Publications by authors named "Richard A Miller"

237 Publications

Cap-independent translation of GPLD1 enhances markers of brain health in long-lived mutant and drug-treated mice.

Aging Cell 2022 Aug 5:e13685. Epub 2022 Aug 5.

Department of Pathology, School of Medicine, University of Michigan, Ann Arbor, Michigan, USA.

Glycosylphosphatidylinositol-specific phospholipase D1 (GPLD1) hydrolyzes inositol phosphate linkages in proteins anchored to the cell membrane. Mice overexpressing GPLD1 show enhanced neurogenesis and cognition. Snell dwarf (DW) and growth hormone receptor knockout (GKO) mice show delays in age-dependent cognitive decline. We hypothesized that augmented GPLD1 might contribute to retained cognitive function in these mice. We report that DW and GKO show higher GPLD1 levels in the liver and plasma. These mice also have elevated levels of hippocampal brain-derived neurotrophic factor (BDNF) and of doublecortin (DCX), suggesting a mechanism for maintenance of cognitive function at older ages. GPLD1 was not increased in the hippocampus of DW or GKO mice, suggesting that plasma GPLD1 increases elevated these brain proteins. Alteration of the liver and plasma GPLD1 was unaltered in mice with liver-specific GHR deletion, suggesting that the GH effect was not intrinsic to the liver. GPLD1 was also induced by caloric restriction and by each of four drugs that extend lifespan. The proteome of DW and GKO mice is molded by selective translation of mRNAs, involving cap-independent translation (CIT) of mRNAs marked by N methyladenosine. Because GPLD1 protein increases were independent of the mRNA level, we tested the idea that GPLD1 might be regulated by CIT. 4EGI-1, which enhances CIT, increased GPLD1 protein without changes in GPLD1 mRNA in cultured fibroblasts and mice. Furthermore, transgenic overexpression of YTHDF1, which promotes CIT by reading m6A signals, also led to increased GPLD1 protein, showing that elevation of GPLD1 reflects selective mRNA translation.
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http://dx.doi.org/10.1111/acel.13685DOI Listing
August 2022

Neuroprotective effects of Canagliflozin: Lessons from aged genetically diverse UM-HET3 mice.

Aging Cell 2022 07 15;21(7):e13653. Epub 2022 Jun 15.

Department of Biological Sciences, IBio (Integrative Biosciences Center), Wayne State University, Detroit, Michigan, USA.

The aging brain is characterized by progressive increases in neuroinflammation and central insulin resistance, which contribute to neurodegenerative diseases and cognitive impairment. Recently, the Interventions Testing Program demonstrated that the anti-diabetes drug, Canagliflozin (Cana), a sodium-glucose transporter 2 inhibitor, led to lower fasting glucose and improved glucose tolerance in both sexes, but extended median lifespan by 14% in male mice only. Here, we show that Cana treatment significantly improved central insulin sensitivity in the hypothalamus and the hippocampus of 30-month-old male mice. Aged males produce more robust neuroimmune responses than aged females. Remarkably, Cana-treated male and female mice showed significant reductions in age-associated hypothalamic gliosis with a decrease in inflammatory cytokine production by microglia. However, in the hippocampus, Cana reduced microgliosis and astrogliosis in males, but not in female mice. The decrease in microgliosis was partially correlated with reduced phosphorylation of S6 kinase in microglia of Cana-treated aged male, but not female mice. Thus, Cana treatment improved insulin responsiveness in aged male mice. Furthermore, Cana treatment improved exploratory and locomotor activity of 30-month-old male but not female mice. Taken together, we demonstrate the sex-specific neuroprotective effects of Cana treatment, suggesting its application for the potential treatment of neurodegenerative diseases.
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http://dx.doi.org/10.1111/acel.13653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9282842PMC
July 2022

Transient early life growth hormone exposure permanently alters brain, muscle, liver, macrophage, and adipocyte status in long-lived Ames dwarf mice.

FASEB J 2022 Jul;36(7):e22394

Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.

The exceptional longevity of Ames dwarf (DF) mice can be abrogated by a brief course of growth hormone (GH) injections started at 2 weeks of age. This transient GH exposure also prevents the increase in cellular stress resistance and decline in hypothalamic inflammation characteristic of DF mice. Here, we show that transient early-life GH treatment leads to permanent alteration of pertinent changes in adipocytes, fat-associated macrophages, liver, muscle, and brain that are seen in DF mice. Ames DF mice, like Snell dwarf and GHRKO mice, show elevation of glycosylphosphatidylinositol specific phospholipase D1 in liver, neurogenesis in brain as indicated by BDNF and DCX proteins, muscle production of fibronectin type III domain-containing protein 5 (a precursor of irisin), uncoupling protein 1 as an index of thermogenic capacity in brown and white fat, and increase in fat-associated anti-inflammatory macrophages. In each case, transient exposure to GH early in life reverts the DF mice to the levels of each protein seen in littermate control animals, in animals evaluated at 15-18 months of age. Thus, many of the traits seen in long-lived mutant mice, pertinent to age-related changes in inflammation, neurogenesis, and metabolic control, are permanently set by early-life GH levels.
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http://dx.doi.org/10.1096/fj.202200143RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9250136PMC
July 2022

Comparative transcriptomics reveals circadian and pluripotency networks as two pillars of longevity regulation.

Cell Metab 2022 Jun 16;34(6):836-856.e5. Epub 2022 May 16.

Department of Biology, University of Rochester, Rochester, NY 14627, USA. Electronic address:

Mammals differ more than 100-fold in maximum lifespan. Here, we conducted comparative transcriptomics on 26 species with diverse lifespans. We identified thousands of genes with expression levels negatively or positively correlated with a species' maximum lifespan (Neg- or Pos-MLS genes). Neg-MLS genes are primarily involved in energy metabolism and inflammation. Pos-MLS genes show enrichment in DNA repair, microtubule organization, and RNA transport. Expression of Neg- and Pos-MLS genes is modulated by interventions, including mTOR and PI3K inhibition. Regulatory networks analysis showed that Neg-MLS genes are under circadian regulation possibly to avoid persistent high expression, whereas Pos-MLS genes are targets of master pluripotency regulators OCT4 and NANOG and are upregulated during somatic cell reprogramming. Pos-MLS genes are highly expressed during embryogenesis but significantly downregulated after birth. This work provides targets for anti-aging interventions by defining pathways correlating with longevity across mammals and uncovering circadian and pluripotency networks as central regulators of longevity.
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http://dx.doi.org/10.1016/j.cmet.2022.04.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9364679PMC
June 2022

Regulation of mTOR complexes in long-lived growth hormone receptor knockout and Snell dwarf mice.

Aging (Albany NY) 2022 03 19;14(6):2442-2461. Epub 2022 Mar 19.

Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

Downregulation of mTOR (mechanistic target of rapamycin) can extend lifespan in multiple species, including mice. Growth hormone receptor knockout mice (GHRKO) and Snell dwarf mice have 40% or greater lifespan increase, and have lower mTORC1 function, which might reflect alteration in mTORC1 components or alteration of upstream proteins that modulate mTOR activity. Here we report reduction of mTORC components DEPTOR and PRAS40 in liver of these long-lived mice; these changes are opposite in direction to those that would be expected to lead to lower mTORC1 function. In contrast, levels of the upstream regulators TSC1 and TSC2 are elevated in GHRKO and Snell liver, kidney and skeletal muscle, and the ratio of phosphorylated TSC2 to total TSC2 is lower in the tissues of the long-lived mutant mice. In addition, knocking down TSC2 in GHRKO fibroblasts reversed the effects of the GHRKO mutation on mTORC1 function. Thus increased amounts of unphosphorylated, active, inhibitory TSC may contribute to lower mTORC1 function in these mice.
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http://dx.doi.org/10.18632/aging.203959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9004569PMC
March 2022

Early Life Interventions Can Shape Aging.

Front Endocrinol (Lausanne) 2022 25;13:797581. Epub 2022 Feb 25.

Department of Pathology and Paul Glenn Center for Biology of Aging Research, University of Michigan, Ann Arbor, MI, United States.

It is well documented that the environment of the developing fetus, including availability of nutrients and presence of toxins, can have major impact on adult phenotype, age-related traits and risk of chronic disease. There is also accumulating evidence that postnatal environment can impact adult characteristics related to evolutionary fitness, health, and aging. To determine whether early life hormonal interventions can alter trajectory of aging, we have examined the effects of early life growth hormone (GH) replacement therapy in Prop1 (Ames dwarf) mice which are GH deficient and remarkably long lived. Twice-daily GH injections between the ages of two and eight weeks completely normalized ("rescued") a number of adult metabolic characteristics believed to contribute to extended longevity of these mutants. Importantly, longevity of Ames dwarf mice was reduced by early life GH treatment. This was associated with histone H3 modifications. We conclude that the trajectory of mammalian aging can be modified by early life interventions. Mechanistic links among interventions during postnatal development, adult metabolic characteristics, aging, and longevity, apparently involve epigenetic phenomena.
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http://dx.doi.org/10.3389/fendo.2022.797581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8916564PMC
April 2022

Rapamycin, Acarbose and 17α-estradiol share common mechanisms regulating the MAPK pathways involved in intracellular signaling and inflammation.

Immun Ageing 2022 Feb 1;19(1). Epub 2022 Feb 1.

Department of Pathology, University of Michigan School of Medicine, Ann Arbor, USA.

Background: Rapamycin (Rapa), acarbose (ACA), and 17α-estradiol (17aE2, males only) have health benefits that increase lifespan of mice. Little is known about how these three agents alter the network of pathways downstream of insulin/IGF1 signals as well as inflammatory/stress responses.

Results: ACA, Rapa, and 17aE2 (in males, but not in females) oppose age-related increases in the MEK1- ERK1/2-MNK1/2 cascade, and thus reduce phosphorylation of eIF4E, a key component of cap-dependent translation. In parallel, these treatments (in both sexes) reduce age-related increases in the MEK3-p38MAPK-MK2 pathway, to decrease levels of the acute phase response proteins involved in inflammation.

Conclusion: Each of three drugs converges on the regulation of both the ERK1/2 signaling pathway and the p38-MAPK pathway. The changes induced by treatments in ERK1/2 signaling are seen in both sexes, but the 17aE2 effects are male-specific, consistent with the effects on lifespan. However, the inhibition of age-dependent p38MAPK pathways and acute phase responses is triggered in both sexes by all three drugs, suggesting new approaches to prevention or reversal of age-related inflammatory changes in a clinical setting independent of lifespan effects.
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http://dx.doi.org/10.1186/s12979-022-00264-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8805398PMC
February 2022

Aging is associated with increased brain iron through cortex-derived hepcidin expression.

Elife 2022 01 11;11. Epub 2022 Jan 11.

Feinberg Cardiovascular and Renal Research Institute, Northwestern University School of Medicine, Chicago, United States.

Iron is an essential molecule for biological processes, but its accumulation can lead to oxidative stress and cellular death. Due to its oxidative effects, iron accumulation is implicated in the process of aging and neurodegenerative diseases. However, the mechanism for this increase in iron with aging, and whether this increase is localized to specific cellular compartment(s), are not known. Here, we measured the levels of iron in different tissues of aged mice, and demonstrated that while cytosolic non-heme iron is increased in the liver and muscle tissue, only the aged brain cortex exhibits an increase in both the cytosolic and mitochondrial non-heme iron. This increase in brain iron is associated with elevated levels of local hepcidin mRNA and protein in the brain. We also demonstrate that the increase in hepcidin is associated with increased ubiquitination and reduced levels of the only iron exporter, ferroportin-1 (FPN1). Overall, our studies provide a potential mechanism for iron accumulation in the brain through increased local expression of hepcidin, and subsequent iron accumulation due to decreased iron export. Additionally, our data support that aging is associated with mitochondrial and cytosolic iron accumulation only in the brain and not in other tissues.
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http://dx.doi.org/10.7554/eLife.73456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8752087PMC
January 2022

Genomes Assembled from Metagenomes Suggest Genetic Drivers of Differential Response to Acarbose Treatment in Mice.

mSphere 2021 12 1;6(6):e0085121. Epub 2021 Dec 1.

Department of Ecology & Evolutionary Biology, University of Michigan, Ann Arbor, Michigan, USA.

The drug acarbose is used to treat diabetes and, by inhibiting α-amylase in the small intestine, increases the amount of starch entering the lower digestive tract. This results in changes to the composition of the microbiota and their fermentation products. Acarbose also increases longevity in mice, an effect that has been correlated with increased production of the short-chain fatty acids propionate and butyrate. In experiments replicated across three study sites, two distantly related species in the bacterial family were dramatically more abundant in acarbose-treated mice, distinguishing these responders from other members of the family. Bacteria in the family are predicted to produce propionate as a fermentation end product and are abundant and diverse in the guts of mice, although few isolates are available. We reconstructed genomes from metagenomes (MAGs) for nine populations of to examine factors that distinguish species that respond positively to acarbose. We found two closely related MAGs (B1A and B1B) from one responsive species that both contain a polysaccharide utilization locus with a predicted extracellular α-amylase. These genomes also shared a periplasmic neopullulanase with another, distantly related MAG (B2) representative of the only other responsive species. This gene differentiated these three MAGs from MAGs representative of nonresponding species. Differential gene content in B1A and B1B may be associated with the inconsistent response of this species to acarbose across study sites. This work demonstrates the utility of culture-free genomics for inferring the ecological roles of gut bacteria, including their response to pharmaceutical perturbations. The drug acarbose is used to treat diabetes by preventing the breakdown of starch in the small intestine, resulting in dramatic changes in the abundance of some members of the gut microbiome and its fermentation products. In mice, several of the bacteria that respond most positively are classified in the family , members of which produce propionate as a primary fermentation product. Propionate has been associated with gut health and increased longevity in mice. We found that genomes of the most responsive showed signs of specialization for starch fermentation, presumably providing them a competitive advantage in the large intestine of animals consuming acarbose. Comparisons among genomes enhance existing models for the ecological niches occupied by members of this family. In addition, genes encoding one type of enzyme known to participate in starch breakdown were found in all three genomes from responding species but none of the other genomes.
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http://dx.doi.org/10.1128/msphere.00851-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8636109PMC
December 2021

Lysosomal targetomics of mice shows chaperone-mediated autophagy degrades nucleocytosolic acetyl-coA enzymes.

Autophagy 2022 07 29;18(7):1551-1571. Epub 2021 Dec 29.

Department of Pathology, University of Michigan, Ann Arbor, MI, USA.

Mice deficient in GHR (growth hormone receptor; KO) have a dramatic lifespan extension and elevated levels of hepatic chaperone-mediated autophagy (CMA). Using quantitative proteomics to identify protein changes in purified liver lysosomes and whole liver lysates, we provide evidence that elevated CMA in KO mice downregulates proteins involved in ribosomal structure, translation initiation and elongation, and nucleocytosolic acetyl-coA production. Following up on these initial proteomics findings, we used a cell culture approach to show that CMA is necessary and sufficient to regulate the abundance of ACLY and ACSS2, the two enzymes that produce nucleocytosolic (but not mitochondrial) acetyl-coA. Inhibition of CMA in NIH3T3 cells has been shown to lead to aberrant accumulation of lipid droplets. We show that this lipid droplet phenotype is rescued by knocking down ACLY or ACSS2, suggesting that CMA regulates lipid droplet formation by controlling ACLY and ACSS2. This evidence leads to a model of how constitutive activation of CMA can shape specific metabolic pathways in long-lived endocrine mutant mice. CMA: chaperone-mediated autophagy; DIA: data-independent acquisition; KO: growth hormone receptor knockout; GO: gene ontology; I-WAT: inguinal white adipose tissue; KFERQ: a consensus sequence resembling Lys-Phe-Glu-Arg-Gln; LAMP2A: lysosomal-associated membrane protein 2A; LC3-I: non-lipidated MAP1LC3; LC3-II: lipidated MAP1LC3; PBS: phosphate-buffered saline; PI3K: phosphoinositide 3-kinase.
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http://dx.doi.org/10.1080/15548627.2021.1990670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9298451PMC
July 2022

Gene-by-environment modulation of lifespan and weight gain in the murine BXD family.

Nat Metab 2021 09 22;3(9):1217-1227. Epub 2021 Sep 22.

Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center (UTHSC), Memphis, TN, USA.

How lifespan and body weight vary as a function of diet and genetic differences is not well understood. Here we quantify the impact of differences in diet on lifespan in a genetically diverse family of female mice, split into matched isogenic cohorts fed a low-fat chow diet (CD, n = 663) or a high-fat diet (HFD, n = 685). We further generate key metabolic data in a parallel cohort euthanized at four time points. HFD feeding shortens lifespan by 12%: equivalent to a decade in humans. Initial body weight and early weight gains account for longevity differences of roughly 4-6 days per gram. At 500 days, animals on a HFD typically gain four times as much weight as control, but variation in weight gain does not correlate with lifespan. Classic serum metabolites, often regarded as health biomarkers, are not necessarily strong predictors of longevity. Our data indicate that responses to a HFD are substantially modulated by gene-by-environment interactions, highlighting the importance of genetic variation in making accurate individualized dietary recommendations.
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http://dx.doi.org/10.1038/s42255-021-00449-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478125PMC
September 2021

Canagliflozin Increases Intestinal Adenoma Burden in Female ApcMin/+ Mice.

J Gerontol A Biol Sci Med Sci 2022 02;77(2):215-220

Department of Pathology, University of Michigan, Ann Arbor, USA.

The diabetes drug canagliflozin extends life span in male mice. Since malignant neoplasms are the major cause of death in most mouse strains, this observation suggests that canagliflozin might exert anti-neoplastic effects in male mice. Here, we treated a mouse neoplasia model, the adenoma-prone ApcMin/+ strain, with canagliflozin, to test the effects of this drug on intestinal tumor burden. Surprisingly, canagliflozin increased the total area of intestine involved by adenomas, an effect most marked in the distal intestine and in female mice. Immunohistochemical analysis suggested that canagliflozin may not influence adenoma growth via direct SGLT1/2 inhibition in neoplastic cells. Our results are most consistent with a model where canagliflozin aggravates adenoma development by altering the anatomic distribution of intestinal glucose absorption, as evidenced by increases in postprandial GLP-1 levels driven by delayed glucose absorption. We hypothesize that canagliflozin exacerbates adenomatosis in the ApcMin/+ model via complex, cell-non-autonomous mechanisms, and that sex differences in GLP-1 responses may in part underlie sexually dimorphic effects of this drug on life span.
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http://dx.doi.org/10.1093/gerona/glab254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8824675PMC
February 2022

The Prognostic Effect of Serum Albumin Level on Outcomes of Hospitalized COVID-19 Patients.

Crit Care Res Pract 2021 9;2021:9963274. Epub 2021 Jun 9.

Saint Michael's Medical Center, Newark, NJ, USA.

As SARS-CoV-2 continues to spread across the globe and significantly impacts health-care systems and strains resources, identifying prognostic factors to predict clinical outcome remains essential. We conducted a retrospective cohort study to further explore the prognostic value of serum hypoalbuminemia and other factors in hospitalized COVID-19 patients. The primary endpoint was defined as the risk of in-hospital mortality. 300 patients were included in the analysis, with 56% being male and a mean (±SD) age of 61.5 ± 15.3 years. The mean (±SD) albumin was 2.86 ± 0.5 g/dL. Our analysis showed that patients with in-hospital mortality had lower albumin levels than patients without in-hospital mortality (2.6 ± 0.49 vs. 2.9 ± 0.48 g/dL, respectively, with value = <0.001). A multivariant logistic regression analysis was subsequently conducted, and after adjustment, the serum albumin level remained a strong predictor of the primary outcome. Based on the data gathered, we were able to create a model predictive of mortality in this patient group based on the serum albumin level and other pertinent factors. In this model, with all other variables remaining constant, each one-unit increase in albumin is estimated to reduce the odds of mortality by 73%. Our results strengthen the current available data on the prognostic value of serum albumin in COVID-19 patients and provide a model to predict in-hospital mortality.
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http://dx.doi.org/10.1155/2021/9963274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339901PMC
June 2021

17-α-Estradiol Has Sex-Specific Effects on Neuroinflammation That Are Partly Reversed by Gonadectomy.

J Gerontol A Biol Sci Med Sci 2022 01;77(1):66-74

Department of Biological Sciences, Integrative Biosciences Center (IBio), Wayne State University, Detroit, Michigan, USA.

17-α-Estradiol (17aE2) treatment from 4 months of age extends life span in male mice and can reduce neuroinflammatory responses in the hypothalamus of 12-month-old males. Although 17aE2 improves longevity in males, female mice are unaffected, suggesting a sexually dimorphic pattern of life-span regulation. We tested whether the sex-specific effects of 17aE2 on neuroinflammatory responses are affected by gonadal removal and whether hypothalamic changes extend to other brain regions in old age. We show that sex-specific effects of 17aE2 on age-associated gliosis are brain region specific and are partially dependent on gonadectomy. 17aE2 treatment started at 4 months of age protected 25-month-old males from hypothalamic inflammation. Castration before 17aE2 exposure reduced the effect of 17aE2 on hypothalamic astrogliosis in males. In contrast, sex-specific inhibition of microgliosis generated by 17aE2 was not significantly affected by castration. In the hippocampus, gonadectomy influenced the severity of gliosis and the responsiveness to 17aE2 in a region-dependent manner. The male-specific effects of 17aE2 correlate with increases in hypothalamic estrogen receptor alpha expression, specifically in gonadally intact males, consistent with the idea that 17aE2 might act through this receptor. Our results indicate that neuroinflammatory responses to 17aE2 are partially controlled by the presence of sex-specific gonads. Loss of gonadal function and age-associated neuroinflammation could, therefore, influence late-life health and disease onset, leading to sexual dimorphism in both aging and in response to drugs that modify the pace of aging.
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http://dx.doi.org/10.1093/gerona/glab216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8751796PMC
January 2022

Dermatologic Applications of : A Literature Review.

J Clin Aesthet Dermatol 2021 Feb 1;14(2):50-60. Epub 2021 Feb 1.

Dr. Segars is with the Nova Southeastern University: College of Osteopathic Medicine and Largo Medical Center Department of Dermatology in Largo, Florida.

(PL) is a natural extract from tropical fern leaves with antioxidant and anti-inflammatory properties. It has been implicated as a potential treatment agent in multiple dermatologic conditions. Here, we review the mechanism of action and current dermatologic applications of PL and extrapolate potential future dermatologic applications of PL. An extensive literature review on Pubmed was conducted in search of relevant background information and human studies utilizing PL for the treatment of dermatologic conditions. Using the PubMed database, a literature search was conducted to identify relevant publications. was input as the key search criterion. The results were filtered by species (human) and language (English). Only papers with dermatologic applications were selected. Additionally, relevant publications found in the reference sections of selected articles were manually searched and selected. Included articles explore the origin, basic science mechanism, and various dermatologic applications of PL studied in humans. Each article was thoroughly studied by all authors and applicable data from each was used for the compilation of this review article. See Table 1 for a summary of dermatologic applications of PL based on available human clinical studies. There was a limited number of human studies concerning the use of PL for treatment of dermatologic conditions and, of the available studies, many were of a small sample size. PL has a clinically significant role for the treatment and prevention of certain dermatologic conditions including: photoprotection, photocarcinogenesis, photoaging, vitiligo, melasma, and polymorphic light eruption. There is supporting evidence for its use in malignant melanoma high-risk patients, for enhanced actinic keratosis clearance following photodynamic therapy, and for symptomatic relief in atopic dermatitis. Potential clinical uses that require additional human clinical studies include solar urticaria, post-inflammatory hyperpigmentation, cutaneous lupus erythematosus, and other photosensitive cutaneous disorders.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211346PMC
February 2021

A TORC1-histone axis regulates chromatin organisation and non-canonical induction of autophagy to ameliorate ageing.

Elife 2021 05 14;10. Epub 2021 May 14.

Max Planck Institute for Biology of Ageing, Cologne, Germany.

Age-related changes to histone levels are seen in many species. However, it is unclear whether changes to histone expression could be exploited to ameliorate the effects of ageing in multicellular organisms. Here we show that inhibition of mTORC1 by the lifespan-extending drug rapamycin increases expression of histones H3 and H4 post-transcriptionally through eIF3-mediated translation. Elevated expression of H3/H4 in intestinal enterocytes in alters chromatin organisation, induces intestinal autophagy through transcriptional regulation, and prevents age-related decline in the intestine. Importantly, it also mediates rapamycin-induced longevity and intestinal health. Histones H3/H4 regulate expression of an autophagy cargo adaptor Bchs (WDFY3 in mammals), increased expression of which in enterocytes mediates increased H3/H4-dependent healthy longevity. In mice, rapamycin treatment increases expression of histone proteins and transcription, and alters chromatin organisation in the small intestine, suggesting that the mTORC1-histone axis is at least partially conserved in mammals and may offer new targets for anti-ageing interventions.
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http://dx.doi.org/10.7554/eLife.62233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186904PMC
May 2021

17-a-estradiol late in life extends lifespan in aging UM-HET3 male mice; nicotinamide riboside and three other drugs do not affect lifespan in either sex.

Aging Cell 2021 05 31;20(5):e13328. Epub 2021 Mar 31.

Department of Pathology and Geriatrics Center, University of Michigan, Ann Arbor, MI, USA.

In genetically heterogeneous mice produced by the CByB6F1 x C3D2F1 cross, the "non-feminizing" estrogen, 17-α-estradiol (17aE2), extended median male lifespan by 19% (p < 0.0001, log-rank test) and 11% (p = 0.007) when fed at 14.4 ppm starting at 16 and 20 months, respectively. 90th percentile lifespans were extended 7% (p = 0.004, Wang-Allison test) and 5% (p = 0.17). Body weights were reduced about 20% after starting the 17aE2 diets. Four other interventions were tested in males and females: nicotinamide riboside, candesartan cilexetil, geranylgeranylacetone, and MIF098. Despite some data suggesting that nicotinamide riboside would be effective, neither it nor the other three increased lifespans significantly at the doses tested. The 17aE2 results confirm and extend our original reports, with very similar results when started at 16 months compared with mice started at 10 months of age in a prior study. The consistently large lifespan benefit in males, even when treatment is started late in life, may provide information on sex-specific aspects of aging.
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http://dx.doi.org/10.1111/acel.13328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8135004PMC
May 2021

CD4 receptor diversity represents an ancient protection mechanism against primate lentiviruses.

Proc Natl Acad Sci U S A 2021 03;118(13)

Lukuru Wildlife Research Foundation, Tshuapa-Lomami-Lualaba Project, BP 2012, Kinshasa, Democratic Republic of the Congo.

Infection with human and simian immunodeficiency viruses (HIV/SIV) requires binding of the viral envelope glycoprotein (Env) to the host protein CD4 on the surface of immune cells. Although invariant in humans, the Env binding domain of the chimpanzee CD4 is highly polymorphic, with nine coding variants circulating in wild populations. Here, we show that within-species CD4 diversity is not unique to chimpanzees but found in many African primate species. Characterizing the outermost (D1) domain of the CD4 protein in over 500 monkeys and apes, we found polymorphic residues in 24 of 29 primate species, with as many as 11 different coding variants identified within a single species. D1 domain amino acid replacements affected SIV Env-mediated cell entry in a single-round infection assay, restricting infection in a strain- and allele-specific fashion. Several identical CD4 polymorphisms, including the addition of -linked glycosylation sites, were found in primate species from different genera, providing striking examples of parallel evolution. Moreover, seven different guenons ( spp.) shared multiple distinct D1 domain variants, pointing to long-term trans-specific polymorphism. These data indicate that the HIV/SIV Env binding region of the primate CD4 protein is highly variable, both within and between species, and suggest that this diversity has been maintained by balancing selection for millions of years, at least in part to confer protection against primate lentiviruses. Although long-term SIV-infected species have evolved specific mechanisms to avoid disease progression, primate lentiviruses are intrinsically pathogenic and have left their mark on the host genome.
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http://dx.doi.org/10.1073/pnas.2025914118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020793PMC
March 2021

Cap-independent translation: A shared mechanism for lifespan extension by rapamycin, acarbose, and 17α-estradiol.

Aging Cell 2021 05 20;20(5):e13345. Epub 2021 Mar 20.

Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.

We hypothesized that rapamycin (Rapa), acarbose (ACA), which both increase mouse lifespan, and 17α-estradiol, which increases lifespan in males (17aE2) all share common intracellular signaling pathways with long-lived Snell dwarf, PAPPA-KO, and Ghr-/- mice. The long-lived mutant mice exhibit reduction in mTORC1 activity, declines in cap-dependent mRNA translation, and increases in cap-independent translation (CIT). Here, we report that Rapa and ACA prevent age-related declines in CIT target proteins in both sexes, while 17aE2 has the same effect only in males, suggesting increases in CIT. mTORC1 activity showed the reciprocal pattern, with age-related increases blocked by Rapa, ACA, and 17aE2 (in males only). METTL3, required for addition of 6-methyl-adenosine to mRNA and thus a trigger for CIT, also showed an age-dependent increase blunted by Rapa, ACA, and 17aE2 (in males). Diminution of mTORC1 activity and increases in CIT-dependent proteins may represent a shared pathway for both long-lived-mutant mice and drug-induced lifespan extension in mice.
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http://dx.doi.org/10.1111/acel.13345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8135077PMC
May 2021

Rapamycin-mediated mouse lifespan extension: Late-life dosage regimes with sex-specific effects.

Aging Cell 2020 11 4;19(11):e13269. Epub 2020 Nov 4.

The Jackson Laboratory, Bar Harbor, ME, USA.

To see if variations in timing of rapamycin (Rapa), administered to middle aged mice starting at 20 months, would lead to different survival outcomes, we compared three dosing regimens. Initiation of Rapa at 42 ppm increased survival significantly in both male and female mice. Exposure to Rapa for a 3-month period led to significant longevity benefit in males only. Protocols in which each month of Rapa treatment was followed by a month without Rapa exposure were also effective in both sexes, though this approach was less effective than continuous exposure in female mice. Interpretation of these results is made more complicated by unanticipated variation in patterns of weight gain, prior to the initiation of the Rapa treatment, presumably due to the use of drug-free food from two different suppliers. The experimental design included tests of four other drugs, minocycline, β-guanidinopropionic acid, MitoQ, and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), but none of these led to a change in survival in either sex.
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http://dx.doi.org/10.1111/acel.13269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681050PMC
November 2020

signatureSearch: environment for gene expression signature searching and functional interpretation.

Nucleic Acids Res 2020 12;48(21):e124

Institute for Integrative Genome Biology, 1207F Genomics Building, University of California, Riverside, CA 92521, USA.

signatureSearch is an R/Bioconductor package that integrates a suite of existing and novel algorithms into an analysis environment for gene expression signature (GES) searching combined with functional enrichment analysis (FEA) and visualization methods to facilitate the interpretation of the search results. In a typical GES search (GESS), a query GES is searched against a database of GESs obtained from large numbers of measurements, such as different genetic backgrounds, disease states and drug perturbations. Database matches sharing correlated signatures with the query indicate related cellular responses frequently governed by connected mechanisms, such as drugs mimicking the expression responses of a disease. To identify which processes are predominantly modulated in the GESS results, we developed specialized FEA methods combined with drug-target network visualization tools. The provided analysis tools are useful for studying the effects of genetic, chemical and environmental perturbations on biological systems, as well as searching single cell GES databases to identify novel network connections or cell types. The signatureSearch software is unique in that it provides access to an integrated environment for GESS/FEA routines that includes several novel search and enrichment methods, efficient data structures, and access to pre-built GES databases, and allowing users to work with custom databases.
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http://dx.doi.org/10.1093/nar/gkaa878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708038PMC
December 2020

Inhibition of class I PI3K enhances chaperone-mediated autophagy.

J Cell Biol 2020 12;219(12)

Department of Pathology, University of Michigan Medical School, Ann Arbor, MI.

Chaperone-mediated autophagy (CMA) is the most selective form of lysosomal proteolysis, where individual peptides, recognized by a consensus motif, are translocated directly across the lysosomal membrane. CMA regulates the abundance of many disease-related proteins, with causative roles in neoplasia, neurodegeneration, hepatosteatosis, and other pathologies relevant to human health and aging. At the lysosomal membrane, CMA is inhibited by Akt-dependent phosphorylation of the CMA regulator GFAP. The INS-PI3K-PDPK1 pathway regulates Akt, but its role in CMA is unclear. Here, we report that inhibition of class I PI3K or PDPK1 activates CMA. In contrast, selective inhibition of class III PI3Ks does not activate CMA. Isolated liver lysosomes from mice treated with either of two orally bioavailable class I PI3K inhibitors, pictilisib or buparlisib, display elevated CMA activity, and decreased phosphorylation of lysosomal GFAP, with no change in macroautophagy. The findings of this study represent an important first step in repurposing class I PI3K inhibitors to modulate CMA in vivo.
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http://dx.doi.org/10.1083/jcb.202001031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557678PMC
December 2020

High-throughput small molecule screening reveals Nrf2-dependent and -independent pathways of cellular stress resistance.

Sci Adv 2020 10 2;6(40). Epub 2020 Oct 2.

Department of Pathology, University of Michigan, Ann Arbor, MI, USA.

Aging is the dominant risk factor for most chronic diseases. Development of antiaging interventions offers the promise of preventing many such illnesses simultaneously. Cellular stress resistance is an evolutionarily conserved feature of longevity. Here, we identify compounds that induced resistance to the superoxide generator paraquat (PQ), the heavy metal cadmium (Cd), and the DNA alkylator methyl methanesulfonate (MMS). Some rescue compounds conferred resistance to a single stressor, while others provoked multiplex resistance. Induction of stress resistance in fibroblasts was predictive of longevity extension in a published large-scale longevity screen in , although not in testing performed in worms and flies with a more restricted set of compounds. Transcriptomic analysis and genetic studies implicated Nrf2/SKN-1 signaling in stress resistance provided by two protective compounds, cardamonin and AEG 3482. Small molecules identified in this work may represent attractive tools to elucidate mechanisms of stress resistance in mammalian cells.
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http://dx.doi.org/10.1126/sciadv.aaz7628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852388PMC
October 2020

Targeting the A2AR in cancer; early lessons from the clinic.

Curr Opin Pharmacol 2020 08 29;53:126-133. Epub 2020 Sep 29.

Corvus Pharmaceuticals, Burlingame, CA 94010, United States.

The immunosuppressive tumor microenvironment (TME) represents a challenge that all immunotherapies must overcome to enable a robust and durable anti-tumor response. One of the dominant mechanisms of immunosuppression in the TME is hypoxia and the generation of extracellular adenosine [1]. Pioneering work from Drs Ohta and Sitkovsky demonstrating that adenosine signaling through the adenosine 2A receptor (A2AR) inhibits T cells has led to the development of several agents designed to inhibit the production or downstream signaling of adenosine [2,3]. This review will focus on the safety, efficacy, and biomarkers associated with A2AR antagonists in clinical development.
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http://dx.doi.org/10.1016/j.coph.2020.08.003DOI Listing
August 2020

Acarbose has sex-dependent and -independent effects on age-related physical function, cardiac health, and lipid biology.

JCI Insight 2020 11 5;5(21). Epub 2020 Nov 5.

Department of Pathology, UM Medical School, Ann Arbor, Michigan, USA.

With an expanding aging population burdened with comorbidities, there is considerable interest in treatments that optimize health in later life. Acarbose (ACA), a drug used clinically to treat type 2 diabetes mellitus (T2DM), can extend mouse life span with greater effect in males than in females. Using a genetically heterogeneous mouse model, we tested the ability of ACA to ameliorate functional, pathological, and biochemical changes that occur during aging, and we determined which of the effects of age and drug were sex dependent. In both sexes, ACA prevented age-dependent loss of body mass, in addition to improving balance/coordination on an accelerating rotarod, rotarod endurance, and grip strength test. Age-related cardiac hypertrophy was seen only in male mice, and this male-specific aging effect was attenuated by ACA. ACA-sensitive cardiac changes were associated with reduced activation of cardiac growth-promoting pathways and increased abundance of peroxisomal proteins involved in lipid metabolism. ACA further ameliorated age-associated changes in cardiac lipid species, particularly lysophospholipids - changes that have previously been associated with aging, cardiac dysfunction, and cardiovascular disease in humans. In the liver, ACA had pronounced effects on lipid handling in both sexes, reducing hepatic lipidosis during aging and shifting the liver lipidome in adulthood, particularly favoring reduced triglyceride (TAG) accumulation. Our results demonstrate that ACA, already in clinical use for T2DM, has broad-ranging antiaging effects in multiple tissues, and it may have the potential to increase physical function and alter lipid biology to preserve or improve health at older ages.
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http://dx.doi.org/10.1172/jci.insight.137474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710286PMC
November 2020

Canagliflozin extends life span in genetically heterogeneous male but not female mice.

JCI Insight 2020 11 5;5(21). Epub 2020 Nov 5.

Sam and Ann Barshop Institute for Longevity and Aging Studies and Departments of Physiology and Molecular Medicine, UT Health San Antonio, San Antonio, Texas, USA; South Texas Veterans Healthcare System, San Antonio, Texas, USA.

Canagliflozin (Cana) is an FDA-approved diabetes drug that protects against cardiovascular and kidney diseases. It also inhibits the sodium glucose transporter 2 by blocking renal reuptake and intestinal absorption of glucose. In the context of the mouse Interventions Testing Program, genetically heterogeneous mice were given chow containing Cana at 180 ppm at 7 months of age until their death. Cana extended median survival of male mice by 14%. Cana also increased by 9% the age for 90th percentile survival, with parallel effects seen at each of 3 test sites. Neither the distribution of inferred cause of death nor incidental pathology findings at end-of-life necropsies were altered by Cana. Moreover, although no life span benefits were seen in female mice, Cana led to lower fasting glucose and improved glucose tolerance in both sexes, diminishing fat mass in females only. Therefore, the life span benefit of Cana is likely to reflect blunting of peak glucose levels, because similar longevity effects are seen in male mice given acarbose, a diabetes drug that blocks glucose surges through a distinct mechanism, i.e., slowing breakdown of carbohydrate in the intestine. Interventions that control daily peak glucose levels deserve attention as possible preventive medicines to protect from a wide range of late-life neoplastic and degenerative diseases.
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http://dx.doi.org/10.1172/jci.insight.140019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710304PMC
November 2020

Muscle-dependent regulation of adipose tissue function in long-lived growth hormone-mutant mice.

Aging (Albany NY) 2020 05 28;12(10):8766-8789. Epub 2020 May 28.

Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.

Altered adipose tissue may contribute to the longevity of Snell dwarf and growth hormone receptor (GHR) knock-out mice. We report here that white (WAT) and brown (BAT) fat have elevated UCP1 in both kinds of mice, and that adipocytes in WAT depots turn beige/brown. These imply increased thermogenesis and are expected to lead to improved glucose control. Both kinds of long-lived mice show lower levels of inflammatory M1 macrophages and higher levels of anti-inflammatory M2 macrophages in BAT and WAT, with correspondingly lower levels of TNFα, IL-6, and MCP1. Experiments with mice with tissue-specific disruption of GHR showed that these adipocyte and macrophage changes were not due to hepatic IGF1 production nor to direct GH effects on adipocytes, but instead reflect GH effects on muscle. Muscles deprived of GH signals, either globally (GKO) or in muscle only (MKO), produce higher levels of circulating irisin and its precursor FNDC5. The data thus suggest that the changes in adipose tissue differentiation and inflammatory status seen in long-lived mutant mice reflect interruption of GH-dependent irisin inhibition, with consequential effects on metabolism and thermogenesis.
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http://dx.doi.org/10.18632/aging.103380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288969PMC
May 2020

A Rare Case of Cutis Verticis Gyrata with Underlying Cerebriform Intradermal Nevus.

Cureus 2019 Dec 29;11(12):e6499. Epub 2019 Dec 29.

Dermatology, Hospital Corporation of America/University of South Florida, Morsani College of Medicine, Largo Medical Center Program, Largo, USA.

Cutis verticis gyrata (CVG) is an uncommon condition of the scalp known for redundant, thickened folds, which emulate the cerebral gyri of the brain. This unusual finding is catalogued as primary essential, primary non-essential, and secondary. While primary essential CVG is an isolated and idiopathic condition, primary non-essential CVG is deemed to be related to neurological, ophthalmological, or psychiatric disorders. Secondary CVG may be due to a variety of systemic disorders, inflammatory dermatoses, or cutaneous neoplasms or infiltrates. This report serves as an example of secondary CVG due to a cerebriform intradermal nevus, with specific focus on clinical course, treatment options, and critical screening guidelines for these patients.
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http://dx.doi.org/10.7759/cureus.6499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988481PMC
December 2019

Long-lived mice with reduced growth hormone signaling have a constitutive upregulation of hepatic chaperone-mediated autophagy.

Autophagy 2021 03 12;17(3):612-625. Epub 2020 Feb 12.

Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.

Chaperone-mediated autophagy (CMA) is the most selective form of lysosomal proteolysis. CMA modulates proteomic organization through selective protein degradation, with targets including metabolic enzymes, cell growth regulators, and neurodegeneration-related proteins. CMA activity is low in -fed rodents but is increased by prolonged fasting. AKT negatively regulates CMA at the lysosomal membrane by phosphorylating and inhibiting the CMA regulator GFAP. We have previously reported that long-lived mutant (Snell) mice and (growth hormone receptor) knockout mice ( KO) have lower AKT activity when fed compared to littermate controls, suggesting the hypothesis that these mice have increased baseline CMA activity. Here, we report that liver lysosomes from fed Snell dwarf mice and KO mice have decreased GFAP phosphorylation and increased CMA substrate uptake activity. Liver lysosomes isolated from fed Snell dwarf mice and KO mice injected with the protease inhibitor leupeptin had increased accumulation of endogenous CMA substrates, compared to littermate controls, suggesting an increase in CMA . Mice with liver-specific ablation of GH (growth hormone) signaling did not have increased liver CMA, suggesting that a signaling effect resulting from a loss of growth hormone in another tissue causes enhanced CMA in Snell dwarf and KO mice. Finally, we find Snell dwarf mice have decreased protein levels (in liver and kidney) of CIP2A, a well-characterized CMA target protein, without an associated change in mRNA. Collectively, these data suggest that CMA is enhanced downstream of an endocrine change resulting from whole-body ablation of GH signaling. CMA: chaperone-mediated autophagy; GH: growth hormone; KO: growth hormone receptor knockout; LAMP2A: splice variant 1 of transcript; LC3-I: non-lipidated MAP1LC3; LC3-II: lipidated MAP1LC3; Li KO: liver-specific knockout; MA: macroautophagy; MTORC1: mechanistic target of rapamycin kinase complex 1; MTORC2: mechanistic target of rapamycin kinase complex 2; PBS: phosphate-buffered saline.
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http://dx.doi.org/10.1080/15548627.2020.1725378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032237PMC
March 2021

Adenosine 2A Receptor Blockade as an Immunotherapy for Treatment-Refractory Renal Cell Cancer.

Cancer Discov 2020 01 15;10(1):40-53. Epub 2019 Nov 15.

Corvus Pharmaceuticals, Burlingame, California.

Adenosine mediates immunosuppression within the tumor microenvironment through triggering adenosine 2A receptors (A2AR) on immune cells. To determine whether this pathway could be targeted as an immunotherapy, we performed a phase I clinical trial with a small-molecule A2AR antagonist. We find that this molecule can safely block adenosine signaling . In a cohort of 68 patients with renal cell cancer (RCC), we also observe clinical responses alone and in combination with an anti-PD-L1 antibody, including subjects who had progressed on PD-1/PD-L1 inhibitors. Durable clinical benefit is associated with increased recruitment of CD8 T cells into the tumor. Treatment can also broaden the circulating T-cell repertoire. Clinical responses are associated with an adenosine-regulated gene-expression signature in pretreatment tumor biopsies. A2AR signaling, therefore, represents a targetable immune checkpoint distinct from PD-1/PD-L1 that restricts antitumor immunity. SIGNIFICANCE: This first-in-human study of an A2AR antagonist for cancer treatment establishes the safety and feasibility of targeting this pathway by demonstrating antitumor activity with single-agent and anti-PD-L1 combination therapy in patients with refractory RCC. Responding patients possess an adenosine-regulated gene-expression signature in pretreatment tumor biopsies...
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http://dx.doi.org/10.1158/2159-8290.CD-19-0980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954326PMC
January 2020
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