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Biomedical subjects

Richard Miller

Publications and source records attributed to Richard Miller.

At least 19 recordsLinked to original sources
PubMed2026

Proportionality-based association metrics in count compositional data.

Compositional data comprise vectors that describe the constituent parts of a whole. Data arising from various -omics platforms such as 16S and RNA sequencing are compositional in nature. In this kind of data, correlations between features on raw counts have no meaningful interpretation. Metrics of proportionality were formulated to address this problem. However, an inherent bias arises when these metrics are calculated empirically on count-based measures due to variability in read depths. We quantify the bias introduced by empirically calculating proportionality-based association metrics in count data. Additionally, we propose a means of estimating these metrics within a logit-normal multinomial model in pursuit of more accurate estimates. The model-based estimates are shown to outperform empirical estimates in simulated data and are applied to a mouse embryonic stem cell single-cell sequencing dataset, as well as a pediatric-onset multiple sclerosis metagenomic dataset.

Animals↗
PubMed2025

Extensive longevity and DNA virus-driven adaptation in nearctic Myotis bats.

The genus Myotis is one of the largest clades of bats, and exhibits some of the most extreme variation in lifespans among mammals alongside unique adaptations to viral tolerance and immune defense. To study the evolution of longevity-associated traits and infectious disease, we generated cell lines and near-complete genome assemblies for 8 closely related species of Myotis. Using genome-wide screens of positive selection, analyses of structural variation, and functional experiments in primary cells, we identify new patterns of adaptation contributing to longevity, cancer resistance, and viral interactions in bats. We show that the recurrent evolution of longevity seen in Myotis leads to some of the highest predicted increases in cancer risk across mammals and demonstrate a unique DNA damage response in primary cells of the long-lived M. lucifugus. We also find evidence of abundant adaptation in response to DNA viruses - but not RNA viruses - in Myotis and other bats in sharp contrast with other mammals, potentially contributing to the role of bats as reservoirs of zoonoses. Together, our results demonstrate how genomics and primary cells derived from diverse taxa uncover the molecular bases of extreme adaptations in non-model organisms.

Aging↗
PubMed2006

Motexafin gadolinium-induced cell death correlates with heme oxygenase-1 expression and inhibition of P450 reductase-dependent activities.

Heme oxygenase-1 (HO1), which oxidizes heme to biliverdin, CO, and free iron, conveys protection against oxidative stress and is antiapoptotic. Under stress conditions, some porphyrin derivatives can inhibit HO1 and trigger cell death. Motexafin gadolinium (MGd) is an expanded porphyrin that selectively targets cancer cells through a process of futile redox cycling that decreases intracellular reducing metabolites and protein thiols. Here, we report that hematopoietic-derived cell lines that constitutively express HO1 are more susceptible to MGd-induced apoptosis than those that do not. MGd used in combination with tin protoporphyrin IX, an inhibitor of HO1, resulted in synergistic cell killing. Consistent with these cell culture observations, we found that MGd is an inhibitor of heme oxygenase-1 activity in vitro. We demonstrate that inhibition of HO1 reflects an interaction of MGd with NADPH-cytochrome P450 reductase, the electron donor for HO1, that results in diversion of reducing equivalents from heme oxidation to oxygen reduction. In accord with this mechanism, MGd is also an in vitro inhibitor of CYP2C9, CYP3A4, and CYP4A1. Inhibition of HO1 by MGd may contribute to its anticancer activity, whereas its in vitro inhibition of a broad spectrum of P450 enzymes indicates that a potential exists for drug-drug interactions.

Antineoplastic Agents↗
PubMed2006

NKG2D splice variants: a reexamination of adaptor molecule associations.

NKG2D is a homodimeric C-type lectin-related receptor expressed on natural killer (NK) cells and T cells. In mice, alternative deoxyribonucleic acid (DNA) splicing generates two isoforms of NKG2D that differ in the length of their cytoplasmic domains. Their ability to induce cellular activation is mediated via association with two membrane-bound, signaling adaptor molecules, DAP10 and DAP12. It has been reported that the long form of NKG2D associates exclusively with DAP10, whereas the short variant can interact with either adaptor. The short isoform was reported to be almost undetectable in naive NK cells. Using two distinct cell types, we demonstrate that like the short isoform, the long variant of NKG2D also associates not only with DAP10 but also with DAP12. Using reporter cells (70Z/3), we demonstrate that DAP12 can compete equally with DAP10 for association with both variants of NKG2D when DAP10 and DAP12 are coexpressed. Cross-linking either isoform of NKG2D induces a calcium flux when associated exclusively with DAP10 or DAP12. Moreover, using quantitative polymerase chain reaction (PCR), we also show that the short isoform of NKG2D is expressed in naive NK cells. Our data suggest that signaling via mouse NKG2D isoforms is more complex than originally presented.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Motexafin gadolinium modulates levels of phosphorylated Akt and synergizes with inhibitors of Akt phosphorylation.

Motexafin gadolinium (MGd, Xcytrin) is a tumor-selective expanded porphyrin that targets oxidative stress-related proteins. MGd treatment of the follicular lymphoma-derived cell line HF-1 resulted in growth suppression and apoptosis whereas MGd treatment of the Burkitt's lymphoma-derived cell line Ramos resulted in growth suppression but not apoptosis. Because phosphorylation status of Akt/protein kinase B is regulated by oxidative stress, we monitored total and phosphorylated Akt (pAkt) in MGd-treated HF-1 and Ramos cells. Levels of pAkt increased within 30 minutes after MGd treatment of HF-1 but after 4 hours began to show a progressive decline to below baseline levels before cells underwent apoptosis. In MGd-treated Ramos cells, pAkt increased approximately 2-fold within 4 hours and remained persistently elevated. Because pAkt activates survival pathways, we determined if MGd-induced cell death could be enhanced by inhibiting phosphorylation of Akt. The addition of specific inhibitors of Akt phosphorylation (Akt inhibitor 1 or SH-5) reduced pAkt levels in MGd-treated HF-1 and Ramos cells and synergistically enhanced MGd-induced cell death. MGd was also evaluated in combination with celecoxib, an inhibitor of Akt phosphorylation, or docetaxel, a microtubule inhibitor that can decrease Akt phosphorylation. The combination of MGd/celecoxib or MGd/docetaxel resulted in decreased Akt phosphorylation and in synergistic cytotoxicity compared with either agent alone. These data point to a potential protective role for pAkt in MGd-induced apoptosis and suggest that MGd activity may be enhanced by combining it with agents that inhibit Akt phosphorylation.

Antineoplastic Agents↗
PubMed2006

Tumor localization and antitumor efficacy of novel sapphyrin compounds.

Sapphyrins are pentapyrrolic metal-free expanded porphyrins with potential medical use as anticancer agents. The novel sapphyrin derivative, PCI-2050, functionalized with 2-[2-(2-methoxyethoxy)ethoxy]ethoxy groups to enhance solubility and a modified bipyrrole moiety was found to be more potent in inducing apoptosis than the previously described sapphyrin PCI-2000. Because some sapphyrins may localize to tumors, we took advantage of the intrinsic fluorescence of these compounds to develop a flow cytometry-based assay to track sapphyrin biodistribution in tumor-bearing mice. Ex vivo analysis of sapphyrin-injected animals revealed that PCI-2050 preferentially localized to tumor, whereas PCI-2000 distributed into normal tissues rather than tumor. PCI-2050 uptake in xenograft tumor cells and resultant tumor cell cytotoxicity was dose dependent. To investigate structure-activity relationships, we focused on PCI-2050 and three derivatives that differ by their alkyl substituents on the bipyrrole moiety: PCI-2051, PCI-2052, and PCI-2053. Treatment of Ramos cells in culture or treatment of Ramos xenograft-bearing animals with each of the sapphyrins followed by ex vivo growth of tumor cells revealed the same pattern of cytotoxicity: PCI-2050 > PCI-2052 > PCI-2051 > PCI-2053. Thus, subtle changes in the alkyl substituents on the bipyrrole moiety result in significant changes in antitumor activity. PCI-2050 displayed significant antitumor efficacy in both Ramos and RKO xenograft models without hematologic, hepatic, or renal abnormalities as assessed by complete blood counts and serum chemistries. On the basis of these findings, it is concluded that the sapphyrin PCI-2050 warrants further evaluation as a potential anticancer agent due to its intrinsic proapoptotic activity and tumor localization ability.

Animals↗
PubMed2006

Extensor hallucis capsularis: frequency and identification on MRI.

BACKGROUND: The extensor hallucis capsularis (EHC) is the most common name given to the accessory tendon sporadically seen medial to the extensor hallucis longus (EHL). We performed cadaver dissections and MRI evaluation to determine the frequency of its occurrence, the pattern of its origin and insertion, and its potential suitability as tendon graft. METHODS: The EHC was examined by dissection in 81 cadaver feet. Physical parameters pertaining to EHC size and location were recorded. MRI was performed on six cadaver legs to determine if the EHC can be identified radiographically. MRI images were evaluated independently by a foot and ankle specialist and a radiologist. RESULTS: The EHC was present in 71 (88%) of the specimens. It originated from the EHL tendon or muscle in 93% and inserted into the first metatarsophalangeal joint capsule in 99% of cases. All EHC tendons were less than or equal to 4 mm in width; only 16% were more than 2 mm wide. Correct prediction of the presence or absence of EHC by MRI varied according to EHC width: two of two in tendons more than 2 mm, five of eight in tendons 1 to 2 mm, and zero of two in tendons 1 mm or less. CONCLUSION: Up to 14% of the population may have an EHC tendon suitable for grafting in reconstructive surgeries, particularly surgeries related to hallux dysfunction. MRI may have a role in the preoperative identification of the EHC.

Cadaver↗
PubMed2005

Colorectal cancer screening: prospects for molecular stool analysis.

Colorectal cancer is common. As many patients present with advanced disease, an effective screening test would have substantial clinical benefits. Recent progress in understanding the biology of colorectal cancer (and of cancer cells in general) has led to possible new approaches to screening. In particular, there are prospects of developing tests based on analysis of stool, which promise improved accuracy, safety, affordability and patient compliance.

Colorectal Neoplasms↗
PubMed2005

Sapphyrins induce apoptosis in hematopoietic tumor-derived cell lines and show in vivo antitumor activity.

Sapphyrins are pentapyrrolic, metal-free, expanded porphyrins. In the present study, the activity of sapphyrins as anticancer agents in hematopoietic-derived tumor cells was explored. It was found that a dihydroxylated water-soluble sapphyrin derivative (PCI-2000) is a potent inducer of apoptosis in a wide variety of tumor cell lines including lymphoma (Ramos, DHL-4, and HF-1), leukemia (Jurkat and HL-60), and myeloma (8226/S, 1-310, C2E3, and 1-414). PCI-2000 triggers an apoptotic pathway in these tumor cells as shown by release of cytochrome c from mitochondria; activation of caspases 9, 8, and 3; cleavage of the caspase substrate poly(ADP-ribose) polymerase; and Annexin V binding. Apoptosis can be partially inhibited by overexpression of the antiapoptotic protein Bcl-2 or treatment with benzyloxycarbonyl-valine-alanine-aspartic acid-fluoromethylketone, a cell-permeable caspase inhibitor. Both PCI-2000 and PCI-2010, a tetrahydroxy bis-carbamate derivative of PCI-2000, result in increased levels of phosphorylated p38 mitogen-activated protein kinase. Inhibition of p38 mitogen-activated protein kinase phosphorylation resulted in a synergistic increase of PCI-2000 cytotoxicity. PCI-2010 showed less toxicity in mice than PCI-2000 and was active in slowing the growth of Ramos and HL-60 tumor xenografts in nude mice. These results provide preclinical rationale for the further study of sapphyrins for potential use in the treatment of hematopoietic-derived tumors.

Angiogenesis Inhibitors↗
PubMed2005

Complications with surgical procedures utilizing connective tissue grafts: a follow-up of 500 consecutively treated cases.

The goal of this study was to evaluate the incidence and severity of the complications that occur after connective tissue grafts are used. Five hundred consecutively treated patients, for whom connective tissue grafts were used for root coverage or gingival augmentation, were included in this study. Complications did occur, but the rates and intensities seemed clinically acceptable. There was no pain reported in 81.4% of the patients, no bleeding in 97.0% of the patients, no infection in 99.2% of the patients, and no swelling in 94.6% of the patients. None of the factors evaluated in this study were associated with a statistically significant increase in the rate or intensity of complications. These factors included: age, sex of patient, smoking status, purpose of the graft (ie, for root coverage or for gingival augmentation), size of the recipient area, and the location of the defect being treated. Based on the results of this study, the incidence and severity of complications seemed to be clinically acceptable.

Adolescent↗
PubMed2004

Case-control study of cancer among US Army veterans exposed to simian virus 40-contaminated adenovirus vaccine.

Simian virus 40 (SV40) was an accidental contaminant of vaccines produced in monkey kidney tissue cultures in the 1950s and early 1960s, including a parenteral adenovirus vaccine given to several hundred thousand US military recruits. Detection of SV40 DNA in tumor tissues by some laboratories suggests that SV40 contributes to human cancers. To determine if entry into US Army service during periods of administration of SV40-contaminated adenovirus vaccine was associated with an increased risk of cancer, the authors conducted a case-control study of cancer occurring in male Army veterans who entered service in 1959-1961. Cases of brain tumors (n = 181), mesothelioma (n = 10), and non-Hodgkin's lymphoma (n = 220) were identified through a Veterans Administration hospital discharge database, as were colon cancer and lung cancer controls (n = 221). Exposure to adenovirus vaccine was assigned on the basis of known periods of adenovirus vaccine administration and dates of Army entry obtained for cancer cases and controls. The odds ratios associated with exposure to SV40-contaminated adenovirus vaccine were 0.81 (95% confidence interval (CI): 0.52, 1.24) for brain tumors, 1.41 (95% CI: 0.39, 5.15) for mesothelioma, and 0.97 (95% CI: 0.65, 1.44) for non-Hodgkin's lymphoma. These findings do not support a role for SV40 in the development of these cancers.

Adenoviridae↗
PubMed2004

Bedside laparotomy for trauma: are there risks?

BACKGROUND: Critically ill trauma patients are often too unstable for safe transfer to the operating room. Damage control laparotomy patients frequently require early reoperation and have a reported mortality of 50-60%. As a result, many of these patients must undergo laparotomy in the intensive care unit. We hypothesized that patients undergoing bedside laparotomy (BSL) and managed with the abdomen left open would have an unacceptably high mortality or intra-abdominal complications. METHODS: We performed a retrospective chart review of our Trauma Registry. Of the 11,096 consecutive trauma admissions from March 1, 1996 to May 20, 2000, 75 patients underwent 95 BSL. Patients were stratified according to injury severity score (ISS), base deficit (BD), lactic acid (LA), total transfusion (TRBC) requirements, indication for BSL, mechanism of injury, infectious complications (intra-abdominal abscess (IAA), fistula), and length of hospital stay. RESULTS: Seventy-five patients underwent 95 BSL. Mean ISS was 50.6 +/- 18.9, mean BD was -11.9 (+/- 5), and the mean LA was 5 +/- 5 for the study group. The TRBC for the group was 43.7 +/- 42.6 units. Indications for the 95 BSL were (1) abdominal compartment syndrome (n = 47, 49.5%); (2) suspected intra-abdominal infection (n = 18, 19.0%); (3) washout/pack removal (n = 14, 14.7%); (4) washout with fascial closure (n = 12, 12.6%); and (5) other (n = 4, 4.2%). Twenty-nine of 75 patients (39.2%; ISS 52.3 +/- 18.8) died within 72 h of operation. Of the 46 remaining patients, an additional eight died 72 h or more after operation, for a late mortality rate of 17.4% and a total mortality rate of 49%. None of these deaths were attributable to either the operation or to post-operative IAA or fistula formation; all late deaths were secondary to multiple organ failure. Intra-abdominal abscesses developed in three of 46 patients (6.5%), each of whom had a TRBC of >100 units (mean, 160 units). Five of 46 patients (10.9%) developed enterocutaneous fistulae. None of these eight patients died. Thirty-eight of 75 patients (50.7%) survived to discharge, with a mean ISS of 40 (+/- 11.9). CONCLUSIONS: Despite the high acuity of the population undergoing BSL, 50.7% of patients survived. Moreover, during BSL, IAA and fistula formation occurred at low rates.

Abdominal Injuries↗
PubMed2004

Quantitative trait locus mapping for age-related cataract severity and synechia prevalence using four-way cross mice.

PURPOSE: The goal of this study was to map mouse quantitative trait loci (QTL) that influence the development of murine age-related cataract and synechia, by using a genetically heterogeneous mouse population bred by a four-way cross. METHODS: The test population consisted initially of 510 mice bred as the progeny of (BALB/cJ x C57BL/6J)F1 females and (C3H/HeJ x DBA/2J)F1 males. Each mouse was examined by slit lamp at 18 and 24 months of age and scored for degree of lens opacity on a 0 to 4+ scale, and the presence or absence of additional anterior chamber disease was noted. The presence of synechia was confirmed by histology. Each mouse was genotyped at 96 maternal and 92 paternal loci, and the significance of association between genotype and eye lesions was tested by permutation analysis. RESULTS: Significant QTL with effects on lens opacity at 24 months were detected on mouse chromosomes 4, 11, and 12. The effects were additive, and severe cataracts were seen in 80% of the mice with all three high-risk alleles, but in only 28% of the mice with all three low-risk alleles. The risk of synechia was associated with paternal chromosome 1 and on both the maternal and paternally inherited chromosome 4. Mice with all three high-risk alleles had a 68% risk of synechia, compared with a 0% incidence in mice with all three counteralleles. CONCLUSIONS: A four-way cross population of mice can be used to map polymorphic loci that influence cataract severity and synechia prevalence in late life. The results provide a first step toward identification of the individual genes involved and may help to guide the search for homologous human genes.

Aging↗
PubMed2004

Pediatric pharmacokinetic data: implications for environmental risk assessment for children.

Pharmacology and toxicology share a common interest in pharmacokinetic data, especially as it is available in pediatric populations. These data have been critical to the clinical pharmacologist for many years in designing age-specific dosing regimens. Now they are being used increasingly by toxicologists to understand the ontogeny of physiologic parameters that may affect the metabolism and clearance of environmental toxicants. This article reviews a wide range of physiologic and metabolic factors that are present in utero and in early postnatal life and that can affect the internal dose of an absorbed chemical and its metabolites. It also presents a child/adult pharmacokinetic database that includes data for 45 therapeutic drugs organized into specific children's age groupings and clearance pathways. Analysis of these data suggests that substantial child/adult differences in metabolism and clearance are likely for a variety of drugs and environmental chemicals in the early postnatal period. These results are also relevant to in utero exposures, where metabolic systems are even more immature, but exposures are greatly modified by the maternal system and placental metabolism. The implications of these child/adult differences for assessing children's risks from environmental toxicants is discussed with special focus on physiologically based pharmacokinetic modeling strategies that could simulate children's abilities to metabolize and eliminate chemicals at various developmental stages.

Adolescent↗
PubMed2004

Repair of giant abdominal hernias: does the type of prosthesis matter?

Closure of the abdominal wall after trauma or major surgery may be difficult due to visceral edema or fascial weakness; thus, the risk of developing a ventral hernia (VH) is high. Commonly, these hernias are repaired using a prosthetic mesh. Complications following mesh repair can develop. We hypothesize that the type of prosthetic material affects outcome. This is a retrospective chart review of patients admitted from 1996 to 2002 undergoing VH (> or = 20 x 10 cm) repair with prosthetic mesh. Data collected included age, sex, and race. Patients were stratified by prosthetic material as follows: Gore-Tex (GR), Marlex + Gore-Tex (MG), Marlex (MR), and Marlex + Vicryl (MV). For the purpose of clinical analysis, the groups were collapsed into subgroups: Gore-Tex exposure (GT) or non-Gore-Tex exposure (NG). Outcome measures were hernia recurrence (HR), wound infection (WI), and fistula formation (FF). Statistical analysis utilized chi2 test and Fisher's exact test. There were 55 VH repairs in 37 patients. The mean age was 43.9 (+/- 16.3), males out-numbered females 22 (59.5%) to 15 (40.5%). The majority of the patients were Caucasian (29; 78.4%). There were 30 trauma patients (81.1%), and 7 general surgery patients (18.9%). The HR for the study (n = 55) was 20 (36.4%), the WI was 17 (30.9%), and the FF was 3 (5.5%). GR group (6; 66.7%) had a significant higher wound IF rate than MR group (8; 26.7%) (Chi P = 0.02, Fisher P = 0.047). All other group comparisons (HR, WI, and FF) were N.S. The Gore-Tex versus non-Gore-Tex subgroup comparison results were as follows: GT (n = 18) had a WI 8 (44.4%), HR 6 (33.3%), and FF 0 (0%). NG (n = 37) had a WI 9 (24.3%), HR 14 (37.8%), and a FF 3 (8.1%). There was a trend toward a higher wound infection in the GT versus NG, but it did not reach statistical significance. We conclude that 1) the wound infection rate was higher in the Gore-Tex versus the Marlex group (Chi P = 0.02, Fisher P = 0.047). Wound infection in the presence of Gore-Tex usually mandates the removal of the mesh resulting in a hernia recurrence. 2) There was a trend toward a higher wound infection in the GT (44.4%) versus NG (24.3%), but it did not reach statistical significance.

Academic Medical Centers↗
PubMed2003

Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer's disease.

The principal pathological features of Alzheimer's disease (AD) are extracellular amyloid plaques and intracellular neurofibrillary tangles, the latter composed of the microtubule-binding protein tau assembled into paired helical and straight filaments. Recent studies suggest that these pathological entities may be functionally linked, although the mechanisms by which amyloid deposition promotes pathological tau filament assembly are poorly understood. Here, we report that tau is proteolyzed by multiple caspases at a highly conserved aspartate residue (Asp421) in its C terminus in vitro and in neurons treated with amyloid-beta (Abeta) (1-42) peptide. Tau is rapidly cleaved at Asp421 in Abeta-treated neurons (within 2 h), and its proteolysis appears to precede the nuclear events of apoptosis. We also demonstrate that caspase cleavage of tau generates a truncated protein that lacks its C-terminal 20 amino acids and assembles more rapidly and more extensively into tau filaments in vitro than wild-type tau. Using a monoclonal antibody that specifically recognizes tau truncated at Asp421, we show that tau is proteolytically cleaved at this site in the fibrillar pathologies of AD brain. Taken together, our results suggest a novel mechanism linking amyloid deposition and neurofibrillary tangles in AD: Abeta peptides promote pathological tau filament assembly in neurons by triggering caspase cleavage of tau and generating a proteolytic product with enhanced polymerization kinetics.

Alzheimer Disease↗