Autophagy processes are dependent on EGF receptor signaling

Autophagy is a not well-understood conserved mechanism activated during nutritional deprivation in order to maintain cellular homeostasis. In the present study, we investigated the correlations between autophagy, apoptosis and the MAPK pathways in melanoma cell lines. We demonstrated that during starvation the EGF receptor mediated signaling activates many proteins involved in the MAPK pathway. Our data also suggest a previously unidentified link between the EGFR and Beclin-1 in melanoma cell line. We demonstrated that, following starvation, EGFR binds and tyrosine-phosphorylates Beclin-1, suggesting that it may play a key inhibitory role in the early stage of starvation, possibly through the Beclin-1 sequestration. Furthermore, EGFR releases Beclin-1 and allows initiating steps of the autophagic process. Interestingly enough, when the EGFR pathway was blocked by anti-EGF antibodies, immunoprecipitated Beclin-1 did not bind the phospho-EGFR. In addition, an extended binding of p-Bcl2 either with Beclin-1 or with Bax was observed with a decreased activation of the stress-induced JNK kinase, thus avoiding the transduction pathways that activate autophagy and apoptosis, respectively. For this reason, we advance the hypothesis that the activation of the EGFR is a necessary event that allows the ignition and progression of the autophagic process, at least in melanoma cells

Psicoter-APP-ia: presencia, fonciòn y rol de las App en la clinica psicoterapéutica

Systemic therapists have always been attentive to changes in the social and life context of their patients. Use of telephone, e-mail, SMS, whatsapp is by now an established practice for any psychotherapist. Besides these commonly used devices, there are more, like Apps, that can be employed within a therapeutic relationship. Use of all these resources anyway is not without consequences on the patient-therapist relationship: from the standpoint of systemic therapists there is an implied relational level even in long distance communication because written communication and a limited number of characters do not transfer only data, but also implicit emotional and relational elements. Given the premise that it is practically impossible today to maintain a relationship without the use of internet and smartphones, it becomes necessary to question the ways in which the online space can become a useful extension of the therapeutic setting. Technology can be of great help to clinicians and the rapid evolution of digital innovation, accentuated by the advent of the Covid-19 pandemic, has aroused further interest in the study of a new variable that increasingly intersects with patients' stories: the use of Apps. Through the study of data derived from a qualitative research based on a specifically designed questionnaire addressed to psychotherapists recruited on social media  and their confrontation with the authors’ own clinical experience, many ways are identified by which  different Apps can play an important role in the therapeutic context, becoming  powerful means of access to the patients’ world. The article explores the use of tools, such as software and applications, which enable therapists and patient to contact outside of the traditional setting but also take into therapy space and time bits of real, not only related, interactions with other significant people, by means for example of messages sent and received, photos, music… The authors describe how Apps make it possible to modernize the traditional technique of introducing an absent person in the therapy session, not only by related accounts or fantasy or an empty chair, but directly by messages and photos and by Apps of dating or music. The use of Apps can prove to be a powerful relational tool, capable of allowing competent and flexible therapists to access the narrative dimension of individuals, including children and adolescents, and their families. Results of the qualitative investigation illustrate what Apps, how often and by whose initiative enter therapy; the description by Authors  of some of their own experience in clinical cases involving use of different Apps makes it possible to integrate results of the qualitative research exemplifying in a more specific way the role Apps can play in the therapeutic interaction and relationship. Related examples illustrate specifically presence and use in therapy of Apps for messaging, for videoconferences, for music, for gaming and dating, Finally, some risks of Apps potentially interfering with therapy are illustrated by the inclusion, by initiative of a mother, of therapists in a family group of an App for messaging titled Emergency! Resumen El terapeuta sistémico siempre ha estado atento a los cambios sociales que caracterizan el contexto del individuo. La rápida evolución de la innovación digital, más evidente aún desde la aparición de la Pandemia de Covid-19, ha requerido sucesivamente el estudio de una nueva variable que se entrecruza cada vez más con las historias de nuestros pacientes: la presencia y el uso de las Apps en psicoterapia. Por eso, se ha realizado una investigación cualitativa a través de un cuestionario y basada en una muestra de psicoterapeutas extraída de las redes sociales, con el objetivo de determinar cómo y cuánto aparecen las Apps a lo largo de una terapia según los terapeutas activos en la clínica. Los resultados de esta investigación cualitativa se han comparado con los deducidos de la experiencia de los autores en diferentes situaciones clínicas, describiendo algunos casos para ilustrar cómo las Apps llegan a desempeñar un papel importante dentro del contexto terapéutico y a convertirse en un medio para adentrarse en el mundo del paciente hasta el punto de generar grandes valores comunicativos y relacionales con el terapeuta. Concretamente representan un nuevo modo de introducir en las terapias, especialmente en las individuales, la figura de otras personas significativas a través de mensajes, fotos, canciones, configurando una versión actualizada de la Presentificación del Tercero, técnica terapéutica histórica por la que estas figuras no se insertan solo mediante el relato y la fantasía, sino con documentos reales que consienten acceder, bajo petición del cliente, a sus relaciones interpersonales. Las mismas Apps se pueden emplear no sólo para evaluaciones diagnósticas y relacionales sino también para fines terapéuticos, pues son capaces de extender, independientemente del espacio y del tiempo de la sesión, la asistencia, el apoyo y el soporte prometidos al paciente, con lo que de este modo la psicoterapia entra en el mundo y el mundo entra en la psicoterapia

differential tbxa2 receptor transcript stability is dependent on the c924t polymorphism

Abstract Background In order to better characterize the molecular mechanisms involved in processing mutated transcripts, we investigated the post-transcriptional role of the C924T polymorphism (rs4523) located in the 3′ region of the TBXA2R gene. Methods and Results Experiments of dose response with Actinomycin D on MEG-01 human cell line showed a significant decrease on cell viability that was more evident on cells treated for 24 h. In addition, we showed that treatments with 5–10 μM, 15 μM and 20 μM of actinomycin D reduced cell viability by 44%, 72% and 75%, respectively, compared to the control group. Conversely, the samples treated with 1 μM of actinomycin D did not show significant difference on cell viability as compared to the control group. Analysis of the steady state mRNA level of TBXA2R by qRT-PCR evidenced an increase in mRNA stability for the wild type (C) compared to the mutant (T) allele. Furthermore, the expression levels of TBXA2R on wild type (CC) and mutant type (TT) patients, based on C924T polymorphism, were analyzed. The wild type showed a higher expression of TBXA2 receptor also with two different degrees of glycosylation (55 and 64 kDa), when compared to the mutant. These observations correlated with platelet aggregation, which was reduced in TT, independently of the platelet aggregation stimuli. Conclusions The instability of the TBXA2R transcript and the lack of effect on platelet aggregation might suggest a protective role for the TBXA2R TT genotype against atherothrombosis and its complications in high-risk aspirin-treated patients

Metabolic Alterations, Aggressive Hormone-Naïve Prostate Cancer and Cardiovascular Disease: A Complex Relationship

Background: Epidemiological studies suggest a possible relationship between metabolic alterations, cardiovascular disease and aggressive prostate cancer, however, no clear consensus has been reached. Objective: The aim of the study was to analyze the recent literature and summarize our experience on the association between metabolic disorders, aggressive hormone-naïve prostate cancer and cardiovascular disease. Method: We identified relevant papers by searching in electronic databases such as Scopus, Life Science Journals, and Index Medicus/Medline. Moreover, we showed our experience on the reciprocal relationship between metabolic alterations and aggressive prostate cancer, without the influence of hormone therapy, as well the role of coronary and carotid vasculopathy in advanced prostate carcinoma. Results: Prostate cancer cells have an altered metabolic homeostatic control linked to an increased aggressivity and cancer mortality. The absence of discrimination of risk factors as obesity, systemic arterial hypertension, diabetes mellitus, dyslipidemia and inaccurate selection of vascular diseases as coronary and carotid damage at initial diagnosis of prostate cancer could explain the opposite results in the literature. Systemic inflammation and oxidative stress associated with metabolic alterations and cardiovascular disease can also contribute to prostate cancer progression and increased tumor aggressivity. Conclusions: Metabolic alterations and cardiovascular disease influence aggressive and metastatic prostate cancer. Therefore, a careful evaluation of obesity, diabetes mellitus, dyslipidemia, systemic arterial hypertension, together with a careful evaluation of cardiovascular status, in particular coronary and carotid vascular disease, should be carried out after an initial diagnosis of prostatic carcinoma

TLR-4/Wnt modulation as new therapeutic strategy in the treatment of glioblastomas

Glioblastomas are highly aggressive brain tumors. Various pathways are involved in gliomagenesis, among which the Wingless (Wnt) signaling. Dickkopf protein-related protein 3 (Dkk-3) interacts with proteins of Wnt pathwayas inhibitor. The Wnt signaling contributes to activity of the claudins, that are critical components of tight junctions, whose expression was altered selectively in cerebral microvessels of glioblastoma. The aim of this study was to determine the role of Wnt pathways in the regulation of tumor growth, apoptosis process by targeting Dkk-3, tight junctions alteration involving claudin-5, suggesting possible therapeutic interactions involving Wnt/Toll-like receptors (TLRs) pathways

[Colorectal cancer: diagnostic paths on the basis of international guidelines] Tumore del colon retto: percorsi diagnostici sulla base di linee guida internazionali

The colorectal cancer (CCR) is still one of the most important neoplastic pathologies whose mortality and metastatic progression is strictly connected to the structural and biological characteristics of the primary tumor. Compared with an overall increase in incidence, there has been a reduction in mortality by almost 35 percent in the last two decades. These features are undoubtedly due to the significant progress of predictive and preventative medicine that employs several new diagnostic tools and surgical exploration devices (i.e. endoscopy) allowing earlier diagnosis and intervention on patient injuries; in this way, the neoplastic transformation of dysplastic and polyposis lesions and invasiveness of the tumoral mass can be prevent. In particular, the review describes the progress achieved in the screening population programs. Of considerable importance is fecal occult blood test (SOF) survey, which allows the identification of areas of minimal bleeding in the gastroenteric district, hiding a putative neoplastic process. SOF has been highly successful in recent times and has allowed, in Regions where the screening process is applied, to significantly reduce the risk of metastatic disease and the associated mortality rate. Another important forward step is the use of new molecular techniques that allow to analyze mutations and epigenetic lesions of genes involved in the pathogenic mechanism of tumor induction (fecal DNA analyses) as a high sensitivity and specificity instrument for the detection of micro-cracks cancer. Is also discussed, according to the evidence-based medicine principles, the role played by serological markers like CEA and Ca 19.9 which represent prediction and prognostic values in the follow-up and monitoring of the therapeutic success

Adoptive immunotherapy using prame-specific t cells in medulloblastoma

Medulloblastoma is the most frequent malignant childhood brain tumor with a high morbidity. Identification of new therapeutic targets would be instrumental in improving patient outcomes. We evaluated the expression of the tumor-associated antigen PRAME in biopsies from 60 patients with medulloblastoma. PRAME expression was detectable in 82% of tissues independent of molecular and histopathologic subgroups. High PRAME expression also correlated with worse overall survival. We next investigated the relevance of PRAME as a target for immunotherapy. Medulloblastoma cells were targeted using genetically modified T cells with a PRAME-specific TCR (SLL TCR T cells). SLL TCR T cells efficiently killed medulloblastoma HLA-A-02+ DAOY cells as well as primary HLA-A-02+ medulloblastoma cells. Moreover, SLL TCR T cells controlled tumor growth in an orthotopic mouse model of medulloblastoma. To prevent unexpected T-cell- related toxicity, an inducible caspase-9 (iC9) gene was introduced in frame with the SLL TCR; this safety switch triggered prompt elimination of genetically modified T cells. Altogether, these data indicate that T cells genetically modified with a high-affinity, PRAME-specific TCR and iC9 may represent a promising innovative approach for treating patients with HLA-A-02+ medulloblastoma. Significance: These findings identify PRAME as a medulloblastoma tumor-associated antigen that can be targeted using genetically modified T cells