effects of a new human recombinant mnsod in the treatment of photoaging and actinic keratosis

Physiological processes, as aerobic metabolism and inflammatory response, generate reactive oxygen species (ROS) that may induce cellular injury when their amount is increased and antioxidant defense mechanisms are overwhelmed. Also, ROS are generated following UV skin irradiation able to deplete the natural antioxidant defenses in the skin. The increase in exposure to UV may lead to photoaging and precancerous skin lesions (actinic keratosis). New antioxidant strategies in the prevention and therapy of skin lesions are urgently needed. In this study, we evaluated the antioxidant efficacy of a recombinant form of human manganese superoxide dismutase able to inhibit reactive oxygen species production in some patients affected by severe photoaging and actinic keratosis

Serum Albumin Is Inversely Associated With Portal Vein Thrombosis in Cirrhosis

We analyzed whether serum albumin is independently associated with portal vein thrombosis (PVT) in liver cirrhosis (LC) and if a biologic plausibility exists. This study was divided into three parts. In part 1 (retrospective analysis), 753 consecutive patients with LC with ultrasound-detected PVT were retrospectively analyzed. In part 2, 112 patients with LC and 56 matched controls were entered in the cross-sectional study. In part 3, 5 patients with cirrhosis were entered in the in vivo study and 4 healthy subjects (HSs) were entered in the in vitro study to explore if albumin may affect platelet activation by modulating oxidative stress. In the 753 patients with LC, the prevalence of PVT was 16.7%; logistic analysis showed that only age (odds ratio [OR], 1.024; P = 0.012) and serum albumin (OR, -0.422; P = 0.0001) significantly predicted patients with PVT. Analyzing the 112 patients with LC and controls, soluble clusters of differentiation (CD)40-ligand (P = 0.0238), soluble Nox2-derived peptide (sNox2-dp; P < 0.0001), and urinary excretion of isoprostanes (P = 0.0078) were higher in patients with LC. In LC, albumin was correlated with sCD4OL (Spearman's rank correlation coefficient [r(s)], -0.33; P < 0.001), sNox2-dp (r(s), -0.57; P < 0.0001), and urinary excretion of isoprostanes (r(s), -0.48; P < 0.0001) levels. The in vivo study showed a progressive decrease in platelet aggregation, sNox2-dp, and urinary 8-iso prostaglandin F2 alpha-III formation 2 hours and 3 days after albumin infusion. Finally, platelet aggregation, sNox2-dp, and isoprostane formation significantly decreased in platelets from HSs incubated with scalar concentrations of albumin. Conclusion: Low serum albumin in LC is associated with PVT, suggesting that albumin could be a modulator of the hemostatic system through interference with mechanisms regulating platelet activation

Contrast-enhanced ultrasound from research to clinical practice: diagnosis of hepatocellular carcinoma with CEUS LI-RADS system and with software of quantification of tissue perfusion

Il carcinoma epatocellulare (HCC) rappresenta il tumore epatico primitivo più comune con una incidenza fino all’85%. È uno dei tumori più frequenti al mondo ed è noto per l’elevata letalità soprattutto in stadio avanzato. La diagnosi precoce attraverso la sorveglianza ecografica è necessaria per migliorare la sopravvivenza dei pazienti a rischio. Il mezzo di contrasto ecografico migliora la sensibilità e la specificità diagnostica dell’ecografia convenzionale. L’ecografia con mezzo di contrasto (contrast-enhanced ultrasound, CEUS) è pertanto considerata una metodica valida per la diagnosi di HCC a livello globale per la sua ottima specificità anche a fronte di una sensibilità subottimale. L’aspetto contrastografico delle lesioni focali epatiche ha portato un team di esperti allo sviluppo del sistema Liver Imaging Reporting and Data System (LI-RADS) con l’obiettivo di standardizzare la raccolta dati e la refertazione delle metodiche di imaging per la diagnosi di HCC. La CEUS è una metodica operatore-dipendente e le discordanze diagnostiche con gli imaging panoramici lasciano spazio a nuove tecniche (Dynamic Contrast Enhanced UltraSound, DCE-US) volte a migliorare l’accuratezza diagnostica della metodica e in particolare la sensibilità. Un software di quantificazione della perfusione tissutale potrebbe essere di aiuto nella pratica clinica per individuare il wash-out non visibile anche all’occhio dell’operatore più esperto. Il nostro studio ha due obiettivi: 1) validare il sistema CEUS LI-RADS nella diagnosi di carcinoma epatocellulare in pazienti ad alto rischio di HCC usando come gold-standard l’istologia quando disponibile oppure metodiche di imaging radiologico accettate da tutte le linee guida (tomografia computerizzata o risonanza magnetica con aspetto tipico) eseguite entro quattro settimane dalla CEUS; 2) valutare l’efficacia di un software di quantificazione della perfusione tissutale nel riscontro di wash-out per la diagnosi di HCC in CEUS.Hepatocellular carcinoma (HCC) is the most common primary liver cancer with an incidence of up to 85%. It is one of the most frequent cancers in the world and is known for its high lethality, especially in the advanced stage. Early diagnosis through ultrasound surveillance is needed to improve survival of at-risk patients. The ultrasound contrast agent improves the sensitivity and diagnostic specificity of conventional ultrasound. Contrast-enhanced ultrasound (CEUS) is therefore considered a valid method for diagnosing HCC globally due to its excellent specificity even if its sensitivity is suboptimal. The aspect of focal hepatic lesions on CEUS led a team of experts to develop the Liver Imaging Reporting and Data System (LI-RADS) with the aim of standardizing data collection and reporting of imaging methods for the diagnosis of HCC. CEUS is an operator-dependent examination and the diagnostic discrepancies with panoramic imaging leave room for new techniques such as the Dynamic Contrast Enhanced UltraSound (DCE-US) aimed at improving the diagnostic accuracy and in particular the sensitivity of the echography. A tissue perfusion quantification software could be of help in clinical practice to identify the wash-out that is not visible even to the eye of the most experienced operator. Our study has two objectives: 1) to validate the CEUS LI-RADS system in the diagnosis of hepatocellular carcinoma in patients at high risk of HCC using histology as a gold standard when available or radiological imaging methods accepted by all guidelines (computed tomography or magnetic resonance imaging) performed within four weeks from CEUS; 2) evaluate the efficacy of a tissue perfusion quantification software in the detection of wash-out for the diagnosis of HCC in CEUS

Contrast-enhanced ultrasound LI-RADS LR-5 in hepatic tuberculosis: Case report and literature review of imaging features

Background: The liver is involved in disseminated tuberculosis in more than 80% of cases while primary liver involvement is rare, representing <1% of all cases. Hepatic tuberculosis (TB) can be treated by conventional anti-TB therapy; however, diagnosing this disease remains a challenge. The diagnosis might be particularly difficult in patients with a single liver lesion that could be misdiagnosed as a tumor or other focal liver lesions. Although computed tomography (CT) and magnetic resonance imaging (MRI) findings have been described, there is a paucity of literature on contrast-enhanced ultrasound (CEUS) features of hepatic TB. Case Summary: herein, we describe a case of a patient with tuberculous lymphadenopathy and chronic Hepatitis C Virus (HCV)- related liver disease who developed a single macronodular hepatic TB lesion. Due to the finding of a hepatocellular carcinoma (HCC) highly suggestive CEUS pattern, specifically a LR5 category according to the Liver Imaging Reporting and Data System (LI-RADS), and a good response to antitubercular therapy, a non-invasive diagnosis of HCC was made, and the patient underwent liver resection. We also review the published literature on imaging features of hepatic TB and discuss the diagnostic challenge represented by hepatic TB when occurs as a single focal liver lesion. Conclusions: this report shows for the first time that the CEUS pattern of hepatic TB might be misinterpreted as HCC and specific imaging features are lacking. Personal history and epidemiological data are mandatory in interpreting CEUS findings of a focal liver lesion even when the imaging pattern is highly suggestive of HCC

Regorafenib Combined with Other Systemic Therapies: Exploring Promising Therapeutic Combinations in HCC

: Regorafenib was the first drug to demonstrate a survival benefit as a second-line agent after sorafenib failure in patients with unresectable hepatocellular carcinoma (HCC). Recent studies have shown that its mechanism of action is not only limited to its very broad spectrum of inhibition of angiogenesis, tumor proliferation, spread, and metastasis, but also to its immunomodulatory properties that have favorable effects on the very intricate role that the tumor microenvironment plays in carcinogenesis and tumor growth. In this review, we discuss rationale and evidence supporting regorafenib efficacy in HCC and that led to its approval as a second-line treatment, after sorafenib failure. We also discuss the evidence from clinical practice studies that confirm the results previously achieved in clinical trials. Finally, we analyze the potential role of regorafenib in emerging combined treatment approach with immunotherapy strategies using immune checkpoint blockade and its potential extension to patient categories not included in the registrative study

Contrast-Enhanced Ultrasound LI-RADS LR-5 in Hepatic Tuberculosis: Case Report and Literature Review of Imaging Features

Background: The liver is involved in disseminated tuberculosis in more than 80% of cases while primary liver involvement is rare, representing <1% of all cases. Hepatic tuberculosis (TB) can be treated by conventional anti-TB therapy; however, diagnosing this disease remains a challenge. The diagnosis might be particularly difficult in patients with a single liver lesion that could be misdiagnosed as a tumor or other focal liver lesions. Although computed tomography (CT) and magnetic resonance imaging (MRI) findings have been described, there is a paucity of literature on contrast-enhanced ultrasound (CEUS) features of hepatic TB. Case Summary: herein, we describe a case of a patient with tuberculous lymphadenopathy and chronic Hepatitis C Virus (HCV)-related liver disease who developed a single macronodular hepatic TB lesion. Due to the finding of a hepatocellular carcinoma (HCC) highly suggestive CEUS pattern, specifically a LR5 category according to the Liver Imaging Reporting and Data System (LI-RADS), and a good response to antitubercular therapy, a non-invasive diagnosis of HCC was made, and the patient underwent liver resection. We also review the published literature on imaging features of hepatic TB and discuss the diagnostic challenge represented by hepatic TB when occurs as a single focal liver lesion. Conclusions: this report shows for the first time that the CEUS pattern of hepatic TB might be misinterpreted as HCC and specific imaging features are lacking. Personal history and epidemiological data are mandatory in interpreting CEUS findings of a focal liver lesion even when the imaging pattern is highly suggestive of HCC

Effects of a New Human Recombinant MnSOD in the Treatment of Photoaging and Actinic Keratosis.

Physiological processes, as aerobic metabolism and inflammatory response, generate reactive oxygen species (ROS) that may induce cellular injury when their amount is increased and antioxidant defense mechanisms are overwhelmed. Also, ROS are generated following UV skin irradiation able to deplete the natural antioxidant defenses in the skin. The increase in exposure to UV may lead to photoaging and precancerous skin lesions (actinic keratosis). New antioxidant strategies in the prevention and therapy of skin lesions are urgently needed. In this study, we evaluated the antioxidant efficacy of a recombinant form of human manganese superoxide dismutase able to inhibit reactive oxygen species pro- duction in some patients affected by severe photoaging and actinic keratosi

Effects of a New Human Recombinant MnSOD in the Treatment of Photoaging and Actinic Keratosis

Physiological processes, as aerobic metabolism and inflammatory response, generate reactive oxygen species (ROS) that may induce cellular injury when their amount is increased and antioxidant defense mechanisms are overwhelmed. Also, ROS are generated following UV skin irradiation able to deplete the natural antioxidant defenses in the skin. The increase in exposure to UV may lead to photoaging and precancerous skin lesions (actinic keratosis). New antioxidant strategies in the prevention and therapy of skin lesions are urgently needed. In this study, we evaluated the antioxidant efficacy of a recombinant form of human manganese superoxide dismutase able to inhibit reactive oxygen species production in some patients affected by severe photoaging and actinic keratosis

Effetti della rMnSOD nella terapia delle discheratosi attiniche

Gli UV sono in grado di indurre modificazioni sia quantitative che qualitative delle cellule immunocompetenti e possono alterare l’immuno-sorveglianza verso i tumori cutanei. L’irradiazione ultravioletta stimola i cheratinociti a secernere citochine e fattori di crescita che intervengono sulle cellule deputate alla risposta immunitaria (Santoianni, 2003 ). Dati sperimentali, epidemiologici e clinici negli ultimi anni hanno messo in evidenza l’importanza dell’ultravioletto lungo nella genesi di cheratosi attiniche (Nino 2006). Organismi esposti a radiazioni ionizzanti sono principalmente danneggiati dai radicali liberi, generati dalla radiolisi dell'acqua contenuta nelle cellule. Inoltre è stata dimostrata una significativa riduzione del danno tissutale da irradiazione utilizzando trattamenti con una manganese superossido dismutasi. Le superossido dismutasi (SOD) sono enzimi che hanno un ruolo chiave nella prevenzione di tutte le patologie determinate dal danno ossidativo (Borrelli et al., 2009). Le SOD sono implicate nella difesa antiossidante di quasi tutte le cellule, poiché catalizzano la dismutazione del radicale superossido a perossido d’idrogeno che, successivamente, è convertito in ossigeno e acqua dall’enzima catalasi. Questi enzimi hanno la capacità di prevenire il danno provocato dagli alti livelli di ROS prodotti, in particolare da radiazioni ionizzanti (Epperly et al., 2003). Nelle cellule sono presenti tre isoforme: la SOD 1 è localizzata nel citosol, la SOD 2 nella matrice mitocondriale, mentre la SOD 3 è secreta nello spazio extracellulare (Oberley, 2005). L’isoforma SOD 2, conosciuta anche come manganese superossido dismutasi (MnSOD), ricopre un ruolo di notevole importanza nella conversione del radicale superossido (O2.-) nei mitocondri e, dunque, rappresenta la prima linea di difesa contro questo radicale (Wang et al., 2001). Recentemente nel laboratorio di ricerca del dott. Aldo Mancini (Istituto Nazionale Tumori G.Pascale) è stata isolata un’isoforma di SOD da cellule di liposarcoma umano in coltura (LSA-Type MnSOD) che ha mostrato sia in vivo che in vitro una azione citotossica specifica e selettiva solo per le cellule esprimenti il recettore per gli estrogeni. Pur avendo la stessa attività enzimatica comune a tutte le SOD, la LSA-Type MnSOD si differenzia dalla sua corrispondente nativa per la presenza del peptide leader (da 24 amminoacidi), evidentemente non clivato, che le conferisce la peculiare capacità di penetrare in tutte le cellule. Tale proteina è stata riprodotta in forma ricombinante, rMnSOD, a partire da uno specifico clone di cDNA derivato da cellule di liposarcoma umano (Mancini et al., 2006). La rMnSOD è risultata, in vitro, essere radioprotettiva per le cellule normali e radiosensibilizzante per quelle tumorali. Inoltre, animali sani, esposti a dosi letali di radiazioni ionizzanti in presenza della rMnSOD (1,4 µM), mediante iniezioni s.c. sono sopravvissuti al danno radiante rimanendo vivi 30 giorni dopo l'irradiazione, tempo in cui è stato interrotta il controllo della loro sopravvivenza. Al contrario, animali irradiati con le stessse dosi letali, in assenza della rMnSOD, morivano dopo 7-8 giorni dall’irradiazione (Borrelli et al.2009). La notevole capacità enzimatica della rMnSOD, in formulazione topica, di neutralizzare i radicali liberi che incontra e che si accumulano nei tessuti danneggiati da qualsivoglia noxa patogena, è stata dimostrata, inoltre, con il suo utilizzo nella cura di una necrosi profonda ed estesa a testa, collo, e natatoie di un esemplare di tartaruga marina Caretta caretta. Il trattamento topico di tali esemplari con rMnSOD ha consentito una piena restitutio ad integrum anche nei siti delle necrosi che avevano provocato esposizione dell'osso (Occhiello A. et al 2009). Sulla base dei risultati precedentemente ottenuti è stato allestito uno studio su pazienti afferenti alla Dermatologia dell'Ospedale Ascalesi di Napoli, i quali si sono spontaneamente dichiarati disponibili al trattamento con la formulazione cosmetica contenente la rMnSOD, Sono stati arruolati per lo studio 30 pazienti di entrambi i sessi di eta’ compresa tra i 35 e i 70 anni con fotodanno medio severo con presenza di discheratosi attiniche. I pazienti hanno praticato terapia topica con una formulazione O/A a base di rMnSOD, mattina e sera per due mesi. Ogni settimana è stato effettuato un controllo e sono state fotografate le lesioni per monitorare l'effetto della terapia. Già nella prima settimana è stato osservata una diminuzione dello stato infiammatorio in tutti i pazienti trattati. A due mesi di trattamento è stato osservato miglioramento consistente del fotodanno, migliorata la compattezza e la luminosità della cute con riduzione della elastosi solare e scomparsa o regressione parziale delle discheratosi. La formulazione topica della rMnSOD merita di essere considerata come un promettente farmaco con potente azione antiinfiammatoria utilizzabile in dermatologia. • Borrelli A, Schiattarella A, Mancini R, Morrica B, Cerciello V, Mormile M, d'Alesio V, Bottalico L, Morelli F, D'Armiento M, D'Armiento FP, Mancini A. Free Radical Biology and Medicine. 2009 Jan 1;46(1):110-6. Epub 2008 . • Epperly M.W., Gretton J. E., Sikora C.A., Jefferson M., Bernarding M., Nie S. and Greenberger J.S. (2003). Radiation Research. 160 (5): 568-578. • Mancini A., Borrelli A., Schiattarella A., Fasano S., Occhiello A., Pica A., Sher P., Tommasino M., Nüesch J. P. F. and Rommelaere J. (2006). International Journal of Cancer. 119 (4): 932-943. • Oberley L.W. Biomedicine & Pharmacotherapy. 59 (4): 143-148. • Occhiello A., Bentivegna F., Borrelli A., Schiattarella A., Mancini A., Pica A. Comparative clinical Pathology. DOI 10.1007/s00580-009-0816-9 • Wang L.I., Miller D.P., Sai Y., Liu G., Su L., Wain J.C., Lynch T.J. and Christiani D.C. (2001). Journal of the National Cancer Institute. 93 (23): 1818-1821. • Santoianni P., Nino M. Giornale italiano di dermatologia e venereologia. 2003. 138(6):455-64 • Nino M., Santoianni P. . Giornale italiano di dermatologia e venereologia 2006. 141(5):471-

Estimation of DNA Degradation in Archaeological Human Remains

The evaluation of the integrity and quantity of DNA extracted from archaeological human remains is a fundamental step before using the latest generation sequencing techniques in the study of evolutionary processes. Ancient DNA is highly fragmented and chemically modified; therefore, the present study aims to identify indices that can allow the identification of potentially amplifiable and sequenceable DNA samples, reducing failures and research costs. Ancient DNA was extracted from five human bone remains from the archaeological site of Amiternum L’Aquila, Italy dating back to the 9th–12th century and was compared with standard DNA fragmented by sonication. Given the different degradation kinetics of mitochondrial DNA compared to nuclear DNA, the mitochondrially encoded 12s RNA and 18s ribosomal RNA genes were taken into consideration; fragments of various sizes were amplified in qPCR and the size distribution was thoroughly investigated. DNA damage degree was evaluated by calculating damage frequency (λ) and the ratio between the amount of the different fragments and that of the smallest fragment (Q). The results demonstrate that both indices were found to be suitable for identifying, among the samples tested, those less damaged and suitable for post-extraction analysis; mitochondrial DNA is more damaged than nuclear, in fact, amplicons up to 152 bp and 253 bp, respectively are obtained