Design of Allosteric Stimulators of the Hsp90 ATPase as New Anticancer Leads

Allosteric compounds that stimulate Hsp90 adenosine triphosphatase (ATPase) activity were rationally designed, showing anticancer potencies in the low micromolar to nanomolar range. In parallel, the mode of action of these compounds was clarified and a quantitative model that links the dynamic ligand-protein cross-talk to observed cellular and in vitro activities was developed. The results support the potential of using dynamics-based approaches to develop original mechanism-based cancer therapeutics

Time series aggregation, disaggregation and long memory

We study the aggregation/disaggregation problem of random parameter AR(1) processes and its relation to the long memory phenomenon. We give a characterization of a subclass of aggregated processes which can be obtained from simpler, "elementary", cases. In particular cases of the mixture densities, the structure (moving average representation) of the aggregated process is investigated

Improvement in the removal of micropollutants at Porto Marghera industrial wastewaters treatment plant by MBR technology.

This paper deals with the case of one of the most important industrial application of membrane technology in the world: the upgrading of the main industrial wastewater treatment plant (WWTP) of the petrochemical site of Porto Marghera, Northern Italy, completed on December 2005 and tested on September 2006. It describes the principal interventions of the plant upgrading and it discusses the removal obtained during the test periods for conventional pollutants as well as for micropollutants. The plant upgrading consisted of a series of improvements of the existing industrial WWTP, in order to increase the removal efficiency of the total suspended solids and the associate removal of ten micropollutant compounds, the so called forbidden substances. The most important intervention was the conversion of the existing activated sludge section into a membrane biological reactor, in order to guarantee adherence to the severe limits imposed by the special law issued to protect the Venice Lagoon, with particular reference to the mentioned 10 forbidden compounds. The experimental results and the numerous test-runs conducted confirmed the respect of the legal limits for the pollutants in the final effluent as well of the required removal rates for the different parameters. Therefore, the upgraded treatment plant was declared agreeing with the approved design

A real world experience with fingolimod in active RRMS patients naïve to second-line agents: a 2 years, intention-to-treat, observational, single center study

Fingolimod is approved by EMA as a second-line treatment for relapsing-remitting multiple sclerosis (RRMS). Experience with fingolimod in real life is still limited. Aim of our study was to report data on fingolimod effectiveness in a real life cohort of Italian active RRMS patients, naive to second-line agents, followed for 2 years. Fingolimod was a part of the patients' regular treatment and is produced by Novartis. We included all consecutive RRMS patients starting fingolimod at our center according to EMA criteria before January 1st 2013. Exclusion criteria were a previous treatment with natalizumab or an immunosuppressant therapy in the previous 12 months. All patients were clinically evaluated quarterly, and performed brain MRI yearly. Definition of "no evidence of disease activity" (NEDA-3): no relapses, no brain MRI activity and no 6-months confirmed worsening in EDSS score. We included 38 RRMS patients, 35 switched from first-line injectable therapies. Six patients were also previously treated with immunosuppressants (5 mitoxantrone, 1 cyclophosphamide). At 24th month 34 patients continued fingolimod treatment. Main adverse events were infections (18 %), liver-enzymes elevation (8 %), and leukopenia (8 %). After 12 and 24 months 79 and 63 % of patients were relapses-free. Fingolimod significantly reduced ARR compared to the previous year (0.3 ± 0.6 vs 1.2 ± 0.5; p < 0.001). After 12 and 24 months 63 and 37 % of patients had NEDA-3. Previous use of immunosuppressants and an ARR ≥1 in the 2 years predicted disease activity. Fingolimod significantly reduce disease activity in active RRMS patients, with no severe/unexpected safety issues. Patients previously treated with immunosuppressants and with a higher ARR at baseline may respond less to fingolimod treatment

Activity of a trinuclear platinum complex in human ovarian cancer cell lines sensitive and resistant to cisplatin: cytotoxicity and induction and gene-specific repair of DNA lesions

A collateral sensitivity or a very modest cross-resistance to BBR 3464 was found in 2 ovarian cancer cell lines with experimentally induced resistance to cisplatin. Loss of mismatch repair proteins (hMLH1, hPMS2) or overexpression of nucleotide excision repair proteins (ERCC1) was not detrimental for the cellular sensitivity to BBR 3464. Moreover, interesting differences in the kinetics of formation and removal of DNA lesions at the single-gene (N- ras) level were observed between BBR 3464 and CDDP. © 2001 Cancer Research Campaign www.bjcancer.co

High level of telomerase RNA gene expression is associated with chromatin modification, the ALT phenotype and poor prognosis in liposarcoma

Telomere length is maintained by two known mechanisms, activation of telomerase or alternative lengthening of telomeres (ALT). The ALT pathway is more commonly activated in tumours of mesenchymal origin, although the mechanisms involved in the decision of a cell to activate either telomerase or ALT are unknown at present and no molecular markers exist to define the ALT phenotype. We have previously shown an association between chromatin remodelling, telomerase gene expression and ALT in cell line models. Here, we evaluate these findings and investigate their prognostic significance in a panel of liposarcoma tissue samples to understand the biology underlying the ALT phenotype. Liposarcoma samples were split into three groups: telomerase positive (Tel+); ALT positive; ALT−/Tel−. Differences in telomerase gene expression were evident between the groups with increased expression of hTR in ALT and Tel+ compared to ALT−/Tel− samples and increased hTERT in Tel+ samples only. Investigation of a small panel of chromatin modifications revealed significantly increased binding of acetyl H3 in association with hTR expression. We confirm that the presence of the ALT phenotype is associated with poor prognosis and in addition, for the first time, we show a direct association between hTR expression and poor prognosis in liposarcoma patients

Vitamin D status in cord blood and newborns: ethnic differences.

BACKGROUND: A deficiency in vitamin D (25OHD) is common throughout the world in both adults and children, being related to skin pigmentation, sun exposure, dietary intake and obesity. Limited data are available for the neonatal age. The aim of the study is to understand the differences in 25OHD levels with respect to skin colour and ethnicity in newborns. METHODS: We randomly enrolled 62 neonates, born at term and appropriate for gestational age. Thirty two were born from Italian mothers with fair skin (FS) and 30 from non-Caucasian mothers (North African, African, Asian and Latin American): 10 with light olive/light brown (LOB) and 20 with medium brown/black skin (MBB). Vitamin D was measured in the cord blood at birth and in neonatal serum during metabolic screening. RESULTS: 25OHD levels were (mean\u2009\ub1\u2009SD) 21.4\u2009\ub1\u200911 ng/ml in cord blood and 14.9\u2009\ub1\u20097 ng/ml in serum after birth. 25OHD values were higher in cord blood (p\u2009<\u20090.01) and neonatal serum (p\u2009<\u20090.001) in subjects supplemented with Vitamin D. Newborn FS showed higher vitamin D levels in cord blood when compared to LOB and MBB (p\u2009<\u20090.01), and higher levels in neonatal serum when compared to LOB (p\u2009<\u20090.01). In cord blood, 25OHD levels were higher in Italian newborns than in North African (p\u2009<\u20090.004) and African (p\u2009<\u20090.01). In neonatal serum, 25OHD levels were higher in Italian infants only when compared with North African infants (p\u2009<\u20090.03). CONCLUSIONS: The present study shows a high prevalence of vitamin D insufficiency and deficiency in newborns with significant differences observed to be due to ethnicity, skin colour and maternal supplementation during the pregnancy

Structural requirements of benzofuran derivatives dehydro-&#948;-and dehydro-&#949;-viniferin for antimicrobial activity against the foodborne pathogen listeria monocytogenes

In a recent study, we investigated the antimicrobial activity of a collection of resveratrol-derived monomers and dimers against a series of foodborne pathogens. Out of the tested molecules, dehydro-\u3b4-viniferin and dehydro-\u3b5-viniferin emerged as the most promising derivatives. To define the structural elements essential to the antimicrobial activity against the foodborne pathogen L. monocytogenes Scott A as a model Gram-positive microorganism, the synthesis of a series of simplified benzofuran-containing derivatives was carried out. The systematic removal of the aromatic moieties of the parent molecules allowed a deeper insight into the most relevant structural features affecting the activity. While the overall structure of compound 1 could not be altered without a substantial loss of antimicrobial activity, the structural simplification of compound 2 (minimal inhibitory concentration (MIC) 16 \u3bc\ub5g/mL, minimal bactericidal concentration (MBC) &gt;512 \u3bc\ub5g/mL) led to the analogue 7 with increased activity (MIC 8 \u3bc\ub5g/mL, MBC 64 \u3bc\ub5g/mL)

Machine Learning-Based Models for Prediction of Toxicity Outcomes in Radiotherapy

In order to limit radiotherapy (RT)-related side effects, effective toxicity prediction and assessment schemes are essential. In recent years, the growing interest toward artificial intelligence and machine learning (ML) within the science community has led to the implementation of innovative tools in RT. Several researchers have demonstrated the high performance of ML-based models in predicting toxicity, but the application of these approaches in clinics is still lagging, partly due to their low interpretability. Therefore, an overview of contemporary research is needed in order to familiarize practitioners with common methods and strategies. Here, we present a review of ML-based models for predicting and classifying RT-induced complications from both a methodological and a clinical standpoint, focusing on the type of features considered, the ML methods used, and the main results achieved. Our work overviews published research in multiple cancer sites, including brain, breast, esophagus, gynecological, head and neck, liver, lung, and prostate cancers. The aim is to define the current state of the art and main achievements within the field for both researchers and clinicians