bluuebunny/crossref_metadata_2025 huggingface dataset:
Cytosine methylation of mature microRNAs inhibits their functions and is associated with poor prognosis in glioblastoma multiforme
Authors: Cheray Mathilde , Etcheverry Amandine , Jacques Camille , Pacaud Romain , Bougras-Cartron Gwenola , Aubry Marc , Denoual Florent , Peterlongo Pierre , Nadaradjane Arulraj , Briand Joséphine , Akcha Farida , Heymann Dominique , Vallette François M. , Mosser Jean , Ory Benjamin , Cartron Pierre-François
Published: February 2020

Background

Literature reports that mature microRNA (miRNA) can be methylated at adenosine, guanosine and cytosine. However, the molecular mechanisms involved in cytosine methylation of miRNAs have not yet been fully elucidated. Here we investigated the biological role and underlying mechanism of cytosine methylation in miRNAs in glioblastoma multiforme (GBM).

Methods

RNA immunoprecipitation with the anti-5methylcytosine (5mC) antibody followed by Array, ELISA, dot blot, incorporation of a radio-labelled methyl group in miRNA, and miRNA bisulfite sequencing were perfomred to detect the cytosine methylation in mature miRNA. Cross-Linking immunoprecipiation qPCR, transfection with methylation/unmethylated mimic miRNA, luciferase promoter reporter plasmid, Biotin-tagged 3’UTR/mRNA or miRNA experiments and in vivo assays were used to investigate the role of methylated miRNAs. Finally, the prognostic value of methylated miRNAs was analyzed in a cohorte of GBM pateints.

Results

Our study reveals that a significant fraction of miRNAs contains 5mC. Cellular experiments show that DNMT3A/AGO4 methylated miRNAs at cytosine residues inhibit the formation of miRNA/mRNA duplex and leading to the loss of their repressive function towards gene expression. In vivo experiments show that cytosine-methylation of miRNA abolishes the tumor suppressor function of miRNA-181a-5p miRNA for example. Our study also reveals that cytosine-methylation of miRNA-181a-5p results is associated a poor prognosis in GBM patients.

Conclusion

Together, our results indicate that the DNMT3A/AGO4-mediated cytosine methylation of miRNA negatively.

Graphical abstract
Oral typhoid vaccine Ty21a elicits antigen-specific resident memory CD4+ T cells in the human terminal ileum lamina propria and epithelial compartments
Authors: Booth Jayaum S. , Goldberg Eric , Barnes Robin S. , Greenwald Bruce D. , Sztein Marcelo B.
Published: February 2020

Background

Salmonellaenterica serovar Typhi (S. Typhi) is a highly invasive bacterium that infects the human intestinal mucosa and causes ~ 11.9–20.6 million infections and ~ 130,000–223,000 deaths annually worldwide. Oral typhoid vaccine Ty21a confers a moderate level of long-lived protection (5–7 years) in the field. New and improved vaccines against enteric pathogens are needed but their development is hindered by a lack of the immunological correlates of protection especially at the site of infection. Tissue resident memory T (TRM) cells provide immediate adaptive effector immune responsiveness at the infection site. However, the mechanism(s) by whichS. Typhi induces TRMin the intestinal mucosa are unknown. Here, we focus on the induction ofS.Typhi-specific CD4+TRMsubsets by Ty21a in the human terminal ileum lamina propria and epithelial compartments.

Methods

Terminal ileum biopsies were obtained from consenting volunteers undergoing routine colonoscopy who were either immunized orally with 4 doses of Ty21a or not. Isolated lamina propria mononuclear cells (LPMC) and intraepithelial lymphocytes (IEL) CD4+TRMimmune responses were determined using eitherS. Typhi-infected or non-infected autologous EBV-B cell lines as stimulator cells. T-CMI was assessed by the production of 4 cytokines [interferon (IFN)γ, interleukin (IL)-2, IL-17A and tumor necrosis factor (TNF)α] in 36 volunteers (18 vaccinees and 18 controls volunteers).

Results

Although the frequencies of LPMC CD103+ CD4+TRMwere significant decreased, both CD103+ and CD103− CD4+TRMsubsets spontaneously produced significantly higher levels of cytokines (IFNγ and IL-17A) following Ty21a-immunization. Importantly, we observed significant increases inS. Typhi-specific LPMC CD103+ CD4+TRM(IFNγ and IL-17A) and CD103− CD4+TRM(IL-2 and IL-17A) responses following Ty21a-immunization. Further, differences inS. Typhi-specific responses between these two CD4+TRMsubsets were observed following multifunctional analysis. In addition, we determined the effect of Ty21a-immunization on IEL and observed significant changes in the frequencies of IEL CD103+ (decrease) and CD103− CD4+TRM(increase) following immunization. Finally, we observed that IEL CD103− CD4+TRM, but not CD103+ CD4+TRM, produced increased cytokines (IFNγ, TNFα and IL-17A) toS. Typhi-specific stimulation following Ty21a-immunization.

Conclusions

Oral Ty21a-immunization elicits distinct compartment specific immune responses in CD4+TRM(CD103+ and CD103−) subsets. This study provides novel insights in the generation of local vaccine-specific responses.

Trial registrationThis study was approved by the Institutional Review Board and registered on ClinicalTrials.gov (identifierNCT03970304, Registered 29 May 2019—Retrospectively registered,http://www.ClinicalTrials.gov/NCT03970304)
Population-level investigation of the knowledge of ocular chemical injuries and proper immediate action
Authors: Seraj Hadeel , Khawandanh Shahad , Fatani Arwa , Saeed Afnan , Alotaibi Ghadeer , Basheikh Ahmed
Published: February 2020

Objective

Although the eyes occupy 0.1% of the total body surface, eye injuries are serious because vision is arguably the most important sense. We aimed to assess knowledge of Saudi Arabian residents regarding steps to be taken in cases of chemical eye injury, in order to promote awareness of such procedures.

Results

A cross-sectional design was done. A random sampling method was utilized to select 888 individuals in the Saudi community. Participants completed an electronic closed ended, validated, anonymous, self-administered questionnaire. Two experts assessed content and face validity. Respondents were 18–29 years of age. 74 (8.3%) had a history of chemical eye injury. Regarding the first step taken in case of chemical eye injury, 697 (78.5%) respondents indicated washing with water, 164 (18.5%) indicated visiting the emergency department, 11 (1.2%) indicated using eye drops, and 5 (0.6%) indicated covering the eye immediately. Seventy-five (8.4%) respondents agreed that an eye injured with an acidic material should be washed with an alkaline solution. These results should be confirmed by health authorities and appropriate interventions should be developed for improving knowledge among masses, thereby promoting a healthier society.
Return to education and financial value of investment in higher education in Indonesia
Authors: Yubilianto
Published: February 2020

While there is extensive literature discussing the return to education using the remarkable semi-log Mincer equation, very few studies utilize the full discounting method to examine the impact of education investment from an individual perspective. This paper tries to analyze the return to higher education in Indonesia through the full discounting method mainly using the Indonesia Family Life Survey wave 5 (IFLS-5) and Synthetic Work-life Earnings (SWE) estimation. The results indicate that the median college graduate workers earn about 60% higher salary than that of secondary school leavers. With 4 years to complete a college degree, this figure indicates that the return to higher education is implicitly around 15%, which is similar to the result of the Mincer earnings equation analysis. Moreover, it takes at least 14 years of working time to compensate for the investment in getting a bachelor’s degree. These findings suggest that households should consider spending their money for university education. Likewise, the government and financial institutions can provide a better loan policy for higher education.
Implementation science made too simple: a teaching tool
Authors: Curran Geoffrey M.
Published: February 2020

Background

The field of implementation science is growing and becoming more complex. When teaching new learners, providing a clear definition of implementation science and a description of “its place” among related fields can be difficult. The author developed a teaching tool using very simple language to help learners grasp key concepts in implementation science.

The teaching tool

The tool consists of a slide (visual aid) which provides simple and jargon-free definitions of implementation science, implementation strategies, and implementation outcomes, as well as a description of how implementation science relates to “effectiveness” research focusing on clinical/preventive interventions.

Conclusion

The tool could be useful to new students in the field, as well as other scholars or stakeholders in need of a brief and plain language introduction to key concepts in implementation science.
Practitioner perspectives on building capacity for evidence-based public health in state health departments in the United States: a qualitative case study
Authors: Mazzucca Stephanie , Valko Cheryl A. , Eyler Amy A. , Macchi Marti , Lau Andrew , Alongi Jeanne , Robitscher John , Brownson Ross C.
Published: February 2020

Background

Public health agencies are responsible for implementing effective, evidence-based public health programs and policies to reduce the burden of chronic diseases. Evidence-based public health can be facilitated by modifiable administrative evidence-based practices (A-EBPs) (e.g., workforce development, organizational climate), yet little is known about how practitioners view A-EBPs. Thus, the purpose of this qualitative study was to understand state health department practitioners’ perceptions about how A-EBPs are implemented and what facilitators and barriers exist to using A-EBPs.

Methods

Chronic disease prevention and health promotion program staff who were members of the National Association of Chronic Disease Directors were recruited to participate in telephone interviews using a snowball sampling technique. Interviews were transcribed verbatim, and transcripts were analyzed using a common codebook and the a priori method in NVivo.

Results

Twenty seven interviews were conducted with practitioners in four states (5–8 interviews per state). All practitioners felt that their work unit culture is positive and that leadership encouraged and expected staff to use evidence-based processes. Participants discussed the provision of trainings and technical assistance as key to workforce development and how leaders communicate their expectations. Access to evidence, partnerships, and funding restrictions were the most commonly discussed barriers to the use of A-EBPs and EBDM.

Conclusions

Results of this study highlight practitioners’ perspectives on promoting evidence-based public health in their departments. Findings can inform the development and refinement of resources to improve A-EBP use and organizational and leadership capacity of state health departments.
How can evidence-based interventions give the best value for users in social services? Balance between adherence and adaptations: a study protocol
Authors: Hasson Henna , Gröndal Hedvig , Rundgren Åsa Hedberg , Avby Gunilla , Uvhagen Håkan , von Thiele Schwarz Ulrica
Published: February 2020

Background

Using evidence-based interventions (EBIs) is a basic premise of contemporary social services (e.g., child and family social services). However, EBIs seldom fit seamlessly into a specific setting but often need to be adapted. Although some adaptions might be necessary, they can cause interventions to be less effective or even unsafe. The challenge of balancing adherence and adaptations when using EBIs is often referred to as the adherence and adaptation dilemma. Although the current literature identifies professionals’ management of this dilemma as problematic, it offers little practical guidance for professionals. This research aims to investigate how the adherence and adaptation dilemma is handled in social services and to explore how structured decision support can impact the management of the dilemma.

Methods

The design is a prospective, longitudinal intervention with a focus on the feasibility and usefulness of the structured decision support. The project is a collaboration between academic researchers, embedded researchers at three research and development units, and social service organizations. A multi-method data collection will be employed. Initially, a scoping review will be performed, and the results will be used in the development of a structured decision support. The decision support will be further developed and tested during a series of workshops with social service professionals. Different forms of data—focus group interviews, questionnaires, and documentation—will be used on several occasions to evaluate the impact of the structured decision support. Qualitative and quantitative analysis will be performed and usefulness for practice prioritized throughout the study.

Discussion

The study will contribute with knowledge on how the adherence and adaption dilemma is handled and experienced by social service professionals. Most importantly, the study will generate rich empirical data on how a structured decision support impacts professionals’ management of adherence and adaptions. The goal is to produce more strategic and context-sensitive implementation of EBIs in social service, which will increase value for service users.
Development of a theory-driven implementation strategy for cancer management guidelines in sub-Saharan Africa
Authors: DeBoer Rebecca J. , Ndumbalo Jerry , Meena Stephen , Ngoma Mamsau T. , Mvungi Nanzoke , Siu Sadiq , Selekwa Msiba , Nyagabona Sarah K. , Luhar Rohan , Buckle Geoffrey , Lin Tracy Kuo , Breithaupt Lindsay , Kennell-Heiling Stephanie , Mushi Beatrice , Philipo Godfrey Sama , Mmbaga Elia J. , Mwaiselage Julius , Van Loon Katherine
Published: February 2020

Background

Despite recent international efforts to develop resource-stratified clinical practice guidelines for cancer, there has been little research to evaluate the best strategies for dissemination and implementation in low- and middle-income countries (LMICs). Guideline publication alone is insufficient. Extensive research has shown that structured, multifaceted implementation strategies that target barriers to guideline use are most likely to improve adherence; however, most of this research has been conducted in high-income countries. There is a pressing need to develop and evaluate guideline implementation strategies for cancer management in LMICs in order to address stark disparities in cancer outcomes.

Methods

In preparation for the launch of Tanzania’s first National Cancer Treatment Guidelines, we developed a theory-driven implementation strategy for guideline-based practice at Ocean Road Cancer Institute (ORCI). Here, we use the Intervention Mapping framework to provide a detailed stepwise description of our process. First, we conducted a needs assessment to identify barriers and facilitators to guideline-based practice at ORCI. Second, we defined both proximal and performance objectives for our implementation strategy. Third, we used the Capability, Opportunity, Motivation and Behavior/Behavior Change Wheel (COM-B/BCW) framework to categorize the barriers and facilitators, choose behavior change techniques most likely to overcome targeted barriers and leverage facilitators, and select a feasible mode of delivery for each technique. Fourth, we organized these modes of delivery into a phased implementation strategy. Fifth, we operationalized each component of the strategy. Sixth, we identified the indicators of the process, outcome, and impact of our intervention and developed an evaluation plan to measure them using a mixed methods approach.

Discussion

We developed a robust, multifaceted guideline implementation strategy derived from a prominent behavior change theory for use in Tanzania. The barriers and strategies we generated are consistent with those well established in the literature, enhancing the validity and generalizability of our process and results. Through our rigorous evaluation plan and systematic account of modifications and adaptations, we will characterize the transferability of “proven” guideline implementation strategies to LMICs. We hope that by describing our process in detail, others may endeavor to replicate it, meeting a widespread need for dedicated efforts to implement cancer guidelines in LMICs.
Improving the implementation and sustainment of evidence-based practices in community mental health organizations: a study protocol for a matched-pair cluster randomized pilot study of the Collaborative Organizational Approach to Selecting and Tailoring Implementation Strategies (COAST-IS)
Authors: Powell Byron J. , Haley Amber D. , Patel Sheila V. , Amaya-Jackson Lisa , Glienke Beverly , Blythe Mellicent , Lengnick-Hall Rebecca , McCrary Stacey , Beidas Rinad S. , Lewis Cara C. , Aarons Gregory A. , Wells Kenneth B. , Saldana Lisa , McKay Mary M. , Weinberger Morris
Published: February 2020

Background

Implementing and sustaining evidence-based programs with fidelity may require multiple implementation strategies tailored to address multi-level, context-specific barriers and facilitators. Ideally, selecting and tailoring implementation strategies should be guided by theory, evidence, and input from relevant stakeholders; however, methods to guide the selection and tailoring of strategies are not well-developed. There is a need for more rigorous methods for assessing and prioritizing implementation determinants (barriers and facilitators) and linking implementation strategies to determinants. The Collaborative Organizational Approach to Selecting and Tailoring Implementation Strategies (COAST-IS) is an intervention designed to increase the effectiveness of evidence-based practice implementation and sustainment. COAST-IS will enable organizational leaders and clinicians to use Intervention Mapping to select and tailor implementation strategies to address their site-specific needs. Intervention Mapping is a multi-step process that incorporates theory, evidence, and stakeholder perspectives to ensure that implementation strategies effectively address key determinants of change.

Methods

COAST-IS will be piloted with community mental health organizations that are working to address the needs of children and youth who experience trauma-related emotional or behavioral difficulties by engaging in a learning collaborative to implement an evidence-based psychosocial intervention (trauma-focused cognitive behavioral therapy). Organizations will be matched and then randomized to participate in the learning collaborative only (control) or to receive additional support through COAST-IS. The primary aims of this study are to (1) assess the acceptability, appropriateness, feasibility, and perceived utility of COAST-IS; (2) evaluate the organizational stakeholders’ fidelity to the core elements of COAST-IS; and (3) demonstrate the feasibility of testing COAST-IS in a larger effectiveness trial.

Discussion

COAST-IS is a systematic method that integrates theory, evidence, and stakeholder perspectives to improve the effectiveness and precision of implementation strategies. If effective, COAST-IS has the potential to improve the implementation and sustainment of a wide range of evidence-based practices in mental health and other sectors.

Trial registration

This study was registered in ClinicalTrials.gov (NCT03799432) on January 10, 2019 (last updated August 5, 2019).
Effectiveness of confidential reports to physicians on their prescribing of antipsychotic medications in nursing homes
Authors: Ivers Noah M. , Taljaard Monica , Giannakeas Vasily , Reis Catherine , Mulhall Cara L. , Lam Jonathan M.C. , Burchell Ann N. , Lebovic Gerald , Bronskill Susan E.
Published: February 2020

Background

Antipsychotic medication use in nursing homes is associated with potential for harms. In Ontario, Canada, an agency of the provincial government offers nursing home physicians quarterly audit and feedback on their antipsychotic prescribing. We compared the characteristics of physicians who did and did not engage with the intervention, and assessed early changes in prescribing.

Methods

This population-level, retrospective cohort study used linked administrative databases to track prescribing practices in nursing homes pre-intervention (baseline), immediately post-initiative (3 months), and at follow-up (6 months). Exposure variables identified whether a physician signed up to participate (or not) or viewed the feedback following sign up (or not). Differences in the proportion of days that residents received antipsychotic medications at 6 months compared to baseline by exposure(s) were assessed using a linear mixed effects regression analysis to adjust for a range of resident, physician, and nursing home factors. Benzodiazepine and statin prescribing were assessed as a balance and tracer measures, respectively.

Results

Of 944 eligible physicians, 210 (22.3%) signed up to recieve the feedback report and 132 (13.9%) viewed their feedback. Physicians who signed up for feedback were more likely to have graduated from a Canadian medical school, work in urban nursing homes, and care for a larger number of residents. The clinical and functional characteristics of residents were similar across physician exposure groups. At 6 months, antipsychotic prescribing had decreased in all exposure groups. Those who viewed their feedback report had a signicantly greater reduction in antipsychotic prescribing than those who did not sign up (0.94% patient-days exposed; 95% CI 0.35 to 1.54%, p = 0.002). Trends in prescribing patterns across exposure groups for benzodiazepines and statins were not statistically significant.

Interpretation

Almost a quarter of eligible physicians engaged early in a voluntary audit and feedback intervention related to antipsychotic prescribing in nursing homes. Those who viewed their feedback achieved a small but statistically significant change in prescribing, equivalent to approximately 14,000 fewer days that nursing home residents received antipsychotic medications over 6 months. This study adds to the literature regarding the role of audit and feedback interventions to improve quality of care.
Welcome to Implementation Science Communications
Authors: Armstrong Rebecca , Sales Anne
Published: February 2020

Implementation research in health is a rapidly growing field. Fourteen years after the launch of Implementation Science, submissions to the journal have grown exponentially, and the journal now uses a high bar for assessing submitted manuscripts. The field of implementation research in health, however, is growing largely through entry of junior researchers with keen interest in the field whose funding histories and research experience are still developing. We consider it essential to support newer entrants to the field and boundary-spanning work that may consist of smaller, pilot studies, as well as those that contribute primarily descriptive findings.

As a companion journal to Implementation Science, Implementation Science Communications will accept a broad and diverse range of article types, and provide an important platform for smaller scale or more descriptive research. As with Implementation Science, no specific discipline, research design, or paradigm will be favoured.
Exploring Integrative Analysis Using the BioMedical Evidence Graph
Authors: Struck Adam , Walsh Brian , Buchanan Alexander , Lee Jordan A. , Spangler Ryan , Stuart Joshua M. , Ellrott Kyle
Published: February 2020

PURPOSE

The analysis of cancer biology data involves extremely heterogeneous data sets, including information from RNA sequencing, genome-wide copy number, DNA methylation data reporting on epigenetic regulation, somatic mutations from whole-exome or whole-genome analyses, pathology estimates from imaging sections or subtyping, drug response or other treatment outcomes, and various other clinical and phenotypic measurements. Bringing these different resources into a common framework, with a data model that allows for complex relationships as well as dense vectors of features, will unlock integrated data set analysis.

METHODS

We introduce the BioMedical Evidence Graph (BMEG), a graph database and query engine for discovery and analysis of cancer biology. The BMEG is unique from other biologic data graphs in that sample-level molecular and clinical information is connected to reference knowledge bases. It combines gene expression and mutation data with drug-response experiments, pathway information databases, and literature-derived associations.

RESULTS

The construction of the BMEG has resulted in a graph containing > 41 million vertices and 57 million edges. The BMEG system provides a graph query–based application programming interface to enable analysis, with client code available for Python, Javascript, and R, and a server online at bmeg.io. Using this system, we have demonstrated several forms of cross–data set analysis to show the utility of the system.

CONCLUSION

The BMEG is an evolving resource dedicated to enabling integrative analysis. We have demonstrated queries on the system that illustrate mutation significance analysis, drug-response machine learning, patient-level knowledge-base queries, and pathway level analysis. We have compared the resulting graph to other available integrated graph systems and demonstrated the former is unique in the scale of the graph and the type of data it makes available.
TBCRC 031: Randomized Phase II Study of Neoadjuvant Cisplatin Versus Doxorubicin-Cyclophosphamide in Germline BRCA Carriers With HER2-Negative Breast Cancer (the INFORM trial)
Authors: Tung Nadine , Arun Banu , Hacker Michele R. , Hofstatter Erin , Toppmeyer Deborah L. , Isakoff Steven J. , Borges Virginia , Legare Robert D. , Isaacs Claudine , Wolff Antonio C. , Marcom Paul Kelly , Mayer Erica L. , Lange Paulina B. , Goss Andrew J. , Jenkins Colby , Krop Ian E. , Winer Eric P. , Schnitt Stuart J. , Garber Judy E.
Published: February 2020

PURPOSE

Platinum compounds have activity in triple-negative breast cancer (TNBC) in germline BRCA mutation carriers ( BRCA carriers). Limited data exist for estrogen receptor (ER)–positive (+) breast cancer among BRCA carriers. INFORM is a randomized, multicenter, phase II trial comparing pathologic complete response (pCR) rates (ypT0/is, N0) after neoadjuvant single-agent cisplatin (CDDP) versus doxorubicin-cyclophosphamide (AC) in BRCA carriers with stage I-III human epidermal growth factor receptor 2 (HER2)–negative breast cancer. Secondary objectives included residual cancer burden scores (RCB) of 0 or 1 (combined) and toxicity. The goal was to determine whether pCR was ≥ 20% higher with CDDP than AC.

PATIENTS AND METHODS

BRCA carriers with cT1-3 (≥ 1.5 cm), cN0-3 HER2-negative breast cancer were randomly assigned to preoperative CDDP (75 mg/m2 every 3 weeks × 4 doses) or AC (doxorubicin 60 mg/m2; cyclophosphamide 600 mg/m2 every 2-3 weeks × 4 doses) followed by surgery. Pathologic responses were confirmed by central review.

RESULTS

A total of 118 patients were randomly assigned; 117 were included in outcome analyses. Mean age was 42 years (range, 24-73 years); 69% were BRCA1+, 30% were BRCA2+, and 2% had both mutations. Clinical stage was I for 19%, II for 63%, and III for 18%; 45% had nodal involvement at baseline. Seventy percent had TNBC. Clinical and tumor characteristics were well matched between treatment arms. The pCR rate was 18% with CDDP and 26% with AC, yielding a risk ratio (RR) of 0.70 (90% CI, 0.39 to 1.2). The risk of RCB 0 or 1 (RCB 0/1) was 33% with CDDP and 46% with AC (RR, 0.73; 90% CI, 0.50 to 1.1). Both regimens were generally well tolerated without unexpected toxicities.

CONCLUSION

pCR or RCB 0/1 is not significantly higher with CDDP than with AC in BRCA carriers with stage I-III HER2-negative breast cancer for both TNBC and ER+/HER2-negative disease.
End of phase I results of ZUMA-3, a phase 1/2 study of KTE-X19, anti-CD19 chimeric antigen receptor (CAR) T cell therapy, in adult patients (pts) with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL).
Authors: Shah Bijal D. , Bishop Michael Russell , Oluwole Olalekan O. , Logan Aaron , Baer Maria R. , Donnellan William Bruce , Carr-O'Dwyer Kristen Marie , Holmes Houston , Arellano Martha Lucia , Ghobadi Armin , Pagel John M. , Lin Yi , Cassaday Ryan Daniel , Park Jae Hong , Mardiros Armen , Shen Tong , Goyal Lovely , Vezan Remus , Jain Rajul K. , Wierda William G.
Published: February 2020

7006

Background: KTE-X19 is an autologous anti-CD19 CAR T cell therapy under investigation for adult R/R ALL. In an interim analysis of Phase 1 of ZUMA-3, we reported manageable safety and encouraging efficacy of KTE-X19; 72% of pts achieved a complete remission (CR) or CR with incomplete bone marrow (BM) recovery (CRi; Wierda et al, ASH 2018. #897). Here, we present end of Phase 1 results. Methods: Adults with R/R B cell ALL, > 5% BM blasts, and ECOG 0-1 received 2, 1, or 0.5 × 106 KTE-X19 cells/kg after conditioning chemotherapy. Revised adverse event management (rAE mgmt) was implemented for additional pts in a 1 × 106 dose cohort: corticosteroids were given earlier at onset of Grade ≥ 2 neurologic events (NEs) and tocilizumab was used only for active toxicity. The primary endpoint was the dose-limiting toxicity (DLT) rate. Key additional endpoints were KTE-X19 levels, incidence of AEs, minimal residual disease (MRD), and CR/CRi rate. Results: As of 9/27/18, 45 pts had received KTE-X19 (median follow-up [f/u], 16 mo). The median age was 46 y (range, 18–77); 30 pts (66%) had ≥ 3 prior therapies and the median pre-conditioning BM blasts was 70% (range, 0–97). Six, 23, and 16 pts received 2, 1, and 0.5 × 106 cells/kg, respectively. There were no DLTs in the DLT-evaluable pts. The most common Grade ≥ 3 AEs were hypotension (38%), pyrexia (38%) and thrombocytopenia (31%). There were 2 previously reported KTE-X19–related Grade 5 AEs of cerebral infarction and multiorgan failure, both in the context of CRS. Grade ≥ 3 CRS and NEs occurred in 13 (29%) and 17 (38%) pts, respectively. Of 41 pts with ≥ 2 mo of f/u, 68% had CR/CRi, and 73% had undetectable MRD. Of 19 pts with ≥ 2 mo of f/u treated with 1 × 106 cells/kg, 16 (84%) had a CR/CRi and the median event-free survival was 15 mo. In 9 pts treated with 1 × 106 cells/kg and rAE mgmt, 2 (22%) had Grade 3 CRS and 1 (11%) had Grade 3 NE with no Grade 4/5 events. Conclusions: KTE-X19 dosing and safety mgmt have been successfully refined by testing 3 cell doses and evaluating a new AE mgmt guideline with altered corticosteroids/tocilizumab use for NE/CRS. Pivotal Phase 2 is ongoing at the 1 × 106 dose with rAE mgmt. Clinical trial information: NCT02614066.
Effective targeted antitumor activity of the antimicrobial agent taurolidine against relapsed/refractory neuroblastoma: Cytotoxicity, target modulation and tumor xenograft studies.
Authors: Swift Lucy , Zhang Chunfen , Pfaffle Antony , Chew Paul , Kovalchuk Olga , Trippett Tanya Maria , Narendran Aru
Published: February 2020

e21502

Background: Neuroblastoma (NB) is the most common extracranial solid tumor and one of the most complex and difficult to treat diseases in pediatrics. Currently, even with highly aggressive treatment protocols, the prognosis for patients with high-risk and relapsed NB remains poor. Hence, there is a clear need to identify new agents and novel therapeutic strategies for the treatment of these children. Taurolidine (TRD) is derived from the aminosulfoacid taurine and has known anti-microbial and anti-inflammatory properties. TRD has demonstrated anti-neoplastic activity against a range of aggressive human tumors. We present mechanistic evidence and supportive preclinical data from in vitro and animal models of refractory NB for the development of an early phase clinical trial incorporating TRD. Methods: For in vitro activity studies, a panel of cell lines derived from patients with relapsed NB (n = 6) and normal control cells were treated with increasing concentrations of TRD and cell viability was measured by alamar blue assay. Phase-contrast light microscopy, western blotting, time-lapse video microscopy and analysis of global gene expression by RNA-Seq were used to evaluate target modulation and induction of cell death pathways. Bioluminescence imaging of mice bearing NB xenografts treated with TRD was used to investigate the efficacy of TRD in vivo. Results: Cell survival data showed that TRD is cytotoxic against NB cell lines in vitro (mean IC50 value 100 µM, range 65-135 µM). Phase-contrast and time-lapse video microscopy confirmed the antitumor effects of TRD. Western blot analyses identified that TRD induced target modulation and an effective apoptotic cascade, resulting in PARP cleavage. Gene expression analyses and signaling pathway activation scores indicated alterations in the Notch, MAPK and IL-10 signaling pathways. Xenograft studies further validated the in vivo activity of TRD with decreased tumor burden in treated mice and a measurable improvement in survival. Conclusions: Our study provides key pre-clinical data on the activity and mechanism of action of TRD against NB. The findings support the rationale for further evaluation of TRD for the treatment of relapsed/refractory NB patients in an early phase clinical trial.
Histone variant dictates fate biasing of neural crest cells to melanocyte lineage
Authors: Raja Desingu Ayyappa , Subramaniam Yogaspoorthi , Aggarwal Ayush , Gotherwal Vishvabandhu , Babu Aswini , Tanwar Jyoti , Motiani Rajender K. , Sivasubbu Sridhar , Gokhale Rajesh S. , Natarajan Vivek T.
Published: February 2020

In the neural crest lineage, progressive fate restriction and stem cell assignment are crucial for both development and regeneration. Whereas fate commitment events have distinct transcriptional footprints, fate biasing is often transitory and metastable, and is thought to be moulded by epigenetic programmes. Therefore, the molecular basis of specification is difficult to define. In this study, we established a role for a histone variant, H2a.z.2, in specification of the melanocyte lineage from multipotent neural crest cells. H2a.z.2 silencing reduces the number of melanocyte precursors in developing zebrafish embryos and from mouse embryonic stem cells in vitro. We demonstrate that this histone variant occupies nucleosomes in the promoter of the key melanocyte determinant mitf, and enhances its induction. CRISPR/Cas9-based targeted mutagenesis of this gene in zebrafish drastically reduces adult melanocytes, as well as their regeneration. Thereby, our study establishes the role of a histone variant upstream of the core gene regulatory network in the neural crest lineage. This epigenetic mark is a key determinant of cell fate and facilitates gene activation by external instructive signals, thereby establishing melanocyte fate identity.
Hypoxia tolerance is unrelated to swimming metabolism of wild, juvenile striped bass (Morone saxatilis)
Authors: Kraskura Krista , Nelson Jay A.
Published: February 2020

Juvenile striped bass reside in the Chesapeake Bay where they are likely to encounter hypoxia that could affect their metabolism and performance. The ecological success of this economically valuable species may depend on their ability to tolerate hypoxia and perform fitness-dependent activities in hypoxic waters. We tested whether there is a link between hypoxia tolerance (HT) and oxygen consumption rate (ṀO2) of juvenile striped bass measured while swimming in normoxic and hypoxic water, and to identify the interindividual variation and repeatability of these measurements. Fish (N=18) had their HT (loss of equilibrium) measured twice collectively, 11 weeks apart, between which each fish had their ṀO2 measured individually while swimming in low flow (10.2 cm s−1) and high flow (∼ 67% Ucrit) under normoxia and hypoxia. Both HT and ṀO2 varied substantially among individuals. HT increased across 11 weeks while the rank order of individual HT was significantly repeatable. Similarly, ṀO2 increased in fish swimming at high flow in a repeatable fashion, but only within a given level of oxygenation. ṀO2 was significantly lower when fish were swimming against high flow under hypoxia. There were no clear relationships between HT and a fish's ṀO2 while swimming under any conditions. Only the magnitude of increase in HT over 11 weeks and an individual's ṀO2 under low flow were correlated. The results suggest that responses to the interacting stressors of hypoxia and exercise vary among individuals, and that HT and change in HT are not simple functions of aerobic metabolic rate.
Visual determinants of prey chasing behavior in a mudflat crab
Authors: Gancedo Brian , Salido Carla , Tomsic Daniel
Published: February 2020

The crab Neohelice inhabits mudflats where it is preyed by gulls and, conversely, preys on smaller crabs. Therefore, to the sight of moving stimuli, this crab can behave as prey or predator. The crab escape response to visual stimuli has been extensively investigated from the behavioral to the neuronal level. The predatory response (PR), however, has not yet been explored. Here, we show that this response can be reliably elicited and investigated in a laboratory arena. By using dummies of three different sizes moved on the ground at three different velocities over multiple trials, we identified important stimulation conditions that boost the occurrence of the PR and its chances of ending in successful prey capture. The PR probability was rather sustained during the first 10 trials of our experiments but then declined. The PR was elicited with high probability by the medium size dummy, less effectively by the small dummy, and hardly brought about by the large dummy, which mostly elicited avoidance responses. A GLMM analysis indicated that the dummy size and the tracking line distance were two strong determinants for eliciting the PR. The rate of successful captures, however, mainly depended on the dummy velocity. Our results suggest that crabs are capable of assessing the distance to the dummy and its absolute size. The PR characterized here, in connection with the substantial knowledge of the visual processing associated to the escape response, provides excellent opportunities for comparative analyses of the organization of two distinct visually-guided behaviors in a single animal.
The effect of diet change and insulin dysregulation on the fecal microbiome of ponies
Authors: Fitzgerald Danielle M. , Spence Robert J. , Stewart Zachary K. , Prentis Peter J. , Sillence Martin N. , de Laat Melody A.
Published: February 2020

The equine microbiome can change in response to dietary alteration and might play a role in insulin dysregulation. The aim of this study was to determine the effect of adding pasture to a hay diet on the fecal bacterial microbiome of both healthy and insulin-dysregulated ponies. Fecal samples were collected from sixteen ponies before and after dietary change to enable bacterial 16S rRNA sequencing of the V3-V4 region. The dominant phyla in all samples were the Firmicutes and Bacteroidetes. The evenness of the bacterial populations decreased after grazing pasture, and when a pony was moderately insulin-dysregulated (P=0.001). Evenness scores negatively correlated with post-prandial glucagon-like peptide-1 concentrations after a hay-only diet (r2;=-0.7, P=0.001). A change in diet explained 3% of fecal microbiome variability. We conclude that metabolically healthy ponies have greater microbial stability when challenged with a subtle dietary change, compared to moderately insulin-dysregulated ponies.
Recent advances in the understanding and management of primary hyperparathyroidism
Authors: Goldfarb Melanie , Singer Frederick R.
Published: February 2020

Primary hyperparathyroidism is a hormonal disorder whose prevalence is approximately 1–2% in the United States of America. The disease has become more recognizable to clinicians in an earlier phase and, at present, patients can be diagnosed with “classic”, “normocalcemic”, “normohormonal”, or “mild, asymptomatic” primary hyperparathyroidism. Surgery, with a focused parathyroidectomy when possible, or a four-gland exploration, is the only way to cure the disease. Cure is determined by use of intra-operative parathyroid hormone monitoring with long-term cure rates ranging from 90–95%. Newer adjuncts to surgery include CT or PET imaging and near-infrared immunofluorescence. This article highlights updates in parathyroid disease and advances in parathyroid surgery; it does not provide a comprehensive summary of the disease process or a review of surgical indications, which can be found in the AAES guidelines or NIH Symposium on primary hyperparathyroidism.
In silico identification of vaccine targets for 2019-nCoV
Authors: Hyun-Jung Lee Chloe , Koohy Hashem
Published: February 2020

Background: The newly identified coronavirus known as 2019-nCoV has posed a serious global health threat. According to the latest report (18-February-2020), it has infected more than 72,000 people globally and led to deaths of more than 1,016 people in China.

Methods: The 2019 novel coronavirus proteome was aligned to a curated database of viral immunogenic peptides. The immunogenicity of detected peptides and their binding potential to HLA alleles was predicted by immunogenicity predictive models and NetMHCpan 4.0.

Results: We report in silico identification of a comprehensive list of immunogenic peptides that can be used as potential targets for 2019 novel coronavirus (2019-nCoV) vaccine development. First, we found 28 nCoV peptides identical to Severe acute respiratory syndrome-related coronavirus (SARS CoV) that have previously been characterized immunogenic by T cell assays. Second, we identified 48 nCoV peptides having a high degree of similarity with immunogenic peptides deposited in The Immune Epitope Database (IEDB). Lastly, we conducted a de novo search of 2019-nCoV 9-mer peptides that i) bind to common HLA alleles in Chinese and European population and ii) have T Cell Receptor (TCR) recognition potential by positional weight matrices and a recently developed immunogenicity algorithm, iPred, and identified in total 63 peptides with a high immunogenicity potential.

Conclusions: Given the limited time and resources to develop vaccine and treatments for 2019-nCoV, our work provides a shortlist of candidates for experimental validation and thus can accelerate development pipeline.
Contrasting impact of rural, versus urban, living on glucose metabolism and blood pressure in Uganda
Authors: Sanya Richard E. , Andia Biraro Irene , Nampijja Margaret , Zziwa Christopher , Nanyunja Carol , Nsubuga Denis , Kiwanuka Samuel , Tumusiime Josephine , Nassuuna Jacent , Walusimbi Bridgious , Cose Stephen , Ocama Ponsiano , Grencis Richard K. , Elliott Alison M. , Webb Emily L.
Published: February 2020

Background: The burden of cardiometabolic diseases, including cardiovascular diseases and diabetes, is increasing in sub-Saharan Africa and this has been linked to urbanisation. Helminths, through their immunomodulatory properties, may protect against these disorders. We hypothesised that the rural environment protects against cardiometabolic diseases and that helminths may influence rural-urban disparity of cardiometabolic disease risk.

Methods: We compared metabolic parameters of individuals aged ≥10 years living in rural, high-helminth-transmission and urban, lower-helminth-transmission settings in Uganda. Cross-sectional surveys were conducted in rural Lake Victoria island communities and in urban sub-wards in Entebbe municipality. Helminth infection and outcomes, including insulin resistance (computed using the homeostatic model assessment of insulin resistance [HOMA-IR]), fasting blood glucose, fasting blood lipids, blood pressure, body mass index (BMI), waist and hip circumference, were assessed.

Results: We analysed 1,898 rural and 930 urban participants. Adjusting for BMI, exercise, smoking, alcohol intake, age and sex, urban residents had lower mean fasting glucose (adjusted mean difference [95%CI] -0.13 [-0.24, -0.01] p=0.04) and HOMA-IR (-0.13 [-0.25, -0.01] p=0.04) but higher blood pressure (systolic, 4.64 [3.23, 6.06] p<0.001; diastolic, 1.89 [0.81, 2.97] p=0.001). Current helminth infection did not explain the observed differences.

Conclusions: In low-income countries, rural living may protect against hypertension but impair glucose metabolism.
Transient-State Natural Gas Transmission in Gunbarrel Pipeline Networks
Authors: Zhang Shixuan , Liu Sheng , Deng Tianhu , Shen Zuo-Jun Max
Published: February 2020

We study the energy consumption minimization problems of natural gas transmission in gunbarrel structured networks. In particular, we consider the transient-state dynamics of natural gas and the compressor’s nonlinear working domain and min-up-and-down constraints. We formulate the problem as a two-level dynamic program (DP), where the upper-level DP problem models each compressor station as a decision stage and each station’s optimization problem is further formulated as a lower-level DP by setting each time period as a stage. The upper-level DP faces the curse of high dimensionality. We propose an approximate dynamic programming (ADP) approach for the upper-level DP using appropriate basis functions and an exact approach for the lower-level DP by exploiting the structure of the problem. We validate the superior performance of the proposed ADP approach on both synthetic and real networks compared with the benchmark simulated annealing (SA) heuristic and the commonly used myopic policy and steady-state policy. On the synthetic networks (SNs), the ADP reduces the energy consumption by 5.8%–6.7% from the SA and 12% from the myopic policy. On the test gunbarrel network with 21 compressor stations and 28 pipes calibrated from China National Petroleum Corporation, the ADP saves 4.8%–5.1% (with an average of 5.0%) energy consumption compared with the SA and the currently deployed steady-state policy, which translates to cost savings of millions of dollars a year. Moreover, the proposed ADP algorithm requires 18.4%–61.0% less computation time than the SA. The advantages in both solution quality and computation time strongly support the proposed ADP algorithm in practice.
Organizational Powers: Contested Innovation and Loss of Professional Jurisdiction in the Case of Retail Medicine
Authors: Galperin Roman V.
Published: February 2020

Innovative technology may reduce organizations’ reliance on professionals in the performance of expert tasks, weakening professions’ control over work. However, professions resist and challenge such innovation, framing it as unsafe and immoral. This paper theorizes a process by which innovative nonprofessional firms overcome the resistance, enter professionalized markets, and weaken professional control over work. It analyzes the rise of a new organizational form—retail health clinics—that deprofessionalized some medical tasks in U.S. primary healthcare. An analysis of newspaper articles, archival documents, and interviews with key industry participants suggests that retail clinic chains capitalized on long-standing jurisdictional tensions between the physician and nursing professions. The clinics operated by relying on nurses’ legal rights to perform physicians’ tasks and defended retail medicine as a safe and morally justified innovation by using the nursing profession’s established repertoire or frames and arguments. Sentiment analysis of over 1,600 newspaper articles suggests that the legitimacy of retail clinic chains in public discourse improved with the proliferation of the clinics, but the legitimacy of nurse practitioners did not. Nonprofessional firms thus introduced an innovation that weakened professional control over medical work by capitalizing on interprofessional tensions and repurposing professions’ own jurisdictional claims.