Characterising PD-L1 expression in circulating melanoma and non-small cell lung cancer cells

Incidence rates for both melanoma and non-small cell lung cancer (NSCLC) have risen in recent decades. While advanced cases of both diseases have previously demonstrated low survivability, novel therapies such as immune checkpoint inhibitors, have significantly improved the outcome of patients suffering from these cancers. Recent clinical trials have led to the United States Food and Drug Administration (FDA) approving the use of antibodies targeting the PD-1 immune checkpoint for both melanoma and NSCLC. Anti-PD-1 antibodies have been seen to illicit responses in up to 40% of patients, however, particularly for melanoma, there is a lack of biomarkers to select for patients likely to respond. PD-L1 expression in tumour tissue is the most studied biomarker of response to anti-PD-1 therapy in melanoma patients and is also the biomarker currently in use as a companion diagnostic test for NSCLC patients. It is believed that circulating tumour cells (CTCs) that break away from the tumour and enter the bloodstream, would share the same immune escape mechanisms as the parent tumour, and so would express PD-L1 in the same way as the tumour. Therefore, we postulate that these cells provide an accessible tumour sample for analysis of PD-L1 expression. A previous study by our group used multi-marker flow cytometry to evaluated PD-L1 expression on CTCs from melanoma patients commencing anti-PD-L1 therapy. Here, the PDL1 expression on CTC from the latter study was compared to PD-L1 expression in matched tumour tissues. Moreover, this study describes the establishment of methodologies for immunocytochemistry analysis and scoring of PD-L1 expression on melanoma CTCs and on carcinomas CTCs, including NSCLC. Cell lines representing negative, low and high PD-L1 expression were identified to serve as controls, again for both melanoma and carcinomas. To further evaluate our methods, CTCs were extracted from the blood samples of patients with melanoma and NSCLC using microfluidic devices and immunostained to investigate the expression of PD-L1. Finally, comparison between CTC and tumour tissue PD-L1 expression was carried out in a small number of cases. Overall, this study successfully developed immunocytochemistry protocols to effectively identify and score PD-L1 expression on both melanoma and carcinoma CTCs, thus providing a basis for further work to evaluate the clinical potential of CTCs

Is the blood an alternative for programmed cell death ligand 1 assessment in non-small cell lung cancer?

Anti-programmed cell death (PD)-1/PD-ligand 1 (L1) therapies have significantly improved the outcomes for non-small cell lung cancer (NSCLC) patients in recent years. These therapies work by reactivating the immune system and enabling it to target cancer cells once more. There is a general agreement that expression of PD-L1 on tumour cells predicts the therapeutic response to PD-1/PD-L1 inhibitors in NSCLC. Hence, immunohistochemical staining of tumour tissue biopsies from NSCLC patients with PD-L1 antibodies is the current standard used to aid selection of patients for treatment with anti-PD-1 as first line therapy. However, issues of small tissue samples, tissue heterogeneity, the emergence of new metastatic sites, and dynamic changes in the expression of PD-L1 may influence PD-L1 status during disease evolution. Re-biopsy would expose patients to the risk of complications and tardy results. Analysis of PD-L1 expression on circulating tumour cells (CTCs) may provide an accessible and non-invasive means to select patients for anti-PD-1 therapies. Additionally, CTCs could potentially provide a useful biomarker in their own right. Several published studies have assessed PD-L1 expression on CTCs from NSCLC patients. Overall, analysis of PD-L1 on CTCs is feasible and could be detected prior to and after frontline therapy. However, there is no evidence on whether PD-L1 expression on CTCs could predict the response to anti-PD-1/PD-L1 treatment. This review examines the challenges that need to be addressed to demonstrate the clinical validity of PD-L1 analysis in CTCs as a biomarker capable of predicting the response to immune checkpoint blockade

Fandom and activism: Experimenting with memetic communication appeals about human rights issues during the 2022 winter Olympic games

In the sports context, activism is a popular focus of inquiry. In fact, scholars have posited that sports present an ideal platform for human rights and political activism and protest (Agyemang, Singer, & DeLorme, 2010; Coombs & Cassilo, 2017; Kaufman & Wolff, 2010). This study aims to analyze the persuasiveness of memetic communication in the global sports context by investigating the influence of exposure to social advocacy memes on issue importance and general attitudes toward global human rights. This experiment relied on MTurk participants in an online experiment using Qualtrics software hosted by the Communication Research Lab at a Midwest University. We measure the persuasive influence of a variety of persuasive strategies (e.g., assertive, comparative, calls to action, and appeals to self-efficacy) as well as explicit affiliations within a real-time global sports context (e.g., 2022 Winter Olympics). These findings add to existing scholarship by focusing on post-exposure behavioral intentions (e.g., diffusion intentions, advocacy intentions, consumption intentions, and information-seeking intentions) likely to spur activism and advocacy. These findings support the position that memetic communications help to serve as a motivational catalyst for information-seeking behaviors about global human rights issues in real-time global sports contexts. Discussion and limitations are provided

Corticosterone enhances formation of non-fear but not fear memory during infectious illness

IntroductionSurvivors of critical illness are at high risk of developing post-traumatic stress disorder (PTSD) but administration of glucocorticoids during the illness can lower that risk. The mechanism is not known but may involve glucocorticoid modulation of hippocampal- and amygdala-dependent memory formation. In this study, we sought to determine whether glucocorticoids given during an acute illness influence the formation and persistence of fear and non-fear memories from the time of the illness.MethodsWe performed cecal ligation and puncture in male and female mice to induce an acute infectious illness. During the illness, mice were introduced to a neutral object in their home cage and separately underwent contextual fear conditioning. We then tested the persistence of object and fear memories after recovery.ResultsGlucocorticoid treatment enhanced object discrimination but did not alter the expression of contextual fear memory. During context re-exposure, neural activity was elevated in the dentate gyrus irrespective of fear conditioning.ConclusionsOur results suggest that glucocorticoids given during illness enhance hippocampal-dependent non-fear memory processes. This indicates that PTSD outcomes in critically ill patients may be improved by enhancing non-fear memories from the time of their illness

A Moist Static Energy Budget–Based Analysis of the Sahel Rainfall Response to Uniform Oceanic Warming

Climate models generate a wide range of precipitation responses to global warming in the African Sahel, but all that use the NOAA Geophysical Fluid Dynamics Laboratory AM2.1 model as their atmospheric component dry the region sharply. This study compares the Sahel’s wet season response to uniform 2-K SST warming in AM2.1 using either its default convective parameterization, relaxed Arakawa–Schubert (RAS), or an alternate, the University of Washington (UW) parameterization, using the moist static energy (MSE) budget to diagnose the relevant mechanisms. UW generates a drier, cooler control Sahel climate than does RAS and a modest rainfall increase with SST warming rather than a sharp decrease. Horizontal advection of dry, low-MSE air from the Sahara Desert—a leading-order term in the control MSE budget with either parameterization—is enhanced with oceanic warming, driven by enhanced meridional MSE and moisture gradients spanning the Sahel. With RAS, this occurs throughout the free troposphere and is balanced by anomalous MSE import through anomalous subsidence, which must be especially large in the midtroposphere where the moist static stability is small. With UW, the strengthening of the meridional MSE gradient is mostly confined to the lower troposphere, due in part to comparatively shallow prevailing convection. This necessitates less subsidence, enabling convective and total precipitation to increase with UW, although both large-scale precipitation and precipitation minus evaporation decrease. This broad set of hydrological and energetic responses persists in simulations with SSTs varied over a wide range

Acute subdural haematoma in the elderly- to operate or not to operate A systematic review and meta-analysis of outcomes following surgery

Objectives Acute subdural haematoma (ASDH) is a devastating pathology commonly found on CT brain scans of patients with traumatic brain injury. The role of surgical intervention in the elderly has been increasingly questioned due to its associated morbidity and mortality. Therefore, a systematic review and meta-analysis of the literature to quantify the mortality and functional outcomes associated with surgical management of ASDH in the elderly was performed. Design/setting A multidatabase literature search between January 1990 and May 2020, and meta-analysis of proportions was performed to quantify mortality and unfavourable outcome (Glasgow Outcome scale 1–3; death/ severe disability) rates. Participants Studies reporting patients aged 60 years or older. Interventions Craniotomy, decompressive craniectomy, conservative management. Outcome measures Mortality and functional outcomes (discharge, long-term follow-up (LTFU)). Results 2572 articles were screened, yielding 21 studies for final inclusion and 15 for meta-analysis. Pooled estimates of mortality were 39.83% (95% CI 32.73% to 47.14%; 10 studies, 308/739 patients, I2=73%) at discharge and 49.30% (95% CI 42.01% to 56.61%; 10 studies, 277/555 patients, I2=63%) at LTFU. Mean duration of follow-up was 7.1 months (range 2–12 months). Pooled estimate of percentage of poor outcomes was 81.18% (95% CI 75.61% to 86.21%; 6 studies, 363/451 patients, I2=45%) at discharge, and 79.25% (95% CI 72.42% to 85.37%; 8 studies, 402/511 patients, I2=66%) at LTFU. Mean duration of follow-up was 6.4 months (range 2–12 months). Potential risk factors for poor outcome included age, baseline functional status, preoperative neurological status and imaging parameters. Conclusions Outcomes following surgical evacuation of ASDH in patients aged 60 years and above are poor. This constitutes the best level of evidence in the current literature that surgical intervention for ASDH in the elderly carries significant risks, which must be weighed against benefits

PD-L1 expression on circulating tumor cells may be predictive of response to Pembrolizumab in advanced melanoma: Results from a pilot study

BACKGROUND: PD-1 inhibitors are routinely used for the treatment of advanced melanoma. This study sought to determine whether PD-L1 expression on circulating tumor cells (CTCs) can serve as a predictive biomarker of clinical benefit and response to treatment with the PD-1 inhibitor pembrolizumab. METHODS: Blood samples were collected from patients with metastatic melanoma receiving pembrolizumab, prior to treatment and 6-12 weeks after initiation of therapy. Multiparametric flow cytometry was used to identify CTCs and evaluate the expression of PD-L1. RESULTS: CTCs were detected in 25 of 40 patients (63%). Patients with detectable PD-L1 CONCLUSION: Our results reveal the potential of CTCs as a noninvasive real-time biopsy to evaluate PD-L1 expression in patients with melanoma. PD-L1 expression on CTCs may be predictive of response to pembrolizumab and longer PFS. IMPLICATIONS FOR PRACTICE: The present data suggest that PD-L1 expression on circulating tumor cells may predict response to pembrolizumab in advanced melanoma. This needs further validation in a larger trial and, if proven, might be a useful liquid biopsy tool that could be used to stratify patients into groups more likely to respond to immunotherapy, hence leading to health cost savings

Multi-marker immunofluorescent staining and pd-l1 detection on circulating tumour cells from ovarian cancer patients

Detection of ovarian cancer (OC) circulating tumour cells (CTCs) is primarily based on targeting epithelial markers, thus failing to detect mesenchymal tumour cells. More importantly, the immune checkpoint inhibitor marker PD-L1 has not been demonstrated on CTCs from OC patients. An antibody staining protocol was developed and tested using SKOV-3 and OVCA432 OC cell lines. We targeted epithelial (cytokeratin (CK) and EpCAM), mesenchymal (vimentin), and OC-specific (PAX8) markers for detection of CTCs, and CD45/16 and CD31 were used for the exclusion of white blood and vascular endothelial cells, respectively. PD-L1 was used for CTC characterisation. CTCs were enriched using the Parsortix™ system from 16 OC patients. Results revealed the presence of CTCs in 10 (63%) cases. CTCs were heterogeneous, with 113/157 (72%) cells positive for CK/EpCAM (epithelial marker), 58/157 (37%) positive for vimentin (mesenchymal marker), and 17/157 (11%) for both (hybrid). PAX8 was only found in 11/157 (7%) CTCs. In addition, 62/157 (39%) CTCs were positive for PD-L1. Positivity for PD-L1 was significantly associated with the hybrid phenotype when compared with the epithelial (p = 0.007) and mesenchymal (p = 0.0009) expressing CTCs. Characterisation of CTC phenotypes in relation to clinical outcomes is needed to provide insight into the role that epithelial to mesenchymal plasticity plays in OC and its relationship with PD-L1

Results from the centers for disease control and prevention's predict the 2013-2014 Influenza Season Challenge

Background: Early insights into the timing of the start, peak, and intensity of the influenza season could be useful in planning influenza prevention and control activities. To encourage development and innovation in influenza forecasting, the Centers for Disease Control and Prevention (CDC) organized a challenge to predict the 2013-14 Unites States influenza season. Methods: Challenge contestants were asked to forecast the start, peak, and intensity of the 2013-2014 influenza season at the national level and at any or all Health and Human Services (HHS) region level(s). The challenge ran from December 1, 2013-March 27, 2014; contestants were required to submit 9 biweekly forecasts at the national level to be eligible. The selection of the winner was based on expert evaluation of the methodology used to make the prediction and the accuracy of the prediction as judged against the U.S. Outpatient Influenza-like Illness Surveillance Network (ILINet). Results: Nine teams submitted 13 forecasts for all required milestones. The first forecast was due on December 2, 2013; 3/13 forecasts received correctly predicted the start of the influenza season within one week, 1/13 predicted the peak within 1 week, 3/13 predicted the peak ILINet percentage within 1 %, and 4/13 predicted the season duration within 1 week. For the prediction due on December 19, 2013, the number of forecasts that correctly forecasted the peak week increased to 2/13, the peak percentage to 6/13, and the duration of the season to 6/13. As the season progressed, the forecasts became more stable and were closer to the season milestones. Conclusion: Forecasting has become technically feasible, but further efforts are needed to improve forecast accuracy so that policy makers can reliably use these predictions. CDC and challenge contestants plan to build upon the methods developed during this contest to improve the accuracy of influenza forecasts. © 2016 The Author(s)

Dark sectors 2016 Workshop: community report

This report, based on the Dark Sectors workshop at SLAC in April 2016, summarizes the scientific importance of searches for dark sector dark matter and forces at masses beneath the weak-scale, the status of this broad international field, the important milestones motivating future exploration, and promising experimental opportunities to reach these milestones over the next 5-10 years