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S Gardner

Publications and source records attributed to S Gardner.

At least 19 recordsLinked to original sources
PubMed2025

Identification and Validation of Novel Combinatorial Genetic Risk Factors for Endometriosis across Multiple UK and US Patient Cohorts.

BACKGROUND: Endometriosis affects about 10% of women usually of reproductive age. It often has severe negative impacts on patients' quality of life, but the average time to a definitive diagnosis remains 7-9 years, and there are few effective therapeutic options. Relatively little is known about the genetic drivers of the disease even though its heritability is fairly high. A recent large genome wide association study (GWAS) meta-analysis identified 42 genomic loci associated with risk of endometriosis, but together these explain only 5% of disease variance. METHODS: We used the PrecisionLife&#xae; combinatorial analytics platform to identify multi-SNP disease signatures significantly associated with endometriosis in a white European UK Biobank (UKB) cohort. We assessed the reproducibility of these multi-SNP disease signatures as well as 35 of the 42 meta-GWAS SNPs in a multi-ancestry American endometriosis cohort from All of Us (AoU) after controlling for population structure. RESULTS: We identified 1,709 disease signatures, comprising 2,957 unique SNPs in combinations of 2-5 SNPs, that were associated with increased prevalence of endometriosis in UKB. Pathways enriched in the disease signatures included cell adhesion, proliferation and migration, cytoskeleton remodeling, angiogenesis as well as biological processes involved in fibrosis and neuropathic pain.We observed a significant enrichment of these signatures (58-88%, p<0.04) that are also positively associated with endometriosis in the AoU cohort, including one 2-SNP signature that is individually significant. Reproducibility rates were greatest for higher frequency signatures, ranging from 80-88% for signatures with greater than 9% frequency (p<0.01) in AoU. Encouragingly, the disease signatures also show high reproducibility rates in non-white European AoU sub-cohorts (66-76%, p<0.04 for signatures with greater than 4% frequency).A total of 195 unique SNPs mapping to 98 genes were identified in the high frequency reproducing signatures (>9%). Of these, 7 genes were previously identified in the endometriosis meta-GWAS study and 16 genes have a previous association with endometriosis. 75 novel genes were identified in this study.We characterized 9 novel genes that occur at the highest frequency in reproducing signatures and that do not contain any SNPs linked to known GWAS genes, providing new evidence for links between endometriosis and autophagy and macrophage biology. Reproducibility rates, ranging between 73% to 85%. are especially strong for the signatures that contain these 9 genes independently of any SNPs mapping to the meta-GWAS genes. CONCLUSION: Although using much smaller, less well-characterized datasets than the previous whole genome meta-GWAS study, combinatorial analysis has provided important new insights into the genetics and biology of endometriosis including reproducible biologically relevant genes that are overlooked by GWAS approaches.The 75 novel gene associations provide new insights and routes for study of the disease and potential new therapies. Several of the novel genes identified are credible targets for drug discovery, repurposing and/or repositioning. Using the disease signatures identified as genetic biomarkers in trials of candidates drugs targeting specific mechanisms will enable precision medicine-based approaches. We hope this will encourage new targeted therapy discovery efforts.

Endometriosis↗
PubMed2025

Reproducibility of genetic risk factors identified for long COVID using combinatorial analysis across US and UK patient cohorts with diverse ancestries.

BACKGROUND: Long COVID is a major public health burden causing a diverse array of debilitating symptoms in tens of millions of patients globally. In spite of this overwhelming disease prevalence, staggering cost, severe impact on patients' lives and intense global research efforts, study of the disease has proved challenging due to its complexity. Genome-wide association studies (GWAS) have identified only four loci potentially associated with the disease, although these results did not statistically replicate between studies. A previous combinatorial analysis study identified a total of 73 genes that were highly associated with two long COVID cohorts in the predominantly (>&#x2009;91%) white European ancestry Sano GOLD population, and we sought to reproduce these findings in the independent and ancestrally more diverse All of Us (AoU) population. METHODS: We assessed the reproducibility of the 5343 long COVID disease signatures from the original study in the AoU population. Because the very small population sizes provide very limited power to replicate findings, we initially tested whether we observed a statistically significant enrichment of the Sano GOLD disease signatures that are also positively correlated with long COVID in the AoU cohort after controlling for population substructure. RESULTS: For the Sano GOLD disease signatures that have a case frequency greater than 5% in AoU, we consistently observed a significant enrichment (77-83%, p&#x2009;<&#x2009;0.01) of signatures that are also positively associated with long COVID in the AoU cohort. These encompassed 92% of the genes identified in the original study. At least five of the disease signatures found in Sano GOLD were also shown to be individually significantly associated with increased long COVID prevalence in the AoU population. Rates of signature reproducibility are strongest among self-identified white patients, but we also observe significant enrichment of reproducing disease associations in self-identified black/African-American and Hispanic/Latino cohorts. Signatures associated with 11 out of the 13 drug repurposing candidates identified in the original Sano GOLD study were reproduced in this study. CONCLUSION: These results demonstrate the reproducibility of long COVID disease signal found by combinatorial analysis, broadly validating the results of the original analysis. They provide compelling evidence for a much broader array of genetic associations with long COVID than previously identified through traditional GWAS studies. This strongly supports the hypothesis that genetic factors play a critical role in determining an individual's susceptibility to long COVID following recovery from acute SARS-CoV-2 infection. It also lends weight to the drug repurposing candidates identified in the original analysis. Together these results may help to stimulate much needed new precision medicine approaches to more effectively diagnose and treat the disease. This is also the first reproduction of long COVID genetic associations across multiple populations with substantially different ancestry distributions. Given the high reproducibility rate across diverse populations, these findings may have broader clinical application and promote better health equity. We hope that this will provide confidence to explore some of these mechanisms and drug targets and help advance research into novel ways to diagnose the disease and accelerate the discovery and selection of better therapeutic options, both in the form of newly discovered drugs and/or the immediate prioritization of coordinated investigations into the efficacy of repurposed drug candidates.

Humans↗
PubMed2006

Seminal plasma and prostaglandin E2 up-regulate fibroblast growth factor 2 expression in endometrial adenocarcinoma cells via E-series prostanoid-2 receptor-mediated transactivation of the epidermal growth factor receptor and extracellular signal-regulated kinase pathway.

BACKGROUND: Prostaglandin E(2) (PGE(2)) has been shown to modulate angiogenesis and tumour progression via the E-series prostanoid-2 (EP2) receptor. Endometrial adenocarcinomas may be exposed to endogenous PGE(2) and exogenous PGE(2), present at high concentration in seminal plasma. METHODS: This study investigated fibroblast growth factor 2 (FGF2) mRNA expression and cell signalling in response to seminal plasma or PGE(2), using an endometrial adenocarcinoma (Ishikawa) cell line stably expressing the EP2 receptor (EP2 sense cells) and endometrial adenocarcinoma explants. RESULTS: Seminal plasma and PGE(2) induced a significant up-regulation of FGF2 expression in EP2 sense but not parental untransfected Ishikawa (wild-type) cells (P < 0.05). These effects were inhibited by co-treatment with EP2 receptor antagonist or inhibitors of protein kinase A, c-Src, epidermal growth factor receptor (EGFR) kinase or extracellular signal-regulated kinase (ERK) signalling. The treatment of EP2 sense cells with seminal plasma induced cAMP accumulation and phosphorylation of c-Src, EGFR kinase and ERK via the EP2 receptor. Finally, seminal plasma and PGE(2) significantly increased FGF2 mRNA expression in endometrial adenocarcinoma tissue explants via the EP2 receptor (P < 0.05). CONCLUSIONS: Seminal plasma and PGE(2) can similarly activate FGF2 expression and EP2 receptor signalling in endometrial adenocarcinoma cells. These data highlight the potential for seminal plasma exposure to facilitate tumorigenesis-angiogenesis in endometrial adenocarcinomas in vivo.

Adenocarcinoma↗
PubMed2004

Decay of intestinal enterococci concentrations in high-energy estuarine and coastal waters: towards real-time T90 values for modelling faecal indicators in recreational waters.

Intestinal enterococci are the principal 'health-evidence-based' parameter recommended by WHO for the assessment of marine recreational water compliance. Understanding the survival characteristics of these organisms in nearshore waters is central to public health protection using robust modelling to effect real-time prediction of water quality at recreation sites as recently suggested by WHO and the Commission of the European Communities Previous models have more often focused on the coliform parameters and assumed two static day-time and night-time T90 values to characterise the decay process. The principal driver for enterococci survival is the received dose of irradiance from sunlight. In the water column, transmission of irradiance is determined by turbidity produced by suspended material. This paper reports the results of irradiated microcosm experiments using simulated sunlight to investigate the decay of intestinal enterococci in relatively turbid estuarine and coastal waters collected from the Severn Estuary and Bristol Channel, UK. High-turbidity estuarine waters produced a T90 value of 39.5 h. Low-turbidity coastal waters produced a much shorter T90 value of 6.6 h. In experiments receiving no irradiation, high-turbidity estuarine waters also produced a longer T90 of 65.1 h compared with corresponding low-turbidity coastal waters, T90 24.8 h. Irradiated T90 values were correlated with salinity, turbidity and suspended solids (r>0.8, p<0.001). The results suggest that enterococci decay in irradiated experiments with turbidity >200 NTU is similar to decay observed under dark conditions. Most significantly, these results suggest that modelling turbidity and or suspended solids offers a potential means of predicting T90 values in 'real-time' for discrete cells of a hydrodynamic model.

Dose-Response Relationship, Radiation↗
PubMed2004

Effect of 4-aminopyridine on gait in ambulatory spinal cord injuries: a double-blind, placebo-controlled, crossover trial.

UNLABELLED: Animal and human research have shown that the drug 4-aminopyridine (4-AP) may improve gait in spinal cord lesions by enhancing nerve transmission to affected muscles. STUDY DESIGN: Prospective, randomized, double-blind, placebo-controlled, crossover trial. OBJECTIVES: To determine the efficacy of 4-AP in improving lower limb muscle strength and biomechanical gait patterns of chronic spinal cord injuries (SCI). SETTING: The Rehabilitation Centre (Ottawa, Canada). METHODS: In all, 15 chronic, ambulatory SCI persons were randomized to an initial 2 weeks of 40 mg/day, oral medication of either placebo or immediate-release, 4-AP and subsequently crossed over to the alternate medication for the following 2 weeks. Evaluations were conducted at baseline (before starting 4-AP or placebo medication), 2 weeks, and 4 weeks. Measures included dynamometer lower limb isometric muscle force and biomechanical gait measures including temporal-spatial parameters, electromyographic activation patterns, joint kinematics and kinetics. Subjective impressions of the drug by the participants were obtained from an exit survey. RESULTS: Despite some positive comments from subjects, statistical and clinical analyses showed no within-subject differences between placebo and 4-AP measures of lower limb muscle force and objective gait analyses (ANOVA statistic P>0.05). CONCLUSION: Results demonstrated the importance of placebo-controlled trials and quantitative outcome measures for the evaluation of 4-AP aimed to enhance gait for chronic, ambulatory SCI persons. Energy expenditure measures and mood may relate more to subjective comments and is suggested for future investigations.

4-Aminopyridine↗
PubMed2002

Effects of fat adaptation on glucose kinetics and substrate oxidation during low-intensity exercise.

This study was designed to determine the effects of fat adaptation on carbohydrate and fat oxidation in conditioned horses during low-intensity exercise. Five mature Arabians were studied. The study was conducted as a crossover design with 2 dietary periods, each of 10 week's duration: a) a control (CON) diet, and b) a fat-supplemented (FAT) diet. The total amount of digestible energy (DE) supplied by the fat in the CON and FAT diets was 7% and 29%, respectively. During each period, the horses completed exercise tests at the beginning of the period (Week 0) and after 5 and 10 weeks on the diet. Tests consisted of 90 min of exercise at a speed calculated to elicit 35% VO2max on a treadmill inclined to 3 degrees. Oxygen consumption (VO2), carbon dioxide production (VCO2), and respiratory exchange ratio (RER) were measured at 15-min intervals. For determination of glucose kinetics, a stable isotope ([6-6-d2] glucose) technique was used. Compared to the CON diet, FAT diet consumption for 5-10 weeks was associated with an altered metabolic response to low-intensity exercise, as evidenced by a more than 30% reduction in the production and utilisation of glucose; a decrease in RER; a decrease in the estimated rate of whole-body carbohydrate utilisation; and an increase in the whole-body rate of lipid oxidation during exercise.

Adaptation, Physiological↗
PubMed2002

Comparison of the metabolic responses of trained Arabians and Thoroughbreds during high- and low-intensity exercise.

In order to compare the metabolic responses to exercise in 2 similarly managed breeds of horses, 5 Arabian (AR) and 5 Thoroughbred (TB) horses, fed an identical diet with a similar diet and exercise training programme for the 2 preceding months, undertook 3 treadmill (3 degree incline) trials with a minimum of 7 days between tests: 1) an incremental test (MAX) for determination of aerobic capacity, V(LA4) and lactate threshold (LT; the percentage of VO2max when plasma lactate = 4 mmol/l); 2) a single high-speed exercise test (SPR) at 115% VO2max for estimation of maximal accumulated oxygen deficit (MAOD) and 3) a 90 min test at 35% VO2max (LO). VO2max (P<0.001) and running speed (P<0.05) at VO2max were higher in TB (mean +/- s.e. 154 +/- 3 ml/kg/min at 12.9 +/- 0.5 m/s) than in AR (129 +/- 2.5 ml/kg/min at 11.8 +/- 0.2 m/s). Total run time during MAX was greater (P<0.05) in TB (10.5 +/- 0.5 min) than in AR (93 +/- 0.3 min). However, V(LA4) and LT were not different between groups. Run time during SPR (TB 149 +/- 16; AR 109 +/- 11 s) and MAOD (TB 88 +/- 4; AR 70 +/- 6 ml O2/kg) were higher (P<0.05) in the TB group. During LO, FFA were higher (P<0.05) and the respiratory exchange ratio (RER) lower (P<0.05) in AR than in TB between 60 and 90 min, of exercise, indicating a greater use of fat for energy. These metabolic differences may reflect breed variation in muscle fibre types. However, further studies are needed to determine the mechanisms underlying the apparent breed differences in energy metabolism during exercise.

Animals↗
PubMed2001

Sharpening low-energy, standard-model tests via correlation coefficients in neutron beta decay.

The correlation coefficients a, A, and B in neutron beta decay are proportional to the ratio of the axial-vector-to-vector weak coupling constants, gA/gV, to leading recoil order. With the advent of the next generation of neutron-decay experiments, the recoil-order corrections to these expressions become experimentally accessible, admitting a plurality of standard model (SM) tests. The measurement of both a and A, e.g., allows one to test the conserved-vector-current (CVC) hypothesis and to search for second-class currents (SCC) independently. The anticipated precision of these measurements suggests that the bounds on CVC violation and SCC from studies of nuclear beta decay can be qualitatively bettered.

Journal Article↗
PubMed2001

Risk factors for prophylaxis failure in patients receiving aerosol pentamidine for Pneumocystis carinii pneumonia prophylaxis.

OBJECTIVE: The purposes of this study were (1) to determine the incidence of prophylaxis failure in HIV-infected patients receiving aerosol pentamidine (AP) for Pneumocystis carinii pneumonia (PCP) prophylaxis, and (2) to identify risk factors for PCP prophylaxis failure. SETTING AND DESIGN: In Ontario, Canada, AP has been made available for outpatient PCP prophylaxis through a centralized government program, the Ontario Drug Distribution and Monitoring Program. Data from this administrative observational database were extracted for 2,227 patients who received AP between May 1989 and December 1998. OUTCOME MEASUREMENTS: The incidence of breakthrough PCP (BPCP) was calculated from the database. A Cox regression model with time-varying covariates was created to examine factors associated with BPCP. The follow-up time was divided into three eras: 1989 to 1991, 1992 to 1994, and 1995 to 1998. These eras were meant to reflect major changes in antiretroviral medication regimens. RESULTS: The overall risk of BPCP was 16.2% over a mean follow-up of 1.67 years. The overall BPCP rate was 9.7/100 patient-years, with rates of 8.8/100, 13.1/100, and 6.3/100 patient-years in each of the three treatment eras. In the multivariate analysis, significant risk factors for prophylaxis failure were low CD4 count, previous diagnosis of PCP, history of AIDS-defining conditions other than PCP, and antiretroviral treatment era defined above. CONCLUSION: The overall rate of PCP prophylaxis failure has decreased significantly after 1995, coincident with the era of highly active antiretroviral therapies. Initiation of PCP prophylaxis remains necessary in patients with risk factors.

Adult↗
PubMed2000

Conus peptides: novel probes for nicotinic acetylcholine receptor structure and function.

Conus is a genus of predatory marine snails that uses venom to capture prey. Among the neurotoxins widely utilized by the cone snails are the alpha-conotoxins which are disulfide-rich peptides that target muscle or neuronal subtypes of nicotinic acetylcholine receptors. The small size and receptor subtype specificity of these peptides make them particularly useful for characterizing both native and heterologously expressed nicotinic receptors. In this report, we demonstrate that alpha-conotoxin MII potently blocks beta3-containing neuronal nicotinic receptors. Furthermore, initial evidence suggests that subpopulations of alpha3beta2beta3-containing receptors are differentially sensitive to alpha-conotoxin MII. Thus, alpha-conotoxin MII promises to be a useful tool for studying neuronal nicotinic receptors containing the beta3 subunit.

Animals↗
PubMed2000

Randomized, dose-escalation study of SD/01 compared with daily filgrastim in patients receiving chemotherapy.

PURPOSE: To explore the use of SD/01 (a polyethylene glycol-conjugated filgrastim shown in preclinical studies to have a prolonged half-life) in patients with chemotherapy-induced neutropenia. PATIENTS AND METHODS: Thirteen patients with non-small-cell lung cancer were randomized to receive daily filgrastim (5 microg/kg/d) or a single injection of SD/01 (30, 100, or 300 microg/kg) 2 weeks before chemotherapy and again 24 hours after administration of carboplatin and paclitaxel. Pharmacodynamic, pharmacokinetic, and safety analyses were performed. RESULTS: Peak serum concentrations of SD/01 and the duration of increased serum concentrations were dependent on the SD/01 dose. SD/01 concentrations remained increased longer in patients with chemotherapy-induced neutropenia. Prechemotherapy median absolute neutrophil counts (ANCs) in patients receiving SD/01 were increased in a dose-dependent fashion, with the duration of this effect also being dose dependent. After chemotherapy, median ANC nadirs were similar in the filgrastim cohort and the cohort receiving SD/01 30 microg/kg, with higher nadirs seen in the cohorts receiving SD/01 100 or 300 microg/kg. Dose-limiting toxicities were not noted. CD34(+) cells were mobilized in all cohorts. CONCLUSION: A single dose of SD/01 increases the serum concentration of SD/01 for several days in a dose-dependent fashion and is not associated with significant toxicity. The effects of SD/01 on ANC and CD34(+) cell mobilization are comparable or greater than those achieved with daily filgrastim. The self-regulation of this molecule provides a potential therapeutic advantage in a variety of clinical settings associated with neutropenia.

Aged↗
PubMed2000

Normalisation of hair follicle morphology in C3H/HeJ alopecia areata mice after treatment with squaric acid dibutylester.

Alopecia areata is a non-scarring, reversible disorder, presumably caused by an autoimmune attack on anagen hair follicles. Treatments are numerous, and most of these are ineffective. However, the elicitation of contact dermatitis on the affected skin is commonly associated with hair regrowth. A major advance in the study of alopecia areata has been the introduction and characterisation of the C3H/HeJ mouse model that exhibits many features of the human disease. In this study we examined the effects of squaric acid dibutylester treatment on hair follicles and the associated leukocyte infiltrate in alopecia areata mice by light and transmission electron microscopic analysis. This was compared with unaffected normal mice and alopecic untreated mice. Experimental mice were treated unilaterally with the contact allergen squaric acid dibutylester and the skin was assessed after hair regrowth. The characteristic pathological picture of alopecia areata was observed in alopecic but not normal mice. Nine of eleven experimental mice regrew hair on the treated side only and this was associated with a reduction in peri/intrafollicular inflammatory cell infiltrates, hair follicle dystrophy, melanin incontinence/clumping, and an increase in the numbers of hair follicles in full anagen. This normalisation of hair follicle status after treatment reflects the successful reversal of disease in these mice. The mechanism of action of topical immunotherapy with a potent contact allergen such as squaric acid dibutylester still needs to be elucidated, but an altered immune milieu is suspected. This study further validates the C3H/HeJ mouse model of alopecia areata in the search for therapeutic interventions in this common hair follicle disorder.

Adjuvants, Immunologic↗
PubMed1999

A new form of Filgrastim with sustained duration in vivo and enhanced ability to mobilize PBPC in both mice and humans.

Granulocyte colony-stimulating factor (G-CSF) has proven effective in the prophylaxis of chemotherapy-induced neutropenia and as a mobilizer of peripheral blood progenitor cells. The longevity of G-CSF action is limited by its removal from the body by two mechanisms. The first is thought to be mediated via receptors (receptor mediated clearance [RMC]) predominantly on neutrophils, the second process is likely the result of renal clearance. With the intention of developing a novel form of Filgrastim (r-met HuG-CSF) with a sustained duration of action in vivo, a new derivative named SD/01 has been made by association of Filgrastim with poly(ethylene glycol). The desired properties of this new agent would include a prolonged duration of action sufficient to cover a complete single course of chemotherapy. SD/01 is shown here to sustain significantly elevated neutrophil counts in hematopoietically normal mice for 5 days. In neutropenic mice effects were noted for at least 9 days, accompanying a significant reduction in the duration of chemotherapy induced neutropenia. Normal human volunteers showed higher than baseline ANC for around 9 to 10 days after a single injection of SD/01. Data from these normal volunteers also indicate that mobilization of CD34+ cells and progenitors may occur in a more timely manner and to around the same absolute numbers as with repeated daily injections of unmodified Filgrastim. These data indicate that SD/01 represents an efficacious novel form of Filgrastim with actions sustained for between one and two weeks from a single injection.

Animals↗