The interplay between an evolving cancer and a dynamic immune microenvironment remains unclear. Here we analyse 258 regions from 88 early-stage, untreated non-small-cell lung cancers using RNA ...sequencing and histopathology-assessed tumour-infiltrating lymphocyte estimates. Immune infiltration varied both between and within tumours, with different mechanisms of neoantigen presentation dysfunction enriched in distinct immune microenvironments. Sparsely infiltrated tumours exhibited a waning of neoantigen editing during tumour evolution, indicative of historical immune editing, or copy-number loss of previously clonal neoantigens. Immune-infiltrated tumour regions exhibited ongoing immunoediting, with either loss of heterozygosity in human leukocyte antigens or depletion of expressed neoantigens. We identified promoter hypermethylation of genes that contain neoantigenic mutations as an epigenetic mechanism of immunoediting. Our results suggest that the immune microenvironment exerts a strong selection pressure in early-stage, untreated non-small-cell lung cancers that produces multiple routes to immune evasion, which are clinically relevant and forecast poor disease-free survival.
Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the ...locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens.
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•LOHHLA enables estimation of allele-specific HLA loss from sequencing data•LOH of the HLA locus occurs in 40% of early stage non-small-cell lung cancers•HLA LOH is associated with a high subclonal neoantigen burden and immune activity•HLA LOH is an immune escape mechanism subject to strong selection pressures
Development of the bioinformatics tool LOHHLA allows precise measurement of allele-specific HLA copy number, improves the accuracy in neoantigen prediction, and uncovers insights into how immune escape contributes to tumor evolution in non-small-cell lung cancer.
The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic ...approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies.
Objective: Although there are many international college students in the state of Georgia, few studies have been conducted on how social determinants affect their health outcomes and academic ...success. This study examined the effects of social determinants on the health outcomes and academic success of international college students in Georgia. Participants: Participants were international college students (n = 136) in Georgia. Methods: A mixed methods cross-sectional design was used for the study. Results: The lack of access to sufficient funds caused study participants to experience anxiety (39.0%), depression (20.6%), and stress (52.9%). Cultural differences (16.9%), lack of access to health care (15.4%), transportation (14.7%), poor housing (7.4%), and financial insecurity (54.5%) affected study participant health outcomes and academic success. Conclusion: Addressing financial insecurity, the lack of access to health care, poor housing, transportation issues, and cultural differences experienced by international college students in Georgia, is crucial to their health outcomes and academic success.Objective: Although there are many international college students in the state of Georgia, few studies have been conducted on how social determinants affect their health outcomes and academic success. This study examined the effects of social determinants on the health outcomes and academic success of international college students in Georgia. Participants: Participants were international college students (n = 136) in Georgia. Methods: A mixed methods cross-sectional design was used for the study. Results: The lack of access to sufficient funds caused study participants to experience anxiety (39.0%), depression (20.6%), and stress (52.9%). Cultural differences (16.9%), lack of access to health care (15.4%), transportation (14.7%), poor housing (7.4%), and financial insecurity (54.5%) affected study participant health outcomes and academic success. Conclusion: Addressing financial insecurity, the lack of access to health care, poor housing, transportation issues, and cultural differences experienced by international college students in Georgia, is crucial to their health outcomes and academic success.
Aim
To examine associations between patterns of language use and early adolescent well‐being.
Methods
Participants were 1763 Australian 11‐ to 12‐year‐olds in the Child Health CheckPoint. Six ...patterns of language use were identified from a writing activity using Linguistic Inquiry and Word Count and factor analysis: Acting in the present and future, Positive emotion, Gender and relationships, Self‐aware, Inquisitive and time focused, and Confident. Well‐being measures represented a spectrum from negatively to positively framed psychosocial health. Associations between language use and well‐being were estimated using linear regression adjusted for age, sex and social disadvantage.
Results
Positive emotion (high emotional tone, positive emotion) was associated with better general well‐being (standardised regression coefficient (SRC) 0.05; 95% confidence interval 0.00 to 0.11; p = 0.04), life satisfaction (0.06; 0.01 to 0.11; p = 0.03), psychosocial health (0.07; 0.02 to 0.12; p = 0.01) and quality of life (QoL) (0.06; 0.01 to 0.11; p = 0.02). Similarly, Self‐aware (high first person singular pronouns, authentic, low clout) was associated with better general well‐being, life satisfaction and psychosocial health (SRC 0.05, 0.09, 0.08), but Confident (high clout, first person plural pronouns, affiliation) was associated with worse life satisfaction, psychosocial health and QoL (SRC −0.06, −0.09, −0.06).
Conclusion
If replicated in ‘real‐world’ settings (e.g., social media), language patterns could provide naturalistic insights into early adolescents’ well‐being.
Background Shared decision‐making (SDM) has the potential to improve hypertension care quality and equity. However, research lacks diverse representation and evidence about how race and ethnicity ...affect SDM. Therefore, this study aims to explore SDM in the context of hypertension management. Methods and Results Explanatory sequential mixed‐methods design was used. Quantitative data were sourced at baseline and 12‐month follow up from RICH LIFE (Reducing Inequities in Care of Hypertension: Lifestyle Improvement for Everyone) participants (n=1212) with hypertension. Qualitative data were collected from semistructured individual interviews, at 12‐month follow‐up, with participants (n=36) selected based on their SDM scores and blood pressure outcome. Patients were cross‐ categorized based on high or low SDM scores and systolic blood pressure reduction of ≥10 or <10 mm Hg. Multinomial logistic regression analysis showed that predictors of SDM scores and blood pressure outcome were race and ethnicity (relative risk ratio RRR, 1.64; P =0.029), age (RRR, 1.03; P =0.002), educational level (RRR, 1.87; P =0.016), patient activation (RRR, 0.98; P <0.001; RRR, 0.99; P =0.039), and hypertension knowledge (RRR, 2.2; P <0.001; and RRR, 1.57; P =0.045). Qualitative and mixed‐methods findings highlight that provider–patient communication and relationship influenced SDM, being emphasized both as facilitators and barriers. Other facilitators were patients' understanding of hypertension; clinicians' interest in the patient, and clinicians' personality and attitudes; and barriers included perceived lack of compassion, relationship hierarchy, and time constraints. Conclusions Participants with different SDM scores and blood pressure outcomes varied in determinants of decision and descriptions of contextual factors influencing SDM. Results provide actionable information, are novel, and expand our understanding of factors influencing SDM in hypertension.
Pf38 is a surface protein of the malarial parasite Plasmodium falciparum. In this study, we produced and purified recombinant Pf38 and a fusion protein composed of red fluorescent protein and Pf38 ...(RFP-Pf38) using a transient expression system in the plant Nicotiana benthamiana. To our knowledge, this is the first description of the production of recombinant Pf38. To verify the quality of the recombinant Pf38, plasma from semi-immune African donors was used to confirm specific binding to Pf38. ELISA measurements revealed that immune responses to Pf38 in this African subset were comparable to reactivities to AMA-1 and MSP119. Pf38 and RFP-Pf38 were successfully used to immunise mice, although titres from these mice were low (on average 1∶11.000 and 1∶39.000, respectively). In immune fluorescence assays, the purified IgG fraction from the sera of immunised mice recognised Pf38 on the surface of schizonts, gametocytes, macrogametes and zygotes, but not sporozoites. Growth inhibition assays using αPf38 antibodies demonstrated strong inhibition (≥60%) of the growth of blood-stage P. falciparum. The development of zygotes was also effectively inhibited by αPf38 antibodies, as determined by the zygote development assay. Collectively, these results suggest that Pf38 is an interesting candidate for the development of a malaria vaccine.
Positive childhood experiences (PCEs), that occur within secure and nurturing social environments, are fundamental to healthy physical, social-emotional, and cognitive development. However, reliable ...measures of these experiences are not yet widely available. We used data from the Longitudinal Study of Australian Children (LSAC) to empirically represent and psychometrically evaluate 3 primary domains of PCEs defined within the Health Outcomes from Positive Experiences (HOPE) framework, specifically: 1) nurturing and supportive relationships; 2) safe and protective environments and; 3) constructive social engagement and connectedness.
LSAC is a nationally representative cohort that has followed young Australians from birth since 2004. LSAC data were used to represent the 3 primary HOPE-PCEs domains (birth to 11 years) across 4 inter-related PCEs constructs: 1) positive parenting, 2) trusting and supportive relationships, 3) supportive neighborhood and home learning environments, and 4) social engagement and enjoyment. Confirmatory factor analysis was used to test the proposed 4-factor structure. Predictive validity was examined through associations with mental health problems and academic difficulties at 14 to 15 years.
The 4-factor structure was supported by empirical data at each time point. Higher exposure to PCEs across each domain was associated with lower reporting of mental health problems (β = -0.20 to -2.05) and academic difficulties (β = -0.01 to -0.13) in adolescence.
The 4 LSAC-based HOPE-PCEs have sufficient internal coherence and predictive validity to offer a potentially useful way of conceptualizing and measuring PCEs in future cohort studies and intervention trials aiming to enhance the understanding of, and mitigate the negative impacts of, adverse childhood experiences.
Deltas are precarious environments experiencing significant biophysical, and socio-economic changes with the ebb and flow of seasons (including with floods and drought), with infrastructural ...developments (such as dikes and polders), with the movement of people, and as a result of climate and environmental variability and change. Decisions are being taken about the future of deltas and about the provision of adaptation investment to enable people and the environment to respond to the changing climate and related changes. The paper presents a framework to identify options for, and trade-offs between, long term adaptation strategies in deltas. Using a three step process, we: (1) identify current policy-led adaptations actions in deltas by conducting literature searches on current observable adaptations, potential transformational adaptations and government policy; (2) develop narratives of future adaptation policy directions that take into account investment cost of adaptation and the extent to which significant policy change/political effort is required; and (3) explore trade-offs that occur within each policy direction using a subjective weighting process developed during a collaborative expert workshop. We conclude that the process of developing policy directions for adaptation can assist policy makers in scoping the spectrum of options that exist, while enabling them to consider their own willingness to make significant policy changes within the delta and to initiate transformative change.
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•We generate a set of observed adaptations that are occurring in three deltas.•We offer a framework for categorising adaptations into 13 distinct classes.•Four future directions for adaptation policy focus on different classes of adaptation.•Future policy directions range from minimum intervention to radical transformation.•Countries can select a policy direction that suits their normative goals.
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