TISMO: syngeneic mouse tumor database to model tumor immunity and immunotherapy response.

Syngeneic mouse models are tumors derived from murine cancer cells engrafted on genetically identical mouse strains. They are widely used tools for studying tumor immunity and immunotherapy response in the context of a fully functional murine immune system. Large volumes of syngeneic mouse tumor expression profiles under different immunotherapy treatments have been generated, although a lack of systematic collection and analysis makes data reuse challenging. We present Tumor Immune Syngeneic MOuse (TISMO), a database with an extensive collection of syngeneic mouse model profiles with interactive visualization features. TISMO contains 605 in vitro RNA-seq samples from 49 syngeneic cancer cell lines across 23 cancer types, of which 195 underwent cytokine treatment. TISMO also includes 1518 in vivo RNA-seq samples from 68 syngeneic mouse tumor models across 19 cancer types, of which 832 were from immune checkpoint blockade (ICB) studies. We manually annotated the sample metadata, such as cell line, mouse strain, transplantation site, treatment, and response status, and uniformly processed and quality-controlled the RNA-seq data. Besides data download, TISMO provides interactive web interfaces to investigate whether specific gene expression, pathway enrichment, or immune infiltration level is associated with differential immunotherapy response. TISMO is available at http://tismo.cistrome.org.

Influence of 0°-15° attack angle on aero-optical imaging deviation of a blunt-nose vehicle.

A turbulent flow field is created in a vehicle's head during high-speed flight, and this flow field causes the airborne optical system's receiving target images to be displaced, blurred, and jittered. In this study, we examine the impact of a 0°-15° angle of attack on the aero-optical imaging deviation. With the use of modeling and meshing software, we created a model of a conventional blunt-headed vehicle. Computational fluid dynamics calculations were performed using finite element analysis software; the ray equations were solved iteratively by the Runge-Kutta method. Finally, the imaging deviation data were obtained by using reverse ray tracing and tracing stop criteria. The findings demonstrate that, as the angle of attack increases from 0° to 15°, the thickness of the nonuniform flow field above the vehicle flow field cross-section axis gradually increases. As the density of the nonuniform flow field through which light propagates increases, so does the corresponding refractive index and the aero-optical imaging deviation.

Effect of boundary angle on aero-optical imaging deviation of the blunt-headed side-window vehicle.

This paper defines the intersection angle between the tangent plane at the boundary of aero-optical flow field and the body axis as the boundary angle and focuses on the influence of the boundary angle on the imaging deviation. This paper shows that the boundary angle of the aero-optical flow field is different at different flight conditions, which means the location of the zero value of imaging deviation is different.  With the increase of the line of sight angle, the imaging deviation decreases first and then increases in the opposite direction.  After the change of flight conditions, the boundary angle decreases with the increase of the compression of the flow field.  The imaging deviation increases if the incident light is on the right side of the normal and decreases in the opposite direction.

Epigenetic modulation of immunotherapy and implications in head and neck cancer.

Cancer progression is facilitated by distinct mechanisms developed by cancer cells to avoid immune recognition and clearance. The clinical application of immune checkpoint blockade (ICB), via monoclonal antibodies blocking PD-1/PD-L1 and CTLA4, has achieved promising durable therapeutic response in various cancer types, including recurrent and metastatic head and neck squamous cell carcinomas (HNSCC). HNSCC represents a rational target of ICB treatment given its relatively high mutation burden and the presence of immune infiltrates. However, the limited response rates and recent negative clinical trials data identify an urgent need for new strategies to overcome immunotherapy resistance. Preclinical studies have revealed an important contribution of epigenetic regulators in the anti-tumor immune response. Multiple components of the tumor and host immune system interaction are under epigenetic regulation, including the cancer cells themselves, cytotoxic T lymphocytes, regulatory T lymphocytes, natural killer cells, and tumor-associated macrophages. Epigenetic targeting drugs such as DNA methyltransferase inhibitors, histone deacetylase, and methyltransferase inhibitors have demonstrated the potential to reverse immune suppression in various cancer models. The aim of this review is to summarize recent preclinical studies focused on investigating the function of epigenetic modulation in the host immune and cancer cell interface. We also provide a perspective on combining epigenetic modulation and immunotherapy in the management of HNSCC to improve outcomes-an area of great interest in future clinical studies.

Personalized cancer vaccination in head and neck cancer.

Cancer is characterized by an accumulation of somatic mutations that represent a source of neoantigens for targeting by antigen-specific T cells. Head and neck squamous cell carcinoma (HNSCC) has a relatively high mutation burden across all cancer types, and cellular immunity to neoantigens likely plays a key role in HNSCC clinical outcomes. Immune checkpoint inhibitors (CPIs) have brought new treatment options and hopes to patients with recurrent and/or metastatic HNSCC. However, many patients do not benefit from CPI therapies, highlighting the need for novel immunotherapy or combinatorial strategies. One such approach is personalized cancer vaccination targeting tumor-associated antigens and tumor-specific antigens, either as single agents or in combination with other therapies. Recent advances in next-generation genomic sequencing technologies and computational algorithms have enabled efficient identification of somatic mutation-derived neoantigens and are anticipated to facilitate the development of cancer vaccine strategies. Here, we review cancer vaccine approaches against HNSCC, including fundamental mechanisms of a cancer vaccine, considerations for selecting appropriate antigens, and combination therapies.

Dihydrotanshinone I inhibits ovarian cancer cell proliferation and migration by transcriptional repression of PIK3CA gene.

Dihydrotanshinone I (DHTS), extracted from Salvia miltiorrhiza, was found to be the most effective compound of tanshen extracts against cancer cells in our previous studies. However, the therapeutic benefits and underlying mechanisms of DHTS on ovarian cancer remain uncertain. In this study, we demonstrated the cytocidal effects of DHTS on chemosensitive ovarian cancer cells with or without platinum-based chemotherapy. DHTS was able to inhibit proliferation and migration of ovarian cancer cells in vitro and in vivo through modulation of the PI3K/AKT signalling pathways. Combinatorial treatment of DHTS and cisplatin exhibited enhanced DNA damage in ovarian cancer cells. Overall, these findings suggest that DHTS induces ovarian cancer cells death via induction of DNA damage and inhibits ovarian cancer cell proliferation and migration.

Sophorolipid biosynthesis and production from diverse hydrophilic and hydrophobic carbon substrates.

Sophorolipids (SLs), mainly synthesized by yeasts, were a sort of biosurfactant with the highest fermentation level at present. In recent years, SLs have drawn extensive attention for their excellent physiochemical properties and physiological activities. Besides, issues such as economics, sustainability, and use of renewable resources also stimulate the shift from chemical surfactants towards green or microbial-derived biosurfactants. SLs' large-scale production and application were restricted by the relatively high production costs. Currently, waste streams from agriculture, food and oil refining industries, etc., have been exploited as low-cost renewable substrates for SL production. Advanced cultivation method, uncommonly used substrates, and new genetically modified SL-producing mutants were also designed and applied to improve the productivity or the special properties of SLs. In this review, a systematic and detailed description of primary and secondary metabolism pathways involved in SL biosynthesis was summarized firstly. Furthermore, based on the pathways of SL biosynthesis from different carbon substrates, we reviewed the current knowledge and advances in the exploration of cost-effective and infrequently used hydrophilic and hydrophobic substrates for large or specialized SL production.

Acute suppression of insulin resistance-associated hepatic miR-29 in vivo improves glycemic control in adult mice.

MicroRNAs (miRNAs) are important posttranscriptional regulators of metabolism and energy homeostasis. Dysregulation of certain miRNAs in the liver has been shown to contribute to the pathogenesis of Type 2 diabetes (T2D), in part by impairing hepatic insulin sensitivity. By small RNA-sequencing analysis, we identified seven hepatic miRNAs (including miR-29b) that are consistently aberrantly expressed across five different rodent models of metabolic dysfunction that share the feature of insulin resistance (IR). We also showed that hepatic miR-29b exhibits persistent dysregulation during disease progression in a rat model of diabetes, UCD-T2DM. Furthermore, we observed that hepatic levels of miR-29 family members are attenuated by interventions known to improve IR in rodent and rhesus macaque models. To examine the function of the miR-29 family in modulating insulin sensitivity, we used locked nucleic acid (LNA) technology and demonstrated that acute in vivo suppression of the miR-29 family in adult mice leads to significant reduction of fasting blood glucose (in both chow-fed lean and high-fat diet-fed obese mice) and improvement in insulin sensitivity (in chow-fed lean mice). We carried out whole transcriptome studies and uncovered candidate mechanisms, including regulation of DNA methyltransferase 3a (Dnmt3a) and the hormone-encoding gene Energy homeostasis associated (Enho). In sum, we showed that IR/T2D is linked to dysregulation of hepatic miR-29b across numerous models and that acute suppression of the miR-29 family in adult mice leads to improved glycemic control. Future studies should investigate the therapeutic utility of miR-29 suppression in different metabolic disease states.Enho; insulin resistance; liver; microRNA-29 (miR-29); UCD-T2DM.

Adenocarcinoma with mixed subtypes is a rare but aggressive histologic subtype in colorectal cancer.

BACKGROUND: Although numerous studies have investigated the clinicopathologic and prognostic relevance of mucinous adenocarcinoma (MAC) and signet-ring cell carcinoma (SRCC) compared with classic adenocarcinoma (CA), little is known about the prognosis of adenocarcinoma with mixed subtypes (AM) and the differences among these four subtypes. METHODS: The statistics of colorectal cancer registered in the Surveillance, Epidemiology and End Results (SEER) database were retrieved and analyzed. We also compared the clinicopathologic and prognostic relevance between CA, SRCC, MAC, and AM. RESULTS: The frequencies of these four subtypes were 69.9% (CA, n = 15,812), 25.1% (MAC, n = 5689), 3.6% (SRCC, n = 814) and 1.4% (AM, n = 321), respectively. All of MAC, SRCC, and AM were significantly related with aggressive features. Only SRCC and AM were identified as independent poor prognostic markers for overall survival by multivariate analysis. The aggressiveness of AM was between MAC and SRCC according to the clinicopathologic associations. The prognosis of AM was significantly worse than MAC but comparable with SRCC. CONCLUSIONS: We confirmed the clinicopathologic relevance with aggressive features of MAC and SRCC, as well as poor prognostic relevance of SRCC by analyzing a large study population data set. Furthermore, we identified AM as a rare but aggressive histologic subtype in colorectal cancer, to which particular attention should be given in clinical practice.

Using structural equation modeling to detect response shift in quality of life in patients with Alzheimer's disease.

ABSTRACTBackground:Our study aims to detect different types of response shifts (RS) and true changes of quality of life (QOL) measurement in patients with Alzheimer's disease (AD) using structural equation modeling (SEM) in domain level. METHODS: Patients with AD aged over 60 years old were collected from the Department of Neurology and Geriatrics in Taiyuan Central Hospital, China. The 12-item Short Form (SF-12) Health Survey was measured in 238 patients with AD prior to hospitalization and one month following discharge. RS was detected by SEM approach. The statistical process consisted of four steps and fitted four models. We interpreted changes of parameters in models to detect RS and to assess true change. RESULTS: The results showed reprioritization of social functioning (SF) (χ2 = 4.13, p < 0.05), reconceptualization of role limitations due to emotional problems (RE) (χ2 = 17.03, p < 0.001), uniform recalibration of bodily pain (BP) (χ2 = 12.24, p < 0.001), and non-uniform recalibration of mental health (MH) (χ2 = 4.41, p < 0.05), respectively. The true changes of common factors were deteriorated in general physical health (PHYS) (-0.10, χ2 = 8.30, p < 0.005) and improved in general mental health (MENT) (+0.29, χ2 = 20.95, p < 0.001). The effect-sizes of RS were only small. CONCLUSION: This study showed that patients with AD occurred three types of RS and true changes one month following discharge. RS had effects on the QOL of patients. Better understanding of potential changes in QOL in patients with AD is crucial.

Human MicroRNA-548p Decreases Hepatic Apolipoprotein B Secretion and Lipid Synthesis.

OBJECTIVE: MicroRNAs (miRs) play important regulatory roles in lipid metabolism. Apolipoprotein B (ApoB), as the only essential scaffolding protein in the assembly of very-low-density lipoproteins, is a target to treat hyperlipidemia and atherosclerosis. We aimed to find out miRs that reduce apoB expression. APPROACH AND RESULTS: Bioinformatic analyses predicted that hsa-miR-548p can interact with apoB mRNA. MiR-548p or control miR was transfected in human and mouse liver cells to test its role in regulating apoB secretion and mRNA expression levels. Site-directed mutagenesis was used to identify the interacting site of miR-548p in human apoB 3'-untranslated region. Fatty acid oxidation and lipid syntheses were examined in miR-548p overexpressing cells to investigate its function in lipid metabolism. We observed that miR-548p significantly reduces apoB secretion from human hepatoma cells and primary hepatocytes. Mechanistic studies showed that miR-548p interacts with the 3'-untranslated region of human apoB mRNA to enhance post-transcriptional degradation. Bioinformatic algorithms suggested 2 potential binding sites of miR-548p on human apoB mRNA. Site-directed mutagenesis studies revealed that miR-548p targets site I involving both seed and supplementary sequences. MiR-548p had no effect on fatty acid oxidation but significantly decreased lipid synthesis in human hepatoma cells by reducing HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase) and ACSL4 (Acyl-CoA synthetase long-chain family member 4) enzymes involved in cholesterol and fatty acid synthesis. In summary, miR-548p reduces lipoprotein production and lipid synthesis by reducing expression of different genes in human liver cells. CONCLUSIONS: These studies suggest that miR-548p regulates apoB secretion by targeting mRNA. It is likely that it could be useful in treating atherosclerosis, hyperlipidemia, and hepatosteatosis.

Caregiver burden in Alzheimer's disease: Moderation effects of social support and mediation effects of positive aspects of caregiving.

OBJECTIVES: Although there are many studies on the relationship between patient-related factors and negative caregiver outcomes, the specifics of this relationship are poorly understood. We aimed to examine whether caregiver social support moderated the relationship between patient factors and negative outcomes for caregivers of community-dwelling older adults with Alzheimer's disease (AD), and whether positive aspects of caregiving mediated this relationship. METHODS: We conducted a cross-sectional study of patients diagnosed with AD from 2 hospitals and 3 communities in Taiyuan, China, and their caregivers. Latent moderated structural equations and the bias-corrected percentile bootstrap method were used to estimate the parameters of moderating and mediating effects, respectively. RESULTS: Social support significantly moderated the effects of AD patient cognitive function (P < 0.001) and depression (P = 0.001) on caregiver burden. Positive aspects of caregiving completely mediated the association between patient depression and caregiver burden (P = 0.006), caregiver anxiety (P = 0.007), and caregiver depression (P = 0.034). CONCLUSIONS: The findings identify social support as a moderator and positive aspects of caregiving as a mediator of the relationship between patient-related factors and negative caregiver outcomes. The results suggest that health care providers must offer more effective social support for caregivers. In addition, prompt identification of patient and caregiver emotional states could help to improve quality of life.

MicroRNAs regulating apolipoprotein B-containing lipoprotein production.

MicroRNAs (miRs) are small, non-coding RNAs that regulate gene expression and have been implicated in many pathological conditions. Significant progress has been made to unveil their role in lipid metabolism. This review aims at summarizing the role of different miRs that regulate hepatic assembly and secretion of apolipoprotein B (apoB)-containing lipoproteins. Overproduction and/or impaired clearance of these lipoproteins from circulation increase plasma concentrations of lipids enhancing risk for cardiovascular disease. So far, three miRs, miR-122, miR-34a, and miR-30c have been shown to modulate hepatic production of apoB-containing low density lipoproteins. In this review, we will first provide a brief overview of lipid metabolism and apoB-containing lipoprotein assembly to orient readers to different steps that have been shown to be regulated by miRs. Then, we will discuss the role of each miR on plasma lipids and atherosclerotic burden. Furthermore, we will summarize mechanistic studies explaining how these miRs regulate hepatic lipid synthesis, fatty acid oxidation, and lipoprotein secretion. Finally, we will briefly highlight the potential use of each miR as a therapeutic drug for treating cardiovascular diseases. This article is part of a Special Issue entitled: MicroRNAs and lipid/energy metabolism and related diseases edited by Carlos Fernández-Hernando and Yajaira Suárez.

Trajectories of health-related quality of life during the natural history of dementia: a six-wave longitudinal study.

OBJECTIVE: The objective of this study was to explore profiles of quality of life (QoL) trajectories during the natural history of dementia and individual variations contributing to QoL trajectories. METHODS: We conducted a longitudinal community-based study of 520 elderly people with mild cognitive impairment and 100 healthy people aged 60 years or over. We conducted six waves of assessment between October 2010 and May 2013 in Taiyuan, mainland China. Cognitively normal, mild cognitive impairment, global impairment, and Alzheimer's disease (AD) were defined as state 1, 2, 3, and 4, respectively. We assessed health-related QoL (HRQoL) via the Quality of Life-Alzheimer's Disease (QoL-AD) Chinese version. We used the latent growth curve model (LGCM) to investigate change in HRQoL over time. RESULTS: Latent growth curve model analysis revealed a mean initial QoL level of 29.865 with substantial variation and a significant mean slope for the whole sample. Multigroup LGCM showed substantial variations across individuals in initial QoL levels for each cognitive state transition group. For the slope factor, we found significant changes and variations for the transition from state 2 to 3 and from state 3 to 4. We estimated mean QoL levels over six assessments based on intercept, slope, and factor loadings for the whole sample and the three cognitive state transition groups. CONCLUSIONS: A decline in subjective QoL is not inevitable during the natural history of dementia in community settings, and there is a degree of individual variation in QoL. Future studies should investigate the factors associated with individual variations in QoL trajectories in AD.

Risk factors of transition from mild cognitive impairment to Alzheimer's disease and death: A cohort study.

BACKGROUND: Knowledge of risk factors is essential for developing strategies that prevent or minimise transitions from mild cognitive impairment (MCI) to Alzheimer's disease (AD) and death. The aim of this study was to assess risk factors for progression to AD and death among Chinese individuals with cognitive impairment. METHODS: We conducted a multisite, population-based cohort study on 437 community-dwelling elderly MCI residents in Taiyuan, China from 2010 to 2014. MCI, AD, death from AD and death from a cause other than AD were specified as disease states during the natural history of dementia. Transition-specific Cox model was fitted and hazard ratio (HR) with 95% confidence intervals (CIs) was estimated. RESULTS: Analyses showed that risk factors played different roles in affecting transitions to AD and death. Risk factors for transition from MCI to AD were being female (HR: 1.82; 95%CI: 1.20-2.77), older age (HR: 3.09; 95%CI: 1.81-5.25), reading occasionally (HR: 1.79; 95%CI: 1.11-2.89), current smoking (HR: 1.74; 95%CI: 1.15-2.65), light-moderate alcohol drinker (HR: 2.24; 95%CI: 1.42-3.53), cerebrovascular disease (HR: 2.70; 95%CI: 1.68-4.34), hyperlipidemia (HR: 1.87; 95%CI: 1.16-3.02) and diabetes (HR: 1.81; 95%CI: 1.18-2.77). Only cerebrovascular disease (HR: 3.04; 95%CI: 1.22-7.58) was a significant risk factor for transition from MCI to death from a cause other than AD. Older age (HR: 10.68; 95%CI: 1.16-97.93) and low level education (HR: 0.14; 95%CI: 0.05-0.44) were significant predictors for transition from AD to death from a cause other than AD. CONCLUSIONS: Participants with advanced age, low-level education, history of harmful alcohol consumption or smoking, cerebrovascular disease, hyperlipidemia, diabetes or who were female were at increased risk of transitioning to AD or death. Strategies to control modifiable risk factors in specific disease stage should be implemented to decrease the conversion to AD or death among Chinese patients with MCI.

Reliability and validity of the quality of life-Alzheimer disease Chinese version.

OBJECTIVES: To evaluate the psychometric properties of the quality of life-Alzheimer disease (QOL-AD) Chinese version in patients with dementia in mainland, China and to compare patient and caregiver reports of patient QOL. METHODS: The QOL-AD Chinese version was established following standard guidelines for cross-cultural adaptation of measures. The reliability was assessed by internal consistency and test-retest reliability. The validity included construct and convergent validity. A paired Student t test was performed to determine differences between patient reports and caregiver reports. RESULTS: The reliability for both patient and caregiver reports on the QOL-AD was good (Cronbach α values of 0.66 and 0.87; intraclass correlation coefficients of 0.84 and 0.90 for patient and caregiver reports, respectively). The validity of patient and caregiver reports was supported by correlation with domain measures. All of the multitrait-multimethod correlations demonstrated a high relationship between patient reports and caregiver reports, ranging from 0.26 to 0.55. The caregivers rated patient QOL significantly higher than did the patients. CONCLUSION: The findings support the use of the Chinese version of the QOL-AD as a generic instrument to measure QOL of AD in mainland China. Further research is needed to clarify the relationship between patient and caregiver reports of patient QOL.

Multi-state Markov model in outcome of mild cognitive impairments among community elderly residents in Mainland China.

BACKGROUND: Although knowledge of established risk factors for Alzheimer's disease (AD) can logically contribute to the search for predictors of the progression of cognitive impairment, it has not yet been firmly established where in the cognitive impairment process these risk factors exert their effects and how to predict quantitatively for the progression of mild cognitive impairments (MCI) to AD. This study aimed to determine whether known risk factors increased the risk of progression from MCI to AD and to make prediction based on transition probabilities. METHODS: Based on ten examinations of 600 community-dwelling MCI residents and cognitive assessments to classify individuals into MCI, global impairment, and AD, a multi-state Markov Cox's regression model was used and the hazard ratios with their confidence intervals and transition probabilities were estimated. RESULTS: Multivariate analysis showed that gender, age, and hypertension were statistically significant predictors of transition from MCI to global impairment; age, education, and reading statistically influenced transition from global impairment to MCI; gender, age, hypertension, diabetes, and apolipoprotein E geneε4 status were statistically associated with transition from global impairment to AD. Subjects at MCI were more likely (67%) to remain in that cognitive state at the next cognitive assessment than to transition to cognitive deterioration. For global impairment, probability of remaining in the same state was only 18% and that of forward transition was three times more likely than that of backward transition. CONCLUSIONS: Known risk factors influenced differently for different transitions. Transition from global impairment was more likely to worsen to severe cognitive deterioration than transition from MCI.

Characterization of a novel picornavirus prevalent in experimental rabbits (Oryctolagus cuniculus).

Here, using viral metagenomic method a novel picornavirus (named UJS-2019picorna, GenBank accession number OP821762) was discovered in fecal and blood samples of experimental rabbits (Oryctolagus cuniculus). The complete genome size of UJS-2019picorna is 7832 bp excluding the poly(A)-tail, with GC content of 44.00% and a nucleotide composition of 28.0% A, 28.0% U, 21.5% G, and 22.5% C. The viral genome has a typical picornavirus organization pattern from the 5'-3' direction: VPg-5' UTR-(L)-P1, (VP4-VP2-VP3-VP1)-P2, (2 A-2B-2C)-P3, (3 A-3B-3C-3D)-3' UTR-poly(A). The P1 region of UJS-2019picorna is related to Erbovirus with amino acid identity of 37.31%, while the P2 and P3 regions are the closest to Bopivirus with amino acid identity of 35.66%-39.53%. According to the Picornaviridae Study Group guidelines, UJS-2019picorna should be presumed to be a new genus belonging to the Picornaviridae family. Epidemiologic study revealed that this novel picornavirus was prevalent in a cohort of experimental rabbits, with prevalence rate of 23.68% (9/38) in feces and 18.4% (7/38) in blood samples. Further work is required to elucidate whether this virus is pathogenic to rabbits and whether it has influence on studies using rabbits as experimental animal.

MicroRNA-541-3p alters lipoproteins to reduce atherosclerosis by degrading Znf101 and Casz1 transcription factors.

High apoB-containing low-density lipoproteins (LDL) and low apoA1-containing high-density lipoproteins (HDL) are associated with atherosclerosis. In search of a molecular regulator that could simultaneously and reciprocally control both LDL and HDL levels, we screened a microRNA (miR) library using human hepatoma Huh-7 cells. We identified miR-541-3p that both decreases apoB and increases apoA1 expression by inducing mRNA degradation of two different transcription factors, Znf101 and Casz1. Znf101 enhances apoB expression while Casz1 represses apoA1 expression. The hepatic knockdown of orthologous Zfp961 and Casz1 genes in mice altered plasma lipoproteins and reduced atherosclerosis without causing hepatic lipid accumulation, most likely by lowering hepatic triglyceride production, increasing HDL cholesterol efflux capacity, and reducing lipogenesis. Notably, human genetic variants in the MIR541, ZNF101, and CASZ1 loci are significantly associated with plasma lipids and lipoprotein levels. This study identifies miR-541-3p and Znf101/Casz1 as potential therapeutic agent and targets, respectively, to reduce plasma lipoproteins and atherosclerosis without causing liver steatosis.

Preexisting tumor-resident T cells with cytotoxic potential associate with response to neoadjuvant anti-PD-1 in head and neck cancer.

About 50% of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) experience recurrences after definitive therapy. The presurgical administration of anti-programmed cell death protein 1 (PD-1) immunotherapy results in substantial pathologic tumor responses (pTR) within the tumor microenvironment (TME). However, the mechanisms underlying the dynamics of antitumor T cells upon neoadjuvant PD-1 blockade remain unresolved, and approaches to increase pathologic responses are lacking. In a phase 2 trial (NCT02296684), we observed that 45% of patients treated with two doses of neoadjuvant pembrolizumab experienced marked pTRs (≥50%). Single-cell analysis of 17,158 CD8+ T cells from 14 tumor biopsies, including 6 matched pre-post neoadjuvant treatment, revealed that responding tumors had clonally expanded putative tumor-specific exhausted CD8+ tumor-infiltrating lymphocytes (TILs) with a tissue-resident memory program, characterized by high cytotoxic potential (CTX+) and ZNF683 expression, within the baseline TME. Pathologic responses after 5 weeks of PD-1 blockade were consistent with activation of preexisting CTX+ZNF683+CD8+ TILs, paralleling loss of viable tumor and associated tumor antigens. Response was associated with high numbers of CD103+PD-1+CD8+ T cells infiltrating pretreatment lesions, whereas revival of nonexhausted persisting clones and clonal replacement were modest. By contrast, nonresponder baseline TME exhibited a relative absence of ZNF683+CTX+ TILs and subsequent accumulation of highly exhausted clones. In HNSCC, revival of preexisting ZNF683+CTX+ TILs is a major mechanism of response in the immediate postneoadjuvant setting.