Resveratrol engages AMPK to attenuate ERK and mTOR signaling in sensory neurons and inhibits incision-induced acute and chronic pain

<p>Abstract</p> <p>Background</p> <p>Despite advances in our understanding of basic mechanisms driving post-surgical pain, treating incision-induced pain remains a major clinical challenge. Moreover, surgery has been implicated as a major cause of chronic pain conditions. Hence, more efficacious treatments are needed to inhibit incision-induced pain and prevent the transition to chronic pain following surgery. We reasoned that activators of AMP-activated protein kinase (AMPK) may represent a novel treatment avenue for the local treatment of incision-induced pain because AMPK activators inhibit ERK and mTOR signaling, two important pathways involved in the sensitization of peripheral nociceptors.</p> <p>Results</p> <p>To test this hypothesis we used a potent and efficacious activator of AMPK, resveratrol. Our results demonstrate that resveratrol profoundly inhibits ERK and mTOR signaling in sensory neurons in a time- and concentration-dependent fashion and that these effects are mediated by AMPK activation and independent of sirtuin activity. Interleukin-6 (IL-6) is thought to play an important role in incision-induced pain and resveratrol potently inhibited IL-6-mediated signaling to ERK in sensory neurons and blocked IL-6-mediated allodynia in vivo through a local mechanism of action. Using a model of incision-induced allodynia in mice, we further demonstrate that local injection of resveratrol around the surgical wound strongly attenuates incision-induced allodynia. Intraplantar IL-6 injection and plantar incision induces persistent nociceptive sensitization to PGE₂injection into the affected paw after the resolution of allodynia to the initial stimulus. We further show that resveratrol treatment at the time of IL-6 injection or plantar incision completely blocks the development of persistent nociceptive sensitization consistent with the blockade of a transition to a chronic pain state by resveratrol treatment.</p> <p>Conclusions</p> <p>These results highlight the importance of signaling to translation control in peripheral sensitization of nociceptors and provide further evidence for activation of AMPK as a novel treatment avenue for acute and chronic pain states.</p

Targeted therapies for advanced and metastatic adenocarcinoma of the gastroesophageal junction: is there something new?

Despite improvements in systemic chemotherapy (CT), the prognosis of metastatic adenocarcinoma of the gastroesophageal junction remains poor. Over the years, new targeting agents have become available and were tested, with or without CT, in first or subsequent lines of therapy. The epidermal growth factor receptor family was targeted with monoclonal antibodies (MoAbs) (trastuzumab, cetuximab, panitumumab) and tyrosin kinase inhibitors (TKIs) (lapatinib, erlotinib, gefitinib). Only trastuzumab, in combination with cisplatin and fluoropyrimidines, significantly improved overall survival (OS) in first-line therapy (13.8 vs. 11.1&nbsp;months). Angiogenesis also was targeted with MoAbs (bevacizumab and ramucirumab); ramucirumab, a vascular endothelial growth factor-receptor 2 antagonist, enhanced OS in two phase III studies in the first (9.6 vs. 7.4&nbsp;months) and subsequent lines of treatment (5.2 vs. 3.8&nbsp;months), while the bevacizumab study was negative. TKIs (sunitinib, sorafenib, regorafenib, apatinib) were tested in this setting in phase II studies in the second/third line, only showing modest antitumor activity. The hepatocyte growth factor receptor (MET) was targeted in untreated patients in a phase III trial with MoAb rilotumumab, with or without CT, but the study was stopped because of mortality excess in the rilotumumab arm. Mammalian target of rapamycin (MTOR) pathway inhibition with everolimus was tested in pretreated patients in a placebo-controlled phase III trial who failed to improve OS (5.4 vs. 4.3&nbsp;months). In conclusion, considering the modest survival gain obtained overall, the high cost of these therapies and the quality of life issue must be primarily considered in treating these patients

Seismic emergency in Molise (2018). Preliminary report of the SISMIKO task force.

Il 16 agosto 2018 alle ore 18:19:04 UTC un terremoto di magnitudo ML 5.2 (Mw 5.1) è stato ben risentito in un’ampia area che comprende molte regioni del Centro Sud Italia. I sismologi in turno presso la sala di monitoraggio e sorveglianza sismica dell’Istituto Nazionale di Geofisica e Vulcanologia (INGV) hanno localizzato l’evento in provincia di Campobasso, a 4 km a Sud-Est di Montecilfone e ad una profondità inizialmente calcolata di 9 km. Nella stessa area si era verificato due giorni prima, il 14 agosto alle ore 23.48 italiane un terremoto di Mw 4.6 anch’esso ben risentito (i dettagli dell’evento sono reperibili alla pagina [http://cnt.rm.ingv.it/event/20375681]). A seguito dell’evento di magnitudo Mw 5.1 e della sequenza ad esso associata, come in ogni emergenza di questo tipo, è stato attivato il Gruppo Operativo SISMIKO [Moretti et al., 2012; 2016; Pondrelli et al., 2016] per l’installazione di alcune stazioni sismiche temporanee ad integrazione di quelle permanenti della Rete Sismica Nazionale (RSN [Michelini et al., 2016]) presenti nella regione.Il 16 agosto 2018 alle ore 18:19:04 UTC un terremoto di magnitudo ML 5.2 (Mw 5.1) è stato ben risentito in un’ampia area che comprende molte regioni del Centro Sud Italia [http://cnt.rm.ingv.it/event/20375681]. I sismologi, in turno presso la sala di monitoraggio e sorveglianza sismica dell’Istituto Nazionale di Geofisica e Vulcanologia (INGV), hanno localizzato l’evento in provincia di Campobasso, a 4 km a Sud-Est di Montecilfone. Nella stessa area si era verificato due giorni prima, il 14 agosto alle ore 21.48 UTC un terremoto di Mw 4.6 [http://cnt.rm.ingv.it/event/20362671]. A seguito dell’evento di magnitudo Mw 5.1 e della sequenza ad esso associata, come avviene in questi casi, si è attivato il Gruppo Operativo SISMIKO [Moretti et al., 2012; 2016; Pondrelli et al., 2016] per l’installazione di stazioni sismiche temporanee ad integrazione di quelle permanenti della Rete Sismica Nazionale (RSN [Michelini et al., 2016; http://cnt.rm.ingv.it/instruments/network/IV]) presenti nella regione.Published1SR. TERREMOTI - Servizi e ricerca per la Societ

AIRO Breast Cancer Group Best Clinical Practice 2022 Update

Introduction: Breast cancer is the most common tumor in women and represents the leading cause of cancer death. Radiation therapy plays a key-role in the treatment of all breast cancer stages. Therefore, the adoption of evidence-based treatments is warranted, to ensure equity of access and standardization of care in clinical practice.Method: This national document on the highest evidence-based available data was developed and endorsed by the Italian Association of Radiation and Clinical Oncology (AIRO) Breast Cancer Group.We analyzed literature data regarding breast radiation therapy, using the SIGN (Scottish Intercollegiate Guidelines Network) methodology (www.sign.ac.uk). Updated findings from the literature were examined, including the highest levels of evidence (meta-analyses, randomized trials, and international guidelines) with a significant impact on clinical practice. The document deals with the role of radiation therapy in the treatment of primary breast cancer, local relapse, and metastatic disease, with focus on diagnosis, staging, local and systemic therapies, and follow up. Information is given on indications, techniques, total doses, and fractionations.Results: An extensive literature review from 2013 to 2021 was performed. The work was organized according to a general index of different topics and most chapters included individual questions and, when possible, synoptic and summary tables. Indications for radiation therapy in breast cancer were examined and integrated with other oncological treatments. A total of 50 questions were analyzed and answered.Four large areas of interest were investigated: (1) general strategy (multidisciplinary approach, contraindications, preliminary assessments, staging and management of patients with electronic devices); (2) systemic therapy (primary, adjuvant, in metastatic setting); (3) clinical aspects (invasive, non-invasive and micro-invasive carcinoma; particular situations such as young and elderly patients, breast cancer in males and cancer during pregnancy; follow up with possible acute and late toxicities; loco-regional relapse and metastatic disease); (4) technical aspects (radiation after conservative surgery or mastectomy, indications for boost, lymph node radiotherapy and partial breast irradiation).Appendixes about tumor bed boost and breast and lymph nodes contouring were implemented, including a dedicated web application. The scientific work was reviewed and validated by an expert group of breast cancer key-opinion leaders.Conclusions: Optimal breast cancer management requires a multidisciplinary approach sharing therapeutic strategies with the other involved specialists and the patient, within a coordinated and dedicated clinical path. In recent years, the high-level quality radiation therapy has shown a significant impact on local control and survival of breast cancer patients. Therefore, it is necessary to offer and guarantee accurate treatments according to the best standards of evidence-based medicine

Acute Delta Hepatitis in Italy spanning three decades (1991–2019): Evidence for the effectiveness of the hepatitis B vaccination campaign

Updated incidence data of acute Delta virus hepatitis (HDV) are lacking worldwide. Our aim was to evaluate incidence of and risk factors for acute HDV in Italy after the introduction of the compulsory vaccination against hepatitis B virus (HBV) in 1991. Data were obtained from the National Surveillance System of acute viral hepatitis (SEIEVA). Independent predictors of HDV were assessed by logistic-regression analysis. The incidence of acute HDV per 1-million population declined from 3.2 cases in 1987 to 0.04 in 2019, parallel to that of acute HBV per 100,000 from 10.0 to 0.39 cases during the same period. The median age of cases increased from 27 years in the decade 1991-1999 to 44 years in the decade 2010-2019 (p &lt; .001). Over the same period, the male/female ratio decreased from 3.8 to 2.1, the proportion of coinfections increased from 55% to 75% (p = .003) and that of HBsAg positive acute hepatitis tested for by IgM anti-HDV linearly decreased from 50.1% to 34.1% (p &lt; .001). People born abroad accounted for 24.6% of cases in 2004-2010 and 32.1% in 2011-2019. In the period 2010-2019, risky sexual behaviour (O.R. 4.2; 95%CI: 1.4-12.8) was the sole independent predictor of acute HDV; conversely intravenous drug use was no longer associated (O.R. 1.25; 95%CI: 0.15-10.22) with this. In conclusion, HBV vaccination was an effective measure to control acute HDV. Intravenous drug use is no longer an efficient mode of HDV spread. Testing for IgM-anti HDV is a grey area requiring alert. Acute HDV in foreigners should be monitored in the years to come

Worldwide comparison of survival from childhood leukaemia for 1995–2009, by subtype, age, and sex (CONCORD-2): a population-based study of individual data for 89 828 children from 198 registries in 53 countries

Background Global inequalities in access to health care are reflected in differences in cancer survival. The CONCORD programme was designed to assess worldwide differences and trends in population-based cancer survival. In this population-based study, we aimed to estimate survival inequalities globally for several subtypes of childhood leukaemia. Methods Cancer registries participating in CONCORD were asked to submit tumour registrations for all children aged 0-14 years who were diagnosed with leukaemia between Jan 1, 1995, and Dec 31, 2009, and followed up until Dec 31, 2009. Haematological malignancies were defined by morphology codes in the International Classification of Diseases for Oncology, third revision. We excluded data from registries from which the data were judged to be less reliable, or included only lymphomas, and data from countries in which data for fewer than ten children were available for analysis. We also excluded records because of a missing date of birth, diagnosis, or last known vital status. We estimated 5-year net survival (ie, the probability of surviving at least 5 years after diagnosis, after controlling for deaths from other causes [background mortality]) for children by calendar period of diagnosis (1995-99, 2000-04, and 2005-09), sex, and age at diagnosis (< 1, 1-4, 5-9, and 10-14 years, inclusive) using appropriate life tables. We estimated age-standardised net survival for international comparison of survival trends for precursor-cell acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML). Findings We analysed data from 89 828 children from 198 registries in 53 countries. During 1995-99, 5-year agestandardised net survival for all lymphoid leukaemias combined ranged from 10.6% (95% CI 3.1-18.2) in the Chinese registries to 86.8% (81.6-92.0) in Austria. International differences in 5-year survival for childhood leukaemia were still large as recently as 2005-09, when age-standardised survival for lymphoid leukaemias ranged from 52.4% (95% CI 42.8-61.9) in Cali, Colombia, to 91.6% (89.5-93.6) in the German registries, and for AML ranged from 33.3% (18.9-47.7) in Bulgaria to 78.2% (72.0-84.3) in German registries. Survival from precursor-cell ALL was very close to that of all lymphoid leukaemias combined, with similar variation. In most countries, survival from AML improved more than survival from ALL between 2000-04 and 2005-09. Survival for each type of leukaemia varied markedly with age: survival was highest for children aged 1-4 and 5-9 years, and lowest for infants (younger than 1 year). There was no systematic difference in survival between boys and girls. Interpretation Global inequalities in survival from childhood leukaemia have narrowed with time but remain very wide for both ALL and AML. These results provide useful information for health policy makers on the effectiveness of health-care systems and for cancer policy makers to reduce inequalities in childhood survival

Emergenza sismica nel centro Italia 2016-2017. Secondo rapporto del gruppo operativo SISMIKO. Sviluppo e mantenimento della rete sismica mobile a seguito del terremoto di Amatrice Mw 6.0 (24 agosto 2016, Italia centrale)

La rete sismica temporanea installata dal gruppo operativo INGV SISMIKO a seguito del terremoto del 24 agosto 2016 tra i Monti della Laga e la Valnerina, è stata ampliata nel settore settentrionale a seguito dei forti terremoti avvenuti alla fine del mese di ottobre 2016. Successivamente alle due scosse di Mw 5.4 e 5.9 che il 26 ottobre hanno interessato l’area al confine Marche-Umbria tra i Comuni di Castelsantangelo sul Nera (MC), Norcia (PG) e Arquata del Tronto (AP), la geometria della rete è stata estesa di circa 25 km verso nord con l’attivazione di ulteriori tre stazioni temporanee di cui una, da subito, disposta per la trasmissione dei dati in tempo reale e per l’inserimento nel sistema di sorveglianza sismica dell’Istituto Nazionale di Geofisica e Vulcanologia (INGV). Un’ultima stazione è stata inoltre installata nei pressi di Campello del Clitunno in provincia di Perugia ad ovest della sequenza, a seguito del terremoto Mw 6.5 che la mattina del 30 ottobre ha interessato l’intera area già fortemente provata dalla sequenza in corso; questo è stato il più forte terremoto registrato negli ultimi 30 in Italia. A circa 5 mesi dall’inizio dell’emergenza sismica, la rete temporanea conta quindi 23 stazioni che da metà dicembre sono tutte trasmesse in tempo reale ai diversi centri di acquisizione INGV, ovvero Milano, Ancona e Grottaminarda ma soprattutto Roma dove i dati vengono contestualmente archiviati nell’European Integrated Data Archive (EIDA) e integrati nel sistema di monitoraggio e sorveglianza sismica dell’INGV; per la sorveglianza sono incluse solo parte delle stazioni. Nelle ultime settimane, le attività di campagna del gruppo operativo SISMIKO sono state costantemente focalizzate alla cura e alla manutenzione della strumentazione per garantire la continuità della trasmissione e dell’acquisizione dei dati, a volte compromesse da malfunzionamenti legati al maltempo. Alla data di aggiornamento del presente report, non è ancora stata decretata una dismissione o una rimodulazione della geometria della rete sismica temporanea, anche in considerazione della attività sismica in corso a tutt’oggi molto sostenuta. Tutti i dati acquisiti dalle stazioni temporanee SISMIKO, sono distribuiti senza alcun vincolo, al pari dei dati della Rete Sismica Nazionale (RSN, codice di rete IV), ed utilizzati per prodotti scientifici in tempo reale (localizzazioni di sala, calcolo dei Time Domain Moment Tensor -TDMT delle ShakeMaps, ecc) e per l’aggiornamento dei database dell’INGV come l’Italian Seismological Instrumental and Parametric Database (ISIDe) con la revisione del Bollettino Sismico Italiano (BSI), dell’INGV Strong Motion Data (ISMD) e dell’ITalian ACcelerometric Archive (ITACA), dell’European-Mediterranean Regional Centroid Moment Tensors (RCMT) e nei lavori scientifici che utilizzano forme d’onda velocimetriche ed accelerometriche (ri- localizzazioni, studi della sorgente sismica ecc.).Istituto Nazionale di Geofisica e Vulcanologia (INGV)Published1SR. TERREMOTI - Servizi e ricerca per la Societ

Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an

Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis

Rapporto Preliminare Sulle Attività Svolte Nel Primo Mese Di Emergenza Dal Gruppo Operativo Sismiko A Seguito Del Terremoto Di Amatrice Mw 6.0 (24 Agosto 2016, Italia Centrale)

Sintesi delle attività svolte dal coordinamento delle reti sismiche mobili INGV in emergenza, denominato SISMIKO, nel primo mese della sequenza sismica “Amatrice” seguita al terremoto di Mw 6.0 del 24 agosto 2016 (01:36 UTC). Descrizione della rete sismica implementata e prime analisi dei dati acquisiti. Report on the activities in the first month of emergency by coordination of mobile seismic networks INGV emergency, called SISMIKO, after the Mw 6.0 Amatrice earthquake (August 24th, 2016, central italy). Description of the temporary seismic network implemented and preliminary analysis of the acquired data.INGV DPCPublished1IT. Reti di monitoraggi