Targeting glioblastoma tumor hyaluronan to enhance therapeutic interventions that regulate metabolic cell properties.

Despite extensive advances in cancer research, glioblastoma (GBM) still remains a very locally invasive and thus challenging tumor to treat, with a poor median survival. Tumor cells remodel their microenvironment and utilize extracellular matrix to promote invasion and therapeutic resistance. We aim here to determine how GBM cells exploit hyaluronan (HA) to maintain proliferation using ligand-receptor dependent and ligand-receptor independent signaling. We use tissue engineering approaches to recreate the three-dimensional tumor microenvironment in vitro, then analyze shifts in metabolism, hyaluronan secretion, HA molecular weight distribution, as well as hyaluronan synthetic enzymes (HAS) and hyaluronidases (HYAL) activity in an array of patient derived xenograft GBM cells. We reveal that endogenous HA plays a role in mitochondrial respiration and cell proliferation in a tumor subtype dependent manner. We propose a tumor specific combination treatment of HYAL and HAS inhibitors to disrupt the HA stabilizing role in GBM cells. Taken together, these data shed light on the dual metabolic and ligand - dependent signaling roles of hyaluronan in glioblastoma. Significance: The control of aberrant hyaluronan metabolism in the tumor microenvironment can improve the efficacy of current treatments. Bioengineered preclinical models demonstrate potential to predict, stratify and accelerate the development of cancer treatments.

Local data commons: the sleeping beauty in the community of data commons.

BACKGROUND: Public Data Commons (PDC) have been highlighted in the scientific literature for their capacity to collect and harmonize big data. On the other hand, local data commons (LDC), located within an institution or organization, have been underrepresented in the scientific literature, even though they are a critical part of research infrastructure. Being closest to the sources of data, LDCs provide the ability to collect and maintain the most up-to-date, high-quality data within an organization, closest to the sources of the data. As a data provider, LDCs have many challenges in both collecting and standardizing data, moreover, as a consumer of PDC, they face problems of data harmonization stemming from the monolithic harmonization pipeline designs commonly adapted by many PDCs. Unfortunately, existing guidelines and resources for building and maintaining data commons exclusively focus on PDC and provide very little information on LDC. RESULTS: This article focuses on four important observations. First, there are three different types of LDC service models that are defined based on their roles and requirements. These can be used as guidelines for building new LDC or enhancing the services of existing LDC. Second, the seven core services of LDC are discussed, including cohort identification and facilitation of genomic sequencing, the management of molecular reports and associated infrastructure, quality control, data harmonization, data integration, data sharing, and data access control. Third, instead of commonly developed monolithic systems, we propose a new data sharing method for data harmonization that combines both divide-and-conquer and bottom-up approaches. Finally, an end-to-end LDC implementation is introduced with real-world examples. CONCLUSIONS: Although LDCs are an optimal place to identify and address data quality issues, they have traditionally been relegated to the role of passive data provider for much larger PDC. Indeed, many LDCs limit their functions to only conducting routine data storage and transmission tasks due to a lack of information on how to design, develop, and improve their services using limited resources. We hope that this work will be the first small step in raising awareness among the LDCs of their expanded utility and to publicize to a wider audience the importance of LDC.

Distal fibular excision: A review of the literature and presentation of our reconstruction technique case series.

Distal fibula resection is a procedure that has been described as early as 1938 for the treatment of neoplastic lesions. There have been several techniques described for the reconstruction of the remaining tibiotalar joint to prevent deformity and maintain as much function as possible. While these reconstruction techniques provide an option for limb salvage with the removal of disease, patients are faced with chronic pain, loss of function, valgus instability, need for long term orthosis, early arthritis, or significant morbidity related to proximal dissection and disruption of native knee anatomy. We present a case series that is compliant with PROCESS1 criteria to demonstrate the effective treatment with distal fibular excision and a reconstruction technique inspired by the original Tommy John procedure of the elbow. This procedure has allowed these two patients long-term stability of the ankle, maintenance of full function, and high levels of function. The first case is a 23-year-old female with high-grade osteosarcoma and the second patient is a 19-year-old female with Ewing sarcoma. Details of the procedure as well as clinical and radiographic follow up of these two patients will be described.

Web-based interactive mapping from data dictionaries to ontologies, with an application to cancer registry.

BACKGROUND: The Kentucky Cancer Registry (KCR) is a central cancer registry for the state of Kentucky that receives data about incident cancer cases from all healthcare facilities in the state within 6 months of diagnosis. Similar to all other U.S. and Canadian cancer registries, KCR uses a data dictionary provided by the North American Association of Central Cancer Registries (NAACCR) for standardized data entry. The NAACCR data dictionary is not an ontological system. Mapping between the NAACCR data dictionary and the National Cancer Institute (NCI) Thesaurus (NCIt) will facilitate the enrichment, dissemination and utilization of cancer registry data. We introduce a web-based system, called Interactive Mapping Interface (IMI), for creating mappings from data dictionaries to ontologies, in particular from NAACCR to NCIt. METHOD: IMI has been designed as a general approach with three components: (1) ontology library; (2) mapping interface; and (3) recommendation engine. The ontology library provides a list of ontologies as targets for building mappings. The mapping interface consists of six modules: project management, mapping dashboard, access control, logs and comments, hierarchical visualization, and result review and export. The built-in recommendation engine automatically identifies a list of candidate concepts to facilitate the mapping process. RESULTS: We report the architecture design and interface features of IMI. To validate our approach, we implemented an IMI prototype and pilot-tested features using the IMI interface to map a sample set of NAACCR data elements to NCIt concepts. 47 out of 301 NAACCR data elements have been mapped to NCIt concepts. Five branches of hierarchical tree have been identified from these mapped concepts for visual inspection. CONCLUSIONS: IMI provides an interactive, web-based interface for building mappings from data dictionaries to ontologies. Although our pilot-testing scope is limited, our results demonstrate feasibility using IMI for semantic enrichment of cancer registry data by mapping NAACCR data elements to NCIt concepts.

Chronic distal biceps avulsion treated with suture button.

BACKGROUND: Distal biceps tendon avulsions account for 3%-10% of all biceps ruptures. Treated nonoperatively, these injuries lead to a loss of endurance, supination strength, and flexion strength compared with operative repair or reconstruction. Operative management of chronic injury has classically been with graft tissue to augment the contracted muscle. We present our results for chronic distal biceps avulsions secured with suture button through a single transverse incision in high flexion without the need for allograft augmentation. MATERIALS AND METHODS: This was a retrospective review of 20 patients with 21 injuries who underwent primary surgical repair of chronic distal biceps tendon avulsions at an average of 10 weeks (range 4-42 weeks). All patients were treated with a single transverse incision with a suture button armed with nonabsorbable no. 2 core sutures. Postoperatively patients were found to have 50°-90° flexion contracture. All patients were placed in a simple sling postoperatively with gentle extension to gravity as tolerated immediately and no formal physical therapy. Patients were surveyed regarding pre- and postoperative American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES) score, visual analog scale (VAS) score, Mayo Elbow Performance Score (MEPS), Oxford Elbow Score (OES), and overall satisfaction. Range of motion (ROM), flexion, and supination strength compared to the contralateral uninjured extremity were evaluated at final follow-up. RESULTS: Mean clinical follow-up was 26 months. All patients regained full ROM and 5/5 flexion and supination strength at final follow-up. MEPSs were 100 for all responding patients compared with an average 47.5 preoperatively (P < .0001). The mean postoperative ASES score was 97.2 compared with 41.9 preoperatively (P < .0001). Mean OESs pre- and postoperatively were 24.2 and 48, respectively (P < .0001). The mean VAS score was 4.4 preoperatively and was reported as 0 by all patients at final follow-up (P < .0001). Two patients had transient sensory radial nerve neuropathy, and 1 patient has persistent palsy. No synostoses occurred. Four patients reported supination fatigue postoperatively compared with the uninjured extremity. CONCLUSION: Given these results, we feel that chronic distal biceps tendon ruptures can be repaired successfully with a single incision using suture button technique without the use of a graft. Though the flexion contracture is significant postoperatively, all patients regained full ROM and had excellent postoperative functional outcome scores.

Tau interacts with SHP2 in neuronal systems and in Alzheimer's disease brains.

Microtubule-associated protein tau, an integral component of neurofibrillary tangles, interacts with a variety of signaling molecules. Previously, our laboratory reported that nerve growth factor (NGF)-induced MAPK activation in a PC12-derived cell line was potentiated by tau, with phosphorylation at T231 being required. Therefore, we sought to identify a signaling molecule involved in the NGF-induced Ras-MAPK pathway that interacted with phospho-T231-tau. Here, we report that the protein tyrosine phosphatase SHP2 (also known as PTPN11) interacted with tau, with phospho-T231 significantly enhancing the interaction. By using proximity ligation assays, we found that endogenous tau-SHP2 complexes were present in neuronal cells, where the number of tau-SHP2 complexes significantly increased when the cells were treated with NGF, with phosphorylation at T231 being required for the increase. The interaction did not require microtubule association, and an association between tau and activated SHP2 was also found. Tau-SHP2 complexes were also found in both primary mouse hippocampal cultures and adult mouse brain. Finally, SHP2 levels were upregulated in samples from patients with mild and severe Alzheimer's disease (AD), and the level of tau-SHP2 complexes were increased in AD patient samples. These findings strongly suggest a role for the tau-SHP2 interaction in NGF-stimulated neuronal development and in AD.This article has an associated First Person interview with the first author of the paper.

Characterization of Squamous Cell Lung Cancers from Appalachian Kentucky.

BACKGROUND: Lung cancer is the leading cause of cancer mortality in the United States (U.S.). Squamous cell carcinoma (SQCC) represents 22.6% of all lung cancers nationally, and 26.4% in Appalachian Kentucky (AppKY), where death from lung cancer is exceptionally high. The Cancer Genome Atlas (TCGA) characterized genetic alterations in lung SQCC, but this cohort did not focus on AppKY residents. METHODS: Whole-exome sequencing was performed on tumor and normal DNA samples from 51 lung SQCC subjects from AppKY. Somatic genomic alterations were compared between the AppKY and TCGA SQCC cohorts. RESULTS: From this AppKY cohort, we identified an average of 237 nonsilent mutations per patient and, in comparison with TCGA, we found that PCMTD1 (18%) and IDH1 (12%) were more commonly altered in AppKY versus TCGA. Using IDH1 as a starting point, we identified a mutually exclusive mutational pattern (IDH1, KDM6A, KDM4E, JMJD1C) involving functionally related genes. We also found actionable mutations (10%) and/or intermediate or high-tumor mutation burden (65%), indicating potential therapeutic targets in 65% of subjects. CONCLUSIONS: This study has identified an increased percentage of IDH1 and PCMTD1 mutations in SQCC arising in the AppKY residents versus TCGA, with population-specific implications for the personalized treatment of this disease. IMPACT: Our study is the first report to characterize genomic alterations in lung SQCC from AppKY. These findings suggest population differences in the genetics of lung SQCC between AppKY and U.S. populations, highlighting the importance of the relevant population when developing personalized treatment approaches for this disease.

Survey of Antibiotic-producing Bacteria Associated with the Epidermal Mucus Layers of Rays and Skates.

Elasmobranchs represent a distinct group of cartilaginous fishes that harbor a remarkable ability to heal wounds rapidly and without infection. To date very little work has addressed this phenomenon although it is suggested that antibiotic capabilities associated with epidermal surfaces may be a factor. The study of benefits derived from mutualistic interactions between unicellular and multicellular organisms is a rapidly growing area of research. Here we survey and identify bacterial associates of three ray and one skate species in order to assess the potential for antibiotic production from elasmobranch associated bacteria as a novel source for new antibiotics.

Evaluation of an alternative extended-infusion piperacillin-tazobactam dosing strategy for the treatment of gram-negative infections.

Introduction To enhance the probability of pharmacodynamic target attainment, piperacillin-tazobactam can be administered as either a continuous or extended-infusion dosage regimen for the treatment of gram-negative infections. Four hour extended-infusions of piperacillin-tazobactam 3.375 g administered intravenously (IV) every 8 h have been widely studied as an alternative to conventional, intermittent dosage regimens with largely favorable outcomes. Objective To assess the clinical and economic impact of a novel 3-h extended-infusion piperacillin-tazobactam dosing strategy for the treatment of gram-negative infections. Setting 433-bed community hospital in Lexington, KY. Methods Retrospective cohort study before and after the implementation of an alternative dosing protocol using a 3-h infusion of piperacillin-tazobactam 3.375 g IV every 6 h. Main outcome measures The primary outcome was in-hospital mortality. Secondary outcomes include length of stay, ICU length of stay, 30-day all-cause hospital readmissions, total cost per admission, complications, and a composite of in-hospital mortality and readmission within 30 days of discharge. Results Readmission within 30 days of hospital discharge was significantly reduced in the extended-infusion arm (1.2 vs. 13.7 %, P = 0.002). A composite endpoint of death or readmission was lower among patients who received the extended-infusion dosing regimen [ORadj 0.20; 95 % CI (0.07-0.57)]. However this was likely driven by reductions in readmission. Conclusion An alternative regimen of extended-infusion piperacillin-tazobactam resulted in a significant reduction in 30-day all-cause hospital readmission. These results indicate that 3-h infusions of piperacillin-tazobactam 3.375 g IV every 6 h may represent a clinically effective alternative to other commonly used regimens and results in fewer readmissions within 30 days.

Collaborative learning in pre-clinical dental hygiene education.

PURPOSE: Dental hygiene education continues to move beyond mastery of content material and skill development to learning concepts that promote critical-thinking and problem-solving skills. The purpose of this research was to evaluate the effectiveness of collaborative learning and determine the growth in intellectual development of 54 first-year dental hygiene students. METHODS: The control group used traditional pre-clinical teaching and the experimental group used collaborative pedagogy for instrument introduction. All students were subjected to a post-test evaluating their ability to apply the principles of instrumentation. Intellectual development was determined using pre- and post-tests based on the Perry Scheme of Intellectual Development. Student attitudes were assessed using daily Classroom Assessment Activities and an end-of-semester departmental course evaluation. RESULTS: Findings indicated no significant difference between collaborative learning and traditional learning in achieving pre-clinical competence as evidenced by the students' ability to apply the principles of instrumentation. Advancement in intellectual development did not differ significantly between groups. Value added benefits of a collaborative learning environment as identified by the evaluation of student attitudes included decreased student reliance on authority, recognition of peers as legitimate sources of learning and increased self-confidence. A significant difference in student responses to daily classroom assessments was evident on the 5 days a collaborative learning environment was employed. CONCLUSION: Dental hygiene students involved in a pre-clinical collaborative learning environment are more responsible for their own learning and tend to have a more positive attitude toward the subject matter. Future studies evaluating collaborative learning in clinical dental hygiene education need to investigate the cost/benefit ratio of the value added outcomes of collaborative learning.

Decentralized formation flying control in a multiple-team hierarchy.

In recent years, formation flying has been recognized as an enabling technology for a variety of mission concepts in both the scientific and defense arenas. Examples of developing missions at NASA include magnetospheric multiscale (MMS), solar imaging radio array (SIRA), and terrestrial planet finder (TPF). For each of these missions, a multiple satellite approach is required in order to accomplish the large-scale geometries imposed by the science objectives. In addition, the paradigm shift of using a multiple satellite cluster rather than a large, monolithic spacecraft has also been motivated by the expected benefits of increased robustness, greater flexibility, and reduced cost. However, the operational costs of monitoring and commanding a fleet of close-orbiting satellites is likely to be unreasonable unless the onboard software is sufficiently autonomous, robust, and scalable to large clusters. This paper presents the prototype of a system that addresses these objectives-a decentralized guidance and control system that is distributed across spacecraft using a multiple team framework. The objective is to divide large clusters into teams of "manageable" size, so that the communication and computation demands driven by N decentralized units are related to the number of satellites in a team rather than the entire cluster. The system is designed to provide a high level of autonomy, to support clusters with large numbers of satellites, to enable the number of spacecraft in the cluster to change post-launch, and to provide for on-orbit software modification. The distributed guidance and control system will be implemented in an object-oriented style using a messaging architecture for networking and threaded applications (MANTA). In this architecture, tasks may be remotely added, removed, or replaced post launch to increase mission flexibility and robustness. This built-in adaptability will allow software modifications to be made on-orbit in a robust manner. The prototype system, which is implemented in Matlab, emulates the object-oriented and message-passing features of the MANTA software. In this paper, the multiple team organization of the cluster is described, and the modular software architecture is presented. The relative dynamics in eccentric reference orbits is reviewed, and families of periodic, relative trajectories are identified, expressed as sets of static geometric parameters. The guidance law design is presented, and an example reconfiguration scenario is used to illustrate the distributed process of assigning geometric goals to the cluster. Next, a decentralized maneuver planning approach is presented that utilizes linear-programming methods to enact reconfiguration and coarse formation keeping maneuvers. Finally, a method for performing online collision avoidance is discussed, and an example is provided to gauge its performance.

Sanguinaria toothpaste and oral rinse regimen clinical efficacy in short- and long-term trials.

Short- and long-term testing of sanguinaria toothpaste and oral rinse used individually have yielded both positive and negative results. This review evaluates the results of a number of clinical trials testing the regimen use of sanguinaria products for periods ranging from 14 days to six months. Review of these trials establishes the clinical efficacy of the two products in combination. The regimen approach produces consistently positive reductions in plaque, gingival inflammation and bleeding parameters for up to six months with no adverse hard tissue effects and only one reversible adverse soft tissue effect observed among the 260 subjects tested. In addition, no adverse microbiological shifts in the normal oral flora were observed.