Search results for: anger expression

Authors: Aisha Musaazi Sebunya Nakitto, Anika E. Wagner, Yusuf B. Byaruhanga, John H. Muyonga

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The prevalence and burden of diabetes are rapidly increasing globally, stemming from changes in lifestyle and dietary habits. Although several drugs are available to treat type 2 diabetes mellitus (T2DM), many are accompanied by several side effects and are often costly. Solanum anguivi Lam. fruits (SALF) are bitter berries that commonly grow in the wild and are traditionally cultivated by many globally as a remedy for T2DM. This effect is likely attributable to the presence of bioactive compounds such as phenolics, flavonoids, saponins, alkaloids, and vitamin C in SALF. In this study, we investigated the morphological characteristics of different SALF accessions and the effect of ripeness stages and thermal treatments on the bioactive compounds contents (BCC) and antioxidant activity (AA) of SALF accessions. Using the fruit fly Drosophila melanogaster (D. melanogaster) model, we explored the potential impact of dietary SALF in preventing and treating T2DM phenotypes. Morphological characterization was conducted based on descriptors of Solanum species. The BCC and AA of SALF at different ripeness stages (unripe, yellow, orange, and red) and after thermal treatments were determined using spectrophotometry, HPLC, and gravimetry. Male and female fruit flies were fed a high-sugar diet (HSD) to induce a T2DM-like phenotype, while control flies were fed on SY10 medium for up to 24 days. Experimental flies were exposed to HSD supplemented with 5 or 10 mg/ml SALF. The therapeutic and prevention effect of SALF in T2DM-like phenotype was investigated on weight, climbing activity, glucose and triglyceride contents, survival, and gene expression of PPARγ co-activator 1α fly homolog Srl and Drosophila insulin-like peptides. Methods in fly studies included Gustatory assay, Climbing assay, Glucose GOD-PAP assay, Triglyceride GPO-PAP assay, Roti-Quant®, and Real Time-PCR analysis. The ripeness stage significantly influenced SALF BCC and AA, and this was dependent on the accession. The unripe stage had the highest AA and total phenolics and flavonoids; the orange stage was rich in saponins, while the red stage had the highest alkaloid contents. Boiling and steaming increased the total phenolics and AA up to 4-fold and 3-fold, respectively. Drying at low temperatures resulted in higher phenolics and AA than the control. In the therapeutic model, the HSD-fed female flies exhibited elevated glucose levels, which exhibited a dose-dependent reduction upon exposure to a SALF-supplemented diet. Female flies fed on a SALF+ HSD exhibited a significant increase in survival compared to HSD-fed and control diet-fed flies. SALF supplementation did not alter the weights, fitness, and triglyceride levels of female flies in comparison with HSD-only-fed flies. The mRNA levels of Srl decreased in HSD-fed flies compared to the control-fed, with no effect observed in females exposed to HSD+SALF. Similarly, in the preventative model, the SALF diet resulted in higher survival of supplemented flies compared to controls. Consumption of boiled unripe SALF may result in the highest health benefits due to the high phenolic contents and antioxidant activity observed. Dietary intake of SALF significantly lowered glucose levels and increased survival of the D. melanogaster model. Additional studies in higher organisms are needed to explore the preventative and therapeutic potential of SALF in T2DM.

Keywords: antioxidant activity, bioactive compounds, bitter berries, Drosophila melanogaster, Solanum anguivi, type 2 diabetes mellitus, survival

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Authors: E. O. Aluta, C. A. Booth, D. G. Proverbs, T. Appleby

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Challenges in the effective management of potable water have attracted global attention in recent years and remain many world regions’ major priorities. Scarcity and unavailability of potable water may potentially escalate poverty, obviate democratic expression of views and militate against inter-sectoral development. These challenges contra-indicate the inherent potentials of the resource. Thus, while creation of poverty may be regarded as a broad-based problem, it is capable of reflecting life-span reduction diseases, the friction of interests manifesting in threats and warfare, the relegation of democratic principles for authoritarian definitions and Human Rights abuse. The challenges may be identified as manifestations of ineffective management of potable water resource and therefore, regarded as major problems in environmental protection. In reaction, some nations have re-examined their laws and policies, while others have developed innovative projects, which seek to ameliorate difficulties of providing sustainable potable water. The problems resonate in Nigeria, where the legal framework supporting the supply and management of potable water has been criticized as ineffective. This has impacted more on rural community members, often regarded as ‘voiceless’. At that level, the participation of non-state actors has been identified as an effective strategy, which can improve water supply. However, there are indications that there is no pragmatic application of this, resulting in over-centralization and top-down management. Thus, this study focuses on how the participatory process may enable the development of participatory water governance framework, for use in Nigeria rural communities. The Rural Advisory Board (RAB) is proposed as a governing body to promote proximal relationships, institute democratisation borne out of participation, while enabling effective accountability and information. The RAB establishes mechanisms for effectiveness, taking into consideration Transparency, Accountability and Participation (TAP), advocated as guiding principles of decision-makers. Other tools, which may be explored in achieving these are, Laws and Policies supporting the water sector, under the direction of the Ministries and Law Courts, which ensure non-violation of laws. Community norms and values, consisting of Nigerian traditional belief system, perceptions, attitude and reality (often undermined in favour of legislations), are relied on to pave the way for enforcement. While the Task Forces consist of community members with specific designation of duties, which ensure compliance and enforceability, a cross-section of community members are assigned duties. Thus, the principle of participation is pragmatically reflected. A review of the literature provided information on the potentials of the participatory process, in potable water governance. Qualitative methodology was explored by using the semi-structured interview as strategy for inquiry. The purposive sampling strategy, consisting of homogeneous, heterogeneous and criterion techniques was applied to enable sampling. The samples, sourced from diverse positions of life, were from the study area of Delta State of Nigeria, involving three local governments of Oshimili South, Uvwie and Warri South. From the findings, there are indications that the application of the participatory process is inhered with empowerment of the rural community members to make legitimate demands for TAP. This includes the obviation of mono-decision making for the supply and management of potable water. This is capable of restructuring the top-down management to a top-down/bottom-up system.

Keywords: participation, participatory process, participatory water governance, rural advisory board

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Authors: Mohammadjavad Sotoudeheian, Navid Farahmandian

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Cardiac hypertrophy arises in response to persistent increases in hemodynamic loads. In comparison, diabetic cardiomyopathy is defined by an abnormal myocardial changes without other cardiac-related risk factors. Pathological cardiac hypertrophy and myocardial remodeling are hallmarks of cardiovascular diseases and are risk factors for heart failure. The transcription factor forkhead box class O (FOXOs) can protect heart tissue by hostile oxidative stress and stimulating apoptosis and autophagy. FOXO proteins, as sensitive elements and mediators in response to environmental changes, have been revealed to prevent and inverse cardiac hypertrophy. FOXOs are inhibited by insulin and are critical mediators of insulin action. Insulin deficiency and uncontrolled diabetes lead to a catabolic state. FOXO1 acts downstream of the insulin-dependent pathways, which are dysregulated in diabetes. It regulates cardiomyocyte hypertrophy downstream of IGF1R/PI3K/Akt activation, which are critical regulators of cardiac hypertrophy. The complex network of signaling pathways comprising insulin/IGF-1 signaling, AMPK, JNK, and Sirtuins regulate the development of cardiovascular dysfunction by modulating the activity of FOXOs. Insulin receptors and IGF1R act via the PI3k/Akt and the MAPK/ERK pathways. Activation of Akt in response to insulin or IGF-1 induces phosphorylation of FOXOs. Increased protein synthesis induced by activation of the IGF-I/Akt/mTOR signaling pathway leads to hypertrophy. This pathway and the myostatin/Smad pathway are potent negative muscle development regulators. In cardiac muscle, insulin receptor substrates (IRS)-1 or IRS-2 activates the Akt signaling pathway and inactivate FOXO1. Under metabolic stress, p38 MAPK promotes degradation of IRS-1 and IRS-2 in cardiac myocytes and activates FOXO1, leading to cardiomyopathy. Sirt1 and FOXO1 interaction play an essential role in starvation-induced autophagy in cardiac metabolism. Inhibition of Angiotensin-II induced cardiomyocyte hypertrophy is associated with reduced FOXO1 acetylation and activation of Sirt1. The NF-κB, ERK, and FOXOs are de-acetylated by SIRT1. De-acetylation of FOXO1 induces the expression of genes involved in autophagy and stimulates autophagy flux. Therefore, under metabolic stress, FOXO1 can cause diabetic cardiomyopathy. The overexpression of FOXO1 leads to decreased cardiomyocyte size and suppresses cardiac hypertrophy through inhibition of the calcineurin–NFAT pathway. Diabetes mellitus is associated with elevation of O-GlcNAcylation. Some of its binding partners regulate the substrate selectivity of O-GlcNAc transferase (OGT). O-GlcNAcylation of essential contractile proteins may inhibit protein-protein interactions, reduce calcium sensitivity, and modulate contractile function. Uridine diphosphate (UDP)-GlcNAc is the obligatory substrate of OGT, which catalyzes a reversible post-translational protein modification. The increase of O-GlcNAcylation is accompanied by impaired cardiac hypertrophy in diabetic hearts. Inhibition of O-GlcNAcylation blocks activation of ERK1/2 and hypertrophic growth. O-GlcNAc modification on NFAT is required for its translocation from the cytosol to the nucleus, where NFAT stimulates the transcription of various hypertrophic genes. Inhibition of O-GlcNAcylation dampens NFAT-induced cardiac hypertrophic growth. Transcriptional activity of FOXO1 is enriched by improved O-GlcNAcylation upon high glucose stimulation or OGT overexpression. In diabetic conditions, the modification of FOXO1 by O-GlcNAc is promoted in cardiac troponin I and myosin light chain 2. Therefore targeting O-GlcNAcylation represents a potential therapeutic option to prevent hypertrophy in the diabetic heart.

Keywords: diabetes, cardiac hypertrophy, O-GlcNAcylation, FOXO1, Akt, PI3K, AMPK, insulin

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Authors: Yogesh Dalvi, Ruby Varghese, Nibu Varghese, C. K. Krishnan Nair

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Introduction: The Genus Phellinus, locally known as Phansomba is a well-known traditional folk medicine. Especially, in Western Ghats of India, many tribes use several species of Phellinus for various ailments related to teeth, throat, tongue, stomach and even wound healing. It is one of the few mushrooms which play a pivotal role in Ayurvedic Dravyaguna. Aim: The present study focuses on to investigate phytochemical analysis, antioxidant, and antitumor (in vitro and in vivo) potential of Phellinus robinae from South India, Kerala Material and Methods: The present study explores the following: 1. Phellinus samples were collected from Ranni, Pathanamthitta district of Kerala state, India from Artocarpus heterophyllus Lam. and species were identified using rDNA region. 2. The fruiting body was shadow dried, powdered and extracted with 50% alcohol using water bath at 60°C which was further condensed by rotary evaporator and lyophilized at minus 40°C temperature. 3. Secondary metabolites were analyzed by using various phytochemical screening assay (Hager’s Test, Wagner’s Test, Sodium hydroxide Test, Lead acetate Test, Ferric chloride Test, Folin-ciocalteu Test, Foaming Test, Benedict’s test, Fehling’s Test and Lowry’s Test). 4. Antioxidant and free radical scavenging activity were analyzed by DPPH, FRAP and Iron chelating assay. 5. The antitumor potential of Water alcohol extract of Phellinus (PAWE) is evaluated through In vitro condition by Trypan blue dye exclusion method in DLA cell line and In vivo by murine model. Result and Discussion: Preliminary phytochemical screening by various biochemical tests revealed presence of a variety of active secondary molecules like alkaloids, flavanoids, saponins, carbohydrate, protein and phenol. In DPPH and FRAP assay PAWE showed significantly higher antioxidant activity as compared to standard Ascorbic acid. While, in Iron chelating assay, PAWE exhibits similar antioxidant activity that of Butylated Hydroxytoluene (BHT) as standard. Further, in the in vitro study, PAWE showed significant inhibition on DLA cell proliferation in dose dependent manner and showed no toxicity on mice splenocytes, when compared to standard chemotherapy drug doxorubicin. In vivo study, oral administration of PAWE showed dose dependent tumor regression in mice and also raised the immunogenicity by restoring levels of antioxidant enzymes in liver and kidney tissue. In both in vitro and in vivo gene expression studies PAWE up-regulates pro-apoptotic genes (Bax, Caspases 3, 8 and 9) and down- regulates anti-apoptotic genes (Bcl2). PAWE also down regulates inflammatory gene (Cox-2) and angiogenic gene (VEGF). Conclusion: Preliminary phytochemical screening revealed that PAWE contains various secondary metabolites which contribute to its antioxidant and free radical scavenging property as evaluated by DPPH, FRAP and Iron chelating assay. PAWE exhibits anti-proliferative activity by the induction of apoptosis through a signaling cascade of death receptor-mediated extrinsic (Caspase8 and Tnf-α), as well as mitochondria-mediated intrinsic (caspase9) and caspase pathways (Caspase3, 8 and 9) and also by regressing angiogenic factor (VEGF) without any inflammation or adverse side effects. Hence, PAWE serve as a potential antioxidant and antitumor agent.

Keywords: antioxidant, antitumor, Dalton lymphoma ascites (DLA), fungi, Phellinus robinae

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Authors: Nanine Fouche

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The Cape Flats is a low-lying sand-covered expanse of approximately 460 square kilometres, situated to the southeast of the central business district of Cape Town in the Western Cape of South Africa. The aeolian sands masking this area are often loose and compressible in the upper 1m to 1.5m of the surface, and there is a general exceedance of the maximum allowable settlement in these sands. The settlement of shallow foundations on Cape Flats sands is commonly predicted using the results of in-situ tests such as the SPT or DPSH due to the difficulty of retrieving undisturbed samples for laboratory testing. Varying degrees of accuracy and reliability are associated with these methods. More recently, shear wave velocity (Vs) profiles obtained from seismic testing, such as continuous surface wave tests (CSW), are being used for settlement prediction. Such predictions have the advantage of considering non-linear stress-strain behaviour of soil and the degradation of stiffness with increasing strain. CSW tests are rarely executed in the Cape Flats, whereas SPT’s are commonly performed. For this reason, and to facilitate better settlement predictions in Cape Flats sand, equations representing shear wave velocity (Vs) as a function of SPT blow count (N60) and vertical effective stress (v’) were generated by statistical regression of site investigation data. To reveal the most appropriate method of overburden correction, analyses were performed with a separate overburden term (Pa/σ’v) as well as using stress corrected shear wave velocity and SPT blow counts (correcting Vs. and N60 to Vs1and (N1)60respectively). Shear wave velocity profiles and SPT blow count data from three sites masked by Cape Flats sands were utilised to generate 80 Vs-SPT N data pairs for analysis. Investigated terrains included sites in the suburbs of Athlone, Muizenburg, and Atlantis, all underlain by windblown deposits comprising fine and medium sand with varying fines contents. Elastic settlement analysis was also undertaken for the Cape Flats sands, using a non-linear stepwise method based on small-strain stiffness estimates, which was obtained from the best Vs-N60 model and compared to settlement estimates using the general elastic solution with stiffness profiles determined using Stroud’s (1989) and Webb’s (1969) SPT N60-E transformation models. Stroud’s method considers strain level indirectly whereasWebb’smethod does not take account of the variation in elastic modulus with strain. The expression of Vs. in terms of N60 and Pa/σv’ derived from the Atlantis data set revealed the best fit with R2 = 0.83 and a standard error of 83.5m/s. Less accurate Vs-SPT N relations associated with the combined data set is presumably the result of inversion routines used in the analysis of the CSW results showcasing significant variation in relative density and stiffness with depth. The regression analyses revealed that the inclusion of a separate overburden term in the regression of Vs and N60, produces improved fits, as opposed to the stress corrected equations in which the R2 of the regression is notably lower. It is the correction of Vs and N60 to Vs1 and (N1)60 with empirical constants ‘n’ and ‘m’ prior to regression, that introduces bias with respect to overburden pressure. When comparing settlement prediction methods, both Stroud’s method (considering strain level indirectly) and the small strain stiffness method predict higher stiffnesses for medium dense and dense profiles than Webb’s method, which takes no account of strain level in the determination of soil stiffness. Webb’s method appears to be suitable for loose sands only. The Versak software appears to underestimate differences in settlement between square and strip footings of similar width. In conclusion, settlement analysis using small-strain stiffness data from the proposed Vs-N60 model for Cape Flats sands provides a way to take account of the non-linear stress-strain behaviour of the sands when calculating settlement.

Keywords: sands, settlement prediction, continuous surface wave test, small-strain stiffness, shear wave velocity, penetration resistance

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Authors: Katie M. Clark, Adriana A. Tienda, Krista C. Paffenroth, Lindsey N. Brigante, Daniel C. Colvin, Jose Maldonado, Erin S. Calipari, Fiona E. Harrison

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Manganese (Mn) is an essential trace element required for human health and is important in antioxidant defenses, as well as in the development and function of dopaminergic neurons. However, chronic low-level Mn exposure, such as through contaminated drinking water, poses risks that may contribute to neurodevelopmental and neurodegenerative conditions, including attention deficit hyperactivity disorder (ADHD). Pharmacological inhibition of the dopamine transporter (DAT) blocks reuptake, elevates synaptic dopamine, and alleviates ADHD symptoms. This study aimed to determine whether Mn exposure in juvenile mice modifies their response to DAT blockers, amphetamine, and methylphenidate and utilize neuroimaging methods to visualize and quantify Mn distribution across dopaminergic brain regions. Male and female heterozygous DATᵀ³⁵⁶ᴹ and wild-type littermates were randomly assigned to receive control (2.5% Stevia) or high Manganese (2.5 mg/ml Mn + 2.5% Stevia) via water ad libitum from weaning (21-28 days) for 4-5 weeks. Mice underwent repeated testing in locomotor activity chambers for three consecutive days (60 mins.) to ensure that they were fully habituated to the environments. On the fourth day, a 3-hour activity session was conducted following treatment with amphetamine (3 mg/kg) or methylphenidate (5 mg/kg). The second drug was administered in a second 3-hour activity session following a 1-week washout period. Following the washout, the mice were given one last injection of amphetamine and euthanized one hour later. Using the ex-vivo brains, magnetic resonance relaxometry (MRR) was performed on a 7Telsa imaging system to map T1- and T2-weighted (T1W, T2W) relaxation times. Mn inherent paramagnetic properties shorten both T1W and T2W times, which enhances the signal intensity and contrast, enabling effective visualization of Mn accumulation in the entire brain. A subset of mice was treated with amphetamine 1 hour before euthanasia. SmartSPIM light sheet microscopy with cleared whole brains and cFos and tyrosine hydroxylase (TH) labeling enabled an unbiased automated counting and densitometric analysis of TH and cFos positive cells. Immunohistochemistry was conducted to measure synaptic protein markers and quantify changes in neurotransmitter regulation. Mn exposure elevated Mn brain levels and potentiated stimulant effects in males. The globus pallidus, substantia nigra, thalamus, and striatum exhibited more pronounced T1W shortening, indicating regional susceptibility to Mn accumulation (p<0.0001, 2-Way ANOVA). In the cleared whole brains, initial analyses suggest that TH and c-Fos co-staining mirrors behavioral data with decreased co-staining in DATT356M+/- mice. Ongoing studies will identify the molecular basis of the effect of Mn, including changes to DAergic metabolism and transport and post-translational modification to the DAT. These findings demonstrate that alterations in T1W relaxation times, as measured by MRR, may serve as an early biomarker for Mn neurotoxicity. This neuroimaging approach exhibits remarkable accuracy in identifying Mn-susceptible brain regions, with a spatial resolution and sensitivity that surpasses current conventional dissection and mass spectrometry approaches. The capability to label and map TH and cFos expression across the entire brain provides insights into whole-brain neuronal activation and its connections to functional neural circuits and behavior following amphetamine and methylphenidate administration.

Keywords: manganese, environmental toxicology, dopamine dysfunction, biomarkers, drinking water, light sheet microscopy, magnetic resonance relaxometry (MRR)

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Authors: Claire Harrison, Raajit K. Rampal, Vikas Gupta, Srdan Verstovsek, Moshe Talpaz, Jean-Jacques Kiladjian, Ruben Mesa, Andrew Kuykendall, Alessandro Vannucchi, Francesca Palandri, Sebastian Grosicki, Timothy Devos, Eric Jourdan, Marielle J. Wondergem, Haifa Kathrin Al-Ali, Veronika Buxhofer-Ausch, Alberto Alvarez-Larrán, Sanjay Akhani, Rafael Muñoz-Carerras, Yury Sheykin, Gozde Colak, Morgan Harris, John Mascarenhas

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Myelofibrosis (MF) is characterized by bone marrow fibrosis, anemia, splenomegaly and constitutional symptoms. Progressive bone marrow fibrosis results from aberrant megakaryopoeisis and expression of proinflammatory cytokines, both of which are heavily influenced by bromodomain and extraterminal domain (BET)-mediated gene regulation and lead to myeloproliferation and cytopenias. Pelabresib (CPI-0610) is an oral small-molecule investigational inhibitor of BET protein bromodomains currently being developed for the treatment of patients with MF. It is designed to downregulate BET target genes and modify nuclear factor kappa B (NF-κB) signaling. MANIFEST-2 was initiated based on data from Arm 3 of the ongoing Phase 2 MANIFEST study (NCT02158858), which is evaluating the combination of pelabresib and ruxolitinib in Janus kinase inhibitor (JAKi) treatment-naïve patients with MF. Primary endpoint analyses showed splenic and symptom responses in 68% and 56% of 84 enrolled patients, respectively. MANIFEST-2 (NCT04603495) is a global, Phase 3, randomized, double-blind, active-control study of pelabresib and ruxolitinib versus placebo and ruxolitinib in JAKi treatment-naïve patients with primary MF, post-polycythemia vera MF or post-essential thrombocythemia MF. The aim of this study is to evaluate the efficacy and safety of pelabresib in combination with ruxolitinib. Here we report updates from a recent protocol amendment. The MANIFEST-2 study schema is shown in Figure 1. Key eligibility criteria include a Dynamic International Prognostic Scoring System (DIPSS) score of Intermediate-1 or higher, platelet count ≥100 × 10^9/L, spleen volume ≥450 cc by computerized tomography or magnetic resonance imaging, ≥2 symptoms with an average score ≥3 or a Total Symptom Score (TSS) of ≥10 using the Myelofibrosis Symptom Assessment Form v4.0, peripheral blast count <5% and Eastern Cooperative Oncology Group performance status ≤2. Patient randomization will be stratified by DIPSS risk category (Intermediate-1 vs Intermediate-2 vs High), platelet count (>200 × 10^9/L vs 100–200 × 10^9/L) and spleen volume (≥1800 cm^3 vs <1800 cm^3). Double-blind treatment (pelabresib or matching placebo) will be administered once daily for 14 consecutive days, followed by a 7 day break, which is considered one cycle of treatment. Ruxolitinib will be administered twice daily for all 21 days of the cycle. The primary endpoint is SVR35 response (≥35% reduction in spleen volume from baseline) at Week 24, and the key secondary endpoint is TSS50 response (≥50% reduction in TSS from baseline) at Week 24. Other secondary endpoints include safety, pharmacokinetics, changes in bone marrow fibrosis, duration of SVR35 response, duration of TSS50 response, progression-free survival, overall survival, conversion from transfusion dependence to independence and rate of red blood cell transfusion for the first 24 weeks. Study recruitment is ongoing; 400 patients (200 per arm) from North America, Europe, Asia and Australia will be enrolled. The study opened for enrollment in November 2020. MANIFEST-2 was initiated based on data from the ongoing Phase 2 MANIFEST study with the aim of assessing the efficacy and safety of pelabresib and ruxolitinib in JAKi treatment-naïve patients with MF. MANIFEST-2 is currently open for enrollment.

Keywords: CPI-0610, JAKi treatment-naïve, MANIFEST-2, myelofibrosis, pelabresib

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Authors: David J. Foran, Nhan Do, Samuel Ajjarapu, Wenjin Chen, Tahsin Kurc, Joel H. Saltz

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The large-scale data and computational requirements of investigators throughout the clinical and research communities demand an informatics infrastructure that supports both existing and new investigative and translational projects in a robust, secure environment. In some subspecialties of medicine and research, the capacity to generate data has outpaced the methods and technology used to aggregate, organize, access, and reliably retrieve this information. Leading health care centers now recognize the utility of establishing an enterprise-wide, clinical data warehouse. The primary benefits that can be realized through such efforts include cost savings, efficient tracking of outcomes, advanced clinical decision support, improved prognostic accuracy, and more reliable clinical trials matching. The overarching objective of the work presented here is the development and implementation of a flexible Intelligent Retrieval and Interrogation System (IRIS) that exploits the combined use of computational imaging, genomics, and data-mining capabilities to facilitate clinical assessments and translational research in oncology. The proposed System includes a multi-modal, Clinical & Research Data Warehouse (CRDW) that is tightly integrated with a suite of computational and machine-learning tools to provide insight into the underlying tumor characteristics that are not be apparent by human inspection alone. A key distinguishing feature of the System is a configurable Extract, Transform and Load (ETL) interface that enables it to adapt to different clinical and research data environments. This project is motivated by the growing emphasis on establishing Learning Health Systems in which cyclical hypothesis generation and evidence evaluation become integral to improving the quality of patient care. To facilitate iterative prototyping and optimization of the algorithms and workflows for the System, the team has already implemented a fully functional Warehouse that can reliably aggregate information originating from multiple data sources including EHR’s, Clinical Trial Management Systems, Tumor Registries, Biospecimen Repositories, Radiology PAC systems, Digital Pathology archives, Unstructured Clinical Documents, and Next Generation Sequencing services. The System enables physicians to systematically mine and review the molecular, genomic, image-based, and correlated clinical information about patient tumors individually or as part of large cohorts to identify patterns that may influence treatment decisions and outcomes. The CRDW core system has facilitated peer-reviewed publications and funded projects, including an NIH-sponsored collaboration to enhance the cancer registries in Georgia, Kentucky, New Jersey, and New York, with machine-learning based classifications and quantitative pathomics, feature sets. The CRDW has also resulted in a collaboration with the Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC) at the U.S. Department of Veterans Affairs to develop algorithms and workflows to automate the analysis of lung adenocarcinoma. Those studies showed that combining computational nuclear signatures with traditional WHO criteria through the use of deep convolutional neural networks (CNNs) led to improved discrimination among tumor growth patterns. The team has also leveraged the Warehouse to support studies to investigate the potential of utilizing a combination of genomic and computational imaging signatures to characterize prostate cancer. The results of those studies show that integrating image biomarkers with genomic pathway scores is more strongly correlated with disease recurrence than using standard clinical markers.

Keywords: clinical data warehouse, decision support, data-mining, intelligent databases, machine-learning.

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