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Neoantigens are peptides derived from non-synonymous mutations presented by human leukocyte antigens (HLAs), which are recognized by antitumour T cells1-14. The large HLA allele diversity and limiting clinical samples have restricted the study of the landscape of neoantigen-targeted T cell responses in patients over their treatment course. Here we applied recently developed technologies15-17 to capture neoantigen-specific T cells from blood and tumours from patients with metastatic melanoma with or without response to anti-programmed death receptor 1 (PD-1) immunotherapy. We generated personalized libraries of neoantigen-HLA capture reagents to single-cell isolate the T cells and clone their T cell receptors (neoTCRs). Multiple T cells with different neoTCR sequences (T cell clonotypes) recognized a limited number of mutations in samples from seven patients with long-lasting clinical responses. These neoTCR clonotypes were recurrently detected over time in the blood and tumour. Samples from four patients with no response to anti-PD-1 also demonstrated neoantigen-specific T cell responses in the blood and tumour to a restricted number of mutations with lower TCR polyclonality and were not recurrently detected in sequential samples. Reconstitution of the neoTCRs in donor T cells using non-viral CRISPR-Cas9 gene editing demonstrated specific recognition and cytotoxicity to patient-matched melanoma cell lines. Thus, effective anti-PD-1 immunotherapy is associated with the presence of polyclonal CD8+ T cells in the tumour and blood specific for a limited number of immunodominant mutations, which are recurrently recognized over time.

Data on the health and social determinants for Native Hawaiians and Pacific Islanders (NHPIs) in the United States are hidden, because data are often not collected or are reported in aggregate with other racial/ethnic groups despite decades of calls to disaggregate NHPI data. As a form of structural racism, data omissions contribute to systemic problems such as inability to advocate, lack of resources, and limitations on political power. The authors conducted a data audit to determine how US federal agencies are collecting and reporting disaggregated NHPI data. Using the COVID-19 pandemic as a case study, they reviewed how states are reporting NHPI cases and deaths. They then used California's neighborhood equity metric-the California Healthy Places Index (HPI)-to calculate the extent of NHPI underrepresentation in communities targeted for COVID-19 resources in that state. Their analysis shows that while collection and reporting of NHPI data nationally has improved, federal data gaps remain. States are vastly underreporting: more than half of states are not reporting NHPI COVID-19 case and death data. The HPI, used to inform political decisions about allocation of resources to combat COVID-19 in at-risk neighborhoods, underrepresents NHPIs. The authors make recommendations for improving NHPI data equity to achieve health equity and social justice.

Data on the health and social determinants for Native Hawaiians and Pacific Islanders (NHPIs) in the United States (US) are hidden because data are often not collected or are reported in aggregate with other racial/ethnic groups, despite decades of calls to disaggregate NHPI data. As a form of structural racism, data omissions contribute to systemic problems such as inability to advocate, lack of resources, and limitations to political power. We conducted a data audit to determine how US federal agencies are collecting and reporting disaggregated NHPI data. Using the COVID-19 pandemic as a case study, we reviewed how states are reporting NHPI cases and deaths. Last, we calculated the extent of NHPI underrepresentation in communities targeted for COVID-19 resources in California using the state's neighborhood equity metric-Healthy Places Index (HPI). Our analysis shows that while there has been improvement in collection and reporting of NHPI data nationally, federal data gaps remain. States are vastly underreporting-over half of states are not reporting NHPI COVID-19 case and death data. The HPI, used to inform political decisions about allocation of resources to combat COVID-19, systematically underrepresents NHPI communities. We make recommendations for improving NHPI data equity to achieve health equity and social justice.

As of March 2021, Native Hawaiians and Pacific Islanders (NHPIs) in the United States have lost more than 800 lives to COVID-19-the highest per capita death rate in 18 of 20 US states reporting NHPI deaths. However, NHPI risks are overlooked in policy discussions. We discuss the NHPI COVID-19 Data Policy Lab and dashboard, featuring the disproportionate COVID-19 mortality burden for NHPIs. The Lab democratized NHPI data, developed community infrastructure and resources, and informed testing site and outreach policies related to health equity.

Targeting somatically activated oncogenes has revolutionized the treatment of non-small cell lung cancer (NSCLC). Mutations in the gene mesenchymal-epithelial transition (MET) near the exon 14 splice sites are recurrent in lung adenocarcinoma and cause exon skipping (METΔ14). Here, we analyzed 4,422 samples from 12 different malignancies to estimate the rate of said exon skipping. METΔ14 mutation and transcript were most common in lung adenocarcinoma. Endogenously expressed levels of METΔ14 transformed human epithelial lung cells in a hepatocyte growth factor-dependent manner. In addition, overexpression of the orthologous mouse allele induced lung adenocarcinoma in a novel, immunocompetent mouse model. Met inhibition showed clinical benefit in this model. In addition, we observed a clinical response to crizotinib in a patient with METΔ14-driven NSCLC, only to observe new missense mutations in the MET activation loop, critical for binding to crizotinib, upon clinical progression. These findings support genomically selected clinical trials directed toward METΔ14 in a fraction of NSCLC patients, confirm second-site mutations for further therapeutic targeting prior to and beyond acquired resistance, and provide an in vivo system for the study of METΔ14 in an immunocompetent host. Cancer Res; 77(16); 4498-505. ©2017 AACR.

Congenital diaphragmatic hernia (CDH) is a common birth malformation with a heterogeneous etiology. In this study, we report that ablation of the heparan sulfate biosynthetic enzyme NDST1 in murine endothelium (Ndst1ECKO mice) disrupted vascular development in the diaphragm, which led to hypoxia as well as subsequent diaphragm hypoplasia and CDH. Intriguingly, the phenotypes displayed in Ndst1ECKO mice resembled the developmental defects observed in slit homolog 3 (Slit3) knockout mice. Furthermore, introduction of a heterozygous mutation in roundabout homolog 4 (Robo4), the gene encoding the cognate receptor of SLIT3, aggravated the defect in vascular development in the diaphragm and CDH. NDST1 deficiency diminished SLIT3, but not ROBO4, binding to endothelial heparan sulfate and attenuated EC migration and in vivo neovascularization normally elicited by SLIT3-ROBO4 signaling. Together, these data suggest that heparan sulfate presentation of SLIT3 to ROBO4 facilitates initiation of this signaling cascade. Thus, our results demonstrate that loss of NDST1 causes defective diaphragm vascular development and CDH and that heparan sulfate facilitates angiogenic SLIT3-ROBO4 signaling during vascular development.

Examines adolescent attitudes towards Christianity, science, creationism, and scientism among high school students (n=1584) between the ages of 14-16. Reports that the apparent independence of attitude towards science and attitude towards Christianity is transformed into a positive relationship after taking into account individual differences in scientism and creationism. (Contains 65 references.) (Author/YDS)

Describes the development of a new measure of attitude towards science for use among secondary school pupils which operationalizes the affective attitudinal domain. Scale norms demonstrate that males record a more positive attitude towards science than females, and that younger pupils record a more positive attitude than older pupils. (Contains 78 references.) (Author/WRM)

Reports on a study of pupils (n=1549) aged 13 to 16 attending 12 Protestant and 12 Catholic schools in Northern Ireland and their attitudes toward science. Concludes that girls, oldest students, and pupils in Catholic schools hold less positive attitudes toward science in the school curriculum and towards science as a career. Contains 36 references. (Author/WRM)

Presents survey findings concerning the moral and religious attitudes of Northern Ireland's adolescents. Seeks to develop reliability and validity criteria for a scale of traditional Christian values. Concludes that Catholic school students are more likely to hold traditional values than are Protestant school students. (DK)

Reviews local, national, and European Community influences on the formation of "integrated" rural development policy in Northern Ireland. Suggests three key issues on the policy formation agenda: agricultural versus more diversified programs as the basis of development, implementation problems, and education and training needs. Contains 43 references. (SV)

Prevention of teacher burnout can be fostered at the preservice level by (1) the development of realistic expectations, (2) encouragement of detached concern, (3) a better understanding of classroom successes and failures, and (4) an introduction to stress reduction strategies. (Author/DB)

Although recent waves of educational reform have prophesied a pessimistic view of educational administration, this article offers evidence to the contrary. Projected vacancies in the professorate, educational administration, and teaching will offer qualified women and minority candidates increased opportunities. Nongraded instructional practices offer exciting possibilities. Includes nine references. (MLH)