Search

Supplementary Figure 1. Sample simulated time-course of paclitaxel and MLN8237 PK after and the pharmacokinetic parameters used for MLN8237 and paclitaxel required to generate the exposure - efficacy model. Supplementary Figure 2. Predicted versus observed % TGI resulting from the best fit of the dose response surface to the xenograft tumor growth data. Supplementary Figure 3. Cleaved caspase 3 staining of tumor xenografts following single agent or combination treatment with MLN8237 and docetaxel in the PHTX-14B and MDA-MB-231 xenografts. Supplementary Figure 4. MLN8237 administered on an intermittent 3 days on / 4 days off schedule combined with paclitaxel results in additive antitumor activity in the MDA-MB-231 model. Supplementary Figure 5. MLN8237 and paclitaxel exposures are similar when dosed alone or in combination.

PDF file, 42KB, Pharmacokinetic profiles of plasma and OCI-LY19-Luc tumor tissue in mice treated with a single oral dose of MLN0905.

PDF file, 45KB, MLN0905 yields significant anti-tumor responses in mice bearing subcutaneous OCI LY-19-Luc tumors.

PDF file, 43KB, Evaluating pHisH3 in OCI LY-19-Luc and OCI LY-10 cells following MLN0905 treatment.

Diffuse large B-cell lymphoma (DLBCL) is the most common of the non–Hodgkin lymphomas, accounting for up to 30% of all newly diagnosed lymphoma cases. Current treatment options for this disease are effective, but not always curative; therefore, experimental therapies continue to be investigated. We have discovered an experimental, potent, and selective small-molecule inhibitor of PLK1, MLN0905, which inhibits cell proliferation in a broad range of human tumor cells including DLBCL cell lines. In our report, we explored the pharmacokinetic, pharmacodynamic, and antitumor properties of MLN0905 in DLBCL xenograft models grown in mice. These studies indicate that MLN0905 modulates the pharmacodynamic biomarker phosphorylated histone H3 (pHisH3) in tumor tissue. The antitumor activity of MLN0905 was evaluated in three human subcutaneous DLBCL xenograft models, OCI LY-10, OCI LY-19, and PHTX-22L (primary lymphoma). In each model, MLN0905 yielded significant antitumor activity on both a continuous (daily) and intermittent dosing schedule, underscoring dosing flexibility. The antitumor activity of MLN0905 was also evaluated in a disseminated xenograft (OCI LY-19) model to better mimic human DLBCL disease. In the disseminated model, MLN0905 induced a highly significant survival advantage. Finally, MLN0905 was combined with a standard-of-care agent, rituximab, in the disseminated OCI LY-19 xenograft model. Combining rituximab and MLN0905 provided both a synergistic antitumor effect and a synergistic survival advantage. Our findings indicate that PLK1 inhibition leads to pharmacodynamic pHisH3 modulation and significant antitumor activity in multiple DLBCL models. These data strongly suggest evaluating PLK1 inhibitors as DLBCL anticancer agents in the clinic. Mol Cancer Ther; 11(9); 2045–53. ©2012 AACR.

PDF file, 59KB.

PDF file, 44KB, Evaluating cell viability in DLBCL cell lines following MLN0905 treatment.

PDF file, 53KB, MLN0905 yields significant anti-tumor responses in mice bearing subcutaneous OCI LY-10 tumors.

PDF file, 48KB, Plasma and OCI LY-19-Luc tumor pharmacokinetic parameters following a single oral dose of MLN0905 in CB-17 SCID mice.

PDF file - 34K

Purpose: Small-molecule inhibitors of Aurora A (AAK) and B (ABK) kinases, which play important roles in mitosis, are currently being pursued in oncology clinical trials. We developed three novel assays to quantitatively measure biomarkers of AAK inhibition in vivo. Here, we describe preclinical characterization of alisertib (MLN8237), a selective AAK inhibitor, incorporating these novel pharmacodynamic assays.Experimental Design: We investigated the selectivity of alisertib for AAK and ABK and studied the antitumor and antiproliferative activity of alisertib in vitro and in vivo. Novel assays were used to assess chromosome alignment and mitotic spindle bipolarity in human tumor xenografts using immunofluorescent detection of DNA and alpha-tubulin, respectively. In addition, 18F-3′-fluoro-3′-deoxy-l-thymidine positron emission tomography (FLT-PET) was used to noninvasively measure effects of alisertib on in vivo tumor cell proliferation.Results: Alisertib inhibited AAK over ABK with a selectivity of more than 200-fold in cells and produced a dose-dependent decrease in bipolar and aligned chromosomes in the HCT-116 xenograft model, a phenotype consistent with AAK inhibition. Alisertib inhibited proliferation of human tumor cell lines in vitro and produced tumor growth inhibition in solid tumor xenograft models and regressions in in vivo lymphoma models. In addition, a dose of alisertib that caused tumor stasis, as measured by volume, resulted in a decrease in FLT uptake, suggesting that noninvasive imaging could provide value over traditional measurements of response.Conclusions: Alisertib is a selective and potent inhibitor of AAK. The novel methods of measuring Aurora A pathway inhibition and application of tumor imaging described here may be valuable for clinical evaluation of small-molecule inhibitors. Clin Cancer Res; 17(24); 7614–24. ©2011 AACR.

PDF file - 27K

PDF file - 65K

PDF file - 36K

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are cardiac hormones located in atria granules. Both peptides respond to cardiac pressure and volume dynamics and accordingly serve as translation biomarkers for the clinical treatment of heart failure. Serum ANP and BNP play central secretary roles in blood pressure and cardiac output regulation and have proven utility as differential biomarkers of cardiovascular proficiency and drug-induced maladaptation, yet both peptides are impervious to exercise-induced hypertrophy. We employed immunoelectron microscopy to examine the effects of 28 days of chronic swim exercise or administration of a PPARγ agonist on atrial granules and their stored natriuretic peptides in Sprague Dawley rats. Chronic swimming and drug treatment both resulted in a 15% increase in heart weight compared with controls, with no treatment effects on perinuclear granule area in the left atria (LAs). Drug treatment resulted in larger size granules with greater BNP density in the right atria. Comparing swimming and PPARγ agonist treatment effects on ANP:BNP granule density ratios between atrial chambers revealed a shift toward a greater proportion of ANP than BNP in LAs of swim-trained rats. These data suggest a distinction in the population of ANP and BNP after chronic swim or PPARγ that makes it a novel metric for the differentiation of pathological and physiological hypertrophy.

Hereditary haemorrhagic telangiectasia (HHT) is a complex, multisystemic vascular dysplasia affecting approximately 85,000 European Citizens. In 2016, eight founding centres operating within 6 countries, set up a working group dedicated to HHT within what became the European Reference Network on Rare Multisystemic Vascular Diseases. By launch, combined experience exceeded 10,000 HHT patients, and Chairs representing 7 separate specialties provided a median of 24 years' experience in HHT. Integrated were expert patients who focused discussions on the patient experience. Following a 2016–2017 survey to capture priorities, and underpinned by more than 40 monthly meetings, and new data acquisitions, VASCERN HHT generated position statements that distinguish expert HHT care from non-expert HHT practice. Leadership was by specialists in the relevant sub-discipline(s), and 100% consensus was required amongst all clinicians before statements were published or disseminated. One major set of outputs targeted all healthcare professionals and their HHT patients, and include the new Orphanet definition; Do's and Don'ts for common situations; Outcome Measures suitable for all consultations; COVID-19; and anticoagulation. The second output set span aspects of vascular pathophysiology where greater understanding will assist organ-specific specialist clinicians to provide more informed care to HHT patients. These cover cerebral vascular malformations and screening; mucocutaneous telangiectasia and differential diagnosis; anti-angiogenic therapies; circulatory interplays between anaemia and arteriovenous malformations; and microbiological strategies to counteract loss of normal pulmonary capillary function. Overall, the integrated outputs, and documented current practices, provide frameworks for approaches that augment the health and safety of HHT patients in diverse health-care settings.

Retinal dystrophies such as Retinitis pigmentosa are among the most prevalent causes of inherited legal blindness, for which treatments are in demand. Retinal prostheses have been developed to stimulate the inner retinal network that, initially spared by degeneration, deteriorates in the late stages of the disease. We recently reported that conjugated polymer nanoparticles persistently rescue visual activities after a single subretinal injection in the Royal College of Surgeons rat model of Retinitis pigmentosa. Here we demonstrate that conjugated polymer nanoparticles can reinstate physiological signals at the cortical level and visually driven activities when microinjected in 10-months-old Royal College of Surgeons rats bearing fully light-insensitive retinas. The extent of visual restoration positively correlates with the nanoparticle density and hybrid contacts with second-order retinal neurons. The results establish the functional role of organic photovoltaic nanoparticles in restoring visual activities in fully degenerate retinas with intense inner retina rewiring, a stage of the disease in which patients are subjected to prosthetic interventions.

RC buildings designed for gravity loads only or according to obsolete seismic codes are widespread worldwide also in seismic prone areas. Numerical and experimental studies highlighted that the presence of masonry infills in Reinforced Concrete (RC) frames leads to the increase in their lateral strength and stiffness. Nevertheless, post-earthquake observed damage showed that infills can also cause potential brittle failures due to the local interaction with structural elements, thus producing a limitation of deformation capacity of the surrounding frame, especially in sub-standard frames. A reliable modelling approach for the assessment of the as-built condition and the design of retrofitting solutions about this kind of failure is still needed. Experimental tests on RC frames designed according to obsolete technical codes and infilled with clay bricks have been performed and presented in this work. The frames have been cyclically loaded with a quasi-static displacement pattern to simulate the seismic action. The experimental occurrence of significant shear damages is discussed, and the main outcomes are described, commented and compared to each other. The work lastly provides further data and modelling remarks towards a reliable numerical simulation of local shear interaction phenomena between infills and RC frames.

L'articolo considera i sistemi di valutazione della produzione scientifica universitaria, la prospettiva in termini di public engagement, il supporto alle attività istituzionali, la carenza di banche dati che garantiscano l'accesso alle conoscenze ma anche alle competenze degli studiosi. Prendendo ad esempio l'anagrafe della ricerca sui temi delle mafie sviluppata attraverso una pubblicazione dagli stessi autori curata e realizzata con 30 studiosi, si prospettano delle soluzioni efficaci per rendere accessibile la produzione scientifica su singole tematiche. Il valore stesso dell'autonomia universitaria che si manifesta attraverso la libertà di ricerca può trovare una più efficace collocazione nei rapporti istituzionali a soddisfacimento di specifiche attività che necessitano di supporto scientifico.

Labour markets across the OECD have polarised in recent decades, as the share of middle skill occupations has declined relative to that of both high- and low skill occupations. This paper shows that, contrary to what is often assumed in the public debate, job polarisation has not resulted in a decline in the share of households with middle-income across 18 OECD countries. Most of the changes in the share of middle-income households result instead from changes in the propensity of workers in different occupations to be in it. In fact the results point to a change in the relationship between occupational skill levels and household income as both middle and high skill jobs increasingly fail to deliver on the promise of the relative income status traditionally associated with their skill level. These changes might help explain some of the social frustration that has been at the centre of the political debate in recent years.

Given the proven utility of natriuretic peptides as serum biomarkers of cardiovascular maladaptation and dysfunction in humans and the high cross-species sequence conservation of atrial natriuretic peptides, natriuretic peptides have the potential to serve as translational biomarkers for the identification of cardiotoxic compounds during multiple phases of drug development. This work evaluated and compared the response of N-terminal proatrial natriuretic peptide (NT-proANP) and N-terminal probrain natriuretic peptide (NT-proBNP) in rats during exercise-induced and drug-induced increases in cardiac mass after chronic swimming or daily oral dosing with a peroxisome proliferator-activated receptor γ agonist. Male Sprague-Dawley rats aged 8 to 10 weeks were assigned to control, active control, swimming, or drug-induced cardiac hypertrophy groups. While the relative heart weights from both the swimming and drug-induced cardiac hypertrophy groups were increased 15% after 28 days of dosing, the serum NT-proANP and NT-proBNP values were only increased in association with cardiac hypertrophy caused by compound administration. Serum natriuretic peptide concentrations did not change in response to adaptive physiologic cardiac hypertrophy induced by a 28-day swimming protocol. These data support the use of natriuretic peptides as fluid biomarkers for the distinction between physiological and drug-induced cardiac hypertrophy.

Table S1. Details of individual patients and treatments. (PDF 403 kb)

Table S2. Dosing regimes. (PDF 279 kb)

This paper provides an overview of the main trends in child income poverty since the mid-2000s, and explores to what extent child poverty trends are linked to demographic, policy and/or labour market changes. Trends in poverty and the standard of living of children in low-income families since the onset of the Great Recession are also closely examined: nearly 1 in 7 children is income-poor in the OECD, and child poverty increased in almost two/thirds of OECD countries with the Great Recession. About 1 in 10 children across the OECD live in a family with a standard of living below the 2005 poverty line. Children in low-income families experienced a decline in their standard of living in many countries, with the largest decline among families with the smallest incomes.

With immunotherapy enjoying a rapid resurgence based on the achievement of durable remissions in some patients with agents that derepress immune function, commonly referred to as "checkpoint inhibitors," enormous attention developed around the IDO1 enzyme as a metabolic mediator of immune escape in cancer. In particular, outcomes of multiple phase 1/2 trials encouraged the idea that small molecule inhibitors of IDO1 may improve patient responses to anti-PD1 immune checkpoint therapy. However, recent results from ECHO-301, the first large phase 3 trial to evaluate an IDO1-selective enzyme inhibitor (epacadostat) in combination with an anti-PD1 antibody (pembrolizumab) in advanced melanoma, showed no indication that epacadostat provided an increased benefit. Here we discuss several caveats associated with this failed trial. First is the uncertainty as to whether the target was adequately inhibited. In particular, there remains a lack of direct evidence regarding the degree of IDO1 inhibition within the tumor, and previous trial data suggest that sufficient drug exposure may not have been achieved at the dose tested in ECHO-301. Second, while there is a mechanistic rationale for the combination tested, the preclinical data were not particularly compelling. More efficacious combinations have been demonstrated with DNA damaging modalities which may therefore be a more attractive alternative. Third, as a highly selective IDO1 inhibitor, epacadostat was advanced aggressively despite preclinical genetic evidence of tumors bypassing IDO1 blockade. Indeed, a well-grounded literature starting in 2011 points to targeting strategies that account for both IDO and tryptophan 2,3-dioxygenase as more appealing directions to pursue, including dual inhibitors and inhibitors of nodal downstream effector pathways such as aryl hydrocarbon receptor blockade. Overall, the clinical readout from a single trial with significant limitations is by no means a definitive test for the field. While biomarker information yet to be gleaned from ECHO-301 may yet reveal useful information regarding IDO1 pathway drugs, better rationalized compounds and better rationalized trial designs will be important in the future to accurately gauge medical impact.

Potentiometric oxygen sensors with metal–metal oxide reference electrodes including Cu/Cu 2 O, Ni/NiO and Fe/Fe 3 O 4 were tested in oxygen saturated lead–bismuth eutectic (LBE) over the temperature range from 200 to 450 °C to assess their minimum operating temperature limit. The performance of sensors with the three reference electrodes was compared to that of a sensor with air/lanthanum strontium manganese oxide (LSM) reference electrode using the same solid electrolyte material and measurement setup. The sensor with Cu/Cu 2 O reference electrode performed well down to 200 °C in oxygen saturated LBE, while those with Ni/NiO and Fe/Fe 3 O 4 showed significant deviations from expected values below 300 °C. Furthermore, the sensor with Cu/Cu 2 O electrode showed a response to temperature variations as fast as that of the air/LSM electrode over the entire temperature range of interest in liquid LBE.

The Aurora kinases are essential for cell mitosis, and the dysregulation of Aurora A and B have been linked to the etiology of human cancers. Investigational agents MLN8054 (8) and alisertib (MLN8237, 10) have been identified as high affinity, selective, orally bioavailable inhibitors of Aurora A that have advanced into human clinical trials. Alisertib (10) is currently being evaluated in multiple Phase II and III clinical trials in hematological malignancies and solid tumors.

Background and Aims Pertussis is a common and potentially serious disease affecting mainly infants and young children. In its non-classic presentation, pertussis can be clinically indistinguishable from other respiratory illnesses. Pertussis today often remains underdiagnosed in adults. Our aims was to report a complicated cases of pertussis. Results A case of serologically confirmed pertussis occurred in an 18-year-old man presenting with pneumomediastinum, subcutaneous emphysema in the neck and chest, and persistent attacks of coughing with apnea that required treatment in the intensive care unit. Conclusion Pneumomediastinum and subcutaneous emphysema have never been described in adult patients with pertussis. Physicians should be aware that patients presenting with persistent cough and pneumomediastinum may have pertussis and include this in their differential diagnosis.

Gli eventi sismici registrati a partire dal 24 agosto 2016 hanno interessato quattro regioni dell’Italia centrale. Nella fase di emergenza particolare attenzione è stata posta alla valutazione danno-agibilità degli edifici scolastici al fine di consentire una rapida ripresa delle attività scolastiche. Il consorzio ReLUIS è stato fortemente coinvolto in tale attività gestendo, organizzando ed effettuando i sopralluoghi speditivi finalizzati a valutare il danno e l’agibilità di un considerevole numero di edifici scolastici sotto il coordinamento del Dipartimento della Protezione Civile. Tali sopralluoghi sono stati condotti da tecnici esperti in materia di rischio sismico di enti di ricerca, università italiane, Regioni, enti locali e nazionali. Lo strumento di rilievo del danno e dell’agibilità post-sismica adottato, la scheda di rilevamento di primo livello AeDES, ha consentito sia di esprimere un giudizio circa l’agibilità degli edifici scolastici sia di archiviare i dati afferenti alle caratteristiche tipologiche ed ai danni indotti dal terremoto alle componenti strutturali e non strutturali. Nel presente lavoro sono analizzati e discussi brevemente gli esiti delle ispezioni condotte su circa 280 complessi scolastici cui corrispondono all’incirca 500 corpi strutturalmente indipendenti. Successivamente la memoria focalizza l’attenzione sull’attività condotta da ReLUIS con riferimento alla valutazione della riparabilità di edifici scolastici dichiarati inagibili.

Increased tryptophan (Trp) catabolism in the tumor microenvironment (TME) can mediate immune suppression by upregulation of interferon (IFN)-γ-inducible indoleamine 2,3-dioxygenase (IDO1) and/or ectopic expression of the predominantly liver-restricted enzyme tryptophan 2,3-dioxygenase (TDO). Whether these effects are due to Trp depletion in the TME or mediated by the accumulation of the IDO1 and/or TDO (hereafter referred to as IDO1/TDO) product kynurenine (Kyn) remains controversial. Here we show that administration of a pharmacologically optimized enzyme (PEGylated kynureninase; hereafter referred to as PEG-KYNase) that degrades Kyn into immunologically inert, nontoxic and readily cleared metabolites inhibits tumor growth. Enzyme treatment was associated with a marked increase in the tumor infiltration and proliferation of polyfunctional CD8+ lymphocytes. We show that PEG-KYNase administration had substantial therapeutic effects when combined with approved checkpoint inhibitors or with a cancer vaccine for the treatment of large B16-F10 melanoma, 4T1 breast carcinoma or CT26 colon carcinoma tumors. PEG-KYNase mediated prolonged depletion of Kyn in the TME and reversed the modulatory effects of IDO1/TDO upregulation in the TME.

Electrochemical oxygen pumping method was applied in order to control the dissolved oxygen concentration in liquid lead–bismuth eutectic (LBE). The oxygen pump was fabricated using yttria partially stabilized zirconia (YPSZ) as a solid electrolyte and LSM (strontium-doped lanthanum manganite)–GDC (gadolinium-doped ceria) composite as a cathode. An oxygen control system, comprising of the oxygen pump, an oxygen sensor and a DC current source as well as a proportional-integral-derivative (PID) controller for the current control, was applied to regulate the dissolved oxygen concentration in liquid LBE. Highly accurate control of the oxygen concentration was achieved by this system. In addition, the feasibility of using the pumping system for measuring corrosion kinetics of structural steels in liquid LBE was demonstrated.

Many countries have carried out over the past decade a series of reforms and measures to encourage longer working lives and to respond to the looming challenges of rapid population ageing. But have these steps gone far enough and have the necessary measures been taken? Much of the focus of this policy action has been on old-age pension reform but, as stressed in the report Live Longer, Work Longer (OECD 2006), a more comprehensive set of reform may be necessary to encourage work at an older age. This includes policy action in three broad areas to: (1) reward work, (2) change employer practices, and (3) improve the employability of workers. The aim of this paper is to provide an overview of recent policy initiatives to give older people better work incentives and choices implemented in France, The Netherlands, Norway and Switzerland since 2006 as well as to identify areas where more could be done, covering both supply-side and demand-side aspects.