68 results on '"Jean, Zhang"'
Search Results
2. Medical history, medication use and physical activity in adults in their eighth and ninth decade of life in the Hertfordshire Cohort Study
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Gregorio Bevilacqua, Jean Zhang, Camille Parsons, Faidra Laskou, Nicholas Fuggle, Cyrus Cooper, and Elaine Dennison
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older ,activity ,medication ,comorbidity ,system ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 ,Biology (General) ,QH301-705.5 - Abstract
While there are many known health benefits to maintained physical activity levels in late adulthood, there have been very few studies that have considered relationships between morbidity profile and physical activity in the eighth decade of life. We studied 1097 participants, 555 men and 542 women from the Hertfordshire Cohort Study, a UK community based sample. Validated questionnaire based data were used to relate self-reported physical activity (PA) levels to medical history, and medication use. Regression analyses were adjusted for age, BMI, smoker status, alcohol consumption. The mean (SD) age of participants in the study was 80.2 (2.7) years for men and 80.2 (2.6) for women. A higher proportion of men (33.7 %) than women (24 %) were in the high activity score group. 20.8 % of female participants and 22.6 % male participants reported having no comorbid disease; 10.5 % men and 8.4 % women were taking no medication. Higher number of chronic conditions was associated with lower levels of PA [men (OR 0.73, 95 % CI 0.63-0.84, p
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- 2022
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3. Physical Activity and Diet in a Global Pandemic: An Investigation of the Impact of COVID-19 on Factors Relevant for Musculoskeletal Health at Two Different Stages of the Lifecourse
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Gregorio Bevilacqua, Stefania D’Angelo, Cathy Linaker, Alice Paul, Ilse Bloom, Jean Zhang, Faidra Laskou, Cyrus Cooper, Kate A. Ward, Karen Walker-Bone, and Elaine M. Dennison
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COVID-19 ,musculoskeletal health ,diet ,physical activity ,older adults ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
BackgroundPhysical activity, nutrition and other lifestyle factors play important roles in maintaining musculoskeletal health. The coronavirus disease (COVID-19) originated in late 2019, spread globally to be declared a pandemic by the World Health Organisation in March 2020, and led to widespread behaviour change. The aim of this study was to use two existing cohorts, the Hertfordshire Cohort Study (HCS) and Health and Employment After Fifty Study (HEAF), to understand how wave one of the COVID-19 pandemic impacted lifestyle factors associated with musculoskeletal health in the UK.Methods125 eligible participants, 65 males and 60 females (drawn from the HCS study, median (IQR) age 84.3 (82.4-86.6) years, all Caucasian, and community dwelling) were contacted by telephone and asked to complete a questionnaire administered by a trained researcher. Data collection occurred over the period July 2020 to February 2021. 2469 participants, 1086 men and 1383 women (drawn from the HEAF study, median age 65.7 (62.0-69.3) years, mostly Caucasian and community dwelling) completed an online questionnaire in March 2021.ResultsIn HCS, 47% respondents reported being less physically active than before the pandemic (and only 5% more so), 27% said they consumed less alcohol compared to pre-pandemic times (and only 3% more so), and 18% reported eating less than before, although quality of diet was generally unchanged over this timeframe surveyed. In HEAF, 44% participants said they were less active than before the pandemic, while 17% reported being more active. The majority of participants reported no changes in alcohol consumption and diet; however, 19% said they drank more than before (32% of which was above recommended levels), 16% said their diet was less healthy, and 19% reported eating more than before.ConclusionWe have reported the experience of the first wave of the COVID-19 pandemic among participants of two Caucasian community dwelling UK cohorts, highlighting the impact of the pandemic on lifestyle factors associated with musculoskeletal health. Changed physical activity levels were reported in a high proportion of respondents in both studies; an investigation of reversibility of these changes is required.
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- 2022
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4. Impact of the COVID-19 pandemic on community-dwelling older adults: A longitudinal qualitative study of participants from the Hertfordshire Cohort Study
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Ilse Bloom, Jean Zhang, Julia Hammond, Gregorio Bevilacqua, Wendy Lawrence, Kate A. Ward, Cyrus Cooper, and Elaine M. Dennison
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Medicine ,Science - Abstract
Background Older adults have been especially vulnerable to adverse effects from the COVID-19 pandemic including higher mortality and more severe disease complications. At the same time, social isolation, malnutrition and physical inactivity are serious concerns among older adults. The pandemic and associated restrictions may serve to exacerbate these issues, presenting increased risks to physical and mental health. The aims of this qualitative study were: i) to explore how community-living older people in the UK experienced the first wave of the COVID-19 pandemic, specifically how it impacted their well-being and associated health behaviours; ii) to explore how older people’s experiences and behaviours changed over time throughout the first wave. Methods Qualitative data were collected by conducting serial telephone interviews, with an interval of approximately three months. Participants were from the Hertfordshire Cohort Study, all aged over 80 years. Discussions were audio-recorded, information related to the COVID-19 pandemic was transcribed verbatim and transcripts analysed thematically. Interviews were conducted from March to October 2020. Results Data for twelve participants (7 men and 5 women) from a total of 35 interviews were used, comprising two or three timepoints per participant. Analysis identified five overarching themes: 1) shopping strategies and food accessibility, 2) limitations on activities and going out, 3) disruption to healthcare, 4) social and psychological repercussions, and 5) coping strategies. Findings highlight challenges associated with accessing shops, healthcare, and usual activities due to pandemic-related restrictions. Longitudinal findings showed that for some, the ongoing pandemic and related restrictions appeared to aggravate mental health issues (low mood, anxiety) over time, as well as greater feelings of isolation or loneliness, reduced activity and functional limitations; this was despite some relaxation of restrictions later on. Coping strategies used by participants included finding ways to keep busy and to do physical activity safely, maintaining social contact remotely, and having an optimistic or positive outlook, a ‘do what you can’ attitude. Conclusions Interventions are likely to be needed in the wake of the COVID-19 pandemic to support health behaviours, such as increasing physical activity, social engagement and improving mental health among community-living older adults.
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- 2022
5. Understanding influences on physical activity participation by older adults: A qualitative study of community-dwelling older adults from the Hertfordshire Cohort Study, UK
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Jean Zhang, Ilse Bloom, Elaine M. Dennison, Kate A. Ward, Sian M. Robinson, Mary Barker, Cyrus Cooper, and Wendy Lawrence
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Medicine ,Science - Abstract
Background The health benefits of physical activity (PA) participation in later life are widely recognised. Understanding factors that can influence the participation of community-dwelling older adults in PA is crucial in an ageing society. This will be paramount in aiding the design of future interventions to effectively promote PA in this population. The main aim of this qualitative study was to explore influences on PA among community-dwelling older people, and the secondary aim was to explore gender differences. Methods Qualitative data were collected in 2014 by conducting focus group discussions using a semi-structured discussion guide with older people resident in Hertfordshire, UK. Discussions were audio-recorded, transcribed verbatim and transcripts analysed thematically. Results Ninety-two participants were recruited to the study (47% women; 74–83 years) and a total of 11 focus groups were conducted. Findings indicated six themes that appeared to affect older adults’ participation in PA: past life experiences; significant life events; getting older; PA environment; psychological/personal factors; and social capital. Overall, the findings emphasised the role of modifiable factors, namely psychological factors (such as self-efficacy, motivation, outcome expectancy) and social factors (such as social support and social engagement). These factors exerted their own influence on physical activity participation, but also appeared to mediate the effect of other largely non-modifiable background and ageing-related factors on participants’ engagement with PA in later life. Conclusion In view of these findings, intervention designers could usefully work with behavioural scientists for insight as to how to enhance psychological and social factors in older adults. Our data suggest that interventions that aim to build self-efficacy, motivation and social networks have the potential to indirectly promote PA participation in older adults. This would be best achieved by developing physical activity interventions through working with participants in an empowering and engaging way.
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- 2022
6. Consumer Pandemic Coping: A Stage Model of COVID-19 Response
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Jean Zhang and On Amir
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Marketing ,Economics and Econometrics ,Applied Psychology - Published
- 2023
7. Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening
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Carl A. Machutta, Christopher S. Kollmann, Kenneth E. Lind, Xiaopeng Bai, Pan F. Chan, Jianzhong Huang, Lluis Ballell, Svetlana Belyanskaya, Gurdyal S. Besra, David Barros-Aguirre, Robert H. Bates, Paolo A. Centrella, Sandy S. Chang, Jing Chai, Anthony E. Choudhry, Aaron Coffin, Christopher P. Davie, Hongfeng Deng, Jianghe Deng, Yun Ding, Jason W. Dodson, David T. Fosbenner, Enoch N. Gao, Taylor L. Graham, Todd L. Graybill, Karen Ingraham, Walter P. Johnson, Bryan W. King, Christopher R. Kwiatkowski, Joël Lelièvre, Yue Li, Xiaorong Liu, Quinn Lu, Ruth Lehr, Alfonso Mendoza-Losana, John Martin, Lynn McCloskey, Patti McCormick, Heather P. O’Keefe, Thomas O’Keeffe, Christina Pao, Christopher B. Phelps, Hongwei Qi, Keith Rafferty, Genaro S. Scavello, Matt S. Steiginga, Flora S. Sundersingh, Sharon M. Sweitzer, Lawrence M. Szewczuk, Amy Taylor, May Fern Toh, Juan Wang, Minghui Wang, Devan J. Wilkins, Bing Xia, Gang Yao, Jean Zhang, Jingye Zhou, Christine P. Donahue, Jeffrey A. Messer, David Holmes, Christopher C. Arico-Muendel, Andrew J. Pope, Jeffrey W. Gross, and Ghotas Evindar
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Science - Abstract
Encoded Library Technology (ELT) has streamlined the identification of chemical ligands for protein targets in drug discovery. Here, the authors optimize the ELT approach to screen multiple proteins in parallel and identify promising targets and antibacterial compounds forS. aureus, A. baumannii and M. tuberculosis.
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- 2017
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8. Nutritional risk and its relationship with physical function in community-dwelling older adults
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Ilse Bloom, Jean Zhang, Camille Parsons, Gregorio Bevilacqua, Elaine M. Dennison, Cyrus Cooper, and Kate A. Ward
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Aged, 80 and over ,Male ,Aging ,Frailty ,Hand Strength ,Frail Elderly ,Malnutrition ,Cohort Studies ,Cross-Sectional Studies ,Humans ,Female ,Independent Living ,Geriatrics and Gerontology ,Geriatric Assessment ,Aged - Abstract
Background Malnutrition is a serious concern in older populations. Simple screening approaches are needed to identify signs of early nutritional risk in older people, to allow intervention before overt malnutrition develops, along with the poorer health outcomes associated with it, such as sarcopaenia and frailty. The main aim of this study was to compare nutrition risk scores, calculated from the DETERMINE Checklist (‘Determine Your Nutritional Health’, also known as the Nutrition Screening Initiative Checklist), with physical function variables in a group of community-dwelling older adults. Another aim was to assess the prevalence of nutrition risk using the DETERMINE and the MUST (Malnutrition Universal Screening Tool). Methods Participants of the Hertfordshire Cohort Study (HCS) were recruited and visited at home by a trained researcher. Self-reported physical function was assessed using the SF-36 PF (Short Form-36 Physical Function) scale. The Short Physical Performance Battery (SPPB) was performed, which included the assessment of gait speed, chair rise time and standing balance. Handgrip strength was measured using a Jamar dynamometer. Frailty was assessed according to the presence of at least three of the following Fried frailty criteria: unintentional weight loss, weakness, self-reported exhaustion, slow gait speed and low physical activity. Nutrition risk scores were calculated from the DETERMINE checklist (range 0–21). Nutritional risk was also assessed using the MUST. Analyses were adjusted for sex, age, age left education and number of comorbidities. Results In the study, 176 participants (94 men and 82 women), median age 83.3 (IQR 81.5–85.7) years, were assessed. Almost half (47%) scored either ‘moderate’ (score 3–5) or ‘high’ (score ≥ 6) nutritional risk (9% were at high risk), using the DETERMINE checklist, whereas 8% were at risk using the MUST. Higher nutrition risk scores, calculated from DETERMINE, were associated with poorer self-reported physical function (difference in SF-36 PF score: − 0.36, 95% CI (− 0.60, − 0.12) SD per unit increase in nutrition risk score, P = 0.004) and higher odds of being frail (odds ratio Fried frailty: 2.23, 95% CI (1.15, 4.33), P = 0.017). There were no significant associations between DETERMINE nutrition risk scores and the other variables examined. Conclusion Cross-sectional associations between higher nutrition risk scores, assessed from the DETERMINE checklist, and poorer self-reported physical function and greater likelihood of frailty suggest that this screening tool may have utility for screening older populations. Prospective studies are required to explore the ability of the tool to predict poor physical function and frailty, though these data suggest it has potential for early, simple detection of nutritional problems in community-living older adults.
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- 2022
9. Is Regular Weight-Bearing Physical Activity Throughout the Lifecourse Associated with Better Bone Health in Late Adulthood?
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Jean Zhang, Camille Parsons, Nicholas Fuggle, Kate A. Ward, Cyrus Cooper, and Elaine Dennison
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Adult ,Cohort Studies ,Male ,Weight-Bearing ,Endocrinology ,Bone Density ,Endocrinology, Diabetes and Metabolism ,Humans ,Female ,Orthopedics and Sports Medicine ,Exercise ,Bone and Bones ,Aged - Abstract
We considered how weight-bearing physical activity (WBPA) through the lifecourse related to bone health in late adulthood in the Hertfordshire Cohort Study (HCS), a cohort of community dwelling adults born 1931–9, to identify sex-specific differences and periods critical for optimal bone health. Available questionnaire data from 258 participants (128 men and 130 women) included current reported lifestyle factors (including physical activity) and WBPA, coded as participation in WBPA aged once a week. Hip bone mineral density (BMD) was measured using a Lunar Prodigy DXA scanner. The mean age was 75.4 (SD 2.5) years in men and 75.7 (SD 2.6) years in women. Men reported significantly higher levels of past WBPA aged p = 0.006) and aged 18–29 years than women (p p = 0.02) and 30–49 years (p = 0.02) compared with those who reported no WBPA (p = 0.019), after adjustment for confounders including current activity levels. In this cohort of older adults, recalled regular WBPA around the time of peak bone mass acquisition was less common in women than men, but associated with higher hip BMD in women in late adulthood.
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- 2022
10. Relationships between non-communicable disease, social isolation and frailty in community dwelling adults in later life: findings from the Hertfordshire Cohort Study
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Elaine M. Dennison, Gregorio Bevilacqua, Karen A. Jameson, Cyrus Cooper, Kate A Ward, Jean Zhang, Nicholas R Fuggle, H P Patel, and Ilse Bloom
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Gerontology ,Male ,Aging ,Frail Elderly ,Odds ,Cohort Studies ,medicine ,Humans ,Non-communicable diseases ,Social isolation ,Noncommunicable Diseases ,Geriatric Assessment ,Aged ,Aged, 80 and over ,Social network ,Frailty ,business.industry ,Multimorbidity ,Odds ratio ,Non-communicable disease ,medicine.disease ,Ageing ,Social Isolation ,Cohort ,Original Article ,Female ,Independent Living ,Geriatrics and Gerontology ,medicine.symptom ,Older people ,business ,Cohort study - Abstract
Background Social relationships play a fundamental role in individuals’ lives and health, and social isolation is prevalent among older people. Chronic non-communicable diseases (NCDs) and frailty are also common in older adults. Aims To examine the association between number of NCDs and social isolation in a cohort of community-dwelling older adults in the UK, and to consider whether any potential association is mediated by frailty. Methods NCDs were self-reported by 176 older community-dwelling UK adults via questionnaire. Social isolation was assessed using the six-item Lubben Social Network Scale. Frailty was assessed by the Fried phenotype of physical frailty. Results The median (IQR) age of participants in this study was 83.1 (81.5–85.5) years for men and 83.8 (81.5–85.9) years for women. The proportion of socially isolated individuals was 19% in men and 20% in women. More women (18%) than men (13%) were identified as frail. The number of NCDs was associated with higher odds of being isolated in women (unadjusted odds ratio per additional NCD: 1.65, 95% CI 1.08, 2.52, p = 0.021), but not in men, and the association remained robust to adjustment, even when accounting for frailty (OR 1.85, 95% CI 1.06, 3.22, p = 0.031). Discussion Number of self-reported NCDs was associated with higher odds of social isolation in women but not in men, and the association remained after considering frailty status. Conclusions Our observations may be considered by healthcare professionals caring for community-dwelling older adults with multiple NCDs, where enquiring about social isolation as part of a comprehensive assessment may be important.
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- 2021
11. Investigating the relationship between self-perception of fracture risk and prior fracture: findings from the Hertfordshire Cohort Study
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Gregorio, Bevilacqua, Leo D, Westbury, Ilse, Bloom, Jean, Zhang, Kate A, Ward, Cyrus, Cooper, and Elaine M, Dennison
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Self-perceived risk of fracture (SPR) is associated with fracture independent of FRAX calculated risk. To understand this better we considered whether lifestyle factors not included in the FRAX algorithm and psychosocial factors (social isolation, self-efficacy, or mental health status) explain the relationship between SPR and fracture.We studied 146 UK community-dwelling older adults from the Hertfordshire Cohort Study. SPR ranked as 'lower', 'similar' and 'higher' relative to others of the same age, was assessed by questionnaire. Social isolation was assessed using the six-item Lubben Social Network Scale; self-efficacy was assessed using a shortened General Self-Efficacy Scale (GSE); mental health status was assessed using the anxiety/depression item from the EuroQoL questionnaire. SPR in relation to previous self-reported fracture was examined using logistic regression.Among participants of median age 83.4 (IQR 81.5-85.5) years, SPR was lower for 54.1% of participants, similar for 30.8%, and higher for 15.1%; 74.7% reported no previous fractures. Greater SPR was associated with increased odds of previous fractures when adjusting for sex and age only (OR 1.72, 95% CI 1.03-2.87, per higher band of SPR). While further individual adjustment for social isolation (1.73, 1.04-2.89), self-efficacy (1.71, 1.02-2.85), or mental health (1.77, 1.06-2.97) did not attenuate the relationship, individual adjustment for diet quality and number of comorbidities did.Adjustment for social isolation, self-efficacy or mental health status did not attenuate the relationship between SPR and fracture. By contrast, lifestyle factors not included in FRAX, such as diet quality, did attenuate relationships, suggesting a possible future area of investigation.
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- 2022
12. OP04 Do social isolation, self-efficacy, or mental health influence the relationship between self-perception of fracture risk and prior fracture? Findings from the Hertfordshire Cohort Study
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Gregorio Bevilacqua, Leo Westbury, Ilse Bloom, Jean Zhang, Kate Ward, Cyrus Cooper, and Elaine Dennison
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- 2022
13. P132 Does weight-bearing physical activity track through the lifecourse? Findings from the Hertfordshire Cohort Study
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Jean Zhang, Karen Jameson, Leo Westbury, Nicholas Fuggle, Kate Ward, Cyrus Cooper, and Elaine Dennison
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Rheumatology ,Pharmacology (medical) - Abstract
Background/Aims Physical activity is known to be beneficial for musculoskeletal health across the lifecourse. We have previously demonstrated that regular participation in weight-bearing physical activity (WBPA) at the time of peak bone mass acquisition is associated with higher hip bone mineral density in late adulthood in women. Understanding how WBPA tracks across the lifecourse may help us develop interventions to promote WBPA for musculoskeletal benefit; we consider these relationships here. Methods The study population consisted of 128 men and 130 women from the Hertfordshire Cohort Study. Questionnaire data on participation in sports and leisure time exercise involving WBPA e.g. running, racquet sports, football, rugby, hockey and dancing, but not walking, cycling or swimming were collected for the following age bands: Results The mean age of participants was 75.4 (SD 2.5) years in men and 75.7 (SD 2.6) years in women. Men tended to report higher levels of past WBPA throughout the lifecourse, with significant differences in WBPA up to the age of 18 years (p = 0.006) and 18-29 years (p < 0.001). Table 1 shows kappa statistics of relationships between reported WBPA levels at different ages. These decreased over time, and while broadly similar, the tracking was generally stronger in women than men. For example, we observed that participants who were active at 30-49 years were more likely to remain active in late adulthood with kappa in men 0.393 (95%CI: 0.295-0.442) and kappa in women 0.492 (95% CI: 0.400-0.555). Conclusion WBPA decreased with advancing age in both sexes, though was generally higher in men than women in this retrospective cohort study. The correlation between WBPA at different stages of the lifecourse weakened as time between the measurements increased in both sexes. Our results highlight the need for further work to understand the drivers to encourage WBPA at different stages in the lifecourse and to facilitate development of appropriate interventions to promote WBPA for musculoskeletal benefit. Disclosure J. Zhang: None. K. Jameson: None. L. Westbury: None. N. Fuggle: None. K. Ward: None. C. Cooper: None. E. Dennison: None.
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- 2022
14. Osteoporosis epidemiology using international cohorts
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Daniel Prieto-Alhambra, Jean Zhang, and Elaine M. Dennison
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0301 basic medicine ,Gerontology ,medicine.medical_specialty ,Internationality ,Bone density ,Osteoporosis ,Population ,MEDLINE ,Comorbidity ,Risk Assessment ,03 medical and health sciences ,0302 clinical medicine ,Cost of Illness ,Rheumatology ,Bone Density ,Risk Factors ,Epidemiology ,medicine ,Humans ,education ,Aged ,Femoral neck ,030203 arthritis & rheumatology ,education.field_of_study ,business.industry ,Middle Aged ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Accidental Falls ,Female ,Risk assessment ,business ,Osteoporotic Fractures - Abstract
Purpose of review The field of osteoporosis research has been active for the past 20 years and has allowed significant advancement in the management of osteoporosis. This review will give an overview of the latest data from international cohorts that relate to current and recent osteoporosis research. Recent findings The clinical diagnosis of osteoporosis relies heavily on bone mineral density (BMD) measured at femoral neck or spine and although BMD has excellent predictive value for future fractures, fracture risk assessment has evolved over the years, resulting in the birth of fracture prediction tools. Fracture risk factors not currently featured in these tools are being considered for inclusion, including imminent risk fracture following a sentinel fracture, number of falls, and previous vertebral fractures. Data from groups with comorbidities such as chronic obstructive pulmonary disease are helping us understand how to best manage patients with multiple comorbidities. Finally, the prevalence of vertebral fracture in the older general population and other selected populations has been explored, alongside the global burden of osteoporosis and its consequences. Summary Our understanding of osteoporosis continues to expand, but knowledge gaps remain.
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- 2020
15. Correction: Author Correction: Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening
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Carl A. Machutta, Christopher S. Kollmann, Kenneth E. Lind, Xiaopeng Bai, Pan F. Chan, Jianzhong Huang, Lluis Ballell, Svetlana Belyanskaya, Gurdyal S. Besra, David Barros-Aguirre, Robert H. Bates, Paolo A. Centrella, Sandy S. Chang, Jing Chai, Anthony E. Choudhry, Aaron Coffin, Christopher P. Davie, Hongfeng Deng, Jianghe Deng, Yun Ding, Jason W. Dodson, David T. Fosbenner, Enoch N. Gao, Taylor L. Graham, Todd L. Graybill, Karen Ingraham, Walter P. Johnson, Bryan W. King, Christopher R. Kwiatkowski, Joël Lelièvre, Yue Li, Xiaorong Liu, Quinn Lu, Ruth Lehr, Alfonso Mendoza-Losana, John Martin, Lynn McCloskey, Patti McCormick, Heather P. O’Keefe, Thomas O’Keeffe, Christina Pao, Christopher B. Phelps, Hongwei Qi, Keith Rafferty, Genaro S. Scavello, Matt S. Steiginga, Flora S. Sundersingh, Sharon M. Sweitzer, Lawrence M. Szewczuk, Amy Taylor, May Fern Toh, Juan Wang, Minghui Wang, Devan J. Wilkins, Bing Xia, Gang Yao, Jean Zhang, Jingye Zhou, Christine P. Donahue, Jeffrey A. Messer, David Holmes, Christopher C. Arico-Muendel, Andrew J. Pope, Jeffrey W. Gross, and Ghotas Evindar
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Science - Abstract
Nature Communications 8: Article number: 16081 (2017); Published: 17 July 2017, Updated: 13 July 2018 The original version of this Article omitted the following from the Acknowledgements: ‘We thank Robert Kirkpatrick for implementing the high throughput protein design strategy that enabled screeningand triage of essential A.
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- 2018
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16. P52 The experiences of community-dwelling older adults during the COVID-19 pandemic: preliminary findings from a qualitative study with hertfordshire cohort study participants
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Wendy Lawrence, Ilse Bloom, Cyrus Cooper, Jean Zhang, Elaine M. Dennison, Kate A Ward, and Gregorio Bevilacqua
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Gerontology ,business.industry ,media_common.quotation_subject ,Loneliness ,Mental health ,Health care ,Pandemic ,medicine ,medicine.symptom ,Social isolation ,Worry ,business ,Cohort study ,Qualitative research ,media_common - Abstract
Background The COVID-19 pandemic has led to dramatic changes in people’s lives globally. Older adults have been especially vulnerable to adverse effects from the pandemic including higher mortality and more severe disease complications. At the same time, social isolation, malnutrition and physical inactivity are serious concerns among older adults. The pandemic and associated restrictions may serve to exacerbate these issues, presenting increased risks to physical and mental health. The aim of this qualitative study was to explore how community-living older people in the UK experienced the first wave of the COVID-19 pandemic and how it impacted their health and well-being, and associated behaviours. Methods Qualitative data were collected by conducting serial telephone interviews, with an interval of approximately three months. Participants were from the Hertfordshire Cohort Study, all aged over 80 years. Discussions were audio-recorded, information related to the COVID-19 pandemic was transcribed verbatim and transcripts analysed thematically. Interviews were conducted from March to October 2020. Results Twelve participants were included in the study (7 men and 5 women). Data from a total of 35 qualitative interviews were used, comprising two or three timepoints per participant. Preliminary analysis identified five overarching themes: 1) shopping strategies and food accessibility, 2) limitations on activities and going out, 3) disruption to healthcare, 4) social and psychological repercussions, and 5) coping strategies. Initial findings highlight challenges associated with accessing shops, healthcare, and usual activities due to restrictions. Findings emphasize the issue of loneliness and isolation for some of the participants, especially those living alone, as well as fear of the virus, with restrictions leading to a loss of purpose for some, along with related effects on mental health (e.g. worry, anxiety). For some, these issues appeared to link to a reprioritisation of their behaviours (for example, exercise and diet were deprioritised). Coping strategies used by participants included finding ways to keep busy and to do physical activity safely, maintaining social contact online or by telephone, and having an optimistic or positive outlook, a ‘do what you can’ attitude. Conclusion Analysis is ongoing and will further aim to explore how older people’s experiences and behaviours might have changed over the duration of the pandemic. The findings from this study could improve understanding of how community-living older adults could be supported to be more resilient in the face of a variety of changing circumstances that might impact their health and well-being.
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- 2021
17. P51 A survey of the impact of wave one of the COVID-19 pandemic on participants of the hertfordshire cohort study
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Ilse Bloom, Kate A Ward, Jean Zhang, Karen A. Jameson, Alice Paul, Cyrus Cooper, Elaine M. Dennison, and Gregorio Bevilacqua
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Coronavirus disease 2019 (COVID-19) ,business.industry ,Spouse ,Cohort ,Pandemic ,Medicine ,Severe disease ,business ,Socioeconomic status ,World health ,Demography ,Cohort study - Abstract
Background Covid-19, a coronavirus that originated in China in late 2019, spread globally to be declared a pandemic by the World Health Organisation in March 2020. The aim of this study was to usean existing cohort of community-dwelling older adults, the Hertfordshire Cohort Study (HCS), to understand how wave one of the Covid-19 pandemic impacted UK older adults, a group particularly vulnerable to severe disease. Methods 71 eligible participants, 39 males and 32 females (drawn from the HCS study, mean age 83.6 (2.5) years, all Caucasian, and community dwelling) were contacted by telephone and asked to complete a questionnaire administered by a trained researcher. Data collection occurred over the period of July to October 2020. Results Over a third (37.1%) of respondents lived alone. Of the remainder, 86.4% lived with a spouse while the remaining 13.6% lived with family. Of concern, 19.7% of participants had felt they needed to go out despite not wanting to; 47.1% had heard of the NHS Volunteer Responders programme, although only 3 (4.2%) had made use of this or other support services. Almost a third (31%) of participants reported they had access to a smartphone, while 62% reported having unlimited internet access, usually using a tablet or computer. Over two thirds (69.0%) of participants rated their understanding of Covid-19 itself as good. Perhaps unsurprisingly, a large majority (88.7%) of participants said their life was different compared to before Covid-19; 80.3% had less social contact and more than half (52%) of respondents reported being less physically active than before the pandemic (and only 4% more so). However, levels of sleep, alcohol consumption and diet were reportedly generally unchanged over the timeframe surveyed. Conclusion We have reported the experience of the first wave of the Covid-19 pandemic among participants of an older Caucasian community-dwelling UK cohort, highlighting the need to consider this group when developing public health interventions to support health and wellbeing, including those employing smartphone technology. Further larger studies in groups of wider socioeconomic status and more diverse racial background are indicated.
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- 2021
18. Understanding influences on physical activity participation by older adults: A qualitative study of community-dwelling older adults from the Hertfordshire Cohort Study, UK
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Jean Zhang, Ilse Bloom, Elaine M. Dennison, Kate A. Ward, Sian M. Robinson, Mary Barker, Cyrus Cooper, and Wendy Lawrence
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Male ,Aging ,Social Psychology ,Physiology ,Science ,Social Sciences ,Walking ,Research and Analysis Methods ,Elderly ,Medicine and Health Sciences ,Humans ,Adults ,Psychology ,Public and Occupational Health ,Exercise ,Aged ,Aged, 80 and over ,Behavior ,Motivation ,Multidisciplinary ,Biological Locomotion ,Cognitive Psychology ,Biology and Life Sciences ,Physical Activity ,Focus Groups ,Qualitative Studies ,Self Efficacy ,United Kingdom ,Age Groups ,Research Design ,People and Places ,Medicine ,Cognitive Science ,Female ,Population Groupings ,Independent Living ,Behavioral and Social Aspects of Health ,Physiological Processes ,Organism Development ,Research Article ,Neuroscience ,Developmental Biology - Abstract
Background The health benefits of physical activity (PA) participation in later life are widely recognised. Understanding factors that can influence the participation of community-dwelling older adults in PA is crucial in an ageing society. This will be paramount in aiding the design of future interventions to effectively promote PA in this population. The main aim of this qualitative study was to explore influences on PA among community-dwelling older people, and the secondary aim was to explore gender differences. Methods Qualitative data were collected in 2014 by conducting focus group discussions using a semi-structured discussion guide with older people resident in Hertfordshire, UK. Discussions were audio-recorded, transcribed verbatim and transcripts analysed thematically. Results Ninety-two participants were recruited to the study (47% women; 74–83 years) and a total of 11 focus groups were conducted. Findings indicated six themes that appeared to affect older adults’ participation in PA: past life experiences; significant life events; getting older; PA environment; psychological/personal factors; and social capital. Overall, the findings emphasised the role of modifiable factors, namely psychological factors (such as self-efficacy, motivation, outcome expectancy) and social factors (such as social support and social engagement). These factors exerted their own influence on physical activity participation, but also appeared to mediate the effect of other largely non-modifiable background and ageing-related factors on participants’ engagement with PA in later life. Conclusion In view of these findings, intervention designers could usefully work with behavioural scientists for insight as to how to enhance psychological and social factors in older adults. Our data suggest that interventions that aim to build self-efficacy, motivation and social networks have the potential to indirectly promote PA participation in older adults. This would be best achieved by developing physical activity interventions through working with participants in an empowering and engaging way.
- Published
- 2021
19. The treatment gap: the missed opportunities for osteoporosis therapy
- Author
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Kate A Ward, Nicholas R Fuggle, Jean Zhang, Muhammad Javaid, Elaine M. Dennison, Cyrus Cooper, Beth Curtis, Michael A. Clynes, and Nicholas C. Harvey
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Histology ,Physiology ,Endocrinology, Diabetes and Metabolism ,Osteoporosis ,030209 endocrinology & metabolism ,Article ,03 medical and health sciences ,Fractures, Bone ,0302 clinical medicine ,Atypical femoral fracture ,Primary prevention ,Epidemiology ,medicine ,Humans ,Intensive care medicine ,Adverse effect ,Bone Density Conservation Agents ,Diphosphonates ,business.industry ,Osteonecrosis ,medicine.disease ,030104 developmental biology ,Female ,business ,Osteonecrosis of the jaw ,Risk assessment - Abstract
Despite substantial advances in delineation of the epidemiology, pathophysiology, risk assessment and treatment of osteoporosis over the last three decades, a substantial proportion of men and women at high risk of fracture remain untreated - the so-called "treatment gap". This review summarises the important patient-, physician- and policyrelated causes of this treatment gap, before discussing in greater detail: (a) the evidence base for the efficacy of bisphosphonates in osteoporosis; (b) recent evidence relating to the adverse effects of this widely used therapeutic class, most notably atypical femoral fracture and osteonecrosis of the jaw; (c) available strategies to improve both secondary and primary prevention pathways for the management of this disorder.
- Published
- 2021
20. The association between social isolation and musculoskeletal health in older community-dwelling adults: findings from the Hertfordshire Cohort Study
- Author
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Kate A Ward, Jean Zhang, Cyrus Cooper, Elaine M. Dennison, Ilse Bloom, Gregorio Bevilacqua, and Karen A. Jameson
- Subjects
Gerontology ,Male ,Anxiety ,Hospital Anxiety and Depression Scale ,Article ,Odds ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,BMD ,Physical capability ,Medicine ,Humans ,030212 general & internal medicine ,Social isolation ,Depression (differential diagnoses) ,Aged ,business.industry ,Depression ,Public Health, Environmental and Occupational Health ,Loneliness ,Social engagement ,Older adults ,Quality of Life ,Female ,Independent Living ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Cohort study - Abstract
Purpose Social isolation has been associated with both physical and psychological adverse outcomes and is prevalent in older adults. We investigated the impact of social isolation on bone mineral density (BMD) and physical capability in community-dwelling older adults. Methods Data were collected in 2011 and 2017 from the Hertfordshire Cohort Study. In 2011, we assessed social isolation using the six-item Lubben Social Network Scale (LSNS-6) and the Maastricht Social Participation Profile (MSSP) and depressive and anxiety symptoms using the Hospital Anxiety and Depression Scale (HADS). Physical capability was assessed by performing tests of gait speed, chair stands, timed up and go and balance at both time points. BMD was assessed using dual X-ray absorptiometry (DXA) at both time points. Results Data were available from 369 participants in 2011 and 184 in 2017. Forty percent of men and 42.4% of women were socially isolated. Isolated participants had higher odds of depressive disorder (OR 3.01, 95% CI 1.27–7.11, p p Conclusions Social isolation was associated with higher odds of having depressive symptoms and predicted the development of poor physical capability 6 years later. Further longitudinal studies that include loneliness as a covariate are warranted.
- Published
- 2021
21. Anabolic and Emerging Therapies
- Author
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Jean Zhang and Elaine M. Dennison
- Subjects
Bone mineral ,Anabolism ,business.industry ,Abaloparatide ,Osteoporosis ,Romosozumab ,medicine.disease ,Bioinformatics ,Bone health ,Anabolic Agents ,medicine ,Teriparatide ,business ,medicine.drug - Abstract
To date conventional osteoporosis therapy has been largely dominated by the use of anti-resorptive therapy but more recently anabolic agents have emerged as an important option for bone health management. Teriparatide is the most well-known anabolic agent. Its efficacy with regard to bone mineral density increase and fracture reduction have been demonstrated in numerous studies while abaloparatide has been licenced in the United States for osteoporosis management. In the last year, a new therapeutic target, romosozumab, an anti-sclerostin monoclonal antibody, achieved approval in both Europe and the United States, for management of osteoporosis. This provides an overview of current and emerging potential therapeutic targets.
- Published
- 2021
22. How Product Unavailability Leads to Choice of Lesser Alternatives—The Role of Hedonic Aggregation
- Author
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Jean Zhang, Gal Smitizsky, and On Amir
- Subjects
Microeconomics ,History ,Polymers and Plastics ,Stockout ,Product (category theory) ,Business ,Business and International Management ,Unavailability ,Industrial and Manufacturing Engineering - Published
- 2021
23. P68 Age-related muscle strength decline in mid-late life varies in men and women and is associated with diet and physical activity: observations from the Hertfordshire Cohort Study
- Author
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Elaine M. Dennison, Cyrus Cooper, Karen A. Jameson, Jean Zhang, and Faidra Laskou
- Subjects
business.industry ,Physical activity ,Mixed anxiety-depressive disorder ,medicine.disease ,Grip strength ,Rheumatology ,Quality of life ,Age related ,Muscle strength ,Medicine ,Pharmacology (medical) ,business ,Depressed mood ,Cohort study ,Demography - Abstract
Background In the context of an aging population, age-related decline in muscle strength is well recognised, and is associated with functional limitation and increased mortality. However, scarce epidemiological data are available regarding its prevalence, or lifestyle associations at a time when intervention is still possible to retard or prevent loss. We considered these issues in the Hertfordshire Cohort Study, a cohort of late-middle aged community dwelling adults. Methods 2,987 participants were seen in 1999-2004, 1,572 men and 1,415 women. A lifestyle questionnaire was administered that asked about social class, physical activity, diet, co-morbidities and cigarette and alcohol consumption. Grip strength was measured with a Jamar dynamometer, three times on each side with the highest value used. Age related muscle strength decline was defined, according to current convention, as a grip strength Results The mean age of participants was 65.8 (IQR 63.5-67.8) years for men and 66.5 (IQR 64.5-68.7) years for women. Muscle strength decline was more common in women (10.3%) than men (3%); the odds ratio (OR) for age-related muscle strength decline was 3.73 (95%CI 2.66-5.23) in women relative to men (p < 0.001). Factors that appeared protective included higher physical activity scores in men (OR 0.97, 95%CI 0.96-0.99, p = 0.003) and in women (OR 0.97, 95%CI 0.96-0.98, p < 0.001) and a higher prudent diet score in women (OR: 0.74, 95%CI 0.60-0.90 p = 0.003). Muscle strength decline was strongly associated with quality of life in women (p ≤ 0.001) as assessed by SF36 and EuroQoL EQ-5D for all domains, although EuroQOL anxiety/depression and SF36 role emotional were less strongly associated (p-value=0.042, p-value=0.006, respectively). Table 1 shows self-reported impaired ability to move, self-care, perform usual activities and increased pain were associated with higher risk of age-related muscle strength decline in women. Conclusion Age related muscle strength decline was more common in community dwelling women than men, and diet and physical activity were predictors of such decline. Research into effective preventative interventions is now warranted. Disclosures J. Zhang None. F. Laskou None. K. Jameson None. C. Cooper None. E.M. Dennison None.
- Published
- 2020
24. P02 Osteoporosis management when denosumab therapy ends: an audit of current practice
- Author
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Elaine M. Dennison, Jean Zhang, Michael A. Clynes, and Cyrus Cooper
- Subjects
medicine.medical_specialty ,business.industry ,Osteoporosis ,Primary health care ,Alternative medicine ,Audit ,Denosumab therapy ,medicine.disease ,Osteopenia ,Denosumab ,Rheumatology ,Current practice ,medicine ,Pharmacology (medical) ,Intensive care medicine ,business ,medicine.drug - Abstract
Background In recent years denosumab therapy has been widely used in the treatment of osteoporosis. However, since its first introduction to clinical practice, evidence has demonstrated discontinuation leads to rebound bone loss and risk of vertebral fracture. In view of this, guidance has been updated recommending transition to an alternative osteoporosis therapy. Given that osteoporosis management is largely managed in primary care, we performed this audit to investigate whether this educational message was being effectively relayed to primary care clinicians. Methods In this study, we closed the audit loop of a previous study of the first 50 patients commenced on denosumab at University Hospital Southampton in 2013; we explored the percentage of patients remaining on denosumab 6 years later, using the hospital electronic system, which is linked to the general practice electronic system, to confirm prescriptions for osteoporosis therapy. In cases where it was unclear, letters were written, or telephone calls were made to general practices for clarification. Continuation of denosumab or use of an alternative agent was then recorded. Results Nineteen (38%) patients had died since the initial audit, reflecting the use of the agent in later life post hip fracture. Of 15 patients no longer on denosumab, 9 (60%) were found not to be on alternative bone protection without other information recorded, 1 (7%) had denosumab suspended by the GP (with the presumption it may be restarted at a later date), 1 (7%) had denosumab suspended due to recurrent cellulitis with the view to reassess in a year and 3 (20%) were on alternative therapy. One patient was recorded as being on a ‘drug holiday’. Of 16 patients remaining on denosumab, 13 (81%) had pre-injection calcium level checks, and 12 (75%) had a recorded pre-injection renal function check. Conclusion These data reflect inappropriate widespread discontinuation of denosumab without follow-on with an alternative osteoporosis therapy, suggesting that targeted education of primary care physicians is necessary. A high proportion of patients on denosumab are having the relevant blood tests in primary care as per clinical guidelines. Disclosures J. Zhang None. M.A. Clynes None. C. Cooper None. E.M. Dennison None.
- Published
- 2020
25. 94. Psoriatic arthritis, rheumatoid arthritis or both?
- Author
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Zoe Cole, Aisling Coy, Jean Zhang, Richard Smith, and Sarah Bartram
- Subjects
Psoriatic arthritis ,medicine.medical_specialty ,Rheumatology ,business.industry ,Rheumatoid arthritis ,D. CASE REPORTS ,Medicine ,d. Biologics in inflammatory arthritis ,business ,medicine.disease ,Dermatology - Published
- 2018
26. Correction: Author Correction: Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening
- Author
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Jeffrey A. Messer, Yun Ding, Jianghe Deng, Paolo A. Centrella, Todd L. Graybill, Jean Zhang, Patti McCormick, Carl A. Machutta, Robert H. Bates, John Martin, Joël Lelièvre, Quinn Lu, Jingye Zhou, Alfonso Mendoza-Losana, Xiaopeng Bai, Christopher S. Kollmann, David J. Holmes, Keith Rafferty, Christina S. Pao, Christopher C. Arico-Muendel, Heather O’Keefe, Aaron Coffin, Taylor L. Graham, David Barros-Aguirre, Sandy Chang, Christopher P. Davie, Hongwei Qi, Flora S. Sundersingh, Minghui Wang, Karen A. Ingraham, Jing Chai, Thomas O’Keeffe, Juan Wang, Gang Yao, Lluis Ballell, Jianzhong Huang, Anthony E. Choudhry, Bryan W. King, Andrew J. Pope, Ghotas Evindar, Xiaorong Liu, May Fern Toh, Christine Patricia Donahue, Jeffrey W. Gross, Pan F. Chan, Walter P. Johnson, Ruth Lehr, Hongfeng Deng, Kenneth E Lind, Matt S. Steiginga, Jason W. Dodson, Gurdyal S. Besra, Amy N. Taylor, Devan J. Wilkins, Yue Li, Lawrence M. Szewczuk, Svetlana L. Belyanskaya, Genaro S. Scavello, Sharon Sweitzer, Christopher R. Kwiatkowski, Lynn McCloskey, Bing Xia, Enoch Gao, Christopher B. Phelps, and David T. Fosbenner
- Subjects
chemistry.chemical_compound ,Multidisciplinary ,chemistry ,Computer science ,Science ,General Physics and Astronomy ,General Chemistry ,Computational biology ,General Biochemistry, Genetics and Molecular Biology ,DNA - Abstract
Nature Communications 8: Article number: 16081 (2017); Published: 17 July 2017, Updated: 13 July 2018 The original version of this Article omitted the following from the Acknowledgements: ‘We thank Robert Kirkpatrick for implementing the high throughput protein design strategy that enabled screeningand triage of essential A.
- Published
- 2018
27. e43 The management of biologics peri-operatively and post-operatively
- Author
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Jean Zhang, Christopher Holroyd, Sarah Bennett, and Ashish Patel
- Subjects
medicine.medical_specialty ,Rheumatology ,business.industry ,Peri ,medicine ,Pharmacology (medical) ,business ,Surgery - Published
- 2018
28. China: Medical device regulatory system
- Author
-
Jean Zhang
- Subjects
Medical device ,business.industry ,Business ,China ,Telecommunications - Published
- 2018
29. Design and synthesis of a hybrid series of potent and selective agonists of α7 nicotinic acetylcholine receptor
- Author
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Simon N. Haydar, Jean Zhang, John Dunlop, Arianna Nencini, Laura Maccari, Elisa Turlizzi, Riccardo Zanaletti, Thomas A. Comery, Chiara Ghiron, Eva Genesio, Iolanda Micco, and Cristiana Castaldo
- Subjects
Male ,Models, Molecular ,Cell Membrane Permeability ,alpha7 Nicotinic Acetylcholine Receptor ,Stereochemistry ,Pyrazole ,Structure-Activity Relationship ,chemistry.chemical_compound ,Dogs ,α7 nicotinic acetylcholine receptor ,Drug Discovery ,Animals ,Humans ,Urea ,Rats, Wistar ,Cognitive impairment ,ADME ,Pharmacology ,Dose-Response Relationship, Drug ,Molecular Structure ,Organic Chemistry ,HEK 293 cells ,General Medicine ,Rats ,chemistry ,Drug Design ,Pyrazoles ,α7 nachr - Abstract
α7 nicotinic acetylcholine receptor agonists are promising therapeutic candidates for the treatment of cognitive impairment. As a follow up of our internal medicinal chemistry program we investigated a novel series of α7 nAChR agonists. Starting from molecular docking studies on two series of molecules recently developed in our laboratories, an alternative scaffold was designed attempting to combine the optimal features of these previously identified urea and pyrazole compounds. Based on our previous SAR knowledge and on predicted drug-like properties, a small library was synthesized in parallel manner, affording compounds with excellent α7 nAChR activity, selectivity and preliminary ADME profile.
- Published
- 2014
30. Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening
- Author
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Todd L. Graybill, John D. Martin, Jason W. Dodson, Hongfeng Deng, Christopher P. Davie, Christopher C. Arico-Muendel, Minghui Wang, Hongwei Qi, Sandy S. Chang, David J. Holmes, Karen A. Ingraham, Kenneth E Lind, Heather O’Keefe, Carl A. Machutta, David Barros-Aguirre, Christine Patricia Donahue, Christina S. Pao, Jeffrey W. Gross, Ghotas Evindar, Jean Zhang, Bing Xia, Juan Wang, Patti McCormick, Xiaorong Liu, Jianzhong Huang, Joël Lelièvre, Quinn Lu, Pan F. Chan, Matt S. Steiginga, Lynn McCloskey, Christopher S. Kollmann, Taylor L. Graham, Xiaopeng Bai, Jing Chai, Yue Li, Walter P. Johnson, Ruth Lehr, Lawrence M. Szewczuk, Jingye Zhou, Lluis Ballell, Genaro S. Scavello, Robert H. Bates, Anthony E. Choudhry, Aaron Coffin, Sharon Sweitzer, Christopher R. Kwiatkowski, Andrew J. Pope, Enoch Gao, Christopher B. Phelps, David T. Fosbenner, Keith Rafferty, Thomas O’Keeffe, Gang Yao, Bryan W. King, Svetlana L. Belyanskaya, May Fern Toh, Gurdyal S. Besra, Amy N. Taylor, Devan J. Wilkins, Alfonso Mendoza-Losana, Paolo A. Centrella, Flora S. Sundersingh, Jeffrey A. Messer, Yun Ding, and Jianghe Deng
- Subjects
0301 basic medicine ,Acinetobacter baumannii ,Staphylococcus aureus ,Computer science ,Science ,Drug Evaluation, Preclinical ,General Physics and Astronomy ,Computational biology ,Bioinformatics ,Article ,General Biochemistry, Genetics and Molecular Biology ,Small Molecule Libraries ,03 medical and health sciences ,chemistry.chemical_compound ,Drug Discovery ,Molecular Targeted Therapy ,Gene Library ,Multidisciplinary ,Drug discovery ,Correction ,General Chemistry ,Mycobacterium tuberculosis ,Anti-Bacterial Agents ,030104 developmental biology ,chemistry ,Identification (biology) ,DNA - Abstract
The identification and prioritization of chemically tractable therapeutic targets is a significant challenge in the discovery of new medicines. We have developed a novel method that rapidly screens multiple proteins in parallel using DNA-encoded library technology (ELT). Initial efforts were focused on the efficient discovery of antibacterial leads against 119 targets from Acinetobacter baumannii and Staphylococcus aureus. The success of this effort led to the hypothesis that the relative number of ELT binders alone could be used to assess the ligandability of large sets of proteins. This concept was further explored by screening 42 targets from Mycobacterium tuberculosis. Active chemical series for six targets from our initial effort as well as three chemotypes for DHFR from M. tuberculosis are reported. The findings demonstrate that parallel ELT selections can be used to assess ligandability and highlight opportunities for successful lead and tool discovery., Encoded Library Technology (ELT) has streamlined the identification of chemical ligands for protein targets in drug discovery. Here, the authors optimize the ELT approach to screen multiple proteins in parallel and identify promising targets and antibacterial compounds for S. aureus, A. baumannii and M. tuberculosis.
- Published
- 2016
31. Accumulation of risk factors associated with poor bone health in older adults
- Author
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Elaine M. Dennison, Cyrus Cooper, Sian M. Robinson, Jean Zhang, Avan Aihie Sayer, and Karen A. Jameson
- Subjects
Male ,Gerontology ,Alcohol Drinking ,Bone density ,Cross-sectional study ,Population ,030209 endocrinology & metabolism ,Clustering ,Cohort Studies ,Fractures, Bone ,03 medical and health sciences ,Grip strength ,0302 clinical medicine ,Bone Density ,Risk Factors ,Bone mineral density ,Humans ,Medicine ,Orthopedics and Sports Medicine ,Femur ,030212 general & internal medicine ,Family history ,education ,Exercise ,Aged ,Bone mineral ,education.field_of_study ,Lumbar Vertebrae ,Hand Strength ,business.industry ,Smoking ,Hazard ratio ,Middle Aged ,Lifestyle ,Diet ,Cross-Sectional Studies ,Original Article ,Female ,Bone Diseases ,Alcohol ,business ,Demography ,Cohort study - Abstract
Summary: Clustering of factors linked with poor bone health is common in older adults and is associated with lower bone density and increased fracture risk in women.Purpose: Many factors are associated with bone mineral density, which in turn is strongly linked with risk of fragility fracture. We assessed how commonly clustering of risk factors occurs and related such clustering to bone mineral density in a population of older community-dwelling men and women.Method: This is a cross-sectional study with 498 men and 498 women aged 59 to 72 years, who were participants in the Hertfordshire Cohort Study, in whom incident fracture was recorded. Physical activity, diet quality, history of prior fracture, family history of fracture, cigarette and alcohol consumption and comorbidities were obtained through baseline questionnaire. Measurements of grip strength and bone mineral density of the lumbar spine and total femur were also taken.Results: Clustering of risk factors was common, with over 30 % having two or more. In women, a graded association between the number of risk factors and low bone density was seen, and strong relationships were also seen between the number of risk factors and incident fracture; women with three or more risk factors had an adjusted hazard ratio (HR) of incident fracture of 5.98 (1.67, 21.43; p?=?0.006) compared to women with no risk factors; women with two risk factors had an adjusted HR of 2.97 (1.14, 7.74; p?=?0.03) and those with one, 2.28 (0.90, 5.75; p?=?0.08).Conclusion: Clustering of risk factors for poor bone health is common in community-dwelling older adults and is associated with increased risk of fracture and adverse bone health in women.
- Published
- 2015
32. Cell-Based Selection Expands the Utility of DNA-Encoded Small-Molecule Library Technology to Cell Surface Drug Targets: Identification of Novel Antagonists of the NK3 Tachykinin Receptor
- Author
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Zining Wu, Sibongile Mataruse, Alex M. Tamburino, Gang Yao, Jeffrey A. Messer, Yun Ding, Jean Zhang, G Joseph Franklin, Jianghe Deng, Todd L. Graybill, Xin Zeng, David D. Wisnoski, Frank T. Coppo, David I. Israel, Genaro S. Scavello, Jennifer Summerfield, Andrew J. Pope, Michael Platchek, Vera Q. Bodmer, Paolo A. Centrella, Jing Chai, and Katie L Sargent Bedard
- Subjects
Cell ,Computational biology ,Acetates ,Ligands ,Small Molecule Libraries ,Structure-Activity Relationship ,medicine ,Humans ,Receptor ,Integral membrane protein ,G protein-coupled receptor ,Dose-Response Relationship, Drug ,Molecular Structure ,Drug discovery ,DNA-encoded chemical library ,Chemistry ,Receptors, Neurokinin-3 ,General Chemistry ,General Medicine ,DNA ,Combinatorial chemistry ,Small molecule ,medicine.anatomical_structure ,HEK293 Cells ,Quinolines ,Tachykinin receptor - Abstract
DNA-encoded small-molecule library technology has recently emerged as a new paradigm for identifying ligands against drug targets. To date, this technology has been used with soluble protein targets that are produced and used in a purified state. Here, we describe a cell-based method for identifying small-molecule ligands from DNA-encoded libraries against integral membrane protein targets. We use this method to identify novel, potent, and specific inhibitors of NK3, a member of the tachykinin family of G-protein coupled receptors (GPCRs). The method is simple and broadly applicable to other GPCRs and integral membrane proteins. We have extended the application of DNA-encoded library technology to membrane-associated targets and demonstrate the feasibility of selecting DNA-tagged, small-molecule ligands from complex combinatorial libraries against targets in a heterogeneous milieu, such as the surface of a cell.
- Published
- 2015
33. Characterization of Vabicaserin (SCA-136), a Selective 5-Hydroxytryptamine 2C Receptor Agonist
- Author
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John Dunlop, Gary Stack, Menelas N. Pangalos, Joseph Coupet, Deborah L. Smith, Sharon Rosenzweig-Lipson, James E. Barrett, Hossein Mazandarani, Boyd Harrison, Jean Zhang, Siva Ramamoorthy, Lee E. Schechter, Guoming Zhang, Stephanie W. Watts, and Stanley Nawoschik
- Subjects
Male ,Agonist ,Serotonin ,medicine.medical_specialty ,medicine.drug_class ,Receptor expression ,CHO Cells ,Vabicaserin ,Pharmacology ,Biology ,Heterocyclic Compounds, 4 or More Rings ,Partial agonist ,Cell Line ,Rats, Sprague-Dawley ,Cricetulus ,Cricetinae ,Internal medicine ,Receptor, Serotonin, 5-HT2B ,Receptor, Serotonin, 5-HT2C ,medicine ,Animals ,Humans ,Receptor, Serotonin, 5-HT2A ,Molecular Targeted Therapy ,Receptor ,5-HT receptor ,Binding Sites ,Muscle, Smooth ,Recombinant Proteins ,Rats ,Endocrinology ,Dopamine receptor ,Serotonin 5-HT2 Receptor Antagonists ,Molecular Medicine ,Antagonism ,Serotonin 5-HT2 Receptor Agonists ,Antipsychotic Agents ,Muscle Contraction ,Protein Binding ,Signal Transduction - Abstract
The 5-hydroxytryptamine 2C (5-HT 2C ) receptor subtype has received considerable attention as a target for drug discovery, having been implicated in a wide variety of disorders. Here, we describe the in vitro pharmacological profile of the novel 5-HT 2C receptor-selective agonist vabicaserin [(−)-4,5,6,7,9,9a,10,11,12,12a-decahydrocyclopenta[c] [1,4]diazepino[6,7,1-ij]quinoline hydrochloride] (SCA-136), including a comprehensive strategy to assess 5-HT 2B receptor selectivity using diverse preparations and assays of receptor activation. Vabicaserin displaced 125 I-(2,5-dimethoxy)phenylisopropylamine binding from human 5-HT 2C receptor sites in Chinese hamster ovary cell membranes with a K i value of 3 nM and was >50-fold selective over a number of serotonergic, noradrenergic, and dopaminergic receptors. Binding affinity determined for the human 5-HT 2B receptor subtype using [ 3 H]5HT was 14 nM. Vabicaserin was a potent and full agonist (EC 50 , 8 nM; E max , 100%) in stimulating 5-HT 2C receptor-coupled calcium mobilization and exhibited 5-HT 2A receptor antagonism and 5-HT 2B antagonist or partial agonist activity in transfected cells, depending on the level of receptor expression. In rat stomach fundus and human colonic longitudinal muscle endogenously expressing 5-HT 2B receptors, vabicaserin failed to induce a 5-HT 2B receptor-dependent contraction and produced a rightward shift of the 5-HT and α-methyl-5-HT concentration-response curves in these preparations, respectively, consistent with 5-HT 2B competitive antagonism. Likewise, vabicaserin failed to induce a 5-HT 2B receptor-mediated contraction in arteries from deoxycorticosterone acetate-salt-treated rats, a model of hypersensitized 5-HT 2B receptor function, and produced a rightward shift in the 5-HT-induced response that was consistent with 5-HT 2B receptor antagonism. In summary, vabicaserin is a novel, potent, and selective 5-HT 2C receptor agonist.
- Published
- 2011
34. Comorbidities, Not Age, Impact Outcomes in Autologous Stem Cell Transplant for Relapsed Non-Hodgkin Lymphoma
- Author
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Kristan M. Augustin, Tanya M. Wildes, Ravi Vij, Qin Jean Zhang, Steven M. Devine, John F. DiPersio, and Diane S. Sempek
- Subjects
Adult ,Male ,Melphalan ,medicine.medical_specialty ,Comorbidity ,Autologous stem cell transplantation ,Severity of Illness Index ,Transplantation, Autologous ,Disease-Free Survival ,Elderly ,Autologous stem-cell transplantation ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,High-dose chemotherapy ,Mucositis ,medicine ,Humans ,Aged ,Podophyllotoxin ,Retrospective Studies ,Non-Hodgkin lymphoma ,Transplantation ,business.industry ,Lymphoma, Non-Hodgkin ,Graft Survival ,Cytarabine ,Retrospective cohort study ,Hematology ,Middle Aged ,medicine.disease ,Carmustine ,Surgery ,Tolerability ,Cohort ,Female ,business ,Stem Cell Transplantation ,medicine.drug - Abstract
High-dose chemotherapy followed by autologous peripheral blood stem cell transplantation is a widely applied treatment for advanced non-Hodgkin lymphoma (NHL), but few studies have analyzed the tolerability and outcomes in older patients compared with younger patients treated in a homogeneous manner. We retrospectively reviewed 152 consecutive patients who underwent autologous stem cell transplantation (ASCT) following BEAM conditioning (carmustine, etoposide, cytarabine, and melphalan) for NHL from January 2000 through August 2004 at our institution. We compared 59 patients age ≥60 years and 93 patients age 20,000/mm3 were similar in younger and older patients, although days to platelet count >50,000/mm3 were longer in the older patients (median 30.0 days versus 22.5 days, P = .01). Patients over the age of 60 were more likely to develop grade III/IV mucositis than their younger counterparts (37.7% versus17.4%, P = .0063). Otherwise, the frequency of other grade III/IV toxicities were similar between younger and older patients. Treatment-related mortality (TRM) was similar between older and younger patients (8.5% versus 5.4%, P = .45). Although age was not associated with TRM, the Charlson Comorbidity Index Score was significantly correlated with TRM (P = .03). Median disease-free survival was similar between older and younger patients (21.8 months versus 29.9 months, P = .93), as was overall survival (OS) (47.7 months versus 62.5 months, P = .20). After controlling for age, the Charlson Comorbidity Index Score influenced OS [P = .013]. Overall, our cohort of patients with NHL over the age of 60 who underwent ASCT following BEAM conditioning experienced toxicities and survival similar to their younger counterparts. Comorbidities significantly influenced TRM and OS in this retrospective cohort. Future study should focus on improving tolerability of conditioning and careful prospective evaluation of comorbidities and their association with outcomes.
- Published
- 2008
35. Bcl2L12 inhibits post-mitochondrial apoptosis signaling in glioblastoma
- Author
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Gregory J. Hannon, Hyunggee Kim, Kevin K. Park, Harald Schulze, David N. Louis, Jean Zhang, Alexander H. Stegh, Robert M. Bachoo, Kristin L. Forloney, Junying Yuan, Ronald A. DePinho, and Lynda Chin
- Subjects
Muscle Proteins ,Apoptosis ,Mice, SCID ,Caspase 7 ,Mice ,Necrosis ,RNA interference ,Apoptosomes ,Glioma ,Genetics ,medicine ,Animals ,Humans ,RNA, Small Interfering ,Gene knockdown ,biology ,Brain Neoplasms ,Cytochrome c ,Cytochromes c ,Proteins ,medicine.disease ,Caspase 9 ,Mitochondria ,Enzyme Activation ,Proto-Oncogene Proteins c-bcl-2 ,Astrocytes ,Immunoglobulin G ,Cancer research ,biology.protein ,Rabbits ,Apoptosome ,Signal transduction ,Apoptosis Regulatory Proteins ,Glioblastoma ,Research Paper ,Signal Transduction ,Developmental Biology - Abstract
Glioblastoma (GBM) is an astrocytic brain tumor characterized by an aggressive clinical course and intense resistance to all therapeutic modalities. Here, we report the identification and functional characterization of Bcl2L12 (Bcl2-like-12) that is robustly expressed in nearly all human primary GBMs examined. Enforced Bcl2L12 expression confers marked apoptosis resistance in primary cortical astrocytes, and, conversely, its RNA interference (RNAi)-mediated knockdown sensitizes human glioma cell lines toward apoptosis in vitro and impairs tumor growth with increased intratumoral apoptosis in vivo. Mechanistically, Bcl2L12 expression does not affect cytochrome c release or apoptosome-driven caspase-9 activation, but instead inhibits post-mitochondrial apoptosis signaling at the level of effector caspase activation. One of Bcl2L12’s mechanisms of action stems from its ability to interact with and neutralize caspase-7. Notably, while enforced Bcl2L12 expression inhibits apoptosis, it also engenders a pronecrotic state, which mirrors the cellular phenotype elicited by genetic or pharmacologic inhibition of post-mitochondrial apoptosis molecules. Thus, Bcl2L12 contributes to the classical tumor biological features of GBM such as intense apoptosis resistance and florid necrosis, and may provide a target for enhanced therapeutic responsiveness of this lethal cancer.
- Published
- 2007
36. 044. Clustering of Lifestyle Risk Factors and Low Bone Density in Older Adults: The Hertfordshire Cohort Study
- Author
-
Avan Aihie Sayer, Jean Zhang, Sian Robinson, K Jameson, Cyrus Cooper, and Elaine M. Dennison
- Subjects
Gerontology ,business.industry ,Life style ,Low bone density ,Medicine ,business ,Cluster analysis ,Cohort study - Published
- 2015
37. Cyst Number but Not the Rate of Cystic Growth Is Associated with the Mutated Gene in Autosomal Dominant Polycystic Kidney Disease
- Author
-
Mark B. Consugar, Lisa M. Guay-Woodford, Bernard F. King, Philip J. Kenney, Qin Jean Zhang, Louis H. Wetzel, Vicente E. Torres, Catherine M. Meyers, Kyongtae T. Bae, Fang Zhu, Paul M. Thompson, Saulo Klahr, Jared J. Grantham, Deborah A. Baumgarten, William M. Bennett, J. Philip Miller, Sandro Rossetti, Peter C. Harris, and Arlene B. Chapman
- Subjects
Adult ,Nephrology ,medicine.medical_specialty ,Pathology ,TRPP Cation Channels ,Adolescent ,Population ,Autosomal dominant polycystic kidney disease ,Biology ,urologic and male genital diseases ,Internal medicine ,medicine ,Humans ,Cyst ,education ,Gene ,education.field_of_study ,PKD1 ,medicine.diagnostic_test ,urogenital system ,Magnetic resonance imaging ,General Medicine ,Middle Aged ,Polycystic Kidney, Autosomal Dominant ,medicine.disease ,female genital diseases and pregnancy complications ,Mutation ,Kidney disease - Abstract
Data from serial renal magnetic resonance imaging of the Consortium of Radiologic Imaging Study of PKD (CRISP) autosomal dominant polycystic kidney disease (PKD) population showed that cystic expansion occurs at a consistent rate per individual, although it is heterogeneous in the population, and that larger kidneys are associated with more rapid disease progression. The significance of gene type to disease progression is analyzed in this study of the CRISP cohort. Gene type was determined in 183 families (219 cases); 156 (85.2%) had PKD1, and 27 (14.8%) had PKD2. PKD1 kidneys were significantly larger, but the rate of cystic growth (PKD1 5.68%/yr; PKD2 4.82%/yr) was not different (P = 0.24). Cyst number increased with age, and more cysts were detected in PKD1 kidneys (P < 0.0001). PKD1 is more severe because more cysts develop earlier, not because they grow faster, implicating the disease gene in cyst initiation but not expansion. These insights will inform the development of targeted therapies in autosomal dominant PKD.
- Published
- 2006
38. WAY-100635 antagonist-induced plasticity of 5-HT1A receptors: regulatory differences between a stable cell line and an in vivo native system
- Author
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Deborah L. Smith, Daniel Wayne Dilks, Jean Zhang, Michael A. Olsen, Xavier Z. Khawaja, Stanley P. Nawoschik, John Dunlop, and Lee E. Schechter
- Subjects
Receptor recycling ,medicine.medical_specialty ,Forskolin ,medicine.drug_class ,media_common.quotation_subject ,Antagonist ,Biology ,Receptor antagonist ,Biochemistry ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Endocrinology ,nervous system ,chemistry ,Cell surface receptor ,Internal medicine ,medicine ,heterocyclic compounds ,MPPF ,Receptor ,Internalization ,media_common - Abstract
We present evidence that the 5-hydroxytryptamine1A (5-HT1A) receptor antagonist, N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl}-N-(2-pyridinyl)cyclohexanecarboxamide (WAY-100635), can induce receptor internalization in a human (h)5-HT1A receptor Chinese hamster ovary (CHO-K1) cell system. Exposure of h5-HT1A CHO cells to WAY-100635 decreased the cell-surface h5-HT1A receptor density in a way that was both time (24–72 h) and concentration (1–100 nm) dependent.[3H]WAY-100635 and [3H]8-hydroxy-dipropylaminotetralin ([3H]8-OH-DPAT) saturation analyses demonstrated a significant reduction (50–60%) in total h5-HT1A receptor number in the WAY-100635-treated (100 nm; 72 h) compared with control cells. In WAY-100635-treated cells, the 8-OH-DPAT-mediated inhibition of forskolin (FSK)-stimulated cAMP accumulation was right-shifted and the maximal inhibitory response of 8-OH-DPAT was impaired compared with control cells. Similar results were obtained for 8-OH-DPAT-mediated Ca2+ mobilization after WAY-100635 treatment. h5-HT1A receptors labeled with [3H]WAY-100635, as well as [3H]4-(2′-Methoxy)-phenyl-1-[2′-(N-2′′-pyridinyl)-p-fluorobenzamido]ethyl-piperazine (MPPF), exhibited a time-dependent rate of cellular internalization that was blocked by endocytotic suppressors and was pertussis-toxin insensitive. In contrast, quantitative autoradiographic studies demonstrated that chronic treatment of rats with WAY-100635 for two weeks produced a region-specific increase in the 5-HT1A receptor density. In conclusion, prolonged exposure of an h5-HT1A cell-based system to the 5-HT1A antagonist, WAY-100635, induced a paradoxical internalization of cell surface receptor resulting in depressed functional activity. This suggests that an antagonist can influence 5-HT1A receptor recycling in vitro differently to in vivo regulatory conditions.
- Published
- 2006
39. Comparison of the Release Profile and Pharmacokinetics of Intact and Fragmented Dexamethasone Intravitreal Implants in Rabbit Eyes
- Author
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Xiao-Yan Li, Rahul Bhagat, Sidiq Farooq, and Jean Zhang
- Subjects
Retinal Vein ,genetic structures ,Eye ,Dexamethasone ,Aqueous Humor ,In vivo ,Tandem Mass Spectrometry ,medicine ,Dexamethasone Intravitreal Implant ,polycyclic compounds ,Animals ,Pharmacology (medical) ,Macular edema ,Glucocorticoids ,Chromatography, High Pressure Liquid ,Pharmacology ,Drug Implants ,business.industry ,Diabetic retinopathy ,Original Articles ,medicine.disease ,eye diseases ,Posterior segment of eyeball ,Vitreous Body ,Ophthalmology ,Anesthesia ,Intravitreal Injections ,sense organs ,Implant ,Rabbits ,business ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug ,New Zealand - Abstract
Dexamethasone intravitreal implant (DEX implant, Ozurdex(®); Allergan, Inc.) is used to treat noninfectious posterior uveitis and macular edema associated with retinal vein occlusion and diabetic retinopathy. Two recently published reports of DEX implant fragmentation shortly after injection have raised concerns about the potential for faster implant dissolution and elevated ocular dexamethasone concentrations. This study compared the in vivo release profile and pharmacokinetic behavior of intact and fragmented DEX implants.DEX implant was surgically implanted as a single unit or fragmented into 3 pieces in the posterior segment of opposing eyes of 36 New Zealand white rabbits. The release of dexamethasone over time from 1-piece and 3-piece fragmented implants dissolved in solution in vitro was compared with that from the 1-piece and 3-piece fragmented implants placed in the rabbit eyes. In addition, dexamethasone concentrations in the vitreous and aqueous humors of each eye were measured at 3 h and days 1, 7, 14, 21, and 28. High-performance liquid chromatography and liquid chromatography-tandem mass spectrometry were used for assays.Dexamethasone release from the 1-piece and 3-piece DEX implants in vivo was not different and was consistent with the in vitro release pattern. Moreover, the concentration profile of dexamethasone in the vitreous and aqueous humors was similar for the 1-piece and 3-piece DEX implants at each time point measured.DEX implant fragmentation neither accelerated its dissolution nor increased the dexamethasone concentration delivered at a given time. Accordingly, DEX implant fragmentation is unlikely to have clinically significant effects in patients.
- Published
- 2014
40. WAY-163909 [(7bR, 10aR)-1,2,3,4,8,9,10,10a-Octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole], a Novel 5-Hydroxytryptamine 2C Receptor-Selective Agonist with Anorectic Activity
- Author
-
Jean Zhang, Boyd L. Harrison, Robert Lewis Vogel, Sharon Rosenzweig-Lipson, John Dunlop, Annmarie Louise Sabb, Stacey J. Sukoff, Eugenia Shukhina, Sachin Kalgaonker, Lee E. Schechter, Hossein Mazandarani, and Gary Paul Stack
- Subjects
Male ,Agonist ,medicine.medical_specialty ,Indoles ,medicine.drug_class ,CHO Cells ,Partial agonist ,Calcium in biology ,Rats, Sprague-Dawley ,Eating ,Mice ,Cricetinae ,Internal medicine ,Appetite Depressants ,Receptor, Serotonin, 5-HT2C ,medicine ,Animals ,Humans ,Binding site ,Receptor ,Pharmacology ,Dose-Response Relationship, Drug ,Chemistry ,Chinese hamster ovary cell ,Azepines ,Receptor antagonist ,Rats ,Serotonin Receptor Agonists ,Mice, Inbred C57BL ,Endocrinology ,Molecular Medicine ,Serotonin ,Serotonin 5-HT2 Receptor Agonists ,Protein Binding - Abstract
The pharmacological profile of WAY-163909 [(7bR, 10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole], a novel 5-hydroxytryptamine (HT)(2C) (serotonin) receptor-selective agonist is presented. WAY-163909 displaced [(125)I]2,5-dimethoxy-4-iodoamphetamine binding from human 5-HT(2C) receptor sites, in Chinese hamster ovary (CHO) cell membranes, with a K(i) value of 10.5 +/- 1.1 nM. Binding affinities determined for the human 5-HT(2A) and 5-HT(2B) receptor subtypes were 212 and 485 nM, respectively. In functional studies, WAY-163909 stimulated the mobilization of intracellular calcium in CHO cells stably expressing the human 5-HT(2C) receptor with an EC(50) value of 8 nM, and E(max) relative to 5-HT of 90%. WAY-163909 failed to stimulate calcium mobilization in cells expressing the human 5-HT(2A) receptor subtype (EC(50) >> 10muM) and was a 5-HT(2B) receptor partial agonist (EC(50) 185 nM, E(max) 40%). WAY-163909 exhibited negligible affinity (
- Published
- 2005
41. The potential of tissue engineering in orthopedics
- Author
-
Jennifer Hillyer, Noritaka Isogai, Lorraine M. Siperko, Susan Chubinskaya, Shinichi Asamura, Robin Jacquet, Jean Zhang, and William J. Landis
- Subjects
Bioprosthesis ,musculoskeletal diseases ,medicine.medical_specialty ,Tissue Engineering ,business.industry ,Cartilage ,Artificial Limbs ,Artificial limbs ,Tendon ,Fingers ,Tendons ,Mice ,Orthopedics ,medicine.anatomical_structure ,Tissue engineering ,Finger Joint ,Periosteum ,Orthopedic surgery ,medicine ,Animals ,Humans ,Orthopedics and Sports Medicine ,business ,Biomedical engineering - Abstract
This article presents models of human phalanges and small joints developed by tissue engineering. Biodegradable polymer scaffolds support growth of osteoblasts, chondrocytes, and tenocytes after implantation of the models in athymic mice. The cell-polymer constructs are vascularized by the host mice, form new bone, cartilage, and tendon with characteristic gene expression and protein synthesis and secretion, and maintain the shape of human phalanges with joints. The study demonstrates critical progress in the design and fabrication of bone, cartilage, and tendon by tissue engineering and the potential of this field for human clinical orthopedic applications.
- Published
- 2005
42. The C-terminus of Gi family G-proteins as a determinant of 5-HT1A receptor coupling
- Author
-
Lee E. Schechter, Rafal Ochalski, Jean Zhang, Angela Vlattas, Qin Shan, John Dunlop, Dianne Kowal, and Stanley P. Nawoschik
- Subjects
Agonist ,G protein ,medicine.drug_class ,Recombinant Fusion Proteins ,Biophysics ,GTP-Binding Protein alpha Subunits, Gi-Go ,Transfection ,Biochemistry ,Tumor Cells, Cultured ,medicine ,Humans ,Calcium Signaling ,Receptor ,Molecular Biology ,5-HT receptor ,Calcium signaling ,chemistry.chemical_classification ,C-terminus ,Cell Biology ,Molecular biology ,Amino acid ,chemistry ,Receptors, Serotonin ,5-HT1A receptor ,Calcium ,Receptors, Serotonin, 5-HT1 - Abstract
Using a universal signaling assay employing G-protein chimeras comprising the C-terminal five amino acids of Gi1/2, Gi3, Go, and Gz fused to Gq, the calcium mobilizing G-protein, we explored the role of the C-terminus of Gi family G-proteins as a determinant for 5-HT(1A) receptor functional coupling. Co-expression of the 5-HT(1A) receptor with each of the Gq/Gi family chimeras resulted in a concentration-dependent increase in calcium upon addition of 5-HT, although the coupling efficiency differed dramatically. Gq/Gi3 resulted in the most efficient coupling based on both potency and relative maximum response to 5-HT. Gq/Go also produced efficient coupling in terms of relative 5-HT efficacy (76% of the Gq/Gi3 maximum response), although 5-HT exhibited 4-fold lower agonist potency, and Gq/Gz and Gq/Gi1/2 conferred poor functional coupling. Agonist potencies and relative efficacies determined for a number of 5-HT(1A) receptor agonists using Gq/Gi3 coupling were significantly weaker than those described previously for coupling through the native G-protein. These results indicate the C-terminus of Gi3 as an important determinant for coupling to the 5-HT(1A) receptor, while the reduced functional agonist activities suggest additional motifs participate in receptor/G-protein coupling.
- Published
- 2002
43. The metabotropic glutamate receptor 7 allosteric modulator AMN082: a monoaminergic agent in disguise?
- Author
-
Sharon Rosenzweig-Lipson, Tim Lock, Deborah L. Smith, Robert H. Ring, Paul Jeffrey Dollings, Jean Zhang, Sarah K. Leonard, Susanna Y. Tse, Andrew D. Randall, Stacey J. Sukoff Rizzo, Sarah J. Neal, Li Di, Adam M. Gilbert, Dianne Kowal, John Dunlop, Meiyi Zhang, John A. Butera, Angela Kramer, Jason M. Dwyer, Christine Huselton, Corey N. Bender, Karthick Vishwanathan, Zoë A. Hughes, and Brian J. Platt
- Subjects
Agonist ,Male ,Allosteric modulator ,medicine.drug_class ,CHO Cells ,Pharmacology ,Receptors, Metabotropic Glutamate ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Mice ,Cricetulus ,AMN082 ,Allosteric Regulation ,Cricetinae ,medicine ,Animals ,Humans ,Biogenic Monoamines ,Benzhydryl Compounds ,Metabotropic glutamate receptor 5 ,Chemistry ,Metabotropic glutamate receptor 7 ,Rats ,HEK293 Cells ,Molecular Medicine ,Metabotropic glutamate receptor 1 ,Metabotropic glutamate receptor 3 ,Metabotropic glutamate receptor 2 ,Protein Binding - Abstract
Metabotropic glutamate receptor 7 (mGluR7) remains the most elusive of the eight known mGluRs primarily because of the limited availability of tool compounds to interrogate its potential therapeutic utility. The discovery of N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082) as the first orally active, brain-penetrable, mGluR7-selective allosteric agonist by Mitsukawa and colleagues (Proc Natl Acad Sci USA 102:18712-18717, 2005) provides a means to investigate this receptor system directly. AMN082 demonstrates mGluR7 agonist activity in vitro and interestingly has a behavioral profile that supports utility across a broad spectrum of psychiatric disorders including anxiety and depression. The present studies were conducted to extend the in vitro and in vivo characterization of AMN082 by evaluating its pharmacokinetic and metabolite profile. Profiling of AMN082 in rat liver microsomes revealed rapid metabolism (t(1/2) < 1 min) to a major metabolite, N-benzhydrylethane-1,2-diamine (Met-1). In vitro selectivity profiling of Met-1 demonstrated physiologically relevant transporter binding affinity at serotonin transporter (SERT), dopamine transporter (DAT), and norepinephrine transporter (NET) (323, 3020, and 3410 nM, respectively); whereas the parent compound AMN082 had appreciable affinity at NET (1385 nM). AMN082 produced antidepressant-like activity and receptor occupancy at SERT up to 4 h postdose, a time point at which AMN082 is significantly reduced in brain and plasma while the concentration of Met-1 continues to increase in brain. Acute Met-1 administration produced antidepressant-like activity as would be expected from its in vitro profile as a mixed SERT, NET, DAT inhibitor. Taken together, these data suggest that the reported in vivo actions of AMN082 should be interpreted with caution, because they may involve other mechanisms in addition to mGluR7.
- Published
- 2011
44. Evaluating the Utility of Tablet PCs in a Software Engineering Capstone Course
- Author
-
Scott Dick, Jean Zhang, and Nelson G. Durdle
- Subjects
Measure (data warehouse) ,Engineering ,Resource (project management) ,Operationalization ,business.industry ,Capstone ,General Medicine ,Capstone course ,business ,Construct (philosophy) ,Software engineering ,Tablet pc ,Exploratory factor analysis - Abstract
The ECE Dept. at the University of Alberta uses Tablet PCs as a key resource in the Software Engineering capstone design course. We are currently developing a survey instrument (piloted in 2009) to measure the utility of these Tablets. The instrument is based on technology adoption theory, which posits that specific psychological states are antecedents to the usage of a new technology. We perform an exploratory factor analysis of the pilot survey, with an emphasis on our operationalization of the construct of Use of the Technology. However, small-sample-size effects prevent us from fully validating the model.
- Published
- 2010
45. P3‐329: SAM‐531, N,N‐dimethyl‐3‐{[3‐(1‐naphthylsulfonyl)‐1H‐indazol‐5‐yl]oxy} propan‐1‐amine, a novel serotonin‐6 receptor antagonist with preclinical pro‐cognitive efficacy
- Author
-
Jean Zhang, Peter H. Reinhart, Deborah L. Smith, Zoë A. Hughes, Geraldine Ruth Mcfarlane, Dianne Kowal, Mei-Yi Zhang, Angela Kramer, Michael M. Monaghan, Guoming Zhang, Al J. Robichaud, Suzan Aschmies, Menelas N. Pangalos, Simon Haydar, Thomas A. Comery, and Christine Huselton
- Subjects
Epidemiology ,medicine.drug_class ,Stereochemistry ,Chemistry ,Health Policy ,Receptor antagonist ,Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Developmental Neuroscience ,medicine ,Amine gas treating ,Neurology (clinical) ,Serotonin ,Geriatrics and Gerontology - Published
- 2010
46. 5-Cyclic amine-3-arylsulfonylindazoles as novel 5-HT6 receptor antagonists
- Author
-
Heedong Yun, James F. Mattes, Simon Haydar, Jean Zhang, Lee E. Schechter, Deborah L. Smith, Radka Graf, Thomas A. Comery, Christine Huselton, Albert J. Robichaud, Angela Kramer, Suzan Aschmies, and Andrae Patrick M
- Subjects
Indazoles ,Pharmacology ,Binding, Competitive ,Structure-Activity Relationship ,Pharmacokinetics ,Drug Discovery ,Receptor, Serotonin, 5-HT2B ,Serotonin 5-HT2 Receptor Antagonists ,Structure–activity relationship ,Animals ,Humans ,Sulfones ,Novel object recognition ,Serotonin Antagonists ,Receptor ,Habituation, Psychophysiologic ,Molecular Structure ,Chemistry ,Brain ,Recognition, Psychology ,Rats ,Models, Chemical ,Receptors, Serotonin ,5-HT6 receptor ,Exploratory Behavior ,Molecular Medicine ,Amine gas treating - Abstract
Novel 5-cyclic amine-3-arylsulfonylindazoles were prepared, and several analogues within this class have been identified as high-affinity 5-HT(6) receptor ligands with improved pharmacokinetic and pharmacological properties. One selected example, 18b, showed good brain penetrability and a generally favorable pharmacokinetic profile with procognitive efficacy in the rat novel object recognition assay. The synthesis and structure-activity relationship of this potent class are discussed.
- Published
- 2010
47. Busulfan-Based Reduced Intensity Conditioning Regimen (RIC) For Lymphoid Malignancies
- Author
-
Geoffrey L. Uy, Ravi Vij, Camille N. Abboud, Sarah E. Witowski, Amanda F. Cashen, Qin Jean Zhang, J. Sekhar, John F. DiPersio, Peter Westervelt, and Keith Stockerl-Goldstein
- Subjects
Oncology ,medicine.medical_specialty ,Regimen ,Transplantation ,business.industry ,Internal medicine ,Reduced Intensity Conditioning ,Medicine ,Hematology ,business ,Busulfan ,medicine.drug - Published
- 2010
- Full Text
- View/download PDF
48. Potent dihydroquinolinone dopamine D2 partial agonist/serotonin reuptake inhibitors for the treatment of schizophrenia
- Author
-
Jean Zhang, Ping Zhou, Tikva Carrick, Albert J. Robichaud, Rolf Feenstra, Jan-Hendrik Reinders, Dianne Kowal, Chris G. Kruse, Martina A.W. van der Neut, Yinfa Yan, David P. Rotella, Mark H. Pausch, Margaret Lai, and Karen L. Marquis
- Subjects
Serotonin reuptake inhibitor ,Clinical Biochemistry ,Pharmaceutical Science ,Pharmacology ,Quinolones ,Biochemistry ,Partial agonist ,Reuptake ,Structure-Activity Relationship ,Dopamine receptor D2 ,Drug Discovery ,Moiety ,Animals ,Molecular Biology ,biology ,Chemistry ,Receptors, Dopamine D2 ,Organic Chemistry ,Disease Models, Animal ,Norepinephrine transporter ,Dopamine Agonists ,Receptor, Serotonin, 5-HT1A ,biology.protein ,Schizophrenia ,Molecular Medicine ,Pharmacophore ,Endogenous agonist ,Selective Serotonin Reuptake Inhibitors ,Antipsychotic Agents - Abstract
A dihydroquinolinone moiety was found to be a potent serotonin reuptake inhibitor pharmacophore when combined with certain amines. This fragment was coupled with selected D2 ligands to prepare a series of dual acting compounds with attractive in vitro profiles as dopamine D2 partial agonists and serotonin reuptake inhibitors. Structure–activity studies revealed that the linker plays a key role in contributing to D2 affinity, function, and SRI activity.
- Published
- 2010
49. Preclinical characterization of BRL 44408: antidepressant- and analgesic-like activity through selective alpha2A-adrenoceptor antagonism
- Author
-
Shendi Lu, Lynn Resnick, Jean Zhang, Stacey J. Sukoff Rizzo, Chad E. Beyer, Sharon Rosenzweig-Lipson, Dianne Kowal, Jianyao Wang, Deborah L. Smith, Claudine Pulicicchio, Liza Leventhal, Caitlin Wantuch, John A. Butera, Corey N. Bender, Adam D. Shilling, Terri Cummons, Lee E. Schechter, Jason M. Dwyer, Mei-Yi Zhang, Brian J. Platt, and S. Johannes R. Rajarao
- Subjects
Male ,medicine.medical_specialty ,Microdialysis ,Drug Evaluation, Preclinical ,CHO Cells ,Pharmacology ,Isoindoles ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Mice ,Radioligand Assay ,Cricetulus ,Dopamine ,Receptors, Adrenergic, alpha-2 ,Internal medicine ,Cricetinae ,medicine ,Animals ,Pharmacology (medical) ,Biogenic Monoamines ,Neurotransmitter ,Swimming ,Analgesics ,Depression ,Imidazoles ,Brain ,Visceral pain ,Adrenergic alpha-2 Receptor Antagonists ,Antidepressive Agents ,Rats ,Psychiatry and Mental health ,Disease Models, Animal ,Endocrinology ,Monoamine neurotransmitter ,chemistry ,Autoreceptor ,Antidepressant ,Serotonin ,medicine.symptom ,Thirst ,Behavioural despair test ,medicine.drug - Abstract
Biogenic amines such as norepinephrine, dopamine, and serotonin play a well-described role in the treatment of mood disorders and some types of pain. As alpha2A-adrenoceptors regulate the release of these neurotransmitters, we examined the therapeutic potential of BRL 44408, a potent (Ki=8.5 nM) and selective (>50-fold) alpha2A-adrenoceptor antagonist (K(B)=7.9 nM). In rats, BRL 44408 penetrated the central nervous system resulting in peak brain and plasma concentrations of 586 ng/g and 1124 ng/ml, respectively. In a pharmacodynamic assay, pretreatment with BRL 44408 to rats responding under a fixed-ratio 30 operant response paradigm resulted in a rightward shift of the clonidine dose-response curve, an effect indicative of alpha2-adrenoceptor antagonism in vivo. Consistent with presynaptic autoreceptor antagonism and tonic regulation of neurotransmitter release, acute administration of BRL 44408 elevated extracellular concentrations of norepinephrine and dopamine, but not serotonin, in the medial prefrontal cortex. Additionally, BRL 44408, probably by inhibiting alpha2A heteroceptors, produced a significant increase in cortical levels of acetylcholine. In the forced swim test and schedule-induced polydipsia assay, BRL 44408 produced an antidepressant-like response by dose-dependently decreasing immobility time and adjunctive water intake, respectively, while in a model of visceral pain, BRL 44408 exhibited analgesic activity by decreasing para-phenylquinone (PPQ)-induced abdominal stretching. Finally, BRL 44408 did not produce deficits in overall motor coordination nor alter general locomotor activity. This preclinical characterization of the neurochemical and behavioural profile of BRL 44408 suggests that selective antagonism of alpha2A-adrenoceptors may represent an effective treatment strategy for mood disorders and visceral pain.
- Published
- 2010
50. Tetrahydrocarbazole-based serotonin reuptake inhibitor/dopamine D2 partial agonists for the potential treatment of schizophrenia
- Author
-
Jean Zhang, Julie A. Brennan, Chris G. Kruse, Jan-Hendrik Reinders, Dianne Kowal, Geraldine Ruth Mcfarlane, Feenstra Roelof W, Sara Núñez-García, Andrew C. McCreary, Karen L. Marquis, Radka Graf, Mark H. Pausch, Alexander Greenfield, Margaret Lai, Albert J. Robichaud, Farhana Pruthi, Tikva Carrick, David P. Rotella, Cristina Grosanu, Steven M. Grauer, Rajiah A. Denny, Kelly Sullivan, Rachel Navarra, and Martina A.W. van der Neut
- Subjects
medicine.medical_treatment ,Serotonin reuptake inhibitor ,Clinical Biochemistry ,Carbazoles ,Pharmaceutical Science ,Pharmacology ,Serotonin 5-HT1 Receptor Antagonists ,Biochemistry ,Partial agonist ,chemistry.chemical_compound ,In vivo ,Dopamine receptor D2 ,Drug Discovery ,medicine ,Animals ,Antipsychotic ,Neurotransmitter ,Molecular Biology ,Receptors, Dopamine D2 ,Organic Chemistry ,Rats ,Disease Models, Animal ,chemistry ,Dopamine Agonists ,Receptor, Serotonin, 5-HT1A ,Schizophrenia ,Molecular Medicine ,Serotonin ,Reuptake inhibitor ,Selective Serotonin Reuptake Inhibitors - Abstract
A 5-fluoro-tetrahydrocarbazole serotonin reuptake inhibitor (SRI) building block was combined with a variety of linkers and dopamine D2 receptor ligands in an attempt to identify potent D2 partial agonist/SRI molecules for treatment of schizophrenia. This approach has the potential to treat a broader range of symptoms compared to existing therapies. Selected compounds in this series demonstrate high affinity for both targets and D2 partial agonism in cell-based and in vivo assays.
- Published
- 2009
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