Gotowa bibliografia na temat „Research Subject Categories – MEDICINE: cell biology”

Background. Mitochondrial biogenesis-related studies have increased rapidly within the last 20 years, whereas there has been no bibliometric analysis on this topic to reveal relevant progress and development trends. Objectives. In this study, a bibliometric approach was adopted to summarize and analyze the published literature in this field of mitochondrial biogenesis over the past 20 years to reveal the major countries/regions, institutions and authors, core literature and journal, research hotspots and frontiers in this field. Methods. The Web of Science Core Collection database was used for literature retrieval and dataset export. The CiteSpace and VOSviewer visual mapping software were used to explore research collaboration between countries/regions, institutions and authors, distribution of subject categories, core journals, research hotspots, and frontiers in this field. Results. In the last 20 years, the annual number of publications has shown an increasing trend yearly. The USA, China, and South Korea have achieved fruitful research results in this field, among which Duke University and Chinese Academy of Sciences are the main research institutions. Rick G Schnellmann, Claude A Piantadosi, and Hagir B Suliman are the top three authors in terms of number of publications, while RC Scarpulla, ZD Wu, and P Puigserver are the top three authors in terms of cocitation frequency. PLOS One, Biochemical and Biophysical Research Communications, and Journal of Biological Chemistry are the top three journals in terms of number of articles published. Three papers published by Richard C Scarpulla have advanced this field and are important literature for understanding the field. Mechanistic studies on mitochondrial biosynthesis have been a long-standing hot topic; the main keywords include skeletal muscle, oxidative stress, gene expression, activation, and nitric oxide, and autophagy and apoptosis have been important research directions in recent years. Conclusion. These results summarize the major research findings in the field of mitochondrial biogenesis over the past 20 years in various aspects, highlighting the major research hotspots and possible future research directions and helping researchers to quickly grasp the overview of the developments in this field.

The article aims at discussing the XIX century’s European studies which influenced the new ethically-themed performance, viewed as the source of the main meaningful (or subject-to-subject) cultural categories. Social and scientific changes, which led to the “cultural upheaval”, made the scientists consider the value system newly and define the existence of the dynamic cultural-ethic elements as a system. Further this approach provided the basis for the division of the cultural categories into fundamental and meaningful. The vectors of ethic norms’ transformation are also under discussion, i.e. the development of philosophical ideas of the following researchers A. Schopenhauer, F. Nietzsche, Ch. Darwin, A. Bergson: voluntaristic (built on the philosophy of the will), evolutionist (based on the Ch. Darwin’s theory of biological evolution) and vital (designed on the metaphysics of Bergson’s Elan Vital). Viewed as a whole, both “philosophy of living” and Ch. Darwin’s theory of the origin of species seem to ground cultural categories of a moral and ethical value. Thanks to them, life turned out to be not only of irrational creative philosophical principle but also of the ultimate value; while the concept struggle for existence moved to Biology. Life as an ultimate value acknowledgment did not mean the full refusal from the morality with the social degradation, it was only associated with relativization of traditional (Christian, primarily) values. This acknowledgment did not involve the recognition of the human being’s unlimited selfishness which in practice had to give way to the “instinct” of solidarity found in animality.

Abstract Background: The phase 3 B-LONG and Kids B-LONG studies demonstrated low annualized bleeding rates (ABRs) with rFIXFc prophylaxis in subjects with severe hemophilia B. Compared with prestudy FIX treatment, rFIXFc prophylaxis reduced weekly factor consumption and infusion frequency. Aims: To evaluate the effect of rFIXFc on subjects' physical activity across age groups using a subject-reported assessment and to examine ABRs with respect to change in physical activity and prestudy treatment regimen (prophylaxis or episodic) in B-LONG and Kids B-LONG. Methods: Previously treated males with severe haemophilia B (≤ 2 IU/dL endogenous FIX activity) were eligible for B-LONG (≥ 12 years of age) and Kids B-LONG (<12 years of age). Subjects in B-LONG were enrolled into 1 of 4 treatment arms: Arm 1, weekly prophylaxis; Arm 2, individualized interval prophylaxis; Arm 3, episodic treatment; or Arm 4, perioperative management (not included in this analysis). All subjects in Kids B-LONG started on weekly rFIXFc prophylaxis. There were no restrictions on physical activity in either study. Physical activity assessments were conducted at Weeks 4, 16, 26, 39, and 52 (B-LONG) and Weeks 3, 12, 24, 36, and 50 (Kids B-LONG). At each visit after their first rFIXFc dose, subjects were asked to report activity levels relative to their prior study visit as: more (or more intensive), fewer (or less intensive), or about the same amount of physical activities. To summarize each subject's change in physical activity during the study compared with baseline, subjects were classified into one of 4 groups: more, the same, less, or undetermined. Within each treatment group, prestudy and on-study ABRs were analyzed according to change in physical activity category and prestudy regimen. Analyses included all subjects who received ≥ 1 dose of rFIXFc during the efficacy period and who completed ≥ 1 physical activity assessment. Results: This analysis included 112 subjects from B-LONG and 30 subjects from Kids B-LONG. The majority of subjects in both studies reported more or the same amount of physical activity during the study; few subjects reported less physical activity. Percent of subjects with changes in physical activity levels (more, same, less, undetermined) in B-LONG were: Arm 1 (n = 60), 35%, 42%, 7%, 17%; Arm 2 (n = 25), 48%, 28%, 16%, 8%; Arm 3 (n = 27), 30%, 26%, 15%, 30%; and in Kids B-LONG (n = 30) were: 57%, 20%, 10%, 13%, respectively. Similar physical activity results were observed in subjects with and without target joints at baseline. Median on-study ABRs with rFIXFc prophylaxis were low in B-LONG and Kids B-LONG for all categories of change in physical activity; for subjects on prestudy prophylaxis who reported more or similar physical activity during B-LONG/Kids B-LONG, median ABRs with rFIXFc were similar or lower compared with prestudy ABR (Table). Summary/Conclusion: The majority of subjects in B-LONG (71%) and Kids B-LONG (77%) maintained or increased physical activity levels during the study. ABRs were low in both studies, regardless of change in physical activity. These results suggest that people with severe hemophilia B across age groups may maintain or increase their physical activity levels with rFIXFc while also maintaining low bleeding rates with reduced infusion frequency. Table 1. Prestudy and On-study Median (IQR) ABR by Physical Activity Level in B-LONG and Kids B-LONG Parent study: B-LONG Kids B-LONG On-study rFIXFc prophylaxis: Arm 1 (weekly) Arm 2 (individualized interval) Weekly Prestudy FIX regimen: Prophylaxis (n = 30) Episodic (n = 28) Prophylaxis (n = 13) Episodic (n = 13) Prophylaxis (n = 30) Median (IQR) ABR by physical activity category More n = 6 n = 11 n = 5 n = 5 n = 17 Prestudy 6.00 (1.00, 15.00) 14.00(11.00, 28.00) 1.00(0, 1.00) 25.00(22.00, 25.00) 2.00(0, 3.00) On-study 4.76 (3.09, 5.62) 3.13(1.14, 4.34) 0(0, 0.72) 2.19(1.66, 2.61) 2.09(0, 3.13) Same n = 15 n = 10 n = 2 n = 5 n = 6 Prestudy 1.00(1.00, 6.00) 26.00(20.00, 40.00) 4.00(1.00, 7.00) 33.00(27.00, 39.00) 2.50(0, 3.00) On-study 1.13(0, 2.30) 2.62(0.99, 5.23) 1.15(0, 2.30) 1.09(0, 4.43) 0.53(0, 2.90) Less n = 3 n = 0 n = 2 n = 1 n = 3 Prestudy 0(0,0) -- 3.00(2.00, 4.00) 22.00 5.00(2.00, 6.00) On-study 0(0,0) -- 3.78(0, 7.56) 0 1.85(1.06, 5.43) Undetermined n = 4 n = 5 n = 1 n = 1 n = 4 Prestudy 4.50(2.50, 8.00) 25.00(20.00, 40.00) 4.00 12.00 7.00(3.50, 13.00) On-study 3.76(1.76, 5.35) 1.04(0, 1.16) 0 3.12 2.21(1.09, 3.92) ABR, annualized bleeding rate; IQR, interquartile range. Disclosures Kulkarni: Baxter: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; BPL: Membership on an entity's Board of Directors or advisory committees; Biogen: Research Funding, Speakers Bureau. Shapiro:Baxalta, Novo Nordisk, Biogen, ProMetic Life Sciences, and Kedrion Biopharma: Consultancy; Biogen: Speakers Bureau; Bayer Healthcare, Baxalta, Biogen, CSL Behring, Daiichi Sankyo, Kedrion Biopharma, Octapharma, OPKO, ProMetic Life Sciences, PTC Therapeutics, and Selexys: Research Funding; Baxalta, Novo Nordisk, Biogen,: Membership on an entity's Board of Directors or advisory committees. Windyga:Baxalta, Novo Nordisk, and Biogen: Research Funding; Baxalta, Novo Nordisk, Sanofi, CSL Behring, Bayer, and Pfizer: Honoraria; Baxalta, Novo Nordisk, Sanofi, Biogen, CSL Behring, Bayer, and Pfizer: Membership on an entity's Board of Directors or advisory committees. Ragni:SPARK: Research Funding; Alnylam: Research Funding; Bristol Myers Squibb: Research Funding; Biomarin: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Genentech Roche: Research Funding; Pfizer: Research Funding; CSL Behring: Research Funding; Vascular Medicine Institute: Research Funding; Dimension: Research Funding; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Research Funding; Tacere Benitec: Membership on an entity's Board of Directors or advisory committees. Pasi:Octapharma: Research Funding; Biogen, Octapharma, Genzyme, and Pfizer: Consultancy, Honoraria. Ozelo:Baxter: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Biogen: Research Funding; Novo Nordisk: Research Funding, Speakers Bureau. Tsao:Biogen: Employment, Equity Ownership. Mei:Biogen: Employment, Equity Ownership.

Introduction: Pediatric non-malignant lymphoproliferative disorders (LPDs) are a clinically and genetically heterogeneous. While transient lymphadenopathy is extremely common and rarely dangerous, long-standing immune dysregulation and lymphoproliferation in children may be life-threatening. Data to guide evaluation and treatment of children with benign LPD are lacking. The primary objective of this study was to define the genomic spectrum and clinical characteristics of a cohort of children with nonmalignant LPD. Identification of the underlying pathogenic mechanisms may facilitate timely interventions and potentially guide optimal therapeutic strategies. Method s: Patients at Texas Children's Hospital and collaborating referral centers who met criteria for non-malignant LPD were offered participation in this study, approved by the Baylor College of Medicine Institutional Review Board. LPD was defined as persistent lymphadenopathy, lymph organ involvement, or lymphocytic infiltration for more than 3 months, with or without chronic or significant EBV infection. Chronic or significant EBV infection was defined as recurrent or persistent EBV viremia more than 3 months, invasive EBV disease, or EBV PCR copies &gt;100,000. All subjects and/or family members provided written informed consent to have their clinical and genetic information published. Genetic testing was performed clinically or through research-based whole-exome sequencing (WES). Results : Fifty-one subjects from 47 different families with non-malignant LPD were identified. Median age at disease presentation was 3.3 years (range 3.9 weeks - 21 years) with nearly equal proportions of males (n = 26) and females (n = 25). Almost half of subjects were Hispanic (49%), and 29% were non-Hispanic white. Fifteen subjects (29%) met HLH-2004 diagnostic criteria for HLH. Twenty-one patients had EBV-associated lymphoproliferative disorders (EBV-LPD) and 6 of the 51 ultimately developed malignancy. Clinical genetic testing was performed in 29 patients, and research-based WES was performed in 44 patients. Potential disease-causing genetic defects were identified in 62% of families. Of these pathogenic variants, targeted therapies may be effective for treatment in at least 10 of the conditions (17 subjects, 33%). Furthermore, genetic results supported potential for curative HSCT in 35% of the patients. Mechanistically, all of the LPD-associated genes could be placed into 1 of 3 categories: 1) defective control of lymphocyte activity; 2) impaired lymphocyte activation, cytoskeletal organization, and apoptosis; and 3) dysregulated inflammation. Ten-year survival for the entire cohort was 72.4% with a median 5.6 years of follow-up (range 0.10 - 26.6). Patients without evidence of a genetic explanation had a lower ten-year survival compared to those patients for whom a genetic explanation was identified (48% versus 82%, respectively, p=0.03). When both EBV-LPD and genetic explanation were considered, the ten-year survival estimate for those with EBV-associated disease and no genetic explanation was significantly worse than those with EBV-associated disease and a genetic explanation (17% vs. 90%; p =0.002). Patients without EBV-associated disease were at lower risk of death than those with EBV-LPD. Evaluating outcomes associated with maximum treatment received, ten-year survival was lowest (25% survival) among those who underwent HSCT. Conclusion s: Pediatric non-malignant LPD represents a group of conditions with high risk of death. WES identified actionable mutations in the majority of LPD cases in this cohort. Early identification of these mutations can guide therapy by confirming diagnosis, revealing molecular targets and/or supporting definitive therapy with stem cell transplant. Disclosures Forbes: Takeda: Consultancy. Jolles:CSL Behring: Consultancy, Honoraria, Research Funding, Speakers Bureau; LFB: Consultancy, Honoraria, Research Funding, Speakers Bureau; UCB Pharma: Consultancy, Other: Drug Safety Committee; Shire/Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharming: Consultancy, Honoraria, Research Funding, Speakers Bureau; Octapharma: Consultancy, Honoraria, Research Funding, Speakers Bureau. Heslop:Marker Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Allovir: Equity Ownership; Gilead Biosciences: Membership on an entity's Board of Directors or advisory committees; Kiadis: Membership on an entity's Board of Directors or advisory committees; Tessa Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cell Medica: Research Funding. Rouce:Novartis: Consultancy, Honoraria; Tessa Therapeutics: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria.

Gliomas are the most common brain tumor in adults, and molecularly targeted therapies to treat gliomas are becoming a frequent topic of investigation. The current state of molecular targeted therapy research for adult-type diffuse gliomas has yet to be characterized, particularly following the 2021 WHO guideline changes for classifying gliomas using molecular subtypes. This systematic review sought to characterize the current state of molecular target therapy research for adult-type diffuse glioma to better inform scientific progress and guide next steps in this field of study. A systematic review was conducted in accordance with PRISMA guidelines. Studies meeting inclusion criteria were queried for study design, subject (patients, human cell lines, mice, etc.), type of tumor studied, molecular target, respective molecular pathway, and details pertaining to the molecular targeted therapy—namely the modality, dose, and duration of treatment. A total of 350 studies met the inclusion criteria. A total of 52 of these were clinical studies, 190 were laboratory studies investigating existing molecular therapies, and 108 were laboratory studies investigating new molecular targets. Further, a total of 119 ongoing clinical trials are also underway, per a detailed query on clinicaltrials.gov. GBM was the predominant tumor studied in both ongoing and published clinical studies as well as in laboratory analyses. A few studies mentioned IDH-mutant astrocytomas or oligodendrogliomas. The most common molecular targets in published clinical studies and clinical trials were protein kinase pathways, followed by microenvironmental targets, immunotherapy, and cell cycle/apoptosis pathways. The most common molecular targets in laboratory studies were also protein kinase pathways; however, cell cycle/apoptosis pathways were the next most frequent target, followed by microenvironmental targets, then immunotherapy pathways, with the wnt/β-catenin pathway arising in the cohort of novel targets. In this systematic review, we examined the current evidence on molecular targeted therapy for adult-type diffuse glioma and discussed its implications for clinical practice and future research. Ultimately, published research falls broadly into three categories—clinical studies, laboratory testing of existing therapies, and laboratory identification of novel targets—and heavily centers on GBM rather than IDH-mutant astrocytoma or oligodendroglioma. Ongoing clinical trials are numerous in this area of research as well and follow a similar pattern in tumor type and targeted pathways as published clinical studies. The most common molecular targets in all study types were protein kinase pathways. Microenvironmental targets were more numerous in clinical studies, whereas cell cycle/apoptosis were more numerous in laboratory studies. Immunotherapy pathways are on the rise in all study types, and the wnt/β-catenin pathway is increasingly identified as a novel target.

The subject of the research is the phenomenon of dissipation of the social identity of young people in modern Russian society. Purpose: to compare the reflection of this phenomenon in the academic and public consciousness. Hypothesis: the dynamics and structure of the idea of the social identity of young people at the present stage of Russia's development is not the same in the academic and public consciousness. The hypothesis was tested on the example of publications included in the RSCI database. There are two categories of publications: 1) scientific journals, dissertations, 2) conference materials. The first reflects ideas about social phenomena in the minds of the academic community; the second is in the mass consciousness of the general scientific community. Search depth 11 years (2012–2021). It included the annexation of Crimea to Russia, pension reform, the C0VID-19 pandemic, and the merger of two social support funds for the population (PF and FSS). The volume of empirical data amounted to 86341 titles of publications. The views of the authors of publications on the phenomenon under study were recorded according to five search queries: “social identity of young people”, “social security”, “social protection”, “social assistance”, “social support”. The algorithm of the relationship between these topics was studied using paired correlation analysis. It was found that the peak of publications for these requests coincided with the three-year period 2016–2018. The reflection of the problem of the social identity of young people in academic publications preceded its active discussion in conference proceedings by 4–6 years. Fundamental differences are found in the ideas about the social identity of young people in the academic and public consciousness. In scientific articles and dissertations, the social identity of young people is considered as a special case of self-organization of complex social systems, in conference materials – as a separate element of a hierarchically built deterministic financial system. The results obtained are regarded by us as proof of the correctness of the null hypothesis put forward. Possible areas of application of the results of the study: youth, social and demographic policy of the state at a new stage of socio-economic reforms. The limitation for the implementation of the research results in the practice of social management may be the effect of inertial public opinion and mass consciousness, as well as the financial interests of individual lobbies currently involved in the implementation of social projects. Directions for future research – targeted monitoring of the transformation of the mass in accordance with the requirements of the modern technological revolution.

Purpose. To evaluate the influence of systemic and ocular factors on the foveal avascular zone (FAZ) area in young Chinese subjects’ healthy eyes. Methods. The current observational, cross-sectional study included 344 eyes from 172 healthy individuals (103 women, 69 men). Optical coherence tomography angiography realized with the split-spectrum amplitude-decorrelation angiography (SSADA) algorithm was used to assess the area of superficial FAZ. To determine the related factors and to reveal their potential correlations with the FAZ area, comprehensive examinations including both systemic and ocular ones were executed. Systemic examination involved factors including age, gender, and body mass index, while ocular examination involved factors including BCVA, refractive error, intraocular pressure, axial length (AL), anterior chamber depth, and central corneal thickness. Especially for fundus examination, central macular thickness (CMT), retinal volume, mean retinal thickness, macular blood flow area/vessel density in the superficial retinal layer (SRL) and deep retinal layer (DRL), mean retinal nerve fiber layer (RNFL) thickness, ganglion cell layer (GCL) thickness, C/D rate, rim area, and subfoveal choroid thickness were assessed, using mixed-effects regression models to appropriately account for intereye correlation. Subgroup analyses were performed based on gender and high myopia categories. Results. The mean FAZ area was 0.30±0.11 mm2 and varied significantly across gender (P=0.0024). AL, CMT, and RNFL thickness were found significantly correlated with the FAZ area in the univariate regression analysis (AL, P=0.0005; CMT, P<0.0001; and RNFL thickness, P=0.0461). According to the multivariate results, CMT and macular blood flow in SRL were negatively correlated with FAZ (CMT: P<0.0001; macular blood flow in SRL: P=0.00223). Mean retinal thickness, mean GCL thickness, and macular blood flow in DRL were positively correlated with FAZ (mean retinal thickness: P=0.0005; mean GCL thickness: P<0.0001; and macular blood flow in DRL: P=0.0099). Correlation results among these filtered factors and FAZ were more pronounced in non-high-myopic eyes than in high-myopic eyes and had a significant difference when data of male and female subjects were processed separately from each other. Conclusion. The present cross-sectional study performed comprehensive systemic and ocular examinations in young Chinese adults and filtered factors affecting FAZ. We indicated that among all the assessed candidate factors, gender, AL, retinal thickness, macular blood flow, RNFL, and GCL thickness affected the FAZ area most significantly. Such findings would facilitate future research concerning the role of FAZ variation in fundus diseases.

Abstract Classification of primary cutaneous lymphomas (PCLs) is the subject of ongoing controversy. Based on a series of 556 patients, the applicability of the European Organization for Research and Treatment of Cancer (EORTC) classification for PCLs was assessed and compared to the proposed World Health Organization (WHO) classification of hematologic malignancies. The large majority of patients could be properly classified according to the scheme proposed by the EORTC. Comparison of estimated 5-year survival for specific diagnostic categories of PCLs demonstrated nearly complete concordance of the present results with those of the EORTC study for most of the indolent cutaneous T-cell lymphomas and cutaneous B-cell lymphomas, whereas differences were found for mycosis fungoides-associated follicular mucinosis and Sezary syndrome. A few patients with newly described entities (CD8+ epidermotropic cytotoxic T-cell lymphoma, primary cutaneous natural killer/T-cell lymphoma) could not be classified according to the EORTC scheme. Comparison of the EORTC with the WHO classification showed that the EORTC scheme allows a more precise categorization of the patients, especially for cutaneous B-cell lymphoma. In conclusion, the study confirmed that the EORTC classification allows a better management of patients with PCL. Small amendments to that classification should be carried out to account for recently described entities and to unify some of the diagnostic categories.

Q fever is a worldwide distributed zoonosis caused by Coxiella burnetii, a Gram-negative bacterium. Despite existence of large amount of research data on the developments related to Q fever, no bibliometric analysis of this subject is available to our knowledge. Bibliometric studies are an essential resource to track scholarly trends and research output in a subject. This study is aimed at reporting a bibliometric analysis of publications related to Q fever (2,840 articles published in the period 1990-2019) retrieved from Science Citation Index Expanded, an online database of Clarivate Analytics Web of Science Core Collection. Data was retrieved using keywords “Q fever” or “Coxiella burnetii” in title, abstract, and author keywords to describe important research indicators such as the kind and language of articles, the most important publications, research journals and categories, authors, institutions, and the countries having the most significant contribution to this subject. Finally, the emerging areas in field of diagnosis, host range, and clinical presentation were identified. Word cluster analysis of research related to Q fever revealed that major focus of research has been on zoonosis, seroprevalence, laboratory diagnosis (mainly using ELISA and PCR), clinical manifestations (abortion and endocarditis), vectors (ticks), and hosts (sheep, goat, and cattle). This bibliometric study is intended to visualize the existing research landscape and future trends in Q fever to assist in future knowledge exchange and research collaborations.

Toxicologic Pathology is the official journal of the Society of Toxicologic Pathology (STP), the British Society of Toxicological Pathology, and the European STP (ESTP). Toxicologic Pathology publishes articles related to topics in various aspects of toxicologic pathology such as anatomic pathology, clinical pathology, experimental pathology, and biomarker research. Publications include society-endorsed Best Practice/Position and Points to Consider publications and ESTP Expert Workshop articles that are relevant to toxicologic pathology and scientific regulatory processes, Opinion articles under the banner of the STP Toxicologic Pathology Forum, Original Articles, Review Articles (unsolicited/contributed, mini, and invited), Brief Communications, Letters to the Editor, Meeting Reports, and Book Reviews. This article provides details on the various publication categories in Toxicologic Pathology and will serve as a reference for authors and readers.

Il melanoma costituisce, ad oggi, ancora una neoplasia a prognosi infausta gravata da un alto tasso di metastatizzazione e da una sensibilita' variabile che lo rende poco responsivo ai trattamenti radio-chemioterapici applicabili. In questo lavoro sono stati confrontati i risultati di studi clinici effettuati su colture cellulari di melanoma HTB 140 sottoposte a radiazione protonica e fotonica e i risultati ottenuti dalla associazione radio-chemioterapica rispetto alle singole applicazioni.

La Corea di Huntington (MH) e' una malattia neurodegenerativa tra le piu' diffuse e studiate all'interno del gruppo di patologie causate da espansione poliglutaminica. La prevalenza e' di 3-10 soggetti affetti per 100000 individui nei paesi dell'ovest (Rawlins 2010; Spinney 2010). La malattia e' stata descritta la prima volta nel 19th secolo da George Huntington, che identifica sia le sue caratteristiche cliniche che la sua natura ereditaria. La MH e' una patologia genetica neurodegenerativa con eredita' autosomico dominante causata da una espansione instabile di triplette CAG nel gene HTT (Huntington's Disease Collaborative Research Group 1993; Kremer et al. 1994) che codifica per una proteina chiamata huntingtina (htt). La lunghezza della mutazione influenza l'eta' di insorgenza e la progressione, mentre la espansione omozigote induce una neuropatologia e un decorso piu' severo (Squitieri et al., 2003). Sebbene l' eta' di insorgenza dei sintomi piu' comune e' intorno ai 40 anni, la malattia puo' iniziare molto presto o molto tardi a seconda della penetranza della mutazione (Rubinsztein et al., 1996). Questo fa si' che negli individui a rischio, che si sottopongono ad un test presintomatico e scoprono di avere la malattia, non sia possibile predire l'eta' di insorgenza dei sintomi solo in base al numero di ripetizioni CAG che influisce sulla variazione dell'eta' di insorgenza solo per il 60-70%. Altri fattori biologici e ambientali, incluso i geni modificatori possano svolgere una grande influenza sull'inizio e lo sviluppo dei sintomi (Squitieri et al. 2000a; Wexler et al. 2004). Solo quando la mutazione e' particolarmente espansa e tossica, la malattia ha inizio in eta' infantile con effetti devastanti (Quarrel et al. 2009). Quindi l'impossibilita' di predire l'eta' di insorgenza e la progressione di malattia fra i diversi soggetti, rende la ricerca sui marcatori necessaria per monitorare lo sviluppo dei sintomi nei portatori a rischio e l'andamento patologico nei pazienti. Infatti, marcatori che traccino la progressione di malattia, in individui sintomatici, risultano ugualmente necessari per il monitoraggio di terapie sperimentali. Un buon biomarcatore dovrebbe essere facilmente rilevabile and ottenibile in maniera non-invasiva e soprattutto riflettere un meccanismo patogenetico della malattia. Attualmente non esistono marcatori con queste caratteristiche nella pratica clinica della MH.
Huntington disease (HD) is the most common and well-studied polyglutamine neurodegenerative disorder. It has a prevalence of 3- 10 affected subjects per 100000 individuals in Western Countries (Rawlins 2010; Spinney 2010). The disorder was first clinically described as a familial neuropsychiatric disease in the 19th century by George Huntington, but the responsible gene and its mutation were identified in 1993 (Huntington's Disease Collaborative Research Group 1993). Since then, the knowledge on clinical and molecular aspects of the disease has been increasing exponentially. HD is an autosomal dominant neurodegenerative disorder caused by the expansion of an unstable CAG triplet repeat beyond 36 in the HTT gene (Kremer et al. 1994), which codes for a large and ubiquitously expressed protein named huntingtin (htt). The mutation length influences the age at onset and the disease progression, the expansion homozygosity causing a particularly more severe disease course and neuropathology (Squitieri et al., 2003). Although, most of cases show an age at onset around 40s, the disease may start early in the life or very late in the elderly according to the penetrance of the mutation (Rubinsztein et al., 1996). This leaves the pathology unpredictable in at risk individuals who undergo a predictive genetic test and discovery to be mutation carriers, the number of CAG repeats accounting for only 60-70% of the age at onset variation. Other factors of biological and/or environmental origin including gene modifiers contribute therefore to the beginning and development of the disease (Squitieri et al., 2000a; Wexler et al., 2004). Only when the mutation is particularly expanded and toxic, the disease starts in children even very early in life with a devastating course (Quarrel et al. 2009). Therefore the age at onset unpredictability of most HD cases and the progression variability among patients strongly advises to search for markers sensitive enough to monitor the devolopmet of the pathological process in absence of symptoms in unaffected at risk subjects. Similarly, markers to test the progression of the disease other than the symptom changes would be crucial for monitoring the efficacy of further, yet unavailable, therapies, in symptomatic patients. Good biomarkers should be easy to get from mutation carrier subjects and must reflect a pathogenic mechanism of the disease. So far, no validate markers have been described and introduced into the clinical practice.

La tesi di Dottorato descrive l'applicazione web denominata miRo', sviluppata nell'ambito delle attivita' di dottorato svolte. miRo' e' una base di conoscenza per l'annotazione funzionale di microRNA e molecole di RNA non codificante coinvolte nella regolazione genica post-trascrizionale. Nella sua prima edizione, miRo' permetteva l'associazione di microRNA con processi e funzioni biologiche nonche' patologie che li coinvolgono attraverso le annotazioni funzionali dei geni da essi regolati. Questo tipo di tool si e' dimostrato utilissimo per la ricerca biologica di base e, soprattutto, biomedica di diversi gruppi internazionali operanti sia negli USA che in Europa ed in Israele. La base di conoscenza permette inoltre di effettuare Data Mining avanzato e di poter valutare le associazioni miRNA - processo/funzione/patologia attraverso una funzione di specificita' che si e' rivelata significativa per le applicazioni. Nella seconda edizione di miRo', sono state introdotte una serie di informazioni su pathway, profili di espressione ed annotazioni genomiche inerenti i microRNA ed i loro target (siti fragili, CpG island, translocation breakpoints), indispensabili per cercare di capire la natura delle associazioni. Contestualmente e' stato progettato un sistema di annotazione con ontologie mediante text mining dei dati di letteratura biologica su Pubmed, con l'obiettivo di sviluppare una funzione di scoring per le associazioni miRNA - fenotipo.

Tesis (Dr. Medicina)--Universidad Nacional de Córdoba. Facultad de Ciencias Médicas, 2019. 80 p.
Fil: Garcia, Pedro Emilio. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Cátedra Biología Celular, Histología y Embriología; Argentina.
Introducción: Los tumores de glándulas salivales son un grupo poco frecuente y heterogéneo de neoplasias, lo que implica dificultades tanto en el diagnóstico como en el pronóstico de esta patologia. Ki67 es un marcador que se expresa en las células en división, se ha visto que está asociado a mayor agresividad en distintos tipos de tumores, y se ha observado en varios estudios que un valor elevado está relacionado con una peor evolución de los pacientes con neoplasias de glándulas salivales. El objetivo de este trabajo fue demostrar la importancia de Ki67 como factor pronóstico en los pacientes con tumores de glándulas salivales tratados con radioterapia. Material y Métodos: Se evaluaron los pacientes con tumores de glándulas salivales localizados, tratados con radioterapia en el Instituto Zunino; se realizó marcación de Ki67 por inmunohistoquimica; se lo estratificó en alto (mayor de 20%), bajo (entre 1% y 20%) y negativo (menor o igual a 1%); y se relacionó la expresión con el porcentaje de recidivas, metástasis a distancia y muertes por enfermedad. Se realizó el cálculo de sobrevida global, sobrevida libre de recidiva, sobrevida libre de metástasis y sobrevida causa específica. Resultados: Se estudiaron 48 pacientes tratados entre 2005 y 2015. Vientiún pacientes(43,7%) tenían Ki67 alto, 21 (43,7%) Ki67 bajo; y 6 (12,6%), Ki67 negativo. El seguimiento medio fue de 48,5 meses. 15 (31,25%) pacientes fallecieron; 11 en el grupo de Ki67 alto, 2 en el grupo de Ki67 bajo y 2 pacientes en el grupo en que fue negativo. Todas las muertes por cáncer fueron por metástasis a distancia; solo 2 pacientes presentaron recidiva locorregional, la cual fue tratada con cirugía o nuevo esquema de radioterapia. La sobrevida global para todo el grupo fue de 85% a 12 meses y 79% a 24 meses. La sobrevida global a 2 años para el grupo de Ki67 alto fue de 67%, mientras que para el grupo de Ki67 bajo y negativo fue de 96%, lo cual es estadísticamente significativo(p<0.015). La sobrevida libre de metástasis a 2 años fue 57% para los pacientes con Ki67 alto, mientras que para los Ki67 bajo-negativo, esta fue de 85%. Estas diferencias fueron significativas (p<0,0008); mientras que no hubo diferencias en la sobrevida libre de recidiva local. Conclusiones: Una alta expresión de Ki67 está asociado con mayor número de metástasis y muertes por enfermedad, con peor sobrevida en los pacientes con tumores de glándulas salivales.
Introduction: Salivary gland tumors are a rare and heterogeneous group of neoplasms, which implies difficulties both in the diagnosis and in the prognosis of this disease. Ki67 is a marker that is expressed in dividing cells, it has been found to be associated with greater aggressiveness in different types of tumors, and it has been observed in several studies that a high value is related to a worse evolution of patients with Salivary gland neoplasms. The objective of this work was to demonstrate the importance of Ki67 as a prognostic factor in patients with salivary gland tumors treated with radiotherapy. Material and Methods: Patients with localized salivary gland tumors treated with radiotherapy at the Zunino Institute were evaluated; Ki67 labeling was performed by immunohistochemistry; it was stratified in high (greater than 20%), low (between 1% and 20%) and negative (less than or equal to 1%); and the expression was related to the percentage of relapses, distant metastases and deaths due to disease. The calculation of global survival, free survival of recurrence, survival free of metastasis and survival specific cause was made. Results: 48 patients treated between 2005 and 2015 were studied. Twenty-one patients (43.7%) had high Ki67, 21 (43.7%) Ki67 low; and 6 (12.6%), Ki67 negative. The mean follow-up was 48.5 months. 15 (31.25%) patients died; 11 in the high Ki67 group, 2 in the low Ki67 group and 2 patients in the negative group. All deaths from cancer were due to distant metastases; Only 2 patients had locoregional recurrence, which was treated with surgery or a new radiotherapy regimen. Overall survival for the entire group was 85% at 12 months and 79% at 24 months. The 2-year global survival for the Ki67 high group was 67%, while for the Ki67 low and negative group it was 96%, which is statistically significant (p <0.015). Metastasis free survival at 2 years was 57% for patients with high Ki67, while for Ki67 low-negative, this was 85%. These differences were significant (p <0.0008); while there were no differences in the free survival of local recurrence. Conclusions: A high expression of Ki67 is associated with a greater number of metastasis and deaths due to disease, with worse survival in patients with salivary gland tumors.
2021-10-07

In questo studio abbiamo analizzato in una linea di alfa cellule pancreatiche gli effetti dell'esposizione cronica a palmitato sul recettore dell'insulina (IR), dell'IGF1 (IGF-1R) e sul segnale intracellulare. Le cellule alfa-TC1-6 sono state coltivate in presenza o assenza di palmitato (0,5 mmol / litro) per 48 h ed alla fine e' stata analizzata la secrezione di glucagone, l'autofosforilazione di IR e IGF-1R, la fosforilazione di IRS-1, IRS-2, PI3K p85alfa, Akt ,Erk 44/42 e P38. Eà ¢ stato dimostrato che MAPK puo' regolare PAX6, un fattore di trascrizione che controlla l'espressione del gene del glucagone; per questo motivo nel nostro studio ci siamo soffermati anche all'analisi genica e proteica di PAX6. Lo studio ha messo in evidenza un aumento della secrezione di glucagone nelle cellule pre-esposte a palmitato rispetto al controllo; tale incremento diminuiva dopo stimolazione con insulina. L'analisi dell'auto-fosforilazione del recettore insulinico ha messo in evidenza una diminuzione dell'attivazione della proteina nelle cellule pre-trattate con palmitato; dati simili sono stati osservati con IRS-1-P, PI3K (p85 alfa), and Akt-P. Al contrario nelle cellule pre-esposte a palmitato, in assenza di stimolazione con insulina, IGF-1, IRS2, ERK44/42 e P38 risultano essere molto attivi; dati simili sono stati ottenuti con PAX6 e il glucagone. Per questo motivo sono stati utilizzati specifici inibitori di MAPKs che hanno messo in evidenza una riduzione di espressione di PAX6 e del Glucagone, sia a livello genico sia a livello proteico. Questi dati ci indicano che le alfa cellule trattate con palmitato per 48 h mostrano insulino resistenza a livello del segnale intracellulare IRS-1/PI3K/Akt che normalmente controlla la secrezione di glucagone. Al contrario il segnale IRS-2/MAPKs risulta essere aumentato, attraverso là ¢ attivazione di IGF-1R, determinando un aumento dellà ¢ espressione del gene del glucagone. I nostri dati supportano l'ipotesi che l'aumento cronico degli acidi grassi contribuiscono alla disregolazione delle alfa-cellule frequentemente osservato nel diabete tipo 2.
This study investigated in a pancreatic alfa-cell line the effects of chronic exposure to palmitate on the insulin and IGF-I receptor (IGF-IR) and intracellular insulin pathways. alfa-TC1â 6 cells were cultured in the presence or absence of palmitate (0.5 mmol/liter) up to 48 h. Glucagon secretion, insulin and IGF-IR autophosphorylation, and insulin receptor substrate (IRS)-1, IRS-2, phosphatidylinositol kinase (PI3K) (p85alfa), and serine-threonine protein kinase (Akt) phosphorylated (active) forms were measured. Erk 44/42 and p38 phosphorylation (P) (MAPK pathway markers) were also measured. Because MAPK can regulate Pax6, a transcription factor that controls glucagon expression, pairedboxgene6 (Pax6) and glucagon gene and protein expression were also measured. Basal glucagon secretion was increased and the inhibitory effect of acute insulin exposure reduced in alfa-TC1 cells cultured with palmitate. Insulin-stimulated insulin receptor phosphorylation was greatly reduced by exposure to palmitate. Similar results were observed with IRS-1-P, PI3K (p85 alfa), and Akt-P. In contrast, with IGF-IR and IRS-2-P, the basal levels (i.e. in the absence of insulin stimulation) were higher in cells cultured with palmitate. Similar data were obtained with Erk 44/42-P and p-38-P. Pax6 and glucagon gene and protein expression were higher in cells cultured with palmitate. In these cells cultured, specifics MAPKs inhibitors were able to reduce both Pax6 and glucagon gene and protein expression. These results indicate that alfa-cells exposed to palmitate show insulin resistance of the IRS-1/PI3K/Akt pathway that likely controls glucagon secretion. In contrast, the IRS-2/MAPKs pathway is stimulated, through an activation of the IGF-IR, leading to increased Pax6 and glucagon expression. Our data support the hypothesis that the chronic elevation of fatty acids contribute to alfa-cell dysregulation frequently observed in type 2 diabetes.

Introduzione: il TSH, agendo attraverso cAMP/PKA, regola la crescita delle cellule follicolari tiroidee e richiede anche l' attivazione di mTOR per esercitare i suoi effetti mitogenici. I carcinomi tiroidei scarsamente differenziati e le linee cellulari tumorali tiroidee cresciute in vitro, perdono la dipendenza dal TSH per la loro crescita; essi mostrano, tuttavia, una incrementata attività di mTOR. Poiche' entrambe le vie di segnale di MAPK e PI3K svolgono un ruolo importante nella patogenesi del carcinoma tiroideo e possono convergere su mTOR, esse potrebbero rappresentare vie di segnale alternative responsabili dell'attivazione di mTOR e della proliferazione di cellule tumorali tiroidee. Materiali e Metodi: come modello di studio sono state usate le cellule non trasformate di tiroide di ratto (PCCL3) e linee cellulari umane di carcinoma tiroideo aventi mutazioni a carico degli oncogeni RET/PTC, RAS e BRAF. Obiettivi: Valutare, nei nostri modelli cellulari, se: 1) la via TSH/cAMP/PKA regola la attivazione di mTOR e la crescita cellulare mediata da tale chinasi; 2) le oncoproteine RET/PTC3, HRASSG12V e BRAFV600E, regolano la attivazione di mTOR; 3) la inibizione farmacologica di mTOR (usando la rapamicina) da sola o in combinazione con inibitori di MAPK e PI3K, esercita degli effetti sulla crescita e proliferazione cellulare. Risultati: 1) nelle PCCL3, la via TSH/cAMP/PKA à à à à ¨ cruciale nel mediare i segnali dipendenti da mTOR. Viceversa, le linee cellulari di carcinoma tiroideo sostituiscono la dipendenza, per la loro crescita e per la attivazione di mTOR, dal segnale TSH/cAMP/PKA alle vie di segnale dipendenti da MAPK e/o PI3K; 2) nelle PCCL3, tutte e tre le oncoproteine RET/PTC3, HRASSG12V e BRAFV600E inducono la attivazione di mTOR e quest'ultimo e' richiesto per la sintesi del DNA indotta dalle oncoproteine tiroidee; 3) nelle linee cellulari tumorali tiroidee, la rapamicina, in monoterapia, inibisce la crescita cellulare in modo variabile. Viceversa, una terapia mirata ad inibire contemporaneamente mTOR e/o MEK e/o AKT1/2 esercita effetti terapeutici benefici in tutte le linee cellulari analizzate, eccetto che in quelle strettamente dipendenti, per la crescita, da una sola via di trasduzione del segnale. Conclusioni: nelle linee cellulari tumorali tiroidee, nelle quali piu' vie di segnale (quali MAPK, PI3K ed mTOR) concorrono a conferire dipendenza per la crescita, terapie multiple mirate, potrebbero avere effetti terapeutici benefici massimali.
Introduction: In thyroid follicular cells, TSH, acting through cAMP, regulates cell growth and requires mTOR to exert its mitogenic response. In poorly differentiated thyroid carcinomas and in human thyroid cancer cell lines the TSH dependence for growth is lost, although mTOR pathway is still activated. MAPK and PI3K pathways are central in thyroid cancer pathogenesis and may converge to mTOR cascade. Thus, these cascades could be responsible for mTOR activation and thyroid cell proliferation. Material and Methods: we employed non-transformed thyroid rat cells (PPCL3) and human thyroid cancer cell lines harboring mutations in thyroid oncoproteins RET/PTC, RAS and BRAF. Aims: 1) to evaluate whether TSH/cAMP/PKA signaling pathway regulates mTOR activation and its proliferative response; 2) to study the role of the thyroid oncoproteins RET/PTC3, HRASG12V or BRAFV600E in regulating mTOR activity in our in vitro models; 3) to investigate the efficacy of combined targeting of MAPK, PI3K and mTOR signaling cascades in inhibiting growth and proliferation of human thyroid cancer cell lines. Results: 1) in PCCL3 cells, TSH/cAMP/PKA cascade was central in mediating mTOR signals. In contrast, thyroid cancer cell lines switched the control of mTOR activation from the TSH/cAMP/PKA signals to either MAPK and/or PI3K; 2) conditional expression of the oncoproteins RET/PTC3, HRASG12V and BRAFV600E induced mTOR activity in PPCL3 cells. Moreover, mTOR was required for DNA synthesis induced by all three oncoproteins; 3) rapamycin alone suppressed growth of human thyroid cancer cell lines to a variable degree, whereas the combination of mTOR, MEK and AKT1/2 inhibitors significantly suppressed growth in all cell lines analyzed, except for those addicted mainly to only one survival pathway. Conclusions: In thyroid cancer cells in which multiple parallel cascades (i.e. mTOR, MAPK and PI3K) mediate the survival signals, the multi-targeted therapy could be exploited to achieve optimal therapeutic benefits.

Il carcinoma del colon-retto (CRC) e' una delle neoplasie piu' frequenti nel mondo occidentale e rappresenta un problema socio-sanitario di notevole rilievo. E' noto che non tutti i pazienti affetti da CRC rispondono in modo positivo alla terapia con i piu' comuni agenti antitumorali (es. Cetuximab): vi sono infatti dei fattori genetici predittivi della risposta, tra i quali sicuramente uno dei piu' noti e' lo stato mutazionale di KRAS. Tuttavia, questo approccio diagnostico molecolare e' comunque invasivo, poiche' presuppone un prelievo bioptico. Per questa ragione, diversi gruppi di ricercatori stanno cercando di individuare biomarcatori che, oltre ad essere specifici, siano identificabili con procedure non invasive. Indubbiamente, tra i possibili marcatori, i microRNA (miRNA) rivestono un ruolo particolarmente rilevante. I miRNA sono piccole molecole di RNA non codificante che svolgono un ruolo critico nella regolazione dell ' espressione genica in tutti i processi cellulari. Ad oggi, sono stati pubblicati diversi dati che suggeriscono come il profilo di espressione dei miRNA vari in modo specifico nei diversi tipi di cellule neoplastiche, in correlazione con il fenotipo del tumore e con la sua evoluzione. L' oggetto di questa tesi e' stato lo studio della relazione tra risposta terapeutica e modifiche del trascrittoma dei miRNA nel tumore colorettale (CRC), che ad oggi rimane sconosciuta. Per raggiungere questo obiettivo abbiamo effettuato il profiling dell'espressione di 667 miRNA in due linee cellulari umane CRC, una sensibile e l'altra resistente al Cetuximab (Caco-2 e HCT-116, rispettivamente) mediante RT-PCR con sonde TaqMan. Le Caco-2 e le HCT-116 esprimono diversi set di miRNA dopo il trattamento: in particolare, mentre nelle Caco-2 sono differenzialmente espressi 21 miRNA (DE miRNA), nelle HCT-116 i DE miRNA sono 22 (t-test, p <0.01). Testando l'espressione dei DE miRNA in campioni paraffinati di pazienti affetti da CRC, abbiamo scoperto che il miR-146b-3p e il miR-486-5p sono piu' abbondanti nei campioni con il gene KRAS mutato rispetto a quelli wild-type (test di Wilcoxon, p <0.05). Dall' analisi dei cluster e delle famiglie geniche dei DE miRNA e' emerso che miRNA localizzati in stretta prossimita' genomica o appartenenti alla stessa famiglia mantengono spesso lo stesso trend di espressione in seguito al trattamento. Secondo dati di letteratura, il 67% dei DE miRNA e' coinvolto nel cancro, incluso il CRC, mentre 19 targets dei DE miRNA sono stati precedentemente associati alla pathway del Cetuximab e del CRC, come ad esempio KRAS (targets dei DE miRNA let-7b e let-7e), PTEN e PIK3R1 (entrambi targets del miR-486-5p). Abbiamo identificato 25 fattori di trascrizione che putativamente controllerebbero questi DE miRNA; 11 di questi sono gia' stati individuati per essere coinvolti nella patogenesi del CRC, come ad esempio MYC, che controlla positivamente l ' espressione del miR-17* (un marcatore del CRC i cui livelli sono abbondanti in biopsie e plasma di pazienti). Sulla base di questi dati, suggeriamo che la sottoespressione di let-7b e let-7e e la sovraespressione del miR-17* potrebbero far considerare questi miRNA come marcatori molecolari candidati per la resistenza al Cetuximab. L'analisi funzionale globale delle network dei targets dei DE miRNA ha mostrato una significativa sovra-rappresentazione di processi biologici correlati al cancro, all' angiogenesi e alla risposta immunitaria, e di moduli centrati sui nodi critici coinvolti nell' internalizzazione di EGFR e sua degradazione ubiquitina-mediata. L'identificazione di miRNA la cui espressione e' legata all' efficacia della terapia, dovrebbe quindi consentire di predire la risposta dei pazienti al trattamento e potrebbe condurre ad una migliore comprensione dei meccanismi molecolari della risposta farmacologica. Il lavoro esposto in questa tesi e' stato pubblicato nel 2010 su Molecular Cancer Therapeutics (E-pub 29 Settembre).
The relationship between therapeutic response and modifications of miRNA transcriptome in Colorectal Cancer (CRC) remains unknown. We investigated this issue by profiling the expression of 667 miRNAs in two human CRC cell lines, one sensitive and the other resistant to cetuximab(Caco-2 and HCT-116, respectively) through TaqMan RT-PCR. Caco-2 and HCT-116 expressed different sets of miRNAs after treatment: specifically, 21 and 22 miRNAs were differentially expressed (DE) in Caco-2 or HCT-116, respectively (t-test, p<0.01). By testing the expression of DE miRNAs in CRC patients, we found that miR-146b-3p and miR-486-5p are more abundant in KRAS mutated samples respect to wild-type ones (Wilcoxon test, p<0.05). 67% of DE miRNAs were involved in cancer, including CRC, while 19 miRNA targets had been previously reported to be involved in the cetuximab pathway and CRC. We identified 25 TFs putatively controlling these miRNAs, 11 of which already reported to be involved in CRC. Based on these data, we suggest that the down regulation of let-7b and let-7e (targeting KRAS) and the up regulation of miR-17* (a CRC marker) could be considered as candidate molecular markers of cetuximab resistance. Global network functional analysis, based on miRNA targets, showed a significant overrepresentation of cancer-related biological processes and networks centered on critical nodes involved in EGFR internalization and ubiquitin-mediated degradation. The identification of miRNAs, whose expression is linked to the efficacy of therapy, should allow to predict the response of patients to treatment and possibly lead to a better understanding of the molecular mechanisms of drug response.