Targeting PGLYRP1 promotes antitumor immunity while inhibiting autoimmune neuroinflammation.

Co-inhibitory and checkpoint molecules suppress T cell function in the tumor microenvironment, thereby rendering T cells dysfunctional. Although immune checkpoint blockade is a successful treatment option for multiple human cancers, severe autoimmune-like adverse effects can limit its application. Here, we show that the gene encoding peptidoglycan recognition protein 1 (PGLYRP1) is highly coexpressed with genes encoding co-inhibitory molecules, indicating that it might be a promising target for cancer immunotherapy. Genetic deletion of Pglyrp1 in mice led to decreased tumor growth and an increased activation/effector phenotype in CD8+ T cells, suggesting an inhibitory function of PGLYRP1 in CD8+ T cells. Surprisingly, genetic deletion of Pglyrp1 protected against the development of experimental autoimmune encephalomyelitis, a model of autoimmune disease in the central nervous system. PGLYRP1-deficient myeloid cells had a defect in antigen presentation and T cell activation, indicating that PGLYRP1 might function as a proinflammatory molecule in myeloid cells during autoimmunity. These results highlight PGLYRP1 as a promising target for immunotherapy that, when targeted, elicits a potent antitumor immune response while protecting against some forms of tissue inflammation and autoimmunity.

Tumor immunogenicity dictates reliance on TCF1 in CD8+ T cells for response to immunotherapy.

Stem-like CD8+ T cells are regulated by T cell factor 1 (TCF1) and are considered requisite for immune checkpoint blockade (ICB) response. However, recent findings indicate that reliance on TCF1+CD8+ T cells for ICB efficacy may differ across tumor contexts. We find that TCF1 is essential for optimal priming of tumor antigen-specific CD8+ T cells and ICB response in poorly immunogenic tumors that accumulate TOX+ dysfunctional T cells, but is dispensable for T cell priming and therapy response in highly immunogenic tumors that efficiently expand transitory effectors. Importantly, improving T cell priming by vaccination or by enhancing antigen presentation on tumors rescues the defective responses of TCF1-deficient CD8+ T cells upon ICB in poorly immunogenic tumors. Our study highlights TCF1's role during the early stages of anti-tumor CD8+ T cell responses with important implications for guiding optimal therapeutic interventions in cancers with low TCF1+CD8+ T cells and low-neo-antigen expression.

Sun protective behaviors in sun-sensitive individuals: a cross-sectional study examining for ethnic and racial differences.

The rates of non-melanoma skin cancer continue to rise in the United States. We investigated if differences exist in skin cancer preventive behaviors among sun-sensitive non-Hispanic whites and other racial and ethnic groups. The National Health Information Survey was used to perform the cross-sectional study. Outcomes of interest included multiple sun-protective methods. Individuals were determined to be sun-sensitive if Fitzpatrick skin phototype (SPT) I/II. Multivariable logistic regression was used to examine the associations between the use of sun-protective practices and race and ethnicity, SPT, and survey year. The study included 67,471 individuals. Adjusted prevalences of skin cancer preventive behaviors revealed that across all SPTs, non-Hispanic whites were more likely to use sunscreen, undergo physician-administered FBSE, and have multiple sunburns or tan indoors in the past year compared to corresponding SPT other racial and ethnic groups. In contrast, other racial and ethnic groups with any SPT were more likely to practice sun avoidance than corresponding SPT non-Hispanic whites. Additionally, other racial and ethnic groups with SPT III+ were more likely to wear sun-protective clothing than non-Hispanic white individuals with similar SPTs. For all SPT and racial and ethnic groups, there were significant increases in sunscreen use and decreases in past-year indoor tanning. Full body skin examination prevalence, regardless of sun sensitivity, increased for all non-Hispanic whites, but remained unchanged for sun-sensitive other racial and ethnic groups. Adjusted prevalence of multiple sunburns and use of protective clothing remained unchanged for all racial and ethnic groups across all SPT categories. There are differences in sun-protective behaviors among sun-sensitive individuals by race and ethnicity with the magnitude of some of these differences increasing. Future research and public health campaigns are needed on photosensitive individuals and the relationship between skin protective behaviors and race/ethnicity. When discussing sun protection, care providers should not only consider the influence of sun-sensitivity, but also race and ethnicity, and its impact on sun prevention behaviors.

State LGBTQ policies and binge drinking among sexual minority youth in the US: a multilevel analysis.

PURPOSE: Though higher rates of binge drinking have been reported among sexual minority (lesbian, gay, and bisexual) youths compared to their heterosexual peers in the United States, questions remain about which specific structural factors drive these inequities. We test whether state LGBTQ (lesbian, gay, bisexual, transgender, queer/questioning) policy climate is associated with youth binge drinking, as well as whether that association is unique to sexual minority youth. METHODS: We use LGBTQ policy scores compiled by the Movement Advancement Project in 2017 and analyze 2017 Youth Risk Behavior Survey data (126,432 youths living in 24 states). We fit multi-level logistic regression models to estimate odds ratios for binge drinking with state-level LGBTQ policy scores. RESULT: More progressive state-level overall LGBTQ policies were associated with lower odds of binge drinking among sexual minority youths (interaction term OR = 0.990, CI 0.984-0.996, p = 0.0009), but not among heterosexuals (OR = 1.001, CI 0.992, 1.009, p = 0.881). For sexual minorities, living in the most LGBTQ-affirming state was associated with a probability of binge drinking 27% lower than that of those living in the least LGBTQ-affirming state. In sensitivity analyses, policies specific to LGBTQ youth (opposed to general LGBTQ people) were even more strongly related to sexual minorities' binge drinking (interaction term: state-level youth policy score × individual-level sexual identity-of OR = 0.949, CI 0.927-0.971, p = 0.00001). In sex-stratified models, associations with overall LGBTQ policy scores were significant only for girls (OR = 0.986, CI 0.979-0.993, p < 0.001), not boys (OR = 0.997, CI 0.986-1.008, p = 0.551), while associations with youth-focused LGBTQ policies were significant for both sexual minority girls and boys. CONCLUSION: Our findings point to state-level LGBTQ policy climate as a potential social determinant of binge drinking problems among sexual minority youths.

Stem-like intestinal Th17 cells give rise to pathogenic effector T cells during autoimmunity.

While intestinal Th17 cells are critical for maintaining tissue homeostasis, recent studies have implicated their roles in the development of extra-intestinal autoimmune diseases including multiple sclerosis. However, the mechanisms by which tissue Th17 cells mediate these dichotomous functions remain unknown. Here, we characterized the heterogeneity, plasticity, and migratory phenotypes of tissue Th17 cells in vivo by combined fate mapping with profiling of the transcriptomes and TCR clonotypes of over 84,000 Th17 cells at homeostasis and during CNS autoimmune inflammation. Inter- and intra-organ single-cell analyses revealed a homeostatic, stem-like TCF1+ IL-17+ SLAMF6+ population that traffics to the intestine where it is maintained by the microbiota, providing a ready reservoir for the IL-23-driven generation of encephalitogenic GM-CSF+ IFN-γ+ CXCR6+ T cells. Our study defines a direct in vivo relationship between IL-17+ non-pathogenic and GM-CSF+ and IFN-γ+ pathogenic Th17 populations and provides a mechanism by which homeostatic intestinal Th17 cells direct extra-intestinal autoimmune disease.

Single-cell analyses identify circulating anti-tumor CD8 T cells and markers for their enrichment.

The ability to monitor anti-tumor CD8+ T cell responses in the blood has tremendous therapeutic potential. Here, we used paired single-cell RNA and TCR sequencing to detect and characterize "tumor-matching" (TM) CD8+ T cells in the blood of mice with MC38 tumors or melanoma patients using the TCR as a molecular barcode. TM cells showed increased activation compared with nonmatching T cells in blood and were less exhausted than matching cells in tumors. Importantly, PD-1, which has been used to identify putative circulating anti-tumor CD8+ T cells, showed poor sensitivity for identifying TM cells. By leveraging the transcriptome, we identified candidate cell surface markers for TM cells in mice and patients and validated NKG2D, CD39, and CX3CR1 in mice. These data show that the TCR can be used to identify tumor-relevant cells for characterization, reveal unique transcriptional properties of TM cells, and develop marker panels for tracking and analysis of these cells.

Does one's geographic location influence their use of sun protection? A survey of 3,185 U.S. Residents.

To determine if geographical differences exist in practice of sun protective behaviors across the United States, we performed a retrospective, cross-sectional analysis of data from the Health Information National Trends Survey 4 Cycle 3. Self-reported sun protective behaviors and demographic information were collected for individuals from nine regions across the United States in 2013. Regions followed United States census divisions, including New England, Middle Atlantic, East North Central, West North Central, South Atlantic, East South Central, West South Central, Mountain, and Pacific. Study participants included 3,185 people from nine census regions. Sun protection was uncommonly practiced in the United States. The use of sunscreen in the West North Central region was the lowest sun protective practice. Long pants were more commonly worn in the West South Central and the Pacific. Sun protective behavior rates are low for all geographic locations across the United States. Future public health campaigns should place less emphasis on geographical influences of sun protective behaviors and focus more so on comprehensive, nationwide sun prevention campaigns.

Water pollution and cyanobacteria's variation of rivers surrounding southern Taihu Lake, China.

The water quality and cyanobacterial variation of rivers surrounding southern Taihu Lake, China were purposively monitored from 2008 to 2010. Trophic level index (TLI) was used to evaluate the trophic levels of southern Taihu Lake. Results showed a considerable decline in the monitored data compared with 2007, and the data showed downward trends year after year. The TLI decreased from 55.6 to 51.3, which implied that southern Taihu Lake was mildly eutrophic. The water quality and cyanobacterial variation indicated a positive response to the adopted control measures in the southern Taihu Lake basin, but the intra- and inter-annual variability was still quite varied. High concentrations of nitrogen and phosphorus typically lead to algae outbreaks, however, the cyanobacteria growth may result in a decline of the concentration of nitrogen and phosphorus. Temperature and other weather conditions are also important factors for algae outbreaks; the risk of blue-green algal blooms still persists.

Catalytic enantioselective synthesis of chiral phthalides by SmI2-mediated reductive cyclization of 2-acylarylcarboxylates.

A significant new and efficient catalytic asymmetric approach for the highly enantioselective synthesis of chiral phthalides by SmI2-induced reductive cyclization of 2-acylarylcarbonylates was developed. The combination of (4S,5R)-4,5-diphenyloxazolidin-2-one and 2,2,6,6-tetramethylpiperidine was found to be a very effective catalyst system in the reaction. This method provides a ready access to a broad range of enantiomerically enriched phthalides (up to 99% ee).

A new entry to asymmetric synthesis of optically active alpha,gamma-substituted gamma-butyrolactones, using a carbohydrate derived amide as both a chiral auxiliary and a proton source.

A new entry for the asymmetric synthesis of optically active alpha,gamma-substituted gamma-butyrolactones was developed by using a carbohydrate-derived amide as both a chiral auxiliary and a proton source. Unlike the previously reported examples, the chiral auxiliary employed in this reaction also successfully functioned as a protonating agent. Excellent asymmetric induction could be achieved by this dual stereoselective control in the reaction process.