1,354,417 research outputs found
Sul senso di Sè nel paziente con demenza: prospettive psicosociali nei processi di cura
No full textLONG PENTRAXIN 3 AS A TUMOR PROMOTER IN MEDULLOBLASTOMA
No full textIl medulloblastoma (MB) è un tumore neuroectodermico aggressivo del cervelletto e rappresenta il tumore cerebrale maligno più comune in età pediatrica.
Il MB può originare da diverse popolazioni di cellule staminali neuronali e in base ad analisi molecolari e di espressione genica viene classificato in 4 sottogruppi principali: WNT, SHH, gruppo 3 e gruppo 4. Nonostante i trattamenti standard (chirurgia, chemioterapia e radioterapia), il 30%-40% dei pazienti sperimenta una recidiva, con un tasso di sopravvivenza del 10%. Quest’ultima varia tra i sottogruppi: in quelli più aggressivi è inferiore al 55%, mentre raggiunge il 95% per quelli meno aggressivi, ma con rischio di scarsa qualità di vita. Per questo motivo, nel trattamento del MB, diventa cruciale trovare un equilibrio tra l’intervento terapeutico ed evitare gravi deficit neurocognitivi.
Sebbene siano stati fatti grandi sforzi per caratterizzare il MB e scoprire nuovi bersagli per il trattamento di questa tipologia tumorale, resta ancora molto da studiare per comprendere la biologia del MB.
La pentraxina lunga 3 (PTX3), un componente dell'immunità innata implicato nella tumorigenesi, ha un ruolo bivalente nel cancro, agendo sia come oncosoppressore sia come fattore pro-tumorale. Nonostante il numero consistente di osservazioni riguardanti l'impatto di PTX3 sul cancro, ad oggi, non sono disponibili dati sul suo possibile ruolo nella biologia del MB.
Lo scopo del lavoro di dottorato di ricerca è stato dunque quello di investigare il ruolo di PTX3 nel MB.
I nostri risultati e i dati ottenuti dal database R2, mostrano che PTX3 è espressa a bassi livelli nei vari sottogruppi del MB, mentre è sovraespressa nel sottogruppo SHH. Questo è stato ulteriormente confermato da analisi su campioni derivati da pazienti utilizzando tecniche di IHC e RNAscope. Test in vitro hanno rivelato che sia il silenziamento, sia l'eliminazione di PTX3 nelle cellule di SHH-MB compromettevano significativamente le principali caratteristiche tumorali, inclusa la proliferazione, la migrazione e il potenziale clonogenico.
In vivo, i cloni PTX3-KO hanno mostrato una riduzione della crescita tumorale quando impiantati sottocute in topi immunodeficienti, e l'IHC ha evidenziato una minore proliferazione (percentuale di cellule Ki67+) e una ridotta vascolarizzazione (cellule CD31+) in assenza di PTX3. Coerentemente, ulteriori saggi in vitro e un saggio in vivo sulla membrana corioallantoidea (CAM) nell'embrione di pollo, hanno supportato questi risultati, dimostrando una riduzione del potenziale angiogenico delle cellule di MB in assenza di PTX3. In aggiunta abbiamo identificato la via di segnalazione di PTX3 implicata nel MB utilizzando diversi saggi di biologia molecolare, che ci hanno permesso di evidenziare i pathway cellulari attivati e le interazioni specifiche coinvolte nella sua funzione biologica. In fine, per testare il potenziale terapeutico della modulazione di PTX3 nel SHH-MB, abbiamo effettuato esperimenti in vitro di chemioterapia e radioterapia, che hanno dimostrato come le cellule silenziate o deplete per PTX3, siano più sensibili ai trattamenti standard per trattamento del MB.
Complessivamente questi dati supportano l'ipotesi di un effetto pro-oncogenico della PTX3 nel SHH-MB e forniscono le basi per studiare meglio i percorsi molecolari regolati da PTX3 in questo sottogruppo tumorale.Medulloblastoma (MB) is an aggressive neuroectodermal tumor of the cerebellum and represents the most common brain tumor of the childhood.
MB can originate from various populations of neuronal stem cells and based on molecular and gene expression analyses, is classified into four main subgroups: WNT, SHH, group 3, and group 4. Despite standard treatments (surgery, chemotherapy, and radiotherapy), 30%-40% of MB patients encounter tumor recurrence, with a survival rate of only 10%. This survival rate varies across subgroups: it is lower than 55% in the more aggressive ones, while it reaches 95% in the less aggressive ones, though with a risk of poor quality of life. For this reason, in the treatment of MB, the balance between effective therapeutic intervention and avoiding severe neurocognitive deficits is crucial.
Although great efforts have been made to characterize MB and identify new targets for treating this type of tumor, much remains to be studied to fully understand the biology of MB. Long pentraxin 3 (PTX3), a component of innate immunity implicated in tumorigenesis, has a dual role in cancer, acting as both a tumor suppressor and a pro-tumor factor. Despite the considerable number of studies regarding the impact of PTX3 on cancer, to date, no data are available regarding the potential role of PTX3 in MB biology.
Our results and those obtained by R2 database analysis, show that PTX3 is expressed at low levels across all MB-subgroups, while is overexpressed in the SHH subgroup. This was further confirmed by additional analyses on patient-derived samples using IHC and RNAscope techniques.
In vitro assays revealed that both the silencing and the KO of PTX3 in DAOY cells significantly impaired key tumor features, including proliferation, migration and clonogenic potential.
In vivo, PTX3-KO clones exhibited a reduced tumor growth when implanted subcutaneously in immune-deficient mice, and IHC showed lower proliferation (Ki67+ cell percentage) and diminished vascularization (CD31+ cells) in the absence of PTX3. Accordingly, further in vitro assay and an in vivo assay on the chicken embryo chorioallantoic membrane (CAM) assay supported these findings, demonstrating a reduction in the angiogenic potential of MB cells in the absence of PTX3.
Moreover, we identified PTX3 signaling pathway in MB through various molecular biology assays, which allowed us to highlight the activated cellular pathways and specific interactions involved in its biological function. Finally, to test the therapeutic potential of PTX3 modulation in SHH-MB, we performed in vitro chemotherapy and radiotherapy experiments, which demonstrated how cells silenced or depleted for PTX3 are more sensitive to standard treatments for MB.
These data support the hypothesis of a pro-oncogenic effect of PTX3 in SHH-MB and provide the basis to better study the molecular pathways driven by PTX3 in this tumor subtype
Fluid flow at interfaces driven by thermal gradients
No full textThermal forces drive several nonequilibrium phenomena able to set a fluid in motion without pressure gradi-ents. Although the most celebrated effect is thermophoresis, also known as Ludwig-Soret effect, probably the simplest example where thermal forces are at play is thermo-osmosis: The motion of a confined fluid exclusively due to the presence of a temperature gradient. We present a concise but complete derivation of the microscopic theory of thermo-osmosis based on linear response theory. This approach is applied to a simple fluid confined in a slab geometry, mimicking the flow through a pore in a membrane separating two fluid reservoirs at different temperatures. We consider both the case of an open channel, where the fluid can flow freely, and that of a closed channel, where mass transport is inhibited and a pressure drop sets in at the boundaries. Quantitative results require the evaluation of generalized transport coefficients, but a preliminary check on a specific prediction of the theory has been successfully performed via nonequilibrium molecular dynamics simulations
Analyzing difficulties in arithmetic word problem solving: An epistemological case study in primary school
No full textThis paper focuses on difficulties that primary school students have in facing mathematical word problems. In particular, we are interested in exploring how they develop in the transition from grade 2 to grade 5. The research basis of the hypothesis is that some difficulties detected in grade 5 are already predictable in grade 2. Starting from the data collected in grade 5 by the National Standardized Assessment, we carry out a quantitative analysis looking for word problems in which students experience difficulties. Subsequently, we conduct a backward analysis of the grade 2 test of the same cohort of students in order to identify a set of word problems linked with those selected in grade 5 test. The analysis shows the presence of many common difficulties in the two grades. We design and carry out specific educational activities concerning word problem-solving in grade 2. These activities produce positive changes in the experimental class compared to the control class. This could suggest that a previous intervention in grade 2 could allow overcoming future difficulties in word problem text comprehension in grade 5
Temperature-driven flows in nanochannels: Theory and simulations
No full textThe motion of a fluid induced by thermal gradients in the absence of external forces is known as thermo-osmosis. The physical explanation of this phenomenon stems from the emergence of gradients in the tangential pressure due to the presence of a confining surface. The microscopic origin of the effect has recently been elucidated in the framework of linear response theory. Here, by use of conservation laws, we provide an explicit solution of the equations governing the fluid flow at stationarity in slab geometry, expressing the thermo-osmotic coefficient as the integrated mass current-heat current correlation function (which vanishes in the bulk). A very simple expression for the pressure gradient in terms of equilibrium properties is also derived. To test the theoretical predictions in a controlled setting, we performed extensive nonequilibrium molecular dynamics simulations in two dimensions. Few simple models of wall-particle interactions are examined, and the resulting pressure drop and velocity profile are compared with the theoretical predictions both in the liquid regime and in the gas regime
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