Use of VEGFR-2 targeted microbubbles (BR55, Bracco imaging) for the early ultrasound evaluation of response to antiangiogenic treatment in a xenograft model of hepatocarcinoma

Aim: To evaluate the early response to treatment to an antiangiogenetic drug (sorafenib) in a heterotopic murine model of hepatocellular carcinoma (HCC) using ultrasonographic molecular imaging. Material and Methods: the xenographt model was established injecting a suspension of HuH7 cells subcutaneously in 19 nude mice. When tumors reached a mean diameter of 5-10 mm, they were divided in two groups (treatment and vehicle). The treatment group received sorafenib (62 mg/kg) by daily oral gavage for 14 days. Molecular imaging was performed using contrast enhanced ultrasound (CEUS), by injecting into the mouse venous circulation a suspension of VEGFR-2 targeted microbubbles (BR55, kind gift of Bracco Swiss, Geneve, Switzerland). Video clips were acquired for 6 minutes, then microbubbles (MBs) were destroyed by a high mechanical index (MI) impulse, and another minute was recorded to evaluate residual circulating MBs. The US protocol was repeated at day 0,+2,+4,+7, and +14 from the beginning of treatment administration. Video clips were analyzed using a dedicated software (Sonotumor, Bracco Swiss) to quantify the signal of the contrast agent. Time/intensity curves were obtained and the difference of the mean MBs signal before and after high MI impulse (Differential Targeted Enhancement-dTE) was calculated. dTE represents a numeric value in arbitrary units proportional to the amount of bound MBs. At day +14 mice were euthanized and the tumors analyzed for VEGFR-2, pERK, and CD31 tissue levels using western blot analysis. Results: dTE values decreased from day 0 to day +14 both in treatment and vehicle groups, and they were statistically higher in vehicle group than in treatment group at day +2, at day +7, and at day +14. With respect to the degree of tumor volume increase, measured as growth percentage delta (GPD), treatment group was divided in two sub-groups, non-responders (GPD>350%), and responders (GPD<200%). In the same way vehicle group was divided in slow growth group (GPD<400%), and fast growth group (GPD>900%). dTE values at day 0 (immediately before treatment start) were higher in non-responders than in responders group, with statistical difference at day 2. While dTE values were higher in the fast growth group than in the slow growth group only at day 0. A significant positive correlation was found between VEGFR-2 tissue levels and dTE values, confirming that level of BR55 tissue enhancement reflects the amount of tissue VEGF receptor. Conclusions: the present findings show that, at least in murine experimental models, CEUS with BR55 is feasable and appears to be a useful tool in the prediction of tumor growth and response to sorafenib treatment in xenograft HCC.

Chemotherapy alone versus chemotherapy plus radiotherapy for early stage Hodgkin lymphoma

Background Combined modality treatment (CMT) consisting of chemotherapy followed by localised radiotherapy is standard treatment for patients with early stage Hodgkin lymphoma (HL). However, due to long term adverse effects such as secondary malignancies, the role of radiotherapy has been questioned recently and some clinical study groups advocate chemotherapy only for this indication. Objectives We performed a systematic review with meta-analysis of randomised controlled trials (RCTs) comparing chemotherapy alone with CMT in patients with early stage Hodgkin lymphoma with respect to response rate, progression-free survival (alternatively tumour control) and overall survival (OS). Search methods We searched MEDLINE, EMBASE and CENTRAL as well as conference proceedings from January 1980 to November 2010 for randomised controlled trials comparing chemotherapy alone to the same chemotherapy regimen plus radiotherapy. Selection criteria Randomised controlled trials comparing chemotherapy alone with CMT in patients with early stage HL. Trials in which the chemotherapy differed between treatment arms were excluded. Trials with more than 20% of patients in advanced stage were also excluded. Data collection and analysis Effect measures used were hazard ratios (HR) for tumour control and OS as well as relative risks for response rates. Two review authors independently extracted data and assessed quality of trials. We contacted study authors to obtain missing information. Since none of the trials reported progression-free survival according to our definitions, all similar outcomes were evaluated as tumour control. Main results Five RCTs involving 1245 patients were included. The HR was 0.41 (95% confidence interval (CI) 0.25 to 0.66) for tumour control and 0.40 (95% CI 0.27 to 0.61) for OS for patients receiving CMT compared to chemotherapy alone. Complete response rates were similar between treatment groups. In sensitivity analyses another six trials were included that did not fulfil the inclusion criteria of our protocol but were considered relevant to the topic. These trials underlined the results of the main analysis. Authors' conclusions Adding radiotherapy to chemotherapy improves tumour control and overall survival in patients with early stage Hodgkin lymphoma.

Feasibility platform for stroke studies: an online tool to improve eligibility criteria for clinical trials

BACKGROUND AND PURPOSE Eligibility criteria are a key factor for the feasibility and validity of clinical trials. We aimed to develop an online tool to assess the potential effect of inclusion and exclusion criteria on the proportion of patients eligible for an acute stroke trial. METHODS We identified relevant inclusion and exclusion criteria of acute stroke trials. Based on these criteria and using a cohort of 1537 consecutive patients with acute ischemic stroke from 3 stroke centers, we developed a web portal feasibility platform for stroke studies (FePASS) to estimate proportions of eligible patients for acute stroke trials. We applied the FePASS resource to calculate the proportion of patients eligible for 4 recent stroke studies. RESULTS Sixty-one eligibility criteria were derived from 30 trials on acute ischemic stroke. FePASS, publicly available at http://fepass.uni-muenster.de, displays the proportion of patients in percent to assess the effect of varying values of relevant eligibility criteria, for example, age, symptom onset time, National Institutes of Health Stroke Scale, and prestroke modified Rankin Scale, on this proportion. The proportion of eligible patients for 4 recent stroke studies ranged from 2.1% to 11.3%. Slight variations of the inclusion criteria could substantially increase the proportion of eligible patients. CONCLUSIONS FePASS is an open access online resource to assess the effect of inclusion and exclusion criteria on the proportion of eligible patients for a stroke trial. FePASS can help to design stroke studies, optimize eligibility criteria, and to estimate the potential recruitment rate.

PEDro or Cochrane to Assess the Quality of Clinical Trials? A Meta-Epidemiological Study.

OBJECTIVE There is debate on how the methodological quality of clinical trials should be assessed. We compared trials of physical therapy (PT) judged to be of adequate quality based on summary scores from the Physiotherapy Evidence Database (PEDro) scale with trials judged to be of adequate quality by Cochrane Risk of Bias criteria. DESIGN Meta-epidemiological study within Cochrane Database of Systematic Reviews. METHODS Meta-analyses of PT trials were identified in the Cochrane Database of Systematic Reviews. For each trial PeDro and Cochrane assessments were extracted from the PeDro and Cochrane databases. Adequate quality was defined as adequate generation of random sequence, concealment of allocation, and blinding of outcome assessors (Cochrane criteria) or as trials with a PEDro summary score ≥5 or ≥6 points. We combined trials of adequate quality using random-effects meta-analysis. RESULTS Forty-one Cochrane reviews and 353 PT trials were included. All meta-analyses included trials with PEDro scores ≥5, 37 (90.2%) included trials with PEDro scores ≥6 and only 22 (53.7%) meta-analyses included trials of adequate quality according to the Cochrane criteria. Agreement between PeDro and Cochrane was poor for PeDro scores of ≥5 points (kappa = 0.12; 95% CI 0.07 to 0.16) and slight for ≥6 points (kappa 0.24; 95% CI 0.16-0.32). When combining effect sizes of trials deemed to be of adequate quality according to PEDro or Cochrane criteria, we found that a substantial difference in the combined effect size (≥0.15) was evident in 9 (22%) out of the 41 meta-analyses for PEDro cutoff ≥5 and 10 (24%) for cutoff ≥6. CONCLUSIONS The PeDro and Cochrane approaches lead to different sets of trials of adequate quality, and different combined treatment estimates from meta-analyses of these trials. A consistent approach to assessing RoB in trials of physical therapy should be adopted.

Addressing missing participant outcome data in dental clinical trials

Missing outcome data are common in clinical trials and despite a well-designed study protocol, some of the randomized participants may leave the trial early without providing any or all of the data, or may be excluded after randomization. Premature discontinuation causes loss of information, potentially resulting in attrition bias leading to problems during interpretation of trial findings. The causes of information loss in a trial, known as mechanisms of missingness, may influence the credibility of the trial results. Analysis of trials with missing outcome data should ideally be handled with intention to treat (ITT) rather than per protocol (PP) analysis. However, true ITT analysis requires appropriate assumptions and imputation of missing data. Using a worked example from a published dental study, we highlight the key issues associated with missing outcome data in clinical trials, describe the most recognized approaches to handling missing outcome data, and explain the principles of ITT and PP analysis.

Eocene to Early Miocene palaeoclimate of Saxony, Germany (Table 4)

In the present study, proxy data concerning changes in atmospheric CO2 and climatic conditions from the Late Eocene to the Early Miocene were acquired by applying palaeobotanical methods. Fossil floras from 10 well-documented locations in Saxony, Germany, were investigated with respect to (1) stomatal density/index of fossil leaves from three different taxa (Eotrigonobalanus furcinervis, Laurophyllum pseudoprinceps and Laurophyllum acutimontanum), (2) the coexistence approach (CA) based on nearest living relatives (NLR) and (3) leaf margin analysis (LMA). Whereas the results of approach (1) indicate changes in atmospheric CO2 concentration, approaches (2) and (3) provide climate data. The results of the analysis of stomatal parameters indicate that the atmospheric CO2 concentration was higher during the Late Eocene than during the Early Oligocene and increased towards the Late Oligocene. A lower atmospheric pCO2 level after the Late Eocene is also suggested by an increase in marine palaeoproductivity at this time. From the Late Oligocene onwards, no changes in atmospheric CO2 concentration can be detected with the present data. For the considered sites, the results of the coexistence approach and of the leaf margin analysis document a significant cooling event from the Late Eocene to the Early Oligocene. The pCO2 decrease from the Late Eocene to the Early Oligocene indicated by the stomatal data raised in this study was thus coupled to a temperature decrease which is reflected by the present datasets. From the Early Oligocene onwards, however, no further fundamental climate change can be inferred for the considered locations. The pCO2 increase from the Early Oligocene to the Late Oligocene, which is indicated by the present data, is thus not accompanied by a climate change at the considered sites. A warming event during the Late Oligocene is, however, recorded by marine climate archives. According to the present data, no change in pCO2 occurred during the cooling event at the Oligocene/Miocene boundary, which is also indicated by marine data. The quality and validity of stomatal parameters as sensors for atmospheric CO2 concentration are discussed.

Eocene to Quaternary benthic foraminifers from the Izu-Bonin Arc

The benthic foraminifer fauna at Sumisu Rift Sites 790 and 791 indicates that a deep open-ocean (>2300 m) or a basin with open-ocean access existed between 1.1 and 0.7 Ma at the time of the initiation of rifting. The appearance of a low- to medium-oxygen fauna (1600-2300 m) between 0.7 and 0.5 Ma suggests that the open-ocean access may have been terminated at this time because of the development of volcanoes and rift flank uplifts around the basin. The occurrence of low-oxygen faunas at 0.03 Ma suggests a secondary closing of the basin. The lower bathyal benthic faunas from lower Pliocene sediments of rift margin Site 788 suggest about 0.6-1.6 km of total basement uplift. This uplift may have led to the formation of the major hiatus between 2.3 and <0.3 Ma. The faunal changes of benthic foraminifers at Sites 792 and 793 in the forearc basin document a shallowing water depth from below the carbonate compensation depth (CCD) (about 3.5 km) in the late early Oligocene to the present depths of 1800 and 2975 m, respectively. These data suggest about 1 km of total basement uplift in the inner part of the forearc basin (Site 792) and about 0.6 km total basement subsidence in the central part of the forearc basin (Site 793) since about 31 Ma. The former uplift led to a thinner sediment accumulation (800 m) and the latter subsidence to a thicker sediment accumulation (1400 m) at these sites. Faunal changes of benthic foraminifers observed in Sites 782 and 786 sequences drilled at the outer-arc high document a deepening water depth from 1.3 to 2.1 km in late Eocene to the present depth of about 3 km. These data suggest about 1.1-1.9 and 1.3-2.1 km of total basement subsidence at Sites 786 and 782, respectively. These results indicate total basement uplift in the inner part of the Bonin arc-trench system since late Oligocene and total basement subsidence in the outer part of the system since late Eocene. The last occurrence (LO) of Stilostomella spp. and Pleurostomella spp. and the first occurrence (F0) of Bulimina aculeata d'Orbigny occurred consistently at 0.7 Ma at all three arc proximal sites (790,791, and 792). This fact is taken to suggest a change of water mass, from one originating from the central part of the ocean to that originating from ocean-margin areas at that time.

Late Miocene to Early Pliocene radiolarians from ODP Hole 178-1095B

Early Pliocene to middle late Miocene hemipelagic and distal turbidite sediments from Hole 1095B, near the Antarctic Peninsula, yield moderately abundant, moderately well preserved radiolarian faunas and other biosiliceous material (diatoms, silicoflagellates, and sponge spicules). Preservation characteristics, however, vary strongly even between closely related samples, and there are many intervals of poor preservation. In the 140- to 460-meters below seafloor interval studied, it was possible to identify the following standard Southern Ocean radiolarian zones: Upsilon, Tau, Amphymenium challengerae, Acrosphaera? labrata, Siphonosphaera vesuvius, and upper Acrosphaera australis (total age range ~4-10 Ma). Some normally common radiolarian groups, such as actinommids, are unusually rare in the studied material, and the relative ranges of several individual species, such as Acrosphaera labrata vs. A. australis, appear to be somewhat anomalous. These observations imply that the ranges of taxa in this section may be somewhat diachronous, due to either local ecologic factors and/or the highly variable preservation of the faunas. Thus, the ages of events reported are probably only approximate, although they are still useful for constraining the age of sediments in this section.

A nucleolar protein related to ribosomal protein L7 is required for an early step in large ribosomal subunit biogenesis

The Saccharomyces cerevisiae Rlp7 protein has extensive identity and similarity to the large ribosomal subunit L7 proteins and shares an RNA-binding domain with them. Rlp7p is not a ribosomal protein; however, it is encoded by an essential gene and therefore must perform a function essential for cell growth. In this report, we show that Rlp7p is a nucleolar protein that plays a critical role in processing of precursors to the large ribosomal subunit RNAs. Pulse–chase labeling experiments with Rlp7p-depleted cells reveal that neither 5.8SS, 5.8SL, nor 25S is produced, indicating that both the major and minor processing pathways are affected. Analysis of processing intermediates by primer extension indicates that Rlp7p-depleted cells accumulate the 27SA3 precursor RNA, which is normally the major substrate (85%) used to produce the 5.8S and 25S rRNAs, and the ratio of 27SBL to 27SBS precursors changes from approximately 1:8 to 8:1 (depleted cells). Because 27SA3 is the direct precursor to 27SBS, we conclude that Rlp7p is specifically required for the 5′ to 3′ exonucleolytic trimming of the 27SA3 into the 27SBS precursor. As it is essential for processing in both the major and minor pathways, we propose that Rlp7p may act as a specificity factor that binds precursor rRNAs and tethers the enzymes that carry out the early 5′ to 3′ exonucleolytic reactions that generate the mature rRNAs. Rlp7p may also be required for the endonucleolytic cleavage in internal transcribed spacer 2 that separates the 5.8S rRNA from the 25S rRNA.

Differential Control of Xanthophylls and Light-Induced Stress Proteins, as Opposed to Light-Harvesting Chlorophyll a/b Proteins, during Photosynthetic Acclimation of Barley Leaves to Light Irradiance

Barley (Hordeum vulgare L.) plants were grown at different photon flux densities ranging from 100 to 1800 μmol m−2 s−1 in air and/or in atmospheres with reduced levels of O2 and CO2. Low O2 and CO2 partial pressures allowed plants to grow under high photosystem II (PSII) excitation pressure, estimated in vivo by chlorophyll fluorescence measurements, at moderate photon flux densities. The xanthophyll-cycle pigments, the early light-inducible proteins, and their mRNA accumulated with increasing PSII excitation pressure irrespective of the way high excitation pressure was obtained (high-light irradiance or decreased CO2 and O2 availability). These findings indicate that the reduction state of electron transport chain components could be involved in light sensing for the regulation of nuclear-encoded chloroplast gene expression. In contrast, no correlation was found between the reduction state of PSII and various indicators of the PSII light-harvesting system, such as the chlorophyll a-to-b ratio, the abundance of the major pigment-protein complex of PSII (LHCII), the mRNA level of LHCII, the light-saturation curve of O2 evolution, and the induced chlorophyll-fluorescence rise. We conclude that the chlorophyll antenna size of PSII is not governed by the redox state of PSII in higher plants and, consequently, regulation of early light-inducible protein synthesis is different from that of LHCII.

Lists of books granted to Harvard by the Massachusetts General Court, ca. 1778

The books listed were sequestered from "Cox & Berry's Collection" (British booksellers Cox and Berry) and from Province House, home to the royal Governors of the Massachusetts Bay Colony prior to the American Revolution. To the left of each book's title is a number indicating how many copies of that title were received.

Coastal Massachusetts, Marblehead to Hampton Harbor, New Hampshire, Nautical Chart, 1776 (Image 1 of 2) (Raster Image)

This layer is a georeferenced raster image of the untitled, historic nautical chart: [A chart of the harbours of Hampton, Newbury, Ipswich, Jebeka, Squam, Cape Ann, Manchester, Beverly, Salem, Marble Head &c.] (sheet originally published in 1776). The map is [sheet 23] from the Atlantic Neptune atlas Vol. 3 : Charts of the coast and harbors of New England, from surveys taken by Samuel Holland and published by J.F.W. Des Barres, 1781. Scale [ca. 1:50,000]. This layer is image 1 of 2 total images of the two sheet source map, representing the southern portion of the map. Covers coastal Massachusetts from Ipswich Harbor to Marblehead. The image is georeferenced to the surface of the earth and fit to the 'World Mercator' (WGS 84) projected coordinate system. All map collar information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, or other information associated with the principal map. This map shows coastal features such as harbors, inlets, rocks, channels, points, coves, shoals, islands, and more. Includes also selected land features such as cities and towns, buildings, and roads. Relief is shown by hachures; depths by soundings. This layer is part of a selection of digitally scanned and georeferenced historic maps from The Harvard Map Collection. The entire Atlantic Neptune atlas Vol. 3 : Charts of the coast and harbors of New England has been scanned and georeferenced as part of this selection.

Massachusetts Bay and Coastline, Nautical Chart, 1776 (Image 1 of 2) (Raster Image)

This layer is a georeferenced raster image of the untitled, historic nautical chart: [A chart of Massachusetts Bay & coast from Cape Ann to Cape Cod] (sheet originally published in 1776). The map is [sheet 15] from the Atlantic Neptune atlas Vol. 3 : Charts of the coast and harbors of New England, from surveys taken by Samuel Holland and published by J.F.W. Des Barres, 1781. Scale [ca. 1:125,000]. This layer is image 1 of 2 total images of the two sheet source map, representing the western portion of the map. Covers coast of Massachusetts, Boston Harbor, and portion of Massachusetts Bay. The image is georeferenced to the surface of the earth and fit to the 'World Mercator' (WGS 84) projected coordinate system. All map collar information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, or other information associated with the principal map. This map shows coastal features such as harbors, inlets, rocks, channels, points, coves, shoals, islands, and more. Includes also selected land features such as cities and towns. This layer is part of a selection of digitally scanned and georeferenced historic maps from The Harvard Map Collection. The entire Atlantic Neptune atlas Vol. 3 : Charts of the coast and harbors of New England has been scanned and georeferenced as part of this selection.

Providence, Rhode Island 15 Minute Digital Raster Graphic

This layer is a digital raster graphic of the historic 15-minute USGS topographic map of the Providence, Rhode Island quadrangle which includes areas in the state of Massachusetts. The survey dates (ground condition) of the original paper map are 1885 and 1887, the edition date is February, 1894 and this map has a reprint date of October, 1911. A digital raster graphic (DRG) is a scanned image of a U.S. Geological Survey (USGS) standard series topographic map, including all map collar information. The image inside the map neatline is geo-referenced to the surface of the earth and fit to the Universal Transverse Mercator projection. The horizontal positional accuracy and datum of the DRG matches the accuracy and datum of the source map.

Five things we need to know about the on-demand economy. CEPS Essay No. 21/8 January 2016

The last few years have witnessed the exponential growth of platforms like Uber and Airbnb and the creation of countless other less well-known examples. The expansion of the on-demand economy puts huge pressure on regulators to adapt it to the existing frameworks for labour and taxation. The rapid growth of the sector also divides experts: it is seen by many as threat for working conditions, and by others as an incredible opportunity. The purpose of this essay is to take a balanced perspective on what we know about the on-demand economy and what needs further investigation. More research is needed on the individual cases before one can draw conclusions on how this new sector works. The political economy of the sector is made even more interesting by the fact that the technology is developing faster than the regulation. Yet, our plea to policy-makers is to refrain from legislating too early and to take the time to understand how the supply and the demand of these services behave and their equilibrium.