Recent Stanford Publications in PubMed
- Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor.Tap WD, Wainberg ZA, Anthony SP, Ibrahim PN, Zhang C, Healey JH, Chmielowski B, Staddon AP, Cohn AL, Shapiro GI, Keedy VL, Singh AS, Puzanov I, Kwak EL, Wagner AJ, Von Hoff DD, Weiss GJ, Ramanathan RK, Zhang J, Habets G, Zhang Y, Burton EA, Visor G, Sanftner L, Severson P, Nguyen H, Kim MJ, Marimuthu A, Tsang G, Shellooe R, Gee C, West BL, Hirth P, Nolop K, van de Rijn M, Hsu HH, Peterfy C, Lin PS, Tong-Starksen S, Bollag GN Engl J Med
- Supporting Medical Students' Pursuit of Longitudinal Patient Experiences: Piloting an Innovative Visit Notification Tool at the Massachusetts General Hospital.Elmore SN, Kopecky KE, Jennings K, de Moya M, Beresin G, Wright DEAcad Med
- Engineering Melanin Nanoparticles as an Efficient Drug-Delivery System for Imaging-Guided Chemotherapy.Zhang R, Fan Q, Yang M, Cheng K, Lu X, Zhang L, Huang W, Cheng ZAdv Mater
- The Effect of an Intense Mentoring Program on Junior Investigators' Preparation for a Patient-Oriented Clinical Research Career.Burns LJ, Clayton CP, George JN, Mitchell BS, Gitlin SDAcad Med
- Targeted Therapy for Cancer in the Genomic Era.Afghahi A, Sledge GWCancer J
- Synthetic biology: Ribosomal ties that bind.Puglisi JDNature
- Molecular Pathogenesis of Anti-NMDAR Encephalitis.Ding H, Jian Z, Stary CM, Yi W, Xiong XBiomed Res Int
- Localized Ambient Solidity Separation Algorithm Based Computer User Segmentation.Sun X, Zhang T, Chai Y, Liu YComput Intell Neurosci
- CaV3.2 calcium channels control NMDA receptor-mediated transmission: a new mechanism for absence epilepsy.Wang G, Bochorishvili G, Chen Y, Salvati KA, Zhang P, Dubel SJ, Perez-Reyes E, Snutch TP, Stornetta RL, Deisseroth K, Erisir A, Todorovic SM, Luo JH, Kapur J, Beenhakker MP, Zhu JJGenes Dev
- The Use of Contact Mode Atomic Force Microscopy in Aqueous Medium for Structural Analysis of Spinach Photosynthetic Complexes.Phuthong W, Huang Z, Wittkopp TM, Sznee K, Heinnickel ML, Dekker JP, Frese RN, Prinz FB, Grossman ARPlant Physiol
- Single-trial dynamics of motor cortex and their applications to brain-machine interfaces.Kao JC, Nuyujukian P, Ryu SI, Churchland MM, Cunningham JP, Shenoy KVNat Commun
- Vasomotor Symptoms and Quality of Life Among Veteran and Non-Veteran Postmenopausal Women.Katon JG, Gray KE, Gerber MR, Harrington LB, Woods NF, Weitlauf JC, Bean-Mayberry B, Goldstein KM, Hunt JR, Katon WJ, Haskell SG, McCutcheon SJ, Gass ML, Gibson CJ, Zephyrin LCGerontologist
- How Does Survey Context Impact Self-reported Fraud Victimization?Beals ME, Carr DC, Mottola GR, Deevy MJ, Carstensen LLGerontologist
- Effects of Posttraumatic Stress Disorder and Metabolic Syndrome on Cognitive Aging in Veterans.Green E, Fairchild JK, Kinoshita LM, Noda A, Yesavage JGerontologist
- Wnt/β-Catenin-Responsive Cells in Prostatic Development and Regeneration.Lee SH, Johnson DT, Luong R, Yu EJ, Cunha GR, Nusse R, Sun ZStem Cells
- Robust self-navigated body MRI using dense coil arrays.Zhang T, Cheng JY, Chen Y, Nishimura DG, Pauly JM, Vasanawala SSMagn Reson Med
- CD161(int)CD8+ T cells: a novel population of highly functional, memory CD8+ T cells enriched within the gut.Fergusson JR, Hühn MH, Swadling L, Walker LJ, Kurioka A, Llibre A, Bertoletti A, Holländer G, Newell EW, Davis MM, Sverremark-Ekström E, Powrie F, Capone S, Folgori A, Barnes E, Willberg CB, Ussher JE, Klenerman PMucosal Immunol
- Exploring Value in Congenital Heart Disease: An Evaluation of Inpatient Admissions.Shin AY, Hu Z, Jin B, Lal S, Rosenthal DN, Efron B, Sharek PJ, Sutherland SM, Cohen HJ, McElhinney DB, Roth SJ, Ling XBCongenit Heart Dis
- Association of 6-Minute Walk Performance and Physical Activity With Incident Ischemic Heart Disease Events and Stroke in Peripheral Artery Disease.McDermott MM, Greenland P, Tian L, Kibbe MR, Green D, Zhao L, Criqui MH, Guralnik JM, Ferrucci L, Liu K, Wilkins JT, Huffman MD, Shah SJ, Liao Y, Lloyd-Jones DMJ Am Heart Assoc
- Mosaic paternal genome-wide uniparental isodisomy with Down syndrome.Darcy D, Atwal PS, Angell C, Gadi I, Wallerstein RAm J Med Genet A
- Functional connectivity for face processing in individuals with body dysmorphic disorder and anorexia nervosa.Moody TD, Sasaki MA, Bohon C, Strober MA, Bookheimer SY, Sheen CL, Feusner JDPsychol Med
- Non-use of health care service among empty-nest elderly in Shandong, China: a cross-sectional study.Zhou C, Ji C, Chu J, Medina A, Li C, Jiang S, Zheng W, Liu J, Rozelle SBMC Health Serv Res
- Potential Adverse Effects of Anesthesia in Children--Reply.Psaty BM, Platt R, Altman RBJAMA
- Structural Insights into the Dynamic Process of β2-Adrenergic Receptor Signaling.Manglik A, Kim TH, Masureel M, Altenbach C, Yang Z, Hilger D, Lerch MT, Kobilka TS, Thian FS, Hubbell WL, Prosser RS, Kobilka BKCell
- Stretchy nerves are an essential component of the extreme feeding mechanism of rorqual whales.Vogl AW, Lillie MA, Piscitelli MA, Goldbogen JA, Pyenson ND, Shadwick RECurr Biol
- Segmental aortic stiffening contributes to experimental abdominal aortic aneurysm development.Raaz U, Zöllner AM, Schellinger IN, Toh R, Nakagami F, Brandt M, Emrich FC, Kayama Y, Eken S, Adam M, Maegdefessel L, Hertel T, Deng A, Jagger A, Buerke M, Dalman RL, Spin JM, Kuhl E, Tsao PSCirculation
- Opinion: Sex inclusion in basic research drives discovery.Klein SL, Schiebinger L, Stefanick ML, Cahill L, Danska J, de Vries GJ, Kibbe MR, McCarthy MM, Mogil JS, Woodruff TK, Zucker IProc Natl Acad Sci U S A
- Leveraging Multi-ethnic Evidence for Mapping Complex Traits in Minority Populations: An Empirical Bayes Approach.Coram MA, Candille SI, Duan Q, Chan KH, Li Y, Kooperberg C, Reiner AP, Tang HAm J Hum Genet
- The Mechanochemical Cycle of Mammalian Kinesin-2 KIF3A/B under Load.Andreasson JO, Shastry S, Hancock WO, Block SMCurr Biol
- "Velcro" engineering of high affinity CD47 ectodomain as signal regulatory protein α (SIRPα) antagonists that enhance antibody-dependent cellular phagocytosis.Ho CC, Guo N, Sockolosky JT, Ring AM, Weiskopf K, Özkan E, Mori Y, Weissman IL, Garcia KCJ Biol Chem
- Suppression of endothelial CD39/ENTPD1 is associated with pulmonary vascular remodeling in pulmonary arterial hypertension.Helenius MH, Vattulainen S, Orcholski M, Aho J, Komulainen A, Taimen P, Wang L, de Jesus Perez VA, Koskenvuo JW, Alastalo TPAm J Physiol Lung Cell Mol Physiol
- Assessment of the genetic basis of rosacea by genome-wide association study.Chang AL, Raber I, Xu J, Li R, Spitale R, Chen J, Kiefer AK, Tian C, Eriksson NK, Hinds DA, Tung JYJ Invest Dermatol
- Clonal evolution of pre-leukemic hematopoietic stem cells precedes human acute myeloid leukemia.Majeti RBest Pract Res Clin Haematol
- False positive 18F-fluorodeoxyglucose positron emission tomography/computed tomography liver lesion mimicking metastasis in 2 patients with gastroesophageal cancer.Paudel N, Kunz PL, Poultsides GA, Koong AC, Chang DTPract Radiat Oncol
- Proliferative epithelial disease identified in nipple aspirate fluid and risk of developing breast cancer: a systematic review.Hornberger J, Chen SC, Li Q, Kakad P, Quay SCCurr Med Res Opin
- Matrix RGD ligand density and L1CAM-mediated Schwann cell interactions synergistically enhance neurite outgrowth.Romano NH, Madl CM, Heilshorn SCActa Biomater
- Role of CSPG receptor LAR phosphatase in restricting axon regeneration after CNS injury.Xu B, Park D, Ohtake Y, Li H, Hayat U, Liu J, Selzer ME, Longo FM, Li SNeurobiol Dis
- Evaluation of a prospectively administered written questionnaire to reduce the incidence of suspected latex anaphylaxis during elective cesarean delivery.Péer L, Brezis ML, Shalit M, Carvalho B, Levin PD, Seri O, Weiniger CFInt J Obstet Anesth
- Inter-episode affective intensity and instability: predictors of depression and functional impairment in bipolar disorder.Gershon A, Eidelman PJ Behav Ther Exp Psychiatry
- Plasma vasopressin concentrations positively predict cerebrospinal fluid vasopressin concentrations in human neonates.Carson DS, Howerton CL, Garner JP, Hyde SA, Clark CL, Hardan AY, Penn AA, Parker KJPeptides
Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor.
N Engl J Med. 2015 Jul 30;373(5):428-437
Authors: Tap WD, Wainberg ZA, Anthony SP, Ibrahim PN, Zhang C, Healey JH, Chmielowski B, Staddon AP, Cohn AL, Shapiro GI, Keedy VL, Singh AS, Puzanov I, Kwak EL, Wagner AJ, Von Hoff DD, Weiss GJ, Ramanathan RK, Zhang J, Habets G, Zhang Y, Burton EA, Visor G, Sanftner L, Severson P, Nguyen H, Kim MJ, Marimuthu A, Tsang G, Shellooe R, Gee C, West BL, Hirth P, Nolop K, van de Rijn M, Hsu HH, Peterfy C, Lin PS, Tong-Starksen S, Bollag G
Background Expression of the colony-stimulating factor 1 (CSF1) gene is elevated in most tenosynovial giant-cell tumors. This observation has led to the discovery and clinical development of therapy targeting the CSF1 receptor (CSF1R). Methods Using x-ray co-crystallography to guide our drug-discovery research, we generated a potent, selective CSF1R inhibitor, PLX3397, that traps the kinase in the autoinhibited conformation. We then conducted a multicenter, phase 1 trial in two parts to analyze this compound. In the first part, we evaluated escalations in the dose of PLX3397 that was administered orally in patients with solid tumors (dose-escalation study). In the second part, we evaluated PLX3397 at the chosen phase 2 dose in an extension cohort of patients with tenosynovial giant-cell tumors (extension study). Pharmacokinetic and tumor responses in the enrolled patients were assessed, and CSF1 in situ hybridization was performed to confirm the mechanism of action of PLX3397 and that the pattern of CSF1 expression was consistent with the pathological features of tenosynovial giant-cell tumor. Results A total of 41 patients were enrolled in the dose-escalation study, and an additional 23 patients were enrolled in the extension study. The chosen phase 2 dose of PLX3397 was 1000 mg per day. In the extension study, 12 patients with tenosynovial giant-cell tumors had a partial response and 7 patients had stable disease. Responses usually occurred within the first 4 months of treatment, and the median duration of response exceeded 8 months. The most common adverse events included fatigue, change in hair color, nausea, dysgeusia, and periorbital edema; adverse events rarely led to discontinuation of treatment. Conclusions Treatment of tenosynovial giant-cell tumors with PLX3397 resulted in a prolonged regression in tumor volume in most patients. (Funded by Plexxikon; ClinicalTrials.gov number, NCT01004861 .).
PMID: 26222558 [PubMed - as supplied by publisher]
Supporting Medical Students' Pursuit of Longitudinal Patient Experiences: Piloting an Innovative Visit Notification Tool at the Massachusetts General Hospital.
Acad Med. 2015 Jul 24;
Authors: Elmore SN, Kopecky KE, Jennings K, de Moya M, Beresin G, Wright DE
PROBLEM: Both medical educators and students have an increasing interest in longitudinal patient experiences (LPE) that allow students to work with patients at multiple points in time, often across multiple clinical settings. Despite this interest in LPE, following patients over time and across health systems remains a challenge.
APPROACH: In August 2012-May 2013, with faculty support, two third-year medical students implemented a pilot program at the Massachusetts General Hospital (MGH) in the third-year block clerkship curriculum. One of the authors modified an existing novel, electronic visit notification tool (VNT) that integrates with the electronic medical record (EMR) to help students follow patients longitudinally. Students added patients to their cohort after obtaining the patient's verbal consent. Each week, the VNT sent students e-mails notifying them of all scheduled appointments for their cohort patients at all Partners HealthCare-affiliated sites.
OUTCOMES: Each pilot student added approximately 20 patients to her cohort and followed 3-5 patients consistently. The pilot students felt the VNT made it significantly easier to follow patients over time, their appreciation of chronic illness care developed, and they gained a greater understanding of the integrated nature of patient care.
NEXT STEPS: On the basis of student interest, the tool was made available to all MGH third-year students in March-May 2013 and offered to all MGH third-year students at the beginning of the next clinical year. Notification tools such as the VNT may enhance a hospital's existing EMR and facilitate longitudinal educational goals across all clinical clerkship models.
PMID: 26222324 [PubMed - as supplied by publisher]
Engineering Melanin Nanoparticles as an Efficient Drug-Delivery System for Imaging-Guided Chemotherapy.
Adv Mater. 2015 Jul 29;
Authors: Zhang R, Fan Q, Yang M, Cheng K, Lu X, Zhang L, Huang W, Cheng Z
In order to promote imaging-guided chemotherapy for preclinical and clinical applications, endogenous nanosystems with both contrast and drug-delivery properties are highly desired. Here, the simple use of melanin is first reported, and this biopolymer with good biocompatibility and biodegradability, binding ability to drugs and ions, and intrinsic photoacoustic properties, can serve as an efficient endogenous nanosystem for imaging-guided tumor chemotherapy in living mice.
PMID: 26222210 [PubMed - as supplied by publisher]
The Effect of an Intense Mentoring Program on Junior Investigators' Preparation for a Patient-Oriented Clinical Research Career.
Acad Med. 2015 Aug;90(8):1061-1066
Authors: Burns LJ, Clayton CP, George JN, Mitchell BS, Gitlin SD
PROBLEM: There is a recognized need to translate scientific discoveries to patient-oriented clinical research (POCR). Several obstacles interfere with the successful recruitment and retention of physicians for POCR careers.
APPROACH: The American Society of Hematology developed a yearlong educational and mentoring experience, the Clinical Research Training Institute (CRTI), for early-career physician-scientists from multiple institutions throughout the United States and Canada pursuing POCR careers. Several academic outcome measures of the 140 participants in the first seven years (2003-2010) of CRTI were evaluated by reviewing former trainee participants' curriculum vitae and survey responses.
OUTCOMES: Ethnic, racial, and gender diversity of CRTI trainees was reflective of the proportions represented across U.S. hematology/oncology fellowship programs. Eighty-six percent (109/126) of trainees reported success establishing a POCR study; nearly half (62/126) had primarily research-focused jobs. Former CRTI trainees received at least 262 external grant awards and published 1,035 peer-reviewed manuscripts, 173 chapters, and 115 review articles.
NEXT STEPS: Because mentorship is key to developing a successful career, the CRTI program is being modified to enhance longitudinal mentorship by CRTI faculty mentors and mentors at trainees' home institutions, as well as to encourage the establishment of collaborations and the potential for research project success. Efforts to make the CRTI experience available to more phy sicians, include more CRTI graduates as faculty, and increase participation by hematologists from backgrounds under represented in medicine are under way.
PMID: 26222198 [PubMed - as supplied by publisher]
Targeted Therapy for Cancer in the Genomic Era.
Cancer J. 2015 Jul-Aug;21(4):294-298
Authors: Afghahi A, Sledge GW
The advent of cancer genomics has led to the development of many highly successful targeted therapies, primarily inhibitors of growth factor receptors and related kinases, including imatinib for chronic myeloid leukemia and trastuzumab for HER2-positive breast cancer. This approach has become highly successful for certain cancers. However, as the list of targeted therapies expands, their efficacy becomes more limited, and toxicity accumulates. What we have learned in the past decades is that while the targeted therapeutics approach may be highly successful in less complex tumors, cancers defined by carcinogen-induced genomic chaos, such a UV-induced melanoma or tobacco-induced lung cancer, are driven by a multitude of competing molecular pathways and, as such, are not as successfully managed by a similar approach. Luckily, in the past years, the field of cancer immunotherapy has become more fully developed with the emergence of checkpoint blockade inhibitor therapy. These promising new agents are particularly well suited for tumors with a high mutational burden due to underlying genomic disarray. While still in its infancy, we predict that cancer immunotherapy will offer a better alternative to our current targeted approach and eagerly await the results of several ongoing clinical trials that will elucidate this new direction in cancer therapy.
PMID: 26222081 [PubMed - as supplied by publisher]
Synthetic biology: Ribosomal ties that bind.
Nature. 2015 Jul 29;
Authors: Puglisi JD
PMID: 26222027 [PubMed - as supplied by publisher]
Molecular Pathogenesis of Anti-NMDAR Encephalitis.
Biomed Res Int. 2015;2015:643409
Authors: Ding H, Jian Z, Stary CM, Yi W, Xiong X
Anti-NMDAR encephalitis is a recently identified autoimmune disease, described by an immune-mediated loss of NMDA glutamate receptors, resulting in progressive mental deterioration. To date, literature on anti-NMDAR encephalitis has been largely clinically oriented, including descriptions of the clinical presentation and course, diagnostic methods, and potential clinical treatments. However, the underlying molecular mechanisms contributing to the complex immunological cellular transformation that is associated with the progression of anti-NMDAR encephalitis remain to be adequately explored. This review will provide a summary of the current literature on anti-NMDAR encephalitis, including the immunologic molecular mechanisms contributing to disease progression. In particular this review will focus on the effect of anti-NMDAR on GluN2-NMDAR expression and the molecular transformation of B and T leukocytes in the loss of self-tolerance. Further research on the immunologic mechanisms contributing to anti-NMDAR encephalitis may provide an avenue for future novel diagnostic approaches, such as immunologic surveillance, as well as new therapeutic strategies for this recently identified autoimmune disease.
PMID: 26221602 [PubMed - in process]
Localized Ambient Solidity Separation Algorithm Based Computer User Segmentation.
Comput Intell Neurosci. 2015;2015:829201
Authors: Sun X, Zhang T, Chai Y, Liu Y
Most of popular clustering methods typically have some strong assumptions of the dataset. For example, the k-means implicitly assumes that all clusters come from spherical Gaussian distributions which have different means but the same covariance. However, when dealing with datasets that have diverse distribution shapes or high dimensionality, these assumptions might not be valid anymore. In order to overcome this weakness, we proposed a new clustering algorithm named localized ambient solidity separation (LASS) algorithm, using a new isolation criterion called centroid distance. Compared with other density based isolation criteria, our proposed centroid distance isolation criterion addresses the problem caused by high dimensionality and varying density. The experiment on a designed two-dimensional benchmark dataset shows that our proposed LASS algorithm not only inherits the advantage of the original dissimilarity increments clustering method to separate naturally isolated clusters but also can identify the clusters which are adjacent, overlapping, and under background noise. Finally, we compared our LASS algorithm with the dissimilarity increments clustering method on a massive computer user dataset with over two million records that contains demographic and behaviors information. The results show that LASS algorithm works extremely well on this computer user dataset and can gain more knowledge from it.
PMID: 26221133 [PubMed - in process]
CaV3.2 calcium channels control NMDA receptor-mediated transmission: a new mechanism for absence epilepsy.
Genes Dev. 2015 Jul 15;29(14):1535-51
Authors: Wang G, Bochorishvili G, Chen Y, Salvati KA, Zhang P, Dubel SJ, Perez-Reyes E, Snutch TP, Stornetta RL, Deisseroth K, Erisir A, Todorovic SM, Luo JH, Kapur J, Beenhakker MP, Zhu JJ
CaV3.2 T-type calcium channels, encoded by CACNA1H, are expressed throughout the brain, yet their general function remains unclear. We discovered that CaV3.2 channels control NMDA-sensitive glutamatergic receptor (NMDA-R)-mediated transmission and subsequent NMDA-R-dependent plasticity of AMPA-R-mediated transmission at rat central synapses. Interestingly, functional CaV3.2 channels primarily incorporate into synapses, replace existing CaV3.2 channels, and can induce local calcium influx to control NMDA transmission strength in an activity-dependent manner. Moreover, human childhood absence epilepsy (CAE)-linked hCaV3.2(C456S) mutant channels have a higher channel open probability, induce more calcium influx, and enhance glutamatergic transmission. Remarkably, cortical expression of hCaV3.2(C456S) channels in rats induces 2- to 4-Hz spike and wave discharges and absence-like epilepsy characteristic of CAE patients, which can be suppressed by AMPA-R and NMDA-R antagonists but not T-type calcium channel antagonists. These results reveal an unexpected role of CaV3.2 channels in regulating NMDA-R-mediated transmission and a novel epileptogenic mechanism for human CAE.
PMID: 26220996 [PubMed - in process]
The Use of Contact Mode Atomic Force Microscopy in Aqueous Medium for Structural Analysis of Spinach Photosynthetic Complexes.
Plant Physiol. 2015 Jul 28;
Authors: Phuthong W, Huang Z, Wittkopp TM, Sznee K, Heinnickel ML, Dekker JP, Frese RN, Prinz FB, Grossman AR
To investigate the dynamics of photosynthetic pigment-protein complexes in vascular plants at high resolution in an aqueous environment, membrane-protruding oxygen-evolving complexes associated with photosystem II (PSII-OEC) on spinach (Spinacia oleracea) grana membranes were examined using Contact Mode Atomic Force Microscopy (CM-AFM). This study represents the use of AFM to distinguish the putative large extrinsic loop of CP47 from the putative PsbO/PsbP/PsbQ/large extrinsic loop of CP43 in the PSII-OEC extrinsic domains of grana membranes under conditions resulting in the disordered arrangement of PSII-OEC particles. Moreover, we observed uncharacterized membrane particles which, based on their physical characteristics and electrophoretic analysis of the polypeptides associated with the grana samples, are hypothesized to be a domain of photosystem I (PSI) that protrudes from the stromal face of single thylakoid bilayers. Our results are interpreted in the context of the results of others that were obtained using cryo-electron microscopy (and single particle analysis), negative staining and freeze fracture electron microscopy, as well as previous AFM studies.
PMID: 26220954 [PubMed - as supplied by publisher]
Single-trial dynamics of motor cortex and their applications to brain-machine interfaces.
Nat Commun. 2015;6:7759
Authors: Kao JC, Nuyujukian P, Ryu SI, Churchland MM, Cunningham JP, Shenoy KV
Increasing evidence suggests that neural population responses have their own internal drive, or dynamics, that describe how the neural population evolves through time. An important prediction of neural dynamical models is that previously observed neural activity is informative of noisy yet-to-be-observed activity on single-trials, and may thus have a denoising effect. To investigate this prediction, we built and characterized dynamical models of single-trial motor cortical activity. We find these models capture salient dynamical features of the neural population and are informative of future neural activity on single trials. To assess how neural dynamics may beneficially denoise single-trial neural activity, we incorporate neural dynamics into a brain-machine interface (BMI). In online experiments, we find that a neural dynamical BMI achieves substantially higher performance than its non-dynamical counterpart. These results provide evidence that neural dynamics beneficially inform the temporal evolution of neural activity on single trials and may directly impact the performance of BMIs.
PMID: 26220660 [PubMed - in process]
Vasomotor Symptoms and Quality of Life Among Veteran and Non-Veteran Postmenopausal Women.
Gerontologist. 2015 Jul 28;
Authors: Katon JG, Gray KE, Gerber MR, Harrington LB, Woods NF, Weitlauf JC, Bean-Mayberry B, Goldstein KM, Hunt JR, Katon WJ, Haskell SG, McCutcheon SJ, Gass ML, Gibson CJ, Zephyrin LC
INTRODUCTION: Vasomotor symptoms (VMS), including hot flashes and night sweats, are common among postmenopausal women and are associated with reduced health related quality of life (HRQOL).
PURPOSE OF THE STUDY: To determine whether Veterans are more likely to report VMS than non-Veterans, and whether the association of VMS with HRQOL varies by Veteran status.
DESIGN AND METHODS: We used data from the Women's Health Initiative Observational Study, including self-reported baseline VMS presence and severity, and HRQOL at follow-up Year 3 (RAND Short Form 36-Item Health Survey). Employing generalized linear models we estimated whether Veteran status was associated with any VMS. We estimated the association between any VMS and HRQOL using linear regression, stratified by Veteran status. Interaction terms were added separately to determine whether the association varied by baseline depression, obesity, or smoking status.
RESULTS: The final analyses included 77,153 postmenopausal women (2,004 Veterans). After adjustment, Veterans were no more likely than non-Veterans to report any VMS at baseline (relative risk [RR] 0.97, 95% confidence interval [CI] 0.90-1.04) or moderate to severe VMS (RR 1.03, 95% CI 0.89-1.18). Any VMS was associated with decreased HRQOL at Year 3, particularly among Veterans (mean difference range: Veterans -2.7 to -4.6, p-values < .001; non-Veterans -2.2 to -2.6, 95% CI -0.13 to -0.09, p values < .001). Baseline depression and obesity, but not smoking, amplified the negative association between VMS and HRQOL.
IMPLICATIONS: Multicondition care models for postmenopausal Veteran and non-Veteran women are needed that incorporate management strategies for VMS, weight, and depression.
PMID: 26220418 [PubMed - as supplied by publisher]
How Does Survey Context Impact Self-reported Fraud Victimization?
Gerontologist. 2015 Jul 28;
Authors: Beals ME, Carr DC, Mottola GR, Deevy MJ, Carstensen LL
PURPOSE OF THE STUDY: This study examines the effect of survey context on self-reported rates of personal fraud victimization, and explores if the effect is influenced by age and gender.
DESIGN AND METHODS: Participants (3,000U.S. adults) were randomly assigned to 1 of the 3 versions of a fraud victimization questionnaire: questions about fraud were identical across conditions, however, the context varies. One questionnaire asked about crime, one about consumer buying experiences, and a third focused only on fraud.
RESULTS: Participants who were asked about fraud victimization in the context of crime reported significantly less victimization (p < .05) than those in the fraud-alone condition, yet the number of reports from those asked within the context of a consumer survey did not differ from the fraud-alone condition. The effect of the crime context interacted with age (p < .05), such that there was no effect of survey context for the middle age group (35-64), and a strong effect for younger (25-34) and older (65 plus) adults. The combined effect of being female and older was associated with the greatest effect of crime context on self-reported fraud victimization.
IMPLICATIONS: These findings inform the production of new surveys and guide the development of effective social and health policies.
PMID: 26220416 [PubMed - as supplied by publisher]
Effects of Posttraumatic Stress Disorder and Metabolic Syndrome on Cognitive Aging in Veterans.
Gerontologist. 2015 Jul 28;
Authors: Green E, Fairchild JK, Kinoshita LM, Noda A, Yesavage J
PURPOSE OF THE STUDY: With the influx of veterans entering older adulthood, it is increasingly important to understand risk factors for cognitive decline. Posttraumatic stress disorder (PTSD) and the metabolic syndrome (MetS) are highly prevalent in older veterans. Although both increase risk for cognitive decline and often co-occur, it is unclear how they may interact to negatively impact cognition. The aim of this cross-sectional study was to investigate associations among PTSD, MetS, and cognitive function in older veterans. We hypothesized that co-occurring PTSD and MetS would be associated with worse cognitive performance than seen in either illness alone.
DESIGN AND METHODS: Participants completed cognitive testing to assess processing speed, verbal memory, and executive function. Data from 204 male veterans aged 55-89 were analyzed with the use of hierarchical multiple regression models.
RESULTS: Veterans with MetS demonstrated poorer performance on tasks of executive function (response inhibition and cognitive set shifting) and immediate verbal memory regardless of PTSD status. There was an interaction between MetS and PTSD on delayed verbal memory, suggesting that the negative impact of MetS on verbal memory was only significant for veterans not classified as having PTSD.
IMPLICATIONS: This is the first study to examine the impact of comorbid PTSD and MetS on cognition. The results suggest that MetS is associated with poorer verbal learning and executive functioning independent of PTSD. We discuss the necessity of monitoring cerebrovascular risk factors and providing early behavioral and/or pharmaceutical interventions to lessen the risk of cognitive decline in older age.
PMID: 26220415 [PubMed - as supplied by publisher]
Wnt/β-Catenin-Responsive Cells in Prostatic Development and Regeneration.
Stem Cells. 2015 Jul 29;
Authors: Lee SH, Johnson DT, Luong R, Yu EJ, Cunha GR, Nusse R, Sun Z
The precise role of Wnt/β-catenin signaling during prostatic development and tumorigenesis is unclear. Axin2 is a direct transcriptional target of β-catenin. Recent studies have shown that Axin2-expressing cells have stem/progenitor cell properties in a variety of mouse tissues. Here, we genetically labeled Axin2-expressing cells at various time points and tracked their cellular behavior at different developmental and mature stages. We found that prostatic Axin2-expressing cells mainly express luminal epithelial cell markers and are able to expand luminal cell lineages during prostatic development and maturation. They can also survive androgen withdrawal and regenerate prostatic luminal epithelial cells following androgen replacement. Deletion of β-catenin or expression of stabilized β-catenin in these Axin2-expressing cells results in abnormal development or oncogenic transformation, respectively. Our study uncovers a critical role of Wnt/β-catenin-responsive cells in prostatic development and regeneration, and that dysregulation of Wnt/β-catenin signaling in these cells contributes to prostatic developmental defects and tumorigenesis. Stem Cells 2015.
PMID: 26220362 [PubMed - as supplied by publisher]
Robust self-navigated body MRI using dense coil arrays.
Magn Reson Med. 2015 Jul 29;
Authors: Zhang T, Cheng JY, Chen Y, Nishimura DG, Pauly JM, Vasanawala SS
PURPOSE: To develop a robust motion estimation method for free-breathing body MRI using dense coil arrays.
METHODS: Self-navigating pulse sequences can measure subject motion without using external motion monitoring devices. With dense coil arrays, individual coil elements can provide localized motion estimates. An averaged motion estimate over all coils is often used for motion compensation. However, this motion estimate may not accurately represent the dominant motion within the imaging volume. In this work, a coil clustering method is proposed to automatically determine the dominant motion for dense coil arrays. The feasibility of the proposed method is investigated in free-breathing abdominal MRI and cardiac MRI, and compared with manual motion estimate selection for respiratory motion estimation and electrocardiography for cardiac motion estimation.
RESULTS: Automated motion estimation achieved similar respiratory motion estimation compared to manual selection (averaged correlation coefficient 0.989 and 0.988 for abdominal MRI and cardiac MRI, respectively), and accurate cardiac triggering compared to electrocardiography (averaged temporal variability 17.5 ms).
CONCLUSION: The proposed method can provide accurate automated motion estimation for body MRI using dense coil arrays. It can enable self-navigated free-breathing abdominal and cardiac MRI without the need for external motion monitoring devices. Magn Reson Med, 2015. © 2015 Wiley Periodicals, Inc.
PMID: 26220204 [PubMed - as supplied by publisher]
CD161(int)CD8+ T cells: a novel population of highly functional, memory CD8+ T cells enriched within the gut.
Mucosal Immunol. 2015 Jul 29;
Authors: Fergusson JR, Hühn MH, Swadling L, Walker LJ, Kurioka A, Llibre A, Bertoletti A, Holländer G, Newell EW, Davis MM, Sverremark-Ekström E, Powrie F, Capone S, Folgori A, Barnes E, Willberg CB, Ussher JE, Klenerman P
The C-type lectin-like receptor CD161 is expressed by lymphocytes found in human gut and liver, as well as blood, especially natural killer (NK) cells, T helper 17 (Th17) cells, and a population of unconventional T cells known as mucosal-associated invariant T (MAIT) cells. The association of high CD161 expression with innate T-cell populations including MAIT cells is established. Here we show that CD161 is also expressed, at intermediate levels, on a prominent subset of polyclonal CD8+ T cells, including antiviral populations that display a memory phenotype. These memory CD161(int)CD8+ T cells are enriched within the colon and express both CD103 and CD69, markers associated with tissue residence. Furthermore, this population was characterized by enhanced polyfunctionality, increased levels of cytotoxic mediators, and high expression of the transcription factors T-bet and eomesodermin (EOMES). Such populations were induced by novel vaccine strategies based on adenoviral vectors, currently in trial against hepatitis C virus. Thus, intermediate CD161 expression marks potent polyclonal, polyfunctional tissue-homing CD8+ T-cell populations in humans. As induction of such responses represents a major aim of T-cell prophylactic and therapeutic vaccines in viral disease and cancer, analysis of these populations could be of value in the future.Mucosal Immunology advance online publication, 29 July 2015; doi:10.1038/mi.2015.69.
PMID: 26220166 [PubMed - as supplied by publisher]
Exploring Value in Congenital Heart Disease: An Evaluation of Inpatient Admissions.
Congenit Heart Dis. 2015 Jul 29;
Authors: Shin AY, Hu Z, Jin B, Lal S, Rosenthal DN, Efron B, Sharek PJ, Sutherland SM, Cohen HJ, McElhinney DB, Roth SJ, Ling XB
OBJECTIVES: Understanding value provides an important context for improvement. However, most health care models fail to measure value. Our objective was to categorize inpatient encounters within an academic congenital heart program based on clinical outcome and the cost to achieve the outcome (value). We aimed to describe clinical and nonclinical features associated with value.
DESIGN: We defined hospital encounters based on outcome per resource utilized. We performed principal component and cluster analysis to classify encounters based on mortality, length of stay, hospital cost and revenue into six classes. We used nearest shrunken centroid to identify discriminant features associated with the cluster-derived classes. These features underwent hierarchical clustering and multivariate analysis to identify features associated with each class.
STUDY SETTING/PATIENTS: We analyzed all patients admitted to an academic congenital heart program between September 1, 2009, and December 31, 2012.
OUTCOME MEASURES/RESULTS: A total of 2658 encounters occurred during the study period. Six classes were categorized by value. Low-performing value classes were associated with greater institutional reward; however, encounters with higher-performing value were associated with a loss in profitability. Encounters that included insertion of a pediatric ventricular assist device (log OR 2.5 [95% CI, 1.78 to 3.43]) and acquisition of a hospital-acquired infection (log OR 1.42 [95% CI, 0.99 to 1.87]) were risk factors for inferior health care value.
CONCLUSIONS: Among the patients in our study, institutional reward was not associated with value. We describe a framework to target quality improvement and resource management efforts that can benefit patients, institutions, and payers alike.
PMID: 26219731 [PubMed - as supplied by publisher]
Association of 6-Minute Walk Performance and Physical Activity With Incident Ischemic Heart Disease Events and Stroke in Peripheral Artery Disease.
J Am Heart Assoc. 2015;4(7)
Authors: McDermott MM, Greenland P, Tian L, Kibbe MR, Green D, Zhao L, Criqui MH, Guralnik JM, Ferrucci L, Liu K, Wilkins JT, Huffman MD, Shah SJ, Liao Y, Lloyd-Jones DM
BACKGROUND: We determined whether poorer 6-minute walk performance and lower physical activity levels are associated with higher rates of ischemic heart disease (IHD) events in people with lower extremity peripheral artery disease (PAD).
METHODS AND RESULTS: Five hundred ten PAD participants were identified from Chicago-area medical centers and followed prospectively for 19.0±9.5 months. At baseline, participants completed the 6-minute walk and reported number of blocks walked during the past week (physical activity). IHD events were systematically adjudicated and consisted of new myocardial infarction, unstable angina, and cardiac death. For 6-minute walk, IHD event rates were 25/170 (14.7%) for the third (poorest) tertile, 10/171 (5.8%%) for the second tertile, and 6/169 (3.5%) for the first (best) tertile (P=0.003). For physical activity, IHD event rates were 21/154 (13.6%) for the third (poorest) tertile, 15/174 (8.6%) for the second tertile, and 5/182 (2.7%) for the first (best) tertile (P=0.001). Adjusting for age, sex, race, smoking, body mass index, comorbidities, and physical activity, participants in the poorest 6-minute walk tertile had a 3.28-fold (95% CI 1.17 to 9.17, P=0.024) higher hazard for IHD events, compared with those in the best tertile. Adjusting for confounders including 6-minute walk, participants in the poorest physical activity tertile had a 3.72-fold (95% CI 1.24 to 11.19, P=0.019) higher hazard for IHD events, compared with the highest tertile.
CONCLUSIONS: Six-minute walk and physical activity predict IHD event rates in PAD. Further study is needed to determine whether interventions that improve 6-minute walk, physical activity, or both can reduce IHD events in PAD.
PMID: 26219563 [PubMed - in process]
Mosaic paternal genome-wide uniparental isodisomy with Down syndrome.
Am J Med Genet A. 2015 Jul 29;
Authors: Darcy D, Atwal PS, Angell C, Gadi I, Wallerstein R
We report on a 6-month-old girl with two apparent cell lines; one with trisomy 21, and the other with paternal genome-wide uniparental isodisomy (GWUPiD), identified using single nucleotide polymorphism (SNP) based microarray and microsatellite analysis of polymorphic loci. The patient has Beckwith-Wiedemann syndrome (BWS) due to paternal uniparental disomy (UPD) at chromosome location 11p15 (UPD 11p15), which was confirmed through methylation analysis. Hyperinsulinemic hypoglycemia is present, which is associated with paternal UPD 11p15.5; and she likely has medullary nephrocalcinosis, which is associated with paternal UPD 20, although this was not biochemically confirmed. Angelman syndrome (AS) analysis was negative but this testing is not completely informative; she has no specific features of AS. Clinical features of this patient include: dysmorphic features consistent with trisomy 21, tetralogy of Fallot, hemihypertrophy, swirled skin hyperpigmentation, hepatoblastoma, and Wilms tumor. Her karyotype is 47,XX,+21/46,XX, and microarray results suggest that the cell line with trisomy 21 is biparentally inherited and represents 40-50% of the genomic material in the tested specimen. The difference in the level of cytogenetically detected mosaicism versus the level of mosaicism observed via microarray analysis is likely caused by differences in the test methodologies. While a handful of cases of mosaic paternal GWUPiD have been reported, this patient is the only reported case that also involves trisomy 21. Other GWUPiD patients have presented with features associated with multiple imprinted regions, as does our patient. © 2015 Wiley Periodicals, Inc.
PMID: 26219535 [PubMed - as supplied by publisher]
Functional connectivity for face processing in individuals with body dysmorphic disorder and anorexia nervosa.
Psychol Med. 2015 Jul 29;:1-13
Authors: Moody TD, Sasaki MA, Bohon C, Strober MA, Bookheimer SY, Sheen CL, Feusner JD
BACKGROUND: Body dysmorphic disorder (BDD) and anorexia nervosa (AN) are both characterized by distorted perception of appearance. Previous studies in BDD suggest abnormalities in visual processing of own and others' faces, but no study has examined visual processing of faces in AN, nor directly compared the two disorders in this respect.
METHOD: We collected functional magnetic resonance imaging data on 60 individuals of equivalent age and gender in each of three groups - 20 BDD, 20 weight-restored AN, and 20 healthy controls (HC) - while they viewed images of others' faces that contained only high or low spatial frequency information (HSF or LSF). We tested hypotheses about functional connectivity within specialized sub-networks for HSF and LSF visual processing, using psychophysiological interaction analyses.
RESULTS: The BDD group demonstrated increased functional connectivity compared to HC between left anterior occipital face area and right fusiform face area (FFA) for LSF faces, which was associated with symptom severity. Both BDD and AN groups had increased connectivity compared to HC between FFA and precuneous/posterior cingulate gyrus for LSF faces, and decreased connectivity between FFA and insula. In addition, we found that LSF connectivity between FFA and posterior cingulate gyrus was significantly associated with thoughts about own appearance in AN.
CONCLUSIONS: Results suggest similar abnormal functional connectivity within higher-order systems for face processing in BDD and AN, but distinct abnormal connectivity patterns within occipito-temporal visual networks. Findings may have implications for understanding relationships between these disorders, and the pathophysiology underlying perceptual distortions.
PMID: 26219399 [PubMed - as supplied by publisher]
Non-use of health care service among empty-nest elderly in Shandong, China: a cross-sectional study.
BMC Health Serv Res. 2015;15:294
Authors: Zhou C, Ji C, Chu J, Medina A, Li C, Jiang S, Zheng W, Liu J, Rozelle S
BACKGROUND: Empty-nest elderly refers to those elderly with no children or whose children have already left home. Few studies have focused on healthcare service use among empty-nest seniors, and no studies have identified the prevalence and profiles of non-use of healthcare services among empty-nest elderly. The purpose of this study is to compare the prevalence of non-use of healthcare services between empty-nest and non-empty-nest elderly and identify risk factors for the non-use of healthcare services among empty-nest seniors.
METHODS: Four thousand four hundred sixty nine seniors (60 years and above) were draw from a cross-sectional study conducted in three urban districts and three rural counties of Shandong Province in China. Non-visiting within the past 2 weeks and non-hospitalization in previous year are used to measure non-use of healthcare services. Chi-square test is used to compare the prevalence of non-use between empty-nesters and non-empty-nesters. Multivariate logistic regression analysis is employed to identify the risk factors of non-use among empty-nest seniors.
RESULTS: Of 4469 respondents, 2667(59.7 %) are empty-nesters. Overall, 35.5 % of the participants had non-visiting and 34.5 % had non-hospitalization. Non-visiting rate among empty-nest elderly (37.7 %) is significantly higher than that among non-empty-nest ones (32.7 %) (P = 0.008). Non-hospitalization rate among empty-nesters (36.1 %) is slightly higher than that among non-empty-nesters (31.6 %) (P = 0.166). Financial difficulty is the leading cause for both non-visiting and non-hospitalization of the participants, and it exerts a larger negative effect on access to healthcare for empty-nest elderly than non-empty-nest ones. Both non-visiting and non-hospitalization among empty-nest seniors are independently associated with low-income households, health insurance status and non-communicable chronic diseases. The non-visiting rate is also found to be higher among the empty-nesters with lower education and those from rural areas.
CONCLUSIONS: Our findings indicate that empty-nest seniors have higher non-use rate of healthcare services than non-empty-nest ones. Financial difficulty is the leading cause of non-use of health services. Healthcare policies should be developed or modified to make them more pro-poor and also pro-empty-nested.
PMID: 26219288 [PubMed - in process]
Potential Adverse Effects of Anesthesia in Children--Reply.
JAMA. 2015 Jul 28;314(4):409
Authors: Psaty BM, Platt R, Altman RB
PMID: 26219066 [PubMed - indexed for MEDLINE]
Structural Insights into the Dynamic Process of β2-Adrenergic Receptor Signaling.
Cell. 2015 May 21;161(5):1101-11
Authors: Manglik A, Kim TH, Masureel M, Altenbach C, Yang Z, Hilger D, Lerch MT, Kobilka TS, Thian FS, Hubbell WL, Prosser RS, Kobilka BK
G-protein-coupled receptors (GPCRs) transduce signals from the extracellular environment to intracellular proteins. To gain structural insight into the regulation of receptor cytoplasmic conformations by extracellular ligands during signaling, we examine the structural dynamics of the cytoplasmic domain of the β2-adrenergic receptor (β2AR) using (19)F-fluorine NMR and double electron-electron resonance spectroscopy. These studies show that unliganded and inverse-agonist-bound β2AR exists predominantly in two inactive conformations that exchange within hundreds of microseconds. Although agonists shift the equilibrium toward a conformation capable of engaging cytoplasmic G proteins, they do so incompletely, resulting in increased conformational heterogeneity and the coexistence of inactive, intermediate, and active states. Complete transition to the active conformation requires subsequent interaction with a G protein or an intracellular G protein mimetic. These studies demonstrate a loose allosteric coupling of the agonist-binding site and G-protein-coupling interface that may generally be responsible for the complex signaling behavior observed for many GPCRs.
PMID: 25981665 [PubMed - indexed for MEDLINE]
Stretchy nerves are an essential component of the extreme feeding mechanism of rorqual whales.
Curr Biol. 2015 May 4;25(9):R360-1
Authors: Vogl AW, Lillie MA, Piscitelli MA, Goldbogen JA, Pyenson ND, Shadwick RE
Rorqual whales (Balaenopteridae) are among the largest vertebrates that have ever lived and include blue (Balaenoptera musculus) and fin (Balaenoptera physalus) whales. Rorquals differ from other baleen whales (Mysticeti) in possessing longitudinal furrows or grooves in the ventral skin that extend from the mouth to the umbilicus. This ventral grooved blubber directly relates to their intermittent lunge feeding strategy, which is unique among vertebrates and was potentially an evolutionary innovation that led to gigantism in this lineage . This strategy involves the rorqual whale rapidly engulfing a huge volume of prey-laden water and then concentrating the prey by more slowly expelling the water through baleen plates (Figure 1A). The volume of water engulfed during a lunge can exceed the volume of the whale itself . During engulfment, the whale accelerates, opens its jaw until it is almost perpendicular to the rostrum, and then the highly compliant floor of the oral cavity is inflated by the incoming water . The floor of the oral cavity expands by inversion of the tongue and ballooning of the adjacent floor of the mouth into the cavum ventrale, an immense fascial pocket between the body wall and overlying blubber layer that reaches as far back as the umbilicus. The ventral grooved blubber in fin whales expands by an estimated 162% in the circumferential direction and 38% longitudinally . In fin whales, multiple lunges can occur during a single dive, and the average time between lunges is just over forty seconds . Here, we show that nerves in the floor of the oral cavity of fin whales are highly extensible.
PMID: 25942546 [PubMed - indexed for MEDLINE]
Segmental aortic stiffening contributes to experimental abdominal aortic aneurysm development.
Circulation. 2015 May 19;131(20):1783-95
Authors: Raaz U, Zöllner AM, Schellinger IN, Toh R, Nakagami F, Brandt M, Emrich FC, Kayama Y, Eken S, Adam M, Maegdefessel L, Hertel T, Deng A, Jagger A, Buerke M, Dalman RL, Spin JM, Kuhl E, Tsao PS
BACKGROUND: Stiffening of the aortic wall is a phenomenon consistently observed in age and in abdominal aortic aneurysm (AAA). However, its role in AAA pathophysiology is largely undefined.
METHODS AND RESULTS: Using an established murine elastase-induced AAA model, we demonstrate that segmental aortic stiffening precedes aneurysm growth. Finite-element analysis reveals that early stiffening of the aneurysm-prone aortic segment leads to axial (longitudinal) wall stress generated by cyclic (systolic) tethering of adjacent, more compliant wall segments. Interventional stiffening of AAA-adjacent aortic segments (via external application of surgical adhesive) significantly reduces aneurysm growth. These changes correlate with the reduced segmental stiffness of the AAA-prone aorta (attributable to equalized stiffness in adjacent segments), reduced axial wall stress, decreased production of reactive oxygen species, attenuated elastin breakdown, and decreased expression of inflammatory cytokines and macrophage infiltration, and attenuated apoptosis within the aortic wall, as well. Cyclic pressurization of segmentally stiffened aortic segments ex vivo increases the expression of genes related to inflammation and extracellular matrix remodeling. Finally, human ultrasound studies reveal that aging, a significant AAA risk factor, is accompanied by segmental infrarenal aortic stiffening.
CONCLUSIONS: The present study introduces the novel concept of segmental aortic stiffening as an early pathomechanism generating aortic wall stress and triggering aneurysmal growth, thereby delineating potential underlying molecular mechanisms and therapeutic targets. In addition, monitoring segmental aortic stiffening may aid the identification of patients at risk for AAA.
PMID: 25904646 [PubMed - indexed for MEDLINE]
Opinion: Sex inclusion in basic research drives discovery.
Proc Natl Acad Sci U S A. 2015 Apr 28;112(17):5257-8
Authors: Klein SL, Schiebinger L, Stefanick ML, Cahill L, Danska J, de Vries GJ, Kibbe MR, McCarthy MM, Mogil JS, Woodruff TK, Zucker I
PMID: 25902532 [PubMed - indexed for MEDLINE]
Leveraging Multi-ethnic Evidence for Mapping Complex Traits in Minority Populations: An Empirical Bayes Approach.
Am J Hum Genet. 2015 May 7;96(5):740-52
Authors: Coram MA, Candille SI, Duan Q, Chan KH, Li Y, Kooperberg C, Reiner AP, Tang H
Elucidating the genetic basis of complex traits and diseases in non-European populations is particularly challenging because US minority populations have been under-represented in genetic association studies. We developed an empirical Bayes approach named XPEB (cross-population empirical Bayes), designed to improve the power for mapping complex-trait-associated loci in a minority population by exploiting information from genome-wide association studies (GWASs) from another ethnic population. Taking as input summary statistics from two GWASs-a target GWAS from an ethnic minority population of primary interest and an auxiliary base GWAS (such as a larger GWAS in Europeans)-our XPEB approach reprioritizes SNPs in the target population to compute local false-discovery rates. We demonstrated, through simulations, that whenever the base GWAS harbors relevant information, XPEB gains efficiency. Moreover, XPEB has the ability to discard irrelevant auxiliary information, providing a safeguard against inflated false-discovery rates due to genetic heterogeneity between populations. Applied to a blood-lipids study in African Americans, XPEB more than quadrupled the discoveries from the conventional approach, which used a target GWAS alone, bringing the number of significant loci from 14 to 65. Thus, XPEB offers a flexible framework for mapping complex traits in minority populations.
PMID: 25892113 [PubMed - indexed for MEDLINE]
The Mechanochemical Cycle of Mammalian Kinesin-2 KIF3A/B under Load.
Curr Biol. 2015 May 4;25(9):1166-75
Authors: Andreasson JO, Shastry S, Hancock WO, Block SM
The response of motor proteins to external loads underlies their ability to work in teams and determines the net speed and directionality of cargo transport. The mammalian kinesin-2, KIF3A/B, is a heterotrimeric motor involved in intraflagellar transport and vesicle motility in neurons. Bidirectional cargo transport is known to result from the opposing activities of KIF3A/B and dynein bound to the same cargo, but the load-dependent properties of kinesin-2 are poorly understood. We used a feedback-controlled optical trap to probe the velocity, run length, and unbinding kinetics of mouse KIF3A/B under various loads and nucleotide conditions. The kinesin-2 motor velocity is less sensitive than kinesin-1 to external forces, but its processivity diminishes steeply with load, and the motor was observed occasionally to slip and reattach. Each motor domain was characterized by studying homodimeric constructs, and a global fit to the data resulted in a comprehensive pathway that quantifies the principal force-dependent kinetic transitions. The properties of the KIF3A/B heterodimer are intermediate between the two homodimers, and the distinct load-dependent behavior is attributable to the properties of the motor domains and not to the neck linkers or the coiled-coil stalk. We conclude that the force-dependent movement of KIF3A/B differs significantly from conventional kinesin-1. Against opposing dynein forces, KIF3A/B motors are predicted to rapidly unbind and rebind, resulting in qualitatively different transport behavior from kinesin-1.
PMID: 25866395 [PubMed - indexed for MEDLINE]
"Velcro" engineering of high affinity CD47 ectodomain as signal regulatory protein α (SIRPα) antagonists that enhance antibody-dependent cellular phagocytosis.
J Biol Chem. 2015 May 15;290(20):12650-63
Authors: Ho CC, Guo N, Sockolosky JT, Ring AM, Weiskopf K, Özkan E, Mori Y, Weissman IL, Garcia KC
CD47 is a cell surface protein that transmits an anti-phagocytic signal, known as the "don't-eat-me" signal, to macrophages upon engaging its receptor signal regulatory protein α (SIRPα). Molecules that antagonize the CD47-SIRPα interaction by binding to CD47, such as anti-CD47 antibodies and the engineered SIRPα variant CV1, have been shown to facilitate macrophage-mediated anti-tumor responses. However, these strategies targeting CD47 are handicapped by large antigen sinks in vivo and indiscriminate cell binding due to ubiquitous expression of CD47. These factors reduce bioavailability and increase the risk of toxicity. Here, we present an alternative strategy to antagonize the CD47-SIRPα pathway by engineering high affinity CD47 variants that target SIRPα, which has restricted tissue expression. CD47 proved to be refractive to conventional affinity maturation techniques targeting its binding interface with SIRPα. Therefore, we developed a novel engineering approach, whereby we augmented the existing contact interface via N-terminal peptide extension, coined "Velcro" engineering. The high affinity variant (Velcro-CD47) bound to the two most prominent human SIRPα alleles with greatly increased affinity relative to wild-type CD47 and potently antagonized CD47 binding to SIRPα on human macrophages. Velcro-CD47 synergizes with tumor-specific monoclonal antibodies to enhance macrophage phagocytosis of tumor cells in vitro, with similar potency as CV1. Finally, Velcro-CD47 interacts specifically with a subset of myeloid-derived cells in human blood, whereas CV1 binds all myeloid, lymphoid, and erythroid populations interrogated. This is consistent with the restricted expression of SIRPα compared with CD47. Herein, we have demonstrated that "Velcro" engineering is a powerful protein-engineering tool with potential applications to other systems and that Velcro-CD47 could be an alternative adjuvant to CD47-targeting agents for cancer immunotherapy.
PMID: 25837251 [PubMed - indexed for MEDLINE]
Suppression of endothelial CD39/ENTPD1 is associated with pulmonary vascular remodeling in pulmonary arterial hypertension.
Am J Physiol Lung Cell Mol Physiol. 2015 May 15;308(10):L1046-57
Authors: Helenius MH, Vattulainen S, Orcholski M, Aho J, Komulainen A, Taimen P, Wang L, de Jesus Perez VA, Koskenvuo JW, Alastalo TP
Endothelial cell (EC) dysfunction plays a role in the pathobiology of occlusive vasculopathy in pulmonary arterial hypertension (PAH). Purinergic signaling pathways, which consist of extracellular nucleotide and nucleoside-mediated cell signaling through specific receptors, are known to be important regulators of vascular tone and remodeling. Therefore, we hypothesized that abnormalities in the vascular purinergic microenvironment are associated with PAH. Enzymatic clearance is crucial to terminate unnecessary cell activation; one of the most abundantly expressed enzymes on the EC surface is E-NTPDase1/CD39, which hydrolyzes ATP and ADP to AMP. we used histological samples from patients and healthy donors, radioisotope-labeled substrates to measure ectoenzyme activity, and a variety of in vitro approaches to study the role of CD39 in PAH. Immunohistochemistry on human idiopathic PAH (IPAH) patients' lungs demonstrated that CD39 was significantly downregulated in the endothelium of diseased small arteries. Similarly, CD39 expression and activity were decreased in cultured pulmonary ECs from IPAH patients. Suppression of CD39 in vitro resulted in EC phenotypic switch that gave rise to apoptosis-resistant pulmonary arterial endothelial cells and promoted a microenvironment that induced vascular smooth muscle cell migration. we also identified that the ATP receptor P2Y11 is essential for ATP-mediated EC survival. Furthermore, we report that apelin, a known regulator of pulmonary vascular homeostasis, can potentiate the activity of CD39 both in vitro and in vivo. we conclude that sustained attenuation of CD39 activity through ATP accumulation is tightly linked to vascular dysfunction and remodeling in PAH and could represent a novel target for therapy.
PMID: 25820525 [PubMed - indexed for MEDLINE]
Assessment of the genetic basis of rosacea by genome-wide association study.
J Invest Dermatol. 2015 Jun;135(6):1548-55
Authors: Chang AL, Raber I, Xu J, Li R, Spitale R, Chen J, Kiefer AK, Tian C, Eriksson NK, Hinds DA, Tung JY
Rosacea is a common, chronic skin disease that is currently incurable. Although environmental factors influence rosacea, the genetic basis of rosacea is not established. In this genome-wide association study, a discovery group of 22,952 individuals (2,618 rosacea cases and 20,334 controls) was analyzed, leading to identification of two significant single-nucleotide polymorphisms (SNPs) associated with rosacea, one of which replicated in a new group of 29,481 individuals (3,205 rosacea cases and 26,262 controls). The confirmed SNP, rs763035 (P=8.0 × 10(-11) discovery group; P=0.00031 replication group), is intergenic between HLA-DRA and BTNL2. Exploratory immunohistochemical analysis of HLA-DRA and BTNL2 expression in papulopustular rosacea lesions from six individuals, including one with the rs763035 variant, revealed staining in the perifollicular inflammatory infiltrate of rosacea for both proteins. In addition, three HLA alleles, all MHC class II proteins, were significantly associated with rosacea in the discovery group and confirmed in the replication group: HLA-DRB1*03:01 (P=1.0 × 10(-8) discovery group; P=4.4 × 10(-6) replication group), HLA-DQB1*02:01 (P=1.3 × 10(-8) discovery group; P=7.2 × 10(-6) replication group), and HLA-DQA1*05:01 (P=1.4 × 10(-8) discovery group; P=7.6 × 10(-6) replication group). Collectively, the gene variants identified in this study support the concept of a genetic component for rosacea, and provide candidate targets for future studies to better understand and treat rosacea.
PMID: 25695682 [PubMed - indexed for MEDLINE]
Clonal evolution of pre-leukemic hematopoietic stem cells precedes human acute myeloid leukemia.
Best Pract Res Clin Haematol. 2014 Sep-Dec;27(3-4):229-34
Authors: Majeti R
Massively parallel DNA sequencing has uncovered recurrent mutations in many human cancers. In acute myeloid leukemia (AML), cancer genome/exome resequencing has identified numerous recurrently mutated genes with an average of 5 mutations in each case of de novo AML. In order for these multiple mutations to accumulate in a single lineage of cells, they are serially acquired in clones of self-renewing hematopoietic stem cells (HSC), termed pre-leukemic HSC. Isolation and characterization of pre-leukemic HSC have shown that their mutations are enriched in genes involved in regulating DNA methylation, chromatin modifications, and the cohesin complex. On the other hand, genes involved in regulating activated signaling are generally absent. Pre-leukemic HSC have been found to persist in clinical remission and may ultimately give rise to relapsed disease through the acquisition of novel mutations. Thus, pre-leukemic HSC may constitute a key cellular reservoir that must be eradicated for long-term cures.
PMID: 25455271 [PubMed - indexed for MEDLINE]
False positive 18F-fluorodeoxyglucose positron emission tomography/computed tomography liver lesion mimicking metastasis in 2 patients with gastroesophageal cancer.
Pract Radiat Oncol. 2014 Nov-Dec;4(6):368-71
Authors: Paudel N, Kunz PL, Poultsides GA, Koong AC, Chang DT
PMID: 25407856 [PubMed - indexed for MEDLINE]
Proliferative epithelial disease identified in nipple aspirate fluid and risk of developing breast cancer: a systematic review.
Curr Med Res Opin. 2015 Feb;31(2):253-62
Authors: Hornberger J, Chen SC, Li Q, Kakad P, Quay SC
BACKGROUND: Guideline panels recognize the need to increase the accuracy of identifying women at high risk of developing breast cancer who would benefit from prevention strategies. The characterization of proliferative epithelial disease found in nipple aspirate fluid (PED-NAF) may be a relevant risk factor.
OBJECTIVE: To comprehensively review the published literature to characterize and summarize abnormal cytology detected by NAF and the association of PED-NAF with subsequent risk of developing breast cancer.
RESEARCH DESIGN AND METHODS: Literature identified by systematic searches in MEDLINE PubMed and the Cochrane Library was screened for articles containing primary data on NAF cytology based on predefined inclusion and exclusion criteria.
MAIN OUTCOME MEASURES: Study characteristics, cytological group distribution, and incidence of breast cancer.
RESULTS: Thirty articles were included after full-text review, of which 16 were analyzed, containing data on 20,808 unique aspirations from over 17,378 subjects. Seven (44%) of the studies used the King cytological classification system. Among aspirations from women free of breast cancer, 51.5% contained fluid, in which over 27.7% had PED on cytology. In the two prospective studies of 7850 cancer-free women, abnormal cytology by NAF carried a 2.1-fold higher risk (95% CI, 1.6-2.6; p < 0.001) of developing breast cancer, compared with women from whom no fluid could be obtained.
CONCLUSIONS: PED-NAF among women free of breast cancer, compared with no fluid being obtained, has an independent risk of developing breast cancer comparable to the risk of a woman with a positive family history of breast cancer. These findings have implications for augmenting risk prediction and clinical decisions concerning breast cancer surveillance and chemoprevention. As with all reviews, heterogeneity across studies may have influenced the results. The limited literature calls for prospective studies on asymptomatic women with long-term follow-up.
PMID: 25405383 [PubMed - indexed for MEDLINE]
Matrix RGD ligand density and L1CAM-mediated Schwann cell interactions synergistically enhance neurite outgrowth.
Acta Biomater. 2015 Jan;11:48-57
Authors: Romano NH, Madl CM, Heilshorn SC
The innate biological response to peripheral nerve injury involves a complex interplay of multiple molecular cues to guide neurites across the injury gap. Many current strategies to stimulate regeneration take inspiration from this biological response. However, little is known about the balance of cell-matrix and Schwann cell-neurite dynamics required for regeneration of neural architectures. We present an engineered extracellular matrix (eECM) microenvironment with tailored cell-matrix and cell-cell interactions to study their individual and combined effects on neurite outgrowth. This eECM regulates cell-matrix interactions by presenting integrin-binding RGD (Arg-Gly-Asp) ligands at specified densities. Simultaneously, the addition or exclusion of nerve growth factor (NGF) is used to modulate L1CAM-mediated Schwann cell-neurite interactions. Individually, increasing the RGD ligand density from 0.16 to 3.2mM resulted in increasing neurite lengths. In matrices presenting higher RGD ligand densities, neurite outgrowth was synergistically enhanced in the presence of soluble NGF. Analysis of Schwann cell migration and co-localization with neurites revealed that NGF enhanced cooperative outgrowth between the two cell types. Interestingly, neurites in NGF-supplemented conditions were unable to extend on the surrounding eECM without the assistance of Schwann cells. Blocking studies revealed that L1CAM is primarily responsible for these Schwann cell-neurite interactions. Without NGF supplementation, neurite outgrowth was unaffected by L1CAM blocking or the depletion of Schwann cells. These results underscore the synergistic interplay between cell-matrix and cell-cell interactions in enhancing neurite outgrowth for peripheral nerve regeneration.
PMID: 25308870 [PubMed - indexed for MEDLINE]
Role of CSPG receptor LAR phosphatase in restricting axon regeneration after CNS injury.
Neurobiol Dis. 2015 Jan;73:36-48
Authors: Xu B, Park D, Ohtake Y, Li H, Hayat U, Liu J, Selzer ME, Longo FM, Li S
Extracellular matrix molecule chondroitin sulfate proteoglycans (CSPGs) are highly upregulated in scar tissues and form a potent chemical barrier for CNS axon regeneration. Recent studies support that the receptor protein tyrosine phosphatase σ (PTPσ) and its subfamily member leukocyte common antigen related phosphatase (LAR) act as transmembrane receptors to mediate CSPG inhibition. PTPσ deficiency increased regrowth of ascending axons into scar tissues and descending corticospinal tract (CST) axons into the caudal spinal cord after spinal cord injury (SCI). Pharmacological LAR inhibition enhanced serotonergic axon growth in SCI mice. However, transgenic LAR deletion on axon growth in vivo and the role of LAR in regulating regrowth of other fiber tracts have not been studied. Here, we studied the role of LAR in restricting regrowth of injured descending CNS axons in deficient mice. LAR deletion increased regrowth of serotonergic axons into scar tissues and caudal spinal cord after dorsal over-hemitransection. LAR deletion also stimulated regrowth of CST fibers into the caudal spinal cord. LAR protein was upregulated days to weeks after injury and co-localized to serotonergic and CST axons. Moreover, LAR deletion improved functional recovery by increasing BMS locomotor scores and stride length and reducing grid walk errors. This is the first transgenic study that demonstrates the crucial role of LAR in restricting regrowth of injured CNS axons.
PMID: 25220840 [PubMed - indexed for MEDLINE]
Evaluation of a prospectively administered written questionnaire to reduce the incidence of suspected latex anaphylaxis during elective cesarean delivery.
Int J Obstet Anesth. 2014 Nov;23(4):335-40
Authors: Péer L, Brezis ML, Shalit M, Carvalho B, Levin PD, Seri O, Weiniger CF
BACKGROUND: Life-threatening anaphylaxis has been reported in women exposed to latex during surgery. We compared a written screening questionnaire to identify suspected latex sensitivity with a verbal inquiry used previously in a historical control group of women undergoing cesarean delivery to determine if the incidence of suspected latex anaphylaxis could be reduced.
METHODS: To identify suspected latex sensitivity among women undergoing elective cesarean delivery in a single-site tertiary unit, a nine-item written screening questionnaire was compared to historical use of a standard verbal inquiry "Are you allergic to medications or latex?". Women who had suspected latex sensitivity risk factors, or who had known latex allergy, underwent latex-free surgery. Women with suspected anaphylaxis during cesarean delivery were recommended to undergo allergen testing. The primary study outcome was suspected anaphylaxis incidence during the two periods: historical control January to December 2008, questionnaire March 2010 to April 2011.
RESULTS: The questionnaire identified suspected latex sensitivity in 66 of 453 women (14.6%) who completed the questionnaire. The standard verbal inquiry group had identified 12 of 460 women (2.6%) with self-reported latex sensitivity. The incidence of suspected anaphylaxis during cesarean delivery was significantly lower during the questionnaire period when compared to historical controls (3/516, 0.6% vs. 11/460, 2.4%, P=0.015). For both groups, 13 of 14 women (92.9%) with suspected latex anaphylaxis were contactable; five of 13 (38.5%) had undergone allergen testing and all were positive for latex.
CONCLUSIONS: Use of the written screening questionnaire was associated with fewer cases of suspected anaphylaxis during cesarean delivery compared with the historical control. Most women with suspected anaphylaxis did not perform allergy testing; however, all who did were positive for latex.
PMID: 25201315 [PubMed - indexed for MEDLINE]
Inter-episode affective intensity and instability: predictors of depression and functional impairment in bipolar disorder.
J Behav Ther Exp Psychiatry. 2015 Mar;46:14-8
Authors: Gershon A, Eidelman P
BACKGROUND AND OBJECTIVES: Dysregulated affect is a hallmark feature of acute episodes of bipolar disorder (BD) and persists during inter-episode periods. Its contribution to course of illness is not yet known. The present report examines the prospective influence of inter-episode affect dysregulation on symptoms and functional impairment in BD.
METHODS: Twenty-seven participants diagnosed with inter-episode bipolar I disorder completed daily measures of negative and positive affect for 49 days (±8 days) while they remained inter-episode. One month following this daily assessment period, symptom severity interviews and a measure of functional impairment were administered by telephone.
RESULTS: More intense negative affect and positive affect during the inter-episode period were associated with higher depressive, but not manic, symptoms at the one-month follow-up assessment. More intense and unstable negative affect, and more unstable positive affect, during the inter-episode period were associated with greater impairment in home and work functioning at the follow-up assessment. All associations remained significant after controlling for concurrent symptom levels.
LIMITATIONS: The findings need to be confirmed in larger samples with longer follow-up periods. A more comprehensive assessment of functional impairment is also warranted.
CONCLUSIONS: The findings suggest that a persistent affective dysregulation between episodes of BD may be an important predictor of depression and functional impairment. Monitoring daily affect during inter-episode periods could allow for a more timely application of interventions that aim to prevent or reduce depressive symptoms and improve functioning for individuals with BD.
PMID: 25164093 [PubMed - indexed for MEDLINE]
Plasma vasopressin concentrations positively predict cerebrospinal fluid vasopressin concentrations in human neonates.
Peptides. 2014 Nov;61:12-6
Authors: Carson DS, Howerton CL, Garner JP, Hyde SA, Clark CL, Hardan AY, Penn AA, Parker KJ
Central arginine vasopressin (AVP) plays a critical role in mammalian social behavior and has been hypothesized to be a biomarker of certain human neurodevelopmental disorders, including autism. However, opportunities to collect post-mortem brain tissue or cerebrospinal fluid (CSF) from children are extremely limited, and the use of less invasive peripheral assessments (e.g., blood, urine, or saliva) of AVP as a proxy for more invasive central measures has not been well validated. Further, almost nothing is known about AVP biology in very young infants. Therefore in the present study we concomitantly collected basal CSF and plasma samples from N = 20 neonates undergoing clinical sepsis evaluation (all were sepsis negative) and quantified AVP concentrations via well-validated enzyme-immunoassay methodology. Plasma AVP concentrations significantly and positively predicted CSF AVP concentrations (r = 0.73, p = 0.0021), and this relationship persisted when variance attributed to sex, gestational age, and sample collection time was controlled for in the statistical model (r = 0.75, p = 0.0047). These findings provide preliminary support for the use of basal plasma AVP measurement as a proxy for basal brain AVP activity in pediatric populations. Future studies are now required to determine the relationship between behavioral measures and AVP concentrations in both central and peripheral compartments in young infants and older children.
PMID: 25148831 [PubMed - indexed for MEDLINE]
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