Academic literature on the topic 'Subgroups Identification'

One of the central issues in the hidden subgroup problem is to bound the sample complexity, i.e., the number of identical samples of coset states sufficient and necessary to solve the problem. In this paper, we present general bounds for the sample complexity of the identification and decision versions of the hidden subgroup problem. As a consequence of the bounds, we show that the sample complexity for both of the decision and identification versions is $\Theta(\log|\HH|/\log p)$ for a candidate set $\HH$ of hidden subgroups in the case \REVISE{where the candidate nontrivial subgroups} have the same prime order $p$, which implies that the decision version is at least as hard as the identification version in this case. In particular, it does so for the important \REVISE{cases} such as the dihedral and the symmetric hidden subgroup problems. Moreover, the upper bound of the identification is attained \REVISE{by a variant of the pretty good measurement}. \REVISE{This implies that the concept of the pretty good measurement is quite useful for identification of hidden subgroups over an arbitrary group with optimal sample complexity}.

AbstractThe identification of patient subgroups with differential treatment effects is the first step towards individualised treatments. A current draft guideline by the EMA discusses potentials and problems in subgroup analyses and formulated challenges to the development of appropriate statistical procedures for the data-driven identification of patient subgroups. We introduce model-based recursive partitioning as a procedure for the automated detection of patient subgroups that are identifiable by predictive factors. The method starts with a model for the overall treatment effect as defined for the primary analysis in the study protocol and uses measures for detecting parameter instabilities in this treatment effect. The procedure produces a segmented model with differential treatment parameters corresponding to each patient subgroup. The subgroups are linked to predictive factors by means of a decision tree. The method is applied to the search for subgroups of patients suffering from amyotrophic lateral sclerosis that differ with respect to their Riluzole treatment effect, the only currently approved drug for this disease.

The incidence of Kaposi’s sarcoma in South Africa is increasing in parallel with the human immunodeficiency virus type 1 epidemic. An 804 bp region in the ORF75 gene of 40 human herpesvirus-8 (HHV-8) isolates from South Africa was sequenced and the phylogenetic relationships were compared to published sequences. Nineteen strains clustered with subgroup B and 11 with subgroup A; however, the bootstrap values supporting these subgroups were not significant. Three strains grouped significantly with the C subgroup, while eight sequences did not cluster with any of the previously classified subgroups and were termed novel (N). The N subgroup differed from the A, B and C subgroups by DNA distances of 4·8, 4·2 and 4·5%, respectively, although within the N subgroup there was only 0·4% variation. The inclusion of this subgroup increased the number of previously described subgroup-specific polymorphisms from 17 to 47 over an 804 bp region. There was sufficient inter-subgroup genetic diversity for a single-strand conformational polymorphism assay to be used to identify them rapidly. Thus, based on analysis of the ORF75 gene, a unique HHV-8 subgroup, termed N, is present in South Africa, which accounts for 20% of circulating strains. Further studies are required to determine the degree of genetic divergence, distribution and pathogenic potential of this novel subgroup.

Advances in flow cytometry enable the acquisition of large and high-dimensional data sets per patient. Novel computational techniques allow the visualization of structures in these data and, finally, the identification of relevant subgroups. Correct data visualizations and projections from the high-dimensional space to the visualization plane require the correct representation of the structures in the data. This work shows that frequently used techniques are unreliable in this respect. One of the most important methods for data projection in this area is the t-distributed stochastic neighbor embedding (t-SNE). We analyzed its performance on artificial and real biomedical data sets. t-SNE introduced a cluster structure for homogeneously distributed data that did not contain any subgroup structure. In other data sets, t-SNE occasionally suggested the wrong number of subgroups or projected data points belonging to different subgroups, as if belonging to the same subgroup. As an alternative approach, emergent self-organizing maps (ESOM) were used in combination with U-matrix methods. This approach allowed the correct identification of homogeneous data while in sets containing distance or density-based subgroups structures; the number of subgroups and data point assignments were correctly displayed. The results highlight possible pitfalls in the use of a currently widely applied algorithmic technique for the detection of subgroups in high dimensional cytometric data and suggest a robust alternative.

In this study we examined intergroup relations between immigrants of different ethnic backgrounds (Croats, Serbs, and Bosniaks) originating from the same conflict area (former Yugoslavia) and living in the same host country (Australia). For these (formerly) conflicted groups we investigated whether interethnic contacts depended on superordinate Yugoslavian and subgroup ethnic identifications as well as two emotionally laden representations of history: Yugonostalgia (longing for Yugoslavia from the past) and collective guilt assignment for the past wrongdoings. Using unique survey data collected among Croats, Serbs and Bosniaks in Australia (N = 87), we found that Yugoslavian identification was related to stronger feelings of Yugonostalgia, and via Yugonostalgia, to relatively more contact with other subgroups from former Yugoslavia. Ethnic identification, in contrast, was related to a stronger assignment of guilt to out-group relative to in-group, and therefore, to relatively less contact with other subgroups in Australia. We discuss implications of transferring group identities and collective memories into the diaspora.

We revise the taxonomically problematic Palearctic Cicindela campestris species complex, a group of green tiger beetle species, using an integrative approach combining morphology, morphometry and biogeography. In this first part, an identification key to all subgroups of these green tiger beetles (Cicindela herbacea-subgroup, Cicindela javetii-subgroup, Cicindela desertorum-subgroup, Cicindela campestris-subgroup, Cicindela turkestanica-subgroup and Cicindela asiatica-subgroup) based on large series taken from private and museum collections as well as on literature sources is provided and diagnostic characters are illustrated by detailed photographs. The Cicindela herbacea- and Cicindela javetii-subgroups are revised and illustrated and identification keys as well as distribution maps for both are given. Four new synonyms are established: Cicindela herbacea herbacea Klug, 1832 = Cicindela herbacea aleppensis Deuve, 2012, syn. n.; Cicindela herbacea turkestanicoides W. Horn, 1938 = Cicindela herbacea perreaui Deuve, 1987, syn. n. = Cicindela herbacea colasi Deuve, 2011, syn. n.; Cicindela javetii javetii Chaudoir, 1861 = Cicindela thughurica Franzen, 2007, syn. n.

Abstract Ewing sarcoma (EwS) tumors are driven by pathognomonic fusions between FET proteins and ETS family transcription factors (most frequently EWS::FLI1). EWS::FLI1 drives tumorigenesis through massive transcriptomic and epigenomic rewiring. Despite mutational homogeneity, EwS are highly transcriptionally heterogeneous suggesting that cell context is a key determinant of EWS::FLI1-driven gene signatures. Fusion protein activity has been revealed as a core source of EwS heterogeneity. However, deep investigation into the transcriptomic and epigenomic heterogeneity of EwS cells has yet to be described. Molecular subtyping of EwS has thus far proven to be difficult to achieve with bulk RNA-sequencing approaches. We hypothesized that single-cell characterization of EwS cells would provide the necessary resolution to allow identification and characterization of transcriptionally distinct tumor subgroups. We subjected eight established EwS cell lines, one PDX-derived EwS line, and five non-EwS cell lines to single-cell multiomic (ATAC + RNA) sequencing. A range of 1300-3800 live cells were captured per sample, with an average of 25,000 transcript and accessible reads per cell. Initial analysis of transcriptomes confirmed the EwS-specific, EWS::FLI1-dependent signature gene sets in EwS samples. Integrated analysis of the multiome data from the 9 EwS samples identified inter-tumor heterogeneity and unsupervised k-means clustering revealed three molecular subgroups that were not evident from expression data alone. Subgroup 1 comprised only the A673 cell line, while the remaining 8 EwS samples were split between subgroups 2 and 3. Gene ontology analysis defined enrichment of distinct gene sets across the 3 subgroups. Interestingly, expression of subgroup 2-defining genes was reduced following knockdown of EWSR1::FLI1, while expression of subgroup 3-defining genes increased. Thus, these data show that transcriptionally distinct subgroups of EwS exist and these are defined, in part, by whether EWS::FLI1-dependent gene activation or gene repression dominates transcriptional rewiring. Our ongoing studies suggest that these molecular subgroups are defined by cooperation between the fusion and cell context-dependent transcription factors. Future analyses will determine if these distinct multiomic programs exist in primary patients tumors and test the pathobiologic and clinical significance of these novel molecular subgroups. Citation Format: April A. Apfelbaum, Olivia Waltner, Shruti S. Bhise, Sami Kanaan, Jay F. Sarthy, Scott N. Furlan, Elizabeth R. Lawlor. Multimodal single-cell analyses reveal identification of unique transcriptional subgroups in ewing sarcoma [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr B020.

Borderline personality disorder (BPD) is a complex psychiatric condition whose severity is compounded by the heterogeneous psychological functioning of those who suffer from the disorder. This heterogeneity has made the identification of a unified treatment strategy difficult and attempts to resolve this variation within the disorder by investigating subtypes of BPD have been made. However, the clinical utility of this approach has not been examined. The major object of this research project was to investigate the presence of subtypes of BPD and to examine whether treatment effectiveness varied as a function of subtype. Data from 61, predominantly female, participants with BPD were entered into a cluster analysis. Using variables that are central to cognitive behavioural models of BPD and have been shown to be heterogeneously distributed in previous BPD samples, two subgroups were identified and defined on the basis of whether participants attributed the causes o f negative events as being themselves or other people. Consistent with hypotheses, the subgroup with a tendency to blame others for negative events showed far lower levels of change between admission and discharge than the subgroup who blamed themselves for negative events, on both measures of statistical and clinical significance. Alternate means of identifying participants who optimally responded to the intervention were explored and a cluster analysis identified two groups of participants that were separated on the basis of whether they had shown clinically significant change on a range of variables. It was found that data from admission to the program could successfully predict which participants would belong in the optimal or mixed response groups upon discharge. Taken together, the findings of this research project suggest that not only can theoretically valid subgroups of BPD be identified, but that they have clinical utility in understanding participants' response to intervention. Further, the findi ngs suggest that profiles of clinical change can be identified and predicted. The findings of this research project are discussed with respect to their methodological limitations, suggestions for future research, and their implications for both theory and practice.

In obesity research, it is assumed that the population is homogeneous. While this approach has yielded important insights, testing this supposition might reveal information that could impact our understanding of the phenomena and its treatment. In this study, data from obese teenagers (N = 248, Mean BMI percentile = 99%; Mean age = 13.9, SD = 1.8) who were predominantly minority (n = 182), female (n = 169), and enrolled in a weight loss intervention were analyzed. Latent profile analysis (LPA) was used to segment patients into groups based on their scores on PedsQL 4.0 scales (physical-, emotional-, social-, and school functioning) and the Coopersmith Self-Esteem Scale. A 3-class solution was parsimonious and demonstrated the best statistical fit (Bayesian information criterion = 10596.96; Lo-Mendell-Rubin-adjusted likelihood ratio test = 73.020, p < .05). The 3 groups were ordinal and composed of respondents with high- (HF; n = 72, 29%), medium- (MF; n = 110, 44%), and low functioning (LF; n = 66, 27%). Further analyses (chi squares and linear regressions) showed that the LF group had a significantly higher proportion of Caucasians and males compared to the HF (referent) group. Also, when controlling for demographics and weight, the LF group had significantly higher blood pressure (diastolic and systolic), lower self-reported physical activity (on two different measures), and a higher total score on a scale of depressed mood. Four groups of ordinal regressions (since the pair of self-reported exercise variables and blood pressure variables were correlated, only one from each pair was included in each set) consistently found that self-reported physical activity and blood pressure improved significantly from the LF to HF groups. However, when depressed mood was included, it became the only significant variable. These findings suggest that LF group members are demographically and clinically distinct and that depressed mood may be the critical factor connecting self-report and metabolic dysfunction. Theory suggests depressed mood is both associated with cognitive schemas that affect responses on self-report measures; skewing them negative, and is also manifested metabolically.

Treatment of pediatric acute lymphoblastic leukemia (ALL) is increasingly successful, achieving cure rates of over 80%. Early identification of patients with high risk for relapse has led to improved outcome, however, two third of patients encountering relapse were initially stratified into low-intermediate risk groups. The identification of better upfront prognostic factors remains an important challenge in childhood ALL. In this thesis, gene expression profiling (GEP) was applied to different research approaches aiming to dissect subgroups and to find novel therapeutic targets in B cell precursor ALL (BCP ALL). Among BCP ALL, the patients lacking major genomic aberrations (B-others) represent the subgroup that is most in need of in depth investigations in order to indentify new prognostic factors and improve of risk stratification. To advance biological knowledge of B-others we performed an integrated study of gene and non coding RNAs expression and genetic aberrancies. Chapter 1 reports a study on profiling by gene expression arrays of 145 Italian B-others BCP ALL patients and in a representative subcohort of patients microRNAs (miRNAs) expression profiling and genome-wide DNA copy number variation analysis. In this study we found that 25% of Italian B-others patients fits in a group with unique signature and is associated to a favourable outcome. MicroRNAs expression profiling of this group revealed an unique miRNAs signature characterized by over expression of hsa-miR-125b, -125b-2*, -99a, -100, -125a-3p and has-miR-491-5p. Over expression of cluster miR-125b-2 in region 21q21.1 goes along with over expression of genes in the same chromosomal region. Genome-wide analysis excluded copy number alteration of the 21q21.1 region. The frequent involvement of human chromosome 21 (Hsa21) aberrations in ALL (e.g. hyperdiploidy (HD), t(12;21) or iAmp21) and the involvement of the 21q21.1 region suggest a direct and functional contribution of Hsa21 genes to the malignant transformation of hematopoietic cells. There for there is high interest in studying ALL in children with Down Syndrome (DS), where trisomy 21 is constitutional and where the incidence of ALL is approximately 20-fold higher than in the general population. In Chapter 2 is presented a study of genomic analysis of a large group of DS ALLs that characterizes molecular abnormalities specific of this ALL group. Gene expression analysis revealed that DS ALL is a highly heterogeneous disease not definable as a unique ALL subtype with an enrichment of DNA damage and BCL6 responsive genes suggesting B-cell lymphocytic genomic instability. Surprisingly, only a single Hsa21 gene, SON was included in the DS ALL signature and it was only slightly upregulated. Furthermore gene expression data suggested that DS ALL and HD ALL are very different leukemias, reflecting the fundamental differences between constitutional and acquired trisomy such as the developmental stage in which the trisomy occurs and the fact that a constitutional trisomy is present both in the leukemia cells and in their microenvironment. The study further revealed that 62% of the DS ALL samples were characterized by aberrant expression of the type I cytokine receptor CRLF2. Two kind of aberrations involving CRLF2 were identified: a cryptic translocation involving IGH@ and CRLF2 in the pseudoautosomal region (PAR1) of the sex chromosomes and a deletion within PAR1. This aberration resulted in the P2RY8-CRLF2 fusion and leads to overexpression of CRLF2. Furthermore a novel activating somatic mutation, F232C, in CRLF2 was identified. We demonstrated that CRLF2 and mutated JAK2 cooperate in conferring cytokine independent growth to pro-B cells suggesting that the DS ALL children with CRLF2 aberrant expression may benefit from therapy blocking the CRLF2-JAK2 pathway. Since CRLF2 aberrations were found also among non DS patients, we further analyzed the incidence and prognostic impact of this potential new marker in BCP ALL Italian patients enrolled into the AIEOP-BFM ALL2000 study. Chapter 3, presents the study of a representative cohort of 464 non DS BCP ALL patients that was analyzed for the expression levels of CRLF2 and for the occurrence of CRLF2 rearrangements. In this study we found that the P2RY8-CRLF2 rearrangements in association with 20 times over expression of CRLF2 identifies BCP ALL patients with a very poor prognosis and, among them, an important subset of patients currently stratified in the intermediate risk need to be considered for treatment adaptation. Investigating the pathways highlighted by GEP analysis and testing drug effects require a substantial availability of leukemia samples. Primary ALL samples are difficult to culture in vitro and currently available cell lines poorly reflect the heterogeneous nature of the disease. Mouse xenotransplantation models are therefore widely used for in vivo testing and to amplify the number of leukemia cells to be used for various analyses. In Chapter 4 study we assessed the capability of xenografted samples to recapitulate their respective primary leukemia, and we investigated whether the murine microenvironment selects for leukemia initiating cells leading to a bulk tumor markedly different from the diagnostic patient sample. We analysed the gene expression profiles of 7 primary paediatric ALL samples at diagnosis as well as of their respective xenograft leukaemia samples after serial primary, secondary and tertiary passages in the NOD/SCID/huALL transplant model. In this study we demonstrated that the NOD/SCID/huALL transplant model recapitulates the primary human leukaemia, mimics the features of the primary malignancy and retains these characteristics over serial passages without selection for a subclone of the initial leukaemia. Chapter 5 reports on a study that investigated engraftment properties of 50 pediatric ALL samples transplanted into NOD/SCID mice. Time to leukemia (TTL) was determined for each patient sample engrafted as weeks from transplant to overt leukemia. The study shows that short TTL was strongly associated with high risk for early relapse, identifying a new independent prognostic factor. The high risk phenotype is reflected by a gene signature that identified patients with early relapse in an independent patient cohort. Gene expression profiling revealed a set of genes associated with this aggressive phenotype providing a potential strategy to identify these high-risk patients. Most importantly, pathways involving mTOR regulating cell growth were identified, providing targets for alternative therapeutic strategies for these high risk patients. Concluding, ten years after its introduction in oncohematology, GEP constitutes to be a valuable research tool, efficacious in subtype discovery, biomarkers identification and discoveries of deregulated molecular pathways.
La cura della leucemia linfoblastica acuta (ALL) sta migliorando con successo, raggiungendo un tasso di guarigione che va oltre l’80%. L’identificazione precoce dei pazienti con alto rischio di ricaduta ha portato ad un miglioramento generale dell’outcome, tuttavia, due terzi dei pazienti che incorrono nell’evento di ricaduta vengono inizialmente stratificati in gruppi a basso rischio o rischio intermedio. L’identificazione di migliori fattori prognostici rimane un’importante sfida nelle ALL pediatriche. In questa tesi, lo studio del profilo di espressione genica è stato applicato a diversi approcci di ricerca, con lo scopo di individuare sottogruppi e trovare nuovi target terapeutici nelle ALL a cellule precursori B (BCP ALL) Tra le BCP ALL, i pazienti privi delle aberrazioni genomiche più riccorrenti (B-others) rappresentano il sottogruppo che più necessita di studi approfonditi, tesi ad identificare nuovi fattori prognostici e migliorare la loro stratificazione nelle classi di rischio. Per aumentare le conoscenze biologiche riferite al gruppo dei B-others, è stato eseguito uno studio integrato di espressione genica, espressione di non coding RNAs e analisi delle aberrazioni genetiche. Il Capitolo 1 riporta lo studio mediante microarrays di espressione genica di 145 pazienti Italiani affetti da BCP ALL e, in una sotto-coorte rappresentativa, lo studio dell’espressione dei microRNAs (miRNAs) e l’analisi di variazione di DNA copy number estesa all’intero genoma. Da questo studio è emerso che il 25% dei pazienti Italiani di tipo B-others rientrano in un gruppo con una signature specifica e sono associati ad un outcome favorevole. Lo studio del profilo di espressione dei miRNAs rivela in questo gruppo una specifica signature di miRNAs caratterizzata dalla sovra espressione di hsa-miR-125b, -125b-2*, -99a, -100, -125a-3p e has-miR-491-5p. La sovra espressione del cluster miR-125b-2 nella regione 21q21.1 è accompagnata dalla concomitante sovra espressione dei geni nella stessa regione cromosomica. Le analisi sul genoma hanno portato ad escludere la presenza di alterazioni di DNA copy number nella regione 21q21.1. Il frequente coinvolgimento di aberrazioni a carico del cromosoma 21 nelle ALL (come nel caso di iperdiploidia (HD), t(12;21) o iAmp21) e il coinvolgimento della regione 21q21.1, suggeriscono un diretto e funzionale contributo dei geni nel cromosoma 21 alla trasformazione maligna delle cellule ematopoietiche. A questo proposito c’è un grande interesse nello studio delle ALL nei bambini affetti dalla Sindrome di Down (DS), nei quali la trisomia 21 è costituzionale e per i quali l’incidenza di ALL è approssimativamente 20 volte maggiore che nel resto della popolazione. Nel Capitolo 2 viene presentato uno studio di analisi genomica di un grande gruppo di DS ALL che mira a caratterizzare le anomalie molecolari specifiche di questo gruppo di ALL. L’analisi di espressione genica ha rivelato che le DS ALL sono leucemie molto eterogenee, non definibili come un unico sottotipo di ALL, con un arricchimento di geni rispondenti al signalling di BCL6 e di risposta al danno al DNA, che suggerisce un’instabilità genomica dei linfociti B. Sorprendentemente, solamente un gene appartenente al cromosoma 21, SON, è compreso nella signature delle DS ALL e risulta solo debolmente up-regolato. Inoltre, i dati di espressione genica suggeriscono che le DS ALL e le HD ALL sono leucemie molto diverse, riflettendo le differenze fondamentali tra trisomia costituzionale e acquisita, quali lo stadio di sviluppo nel quale la leucemia insorge e il fatto che la trisomia costituzionale è presente sia nelle cellule leucemiche che nel microambiente. Lo studio ha inoltre rilevato che il 62% delle DS ALL sono caratterizzate da un’aberrante espressione del recettore per le citochine di tipo I CRLF2. Due tipi di aberrazioni che coinvolgono CRLF2 sono state identificate: una traslocazione criptica che coinvolge il locus IGH@ e CRLF2 nella regione pseudoautosomale PAR1 dei cromosomi sessuali e una delezione in PAR1. Queste aberrazioni danno luogo alla formazione del trascritto di fusione P2RY8-CRLF2 che determina la sovra espressione di CRLF2. Inoltre una nuova mutazione somatica attivante, F232C, in CRLF2 è stata identificata. E’ stato dimostrato che CRLF2 e JAK2 mutato cooperano nel conferire capacità di crescita indipendente da citochine a cellule pro-B suggerendo che i bambini affetti da DS e ALL con un’espressione aberrante di CRLF2 possono trarre beneficio da terapie mirate a bloccare il pathway di CRLF2-JAK. Dal momento che le aberrazioni a carico di CRLF2 sono state trovate anche tra i pazienti non affetti dalla Sindrome di Down, è stata analizzata l’incidenza e l’impatto prognostico di questo potenziale nuovo marcatore nei pazienti Italiani con BCP ALL arruolati nello studio AIEOP-BFM ALL2000. Il Capitolo 3 presenta lo studio di una coorte rappresentativa di 464 pazienti con BCP ALL non affetti da DS che è stata analizzata per l’espressione di CRLF2 e per la presenza di riarrangiamenti a carico di CRLF2. Da questo studio è emerso che il riarrangiamento P2RY8-CRLF2 in associazione con la sovra espressione di CRLF2 (di almeno 20 volte maggiore che nel resto della coorte), identifica pazienti con una prognosi molto sfavorevole e, tra essi, un inportante sottogruppo di pazienti attualmente stratificati nella classe di rischio intermedia e che necessitano di essere considerati per un adeguamento della terapia. Per investigare i pathways emersi dalle analisi di espressione genica e per testare l’effetto dei farmaci è necessaria una grande disponibilità di cellule leucemiche. Le cellule da leucemia primaria sono difficili da coltivare in vitro e le linee cellulari attualmente disponibili non riescono a riflettere la natura eterogenea della malattia. Per questo motivo i modelli di xenotrapianto in topo sono ampiamente usati sia per lo studio in vivo che per amplificare il numero di cellule leucemiche da usare nelle varie analisi. Nello studio riportato nel Capitolo 4 è stata verificata la capacità delle cellule leucemiche ottenute da xenotrapianto di ricapitolare la loro rispettiva leucemia primaria ed è stata valutata la possibilità di una selezione da parte del microambiente murino per particolari cellule “inizianti” la leucemia che portino ad una massa tumorale marcatamente diversa da quella dei pazienti alla diagnosi. E’stato analizzato il profilo di espressione genica di 7 ALL primarie pediatriche alla diagnosi e le rispettive cellule leucemiche ottenute da xenotrapianto dopo un primo, un secondo ed un terzo passaggio seriale nel modello di trapianto di leucemia umana in topo NOD/SCID/huALL. In questo studio è stato dimostrato che il modello di trapianto NOD/SCID/huALL ricapitola la leucemia primaria umana, mima le caratteristiche del tumore primario e ne trattiene le caratteristiche durante i passaggi seriali senza selezionare per un sottoclone della leucemia primaria iniziale. Il Capitolo 5 riporta uno studio che ha investigato le proprietà di attecchimento di 50 ALL pediatriche trapiantate in topi NOD/SCID. Il tempo di attecchimento (Time To Leukemia – TTL) è stato determinato per ogni campione attecchito in termini di settimane trascorse dal trapianto alla manifestazione della leucemia. Lo studio ha mostrato che un breve TTL è fortemente associato con un alto rischio di ricaduta precoce, costituendo di fatto un nuovo marcatore prognostico indipendente. Il fenotipo di alto rischio è riflesso in una signature in grado di identificare pazienti incorsi precocemente nell’evento di ricaduta in una coorte di pazienti indipendente. Lo studio di espressione genica rivela una serie di geni associati con questo fenotipo aggressivo, mettendo a diposizione una potenziale strategia per identificare i pazienti ad alto rischio. In modo ancora più importante, pathways che regolano la crescita cellulare e che coinvolgono mTOR sono stati identificati, indicando dei target per strategie terapeutiche alternative per i pazienti ad alto rischio di riaduta. Concludendo, dieci anni dopo la sua introduzione in oncoematologia, lo studio del profilo di espressione genica si conferma essere un valido strumento di ricerca, efficace nella scoperta di nuovi sottotipi, nell’individuazione di biomarcatori e nel portare alla luce pathways molecolari deregolati.

Disertacijos darbo tikslas – aptikti ir identifikuoti Lietuvoje paplitusias fitoplazmas vabzdžiuose, surinktuose nuo įvairių augalų su fitoplazminiais simptomais ir nustatyti fitoplazmų vabzdžius pernešėjus bei atskleisti identifikuotų ir kitų fitoplazmų filogenetinius giminingumus. Lietuvoje jau žinomos keletas labiausiai paplitusių fitoplazmų grupių bei pogrupių, taip pat aptikta nemažai jų augalų-šeimininkų. Duomenų apie galimus šių bakterijų pernešėjus Lietuvoje beveik nėra. Pernešėjų identifikavimas ir tyrimas padės kurti veiksmingesnes strategijas bei sistemas kovai su fitoplazminėmis infekcijomis. Fitoplazmų ir jų pernešėjų identifikavimas suteiks svarbių duomenų tiriant šių patogenų ekologiją, paplitimą, kilmę, epidemiologiją, plitimo kelius. Informacija bus naudinga Lietuvos ir kaimyninių šalių augalų apsaugai. Taip pat galės padėti nustatant galimų invazinių vabzdžių rūšių bei fitoplazmų kamienų atsiradimą Lietuvoje dėl klimato kaitos. Šio darbo metu pirmą kartą Lietuvoje molekuliniais metodais buvo išaiškinti fitoplazmų vabzdžiai pernešėjai. Daugelis aptiktų fitoplazmų pogrupių nustatytos identifikotuose vabzdžiuose pirmą kartą, kaip Lietuvoje taip ir pasaulyje. Penkiose augalų rūšyse fitoplazmos aptiktos pirmą kartą Lietuvoje. Darbo metu nustatytas vienas visiškai naujas Lietuvai ir pasauliui ir vienas naujas Lietuvai fitoplazmų pogrupiai bei jų augalai šeimininkai, kas prisideda prie Lietuvoje bei pasaulyje aptinkamų fitoplazmų paplitimo ir bioįvairovės tyrimo... [toliau žr. visą tekstą]
The aim of the research was to identify the phytoplasmas detected in insects that were found on various phytoplasma-infected plants, and to reveal phytoplasma insect-vectors as well as phytogenetical relationships of identified phytoplasmas. From previous research, we already know a few mostly widespread phytoplasma groups, subgroups, and many of their host plants in Lithuania. The data on potential vectors of these bacteria are very scarce in Lithuania. The identification and research of insect vectors will help to create more effective strategies and systems to fight with phytoplasmal infections. Identification of phytoplasmas and their vectors will provide important data for research of ecology, distribution, origin, epidemiology, and ways of spreading of these pathogens. Such information is beneficial for plant protection institutions and plant growers in Lithuania and neighbouring countries. It will help to ascertain possible invasive insect species and phytoplasma strains in Lithuania. During this research for the first time in Lithuania, we determined possible phytoplasma insect vectors using molecular biology methods. Most of the detected phytoplasma subgroups were found in the identified insect species for the first time in Lithuania and worldwide. Our data on new potential insect vector species extend the spectrum of phytoplasma vectors in our region. Phytoplasmas were detected for the first time in five plant species in Lithuania. We identified in this work one... [to full text]

The aim of the research was to identify the phytoplasmas detected in insects that were found on various phytoplasma-infected plants, and to reveal phytoplasma insect-vectors as well as phytogenetical relationships of identified phytoplasmas. From previous research, we already know a few mostly widespread phytoplasma groups, subgroups, and many of their host plants in Lithuania. The data on potential vectors of these bacteria are very scarce in Lithuania. The identification and research of insect vectors will help to create more effective strategies and systems to fight with phytoplasmal infections. Identification of phytoplasmas and their vectors will provide important data for research of ecology, distribution, origin, epidemiology, and ways of spreading of these pathogens. Such information is beneficial for plant protection institutions and plant growers in Lithuania and neighbouring countries. It will help to ascertain possible invasive insect species and phytoplasma strains in Lithuania. During this research for the first time in Lithuania, we determined possible phytoplasma insect vectors using molecular biology methods. Most of the detected phytoplasma subgroups were found in the identified insect species for the first time in Lithuania and worldwide. Our data on new potential insect vector species extend the spectrum of phytoplasma vectors in our region. Phytoplasmas were detected for the first time in five plant species in Lithuania. We identified in this work one... [to full text]
Disertacijos darbo tikslas – aptikti ir identifikuoti Lietuvoje paplitusias fitoplazmas vabzdžiuose, surinktuose nuo įvairių augalų su fitoplazminiais simptomais ir nustatyti fitoplazmų vabzdžius pernešėjus bei atskleisti identifikuotų ir kitų fitoplazmų filogenetinius giminingumus. Lietuvoje jau žinomos keletas labiausiai paplitusių fitoplazmų grupių bei pogrupių, taip pat aptikta nemažai jų augalų-šeimininkų. Duomenų apie galimus šių bakterijų pernešėjus Lietuvoje beveik nėra. Pernešėjų identifikavimas ir tyrimas padės kurti veiksmingesnes strategijas bei sistemas kovai su fitoplazminėmis infekcijomis. Fitoplazmų ir jų pernešėjų identifikavimas suteiks svarbių duomenų tiriant šių patogenų ekologiją, paplitimą, kilmę, epidemiologiją, plitimo kelius. Informacija bus naudinga Lietuvos ir kaimyninių šalių augalų apsaugai. Taip pat galės padėti nustatant galimų invazinių vabzdžių rūšių bei fitoplazmų kamienų atsiradimą Lietuvoje dėl klimato kaitos. Šio darbo metu pirmą kartą Lietuvoje molekuliniais metodais buvo išaiškinti fitoplazmų vabzdžiai pernešėjai. Daugelis aptiktų fitoplazmų pogrupių nustatytos identifikotuose vabzdžiuose pirmą kartą, kaip Lietuvoje taip ir pasaulyje. Penkiose augalų rūšyse fitoplazmos aptiktos pirmą kartą Lietuvoje. Darbo metu nustatytas vienas visiškai naujas Lietuvai ir pasauliui ir vienas naujas Lietuvai fitoplazmų pogrupiai bei jų augalai šeimininkai, kas prisideda prie Lietuvoje bei pasaulyje aptinkamų fitoplazmų paplitimo ir bioįvairovės tyrimo... [toliau žr. visą tekstą]

The subgroup identification field which sometimes is called personalized medicine, tries to group individuals such that the effects of a treatment are the most beneficial for them. One of the methods developed for this purpose is called PSICA. Currently this method works in a setting of multiple treatments and real valued response variables. In this thesis, this methodology is extended to the degree that it can also handle ordinal response variables that can take a finite number of values. It is also compared to a competitor method which results in similar performance but with the added value of a probabilistic output and a model that is interpretable and ready for policy making. This is achieved at the expense of a higher execution time. Finally, this extension is applied to a longitudinal study done in Nicaragua in the los Cuatro Santos population in which some interventions were applied in order to reduce poverty. The results showed which were the most beneficial treatments for different population subgroups.

There is a vast diversity of karyotypes in nature, yet mechanisms that have facilitated such diversity are unclear. Alterations to an organism’s karyotype can have major negative fitness consequences in meiosis through non-disjunction and aneuploidy. Here, I investigated the role of biased segregation in female meiosis, i.e., meiotic drive, as a force that contributes to the evolution of karyotype form. The closely related species pair, Drosophila americana and Drosophila novamexicana, is an exemplar for understanding mechanisms of karyotype evolution. Since their recent divergence nearly half a million years ago, D. americana has evolved two different centromeric fusions: one fusion between the 2nd and 3rd chromosomes (Muller elements C and D), and the other fusion between the X and 4th chromosomes (Muller elements A and B). The 2-3 fusion is fixed in D. americana. However, the X-4 centromeric fusion remains polymorphic within the species. I uncovered biased transmissions for both fused chromosomes in D. americana such that the X-4 fused chromosome was inherited by 57% of the offspring from heterozygous females and the 2-3 chromosome was inherited by 62% of the offspring. Introgression experiments shoed the fused X-4 and the unfused X and 4th chromosomes are segregating at a 50/50 ratio in D. novamexicana. I have isolated the fused X-4 centromeric region as a possible player in the observed meiotic drive. However, the centromere is not sufficient to cause meiotic drive without a secondary factor. I also measured heterochromatin content between the fused and unfused X and 4th homologs. No obvious size differences were uncovered, but possible compositional differences were revealed. This suggests that if the centromere itself is involved in meiotic drive, either differences in the number of centromeres or compositional differences between the centromeres are influencing meiotic drive. Overall, I have identified and characterized meiotic drive as a force driving karyotype evolution in D. americana but appears to be absent in D. novamexicana, and I have begun to dissect the mechanisms of meiotic drive.

The monograph presents the modern concept of identification of firearms. The processes of weapons production necessitated adjustments to the traditional foundations of forensic ballistic identification, and a third group, subclass (subgroup) signs, is included in the binary system of general and particular signs of traces. An analysis of the modern practice of identifying firearms shows that the main obstacles in this process are subclass characteristics and prejudice. The first are related to the manufacture of parts and parts of weapons, and prejudice is associated with the subjective interpretation by an expert of the results of comparing signs in traces, which underlies the formation of conclusions of a comparative study. In addition, currently an urgent task is to confirm the ability of a qualified expert to draw reliable conclusions on identification. For students, cadets, trainees, postgraduates, adjuncts and teachers of the faculties of training forensic experts, as well as practitioners in the field of forensic ballistics and anyone interested in this branch of knowledge.

Glutaric aciduria type I is a rare organic aciduria caused by inherited deficiency of glutaryl-CoA dehydrogenase, a mitochondrial enzyme involved in the final common catabolic pathways of L-lysine, L-hydroxylysine, and L-trytophan. The majority of untreated patients develop striatal injury and secondary dystonia during infancy and childhood, whereas identification by newborn screening and immediate start of metabolic treatment (low-lysine diet, carnitine supplementation, metabolic emergency treatment) helps to prevent severe neurological complications in the majority of patients. The morbidity and mortality of dystonic patients is high, whereas asymptomatic patients have normal life expectancy. Effective antidystonic treatment requires a multidisciplinary approach. In a subgroup of patients, first clinical symptoms (headaches, vertigo, gait disturbance, hand tremor) may not manifest before adulthood. Cranial MRI studies in these patients reveal T2 hyperintensities of supratentorial white matter. A few women with glutaric aciduria type I have had unremarkable pregnancies, deliveries, and postpartal periods.

Review question / Objective: Early identification of women potentially who develop POI and POF is essential for early screening and treatment to improve clinical outcomes. We aim to conduct a comprehensive meta-analysis update, subgroup, ranking and network analysis for all available genetic polymorphism and associated with the POI and POF risk. Information sources: Six electronic databases will be included such as PubMed, Web of Science, Embase, MEDLINE, WANFANG DATA, CNKI. Will contact with authors by emails when necessary.