Inhibition of Heat Shock Protein 27 (Hsp27) sensitizes Non-Small Cell Lung Cancer Cells to Epidermal Growth Factor Receptor (EGFR) inhibitors

Non-small cell lung cancer (NSCLC) is the most frequent cause of death from cancer worldwide. Despite the availability of active chemotherapy regimens and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, all advanced patients develop recurrent disease after first-line therapy. While heat shock protein 27 (Hsp27) is a stress-induced chaperone that promotes acquired resistance in several cancers, its relationship to treatment resistance in NSCLC has not been defined. Understanding adaptive responses of acquired resistance will help guide new strategies to control NSCLC. Hsp27 levels were evaluated in an HCC827 erlotinib-resistant derived cell line (HCC-827Resistant), and sensitivity to erlotinib was examined in Hsp27 over-expressing A549 cells. The role of Hsp27 in both erlotinib and cytotoxic treatment resistance was evaluated in HCC827 and A549 NSCLC cells using the Hsp27 antisense drug OGX-427 and VPC-27, a new functional small molecule inhibitor of Hsp27. The effect of Hsp27 inhibitors in combination with erlotinib was also assessed in mice bearing A549 or HCC827 xenografts. Hsp27 is induced by erlotinib and protects NSCLC cells from treatment-induced apoptosis, while Hsp27 inhibition sensitizes NSCLC cells to erlotinib. Interestingly, increased resistance to erlotinib was observed when Hsp27 was increased either in HCC827 ER or over-expressing A549 cells. Combining OGX-427 or VPC-27 with erlotinib significantly enhanced antitumor effects in vitro and delayed NSCLC cells growth in vivo. These data indicate that treatment-induced Hsp27 (by inhibition of EGFR) contributes to the development of resistance, and provides pre-clinical proof-of-principle that inhibition of stress adaptive pathways mediated by Hsp27 enhances the activity of erlotinib in NSCLC

Sulle tracce del terremoto del 20 febbraio 1743 nei comuni danneggiati del Salento (Puglia meridionale, Italia)

L’area del Salento (Puglia meridionale) è considerata l’avampaese stabile della catena appenninica (Cinque et al., 1993). La sismicità strumentale, registrata dagli anni Settanta a oggi, è scarsa e di bassa energia, prevalentemente concentrata ad ovest della penisola salentina e nel canale d’Otranto, dove il massimo evento registrato è stato quello del 20 ottobre del 1974 di Mw = 5.0 (CPTI11, 2011) (Fig.1). I terremoti storici più forti degli ultimi 1.000 anni, riportati dai cataloghi disponibili in letteratura, sono stati quelli del 10 settembre 1087 di Bari (Imax = 6-7), (CPTI11, 2011), del 20 febbraio 1743 del basso Ionio (Imax=IX), (CFTIMED04, 2007; CPTI11, 2011) e del 26 ottobre 1826 di Manduria (Imax = 6-7, CPTI11, 2011). Tra questi l’evento a maggiore energia è stato il terremoto del 1743, che ha colpito la Puglia e le coste occidentali della Grecia, ma è stato avvertito anche nelle regioni dell’Italia meridionale e in alcune località dell’Italia Centrale e Settentrionale, fino a Trento e a Udine, e finanche nell’isola di Malta. É stato un evento sismico complesso, percepito come una sequenza di tre violente scosse, prodotte probabilmente dall’attivazione di diversi segmenti di faglia (CFTIMED04, 2007). Sono state formulate due ipotesi di localizzazione di questo evento: secondo la prima, l’epicentro è riportato a mare, a est di S. Maria di Leuca, ipotesi avvalorata anche dalla distribuzione dei depositi da tsunami, attribuiti a questo terremoto, lungo le coste adriatiche meridionali del Salento (Torre Sasso e Torre S. Emiliano) (Mastronuzzi et al., 2007) fino a Brindisi; per la seconda, come revisionato nel catalogo CFTIMED04 (2007), l’epicentro è riportato a terra, tra Nardò e Galatina. In Italia i danni maggiori si sono registrati in Salento, nelle cittadine di Nardò, in provincia di Lecce, e Francavilla Fontana, in provincia di Brindisi; in Grecia a Levkas e nelle isole Ionie. I morti furono circa 180, 150 nella sola Nardò. L’evento è descritto in alcune centinaia di documenti storici, da cui si evince che furono oltre 86 le località interessate. Lo studio degli effetti prodotti ha permesso di attribuire all’evento una intensità massima di Imax = 9 (per Nardò e per Levkas) e Me = 6.9 (CFTIMED04, 2007). Nonostante ci siano stati danni notevoli in tutto il Salento, la mappa di pericolosità sismica di riferimento per il territorio nazionale (MPSO4 - Ordinanza PCM 3519/2006) attribuisce bassi valori di pericolosità nell’area del Salento e alti valori nell’area a mare, nel canale di Otranto. Questo lavoro si propone di andare alla scoperta delle evidenze architettoniche distrutte e ricostruite in seguito all’evento, con l’obiettivo di creare un itinerario geoturistico sulle “tracce” di questo terremoto nel tessuto urbano delle città salentine coinvolte

Associations Between Personality Traits, Perceived Stress and Depressive Symptoms in Gynecological Cancer Patients Characterized by the Short and Long Allele Variant of the 5-HTTLPR Genotype: Preliminary Results

Objective: The study explored associations between personality traits, perceived stress and symptoms of depression in oncological patients characterized by the two variants of the serotonin transporter (5-HTTLPR) polyrnorphisms.Method: The sample was composed of 41 gynecological cancer patients who completed self-reported questionnaires including the NEO Five-Factor Inventory, the dimension of depression-dejection (D/D) of the Profile of Moods State and the Perceived Stress Scale (PSS). The polymerase chain reaction was also employed to identify genotypes in the serotonin (5HTT) polymorphism.Results: The one-way ANOVA test, across the 5-HTTLPR genotype groups, showed significant effects of the short variants on neuroticism (p=0.009) and of the long variant on agreeableness (p=0.022), as well as a tendency to a statistical significance of the 1/1 variant on consciousness (p=0.074). Bivariate correlations showed positive correlations of neuroticism with both psychopathological symptoms (D/D r=0.522; PSS r=0.586) in the combined group S, negative association of agreeableness with depression (D/D 1=-0.613) and of consciousness with depression (DID r=0.750) and perceived stress (PSS r=-0.702) in the group of the long variant of 5-HTTLPR genotype.Conclusions: Personalized medicine should consider the interaction between genotype and phenotype in reducing levels of clinical psychological distress, highlighting how psychotherapeutic processes should improve patients' quality of life

Itinerari geologico - naturalistici nelle aree vulcaniche campane: un’opportunità per conoscere e valorizzare un paesaggio naturale e culturale unico

Questo lavoro propone quattro percorsi geoturistici a tema nello straordinario mondo dei paesaggi vulcanici campani, lungo la costa del Tirreno, per scoprire la notevole geo-diversità e biodiversità che in un territorio dal ricco patrimonio naturale, scientifico e culturale quale la Campania, è possibile sperimentare. Il nostro percorso è un viaggio di scoperta con occhi nuovi che, attraverso l’osservazione delle morfologie e delle peculiarità naturalistiche degli ambienti vulcanici proposti, ci permette di comunicare con la natura che svela i suoi segreti a chi entra in sintonia con essa, risvegliando emozioni. Questo lavoro ha altresì come obiettivo la divulgazione delle caratteristiche geologico- naturalistiche dei molteplici ambienti dei rilievi vulcanici campani, anche perché la crescente frequentazione dei luoghi è spesso accompagnata da scarsa informazione scientifica disponibile relativa ai percorsi effettuati, e dalla volontà di una fruizione più consapevole, che possa condurre ad azioni di difesa di un territorio non ancora del tutto adeguatamente conosciuto (Hose, 2012)

Loss of Nuclear Functions of HOXA10 Is Associated With Testicular Cancer Proliferation

Background: HOXA10 is a key transcriptional factor that regulates testis development as reported from previous transgenic mouse models and human inherited diseases. However, whether it also plays important roles in promoting the development of testicular cancer is not well-understood.Objective: To study the expression of HOXA10 and its regulated signaling pathways in testicular cancers.Design, Setting, and Participants: A tissue microarray was constructed with benign and cancerous testis. TCam2, NT-2, and NCCIT cell models were applied in this study.Intervention: Immunohistochemistry and immunofluorescence were performed to measure the expression and cellular localization of HOXA10 in testicular cancer tissues and cell models. Cell proliferation and cell cycling rates were determined by BrdU incorporation and flow cytometry assays. HOXA10 transcriptomes were profiled with Ampliseq RNA-seq in testicular cancer cells. Immunoblotting assays were used to detect HOXA10-regulated signaling.Results: HOXA10 is a nuclear protein in benign spermatocytes. Reduced nuclear expression and increased cytoplasmic expression of HOXA10 are associated with testicular cancers. These changes are consistent in both seminoma and non-seminoma. Enhanced HOXA10 expression in testicular cancer cell models inhibits cell proliferation and delays cell cycle progression through G2/M phases. These functions of HOXA10 mainly affect the TP53, cKit, STAT3, AKT, and ERK signaling pathways.Conclusions: Loss of nuclear functions of HOXA10 enhances proliferation of testicular cancer cells, suggesting that downregulation of HOXA10 transcription activity may promote the development of testicular cancers

“I luoghi di Mercalli”: a travelling exhibition as a tool for scientists to dialogue with the public on volcanoes and earthquakes

On March 19, 1914 Giuseppe Mercalli, a seismologist and volcanologist, well-known around the world for the Intensity scale of earthquakes bearing his name, died tragically. A hundred years after, the Istituto Nazionale di Geofisica e Vulcanologia (INGV) has promoted a variety of activities and cultural events that will take place under the Patronage of the President of the Italian Republic within a year, the so called “Anno Mercalliano” (the Year of Mercalli). The opening ceremony took place in Naples, Italy, on March 19, 2014, in the Convitto Nazionale Vittorio Emanuele II. A scientific conference was held with the participation of experts from INGV and the university of Milano – Bicocca, and presentations of students. On that day the exhibition entitled “I luoghi di Mercalli” (Mercalli's places) was also inaugurated, at the presence of local authorities. The exhibition, organized by INGV, was realized in collaboration with the high school Vittorio Emanuele II, where Mercalli has been teaching for 19 years, and the Università degli Studi Suor Orsola Benincasa, where he was professor of natural sciences. A biographical and geographical description of the places where Mercalli operated introduces the exhibition, which is organized in sections: - Mercalli educator (he taught at high schools in Reggio Calabria and Naples); - Mercalli volcanologist (Mercalli studied Vesuvius volcanic activity for more than twenty years, he was a scientific witness of the Vesuvius 1906 eruption, and of the eruptions occurred at Vulcano (1888-90) and Stromboli (1891) islands. - Mercalli seismologist (Mercalli Intensity scale definition, based on his experience as witness of catastrophic earthquakes, such as Casamicciola in 1883 and Messina in 1908). Another section deals with the Vesuvius Observatory, directed by Mercalli between 1911 and 1914, and the description of the three active volcanoes of the Campania region (Vesuvius, Campi Flegrei and Ischia island), which have been the subject of studies by the well-known scientist. The exhibition is enriched by documents, manuscripts, photos and field notebooks of Mercalli. It is not intended to be only a celebratory exhibition; rather it is designed as a tool for dissemination of scientific culture and to raise awareness about seismic and volcanic hazards. In the exhibition path a continuous thread between the figure of Mercalli as a researcher and the role of an Earth Science researcher today is highlighted, pointing to the development of scientific knowledge in the past century. The goal is to improve the capability of learning from the disasters occurred in the past to implement preventive actions to safely deal with future events. The exhibition is travelling and will be provided on request to institutions and schools.PublishedMilano, Italia1V. Storia e struttura dei sistemi vulcaniciope

Management of Germ Cell Tumors During the Outbreak of the Novel Coronavirus Disease-19 Pandemic:A Survey of International Expertise Centers

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has become a public health emergency affecting frail populations, including patients with cancer. This poses the question of whether cancer treatments can be postponed or modified without compromising their efficacy, especially for highly curable cancers such as germ cell tumors (GCTs). MATERIALS AND METHODS: To depict the state-of-the-art management of GCTs during the COVID-19 pandemic, a survey including 26 questions was circulated by e-mail among the physicians belonging to three cooperative groups: (a) Italian Germ Cell Cancer Group; (b) European Reference Network-Rare Adult Solid Cancers, Domain G3 (rare male genitourinary cancers); and (c) Genitourinary Medical Oncologists of Canada. Percentages of agreement between Italian respondents (I) versus Canadian respondents (C), I versus European respondents (E), and E versus C were compared by using Fisher's exact tests for dichotomous answers and chi square test for trends for the questions with three or more options. RESULTS: Fifty-three GCT experts responded to the survey: 20 Italian, 6 in other European countries, and 27 from Canada. Telemedicine was broadly used; there was high consensus to interrupt chemotherapy in COVID-19-positive patients (I = 75%, C = 55%, and E = 83.3%) and for use of granulocyte colony-stimulating factor primary prophylaxis for neutropenia (I = 65%, C = 62.9%, and E = 50%). The main differences emerged regarding the management of stage I and stage IIA disease, likely because of cultural and geographical differences. CONCLUSION: Our study highlights the common efforts of GCT experts in Europe and Canada to maintain high standards of treatment for patients with GCT with few changes in their management during the COVID-19 pandemic. IMPLICATIONS FOR PRACTICE: Despite the chaos, disruptions, and fears fomented by the COVID-19 illness, oncology care teams in Italy, other European countries, and Canada are delivering the enormous promise of curative management strategies for patients with testicular cancer and other germ cell tumors. At the same time, these teams are applying safe and innovative solutions and sharing best practices to minimize frequency and intensity of patient contacts with thinly stretched health care capacity

Specific versus Non-Specific Immune Responses in an Invertebrate Species Evidenced by a Comparative de novo Sequencing Study

Our present understanding of the functioning and evolutionary history of invertebrate innate immunity derives mostly from studies on a few model species belonging to ecdysozoa. In particular, the characterization of signaling pathways dedicated to specific responses towards fungi and Gram-positive or Gram-negative bacteria in Drosophila melanogaster challenged our original view of a non-specific immunity in invertebrates. However, much remains to be elucidated from lophotrochozoan species. To investigate the global specificity of the immune response in the fresh-water snail Biomphalaria glabrata, we used massive Illumina sequencing of 5′-end cDNAs to compare expression profiles after challenge by Gram-positive or Gram-negative bacteria or after a yeast challenge. 5′-end cDNA sequencing of the libraries yielded over 12 millions high quality reads. To link these short reads to expressed genes, we prepared a reference transcriptomic database through automatic assembly and annotation of the 758,510 redundant sequences (ESTs, mRNAs) of B. glabrata available in public databases. Computational analysis of Illumina reads followed by multivariate analyses allowed identification of 1685 candidate transcripts differentially expressed after an immune challenge, with a two fold ratio between transcripts showing a challenge-specific expression versus a lower or non-specific differential expression. Differential expression has been validated using quantitative PCR for a subset of randomly selected candidates. Predicted functions of annotated candidates (approx. 700 unisequences) belonged to a large extend to similar functional categories or protein types. This work significantly expands upon previous gene discovery and expression studies on B. glabrata and suggests that responses to various pathogens may involve similar immune processes or signaling pathways but different genes belonging to multigenic families. These results raise the question of the importance of gene duplication and acquisition of paralog functional diversity in the evolution of specific invertebrate immune responses

Solid Organ Transplantation During COVID-19 Pandemic: An International Web-based Survey on Resources’ Allocation

Background. Solid organ transplants (SOTs) are life-saving interventions, recently challenged by coronavirus disease 2019 (COVID-19). SOTs require a multistep process, which can be affected by COVID-19 at several phases. Methods. SOT-specialists, COVID-19-specialists, and medical ethicists designed an international survey according to CHERRIES guidelines. Personal opinions about continuing SOTs, safe managing of donors and recipients, as well as equity of resources' allocation were investigated. The survey was sent by e-mail. Multiple approaches were used (corresponding authors from Scopus, websites of scientific societies, COVID-19 webinars). After the descriptive analysis, univariate and multivariate ordinal regression analysis was performed. Results. There were 1819 complete answers from 71 countries. The response rate was 49%. Data were stratified according to region, macrospecialty, and organ of interest. Answers were analyzed using univariate- multivariate ordinal regression analysis and thematic analysis. Overall, 20% of the responders thought SOTs should not stop (continue transplant without restriction); over 70% suggested SOTs should selectively stop, and almost 10% indicated they should completely stop. Furthermore, 82% agreed to shift resources from transplant to COVID-19 temporarily. Briefly, main reason for not stopping was that if the transplant will not proceed, the organ will be wasted. Focusing on SOT from living donors, 61% stated that activity should be restricted only to "urgent"cases. At the multivariate analysis, factors identified in favor of continuing transplant were Italy, ethicist, partially disagreeing on the equity question, a high number of COVID-19- related deaths on the day of the answer, a high IHDI country. Factors predicting to stop SOTs were Europe except-Italy, public university hospital, and strongly agreeing on the equity question. Conclusions. In conclusion, the majority of responders suggested that transplant activity should be continued through the implementation of isolation measures and the adoption of the COVID-19-free pathways. Differences between professional categories are less strong than supposed