Digital Commons Network^™

Biomarkers Of Response And Resistance To Palbociclib Plus Letrozole In Patients With Er+/Her2- Breast Cancer, Mitch Dowsett, Lucy Kilburn, Mothaffar F Rimawi, C Kent Osborne, Katherine Pogue-Geile, Yuan Liu, Samuel A Jacobs, Melanie Finnigan, Shannon Puhalla, Andrew Dodson, Vera Martins, Maggie Cheang, Sophie Perry, Chris Holcombe, Nick Turner, Claire Swift, Judith M Bliss, Stephen Johnston

Faculty, Staff and Students Publications

PURPOSE: To determine (i) the relationship between candidate biomarkers of the antiproliferative (Ki67) response to letrozole and palbociclib alone and combined in ER

EXPERIMENTAL DESIGN: 307 postmenopausal women with ER+/HER2− primary breast cancer were randomly assigned to neoadjuvant treatment with letrozole for 14 weeks; letrozole for 2 weeks, then letrozole+palbociclib to 14 weeks; palbociclib for 2 weeks, then letrozole+palbociclib to 14 weeks; or letrozole+palbociclib for 14 weeks. Biopsies were taken at baseline, 2 and 14 weeks and surgery at varying times after stopping palbociclib. Immunohistochemical analyses were conducted for Ki67, c-PARP, ER, PgR, RB1, CCNE1, and CCND1.

RESULTS: Higher baselines …

Modified Vaccinia Ankara Expressing Eehv1a Glycoprotein B Elicits Humoral And Cell-Mediated Immune Responses In Mice, Taylor Pursell, Jennifer L Spencer Clinton, Jie Tan, Rongsheng Peng, Paul D Ling

Faculty, Staff and Students Publications

Elephant endotheliotropic herpesvirus (EEHV) can cause lethal hemorrhagic disease (EEHV-HD) in Asian elephants and is the largest cause of death in captive juvenile Asian elephants in North America and Europe. EEHV-HD also has been documented in captive and wild elephants in their natural range countries. A safe and effective vaccine to prevent lethal EEHV infection would significantly improve conservation efforts for this endangered species. Recent studies from our laboratory suggest that EEHV morbidity and mortality are often associated with primary infection. Therefore, we aim to generate a vaccine, particularly for EEHV1 naïve animals, with the goal of preventing lethal EEHV-HD. …

Clonal Hematopoiesis Analyses In Clinical, Epidemiologic, And Genetic Aging Studies To Unravel Underlying Mechanisms Of Age-Related Dysfunction In Humans, Kenneth Walsh, Nalini Raghavachari, Candace Kerr, Alexander G Bick, Steven R Cummings, Todd Druley, Cynthia E Dunbar, Giulio Genovese, Margaret A Goodell, Siddhartha Jaiswal, Jaroslaw Maciejewski, Pradeep Natarajan, Anastasia V Shindyapina, Alan R Shuldiner, Erik B Van Den Akker, Jan Vijg

Faculty, Staff and Students Publications

Aging is characterized by increased mortality, functional decline, and exponential increases in the incidence of diseases such as cancer, stroke, cardiovascular disease, neurological disease, respiratory disease, etc. Though the role of aging in these diseases is widely accepted and considered to be a common denominator, the underlying mechanisms are largely unknown. A significant age-related feature observed in many population cohorts is somatic mosaicism, the detectable accumulation of somatic mutations in multiple cell types and tissues, particularly those with high rates of cell turnover (e.g., skin, liver, and hematopoietic cells). Somatic mosaicism can lead to the development of cellular clones that …

Hypermethylation Of Pi3k-Akt Signalling Pathway Genes Is Associated With Human Neural Tube Defects, Tian Tian, Xinyuan Lai, Kuanhui Xiang, Xiao Han, Shengju Yin, Robert M Cabrera, John W Steele, Yunping Lei, Xuanye Cao, Richard H Finnell, Linlin Wang, Aiguo Ren

Faculty, Staff and Students Publications

Neural tube defects (NTDs) are a group of common and severe congenital malformations. The PI3K-AKT signalling pathway plays a crucial role in the neural tube development. There is limited evidence concerning any possible association between aberrant methylation in PI3K-AKT signalling pathway genes and NTDs. Therefore, we aimed to investigate potential associations between aberrant methylation of PI3K-AKT pathway genes and NTDs. Methylation studies of PI3K-AKT pathway genes utilizing microarray genome-methylation data derived from neural tissues of ten NTD cases and eight non-malformed controls were performed. Targeted DNA methylation analysis was subsequently performed in an independent cohort of 73 NTD cases and …

Nuclear Progesterone Receptor Expressed By The Cortical Thymic Epithelial Cells Dictates Thymus Involution In Murine Pregnancy, Soo Hyun Ahn, Sean L Nguyen, Tae Hoon Kim, Jae-Wook Jeong, Ripla Arora, John P Lydon, Margaret G Petroff

Faculty, Staff and Students Publications

Progesterone is a gonadal pro-gestational hormone that is absolutely necessary for the success of pregnancy. Most notable actions of progesterone are observed in the female reproductive organs, the uterus and the ovary. Acting through the nuclear progesterone receptor (PGR), progesterone prepares the endometrium for implantation of the embryo. Interestingly, the maternal thymus also is a known expressor of Pgr; its absence is associated with murine pregnancy complications. However, the localization of its expression and its functional importance were not known. Here, we used a transgenic dual fluorescent reporter mouse model and genetic deletion of Pgr in Foxn1+ thymic epithelial …

Prefrontal Glutamate Neurotransmission In Ptsd: A Novel Approach To Estimate Synaptic Strength In Vivo In Humans, Lynnette A Averill, Lihong Jiang, Prerana Purohit, Anastasia Coppoli, Christopher L Averill, Jeremy Roscoe, Benjamin Kelmendi, Henk M De Feyter, Robin A De Graaf, Ralitza Gueorguieva, Gerard Sanacora, John H Krystal, Douglas L Rothman, Graeme F Mason, Chadi G Abdallah

Staff and Researcher Publications

Background: Trauma and chronic stress are believed to induce and exacerbate psychopathology by disrupting glutamate synaptic strength. However, in vivo in human methods to estimate synaptic strength are limited. In this study, we established a novel putative biomarker of glutamatergic synaptic strength, termed energy-per-cycle (EPC). Then, we used EPC to investigate the role of prefrontal neurotransmission in trauma-related psychopathology.

Methods: Healthy controls (n = 18) and patients with posttraumatic stress (PTSD; n = 16) completed 13C-acetate magnetic resonance spectroscopy (MRS) scans to estimate prefrontal EPC, which is the ratio of neuronal energetic needs per glutamate neurotransmission cycle (VTCA/VCycle).

Results: Patients …

A Novel Approach To Link Genetics And Human Mri Identifies Akap7-Dependent Subicular/Prefrontal Functional Connectivity As Altered In Suicidality, Guillermo Poblete, Tien Nguyen, Savannah Gosnell, Olutayo Sofela, Michelle Patriquin, Sanjay J Mathew, Alan Swann, David A Nielsen, Thomas R Kosten, Ramiro Salas

Staff and Researcher Publications

Background: Brain imaging and genetics are fields acquiring data at increasing speed, but more information does not always result in a better understanding of the underlying biology. We developed the ProcessGeneLists (PGL) approach to use genetics and mRNA gene expression data to generate regions of interest for imaging studies.

Methods: We applied PGL to past suicide attempt (ATT): We averaged the mRNA expression levels of genes (n = 130) possibly associated with ATT (p ≤ 10-3 in a published genome-wide association study, GWAS) in each brain region studied in the Human Allen Brain Atlas (6 ex-vivo brains, 158 to 946 …

Decreased Brain Ventricular Volume In Psychiatric Inpatients With Serotonin Reuptake Inhibitor Treatment, P K Bolin, S N Gosnell, K Brandel-Ankrapp, N Srinivasan, A Castellanos, R Salas

Staff and Researcher Publications

Background: Brain ventricles have been reported to be enlarged in several neuropsychiatric disorders and in aging. Whether human cerebral ventricular volume can decrease over time with psychiatric treatment is not well-studied. The aim of this study was to examine whether inpatients taking serotonin reuptake inhibitors (SRI) exhibited reductions in cerebral ventricular volume.

Methods: Psychiatric inpatients, diagnosed mainly with depression, substance use, anxiety, and personality disorders, underwent two imaging sessions (Time 1 and Time 2, approximately 4 weeks apart). FreeSurfer was used to quantify volumetric features of the brain, and ANOVA was used to analyze ventricular volume differences between Time 1 …

Turning Data Into Better Mental Health: Past, Present, And Future, Nidal Moukaddam, Akane Sano, Ramiro Salas, Zakia Hammal, Ashutosh Sabharwal

Staff and Researcher Publications

In this mini-review, we discuss the fundamentals of using technology in mental health diagnosis and tracking. We highlight those principles using two clinical concepts: (1) cravings and relapse in the context of addictive disorders and (2) anhedonia in the context of depression. This manuscript is useful for both clinicians wanting to understand the scope of technology use in psychiatry and for computer scientists and engineers wishing to assess psychiatric frameworks useful for diagnosis and treatment. The increase in smartphone ownership and internet connectivity, as well as the accelerated development of wearable devices, have made the observation and analysis of human …

Selective Vulnerability Of The Intermediate Retinal Capillary Plexus Precedes Retinal Ganglion Cell Loss In Ocular Hypertension, Priyamvada M Pitale, Guofu Shen, Rohini R Sigireddi, Maria Polo-Prieto, Yong H Park, Solomon E Gibson, Peter D Westenskow, Roomasa Channa, Benjamin J Frankfort

Faculty, Staff and Students Publications

Introduction: Glaucoma, a disease of retinal ganglion cell (RGC) injury and potentially devastating vision loss, is associated with both ocular hypertension (OHT) and reduced ocular blood flow. However, the relationship between OHT and retinal capillary architecture is not well understood. In this project, we studied microvasculature damage in mice exposed to mild levels of induced OHT.

Methods: Mild OHT was induced with the microbead model for 2 weeks. At this time point, some retinas were immunostained with CD31 (endothelium), Collagen IV (basement membrane), and RBPMS (RGCs) for z-stack confocal microscopy. We processed these confocal images to distinguish the three retinal …

Systematic Profiling Of Dnmt3a Variants Reveals Protein Instability Mediated By The Dcaf8 E3 Ubiquitin Ligase Adaptor, Yung-Hsin Huang, Chun-Wei Chen, Venkatasubramaniam Sundaramurthy, Mikołaj Słabicki, Dapeng Hao, Caroline J Watson, Ayala Tovy, Jaime M Reyes, Olga Dakhova, Brielle R Crovetti, Christina Galonska, Minjung Lee, Lorenzo Brunetti, Yubin Zhou, Katrina Tatton-Brown, Yun Huang, Xiaodong Cheng, Alexander Meissner, Peter J M Valk, Lionel Van Maldergem, Mathijs A Sanders, Jamie R Blundell, Wei Li, Benjamin L Ebert, Margaret A Goodell

Faculty, Staff and Students Publications

Clonal hematopoiesis is a prevalent age-related condition associated with a greatly increased risk of hematologic disease; mutations in DNA methyltransferase 3A (DNMT3A) are the most common driver of this state. DNMT3A variants occur across the gene with some particularly associated with malignancy, but the functional relevance and mechanisms of pathogenesis of the majority of mutations are unknown. Here, we systematically investigated the methyltransferase activity and protein stability of 253 disease-associated DNMT3A mutations, and found that 74% were loss-of-function mutations. Half of these variants exhibited reduced protein stability and, as a class, correlated with greater clonal expansion and acute …

Crispr/Cas9-Mediated Genome Editing Reveals 12 Testis-Enriched Genes Dispensable For Male Fertility In Mice, Yuki Oyama, Haruhiko Miyata, Keisuke Shimada, Yoshitaka Fujihara, Keizo Tokuhiro, Thomas X Garcia, Martin M Matzuk, Masahito Ikawa

Faculty, Staff and Students Publications

Gene expression analyses suggest that more than 1000-2000 genes are expressed predominantly in mouse and human testes. Although functional analyses of hundreds of these genes have been performed, there are still many testis-enriched genes whose functions remain unexplored. Analyzing gene function using knockout (KO) mice is a powerful tool to discern if the gene of interest is essential for sperm formation, function, and male fertility in vivo. In this study, we generated KO mice for 12 testis-enriched genes, 1700057G04Rik, 4921539E11Rik, 4930558C23Rik, Cby2, Ldhal6b, Rasef, Slc25a2, Slc25a41, Smim8, Smim9, Tmem210, and Tomm20l, using the clustered regularly interspaced short palindromic repeats /CRISPR-associated …

Doctoral Education In Business And Management, Jonathan Lean, Stephen Wilkins, Jonathan Moizer, Troy Heffernan

Plymouth Business School

No abstract provided.

What Matters Most To Adults With A Tracheostomy In Icu And The Implications For Clinical Practice: A Qualitative Systematic Review And Metasynthesis, Helen Newman, Gemma Clunie, Sarah Wallace, Christina Smith, Daniel Martin, Natalie Pattison

Peninsula Medical School

Purpose Tracheostomy is a common surgical procedure in ICU. Whilst often life-saving, it can have important impacts on patients. Much of the literature on tracheostomy focuses on timing and technique of insertion, risk factors and complications. More knowledge of patient experience of tracheostomy in ICU is needed to support person-centred care. Materials and methods Qualitative systematic review and metasynthesis of the literature on adult experience of tracheostomy in ICU. Comprehensive search of four bibliographic databases and grey literature. Title and abstract screening and full text eligibility was completed independently by two reviewers. Metasynthesis was achieved using thematic synthesis, supported by …

Optimizing Opportunities For Oak Woodland Expansion Into Upland Pastures, Thomas R. Murphy, Mick E. Hanley, Jonathan S. Ellis, Paul H. Lunt

School of Geography, Earth and Environmental Sciences

No abstract provided.

Microbial Selenate Detoxification Linked To Elemental Sulfur Oxidation: Independent And Synergic Pathways, L Li, Baogang Zhang, L Li, Alistair G.L. Borthwick

School of Engineering, Computing and Mathematics

No abstract provided.

A Neural Network-Based Model For Lower Limb Continuous Estimation Against The Disturbance Of Uncertainty, Wanting Li, Keping Liu, Zhongbo Sun, C Li, Yuanyuan Chai, Jian Gu

School of Engineering, Computing and Mathematics

In this paper, a novel prediction model is proposed to estimate human continuous motion intention using a fuzzy wavelet neural network (FWNN) and a zeroing neural network (ZNN). During walking, seven channel surface electromyography (sEMG) signals and motion data of hip and knee are collected, and two signals are selected and processed from the seven muscles based on physiological and correlation analysis. Then, FWNN is built as an intention recognition model, with sEMG signals as input and physical hip and knee information as output. Meanwhile, ZNN is exploited into the FWNN model, forming a hybrid model to eliminate the prediction …

Heterogeneous Weathering Of Polypropylene In The Marine Environment, John W. Scott, Andrew Turner, Andres F. Prada, Linduo Zhao

School of Geography, Earth and Environmental Sciences

No abstract provided.

Mesoscale Eddies And The Impact Of Coastal Iron Supply On Primary Production In The South Pacific Subtropical Front, Stephen M. Chiswell, Philip W. Boyd, Sylvia G. Sander, Michael J. Ellwood, Angela Milne

School of Geography, Earth and Environmental Sciences

No abstract provided.

Pleistocene Depositional Environments And Links To Cryosphere-Ocean Interactions On The Eastern Ross Sea Continental Slope, Antarctica (Iodp Hole U1525a)., Maxine V. King, Jenny A. Gales, Jan Sverre Laberg, Robert M. Mckay, Santis L De, Denise K. Kulhanek, Phil J. Hosegood, Antony Morris

School of Biological and Marine Sciences

No abstract provided.

Mothers’ Understanding Of Brain Development In Early Childhood: A Qualitative Study In Brazil, Marina Sayuri Yakuwa, Letícia Pancieri, Sarah Neill, Mello Df De

School of Nursing and Midwifery

To analyze mothers’ understanding of child brain development and their stimulus practices with children in the first months of life. Qualitative research, with 18 Brazilian mothers, over 18 years of age, used semi-structured interviews to identify their perspectives on important healthcare outcomes, based on reflexive thematic analysis. Mother’s accounts displayed little understanding of child brain development, focusing on the development of neuropsychomotor skills. There was relative uncertainty about the daily care practices that would provide appropriate child stimuli, through which to provide promotion and protection of child development. Maternal knowledge about child brain development indicates a need to strengthen parenting …

Coral Reef Benthic Community Changes In The Anthropocene: Biogeographic Heterogeneity, Overlooked Configurations, And Methodology, Miriam Reverter, Stephanie B. Helber, Sven Rohde, Jm Goeij, Peter J. Schupp

School of Biological and Marine Sciences

Non-random community changes are becoming more frequent in many ecosystems. In coral reefs, changes towards communities dominated by other than hard corals are increasing in frequency, with severe impacts on ecosystem functioning and provision of ecosystem services. Although new research suggests that a variety of alternative communities (i.e. not dominated by hard corals) exist, knowledge on the global diversity and functioning of alternative coral reef benthic communities, especially those not dominated by algae, remains scattered. In this systematic review and meta-analysis of 523 articles, we analyse the different coral reef benthic community changes reported to date and discuss the advantages …

Life In The Freezer: Protein Metabolism In Antarctic Fish, Keiron P.P. Fraser, Lloyd S. Peck, Melody S. Clark, Andrew Clarke, Simeon L. Hill

School of Biological and Marine Sciences

Whole-animal, in vivo protein metabolism rates have been reported in temperate and tropical, but not Antarctic fish. Growth in Antarctic species is generally slower than lower latitude species. Protein metabolism data for Antarctic invertebrates show low rates of protein synthesis and unusually high rates of protein degradation. Additionally, in Antarctic fish, increasing evidence suggests a lower frequency of successful folding of nascent proteins and reduced protein stability. This study reports the first whole-animal protein metabolism data for an Antarctic fish. Groups of Antarctic, Harpagifer antarcticus, and temperate, Lipophrys pholis, fish were acclimatized to a range of overlapping water temperatures and …

The Angle Of Attack: Rapping Technique Predicts Skill In Hermit Crab Contests, Sarah M. Lane, Tomas O. Cornwell, Mark Briffa

School of Biological and Marine Sciences

No abstract provided.

Fast And Accurate Mapping Of Fine Scale Abundance Of A Vme In The Deep Sea With Computer Vision, Nils Piechaud, Kerry L. Howell

School of Biological and Marine Sciences

No abstract provided.

A Decade Implementing Ecosystem Approach To Fisheries Management Improves Diversity Of Taxa And Traits Within A Marine Protected Area In The Uk, Bede F.R. Davies, Luke Holmes, Anthony Bicknell, Martin J. Attrill, Emma V. Sheehan

School of Biological and Marine Sciences

AimEcosystem Approach to Fisheries Management has highlighted the importance of studying ecosystem functions and services, and the biological traits that drive them. Yet, ecosystem services and the associated benefits that they provide are rarely the motive for creating marine protected area (MPA). Therefore, many MPA monitoring projects do not explicitly study these functions and services or the underlying biological traits linked to them.LocationLyme Bay MPA, located in the SW of England, was established in 2008 to protect the reef biodiversity across a 206-km2 area, which includes rocky reef habitats, pebbly sand and soft muddy sediments. Mobile demersal fishing was excluded …

Regulation Of Gene Expression During Ontogeny Of Physiological Function In The Brackishwater Amphipod Gammarus Chevreuxi, C. Mcandry, M. Collins, O. Tills, J. I. Spicer, M. Truebano

School of Biological and Marine Sciences

No abstract provided.

Consequences Of Thermal Plasticity For Hypoxic Performance In Coastal Amphipods, Michael Collins, Manuela Truebano, John I. Spicer

School of Biological and Marine Sciences

No abstract provided.

Synchronized Seed Germination And Seedling Growth Of Black Cumin, Mohammed Elsayed El-Mahrouk, Mossad Khairy Maamoun, Yaser Hassan Dewir, Antar Nasr El-Banna, Hail Z. Rihan, Ahmed Salamh, Ahmed A. Al-Aizari, Michael P. Fuller

School of Biological and Marine Sciences

Black cumin (Nigella sativa) is an important medicinal plant in the pharmacological industry. It is cultivated on a commercial scale, but its seeds have a slow, unsynchronized germination rate. Enhancing seed germination is crucial for improving the production of black cumin. The influence of presowing treatments [gibberellic acid (GA3), potassium nitrate, salicylic acid, and stratification at 4 °C] on seed germination was assessed. Seed germination was determined daily for 30 days, and germination parameters, including final germination percentage (FGP), corrected germination rate, number of days to reach 50% of FGP, and seedling length vigor index, were evaluated. Endogenous contents of …

The Need, Opportunities, And Challenges For Creating A Standardized Framework For Marine Restoration Monitoring And Reporting, Aaron M. Eger, Hannah S. Earp, Kim Friedman, Yasmine Gatt, Valerie Hagger, Boze Hancock, Ratchanee Kaewsrikhaw, Elizabeth Mcleod, Abigail Mary Moore, Holly J. Niner, Frida Razafinaivo, Ana I. Sousa, Milica Stankovic, Thomas A. Worthington, Elisa Bayraktarov, Megan Saunders, Adriana Vergés, Simon Reeves

School of Biological and Marine Sciences

Marine ecosystems have been used, impacted by, and managed by human populations for millennia. As ecosystem degradation has been a common outcome of these activities, marine management increasingly considers ecosystem restoration. Currently, there is no coherent data recording format or framework for marine restoration projects. As a result, data are inconsistently recorded and it is difficult to universally track progress, assess restoration's global effectiveness, reduce reporting bias, collect a holistic suite of metrics, and share information. Barriers to developing a unified system for reporting marine restoration outcomes include: reaching agreement on a framework that meets the needs of all users, …