The potential for using MRI technologies to visualize amyloid deposits has been increasingly reco... more The potential for using MRI technologies to visualize amyloid deposits has been increasingly recognized. The present study utilized a New World non‐human primate (NHP) model of amyloid pathology, squirrel monkey (SQM), which unlike other NHPs, develops age‐dependent abundant cerebral amyloid angiopathy (CAA). The transverse relaxation rate (R2*) has a linear correlation with iron content, a component of amyloid deposits and microhemorrhages. Here we assessed whether the region of interest (ROI)‐based quantitative R2* assessment is able to detect differences in SQM neuropathology between varying age cohorts as well as longitudinally. An additional focus was to examine the presence of naturally occurring ARIA‐E like pathologies in geriatric SQMs.
Diabetes mellitus (DM) is a group of chronic metabolic diseases characterized by persistent fasti... more Diabetes mellitus (DM) is a group of chronic metabolic diseases characterized by persistent fasting hyperglycemia, and it can be of either polygenic or monogenic origin. Animal models have played an important role in elucidating the pathophysiology of the polygenic Type 1 and type 2 DM forms; however, useful animal models of the monogenic forms do not exist. The authors describe 4 cases of naturally occurring DM in vervet monkeys ( Chlorocebus aethiops sabaeus), 1 of which has clinicopathologic findings consistent with type 2 DM, including persistent hyperglycemia, hypertriglyceridemia, islet amyloidosis, and reduced islet insulin immunostaining. In contrast, the 3 remaining animals have clinicopathologic similarities to a monogenic form of the disease, including a lack of islet amyloidosis and hypertriglyceridemia, as well as normal islet insulin immunostaining. In addition, pedigree analysis conducted on one of these animals is consistent with either an autosomal dominant or mitoc...
A 6-year-old adult male rhesus macaque (Macaca mulatta) developed a vasocutaneous fistula followi... more A 6-year-old adult male rhesus macaque (Macaca mulatta) developed a vasocutaneous fistula following an anatomic inguinal hernia repair years earlier. The vasocutaneous fistula was surgically repaired, the vas deferens was ligated, and the wound was closed in layers with non-overlapping suture lines with no further adverse sequalae of events.
Tumor necrosis factor is a cytokine that plays critical roles in inflammation, the innate immune ... more Tumor necrosis factor is a cytokine that plays critical roles in inflammation, the innate immune response, and a variety of other physiologic and pathophysiologic processes. In addition, TNF has recently been shown to mediate an intersection of chronic, low-grade inflammation and concurrent metabolic dysregulation associated with obesity and its comorbidities. As part of an ongoing initiative to further characterize vervet monkeys originating from St Kitts as an animal model of obesity and inflammation, we sequenced and genotyped the human ortholog vervet TNF gene and approximately 1 kb of the flanking 3' and 5' regions from 265 monkeys in a closed, pedigreed colony. This process revealed a total of 11 single-nucleotide polymorphisms (SNPs) and a single 4-bp insertion-deletion, with minor allele frequencies of 0.08 to 0.39. Many of these polymorphisms were in strong or complete linkage disequilibrium with each other, and all but 1 were contained within a single haplotype blo...
Colorectal cancer (CRC) remains the third most common cancer in the US with 15% of cases displayi... more Colorectal cancer (CRC) remains the third most common cancer in the US with 15% of cases displaying Microsatellite Instability (MSI) secondary to Lynch Syndrome (LS) or somatic hypermethylation of the MLH1 promoter. A cohort of rhesus macaques from our institution developed spontaneous mismatch repair deficient (MMRd) CRC with a notable fraction harboring a pathogenic germline mutation in MLH1 (c.1029C<G, p.Tyr343Ter). Our study incorporated a detailed molecular characterization of rhesus CRC for cross-comparison with human MMRd CRC. We performed PCR-based MSI testing, transcriptomic analysis, and reduced-representation bisulfite sequencing (RRBS) of rhesus CRC (n=41 samples) using next-generation sequencing (NGS). Systems biology pipelines were used for gene set enrichment analysis (GSEA) for pathway discovery, consensus molecular subtyping (CMS), and somatic mutation profiling. Overall, the majority of rhesus tumors displayed high levels of MSI (MSI-high) and differential gene ...
The rhesus macaque (Macaca mulatta) is the most widely studied nonhuman primate (NHP) in biomedic... more The rhesus macaque (Macaca mulatta) is the most widely studied nonhuman primate (NHP) in biomedical research. We present an updated reference genome assembly (Mmul_10, contig N50 = 46 Mbp) that increases the sequence contiguity 120-fold and annotate it using 6.5 million full-length transcripts, thus improving our understanding of gene content, isoform diversity, and repeat organization. With the improved assembly of segmental duplications, we discovered new lineage-specific genes and expanded gene families that are potentially informative in studies of evolution and disease susceptibility. Whole-genome sequencing (WGS) data from 853 rhesus macaques identified 85.7 million single-nucleotide variants (SNVs) and 10.5 million indel variants, including potentially damaging variants in genes associated with human autism and developmental delay, providing a framework for developing noninvasive NHP models of human disease.
Hemangiosarcoma is a malignant tumor of vascular endothelial origin that is sporadically reported... more Hemangiosarcoma is a malignant tumor of vascular endothelial origin that is sporadically reported in rhesus macaques. This report describes the clinicopathologic features of a 1-y-old rhesus macaque with spontaneous disseminated hemangiosarcoma that originally presented as a focal cutaneous mass. Histopathologic examination of multiple tumor foci revealed regions in which the neoplastic cells formed diffuse sheets, as well as the well-defined vascular channels typically associated with hemangiosarcoma. Multiple endothelial cell immunomarkers were used to confirm the diagnosis in this rhesus macaque. The tumor exhibited staining properties consistent with those seen in domestic animals and humans. In addition, to our knowledge, this animal represents the youngest case of any form of spontaneous hemangiosarcoma reported in the rhesus macaque to date.
Chagas disease is a zoonotic vector-borne disease caused by infection with the protozoan parasite... more Chagas disease is a zoonotic vector-borne disease caused by infection with the protozoan parasite Trypanosoma cruzi. T. cruzi is found in Latin America and the Southern United States, where it infects many species, including humans and nonhuman primates (NHPs). NHPs are susceptible to natural infection and can develop clinical symptoms consistent with human disease, including Chagasic cardiomyopathy, gastrointestinal disease and transplacental transmission, leading to congenital infection. Due to evidence of Chagas transmission in Texas, this study hypothesized T. cruzi infection was present in a closed, outdoor-housed breeding colony of rhesus macaques (Macaca mulatta) located at a biomedical research facility in Central Texas. In addition, we questioned whether seropositive female rhesus macaques might experience reproductive complications consistent with maternal-fetal Chagas disease. The seroprevalence of T. cruzi infection in the colony was assessed using an Enzyme Linked Immun...
Colorectal cancer accounts for a substantial number of deaths each year worldwide. Lynch Syndrome... more Colorectal cancer accounts for a substantial number of deaths each year worldwide. Lynch Syndrome is a genetic form of colorectal cancer (CRC) caused by inherited mutations in DNA mismatch repair (MMR) genes. Although researchers have developed mouse models of Lynch Syndrome through targeted mutagenesis of MMR genes, the tumors that result differ in important ways from those in Lynch Syndrome patients. We identified 60 cases of CRC in rhesus macaques () at our facility since 2001. The tumors occur at the ileocecal junction, cecum and proximal colon and display clinicopathologic features similar to human Lynch Syndrome. We conducted immunohistochemical analysis of CRC tumors from several rhesus macaques, finding they frequently lack expression of MLH1 and PMS2 proteins, both critical MMR proteins involved in Lynch Syndrome. We also found that most macaque cases we tested exhibit microsatellite instability, a defining feature of Lynch Syndrome. Whole genome sequencing of rhesus macaqu...
Hemangiosarcoma is a malignant tumor of vascular endothelial origin that is sporadically reported... more Hemangiosarcoma is a malignant tumor of vascular endothelial origin that is sporadically reported in rhesus macaques. This report describes the clinicopathologic features of a 1-y-old rhesus macaque with spontaneous disseminated hemangiosarcoma that originally presented as a focal cutaneous mass. Histopathologic examination of multiple tumor foci revealed regions in which the neoplastic cells formed diffuse sheets, as well as the well-defined vascular channels typically associated with hemangiosarcoma. Multiple endothelial cell immunomarkers were used to confirm the diagnosis in this rhesus macaque. The tumor exhibited staining properties consistent with those seen in domestic animals and humans. In addition, to our knowledge, this animal represents the youngest case of any form of spontaneous hemangiosarcoma reported in the rhesus macaque to date.
... V. CLINICOPATHOLOGIC CHARACTERIZATION OF NATURALLY OCCURRING DIABETES MELLITUS IN VERVET MONK... more ... V. CLINICOPATHOLOGIC CHARACTERIZATION OF NATURALLY OCCURRING DIABETES MELLITUS IN VERVET MONKEYS ... This revealed a total of 11 single nucleotide polymorphisms (SNPs), ... variation in body weight may be determined by genetic factors in humans ...
Specific pathogen free (SPF) macaques provide valuable animal models for biomedical research. In ... more Specific pathogen free (SPF) macaques provide valuable animal models for biomedical research. In 1989, the National Center for Research Resources [now Office of Research Infrastructure Programs (ORIP)] of the National Institutes of Health initiated experimental research contracts to establish and maintain SPF colonies. The derivation and maintenance of SPF macaque colonies is a complex undertaking requiring knowledge of the biology of the agents for exclusion and normal physiology and behavior of macaques, application of the latest diagnostic technology, facilitiy management, and animal husbandry. This review provides information on the biology of the four viral agents targeted for exclusion in ORIP SPF macaque colonies, describes current state-of-the-art viral diagnostic algorithms, presents data from proficiency testing of diagnostic assays between laboratories at institutions participating in the ORIP SPF program, and outlines management strategies for maintaining the integrity o...
Tumor necrosis factor is a cytokine that plays critical roles in inflammation, the innate immune ... more Tumor necrosis factor is a cytokine that plays critical roles in inflammation, the innate immune response, and a variety of other physiologic and pathophysiologic processes. In addition, TNF has recently been shown to mediate an intersection of chronic, low-grade inflammation and concurrent metabolic dysregulation associated with obesity and its comorbidities. As part of an ongoing initiative to further characterize vervet monkeys originating from St Kitts as an animal model of obesity and inflammation, we sequenced and genotyped the human ortholog vervet TNF gene and approximately 1 kb of the flanking 3' and 5' regions from 265 monkeys in a closed, pedigreed colony. This process revealed a total of 11 single-nucleotide polymorphisms (SNPs) and a single 4-bp insertion-deletion, with minor allele frequencies of 0.08 to 0.39. Many of these polymorphisms were in strong or complete linkage disequilibrium with each other, and all but 1 were contained within a single haplotype blo...
The potential for using MRI technologies to visualize amyloid deposits has been increasingly reco... more The potential for using MRI technologies to visualize amyloid deposits has been increasingly recognized. The present study utilized a New World non‐human primate (NHP) model of amyloid pathology, squirrel monkey (SQM), which unlike other NHPs, develops age‐dependent abundant cerebral amyloid angiopathy (CAA). The transverse relaxation rate (R2*) has a linear correlation with iron content, a component of amyloid deposits and microhemorrhages. Here we assessed whether the region of interest (ROI)‐based quantitative R2* assessment is able to detect differences in SQM neuropathology between varying age cohorts as well as longitudinally. An additional focus was to examine the presence of naturally occurring ARIA‐E like pathologies in geriatric SQMs.
Diabetes mellitus (DM) is a group of chronic metabolic diseases characterized by persistent fasti... more Diabetes mellitus (DM) is a group of chronic metabolic diseases characterized by persistent fasting hyperglycemia, and it can be of either polygenic or monogenic origin. Animal models have played an important role in elucidating the pathophysiology of the polygenic Type 1 and type 2 DM forms; however, useful animal models of the monogenic forms do not exist. The authors describe 4 cases of naturally occurring DM in vervet monkeys ( Chlorocebus aethiops sabaeus), 1 of which has clinicopathologic findings consistent with type 2 DM, including persistent hyperglycemia, hypertriglyceridemia, islet amyloidosis, and reduced islet insulin immunostaining. In contrast, the 3 remaining animals have clinicopathologic similarities to a monogenic form of the disease, including a lack of islet amyloidosis and hypertriglyceridemia, as well as normal islet insulin immunostaining. In addition, pedigree analysis conducted on one of these animals is consistent with either an autosomal dominant or mitoc...
A 6-year-old adult male rhesus macaque (Macaca mulatta) developed a vasocutaneous fistula followi... more A 6-year-old adult male rhesus macaque (Macaca mulatta) developed a vasocutaneous fistula following an anatomic inguinal hernia repair years earlier. The vasocutaneous fistula was surgically repaired, the vas deferens was ligated, and the wound was closed in layers with non-overlapping suture lines with no further adverse sequalae of events.
Tumor necrosis factor is a cytokine that plays critical roles in inflammation, the innate immune ... more Tumor necrosis factor is a cytokine that plays critical roles in inflammation, the innate immune response, and a variety of other physiologic and pathophysiologic processes. In addition, TNF has recently been shown to mediate an intersection of chronic, low-grade inflammation and concurrent metabolic dysregulation associated with obesity and its comorbidities. As part of an ongoing initiative to further characterize vervet monkeys originating from St Kitts as an animal model of obesity and inflammation, we sequenced and genotyped the human ortholog vervet TNF gene and approximately 1 kb of the flanking 3' and 5' regions from 265 monkeys in a closed, pedigreed colony. This process revealed a total of 11 single-nucleotide polymorphisms (SNPs) and a single 4-bp insertion-deletion, with minor allele frequencies of 0.08 to 0.39. Many of these polymorphisms were in strong or complete linkage disequilibrium with each other, and all but 1 were contained within a single haplotype blo...
Colorectal cancer (CRC) remains the third most common cancer in the US with 15% of cases displayi... more Colorectal cancer (CRC) remains the third most common cancer in the US with 15% of cases displaying Microsatellite Instability (MSI) secondary to Lynch Syndrome (LS) or somatic hypermethylation of the MLH1 promoter. A cohort of rhesus macaques from our institution developed spontaneous mismatch repair deficient (MMRd) CRC with a notable fraction harboring a pathogenic germline mutation in MLH1 (c.1029C<G, p.Tyr343Ter). Our study incorporated a detailed molecular characterization of rhesus CRC for cross-comparison with human MMRd CRC. We performed PCR-based MSI testing, transcriptomic analysis, and reduced-representation bisulfite sequencing (RRBS) of rhesus CRC (n=41 samples) using next-generation sequencing (NGS). Systems biology pipelines were used for gene set enrichment analysis (GSEA) for pathway discovery, consensus molecular subtyping (CMS), and somatic mutation profiling. Overall, the majority of rhesus tumors displayed high levels of MSI (MSI-high) and differential gene ...
The rhesus macaque (Macaca mulatta) is the most widely studied nonhuman primate (NHP) in biomedic... more The rhesus macaque (Macaca mulatta) is the most widely studied nonhuman primate (NHP) in biomedical research. We present an updated reference genome assembly (Mmul_10, contig N50 = 46 Mbp) that increases the sequence contiguity 120-fold and annotate it using 6.5 million full-length transcripts, thus improving our understanding of gene content, isoform diversity, and repeat organization. With the improved assembly of segmental duplications, we discovered new lineage-specific genes and expanded gene families that are potentially informative in studies of evolution and disease susceptibility. Whole-genome sequencing (WGS) data from 853 rhesus macaques identified 85.7 million single-nucleotide variants (SNVs) and 10.5 million indel variants, including potentially damaging variants in genes associated with human autism and developmental delay, providing a framework for developing noninvasive NHP models of human disease.
Hemangiosarcoma is a malignant tumor of vascular endothelial origin that is sporadically reported... more Hemangiosarcoma is a malignant tumor of vascular endothelial origin that is sporadically reported in rhesus macaques. This report describes the clinicopathologic features of a 1-y-old rhesus macaque with spontaneous disseminated hemangiosarcoma that originally presented as a focal cutaneous mass. Histopathologic examination of multiple tumor foci revealed regions in which the neoplastic cells formed diffuse sheets, as well as the well-defined vascular channels typically associated with hemangiosarcoma. Multiple endothelial cell immunomarkers were used to confirm the diagnosis in this rhesus macaque. The tumor exhibited staining properties consistent with those seen in domestic animals and humans. In addition, to our knowledge, this animal represents the youngest case of any form of spontaneous hemangiosarcoma reported in the rhesus macaque to date.
Chagas disease is a zoonotic vector-borne disease caused by infection with the protozoan parasite... more Chagas disease is a zoonotic vector-borne disease caused by infection with the protozoan parasite Trypanosoma cruzi. T. cruzi is found in Latin America and the Southern United States, where it infects many species, including humans and nonhuman primates (NHPs). NHPs are susceptible to natural infection and can develop clinical symptoms consistent with human disease, including Chagasic cardiomyopathy, gastrointestinal disease and transplacental transmission, leading to congenital infection. Due to evidence of Chagas transmission in Texas, this study hypothesized T. cruzi infection was present in a closed, outdoor-housed breeding colony of rhesus macaques (Macaca mulatta) located at a biomedical research facility in Central Texas. In addition, we questioned whether seropositive female rhesus macaques might experience reproductive complications consistent with maternal-fetal Chagas disease. The seroprevalence of T. cruzi infection in the colony was assessed using an Enzyme Linked Immun...
Colorectal cancer accounts for a substantial number of deaths each year worldwide. Lynch Syndrome... more Colorectal cancer accounts for a substantial number of deaths each year worldwide. Lynch Syndrome is a genetic form of colorectal cancer (CRC) caused by inherited mutations in DNA mismatch repair (MMR) genes. Although researchers have developed mouse models of Lynch Syndrome through targeted mutagenesis of MMR genes, the tumors that result differ in important ways from those in Lynch Syndrome patients. We identified 60 cases of CRC in rhesus macaques () at our facility since 2001. The tumors occur at the ileocecal junction, cecum and proximal colon and display clinicopathologic features similar to human Lynch Syndrome. We conducted immunohistochemical analysis of CRC tumors from several rhesus macaques, finding they frequently lack expression of MLH1 and PMS2 proteins, both critical MMR proteins involved in Lynch Syndrome. We also found that most macaque cases we tested exhibit microsatellite instability, a defining feature of Lynch Syndrome. Whole genome sequencing of rhesus macaqu...
Hemangiosarcoma is a malignant tumor of vascular endothelial origin that is sporadically reported... more Hemangiosarcoma is a malignant tumor of vascular endothelial origin that is sporadically reported in rhesus macaques. This report describes the clinicopathologic features of a 1-y-old rhesus macaque with spontaneous disseminated hemangiosarcoma that originally presented as a focal cutaneous mass. Histopathologic examination of multiple tumor foci revealed regions in which the neoplastic cells formed diffuse sheets, as well as the well-defined vascular channels typically associated with hemangiosarcoma. Multiple endothelial cell immunomarkers were used to confirm the diagnosis in this rhesus macaque. The tumor exhibited staining properties consistent with those seen in domestic animals and humans. In addition, to our knowledge, this animal represents the youngest case of any form of spontaneous hemangiosarcoma reported in the rhesus macaque to date.
... V. CLINICOPATHOLOGIC CHARACTERIZATION OF NATURALLY OCCURRING DIABETES MELLITUS IN VERVET MONK... more ... V. CLINICOPATHOLOGIC CHARACTERIZATION OF NATURALLY OCCURRING DIABETES MELLITUS IN VERVET MONKEYS ... This revealed a total of 11 single nucleotide polymorphisms (SNPs), ... variation in body weight may be determined by genetic factors in humans ...
Specific pathogen free (SPF) macaques provide valuable animal models for biomedical research. In ... more Specific pathogen free (SPF) macaques provide valuable animal models for biomedical research. In 1989, the National Center for Research Resources [now Office of Research Infrastructure Programs (ORIP)] of the National Institutes of Health initiated experimental research contracts to establish and maintain SPF colonies. The derivation and maintenance of SPF macaque colonies is a complex undertaking requiring knowledge of the biology of the agents for exclusion and normal physiology and behavior of macaques, application of the latest diagnostic technology, facilitiy management, and animal husbandry. This review provides information on the biology of the four viral agents targeted for exclusion in ORIP SPF macaque colonies, describes current state-of-the-art viral diagnostic algorithms, presents data from proficiency testing of diagnostic assays between laboratories at institutions participating in the ORIP SPF program, and outlines management strategies for maintaining the integrity o...
Tumor necrosis factor is a cytokine that plays critical roles in inflammation, the innate immune ... more Tumor necrosis factor is a cytokine that plays critical roles in inflammation, the innate immune response, and a variety of other physiologic and pathophysiologic processes. In addition, TNF has recently been shown to mediate an intersection of chronic, low-grade inflammation and concurrent metabolic dysregulation associated with obesity and its comorbidities. As part of an ongoing initiative to further characterize vervet monkeys originating from St Kitts as an animal model of obesity and inflammation, we sequenced and genotyped the human ortholog vervet TNF gene and approximately 1 kb of the flanking 3' and 5' regions from 265 monkeys in a closed, pedigreed colony. This process revealed a total of 11 single-nucleotide polymorphisms (SNPs) and a single 4-bp insertion-deletion, with minor allele frequencies of 0.08 to 0.39. Many of these polymorphisms were in strong or complete linkage disequilibrium with each other, and all but 1 were contained within a single haplotype blo...
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Papers by Stanton Gray