Constitutive PD-L1 expression in melanoma

Treatment of melanoma based on targeted therapy and immunotherapy has dramatically advanced over the past decade. Advances in targeted therapy have been based on inhibition of the MAPK pathway while for immunotherapy, advances have been based on blocking immune checkpoint proteins such as the PD-1/PD-L1 axis. PD-L1 serves as a potent immune suppressor of the immune response enabling cancer cells to escape the immune surveillance. Recently, it was reported in several studies that resistance to MAPK pathway inhibitors can be accompanied by increases in constitutive PD-L1 expression in melanoma, highlighting the importance of understanding the underlying regulation of PD-L1 expression. However, the mechanism regulating constitutive PD-L1 expression remains unclear in melanoma. In this study, one of the aims was to investigate whether DNA methylation plays a role in PD-L1 expression. Firstly, it was found that melanoma cell lines with constitutive PD-L1 expression have a marked loss of global DNA methylation (hypomethylation), particularly in the intergenic regions and repeat elements, which suggested an altered epigenomic landscape. A number of endogenous retrovirus (ERV) elements that reside in the intergenic region were increased in expression in the constitutive PD-L1 cell lines. This was accompanied by activation of the innate immune response and transcription factors that can upregulate PD-L1 levels. Intergenic lncRNAs that are in close proximity to immune related genes were also upregulated in the constitutive PD-L1 cell lines. Moreover, DNMTi (global demethylation) mediated PD-L1 upregulation was revealed to increase many of the same innate immune response genes and transcription factors that were upregulated in the constitutive PD-L1 samples supporting the role of DNA hypomethylation in PD-L1 expression. Furthermore, how PD-L1 expression is associated with resistance to MAPK targeted inhibitors remains unclear. Here, it was found that constitutive PD-L1 expression is associated with a transcriptomic state that is characteristic for dedifferentiation which is mediated by the loss of SOX10 expression and upregulation of other transcription factors such as SOX9. Moreover, constitutive PD-L1 samples were associated with a reduced expression of genes involved in oxidative phosphorylation demonstrating an altered metabolic program. Overall, we found evidence that supports constitutive PD-L1 expression in melanoma is regulated by the viral mimicry pathway via global hypomethylation. Furthermore, constitutive PD-L1 expression is closely associated with dedifferentiation mediated by loss of SOX10 which provides insight as to why PD-L1 expression increases upon development of therapy resistance

Phenomenology of flavor oscillations with non-perturbative effects from quantum field theory

We analyze phenomenological aspects of the quantum field theoretical formulation of meson mixing and obtain the exact oscillation formula in the presence of the decay. This formula is different from quantum mechanical formula by additional high-frequency oscillation terms. In the infinite volume limit, the space of the flavor quantum states is unitarily inequivalent to the space of energy eigenstates

Simplifying superstring and D-brane actions in AdS(4) x CP(3) superbackground

By making an appropriate choice for gauge fixing kappa-symmetry we obtain a relatively simple form of the actions for a D=11 superparticle in AdS(4) x S(7)/Z_k, and for a D0-brane, fundamental string and D2-branes in the AdS(4) x CP(3) superbackground. They can be used to study various problems of string theory and the AdS4/CFT3 correspondence, especially in regions of the theory which are not reachable by the OSp(6|4)/U(3) x SO(1,3) supercoset sigma-model. In particular, we present a simple form of the gauge-fixed superstring action in AdS(4) x CP(3) and briefly discuss issues of its T-dualization.Comment: 1+36 pages, v2,v3 clarifications and references adde

A Predictive Seesaw Scenario for EDMs

The generation of electric dipole moments (EDMs) is addressed in the supersymmetric seesaw scenario realized through the exchange of SU(2)_W triplet states. In particular, we show that the triplet soft-breaking bilinear term can induce finite contributions to lepton and quark EDMs. Moreover, the peculiar flavour structure of the model allows us to predict the EDM ratios d_e/d_mu and d_mu/d_tau only in terms of the neutrino parameters.Comment: 5 pages, uses axodraw.sty. Remarks and few references added. To appear on Phys. Lett.

Home-Based Tdcs for Apathy in Alzheimer’s Disease: A Protocol for a Randomized Double-Blinded Controlled Pilot Study

BACKGROUND: Apathy is among the most common behavioral symptoms in dementia and is consistently associated with negative outcomes in Alzheimer\u27s disease (AD). Despite its prevalence and clinical relevance, available pharmacological and non-pharmacological strategies to treat apathy in AD have been marked, respectively, by potentially severe side effects and/or limited efficacy. Transcranial direct current stimulation (tDCS) is a relatively novel non-pharmacological method of neuromodulation with promising results. Compared to previous tDCS formats, recent technological advances have increased the portability of tDCS, which creates the potential for caregiver-administered, home use. Our study aims to evaluate the feasibility, safety, and efficacy of home-based tDCS for the treatment of apathy in AD. METHODS/DESIGN: This is an experimenter- and participant-blinded, randomized, sham-controlled, parallel-group (1:1 for two groups) pilot clinical trial, involving 40 subjects with AD. After a brief training, caregivers will administer tDCS for participants at home under remote televideo supervision by research staff to ensure the use of proper technique. Participants will be assessed at baseline, during treatment (week 2, week 4, and week 6), and 6 weeks post-treatment. Dependent measures will cover cognitive performance, apathy, and other behavioral symptoms. Data about side effects and acceptability will also be collected. DISCUSSION: Our study will address apathy, an overlooked clinical problem in AD. Our findings will advance the field of non-pharmacological strategies for neuropsychiatric symptoms, presenting a great potential for clinical translation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04855643

Health-Related Quality of Life in Patients with Advanced Nonsquamous Non–Small-Cell Lung Cancer Receiving Bevacizumab or Bevacizumab-Plus-Pemetrexed Maintenance Therapy in AVAPERL (MO22089)

IntroductionIn the phase III AVAPERL trial, patients with advanced nonsquamous non–small-cell lung cancer receiving bevacizumab-plus-pemetrexed maintenance after first-line induction had a significant progression-free survival benefit relative to those treated with single-agent bevacizumab maintenance but with an increase in grade ≥3 adverse events. Here, we compare health-related quality of life (HRQOL) between AVAPERL maintenance arms.MethodsPatient-reported outcomes were collected at designated intervals from preinduction to final visits. HRQOL was assessed using the self-administered European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and the Quality of Life Lung Cancer–Specific Module 13. Differences in scores of 10 points or more between arms were above the minimum important difference threshold and considered clinically meaningful.ResultsDuring induction, patient-reported coughing symptoms improved slightly, whereas fatigue and appetite loss scores worsened relative to preinduction baseline. During maintenance, changes in mean global health status and the majority of Quality of Life Questionnaire Core 30 and Quality of Life Lung Cancer–Specific Module 13 subscale scores did not differ between trial arms by the minimum important difference defining clinically meaningful (better or worse) patient-reported outcomes. Exceptions were patient-reported role functional status, fatigue symptoms and appetite loss symptoms (favoring bevacizumab), and pain in arm or shoulder symptoms (favoring bevacizumab-plus-pemetrexed maintenance), which differed by clinically meaningful amounts at more than one maintenance assessment.ConclusionsIn AVAPERL, HRQOL remained relatively stable throughout maintenance and was generally similar in both arms. Despite an increase in adverse event rates, the addition of pemetrexed to bevacizumab maintenance resulted in similar stabilization of disease symptoms with improved efficacy outcomes

A Novel Swing Adsorption Reactor Cluster (SARC) for cost effective post-combustion CO2 capture: A thermodynamic assessment

The SARC consists of a number of standalone reactors where a solid sorbent is carbonated by a flue gas and regenerated by a combination of vacuum and temperature swing. Efficiency is maximized through heat integration between carbonation and regeneration using a heat pump. Initial power plant simulations showed 9.4%-points energy penalty when integrated into a pulverized coal plant. This is in-line with reported energy penalty for MEA and VPSA technologies, but great potential for further efficiency improvements exists. Future studies will investigate the effect of SARC process parameters and sorbent material selection on the energy penalty

The CDKN2A G500 Allele Is More Frequent in GBM Patients with No Defined Telomere Maintenance Mechanism Tumors and Is Associated with Poorer Survival

Prognostic markers for glioblastoma multiforme (GBM) are important for patient management. Recent advances have identified prognostic markers for GBMs that use telomerase or the alternative lengthening of telomeres (ALT) mechanism for telomere maintenance. Approximately 40% of GBMs have no defined telomere maintenance mechanism (NDTMM), with a mixed survival for affected individuals. This study examined genetic variants in the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene that encodes the p16INK4a and p14ARF tumor suppressors, and the isocitrate dehydrogenase 1 (IDH1) gene as potential markers of survival for 40 individuals with NDTMM GBMs (telomerase negative and ALT negative by standard assays), 50 individuals with telomerase, and 17 individuals with ALT positive tumors. The analysis of CDKN2A showed NDTMM GBMs had an increased minor allele frequency for the C500G (rs11515) polymorphism compared to those with telomerase and ALT positive GBMs (p = 0.002). Patients with the G500 allele had reduced survival that was independent of age, extent of surgery, and treatment. In the NDTMM group G500 allele carriers had increased loss of CDKN2A gene dosage compared to C500 homozygotes. An analysis of IDH1 mutations showed the R132H mutation was associated with ALT positive tumors, and was largely absent in NDTMM and telomerase positive tumors. In the ALT positive tumors cohort, IDH1 mutations were associated with a younger age for the affected individual. In conclusion, the G500 CDKN2A allele was associated with NDTMM GBMs from older individuals with poorer survival. Mutations in IDH1 were not associated with NDTMM GBMs, and instead were a marker for ALT positive tumors in younger individuals

Investigation on Metal–Oxide Graphene Field-Effect Transistors With Clamped Geometries

In this work, we report on the design, fabrication and characterization of Metal-Oxide Graphene Field-effect Transistors (MOGFETs) exploiting novel clamped gate geometries aimed at enhancing the device transconductance. The fabricated devices employ clamped metal contacts also for source and drain, as well as an optimized graphene meandered pattern for source contacting, in order to reduce parasitic resistance. Our experimental results demonstrate that MOGFETs with the proposed structure show improved high frequency performance, in terms of maximum available gain and transition frequency values, as a consequence of the higher equivalent transconductance obtained

The clustering of galaxies at z~0.5 in the SDSS-III Data Release 9 BOSS-CMASS sample: a test for the LCDM cosmology

We present results on the clustering of 282,068 galaxies in the Baryon Oscillation Spectroscopic Survey (BOSS) sample of massive galaxies with redshifts 0.4<z<0.7 which is part of the Sloan Digital Sky Survey III project. Our results cover a large range of scales from ~0.5 to ~90 Mpc/h. We compare these estimates with the expectations of the flat LCDM cosmological model with parameters compatible with WMAP7 data. We use the MultiDark cosmological simulation together with a simple halo abundance matching technique, to estimate galaxy correlation functions, power spectra, abundance of subhaloes and galaxy biases. We find that the LCDM model gives a reasonable description to the observed correlation functions at z~0.5, which is a remarkably good agreement considering that the model, once matched to the observed abundance of BOSS galaxies, does not have any free parameters. However, we find a deviation (>~10%) in the correlation functions for scales less than ~1 Mpc/h and ~10-40 Mpc/h. A more realistic abundance matching model and better statistics from upcoming observations are needed to clarify the situation. We also estimate that about 12% of the "galaxies" in the abundance-matched sample are satellites inhabiting central haloes with mass M>~1e14 M_sun/h. Using the MultiDark simulation we also study the real space halo bias b(r) of the matched catalogue finding that b=2.00+/-0.07 at large scales, consistent with the one obtained using the measured BOSS projected correlation function. Furthermore, the linear large-scale bias depends on the number density n of the abundance-matched sample as b=-0.048-(0.594+/-0.02)*log(n/(h/Mpc)^3). Extrapolating these results to BAO scales we measure a scale-dependent damping of the acoustic signal produced by non-linear evolution that leads to ~2-4% dips at ~3 sigma level for wavenumbers k>~0.1 h/Mpc in the linear large-scale bias.Comment: Replaced to match published version. Typos corrected; 25 pages, 17 figures, 9 tables. To appear in MNRAS. Correlation functions (projected and redshift-space) and correlation matrices of CMASS presented in Appendix B. Correlation and covariance data for the combined CMASS sample can be downloaded from http://www.sdss3.org/science/boss_publications.ph