Mechanism-based strategies to overcome resistance to PD-1 blockade therapy are urgently needed. We developed genetic acquired resistant models of JAK1, JAK2, and B2M loss-of-function mutations by gene knockout in human and murine cell lines. Human melanoma cell lines with JAK1/2 knockout became insensitive to IFN-induced antitumor effects, while B2M knockout was no longer recognized by antigen-specific T cells and hence was resistant to cytotoxicity. All of these mutations led to resistance to anti-PD-1 therapy in vivo. JAK1/2-knockout resistance could be overcome with the activation of innate and adaptive immunity by intratumoral Toll-like receptor 9 agonist administration together with anti-PD-1, mediated by natural killer (NK) and CD8 T cells. B2Mknockout resistance could be overcome by NK-cell and CD4 T-cell activation using the CD122 preferential IL2 agonist bempegaldesleukin. Therefore, mechanistically designed combination therapies can overcome genetic resistance to PD-1 blockade therapy. SiGNifiCANCe:The activation of IFN signaling through pattern recognition receptors and the stimulation of NK cells overcome genetic mechanisms of resistance to PD-1 blockade therapy mediated through deficient IFN receptor and antigen presentation pathways. These approaches are being tested in the clinic to improve the antitumor activity of PD-1 blockade therapy.

Acid taste, evoked mainly by protons (H+), is a core taste modality for many organisms. The hedonic valence of acid taste is bidirectional: animals prefer slightly but avoid highly acidic foods. However, how animals discriminate low from high acidity remains poorly understood. To explore the taste perception of acid, we use the fruit fly as a model organism. We find that flies employ two competing taste sensory pathways to detect low and high acidity, and the relative degree of activation of each determines either attractive or aversive responses. Moreover, we establish one member of the fly Otopetrin family, Otopetrin-like a (OtopLa), as a proton channel dedicated to the gustatory detection of acid. OtopLa defines a unique subset of gustatory receptor neurons and is selectively required for attractive rather than aversive taste responses. Loss of otopla causes flies to reject normally attractive low-acid foods. Therefore, the identification of OtopLa as a low-acid sensor firmly supports our competition model of acid taste sensation. Altogether, we have discovered a binary acid-sensing mechanism that may be evolutionarily conserved between insects and mammals.

Despite the rapid aging of the world's population, comprehensive assessment tools to meet the mental health needs of older adults are lacking. The aim of the current study was to assess the multidimensionality of Chinese versions of U.S.-derived instruments designed to evaluate a broad spectrum of emotional, behavioral, social, and thought problems in older adults. The Older Adult Self-Report (OASR) and Older Adult Behavior Checklist (OABCL) were completed by 686 and 639 older adults, respectively, aged 60 to 99 years, from a sample of 755 older adults. Confirmatory factor analyses (CFAs) on the 97 OASR/OABCL problem items found that the models showed good fit according to our primary and secondary fit indices. None of the seven syndromes showed informant effects, whereas four showed small sex effects, and three showed small age effects. Overall, findings demonstrate the applicability of the seven syndrome OASR/OABCL model to Chinese older adults and support the use of these instruments to assess older adult mental health in Chinese clinical and research settings. These standardized tools can help health care professionals more comprehensively assess cognitive, behavioral, and mental health problems among Chinese-speaking older adult populations. [ Journal of Gerontological Nursing, 48 (8), 26–32.]

Given the global public health burden of mental illness, there is a critical need for culturally validated psychopathology assessment tools that perform well in diverse societies. This study examines the psychometric properties of the Adult Self-Report (ASR) and Adult Behavioral Checklist (ABCL) from the Achenbach System of Empirically Based Assessments in adults in China. Chinese adults (N = 1276) and their spouses completed the ASR and ABCL, respectively. We conducted confirmatory factor analysis on 99 ASR items and 93 ABCL items. Estimators of model fit confirmed that both measures demonstrated excellent fit (e.g., root mean square error of approximation = 0.016 and 0.018, respectively). Syndrome loadings on both measures were satisfactory but generally higher on the ASR. Neither gender nor education had significant effects, but there were informant x gender effects on most problem scales. Cross-informant agreement correlations between the ASR and ABCL were medium to large. Findings from this novel sample of Chinese adults are consistent with previous validation studies supporting the dimensionality, syndrome structure, gender differences, and inter-informant agreement of the ASR and ABCL. Our findings contribute to the cross-cultural understanding of mental health assessment and offer a psychometrically sound approach to measuring adult psychopathology in Chinese populations.

BackgroundType 2 diabetes (T2D) is a chronic condition affecting more than 34.2 million U.S. adults, and people of African descent have a disproportionate burden. Haitian immigrants’ unique cultural and biological factors put them at elevated risk for T2D-related complications. Despite prior research highlighting the success of multimethod approaches to T2D self-management behaviors on glycemic targets, a dearth of studies have used these methods to improve diabetes self-management in this marginalized population.ObjectivesThis article describes a repeated-measures design protocol of a going study about self-management behaviors among adult Haitian immigrants with T2D and characterizing their barriers to T2D self-management.MethodsWe will enroll 100 Haitian immigrants aged 18–64 years who have lived with T2D for at least 1 year. Using multiple recruitment methods and Research Electronic Data Capture, subjective and objective data on T2D self-management practices, glucose variability via continuous glucose monitor, and a comprehensive view of physical activity via actigraphy are collected.ResultsData analysis will follow a two-part approach mirroring the two primary study objectives.DiscussionFindings from the study will guide the development and testing of a culturally tailored diabetes self-management education program that will contribute essential information about best practices for this population and break barriers that may impede research on unique individuals and subsequent effective self-management.