Radiotherapy (XRT), a well-known activator of the inflammasome and immune priming, is in part capable of reversing resistance to anti-PD1 treatment. The NLRP3 inflammasome is a pattern recognition ...receptor which is activated by both exogenous and endogenous stimuli, leading to a downstream inflammatory response. Although NLRP3 is typically recognized for its role in exacerbating XRT-induced tissue damage, the NLRP3 inflammasome can also yield an effective antitumor response when used in proper dosing and sequencing with XRT. However, whether NLRP3 agonist boosts radiation-induced immune priming and promote abscopal responses in anti-PD1 resistant model is still unknown. Therefore, in this study, we paired intratumoral injection of an NLRP3 agonist with XRT to stimulate the immune system in both wild type (344SQ-P) and anti-PD1 resistant (344SQ-R) murine-implanted lung adenocarcinoma models. We found that the combination of XRT + NLPR3 agonist enhanced the control of implanted lung adenocarcinoma primary as well as secondary tumors in a radiological dose-dependent manner, in which 12Gyx3 fractions of stereotactic XRT was better than 5Gyx3, while 1Gyx2 did not improve the NLRP3 effect. Survival and tumor growth data also showed significant abscopal response with the triple therapy (12Gyx3 + NLRP3 agonist + α-PD1) in both 344SQ-P and 344SQ-R aggressively growing models. Multiple pro-inflammatory cytokines (IL-1b, IL-4, IL-12, IL-17, IFN-γ and GM-CSF) were elevated in the serum of mice treated with XRT + NLRP3 or triple therapy. The Nanostring results showed that NLRP3 agonist is capable of increasing antigen presentation, innate function, and T-cell priming. This study can be of particular importance to treat patients with immunologically-cold solid tumors whom are also refractory to prior checkpoint treatments.
Lipids are a diverse class of biomolecules that have been implicated in cancer pathophysiology and in an array of immune responses, making them potential targets for improving immune responsiveness. ...Lipid and lipid oxidation also can affect tumor progression and response to treatment. Although their importance in cellular functions and their potential as cancer biomarkers have been explored, lipids have yet to be extensively investigated as a possible form of cancer therapy. This review explores the role of lipids in cancer pathophysiology and describes how further understanding of these macromolecules could prompt novel treatments for cancer.
Immunotherapy has revolutionized cancer treatment and revitalized efforts to harness the power of the immune system to combat a variety of cancer types more effectively. However, low clinical ...response rates and differences in outcomes due to variations in the immune landscape among patients with cancer continue to be major limitations to immunotherapy. Recent efforts to improve responses to immunotherapy have focused on targeting cellular metabolism, as the metabolic characteristics of cancer cells can directly influence the activity and metabolism of immune cells, particularly T cells. Although the metabolic pathways of various cancer cells and T cells have been extensively reviewed, the intersections among these pathways, and their potential use as targets for improving responses to immune-checkpoint blockade therapies, are not completely understood. This review focuses on the interplay between tumor metabolites and T-cell dysfunction as well as the relationship between several T-cell metabolic patterns and T-cell activity/function in tumor immunology. Understanding these relationships could offer new avenues for improving responses to immunotherapy on a metabolic basis.
Since the momentous discovery of X-rays, high-dose radiotherapy (H-XRT) has been a cornerstone for combating cancer. The high-energy electromagnetic waves induce direct damage to tumor-cells’ DNA, ...thereby halting cell growth and proliferation, and eventually leading to tumor eradication. Furthermore, recent evidence suggests that H-XRT may have immunomodulatory properties which arise from its ability to induce the release of neoantigens, which in turn prime T-cells and contribute to T-cell repertoire diversity. Throughout the years, there have been different treatment modalities introduced as complements to H-XRT that have yielded greater results than monotherapy alone. In this review, we will discuss preclinical and clinical data related to the recently introduced low-dose radiotherapy (L-XRT) modality. We will also explore the justification for combining L-XRT and H-XRT, which became known as the “RadScopal Technique”, as a novel immune adjuvant to treat cancer. In this analysis, we detail and dissect the physiological mechanisms of action of each modality and describe the synergistic amalgamation effect observed on primary and metastatic tumors. Finally, we will explore the impetus for further studies to investigate combinations of the “RadScopal Technique” with various immune-oncology drug candidates.
The prediction of the public health impact of a preventive strategy provides valuable support for decision-making. International guidelines for hypertension management have introduced the level of ...absolute cardiovascular risk in the definition of the treatment target population. The public health impact of implementing such a recommendation has not been measured.
We assessed the efficiency of three treatment scenarios according to historical and current versions of practice guidelines on a Realistic Virtual Population representative of the French population aged from 35 to 64 years: 1) BP≥160/95 mm Hg; 2) BP≥140/90 mm Hg and 3) BP≥140/90 mm Hg plus increased CVD risk. We compared the eligibility following the ESC guidelines with the recently observed proportion of treated amongst hypertensive individuals reported by the Etude Nationale Nutrition Santé survey. Lowering the threshold to define hypertension multiplied by 2.5 the number of eligible individuals. Applying the cardiovascular risk rule reduced this number significantly: less than 1/4 of hypertensive women under 55 years and less than 1/3 of hypertensive men below 45 years of age. This was the most efficient strategy. Compared to the simulated guidelines application, men of all ages were undertreated (between 32 and 60%), as were women over 55 years (70%). By contrast, younger women were over-treated (over 200%).
The global CVD risk approach to decide for treatment is more efficient than the simple blood pressure level. However, lack of screening rather than guideline application seems to explain the low prescription rates among hypertensive individuals in France. Multidimensional analyses required to obtain these results are possible only through databases at the individual level: realistic virtual populations should become the gold standard for assessing the impact of public health policies at the national level.
We present a new design of highly specialized small storage rings for low energy polarized electron beams. The new design is based on the transparent spin methodology that cancels the spin precession ...due to the magnetic dipole moment at any energy while allowing for spin precession induced by the fundamental physics of interest to accumulate. The buildup of the vertical component of beam polarization can be measured using standard Mott polarimetry that is optimal at low electron energy. Systematic effects are suppressed using counter-rotating bunched beams with various polarization orientations. These rings can be used to directly measure the permanent electric dipole moment of the electron, relevant to CP violation and matter-antimatter asymmetry in the universe, and to search for dark energy and ultra-light dark matter.
A concise demonstrative summary of the Symmetric Hybrid ring design for the storage ring proton electric dipole moment experiment is presented. In this paper, critical issues such as lattice design, ...background electrical fields, geometrical phase, general relativity, spin coherence time and polarimeter systematics are presented. Overall, we find that with the currently proposed design iteration, systematic error sources are reduced by orders of magnitude and that the ring alignment requirements are within the currently available technology.
Background American Society for Gastrointestinal Endsocopy (ASGE) guidelines for assessing minimal competence in EUS are based on expert opinion and retrospective studies. Objective To prospectively ...define learning curves in EUS among advanced endoscopy trainees (AETs). Design Prospective trial. Setting Three tertiary-care referral centers. Patients AETs with no prior EUS experience. Intervention AETs were evaluated by attending endosonographers at intervals of 10 EUS examinations (beginning at the 25th examination) during a 12-month training period. A standardized data collection form was used to grade examination of EUS anatomic stations and, when applicable, lesion of interest, accurate uTNM staging, wall layer origin of subepithelial lesions, and technical success with FNA. Main Outcome Measurements Cumulative sum analysis was applied to assess competency and produce a learning curve for each trainee for overall performance and for each anatomic station. Acceptable and unacceptable failure rates of 10% and 20%, respectively, were used. Results Five AETs were included, with a total of 1412 EUS examinations (AET1-225, T2-175, T3-402, T4-315, T5-295). Two AETs crossed the threshold for acceptable performance at cases number 255 and 295, two AETs showed a trend toward acceptable performance after 225 and 196 cases but needed ongoing training, and 1 AET demonstrated the need for ongoing training after 402 cases. Similar variable results were noted for individual stations. Limitations Results from this study may not be generalizable to other centers' AETs. Conclusion We observed substantial variability in achieving competency and a consistent need for more supervision in all AETs than current recommendations (150 cases). Future studies should focus on standardization of trainee performance, definition of competency, and widespread applicability of AET evaluation.
This contribution describes the latest milestones of a multiyear program to build and operate a compact−300kVdc high voltage photogun with inverted insulator geometry and alkali-antimonide ...photocathodes. Photocathode thermal emittance measurements and quantum efficiency charge lifetime measurements at average current up to 4.5 mA are presented, as well as an innovative implementation of ion generation and tracking simulations to explain the benefits of a biased anode to repel beam line ions from the anode-cathode gap, to dramatically improve the operating lifetime of the photogun and eliminate the occurrence of micro-arc discharges.
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