transplantation.

BACKGROUND: Acute cellular rejection (ACR) is a major complication in heart transplantation (HTx). Endomyocardial biopsy is the reference method for early detection of ACR, but a new non-invasive approach is needed. Tentative candidates could be circulating microRNAs. This study aimed to discover and validate microRNAs in serum for ACR detection after HTx. METHODS: This prospective, observational, single-center study included 121 HTx patients. ACR was graded according to International Society of Heart and Lung Transplantation classification (0R-3R). First, in the discovery phase, microRNA expression profile was carried out in serum samples from patients at pre-rejection, during, and post-rejection time (0RS1 → 2RS2` → 0RS3). Relative expression (2-∆Cq) of 179 microRNAs per sample was analyzed by reverse transcription quantitative polymerase chain reaction. Second, a microRNA with a significant rise and fall pattern during ACR was selected for the next validation phase, where it was analyzed (reverse transcription quantitative polymerase chain reaction) in serum samples from 2 groups of patients: the no-ACR group (0R grade) and the ACR group (≥2R grade). Finally, a sensitivity analysis (receiver operating characteristic curve) was done to assess microRNA accuracy for ACR detection in HTx. RESULTS: A total of 21 ACR episodes (0RS1 → 2RS2 → 0RS3) with their respective serum samples (n = 63) were included in the discovery phase. Among the 179 microRNAs analyzed, only miR-181a-5p met the rise and fall criteria. In the validation phase, miR-181a-5p relative expression (2-∆Cq) in the ACR group (n = 45) was significantly overexpressed (p < 0.0001) vs the no-ACR group (n = 45). miR-181a-5p showed an area under the curve of 0.804 (95% confidence interval: 0.707-0.880); sensitivity and specificity of 78% and 76%, respectively; and a negative predicted value of 98%. CONCLUSIONS: miR-185a-5p in serum is a candidate as a non-invasive ACR biomarker (area under the curve = 0.80 and negative predicted value = 98%). Thus, this biomarker could reduce the need for endomyocardial biopsies and the associated risks and costs of this invasive procedure.

Use of lip photoprotection in patients suffering from actinic cheilitis.

BACKGROUND: Actinic cheilitis (AC) is a chronic condition that affects mainly the lower lip. OBJECTIVES: To investigate the use of lip photoprotection in patients with AC. MATERIALS AND METHODS: A cross-sectional multicentre study of patients, ≥45 years of age, was performed in eight dermatology departments in the Galicia region over a period of one year. From 1,239 patients included in the study, 410 were diagnosed with AC and complete data were available for 408. An analysis of lip photoprotection habits and possible associations in patients with AC is reported. RESULTS: Mean age of patients with AC was 71.9 years and 53.8% were women. More than 90% of AC patients (370/408) had never used lip photoprotection. In the group of patients who used it, 62.16% of them had only used a single stick within the previous year. The only variable significantly associated with the use of lip sun protection was low Fitzpatrick's skin types I and II (p=0.039). Study limitations include the inclusion of patients 45 years or older and the use of a semiquantitative scale for measuring the frequency of application of lip photoprotection. CONCLUSION: To our knowledge, this is the first European study focused on lip photoprotection in patients suffering from AC. Only a minority of AC patients protect their lips from UV radiation. Specific lip sun protection recommendations should be promoted, especially in high-risk populations.

Actinic Cheilitis Prevalence and Risk Factors: A Cross-sectional, Multicentre Study in a Population Aged 45 Years and Over in North-west Spain.

Actinic cheilitis is thought to be a premalignant lesion or a superficial squamous cell carcinoma. The prevalence of actinic cheilitis in Europe is unknown. The aim of this study was to determine the prevalence of actinic cheilitis in the Galicia region (north-west Spain). Secondary objectives were the description of risk factors of actinic cheilitis. A cross-sectional multicentre study in patients ≥ 45 years of age was performed in 8 dermatology departments in Galicia region during a 1-year period. The prevalence of actinic cheilitis was 31.3%. Significant and independent risk factors of actinic cheilitis after multivariate analysis were age ≥ 60 years, Fitzpatrick skin phototype II, outdoor working for more than 25 years, and previous history of non-melanoma skin cancer. This is the first cross-sectional multicentre study of the prevalence of actinic cheilitis in Europe. Actinic cheilitis was present in almost one-third of the screened patients. Lip examination should be performed in all patients with chronic actinic damage.

Male pattern hair loss: Taking one for the team: The selfless gene.

Male pattern hair loss (MPHL) is exceedingly common. It is characterised by onset in early adulthood and progression with age. It has a strong heritable component. The reason for its existence remains unexplained. Given that MPHL is progressive and has its earliest manifestations in young adults it may be a barometer of age. Here we suggest that MPHL may have atavistically allowed women in our species and ancestor species to select younger (but not necessarily the youngest) adult mates. Evidence suggests that conceptions by younger fathers are more likely to lead to live births and less likely to result in miscarriage. Further children fathered by younger men may have improved health and be less likely to suffer from a number of co-morbidities. This is collectively known as the "paternal age affect". Hence the selection of younger males mediated by the MPHL may improve the fitness of the population and of the species at the expense of the individual. Indeed MPHL may have been an evolutionary "nudge" directing women to favour younger partners. It is conceivable that for a species whose success is predicated upon co-operation, collaboration and altruism the gene cannot be exclusively selfish and must have a selfless allele.

Multiscale modelling of palisade formation in gliobastoma multiforme.

Palisades are characteristic tissue aberrations that arise in glioblastomas. Observation of palisades is considered as a clinical indicator of the transition from a noninvasive to an invasive tumour. In this paper we propose a computational model to study the influence of the hypoxic switch in palisade formation. For this we produced three-dimensional realistic simulations, based on a multiscale hybrid model, coupling the evolution of tumour cells and the oxygen diffusion in tissue, that depict the shape of palisades during its formation. Our results can be summarized as follows: (1) the presented simulations can provide clinicians and biologists with a better understanding of three-dimensional structure of palisades as well as of glioblastomas growth dynamics; (2) we show that heterogeneity in cell response to hypoxia is a relevant factor in palisade and pseudopalisade formation; (3) we show how selective processes based on the hypoxia switch influence the tumour proliferation.

Multi-scale modelling of the dynamics of cell colonies: insights into cell-adhesion forces and cancer invasion from in silico simulations.

Studying the biophysical interactions between cells is crucial to understanding how normal tissue develops, how it is structured and also when malfunctions occur. Traditional experiments try to infer events at the tissue level after observing the behaviour of and interactions between individual cells. This approach assumes that cells behave in the same biophysical manner in isolated experiments as they do within colonies and tissues. In this paper, we develop a multi-scale multi-compartment mathematical model that accounts for the principal biophysical interactions and adhesion pathways not only at a cell-cell level but also at the level of cell colonies (in contrast to the traditional approach). Our results suggest that adhesion/separation forces between cells may be lower in cell colonies than traditional isolated single-cell experiments infer. As a consequence, isolated single-cell experiments may be insufficient to deduce important biological processes such as single-cell invasion after detachment from a solid tumour. The simulations further show that kinetic rates and cell biophysical characteristics such as pressure-related cell-cycle arrest have a major influence on cell colony patterns and can allow for the development of protrusive cellular structures as seen in invasive cancer cell lines independent of expression levels of pro-invasion molecules.

Experiencia del grupo de trabajo del Hospital Juan A. Fernández en la investigación del ganglio centinela en cáncer de mama / Experience of working Group of the Hospital Juan A. Fernández in the investigation of centinela node in breast cancer

Objetivo: Presentar la experiencia en ganglio centinela (GC) en cáncer de mama del grupo de trabajo del Hospital Juan A. Fernández. Material y métodos: Estudio retrospectivo de 509 pacientes operadas por cáncer de mama estadios iniciales, incluyendo los carcinomas in situ, en las cuales se realizó la biopsia del GC y linfadenectomía axilar (LA) en los casos con GC comprometidos. Para la identificación del GC se utilizó la técnica combinada (azul y tecnecio 99). Se utilizó la impronta citológica para el examen intraoperatorio y la tinción con hematoxilina-eosina (HE) para el examen diferido. La inmunohistoquímica (IHQ) se realizó en caso de duda diagnóstica. Se realizó LA en los casos en los que no se halló el GC y en los casos de GC positivo en el estudio diferido. Resultados: La tasa de detección del GC fue 97%. Se encontró compromiso tumoral en el 22% de los casos. En las pacientes con GC positivo se halló un 45,8% de ganglios no centinela comprometidos. La sensibilidad de la impronta intraoperatoria fue 84,4% . La curva ROC de la impronta intraoperatoria muestra un área bajo la curva de 0,915. Hubo una recaída axilar con GC negativo (0,20%) con una media de seguimiento de 36 meses. Conclusión: La impronta intraoperatoria es un método confiable para el diagnóstico de GC. La biopsia de GC es una técnica que permite estadificar el compromiso axilar de forma segura, con adecuado control local de la axila y baja tasa de recurrencia axilar, similar a la obtenida con LA axilar convencional.(AU)

Experiencia del grupo de trabajo del Hospital Juan A. Fernández en la investigación del ganglio centinela en cáncer de mama / Experience of working Group of the Hospital Juan A. Fernández in the investigation of centinela node in breast cancer

Objetivo: Presentar la experiencia en ganglio centinela (GC) en cáncer de mama del grupo de trabajo del Hospital Juan A. Fernández. Material y métodos: Estudio retrospectivo de 509 pacientes operadas por cáncer de mama estadios iniciales, incluyendo los carcinomas in situ, en las cuales se realizó la biopsia del GC y linfadenectomía axilar (LA) en los casos con GC comprometidos. Para la identificación del GC se utilizó la técnica combinada (azul y tecnecio 99). Se utilizó la impronta citológica para el examen intraoperatorio y la tinción con hematoxilina-eosina (HE) para el examen diferido. La inmunohistoquímica (IHQ) se realizó en caso de duda diagnóstica. Se realizó LA en los casos en los que no se halló el GC y en los casos de GC positivo en el estudio diferido. Resultados: La tasa de detección del GC fue 97%. Se encontró compromiso tumoral en el 22% de los casos. En las pacientes con GC positivo se halló un 45,8% de ganglios no centinela comprometidos. La sensibilidad de la impronta intraoperatoria fue 84,4% . La curva ROC de la impronta intraoperatoria muestra un área bajo la curva de 0,915. Hubo una recaída axilar con GC negativo (0,20%) con una media de seguimiento de 36 meses. Conclusión: La impronta intraoperatoria es un método confiable para el diagnóstico de GC. La biopsia de GC es una técnica que permite estadificar el compromiso axilar de forma segura, con adecuado control local de la axila y baja tasa de recurrencia axilar, similar a la obtenida con LA axilar convencional.

Computational modeling of single-cell migration: the leading role of extracellular matrix fibers.

Cell migration is vitally important in a wide variety of biological contexts ranging from embryonic development and wound healing to malignant diseases such as cancer. It is a very complex process that is controlled by intracellular signaling pathways as well as the cell's microenvironment. Due to its importance and complexity, it has been studied for many years in the biomedical sciences, and in the last 30 years it also received an increasing amount of interest from theoretical scientists and mathematical modelers. Here we propose a force-based, individual-based modeling framework that links single-cell migration with matrix fibers and cell-matrix interactions through contact guidance and matrix remodelling. With this approach, we can highlight the effect of the cell's environment on its migration. We investigate the influence of matrix stiffness, matrix architecture, and cell speed on migration using quantitative measures that allow us to compare the results to experiments.

From genotypes to phenotypes: classification of the tumour profiles for different variants of the cadherin adhesion pathway.

The E-cadherin adhesive profile expressed by a tumour is a characterization of the intracellular and intercellular protein interactions that control cell-cell adhesion. Within the intracellular proteins that determine the tumour adhesive profile, Src and PI3 are two essentials to initiate the formation of the E-cadherin adhesion complex. On the other hand, Src has also the capability of disrupting the ß-catenin-E-cadherin complex and down-regulating cell-cell adhesion. In this paper, using a multi-scale mathematical model, we study the role of each of these proteins in the adhesive profile and invasive properties of the tumour. To do this, we create three versions of an intracellular model that explains the interplay between the proteins E-cadherin, ß-catenin, Src and PI3; and we couple them to the strength of the cell-cell adhesion forces within an individual-cell-based model. The simulation results show how the tumour profile and its aggressive potential may change depending on the intrinsic characteristics of the protein pathways, and how these pathways may influence the early stages of cancer invasion. Our major findings may be summarized as follows. (1) Intermediate levels of Src synthesis rates generate the least invasive tumour phenotype. (2) Conclusions drawn from findings obtained from the intracellular molecular dynamics (here cadherin-catenin binding complexes) to the multi-cellular invasive potential of a tumour may be misleading or erroneous. The conclusions should be validated in a multi-cellular context on timescales relevant for population growth. (3) Monoclonal populations of more cohesive cells with otherwise equal properties tend to grow slower. (4) Less cohesive cells tend to outcompete more cohesive cells. (5) Less cohesive cells have a larger probability of invasion as migration forces can more easily outbalance cohesive forces.

Multi-scale modelling of cancer cell intravasation: the role of cadherins in metastasis.

Transendothelial migration is a crucial process of the metastatic cascade in which a malignant cell attaches itself to the endothelial layer forming the inner wall of a blood or lymph vessel and creates a gap through which it enters into the bloodstream (or lymphatic system) and then is transported to distant parts of the body. In this process both biological pathways involving cell adhesion molecules such as VE-cadherin and N-cadherin, and the biophysical properties of the cells play an important role. In this paper, we present one of the first mathematical models considering the problem of cancer cell intravasation. We use an individual force-based multi-scale approach which accounts for intra- and inter-cellular protein pathways and for the physical properties of the cells, and a modelling framework which accounts for the biological shape of the vessel. Using our model, we study the influence of different protein pathways in the achievement of transendothelial migration and give quantitative simulation results comparable with real experiments.

Modeling the influence of the E-cadherin-beta-catenin pathway in cancer cell invasion: a multiscale approach.

In this article, we show, using a mathematical multiscale model, how cell adhesion may be regulated by interactions between E-cadherin and beta-catenin and how the control of cell adhesion may be related to cell migration, to the epithelial-mesenchymal transition and to invasion in populations of eukaryotic cells. E-cadherin mediates cell-cell adhesion and plays a critical role in the formation and maintenance of junctional contacts between cells. Loss of E-cadherin-mediated adhesion is a key feature of the epithelial-mesenchymal transition. beta-catenin is an intracellular protein associated with the actin cytoskeleton of a cell. E-cadherins bind to beta-catenin to form a complex which can interact both with neighboring cells to form bonds, and with the cytoskeleton of the cell. When cells detach from one another, beta-catenin is released into the cytoplasm, targeted for degradation, and downregulated. In this process there are multiple protein-complexes involved which interact with beta-catenin and E-cadherin. Within a mathematical individual-based multiscale model, we are able to explain experimentally observed patterns solely by a variation of cell-cell adhesive interactions. Implications for cell migration and cancer invasion are also discussed.

Un caso inusual de sarcoidosis de las cicatrices / An unusual case of scar sarcoidosis

La sarcoidosis es una enfermedad multisistémica de etiología desconocida que afecta sobre todo a adultos jóvenes y que se caracteriza por la formación de granulomas epitelioides no caseificantes en diversos órganos. Afecta principalmente a pulmones, ganglios linfáticos, ojos y piel. Las manifestaciones de la sarcoidosis cutánea son de dos tipos: unas son específicas, con formación de granulomas no caseificantes; las otras son inespecíficas, como el eritema nudoso. La infiltración de cicatrices antiguas es una manifestación específica de sarcoidosis. Aportamos el caso de una mujer joven que refería cambios en sus cicatrices, secundarias a una explosión de gas. El estudio histológico mostró granulomas sarcoideos que afectaban a casi toda la dermis. Se objetivaron alteraciones en las pruebas de función hepática. Cinco meses después sufrió una uveítis. Se comentan los aspectos etiopatogénicos, diagnóstico diferencial, tratamiento y pronóstico de la sarcoidosis de las cicatrices. Ésta puede ser la primera y única manifestación de una sarcoidosis sistémica (AU)

Vasculitis cutánea, neutropenia y fiebre, en una paciente con artritis reumatoide grave / Cutaneous vasculitis, neutropenia and fever, in a patient with severe rheumatoid arthritis

La vasculitis reumatoide es una complicación rara de la artritis reumatoide con una alta tasa de mortalidad debido a vasculitis sistémica y a infecciones. Presentamos el caso de una mujer de 70 años con una artritis reumatoide grave que presentó un brote intenso de vasculitis reumatoide, afectando a la piel, así como neutropenia y fiebre. En este caso la neutropenia autoinmune incrementa la susceptibilidad a infecciones bacterianas y es una factor limitante para el tratamiento con agentes citostáticos. Creemos que es una paciente interesante debido a la combinación de vasculitis, neutropenia y fiebre que represena una situación crítica en dermatología, y estas situaciones son poco frecuentes en nuestra práctica diaria (AU)