A general piecewise multi-state survival model: Application to breast cancer

Multi-state models are considered in the field of survival analysis for modelling illnesses that evolve through several stages over time. Multi-state models can be developed by applying several techniques, such as non-parametric, semi-parametric and stochastic processes, particularly Markov processes. When the development of an illness is being analysed, its progression is tracked periodically. Medical reviews take place at discrete times, and a panel data analysis can be formed. In this paper, a discrete-time piecewise non-homogeneous Markov process is constructed for modelling and analysing a multi-state illness with a general number of states. The model is built, and relevant measures, such as survival function, transition probabilities, mean total times spent in a group of states and the conditional probability of state change, are determined. A likelihood function is built to estimate the parameters and the general number of cut-points included in the model. Time-dependent covariates are introduced, the results are obtained in a matrix algebraic form and the algorithms are shown. The model is applied to analyse the behaviour of breast cancer. A study of the relapse and survival times of 300 breast cancer patients who have undergone mastectomy is developed. The results of this paper are implemented computationally with MATLAB and R.Ministerio de Economía y Competitividad FQM-307European Regional Development Fund (ERDF) MTM2017-88708-PUniversity of Milano-Bicocca 2014-ATE-022

Endothelin receptor B antagonists decrease glioma cell viability independently of their cognate receptor

Background: Endothelin receptor antagonists inhibit the progression of many cancers, but research into their influence on glioma has been limited. Methods: We treated glioma cell lines, LN-229 and SW1088, and melanoma cell lines, A375 and WM35, with two endothelin receptor type B (ETRB)-specific antagonists, A-192621 and BQ788, and quantified viable cells by the capacity of their intracellular esterases to convert non-fluorescent calcein AM into green-fluorescent calcein. We assessed cell proliferation by labeling cells with carboxyfluorescein diacetate succinimidyl ester and quantifying the fluorescence by FACS analysis. We also examined the cell cycle status using BrdU/propidium iodide double staining and FACS analysis. We evaluated changes in gene expression by microarray analysis following treatment with A-192621 in glioma cells. We examined the role of ETRB by reducing its expression level using small interfering RNA (siRNA). Results: We report that two ETRB-specific antagonists, A-192621 and BQ788, reduce the number of viable cells in two glioma cell lines in a dose- and time-dependent manner. We describe similar results for two melanoma cell lines. The more potent of the two antagonists, A-192621, decreases the mean number of cell divisions at least in part by inducing a G2/M arrest and apoptosis. Microarray analysis of the effects of A-192621 treatment reveals up-regulation of several DNA damage-inducible genes. These results were confirmed by real-time RT-PCR. Importantly, reducing expression of ETRB with siRNAs does not abrogate the effects of either A-192621 or BQ788 in glioma or melanoma cells. Furthermore, BQ123, an endothelin receptor type A (ETRA)-specific antagonist, has no effect on cell viability in any of these cell lines, indicating that the ETRB-independent effects on cell viability exhibited by A-192621 and BQ788 are not a result of ETRA inhibition. Conclusion: While ETRB antagonists reduce the viability of glioma cells in vitro, it appears unlikely that this effect is mediated by ETRB inhibition or cross-reaction with ETRA. Instead, we present evidence that A-192621 affects glioma and melanoma viability by activating stress/DNA damage response pathways, which leads to cell cycle arrest and apoptosis. This is the first evidence linking ETRB antagonist treatment to enhanced expression of DNA damage-inducible genes

A detailed clinical and molecular survey of subjects with nonsyndromic USH2A retinopathy reveals an allelic hierarchy of disease-causing variants.

Defects in USH2A cause both isolated retinal disease and Usher syndrome (ie, retinal disease and deafness). To gain insights into isolated/nonsyndromic USH2A retinopathy, we screened USH2A in 186 probands with recessive retinal disease and no hearing complaint in childhood (discovery cohort) and in 84 probands with recessive retinal disease (replication cohort). Detailed phenotyping, including retinal imaging and audiological assessment, was performed in individuals with two likely disease-causing USH2A variants. Further genetic testing, including screening for a deep-intronic disease-causing variant and large deletions/duplications, was performed in those with one likely disease-causing change. Overall, 23 of 186 probands (discovery cohort) were found to harbour two likely disease-causing variants in USH2A. Some of these variants were predominantly associated with nonsyndromic retinal degeneration ('retinal disease-specific'); these included the common c.2276 G>T, p.(Cys759Phe) mutation and five additional variants: c.2802 T>G, p.(Cys934Trp); c.10073 G>A, p.(Cys3358Tyr); c.11156 G>A, p.(Arg3719His); c.12295-3 T>A; and c.12575 G>A, p.(Arg4192His). An allelic hierarchy was observed in the discovery cohort and confirmed in the replication cohort. In nonsyndromic USH2A disease, retinopathy was consistent with retinitis pigmentosa and the audiological phenotype was variable. USH2A retinopathy is a common cause of nonsyndromic recessive retinal degeneration and has a different mutational spectrum to that observed in Usher syndrome. The following model is proposed: the presence of at least one 'retinal disease-specific' USH2A allele in a patient with USH2A-related disease results in the preservation of normal hearing. Careful genotype-phenotype studies such as this will become increasingly important, especially now that high-throughput sequencing is widely used in the clinical setting.European Journal of Human Genetics advance online publication, 4 February 2015; doi:10.1038/ejhg.2014.283

Epidermólisis ampollosa, reporte de un caso

Introduction: epidermolysis bullosa refers to a heterogeneous group of chronic hereditary pimple-like diseases affecting the skin and mucosae with blisters and vesicles after minimal injury, with variable involvement of other organs.Case report: 3-year-old female patient with exulcerated skin lesions and some erythema crust-plaques, with scaling at exposure sites such as hands, knees, feet, back of the neck and genitals. She was admitted to “Hermanos Cordové” Pediatric Teaching Hospital in Manzanillo. The medical care was based on maintaining the integrity of the skin avoiding trauma, temperature control, nutrition and prevention of secondary infections. A simple epidermolysis bullosa is diagnosed by skin biopsy.Conclusions: the disease is scarcely known with low incidence and prevalence. It is a major problem in the family and social environment, as parents are dealing with a rare disease of genetic origin and poor prognosis. Medical-social support helps to minimize the problems by means of information and coordination. Treatment requires the care of a multidisciplinary and specialized team.Introducción: la epidermólisis bulosa se refiere a un grupo heterogéneo de enfermedades hereditarias ampulosas crónicas, que afectan a la piel y las mucosas con formación de ampollas y vesículas tras mínimos traumatismos, con afectación variable de otros órganos.Presentación de caso: paciente femenina de 3 años de edad con lesiones de piel exulceradas y algunas eritematocostrosas en placas, con descamación en sitios de exposición como manos, rodillas, pies, parte posterior del cuello y genitales. Se encontraba ingresada en el Hospital Pediátrico Docente “Hermanos Cordové", de Manzanillo. Los cuidados médicos se basaron en mantener la entereza de la piel evitando traumatismo, control de la temperatura, nutrición y prevención de infecciones secundarias. Se diagnostica por biopsia de piel una epidermólisis bulosa simple. Conclusiones: la enfermedad es poco conocida con baja incidencia y prevalencia. Supone un problema de gran magnitud en el entorno familiar y social, al enfrentarse los padres a una enfermedad rara con origen genético y de mal pronóstico. El apoyo médico-social ayuda a minimizar los problemas, a través de la información y coordinación. Para su tratamiento es necesaria la atención de un equipo multidisciplinario y especializado.

Prediction of peptide and protein propensity for amyloid formation

Understanding which peptides and proteins have the potential to undergo amyloid formation and what driving forces are responsible for amyloid-like fiber formation and stabilization remains limited. This is mainly because proteins that can undergo structural changes, which lead to amyloid formation, are quite diverse and share no obvious sequence or structural homology, despite the structural similarity found in the fibrils. To address these issues, a novel approach based on recursive feature selection and feed-forward neural networks was undertaken to identify key features highly correlated with the self-assembly problem. This approach allowed the identification of seven physicochemical and biochemical properties of the amino acids highly associated with the self-assembly of peptides and proteins into amyloid-like fibrils (normalized frequency of β-sheet, normalized frequency of β-sheet from LG, weights for β-sheet at the window position of 1, isoelectric point, atom-based hydrophobic moment, helix termination parameter at position j+1 and ΔGº values for peptides extrapolated in 0 M urea). Moreover, these features enabled the development of a new predictor (available at http://cran.r-project.org/web/packages/appnn/index.html) capable of accurately and reliably predicting the amyloidogenic propensity from the polypeptide sequence alone with a prediction accuracy of 84.9 % against an external validation dataset of sequences with experimental in vitro, evidence of amyloid formation

Forced migrants involved in setting the agenda and designing research to reduce impacts of complex emergencies: combining Swarm with patient and public involvement

Background: Many events with wide-ranging negative health impacts are notable for complexity: lack of predictability, non-linear feedback mechanisms and unexpected consequences. A multi-disciplinary research team was tasked with reducing the public health impacts from complex events, but without a pre-specified topic area or research design. This report describes using patient and public involvement within an adaptable but structured development process to set research objectives and aspects of implementation. Methods: An agile adaptive development approach, sometimes described as swarm, was used to identify possible research areas. Swarm is meant to quickly identify strengths and weaknesses of any candidate project, to accelerate early failure before resources are invested. When aspects of the European migration crisis were identified as a potential priority topic area, two representatives of forced migrant communities were recruited to explore possible research ideas. These representatives helped set the specific research objectives and advised on aspects of implementation, still within the swarm framework for project development. Results: Over ten months, many research ideas were considered by the collaborative working group in a series of six group meetings, supplemented by email contact in between. Up to four possible research ideas were scrutinised at any one meeting, with a focus on identifying practical or desirable aspects of each proposed project. Interest settled on a study to solicit original data about successful strategies that forced migrants use to adapt to life in the UK, with an emphasis on successfully promoting resilience and minimizing emotional distress. “Success in resettlement” was identified to be a more novel theme than “barriers to adaption” research. A success approach encourages participation when individuals may find discussion of mental illness stigmatising. The patient representatives helped with design of patient-facing and interview training materials, interviewer training (mock interviews), and aspects of the recruitment. Conclusion: Using patient and public involvement (PPI) within an early failure development approach that itself arises from theory on complex adaptive systems, we successfully implemented a dynamic development process to determine research topic and study design. The PPI representatives were closely involved in setting research objectives and aspects of implementation

Transcriptome-scale similarities between mouse and human skeletal muscles with normal and myopathic phenotypes

BACKGROUND: Mouse and human skeletal muscle transcriptome profiles vary by muscle type, raising the question of which mouse muscle groups have the greatest molecular similarities to human skeletal muscle. METHODS: Orthologous (whole, sub-) transcriptome profiles were compared among four mouse-human transcriptome datasets: (M) six muscle groups obtained from three mouse strains (wildtype, mdx, mdx(5cv)); (H1) biopsied human quadriceps from controls and Duchenne muscular dystrophy patients; (H2) four different control human muscle types obtained at autopsy; and (H3) 12 different control human tissues (ten non-muscle). RESULTS: Of the six mouse muscles examined, mouse soleus bore the greatest molecular similarities to human skeletal muscles, independent of the latters' anatomic location/muscle type, disease state, age and sampling method (autopsy versus biopsy). Significant similarity to any one mouse muscle group was not observed for non-muscle human tissues (dataset H3), indicating this finding to be muscle specific. CONCLUSION: This observation may be partly explained by the higher type I fiber content of soleus relative to the other mouse muscles sampled

Modelers' Perception of Mathematical Modeling in Epidemiology: A Web-Based Survey

International audienceBackground: Mathematical modeling in epidemiology (MME) is being used increasingly. However, there are many uncertainties in terms of definitions, uses and quality features of MME. Methodology/Principal Findings: To delineate the current status of these models, a 10-item questionnaire on MME was devised. Proposed via an anonymous internet-based survey, the questionnaire was completed by 189 scientists who had published in the domain of MME. A small minority (18%) of respondents claimed to have in mind a concise definition of MME. Some techniques were identified by the researchers as characterizing MME (e.g. Markov models), while others–at the same level of sophistication in terms of mathematics–were not (e.g. Cox regression). The researchers' opinions were also contrasted about the potential applications of MME, perceived as higly relevant for providing insight into complex mechanisms and less relevant for identifying causal factors. The quality criteria were those of good science and were not related to the size and the nature of the public health problems addressed. Conclusions/Significance: This study shows that perceptions on the nature, uses and quality criteria of MME are contrasted, even among the very community of published authors in this domain. Nevertheless, MME is an emerging discipline in epidemiology and this study underlines that it is associated with specific areas of application and methods. The development of this discipline is likely to deserve a framework providing recommendations and guidance at various steps of the studies, from design to report

Microarray profiling reveals the integrated stress response is activated by halofuginone in mammary epithelial cells

<p>Abstract</p> <p>Background</p> <p>The small molecule Halofuginone (HF) is a potent regulator of extracellular matrix (ECM ) gene expression and is unique in its therapeutic potential. While the basis for HF effects is unknown, inhibition of TGFβ signaling and activation of the amino acid restriction response (AAR) have been linked to HF transcriptional control of a number of ECM components and amelioration of fibrosis and alleviation of autoimmune disease by regulation of Th17 cell differentiation, respectively. The aim of this study was to generate a global expression profile of HF targets in epithelial cells to identify potential mediators of HF function in this cell type.</p> <p>Results</p> <p>We report that HF modulation of the expression of the ECM remodeling protein Mmp13 in epithelial cells is separable from previously reported effects of HF on TGFβ signal inhibition, and use microarray expression analysis to correlate this with transcriptional responses characteristic of the Integrated Stress Response (ISR).</p> <p>Conclusions</p> <p>Our findings suggest activation of the ISR may be a common mechanism underlying HF biological effects.</p

Primary graft failure associated with epithelial downgrowth: a case report

BACKGROUND: Epithelial downgrowth is a rare complication of ocular surgery. While the features of epithelial downgrowth following corneal transplantation are well described, its association with primary graft failure has only been reported once previously. We report a case of primary corneal graft failure (PGF) associated with retrocorneal epithelial cell ingrowth. CASE PRESENTATION: A 59 year-old male underwent an uncomplicated penetrating keratoplasty for Fuchs' corneal dystrophy. The patient developed PGF, and a second transplant was performed 5 weeks after the initial surgery. The initial host corneal button and the failed corneal graft were examined with light microscopy. Histopathologic examination of the excised corneal button demonstrated multilaminar epithelial cells on the posterior corneal surface and absence of endothelial cells. DNA extraction and polymerase chain reaction (PCR) for herpes simplex virus (HSV) DNA was performed on the failed corneal graft. Polymerase chain reaction performed on the failed corneal graft was negative for HSV DNA, which has been implicated in selected cases of PGF. Three years following repeat penetrating keratoplasty, there was no evidence of recurrent epithelial ingrowth. CONCLUSION: This is only the second report of PGF associated with epithelialization of the posterior corneal button, which most likely developed subsequent to, instead of causing, the diffuse endothelial cell loss and primary graft failure