Publications by authors named "Jane Xu"

29 Publications

  • Page 1 of 1

Genome-wide screening identifies cell cycle control as a synthetic lethal pathway with SRSF2P95H mutation.

Blood Adv 2021 Aug 31. Epub 2021 Aug 31.

Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy, Victoria 3065 Australia, Australia.

Current strategies to target RNA splicing mutant myeloid cancers proposes targeting the remaining splicing apparatus. This approach has only been modestly sensitizing and is also toxic to non-mutant bearing wild-type cells. To explore potentially exploitable genetic interactions with spliceosome mutations, we combined data mining and functional screening for synthetic lethal interactions with an Srsf2P95H/+ mutation. Analysis of mis-splicing events in a series of both human and murine SRSF2P95H mutant samples across multiple myeloid diseases (AML, MDS, CMML) was performed to identify conserved mis-splicing events. From this analysis, we identified that the cell cycle and DNA repair pathways were overrepresented within the conserved mis-spliced transcript sets. In parallel, to functionally define pathways essential for survival and proliferation of Srsf2P95H/+ cells, we performed a genome-wide CRISPR loss of function screen using Hoxb8 immortalized R26-CreERki/+ Srsf2P95H/+ and R26-CreERki/+ Srsf2+/+ cell lines. We assessed loss of sgRNA representation at three timepoints: immediately after Srsf2P95H/+ activation, and at one week and two weeks post Srsf2P95H/+ mutation. Pathway analysis demonstrated that the cell cycle and DNA damage response pathways were amongst the top synthetic lethal pathways with Srsf2P95H/+ mutation. Based on the loss of guide RNAs targeting Cdk6, we identified that Palbociclib, a CDK6 inhibitor, showed preferential sensitivity in Srsf2P95H/+ cell lines and in primary non-immortalized lin-cKIT+Sca-1+ cells compared to wild type controls. Our data strongly suggest that the cell cycle and DNA damage response pathways are required for Srsf2P95H/+ cell survival, and that Palbociclib could be an alternative therapeutic option for targeting SRSF2 mutant cancers.
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http://dx.doi.org/10.1182/bloodadvances.2021004571DOI Listing
August 2021

Sarcopenia Is Associated with Mortality in Adults: A Systematic Review and Meta-Analysis.

Gerontology 2021 Jul 27:1-16. Epub 2021 Jul 27.

Department of Medicine and Aged Care, @AgeMelbourne, The Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia.

Background: Sarcopenia can predispose individuals to falls, fractures, hospitalization, and mortality. The prevalence of sarcopenia depends on the population studied and the definition used for the diagnosis.

Objective: This systematic review and meta-analysis aimed to investigate the association between sarcopenia and mortality and if it is dependent on the population and sarcopenia definition.

Methods: A systematic search was conducted in MEDLINE, EMBASE, and Cochrane from 1 January 2010 to 6 April 2020 for articles relating to sarcopenia and mortality. Articles were included if they met the following criteria - cohorts with a mean or median age ≥18 years and either of the following sarcopenia definitions: Asian Working Group for Sarcopenia (AWGS and AWGS2019), European Working Group on Sarcopenia in Older People (EWGSOP and EWGSOP2), Foundation for the National Institutes of Health (FNIH), International Working Group for Sarcopenia (IWGS), or Sarcopenia Definition and Outcomes Consortium (SDOC). Hazard ratios (HR) and odds ratios (OR) were pooled separately in meta-analyses using a random-effects model, stratified by population (community-dwelling adults, outpatients, inpatients, and nursing home residents). Subgroup analyses were performed for sarcopenia definition and follow-up period.

Results: Out of 3,025 articles, 57 articles were included in the systematic review and 56 in the meta-analysis (42,108 participants, mean age of 49.4 ± 11.7 to 86.6 ± 1.0 years, 40.3% females). Overall, sarcopenia was associated with a significantly higher risk of mortality (HR: 2.00 [95% CI: 1.71, 2.34]; OR: 2.35 [95% CI: 1.64, 3.37]), which was independent of population, sarcopenia definition, and follow-up period in subgroup analyses.

Conclusions: Sarcopenia is associated with a significantly higher risk of mortality, independent of population and sarcopenia definition, which highlights the need for screening and early diagnosis in all populations.
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http://dx.doi.org/10.1159/000517099DOI Listing
July 2021

Sarcopenia is associated with 3-month and 1-year mortality in geriatric rehabilitation inpatients: RESORT.

Age Ageing 2021 Jul 12. Epub 2021 Jul 12.

Department of Medicine and Aged Care, @AgeMelbourne, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, Australia.

Background: Sarcopenia is highly prevalent in geriatric rehabilitation patients and can worsen prognosis. This study aimed to investigate the association of sarcopenia and components of sarcopenia with 3-month and 1-year post-discharge mortality in geriatric rehabilitation inpatients.

Methods: REStORing health of acutely unwell adulTs (RESORT) is an observational, prospective longitudinal cohort of geriatric rehabilitation inpatients. Sex-stratified Cox proportional-hazards analyses were used to associate sarcopenia (and its components) at admission, by the European Working Group on Sarcopenia in Older People (EWGSOP, EWGSOP2) and the Asian Working Group for Sarcopenia 2019 (AWGS 2019), with 3-month and 1-year post-discharge all-cause mortality.

Results: Patients (n = 1,406) had a median interquartile ranges [IQR] age of 83.0 [77.4-88.2] years (58% females). Sarcopenia was significantly associated with 3-month and 1-year mortality in females (EWGSOP, EWGSOP2 and AWGS 2019) and males (EWGSOP2, AWGS 2019). In females, low muscle mass (EWGSOP, EWGSOP2 and AWGS 2019) was significantly associated with 3-month and 1-year mortality; low muscle strength (EWGSOP, EWGSOP2 and AWGS 2019) was significantly associated with 1-year mortality. For males, low muscle mass (EWGSOP2, AWGS 2019) was significantly associated with 3-month and 1-year mortality; low muscle strength (EWGSOP2, AWGS 2019) was significantly associated with 3-month mortality. The association between physical performance with mortality was not analysed due to less than five events (death) in patients with normal physical performance.

Conclusions: Sarcopenia, low muscle mass and low muscle strength at admission are associated with a significantly higher risk of mortality post-discharge from geriatric rehabilitation, highlighting the need to measure muscle mass and strength in clinical practice.
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http://dx.doi.org/10.1093/ageing/afab134DOI Listing
July 2021

Selective Estrogen Receptor Modulators: A Potential Option For Non-Binary Gender-Affirming Hormonal Care?

Front Endocrinol (Lausanne) 2021 18;12:701364. Epub 2021 Jun 18.

Clinical Sciences and Genetics Themes, Murdoch Children's Research Institute, Parkville, VIC, Australia.

Gender dysphoria describes the distress associated with having a gender identity that differs from one's birth-assigned sex. To relieve this distress, transgender, and gender diverse (henceforth, trans) individuals commonly undergo medical transition involving hormonal treatments. Current hormonal treatment guidelines cater almost exclusively for those who wish to transition from male to female or vice versa. In contrast, there is a dearth of hormonal options for those trans individuals who identify as non-binary and seek an androgynous appearance that is neither overtly male nor female. Though prolonged puberty suppression with gonadotrophin releasing hormone agonists (GnRHa) could in theory be gender-affirming by preventing the development of unwanted secondary sex characteristics, this treatment option would be limited to pre- or peri-pubertal adolescents and likely have harmful effects. Here, we discuss the theoretical use of Selective Estrogen Receptor Modulators (SERMs) for non-binary people assigned male at birth (AMAB) who are seeking an androgynous appearance through partial feminization without breast growth. Given their unique range of pharmacodynamic effects, SERMs may represent a potential gender-affirming treatment for this population, but there is a lack of knowledge regarding their use and potentially adverse effects in this context.
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http://dx.doi.org/10.3389/fendo.2021.701364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253879PMC
June 2021

Learning arbitrary stimulus-reward associations for naturalistic stimuli involves transition from learning about features to learning about objects.

Cognition 2020 12 19;205:104425. Epub 2020 Sep 19.

Department of Psychological and Brain Sciences, Dartmouth College, NH 03755, United States of America. Electronic address:

Most cognitive processes are studied using abstract or synthetic stimuli with specific features to fully control what is presented to subjects. However, recent studies have revealed enhancements of cognitive capacities (such as working memory) when processing naturalistic versus abstract stimuli. Using abstract stimuli constructed from distinct visual features (e.g., color and shape), we have recently shown that human subjects can learn multidimensional stimulus-reward associations via initially estimating reward value of individual features (feature-based learning) before gradually switching to learning about reward value of individual stimuli (object-based learning). Here, we examined whether similar strategies are adopted during learning about naturalistic stimuli that are clearly perceived as objects (instead of a combination of features) and contain both task-relevant and irrelevant features. We found that similar to learning about abstract stimuli, subjects initially adopted feature-based learning more strongly before transitioning to object-based learning. However, there were three key differences between learning about naturalistic and abstract stimuli. First, compared with abstract stimuli, the initial learning strategy was less feature-based for naturalistic stimuli. Second, subjects transitioned to object-based learning faster for naturalistic stimuli. Third, unexpectedly, subjects were more likely to adopt feature-based learning for naturalistic stimuli, both at the steady state and overall. These results suggest that despite the stronger tendency to perceive naturalistic stimuli as objects, which leads to greater likelihood of using object-based learning as the initial strategy and a faster transition to object-based learning, the influence of individual features on learning is stronger for these stimuli such that ultimately the object-based strategy is adopted less. Overall, our findings suggest that feature-based learning is a general initial strategy for learning about reward value of all types of multi-dimensional stimuli.
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http://dx.doi.org/10.1016/j.cognition.2020.104425DOI Listing
December 2020

Switching to Lurasidone following 12 months of treatment with Risperidone: results of a 6-month, open-label study.

BMC Psychiatry 2020 05 5;20(1):199. Epub 2020 May 5.

Sunovion Pharmaceuticals Inc., Fort Lee, NJ, 84 Waterford Dr, Marlborough, MA, 01752, USA.

Background: Patients with a diagnosis of schizophrenia are at an increased risk for developing metabolic syndrome, which is associated with greater cardiovascular morbidity and mortality. Treatment with some commonly used antipsychotic medications may increase the risk of developing metabolic syndrome. The aim of the study was to evaluate the safety of lurasidone in patients who continued lurasidone or switched from risperidone to lurasidone. A secondary aim was assessment of the effect of long-term lurasidone on the Positive and Negative Syndrome Scale (PANSS).

Methods: The treatment sample in the current study consisted of clinically stable patients with schizophrenia (N = 223) who had completed a 12-month, double-blind study of lurasidone vs. risperidone. In the current extension study, all patients received 6 months of open-label treatment with lurasidone, either continuing lurasidone assigned during the preceding double-blind trial, or switching from double-blind risperidone to lurasidone. Safety and tolerability parameters included body weight, prolactin, and metabolic laboratory tests.

Results: Six months of OL treatment with lurasidone was generally well-tolerated, with a low incidence of parkinsonism (4.5%) and akathisia (3.1%). Overall, few adverse events were rated as severe (4.9%), and discontinuation due to an adverse event was low in the lurasidone continuation vs. risperidone switch groups (3.7% vs. 6.9%). In the lurasidone continuation versus risperidone switch groups, change from OL baseline to 6-month endpoint (observed case) was observed in mean body weight (- 0.6 vs. -2.6 kg), median total cholesterol (- 4.0 vs. + 4.5 mg/dL), triglycerides (- 4.5 vs. -5.5 mg/dL), glucose (0.0 vs. -3.0 mg/dL) and prolactin (males, + 0.15 vs. -11.2 ng/mL; females, + 1.3 vs. -30.8 ng/mL). Improvement in PANSS total score was maintained, from OL baseline to endpoint in the continuation vs. switch groups (+ 1.0 vs. -1.0; OC).

Conclusions: In this 6-month extension study, lurasidone treatment was generally well-tolerated and associated with minimal effects on weight, metabolic parameters, and prolactin levels. Patients who switched from risperidone to lurasidone experienced reductions in weight, metabolic parameters and prolactin levels commensurate with increases in these safety parameters experienced during the previous 12 months of treatment with risperidone.

Trial Registration: ClinicalTrials.gov NCT00641745 (Date of Registration: March 24, 2008).
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http://dx.doi.org/10.1186/s12888-020-02523-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201608PMC
May 2020

Gastric Cancer Peritoneal Carcinomatosis Risk Score.

Ann Surg Oncol 2020 Jan 25;27(1):240-247. Epub 2019 Jul 25.

Division of Surgical Oncology, Loma Linda University Health, Loma Linda, CA, USA.

Background: Gastric cancer (GC) peritoneal carcinomatosis (PC) is associated with a poor prognosis. Although grade, histology, and stage are associated with PC, the cumulative risk of PC when multiple risk factors are present is unknown. This study aimed to develop a cumulative GCPC risk score based on individual demographic/tumor characteristics.

Methods: Patient-level data (2004-2014) from the California Cancer Registry were reviewed by creating a keyword search algorithm to identify patients with gastric PC. Multivariable logistic regression was used to assess demographic/tumor characteristics associated with PC in a randomly selected testing cohort. Scores were assigned to risk factors based on beta coefficients from the logistic regression result, and these scores were applied to the remainder of the subjects (validation cohort). The summed scores of each risk factor formed the total risk score. These were grouped, showing the percentages of patients with PC.

Results: The study identified 4285 patients with gastric adenocarcinoma (2757 males, 64.3%). The median age of the patients was 67 years (interquartile range [IQR], 20 years). Most of the patients were non-Hispanic white (n = 1748, 40.8%), with proximal (n = 1675, 39.1%) and poorly differentiated (n = 2908, 67.9%) tumors. The characteristics most highly associated with PC were T4 (odds ratio [OR], 3.12; 95% confidence interval [CI], 2.19-4.44), overlapping location (OR 2.27; 95% CI 1.52-3.39), age of 20-40 years (OR 3.42; 95% CI 2.24-5.21), and Hispanic ethnicity (OR 1.86; 95% CI 1.36-2.54). The demographic/tumor characteristics used in the risk score included age, race/ethnicity, T stage, histology, tumor grade, and location. Increasing GCPC score was associated with increasing percentage of patients with PC.

Conclusion: Based on demographic/tumor characteristics in GC, it is possible to distinguish groups with varying odds for PC. Understanding the risk for PC based on the cumulative effect of high-risk features can help clinicians to customize surveillance strategies and can aid in early identification of PC.
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http://dx.doi.org/10.1245/s10434-019-07624-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925067PMC
January 2020

Modeling human RNA spliceosome mutations in the mouse: not all mice were created equal.

Exp Hematol 2019 02 6;70:10-23. Epub 2018 Nov 6.

St. Vincent's Institute, Fitzroy, Victoria 3065, Australia; Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, Victoria 3065, Australia; Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Victoria 3000, Australia. Electronic address:

Myelodysplastic syndromes (MDS) and related myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) are clonal stem cell disorders, primarily affecting patients over 65 years of age. Mapping of the MDS and MDS/MPN genome identified recurrent heterozygous mutations in the RNA splicing machinery, with the SF3B1, SRSF2, and U2AF1 genes being frequently mutated. To better understand how spliceosomal mutations contribute to MDS pathogenesis in vivo, numerous groups have sought to establish conditional murine models of SF3B1, SRSF2, and U2AF1 mutations. The high degree of conservation of hematopoiesis between mice and human and the well-established phenotyping and genetic modification approaches make murine models an effective tool with which to study how a gene mutation contributes to disease pathogenesis. The murine models of spliceosomal mutations described to date recapitulate human MDS or MDS/MPN to varying extents. Reasons for the differences in phenotypes reported between alleles of the same mutation are varied, but the nature of the genetic modification itself and subsequent analysis methods are important to consider. In this review, we summarize recently reported murine models of SF3B1, SRSF2, and U2AF1 mutations, with a particular focus on the genetically engineered modifications underlying the models and the experimental approaches applied.
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http://dx.doi.org/10.1016/j.exphem.2018.11.001DOI Listing
February 2019

initiates myeloid bias and myelodysplastic/myeloproliferative syndrome from hemopoietic stem cells.

Blood 2018 08 14;132(6):608-621. Epub 2018 Jun 14.

St. Vincent's Institute, Fitzroy, VIC, Australia.

Mutations in occur in myelodysplastic syndromes (MDS) and MDS/myeloproliferative neoplasms (MPN). mutations cluster at proline 95, with the most frequent mutation being a histidine (P95H) substitution. They undergo positive selection, arise early in the course of disease, and have been identified in age-related clonal hemopoiesis. It is not clear how mutation of modifies hemopoiesis or contributes to the development of myeloid bias or MDS/MPN. Two prior mouse models of mutation have been reported; however, these models do not recapitulate many of the clinical features of -mutant disease and relied on bone marrow (BM) transplantation stress to elicit the reported phenotypes. We describe a new conditional murine mutation model, where the P95H mutation is expressed physiologically and heterozygously from its endogenous locus after Cre activation. Using multiple Cre lines, we demonstrate that during native hemopoiesis (ie, no BM transplantation), the mutation needs to occur within the hemopoietic stem-cell-containing populations to promote myelomonocytic bias and expansion with corresponding transcriptional and RNA splicing changes. With age, nontransplanted animals developed a progressive, transplantable disease characterized by myeloid bias, morphological dysplasia, and monocytosis, hallmarks of MDS/MPN in humans. Analysis of cooccurring mutations within the BM demonstrated the acquisition of additional mutations that are recurrent in humans with mutations. The tractable knock-in model we have generated is highly relevant to human disease and will serve to elucidate the effect of mutations on initiation and maintenance of MDS/MPN.
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http://dx.doi.org/10.1182/blood-2018-04-845602DOI Listing
August 2018

Five lessons in uncomplicated appendicitis: Can we remove the surgery?

J Paediatr Child Health 2017 Nov;53(11):1127-1130

Department of Paediatric Surgery, Children's Hospital at Westmead, Sydney, New South Wales, Australia.

Appendicectomy has remained the treatment of choice for appendicitis for over a century and is the most commonly performed emergency operation in children. However, emerging evidence suggests that appendicectomy may not always be necessary in uncomplicated appendicitis, with early paediatric trials demonstrating that antibiotic-only therapy can be safe and effective. Further rigorously designed and appropriately powered studies are necessarily to establish the place of non-operative management of uncomplicated appendicitis in the future.
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http://dx.doi.org/10.1111/jpc.13741DOI Listing
November 2017

Nonoperative management in children with early acute appendicitis: A systematic review.

J Pediatr Surg 2017 Sep 11;52(9):1409-1415. Epub 2017 May 11.

Division of Child and Adolescent Health, The University of Sydney, New South Wales, Australia; Department of Pediatric Surgery, The Children's Hospital at Westmead, New South Wales, Australia.

Purpose: Appendectomy has remained the gold standard treatment of acute appendicitis for more than 100years. Nonoperative management (NOM) has been shown to be a valid treatment alternative for acute uncomplicated appendicitis in adults. A systematic review of available evidence comparing operative management (OM) and NOM in children with acute uncomplicated appendicitis was performed.

Methods: Systematic searches of MedLine, Embase, and a clinical trial register (https://clinicaltrials.gov/) were performed in March 2016. Only articles that studied NOM for uncomplicated appendicitis in children were included. Data generation was performed independently by two authors, and quality was assessed using the rating schema by the Oxford Centre for Evidence-Based Medicine.

Results: 15 articles were selected: four retrospective analyses, four prospective cohort studies, four prospective nonrandomized comparative trials and one randomized controlled trial (RCT). Initial success of the NOM groups (a cure within two weeks of intervention) ranged from 58 to 100%, with 0.1-31.8% recurrence at one year.

Conclusion: Although present literature is scarce, publications support the feasibility of further studies investigating NOM of acute uncomplicated appendicitis in children. Higher quality prospective RCTs with larger sample sizes and robust randomization methods, studying the noninferiority of NOM with antibiotics compared with OM are required to establish its utility.

Level Of Evidence: This manuscript is a systematic review and thus assigned the lowest evidence used from the manuscripts analyzed which is a Level IV.
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http://dx.doi.org/10.1016/j.jpedsurg.2017.05.003DOI Listing
September 2017

Acute uncomplicated appendicitis study: rationale and protocol for a multicentre, prospective randomised controlled non-inferiority study to evaluate the safety and effectiveness of non-operative management in children with acute uncomplicated appendicitis.

BMJ Open 2016 12 21;6(12):e013299. Epub 2016 Dec 21.

Division of Child and Adolescent Health, The University of Sydney, Sydney, New South Wales, Australia.

Introduction: This article presents an overview of a prospective randomised controlled non-inferiority study designed to evaluate the safety and effectiveness of non-operative management (NOM) with operative management in children with acute uncomplicated appendicitis (AUA). Here, we present the study protocol for this APRES study, a multicentre Australian study. The rationale and details of future analysis, in particular, non-inferiority calculations, cost-effectiveness, feasibility and acceptability of each intervention.

Design: A multicentre, prospective randomised controlled clinical trial, conducted in 2 Australian tertiary paediatric hospitals.

Participants: Children who meet the inclusion criteria of an age between 5 and 15 years and a clinical diagnosis of AUA will be invited to participate, and after consent will be randomised via a computer-based program into treatment groups. The study started in June 2016, and the target recruitment is 220 patients.

Interventions: Children in the control group will be treated with prophylactic antibiotics and appendicectomy, and those in the intervention group will be treated with antibiotic therapy alone. Primary outcome measures include unplanned or unnecessary operation and complications at 30 days. Secondary outcomes include longer term complications within 1 year, length of stay, time off work and school analgesic requirements and cost.

Analysis: Data analyses will be on the intention-to-treat principle using non-inferiority analysis. Analysis will include the Pearson χ test for categorical variables and independent sample t-test or Mann-Whitney test for continuous variables. Non-inferiority for NOM will be tested using 1-sided Wald tests with an α level of 0.05.

Ethics And Dissemination: The research has been approved by the Human Research Ethics Committee of the Sydney Children's Hospital Network. In addition, results will be reported through academic journals, seminars and conference presentations.

Trial Registration Numbers: NCT02795793; ACTRN12616000788471.
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http://dx.doi.org/10.1136/bmjopen-2016-013299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5223693PMC
December 2016

The development of lurasidone for bipolar depression.

Ann N Y Acad Sci 2015 Nov;1358:95-104

Sunovion Pharmaceuticals Inc., Fort Lee, New Jersey, and Marlborough, Massachusetts.

Bipolar disorder is a chronic, recurrent illness that ranks among the top 10 causes of disability in the developed world. As the illness progresses, major depressive episodes increasingly predominate. However, few treatment options are available that have demonstrated efficacy in the treatment of bipolar depression, either as monotherapy or adjunctive therapy in combination with mood stabilizers. Lurasidone is an atypical antipsychotic drug that was initially developed for the treatment of schizophrenia. Since no previous atypical antipsychotic development program had proceeded directly from work on schizophrenia to bipolar depression, the decision to focus on this indication represented an innovation in central nervous system drug development and was designed to address a clinically significant unmet need. The current review summarizes key results of a clinical development program undertaken to characterize the efficacy and safety of lurasidone in patients diagnosed with bipolar depression. Lurasidone is currently the only treatment for bipolar depression approved in the United States as both a monotherapy and an adjunctive therapy with lithium or valproate. The approval of lurasidone expands available treatment options for patients with bipolar depression and provides a therapy with an overall favorable risk-benefit profile.
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http://dx.doi.org/10.1111/nyas.12965DOI Listing
November 2015

The Correlation of the Tinnitus Handicap Inventory with Depression and Anxiety in Veterans with Tinnitus.

Int J Otolaryngol 2015 30;2015:689375. Epub 2015 Nov 30.

Department of Otolaryngology and Head & Neck Surgery, Loma Linda University Medical Center, Loma Linda, CA, USA ; Loma Linda Veterans Affairs Medical Center, Loma Linda, CA, USA ; Cell & Molecular Pathology Laboratory, Department of Communication Sciences and Disorders, Northern Arizona University, Flagstaff, AZ, USA.

Objective. The mechanisms of tinnitus are known to alter neuronal circuits in the brainstem and cortex, which are common to several comorbid conditions. This study examines the relationship between tinnitus and anxiety/depression. Subjects and Methods. Ninety-one male veterans with subjective tinnitus were enrolled in a Veterans Affairs Tinnitus Clinic. The Tinnitus Handicap Inventory (THI) was used to assess tinnitus severity. ICD-9 codes for anxiety/depression were used to determine their prevalence. Pure tone averages (PTA) were used to assess hearing status. Results. Descriptive analyses revealed that 79.1% of the 91 tinnitus sufferers had a diagnosis of anxiety, 59.3% had depression, and 58.2% suffered from both anxiety/depression. Patients with anxiety had elevated total THI scores as compared to patients without anxiety (p < 0.05). Patients with anxiety or depression had significantly increased Functional and Emotional THI scores, but not Catastrophic THI score. Significant positive correlations were illustrated between the degree of tinnitus and anxiety/depression (p < 0.05). There were no differences in PTA among groups. Conclusions. A majority of patients with tinnitus exhibited anxiety and depression. These patients suffered more severe tinnitus than did patients without anxiety and depression. The data support the need for multidisciplinary intervention of veterans with tinnitus.
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http://dx.doi.org/10.1155/2015/689375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4677242PMC
December 2015

Treatment of early non-response in patients with schizophrenia: assessing the efficacy of antipsychotic dose escalation.

BMC Psychiatry 2015 Oct 31;15:271. Epub 2015 Oct 31.

The Zucker Hillside Hospital, Glen Oaks, and the Hofstra North Shore-LIJ School of Medicine, Hempstead, NY, USA.

Background: Early non-response to antipsychotic treatment in patients with schizophrenia has been shown in multiple studies to predict poor response at short-term trial endpoint. Therefore, strategies to address the challenge of non-improvement early in the course of treatment are needed. A novel trial design was developed to assess the potential utility of antipsychotic dose escalation in patients with an inadequate initial treatment response. This design was embedded in a study intended to assess the efficacy of low dose lurasidone in patients with schizophrenia. The purpose of this report is to describe the background, rationale and design of this study that included a novel method for the assessment of the potential for dose-response in early non-responding patients with schizophrenia.

Methods/design: In this 6-week, international, multicenter, double-blind trial, eligible adults with acute schizophrenia were randomized to receive fixed doses of lurasidone 20 mg/day, 80 mg/day (active control), or placebo in a 1:2:1 ratio. Patients initially randomized to lurasidone 80 mg/day who did not have a Positive and Negative Syndrome Scale total score improvement ≥ 20% at Week 2 were re-randomized on a 1:1 basis to receive either lurasidone 80 mg/day or lurasidone 160 mg/day for the remainder of the trial. All other groups remained on their initially assigned treatment. The formal primary objective of the study was to evaluate the efficacy of low-dose lurasidone (20 mg/day) compared to placebo; secondary objectives included evaluating the efficacy of lurasidone 80 mg/day versus 160 mg/day in early non-responders, and evaluating the efficacy of lurasidone in all subjects initially randomized to 80 mg/day versus placebo.

Discussion: Since a lack of early improvement predicts poor response to short-term antipsychotic treatment in patients with schizophrenia, several treatment strategies have been proposed to enhance treatment outcome in early non-responders. A novel clinical trial design involving a placebo arm and re-randomization of early non-responders to increased or maintained antipsychotic dose was developed. The study design described in this report provides a robust method to assess the value of antipsychotic dose escalation in patients with schizophrenia who demonstrate poor initial treatment response.

Trial Registration: ClinicalTrials.gov NCT01821378; initial registration March 22, 2013.
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http://dx.doi.org/10.1186/s12888-015-0629-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4628370PMC
October 2015

Enhanced Antitumor Activity of an Anti-5T4 Antibody-Drug Conjugate in Combination with PI3K/mTOR inhibitors or Taxanes.

Clin Cancer Res 2016 Jan 28;22(2):383-94. Epub 2015 Aug 28.

Oncology Research Unit, Pfizer Worldwide Research and Development, Pearl River, New York.

Purpose: Targeted treatment of solid or liquid tumors with antibody-drug conjugates (ADCs) can lead to promising clinical benefit. The aim of the study is to investigate combination regimens of auristatin-based ADCs in preclinical models of cancer.

Experimental Design: An auristatin-based anti-5T4 antibody conjugate (5T4-ADC) and auristatin payloads were combined with the dual PI3K/mTOR catalytic site inhibitor PF-05212384 (PF-384) or taxanes in a panel of tumor cell lines. Drug interactions in vitro were evaluated using cell viability assays, apoptosis induction, immunofluorescence, mitotic index, and immunoblotting. Breast cancer cells treated with auristatin analogue or 5T4-ADC were profiled by total- and phospho-proteomics. Antitumor efficacy of selected combinations was evaluated in 5T4-positive human breast or lung tumor xenografts in vivo.

Results: In vitro, auristatin-based agents displayed strong synergistic or additive activity when combined with PF-384 or taxanes, respectively. Further, treatment of 5T4-ADC plus PF-384 resulted in stronger induction of apoptosis and cell line-specific attenuation of pAKT and pGSK. Interestingly, proteomic analysis revealed unique effects of auristatins on multiple components of mRNA translation. Addition of PF-384 further amplified effects of 5T4-ADC on translational components, providing a potential mechanism of synergy between these drugs. In human tumor xenografts, dual targeting with 5T4-ADC/PF-384 or 5T4-ADC/paclitaxel produced substantially greater antitumor effects with longer average survival as compared with monotherapy treatments.

Conclusions: Our results provide a biologic rationale for combining 5T4-ADC with either PI3K/mTOR pathway inhibitors or taxanes and suggest that mechanisms underlying the synergy may be attributed to cellular effects of the auristatin payload.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-1166DOI Listing
January 2016

Contemporary changes with the use of facial nerve monitoring in chronic ear surgery.

Otolaryngol Head Neck Surg 2014 Sep 3;151(3):473-7. Epub 2014 Jun 3.

Department of Otolaryngology-Head & Neck Surgery, Loma Linda University Medical Center, Loma Linda, California, USA

Objective: There is a growing trend for the routine use of the facial nerve monitor (FNM) in chronic ear surgery. We aimed to examine current patterns in the use of FNMs in chronic ear surgery.

Study Design: Descriptive design (survey).

Setting: Academic health center.

Methods: A 10-question survey was designed to identify level of training, scope of practice, specific otologic surgeries where monitoring was most used, and the opinion of respondents regarding the use of FNMs as standard of care for chronic and/or middle ear surgery. A randomized list of 2000 board-certified members of the American Academy of Otolaryngology-Head and Neck Surgery was generated. One thousand subjects received a mailed survey with a self-addressed return envelope and 1000 subjects received an emailed survey through Surveymonkey.com.

Results: There were 359 (36%) surveys returned by mail and 258 (26%) surveys returned electronically. Forty-three percent of respondents were in private practice, and 31% were fellowship trained in otology/neurotology. Sixty-five percent used a FNM in their training and 95% had regular access to a FNM. Revision mastoid surgery, cholesteatoma, canal wall down mastoidectomy, and facial recess approach were the settings where a FNM was most used. Forty-nine percent of respondents felt that a FNM should be used as the standard of care in chronic ear surgery; this represents an increase from 32% in a similar study done approximately 10 years ago.

Conclusion: There is a growing trend for routine facial nerve monitoring in the setting of chronic ear surgery.
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http://dx.doi.org/10.1177/0194599814537223DOI Listing
September 2014

Lurasidone as adjunctive therapy with lithium or valproate for the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study.

Am J Psychiatry 2014 Feb;171(2):169-77

OBJECTIVE Few studies have been reported that support the efficacy of adjunctive therapy for patients with bipolar I depression who have had an insufficient response to monotherapy with mood-stabilizing agents. The authors investigated the efficacy of lurasidone, a novel antipsychotic agent, as adjunctive therapy with lithium or valproate for the treatment of bipolar I depression. METHOD Patients were randomly assigned to receive 6 weeks of double-blind adjunctive treatment with lurasidone (N=183) or placebo (N=165), added to therapeutic levels of either lithium or valproate. Primary and key secondary endpoints were change from baseline to week 6 on the Montgomery-Åsberg Depression Rating Scale (MADRS) and depression severity score on the Clinical Global Impressions scale for use in bipolar illness (CGI-BP), respectively. RESULTS Lurasidone treatment significantly reduced mean MADRS total score at week 6 compared with the placebo group (-17.1 versus -13.5; effect size=0.34). Similarly, lurasidone treatment resulted in significantly greater endpoint reduction in CGI-BP depression severity scores compared with placebo (-1.96 versus -1.51; effect size=0.36) as well as significantly greater improvement in anxiety symptoms and in patient-reported measures of quality of life and functional impairment. Discontinuation rates due to adverse events were 6.0% and 7.9% in the lurasidone and placebo groups, respectively. Adverse events most frequently reported for lurasidone were nausea, somnolence, tremor, akathisia, and insomnia. Minimal changes in weight, lipids, and measures of glycemic control were observed during treatment with lurasidone. CONCLUSIONS In patients with bipolar I depression, treatment with lurasidone adjunctive to lithium or valproate significantly improved depressive symptoms and was generally well tolerated.
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http://dx.doi.org/10.1176/appi.ajp.2013.13070985DOI Listing
February 2014

Effectiveness of lurasidone vs. quetiapine XR for relapse prevention in schizophrenia: a 12-month, double-blind, noninferiority study.

Schizophr Res 2013 Jun 11;147(1):95-102. Epub 2013 Apr 11.

Department of Psychiatry, The Zucker Hillside Hospital, Glen Oaks, NY, United States; Hofstra North Shore-LIJ School of Medicine, United States.

Objective: To evaluate the relapse prevention efficacy of lurasidone compared with quetiapine XR (QXR) in adults patients with schizophrenia.

Method: This double-blind study evaluated the relapse prevention efficacy of 12 months of flexible-dose treatment with lurasidone (40-160 mg/day) compared with QXR (200-800 mg/day), in outpatients with an acute exacerbation of chronic schizophrenia who had recently completed a 6-week placebo-controlled trial of treatment with either lurasidone or QXR. The primary endpoint, time-to-relapse, was analyzed using a Cox proportional hazards model in this noninferiority trial.

Results: The Kaplan-Meier estimate of the probability of relapse over 12 months was 23.7% for subjects receiving lurasidone vs. 33.6% for QXR. The hazard ratio [95% CI] for probability of relapse was 0.728 [0.410, 1.295] (log-rank p=0.280). Since the upper limit of the hazard ratio (1.295) was smaller than the prespecified noninferiority margin (1.93), noninferiority of lurasidone compared with QXR was demonstrated in this study. The probability of hospitalization at 12 months was lower for the lurasidone group compared with the QXR group (9.8% vs. 23.1%; log-rank p=0.049). A significantly higher proportion of lurasidone subjects achieved remission at study endpoint compared with the QXR group (61.9% vs. 46.3%; p=0.043). Discontinuation rates due to AEs were similar for lurasidone and QXR (7% vs. 5%). Treatment with lurasidone was not associated with clinically significant changes in weight or metabolic parameters.

Conclusions: Twelve months of treatment with lurasidone met noninferiority criteria, and was associated with higher rates of remission, and reduced risk of hospitalization compared with QXR. No clinically significant effects on weight or metabolic parameters were observed during maintenance treatment with lurasidone.
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http://dx.doi.org/10.1016/j.schres.2013.03.013DOI Listing
June 2013

Lurasidone for the treatment of acutely psychotic patients with schizophrenia: a 6-week, randomized, placebo-controlled study.

J Psychiatr Res 2013 May 17;47(5):670-7. Epub 2013 Feb 17.

Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, 260 Stetson St., Suite 3224, Cincinnati, OH 45219, USA.

Despite the availability of established antipsychotic agents for the treatment of schizophrenia, continued unmet needs exist for effective medications with lower adverse-effect burden. The present study evaluated the efficacy, safety, and tolerability of treatment with the atypical antipsychotic lurasidone for patients with an acute exacerbation of schizophrenia. Patients were randomized to 6 weeks of double-blind treatment with lurasidone 40 mg/day, 80 mg/day, or 120 mg/day, or placebo. Changes in Positive and Negative Syndrome Scale (PANSS) scores were evaluated using mixed-model repeated-measures (MMRM) analysis. Vital signs, laboratory parameters, extrapyramidal symptoms, and electrocardiogram were assessed. Treatment with lurasidone 80 mg/day resulted in significantly greater improvement in PANSS total score compared with placebo (-23.4 versus -17.0; p < 0.05) at study endpoint (MMRM); lurasidone 40 mg/day and 120 mg/day achieved clinically meaningful overall PANSS score reductions from baseline (-19.2 and -20.5), but not significant separation from placebo. Differences between all lurasidone groups and placebo for changes in laboratory parameters and electrocardiographic measures were minimal. Weight gain ≥ 7% occurred in 8.2% of patients receiving lurasidone and 3.2% receiving placebo. Modest increases in prolactin (median increase, 0.7 ng/mL) and extrapyramidal symptoms were observed following treatment with lurasidone compared with placebo. Akathisia was the most commonly reported adverse event with lurasidone (17.6%, versus 3.1% with placebo). In this study, in which a large placebo response was observed, lurasidone 80 mg/day, but not 40 mg/day or 120 mg/day, was statistically superior to placebo in treating acute exacerbation of chronic schizophrenia. All lurasidone doses were generally well tolerated.
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http://dx.doi.org/10.1016/j.jpsychires.2013.01.020DOI Listing
May 2013

Lurasidone in the treatment of schizophrenia: a randomized, double-blind, placebo- and olanzapine-controlled study.

Am J Psychiatry 2011 Sep 15;168(9):957-67. Epub 2011 Jun 15.

Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, Tenn., USA.

Objective: The study was designed to evaluate the short-term efficacy and safety of lurasidone in the treatment of acute schizophrenia.

Method: Participants, who were recently admitted inpatients with schizophrenia with an acute exacerbation of psychotic symptoms, were randomly assigned to 6 weeks of double-blind treatment with 40 mg of lurasidone, 120 mg of lurasidone, 15 mg of olanzapine (included to test for assay sensitivity), or placebo, dosed once daily. Efficacy was evaluated using a mixed-model repeated-measures analysis of the change from baseline to week 6 in Positive and Negative Syndrome Scale (PANSS) total score (as the primary efficacy measure) and Clinical Global Impressions severity (CGI-S) score (as the key secondary efficacy measure).

Results: Treatment with both doses of lurasidone or with olanzapine was associated with significantly greater improvement at week 6 on PANSS total score, PANSS positive and negative subscale scores, and CGI-S score compared with placebo. There was no statistically significant difference in mean PANSS total or CGI-S change scores for the lurasidone groups compared with the olanzapine group. With responders defined as those with an improvement of at least 20% on the PANSS, endpoint responder rates were significant compared with placebo for olanzapine only. The incidence of akathisia was higher with 120 mg of lurasidone (22.9%) than with 40 mg of lurasidone (11.8%), olanzapine (7.4%), or placebo (0.9%). The proportion of patients experiencing ≥ 7% weight gain was 5.9% for the lurasidone groups combined, 34.4% for the olanzapine group, and 7.0% for the placebo group.

Conclusions: Lurasidone was an effective treatment for patients with acute schizophrenia. Safety assessments indicated a higher frequency of adverse events associated with 120 mg/day of lurasidone compared with 40 mg/day.
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http://dx.doi.org/10.1176/appi.ajp.2011.10060907DOI Listing
September 2011

A mixture gatekeeping procedure based on the Hommel test for clinical trial applications.

J Biopharm Stat 2011 Jul;21(4):748-67

Dainippon Sumitomo Pharma Co., Ltd., Suita, Osaka 564-0053, Japan.

When conducting clinical trials with hierarchically ordered objectives, it is essential to use multiplicity adjustment methods that control the familywise error rate in the strong sense while taking into account the logical relations among the null hypotheses. This paper proposes a gatekeeping procedure based on the Hommel (1988) test, which offers power advantages compared to other p value-based tests proposed in the literature. A general description of the procedure is given and details are presented on how it can be applied to complex clinical trial designs. Two clinical trial examples are given to illustrate the methodology developed in the paper.
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http://dx.doi.org/10.1080/10543406.2011.551334DOI Listing
July 2011

Care providers' satisfaction with restructured clinical pharmacy services in a tertiary care teaching hospital.

Can J Hosp Pharm 2010 Mar;63(2):105-12

, BSP, PharmD, is Clinical Practice Manager with Pharmacy Services, Alberta Health Services, Edmonton, Alberta. She is also a Clinical Adjunct Professor, Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta.

Background: At the time this study was undertaken, clinical pharmacy services at the authors' institution, a tertiary care teaching hospital, were largely reactive in nature, with patients and units receiving inconsistent coverage.

Objective: To develop an evidence-based model of proactive practice and to evaluate the satisfaction of pharmacists and other stakeholders after restructuring of clinical pharmacy services.

Methods: The literature was reviewed to determine a core set of pharmacist services associated with the greatest beneficial impact on patients' health. On the basis of established staffing levels, the work schedule was modified, and pharmacists were assigned to a limited number of patient care teams to proactively and consistently provide these core services. Other patient care teams continued to receive reactive troubleshooting-based services, as directed by staff in the pharmacy dispensary. A satisfaction survey was distributed to all pharmacists, nurses, and physicians 18 months after the restructuring.

Results: Of the 26 pharmacists who responded to the survey, all agreed or strongly agreed that the restructuring of services had improved job satisfaction and patient safety and that other health care professionals valued their contribution to patient care. Nurses and physicians from units where pharmacists had been assigned to provide proactive services perceived pharmacist services more favourably than those from units where pharmacist services were reactive. Pharmacists, nurses, and physicians all felt that proactive pharmacist services should be more widely available. Challenges reported by pharmacists included increased expectations for documentation and guilt about "cutting back" services where they had previously been provided.

Conclusions: Restructuring clinical pharmacy services in an evidence-based manner improved pharmacists' satisfaction and created demand from other stakeholders to provide this level of service for all patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2858499PMC
http://dx.doi.org/10.4212/cjhp.v63i2.893DOI Listing
March 2010

Influence of stationary phase chemistry and mobile-phase composition on retention, selectivity, and MS response in hydrophilic interaction chromatography.

J Sep Sci 2010 Mar;33(6-7):740-51

Waters Corporation, Milford, MA 01757, USA.

A comprehensive retention and selectivity characterization of several hydrophilic interaction chromatography (HILIC) stationary phases was performed with 28 test probes in order to study the influence of particle type, surface chemistry, and mobile-phase pH on chromatographic retention, selectivity, and MS response. Selectivity differences were compared for columns operated at both low and high pH, while ESI-MS was used to study the effects of mobile-phase pH on signal response. Additionally, acetone was explored as a potential alternative to ACN as the weak HILIC solvent. Moderate differences in selectivity were observed on the same column operated at different pH, mostly due to acidic compounds. In addition, the MS response increased when a high pH mobile phase was used, particularly for analytes that were ionized with negative ESI-MS. Even larger selectivity differences were observed for different stationary phases evaluated with the same mobile phase. Acetone was not a suitable replacement for ACN in routine HILIC separations due to differences in selectivity and MS response. Finally, the data from this study were used to establish guidelines for rapid HILIC method development of polar compounds, which is demonstrated with a mixture of histidine dipeptides and organophosphonate nerve agent metabolites.
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http://dx.doi.org/10.1002/jssc.200900660DOI Listing
March 2010

Begacestat (GSI-953): a novel, selective thiophene sulfonamide inhibitor of amyloid precursor protein gamma-secretase for the treatment of Alzheimer's disease.

J Pharmacol Exp Ther 2009 Nov 11;331(2):598-608. Epub 2009 Aug 11.

Wyeth Research, Departments of Discovery Neuroscience, Princeton, New Jersey 08543, USA.

The presenilin containing gamma-secretase complex is responsible for the regulated intramembraneous proteolysis of the amyloid precursor protein (APP), the Notch receptor, and a multitude of other substrates. gamma-Secretase catalyzes the final step in the generation of Abeta(40) and Abeta(42) peptides from APP. Amyloid beta-peptides (Abeta peptides) aggregate to form neurotoxic oligomers, senile plaques, and congophilic angiopathy, some of the cardinal pathologies associated with Alzheimer's disease. Although inhibition of this protease acting on APP may result in potentially therapeutic reductions of neurotoxic Abeta peptides, nonselective inhibition of the enzyme may cause severe adverse events as a result of impaired Notch receptor processing. Here, we report the preclinical pharmacological profile of GSI-953 (begacestat), a novel thiophene sulfonamide gamma-secretase inhibitor (GSI) that selectively inhibits cleavage of APP over Notch. This GSI inhibits Abeta production with low nanomolar potency in cellular and cell-free assays of gamma-secretase function, and displaces a tritiated analog of GSI-953 from enriched gamma-secretase enzyme complexes with similar potency. Cellular assays of Notch cleavage reveal that this compound is approximately 16-fold selective for the inhibition of APP cleavage. In the human APP-overexpressing Tg2576 transgenic mouse, treatment with this orally active compound results in a robust reduction in brain, plasma, and cerebral spinal fluid Abeta levels, and a reversal of contextual fear-conditioning deficits that are correlated with Abeta load. In healthy human volunteers, oral administration of a single dose of GSI-953 produces dose-dependent changes in plasma Abeta levels, confirming pharmacodynamic activity of GSI-953 in humans.
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http://dx.doi.org/10.1124/jpet.109.152975DOI Listing
November 2009

Impact of apolipoprotein E (ApoE) polymorphism on brain ApoE levels.

J Neurosci 2008 Nov;28(45):11445-53

Discovery Neuroscience, Wyeth Research, CN8000, Princeton, New Jersey 08543, USA.

Inheritance of the apoE4 allele (epsilon4) increases the risk of developing Alzheimer's disease; however, the mechanisms underlying this association remain elusive. Recent data suggest that inheritance of epsilon4 may lead to reduced apoE protein levels in the CNS. We therefore examined apoE protein levels in the brains, CSF and plasma of epsilon2/2, epsilon3/3, and epsilon4/4 targeted replacement mice. These apoE mice showed a genotype-dependent decrease in apoE levels; epsilon2/2 >epsilon3/3 >epsilon4/4. Next, we sought to examine the relative contributions of apoE4 and apoE3 in the epsilon3/4 mouse brains. ApoE4 represented 30-40% of the total apoE. Moreover, the absolute amount of apoE3 per allele was similar between epsilon3/3 and epsilon3/4 mice, implying that the reduced levels of total apoE in epsilon3/4 mice can be explained by the reduction in apoE4 levels. In culture medium from epsilon3/4 human astrocytoma or epsilon3/3, epsilon4/4 and epsilon3/4 primary astrocytes, apoE4 levels were consistently lower than apoE3. Secreted cholesterol levels were also lower from epsilon4/4 astrocytes. Pulse-chase experiments showed an enhanced degradation and reduced half-life of newly synthesized apoE4 compared with apoE3. Together, these data suggest that astrocytes preferentially degrade apoE4, leading to reduced apoE4 secretion and ultimately to reduced brain apoE levels. Moreover, the genotype-dependent decrease in CNS apoE levels, mirror the relative risk of developing AD, and suggest that low levels of total apoE exhibited by epsilon4 carriers may directly contribute to the disease progression, perhaps by reducing the capacity of apoE to promote synaptic repair and/or Abeta clearance.
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http://dx.doi.org/10.1523/JNEUROSCI.1972-08.2008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6671315PMC
November 2008

Enhanced clearance of Abeta in brain by sustaining the plasmin proteolysis cascade.

Proc Natl Acad Sci U S A 2008 Jun 16;105(25):8754-9. Epub 2008 Jun 16.

Departments of Discovery Neuroscience and Chemical and Screening Sciences, Wyeth Research, CN-8000, Princeton, NJ 08543, USA.

The amyloid hypothesis states that a variety of neurotoxic beta-amyloid (Abeta) species contribute to the pathogenesis of Alzheimer's disease. Accordingly, a key determinant of disease onset and progression is the appropriate balance between Abeta production and clearance. Enzymes responsible for the degradation of Abeta are not well understood, and, thus far, it has not been possible to enhance Abeta catabolism by pharmacological manipulation. We provide evidence that Abeta catabolism is increased after inhibition of plasminogen activator inhibitor-1 (PAI-1) and may constitute a viable therapeutic approach for lowering brain Abeta levels. PAI-1 inhibits the activity of tissue plasminogen activator (tPA), an enzyme that cleaves plasminogen to generate plasmin, a protease that degrades Abeta oligomers and monomers. Because tPA, plasminogen and PAI-1 are expressed in the brain, we tested the hypothesis that inhibitors of PAI-1 will enhance the proteolytic clearance of brain Abeta. Our data demonstrate that PAI-1 inhibitors augment the activity of tPA and plasmin in hippocampus, significantly lower plasma and brain Abeta levels, restore long-term potentiation deficits in hippocampal slices from transgenic Abeta-producing mice, and reverse cognitive deficits in these mice.
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http://dx.doi.org/10.1073/pnas.0710823105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2438386PMC
June 2008

The LXR agonist TO901317 selectively lowers hippocampal Abeta42 and improves memory in the Tg2576 mouse model of Alzheimer's disease.

Mol Cell Neurosci 2007 Apr 25;34(4):621-8. Epub 2007 Jan 25.

Discovery Neuroscience, Wyeth Research, CN8000, Princeton, NJ 08543, USA.

Recent studies show that intracellular cholesterol levels can modulate the processing of amyloid precursor protein to Abeta peptide. Moreover, cholesterol-rich apoE-containing lipoproteins may also promote Abeta clearance. Agonists of the liver X receptor (LXR) transcriptionally induce genes involved in intracellular lipid efflux and transport, including apoE. Thus, LXR agonists have the potential to both inhibit APP processing and promote Abeta clearance. Here we show that LXR agonist, TO901317, increased hippocampal ABCA1 and apoE and decreased Abeta42 levels in APP transgenic mice. TO901317 had no significant effects on levels of Abeta40, full length APP, or the APP processing products. Next, we examined the effects of TO901317 in the contextual fear conditioning paradigm; TO901317 completely reversed the contextual memory deficit in these mice. These data demonstrate that LXR agonists do not directly inhibit APP processing but rather facilitate the clearance of Abeta42 and may represent a novel therapeutic approach to Alzheimer's disease.
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http://dx.doi.org/10.1016/j.mcn.2007.01.011DOI Listing
April 2007

Characterizing the grape transcriptome. Analysis of expressed sequence tags from multiple Vitis species and development of a compendium of gene expression during berry development.

Plant Physiol 2005 Oct;139(2):574-97

Department of Plant Pathology, University of California, Davis, 95616, USA.

We report the analysis and annotation of 146,075 expressed sequence tags from Vitis species. The majority of these sequences were derived from different cultivars of Vitis vinifera, comprising an estimated 25,746 unique contig and singleton sequences that survey transcription in various tissues and developmental stages and during biotic and abiotic stress. Putatively homologous proteins were identified for over 17,752 of the transcripts, with 1,962 transcripts further subdivided into one or more Gene Ontology categories. A simple structured vocabulary, with modules for plant genotype, plant development, and stress, was developed to describe the relationship between individual expressed sequence tags and cDNA libraries; the resulting vocabulary provides query terms to facilitate data mining within the context of a relational database. As a measure of the extent to which characterized metabolic pathways were encompassed by the data set, we searched for homologs of the enzymes leading from glycolysis, through the oxidative/nonoxidative pentose phosphate pathway, and into the general phenylpropanoid pathway. Homologs were identified for 65 of these 77 enzymes, with 86% of enzymatic steps represented by paralogous genes. Differentially expressed transcripts were identified by means of a stringent believability index cutoff of > or =98.4%. Correlation analysis and two-dimensional hierarchical clustering grouped these transcripts according to similarity of expression. In the broadest analysis, 665 differentially expressed transcripts were identified across 29 cDNA libraries, representing a range of developmental and stress conditions. The groupings revealed expected associations between plant developmental stages and tissue types, with the notable exception of abiotic stress treatments. A more focused analysis of flower and berry development identified 87 differentially expressed transcripts and provides the basis for a compendium that relates gene expression and annotation to previously characterized aspects of berry development and physiology. Comparison with published results for select genes, as well as correlation analysis between independent data sets, suggests that the inferred in silico patterns of expression are likely to be an accurate representation of transcript abundance for the conditions surveyed. Thus, the combined data set reveals the in silico expression patterns for hundreds of genes in V. vinifera, the majority of which have not been previously studied within this species.
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http://dx.doi.org/10.1104/pp.105.065748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1255978PMC
October 2005
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