RP11-495P10.1 promotes HCC cell proliferation by regulating reprogramming of glucose metabolism and acetylation of the NR4A3 promoter via the PDK1/PDH axis.

The incidence and related death of hepatocellular carcinoma (HCC) have increased over the past decades. However, the molecular mechanisms underlying HCC pathogenesis are not fully understood. Long noncoding RNA (lncRNA) RP11-495P10.1 has been proven to be closely associated with the progression of prostate cancer, but its role and specific mechanism in HCC are still unknown. Here, we identify that RP11-495P10.1 is highly expressed in HCC tissues and cells and contributes to the proliferation of HCC cells. Moreover, this study demonstrates that RP11-495P10.1 affects the proliferation of HCC by negatively regulating the expression of nuclear receptor subfamily 4 group a member 3 (NR4A3). Glycometabolism reprogramming is one of the main characteristics of tumor cells. In this study, we discover that RP11-495P10.1 regulates glycometabolism reprogramming by changing the expression of pyruvate dehydrogenase kinase 1 (PDK1) and pyruvate dehydrogenase (PDH), thus contributing to the proliferation of HCC cells. Furthermore, knockdown of RP11-495P10.1 increases enrichment of H3K27Ac in the promoter of NR4A3 by promoting the activity of PDH and the production of acetyl-CoA, which leads to the increased transcription of NR4A3. Altogether, RP11-495P10.1 promotes HCC cell proliferation by regulating the reprogramming of glucose metabolism and acetylation of the NR4A3 promoter via the PDK1/PDH axis, which provides an lncRNA-oriented therapeutic strategy for the diagnosis and treatment of HCC.

An improved epidemiological-unscented Kalman filter (hybrid SEIHCRDV-UKF) model for the prediction of COVID-19. Application on real-time data.

The prevalence of COVID-19 has been the most serious health challenge of the 21th century to date, concerning national health systems on a daily basis, since December 2019 when it appeared in Wuhan City. Nevertheless, most of the proposed mathematical methodologies aiming to describe the dynamics of an epidemic, rely on deterministic models that are not able to reflect the true nature of its spread. In this paper, we propose a SEIHCRDV model - an extension/improvement of the classic SIR compartmental model - which also takes into consideration the populations of exposed, hospitalized, admitted in intensive care units (ICU), deceased and vaccinated cases, in combination with an unscented Kalman filter (UKF), providing a dynamic estimation of the time dependent system's parameters. The stochastic approach is considered necessary, as both observations and system equations are characterized by uncertainties. Apparently, this new consideration is useful for examining various pandemics more effectively. The reliability of the model is examined on the daily recordings of COVID-19 in France, over a long period of 265 days. Two major waves of infection are observed, starting in January 2021, which signified the start of vaccinations in Europe providing quite encouraging predictive performance, based on the produced NRMSE values. Special emphasis is placed on proving the non-negativity of SEIHCRDV model, achieving a representative basic reproductive number R 0 and demonstrating the existence and stability of disease equilibria according to the formula produced to estimate R 0 . The model outperforms in predictive ability not only deterministic approaches but also state-of-the-art stochastic models that employ Kalman filters. Furthermore, the relevant analysis supports the importance of vaccination, as even a small increase in the dialy vaccination rate could lead to a notable reduction in mortality and hospitalizations.

Oscillating neural circuits: Phase, amplitude, and the complex normal distribution.

Multiple oscillating time series are typically analyzed in the frequency domain, where coherence is usually said to represent the magnitude of the correlation between two signals at a particular frequency. The correlation being referenced is complex-valued and is similar to the real-valued Pearson correlation in some ways but not others. We discuss the dependence among oscillating series in the context of the multivariate complex normal distribution, which plays a role for vectors of complex random variables analogous to the usual multivariate normal distribution for vectors of real-valued random variables. We emphasize special cases that are valuable for the neural data we are interested in and provide new variations on existing results. We then introduce a complex latent variable model for narrowly band-pass-filtered signals at some frequency, and show that the resulting maximum likelihood estimate produces a latent coherence that is equivalent to the magnitude of the complex canonical correlation at the given frequency. We also derive an equivalence between partial coherence and the magnitude of complex partial correlation, at a given frequency. Our theoretical framework leads to interpretable results for an interesting multivariate dataset from the Allen Institute for Brain Science.

Les séries temporelles à oscillations multiples sont généralement étudiées dans le domaine fréquentiel, où la cohérence est souvent considérée comme l'amplitude de la corrélation entre deux signaux à une fréquence spécifique. Cette corrélation est à valeurs complexes et présente des similitudes avec la corrélation de Pearson pour les valeurs réelles, tout en présentant des différences distinctes. Dans cette étude, les auteurs explorent la dépendance entre les séries oscillantes en utilisant la distribution normale complexe multivariée. Cette distribution est l'équivalent de la distribution normale multivariée classique, mais adaptée aux vecteurs de variables aléatoires complexes plutôt qu'aux vecteurs de variables aléatoires réelles. Les auteurs mettent l'accent sur des cas spécifiques qui revêtent une importance particulière pour les données neuronales qui les intéressent, tout en proposant de nouvelles approches et des variations des résultats existants. Ils introduisent un modèle de variables latentes complexes pour les signaux filtrés en bande passante étroite à une fréquence donnée. Ils démontrent ensuite que l'estimation du maximum de vraisemblance dans ce modèle produit une cohérence latente équivalente à l'amplitude de la corrélation canonique complexe à la fréquence spécifiée. Ils établissent également une équivalence entre la cohérence partielle et l'amplitude de la corrélation partielle complexe, toujours à une fréquence donnée. Leur approche théorique conduit à des résultats interprétables pour un ensemble de données multivariées intéressant provenant de l'Allen Institute for Brain Science.

Predicting and explaining absenteeism risk in hospital patients before and during COVID-19.

In order to address one of the most challenging problems in hospital management - patients' absenteeism without prior notice - this study analyses the risk factors associated with this event. To this end, through real data from a hospital located in the North of Portugal, a prediction model previously validated in the literature is used to infer absenteeism risk factors, and an explainable model is proposed, based on a modified CART algorithm. The latter intends to generate a human-interpretable explanation for patient absenteeism, and its implementation is described in detail. Furthermore, given the significant impact, the COVID-19 pandemic had on hospital management, a comparison between patients' profiles upon absenteeism before and during the COVID-19 pandemic situation is performed. Results obtained differ between hospital specialities and time periods meaning that patient profiles on absenteeism change during pandemic periods and within specialities.

[Myelodysplastic syndrome with der (1;7)(q10;p10) complicated with eosinophilia and organizing pneumonia].

The unbalanced translocation der (1;7)(q10;p10) is a characteristic cytogenetic abnormality observed in myelodysplastic syndrome (MDS). A 63-year-old man presented to our hospital with fever and lung disease. The chromosomal analysis of bone marrow cells showed 46, XY, +1, der (1;7)(q10;p10) in all four metaphases. The patient was diagnosed with MDS. Bronchoscope examination revealed organizing pneumonia. The patient's eosinophil count rose to 39% after 30 days. His fever and dyspnea worsened, and a skin rash (systemic erythema) appeared simultaneously. Therefore, the patient was commenced on azacitidine and corticosteroids. Although treatment with both drugs could control disease progression transiently, the WT-1 value and the percentage of myeloblasts in the patient's bone marrow increased. Therefore, the patient received hematopoietic stem cell transplantation from his haplo-identical donor daughter. Some reports have demonstrated that patients with MDS with der (1;7)(q10;p10) have better prognosis than those with other abnormalities, such as -7/7q-. However, reported cases with severe complications show very poor prognosis. MDS with der (1;7)(q10;p10) complicated by eosinophilia and organizing pneumonia have not been reported, and its prognosis is expected to be very poor. Our case suggests that such cases might quickly require hematopoietic stem cell transplantation before the disease worsens.

[Characteristics of myelodysplastic syndromes with der(1;7)(q10;p10)].

der(1;7)(q10;p10) is a derivative chromosome generated by an unbalanced translocation between chromosomes 1 and 7 during DNA replication. It was first described in 1980, over 40 years ago, in a case report of three patients with myelofibrosis and myeloid metaplasia. This unbalanced translocation has been identified as a characteristic entity within myeloid neoplasms. Recent clinical and genetic studies comparing der(1;7)(q10;p10)(+) against -7/del(7q) have revealed that patients with der(1;7)(q10;p10)(+) MDS have a better prognosis and a unique mutational profile. This review discusses the clinical and genetic features of der(1;7)(q10;p10)(+) myeloid neoplasms.

Phosphorylation of the Autographa californica multiple nucleopolyhedrovirus polyhedron envelope protein plays an important role in the formation of the occlusion body envelope.

During the life cycle of a baculovirus, a crystallized protein matrix, formed by polyhedrin (POLH), is produced. The protein matrix is surrounded by a multilayered protein/carbohydrate envelope, and matrix and envelope together form a mature occlusion body (OB). The polyhedron envelope plays an important role in resistance against adverse external environments. The polyhedron envelope protein (PEP) is the main protein that forms the polyhedron envelope, but the mechanism of formation of the polyhedron envelope is unclear. Here, through immunofluorescence localization observations, we found that PEP interacted with both POLH and P10 during formation of the polyhedron envelope in the late stages of infection, and PEP was also required for P10 incorporation on the surface of OBs. In this process, the phosphorylation of PEP played an important role. PEP was determined to be a phosphorylated protein using the Phos-tag technique, and PK1 was determined to be the phosphokinase of PEP by co-immunoprecipitation and in vitro phosphorylation. Immunofluorescence localization revealed that PEP was continuously phosphorylated by PK1 after PEP entered the nucleus until PEP was correctly packaged on the OB surface. Multi-point mutations of PEP conservative potential phosphorylation sites showed that the simultaneous mutation of S85, T86 and Y92 caused changes in the location of PEP and P10 in the late stages of infection, and resulted in an OB surface that lacked the polyhedron envelope. These data suggested that the phosphorylation of PEP at particular sites, i.e. S85, T86 and Y92, plays an important role in the formation of the polyhedron envelope.

From individual-based epidemic models to McKendrick-von Foerster PDEs: a guide to modeling and inferring COVID-19 dynamics.

We present a unifying, tractable approach for studying the spread of viruses causing complex diseases requiring to be modeled using a large number of types (e.g., infective stage, clinical state, risk factor class). We show that recording each infected individual's infection age, i.e., the time elapsed since infection, has three benefits. First, regardless of the number of types, the age distribution of the population can be described by means of a first-order, one-dimensional partial differential equation (PDE) known as the McKendrick-von Foerster equation. The frequency of type i is simply obtained by integrating the probability of being in state i at a given age against the age distribution. This representation induces a simple methodology based on the additional assumption of Poisson sampling to infer and forecast the epidemic. We illustrate this technique using French data from the COVID-19 epidemic. Second, our approach generalizes and simplifies standard compartmental models using high-dimensional systems of ordinary differential equations (ODEs) to account for disease complexity. We show that such models can always be rewritten in our framework, thus, providing a low-dimensional yet equivalent representation of these complex models. Third, beyond the simplicity of the approach, we show that our population model naturally appears as a universal scaling limit of a large class of fully stochastic individual-based epidemic models, where the initial condition of the PDE emerges as the limiting age structure of an exponentially growing population starting from a single individual.

Statistical Inference for High-Dimensional Pathway Analysis with Multiple Responses.

Pathway analysis, i.e., grouping analysis, has important applications in genomic studies. Existing pathway analysis approaches are mostly focused on a single response and are not suitable for analyzing complex diseases that are often related with multiple response variables. Although a handful of approaches have been developed for multiple responses, these methods are mainly designed for pathways with a moderate number of features. A multi-response pathway analysis approach that is able to conduct statistical inference when the dimension is potentially higher than sample size is introduced. Asymptotical properties of the test statistic are established and theoretical investigation of the statistical power is conducted. Simulation studies and real data analysis show that the proposed approach performs well in identifying important pathways that influence multiple expression quantitative trait loci (eQTL).

Synergistic effect of two antimicrobial peptides, Nisin and P10 with conventional antibiotics against extensively drug-resistant Acinetobacter baumannii and colistin-resistant Pseudomonas aeruginosa isolates.

BACKGROUND: Infections caused by drug-resistant strains of Acinetobacter baumannii and Pseudomonas aeruginosa are now a global problem that requires the immediate development of new antimicrobial drugs. Combination therapy and using antimicrobial peptides are two strategies with high potential to solve this issue. By these strategies, this study aimed to determine the antimicrobial effect of Nisin and P10 antimicrobial peptides on extensively drug-resistant Acinetobacter baumannii and colistin-resistant Pseudomonas aeruginosa isolates, and investigate the most effective combination of an antimicrobial peptide with an antibiotic. MATERIAL AND METHODS: This study was performed on five resistant clinical isolates and one standard strain for each kind of bacterium. First, the minimum inhibitory concentrations of two antimicrobial peptides (Nisin and P10) and five common antibiotics for the treatment of Gram-negative bacteria (ceftazidime, tobramycin, ciprofloxacin, doripenem, and colistin) was determined using Scanner-Assisted Colorimetric MIC Method. Then, the combination effect of P10+Nisin, P10+antibiotics, Nisin + antibiotics was investigated using checkerboard method. RESULTS: The MIC value of Nisin and P10 against studied pathogens were 64-256 and 8-32 µg/ml, respectively. P10+Nisin combination showed synergistic effect against standard strains and additive effect against drug-resistant clinical isolates. It was also found that the combination effect of P10+ceftazidim, P10+doripenem, and Nisin + colistin was synergistic in most cases. Nisin + tobramycin combination showed synergistic effect in exposure to standard strains, while the synergy is strain-dependent against drug-resistant clinical isolates. CONCLUSION: In conclusion, the synergism of Nisin + colistin and P10+ceftazidime/doripenem could be of great therapeutic value as antimicrobial drugs against infections caused by colistin-resistant P.aeruginosa and XDR A. baumannii.

Molecular Diagnosis in House Dust Mite-Allergic Patients Suggests That Der p 23 Is Clinically Relevant in Asthmatic Children.

BACKGROUND: Patterns of sensitization to house dust mites depend on geographic area and are important in clinical practice. However, the role of molecular diagnosis is not currently defined. We sought to characterize a pediatric population by focusing on sensitization to different mite species and major mite components in order to assess the clinical relevance of sensitization to allergenic components in our practice. METHODS: Consecutive children with respiratory allergy sensitized to house dust mites (determined by skin prick test [SPT]) were recruited. We determined specific IgE to nDer p 1, rDer p 2, and rDer p 23 using ImmunoCAP and sIgE using ImmunoCAP-ISAC microarray. Patients were followed up for 3 years. RESULTS: A total of 276 children were recruited. The frequency of sensitization was 86.6% for nDer p 1, 79.3% for rDer p 2, and 75.8% for rDer p 23. Lepidoglyphus species was the most common storage mite detected by SPT. Twenty-six patients (9.4%) were not sensitized to Der p 1 or Der p 2. It is noteworthy that IgE binding to Der p 23 was positive in 14 (53.8%). Asthmatic patients, especially those with a persistent moderate-severe phenotype, more frequently recognized the 3 major allergens. CONCLUSIONS: Most patients with mite allergy were sensitized to the major allergens Der p 1, Der p 2, and Der p 23. Of the allergens evaluated, 5% were sensitized to Der p 23 but not to Der p 1 or Der p 2. Sensitization to Der p 23 should be considered in the diagnosis and treatment of mite allergy, especially in patients with moderate-severe asthma, because it may worsen the clinical phenotype.

The E3 Ubiquitin Ligase Siah-1 Suppresses Avian Reovirus Infection by Targeting p10 for Degradation.

Avian reovirus (ARV) causes viral arthritis, chronic respiratory diseases, retarded growth, and malabsorption syndrome. The ARV p10 protein, a viroporin responsible for the induction of cell syncytium formation and apoptosis, is rapidly degraded in host cells. Our previous report demonstrated that cellular lysosome-associated membrane protein 1 (LAMP-1) interacted with p10 and was involved in its degradation. However, the molecular mechanism underlying LAMP-1-mediated p10 degradation remains elusive. We report here that the E3 ubiquitin ligase seven in absentia homolog 1 (Siah-1) is critical for p10 ubiquitylation. Our data show that Siah-1 ubiquitylated p10 and targeted it for proteasome degradation. Furthermore, the ubiquitylation of p10 by Siah-1 required the participation of LAMP-1 by forming a multicomponent complex. Thus, LAMP-1 promotes the proteasomal degradation of p10 via interacting with both p10 and the E3 ligase Siah-1. These data establish a novel host defense mechanism where LAMP-1 serves as a scaffold for both Siah-1 and p10 that allows the E3 ligase targeting p10 for ubiquitylation and degradation to suppress ARV infection.IMPORTANCE Avian reovirus (ARV) is an important poultry pathogen causing viral arthritis, chronic respiratory diseases, retarded growth, and malabsorption syndrome, leading to considerable economic losses to the poultry industry across the globe. The ARV p10 protein is a virulence factor responsible for the induction of cell syncytium formation and apoptosis and is rapidly degraded in host cells. We previously found that cellular lysosome-associated membrane protein 1 (LAMP-1) interacts with p10 and is involved in its degradation. Here we report that the E3 ubiquitin ligase seven in absentia homolog 1 (Siah-1) ubiquitylated p10 and targeted it for proteasomal degradation. Furthermore, the ubiquitylation of p10 by Siah-1 required the participation of LAMP-1 by forming a multicomponent complex. Thus, LAMP-1 serves as an adaptor to allow Siah-1 to target p10 for degradation, thereby suppressing ARV growth in host cells.

Efficacy and safety of switching from rituximab to biosimilar CT-P10 in rheumatoid arthritis: 72-week data from a randomized Phase 3 trial.

OBJECTIVE: To evaluate the efficacy and safety of CT-P10, a rituximab biosimilar after a single switch, during a multinational, randomized, double-blind Phase 3 trial involving patients with RA. METHODS: Patients received 48 weeks' treatment with CT-P10 or United States- or European Union-sourced reference rituximab (US-RTX and EU-RTX, respectively). Patients entering the extension period (weeks 48-72) remained on CT-P10 (CT-P10/CT-P10; n = 122) or US-RTX (US-RTX/US-RTX; n = 64), or switched to CT-P10 from US-RTX (US-RTX/CT-P10; n = 62) or EU-RTX (EU-RTX/CT-P10; n = 47) for an additional course. Efficacy endpoints included Disease Activity Score using 28 joints (DAS28), American College of Rheumatology (ACR) response rates, and quality of life-related parameters. Pharmacodynamics, immunogenicity and safety were also assessed. RESULTS: At week 72, similar improvements were observed by disease activity parameters including DAS28 and ACR response rate in the four extension period treatment groups. Quality of life improvements at week 72 vs baseline were similarly shown during the extension period in all groups. Newly developed anti-drug antibodies were detected in two patients following study drug infusion in the extension period. Similar pharmacodynamic and safety profiles were observed across groups. CONCLUSION: Long-term use of CT-P10 up to 72 weeks was effective and well tolerated. Furthermore, switching from reference rituximab to CT-P10 in RA was well tolerated and did not result in any clinically meaningful differences in terms of efficacy, pharmacodynamics, immunogenicity and safety. TRAIL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT02149121.

CD62P and P10 as predictive markers for assessing the efficacy of hemodialysis in treating end-stage renal disease.

BACKGROUND: CD62P is a platelet α-granule membrane protein, and P10 is a platelet membrane glycoprotein thrombospondin. To better understand the effects of hemodialysis (HD), we have conducted this study to investigate CD62P and P10 in assessing the efficacy of HD in treating patients with end-stage renal disease (ESRD). METHODS: The case group consisted of 111 patients suffering ESRD treated with regular HD and the control group enrolled 117 healthy subjects. Before and after HD treatment, a series of parameters were observed, based on which, CD62P and P10 levels were detected in the patients in two groups before and after HD therapy. The correlation analysis analyzed the correlations of CD62P and P10 markers with serum creatinine (Scr), blood urea nitrogen (BUN), and subjective score; and logistic regression analysis was performed to reveal factors affecting the efficacy of HD. RESULTS: BUN, Scr, serum phosphorus, intact parathyroid hormone (iPTH), fibrinogen, and ß2-microglobulin (ß2-MG) decreased while hemoglobin, albumin, and activated partial thromboplastin time increased in the patients suffering ESRD; patients presented with improvements in subjective symptoms and an increase in dry weight. CD62P and P10 levels were lower in post-treatment patients. CD62P and P10 positively correlated with Scr, BUN and subjective score; post-treatment CD62P and P10 levels, BUN, hemoglobin, albumin, triglyceride, iPTH, ß2-MG, and fibrinogen were correlated with the efficacy of HD. CONCLUSION: CD62P and P10 might be correlated to the efficacy of HD in treating ESRD, in turn providing predictive markers for assessing the ability of HD in treating ESRD.

Phosphorylation Induces Structural Changes in the Autographa californica Nucleopolyhedrovirus P10 Protein.

Baculoviruses encode a variety of auxiliary proteins that are not essential for viral replication but provide them with a selective advantage in nature. P10 is a 10-kDa auxiliary protein produced in the very late phase of gene transcription by Autographa californica multiple nucleopolyhedrovirus (AcMNPV). The P10 protein forms cytoskeleton-like structures in the host cell that associate with microtubules varying from filamentous forms in the cytoplasm to aggregated perinuclear tubules that form a cage-like structure around the nucleus. These P10 structures may have a role in the release of occlusion bodies (OBs) and thus mediate the horizontal transmission of the virus between insect hosts. Here, using mass spectrometric analysis, it is demonstrated that the C terminus of P10 is phosphorylated during virus infection of cells in culture. Analysis of P10 mutants encoded by recombinant baculoviruses in which putative phosphorylation residues were mutated to alanine showed that serine 93 is a site of phosphorylation. Confocal microscopy examination of the serine 93 mutant structures revealed aberrant formation of the perinuclear tubules. Thus, the phosphorylation of serine 93 may induce the aggregation of filaments to form tubules. Together, these data suggest that the phosphorylation of serine 93 affects the structural conformation of P10.IMPORTANCE The baculovirus P10 protein has been researched intensively since it was first observed in 1969, but its role during viral infection remains unclear. It is conserved in the alphabaculoviruses and expressed at high levels during virus infection. Producing large amounts of a protein is wasteful for the virus unless it is advantageous for the survival of its progeny, and therefore, P10 presents an enigma. As P10 polymerizes to form organized cytoskeletal structures that colocalize with host cell microtubules, the structural relationship of the protein with the host cell may present a key to help understand the function and importance of this protein. This study addresses the importance of the structural changes in P10 during infection and how they may be governed by phosphorylation. The P10 structures affected by phosphorylation are closely associated with the viral progeny and thus may potentially be responsible for its dissemination and survival.

Glycan binding patterns of human rotavirus P[10] VP8* protein.

BACKGROUND: Rotaviruses (RVs) are a major cause of acute children gastroenteritis. The rotavirus P [10] belongs to P[I] genogroup of group A rotaviruses that mainly infect animals, while the rotavirus P [10] was mainly identified from human infection. The rotavirus P [10] is an unusual genotype and the recognition pattern of cellular receptors remains unclear. METHODS: We expressed and purified the RV P [10] VP8* protein and investigated the saliva and oligosaccharide binding profiles of the protein. A homology model of the P [10] VP8* core protein was built and the superimposition structural analysis of P [10] VP8* protein on P [19] VP8* in complex with mucin core 2 was performed to explore the possible docking structural basis of P [10] VP8* and mucin cores. RESULTS: Our data showed that rotavirus P [10] VP8* protein bound to all ABO secretor and non-secretor saliva. The rotavirus P [10] could bind strongly to mucin core 2 and weakly to mucin core 4. The homology modeling indicated that RV P [10] VP8* binds to mucin core 2 using a potential glycan binding site that is the same to P [19] VP8* belonging to P[II] genogroup. CONCLUSION: Our results suggested an interaction of rotavirus P [10] VP8* protein with mucin core 2 and mucin core 4. These findings offer potential for elucidating the mechanism of RV A host specificity, evolution and epidemiology.

Variable selection for recurrent event data with broken adaptive ridge regression.

Recurrent event data occur in many areas such as medical studies and social sciences and a great deal of literature has been established for their analysis. On the other hand, only limited research exists on the variable selection for recurrent event data, and the existing methods can be seen as direct generalizations of the available penalized procedures for linear models and may not perform as well as expected. This article discusses simultaneous parameter estimation and variable selection and presents a new method with a new penalty function, which will be referred to as the broken adaptive ridge regression approach. In addition to the establishment of the oracle property, we also show that the proposed method has the clustering or grouping effect when covariates are highly correlated. Furthermore, a numerical study is performed and indicates that the method works well for practical situations and can outperform existing methods. An application is provided.

Une riche littérature traite de l'analyse des événements récurrents, un type de données observé notamment dans les études médicales et dans les projets de recherche en sciences sociales. Par contre, peu de résultats de recherche portent sur la sélection de variables pour ces modèles. Les méthodes existantes peuvent être vues comme une généralisation directe de procédures pénalisées disponibles pour les modèles linéaires et peuvent offrir des performances inférieures aux attentes. Les auteurs proposent l'approche de régression ridge brisée adaptative où ils procèdent simultanément à l'estimation de paramètres et à la sélection de variables en exploitant une nouvelle fonction de pénalité. Ils prouvent la propriété d'oracle de leur méthode et montrent qu'elle possède une propriété de regroupement lorsque les covariables sont hautement corrélées. Ils présentent une étude numérique qui indique que leur méthode fonctionne bien dans des situations pratiques et peut même s'avérer plus performante que les approches existantes. Ils fournissent également un exemple d'application.

Clinical development of CT-P10 and other biosimilar cancer therapeutics.

Biosimilars are highly similar versions of approved biologic drugs that may confer equivalent efficacy at a reduced cost. Patents for several biological cancer therapeutics are past or approaching expiry, presenting an opportunity to increase affordability and global accessibility of key drugs through the development of biosimilars. To receive approval, a biosimilar must show no clinically meaningful differences from the reference product in terms of efficacy or safety. The first monoclonal antibody biosimilar cancer therapeutic to gain approval was CT-P10, a biosimilar of rituximab. Here, we review the oncology clinical development program for CT-P10, providing insights into the rationale for, and design of, CT-P10 clinical trials in patients with cancer. Trials of biosimilar cancer therapeutics in development are also discussed.

Looking to the future and learning lessons from the recent past: changing stakeholder perceptions of biosimilars in cancer.

As the patents for many biologic anticancer drugs expire, significant growth in the use of biosimilars is predicted, offering an opportunity to help combat the rising costs of treatment and increase patient access to biologic therapy. Attainment of regulatory approval, involving numerous nonclinical and clinical comparative studies versus each reference product, is only one of several barriers to realize the potential gains offered by biosimilars. It is important to understand the current perceptions and informational needs of different stakeholders if biosimilars are to be accepted and widely used in the clinic. We discuss these considerations and refer to recent experiences with CT-P13, a biosimilar of the TNF inhibitor infliximab used to treat rheumatoid arthritis and other inflammatory disorders.

Scientific rationale for extrapolation of biosimilar data across cancer indications: case study of CT-P10.

For a biosimilar to gain regulatory approval, a comprehensive comparability exercise must demonstrate that it is highly similar to its originator biologic, or reference product. Once biosimilarity has been shown, it is possible to approve the biosimilar for additional indications held by the reference product, without clinical trials in these indications. Extrapolation of clinical data is permitted by regulatory agencies as long as it is scientifically justified. CT-P10, a biosimilar of rituximab, was recently approved in Europe for all indications held by its reference product, incorporating both autoimmune diseases and hematological cancers. Here, we review the scientific rationale for extrapolation in biosimilar development using the example of CT-P10 as a case study.