Cisplatin liposome and 6-amino nicotinamide combination to overcome drug resistance in ovarian cancer cells

Ovarian cancer is an aggressive and lethal cancer usually treated by cytoreductive surgery followed by chemotherapy. Unfortunately, after an initial response, many patients relapse owing mainly to the development of resistance against the standard chemotherapy regime, carboplatin/paclitaxel, which is also affected by heavy side effects. In view to addressing such issues here, an association of liposomal cisplatin with 6-amino nicotinamide is investigated. It is known that resistant cells increase their demand for glucose, which is partially redirected toward the pentose phosphate pathway (PPP). Interestingly, we have found that also a cisplatin-resistant subclone of the ovarian cancer cells IGROV1 switch their metabolism toward the glycolytic pathway and rely on PPP to elude cisplatin cytotoxicity. The drug 6-amino nicotinamide, an inhibitor of the enzyme glucose-6-phosphate dehydrogenase (the rate-limiting step of the PPP) can restore the sensitivity of resistant cells to cisplatin. Then, to reduce the toxicity of cisplatin and prolong its action, a lyophilized stealth liposomal formulation of cisplatin was developed. The combination treatment of liposomal cisplatin and 6-amino nicotinamide showed promising cytotoxic activities in drug-resistant cells and a prolonged pharmacokinetics in rats, thus opening the way for a new therapeutic option against ovarian cancer

Nuovi dati stratigrafici sull’ambra di Castelvecchio di Prignano (MO)

L’ambra dell’Appennino settentrionale è nota nel Bolognese fin dal XVII secolo (Masini, 1650; Boccone, 1684). La prima segnalazione dal Modenese risale a Strobel (1886), che parla di ambra da “Sassuolo nella provincia di Modena”; l’età di tale ambra rimane però indefinita. Skalski & Veggiani (1990), nella loro rassegna di ambre della Sicilia e dell’Appennino settentrionale, attribuiscono l’ambra del Bolognese (Scanello vicino a Loiano, provincia di Bologna) alla Formazione di Ranzano (o Loiano? L’equivalenza tra le due formazioni dichiarata dagli autori non è valida), assegnandole all’Oligocene inferiore. L’ambra del Modenese, più precisamente localizzata da Skalski & Veggiani (1990) nelle “Castelvecchio sandstones” (sic), vicino a Prignano (MO), viene dagli stessi autori attribuita alla Formazione di Ranzano e quindi datata anch’essa all’Oligocene inferiore. Angelini & Bellintani (2005), nella loro rassegna sulle ambre di provenienza archeologica dell’Italia settentrionale, hanno analizzato con metodi spettroscopici ambre di Scanello Bolognese (BO) e di Castelvecchio di Prignano (MO), evidenziando una marcata differenza tra i campioni provenienti dal Bolognese e dal Modenese. Inoltre, l’attribuzione dell’ambra di Castelvecchio all’Oligocene non è sostenuta da alcun dato diretto, se si esclude una possibile somiglianza litologica tra gli strati campionati e quelli della Formazione di Ranzano. In sintesi, l’attribuzione di un’età oligocenica all’ambra proveniente da Castelvecchio di Prignano risulta quantomeno dubbia. Un affioramento contenente ambra da questa località del Modenese è stato recentemente localizzato con precisione, misurato e campionato. L’esposizione comprende circa 5 m di successione, costituita da arenarie più o meno calcaree intercalate a livelli siltitici e argillosi variamente bioturbati. All’interno dei livelli arenitici (di solito nella loro parte superiore) si trovano livelli ricchi di frustoli vegetali, contenenti ambra e pezzi di carbone. L’ambra si presenta in frammenti e gocce, generalmente di colore rosso molto scuro, di dimensioni che vanno da 0,5 cm fino a oltre 6-7 cm. Al momento non sono state osservate inclusioni animali, soltanto alcuni minuscoli frammenti carboniosi che rendono scuro il colore della resina fossile. Sull’ambra è stata effettuata l’analisi agli infrarossi a trasformata di Fourier (FTIR). Per chiarire il contesto stratigrafico della resina fossile di Castelvecchio, sono stati raccolti campioni per lo studio del plancton calcareo, che ha consentito di attribuire i livelli fossiliferi alla parte superiore del Maastrichtiano. Questo dato diretto ha permesso, per la prima volta, di far risalire un’ambra dell’Appennino settentrionale al Cretaceo, diversamente da quanto finora riportato in letteratura. Bibliografia: Angelini I. & Bellintani P. (2005). Archaeological ambers from Northern Italy: an FTIR-DRIFT study of provenance by comparison with the geological amber database. Archaeometry, 47: 441-454. Boccone P. (1684). Osservazioni naturali ove si contengono Materie Medico-Fisiche, e di Botanica, Produzioni Naturali, Fosfori diversi, Fuochi sotterranei d’Italia, et altre curiosità. Manolessi Stamp., Bologna, p. 156-157. Masini A. (1650). Bologna perlustrata. Zenero, Bologna, p. 180. Skalski A.W. & Veggiani A. (1990). Fossil Resin in Sicily and the Northern Apennines: Geology and Organic content. Prace Muzeum Ziemi, 41: 37-49. Strobel P. (1886). L’ambra padana. Bullettino di Paletnologia Italiana, 12: 42-49

TERT Promoter Mutations in Papillary Thyroid Microcarcinomas

Small papillary thyroid carcinomas have contributed to the worldwide increased incidence of differentiated thyroid cancer observed over the past decades. However, the mortality rate has not changed over the same period of time, raising questions about the possibility that thyroid cancer patients, especially those with small tumors, are overdiagnosed and overtreated. Molecular prognostic marker able to discriminate aggressive thyroid cancers from those with an indolent course would be of great relevance to tailor the therapeutic approach and reduce overtreatment. Mutations in the TERT promoter were recently reported to correlate strongly with aggressiveness in advanced forms of thyroid cancer, holding promise for a possible clinical application. The occurrence and potential clinical relevance of TERT mutations in papillary thyroid microcarcinomas (mPTCs) is currently unknown. This study aimed to analyze the occurrence of two TERT promoter mutations (-124C>T and -146C>T) and their potential association with unfavorable clinical features in a large cohort of mPTCs

Inhibition of glucose-6-phosphate dehydrogenase sensitizes cisplatin-resistant cells to death.

The mechanisms of cisplatin resistance, one of the major limitations of current chemotherapy, has only partially been described. We previously demonstrated that cisplatin-resistant ovarian cancer cells (C13), are characterized by reduced mitochondrial activity and higher glucose-dependency when compared to the cisplatin-sensitive counterpart (2008). In this work we further characterized the role of metabolic transformation in cisplatin resistance. By using transmitochondrial hybrids we show that metabolic reprogramming of cisplatin-resistant cell is not caused by inherent mtDNA mutations. We also found that C13 cells not only present an increased glucose-uptake and consumption, but also exhibit increased expression and enzymatic activity of the Pentose Phosphate pathway (PPP) enzyme Glucose-6-Phosphate Dehydrogenase (G6PDH). Moreover, we show that cisplatin-resistant cells are more sensitive to G6PDH inhibition. Even if the metabolomic fingerprint of ovarian cancer cells remains to be further elucidated, these findings indicate that PPP offers innovative potential targets to overcome cisplatin resistance.This work was financially supported by PRAT (University of Padova), grant no. CPDA124517/12 and MIUR grant no 60A04–0443. DC fellowship was supported by grant no. CPDR134012. AR was supported by the AIRC grant no. IG 15863 and by the University of Padova grant no. CPDA 123598.This is the final version of the article. It first appeared from Impact Journals via http://dx.doi.org/10.18632/oncotarget.494

Contrast-enhanced spectral mammography in neoadjuvant chemotherapy monitoring: a comparison with breast magnetic resonance imaging

Background: Neoadjuvant-chemotherapy (NAC) is considered the standard treatment for locally advanced breast carcinomas. Accurate assessment of disease response is fundamental to increase the chances of successful breast-conserving surgery and to avoid local recurrence. The purpose of this study was to compare contrast-enhanced spectral mammography (CESM) and contrast-enhanced-MRI (MRI) in the evaluation of tumor response to NAC.Methods: This prospective study was approved by the institutional review board and written informed consent was obtained. Fifty-four consenting women with breast cancer and indication of NAC were consecutively enrolled between October 2012 and December 2014. Patients underwent both CESM and MRI before, during and after NAC. MRI was performed first, followed by CESM within 3 days. Response to therapy was evaluated for each patient, comparing the size of the residual lesion measured on CESM and MRI performed after NAC to the pathological response on surgical specimens (gold standard), independently of and blinded to the results of the other test. The agreement between measurements was evaluated using Lin's coefficient. The agreement between measurements using CESM and MRI was tested at each step of the study, before, during and after NAC. And last of all, the variation in the largest dimension of the tumor on CESM and MRI was assessed according to the parameters set in RECIST 1.1 criteria, focusing on pathological complete response (pCR).Results: A total of 46 patients (85%) completed the study. CESM predicted pCR better than MRI (Lin's coefficient 0.81 and 0.59, respectively). Both methods tend to underestimate the real extent of residual tumor (mean 4.1mm in CESM, 7.5mm in MRI). The agreement between measurements using CESM and MRI was 0.96, 0.94 and 0.76 before, during and after NAC respectively. The distinction between responders and non-responders with CESM and MRI was identical for 45/46 patients. In the assessment of CR, sensitivity and specificity were 100% and 84%, respectively, for CESM, and 87% and 60% for MRI.Conclusion: CESM and MRI lesion size measurements were highly correlated. CESM seems at least as reliable as MRI in assessing the response to NAC, and may be an alternative if MRI is contraindicated or its availability is limited

The Others in Europe

This edited volume addresses the construction of identity classifications underlying the new forms of inclusion and exclusion that are to be found in contemporary Europe. Its scope covers practices of categorization and of resistance, both by majority groups

Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV

The performance of muon reconstruction, identification, and triggering in CMS has been studied using 40 inverse picobarns of data collected in pp collisions at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection criteria covering a wide range of physics analysis needs have been examined. For all considered selections, the efficiency to reconstruct and identify a muon with a transverse momentum pT larger than a few GeV is above 95% over the whole region of pseudorapidity covered by the CMS muon system, abs(eta) < 2.4, while the probability to misidentify a hadron as a muon is well below 1%. The efficiency to trigger on single muons with pT above a few GeV is higher than 90% over the full eta range, and typically substantially better. The overall momentum scale is measured to a precision of 0.2% with muons from Z decays. The transverse momentum resolution varies from 1% to 6% depending on pseudorapidity for muons with pT below 100 GeV and, using cosmic rays, it is shown to be better than 10% in the central region up to pT = 1 TeV. Observed distributions of all quantities are well reproduced by the Monte Carlo simulation.Comment: Replaced with published version. Added journal reference and DO

Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV

The performance of muon reconstruction, identification, and triggering in CMS has been studied using 40 inverse picobarns of data collected in pp collisions at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection criteria covering a wide range of physics analysis needs have been examined. For all considered selections, the efficiency to reconstruct and identify a muon with a transverse momentum pT larger than a few GeV is above 95% over the whole region of pseudorapidity covered by the CMS muon system, abs(eta) < 2.4, while the probability to misidentify a hadron as a muon is well below 1%. The efficiency to trigger on single muons with pT above a few GeV is higher than 90% over the full eta range, and typically substantially better. The overall momentum scale is measured to a precision of 0.2% with muons from Z decays. The transverse momentum resolution varies from 1% to 6% depending on pseudorapidity for muons with pT below 100 GeV and, using cosmic rays, it is shown to be better than 10% in the central region up to pT = 1 TeV. Observed distributions of all quantities are well reproduced by the Monte Carlo simulation.Comment: Replaced with published version. Added journal reference and DO

X-ray emission from the Sombrero galaxy: discrete sources

We present a study of discrete X-ray sources in and around the bulge-dominated, massive Sa galaxy, Sombrero (M104), based on new and archival Chandra observations with a total exposure of ~200 ks. With a detection limit of L_X = 1E37 erg/s and a field of view covering a galactocentric radius of ~30 kpc (11.5 arcminute), 383 sources are detected. Cross-correlation with Spitler et al.'s catalogue of Sombrero globular clusters (GCs) identified from HST/ACS observations reveals 41 X-rays sources in GCs, presumably low-mass X-ray binaries (LMXBs). We quantify the differential luminosity functions (LFs) for both the detected GC and field LMXBs, whose power-low indices (~1.1 for the GC-LF and ~1.6 for field-LF) are consistent with previous studies for elliptical galaxies. With precise sky positions of the GCs without a detected X-ray source, we further quantify, through a fluctuation analysis, the GC LF at fainter luminosities down to 1E35 erg/s. The derived index rules out a faint-end slope flatter than 1.1 at a 2 sigma significance, contrary to recent findings in several elliptical galaxies and the bulge of M31. On the other hand, the 2-6 keV unresolved emission places a tight constraint on the field LF, implying a flattened index of ~1.0 below 1E37 erg/s. We also detect 101 sources in the halo of Sombrero. The presence of these sources cannot be interpreted as galactic LMXBs whose spatial distribution empirically follows the starlight. Their number is also higher than the expected number of cosmic AGNs (52+/-11 [1 sigma]) whose surface density is constrained by deep X-ray surveys. We suggest that either the cosmic X-ray background is unusually high in the direction of Sombrero, or a distinct population of X-ray sources is present in the halo of Sombrero.Comment: 11 figures, 5 tables, ApJ in pres