bluuebunny/crossref_metadata_2025_split huggingface dataset:
The role of community pharmacists and their position in the delivery of diabetes care: an update for medical professionals
Authors: Brewster Sarah , Holt Richard , Portlock Jane , Price Hermione 
Published: March 2020

AbstractPharmacists are the third largest group of healthcare professionals worldwide, but are underused in the delivery of diabetes care. The aim of this narrative was to describe how integration of community pharmacy services into existing healthcare models may improve diabetes care. Relevant literature exploring pharmacy-led interventions for diabetes were identified from a search of Medline, Embase and Cinahl online databases. This review highlights that community pharmacists are accessible, experts in medicine management, trusted by the public and able to achieve financial savings. They are poorly integrated into existing healthcare models, and commissioning arrangements can be poorly perceived by the public and those working in primary care. Community pharmacy interventions in type 2 diabetes have similar, if not greater effects compared to those delivered by other healthcare professionals. It was concluded that community pharmacy interventions in diabetes are feasible, acceptable and deliver improved health outcomes. Future work should build public recognition of pharmacists and improve communication between them and other healthcare professionals.
Iterative approach to journal club
Authors: Summey Rebekah Mynatt , Leonard Whitney , Schiele Kristan , Tristan Sigrid , Young Amy , Vinas Emily , Ferriss James Stuart 
Published: March 2020

AbstractTo identify, evaluate and refine a journal club (JC) format that increases faculty and resident engagement. An initial needs assessment followed by a trial of three JC formats: traditional single presenter, debate style and facilitated small group discussion was piloted over 6 months. Anonymous feedback was collected. The facilitated small group format was chosen. Narrative and quantitative feedback were collected from residents and faculty at 6-month intervals for the next 24 months. Changes to the format were made using feedback. Fourteen residents (n=20, 70%) and 10 faculty (n=20, 50%) completed baseline surveys. We initially observed low resident (8/14, 57%) interest in JCs. Additionally, 9/14 (64%) of residents and 1/15 (7%) of faculty reported low confidence presenting articles publicly. After implementation of the new JC format, resident reported enjoyment, on a scale of 1–5, improved from 3.6 to 4.4 (p&lt;0.01). We observed improvement in resident confidence in the ability to critique a paper (2.7 to 4.1, p&lt;0.01) and in confidence speaking in front of both peers (3.8 to 4.6, p&lt;0.01) and faculty (3.0 to 3.8, p=0.04). Faculty confidence with literature critique decreased (from 4.2 to 3.8), but enjoyment remained stable (4.3 to 4.2). A facilitated small group JC format was preferred in our programme. We observed measurable improvements in both resident interest and confidence, as well as sustained faculty interest in JCs. We fostered an environment of inquiry and identified areas of continued professional development.
Energy conservation technique improves dyspnoea when patients with severe COPD climb stairs: a randomised crossover study
Authors: Prieur Guillaume , Combret Yann , Medrinal Clement , Arnol Nathalie , Bonnevie Tristan , Gravier Francis-Edouard , Quieffin Jean , Lamia Bouchra , Reychler Gregory , Borel Jean-Christian 
Published: March 2020

In this randomised, crossover trial, 22 patients with severe chronic obstructive pulmonary disease climbed six flights of stairs (108 steps) twice, under two test conditions: (1) energy conservation technique (ECT): participants were asked to rest for at least 5 seconds every three steps and (2) control condition: participants climbed the stairs at their own pace. Significant lower dyspnoea (primary outcome), leg discomfort, minute ventilation and capillary blood lactate under the ECT condition were found, with no change in total task time.Clinical trial registrationNCT03564028
Counting metastable states of Ising spin glasses on hypercubic lattices
Authors: Schnabel Stefan , Janke Wolfhard 
Published: March 2020

Abstract
We describe how metastable states of Ising spin glasses can be counted by means of Monte Carlo computer simulations. The method is applied to systems defined on hypercubic lattices in one to six dimensions with up to about 103 spins. It is shown that the number of metastable states obtained for different disorder realizations satisfies a log-normal distribution. We investigate the distribution of energies of metastable states by means of moments and cumulants.

Graphical abstract
Quantification of quantumness in neutrino oscillations
Authors: Ming Fei , Song Xue-Ke , Ling Jiajie , Ye Liu , Wang Dong 
Published: March 2020

AbstractNeutrino oscillation is an important physical phenomenon in elementary particle physics, and its nonclassical features can be revealed by the Leggett–Garg inequality. It shows that its quantum coherence can be sustained over astrophysical length scales. In this work, we investigate the measure of quantumness in experimentally observed neutrino oscillations via the nonlocal advantage of quantum coherence (NAQC), quantum steering, and Bell nonlocality. From various neutrino sources, ensembles of reactor and accelerator neutrinos are analyzed at distinct energies, such as Daya Bay (0.5 km and 1.6 km) and MINOS (735 km) collaborations. The NAQC of two-flavor neutrino oscillation is characterized experimentally compared to the theoretical prediction. It exhibits non-monotonously evolutive phenomenon with the increase of energy. Furthermore, it is found that the NAQC is a stronger quantum correlation than quantum steering and Bell nonlocality even in the order of km. Hence, for an arbitrary bipartite neutrino-flavor state with achieving a NAQC, it must be also a steerable and Bell nonlocal state. The results might offer an insight into the neutrino oscillation for the further applications on quantum information processing.
Minimal vectorlike model in supersymmetric unification
Authors: Zheng Sibo 
Published: March 2020

AbstractCompared to the minimal supersymmetric standard model, an extension by vectorlike fermions is able to explain the Higgs mass while retains the grand unification. We investigate the minimal vectorlike model by focusing on the vectorlike electroweak sector. We firstly derive the mass spectrum in the electroweak sector, then calculate the one-loop effects on the Higgs physics, and finally explore either vectorlike or neutralino dark matter. Collider constraints are briefly discussed.
USP10 Promotes Proliferation of Hepatocellular Carcinoma by Deubiquitinating and Stabilizing YAP/TAZ
Authors: Zhu Hong , Yan Fangjie , Yuan Tao , Qian Meijia , Zhou Tianyi , Dai Xiaoyang , Cao Ji , Ying Meidan , Dong Xiaowu , He Qiaojun , Yang Bo 
Published: March 2020

Abstract

Yes-associated protein (YAP) and its paralog, transcriptional coactivator with PDZ-binding motif (TAZ), play pivotal roles in promoting the progression of hepatocellular carcinoma. However, the regulatory mechanism underpinning aberrant activation of YAP/TAZ in hepatocellular carcinoma remains unclear. In this study, we globally profiled the contribution of deubiquitinating enzymes (DUB) to both transcriptional activity and protein abundance of YAP/TAZ in hepatocellular carcinoma models and identified ubiquitin-specific peptidase 10 (USP10) as a potent YAP/TAZ-activating DUB. Mechanistically, USP10 directly interacted with and stabilized YAP/TAZ by reverting their proteolytic ubiquitination. Depletion of USP10 enhanced polyubiquitination of YAP/TAZ, promoted their proteasomal degradation, and ultimately arrested the proliferation of hepatocellular carcinoma in vitro and in vivo. Expression levels of USP10 positively correlated with the abundance of YAP/TAZ in hepatocellular carcinoma patient samples as well as in N-nitrosodiethylamine (DEN)-induced liver cancer mice models. Collectively, this study establishes the causal link between USP10 and hyperactivated YAP/TAZ in hepatocellular carcinoma cells and provides a rationale for potential therapeutic interventions in the treatment of patients with hepatocellular carcinoma harboring a high level of YAP/TAZ.

Significance:
These findings identify USP10 as a DUB of YAP/TAZ and its role in hepatocellular carcinoma progression, which may serve as a potential therapeutic target for hepatocellular carcinoma treatment.
FDA Approval Summary: Ado-Trastuzumab Emtansine for the Adjuvant Treatment of HER2-positive Early Breast Cancer
Authors: Wedam Suparna , Fashoyin-Aje Lola , Gao Xin , Bloomquist Erik , Tang Shenghui , Sridhara Rajeshwari , Goldberg Kirsten B. , King-Kallimanis Bellinda L. , Theoret Marc R. , Ibrahim Amna , Amiri-Kordestani Laleh , Pazdur Richard , Beaver Julia A. 
Published: March 2020

Abstract
On May 3, 2019, the FDA granted regular approval to ado-trastuzumab emtansine (KADCYLA), for the adjuvant treatment of patients with HER2-positive early-breast cancer (EBC) who have residual invasive disease after neoadjuvant taxane-based chemotherapy and trastuzumab-based treatment. Approval was based on data from the KATHERINE trial, which randomized patients to receive ado-trastuzumab emtansine or trastuzumab. At 3 years, the event-free rate for invasive disease-free survival in the ado-trastuzumab emtansine arm was 88.3% [95% confidence interval (CI), 85.8–90.7] compared with 77.0% (95% CI, 73.8–80.7) in the trastuzumab arm, (HR, 0.50; 95% CI, 0.39–0.64; P &lt; 0.0001). Results from secondary endpoints, subgroup analyses, and sensitivity analyses generally supported the primary efficacy endpoint results. Common adverse reactions (&gt;25% and higher incidence in ado-trastuzumab emtansine arm) with ado-trastuzumab emtansine were fatigue, nausea, increased transaminases, musculoskeletal pain, hemorrhage, thrombocytopenia, headache, peripheral neuropathy, and arthralgia. Ado-trastuzumab emtansine is the first drug approved for the treatment of patients with residual disease after neoadjuvant treatment and surgery. This article summarizes the FDA review and the data supporting the approval of ado-trastuzumab emtansine as a component of treatment for patients with HER2-positive EBC with residual disease.
Resistance to First-line Osimertinib in EGFR-mutant NSCLC: Tissue is the Issue
Authors: Piotrowska Zofia , Hata Aaron N. 
Published: March 2020

Abstract
Matched pre-/posttreatment tissue biopsies from patients with EGFR-mutant non–small cell lung cancer demonstrate that histologic transformations, including both small-cell carcinoma and squamous transformation, are unexpectedly common among patients progressing on first-line osimertinib. The study highlights the key role of tissue testing and underscores the need for innovative therapeutic approaches to prevent, rather than treat, resistance.
See related article by Schoenfeld et al., p. 2654
A Highly Potent TACC3 Inhibitor as a Novel Anticancer Drug Candidate
Authors: Akbulut Ozge , Lengerli Deniz , Saatci Ozge , Duman Elif , Seker Urartu O.S. , Isik Aynur , Akyol Aytekin , Caliskan Burcu , Banoglu Erden , Sahin Ozgur 
Published: March 2020

AbstractTACC3, a transforming acidic coiled-coil (TACC) family member, is frequently upregulated in a broad spectrum of cancers, including breast cancer. It plays critical roles in protecting microtubule stability and centrosome integrity that is often dysregulated in cancers; therefore, making TACC3 a highly attractive therapeutic target. Here, we identified a new TACC3-targeting chemotype, BO-264, through the screening of in-house compound collection. Direct interaction between BO-264 and TACC3 was validated by using several biochemical methods, including drug affinity responsive target stability, cellular thermal shift assay, and isothermal titration calorimetry. BO-264 demonstrated superior antiproliferative activity to the two currently reported TACC3 inhibitors, especially in aggressive breast cancer subtypes, basal and HER2+, via spindle assembly checkpoint–dependent mitotic arrest, DNA damage, and apoptosis, while the cytotoxicity against normal breast cells was negligible. Furthermore, BO-264 significantly decreased centrosomal TACC3 during both mitosis and interphase. BO-264 displayed potent antiproliferative activity (∼90% have less than 1 μmol/L GI50 value) in the NCI-60 cell line panel compromising of nine different cancer types. Noteworthy, BO-264 significantly inhibited the growth of cells harboring FGFR3–TACC3 fusion, an oncogenic driver in diverse malignancies. Importantly, its oral administration significantly impaired tumor growth in immunocompromised and immunocompetent breast and colon cancer mouse models, and increased survival without any major toxicity. Finally, TACC3 expression has been identified as strong independent prognostic factor in breast cancer and strongly prognostic in several different cancers. Overall, we identified a novel and highly potent TACC3 inhibitor as a novel potential anticancer agent, inducing spindle abnormalities and mitotic cell death.
Abstract A017: Development and characterization of HER2+ T-DM1-resistant breast PDX models in athymic nude mice
Authors: Moriarty Alyssa , Gamez Lizette , Mashimo Tomoyuki , Papadopoulos Kyriakos , Patnaik Amita , Rasco Drew , Lang Amy , Drengler Ronald , Wick Michael J 
Published: March 2020

Abstract
Background: Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) approved for treatment of HER2 positive (HER2+), trastuzumab-resistant breast cancers. While this agent is initially effective, resistance often develops. To aid in developing new therapies for HER2+, T-DM1-resistant breast cancer and better understanding resistance mechanisms, we established PDX models designated ST340, ST1339, and ST2167 from three patients with trastuzumab-resistant HER2+ breast cancer and sensitive to T-DM1 treatment in vivo. A cohort of each model was conditioned in vivo with chronic T-DM1 treatment to generate drug resistance. These models, designated ST340/TDR, ST1339/TDR, and ST2167/TDR were subjected to characterization and efficacy studies, and the results compared with parent models. Methods: ST340, ST1339, and ST2167 were established from patients who responded then progressed on trastuzumab and other therapies. The models were passaged, and cohorts were challenged with chronic T-DM1 treatment to produce drug resistance. The parent and resistant models were subjected to various comparative analyses including receptor expression, RNAseq, and response to various relevant therapies. Results: T-DM1-resistant models retained high HER2 expression and demonstrated receptor staining and histopathology comparable to respective parent lines. Comparison of parent and resistant clones using RNAseq identified several alterations in variants and expression. In vivo T-DM1 reported significant activity towards ST340: %T/C=3%, ST1339: %T/C=-40% and ST2167: %T/C=13% versus control, including tumor regressions in ST1339. T-DM1-resistant models reported the following values following treatment: ST340/TDR: %T/C=65%, ST1339/TDR: %T/C=58% and ST2167/TDR: T/C=91%. Conclusion: We have established and characterized three paired T-DM1-sensitive and resistant breast PDX models, which can be utilized as valuable tools in developing new therapies for T-DM1-resistant patients.
Citation Format: Alyssa Moriarty, Lizette Gamez, Tomoyuki Mashimo, Kyriakos Papadopoulos, Amita Patnaik, Drew Rasco, Amy Lang, Ronald Drengler, Michael J Wick. Development and characterization of HER2+ T-DM1-resistant breast PDX models in athymic nude mice [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A017. doi:10.1158/1535-7163.TARG-19-A017
Abstract A030: Evaluation of phosphoprotein- and transcript-based pharmacodynamic biomarkers in pre-clinical studies of the novel SOS1::KRAS inhibitor BI-3406
Authors: Gerlach Daniel , Savarese Fabio , Hofmann Marco H , Trapani Francesca , Gmachl Michael , Botesteanu Dana-Adriana , Ramharter Jürgen , Arnhof Heribert , Schweifer Norbert , McConnell Darryl B , Kraut Norbert 
Published: March 2020

Abstract
KRAS is among the most frequently mutated oncogenes across all human cancers. Targeting KRAS-mutant cancers either directly or at the effector level has so far failed in the clinic, with adoptive responses and toxicities being the major limiting factors. Nevertheless, direct targeting of the mutant KRAS-G12C allele has shown promising results in early clinical trials. BI-3406 is an inhibitor of the interaction between KRAS and its Guanine Nucleotide Exchange Factor (GEF) SOS1. The efficient loading of both mutant as well as wild-type KRAS with GTP depends on SOS1. We present the activity of the potent and selective SOS1::KRAS inhibitor BI-3406 in monotherapy and combinations in a different presentation at this meeting (Marco H Hofmann et al.). In this work, we focus on the characterization of suitable pharmacodynamic biomarkers in pre-clinical studies. Analysis of the well-studied RAS-MAPK effector p-ERK demonstrates BI-3406 treatment induced modulation in the majority of tested cell lines, independent of their KRAS mutation status. Interestingly, the effects on p-AKT levels, linked to PI3K signaling, were much less pronounced, indicating that the MAPK pathway is the major effector pathway of mutant KRAS singnaling. Confirmatory results were obtained from a technically independent and orthogonal platform. These findings are supported by a genome-wide transcriptome analysis, which revealed well established feedback regulators and p-ERK targets such as DUSP6, EGR1, or ETV5 as robust pharmacodynamic biomarkers in response to SOS1::KRAS inhibitor treatment. Importantly, we also compare biomarker responses of SOS1::KRAS inhibition to direct KRAS-G12C inhibition. In summary, these transcript-based biomarkers add value over conventional downstream signaling protein biomarkers such as p-ERK and will be implemented in future clinical trials.
Citation Format: Daniel Gerlach, Fabio Savarese, Marco H Hofmann, Francesca Trapani, Michael Gmachl, Dana-Adriana Botesteanu, Jürgen Ramharter, Heribert Arnhof, Norbert Schweifer, Darryl B McConnell, Norbert Kraut. Evaluation of phosphoprotein- and transcript-based pharmacodynamic biomarkers in pre-clinical studies of the novel SOS1::KRAS inhibitor BI-3406 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A030. doi:10.1158/1535-7163.TARG-19-A030
Abstract A064: MK2 inhibition stabilizes wild-type and mutated p53 in glioblastoma cells and leads to different cellular responses
Authors: Phoa Athena Frances , Recasens Ariadna , Munoz Lenka 
Published: March 2020

Abstract
MAPK-activated protein kinase 2 (MK2) has diverse roles in inflammation and cancer. In this study we show that in glioblastoma cells, MK2 plays a role in the degradation of p53, the main determinant of cell fate. Importantly, we provide evidence that the MK2-dependent regulation of p53 is a common regulatory mechanism for both wild-type and mutated p53. Through the use of both pharmacological inhibitors and MK2 knockout models in glioblastoma cells with different p53 background, we show that MK2 inhibition leads to different cellular responses in response to DNA damage stimuli. In p53 wild-type cells, MK2 inhibition strongly attenuated cell proliferation. This effect was achieved through the deactivation of HDM2 ligase and this led to increased p53 wild-type expression and the transcription of senescent and apoptotic genes. MK2 inhibition increased the stability of p53 mutants, and this is key for their ability to phenotypically exhibit gain-of function properties. Thus, as a destabilizer of wild-type p53, MK2 represents a potential drug target in glioblastomas that contain p53 wild-type. However, the administration of an MK2 inhibitor in cells expressing p53 mutants may cause accelerated disease progression. These findings are highly relevant since p53 mutations occur over 50% of all cancers.
Citation Format: Athena Frances Phoa, Ariadna Recasens, Lenka Munoz. MK2 inhibition stabilizes wild-type and mutated p53 in glioblastoma cells and leads to different cellular responses [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A064. doi:10.1158/1535-7163.TARG-19-A064
Abstract A091: Targeting homologous recombination repair defects in lung cancer
Authors: Muvaffak Asli , Zhou Yinghui , Feng Bin , Wang Sarah , Wang Jing Ju , Ramaswamy Sridhar , Coleman Kevin G 
Published: March 2020

Abstract
Non-Small Cell Lung Cancer (NSCLC) is the leading cause of cancer related mortality worldwide, and accounts for 80-85% of all lung cancer diagnoses. While targeted therapies against epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) fusions have proven to be effective for the treatment of NSCLC, only a fraction of NSCLC patients (i.e. &lt;20%) benefit from these targeted agents. Although immunotherapy approaches, specifically PD-1:PD-L1 blockade, appear to be more broadly efficacious, there are still a substantial proportion of patients who may not benefit from these treatments. To investigate the potential of targeting the DNA Damage Response (DDR) pathway in lung cancer, as an alternative therapeutic approach for these patients we sought to identify whether functionally relevant HRR (Homologous Recombination Repair)-defects could be synthetically lethal with niraparib monotherapy in NSCLC PDX models. Approximately 3% of lung cancers harbor mutations in ATM (i.e. 3.5% in lung adenocarcinomas & 1.4% in lung squamous cell carcinoma), which is involved in HRR as well as multiple other DNA repair and checkpoint functions, but the functional consequences of this alteration remain to be established. Studies in the past few years have demonstrated the potential of targeting the DDR pathway as a promising therapeutic strategy for lung cancer, i.e. in small cell lung cancer (SCLC) where overall response rates to immune checkpoint blockade remain poor. In addition, inhibitors targeting DDR proteins have shown promise in preclinical models of lung cancer, and are under clinical investigation as single agents and in combination with other targeted and immunotherapy agents. In this study, we have evaluated niraparib sensitivity in 57 NSCLC PDX models containing both BRCA and non-BRCA HRR mutations (n=17) as well as HRR WT models (n=40). This analysis demonstrated that niraparib sensitive models include both HRR mutant and HRR WT lung tumors (TGI &gt; 70%). Amongst the PDX models containing a biallelic HRR mutation (ATM, BAP1, RAD51D & XRCC2), only ATM biallelic mutant models were sensitive to niraparib (2 out of 6). Furthermore, none of the of nine monoallelic mutant models (ATM, ATR, BRCA1/2, RAD50 & RAD52) were sensitive to niraparib. Surprisingly, 7.5% (3 out of 40) of the HRR WT PDX models were sensitive to niraparib. Further analysis is required to elucidate the molecular mechanisms driving niraparib sensitivity in HRR WT NSCLC.
Citation Format: Asli Muvaffak, Yinghui Zhou, Bin Feng, Sarah Wang, Jing Ju Wang, Sridhar Ramaswamy, Kevin G Coleman. Targeting homologous recombination repair defects in lung cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A091. doi:10.1158/1535-7163.TARG-19-A091