Hsa-miR-210-3p expression in breast cancer and its putative association with worse outcome in patients treated with Docetaxel

MicroRNA-210-3p is the most prominent hypoxia regulated microRNA, and it has been found significantly overexpressed in different human cancers. We performed the expression analysis of miR-210-3p in a retrospective cohort of breast cancer patients with a median follow-up of 76 months (n = 283). An association between higher levels of miR-210-3p and risk of disease progression (HR: 2.13, 95%CI: 1.33-3.39, P = 0.002) was found in the subgroup of patients treated with Epirubicin and Cyclophosphamide followed by Docetaxel. Moreover, a cut off value of 20.966 established by ROC curve analyses allowed to discriminate patients who developed distant metastases with an accuracy of 85% at 3- (AUC: 0.870, 95%CI: 0.690-1.000) and 83% at 5-years follow up (AUC: 0.832, 95%CI: 0.656-1.000). Whereas the accuracy in discriminating patients who died for the disease was of 79.6% at both 5- (AUC: 0.804, 95%CI: 0.517-1.000) and 10-years (AUC: 0.804. 95%CI: 0.517-1.000) follow-up. In silico analysis of miR-210-3p and Docetaxel targets provided evidence for a putative molecular cross-talk involving microtubule regulation, drug efflux metabolism and oxidative stress response. Overall, our data point to the miR-210-3p involvement in the response to therapeutic regimens including Docetaxel in sequential therapy with anthracyclines, suggesting it may represent a predictive biomarker in breast cancer patients

Hsa-miR155-5p up-regulation in Breast Cancer and its relevance for treatment with Poly [ADP-ribose] polymerase 1 (PARP-1) inhibitors

miR-155-5p is a well-known oncogenic microRNA, showing frequent overexpression in human malignancies, including breast cancer. Here, we show that high miR-155-5p levels are associated with unfavorable prognostic factors in two independent breast cancer cohorts (CSS cohort, n = 283; and TCGA-BRCA dataset, n = 1,095). Consistently, miR-155-5p results as differentially expressed in the breast cancer subgroups identified by the surrogate molecular classification in the CSS cohort and the PAM50 classifier in TCGA-BRCA dataset, with the TNBC and HER2-amplified tumors carrying the highest levels. Since the analysis of TCGA-BC dataset also demonstrated a significant association between miR-155-5p levels and the presence of mutations in homologous recombination (HR) genes, we hypothesized that miR-155-5p might affect cell response to the PARP-1 inhibitor Olaparib. As expected, miR-155-5p ectopic overexpression followed by Olaparib administration resulted in a greater reduction of cell viability as compared to Olaparib administration alone, suggesting that miR-155-5p might induce a synthetic lethal effect in cancer cells when coupled with PARP-1-inhibition. Overall, our data point to a role of miR-155-5p in homologous recombination deficiency and suggest miR-155-5p might be useful in predicting response to PARP1 inhibitors in the clinical setting

Stepwise analysis of MIR9 loci identifies miR-9-5p to be involved in Oestrogen regulated pathways in breast cancer patients

miR-9 was initially identified as an epigenetically regulated miRNA in tumours, but inconsistent findings have been reported so far. We analysed the expression of miR-9-5p, miR-9-3p, pri-miRs and MIR9 promoters methylation status in 131 breast cancer cases and 12 normal breast tissues (NBTs). The expression of both mature miRs was increased in tumours as compared to NBTs (P < 0.001) and negatively correlated with ER protein expression (P = 0.005 and P = 0.003, for miR-9-3p and miR-9-5p respectively). In addition, miR-9-5p showed a significant negative correlation with PgR (P = 0.002). Consistently, miR-9-5p and miR-9 3p were differentially expressed in the breast cancer subgroups identified by ER and PgR expression and HER2 amplification. No significant correlation between promoter methylation and pri-miRNAs expressions was found either in tumours or in NBTs. In the Luminal breast cancer subtype the expression of miR-9-5p was associated with a worse prognosis in both univariable and multivariable analyses. Ingenuity Pathway Analysis exploring the putative interactions among miR-9-5p/miR-9-3p, ER and PgR upstream and downstream regulators suggested a regulatory loop by which miR-9-5p but not miR-9-3p is induced by steroid hormone receptor and acts within hormone-receptor regulated pathways

Il carcinoma neuroendocrino della mammella. Nostra esperienza e proposta di un algoritmo terapeutico per un tumore raro

Il carcinoma neuroendocrino della mammella rappresenta un istotipo di rarissima osservazione nella pratica clinica. In questo lavoro viene descritta la nostra esperienza nel trattamento di 10 casi e presentata una proposta diagnostico-terapeutica integrata per questo tipo di neoplasia. Poiché non è stata dimostrata alcuna correlazione positiva tra differenziazione neuroendocrina e dimensioni, grading, stadio della neoplasia, sopravvivenza a distanza e dunque prognosi, anche sulla base dell’esperienza acquisita riteniamo che la terapia chirurgica delle neoplasie a differenziazione neuroendocrina debba essere sovrapponibile a quella delle più comuni forme invasive. La presenza di recettori specifici per la somatostatina sulla superficie delle cellule tumorali in questo tipo di neoplasie determina la possibilità che tale molecola possa essere utilizzata sia in fase diagnostica (Octreoscan) che terapeutica (nelle forme metastatiche captanti). Riguardo all’utilizzo terapeutico, in considerazione della breve emivita della somatostatina nativa, risulta preferibile l’impiego di analoghi sintetici, meglio se marcati con radionuclidi, che consentono di erogare dosi radianti efficaci a livello del tessuto neoplastico che esprime i recettori specifici. Tra questi analoghi marcati citiamo il 90 Y-Dotatoc, da noi già utilizzato nel trattamento dei tumori neuroendocrini polmonari. Il nostro algoritmo procedurale per i tumori neuroendocrini della mammella, in fase di implementazione, prevede l’utilizzo dell’Octreoscan per la diagnosi e del 90 Y-Dotatoc per la terapia delle forme metastatiche

Ageing and Low-Level Chronic Inflammation: The Role of the Biological Clock

Ageing is a multifactorial physiological manifestation that occurs inexorably and gradually in all forms of life. This process is linked to the decay of homeostasis due to the progressive decrease in the reparative and regenerative capacity of tissues and organs, with reduced physiological reserve in response to stress. Ageing is closely related to oxidative damage and involves immunosenescence and tissue impairment or metabolic imbalances that trigger inflammation and inflammasome formation. One of the main ageing-related alterations is the dysregulation of the immune response, which results in chronic low-level, systemic inflammation, termed “inflammaging”. Genetic and epigenetic changes, as well as environmental factors, promote and/or modulate the mechanisms of ageing at the molecular, cellular, organ, and system levels. Most of these mechanisms are characterized by time-dependent patterns of variation driven by the biological clock. In this review, we describe the involvement of ageing-related processes with inflammation in relation to the functioning of the biological clock and the mechanisms operating this intricate interaction

Added value of SPECT/CT over planar imaging in improving sentinel node detection in breast cancer patients. Il valore aggiunto della SPECT/CT rispetto all’imaging planare nel migliorare la ricerca del linfonodo sentinella in pazienti con carcinoma mammario

The aim of the study was to assess the diagnostic contribution of hybrid SPECT/CT lymphoscintigraphy compared to planar imaging for the correct identification of sentinel lymph nodes (SLN) in breast cancer (BC) patients.Obiettivo dello studio è stato valutare il contributo diagnostico della linfoscintigrafia ibrida SPECT/CT rispetto alla tecnica planare per la corretta identificazione del linfonodo sentinella (LS) in pazienti con carcinoma mammario (CM). Materiali e metodi. 73 linfoscintigrafie planari e SPECT/CT sono state eseguite in 70 pazienti consecutivi con CM (70 donne, età media 55,7±12,0 anni, range 26-84) per la ricerca pre-chirurgica del LS. Il coefficiente K di Cohen è stato utilizzato per valutare la concordanza tra le due tecniche linfoscintigrafiche; la capacità diagnostica è stata valutata mediante il test t-Student per dati appaiati. Risultati. In 54/73 (73,9%) linfoscintigrafie, i LLSS sono stati rilevati sia nelle immagini planari sia nella SPECT/CT. Nei 19/73 (26,1%) casi di discordanza, la tecnica planare ha mostrato un maggior numero di LLSS in 4/19 linfoscintigrafie, mentre la SPECT/CT in 15/19. La chirurgia radioguidata ha confermato i risultati della SPECT/CT. La concordanza tra le due tecniche è risultata bassa (K=-0,095). Complessivamente la SPECT/CT ha rilevato 13 LLSS in più rispetto all’imaging planare (p=0,07). Inoltre, in 17/73 (23,2%) linfoscintigrafie, la SPECT/CT ha definito l’esatta localizzazione anatomica dei LLSS, risultata equivoca alle immagini planari. Conclusioni. La SPECT/CT dimostra un valore aggiunto rispetto alle immagini planari, fornendo ulteriori informazioni per la corretta pianificazione dell’intervento chirurgico. La SPECT/CT è utile specialmente in pazienti con l’imaging planare negativo, inconcludente o dubbio

Potential Short-Term Air Pollution Effects on Rheumatoid Arthritis Activity in Metropolitan Areas in the North of Italy: A Cross-Sectional Study

Rheumatoid arthritis (RA) flare is related to increased joint damage, disability, and healthcare use. The impact of short-term air pollution exposure on RA disease activity is still a matter of debate. In this cross-sectional study, we investigated whether short-term exposure to particulate matter (PM)10, PM2.5, nitrogen dioxide (NO2), and ozone (O3) affected RA disease activity (DAS28 and SDAI) in 422 consecutive RA residents in Lombardy, North of Italy. Air pollutant concentrations, estimated by Regional Environmental Protection Agency (Lombardy—Italy) at the municipality level, were used to assign short-term exposure from the day of enrolment, back to seven days. Some significant negative associations emerged between RA disease activity, PM10, and NO2, whereas some positive associations were observed for O3. Patients were also stratified according to their ongoing Disease-Modifying anti-Rheumatic Drugs (DMARDs) treatment: no DMARDs (n = 25), conventional synthetic DMARDs (n = 108), and biological or targeted synthetic DMARDs (n = 289). Therapy interaction seemed partially able to influence the relationship between short-term air pollution exposure and RA disease activity (PM2.5 levels and DAS28 at the day of the visit-O3 levels and disease activity scores for the seven days before the evaluation). According to our results, the impact of short-term air pollution exposure (seven days) minimally impacts disease activity. Moreover, our study suggests therapy could alter the response to environmental factors. Further evidence is needed to elucidate determinants of RA flare and its management

Circadian Genes Expression Patterns in Disorders Due to Enzyme Deficiencies in the Heme Biosynthetic Pathway

Heme is a member of the porphyrins family of cyclic tetrapyrroles and influences various cell processes and signalling pathways. Enzyme deficiencies in the heme biosynthetic pathway provoke rare human inherited metabolic diseases called porphyrias. Protein levels and activity of enzymes involved in the heme biosynthetic pathway and especially 5&prime;-Aminolevulinate Synthase 1 are featured by 24-h rhythmic oscillations driven by the biological clock. Heme biosynthesis and circadian pathways intermingle with mutual modulatory roles. Notably, heme is a ligand of important cogs of the molecular clockwork, which upon heme binding recruit co-repressors and inhibit the transcription of numerous genes enriching metabolic pathways and encoding functional proteins bringing on crucial cell processes. Herein, we assessed mRNA levels of circadian genes in patients suffering from porphyrias and found several modifications of core clock genes and clock-controlled genes expression, associated with metabolic and electrolytic changes. Overall, our results show an altered expression of circadian genes accompanying heme biosynthesis disorders and confirm the need to deepen the knowledge of the mechanisms through which the alteration of the circadian clock circuitry could take part in determining signs and symptoms of porphyria patients and then again could represent a target for innovative therapeutic strategies

Comparison between real-time quantitative PCR detection of HER2 mRNA copy number in peripheral blood and ELISA of serum HER2 protein for determining HER2 status in breast cancer patients

Background: The development of non-invasive procedure to determine HER2 status may represent a powerful method for monitoring disease progression and response to the treatment