Checkpoint blockade-induced CD8+ T cell differentiation in head and neck cancer responders

BACKGROUND: Immune checkpoint blockade (ICB) response in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) is limited to 15%-20% of patients and underpinnings of resistance remain undefined. METHODS: Starting with an anti-PD1 sensitive murine HNSCC cell line, we generated an isogenic anti-PD1 resistant model. Mass cytometry was used to delineate tumor microenvironments of both sensitive parental murine oral carcinoma (MOC1) and resistant MOC1esc1 tumors. To examine heterogeneity and clonal dynamics of tumor infiltrating lymphocytes (TILs), we applied paired single-cell RNA and TCR sequencing in three HNSCC models. RESULTS: Anti-PD1 resistant MOC1esc1 line displayed a conserved cell intrinsic immune evasion signature. Immunoprofiling showed distinct baseline tumor microenvironments of MOC1 and MOC1esc1, as well as the remodeling of immune compartments on ICB in MOC1esc1 tumors. Single cell sequencing analysis identified several CD8 +TIL subsets including Tcf7 +Pd1- (naïve/memory-like), Tcf7 +Pd1+ (progenitor), and Tcf7-Pd1+ (differentiated effector). Mapping TCR shared fractions identified that successful anti-PD1 or anti-CTLA4 therapy-induced higher post-treatment T cell lineage transitions. CONCLUSIONS: These data highlight critical aspects of CD8 +TIL heterogeneity and differentiation and suggest facilitation of CD8 +TIL differentiation as a strategy to improve HNSCC ICB response

Projecting future impacts of cropland reclamation policies on carbon storage

Cropland reclamation policies result in carbon storage loss by the conversion of natural land. However, the future impacts of cropland reclamation policies (CRP) on carbon storage have seldom been explored. Taking Hubei, China as study area, this study assesses the impacts of cropland reclamation policies before and after optimization on carbon storage from 2010 to 2030. The LAND System Cellular Automata model for Potential Effects (LANDSCAPE) was used to simulate the land use patterns in 2030, while the Integrated Valuation of Ecosystem Services and Trade-offs (InVEST) Carbon Storage and Sequestration model was applied to calculate the changes in carbon storage. Results indicate that carbon storage loss due to cropland reclamation policies is expected to increase from 0.48 Tg·C to 4.34 Tg·C between 2010 and 2030 in Hubei. This increase is related to the loss of wetland and forest. Carbon storage loss can be reduced by 52%–73% by protecting carbon-rich lands. This study highlights the importance of considering the carbon storage loss when implementing cropland reclamation policies

Translational progress on tumor biomarkers

There is an urgent need to apply basic research achievements to the clinic. In particular, mechanistic studies should be developed by bench researchers, depending upon clinical demands, in order to improve the survival and quality of life of cancer patients. To date, translational medicine has been addressed in cancer biology, particularly in the identification and characterization of novel tumor biomarkers. This review focuses on the recent achievements and clinical application prospects in tumor biomarkers based on translational medicine.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/115962/1/tca12294.pd

Proteomic Analysis of Ubiquitinated Proteins in Rice (\u3ci\u3eOryza sativa\u3c/i\u3e) After Treatment With Pathogen-Associated Molecular Pattern (PAMP) Elicitors

Reversible protein ubiquitination plays essential roles in regulating cellular processes. Although many reports have described the functions of ubiquitination in plant defense responses, few have focused on global changes in the ubiquitome. To better understand the regulatory roles of ubiquitination in rice pattern-triggered immunity (PTI), we investigated the ubiquitome of rice seedlings after treatment with two pathogen-associated molecular patterns, the fungal-derived chitin or the bacterialderived flg22, using label-free quantitative proteomics. In chitin-treated samples, 144 and 167 lysine-ubiquitination sites in 121 and 162 proteins showed increased and decreased ubiquitination, respectively. In flg22-treated samples, 151 and 179 lysine-ubiquitination sites in 118 and 166 proteins showed increased and decreased ubiquitination, respectively. Bioinformatic analyses indicated diverse regulatory roles of these proteins. The ubiquitination levels of many proteins involved in the ubiquitination system, protein transportation, ligand recognition, membrane trafficking, and redox reactions were significantly changed in response to the elicitor treatments. Notably, the ubiquitination levels of many enzymes in the phenylpropanoid metabolic pathway were up-regulated, indicating that this pathway is tightly regulated by ubiquitination during rice PTI. Additionally, the ubiquitination levels of some key components in plant hormone signaling pathways were up- or down-regulated, suggesting that ubiquitination may fine-tune hormone pathways for defense responses. Our results demonstrated that ubiquitination, by targeting a wide range of proteins for degradation or stabilization, has a widespread role in modulating PTI in rice. The large pool of ubiquitination targets will serve as a valuable resource for understanding how the ubiquitination system regulates defense responses to pathogen attack

The effects of tai chi on markers of atherosclerosis, lower-limb physical function, and cognitive ability in adults aged over 60: A randomized controlled trial

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. Objective: The purpose of this study was to investigate the effects of Tai Chi (TC) on arterial stiffness, physical function of lower-limb, and cognitive ability in adults aged over 60. Methods: This study was a prospective and randomized 12-week intervention trial with three repeated measurements (baseline, 6, and 12 weeks). Sixty healthy adults who met the inclusion criteria were randomly allocated into three training conditions (TC-24, TC-42, and TC-56) matched by gender, with 20 participants (10 males, 10 females) in each of the three groups. We measured the following health outcomes, including markers of atherosclerosis, physical function (leg power, and static and dynamic balance) of lower-limb, and cognitive ability. Results: When all three TC groups (p \u3c 0.05) have showed significant improvements on these outcomes but overall cognitive ability at 6 or 12 weeks training period, TC-56 appears to have superior effects on arterial stiffness and static/dynamic balance in the present study. Conclusions: Study results of the present study add to growing body of evidence regarding therapeutic TC for health promotion and disease prevention in aging population. Future studies should further determine whether TC-42 and TC-56 are beneficial for other non-Chinese populations, with rigorous research design and follow-up assessment

Colorimetric and Fluorescent Dual-Mode Detection of Aflatoxin B1 Using Composite Nanomaterial

In this study, a highly sensitive portable platform with colorimetric and fluorescent dual-mode signal output for the detection of aflatoxin B1 (AFB1) was developed based on the reaction between glutathione and a composite nanomaterial consisting of manganese dioxide (MnO2) nanoparticles and graphene quantum dots (GQDs) as a substrate. The recognition probe was prepared by using silica nanoparticles as a carrier to enrich glutathione and AFB1 aptamers. Under optimal conditions, analytical figures of merit such as specificity of this method were studied. The regression equation for colorimetric signal was ΔA = − 0.275 − 0.021lgC and the detection limit was 2.732 × 10-12 g/mL; the regression equation for fluorescence signal was ΔF = 928.733 + 71.779lgC and the detection limit was 1.667 × 10-12 g/mL. Both methods had good detection specificity. The proposed method was applied in the detection of food samples, such as milk, rice, oatmeal, soy sauce and white vinegar with higher accuracy, compared with the traditional method

Population genomics of wild Chinese rhesus macaques reveals a dynamic demographic history and local adaptation, with implications for biomedical research

Background The rhesus macaque (RM, Macaca mulatta) is the most important nonhuman primate model in biomedical research. We present the first genomic survey of wild RMs, sequencing 81 geo-referenced individuals of five subspecies from 17 locations in China, a large fraction of the species’ natural distribution. Results Populations were structured into five genetic lineages on the mainland and Hainan Island, recapitulating current subspecies designations. These subspecies are estimated to have diverged 125.8 to 51.3 thousand years ago, but feature recent gene flow. Consistent with the expectation of a larger body size in colder climates and smaller body size in warmer climates (Bergman's rule), the northernmost RM lineage (M. m. tcheliensis), possessing the largest body size of all Chinese RMs, and the southernmost lineage (M. m. brevicaudus), with the smallest body size of all Chinese RMs, feature positively selected genes responsible for skeletal development. Further, two candidate selected genes (Fbp1, Fbp2) found in M. m. tcheliensis are involved in gluconeogenesis, potentially maintaining stable blood glucose levels during starvation when food resources are scarce in winter. The tropical subspecies M. m. brevicaudus showed positively selected genes related to cardiovascular function and response to temperature stimuli, potentially involved in tropical adaptation. We found 118 single-nucleotide polymorphisms matching human disease-causing variants with 82 being subspecies specific. Conclusions These data provide a resource for selection of RMs in biomedical experiments. The demographic history of Chinese RMs and their history of local adaption offer new insights into their evolution and provide valuable baseline information for biomedical investigation

Lexis and grammar of mitochondrial RNA processing in Trypanosomes

Trypanosoma brucei spp. cause African human and animal trypanosomiasis, a burden on health and economy in Africa. These hemoflagellates are distinguished by a kinetoplast nucleoid containing mitochondrial DNAs of two kinds: maxicircles encoding ribosomal RNAs (rRNAs) and proteins and minicircles bearing guide RNAs (gRNAs) for mRNA editing. All RNAs are produced by a phage-type RNA polymerase as 3' extended precursors, which undergo exonucleolytic trimming. Most pre-mRNAs proceed through 3' adenylation, uridine insertion/deletion editing, and 3' A/U-tailing. The rRNAs and gRNAs are 3' uridylated. Historically, RNA editing has attracted major research effort, and recently essential pre- and postediting processing events have been discovered. Here, we classify the key players that transform primary transcripts into mature molecules and regulate their function and turnover

Cancer immunogenomic approach to neoantigen discovery in a checkpoint blockade responsive murine model of oral cavity squamous cell carcinoma

Head and neck squamous cell carcinomas (HNSCC) are an ideal immunotherapy target due to their high mutation burden and frequent infiltration with lymphocytes. Preclinical models to investigate targeted and combination therapies as well as defining biomarkers to guide treatment represent an important need in the field. Immunogenomics approaches have illuminated the role of mutation-derived tumor neoantigens as potential biomarkers of response to checkpoint blockade as well as representing therapeutic vaccines. Here, we aimed to define a platform for checkpoint and other immunotherapy studies using syngeneic HNSCC cell line models (MOC2 and MOC22), and evaluated the association between mutation burden, predicted neoantigen landscape, infiltrating T cell populations and responsiveness of tumors to anti-PD1 therapy. We defined dramatic hematopoietic cell transcriptomic alterations in the MOC22 anti-PD1 responsive model in both tumor and draining lymph nodes. Using a cancer immunogenomics pipeline and validation with ELISPOT and tetramer analysis, we identified the H-2Kb-restricted ICAM1P315L (mICAM1) as a neoantigen in MOC22. Finally, we demonstrated that mICAM1 vaccination was able to protect against MOC22 tumor development defining mICAM1 as a bona fide neoantigen. Together these data define a pre-clinical HNSCC model system that provides a foundation for future investigations into combination and novel therapeutics