A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of Simtuzumab in Combination with FOLFIRI for the Second-Line Treatment of Metastatic KRAS Mutant Colorectal Adenocarcinoma.

Lessons learnedThe safety profile in the patient groups who received FOLFIRI and simtuzumab did not differ from that in the FOLFIRI and placebo group.The addition of simtuzumab to chemotherapy with FOLFIRI does not improve clinical outcomes in patients with metastatic KRAS mutant colorectal carcinoma.BackgroundSimtuzumab, a humanized IgG4 monoclonal antibody to lysyl oxidase-like 2 (LOXL2), blocks desmoplastic reaction in colorectal carcinoma (CRC) cells in vitro.MethodsPatients with metastatic Kirsten rat sarcoma viral oncogene homolog (KRAS) mutant CRC were randomized to receive second-line 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) with either 200 or 700 mg simtuzumab or placebo every 2 weeks in cycles of 28 days. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and safety were assessed.ResultsIn total, 249 patients were randomized and treated with FOLFIRI/simtuzumab 700 mg (n = 84), FOLFIRI/simtuzumab 200 mg (n = 85), and FOLFIRI/placebo (n = 80). After a median follow-up of 5.1, 3.8, and 5.5 months, respectively, median PFS for each of the respective treatment groups was 5.5 months (adjusted HR [95% CI], p value versus placebo; 1.32 [0.92, 1.89]; p = .10), 5.4 months (1.45 [1.01, 2.06]; p = .04), and 5.8 months. Median OS was 11.4 months (1.23 [0.80, 1.91]; p = .25), 10.5 months (1.50 [0.98, 2.30]; p = .06), and 16.3 months, respectively. ORR was 11.9%, 5.9%, and 10%, respectively. Simtuzumab was tolerable in metastatic KRAS mutant CRC patients.ConclusionThe addition of simtuzumab to FOLFIRI did not improve clinical outcomes in patients with metastatic KRAS mutant CRC. The Oncologist 2017;22:243-e8

Automated Image Analysis of Transmission Electron Micrographs: Nanoscale Evaluation of Radiation-Induced DNA Damage in the Context of Chromatin

Background: Heavy ion irradiation (IR) with high-linear energy transfer (LET) is characterized by a unique depth dose distribution and increased biological effectiveness. Following high-LET IR, localized energy deposition along the particle trajectories induces clustered DNA lesions, leading to low electron density domains (LEDDs). To investigate the spatiotemporal dynamics of DNA repair and chromatin remodeling, we established the automated image analysis of transmission electron micrographs. Methods: Human fibroblasts were irradiated with high-LET carbon ions or low-LET photons. At 0.1 h, 0.5 h, 5 h, and 24 h post-IR, nanoparticle-labeled repair factors (53BP1, pKu70, pKu80, DNA-PKcs) were visualized using transmission electron microscopy in interphase nuclei to monitor the formation and repair of DNA damage in the chromatin ultrastructure. Using AI-based software tools, advanced image analysis techniques were established to assess the DNA damage pattern following low-LET versus high-LET IR. Results: Low-LET IR induced single DNA lesions throughout the nucleus, and most DNA double-strand breaks (DSBs) were efficiently rejoined with no visible chromatin decondensation. High-LET IR induced clustered DNA damage concentrated along the particle trajectories, resulting in circumscribed LEDDs. Automated image analysis was used to determine the exact number of differently sized nanoparticles, their distance from one another, and their precise location within the micrographs (based on size, shape, and density). Chromatin densities were determined from grayscale features, and nanoparticles were automatically assigned to euchromatin or heterochromatin. High-LET IR-induced LEDDs were delineated using automated segmentation, and the spatial distribution of nanoparticles in relation to segmented LEDDs was determined. Conclusions: The results of our image analysis suggest that high-LET IR induces chromatin relaxation along particle trajectories, enabling the critical repair of successive DNA damage. Following exposure to different radiation qualities, automated image analysis of nanoparticle-labeled DNA repair proteins in the chromatin ultrastructure enables precise characterization of specific DNA damage patterns

Spiral Microchannels with Trapezoidal Cross Section Fabricated by Femtosecond Laser Ablation in Glass for the Inertial Separation of Microparticles

The fabrication and testing of spiral microchannels with a trapezoidal cross section for the passive separation of microparticles is reported in this article. In contrast to previously reported fabrication methods, the fabrication of trapezoidal spiral channels in glass substrates using a femtosecond laser is reported for the first time in this paper. Femtosecond laser ablation has been proposed as an accurate and fast prototyping method with the ability to create 3D features such as slanted-base channels. Moreover, the fabrication in borosilicate glass substrates can provide high optical transparency, thermal resistance, dimensional stability, and chemical inertness. Post-processing steps of the laser engraved glass substrate are also detailed in this paper including hydrogen fluoride (HF) dipping, chemical cleaning, surface activation, and thermal bonding. Optical 3D images of the fabricated chips confirmed a good fabrication accuracy and acceptable surface roughness. To evaluate the particle separation function of the microfluidic chip, 5 μm, 10 μm, and 15 μm particles were focused and recovered from the two outlets of the spiral channel. In conclusion, the new chemically inert separation chip can be utilized in biological or chemical processes where different sizes of cells or particles must be separated, i.e., red blood cells, circulating tumor cells, and technical particle suspensions

Demographic Inference and Representative Population Estimates from Multilingual Social Media Data

Social media provide access to behavioural data at an unprecedented scale and granularity. However, using these data to understand phenomena in a broader population is difficult due to their non-representativeness and the bias of statistical inference tools towards dominant languages and groups. While demographic attribute inference could be used to mitigate such bias, current techniques are almost entirely monolingual and fail to work in a global environment. We address these challenges by combining multilingual demographic inference with post-stratification to create a more representative population sample. To learn demographic attributes, we create a new multimodal deep neural architecture for joint classification of age, gender, and organization-status of social media users that operates in 32 languages. This method substantially outperforms current state of the art while also reducing algorithmic bias. To correct for sampling biases, we propose fully interpretable multilevel regression methods that estimate inclusion probabilities from inferred joint population counts and ground-truth population counts. In a large experiment over multilingual heterogeneous European regions, we show that our demographic inference and bias correction together allow for more accurate estimates of populations and make a significant step towards representative social sensing in downstream applications with multilingual social media.Comment: 12 pages, 10 figures, Proceedings of the 2019 World Wide Web Conference (WWW '19

Determination of the characteristic directions of lossless linear optical elements

We show that the problem of finding the primary and secondary characteristic directions of a linear lossless optical element can be reformulated in terms of an eigenvalue problem related to the unimodular factor of the transfer matrix of the optical device. This formulation makes any actual computation of the characteristic directions amenable to pre-implemented numerical routines, thereby facilitating the decomposition of the transfer matrix into equivalent linear retarders and rotators according to the related Poincare equivalence theorem. The method is expected to be useful whenever the inverse problem of reconstruction of the internal state of a transparent medium from optical data obtained by tomographical methods is an issue.Comment: Replaced with extended version as published in JM

A cross-sectional survey investigating the desensitisation of graphic health warning labels and their impact on smokers, non-smokers and patients with COPD in a London cohort.

OBJECTIVES: There is a lack of evidence regarding the effectiveness of graphic health warning labels (GHWL) in different individuals, including patients with chronic obstructive pulmonary disease (COPD). Investigating knowledge and attitudes may allow better implementation of future public health policies. We hypothesised that differences in the impact of GHWL exist between non-smokers, smokers and patients with COPD, with decreased efficacy in those groups who are longer and more frequently exposed to them. PARTICIPANTS AND SETTING: 163 participants (54% male, aged 21-80) including 60 non-smokers, 53 smokers and 50 patients with COPD (Gold stage II-IV), attending London respiratory outpatient clinics, participated in case-controlled surveys (50 items). OUTCOME MEASURES: Ten different GHWL were shown and demographics, smoking history, plans to quit, smoking-risk awareness, emotional response, processing and impact of GHWL on behaviour were recorded. Patients were further asked to prioritise the hypothetical treatment or prevention of five specific smoking-related diseases. RESULTS: Smokers, in particular those with COPD, were less susceptible to GHWL than non-smokers; 53.4% of all participants expressed fear when looking at GHWL, non-smokers (71.9%) more so than smokers (39.8%, p<0.001). COPD participants were less aware of the consequences than non-COPD participants (p<0.001), including an awareness of lung cancer (p=0.001). Lung cancer (95%), oral cancer (90.2%), heart disease (84.7%) and stroke (71.2%) were correctly associated with smoking, whereas blindness was least associated (23.9%). However, blindness was prioritised over oral cancer, stroke and in patients with COPD also over heart disease when participants were asked about hypothetical treatment or prevention. CONCLUSIONS: GHWL are most effective in non-smokers and a desensitisation effect was observed in smokers and patients with COPD. As a consequence, a tailored and concerted public health approach to use such messages is required and 'blindness' deserves to be mentioned in this context because of an unexpectedly high-deterring impact

Formulation of a 1D finite element of heat exchanger for accurate modelling of the grouting behaviour: Application to cyclic thermal loading

This paper presents a comprehensive formulation of a finite element for the modelling of borehole heat exchangers. This work focuses on the accurate modelling of the grouting and the field of temperature near a single borehole. Therefore the grouting of the BHE is explicitly modelled. The purpose of this work is to provide tools necessary to the further modelling of thermo-mechanical couplings. The finite element discretises the classical governing equation of advection-diffusion of heat within a 1D pipe connected to ground nodes. Petrov-Galerkin weighting functions are used to avoid numerical disturbances. The formulation is able to capture highly transient and steady-state phenomena. The proposed finite element is validated with respect to analytical solutions. An example consisting of a 100 m depth U-pipe is finally simulated. A first continuous heating simulation highlights the nonsymmetric distribution of temperature inside and near the borehole. An estimation of the error on the results as a function of the resolution parameters is also carried out. Finally simulations of cyclic thermal loading exhibit the need to take into account all daily variations if the grouting behaviour must be modelled. This is true especially in case of freeze-thaw damaging risk.Geotherwa

Venture capital on a shoestring: Bioventures’ pioneering life sciences fund in South Africa

<p>Abstract</p> <p>Background</p> <p>Since 2000, R&D financing for global health has increased significantly, with innovative proposals for further increases. However, although venture capital (VC) funding has fostered life sciences businesses across the developed world, its application in the developing world and particularly in Africa is relatively new. Is VC feasible in the African context, to foster the development and application of local health innovation?</p> <p>As the most industrially advanced African nation, South Africa serves as a test case for life sciences venture funding. This paper analyzes Bioventures, the first VC company focused on life sciences investment in sub-Saharan Africa. The case study method was used to analyze the formation, operation, and investment support of Bioventures, and to suggest lessons for future health venture funds in Africa that aim to develop health-oriented innovations.</p> <p>Discussion</p> <p>The modest financial success of Bioventures in challenging circumstances has demonstrated a proof of concept that life sciences VC can work in the region. Beyond providing funds, support given to investees included board participation, contacts, and strategic services. Bioventures had to be proactive in finding and supporting good health R&D.</p> <p>Due to the fund’s small size, overhead and management expenses were tightly constrained. Bioventures was at times unable to make follow-on investments, being forced instead to give up equity to raise additional capital, and to sell health investments earlier than might have been optimal. With the benefit of hindsight, the CFO of Bioventures felt that partnering with a larger fund might benefit similar future funds. Being better linked to market intelligence and other entrepreneurial investors was also seen as an unmet need.</p> <p>Summary</p> <p>BioVentures has learned lessons about how the traditional VC model might evolve to tackle health challenges facing Africa, including how to raise funds and educate investors; how to select, value, and support investments; and how to understand the balance between financial and social returns. The experience of the fund suggests that future health funds targeting ailments of the poor might require investors that accept health benefits as part of their overall “return.” Learning from Bioventures may help develop health innovation funding for sub-Saharan African that has combined health, financial, and economic development impacts.</p

Recent Advances in Printed Capacitive Sensors

In this review paper, we summarize the latest advances in the field of capacitive sensors fabricated by printing techniques. We first explain the main technologies used in printed electronics, pointing out their features and uses, and discuss their advantages and drawbacks. Then, we review the main types of capacitive sensors manufactured with different materials and techniques from physical to chemical detection, detailing the main substrates and additives utilized, as well as the measured ranges. The paper concludes with a short notice on status and perspectives in the field.H2020-MSCA-IF-2017-794885-SELFSEN