Structural optimization of reversible dibromomaleimide peptide stapling

Methods to constrain peptides in a bioactive α‐helical conformation for inhibition of protein‐protein interactions represent an ongoing area of investigation in chemical biology. Recently, the first example of a reversible “stapling” methodology was described which exploits native cysteine or homocysteine residues spaced at the i and i + 4 positions in a peptide sequence together with the thiol selective reactivity of dibromomaleimides (a previous study). This manuscript reports on the optimization of the maleimide based constraint, focusing on the kinetics of macrocyclization and the extent to which helicity is promoted with different thiol containing amino acids. The study identified an optimal stapling combination of X1 = L‐Cys and X5 = L‐hCys in the context of the model peptide Ac‐X1AAAX5‐NH2, which should prove useful in implementing the dibromomaleimide stapling strategy in peptidomimetic ligand discovery programmes

A review of the epidemiology of oral and pharyngeal carcinoma: update

Oral and pharyngeal cancers are the sixth most common cancers internationally. In the United States, there are about 30,000 new cases of oral and pharyngeal cancers diagnosed each year. Furthermore, survival rates for oral and pharyngeal cancers have not significantly improved over the last three decades. This review examines the scientific literature surrounding the epidemiology of oral and pharyngeal cancers, including but not limited to risk factors, disparities, preventative factors, and the epidemiology in countries outside the United States. The literature review revealed that much of the research in this field has been focused on alcohol, tobacco, and their combined effects on oral and pharyngeal cancers. The literature on oral and pharyngeal cancer disparities among racial groups also appears to be growing. However, less literature is available on the influence of dietary factors on these cancers. Finally, effective interventions for the reduction of oral and pharyngeal cancers are discussed

Accurate gamma and MeV-electron track reconstruction with an ultra-low diffusion Xenon/TMA TPC at 10 atm

We report the performance of a 10 atm Xenon/trimethylamine time projection chamber (TPC) for the detection of X-rays (30 keV) and gamma-rays (0.511-1.275 MeV) in conjunction with the accurate tracking of the associated electrons. When operated at such a high pressure and in similar to 1%-admixtures, trimethylamine (TMA) endows Xenon with an extremely low electron diffusion (1.3 +/- 0.13 mm-sigma (longitudinal), 0.95 +/- 0.20 mm-sigma (transverse) along 1 m drift) besides forming a convenient Penning-Fluorescent' mixture. The TPC, that houses 1.1 kg of gas in its fiducial volume, operated continuously for 100 live-days in charge amplification mode. The readout was performed through the recently introduced microbulk Micromegas technology and the AFTER chip, providing a 3D voxelization of 8 mm x 8 mm x 1.2 mm for approximately 10 cm/MeV-long electron tracks. Resolution in energy (epsilon) at full width half maximum (R) inside the fiducial volume ranged from R = 14.6% (30 keV) to R = 4.6% (1.275 MeV). This work was developed as part of the R&D program of the NEXT collaboration for future detector upgrades in the search of the neutrino-less double beta decay (beta beta 0 nu) in Xe-136, specifically those based on novel gas mixtures. Therefore we ultimately focus on the calorimetric and topological properties of the reconstructed MeV-electron tracks. In particular, the obtained energy resolution has been decomposed in its various contributions and improvements towards achieving the R =1.4%root MeV/epsilon levels obtained in small sensors are discussedThe NEXT collaboration acknowledges funding support from the following agencies and institutions: European Research Council under Advanced Grant 339787-NEXT and Starting Grant 240054-TREX, Spanish Ministerio de Economia y Competitividad under grants Consolider-Ingenio 2010 CSD2008-0037 (CUP) and CSD2007-00042 (CPAN), contracts FPA2008-03456 and FPA2009-13697; Portuguese Fundacao para a Ciencia e a Tecnologia; European FEDER under grant PPTDC/FIS/103860/2008; US Department Of Energy under contract DE-AC02-05CH11231.Gonzalez Diaz, D.; Álvarez Puerta, V.; Borges, FIG.; Camargo, M.; Carcel, S.; Cebrian, S.; Cervera, A.... (2015). Accurate gamma and MeV-electron track reconstruction with an ultra-low diffusion Xenon/TMA TPC at 10 atm. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment. 804:8-24. https://doi.org/10.1016/j.nima.2015.08.033S82480

The NEXT White (NEW) detector

Conceived to host 5 kg of xenon at a pressure of 15 bar in the fiducial volume, the NEXT-White apparatus is currently the largest high pressure xenon gas TPC using electroluminescent amplification in the world. It is also a 1:2 scale model of the NEXT-100 detector for Xe-136 beta beta 0 nu decay searches, scheduled to start operations in 2019. Both detectors measure the energy of the event using a plane of photomultipliers located behind a transparent cathode. They can also reconstruct the trajectories of charged tracks in the dense gas of the TPC with the help of a plane of silicon photomultipliers located behind the anode. A sophisticated gas system, common to both detectors, allows the high gas purity needed to guarantee a long electron lifetime. NEXT-White has been operating since October 2016 at the Laboratorio Subterraneo de Canfranc (LSC), in Spain. This paper describes the detector and associated infrastructures, as well as the main aspects of its initial operation

Radio Frequency and DC High Voltage Breakdown of High Pressure Helium, Argon, and Xenon

[EN] Motivated by the possibility of guiding daughter ions from double beta decay events to single-ion sensors for barium tagging, the NEXT collaboration is developing a program of R&D to test radio frequency (RF) carpets for ion transport in high pressure xenon gas. This would require carpet functionality in regimes at higher pressures than have been previously reported, implying correspondingly larger electrode voltages than in existing systems. This mode of operation appears plausible for contemporary RF-carpet geometries due to the higher predicted breakdown strength of high pressure xenon relative to low pressure helium, the working medium in most existing RF carpet devices. In this paper we present the first measurements of the high voltage dielectric strength of xenon gas at high pressure and at the relevant RF frequencies for ion transport (in the 10MHz range), as well as new DC and RF measurements of the dielectric strengths of high pressure argon and helium gases at small gap sizes. We find breakdown voltages that are compatible with stable RF carpet operation given the gas, pressure, voltage, materials and geometry of interest.Woodruff, K.; Baeza-Rubio, J.; Huerta, D.; Jones, BJP.; Mcdonald, AD.; Norman, L.; Nygren, DR.... (2020). Radio Frequency and DC High Voltage Breakdown of High Pressure Helium, Argon, and Xenon. Journal of Instrumentation. 15(4):1-15. https://doi.org/10.1088/1748-0221/15/04/P04022S115154Dehmelt, H. G., & Major, F. G. (1962). Orientation of(He4)+Ions by Exchange Collisions with Cesium Atoms. 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Physical Review C, 44(3), R931-R934. doi:10.1103/physrevc.44.r931Sinclair, D., Rollin, E., Smith, J., Mommers, A., Ackeran, N., Aharmin, B., … Breidenbach, M. (2011). Prospects for Barium Tagging in Gaseous Xenon. Journal of Physics: Conference Series, 309, 012005. doi:10.1088/1742-6596/309/1/012005Brunner, T., Fudenberg, D., Sabourov, A., Varentsov, V. L., Gratta, G., & Sinclair, D. (2013). A setup for Ba-ion extraction from high pressure Xe gas for double-beta decay studies with EXO. Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms, 317, 473-475. doi:10.1016/j.nimb.2013.05.086Twelker, K., Kravitz, S., Díez, M. M., Gratta, G., Fairbank, W., Albert, J. B., … Benitez-Medina, C. (2014). An apparatus to manipulate and identify individual Ba ions from bulk liquid Xe. Review of Scientific Instruments, 85(9), 095114. doi:10.1063/1.4895646Mong, B., Cook, S., Walton, T., Chambers, C., Craycraft, A., Benitez-Medina, C., … Auty, D. J. (2015). Spectroscopy of Ba andBa+deposits in solid xenon for barium tagging in nEXO. Physical Review A, 91(2). doi:10.1103/physreva.91.022505Brunner, T., Fudenberg, D., Varentsov, V., Sabourov, A., Gratta, G., Dilling, J., … Albert, J. B. (2015). An RF-only ion-funnel for extraction from high-pressure gases. International Journal of Mass Spectrometry, 379, 110-120. doi:10.1016/j.ijms.2015.01.003Nygren, D. R. (2016). Detection of the barium daughter in 136Xe →136Ba+2e− by in situ single-molecule fluorescence imaging. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 824, 2-5. doi:10.1016/j.nima.2015.11.038Jones, B. J. P., McDonald, A. D., & Nygren, D. R. (2016). Single molecule fluorescence imaging as a technique for barium tagging in neutrinoless double beta decay. Journal of Instrumentation, 11(12), P12011-P12011. doi:10.1088/1748-0221/11/12/p12011Byrnes, N., Foss, F. W., Jones, B. J. ., McDonald, A. D., Nygren, D. R., … Thapa, P. (2019). Progress toward Barium Tagging in High Pressure Xenon Gas with Single Molecule Fluorescence Imaging. Journal of Physics: Conference Series, 1312, 012001. doi:10.1088/1742-6596/1312/1/012001McDonald, A. D., Jones, B. J. P., Nygren, D. R., Adams, C., Álvarez, V., Azevedo, C. D. R., … Cárcel, S. (2018). Demonstration of Single-Barium-Ion Sensitivity for Neutrinoless Double-Beta Decay Using Single-Molecule Fluorescence Imaging. Physical Review Letters, 120(13). doi:10.1103/physrevlett.120.132504(2019). Imaging individual barium atoms in solid xenon for barium tagging in nEXO. Nature, 569(7755), 203-207. doi:10.1038/s41586-019-1169-4Thapa, P., Arnquist, I., Byrnes, N., Denisenko, A. A., Foss, F. W., Jones, B. J. P., … Woodruff, K. (2019). Barium Chemosensors with Dry-Phase Fluorescence for Neutrinoless Double Beta Decay. 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Prospective Observational Study of Pazopanib in Patients with Advanced Renal Cell Carcinoma (PRINCIPAL Study)

Background: Real-world data are essential to accurately assessing efficacy and toxicity of approved agents in everyday practice. PRINCIPAL, a prospective, observational study, was designed to confirm the real-world safety and efficacy of pazopanib in patients with advanced renal cell carcinoma (RCC). Subjects, Materials, and Methods: Patients with clear cell advanced/metastatic RCC and a clinical decision to initiate pazopanib treatment within 30 days of enrollment were eligible. Primary objectives included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), relative dose intensity (RDI) and its effect on treatment outcomes, change in health-related quality of life (HRQoL), and safety. We also compared characteristics and outcomes of clinical-trial-eligible (CTE) patients, defined using COMPARZ trial eligibility criteria, with those of non-clinical-trial-eligible (NCTE) patients. Secondary study objectives were to evaluate clinical efficacy, safety, and RDI in patient subgroups. Results: Six hundred fifty-seven patients were enrolled and received ≥1 dose of pazopanib. Median PFS and OS were 10.3 months (95% confidence interval [CI], 9.2–12.0) and 29.9 months (95% CI, 24.7 to not reached), respectively, and the ORR was 30.3%. HRQoL showed no or little deterioration over time. Treatment-related serious adverse events (AEs) and AEs of special interest occurred in 64 (9.7%), and 399 (60.7%) patients, respectively. More patients were classified NCTE than CTE (85.2% vs. 14.8%). Efficacy of pazopanib was similar between the two groups. Conclusion: PRINCIPAL confirms the efficacy and safety of pazopanib in patients with advanced/metastatic RCC in a real-world clinical setting. Implications for Practice: PRINCIPAL is the largest (n = 657) prospective, observational study of pazopanib in patients with advanced/metastatic renal cell carcinoma, to the authors’ knowledge. Consistent with clinical trial results that often contain specific patient types, the PRINCIPAL study demonstrated that the effectiveness and safety of pazopanib is similarly safe and effective in patients with advanced kidney cancer in a real-world clinical setting. The PRINCIPAL study showed that patients with advanced kidney cancer who are treated with first-line pazopanib generally do not show disease progression for approximately 10 months and generally survive for nearly 30 months

Radio frequency and DC high voltage breakdown of high pressure helium, argon, and xenon

Motivated by the possibility of guiding daughter ions from double beta decay events to single-ion sensors for barium tagging, the NEXT collaboration is developing a program of R&D to test radio frequency (RF) carpets for ion transport in high pressure xenon gas. This would require carpet functionality in regimes at higher pressures than have been previously reported, implying correspondingly larger electrode voltages than in existing systems. This mode of operation appears plausible for contemporary RF-carpet geometries due to the higher predicted breakdown strength of high pressure xenon relative to low pressure helium, the working medium in most existing RF carpet devices. In this paper we present the first measurements of the high voltage dielectric strength of xenon gas at high pressure and at the relevant RF frequencies for ion transport (in the 10 MHz range), as well as new DC and RF measurements of the dielectric strengths of high pressure argon and helium gases at small gap sizes. We find breakdown voltages that are compatible with stable RF carpet operation given the gas, pressure, voltage, materials and geometry of interest