MicroRNA Detection in Plasma Samples

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Autoimmune polyglandular syndrome type 4: experience from a single reference center

Purpose: To characterize patients with APS type 4 among those affected by APS diagnosed and monitored at our local Reference Center for Autoimmune Polyglandular Syndromes. Methods: Monocentric observational retrospective study enrolling patients affected by APS diagnosed and monitored in a Reference Center. Clinical records were retrieved and analyzed. Results: 111 subjects (51 males) were affected by APS type 4, mean age at the onset was 23.1 ± 15.1 years. In 15 patients the diagnosis of APS was performed during the first clinical evaluation, in the other 96 after a latency of 11 years (range 1-46). The most frequent diseases were type I diabetes mellitus and celiac disease, equally distributed among sexes. Conclusions: The prevalence of APS type 4 is 9:100,000 people. Type I diabetes mellitus was the leading indicator of APS type 4 in 78% subjects and in 9% permitted the diagnosis occurring as second manifestation of the syndrome. Our data, showing that 50% of patients developed APS type 4 within the first ten years, don't suggest any particular follow-up time and, more importantly, don't specify any particular disease. It is important to emphasize that 5% of women developed premature ovarian failure

Circulating tumor DNA to anticipate loco-regional recurrence in early-stage breast cancer: a proof-of-concept study

BackgroundLoco-regional recurrence (LRR) poses a clinical challenge for the follow-up of patients treated with curative intent for early-stage breast cancer (EBC). While circulating tumor DNA (ctDNA) has been shown to predict distant metastases, its value for LRR is less characterized.MethodsStarting from an index case with documented LRR and available tumor and plasma samples, we report the analysis of the prospective phase III fenretinide prevention trial, which primarily aimed to assess the incidence of second malignancy in women with T1-T2 N0 EBC. Patients were eligible if they had FFPE and/or frozen tissue from primary or recurrent invasive tumor for next generation sequencing, and at least three serial plasma samples for ctDNA analysis by digital PCR.ResultsThe TP53 R196* mutation was identified in the primary tumor of the index case with a variant allele frequency (VAF) of 29%, and in the LRR with a VAF of 58%. The same mutation was also detected in plasma prior to both the primary and LRR surgeries with VAFs of 0.19% and 0.12%, respectively. Following treatment, the mutation became undetectable in plasma samples during follow-up, consistent with the absence of recurrence. Among 40 eligible patients from the fenretinide prevention trial, 27 (67.5%) had primary tumor somatic variants trackable in plasma. Median age was 55 years (range, 35-78); stage I (16, 59%) and stage II (11, 41%); mostly luminal-like (19, 70%); median follow-up 173 months (range, 98-193); common mutations included PIK3CA (50%), TP53 (30.7%), and PTEN (5.9%). Six patients developed LRR as first event; 4 distant metastases. In all LRR cases, except one, ctDNA was detected prior to surgery and anticipated the clinical diagnosis up to 28 months. Three patients with LRR developed distant metastases 1 to 2 years later.ConclusionThese findings show the potential of ctDNA for the early detection of LRR in EBC, and its promise as a tool for timely interventions and personalized surveillance strategies

4-oxo-N-(4-hydroxyphenyl)retinamide: Two Independent Ways to Kill Cancer Cells

BACKGROUND: The retinoid 4-oxo-N-(4-hydroxyphenyl)retinamide (4-oxo-4-HPR) is a polar metabolite of fenretinide (4-HPR) very effective in killing cancer cells of different histotypes, able to inhibit 4-HPR-resistant cell growth and to act synergistically in combination with the parent drug. Unlike 4-HPR and other retinoids, 4-oxo-4-HPR inhibits tubulin polymerization, leading to multipolar spindle formation and mitotic arrest. Here we investigated whether 4-oxo-4-HPR, like 4-HPR, triggered cell death also via reactive oxygen species (ROS) generation and whether its antimicrotubule activity was related to a ROS-dependent mechanism in ovarian (A2780), breast (T47D), cervical (HeLa) and neuroblastoma (SK-N-BE) cancer cell lines. METHODOLOGY/PRINCIPAL FINDINGS: We provided evidence that 4-oxo-4-HPR, besides acting as an antimicrotubule agent, induced apoptosis through a signaling cascade starting from ROS generation and involving endoplasmic reticulum (ER) stress response, Jun N-terminal Kinase (JNK) activation, and upregulation of the proapoptotic PLAcental Bone morphogenetic protein (PLAB). Through time-course analysis and inhibition of the ROS-related signaling pathway (upstream by vitamin C and downstream by PLAB silencing), we demonstrated that the antimitotic activity of 4-oxo-4-HPR was independent from the oxidative stress induced by the retinoid. In fact, ROS generation occurred earlier than mitotic arrest (within 30 minutes and 2 hours, respectively) and abrogation of the ROS-related signaling pathway did not prevent the 4-oxo-4-HPR-induced mitotic arrest. CONCLUSIONS/SIGNIFICANCE: These data indicate that 4-oxo-4-HPR anticancer activity is due to at least two independent mechanisms and provide an explanation of the ability of 4-oxo-4-HPR to be more potent than the parent drug and to be effective also in 4-HPR-resistant cell lines. In addition, the double mechanism of action could allow 4-oxo-4-HPR to efficiently target tumour and to eventually counteract the development of drug resistance

Exchange Rate Exposure of the Euro Area

The aim of this paper is to perform an analysis of exchange rate exposure of companies and industries of the Euro Area. In the first part of our analysis we want to estimate company-specific exchange rate exposures. The second part aims to investigate the extent to which different company-, industry- and country-level variables influence the exchange rate exposure

Passaggio alla psicoterapia online durante la pandemia da Coronavirus (Covid-19): precedente esperienza, familiarità con la tecnologia e conoscenze teoriche sulla psicoterapia online da parte del terapeuta. Il caso del Centro Medico Santagostino

Durante la pandemia da Coronavirus (Covid-19), l'uso della psicoterapia online (PO) è stato ampiamente rivalutato. In situazioni in cui il passaggio alla PO siano caratterizzati da necessità e urgenza, la preparazione tecnica e teorica del terapeuta può essere cruciale. Nel presente studio abbiamo pertanto indagato il ruolo di tale preparazione sul passaggio alla PO durante l'emergenza Covid-19, nel contesto di un servizio privato di psicoterapia (Santagostino). Un questionario costruito ad hoc è stato utilizzato per rilevare l'esperienza pregressa di PO di 86 terapeuti, il grado riferito di familiarità con i sistemi di videocomunicazione, di conoscenza teorica e scientifica della PO, e la percentuale di pazienti in cura passati in PO. Sono state inoltre raccolte informazioni riguardo all'orientamento terapeutico e al grado personale di scetticismo nei confronti della PO prima della pandemia. Su 158 terapeuti contattati, 86 hanno completato il questionario. L'esperienza pregressa del terapeuta in PO si è dimostrata la variabile più predittiva per il passaggio dei pazienti alla PO. Accanto a essa la familiarità tecnica dei terapeuti, associata a un basso scetticismo. I risultati dello studio suggeriscono che una precedente esperienza, e dunque formazione, all'uso della PO, potrebbe favorire sia il suo utilizzo da parte del terapeuta, che l'adesione dei pazienti alla PO stessa. Una adeguata formazione tecnica e teorica potrebbe incrementare il senso di padronanza e fiducia (vs. scetticismo) nella PO.</jats:p