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Find video protocols related to scientific articles indexed in Pubmed.
Purpose in life and use of preventive health care services.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 11-03-2014
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Purpose in life has been linked with better health (mental and physical) and health behaviors, but its link with patterns of health care use are understudied. We hypothesized that people with higher purpose would be more proactive in taking care of their health, as indicated by a higher likelihood of using preventive health care services. We also hypothesized that people with higher purpose would spend fewer nights in the hospital. Participants (n = 7,168) were drawn from the Health and Retirement Study, a nationally representative panel study of American adults over the age of 50, and tracked for 6 y. After adjusting for sociodemographic factors, each unit increase in purpose (on a six-point scale) was associated with a higher likelihood that people would obtain a cholesterol test [odds ratio (OR) = 1.18, 95% confidence interval (CI) = 1.08-1.29] or colonoscopy (OR = 1.06, 95% CI = 0.99-1.14). Furthermore, females were more likely to receive a mammogram/X-ray (OR = 1.27, 95% CI = 1.16-1.39) or pap smear (OR = 1.16, 95% CI = 1.06-1.28), and males were more likely to receive a prostate examination (OR = 1.31, 95% CI = 1.18-1.45). Each unit increase in purpose was also associated with 17% fewer nights spent in the hospital (rate ratio = 0.83, 95% CI = 0.77-0.89). An increasing number of randomized controlled trials show that purpose in life can be raised. Therefore, with additional research, findings from this study may inform the development of new strategies that increase the use of preventive health care services, offset the burden of rising health care costs, and enhance the quality of life among people moving into the ranks of our aging society.
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The Neuropathology of Huntington's Disease.
Curr Top Behav Neurosci
PUBLISHED: 10-11-2014
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The basal ganglia are a highly interconnected set of subcortical nuclei and major atrophy in one or more regions may have major effects on other regions of the brain. Therefore, the striatum which is preferentially degenerated and receives projections from the entire cortex also affects the regions to which it targets, especially the globus pallidus and substantia nigra pars reticulata. Additionally, the cerebral cortex is itself severely affected as are many other regions of the brain, especially in more advanced cases. The cell loss in the basal ganglia and the cerebral cortex is extensive. The most important new findings in Huntington's disease pathology is the highly variable nature of the degeneration in the brain. Most interestingly, this variable pattern of pathology appears to reflect the highly variable symptomatology of cases with Huntington's disease even among cases possessing the same number of CAG repeats.
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Telomere length and recurrence risk after curative resection in patients with early-stage non-small cell lung cancer: a prospective cohort study.
J Thorac Oncol
PUBLISHED: 10-10-2014
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We hypothesized that telomere length in peripheral blood would have significant predictive value for risk of recurrence after curative resection in non-small cell lung cancer (NSCLC).
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Patients with Pathologically Proven Renal Disease Have Similar Declines in Renal Function Following Robot-Assisted Partial Nephrectomy.
J. Endourol.
PUBLISHED: 09-20-2014
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Abstract Objective: To determine if patients with pathological, medical renal disease, defined as evidence of pathological abnormalities indicative of renal damage in the non-neoplastic partial nephrectomy specimens, have worsened functional outcomes following robot-assisted partial nephrectomy (RPN). Materials and Methods: Sixty patients with and 101 without pathologically proven renal disease on non-neoplastic renal specimens were evaluated for differences in postoperative outcomes following RPN. Multiple linear regression modeling assessed for factors influencing early and late declines in renal function. Results: The two groups were similar in all preoperative parameters. Both patients with and without pathological renal disease had similar lengths of hospitalization, transfusions, and complication rates. The percent change in the glomerular filtration rate was similar for patients with and without pathological renal disease (-8.8% vs -12.2%, p=0.194). Patients with pathological renal disease had less chronic kidney disease (CKD) upstaging than patients without renal disease (18.3% vs 39.6%, p=0.006). Increasing age (p=0.030) and higher preoperative glomerular filtration rates (p=0.044) predicted worse late percentage declines in renal function, while increased warm ischemia time predicted late CKD upstaging (p=0.043). Conclusion: The presence of pathological renal disease in non-neoplastic renal tissue did not place patients at risk for worsened postoperative complications or renal function deterioration following RPN.
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Perioperative complications of robot-assisted partial nephrectomy.
Curr Urol Rep
PUBLISHED: 09-01-2014
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The incidence of renal cell carcinoma continues to increase with utilization of diagnostic abdominal imaging with migration towards a proportionally greater detection of small renal masses (SRM). Robot-assisted partial nephrectomy (RAPN) has become an attractive minimally invasive treatment modality for SRM's due to the technical advantages and shortened learning curve compared to laparoscopic partial nephrectomy (LPN) while preserving comparable perioperative outcomes. With advances in ablative approaches for stage I renal cell carcinoma (RCC) and controversy surrounding the role of extirpative surgery for SRM's, systematic understanding of the complications associated with RAPN has become even more imperative. This review aims to summarize and evaluate the contemporary literature, compile reported intraoperative complications, describe conventional and nephron-sparing surgery (NSS) specific postoperative complications, and assess factors associated with an increased likelihood for perioperative complications following RAPN.
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Perceived neighbourhood social cohesion and myocardial infarction.
J Epidemiol Community Health
PUBLISHED: 08-18-2014
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The main strategy for alleviating heart disease has been to target individuals and encourage them to change their health behaviours. Although important, emphasis on individuals has diverted focus and responsibility away from neighbourhood characteristics, which also strongly influence people's behaviours. Although a growing body of research has repeatedly demonstrated strong associations between neighbourhood characteristics and cardiovascular health, it has typically focused on negative neighbourhood characteristics. Only a few studies have examined the potential health enhancing effects of positive neighbourhood characteristics, such as perceived neighbourhood social cohesion.
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Scleral-Fixated Capsular Tension Rings and Segments for Ectopia Lentis in Children.
Am. J. Ophthalmol.
PUBLISHED: 08-12-2014
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To report the short-term outcomes and complications of implantation of scleral-fixated capsular tension rings and/or capsular tension segments with intraocular lenses (IOL) in pediatric patients with ectopia lentis.
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Patients with Pathologically Proven Renal Disease Have Similar Declines in Renal Function Following Robot-Assisted Partial Nephrectomy.
J. Endourol.
PUBLISHED: 08-08-2014
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To determine if patients with pathological, medical renal disease, defined as evidence of pathological abnormalities indicative of renal damage in the non-neoplastic partial nephrectomy specimens, have worsened functional outcomes following robot-assisted partial nephrectomy.
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Widespread heterogeneous neuronal loss across the cerebral cortex in Huntington's disease.
J Huntingtons Dis
PUBLISHED: 07-27-2014
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Huntington's disease is an autosomal dominant neurodegenerative disease characterized by neuronal degeneration in the basal ganglia and cerebral cortex, and a variable symptom profile. Although progressive striatal degeneration is known to occur and is related to symptom profile, little is known about the cellular basis of symptom heterogeneity across the entire cerebral cortex. To investigate this, we have undertaken a double blind study using unbiased stereological cell counting techniques to determine the pattern of cell loss in six representative cortical regions from the frontal, parietal, temporal, and occipital lobes in the brains of 14 Huntington's disease cases and 15 controls. The results clearly demonstrate a widespread loss of total neurons and pyramidal cells across all cortical regions studied, except for the primary visual cortex. Importantly, the results show that cell loss is remarkably variable both within and between Huntington's disease cases. The results also show that neuronal loss in the primary sensory and secondary visual cortices relate to Huntington's disease motor symptom profiles, and neuronal loss across the associational cortices in the frontal, parietal and temporal lobes is related to both Huntington's disease motor and to mood symptom profiles. This finding considerably extends a previous study (Thu et al., Brain, 2010; 133:1094-1110) which showed that neuronal loss in the primary motor cortex was related specifically to the motor symptom profiles while neuronal loss in the anterior cingulate cortex was related specifically to mood symptom profiles. The extent of cortical cell loss in the current study was generally related to the striatal neuropathological grade, but not to CAG repeat length on the HTT gene. Overall our findings show that Huntington's disease is characterized by a heterogeneous pattern of neuronal cell loss across the entire cerebrum which varies with symptom profile.
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Anisotropic poly(ethylene glycol)/polycaprolactone hydrogel-fiber composites for heart valve tissue engineering.
Tissue Eng Part A
PUBLISHED: 07-16-2014
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The recapitulation of the material properties and structure of the native aortic valve leaflet, specifically its anisotropy and laminate structure, is a major design goal for scaffolds for heart valve tissue engineering. Poly(ethylene glycol) (PEG) hydrogels are attractive scaffolds for this purpose as they are biocompatible, can be modified for their mechanical and biofunctional properties, and can be laminated. This study investigated augmenting PEG hydrogels with polycaprolactone (PCL) as an analog to the fibrosa to improve strength and introduce anisotropic mechanical behavior. However, due to its hydrophobicity, PCL must be modified prior to embedding within PEG hydrogels. In this study, PCL was electrospun (ePCL) and modified in three different ways, by protein adsorption (pPCL), alkali digestion (hPCL), and acrylation (aPCL). Modified PCL of all types maintained the anisotropic elastic moduli and yield strain of unmodified anisotropic ePCL. Composites of PEG and PCL (PPCs) maintained anisotropic elastic moduli, but aPCL and pPCL had isotropic yield strains. Overall, PPCs of all modifications had elastic moduli of 3.79±0.90?MPa and 0.46±0.21?MPa in the parallel and perpendicular directions, respectively. Valvular interstitial cells seeded atop anisotropic aPCL displayed an actin distribution aligned in the direction of the underlying fibers. The resulting scaffold combines the biocompatibility and tunable fabrication of PEG with the strength and anisotropy of ePCL to form a foundation for future engineered valve scaffolds.
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Foreign body induced sialolithiasis treated by sialoendoscopic intervention.
J Craniofac Surg
PUBLISHED: 07-10-2014
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The study aims to identify the impact of sialolith formation by reviewing the foreign body induced sialolithiasis treated by sialoendoscopic intervention.
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A tumor-targeting p53 nanodelivery system limits chemoresistance to temozolomide prolonging survival in a mouse model of glioblastoma multiforme.
Nanomedicine
PUBLISHED: 07-03-2014
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Development of temozolomide (TMZ) resistance contributes to the poor prognosis for glioblastoma multiforme (GBM) patients. It was previously demonstrated that delivery of exogenous wild-type tumor suppressor gene p53 via a tumor-targeted nanocomplex (SGT-53) which crosses the blood-brain barrier could sensitize highly TMZ-resistant GBM tumors to TMZ. Here we assessed whether SGT-53 could inhibit development of TMZ resistance. SGT-53 significantly chemosensitized TMZ-sensitive human GBM cell lines (U87 and U251), in vitro and in vivo. Furthermore, in an intracranial GBM tumor model, two cycles of concurrent treatment with systemically administered SGT-53 and TMZ inhibited tumor growth, increased apoptosis and most importantly, significantly prolonged median survival. In contrast TMZ alone had no significant effect on median survival compared to a single cycle of TMZ. These results suggest that combining SGT-53 with TMZ appears to limit development of TMZ resistance, prolonging its anti-tumor effect and could be a more effective therapy for GBM.
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Membrane interaction of bound ligands contributes to the negative binding cooperativity of the EGF receptor.
PLoS Comput. Biol.
PUBLISHED: 07-01-2014
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The epidermal growth factor receptor (EGFR) plays a key role in regulating cell proliferation, migration, and differentiation, and aberrant EGFR signaling is implicated in a variety of cancers. EGFR signaling is triggered by extracellular ligand binding, which promotes EGFR dimerization and activation. Ligand-binding measurements are consistent with a negatively cooperative model in which the ligand-binding affinity at either binding site in an EGFR dimer is weaker when the other site is occupied by a ligand. This cooperativity is widely believed to be central to the effects of ligand concentration on EGFR-mediated intracellular signaling. Although the extracellular portion of the human EGFR dimer has been resolved crystallographically, the crystal structures do not reveal the structural origin of this negative cooperativity, which has remained unclear. Here we report the results of molecular dynamics simulations suggesting that asymmetrical interactions of the two binding sites with the membrane may be responsible (perhaps along with other factors) for this negative cooperativity. In particular, in our simulations the extracellular domains of an EGFR dimer spontaneously lay down on the membrane in an orientation in which favorable membrane contacts were made with one of the bound ligands, but could not be made with the other. Similar interactions were observed when EGFR was glycosylated, as it is in vivo.
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Meta-analysis of genome-wide association studies in East Asian-ancestry populations identifies four new loci for body mass index.
Wanqing Wen, Wei Zheng, Yukinori Okada, Fumihiko Takeuchi, Yasuharu Tabara, Joo-Yeon Hwang, Rajkumar Dorajoo, Huaixing Li, Fuu-Jen Tsai, Xiaobo Yang, Jiang He, Ying Wu, Meian He, Yi Zhang, Jun Liang, Xiuqing Guo, Wayne Huey-Herng Sheu, Ryan Delahanty, Xingyi Guo, Michiaki Kubo, Ken Yamamoto, Takayoshi Ohkubo, Min Jin Go, Jian Jun Liu, Wei Gan, Ching-Chu Chen, Yong Gao, Shengxu Li, Nanette R Lee, Chen Wu, Xueya Zhou, Huaidong Song, Jie Yao, I-Te Lee, Jirong Long, Tatsuhiko Tsunoda, Koichi Akiyama, Naoyuki Takashima, Yoon Shin Cho, Rick Th Ong, Ling Lu, Chien-Hsiun Chen, Aihua Tan, Treva K Rice, Linda S Adair, Lixuan Gui, Matthew Allison, Wen-Jane Lee, Qiuyin Cai, Minoru Isomura, Satoshi Umemura, Young Jin Kim, Mark Seielstad, James Hixson, Yong-Bing Xiang, Masato Isono, Bong-Jo Kim, Xueling Sim, Wei Lu, Toru Nabika, Juyoung Lee, Wei-Yen Lim, Yu-Tang Gao, Ryoichi Takayanagi, Dae-Hee Kang, Tien Yin Wong, Chao Agnes Hsiung, I-Chien Wu, Jyh-Ming Jimmy Juang, Jiajun Shi, Bo Youl Choi, Tin Aung, Frank Hu, Mi Kyung Kim, Wei Yen Lim, Tzung-Dao Wang, Min-Ho Shin, Jeannette Lee, Bu-Tian Ji, Young-Hoon Lee, Terri L Young, Dong Hoon Shin, Byung-Yeol Chun, Myeong-Chan Cho, Bok-Ghee Han, Chii-Min Hwu, Themistocles L Assimes, Devin Absher, Xiaofei Yan, Eric Kim, Jane Z Kuo, Soonil Kwon, Kent D Taylor, Yii-Der I Chen, Jerome I Rotter, Lu Qi, Dingliang Zhu, Tangchun Wu, Karen L Mohlke, Dongfeng Gu, Zengnan Mo, Jer-Yuarn Wu, Xu Lin, Tetsuro Miki, E Shyong Tai, Jong-Young Lee, Norihiro Kato, Xiao-Ou Shu, Toshihiro Tanaka.
Hum. Mol. Genet.
PUBLISHED: 05-26-2014
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Recent genetic association studies have identified 55 genetic loci associated with obesity or body mass index (BMI). The vast majority, 51 loci, however, were identified in European-ancestry populations. We conducted a meta-analysis of associations between BMI and ?2.5 million genotyped or imputed single nucleotide polymorphisms among 86 757 individuals of Asian ancestry, followed by in silico and de novo replication among 7488-47 352 additional Asian-ancestry individuals. We identified four novel BMI-associated loci near the KCNQ1 (rs2237892, P = 9.29 × 10(-13)), ALDH2/MYL2 (rs671, P = 3.40 × 10(-11); rs12229654, P = 4.56 × 10(-9)), ITIH4 (rs2535633, P = 1.77 × 10(-10)) and NT5C2 (rs11191580, P = 3.83 × 10(-8)) genes. The association of BMI with rs2237892, rs671 and rs12229654 was significantly stronger among men than among women. Of the 51 BMI-associated loci initially identified in European-ancestry populations, we confirmed eight loci at the genome-wide significance level (P < 5.0 × 10(-8)) and an additional 14 at P < 1.0 × 10(-3) with the same direction of effect as reported previously. Findings from this analysis expand our knowledge of the genetic basis of obesity.
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Concordant provocation as a prognostic indicator during interlaminar lumbosacral epidural steroid injections.
Pain Physician
PUBLISHED: 05-23-2014
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Interlaminar epidural steroid injection is a well-established intervention for the treatment of radicular pain. Pain is commonly reported during the injection into the epidural space; this provocation is typically either concordant or discordant with the patient's baseline pain. It is not well known how this provocation pain relates to treatment outcomes.
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A nanoparticle carrying the p53 gene targets tumors including cancer stem cells, sensitizes glioblastoma to chemotherapy and improves survival.
ACS Nano
PUBLISHED: 05-15-2014
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Temozolomide (TMZ)-resistance in glioblastoma multiforme (GBM) has been linked to upregulation of O(6)-methylguanine-DNA methyltransferase (MGMT). Wild-type (wt) p53 was previously shown to down-modulate MGMT. However, p53 therapy for GBM is limited by lack of efficient delivery across the blood brain barrier (BBB). We have developed a systemic nanodelivery platform (scL) for tumor-specific targeting (primary and metastatic), which is currently in multiple clinical trials. This self-assembling nanocomplex is formed by simple mixing of the components in a defined order and a specific ratio. Here, we demonstrate that scL crosses the BBB and efficiently targets GBM, as well as cancer stem cells (CSCs), which have been implicated in recurrence and treatment resistance in many human cancers. Moreover, systemic delivery of scL-p53 down-modulates MGMT and induces apoptosis in intracranial GBM xenografts. The combination of scL-p53 and TMZ increased the antitumor efficacy of TMZ with enhanced survival benefit in a mouse model of highly TMZ-resistant GBM. scL-p53 also sensitized both CSCs and bulk tumor cells to TMZ, increasing apoptosis. These results suggest that combining scL-p53 with standard TMZ treatment could be a more effective therapy for GBM.
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The microfluidic multitrap nanophysiometer for hematologic cancer cell characterization reveals temporal sensitivity of the calcein-AM efflux assay.
Sci Rep
PUBLISHED: 05-06-2014
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Cytometric studies utilizing flow cytometry or multi-well culture plate fluorometry are often limited by a deficit in temporal resolution and a lack of single cell consideration. Unfortunately, many cellular processes, including signaling, motility, and molecular transport, occur transiently over relatively short periods of time and at different magnitudes between cells. Here we demonstrate the multitrap nanophysiometer (MTNP), a low-volume microfluidic platform housing an array of cell traps, as an effective tool that can be used to study individual unattached cells over time with precise control over the intercellular microenvironment. We show how the MTNP platform can be used for hematologic cancer cell characterization by measuring single T cell levels of CRAC channel modulation, non-translational motility, and ABC-transporter inhibition via a calcein-AM efflux assay. The transporter data indicate that Jurkat T cells exposed to indomethacin continue to accumulate fluorescent calcein for over 60 minutes after calcein-AM is removed from the extracellular space.
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Cortical interneuron loss and symptom heterogeneity in Huntington disease.
Ann. Neurol.
PUBLISHED: 04-22-2014
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The cellular basis of variable symptoms in Huntington disease (HD) is unclear. One important possibility is that degeneration of the interneurons in the cerebral cortex, which play a critical role in modulating cortical output to the basal ganglia, might play a significant role in the development of variable symptomatology in HD. This study aimed to examine whether symptom variability in HD is specifically associated with variable degeneration of cortical interneurons.
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Satisfaction with aging and use of preventive health services.
Prev Med
PUBLISHED: 04-08-2014
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Preventive health service use is relatively low among older age groups. We hypothesized that aging satisfaction would be associated with increased use of preventive health services four years later.
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Are people healthier if their partners are more optimistic? The dyadic effect of optimism on health among older adults.
J Psychosom Res
PUBLISHED: 03-27-2014
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Optimism has been linked with an array of positive health outcomes at the individual level. However, researchers have not examined how a spouse's optimism might impact an individual's health. We hypothesized that being optimistic (and having an optimistic spouse) would both be associated with better health.
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Prospective study of the association between dispositional optimism and incident heart failure.
Circ Heart Fail
PUBLISHED: 03-19-2014
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Although higher optimism has been linked with an array of positive health behaviors, biological processes, and cardiovascular outcomes, the relationship between optimism and heart failure has not been examined. In the United States, 80% of heart failures occur in adults aged 65+ years. Therefore, we examined whether higher optimism was linked with a reduced incidence of heart failure among older adults.
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Molecular basis for pseudokinase-dependent autoinhibition of JAK2 tyrosine kinase.
Nat. Struct. Mol. Biol.
PUBLISHED: 03-02-2014
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Janus kinase-2 (JAK2) mediates signaling by various cytokines, including erythropoietin and growth hormone. JAK2 possesses tandem pseudokinase and tyrosine-kinase domains. Mutations in the pseudokinase domain are causally linked to myeloproliferative neoplasms (MPNs) in humans. The structure of the JAK2 tandem kinase domains is unknown, and therefore the molecular bases for pseudokinase-mediated autoinhibition and pathogenic activation remain obscure. Using molecular dynamics simulations of protein-protein docking, we produced a structural model for the autoinhibitory interaction between the JAK2 pseudokinase and kinase domains. A striking feature of our model, which is supported by mutagenesis experiments, is that nearly all of the disease mutations map to the domain interface. The simulations indicate that the kinase domain is stabilized in an inactive state by the pseudokinase domain, and they offer a molecular rationale for the hyperactivity of V617F, the predominant JAK2 MPN mutation.
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Physiological acoustic sensing based on accelerometers: a survey for mobile healthcare.
Ann Biomed Eng
PUBLISHED: 02-28-2014
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This paper reviews the applications of accelerometers on the detection of physiological acoustic signals such as heart sounds, respiratory sounds, and gastrointestinal sounds. These acoustic signals contain a rich reservoir of vital physiological and pathological information. Accelerometer-based systems enable continuous, mobile, low-cost, and unobtrusive monitoring of physiological acoustic signals and thus can play significant roles in the emerging mobile healthcare. In this review, we first briefly explain the operation principle of accelerometers and specifications that are important for mobile healthcare. Applications of accelerometer-based monitoring systems are then presented. Next, we review a variety of accelerometers which have been reported in literatures for physiological acoustic sensing, including both commercial products and research prototypes. Finally, we discuss some challenges and our vision for future development.
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Comparison of laparoscopic and percutaneous cryoablation for treatment of renal masses.
Urology
PUBLISHED: 02-21-2014
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To compare perioperative and oncologic outcomes between laparoscopic (LCA) and percutaneous cryoablation (PCA) and identify predictors of treatment failure after cryoablation.
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Port site metastasis after surgery for renal cell carcinoma: harbinger of future metastasis.
J. Urol.
PUBLISHED: 02-18-2014
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Port site metastasis is a rare occurrence after minimally invasive treatment for renal cell carcinoma. However, its prognostic implications are unclear because reports in the literature are heterogeneous in detail and followup. We clarify the significance of port site metastasis in cancer specific survival and broaden our understanding of this phenomenon.
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Potentially traumatic events and serious life stressors are prospectively associated with frequency of doctor visits and overnight hospital visits.
J Psychosom Res
PUBLISHED: 02-10-2014
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Cumulative lifetime exposure to potentially traumatic events and serious life stressors has been linked with both mental and physical health problems; however, less is known about the association between exposure to potentially traumatic events and serious life stressors with health care use. We investigated whether a higher number of potentially traumatic events and serious life stressors were prospectively associated with an increased number of doctor visits and nights spent in the hospital.
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Comparison of fenestrated and nonfenestrated patients undergoing extracardiac Fontan.
Ann. Thorac. Surg.
PUBLISHED: 02-02-2014
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The purpose of this study is to compare morbidity and mortality between fenestrated (F, 61 patients) and nonfenestrated (NF, 54 patients) extracardiac Fontan patients during two eras from July 1995 to December 2010: era 1(1995 to 2004) and era 2 (2005 to 2010).
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Copper transporter CTR1 expression and tissue platinum concentration in non-small cell lung cancer.
Lung Cancer
PUBLISHED: 01-30-2014
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Platinum resistance is a major limitation in the treatment of advanced non-small cell lung cancer (NSCLC). We previously demonstrated that low tissue platinum concentration in NSCLC specimens was significantly associated with reduced tumor response. Furthermore, low expression of the copper transporter CTR1, a transporter of platinum uptake was associated with poor clinical outcome following platinum-based therapy in NSCLC patients. We investigated the relationship between tissue platinum concentrations and CTR1 expression in NSCLC specimens.
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A randomized, double-blind, placebo-controlled, multiple-dose, parallel-group clinical trial to assess the effects of teduglutide on gastric emptying of liquids in healthy subjects.
BMC Gastroenterol
PUBLISHED: 01-24-2014
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Teduglutide, a recombinant analog of human glucagon-like peptide (GLP)-2, is a novel therapy recently approved for the treatment of adult patients with short bowel syndrome who are dependent on parenteral support. Previous studies assessing the effect of GLP-2 on gastric emptying in humans have yielded inconsistent results, with some studies showing no effect and others documenting a GLP-2-dependent delay in gastric emptying. The primary objective of this study was to assess the effect of teduglutide on gastric emptying of liquids in healthy subjects, as measured by the pharmacokinetics of acetaminophen.
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Life Satisfaction and Frequency of Doctor Visits.
Psychosom Med
PUBLISHED: 12-12-2013
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ObjectiveIdentifying positive psychological factors that reduce health care use may lead to innovative efforts that help build a more sustainable and high-quality health care system. Prospective studies indicate that life satisfaction is associated with good health behaviors, enhanced health, and longer life, but little information about the association between life satisfaction and health care use is available. We tested whether higher life satisfaction was prospectively associated with fewer doctor visits. We also examined potential interactions between life satisfaction and health behaviors.MethodsParticipants were 6379 adults from the Health and Retirement Study, a prospective and nationally representative panel study of American adults older than 50 years. Participants were tracked for 4 years. We analyzed the data using a generalized linear model with a gamma distribution and log link.ResultsHigher life satisfaction was associated with fewer doctor visits. On a 6-point life satisfaction scale, each unit increase in life satisfaction was associated with an 11% decrease in doctor visits-after adjusting for sociodemographic factors (relative risk = 0.89, 95% confidence interval = 0.86-0.93). The most satisfied respondents (n = 1121; 17.58%) made 44% fewer doctor visits than did the least satisfied (n = 182; 2.85%). The association between higher life satisfaction and reduced doctor visits remained even after adjusting for baseline health and a wide range of sociodemographic, psychosocial, and health-related covariates (relative risk = 0.96, 95% confidence interval = 0.93-0.99).ConclusionsHigher life satisfaction is associated with fewer doctor visits, which may have important implications for reducing health care costs.
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Renal cryoablation versus robot-assisted partial nephrectomy: washington university long-term experience.
J. Endourol.
PUBLISHED: 11-27-2013
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Abstract Background and Purpose: American Urological Association guidelines endorse partial nephrectomy as the preferred treatment for patients with small renal masses, while considering patients with significant comorbidities potential candidates for ablative therapy. We compared perioperative, renal functional, and oncologic outcomes of renal cryoablation and robot-assisted partial nephrectomy (RAPN) based on our long-term institutional experience. Patients and Methods: A retrospective review evaluated 267 patients who underwent laparoscopic or percutaneous cryoablation (July 2000-June 2011) and 233 patients who underwent RAPN (June 2007-September 2012) for enhancing renal masses at Washington University. Results: The perioperative complication rate was 8.6% in the cryoablation group vs 9.4% in the RAPN group (P=0.75). There was no significant difference in complication risk between the two treatment modalities on multivariate analysis. Estimated glomerular filtration rate (eGFR) at last follow-up was 6% lower than preoperative eGFR in the cryoablation group and 13% lower in the RAPN group (P<0.01). The advantage of cryoablation in preserving renal function persisted on multivariate analysis (P=0.02). In patients with pathologically proven renal-cell carcinoma, 5-year Kaplan-Meier disease-free survival (DFS), cancer-specific survival (CSS), and overall survival was 83.1%, 96.4%, and 77.1% in the cryoablation cohort vs 100%, 100%, and 91.7% in the RAPN group. Mean time to recurrence was 16.2 months (range 0.03-42.0 mos). Cryoablation was associated with increased recurrence risk (hazard ratio [HR]=11.4, P=0.01) on multivariate analysis. Conclusions: Cryoablation and RAPN are safe alternatives for managing renal masses amenable to nephron-sparing interventions, offering acceptable morbidity and excellent renal preservation. While RAPN offers improved DFS, for those willing to undergo close postoperative monitoring and accept the potential need for re-treatment of recurrent disease, cryoablation offers excellent long-term CSS.
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Renal Cryoablation versus Robot-Assisted Partial Nephrectomy: Washington University Long-Term Experience.
J. Endourol.
PUBLISHED: 11-02-2013
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Background and Purpose: AUA guidelines endorse partial nephrectomy as the preferred treatment for small renal masses, while considering patients with significant comorbidities potential candidates for ablative therapy. We compared perioperative, renal functional, and oncological outcomes of renal cryoablation and robot-assisted partial nephrectomy (RAPN) based on our long-term institutional experience. Materials and Methods: A retrospective review evaluated 267 patients who underwent laparoscopic or percutaneous cryoablation (7/2000-6/2011) and 233 patients who underwent RAPN (6/2007-9/2012) for enhancing renal masses at Washington University. Results: The perioperative complication rate was 8.6% in the cryoablation group vs. 9.4% in the RAPN group (p=0.75). There was no significant difference in complication risk between the two treatment modalities on multivariate analysis. Glomerular filtration rate (eGFR) at last follow-up was 6.0% lower than preoperative eGFR in the cryoablation group and 13.0% lower in the RAPN group (p<0.01). The advantage of cryoablation in preserving renal function persisted on multivariate analysis (p=0.02). In patients with pathologically proven renal cell carcinoma, 5-year Kaplan-Meier disease-free survival (DFS), cancer-specific survival (CSS), and overall survival was 83.1%, 96.4%, and 77.1% in the cryoablation cohort vs. 100%, 100%, and 91.7% in the RAPN group. Mean time to recurrence was 16.2 months (range=0.03-42.0). Cryoablation was associated with increased recurrence risk (HR=11.4, p=0.01) on multivariate analysis. Conclusions: Cryoablation and RAPN are safe alternatives for managing renal masses amenable to nephron-sparing interventions, offering acceptable morbidity and excellent renal preservation. While RAPN offers improved DFS, for those willing to undergo close postoperative monitoring and accept the potential need for retreatment of recurrent disease, cryoablation offers excellent long-term CSS.
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State of the Field Survey: Spinal Cord Stimulator Use by Academic Pain Medicine Practices.
Pain Med
PUBLISHED: 10-18-2013
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The concept of neuromodulation via the use of spinal cord stimulators (SCS) was first established over forty years ago. Since then, its popularity has grown as numerous studies have demonstrated its utility to reduce chronic pain, improve patient function, and reduce long-term health care costs. The aim of this study was to update the pain medicine community on the evolution of SCS practice trends in academic centers.
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Discovery and refinement of loci associated with lipid levels.
, Cristen J Willer, Ellen M Schmidt, Sebanti Sengupta, Gina M Peloso, Stefan Gustafsson, Stavroula Kanoni, Andrea Ganna, Jin Chen, Martin L Buchkovich, Samia Mora, Jacques S Beckmann, Jennifer L Bragg-Gresham, Hsing-Yi Chang, Ayse Demirkan, Heleen M den Hertog, Ron Do, Louise A Donnelly, Georg B Ehret, Tonu Esko, Mary F Feitosa, Teresa Ferreira, Krista Fischer, Pierre Fontanillas, Ross M Fraser, Daniel F Freitag, Deepti Gurdasani, Kauko Heikkilä, Elina Hyppönen, Aaron Isaacs, Anne U Jackson, Asa Johansson, Toby Johnson, Marika Kaakinen, Johannes Kettunen, Marcus E Kleber, Xiaohui Li, Jian'an Luan, Leo-Pekka Lyytikäinen, Patrik K E Magnusson, Massimo Mangino, Evelin Mihailov, May E Montasser, Martina Müller-Nurasyid, Ilja M Nolte, Jeffrey R O'Connell, Cameron D Palmer, Markus Perola, Ann-Kristin Petersen, Serena Sanna, Richa Saxena, Susan K Service, Sonia Shah, Dmitry Shungin, Carlo Sidore, Ci Song, Rona J Strawbridge, Ida Surakka, Toshiko Tanaka, Tanya M Teslovich, Gudmar Thorleifsson, Evita G van den Herik, Benjamin F Voight, Kelly A Volcik, Lindsay L Waite, Andrew Wong, Ying Wu, Weihua Zhang, Devin Absher, Gershim Asiki, Inês Barroso, Latonya F Been, Jennifer L Bolton, Lori L Bonnycastle, Paolo Brambilla, Mary S Burnett, Giancarlo Cesana, Maria Dimitriou, Alex S F Doney, Angela Döring, Paul Elliott, Stephen E Epstein, Gudmundur Ingi Eyjolfsson, Bruna Gigante, Mark O Goodarzi, Harald Grallert, Martha L Gravito, Christopher J Groves, Göran Hallmans, Anna-Liisa Hartikainen, Caroline Hayward, Dena Hernandez, Andrew A Hicks, Hilma Holm, Yi-Jen Hung, Thomas Illig, Michelle R Jones, Pontiano Kaleebu, John J P Kastelein, Kay-Tee Khaw, Eric Kim, Norman Klopp, Pirjo Komulainen, Meena Kumari, Claudia Langenberg, Terho Lehtimäki, Shih-Yi Lin, Jaana Lindström, Ruth J F Loos, François Mach, Wendy L McArdle, Christa Meisinger, Braxton D Mitchell, Gabrielle Müller, Ramaiah Nagaraja, Narisu Narisu, Tuomo V M Nieminen, Rebecca N Nsubuga, Isleifur Olafsson, Ken K Ong, Aarno Palotie, Theodore Papamarkou, Cristina Pomilla, Anneli Pouta, Daniel J Rader, Muredach P Reilly, Paul M Ridker, Fernando Rivadeneira, Igor Rudan, Aimo Ruokonen, Nilesh Samani, Hubert Scharnagl, Janet Seeley, Kaisa Silander, Alena Stančáková, Kathleen Stirrups, Amy J Swift, Laurence Tiret, André G Uitterlinden, L Joost van Pelt, Sailaja Vedantam, Nicholas Wainwright, Cisca Wijmenga, Sarah H Wild, Gonneke Willemsen, Tom Wilsgaard, James F Wilson, Elizabeth H Young, Jing Hua Zhao, Linda S Adair, Dominique Arveiler, Themistocles L Assimes, Stefania Bandinelli, Franklyn Bennett, Murielle Bochud, Bernhard O Boehm, Dorret I Boomsma, Ingrid B Borecki, Stefan R Bornstein, Pascal Bovet, Michel Burnier, Harry Campbell, Aravinda Chakravarti, John C Chambers, Yii-Der Ida Chen, Francis S Collins, Richard S Cooper, John Danesh, George Dedoussis, Ulf de Faire, Alan B Feranil, Jean Ferrières, Luigi Ferrucci, Nelson B Freimer, Christian Gieger, Leif C Groop, Vilmundur Gudnason, Ulf Gyllensten, Anders Hamsten, Tamara B Harris, Aroon Hingorani, Joel N Hirschhorn, Albert Hofman, G Kees Hovingh, Chao Agnes Hsiung, Steve E Humphries, Steven C Hunt, Kristian Hveem, Carlos Iribarren, Marjo-Riitta Järvelin, Antti Jula, Mika Kähönen, Jaakko Kaprio, Antero Kesäniemi, Mika Kivimäki, Jaspal S Kooner, Peter J Koudstaal, Ronald M Krauss, Diana Kuh, Johanna Kuusisto, Kirsten O Kyvik, Markku Laakso, Timo A Lakka, Lars Lind, Cecilia M Lindgren, Nicholas G Martin, Winfried März, Mark I McCarthy, Colin A McKenzie, Pierre Meneton, Andres Metspalu, Leena Moilanen, Andrew D Morris, Patricia B Munroe, Inger Njølstad, Nancy L Pedersen, Chris Power, Peter P Pramstaller, Jackie F Price, Bruce M Psaty, Thomas Quertermous, Rainer Rauramaa, Danish Saleheen, Veikko Salomaa, Dharambir K Sanghera, Jouko Saramies, Peter E H Schwarz, Wayne H-H Sheu, Alan R Shuldiner, Agneta Siegbahn, Tim D Spector, Kari Stefansson, David P Strachan, Bamidele O Tayo, Elena Tremoli, Jaakko Tuomilehto, Matti Uusitupa, Cornelia M van Duijn, Peter Vollenweider, Lars Wallentin, Nicholas J Wareham, John B Whitfield, Bruce H R Wolffenbuttel, José M Ordovás, Eric Boerwinkle, Colin N A Palmer, Unnur Thorsteinsdottir, Daniel I Chasman, Jerome I Rotter, Paul W Franks, Samuli Ripatti, L Adrienne Cupples, Manjinder S Sandhu, Stephen S Rich, Michael Boehnke, Panos Deloukas, Sekar Kathiresan, Karen L Mohlke, Erik Ingelsson, Gonçalo R Abecasis.
Nat. Genet.
PUBLISHED: 09-13-2013
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Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.
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Advances in personalized therapy for lung cancer.
Expert Opin Med Diagn
PUBLISHED: 08-12-2013
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Personalized medicine based on tumor characteristics is transforming the management of lung cancer. This review provides an overview of clinically approved strategies to personalize treatment for lung cancer as well as evolving strategies in various stages of clinical development.
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Compact solar autoclave based on steam generation using broadband light-harvesting nanoparticles.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 07-08-2013
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The lack of readily available sterilization processes for medicine and dentistry practices in the developing world is a major risk factor for the propagation of disease. Modern medical facilities in the developed world often use autoclave systems to sterilize medical instruments and equipment and process waste that could contain harmful contagions. Here, we show the use of broadband light-absorbing nanoparticles as solar photothermal heaters, which generate high-temperature steam for a standalone, efficient solar autoclave useful for sanitation of instruments or materials in resource-limited, remote locations. Sterilization was verified using a standard Geobacillus stearothermophilus-based biological indicator.
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Perceived neighborhood social cohesion and stroke.
Soc Sci Med
PUBLISHED: 07-07-2013
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Research in the last three decades has shown that negative neighborhood factors such as neighborhood violence, noise, traffic, litter, low neighborhood socioeconomic status, and poor air quality increase the risk of poor health. Fewer studies have examined the potential protective effect that neighborhood factors can have on health, particularly stroke. We examined whether higher perceived neighborhood social cohesion was associated with lower stroke incidence after adjusting for traditional risk and psychological factors that have been linked with stroke risk. Prospective data from the Health and Retirement Study--a nationally representative panel study of American adults over the age of 50--were used. Analyses were conducted on a subset of 6740 adults who were stroke-free at baseline. Analyses adjusted for chronic illnesses and relevant sociodemographic, behavioral, and psychosocial factors. Over a four-year follow-up, higher perceived neighborhood social cohesion was associated with a lower risk of stroke. Each standard deviation increase in perceived neighborhood social cohesion was associated with a multivariate-adjusted odds ratio (O.R.) of 0.85 for stroke incidence (95% CI, 0.75-0.97, p < 0.05). The effect of perceived neighborhood social cohesion remained significant after adjusting for a comprehensive set of risk factors. Therefore, perceived neighborhood social cohesion plays an important role in protecting against stroke.
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Spontaneous regression of herniated lumbar discs.
J Clin Neurosci
PUBLISHED: 06-28-2013
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The spontaneous regression of a lumbar herniated disc is a common occurrence. Studies using imaging techniques as well as immunohistologic analyses have attempted to explain the mechanism for regression. However, the exact mechanism remains elusive. Understanding the process by which herniated discs disappear in the absence of surgery may better guide treatment. Recent case reports, radiographic and immunohistologic studies show that the extent of extrusion of the nucleus pulposus is related to a higher likelihood of regression. To our knowledge, Patient 3 is the first report of spontaneous regression occurring within 2months. This occurrence was discovered intraoperatively. We present three illustrative patients. Patient 1, a 53-year-old man, presented with a large L2-L3 disc herniation. His 2year follow-up MRI revealed a complete regression of the extruded fragment. Patient 2, a 58-year-old man, presented with an L3-L4 disc herniation with cephalad migration of a free fragment. MRI 9months later showed no free fragment but progression of a disc bulge. Intraoperative exploration during the L3-L4 microdiscectomy confirmed the absence of the free fragment. Patient 3, a 58-year-old woman, presented with a large L2-L3 disc extrusion with cephalad migration. An imaging study performed 2months after the initial study revealed an absence of the free fragment. Our case reports demonstrate the temporal variance in disc regression. While the time course and extent of regression vary widely, the rapid time in which regression can occur should caution surgeons contemplating discectomy based on an MRI performed a significant period prior to surgery.
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Transitions to catalytically inactive conformations in EGFR kinase.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 04-01-2013
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The epidermal growth factor receptor (EGFR) is a key protein in cellular signaling, and its kinase domain (EGFR kinase) is an intensely pursued target of small-molecule drugs. Although both catalytically active and inactive conformations of EGFR kinase have been resolved crystallographically, experimental characterization of the transitions between these conformations remains difficult. Using unbiased, all-atom molecular dynamics simulations, we observed EGFR kinase spontaneously transition from the active to the so-called "Src-like inactive" conformation by way of two sets of intermediate conformations: One corresponds to a previously identified locally disordered state and the other to previously undescribed "extended" conformations, marked by the opening of the ATP-binding site between the two lobes of the kinase domain. We also simulated the protonation-dependent transition of EGFR kinase to another ["Asp-Phe-Gly-out" ("DFG-out")] inactive conformation and observed similar intermediate conformations. A key element observed in the simulated transitions is local unfolding, or "cracking," which supports a prediction of energy landscape theory. We used hydrogen-deuterium (H/D) exchange measurements to corroborate our simulations and found that the simulated intermediate conformations correlate better with the H/D exchange data than existing active or inactive EGFR kinase crystal structures. The intermediate conformations revealed by our simulations of the transition process differ significantly from the existing crystal structures and may provide unique possibilities for structure-based drug discovery.
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Camera-port site metastasis of a renal-cell carcinoma after robot-assisted partial nephrectomy.
J. Endourol.
PUBLISHED: 03-18-2013
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Port-site metastasis (PSM) is a rare complication of laparoscopic intervention in urologic malignancies. Of the greater than 50 reported cases of PSM in the urologic oncology literature, only 9 have occurred after surgery for renal-cell carcinoma (RCC). We report a 10th instance of RCC metastasis-in this case to the camera-port site after robot-assisted partial nephrectomy (RAPN). To our knowledge, this case is the first reported PSM of RCC after RAPN.
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Common variants associated with plasma triglycerides and risk for coronary artery disease.
Ron Do, Cristen J Willer, Ellen M Schmidt, Sebanti Sengupta, Chi Gao, Gina M Peloso, Stefan Gustafsson, Stavroula Kanoni, Andrea Ganna, Jin Chen, Martin L Buchkovich, Samia Mora, Jacques S Beckmann, Jennifer L Bragg-Gresham, Hsing-Yi Chang, Ayse Demirkan, Heleen M den Hertog, Louise A Donnelly, Georg B Ehret, Tonu Esko, Mary F Feitosa, Teresa Ferreira, Krista Fischer, Pierre Fontanillas, Ross M Fraser, Daniel F Freitag, Deepti Gurdasani, Kauko Heikkilä, Elina Hyppönen, Aaron Isaacs, Anne U Jackson, Asa Johansson, Toby Johnson, Marika Kaakinen, Johannes Kettunen, Marcus E Kleber, Xiaohui Li, Jian'an Luan, Leo-Pekka Lyytikäinen, Patrik K E Magnusson, Massimo Mangino, Evelin Mihailov, May E Montasser, Martina Müller-Nurasyid, Ilja M Nolte, Jeffrey R O'Connell, Cameron D Palmer, Markus Perola, Ann-Kristin Petersen, Serena Sanna, Richa Saxena, Susan K Service, Sonia Shah, Dmitry Shungin, Carlo Sidore, Ci Song, Rona J Strawbridge, Ida Surakka, Toshiko Tanaka, Tanya M Teslovich, Gudmar Thorleifsson, Evita G van den Herik, Benjamin F Voight, Kelly A Volcik, Lindsay L Waite, Andrew Wong, Ying Wu, Weihua Zhang, Devin Absher, Gershim Asiki, Inês Barroso, Latonya F Been, Jennifer L Bolton, Lori L Bonnycastle, Paolo Brambilla, Mary S Burnett, Giancarlo Cesana, Maria Dimitriou, Alex S F Doney, Angela Döring, Paul Elliott, Stephen E Epstein, Gudmundur Ingi Eyjolfsson, Bruna Gigante, Mark O Goodarzi, Harald Grallert, Martha L Gravito, Christopher J Groves, Göran Hallmans, Anna-Liisa Hartikainen, Caroline Hayward, Dena Hernandez, Andrew A Hicks, Hilma Holm, Yi-Jen Hung, Thomas Illig, Michelle R Jones, Pontiano Kaleebu, John J P Kastelein, Kay-Tee Khaw, Eric Kim, Norman Klopp, Pirjo Komulainen, Meena Kumari, Claudia Langenberg, Terho Lehtimäki, Shih-Yi Lin, Jaana Lindström, Ruth J F Loos, François Mach, Wendy L McArdle, Christa Meisinger, Braxton D Mitchell, Gabrielle Müller, Ramaiah Nagaraja, Narisu Narisu, Tuomo V M Nieminen, Rebecca N Nsubuga, Isleifur Olafsson, Ken K Ong, Aarno Palotie, Theodore Papamarkou, Cristina Pomilla, Anneli Pouta, Daniel J Rader, Muredach P Reilly, Paul M Ridker, Fernando Rivadeneira, Igor Rudan, Aimo Ruokonen, Nilesh Samani, Hubert Scharnagl, Janet Seeley, Kaisa Silander, Alena Stančáková, Kathleen Stirrups, Amy J Swift, Laurence Tiret, André G Uitterlinden, L Joost van Pelt, Sailaja Vedantam, Nicholas Wainwright, Cisca Wijmenga, Sarah H Wild, Gonneke Willemsen, Tom Wilsgaard, James F Wilson, Elizabeth H Young, Jing Hua Zhao, Linda S Adair, Dominique Arveiler, Themistocles L Assimes, Stefania Bandinelli, Franklyn Bennett, Murielle Bochud, Bernhard O Boehm, Dorret I Boomsma, Ingrid B Borecki, Stefan R Bornstein, Pascal Bovet, Michel Burnier, Harry Campbell, Aravinda Chakravarti, John C Chambers, Yii-Der Ida Chen, Francis S Collins, Richard S Cooper, John Danesh, George Dedoussis, Ulf de Faire, Alan B Feranil, Jean Ferrières, Luigi Ferrucci, Nelson B Freimer, Christian Gieger, Leif C Groop, Vilmundur Gudnason, Ulf Gyllensten, Anders Hamsten, Tamara B Harris, Aroon Hingorani, Joel N Hirschhorn, Albert Hofman, G Kees Hovingh, Chao Agnes Hsiung, Steve E Humphries, Steven C Hunt, Kristian Hveem, Carlos Iribarren, Marjo-Riitta Järvelin, Antti Jula, Mika Kähönen, Jaakko Kaprio, Antero Kesäniemi, Mika Kivimäki, Jaspal S Kooner, Peter J Koudstaal, Ronald M Krauss, Diana Kuh, Johanna Kuusisto, Kirsten O Kyvik, Markku Laakso, Timo A Lakka, Lars Lind, Cecilia M Lindgren, Nicholas G Martin, Winfried März, Mark I McCarthy, Colin A McKenzie, Pierre Meneton, Andres Metspalu, Leena Moilanen, Andrew D Morris, Patricia B Munroe, Inger Njølstad, Nancy L Pedersen, Chris Power, Peter P Pramstaller, Jackie F Price, Bruce M Psaty, Thomas Quertermous, Rainer Rauramaa, Danish Saleheen, Veikko Salomaa, Dharambir K Sanghera, Jouko Saramies, Peter E H Schwarz, Wayne H-H Sheu, Alan R Shuldiner, Agneta Siegbahn, Tim D Spector, Kari Stefansson, David P Strachan, Bamidele O Tayo, Elena Tremoli, Jaakko Tuomilehto, Matti Uusitupa, Cornelia M van Duijn, Peter Vollenweider, Lars Wallentin, Nicholas J Wareham, John B Whitfield, Bruce H R Wolffenbuttel, David Altshuler, José M Ordovás, Eric Boerwinkle, Colin N A Palmer, Unnur Thorsteinsdottir, Daniel I Chasman, Jerome I Rotter, Paul W Franks, Samuli Ripatti, L Adrienne Cupples, Manjinder S Sandhu, Stephen S Rich, Michael Boehnke, Panos Deloukas, Karen L Mohlke, Erik Ingelsson, Gonçalo R Abecasis, Mark J Daly, Benjamin M Neale, Sekar Kathiresan.
Nat. Genet.
PUBLISHED: 02-20-2013
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Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphisms effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
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Dissociated expression of mitochondrial and cytosolic creatine kinases in the human brain: a new perspective on the role of creatine in brain energy metabolism.
J. Cereb. Blood Flow Metab.
PUBLISHED: 02-14-2013
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The phosphocreatine/creatine kinase (PCr/CK) system in the brain is defined by the expression of two CK isozymes: the cytosolic brain-type CK (BCK) and the ubiquitous mitochondrial CK (uMtCK). The system plays an important role in supporting cellular energy metabolism by buffering adenosine triphosphate (ATP) consumption and improving the flux of high-energy phosphoryls around the cell. This system is well defined in muscle tissue, but there have been few detailed studies of this system in the brain, especially in humans. Creatine is known to be important for neurologic function, and its loss from the brain during development can lead to mental retardation. This study provides the first detailed immunohistochemical study of the expression pattern of BCK and uMtCK in the human brain. A strikingly dissociated pattern of expression was found: uMtCK was found to be ubiquitously and exclusively expressed in neuronal populations, whereas BCK was dominantly expressed in astrocytes, with a low and selective expression in neurons. This pattern indicates that the two CK isozymes are not widely coexpressed in the human brain, but rather are selectively expressed depending on the cell type. These results suggest that the brain cells may use only certain properties of the PCr/CK system depending on their energetic requirements.
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Purpose in life and reduced incidence of stroke in older adults: The Health and Retirement Study.
J Psychosom Res
PUBLISHED: 01-19-2013
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To determine whether purpose in life is associated with reduced stroke incidence among older adults after adjusting for relevant sociodemographic, behavioral, biological, and psychosocial factors.
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Trans-ethnic fine-mapping of lipid loci identifies population-specific signals and allelic heterogeneity that increases the trait variance explained.
PLoS Genet.
PUBLISHED: 01-19-2013
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Genome-wide association studies (GWAS) have identified ~100 loci associated with blood lipid levels, but much of the trait heritability remains unexplained, and at most loci the identities of the trait-influencing variants remain unknown. We conducted a trans-ethnic fine-mapping study at 18, 22, and 18 GWAS loci on the Metabochip for their association with triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), respectively, in individuals of African American (n = 6,832), East Asian (n = 9,449), and European (n = 10,829) ancestry. We aimed to identify the variants with strongest association at each locus, identify additional and population-specific signals, refine association signals, and assess the relative significance of previously described functional variants. Among the 58 loci, 33 exhibited evidence of association at P<1 × 10(-4) in at least one ancestry group. Sequential conditional analyses revealed that ten, nine, and four loci in African Americans, Europeans, and East Asians, respectively, exhibited two or more signals. At these loci, accounting for all signals led to a 1.3- to 1.8-fold increase in the explained phenotypic variance compared to the strongest signals. Distinct signals across ancestry groups were identified at PCSK9 and APOA5. Trans-ethnic analyses narrowed the signals to smaller sets of variants at GCKR, PPP1R3B, ABO, LCAT, and ABCA1. Of 27 variants reported previously to have functional effects, 74% exhibited the strongest association at the respective signal. In conclusion, trans-ethnic high-density genotyping and analysis confirm the presence of allelic heterogeneity, allow the identification of population-specific variants, and limit the number of candidate SNPs for functional studies.
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Comparison of multi-space infections of the head and neck in the elderly and non-elderly: part I the descriptive data.
J Craniomaxillofac Surg
PUBLISHED: 01-09-2013
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This study aims to analyze the difference between the aged patients and non-elderly with multi-space infections of the head and neck.
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A retrospective case series illustrating a possible association between a widened hilum and sialolith formation in the submandibular gland.
J Craniomaxillofac Surg
PUBLISHED: 01-03-2013
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The purpose of this study was to explore any association between anatomical variances in the ductal system and sialolith formation using sialoendoscopy and acrylic resin replication of the ductal system.
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Long-term imaging of Caenorhabditis elegans using nanoparticle-mediated immobilization.
PLoS ONE
PUBLISHED: 01-03-2013
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One advantage of the nematode Caenorhabditis elegans as a model organism is its suitability for in vivo optical microscopy. Imaging C. elegans often requires animals to be immobilized to avoid movement-related artifacts. Immobilization has been performed by application of anesthetics or by introducing physical constraints using glue or specialized microfluidic devices. Here we present a method for immobilizing C. elegans using polystyrene nanoparticles and agarose pads. Our technique is technically simple, does not expose the worm to toxic substances, and allows recovery of animals. We evaluate the method and show that the polystyrene beads increase friction between the worm and agarose pad. We use our method to quantify calcium transients and long-term regrowth in single neurons following axotomy by a femtosecond laser.
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Her2 activation mechanism reflects evolutionary preservation of asymmetric ectodomain dimers in the human EGFR family.
Elife
PUBLISHED: 01-01-2013
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The receptor tyrosine kinase Her2, an intensely pursued drug target, differs from other members of the EGFR family in that it does not bind EGF-like ligands, relying instead on heterodimerization with other (ligand-bound) EGFR-family receptors for activation. The structural basis for Her2 heterodimerization, however, remains poorly understood. The unexpected recent finding of asymmetric ectodomain dimer structures of Drosophila EGFR (dEGFR) suggests a possible structural basis for Her2 heterodimerization, but all available structures for dimers of human EGFR family ectodomains are symmetric. Here, we report results from long-timescale molecular dynamics simulations indicating that a single ligand is necessary and sufficient to stabilize the ectodomain interface of Her2 heterodimers, which assume an asymmetric conformation similar to that of dEGFR dimers. This structural parallelism suggests a dimerization mechanism that has been conserved in the evolution of the EGFR family from Drosophila to human. DOI:http://dx.doi.org/10.7554/eLife.00708.001.
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Partial nephrectomy in two patients with known T3a tumours involving the renal vein.
BJU Int.
PUBLISHED: 08-24-2011
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Study Type--Therapy (case series). Level of Evidence 4. Whats known on the subject? And what does the study add? Although nephron-sparing surgery (NSS) has became accepted therapy for T1 tumours, radical nephrectony is considered the best therapy for T3a tumours involving the renal vein. NSS can be considered in T3a or greater tumours if imperative indications exist, such as bilateral disease or solitary kidney. However, there is little published data on the characteristics of these patients, the impact of surgery on their renal function, and long-term oncologic outcomes. This study profiles single-institution experience with nephron-sparing surgery for known T3a tumours involving the renal vein, including patient characteristics, tumour characteristics, preoperative and follow-up imaging, preoperative and follow-up estimated glomerular filtration rate, length of temporary postoperative haemodialysis, and oncologic outcome. Additionally, we compare this to other published data on nephron-sparing surgery for similar tumors.
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Dispositional optimism protects older adults from stroke: the Health and Retirement Study.
Stroke
PUBLISHED: 07-21-2011
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Although higher optimism has been linked to an array of positive health outcomes, the association between optimism and incidence of stroke remains unclear, especially among older adults. We examined whether higher optimism was associated with a lower incidence of stroke.
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How does a drug molecule find its target binding site?
J. Am. Chem. Soc.
PUBLISHED: 05-13-2011
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Although the thermodynamic principles that control the binding of drug molecules to their protein targets are well understood, detailed experimental characterization of the process by which such binding occurs has proven challenging. We conducted relatively long, unguided molecular dynamics simulations in which a ligand (the cancer drug dasatinib or the kinase inhibitor PP1) was initially placed at a random location within a box that also contained a protein (Src kinase) to which that ligand was known to bind. In several of these simulations, the ligand correctly identified its target binding site, forming a complex virtually identical to the crystallographically determined bound structure. The simulated trajectories provide a continuous, atomic-level view of the entire binding process, revealing persistent and noteworthy intermediate conformations and shedding light on the role of water molecules. The technique we employed, which does not assume any prior knowledge of the binding sites location, may prove particularly useful in the development of allosteric inhibitors that target previously undiscovered binding sites.
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A comparison of the modified Blalock-Taussig shunt with the right ventricle-to-pulmonary artery conduit.
Ann. Thorac. Surg.
PUBLISHED: 04-29-2011
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This study compared the modified Blalock-Taussig (MBT) shunt with the right ventricle-to-pulmonary artery (RVPA) conduit with respect to outcome and PA growth.
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Is there association between severe multispace infections of the oral maxillofacial region and diabetes mellitus?
J. Oral Maxillofac. Surg.
PUBLISHED: 01-06-2011
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This study aims to identify the impact of diabetes on the final outcome (length of hospital stay and development of complications) in patients with severe multispace infections in the head and neck. Furthermore, it intends to characterize significant clinical features of these patients compared with nondiabetics.
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Assessment of growth factor treatment on fibrochondrocyte and chondrocyte co-cultures for TMJ fibrocartilage engineering.
Acta Biomater
PUBLISHED: 08-31-2010
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Treatments for patients suffering from severe temporomandibular joint (TMJ) dysfunction are limited, motivating the development of strategies for tissue regeneration. In this study, co-cultures of fibrochondrocytes (FCs) and articular chondrocytes (ACs) were seeded in agarose wells, and supplemented with growth factors, to engineer tissue with biomechanical properties and extracellular matrix composition similar to native TMJ fibrocartilage. In the first phase, growth factors were applied alone and in combination, in the presence or absence of serum, while in the second phase, the best overall treatment was applied at intermittent dosing. Continuous treatment of AC/FC co-cultures with TGF-?1 in serum-free medium resulted in constructs with glycosaminoglycan/wet weight ratios (12.2%), instantaneous compressive moduli (790 kPa), relaxed compressive moduli (120 kPa) and Youngs moduli (1.87 MPa) that overlap with native TMJ disc values. Among co-culture groups, TGF-?1 treatment increased collagen deposition ?20%, compressive stiffness ?130% and Youngs modulus ?170% relative to controls without growth factor. Serum supplementation, though generally detrimental to functional properties, was identified as a powerful mediator of FC construct morphology. Finally, both intermittent and continuous TGF-?1 treatment showed positive effects, though continuous treatment resulted in greater enhancement of construct functional properties. This work proposes a strategy for regeneration of TMJ fibrocartilage and its future application will be realized through translation of these findings to clinically viable cell sources.
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Antigenic variation in Treponema pallidum: TprK sequence diversity accumulates in response to immune pressure during experimental syphilis.
J. Immunol.
PUBLISHED: 02-26-2010
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Pathogens that cause chronic infections often employ antigenic variation to evade the immune response and persist in the host. In Treponema pallidum (T. pallidum), the causative agent of syphilis, the TprK Ag undergoes variation of seven V regions (V1-V7) by nonreciprocal recombination of silent donor cassettes with the tprK expression site. These V regions are the targets of the host humoral immune response during experimental infection. The present study addresses the causal role of the acquired immune response in the selection of TprK variants in two ways: 1) by investigating TprK variants arising in immunocompetent versus immunosuppressed hosts; and 2) by investigating the effect of prior specific immunization on selection of TprK variants during infection. V region diversity, particularly in V6, accumulates more rapidly in immunocompetent rabbits than in pharmacologically immunosuppressed rabbits (treated with weekly injections of methylprednisolone acetate). In a complementary experiment, rabbits preimmunized with V6 region synthetic peptides had more rapid accumulation of V6 variant treponemes than control rabbits. These studies demonstrate that the host immune response selects against specific TprK epitopes expressed on T. pallidum, resulting in immune selection of new TprK variants during infection, confirming a role for antigenic variation in syphilis.
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A meta-analytic review of the Penn Resiliency Programs effect on depressive symptoms.
J Consult Clin Psychol
PUBLISHED: 12-09-2009
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The purpose of this review was to evaluate whether the Penn Resiliency Program (PRP), a group cognitive-behavioral intervention, is effective in targeting depressive symptoms in youths. We identified 17 controlled evaluations of PRP (N = 2,498) in which depressive symptoms had been measured via an online search of PsycINFO, Medline, ERIC, and ProQuest Dissertations and Theses and by requesting data from PRP researchers. We combined effect sizes (ESs; Glasss d), using random effects models at postintervention and two follow-up assessments (6-8 and 12 months postintervention). PRP participants reported fewer depressive symptoms at postintervention and both follow-up assessments compared with youths receiving no intervention, with ESs ranging from 0.11 to 0.21. Subgroup analyses showed that PRPs effects were significant at 1 or more follow-up assessments among studies with both targeted and universal approaches, when group leaders were research team members and community providers, among participants with both low and elevated baseline symptoms, and among boys and girls. Limited data showed no evidence that PRP is superior to active control conditions. Preliminary analyses suggested that PRPs effects on depressive disorders may be smaller than those reported in a larger meta-analysis of depression prevention programs for older adolescents and adults. We found evidence that PRP significantly reduces depressive symptoms through at least 1-year postintervention. Future PRP research should examine whether PRPs effects on depressive symptoms lead to clinically meaningful benefits for its participants, whether the program is cost-effective, whether CB skills mediate program effects, and whether PRP is effective when delivered under real-world conditions.
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RosettaAntibody: antibody variable region homology modeling server.
Nucleic Acids Res.
PUBLISHED: 05-20-2009
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The RosettaAntibody server (http://antibody.graylab.jhu.edu) predicts the structure of an antibody variable region given the amino-acid sequences of the respective light and heavy chains. In an initial stage, the server identifies and displays the most sequence homologous template structures for the light and heavy framework regions and each of the complementarity determining region (CDR) loops. Subsequently, the most homologous templates are assembled into a side-chain optimized crude model, and the server returns a picture and coordinate file. For users requesting a high-resolution model, the server executes the full RosettaAntibody protocol which additionally models the hyper-variable CDR H3 loop. The high-resolution protocol also relieves steric clashes by optimizing the CDR backbone torsion angles and by simultaneously perturbing the relative orientation of the light and heavy chains. RosettaAntibody generates 2000 independent structures, and the server returns pictures, coordinate files, and detailed scoring information for the 10 top-scoring models. The 10 models enable users to use rational judgment in choosing the best model or to use the set as an ensemble for further studies such as docking. The high-resolution models generated by RosettaAntibody have been used for the successful prediction of antibody-antigen complex structures.
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MET pathway as a therapeutic target.
J Thorac Oncol
PUBLISHED: 04-01-2009
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Dysregulation of mesenchymal-epithelial transition factor receptor tyrosine kinase pathway leads to cell proliferation, protection from apoptosis, angiogenesis, invasion, and metastasis. It can be dysregulated through overexpression, constitutive activation, gene amplification, ligand-dependent activation or mutation. New drugs targeting various mesenchymal-epithelial transition factor pathways are being investigated with promising results.
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Percutaneous cryoablation of renal masses: Washington University experience of treating 129 tumours.
BJU Int.
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WHATS KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: For patients who are unfit for extirpative surgery, percutaneous cryoablation (PCA) presents a minimally-invasive alternative for the treatment of renal masses. PCA has been demonstrated to be safe, with complication rates <10% being reported consistently. Studies have suggested that a minimal and insignificant decline in renal function can occur after PCA. Finally, among studies with a follow-up >20 months, treatment success rates range from 75% to 96%. However, longer-term oncological and functional results for patients treated with PCA are relatively limited. The present study profiles one of the largest reported experiences with PCA for renal masses: 129 tumours in 124 patients. Our complication rate was comparable to that observed in other reported studies. At a mean follow-up of 30 months, treatment success was achieved in 87% of tumours, which is in line with published PCA success rates. On multivariable analysis, tumour size >3.0 cm was found to be significantly associated with treatment failure. A minimal but statistically significant renal functional decline was observed, with 20% of patients experiencing a progression in National Kidney Foundation-Chronic Kidney Disease stage. On multivariable analysis, age >70 years, hilar tumour location and postoperative day 1 estimated glomerular filtration rate <60 mL/min/1.73 m(2) were found to be significantly associated with renal functional decline. The present study confirms that PCA of renal masses represents a safe alternative to surgery in patients with substantial medical comorbidities. In the present cohort, baseline patient and tumour characteristics probably impact the risk of tumour recurrence, as well as renal disease progression, after PCA.
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Variants identified in a GWAS meta-analysis for blood lipids are associated with the lipid response to fenofibrate.
PLoS ONE
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A recent large-scale meta-analysis of genome-wide studies has identified 95 loci, 59 of them novel, as statistically significant predictors of blood lipid traits; we tested whether the same loci explain the observed heterogeneity in response to lipid-lowering therapy with fenofibrate. Using data from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN, n?=?861) we fit linear mixed models with the genetic markers as predictors and high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, total cholesterol, and triglyceride concentrations as outcomes. For all four traits, we analyzed both baseline levels and changes in response to treatment with fenofibrate. For the markers that were significantly associated with fenofibrate response, we fit additional models evaluating potential epistatic interactions. All models were adjusted for age, sex, and study center as fixed effects, and pedigree as a random effect. Statistically significant associations were observed between the rs964184 polymorphism near APOA1 (P-value?0.0001) and fenofibrate response for HDL and triglycerides. The association was replicated in the Pharmacogenetics of Hypertriglyceridemia in Hispanics study (HyperTG, n?=?267). Suggestive associations with fenofibrate response were observed for markers in or near PDE3A, MOSC1, FLJ36070, CETP, the APOE-APOC1-APOC4-APOC2, and CILP2. Finally, we present strong evidence for epistasis (P-value for interaction?=? 0.0006 in GOLDN, 0.05 in HyperTG) between rs10401969 near CILP2 and rs4420638 in the APOE-APOC1-APOC4-APOC2 cluster with total cholesterol response to fenofibrate. In conclusion, we present evidence linking several novel and biologically relevant genetic polymorphisms to lipid lowering drug response, as well as suggesting novel gene-gene interactions in fenofibrate pharmacogenetics.
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Robot-assisted partial nephrectomy: off-clamp technique.
J. Endourol.
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Robot-assisted partial nephrectomy (RAPN) has been established as a viable alternative to open and laparoscopic partial nephrectomy for small renal tumors. Multiple variations in surgical technique have been described to reduce warm ischemia time (WIT). We present our off-clamp technique for RAPN. From August 2007 to January 2012, off-clamp RAPN was performed on 47 tumors in 39 patients. WIT was 0 minutes in all cases. The mean operative time was 147 minutes (SD=58); the mean and median estimated blood loss were 219 mL (SD=253) and 150 mL (range 50-1500), respectively; the mean length of stay was 1.9 days (SD=1.1). There were no intraoperative complications, and results for all surgical margins were negative. In experienced hands, our off-clamp technique for RAPN is a safe and feasible technique that eliminates WIT.
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Endopyelotomy for pediatric ureteropelvic junction obstruction: a review of our 25-year experience.
J. Urol.
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We elucidate the role of endopyelotomy as a primary and secondary intervention for ureteropelvic junction obstruction in children.
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Tissue platinum concentration and tumor response in non-small-cell lung cancer.
J. Clin. Oncol.
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Platinum resistance is a major limitation in the treatment of advanced non-small-cell lung cancer (NSCLC). Reduced intracellular drug accumulation is one of the most consistently identified features of platinum-resistant cell lines, but clinical data are limited. We assessed the effects of tissue platinum concentrations on response and survival in NSCLC.
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Laparoscopic cryoablation of renal masses: single-center long-term experience.
Urology
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To evaluate perioperative and long-term functional and oncological outcomes of laparoscopic cryoablation (LCA) performed at Washington University.
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Identification of small molecules that antagonize diguanylate cyclase enzymes to inhibit biofilm formation.
Antimicrob. Agents Chemother.
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Bacterial biofilm formation is responsible for numerous chronic infections, causing a severe health burden. Many of these infections cannot be resolved, as bacteria in biofilms are resistant to the hosts immune defenses and antibiotic therapy. New strategies to treat biofilm-based infections are critically needed. Cyclic di-GMP (c-di-GMP) is a widely conserved second-messenger signal essential for biofilm formation. As this signaling system is found only in bacteria, it is an attractive target for the development of new antibiofilm interventions. Here, we describe the results of a high-throughput screen to identify small-molecule inhibitors of diguanylate cyclase (DGC) enzymes that synthesize c-di-GMP. We report seven small molecules that antagonize these enzymes and inhibit biofilm formation by Vibrio cholerae. Moreover, two of these compounds significantly reduce the total concentration of c-di-GMP in V. cholerae, one of which also inhibits biofilm formation by Pseudomonas aeruginosa in a continuous-flow system. These molecules represent the first compounds described that are able to inhibit DGC activity to prevent biofilm formation.
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Off-clamp robot-assisted partial nephrectomy for complex renal tumors.
J. Endourol.
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Considering the potential impact of warm ischemia time (WIT) on renal functional outcomes after robot-assisted partial nephrectomy (RAPN), many techniques that reduce or eliminate WIT have been studied. We present our institutional experience and progression using one such technique-off-clamp RAPN-as well as the results of this technique in the management of complex cases.
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Regulation of RAS oncogenicity by acetylation.
Proc. Natl. Acad. Sci. U.S.A.
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Members of the RAS small GTPase family regulate cellular responses to extracellular stimuli by mediating the flux through downstream signal transduction cascades. RAS activity is strongly dependent on its subcellular localization and its nucleotide-binding status, both of which are modulated by posttranslational modification. We have determined that RAS is posttranslationally acetylated on lysine 104. Molecular dynamics simulations suggested that this modification affects the conformational stability of the Switch II domain, which is critical for the ability of RAS to interact with guanine nucleotide exchange factors. Consistent with this model, an acetylation-mimetic mutation in K-RAS4B suppressed guanine nucleotide exchange factor-induced nucleotide exchange and inhibited in vitro transforming activity. These data suggest that lysine acetylation is a negative regulatory modification on RAS. Because mutations in RAS family members are extremely common in cancer, modulation of RAS acetylation may constitute a therapeutic approach.
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Oncogenic mutations counteract intrinsic disorder in the EGFR kinase and promote receptor dimerization.
Cell
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The mutation and overexpression of the epidermal growth factor receptor (EGFR) are associated with the development of a variety of cancers, making this prototypical dimerization-activated receptor tyrosine kinase a prominent target of cancer drugs. Using long-timescale molecular dynamics simulations, we find that the N lobe dimerization interface of the wild-type EGFR kinase domain is intrinsically disordered and that it becomes ordered only upon dimerization. Our simulations suggest, moreover, that some cancer-linked mutations distal to the dimerization interface, particularly the widespread L834R mutation (also referred to as L858R), facilitate EGFR dimerization by suppressing this local disorder. Corroborating these findings, our biophysical experiments and kinase enzymatic assays indicate that the L834R mutation causes abnormally high activity primarily by promoting EGFR dimerization rather than by allowing activation without dimerization. We also find that phosphorylation of EGFR kinase domain at Tyr845 may suppress the intrinsic disorder, suggesting a molecular mechanism for autonomous EGFR signaling.
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Off-clamp robot-assisted partial nephrectomy: initial Washington University experience.
J. Endourol.
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Because of the impact warm ischemia time may have on renal function, various surgical techniques have been proposed to minimize or eliminate warm ischemia. The purpose of this study is to evaluate our initial renal functional outcomes of off-clamp robot-assisted partial nephrectomy (RAPN), while assessing the safety profile of this unconventional surgical approach.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.