Therapeutic targeting of "undruggable" MYC

c-MYC controls global gene expression and regulates cell proliferation, cell differentiation, cell cycle, metabolism and apoptosis. According to some estimates, MYC is dysregulated in ≈70% of human cancers and strong evidence implicates aberrantly expressed MYC in both tumor initiation and maintenance. In vivo studies show that MYC inhibition elicits a prominent anti-proliferative effect and sustained tumor regression while any alteration on healthy tissue remains reversible. This opens an exploitable window for treatment that makes MYC one of the most appealing therapeutic targets for cancer drug development. This review describes the main functional and structural features of the protein structure of MYC and provides a general overview of the most relevant or recently identified interactors that modulate MYC oncogenic activity. This review also summarizes the different approaches aiming to abrogate MYC oncogenic function, with a particular focus on the prototype inhibitors designed for the direct and indirect targeting of MYC

Early imaging and molecular changes with neoadjuvant bevacizumab in stage ii/iii breast cancer

This prospective, phase II study evaluated novel biomarkers as predictors of response to bevacizumab in patients with breast cancer (BC), using serial imaging methods and gene expression analysis. Patients with primary stage II/III BC received bevacizumab 15 mg/kg (cycle 1; C1), then four cycles of neoadjuvant docetaxel doxorubicin, and bevacizumab every 3 weeks (C2–C5). Tumour proliferation and hypoxic status were evaluated using18F-fluoro-3'-deoxy-3'-L-fluorothymidine (FLT)-and18F-fluoromisonidazole (FMISO)-positron emission tomography (PET) at baseline, and during C1 and C5. Pre-and post-bevacizumab vascular changes were evaluated using dynamic contrastenhanced magnetic resonance imaging (DCE-MRI). Molecular biomarkers were assessed using microarray analysis. A total of 70 patients were assessed for treatment efficacy. Significant decreases from baseline in tumour proliferation (FLT-PET), vascularity, and perfusion (DCE-MRI) were observed during C1 (p = 0.001), independent of tumour subtype. Bevacizumab treatment did not affect hypoxic tumour status (FMISO-PET). Significant changes in the expression of 28 genes were observed after C1. Changes in vascular endothelial growth factor receptor (VEGFR)-2p levels were observed in 65 patients, with a > 20% decrease in VEGFR-2p observed in 13/65. Serial imaging techniques. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

The microbiome of the ice-capped Cayambe Volcanic Complex in Ecuador

A major challenge in microbial ecology is to understand the principles and processes by which microbes associate and interact in community assemblages. Microbial communities in mountain glaciers are unique as first colonizers and nutrient enrichment drivers for downstream ecosystems. However, mountain glaciers have been distinctively sensitive to climate perturbations and have suffered a severe retreat over the past 40  years, compelling us to understand glacier ecosystems before their disappearance. This is the first study in an Andean glacier in Ecuador offering insights into the relationship of physicochemical variables and altitude on the diversity and structure of bacterial communities. Our study covered extreme Andean altitudes at the Cayambe Volcanic Complex, from 4,783 to 5,583 masl. Glacier soil and ice samples were used as the source for 16S rRNA gene amplicon libraries. We found (1) effects of altitude on diversity and community structure, (2) the presence of few significantly correlated nutrients to community structure, (3) sharp differences between glacier soil and glacier ice in diversity and community structure, where, as quantified by the Shannon γ-diversity distribution, the meta-community in glacier soil showed more diversity than in glacier ice; this pattern was related to the higher variability of the physicochemical distribution of variables in the former substrate, and (4) significantly abundant genera associated with either high or low altitudes that could serve as biomarkers for studies on climate change. Our results provide the first assessment of these unexplored communities, before their potential disappearance due to glacier retreat and climate change

Soil Bacterial Community Along an Altitudinal Gradient in the Sumaco, a Stratovolcano in the Amazon Region

Our study is a pioneering exploration of the microbiome in the soil of the Sumaco stratovolcano and an assessment of the effects of an elevational gradient and related physicochemical soil parameters on richness and community structure. The Sumaco, as an isolated Amazonian stratovolcano, may be among one of the least studied ecosystems in Ecuador and perhaps the Amazon region. Universal patterns remain unresolved or available information inconclusive to establish a supported consensus on general governing processes by which elevation and its associated environmental gradients may determine the microbial richness and community structure. We tested a recent proposal on how microbial diversity responds to montane gradients, placing a central role in soils as potentially independent of altitude along an elevational gradient. Correlations and effects among soil physicochemical parameters and altitude were contrasted against richness and community structure through quantitative ecology. The most informative physicochemical parameter in our assessment of bacterial community structure was neither pH nor altitude, but sulfur, which was mostly independent of the other tested parameters. We established a positive effect of richness by parameters associated with metallic cations such as Mn2+, and CEC, which were negatively correlated to altitude and pH. The possible relation between the significant role of sulfur on bacterial community structure with the unique geological origin of the Sumaco stratovolcano should be examined in the context of specialized sulfur metabolisms and additional information on community structure and environmental constraints. Our study establishes an initial baseline for further explorations of microbial diversity in this unexplored tropical stratovolcano

Disconnecting Symmetry Breaking from Seeded Growth for the Reproducible Synthesis of High Quality Gold Nanorods

https://pubs.acs.org/doi/suppl/10.1021/acsnano.8b09658/suppl_file/nn8b09658_si_002.pdfOne of the major difficulties hindering the widespread application of colloidal anisotropic plasmonic nanoparticles is the limited robustness and reproducibility of multistep synthetic methods. We demonstrate herein that the reproducibility and reliability of colloidal gold nanorod (AuNR) synthesis can be greatly improved by disconnecting the symmetry-breaking event from the seeded growth process. We have used a modified silver-assisted seeded growth method in the presence of the surfactant hexadecyltrimethylammonium bromide and n-decanol as a co-surfactant to prepare small AuNRs in high yield, which were then used as seeds for the growth of high quality AuNR colloids. Whereas the use of n-decanol provides a more-rigid micellar system, the growth on anisotropic seeds avoids sources of irreproducibility during the symmetry breaking step, yielding uniform AuNR colloids with narrow plasmon bands, ranging from 600 to 1270 nm, and allowing the fine-tuning of the final dimensions. This method provides a robust route for the preparation of high quality AuNR colloids with tunable morphology, size, and optical response in a reproducible and scalable manner

BICEP2 II: Experiment and Three-Year Data Set

We report on the design and performance of the BICEP2 instrument and on its three-year data set. BICEP2 was designed to measure the polarization of the cosmic microwave background (CMB) on angular scales of 1 to 5 degrees ($\ell$=40-200), near the expected peak of the B-mode polarization signature of primordial gravitational waves from cosmic inflation. Measuring B-modes requires dramatic improvements in sensitivity combined with exquisite control of systematics. The BICEP2 telescope observed from the South Pole with a 26~cm aperture and cold, on-axis, refractive optics. BICEP2 also adopted a new detector design in which beam-defining slot antenna arrays couple to transition-edge sensor (TES) bolometers, all fabricated on a common substrate. The antenna-coupled TES detectors supported scalable fabrication and multiplexed readout that allowed BICEP2 to achieve a high detector count of 500 bolometers at 150 GHz, giving unprecedented sensitivity to B-modes at degree angular scales. After optimization of detector and readout parameters, BICEP2 achieved an instrument noise-equivalent temperature of 15.8 $\mu$K sqrt(s). The full data set reached Stokes Q and U map depths of 87.2 nK in square-degree pixels (5.2 $\mu$K arcmin) over an effective area of 384 square degrees within a 1000 square degree field. These are the deepest CMB polarization maps at degree angular scales to date. The power spectrum analysis presented in a companion paper has resulted in a significant detection of B-mode polarization at degree scales.Comment: 30 pages, 24 figure

Future care for long-term cancer survivors: towards a new model

Purpose: The increase in the prevalence "long-term cancer survivor” (LCS) patients is expected to increase the cost of LCS care. The aim of this study was to obtain information that would allow to optimise the current model of health management in Spain to adapt it to one of efficient LCS patient care. Methods: This qualitative study was carried out using Delphi methodology. An advisory committee defined the criteria for participation, select the panel of experts, prepare the questionnaire, interpret the results and draft the final report. Results: 232 people took part in the study (48 oncologists). Absolute consensus was reached in three of the proposed sections: oncological epidemiology, training of health professionals and ICT functions. Conclusion: The role of primary care in the clinical management of LCS patients needs to be upgraded, coordination with the oncologist and hospital care is essential. The funding model needs to be adapted to determine the funding conditions for new drugs and technologiesOpen Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This project was funded by AZ. The funding party did not influence the opinion of the authors. All the authors have accepted the participation as advisers of the ASISTO group and give their consent for the publication of the documen

Fast high-resolution terahertz radar imaging at 25 meters

We report improvements in the scanning speed and standoff range of an ultra-wide bandwidth terahertz (THz) imaging radar for person-borne concealed object detection. Fast beam scanning of the single-transceiver radar is accomplished by rapidly deflecting a flat, light-weight subreflector in a confocal Gregorian optical geometry. With RF back-end improvements also implemented, the radar imaging rate has increased by a factor of about 30 compared to that achieved previously in a 4 m standoff prototype instrument. In addition, a new 100 cm diameter ellipsoidal aluminum reflector yields beam spot diameters of approximately 1 cm over a 50×50 cm field of view at a range of 25 m, although some aberrations are observed that probably arise from misaligned optics. Through-clothes images of concealed pipes at 25 m range, acquired in 5 seconds, are presented, and the impact of reduced signal-to-noise from an even faster frame rate is analyzed. These results inform the requirements for eventually achieving sub-second or video-rate THz radar imaging

Antenna-coupled TES bolometers used in BICEP2, Keck array, and SPIDER

We have developed antenna-coupled transition-edge sensor (TES) bolometers for a wide range of cosmic microwave background (CMB) polarimetry experiments, including BICEP2, Keck Array, and the balloon borne SPIDER. These detectors have reached maturity and this paper reports on their design principles, overall performance, and key challenges associated with design and production. Our detector arrays repeatedly produce spectral bands with 20%-30% bandwidth at 95, 150, or 220~GHz. The integrated antenna arrays synthesize symmetric co-aligned beams with controlled side-lobe levels. Cross-polarized response on boresight is typically ~0.5%, consistent with cross-talk in our multiplexed readout system. End-to-end optical efficiencies in our cameras are routinely 35% or higher, with per detector sensitivities of NET~300 uKrts. Thanks to the scalability of this design, we have deployed 2560 detectors as 1280 matched pairs in Keck Array with a combined instantaneous sensitivity of ~9 uKrts, as measured directly from CMB maps in the 2013 season. Similar arrays have recently flown in the SPIDER instrument, and development of this technology is ongoing.Comment: 16 pgs, 20 fig