Search

Understanding the genomic landscape of breast cancer brain metastases (BCBMs) is key to developing targeted treatments. In this study, targetable genomic profiling was performed on 822 BCBMs, 11,988 local breast cancer (BC) biopsies and 15,516 non-central nervous system (N-CNS) metastases (all unpaired samples) collected during the course of routine clinical care by Foundation Medicine Inc (Boston, MA). Clinically relevant genomic alterations were significantly enriched in BCBMs compared to local BCs and N-CNS metastases. Homologous recombination deficiency as measured by BRCA1/2 alteration prevalence and loss-of-heterozygosity and immune checkpoint inhibitor (ICI) biomarkers [Tumor mutation burden (TMB)-High, Microsatellite instability (MSI)-High, PD-L1/L2)] were significantly more prevalent in BCBM than local BC and N-CNS. High PD-L1 protein expression was observed in ER-negative/HER2-negative BCBMs (48.3% vs 50.0% in local BCs, 21.4% in N-CNS). Our data highlights that a high proportion of BCBMs are potentially amenable to treatment with targeted therapeutic agents including PARP inhibitors and ICIs. [ABSTRACT FROM AUTHOR]

Introduction: Matching patients to an effective targeted therapy or immunotherapy is a challenge for advanced and metastatic non-small cell lung cancer (NSCLC), especially when relying on assays that test one marker at a time. Unlike traditional single marker tests, comprehensive genomic profiling (CGP) can simultaneously assess NSCLC tumors for hundreds of genomic biomarkers and markers for immunotherapy response, leading to quicker and more precise matches to therapeutics. Methods: In this study, we performed CGP on 7,606 patients with advanced or metastatic NSCLC using the Illumina TruSight Oncology 500 (TSO 500) CGP assay to show its coverage and utility in detecting known and novel features of NSCLC. Results: Testing revealed distinct genomic profiles of lung adenocarcinoma and squamous cell carcinomas and detected variants with a current targeted therapy or clinical trial in >72% of patient tumors. Known associations between genomic alterations and immunotherapy markers were observed including significantly lower TMB levels in tumors with therapy-associated alterations and significantly higher PD-L1 levels in tumors with ALK , MET , BRAF , or ROS1 driver mutations. Co-occurrence analysis followed by network analysis with gene module detection revealed known and novel co-occurrences between genomic alterations. Further, certain modules of genes with co-occurring genomic alterations had dose-dependent relationships with histology and increasing or decreasing levels of PD-L1 and TMB, suggesting a complex relationship between PD-L1, TMB, and genomic alterations in these gene modules. Discussion: This study is the largest clinical study to date utilizing the TSO 500. It provides an opportunity to further characterize the landscape of NSCLC using this newer technology and show its clinical utility in detecting known and novel facets of NSCLC to inform treatment decision-making. [ABSTRACT FROM AUTHOR]

Determination of the psychological factors of human activity towards species supports the achievement of conservation-oriented management goals in an ecotourism setting. This paper develops measures related to the causes that predict intentions toward disturbance behaviour on birds among Malaysian birdwatchers. The theory of planned behaviour (TPB), the theory of normative conduct and the cognitive hierarchy model are incorporated into a comprehensive model of study as the Predictor Bird Conservation Model (PBCM) based on a quantitative approach, a five-point Likert scale of measurement was developed for the items. The measures were assessed for convergent validity, collinearity, significance and relevance of the formative indicators for each construct. The structural equation model (SEM), specifically the partial least squares method, was used to assess the convergent validity of the formative measurement model. Results from 50 birders in the initial test and 421 birders in the primary test show that the instrument is reliable and valid for further study to assess the structural model in the future. Our results supported a conservation measurement model of birdwatchers' behaviours towards birds. This research can also provide useful instruction for developing psychological measures to monitor tourist behaviour towards wildlife. [ABSTRACT FROM AUTHOR]

Clinical management of non-small cell lung cancer (NSCLC) requires accurate identification of tumor-specific genetic alterations to inform treatment options. Historically, providers have relied on single-gene testing (SGT) for actionable variants due to a perception of cost-effectiveness and/or efficient turnaround time compared to next-generation sequencing (NGS). However, not all actionable variants may be evaluated through SGT modalities, and an SGT approach can exhaust valuable tissue needed for more comprehensive analyses. In contrast, comprehensive genomic profiling (CGP) tests employ NGS to sequence megabases of DNA and RNA to evaluate all relevant molecular alterations, providing a broader genetic profile to identify actionable alterations that SGT may not accurately or efficiently assess. Here, we briefly describe four cases from a large reference laboratory in which actionable alterations were identified by CGP but not SGT. The discussion highlights the utility and advantages of using CGP to provide complete and timely treatment options and clinical trial opportunities for patients with NSCLC. [ABSTRACT FROM AUTHOR]

Disparities in cancer diagnosis, treatment, and outcomes based on self-identified race and ethnicity (SIRE) are well documented, yet these variables have historically been excluded from clinical research. Without SIRE, genetic ancestry can be inferred using single-nucleotide polymorphisms (SNPs) detected from tumor DNA using comprehensive genomic profiling (CGP). However, factors inherent to CGP of tumor DNA increase the difficulty of identifying ancestry-informative SNPs, and current workflows for inferring genetic ancestry from CGP need improvements in key areas of the ancestry inference process. This study used genomic data from 4274 diverse reference subjects and CGP data from 491 patients with solid tumors and SIRE to develop and validate a workflow to obtain accurate genetically inferred ancestry (GIA) from CGP sequencing results. We use consensus-based classification to derive confident ancestral inferences from an expanded reference dataset covering eight world populations (African, Admixed American, Central Asian/Siberian, European, East Asian, Middle Eastern, Oceania, South Asian). Our GIA calls were highly concordant with SIRE (95%) and aligned well with reference populations of inferred ancestries. Further, our workflow could expand on SIRE by (i) detecting the ancestry of patients that usually lack appropriate racial categories, (ii) determining what patients have mixed ancestry, and (iii) resolving ancestries of patients in heterogeneous racial categories and who had missing SIRE. Accurate GIA provides needed information to enable ancestry-aware biomarker research, ensure the inclusion of underrepresented groups in clinical research, and increase the diverse representation of patient populations eligible for precision medicine therapies and trials. [ABSTRACT FROM AUTHOR]

The prevalence of manipulated videos presents a significant challenge in today's era dominated by social media. Various types of fake videos, including notable examples such as Neural Textures, exist. Identifying such deceptive videos is a complex task. This research aims to understand the unique characteristics associated with Neural Texture videos. In the pursuit of comprehending these videos, the study explores the distinguishing traits that define them. The research employs techniques for scene and texture detection to formulate a distinct set of nineteen data features. This feature set is crafted to determine whether a video exhibits Neural Texture characteristics. To validate this set, a standard dataset of video attributes is utilized. These attributes undergo analysis using a machine learning classification model. The results of these experiments are assessed through four distinct methodologies. The evaluation reveals favourable performance outcomes when the machine learning approach and the proposed feature set are used. Based on these findings, it can be concluded that employing the suggested feature set enables the prediction of whether a video displays Neural Texture characteristics. This confirms the hypothesis that a correlation exists between a video's attributes and its authenticity, specifically in determining whether the video qualifies as a Neural Texture. [ABSTRACT FROM AUTHOR]

Infrastructureless social networks (ISNs) are created by the interconnection of spectral-constrained mobile devices. One such type of ISN are the mobile ad hoc networks (MANETs). One of the issues that consumers of content on ISNs face is the inability to detect fake news in messages sent through the network. To address the fake news detection issue in ISNs, the ensemble-based veracity architecture, an ensemble-based computational social system for fake news detection in infrastructureless social networks, has been proposed. Ensemble-based Veracity detects fake news using both the publisher's credibility and the content of the news. To understand the effect that ensemble-based Veracity has on network performance, this work investigates the network performance of the ensemble-based Veracity architecture. Ensemble-based Veracity is fully evaluated using a MANET-based experimental design and simulation environment. The network performance results of the experiments on ensemble-based Veracity are thoroughly analysed, and all the observations are noted. According to the experimental results, the throughputs were 2,445,528 bps, 2,391,905 bps and 2,236,778 bps for 20, 50 and 100 nodes, respectively. The experimental results show that ensemble-based Veracity negligibly affects the throughput, queuing time, queue length and number of packets passed to the upper layers of the network and the network performance. [ABSTRACT FROM AUTHOR]

Background: Workplace atmospheric exposure monitoring is the standard method to assess and control hazardous dust exposure; however, feasibility and cost constraints often limit its application. In recent decades, evidence-based tools supporting exposure modelling and control banding have been developed to aid in predicting and/or controlling occupational exposure to various contaminants. However, there is limited information on the availability and applicability of evidence-based tools for predicting and/or controlling occupational dust exposure, as well as on the methods for evaluating these tools across different exposure scenarios. Therefore, this planned scoping review aims to identify existing evidence-based tools for dust exposure predicting and/or controlling and to present evaluation approaches. Methods: We will employ the scoping review methods developed by the Joanna Briggs Institute (JBI). The search will be conducted on PubMed, Scopus, and Web of Science databases, in addition to grey literature from the National Institute for Occupational Safety and Health (NIOSH) and advanced Google searches. Studies will be included if they report evidence-based tools for predicting and/or controlling dust exposure using quantitative or semi-quantitative designs and provide a detailed explanation of the methods used for tool development. There will be no restrictions on publication date or geographical location; however, only studies published in English will be considered. Studies focusing exclusively on dust exposure in environmental settings will be excluded. Each member of the review team will screen titles, abstracts, and full texts independently and in collaboration, based on the inclusion criteria. The extracted data will encompass details such as author, title, country, accessible platforms, method/tool names, intended users, types of dust, and occupational settings. Descriptions of the identified tools will include numerical data and narrative summaries to ensure a comprehensive overview. Trial registration: OSF (https://doi.org/10.17605/OSF.IO/S6EZJ). [ABSTRACT FROM AUTHOR]

Purpose: The introduction of artificial intelligence (AI) applications in the Global South brings tremendous potential for both good and harm. This paper aims to highlight the guiding ethical principles and normative frameworks for the ethical use of AI in the lens of the traditional Ga (a tribe in Ghana) philosophy and add to the academic literature and research on AI and ethics within the African context. Design/methodology/approach: Literature overview on the African philosophy of Ga tradition as applied to AI and application of it to the AI4people ethical framework for a good AI society. Findings: Existing principles in AI are based on and mostly influenced by western principles, which may give rise to biases in AI outcomes and design implications in Africa. The research finds a high degree of overlap in the AI4People ethical framework for a good AI society and the Ga philosophy. Research limitations/implications: There are a few existing literatures on AI ethics in Africa and on Ga philosophy. Originality/value: This research offers valuable contribution to the ongoing discourse of Africa's adoption of AI and widens the debate on AI and ethics beyond the western ethical approaches. [ABSTRACT FROM AUTHOR]

Background: The understanding of molecular characteristics of HER2-low breast cancer is evolving since the establishment of trastuzumab deruxtecan. Here, we explore the differences in expression patterns of immune-related genes in the tumor immune microenvironment (TME) and survival between HER2-low and HER2-zero breast cancers. Methods: Comprehensive genomic and immune profiling, including RNA-seq gene expression assessment of 395 immune genes, was performed on FFPE samples from 129 patients with advanced HER2-negative (immunohistochemistry (IHC) 0, 1+ or 2+ with negative ERBB2 amplification by in-situ hybridization) breast cancer. Both estrogen receptor (ER) and HER2 statuses were obtained from available pathology reports. mRNA expressions of immune biomarkers, except for PD-L1 IHC and TMB, were derived from RNA-seq. Statistical comparisons were performed using the Kruskal–Wallis or Wilcoxon Rank-Sum test or the two-sample test for equality of proportions with continuity correction (p≤ 0.05 for significance). Survival differences were calculated using Kaplan-Meier analysis (p≤ 0.05 for significance). Results: There were no significant differences in mRNA expressions of immune-related genes between HER2-low and HER2-zero breast cancers. However, HER2-low breast cancers were associated with a higher proportion of ER-positivity. When ER was analyzed along with HER2, we observed a significantly higher tumor immunogenic signature (TIGS) expression in HER2-zero/ER-negative tumors than in HER2-low/ER-positive tumors (p=0.0088). Similarly, lower expression of PD-L1 and T cell immunoglobulin and ITIM domain (TIGIT) mRNA was observed in HER2-low/ER-positive tumors when compared to HER2-zero/ER-negative tumors (p=0.014 and 0.012, respectively). Patients with HER2-low tumors had a longer median OS than those with HER2-zero tumors (94 months vs 42 months, p=0.0044). Conclusion: Patients with HER2-low breast cancer have longer survivals yet display no differences in immune-related gene expression when compared to those with HER2-zero cancers. The differences in survival can be attributed to the higher rate of ER-positivity seen in HER2-low breast cancers, compared to HER2-zero tumors. [ABSTRACT FROM AUTHOR]

Introduction: Younger patients with non-small cell lung cancer (NSCLC) (<50 years) represent a significant patient population with distinct clinicopathological features and enriched targetable genomic alterations compared to older patients. However, previous studies of younger NSCLC suffer from inconsistent findings, few studies have incorporated sex into their analyses, and studies targeting age-related differences in the tumor immune microenvironment are lacking. Methods: We performed a retrospective analysis of 8,230 patients with NSCLC, comparing genomic alterations and immunogenic markers of younger and older patients while also considering differences between male and female patients. We defined older patients as those ≥65 years and used a 5-year sliding threshold from <45 to <65 years to define various groups of younger patients. Additionally, in an independent cohort of patients with NSCLC, we use our observations to inform testing of the combinatorial effect of age and sex on survival of patients given immunotherapy with or without chemotherapy. Results: We observed distinct genomic and immune microenvironment profiles for tumors of younger patients compared to tumors of older patients. Younger patient tumors were enriched in clinically relevant genomic alterations and had gene expression patterns indicative of reduced immune system activation, which was most evident when analyzing male patients. Further, we found younger male patients treated with immunotherapy alone had significantly worse survival compared to male patients ≥65 years, while the addition of chemotherapy reduced this disparity. Contrarily, we found younger female patients had significantly better survival compared to female patients ≥65 years when treated with immunotherapy plus chemotherapy, while treatment with immunotherapy alone resulted in similar outcomes. Discussion: These results show the value of comprehensive genomic and immune profiling (CGIP) for informing clinical treatment of younger patients with NSCLC and provides support for broader coverage of CGIP for younger patients with advanced NSCLC. [ABSTRACT FROM AUTHOR]

This research investigates residents' pro-environmental behavior from the unique perspective of government-resident interactions. Guided by social movement theory, how local governments regulate residents' waste-sorting behavior in Chinese rural tourism destinations is assessed. This longitudinal study (lasting from 2016 to 2022) uses participant observation, in-depth interviews (N = 25), and secondary data as the key research techniques. The dual roles of local governments (i.e., resource mobilization and power redistribution) jointly shape residents' pro-environmental behavior in the waste-sorting campaign. Resource mobilization enhances knowledge of waste-sorting and raises individuals' environmental consciousness. Power redistribution within groups activates social networks in rural communities and changes groups' social capital to influence residents' collective behavior. Results are discussed in relation to how the organizational-level resource mobilization and power redistribution influence the individual-level environmental psychological and sociological factors in shaping residents' waste-sorting behavior. Practical recommendations are offered for sustainable tourism management from a social interaction perspective. [ABSTRACT FROM AUTHOR]

This study investigates how tourists' Green Environmental Knowledge, Green Hotel Knowledge, and environment concern impact pro-environmental (PE) attitudes. Using mixed methods, it examines how PE attitudes influence the intention to stay at eco-friendly hotels, based on the theory of planned behavior. The study further explores the moderating role of the "Greta Effect" in connecting PE attitudes and hotel choice. This study utilizes a mixed-methods approach to enhance the comprehension of quantitative findings, on exploring the moderating impact of the "Greta Effect". The findings highlight the important role of environmental activism in inspiring action for green hotel choice. [ABSTRACT FROM AUTHOR]

Introduction: Tissue-based broad molecular profiling of guideline-recommended biomarkers is advised for the therapeutic management of patients with non-small cell lung cancer (NSCLC). However, practice variation can affect whether all indicated biomarkers are tested. We aimed to evaluate the impact of common single-gene testing (SGT) on subsequent comprehensive genomic profiling (CGP) test outcomes and results in NSCLC. Methods: Oncologists who ordered SGT for guideline-recommended biomarkers in NSCLC patients were prospectively contacted (May–December 2022) and offered CGP (DNA and RNA sequencing), either following receipt of negative SGT findings, or instead of SGT for each patient. We describe SGT patterns and compare CGP completion rates, turnaround time, and recommended biomarker detection for NSCLC patients with and without prior negative SGT results. Results: Oncologists in > 80 community practices ordered CGP for 561 NSCLC patients; 135 patients (27%) first had negative results from 30 different SGT combinations; 84% included ALK, EGFR and PD-L1, while only 3% of orders included all available SGTs for guideline-recommended genes. Among patients with negative SGT results, CGP was attempted using the same tissue specimen 90% of the time. There were also significantly more CGP order cancellations due to tissue insufficiency (17% vs. 7%), DNA sequencing failures (13% vs. 8%), and turnaround time > 14 days (62% vs. 29%) than among patients who only had CGP. Forty-six percent of patients with negative prior SGT had positive CGP results for recommended biomarkers, including targetable genomic variants in genes beyond ALK and EGFR, such as ERBB2, KRAS (non-G12C), MET (exon 14 skipping), NTRK2/3, and RET. Conclusion: For patients with NSCLC, initial use of SGT increases subsequent CGP test cancellations, turnaround time, and the likelihood of incomplete molecular profiling for guideline-recommended biomarkers due to tissue insufficiency. Plain Language Summary: Patients with non-small cell lung cancer (NSCLC) should have their tumor tissue tested for all recommended biomarkers that can help identify their best treatment options. Traditional tests look at gene biomarkers one by one (single-gene testing), and doctors can order some or all these tests individually or in a group. However, some recommended biomarkers cannot be tested by traditional single-gene tests at all. Newer technology (next-generation sequencing) covers all current recommended treatment biomarkers in one test (comprehensive genomic profiling), but this testing is more expensive and can take more time. Our study shows that NSCLC patients do not get all recommended treatment biomarkers tested when a single-gene testing approach is taken. Single-gene testing also used up some patients' tumor tissue entirely, such that further testing by comprehensive genomic profiling could not be done at all (17% vs. 7% for patients with no prior single-gene tests), resulted in more sequencing failures (13% vs. 8%), and had turnaround time for results greater than 14 days for more patients (62% vs. 29%). When comprehensive genomic profiling was completed, 46% of patients with negative results from prior single-gene testing had positive results for recommended treatment biomarkers that were not included in the initial single-gene tests. To ensure that NSCLC patients receive testing for all recommended biomarkers, comprehensive genomic profiling must be performed first. [ABSTRACT FROM AUTHOR]

Background: KEYNOTE-522 resulted in FDA approval of the immune checkpoint inhibitor pembrolizumab in combination with neoadjuvant chemotherapy for patients with early-stage, high-risk, triple-negative breast cancer (TNBC). Unfortunately, pembrolizumab is associated with several immune-related adverse events (irAEs). We aimed to identify potential tumor microenvironment (TME) biomarkers which could predict patients who may attain pathological complete response (pCR) with chemotherapy alone and be spared the use of anti-PD-1 immunotherapy. Methods: Comprehensive immune profiling, including RNA-seq gene expression assessment of 395 immune genes, was performed on matched FFPE tumor samples from 22 stage I-III TNBC patients (14 patients treated with neoadjuvant chemotherapy alone (NAC) and 8 treated with neoadjuvant chemotherapy combined with pembrolizumab (NAC+I)). Results: Differential gene expression analysis revealed that in the NAC group, IL12B and IL13 were both significantly associated with pCR. In the NAC+I group, LCK and TP63 were significantly associated with pCR. Patients in both treatment groups exhibiting pCR tended to have greater tumor inflammation than non-pCR patients. In the NAC+I group, patients with pCR tended to have greater cell proliferation and higher PD-L1 expression, while in the NAC group, patients with pCR tended to have lower cancer testis antigen expression. Additionally, the NAC+I group trended toward a lower relative dose intensity averaged across all chemotherapy drugs, suggesting that more dose reductions or treatment delays occurred in the NAC+I group than the NAC group. Conclusions: A comprehensive understanding of immunologic factors could potentially predict pCR to chemotherapy alone, enabling the avoidance of the unnecessary treatment of these patients with checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

There is an emerging view that remittances improve health outcomes in developing countries, though less is known about the conditions under which they may be effective. This study investigates whether and how the impact of remittances on child mortality depends on the level of mortality itself. Using a sample of 134 developing countries over the period 1990 to 2018, we estimate unconditional quantile treatment effects with an endogenous treatment variable, on aggregate child mortality and the three leading cause-specific child mortality rates: mortality from neonatal disorders, lower respiratory infections, and diarrheal diseases. We find that the impact of remittances differs systematically across the mortality distribution and across mortality indicators. Remittances appear less effective at reducing child mortality at the lowest and highest mortality rates than at the average. [ABSTRACT FROM AUTHOR]

Purpose: The objective of this study was to examine the relationships among festival personality, satisfaction and loyalty. Also, the study further analyzed the moderation effect of involvement on the relationships between festival personality, satisfaction and loyalty. Design/methodology/approach: The authors adopt a two-stage mixed-method approach. Through a list of brand personality traits from previous research and in-depth interviews with participants of a film festival, festival personality constructs were identified: exceptional, competent, reliable and cozy. The authors then analyzed an integrative model of festival personality, satisfaction, involvement and loyalty from the qualitative findings. A survey with a convenience sample of 279 film festival participants was conducted. Findings: The findings suggest that festival personality influence satisfaction and loyalty. Furthermore, this study confirms the significant impact of involvement on the relationships between festival personality, satisfaction and loyalty. Originality/value: This study enables authors to understand the festival personality from the perspective of the visitors and expands the theoretical understanding of how the personality of the festival affects the visitors. The findings of this study suggest that the festival personality can be predictors and determinants of participants' satisfaction and loyalty. Also, this is one of the first attempts to identify the effects of involvement on festival personality and its outcomes. Current research findings demonstrated involvement as a moderator variable in the relationships between festival personality and festival satisfaction and loyalty. [ABSTRACT FROM AUTHOR]

This study explores the tourism behavior of an underdeveloped destination-Yozgat located in Turkey using different techniques of ethnographic research approach. We use longitudinal data, gathered sequentially from the same place over time for the data analysis. Three main factors (18 themes including 58 indicators) that identify characteristics of an underdeveloped destination are determined and illustrated. The research outputs will aid scholars and destination practitioners in understanding such a destination characteristic. [ABSTRACT FROM AUTHOR]

Background and Objective: The resurgence of severe and progressive silicosis among engineered stone benchtop industry workers is a global health crisis. We investigated the link between the physico‐chemical characteristics of engineered stone dust and lung cell responses to understand components that pose the greatest risk. Methods: Respirable dust from 50 resin‐based engineered stones, 3 natural stones and 2 non‐resin‐based materials was generated and analysed for mineralogy, morphology, metals, resin, particle size and charge. Human alveolar epithelial cells and macrophages were exposed in vitro to dust and assessed for cytotoxicity and inflammation. Principal component analysis and stepwise linear regression were used to explore the relationship between engineered stone components and the cellular response. Results: Cutting engineered stone generated fine particles of <600 nm. Crystalline silica was the main component with metal elements such as Ti, Cu, Co and Fe also present. There was some evidence to suggest differences in cytotoxicity (p = 0.061) and IL‐6 (p = 0.084) between dust samples. However, IL‐8 (CXCL8) and TNF‐α levels in macrophages were clearly variable (p < 0.05). Quartz explained 11% of the variance (p = 0.019) in macrophage inflammation while Co and Al accounted for 32% of the variance (p < 0.001) in macrophage toxicity, suggesting that crystalline silica only partly explains the cell response. Two of the reduced‐silica, non‐engineered stone products induced considerable inflammation in macrophages. Conclusion: These data suggest that silica is not the only component of concern in these products, highlighting the caution required as alternative materials are produced in an effort to reduce disease risk. To understand the drivers of severe silicosis among engineered stone workers, we performed the most comprehensive multidisciplinary study linking engineered stone particle chemistry to the lung cell response published to date. We found that silica, aluminium and cobalt were associated with the cell response, highlighting the importance of non‐silica elements. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICI) have emerged as an important therapeutic approach for patients with cancers including bladder cancer (BC). This commentary describes a recent study that demonstrated that the loss of Y chromosome (LOY) and/or loss of specific genes on Y chromosome confers an aggressive phenotype to BC because of T cell dysfunction resulting in CD8+T cell exhaustion. Loss of expression of Y chromosome genes KDM5D and UTY was similarly associated with an unfavorable prognosis in patients with BC as these genes were partially responsible for the impaired anti-tumor immunity in LOY tumors. From a clinical perspective, the study showed that tumors with LOY may be susceptible to treatment with ICIs. [ABSTRACT FROM AUTHOR]

Background: Cancer-testis antigens (CTAs) are tumor antigens that are normally expressed in the testes but are aberrantly expressed in several cancers. CTA overexpression drives the metastasis and progression of lung cancer, and is associated with poor prognosis. To improve lung cancer diagnosis, prognostic prediction, and drug discovery, robust CTA identification and quantitation is needed. In this study, we examined and quantified the co-expression of CTAs in lung cancer to derive cancer testis antigen burden (CTAB), a novel biomarker of immunotherapy response. Methods: Formalin fixed paraffin embedded (FFPE) tumor samples in discovery cohort (n = 5250) and immunotherapy and combination therapy treated non-small cell lung cancer (NSCLC) retrospective (n = 250) cohorts were tested by comprehensive genomic and immune profiling (CGIP), including tumor mutational burden (TMB) and the mRNA expression of 17 CTAs. PD-L1 expression was evaluated by IHC. CTA expression was summed to derive the CTAB score. The median CTAB score for the discovery cohort of 170 was applied to the retrospective cohort as cutoff for CTAB “high” and “low”. Biomarker and gene expression correlation was measured by Spearman correlation. Kaplan–Meier survival analyses were used to detect overall survival (OS) differences, and objective response rate (ORR) based on RECIST criteria was compared using Fisher’s exact test. Results: The CTAs were highly co-expressed (p < 0.05) in the discovery cohort. There was no correlation between CTAB and PD-L1 expression (R = 0.011, p = 0.45) but some correlation with TMB (R = 0.11, p = 9.2 × 10–14). Kaplan–Meier survival analysis of the immunotherapy-treated NSCLC cohort revealed better OS for the pembrolizumab monotherapy treated patients with high CTAB (p = 0.027). The combination group demonstrated improved OS compared to pembrolizumab monotherapy group (p = 0.04). The pembrolizumab monotherapy patients with high CTAB had a greater ORR than the combination therapy group (p = 0.02). Conclusions: CTA co-expression can be reliably measured using CGIP in solid tumors. As a biomarker, CTAB appears to be independent from PD-L1 expression, suggesting that CTAB represents aspects of tumor immunogenicity not measured by current standard of care testing. Improved OS and ORR for high CTAB NSCLC patients treated with pembrolizumab monotherapy suggests a unique underlying aspect of immune response to these tumor antigens that needs further investigation. [ABSTRACT FROM AUTHOR]

A large-scale genomic analysis of patients with ASXL1-mutated myeloid disease has not been performed to date. We reviewed comprehensive genomic profiling results from 6043 adults to characterize clinicopathologic features and co-mutation patterns by ASXL1 mutation status. ASXL1 mutations occurred in 1414 patients (23%). Mutation co-occurrence testing revealed strong co-occurrence (p < 0.01) between mutations in ASXL1 and nine genes (SRSF2, U2AF1, RUNX1, SETBP1, EZH2, STAG2, CUX1, CSF3R, CBL). Further analysis of patients with these co-mutations yielded several novel findings. Co-mutation patterns supported that ASXL1/SF3B1 co-mutation may be biologically distinct from ASXL1/non-SF3B1 spliceosome co-mutation. In AML, ASXL1/SRSF2 co-mutated patients frequently harbored STAG2 mutations (42%), which were dependent on the presence of both ASXL1 and SRSF2 mutation (p < 0.05). STAG2 and SETBP1 mutations were also exclusive in ASXL1/SRSF2 co-mutated patients and associated with divergent chronic myeloid phenotypes. Our findings support that certain multi-mutant genotypes may be biologically relevant in ASXL1-mutated myeloid disease. [ABSTRACT FROM AUTHOR]

This study examines a moderated mediation model based on hypothesized relationships between loneliness, travel nostalgia, subjective well-being and prevention regulatory focus. We adopt a two-stage mixed-method approach. We develop and propose an integrative model of loneliness, travel nostalgia and subjective well-being from our qualitative findings. We then test the model on 774 participants from two different samples. Findings indicate that loneliness has a negative effect on individuals' subjective well-being, and a positive and significant effect between travel nostalgia and individuals' subjective well-being. Furthermore, this study confirms the significant impact of prevention regulatory focus on the relationship between travel nostalgia and subjective well-being. Theoretical and practical implications are discussed. [ABSTRACT FROM AUTHOR]

The authors present a cohort of 661 young adult glioblastomas diagnosed using 2016 WHO World Health Organization Classification of Tumors of the Central Nervous System , utilizing comprehensive genomic profiling (CGP) to explore their genomic landscape and assess their relationship to currently defined disease entities. This analysis explored variants with evidence of pathogenic function, common copy number variants (CNVs), and several novel fusion events not described in literature. Tumor mutational burden (TMB) mutational signatures, anatomic location, and tumor recurrence are further explored. Using data collected from CGP, unsupervised machine-learning techniques were leveraged to identify 10 genomic classes in previously assigned young adult glioblastomas. The authors relate these molecular classes to current World Health Organization guidelines and reference current literature to give therapeutic and prognostic descriptions where possible. [ABSTRACT FROM AUTHOR]

The study examines seven key dimensions of online customer engagement behaviour and uses these to build ideal and baseline profiles. This ensures verbal and statistical correspondence. This approach allows identification of critical customer engagement behaviour to invest in and which one to invest in for maintenance. The study finds that deviating from the critical behaviours has negative implications for the spreading of positive word of mouth and brand loyalty. The findings and the methodological procedures are of interest to hospitality managers and academics. Data for the study was obtained from 326 customers at various hotels in Mauritius. The configural conceptual framework was tested using profile deviation to assure verbal and statistical correspondence leading to clear actionable recommendations for managers. The analysis goes beyond the approach in extant research by examining both the global and disaggregated impacts on PWOM and brand loyalty. The theoretical and managerial implications of the study are further discussed. [ABSTRACT FROM AUTHOR]

Interpretive marine turtle tours in Cyprus yields an alluring ground to unfold the complex nature of pro-environmental behavior among travelers in nature-based destinations. Framing on Collins (2004) interaction ritual concept and the complexity theory, the current study proposes a configurational model and probes the interactional effect of visitors' memorable experiences with environmental passion and their demographics to identify the causal recipes leading to travelers' sustainable behaviors. Data was collected from tourists in the marine protected areas located in Cyprus. Such destinations are highly valuable not only for their function as an economic source for locals but also as a significant habitat for biodiversity preservation. Using fuzzy-set Qualitative Comparative Analysis (fsQCA), this empirical study revealed that three recipes predict the high score level of visitors' environmentally friendly behavior. Additionally, an adaptive neuro-fuzzy inference system (ANFIS) method was applied to train and test the patterns of visitors' proenvironmental behavior in a machine learning environment to come up with a model which can best predict the outcome variable. The unprecedented implications on the use of technology to simulate and encourage pro-environmental behaviors in sensitive protected areas are discussed accordingly. [ABSTRACT FROM AUTHOR]

Thermally activated delayed fluorescence (TADF) emitters suffer from molecular aggregation that limits their applicability in light emitting devices. Aggregation-induced excimer formation often leads to a larger Stokes shift, broader emission spectrum, and reduced emission quantum yields, limiting emitter dye loading to a few weight percent in organic light emitting devices. Here, we demonstrate suppression of excimer emission by dispersing a synthesised multi-resonance TADF emitter dye (OQAO(mes)2) in a PMMA host matrix and embedding the host–guest photoactive layer into an optical cavity. Rabi splitting up to 0.24 eV is obtained at 35 wt% dye loading. Under the strong coupling regime, prompt and delayed emission through excimer states is suppressed due to efficient energy transfer to the lower polariton (LP) states, demonstrated by the blue shift of the emission spectrum and narrowing of the emission linewidth. We also observe an increase in reverse intersystem crossing (RISC) rate constants up to 33% that we attribute to a decrease in activation energy by ≈2kT. This work highlights that strong light-matter interactions can be exploited to overcome aggregation-induced excimer losses providing a pathway towards efficient organic light-emitting diodes with high colour purity and organic semiconductor polariton lasing. [ABSTRACT FROM AUTHOR]

Simple Summary: We compared RNA next-generation sequencing (RNA-seq) to standard immunohistochemistry (IHC) for PD-L1 expression measurement and associations with pembrolizumab immunotherapy outcomes in NSCLC patient tumors. RNA-seq and IHC PD-L1 score interpretation agreed for 80% of patients, and an RNA-seq "high" cutoff that accurately separated IHC high versus low or negative expression was identified. However, RNA-seq could not discern PD-L1 IHC from negative expression due to the limited sensitivity of IHC as a reference test. High PD-L1 expression by RNA-seq alone and in combination with IHC high or low status was associated with better pembrolizumab outcomes in NSCLC patients than IHC alone. Programmed cell death ligand (PD-L1) expression by immunohistochemistry (IHC) lacks sensitivity for pembrolizumab immunotherapy selection in non-small cell lung cancer (NSCLC), particularly for tumors with low expression. We retrospectively evaluated transcriptomic PD-L1 by mRNA next-generation sequencing (RNA-seq). In an unselected NSCLC patient cohort (n = 3168) tested during standard care (2017–2021), PD-L1 IHC and RNA-seq demonstrated moderate concordance, with 80% agreement overall. Most discordant cases were either low or negative for PD-L1 expression by IHC but high by RNA-seq. RNA-seq accurately discriminated PD-L1 IHC high from low tumors by receiver operator curve (ROC) analysis but could not distinguish PD-L1 IHC low from negative tumors. In a separate pembrolizumab monotherapy cohort (n = 102), NSCLC tumors classified as PD-L1 high versus not high by RNA-seq had significantly improved response, progression-free survival, and overall survival as an individual measure and in combination with IHC high or low status. PD-L1 IHC status (high or low) trended toward but had no significant associations with improved outcomes. Conventional PD-L1 IHC testing has inherent limitations, making it an imperfect reference standard for evaluating novel testing technologies. RNA-seq offers an objective PD-L1 measure that could represent a complementary method to IHC to improve NSCLC patient selection for immunotherapy. [ABSTRACT FROM AUTHOR]

Intense global competition for natural resources, manifesting in negative environmental externalities, has forced hospitality and tourism stakeholders to adopt strategies that may result in economic growth in tandem with environmental conservation. One such strategy is to cultivate travellers' loyalty to the tourism destinations and encourage them to participate in environmentally friendly activities. Using the affective theory of social exchange, social identity, stimulus–organism–response, tourism consumption system and attachment theories, this study proposes and tests a configurational model that predicts the antecedents of visitors' pro-environmental behavioural intentions (PEBIs) regarding their desire to revisit (REVI) and recommend (RECI) the services that they experienced. Fuzzy-set qualitative comparative analysis was applied to assess the effect of memorable tourism experiences, place attachment, and demographics on these outcomes. The findings revealed that multiple configurations can predict visitors' intentions at tourist destinations. This study's implications for theory, practice, and future research directions are also discussed. [ABSTRACT FROM AUTHOR]

The efficacy of cancer therapies is limited to a great extent by immunosuppressive mechanisms within the tumor microenvironment (TME). Numerous immune escape mechanisms have been identified. These include not only processes associated with tumor, immune or stromal cells, but also humoral, metabolic, genetic and epigenetic factors within the TME. The identification of immune escape mechanisms has enabled the development of small molecules, nanomedicines, immune checkpoint inhibitors, adoptive cell and epigenetic therapies that can reprogram the TME and shift the host immune response towards promoting an antitumor effect. These approaches have translated into series of breakthroughs in cancer therapies, some of which have already been implemented in clinical practice. In the present article the authors provide an overview of some of the most important mechanisms of immunosuppression within the TME and the implications for targeted therapies against different cancers. [ABSTRACT FROM AUTHOR]

Across all I ASXL1 i -mutated patients, I STAG2 i mutations were more likely to be seen with I ASXL1 i SP c.1934dupG sp (21% vs. 16%, I p i = 0.02), whereas I SETBP1 i mutations were more commonly co-mutated with I ASXL1 i SP other sp (15% vs. 10%, I p i = 0.01). The most common I ASXL1 i mutation was c.1934dupG (p.G646Xfs*12), and this was the sole or dominant I ASXL1 i mutation in 520 cases (37%, collectively referred to as I ASXL1 i SP c.1934dupG sp hereafter, Supplementary Fig. Dear Editor, Emerging evidence supports that I ASXL1 i mutation in myeloid neoplasia leads to aberrant protein gain-of-function rather than loss-of-function as initially thought [[1]]. Independent of cohesin mutation status, we found that I EZH2 i , I SETBP1 i , and I CUX1 i mutations were significantly more likely to co-occur with CBM mutations than non-CBM I ASXL1 i mutations. [Extracted from the article]

Engineered stones are often characterized for their crystalline silica content. Their organic composition, particularly that of the emissions generated during fabrication work using hand-held power tools, is relatively unexplored. We forensically screened the emissions from dry-cutting 12 engineered stone products in a test chamber for their organic composition by pyrolysis-gas chromatography-mass spectrometry (GC-MS) plus selected traditional capture and analysis techniques. Phthalic anhydride, which has a Respiratory Sensitization (RSEN) Notation by the American Conference of Governmental Industrial Hygienists (ACGIH), was the most common and abundant compound, at 26–85% of the total organic composition of engineered stone emissions. Benzaldehyde and styrene were also present in all twelve samples. During active cutting, the predominant volatile organic compound (VOC) emitted was styrene, with phthalic anhydride, benzene, ethylbenzene, and toluene also detected. These results have important health implications as styrene and phthalic anhydride are irritants to the respiratory tract. This study suggests a risk of concurrent exposure to high levels of respirable crystalline silica and organic lung irritants during engineered stone fabrication work. [ABSTRACT FROM AUTHOR]

Background Assessment of mucosal visualization during esophagogastroduodenoscopy (EGD) can be improved with a standardized scoring system. To address this need, we created the Toronto Upper Gastrointestinal Cleaning Score (TUGCS). Methods We developed the TUGCS using Delphi methodology, whereby an international group of endoscopy experts iteratively rated their agreement with proposed TUGCS items and anchors on a 5-point Likert scale. After each Delphi round, we analyzed responses and refined the TUGCS using an 80 % agreement threshold for consensus. We used the intraclass correlation coefficient (ICC) to assess inter-rater and test–retest reliability. We assessed internal consistency with Cronbach's alpha and item-total and inter-item correlations with Pearson's correlation coefficient. We compared TUGCS ratings with an independent endoscopist's global rating of mucosal visualization using Spearman's ρ. Results We achieved consensus with 14 invited participants after three Delphi rounds. Inter-rater reliability was high at 0.79 (95 %CI 0.64–0.88). Test–retest reliability was excellent at 0.83 (95 %CI 0.77–0.87). Cronbach's α was 0.81, item-total correlation range was 0.52–0.70, and inter-item correlation range was 0.38–0.74. There was a positive correlation between TUGCS ratings and a global rating of visualization (r = 0.41, P = 0.002). TUGCS ratings for EGDs with global ratings of excellent were significantly higher than those for EGDs with global ratings of fair (P = 0.01). Conclusion The TUGCS had strong evidence of validity in the clinical setting. The international group of assessors, broad variety of EGD indications, and minimal assessor training improves the potential for dissemination. [ABSTRACT FROM AUTHOR]

Residents' overall well-being and quality-of-life require a deeper understanding of their perceived social impacts of tourism to determine appropriate management strategies to promote behaviours in support of tourism development. Aligning with the 2030 Agenda for sustainable development, this paper proposes a new framework for residents' quality-of-life. Bringing together multi-disciplinary evidence from environmental, social and cognitive psychology, political science and tourism, this study critically examines how residents' perceived social impacts of tourism and their interpersonal trust can make them become more place attached and protect their tourism resources. The framework proposes that residents' perceived social impacts of tourism exerts a direct influence on residents' interpersonal trust. It further posits that residents' perceived social impacts of tourism and their interpersonal trust exert a direct influence on residents' place attachment. The proposed model further considers place attachment to exert a direct influence on residents' pro-social and pro-environmental behavioural intentions. Pro-social behaviour is proposed to influence pro-environmental behaviour. Further pro-social and pro-environmental behaviours are proposed to influence residents' support for tourism development. The framework then considers residents' support for tourism development to exert a direct influence on residents' overall quality-of-life. The theoretical contributions, practical implications for sustainable community tourism and sustainable tourism in general and the limitations of the study are discussed. [ABSTRACT FROM AUTHOR]

Purpose: Clinical trials advance the standard of care for patients. Patients enrolled in trials should represent the population who would benefit from the intervention in clinical practice. The aim of this study was to assess whether clinical trials enrolling patients with gynecologic cancers report racial and ethnic participant composition and to examine the level of diversity in clinical trials. Methods: Using ClinicalTrials.gov, we identified clinical trials enrolling patients with ovarian, uterine/endometrial, cervical, vaginal, and vulvar cancers from 1988 to 2019. Race and ethnicity data were extracted from participant demographics. Descriptive statistics on race, ethnicity, cancer type, location, study status, and sponsor type were calculated. Among trials which reported race and/or ethnicity, sub-analyses were performed on composition of race and ethnicity by funding source, location, and completed study status. Results: A total of 1,882 trials met inclusion criteria; only 179 trials (9.5%) reported race information. Of these, the racial distribution of enrollees was 66.9% White, 8.6% Asian, 8.5% Black/African American, 0.4% Indian/Alaskan Native, 0.1% Native Hawaiian/Pacific Islander, 1.0% more than one race, and 14.5% unknown. Only 100 (5.3%) trials reported ethnicity. Except for trials enrolling patients with cervical cancer which enrolled 65.2% White and 62.1% Non-Hispanic/Latino/a patients, enrollees in trials for other gynecologic cancers were over 80% White and 88% Non-Hispanic/Latino/a. Industry funded trials enrolled higher proportions of White (68.4%) participants than non-industry funded trials (57.5%). Domestic trials report race (11.5%) and ethnicity (7.6%) at higher rates than international trials (6.9% and 2.3%, respectively). Reporting of race (1.7% vs. 13.9%) and ethnicity (1.7% vs. 11.1%) has increased over time for patients enrolled in 2000 vs. 2018. Conclusion: Less than 10% of trials enrolling patients with gynecologic malignancies report racial/ethnic participant composition on ClinicalTrials.gov. Accurate reporting of participant race/ethnicity is imperative to ensuring minority representation in clinical trials. [ABSTRACT FROM AUTHOR]

This study investigates yoga travellers' experiences in guided tours organized by the renowned online travel platform, Tripaneer. Travellers' online narratives (N = 880) regarding three main yoga destinations were collected and examined through content analysis. Six main components were revealed: yoga facilities and services, a sense of awe, the overall benefits of yoga, a memorable experience, social interaction and learning about the local culture. [ABSTRACT FROM AUTHOR]

Introduction: New treatment strategies for advanced non‐small‐cell lung carcinoma (NSCLC) include synthetic lethality targets focused on protein arginine methyl transferases such as PRMT5 that exploit the impact of genomic loss of methylthioadenosine phosphorylase (MTAP). Methods: Twenty nine thousand three hundred seventy nine advanced NSCLC cases underwent hybrid‐capture based comprehensive genomic profiling between June 1, 2018 and May 31, 2020. PD‐L1 expression was determined by immunohistochemistry (Dako 22C3 PharmDx assay). Results: 13.4% (3928/29,379) NSCLC cases exhibited MTAP loss distributed in adenocarcinoma (59%), squamous cell carcinoma (22%), NSCLC not otherwise specified (16%), and 1% each for large‐cell neuroendocrine, sarcomatoid, and adenosquamous carcinoma. Statistically significant differences in mitogenic driver alterations included more KRAS G12C mutations in MTAP‐intact versus MTAP‐lost (12% vs. 10%, p = 0.0003) and fewer EGFR short variant mutations in MTAP‐intact versus MTAP‐lost NSCLC (10% vs. 13%, p < 0.0001). Statistically significant differences in currently untargetable genomic alterations included higher frequencies of TP53 (70% vs. 63%, p < 0.0001) and RB1 inactivation (10% vs. 2%, p < 0.0001) in MTAP‐intact compared to MTAP‐lost NSCLC. SMARCA4 inactivation (7% vs. 10%, p < 0.0001) was less frequent in MTAP‐intact versus MTAP‐lost NSCLC. Alterations in ERBB2, MET, ALK, ROS1, and NTRK1 did not significantly differ between the two groups. Predictors of immunotherapy efficacy were higher in MTAP‐intact versus MTAP‐lost NSCLC including tumor mutational burden (9.4 vs. 8.6 mut/Mb, p = 0.001) and low (30% vs. 28%, p = 0.01) and high PD‐L1 (32% vs. 30%, p = 0.01) expression. Alterations in biomarkers potentially predictive of immune checkpoint inhibitor resistance (STK11, KEAP1, and MDM2) were similar in the two groups. Conclusions: MTAP loss occurs in 13% of NSCLC, supporting the development of targeted therapies to exploit PRMT5 hyper‐dependence. MTAP loss is accompanied by small differences in targeted and immunotherapy options which may impact future combination strategies. [ABSTRACT FROM AUTHOR]

This study uncovers the complex inter-relations among natural environmental quality as nature-based solutions (NBS), emotional well-being, mental health, and life satisfaction in state park travelers' behavioral intention formation. This research also explores the moderating influence of national culture. A quantitative approach was made by using the data collected from three distinct cultures (India, the United States, and Korea). The proposed theoretical framework contained a sufficient prediction power for intention. A vital role of study variables in life satisfaction and intention generation was evident. National culture moderates the relationship among constructs in India and Korea but not in the US. [ABSTRACT FROM AUTHOR]

Stakeholder tourism development has revolved around the sustainable branding concept and brand engagement challenges. Addressing concerns on branding and sustainability, this study aims to investigate the stakeholder destination image (socioenvironment, infrastructure, natural and cultural resources, and pleasant atmosphere) impact on destination brand (brand meaning, presented brand, brand awareness, and brand equity) with the mediating role of stakeholder brand engagement (behavioral, affective and cognitive). We draw on the self-congruity theory to develop hypotheses and collect data from different stakeholder groups (local people, visitors, and entrepreneurs) (N = 350). Structural equation modeling with second-order analysis was undertaken using SmartPLS 3.3.9. Our results show the significance of stakeholder destination image in positively building destination brand. The results also showed that stakeholder brand engagement partially mediates between destination image and destination brand. Our study provides implications for theory and practice. [ABSTRACT FROM AUTHOR]

Background B-cell primary central nervous system (CNS) lymphoma (PCL) is diffuse large B-cell lymphoma (DLBCL) confined to the CNS. Less than 50% of patients with PCL achieve complete remission with current therapies. We describe the findings from comprehensive genomic profiling (CGP) of a cohort of 69 patients with PCL, 36 cases of secondary CNS lymphoma (SCL), and 969 cases of DLBCL to highlight their differences and characterize the PCL cohort. In addition, we highlight the differences in frequency of germinal center B-cell like (GCB) and non-GCB subtypes and molecular subtypes, particularly MCD and EZH subtypes, between PCL and DLBCL. Materials and Methods Sixty-nine cases of B-cell PCL, 36 cases of secondary CNS lymphoma (SCL), and 969 cases of DLBCL were evaluated by CGP of 405 genes via DNAseq and 265 genes via RNAseq for fusions (FoundationOne Heme). Tumor mutational burden (TMB) was calculated from 1.23 Mb of sequenced DNA. Results Genomic alterations with significant differences between PCL and DLBCL included MYD88 , ETV6 , PIM1 , PRDM1 , CXCR4 , TP53 , and CREBBP , while only MYD88 was significantly different between SCL and DLBCL. PCL cases were significantly enriched for the MCD molecular subtypes, which have an excellent response to BTKi. We report a patient with a durable complete response to BTKi consistent with their genomic profile. EBV status, CD274 amplification, and TMB status suggest that 38% of PCL patients may benefit from ICPI; however further study is warranted. Conclusion CGP of PCLs reveals biomarkers, genomic alterations, and molecular classifications predictive of BTKi efficacy and potential ICPI efficacy. Given the limitations of standard of care for PCL, CGP is critical to identify potential therapeutic approaches for patients in this rare form of lymphoma. [ABSTRACT FROM AUTHOR]