OGO-6 gas-surface energy transfer experiment

The kinetic energy flux of the upper atmosphere was analyzed using OGO-6 data. Energy transfer between 10 microwatts/sq cm and 0.1 W/sq cm was measured by short-term frequency changes of temperature-sensitive quartz crystals used in the energy transfer probe. The condition of the surfaces was continuously monitored by a quartz crystal microbalance to determine the effect surface contamination had on energy accommodation. Results are given on the computer analysis and laboratory tests performed to optimize the operation of the energy transfer probe. Data are also given on the bombardment of OGO-6 surfaces by high energy particles. The thermoelectrically-cooled quartz crystal microbalance is described in terms of its development and applications

The Focal plane Detector Package on the TUNL Split-pole Spectrograph

A focal plane detector for the Enge Split-pole Spectrograph at Triangle Universities Nuclear Laboratory has been designed. The detector package consists of two position sensitive gas avalanche counters, a gas proportionality energy loss section, and a residual energy scintillator. This setup allows both particle identification and focal plane reconstruction. In this paper we will detail the construction of each section along with their accompanying electronics and data acquisition. Effects of energy loss throughout the detector, ray tracing procedures, and resolution as a function of fill pressure and bias voltage are also investigated. A measurement of the $^{27}\!$Al$(d,p)$ reaction is used to demonstrate detector performance and to illustrate a Bayesian method of energy calibration

In vivo E2F reporting reveals efficacious schedules of MEK1/2–CDK4/6 targeting and mTOR–s6 resistance mechanisms

Targeting cyclin-dependent kinases 4/6 (CDK4/6) represents a therapeutic option in combination with BRAF inhibitor and/or MEK inhibitor (MEKi) in melanoma; however, continuous dosing elicits toxicities in patients. Using quantitative and temporal in vivo reporting, we show that continuous MEKi with intermittent CDK4/6 inhibitor (CDK4/6i) led to more complete tumor responses versus other combination schedules. Nevertheless, some tumors acquired resistance that was associated with enhanced phosphorylation of ribosomal S6 protein. These data were supported by phospho-S6 staining of melanoma biopsies from patients treated with CDK4/6i plus targeted inhibitors. Enhanced phospho-S6 in resistant tumors provided a therapeutic window for the mTORC1/2 inhibitor AZD2014. Mechanistically, upregulation or mutation of NRAS was associated with resistance in in vivo models and patient samples, respectively, and mutant NRAS was sufficient to enhance resistance. This study utilizes an in vivo reporter model to optimize schedules and supports targeting mTORC1/2 to overcome MEKi plus CDK4/6i resistance. SIGnIFICAnCE: Mutant BRAF and NRAS melanomas acquire resistance to combined MEK and CDK4/6 inhibition via upregulation of mTOR pathway signaling. This resistance mechanism provides the preclinical basis to utilize mTORC1/2 inhibitors to improve MEKi plus CDK4/6i drug regimens

Evaluation of the Interplay between the ADAR Editome and Immunotherapy in Melanoma.

RNA editing is a highly conserved posttranscriptional mechanism that contributes to transcriptome diversity. In mammals, it includes nucleobase deaminations that convert cytidine (C) into uridine (U) and adenosine (A) into inosine (I). Evidence from cancer studies indicates that RNA-editing enzymes promote certain mechanisms of tumorigenesis. On the other hand, recoding editing in mRNA can generate mutations in proteins that can participate in the Major Histocompatibility Complex (MHC) ligandome and can therefore be recognized by the adaptive immune system. Anti-cancer treatment based on the administration of immune checkpoint inhibitors enhance these natural anti-cancer immune responses. Based on RNA-Seq datasets, we evaluated the editome of melanoma cell lines generated from patients pre- and post-immunotherapy with immune checkpoint inhibitors. Our results reveal a differential editing in Arthrobacter luteus (Alu) sequences between samples pre-therapy and relapses during therapy with immune checkpoint inhibitors. These data pave the way towards the development of new diagnostics and therapies targeted to editing that could help in preventing relapses during immunotherapies

Health‐related quality of life in survivors of advanced melanoma treated with anti‐PD1‐based immune checkpoint inhibitors

Background: Immune checkpoint inhibitors (ICIs) have significantly improved survival in advanced melanoma but are associated with immune-related adverse events (irAEs). This single center, cross-sectional survey aimed to describe the long-term symptom burden and impact on health-related quality of life (HRQL) of advanced melanoma patients with sustained disease control following treatment with ICIs. Methods: Advanced melanoma patients (stage IIB, III or IV, AJCCv8), treated with anti-PD1-based ICIs, who were off-treatment and had at least 6 months follow-up from their last infusion with an ongoing response in the metastatic setting or no evidence of disease recurrence in the adjuvant setting. A paper-based questionnaire, consisting of the EORTC QLQ-C30, EORTC QLQ-FA12, and the PRO-CTCAE was administered. Results: Of 90 participants, 61 (68%) completed the questionnaire; 40 received single-agent anti-PD1, and 21 anti-PD1/anti-CTLA4. Thirty-three (54%) were treated in the adjuvant setting. At the time of enrolment, 31 (51%) participants had active treatment for a previous irAE. Overall, 18/61 (30%) participants reported long-term symptoms and trouble in physical and emotional functioning. Physical fatigue was common and interfered with daily activities (n = 12, 20%). In the PRO-CTCAE questionnaire, muscle ache (n = 12, 20%) and joint ache (n = 9, 15%) were commonly reported. Despite this, participants reported overall good health (6.00, range 2.00-7.00) and reasonable level of HRQL (6.00, range 3.00-7.00). Discussion: Melanoma survivors experience long-term symptoms in physical and psychosocial HRQL domains after ICI treatment. These results underline the importance to address existing gaps in survivorship care, implement these findings in clinical practice and increase awareness for long-term symptoms in these patients

Preferred reporting items for animal studies in endodontology (PRIASE): a development protocol

The regulated use of animals in endodontic research is often necessary to investigate the biological mechanisms of endodontic diseases and to measure the preclinical efficacy, biocompatibility, toxicology and safety of new treatments, biomaterials, sealers, drugs, disinfectants, irrigants, devices and instruments. Animal testing is most crucial in situations when research on humans is not ethical, practical or has unknown health risks. Currently, there is a wide variability in the quality of manuscripts that report the results of animal studies. Towards the goal of improving the quality of publications, guidelines for preventing disability, pain, and suffering to animals, and enhanced reporting requirements for animal research have been developed. These guidelines are referred to as Animals in Research: Reporting In Vivo Experiments (ARRIVE). Henceforth, causing any form of animal suffering for research purposes is not acceptable and cannot be justified under any circumstances. The present report describes a protocol for the development of welfare and reporting guidelines for animal studies conducted in the specialty of Endodontology: the Preferred Reporting Items for Animal Studies in Endodontology (PRIASE) guidelines. The PRIASE guidelines will be developed by adapting and modifying the ARRIVE guidelines and the Clinical and Laboratory Images in Publication (CLIP) principles. The development of the new PRIASE guidelines will include a five‐step consensus process. An initial draft of the PRIASE guidelines will be developed by a steering committee. Each item in the draft guidelines will then be evaluated by members of a PRIASE Delphi Group (PDG) for its clarity using a dichotomous scale (yes or no) and suitability for its inclusion using a 9‐point Likert scale. The online surveys will continue until each item achieves this standard, and a set of items are agreed for further analysis by a PRIASE Face‐to‐face Consensus Meeting Group (PFCMG). Following the consensus meeting, the steering committee will finalize and confirm the PRIASE guidelines taking into account the responses and comments of the PFCMG. The PRIASE guidelines will be published and disseminated internationally and updated periodically based on feedback from stakeholders