bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 661: Synergistic antitumor activity of futibatinib, an FGFR1-4 inhibitor, and TAS-117, a selective AKT inhibitor, in FGFR-deregulated cancer models
Authors: Iwasaki Junya , Kuramoto Takuya , Komori Toshiharu , Saito Hitoshi , Hirai Hiroshi 
Published: September 2020

Abstract
Background: TAS-117 is a potent oral allosteric non-ATP inhibitor selective for AKT. A phase 1 study with TAS-117 is ongoing in patients with endometrial cancer and ovarian clear cell carcinoma. Futibatinib (TAS-120) is a selective, irreversible small-molecule fibroblast growth factor receptor (FGFR) 1-4 inhibitor, with potent antiproliferative activity in preclinical models with FGFR aberrations. Phase 2 studies are ongoing in patients with various FGFR-deregulated cancers. We evaluated the antitumor activity of futibatinib plus TAS-117 in FGFR-aberrant cancer models.
Methods: Effects of futibatinib plus TAS-117 were investigated in human endometrial FGFR2-N549K-mutated AN3CA cancer cells and small-cell lung cancer FGFR1-amplified DMS114 cells. Activation of RAS and PI3K pathways was assessed by detecting phosphorylation of ERK1/2, AKT, and S6. Antitumor combination indices (CI) for cell viability over time were determined with the Chou-Talalay median-effect method and CalcuSyn software; a CI&lt;0.9 indicates synergy. Antitumor effects of futibatinib (15 mg/kg/d) plus TAS-117 (4 or 8 mg/kg/d) or monotherapy were also evaluated in a mouse AN3CA xenograft model. FGFR signaling, apoptosis (via caspase activity and PARP cleavage), and relative tumor volume (RTV; compared with Day 0) were assessed.
Results: Futibatinib and TAS-117 synergistically increased cell death and decreased cell growth in AN3CA (CI&lt;0.40) and DMS114 (CI&lt;0.40) cells, respectively. Apoptosis induction was readily detected with futibatinib plus TAS-117 in AN3CA cells, but low activity was observed with monotherapy. In both AN3CA and DMS114 cells, futibatinib suppressed ERK1/2, but not AKT phosphorylation; the futibatinib plus TAS-117 combination suppressed phosphorylation of both ERK1/2 and AKT. In AN3CA xenografts, combination therapy inhibited the FGFR, PI3K, and MEK pathways. Futibatinib plus TAS-117 increased PARP cleavage more than monotherapy. Compared with Day 0, RTV on Day 15 was 60.71 in the control, 13.40 with futibatinib monotherapy, and 33.63 with TAS-117 (8 mg/kg/d) monotherapy. Treatment with 3 different futibatinib plus TAS-117 combination dosing regimens resulted in marked reductions in RTVs on Day 15 (2.16, 0.53, and 0.22).
Conclusions: Our findings suggest that futibatinib plus TAS-117 has synergistic antitumor effects in FGFR-aberrant tumors. A phase 1/2 study of this combination in advanced solid tumors (JapicCTI-194864) is ongoing.
Citation Format: Junya Iwasaki, Takuya Kuramoto, Toshiharu Komori, Hitoshi Saito, Hiroshi Hirai. Synergistic antitumor activity of futibatinib, an FGFR1-4 inhibitor, and TAS-117, a selective AKT inhibitor, in FGFR-deregulated cancer models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 661.
Abstract 664: BGB-10188, a highly selective PI3Kδ inhibitor with improved safety profile and superior anti-tumor activities in vivo
Authors: Yang Xiao , Yang Xiaolong , Cui Xinxin , Su Dan , Wu Yue , Sun Xuebing , Wang Jingyuan , Bai Huichen , Wei Wei , Li Jing , Yuan Xi , Liu Ye , Wang Fan , Wang Zhiwei , Wang Lai , Liu Xuesong , Song Xiaomin 
Published: September 2020

Abstract
Phosphoinositide 3-kinases (PI3Ks) are a family of enzymes capable of phosphorylating phosphatidylinositol to phosphoinositides, which are important secondary messengers involved in various cell signaling and functions. PI3Kδ is one of four isoforms (PI3Kα, β, δ and γ) of the PI3K class I family. It is restrictively expressed in leukocytes. PI3Kδ is a key signal transduction component for normal and malignant B cells and also important for the homeostasis and function of T-regulatory cells (Treg), making it a promising target for treatment of both hematologic malignancies and solid tumors.
BGB-10188 is a highly selective inhibitor of PI3Kδ, showing no significant inhibition over 376 protein kinases and 17 lipid kinases, and more than three-thousand folds selectivity over PI3Kα, PI3Kβ, and PI3Kγ. BGB-10188 potently inhibited PI3Kδ in biochemical, cellular and human whole blood assays with IC50s ranging from 1.7-16 nM. It also showed a long-lasting and strong target inhibition activity in mouse pharmacodynamics (PD) studies at doses as low as 10mg/kg. The elimination half-life (t1/2) of BGB-10188 in plasma was 12.6 hours and 10.4 hours in rats and dogs, respectively.
BGB-10188 showed significant antitumor effects in different types of B cell Lymphoma xenograft models. The liver toxicities of BGB-10188 were evaluated in mice and significantly improved safety margin was observed for BGB-10188 in comparison with other PI3Kδ inhibitors.
In summary, BGB-10188 is a novel PI3Kδ inhibitor with high selectivity, potency and improved safety profile shown in preclinical studies, which is promising and warrants the testing of the compound in human.
Citation Format: Xiao Yang, Xiaolong Yang, Xinxin Cui, Dan Su, Yue Wu, Xuebing Sun, Jingyuan Wang, Huichen Bai, Wei Wei, Jing Li, Xi Yuan, Ye Liu, Fan Wang, Zhiwei Wang, Lai Wang, Xuesong Liu, Xiaomin Song. BGB-10188, a highly selective PI3Kδ inhibitor with improved safety profile and superior anti-tumor activities in vivo [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 664.
Abstract 6710: AVID200, a first-in-class selective TGF-beta 1 and -beta 3 inhibitor, sensitizes tumors to immune checkpoint blockade therapies
Authors: Tremblay Gilles , Gruosso Tina , Denis Jean-François , Figueredo Rene , Koropatnick Jim , O'Connor-McCourt Maureen 
Published: September 2020

Abstract
AVID200 is a first-in-class rationally designed receptor ectodomain trap that selectively neutralizes TGF-beta 1 and -beta 3 with pM potency while sparing TGF-beta 2, thereby reducing the potential for toxicities associated with neutralization of this isoform. A Phase 1 dose-escalation clinical study of AVID200 monotherapy has recently been completed and established that the agent was well tolerated and exhibited target engagement at all dose levels tested without reaching a maximally tolerated dose.
To explore the potential of AVID200 as a combination agent with immunotherapy, expression analysis of TGF-beta isoforms across various solid tumors has been carried out and the ability of AVID200 to increase anti-tumor immunity as a single agent and in combination has been explored in vivo.
Analysis of &gt;10,000 tumor samples from TCGA revealed that TGF-beta1 and -beta3 are the predominant isoforms expressed in solid tumors, with TGF-beta2 showing only minimal expression. This corroborates the attractiveness of TGF-beta1 and -beta3 as promising anti-cancer targets and emphasizes the need to target both isoforms simultaneously. Furthermore, AVID200 increased T-cell-mediated cytotoxicity as a single agent as well as potentiating the efficacy of immune checkpoint inhibitors (ICI) in syngeneic mouse tumor models. In line with these observations, we have found that AVID200 increases the infiltration of T-cells in the tumor microenvironment.
In conclusion, AVID200, a first-in-class, potent and selective TGF-beta trap, enhances the activity of ICI agents in vivo and holds promise as a potential novel immunotherapy combination regimen which warrants exploration in patients with solid tumor malignancies. Phase 1 clinical trials are underway in various indications.
Citation Format: Gilles Tremblay, Tina Gruosso, Jean-François Denis, Rene Figueredo, Jim Koropatnick, Maureen O'Connor-McCourt. AVID200, a first-in-class selective TGF-beta 1 and -beta 3 inhibitor, sensitizes tumors to immune checkpoint blockade therapies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6710.
Abstract 971: Effects of tumor cryo-ablation on cGAS-STING pathway and antitumor immunity in syngeneic murine rhabdomyosarcoma
Authors: Alshebremi Mohammad Abdulaziz , Myers Jay T. , Kingsley Daniel T. , Huang Alex Y. 
Published: September 2020

Abstract
Even with current improvement in cancer therapy, tumor immunosuppressive microenvironment and metastatic tumors are important factors which have shown to be a challenge for cancer treatment. Thus, targeting the tumor microenvironment (TME) locally are required to modify the activation of innate immunity, which can provoke subsequent global adaptive anti-tumor immunity. Tumor cryo-ablation, a medical procedure that utilizes ultra-cold temperatures to destroy in situ local tumor tissues, has the capability to induce the release of immune danger signals that activate antigen-presenting cells to initiate the anti-tumor immunity. To understand the mechanism of immune activation by cryo-ablation, we performed comprehensive analyses on the effects of tumor cryo-ablation on mononuclear phagocytic lineage cells and the antitumor immunity. Here, we show that cryo-ablation of syngeneic Rhabdomyosarcoma (RMS) tumor, an aggressive sarcoma affecting children and young adults, was able to induce both the regression of tumor and the upregulation of the critical immune cytokines and chemokines profile. Moreover, cryo-ablation of RMS tumor initiates cGAS-STING signaling activation and type I interferon production in dendritic cells, which are consequential in pro-inflammatory TME. We also report that antitumor effects of cryo-ablation was more inhibitive, but not completely abrogated, in STING-deficient mice comparing with wild-type mice, demonstrating that both host-derived and tumor-intrinsic cGAS-STING signaling plays an important role in antitumor effects of tumor cryo-ablation. Ongoing experiments will address the efficacy of RMS tumor cryo-ablation on systemic anti-tumor immune activation leading to an abscopal effect on tumor regression at metastatic tumor. Taken together, our results demonstrate that tumor cryo-ablation affects antitumor immunity and cGAS-STING signaling in RMS tumor, and this approach may help guide future immunotherapy to improve cancer treatment outcomes.
Citation Format: Mohammad Abdulaziz Alshebremi, Jay T. Myers, Daniel T. Kingsley, Alex Y. Huang. Effects of tumor cryo-ablation on cGAS-STING pathway and antitumor immunity in syngeneic murine rhabdomyosarcoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 971.
CRISPR-GEMM Pooled Mutagenic Screening Identifies KMT2D as a Major Modulator of Immune Checkpoint Blockade
Authors: Wang Guangchuan , Chow Ryan D. , Zhu Lvyun , Bai Zhigang , Ye Lupeng , Zhang Feifei , Renauer Paul A. , Dong Matthew B. , Dai Xiaoyun , Zhang Xiaoya , Du Yaying , Cheng Yujing , Niu Leilei , Chu Zhiyuan , Kim Kristin , Liao Cun , Clark Paul , Errami Youssef , Chen Sidi 
Published: September 2020

AbstractImmune checkpoint blockade (ICB) has shown remarkable clinical efficacy in several cancer types. However, only a fraction of patients will respond to ICB. Here, we performed pooled mutagenic screening with CRISPR-mediated genetically engineered mouse models (CRISPR-GEMM) in ICB settings, and identified KMT2D as a major modulator of ICB response across multiple cancer types. KMT2D encodes a histone H3K4 methyltransferase and is among the most frequently mutated genes in patients with cancer. Kmt2d loss led to increased DNA damage and mutation burden, chromatin remodeling, intron retention, and activation of transposable elements. In addition, Kmt2d-mutant cells exhibited increased protein turnover and IFNγ-stimulated antigen presentation. In turn, Kmt2d-mutant tumors in both mouse and human were characterized by increased immune infiltration. These data demonstrate that Kmt2d deficiency sensitizes tumors to ICB by augmenting tumor immunogenicity, and also highlight the power of CRISPR-GEMMs for interrogating complex molecular landscapes in immunotherapeutic contexts that preserve the native tumor microenvironment.Significance:ICB is ineffective in the majority of patients. Through direct in vivo CRISPR mutagenesis screening in GEMMs of cancer, we find Kmt2d deficiency sensitizes tumors to ICB. Considering the prevalence of KMT2D mutations, this finding potentially has broad implications for patient stratification and clinical decision-making.This article is highlighted in the In This Issue feature, p. 1775
Face recognition using viola-jones depending on python
Authors: Dheyaa Ismael Khansaa , Irina Stanciu 
Published: September 2020

<p>In this paper, the proposed software system based on face recognition the proposed system can be implemented in the smart building or any VIP building need security interring in general, The human face will be recognized from a stream of pictures or video feed, this technology recognizes the person according to the specific algorithm, the algorithm that employed in this paper is the Viola–Jones object detection framework by using Python. The task of the proposed facial recognition system consists of two steps, the first one was detected the human face from live video using the webcamera in the computer, and the second step recognizes if this face allowed to enter the building or not by comparing it with the existing database, the two steps depending on the OpenCV python by importing cv2 method for detecting the human face, the frames can be read or written to file with the cv2.imread and cv2.imwrite functions respectively Finally, this proposed software system can be used to control access in smart buildings as a rule and the advancement of techniques connected around there, Providing a security system is one of the most important features must be achieved in the smart buildings, this proposed system can be used as an application in a smart building as a security system. Face recognition is one of the most important applications using today for practical facial recognition, The proposed software system, depending on using OpenCV (Open Source Computer Vision) is a popular computer vision library, in 1999 this library started by Intel. The platform library sets its focus on real-time image processing and includes patent-free implementations of the latest computer vision algorithms. OpenCV 2.3.1 now comes with a programming interface to C, C++, Python, and Android. OpenCV library of python, the three algorithms that will be used in this proposed system. The currently available algorithms are:</p><p>Eigenfaces → createEigenFaceRecognizer()</p><p>Fisherfaces → createFisherFaceRecognizer()</p><p>Local Binary Patterns Histograms → createLBPHFaceRecognizer()</p>Finally the proposed system provide entering to the building just for the authorized person according to face recognition algorithem.<p> </p>
Prevalence of Abnormal Heart Weight After Sudden Death in People Younger than 40 Years of Age
Authors: Schoppen Zachary J. , Balmert Lauren C. , White Steven , Olson Rachael , Arunkumar Ponni , Dellefave‐Castillo Lisa M. , Puckelwartz Megan J. , George Alfred L. , McNally Elizabeth M. , Webster Gregory 
Published: September 2020

Background
After sudden cardiac death in people aged <40 years, heart weight is a surrogate for cardiomegaly and a marker for cardiomyopathy. However, thresholds for cardiomegaly based on heart weight have not been validated in a cohort of cases of sudden cardiac death in young people.

Methods and Results
We surveyed medical examiner offices to determine which tools were used to assess heart weight norms. The survey determined that there was no gold standard for cardiomegaly (52 centers reported 22 different methods). We used a collection of heart weight data from sudden deaths in the Northwestern Sudden Death Collaboration (NSDC) to test the 22 methods. We found that the methods reported in our survey had little consistency: they classified between 18% and 81% of NSDC hearts with cardiomegaly. Therefore, we obtained biometric and postmortem data from a reference population of 3398 decedents aged <40 years. The reference population was ethnically diverse and had no known cardiac pathology on autopsy or histology. We derived and validated a multivariable regression model to predict normal heart weights and a threshold for cardiomegaly (upper 95% CI limit) in the young reference population (the Chicago model). Using the new model, the prevalence of cardiomegaly in hearts from the NSDC was 19%.

Conclusions
Medical examiner offices use a variety of tools to classify cardiomegaly. These approaches produce inconsistent results, and many overinterpret cardiomegaly. We recommend the model proposed to classify postmortem cardiomegaly in cases of sudden cardiac death in young people.
The Role of Speech-Language Pathologists in Otolaryngology Resident Education
Authors: Abdel-Aty Yassmeen , Charney Sara , Lott David G. 
Published: September 2020

Objectives/Introduction: Laryngology is an expanding field that has been increasingly incorporated into otolaryngology resident training programs nationwide. The exposure to the field is variable across training programs, despite the fact that laryngological complaints comprise a large proportion of consultations to otolaryngologists. Laryngology education is vital for the care of patients with voice, swallowing, and airway complaints as well as for the appropriate referral of patients to the laryngology team for specialized care. Speech-language pathologists (SLPs) specialized in voice and swallowing disorders are well-trained in the assessment and treatment for these populations. This team recently published a paper regarding the experience of laryngology education in residency. During analysis of the results, an interesting beneficial trend developed regarding the positive impact of exposure to SLPs. This appeared to be distinct and deserved further analysis and discussion. We propose that involving SLPs in resident education may greatly enhance their training in laryngology. Methods: As per our previous paper, a cross sectional, multi-institutional study was designed to assess the exposure of residents to laryngology. Descriptive statistics were obtained for questions involving exposure to SLPs. Fisher’s exact test was used to compare differences between groups. Results: Most respondents (135/151, 89.4%) indicated having SLPs specializing in voice and swallowing disorders in their departments, although only half (77/151, 51.0%) stated that they spent formal time with them during training. Results show that residents with formal training with SLPs were more comfortable interpreting videofluoroscopic swallow studies (VFSS) ( P = .0032). Residents with SLPs in their departments were also more likely to feel confident in terminology to describe different dysphonic voices ( P = .0213). Conclusion: Formal time with SLPs within otolaryngology residency programs varies across the country. Speech-language pathologists are a useful resource for laryngology resident training and should be included in their education.
A peer-led non-diet behaviour change intervention: FitU
Authors: Lee Sae-Mi , Li Shuang , Newland Aubrey , Leedeman Juliana , Clifford Dawn E , Keeler Linda A 
Published: September 2020

Objective: Despite the popularity of weight loss interventions, research indicates these methods are ineffective for promoting long-term health. College age is a developmentally important age for developing lifelong health habits. FitU is a peer-led non-diet nutrition and physical activity (PA) mentoring intervention developed to promote lifelong health habits for college students. The purpose of this study was to examine the nutrition and PA outcomes of FitU participants. Design: Pre-experimental single group repeated-measures field study design with qualitative programme evaluation feedback at post-test. Setting: FitU participants met with both a nutrition and PA peer mentor four times each for a total of eight sessions. Method: Participants ( N = 125) completed pre- and post-surveys about their nutrition and PA attitudes and behaviours. Results: FitU participants increased their eating competence from pre-to-post assessment and decreased their perceived barriers to healthy eating. Participants also increased their readiness to exercise and reported being more physically active. Conclusion: Findings demonstrate the effectiveness of a peer-led, non-diet mentoring intervention in promoting health-supporting habits among college students.
Prevalence of self-reported pain-related temporomandibular disorders and association with psychological distress in a dental clinic setting
Authors: Chuinsiri Nontawat , Jitprasertwong Paiboon 
Published: September 2020

Objectives To investigate the prevalence of self-reported pain-related temporomandibular disorders (TMDs) and its association with psychological status in a dental clinic setting. Methods In this cross-sectional study, patients were asked to complete a TMD pain screener and the Patient Health Questionnaire-4 (PHQ-4). Correlations between symptoms of pain-related TMDs and PHQ-4 scores were analysed using Spearman’s correlation test. Symptoms of pain-related TMDs were compared between four groups of participants with different psychological profiles using the Kruskal–Wallis test followed by multiple comparisons. The level of significance was adjusted using the Dunn–Bonferroni test. Results The prevalence of self-reported pain-related TMDs was 22.2%. TMD pain score was positively correlated with PHQ-4 score. The high anxiety and the comorbidity groups had significantly higher TMD pain scores than the controls. Conclusion There was a high prevalence of self-reported pain-related TMDs, which was correlated with scores on all psychological assessment scales. Symptoms of pain-related TMDs were significantly greater in patients with high anxiety scores, regardless of depression level.
Does board independence constrain insider opportunism?
Authors: Rahman Dewan , Faff Robert , Oliver Barry 
Published: September 2020

We examine whether insider opportunism is reduced by board independence. Using a sample of 18,194 firm-year observations over the period 1996–2016, we show that board independence constrains opportunistic insider trading. Our identification strategy uses the Sarbanes–Oxley Act of 2002 (SOX Act) and associated changes to the listing rules of NYSE/NASDAQ as a source of exogenous shocks in board independence. Our results are economically significant as insider opportunism declines by about 10.5%. We find that insider trading restrictions is the channel through which board independence reduces insider opportunism. Our additional analyses show that in competitive and R&D (research and development) intensive firms, the impact of board independence on opportunism is less pronounced. We also find that board independence constrains opportunism only in less complex firms. However, in co-opted boards, independent directors are less effective. Overall, we support the monitoring channel of board independence for reducing insider opportunism. JEL Classification: G14, G34, G40