Publications by authors named "Sonia Sequeira"

18 Publications

  • Page 1 of 1

Use of Ultrasmall Core-Shell Fluorescent Silica Nanoparticles for Image-Guided Sentinel Lymph Node Biopsy in Head and Neck Melanoma: A Nonrandomized Clinical Trial.

JAMA Netw Open 2021 Mar 1;4(3):e211936. Epub 2021 Mar 1.

Head and Neck Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.

Importance: Sentinel lymph node (SLN) mapping agents approved for current surgical practice lack sufficient brightness and target specificity for high-contrast, sensitive nodal visualization.

Objective: To evaluate whether an ultrasmall, molecularly targeted core-shell silica nanoparticle (Cornell prime dots) can safely and reliably identify optically avid SLNs in head and neck melanoma during fluorescence-guided biopsy.

Design, Setting, And Participants: This nonrandomized clinical trial enrolled patients aged 18 years or older with histologically confirmed melanoma in whom SLN mapping was indicated. Exclusion criteria included known pregnancy, breast-feeding, or medical illness unrelated to the tumor. The trial was conducted between February 2015 and March 2018 at Memorial Sloan Kettering Cancer Center, with postoperative follow-up of 2 years. Data analysis was conducted from February 2015 to March 2018.

Interventions: Patients received standard-of-care technetium Tc 99m sulfur colloid followed by a microdose administration of integrin-targeting, dye-encapsulated nanoparticles, surface modified with polyethylene glycol chains and cyclic arginine-glycine-aspartic acid-tyrosine peptides (cRGDY-PEG-Cy5.5-nanoparticles) intradermally.

Main Outcomes And Measures: The primary end points were safety, procedural feasibility, lowest particle dose and volume for maximizing nodal fluorescence signal, and proportion of nodes identified by technetium Tc 99m sulfur colloid that were optically visualized by cRGDY-PEG-Cy5.5-nanoparticles. Secondary end points included proportion of patients in whom the surgical approach or extent of dissection was altered because of nodal visualization.

Results: Of 24 consecutive patients enrolled (median [interquartile range] age, 64 [51-71] years), 18 (75%) were men. In 24 surgical procedures, 40 SLNs were excised. Preoperative localization of SLNs with technetium Tc 99m sulfur colloid was followed by particle dose-escalation studies, yielding optimized doses and volumes of 2 nmol and 0.4 mL, respectively, and maximum SLN signal-to-background ratios of 40. No adverse events were observed. The concordance rate of evaluable SLNs by technetium Tc 99m sulfur colloid and cRGDY-PEG-Cy5.5-nanoparticles was 90% (95% CI, 74%-98%), 5 of which were metastatic. Ultrabright nanoparticle fluorescence enabled high-sensitivity SLN visualization (including difficult-to-access anatomic sites), deep tissue imaging, and, in some instances, detection through intact skin, thereby facilitating intraoperative identification without extensive dissection of adjacent normal tissue or nerves.

Conclusions And Relevance: This study found that nanoparticle-based fluorescence-guided SLN biopsy in head and neck melanoma was feasible and safe. This technology holds promise for improving lymphatic mapping and SLN biopsy procedures, while potentially mitigating procedural risks. This study serves as a first step toward developing new multimodal approaches for perioperative care.

Trial Registration: ClinicalTrials.gov Identifier: NCT02106598.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.1936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7974643PMC
March 2021

The epichaperome is a mediator of toxic hippocampal stress and leads to protein connectivity-based dysfunction.

Nat Commun 2020 01 16;11(1):319. Epub 2020 Jan 16.

Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.

Optimal functioning of neuronal networks is critical to the complex cognitive processes of memory and executive function that deteriorate in Alzheimer's disease (AD). Here we use cellular and animal models as well as human biospecimens to show that AD-related stressors mediate global disturbances in dynamic intra- and inter-neuronal networks through pathologic rewiring of the chaperome system into epichaperomes. These structures provide the backbone upon which proteome-wide connectivity, and in turn, protein networks become disturbed and ultimately dysfunctional. We introduce the term protein connectivity-based dysfunction (PCBD) to define this mechanism. Among most sensitive to PCBD are pathways with key roles in synaptic plasticity. We show at cellular and target organ levels that network connectivity and functional imbalances revert to normal levels upon epichaperome inhibition. In conclusion, we provide proof-of-principle to propose AD is a PCBDopathy, a disease of proteome-wide connectivity defects mediated by maladaptive epichaperomes.
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http://dx.doi.org/10.1038/s41467-019-14082-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965647PMC
January 2020

Molecular phenotyping and image-guided surgical treatment of melanoma using spectrally distinct ultrasmall core-shell silica nanoparticles.

Sci Adv 2019 12 4;5(12):eaax5208. Epub 2019 Dec 4.

Department of Radiology, Sloan Kettering Institute for Cancer Research, New York, NY 10065, USA.

Accurate detection and quantification of metastases in regional lymph nodes remain a vital prognostic predictor for cancer staging and clinical outcomes. As intratumoral heterogeneity poses a major hurdle to effective treatment planning, more reliable image-guided, cancer-targeted optical multiplexing tools are critically needed in the operative suite. For sentinel lymph node mapping indications, accurately interrogating distinct molecular signatures on cancer cells in vivo with differential levels of sensitivity and specificity remains largely unexplored. To address these challenges and demonstrate sensitivity to detecting micrometastases, we developed batches of spectrally distinct 6-nm near-infrared fluorescent core-shell silica nanoparticles, each batch surface-functionalized with different melanoma targeting ligands. Along with PET imaging, particles accurately detected and molecularly phenotyped cancerous nodes in a spontaneous melanoma miniswine model using image-guided multiplexing tools. Information afforded from these tools offers the potential to not only improve the accuracy of targeted disease removal and patient safety, but to transform surgical decision-making for oncological patients.
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http://dx.doi.org/10.1126/sciadv.aax5208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892625PMC
December 2019

Cancer-Targeting Ultrasmall Silica Nanoparticles for Clinical Translation: Physicochemical Structure and Biological Property Correlations.

Chem Mater 2017 Oct 15;29(20):8766-8779. Epub 2017 Sep 15.

Department of Radiology, Sloan Kettering Institute for Cancer Research, New York, New York 10065, United States.

Although a large body of literature exists on the potential use of nanoparticles for medical applications, the number of probes translated into human clinical trials is remarkably small. A major challenge of particle probe development and their translation is the elucidation of safety profiles associated with their structural complexity, not only in terms of size distribution and heterogeneities in particle composition but also their effects on biological activities and the relationship between particle structure and pharmacokinetics. Here, we report on the synthesis, characterization, and long-term stability of ultrasmall (<10 nm diameter) dual-modality (optical and positron emission tomography) and integrintargeting silica nanoparticles (cRGDY-PEG-Cy5-C' dots and I-(or I-) cRGDY-PEG-Cy5-C'dots) and the extent to which their surface ligand density differentially modulates key in vitro and in vivo biological activities in melanoma models over a range of ligand numbers (i.e., ~6-18). Gel permeation chromatography, established as an important particle characterization tool, revealed a two-year shelf life for cRGDY-PEG-Cy5-C' dots. Radiochromatography further demonstrated the necessary radiochemical stability for clinical applications. The results of subsequent ligand density-dependent studies elucidate strong modulations in biological response, including statistically significant increases in integrin-specific targeting and particle uptake, cellular migration and adhesion, renal clearance, and tumor-to-blood ratios with increasing ligand number. We anticipate that nanoprobe characteristics and a better understanding of the structure-function relationships determined in this study will help guide identification of other lead nanoparticle candidates for in vitro and in vivo biological assessments and product translation.
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http://dx.doi.org/10.1021/acs.chemmater.7b03033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5679295PMC
October 2017

Target-or-Clear Zirconium-89 Labeled Silica Nanoparticles for Enhanced Cancer-Directed Uptake in Melanoma: A Comparison of Radiolabeling Strategies.

Chem Mater 2017 Oct 6;29(19):8269-8281. Epub 2017 Sep 6.

Department of Radiology, Sloan Kettering Institute for Cancer Research, New York, New York 10065, United States.

Designing a nanomaterials platform with high target-to-background ratios has long been one of the major challenges in the field of nanomedicine. Here, we introduce a "target-or-clear" multifunctional nanoparticle platform that demonstrates high tumor-targeting efficiency and retention while minimizing off-target effects. Encouraged by the favorable preclinical and clinical pharmacokinetic profiles derived after fine-tuning surface chemical properties of radioiodinated (I, = 100.2 h) ultrasmall cRGDY-conjugated fluorescent silica nanoparticles (C dots), we sought to investigate how the biological properties of these radioconjugates could be influenced by the conjugation of radiometals such as zirconium-89 (Zr, = 78.4 h) using two different strategies: chelator-free and chelator-based radiolabeling. The attachment of Zr to newer, surface-aminated, integrin-targeting C' dots using a two-pot synthesis approach led to favorable pharmacokinetics and clearance profiles as well as high tumor uptake and target-to-background ratios in human melanoma models relative to biological controls while maintaining particle sizes below the effective renal glomerular filtration size cutoff <10 nm. Nanoconjugates were also characterized in terms of their radiostability and plasma residence half-lives. Our Zr-labeled ultrasmall hybrid organic-inorganic particle is a clinically promising positron emission tomography tracer offering radiobiological properties suitable for enhanced molecularly targeted cancer imaging applications.
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http://dx.doi.org/10.1021/acs.chemmater.7b02567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5675572PMC
October 2017

A Customizable Model for Chronic Disease Coordination: Lessons Learned From the Coordinated Chronic Disease Program.

Prev Chronic Dis 2016 Mar 31;13:E43. Epub 2016 Mar 31.

National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia; Oak Ridge Institute for Science and Education, Oak Ridge, Tennessee.

In 2012, the Centers for Disease Control and Prevention provided funding and technical assistance to all states and territories to implement the Coordinated Chronic Disease Program, marking the first time that all state health departments had federal resources to coordinate chronic disease prevention and control programs. This article describes lessons learned from this initiative and identifies key elements of a coordinated approach. We analyzed 80 programmatic documents from 21 states and conducted semistructured interviews with 7 chronic disease directors. Six overarching themes emerged: 1) focused agenda, 2) identification of functions, 3) comprehensive planning, 4) collaborative leadership and expertise, 5) managed resources, and 6) relationship building. These elements supported 4 essential activities: 1) evidence-based interventions, 2) strategic use of staff, 3) consistent communication, and 4) strong program infrastructure. On the basis of these elements and activities, we propose a conceptual model that frames overarching concepts, skills, and strategies needed to coordinate state chronic disease prevention and control programs.
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http://dx.doi.org/10.5888/pcd13.150509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4825748PMC
March 2016

Ultrasmall dual-modality silica nanoparticle drug conjugates: Design, synthesis, and characterization.

Bioorg Med Chem 2015 Nov 11;23(22):7119-30. Epub 2015 Oct 11.

Department of Radiology, Sloan Kettering Institute for Cancer Research, New York, NY 10065, United States; Molecular Pharmacology and Chemistry Program, Sloan Kettering Institute for Cancer Research, New York, NY 10065, United States. Electronic address:

The physicochemical design and synthesis of effective cancer-directed and particle-based nanotherapeutic imaging agents remains a challenging task. Of critical importance is the ability to demonstrate maximum delivery, retention, and treatment efficacy for platforms designed to deposit their cargo at sites of disease without attendant dose-limiting toxicity. In this work, we describe dual-modality nanoparticle drug conjugates (NDCs) which utilize protease sensitive linkers to attached drug compounds and imaging labels to a clinically translated class of ultrasmall silica nanoparticle (C' dots). We describe the synthesis and characterization of these linker-drug constructs. Linkers incorporating dipeptide enzyme substrates are attached to analogs of a prototypical epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), through a cleavable amide bond or para-aminobenzyloxycarbonyl (PABC) group. These constructs are conjugated onto C' dots leading to the desired NDCs. These NDCs exhibit fast and predictable release kinetics in the presence of model proteases, and are stable in various biological media. Finally, in vitro assays show NDCs to be highly active in reducing phosphorylated EGFR levels in H1650 cells, a human tumor-derived cell line. The data suggests that NDCs exhibit desirable properties that warrant further development toward oncological therapy.
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http://dx.doi.org/10.1016/j.bmc.2015.09.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4842310PMC
November 2015

Corrigendum: use of emerging technologies to assess differences in outdoor physical activity in st. Louis, missouri.

Front Public Health 2015 16;3:41. Epub 2015 Mar 16.

Brown School, Washington University in St. Louis , St. Louis, MO , USA.

[This corrects the article on p. 41 in vol. 2, PMID: 24904908.].
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http://dx.doi.org/10.3389/fpubh.2015.00041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4360572PMC
April 2015

Training needs and supports for evidence-based decision making among the public health workforce in the United States.

BMC Health Serv Res 2014 Nov 14;14:564. Epub 2014 Nov 14.

Background: Preparing the public health workforce to practice evidence-based decision making (EBDM) is necessary to effectively impact health outcomes. Few studies report on training needs in EBDM at the national level in the United States. We report competency gaps to practice EBDM based on four U.S. national surveys we conducted with the state and local public health workforce between 2008 and 2013.

Methods: We compared self-reported data from four U.S. national online surveys on EBDM conducted between 2008 and 2013. Participants rated the importance of each EBDM competency then rated how available the competency is to them when needed on a Likert scale. We calculated a gap score by subtracting availability scores from importance scores. We compared mean gaps across surveys and utilized independent samples t tests and Cohen's d values to compare state level gaps. In addition, participants in the 2013 state health department survey selected and ranked three items that "would most encourage you to utilize EBDM in your work" and items that "would be most useful to you in applying EBDM in your work". We calculated the percentage of participants who ranked each item among their top three.

Results: The largest competency gaps were consistent across all four surveys: economic evaluation, communicating research to policymakers, evaluation designs, and adapting interventions. Participants from the 2013 state level survey reported significantly larger mean importance and availability scores (p <0.001, d =1.00, and p <0.001, d = .78 respectively) and smaller mean gaps (p <0.01, d = .19) compared to the 2008 survey. Participants most often selected "leaders prioritizing EBDM" (67.9%) among top ways to encourage EBDM use. "EBDM training for specific areas" was most commonly ranked as important in applying EBDM (64.3%).

Conclusion: Perceived importance and availability of EBDM competencies may be increasing as supports for EBDM continue to grow through trends in funding, training, and resources. However, more capacity building is needed overall, with specific attention to the largest competency gaps. More work with public health departments to both situate trainings to boost competency in these areas and continued improvements for organizational practices (leadership prioritization) are possible next steps to sustain EBDM efforts.
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http://dx.doi.org/10.1186/s12913-014-0564-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4245845PMC
November 2014

Use of emerging technologies to assess differences in outdoor physical activity in st. Louis, missouri.

Front Public Health 2014 23;2:41. Epub 2014 May 23.

Brown School, Washington University in St. Louis , St. Louis, MO , USA.

Introduction: Abundant evidence shows that regular physical activity (PA) is an effective strategy for preventing obesity in people of diverse socioeconomic status (SES) and racial groups. The proportion of PA performed in parks and how this differs by proximate neighborhood SES has not been thoroughly investigated. The present project analyzes online public web data feeds to assess differences in outdoor PA by neighborhood SES in St. Louis, MO, USA.

Methods: First, running and walking routes submitted by users of the website MapMyRun.com were downloaded. The website enables participants to plan, map, record, and share their exercise routes and outdoor activities like runs, walks, and hikes in an online database. Next, the routes were visually illustrated using geographic information systems. Thereafter, using park data and 2010 Missouri census poverty data, the odds of running and walking routes traversing a low-SES neighborhood, and traversing a park in a low-SES neighborhood were examined in comparison to the odds of routes traversing higher-SES neighborhoods and higher-SES parks.

Results: RESULTS show that a majority of running and walking routes occur in or at least traverse through a park. However, this finding does not hold when comparing low-SES neighborhoods to higher-SES neighborhoods in St. Louis. The odds of running in a park in a low-SES neighborhood were 54% lower than running in a park in a higher-SES neighborhood (OR = 0.46, CI = 0.17-1.23). The odds of walking in a park in a low-SES neighborhood were 17% lower than walking in a park in a higher-SES neighborhood (OR = 0.83, CI = 0.26-2.61).

Conclusion: The novel methods of this study include the use of inexpensive, unobtrusive, and publicly available web data feeds to examine PA in parks and differences by neighborhood SES. Emerging technologies like MapMyRun.com present significant advantages to enhance tracking of user-defined PA across large geographic and temporal settings.
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http://dx.doi.org/10.3389/fpubh.2014.00041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4033201PMC
June 2014

Perceived benefits and challenges of coordinated approaches to chronic disease prevention in state health departments.

Prev Chronic Dis 2014 May 8;11:E76. Epub 2014 May 8.

Washington University in St. Louis and Washington University School of Medicine, St. Louis, Missouri.

Introduction: Chronic disease prevention efforts have historically been funded categorically according to disease or risk factor. Federal agencies are now progressively starting to fund combined programs to address common risk. The purpose of this study was to inform transitions to coordinated chronic disease prevention by learning views on perceived benefits and challenges of a coordinated approach to funding.

Methods: A national survey on evidence-based public health was conducted from March through May 2013 among state health department employees working in chronic disease prevention (N = 865). Participants were asked to rank the top 3 benefits and top 3 challenges in coordinating chronic disease approaches from provided lists and could provide additional responses. Descriptive analyses, χ(2) tests, and analysis of variance were conducted.

Results: The most common perceived benefits of coordinated approaches to chronic disease prevention were improved health outcomes, common risk factors better addressed, and reduced duplication of program efforts. The most common perceived challenges were funding restrictions, such as disease-specific performance measures; competing priorities; lack of communication across programs; funding might be reduced; agency not structured for program coordination; and loss of disease-specific partner support. Rankings of benefits and challenges were similar across states and participant roles; the perceived challenges "lack of communication across programs" (P = .02) and "funding might be reduced" differed by program area (P < .001).

Conclusion: Findings can be used by funding agencies and state health departments for planning, training, and technical assistance. The information on perceived challenges demonstrates the need to improve communication across programs, enhance organizational support for coordinated approaches, and create benefits for organizational partners.
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http://dx.doi.org/10.5888/pcd11.130350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4015301PMC
May 2014

Foreword to Advances in Meditation Research: neuroscience and clinical applications.

Authors:
Sonia Sequeira

Ann N Y Acad Sci 2014 Jan;1307:v-vi

Memorial Sloan-Kettering Cancer Center New York, New York.

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http://dx.doi.org/10.1111/nyas.12305DOI Listing
January 2014

Promoting state health department evidence-based cancer and chronic disease prevention: a multi-phase dissemination study with a cluster randomized trial component.

Implement Sci 2013 Dec 13;8:141. Epub 2013 Dec 13.

Prevention Research Center in St, Louis, Brown School, Washington University in St, Louis, 621 Skinker Blvd,, St, Louis, MO 63130-4838, USA.

Background: Cancer and other chronic diseases reduce quality and length of life and productivity, and represent a significant financial burden to society. Evidence-based public health approaches to prevent cancer and other chronic diseases have been identified in recent decades and have the potential for high impact. Yet, barriers to implement prevention approaches persist as a result of multiple factors including lack of organizational support, limited resources, competing emerging priorities and crises, and limited skill among the public health workforce. The purpose of this study is to learn how best to promote the adoption of evidence based public health practice related to chronic disease prevention.

Methods/design: This paper describes the methods for a multi-phase dissemination study with a cluster randomized trial component that will evaluate the dissemination of public health knowledge about evidence-based prevention of cancer and other chronic diseases. Phase one involves development of measures of practitioner views on and organizational supports for evidence-based public health and data collection using a national online survey involving state health department chronic disease practitioners. In phase two, a cluster randomized trial design will be conducted to test receptivity and usefulness of dissemination strategies directed toward state health department chronic disease practitioners to enhance capacity and organizational support for evidence-based chronic disease prevention. Twelve state health department chronic disease units will be randomly selected and assigned to intervention or control. State health department staff and the university-based study team will jointly identify, refine, and select dissemination strategies within intervention units. Intervention (dissemination) strategies may include multi-day in-person training workshops, electronic information exchange modalities, and remote technical assistance. Evaluation methods include pre-post surveys, structured qualitative phone interviews, and abstraction of state-level chronic disease prevention program plans and progress reports.

Trial Registration: clinicaltrials.gov: NCT01978054.
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http://dx.doi.org/10.1186/1748-5908-8-141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3878781PMC
December 2013

Acute pain relief after Mantram meditation in children with neuroblastoma undergoing anti-GD2 monoclonal antibody therapy.

J Pediatr Hematol Oncol 2014 Mar;36(2):152-5

*Department of Pediatrics †Office of Clinical Research, Memorial Sloan-Kettering Cancer Center, New York, NY.

Nonpharmacologic, mind-body interventions are used to reduce anxiety in pediatric patients. Anti-ganglioside GD2 monoclonal antibody (anti-GD2 MoAb 3F8) therapy is the standard of care for high-risk neuroblastoma and pain is its major side effect. We performed a retrospective analysis of children undergoing anti-GD2 MoAb 3F8 treatment who received guided meditation. Meditation involved concentrating on the repetition of rhythmic, melodic sounds purported to slow breathing and induce a relaxation response. A total of 71% patients completed a session at first (n=19) or second attempt (n=5). Patients received fewer analgesic doses to manage anti-GD2 MoAb 3F8-induced pain when participating in meditation (n=17, mean=-0.4 dose, P<0.01). Mantram meditation is a feasible outpatient intervention associated with reduced analgesic requirements.
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http://dx.doi.org/10.1097/MPH.0000000000000024DOI Listing
March 2014

Meditation as a potential therapy for autism: a review.

Autism Res Treat 2012 4;2012:835847. Epub 2012 Jun 4.

Office of Clinical Research, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.

Autism is a chronic neurodevelopmental disorder of unknown cause that affects approximately 1-3 percent of children and four times more boys than girls. Its prevalence is global and its social impact is devastating. In autism, the brain is unable to process sensory information normally. Instead, simple stimuli from the outside world are experienced as overwhelmingly intense and strain the emotional centers of the brain. A stress response to the incoming information is initiated that destabilizes cognitive networks and short-circuits adequate behavioral output. As a result, the child is unable to respond adequately to stimulation and initiate social behavior towards family, friends, and peers. In addition, these children typically face immune-digestive disorders that heighten social fears, anxieties, and internal conflicts. While it is critical to treat the physical symptoms, it is equally vital to offer an evidence-based holistic solution that harmonizes both their emotional and physical well-being as they move from childhood into adult life. Here, we summarize evidence from clinical studies and neuroscience research that suggests that an approach built on yogic principles and meditative tools is worth pursuing. Desired outcomes include relief of clinical symptoms of the disease, greater relaxation, and facilitated expression of feelings and skills, as well as improved family and social quality of life.
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http://dx.doi.org/10.1155/2012/835847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3420737PMC
August 2012

Crystallographic identification of Ca2+ and Sr2+ coordination sites in synaptotagmin I C2B domain.

Protein Sci 2004 Oct 31;13(10):2665-72. Epub 2004 Aug 31.

Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.

Synaptotagmin I has two tandem Ca(2+)-binding C(2) domains, which are essential for fast synchronous synaptic transmission in the central nervous system. We have solved four crystal structures of the C(2)B domain, one of them in the cation-free form at 1.50 A resolution, two in the Ca(2+)-bound form at 1.04 A (two bound Ca(2+) ions) and 1.65 A (three bound Ca(2+) ions) resolution and one in the Sr(2+)-bound form at 1.18 A (one bound Sr(2+) ion) resolution. The side chains of four highly conserved aspartic acids (D303, D309, D363, and D365) and two main chain oxygens (M302:O and Y364:O), together with water molecules, are in direct contact with two bound Ca(2+) ions (sites 1 and 2). At higher Ca(2+) concentrations, the side chain of N333 rotates and cooperates with D309 to generate a third Ca(2+) coordination site (site 3). Divalent cation binding sites 1 and 2 in the C(2)B domain were previously identified from NMR NOE patterns and titration studies, supplemented by site-directed mutation analysis. One difference between the crystal and NMR studies involves D371, which is not involved in coordination with any of the identified Ca(2+) sites in the crystal structures, while it is coordinated to Ca(2+) in site 2 in the NMR structure. In the presence of Sr(2+), which is also capable of triggering exocytosis, but with lower efficiency, only one cation binding site (site 1) was occupied in the crystallographic structure.
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http://dx.doi.org/10.1110/ps.04832604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2286539PMC
October 2004

S-nitrosylation of NSF controls membrane trafficking.

Cell 2003 Oct;115(2):127-9

Memorial Sloan-Kettering Cancer Center, Cellular Biochemistry & Biophysics Program, New York, NY 10021, USA.

Nitric oxide is a diffusible molecule with profound effects on regulated exocytosis in several biological systems-however, the molecular targets remain elusive. In this issue of Cell, Matsushita et al. report that in aortic endothelial cells, S-nitrosylation of NSF, an ATPase essential for the activation of the membranefusion machinery, inhibits the exocytosis of Weibel-Palade bodies, secretory granules containing a cocktail of mediators essential to the regulation of vascular vessel tone.
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http://dx.doi.org/10.1016/s0092-8674(03)00811-0DOI Listing
October 2003

Calcium-independent stimulation of membrane fusion and SNAREpin formation by synaptotagmin I.

J Cell Biol 2002 Jul 15;158(2):273-82. Epub 2002 Jul 15.

Cellular Biochemistry and Biophysics Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.

Neurotransmitter release requires the direct coupling of the calcium sensor with the machinery for membrane fusion. SNARE proteins comprise the minimal fusion machinery, and synaptotagmin I, a synaptic vesicle protein, is the primary candidate for the main neuronal calcium sensor. To test the effect of synaptotagmin I on membrane fusion, we incorporated it into a SNARE-mediated liposome fusion assay. Synaptotagmin I dramatically stimulated membrane fusion by facilitating SNAREpin zippering. This stimulatory effect was topologically restricted to v-SNARE vesicles (containing VAMP 2) and only occurred in trans to t-SNARE vesicles (containing syntaxin 1A and SNAP-25). Interestingly, calcium did not affect the overall fusion reaction. These results indicate that synaptotagmin I can directly accelerate SNARE-mediated membrane fusion and raise the possibility that additional components might be required to ensure tight calcium coupling.
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http://dx.doi.org/10.1083/jcb.200203135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2173117PMC
July 2002