Beta Site Research Articles

Remote nurse triage and standardization of clinical pathway utilization.

574 Background: In March of 2022, Texas Oncology (community oncology practice) initiated a state-wide rollout for Remote Nurse Triage. This program implemented and standardized the utilization of Clinical Pathways within the Navigating Care system with a goal to decrease time to patient first call back, increase first touch resolution for patient-initiated contact, and increase patient satisfaction related to patient-initiated communication resolution. Methods: To determine an appropriate plan of action, a needs assessment was conducted to evaluate current pathway utilization, call volumes and patient satisfaction. Based on the findings of this assessment, triage nurses were trained to resolve incidents using standardized care pathways and standing orders within the Navigating Care System. This implementation was monitored on a weekly basis with metrics from Navigating Care and the Relatient dashboard and compared to the 12-month baseline data for 2 beta sites. Results: In the 12-month pilot, standardized pathway utilization increased from 1% pre-pilot to 78% post-pilot for clinical symptom management calls. With standardized pathways and better first touch resolution clinical calls decreased 8% overall from 4,302/month to 3,987/month while patient volumes (billable visits) increased 25%. Patient satisfaction scores, in relation to their phone experience and needs resolution, went up to 4.5/5 from 3.9/5. Symptom management resolution times also trended down since beginning the pilot. Conclusions: Standardizing the usage of clinical pathways by virtual triage nurses reduced clinical call volumes despite a positive growth in the number of billable visits at the pilot sites. This increase in pathway utilization also led to decreased time for symptom management resolution. Additionally, these measures resulted in an increased patient satisfaction related to patient-initiated communication.

Biological activity of some thiazolyl‐thiadiazines as BACE‐1 inhibitors for Alzheimer's disease in the light of density functional theory based quantum descriptors

AbstractThis paper presents first report on a systematic investigation on developing quantum chemical descriptors on understanding biological activity (pIC50) of a series of 10 thiazolyl‐thiadiazines (ID‐01 to ID‐10) as Beta site amyloid precursor protein cleaving enzyme 1 (BACE‐1) protein inhibitors for Alzheimer diseases, under density functional theory. The interactions between inhibitors and model biomolecule are studied in terms of charge and energy transfer, where the target biomolecule at the host BACE‐1 protein is identified from the family of 20 amino acids, which are universal to all living organisms. The present study identifies electron affinity (EA), total electronic energy (E), and the electron transfer with amino acid (∆E) of thiazolyl‐thiadiazines as promising descriptors, which can explain about 90% of observed biological activity. The developed regression model for training set is also validated for unknown test set of homologous compounds. The developed quantum chemical descriptors for prediction of the biological activity of thiazolyl‐thiadiazines will certainly be an excellent addition in the QSAR parlance of drug development.

Signal transduction pathway activity in high-grade serous carcinoma, its precursors and Fallopian tube epithelium

ObjectiveTo determine the activity of key signal transduction pathways in serous tubal intraepithelial carcinoma (STIC) and concurrent high-grade serous carcinoma (HGSC) and compare this to pathway activity in normal Fallopian tube epithelium (FTE). MethodsWe assessed mRNA expression levels of pathway-specific target genes with RT-qPCR in STIC and concurrent HGSC (n = 8) and normal FTE (n = 8). Subsequently, signal transduction pathway assays were used to assess functional activity of the androgen (AR) and estrogen receptor (ER), phosphoinositide-3-kinase (PI3K), Hedgehog (HH), transforming growth factor beta (TGF-β) and canonical wingless-type MMTV integration site (Wnt) pathways. ResultsThere were no statistically significant differences in pathway activity between STIC and HGSC, but STIC and HGSC demonstrated significantly lower ER and higher PI3K and HH pathway activity in comparison to normal FTE, suggesting these pathways as putative early drivers. In addition, we determined FOXO3a protein expression by immunohistochemistry and found loss of FOXO3a protein expression in STIC and HGSC compared to normal FTE. This observation confirmed that activation of PI3K signaling by loss of FOXO is an early hallmark of serous carcinogenesis. Furthermore, HGSC demonstrated significant loss of AR and Wnt pathway activity in relation to FTE, suggesting these pathways contribute to disease progression. ConclusionOur observations, together with the previously described associations between p53 signaling and both PI3K and HH pathway activity, provide evidence that increased PI3K and HH pathway activity and loss of ER pathway activity may be underlying events contributing to neoplastic transformation of FTE into STIC.

Survival Is Related to Estrogen Signal Transduction Pathway Activity in Postmenopausal Women Diagnosed with High-Grade Serous Ovarian Carcinoma.

Simple SummaryAll cells have a complex internal network of ‘communication chains’ called signal transduction pathways (STPs). Through interaction of different proteins in STPs, they are partly responsible for the behavior of a cell. In our study, we investigated the activity of six STPs in 85 women with advanced stage high-grade serous ovarian cancer (HGSC). To investigate the relation between and differences in survival and STP activity, women with a short disease-free survival (below 12 months) and a long disease-free survival (above 24 months) were included. We found no differences in mean STP activity between short-term survivors (52 women) and long-term survivors (33 women). However, when we analyzed postmenopausal women, we found that both disease-free and overall survival were related to estrogen receptor (ER) pathway signaling. This indicates that a better survival outcome was related to a more active ER pathway in this subgroup.High-grade serous ovarian carcinoma (HGSC), the most common subtype of ovarian cancer, has a high mortality rate. Although there are some factors associated with survival, such as stage of disease, there are remarkable differences in survival among women diagnosed with advanced stage disease. In this study, we investigate possible relations between survival and signal transduction pathway (STP) activity. We assessed the functional activity of the androgen receptor (AR), estrogen receptor (ER), phosphoinositide-3-kinase (PI3K), Hedgehog (HH), transforming growth factor beta (TGF-β) and canonical wingless-type MMTV integration site (Wnt) pathway in 85 primary tumor samples of patients with FIGO stage IIIC to IVB HGSC and disease-free survival (DFS) below 12 (n = 52) or over 24 months (n = 33). There were no significant differences in median pathway activity between patients with a short and long DFS. In univariate Cox proportional hazards analysis, ER pathway activity was related to a favorable DFS and overall survival (OS) in postmenopausal women (p = 0.033 and p = 0.041, respectively), but not in premenopausal women. We divided the postmenopausal group into subgroups based on ER pathway activity quartiles. Survival analysis revealed that postmenopausal women in the lowest ER quartile had a shorter DFS and OS (log-rank p = 0.006 and p < 0.001, respectively). Furthermore, we were able to form subgroups of patients based on an inverse relation between ER and PI3K pathway activity. In conclusion, in postmenopausal patients with advanced stage HGSC, a poorer survival outcome was associated with low functional ER pathway activity.

Effects of the acidity and shape selectivity of dealuminated zeolite beta on butene transformations

The acidity and shape selectivity of zeolites are two important catalytic properties, and they have been extensively applied to the chemical and petrochemical industries. Here, we investigated the various effect mechanisms of Brønsted acid sites (BASs) from bridged hydroxyl groups in zeolite Beta and Lewis acid sites (LASs) from silanol nests in Si-Beta on butene transformation and their reaction pathways by diffuse-reflectance infrared Fourier-transform spectroscopy. BAS catalysis of butenes double bond activation and isomerization follows the classical carbenium ion mechanism, while catalysis by silanol nests as weak LASs due to hydrogen bond interaction is achieved by formation of allyl species and alkoxyl groups. Moreover, the oligomerization reactions of butene isomers are affected by the dynamic diameters and activation energies of the butene isomers and the synergy between acidity and shape selectivity of the zeolite. Oligomerization of n-butene and cis-2-butene is more likely to be affected by acids on the sample, while oligomerization of trans-2-butene and isobutene is influenced by the shape selectivity of the channel, in addition to the acidity on partly dealuminated zeolite Beta.

Coordination and activation of nitrous oxide by iron zeolites

Iron-containing zeolites are heterogeneous catalysts that exhibit remarkable activity in the selective oxidation of inert hydrocarbons and catalytic decomposition of nitrous oxide (N2O). The reduction of N2O is critical to both these functions, but experimental data tracking the iron active sites during N2O binding and activation are limited. Here, the N2O-ligated Fe(ii) active site in iron-exchanged zeolite beta is isolated and characterized by variable-temperature Mössbauer, diffuse reflectance UV-vis-NIR and Fourier transform infrared spectroscopy. N2O binds through the terminal nitrogen atom with substantial backbonding from the Fe(ii) centre at low temperature. At higher temperatures, the Fe–N2O interaction is weakened, facilitating isomerization to the O-bound form, which is competent in O-atom transfer. Density functional theory calculations show the geometric and electronic structure requirements for N2O binding and activation. A geometric distortion imposed by the zeolite lattice plays an important role in activating N2O. This highlights a mechanism for structural control over function in Fe-zeolite catalysts.

Cyber Insurance As Cyber Diplomacy

The delicate art of managing foreign affairs is one of the oldest in human history. This long- established practice has recently experienced a renaissance with the introduction of “cyber diplomacy” as an exciting new frontier for traditional diplomatic work. Under this novel banner a pincer movement is gradually taking form: While ambassadors and foreign relations experts are being called to engage further with “the geopolitics of cyberspace,” computer scientists and cybersecurity specialists are invited, perhaps for the first time, to meaningfully contribute to discussions at “the heart of foreign policy.” Cyber risk insurance is a type of insurance that provides coverage for businesses and individuals for the perils of the internet age, such as data breaches, computer network interruptions, and ransomware attacks. Cyber insurance is gradually proving to be an important tool for cyber risk prevention and mitigation on the local, regional, national, and international levels. If cyber diplomacy is truly concerned with enhancing cyber deterrence and promoting norms that ensure global cyber stability and cyber peace, it must broaden its perspective to include international insurance norms for modeling and indemnifying harms in cyberspace. In this chapter I therefore argue that norms surrounding cyber insurance should be added to the diplomatic portfolio of nation states. To illustrate this point, I discuss a recent initiative of the Israeli National Cyber Directorate to transform Israel into a beta site for cyber insurance regulation. The goal of this trial is to experiment with various prescriptive and regulatory solutions for some of the most intrinsic problems that plague the still-emerging cyber insurance market. By collaborating with a number of reinsurers and foreign governments, Israel hopes to successfully chart the way forward for other commercial insurers and insurance regulators around the world. In so doing, it is demonstrating how cyber diplomacy might be augmented and expanded to encompass certain norms, best practices, and governance mechanisms that have so far been deemed wholly domestic, jurisdiction-specific, and purely technical. The chapter proceeds in the following order. Section I briefly explores the current state of the cyber insurance market and its existing global limitations. Section II moves to discuss the new initiative to turn Israel into a cyber insurance beta site, its scope and rationale. The chapter concludes by extrapolating from the Israeli case study to propose a broader research agenda for international norms around cyber insurance.

Health Heatmap of India: An Open Data Platform.

Health Heatmap of India is an open data platform built for bringing together data from diverse sources and facilitating visualization, analysis, and insight building from such data. In this paper, we describe the context and need for such an open data platform and describe the technical aspects of building it. The beta site of the portal is available at https://healthheatmapindia.org.

17.C. Workshop: I-Care Lab: Puglia scaling up in integrated care for the future of digital health and social system

Abstract Background Healthcare systems around the world are under great pressure to drive forward transformation in order to meet the evolving needs of their populations. Ageing and chronicity are the main challenges to be tackled. In many countries care is too often fragmented and has clear deficiencies in quality, inducing low responsiveness of the healthcare system and low satisfaction with healthcare services. To address these challenges, the transformation towards integrated care has the potential to address deficiencies in order to obtain accessible, quality, effective and sustainable health care. Objectives The objectives of this workshop are to present 3 innovative projects undertaken by Puglia Region, by means of its Strategic Regional Agency for Health and Social Care AReSS, within the framework of the I-CARE LAB, a think tank and beta site for integrated care focused on the production of evidence-based knowledge and systematic approaches to exploitation and scaling up of good practices. The workshop will present the results of the research that has taken place around the above-mentioned projects and to gather feedback from the participants on their opinions and perspectives about integrate care models, policies, tools and practices. Results The featured projects are based on the collaboration with national and international partners interested in developing tools and approaches to stimulate changes towards more sustainable health and care systems, and in supporting scalability and transferability of good practices in Europe. The knowledge transfer among these institutions represents the added value that can establish a common language and framework of integrated care. The showcased projects focus on vulnerable populations for which integrated care might be most beneficial, e.g., chronically ill, frail elderly, and multi-morbid persons; the projects have identified and described an impressive number of promising practices; there are several plans to evaluate these in the coming years, and other plans to facilitate the wider-spread implementation and scaling up of such programs. During this session, 3 of such projects will present their findings, approaches and connections: SCIROCCO Exchange (assessment of integrated care interventions), FooDia-NET (patient engagement and literacy), EURIPHI (innovation procurement). Conclusions The workshop will be a 90-minute session with 3 presentations with ample time for audience interaction (30-minutes). Three individual members of the above-mentioned projects will be responsible for conducting the workshop (the chair, and 3 people making 3 presentations). The session will be chaired by the AReSS Puglia CEO, who will introduce the workshop. A set of presentations will follow, covering the different session topics corresponded to the 3 projects of the Puglia I-Care Lab. Participants will be asked to actively join in the discussion on the further projects enhancement. Key messages The first impact of the proposed workshop consists of stimulating knowledge and discussion about emerging tools and approaches in Europe towards more sustainable health and care systems. The second expected impact is to create awareness and to support scalability and transferability of good practices in Europe and abroad.

The &#946;-Secretase Enzyme BACE1: A Biochemical Enigma for Alzheimer's Disease.

Beta site amyloid precursor protein cleaving enzyme 1 (BACE1) is a rational target in Alzheimer's Disease (AD) drug development due to its role in amyloidogenic cleavage of Amyloid Precursor Protein (APP) in generating Amyloid β (Aβ). This β-secretase cleaves not only Amyloid Precursor Protein (APP) and its homologues, but also small series of substrates including neuregulin and β subunit of voltage-gated sodium channel that play a very important role in the development and normal function of the brain. Moreover, BACE1 is modulated at the post-translational level by several factors that are associated with both physiological and pathological functions. Since the discovery of BACE1 over a decade ago, medicinal chemistry and pharmacokinetics of BACE1 small molecule inhibitors have proven challenging for the treatment of Alzheimer's disease.

The anti-Alzheimer effect of telmisartan in a hyperglycemic ovariectomized rat model; role of central angiotensin and estrogen receptors

The central renin angiotensin system (RAS) is implicated in Alzheimer's disease (AD). Here, induction of experimental AD simulation was performed by D-galactose (D-Gal) injection to ovariectomized (OVX) rats fed on high fat high fructose diet (HFFD). Telmisartan administration to OVX/HFFD/D-Gal rats lowered the expression of hippocampal angiotensin 1 and 2 receptors and glucose transporter 2 in addition to lowering of the peripheral and central glucose levels. Furthermore, it improved cognitive impairment and suppressed hippocampal amyloidogenic markers including amyloid-beta level, phosphorylated tau protein and beta site amyloid precursor protein cleaving enzyme 1 expression, while elevated levels of insulin degrading enzyme and recovered permeability of blood brain barrier (BBB). In addition, it inhibited hippocampal oxido-nitrosative stress as well as neuroinflammatory and apoptotic biomarkers. Telmisartan improved memory and cognitive impairment as shown in the behavioral Morris water maze, Y-maze, novel object recognition and open field tests in addition to amelioration of depressive like behavior as shown in forced swimming test. Histopathological examination of brain and immune expression of glial fibrillary acidic protein were also improved together with astrogliosis improvement. In conclusion, telmisartan improved memory and cognitive impairment, recovered amyloidogenesis-hyperglycemic axis, astrogliosis, integrity of BBB, memory deficit and oxidonitrosative stress induced in OVX/HFFD/D-Gal rats.

Decentralization of Next-Generation RNA Sequencing-Based MammaPrint® and BluePrint® Kit at University Hospitals Leuven and Curie Institute Paris

A previously developed and centrally validated MammaPrint® (MP) and BluePrint® (BP) targeted RNA next-generation sequencing (NGS) kit was implemented and validated in two large academic European hospitals. Additionally, breast cancer molecular subtypes by MP and BP RNA sequencing were compared with immunohistochemistry (IHC). Patients with early breast cancer diagnosed at University Hospitals Leuven and Curie Institute Paris were prospectively included between September 2017 and January 2018. Formalin-fixed paraffin-embedded tissue sections were analyzed with MP and BP NGS technology at the beta sites and with both NGS and microarray technology at Agendia. Raw NGS data generated on Illumina MiSeq instruments at the beta sites were interpreted and compared with NGS and microarray data at Agendia. MP and BP NGS molecular subtypes were compared to surrogate IHC breast cancer subtypes. Equivalence of MP and BP indices was determined by Pearson's correlation coefficient. Acceptable limits were defined a priori, based on microarray data generated at Agendia between 2012 and 2016. The concordance, the Negative Percent Agreement and the Positive Percent Agreement were calculated based on the contingency tables and had to be equal to or higher than 90%. Out of 124 included samples, 48% were MP Low and 52% High Risk with microarray. Molecular subtypes were BP luminal, HER2 or basal in 82%, 8% and 10% respectively. Concordance between MP microarray at Agendia and MP NGS at the beta sites was 91.1%. Concordance of MP High and Low Risk classification between NGS at the beta sites and NGS at Agendia was 93.9%. Concordance of MP and BP molecular subtyping using NGS at the beta sites and microarray at Agendia was 89.5%. Concordance between MP and BP NGS subtyping, and IHC was 71.8% and 76.6%, for two IHC surrogate models. The MP/BP NGS kit was successfully validated in a decentralized setting.

A work lifetime of passion! Is it worth the time, money, stress and relationship changes when you disagree with hierarchy?

A previously developed and centrally validated MammaPrint® (MP) and BluePrint® (BP) targeted RNA next-generation sequencing (NGS) kit was implemented and validated in two large academic European hospitals. Additionally, breast cancer molecular subtypes by MP and BP RNA sequencing were compared with immunohistochemistry (IHC). Patients with early breast cancer diagnosed at University Hospitals Leuven and Curie Institute Paris were prospectively included between September 2017 and January 2018. Formalin-fixed paraffin-embedded tissue sections were analyzed with MP and BP NGS technology at the beta sites and with both NGS and microarray technology at Agendia. Raw NGS data generated on Illumina MiSeq instruments at the beta sites were interpreted and compared with NGS and microarray data at Agendia. MP and BP NGS molecular subtypes were compared to surrogate IHC breast cancer subtypes. Equivalence of MP and BP indices was determined by Pearson's correlation coefficient. Acceptable limits were defined a priori, based on microarray data generated at Agendia between 2012 and 2016. The concordance, the Negative Percent Agreement and the Positive Percent Agreement were calculated based on the contingency tables and had to be equal to or higher than 90%. Out of 124 included samples, 48% were MP Low and 52% High Risk with microarray. Molecular subtypes were BP luminal, HER2 or basal in 82%, 8% and 10% respectively. Concordance between MP microarray at Agendia and MP NGS at the beta sites was 91.1%. Concordance of MP High and Low Risk classification between NGS at the beta sites and NGS at Agendia was 93.9%. Concordance of MP and BP molecular subtyping using NGS at the beta sites and microarray at Agendia was 89.5%. Concordance between MP and BP NGS subtyping, and IHC was 71.8% and 76.6%, for two IHC surrogate models. The MP/BP NGS kit was successfully validated in a decentralized setting.

Acylguanidine-BACE1 complex: Insights of intermolecular interactions and dynamics

Alzheimer disease (AD) is a harmful neurodegenerative disorder which arises mainly due to awful deposition of amyloid β (Aβ) peptide in the brain of AD patients. Aβ aggregates from the amyloid precursor protein (APP) by the sequential action of β-Secretase (Beta site APP Cleaving Enzyme, BACE1); hence, inhibition of BACE1 is the primary target for the treatment of AD. As per the experimental report, acylguanidine is a synthetic inhibitor of BACE1, it exhibits high binding affinity towards BACE1. In the present computational study, we aimed to understand the molecular binding mechanism of acylguanidine with BACE1 from the structure and conformation, intermolecular interactions, charge density and electrostatic properties, stability and binding free energy of acylguanidine molecule in the active site of BACE1. To investigate this, molecular docking, QM/MM based charge density analysis and MD simulation have been performed on acylguanidine with BACE1. Acylguanidine shows large binding affinity towards BACE1 and it gives strong hydrogen bonding and hydrophobic interactions with the active site amino acid residues of BACE1. In addition, QM/MM based charge density analysis of acylguanidine was carried out to understand its charge density distribution in the active site of BACE1. The conformational flexibility, charge density redistribution and the modification of electrostatic properties of acylguanidine in the active site have been compared to its corresponding gas phase structure. Further, the molecular dynamics simulation on acylguanidine-BACE1 was carried out, which gives the stability of acylguanidine in the active site of BACE1. The MM-GBSA free energy displays the binding affinity of the acylguanidine and further the decomposition energy reveals the validity of intermolecular interactions.

Neuroinflammatory Cytokines Induce Amyloid Beta Neurotoxicity through Modulating Amyloid Precursor Protein Levels/Metabolism.

Neuroinflammation has been observed in association with neurodegenerative diseases including Alzheimer's disease (AD). In particular, a positive correlation has been documented between neuroinflammatory cytokine release and the progression of the AD, which suggests these cytokines are involved in AD pathophysiology. A histological hallmark of the AD is the presence of beta-amyloid (Aβ) plaques and tau neurofibrillary tangles. Beta-amyloid is generated by the sequential cleavage of beta (β) and gamma (γ) sites in the amyloid precursor protein (APP) by β- and γ-secretase enzymes and its accumulation can result from either a decreased Aβ clearance or increased metabolism of APP. Previous studies reported that neuroinflammatory cytokines reduce the efflux transport of Aβ, leading to elevated Aβ concentrations in the brain. However, less is known about the effects of neuroinflammatory mediators on APP expression and metabolism. In this article, we review the modulatory role of neuroinflammatory cytokines on APP expression and metabolism, including their effects on β- and γ-secretase enzymes.

Sustaining and spreading quality improvement: Decreasing intrapartum malpractice risk.

Malpractice liability is an ongoing problem in obstetrics. However, developing, sustaining, and spreading effective interventions is challenging. The aim of this study is to examine the spread and sustainability of a multilevel integrated practice and coordinated communication model 66 months after its original implementation. Data on labor and delivery patients from 37 hospitals (5 beta sites and 32 expansion sites) were analyzed for the 81-month time period from January 2010 through September 2016. High-risk occurrence rates per 1000 live births decreased by over 70% at both beta and expansion sites. The likelihood of a high-risk occurrence was statistically significantly lower during the final study period than in the preintervention period at both beta sites (odds ratio [OR]=0.218; p<.0001) and expansion sites (OR=0.288; p<.001). The multilevel integrated practice and coordinated communication model was successfully spread and sustained. Key elements contributing to this success included developing and maintaining evidence-based guidelines, ensuring leadership buy-in and support, collecting and reporting performance measures, holding teams accountable, providing training, and ensuring transparent communication.

Thiazolyl-thiadiazines as Beta Site Amyloid Precursor Protein Cleaving Enzyme-1 (BACE-1) Inhibitors and Anti-inflammatory Agents: Multitarget-Directed Ligands for the Efficient Management of Alzheimer's Disease.

Alzheimer's disease (AD) is associated with multiple neuropathological events including β-site amyloid precursor protein cleaving enzyme-1 (BACE-1) inhibition and neuronal inflammation, ensuing degeneracy, and death to neuronal cells. Targeting such a complex disease via a single target directed treatment was found to be inefficacious. Hence, with an intention to incorporate multiple therapeutic effects within a single molecule, multitarget-directed ligands (MTDLs) have been evolved. Herein, for the first time, we report the discovery of novel thiazolyl-thiadiazines that can serve as MTDLs as evident from the in vitro and in vivo studies. These MTDLs exhibited BACE-1 inhibition down to micromolar range, and results from the in vivo studies demonstrated efficient anti-inflammatory activity with inherent gastrointestinal safety. Moreover, compound 6d unveiled noteworthy antioxidant, antiamyloid, neuroprotective, and antiamnesic properties. Overall, results of the present study manifest the potential outcome of thiazolyl-thiadiazines for AD treatment.

Diagnosis and monitoring of Alzheimer Disease with saliva biomarker BACE1

Alzheimer’s disease (AD) is characterized by the slow decline of cognition and functional abilities over time. The diagnosis for probable and possible AD relies principally on clinical criteria. The confirmation of the disease is made post-mortem by identifying extracellular senile plaques and intraneuronal fibrillary tangles in the brains of subjects with clinically defined dementia. However, the field critically lacks validated AD specific peripheral biomarkers to support the diagnosis in living patients or for early detection of patients at risk before symptoms appear. BACE1 (Beta site amyloid precursor protein cleaving enzyme 1) cleaves Amyloid Precursor Protein (APP) at two beta sites and represents a key target enzyme in the monitoring and possible treatment of AD. In our preliminary study, we evaluated the usefulness of salivary BACE1 to determine risk to develop AD in clinically normal patients. A preliminary in house laboratory grading system for BACE1 content in saliva was established with high levels of salivary BACE1 present in older patients and putatively at risk to develop AD. BACE1 seems to be a useful biomarker to help diagnose AD and to monitor disease progression, and remarkably regression, when treated with stem cell secretome.

Nitric Oxide Mediates Crosstalk between Interleukin 1β and WNT Signaling in Primary Human Chondrocytes by Reducing DKK1 and FRZB Expression.

Interleukin 1 beta (IL1β) and Wingless-Type MMTV Integration Site Family (WNT) signaling are major players in Osteoarthritis (OA) pathogenesis. Despite having a large functional overlap in OA onset and development, the mechanism of IL1β and WNT crosstalk has remained largely unknown. In this study, we have used a combination of computational modeling and molecular biology to reveal direct or indirect crosstalk between these pathways. Specifically, we revealed a mechanism by which IL1β upregulates WNT signaling via downregulating WNT antagonists, DKK1 and FRZB. In human chondrocytes, IL1β decreased the expression of Dickkopf-1 (DKK1) and Frizzled related protein (FRZB) through upregulation of nitric oxide synthase (iNOS), thereby activating the transcription of WNT target genes. This effect could be reversed by iNOS inhibitor 1400W, which restored DKK1 and FRZB expression and their inhibitory effect on WNT signaling. In addition, 1400W also inhibited both the matrix metalloproteinase (MMP) expression and cytokine-induced apoptosis. We concluded that iNOS/NO play a pivotal role in the inflammatory response of human OA through indirect upregulation of WNT signaling. Blocking NO production may inhibit the loss of the articular phenotype in OA by preventing downregulation of the expression of DKK1 and FRZB.

Development and Implementation of Quality Measures for the Survey Based Performance Assessment of Radiation Therapy in the VA

The U.S. Veterans Health Administration, with oversight of 40 radiation therapy clinics, has begun a program for practice assessment with the goal of identifying, quantifying, and reducing quality variation across its network. Practice assessments will be conducted by teams of surveyors to abstract data from the medical records of patients with a diagnosis of lung or prostate cancer. ASTRO disease-site panels were convened to develop a series of prostate and lung cancer specific quality measures (QMs). For each QM, the set of assessed patients (denominator, exclusions) and the criteria to be satisfied for quality care (numerator) were defined. Additionally, an expected performance rate was specified. An interdisciplinary team of the surveyors, radiation oncologists, medical physicists, and software engineers was convened to review the data sourcing and overall feasibility of the survey process. Software was developed to capture data elements for evaluation of the QMs for each patient cohort. The ASTRO disease site panels generated a series of 27 and 24 QMs for lung cancer and prostate cancer, respectively. The cohorts addressed by the QMs are patients with locally advanced non-small cell lung cancer, limited stage small cell lung cancer, and intermediate and high risk prostate cancer. The QMs span the clinical, dosimetric, and physics components of the medical record. Each QM is designed to be evaluated for each chart under survey for a disease site and to yield pass, fail, or not applicable evaluations. Thus, at an institution level, a passing rate can be calculated for each QM. The disease site panels provided expected institutional performance levels. The survey team evaluated a series of charts at a VA beta site, allowing surveyors to locate, collect, and analyze QMs for prostate and lung cancer cohorts. This process allowed for the design of an efficient software interface and abstraction process. Software to capture metrics for evaluation of QMs has been implemented as a web application with secure transport of anonymized datasets over encrypted connections. The application also supports the remote upload and automatic anonymization of DICOM RT datasets to evaluate dosimetric QMs. Analysis and reporting of results are centralized. After the development of QMs by ASTRO and the implementation of these into a UI, the survey team proceeded to test practice assessments at a beta site. Two surveyors have demonstrated an accrual of 50 cases, at a rate of 20-30 minutes per chart, over the course of a work week. Supporting processes, logistics, and access to target sites have been developed. Initiation of a first site survey is targeted for March of 2017.