bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improving medical consults for surgical inpatients: a quality improvement project using an e-referral system linked to clinical pathways
Authors: Amer Mahmoud , Ghosh Prosen , Chatterjee Animesh 
Published: June 2022

Surgical inpatients referred to medicine with acute medical problems represent a complex patient population, vulnerable to fragmented care and suboptimal outcomes. They can also be a source of staff dissatisfaction in busy or understaffed departments. Comanagement by surgical and medical staff may improve outcomes but requires dedicated resources and the evidence for other interventions is scarce. We aimed to assess staff experience, demographics and clinical outcomes of this patient population at our hospital and develop an intervention aiming to improve medical staff experience, without compromising clinical outcomes.Staff were surveyed before and after the intervention to measure staff experience. Demographics and clinical outcomes were collected for 60 referrals at baseline and 29 referrals postintervention (an e-referral system linked to locally developed clinical pathways). Clinical outcomes were delay time (time from referral submission to review), length of stay, 30-day mortality and 30-day readmissions.Medical staff experience improved from majority negative or neutral ratings to majority positive ratings postintervention and 100% of staff surveyed supported ongoing use of the intervention. There were no negative impacts on clinical outcomes, which acted as balancing measures.Medical staff experience improved, without compromising clinical outcomes. The e-referral system doubles as a platform for ongoing quality improvement.
Association of the COVID-19 pandemic with bystander cardiopulmonary resuscitation for out-of-hospital cardiac arrest: a population-based analysis in Tokyo, Japan
Authors: Shibahashi Keita , Kawabata Hiromitsu , Sugiyama Kazuhiro , Hamabe Yuichi 
Published: June 2022

BackgroundThe impact of the COVID-19 pandemic on bystander cardiopulmonary resuscitation (CPR) for out-of-hospital cardiac arrest (OHCA) is unclear. This study aimed to investigate whether rates of bystander CPR and patient outcomes changed during the initial state of emergency declared in Tokyo for the COVID-19 pandemic.MethodsThis retrospective study used data from a population-based database of OHCA maintained by the Tokyo Fire Department. By comparing data from the periods before (18 February to 6 April 2020) and during the declaration of a state of emergency (7 April 2020 to 25 May 2020), we estimated the change in bystander CPR rate, prehospital return of spontaneous circulation, and survival and neurological outcomes 1 month after OHCA, accounting for outcome trends in 2019. We performed a multivariate regression analysis to evaluate the potential mechanisms for associations between the state of emergency and these outcomes.ResultsThe witnessed arrest rates before and after the declaration periods in 2020 were 42.5% and 45.1%, respectively, compared with 44.1% and 44.7% in the respective corresponding periods in 2019. The difference between the two periods in 2020 was not statistically significant when the trend in 2019 was considered. The bystander CPR rates before and after the declaration periods significantly increased from 34.4% to 43.9% in 2020, an 8.3% increase after adjusting for the trend in 2019. This finding was significant even after adjusting for patient and bystander characteristics and the emergency medical service response. There were no significant differences between the two periods in the other study outcomes.ConclusionThe COVID-19 pandemic was associated with an improvement in the bystander CPR rate in Tokyo, while patient outcomes were maintained. Pandemic-related changes in patient and bystander characteristics do not fully explain the underlying mechanism; there may be other mechanisms through which the community response to public emergency increased during the pandemic.
Search for vector-like bottom with decay B → Zb considering large width effect at high energy e−γ collision
Authors: Li Haitao , Zhang Guoqing 
Published: June 2022

We focus on the large width effect on the possibility of excluding or discovering the vector-like bottom quark that is singlet under SU(2) transform at the [Formula: see text] collisions. Focusing on the 3 TeV stage of the future Compact Linear Collider (CLIC), the process of single vector-like bottom quark production [Formula: see text] is investigated. Subsequently, the [Formula: see text] boson decays to one light-flavor lepton pair [Formula: see text], and the top quark decay to [Formula: see text] boson and bottom quark following with [Formula: see text] boson hadronic decay [Formula: see text]. By launching a comprehensive signal and background collider simulation, we obtain [Formula: see text] exclusion limit and [Formula: see text] discovering prospect based on coupling strength and mass of vector-like quark. We assume the integrated luminosity is 5 ab[Formula: see text]. Specially, we take the systemic uncertainty effect on the possibility of excluding or discovering the vector-like bottom quark into account. We find that the excluding irrelated region is [Formula: see text] and [Formula: see text] GeV, and the discovering irrelated region is [Formula: see text] and [Formula: see text] GeV in view of the systemic uncertainty [Formula: see text].
Abstract 10: Development of single cell spheroid as a tool to capture functional heterogeneity in head and neck cancer
Authors: Pandey Jyoti , Shyanti Ritis , Malhotra Sanjay V. , Chaturvedi Rupesh , Singh Rana P. 
Published: June 2022

Abstract
Introduction: Head and neck cancer squamous cell carcinomas (HNSCC) are diverse and complex with inter-tumor and intra-tumor heterogeneity and discrepancies in therapy response regardless of the clinical stage. Tumors are thought to be heterogeneous at the single-cell level involving cancer stem cells. Therefore, cancer diagnosis and treatment are difficult because single cells might have intrinsic functional and genetic heterogeneity. Single cell transcriptome is used for mapping the genetic heterogeneity of a tumor. Currently, no model is available to provide a genotype to phenotype correlations for the heterogeneity, a crucial step for successful treat of a cancer. Here, our focus is to develop a single-cell clonal spheroid model system as a valuable tool for studying functional heterogeneity, including growth, proliferation, angiogenesis, metastasis, and genetic heterogeneity.
Material and methods: HNSCC cell lines namely, UMSCC-22B, FaDu and A-253, and patients derived primary cells were cultured in 96-well ultra-low attachment to develop spheroids. Spheroids were cultured from 2, 4 and 128 cells per well with media, growth factors and supplements. Confocal microscopy was done using cocktail dyes including Hoechst, Calcein-AM and Ethidium bromide to check the functionality of spheroids.
Results: We have established a method for the development of single-cell derived clonal spheroids. The frequency of spheroids formation from 2, 4 and 128 UMSCC-22B cells per well were higher than FaDu and A-253 cell lines. The growth measurement showed clones of single cell derived spheroids with hyperproliferation as well as with low proliferative activity. UMSCC-22B and A-253 hypoproliferative spheroids had significant higher migration capabilities compared to spheroids with hyperproliferative activity. Confocal microscopy of single-cell derived clonally propagated spheroids revealed a different zone viz proliferating, quiescent and necrotic zone in intact spheroids. This condition mimics in vivo conditions and suitable tool for drug penetration studies.
Conclusion: Together, our results suggest that single cell-derived clonal spheroid from different wells would represent the genetic and functional heterogeneity of the cell population. Such a spheroid model can reveal heterogeneity inside a tumor formed by the proliferation of a single-cell and heterogeneity between tumors resulting from a different single cell and thus has great potential for drug discovery and tumor biology research.
Citation Format: Jyoti Pandey, Ritis Shyanti, Sanjay V. Malhotra, Rupesh Chaturvedi, Rana P. Singh. Development of single cell spheroid as a tool to capture functional heterogeneity in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 10.
Abstract 1101: CTNNB1 mutation can mediate resistance to EGFR, ALK and KRAS targeted therapies
Authors: Majumder Anurima , Meyer Benjamin S. , Hicks J Kevin , Boyle Theresa A. , Haura Eric B. 
Published: June 2022

Abstract
Resistance to targeted therapy remains an ongoing and elusive challenge in lung cancer. β-Catenin (CTNNB1) mutations have been reported in lung cancer patients, often co-occurring with known oncogenic drivers such as rearranged ALK, and mutant EGFR and KRAS. Oncogenic CTNNB1 mutations result in aberrant accumulation of the encoded β-catenin protein and may cause resistance to targeted therapy. However, different CTNNB1 mutations may activate β-catenin differentially and thereby have varying phenotypic effects. A CTNNB1 T41A mutation was identified in donated lung cancer tissue from a patient with a clinical history of an EGFR exon 20 insertion. To investigate the functional significance of this mutation, CTNNB1 T41A was transduced into an EGFR-mutated cell line (HCC827) and one cell line harboring ALK translocation (STE1). Response to EGFR and ALK targeted therapy was then compared in the GFP-transduced control cell lines versus the CTNNB1 T41A transduced cell lines to assess for effects of this CTNNB1 mutation on targeted therapy. Both HCC827 and STE1 cells harboring the CTNNB1 T41A mutation were more resistant to EGFR and ALK targeted therapy than the control cell lines. Since, different CTNNB1 mutations may exert different phenotypic effects, the CTNNB1 mutation spectrum was analyzed in lung cancer patients at the Moffitt Cancer Center. Mutations in 19 unique residues of CTNNB1 (D32, S33, G34, S37, T41, S45, A215, C419, S29, G757, K335, N287, Q72, R151, R710, S352, S681, V62 and W383) were detected in 50 lung cancer patients. Of these, 23 had some type of EGFR abnormality that co-existed with the CTNNB1 mutation while others had ROS1, RET, BRAF, NTRK3, ALK or KRAS mutations. The most frequent Exon 3 hotspot CTNNB1 mutations (at residues D32, S33, G34, S37, and S45) were chosen for further analysis wherein these mutations were transduced into HCC827, STE1 and two KRAS mutant cell lines (H358 and LU65) to assess their ability to drive resistance to EGFR, ALK and KRAS targeted therapies in ongoing studies. Our data shows that CTNNB1 mutations can cause resistance to EGFR, ALK and KRAS inhibitor therapy to different extents. Hence, further investigation of the mechanism of action of these beta-catenin mutations and the ability of beta-catenin/other inhibitors to reverse resistance is needed. This data also suggests that CTNNB1 may be an important co-occurring alteration in the context of development of resistance to targeted therapy and should be included in comprehensive clinical genetic testing panels.
Citation Format: Anurima Majumder, Benjamin S. Meyer, J Kevin Hicks, Theresa A. Boyle, Eric B. Haura. CTNNB1 mutation can mediate resistance to EGFR, ALK and KRAS targeted therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1101.
Abstract 1330: Role of ENPP1 mediated extracellular cGAMP hydrolysis in cancer metastasis and immune evasion
Authors: Kwon John Young Ho , Li Jun , Duran Mercedes , Dhanota Ninjit , Bakhoum Samuel 
Published: June 2022

Abstract
Chromosome instability (CIN) promotes metastasis through sustained tumor-cell autonomous response to cytosolic DNA. Chromosome mis-segregation engenders the formation of micronuclei, which upon rupture chronically activates the cGAS-STING DNA sensing pathway. Tumor cGAS recognizes cytosolic DNA to generate cGAMP, a potent immune-stimulatory molecule that is readily exported into the extracellular space to enforce a type 1 IFN-mediated anti-tumor response in a host STING dependent manner. However, it is unclear how highly aggressive, unstable tumors have evolved to co-opt this chronic inflammatory signaling to drive tumorigenic behaviors and immune evasion. Here, we show that ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) may drive tumor metastasis through degradation of extracellular cGAMP. Using RNA sequencing of isogenic tumors, we uncovered a link between ENPP1 and CIN. We leveraged syngeneic mouse models to demonstrate that genetic perturbation of tumor ENPP1 and overexpression of a catalytically inactive ENPP1 mutant suppress metastasis. Furthermore, loss of ENPP1 increases tumor immune infiltration, reduces extracellular adenosine, and enhances response to immune checkpoint blockade in a manner dependent on tumor cGAS and host STING. In line with these findings, ENPP1 expression correlates with immune suppression in human cancers. These results suggest that ENPP1-mediated hydrolysis of cGAMP may facilitate metastasis through evasion of immune surveillance, perhaps in part through cGAMP breakdown into immune-suppressive adenosine, in which the contributions of tumor and host adenosine can be further explored. Taken together, our study demonstrates how ENPP1-mediated hydrolysis of cGAMP can transform an otherwise inflammatory pathway into an immune-suppressive mechanism to promote tumor progression and metastasis.
Citation Format: John Young Ho Kwon, Jun Li, Mercedes Duran, Ninjit Dhanota, Samuel Bakhoum. Role of ENPP1 mediated extracellular cGAMP hydrolysis in cancer metastasis and immune evasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1330.
Abstract 1402: Monitoring the concentration of cGAMP using homogenous bioluminescent HTS-formatted assay
Authors: Goueli Said A. , Hsiao kevin 
Published: June 2022

Abstract
Genomic instability engages the cGAS (cytosolic DNA sensor cyclic AMP-GMP synthase)-STING (stimulator of interferon genes) signaling (cGAS-cGAMP-STI NG) pathway on both sides of cancer either by being instrumental for antitumor immunity and blocking malignancy or by promoting inflammation-driven carcinogenesis and metastasis. The cGAS-STING axis also plays an essential role in initiating host immune defense against microbial invasion and STING-deficient mice are more susceptible to some viral infections. Credible evidence suggests that the cGAS-cGAMP-STI NG pathway makes fundamental contributions to at least three major cancer therapies, radiation therapy, chemotherapy, immunotherapy, and thus represents a promising pharmaceutical target. cGAS is well-positioned to act as a DNA sensor that triggers innate immune responses through production of the second messenger cyclic GMP-AMP (cGAMP) upon binding to DNA and initiating host immune responses against pathogens and cancer. However, inappropriate activation of STING signaling causes severe and often fatal autoimmune or autoinflammatory diseases. Hence, STING is an attractive drug target for the treatment of STING-driven autoimmune and inflammatory disorders. Therefore, there is a need to identify lead compounds that effectively inhibit human STING for further drug development. An attempt to search for such molecules have been described recently with the report on a STING-specific inhibitor that showed high efficiency, specificity, and safety, paving the way for therapeutically manipulating STING-mediated clinical diseases. Towards this goal, we have developed a bioluminescent assay to monitor the concentration of cGAMP in intracellular as well as extracellular compartments. The assay relies on the use of ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) to release AMP which can be converted to ATP via a coupled enzyme reaction. The ATP generated can be quantified using luciferase/luciferin detection reagents. The assay is homogenous, HTS formatted and can be completed in less than one hour. The assay is sensitive and can detect as low as 10 nM cGAMP. We will show data on the use of agents that stimulate GAS activity such as dsDNA, and the use of reporter assays to detect cytokine release upon cGAS-STING activation.
Citation Format: Said A. Goueli, kevin Hsiao. Monitoring the concentration of cGAMP using homogenous bioluminescent HTS-formatted assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1402.
Abstract 1640: Enhanced development of functional human innate immune cells in a novel FLT3nullNSG mouse strain expressing human FLT3L
Authors: Yao Li-Chin , Vaidya Shantashri , Kaur Pali , Keck James G. , Shultz Leonard D. , Greiner Dale L. , Brehm MIchael A. 
Published: June 2022

Abstract
Humanized mice are being applied widely to study human immune system homeostasis, function, and as a testing platform for cancer immunotherapies. A major limitation for many humanized mouse models is the lack of functional and mature human innate immune cells, which are critical for effective human immune system-tumor interactions. Previous studies have demonstrated that delivery of human FLT3L into immunodeficient mice that lack mouse FLT3, promotes the development of human innate immune cell subsets following engraftment with human hematopoietic stem cells (HSC). Here we describe a NOD-scid IL2rgnull (NSG) mouse that lacks the expression of mouse FLT3 and expresses human FLT3L transgenically (NSG-mFLT3nullTg (HuFLT3L) or NSG-FLT3L. In these studies, NSG-FLT3L and NSG mice were engrafted with human umbilical cord blood (UCB) CD34+ HSC and compared for human immune system development and function. HSC-engrafted NSG-FLT3L and NSG mice show similar levels of total human CD45+ cells in blood over the course of 18 weeks post-engraftment. However, HSC-engrafted NSG-FLT3L mice show significantly higher levels of human CD141+ and CD1c+ DC subsets, CD123+ pDC, CD14+ monocytes, CD56+ NK cells and CD3+ T cells in the blood as compared to NSG mice. CD34-FLT3L mice also show increased levels of human immune cell infiltration into the gut mucosa. CD56+ NK cells and CD3+ T cells from HSC-engrafted NSG-FLT3L mice express granzyme A and granzyme B, indicating cytotoxic activity. Following treatment of HSC-engrafted NSG-FLT3L mice with LPS, heightened levels of human cytokines were detected in serum samples, confirming innate immune system function. The growth kinetics of tumor cells from a triple negative breast cancer cell line MDA-MB-231 and a lung PDX model LG1306 in HSC-engrafted NSG-FLT3L mice are work in progress and will be compared with HSG-engrafted NSG mice. Overall these results demonstrate that the NSG-FLT3L model supports enhanced development of functional, human innate immune cells and is a novel tool to study human immuno-oncology.
Citation Format: Li-Chin Yao, Shantashri Vaidya, Pali Kaur, James G. Keck, Leonard D. Shultz, Dale L. Greiner, MIchael A. Brehm. Enhanced development of functional human innate immune cells in a novel FLT3nullNSG mouse strain expressing human FLT3L [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1640.
Abstract 168: DDR2 regulates angiogenesis via HSP-90 modulation in ovarian cancer
Authors: Akinjiyan Favour A. , Dave Ritu M. , Longmore Gregory , Fuh Katherine C. 
Published: June 2022

Abstract
Ovarian cancer is often diagnosed in later stages and patients have low five-year survival. There is a need to develop better therapies for this patient population. Solid tumors like ovarian cancer respond to hypoxia by inducing the sprouting of new blood cells. This process is called angiogenesis. Angiogenesis leads to formation of disordered and immature vessels that precludes efficient drug delivery. Prior work has shown that overexpressing DDR2 in endothelial cells leads to increased angiogenic activity, measured by tube formation and sprouting. We show that DDR2 expression in ovarian cancer tumor cells modulates angiogenic activity in endothelial cells. Human umbilical vein endothelial cells (HUVECs) cultured in conditioned media from DDR2-expressing tumor cells (ES2 shSCRM) have 20% increase in tube length and 18% increase in sprout network area than HUVECs cultured in conditioned media from DDR2-depleted tumor cells (ES2 shDDR2) (P=0.032). This difference in HUVEC angiogenesis is mediated by vascular endothelial growth factor (VEGF). We observed a 16% decrease in VEGF levels in conditioned media from ES2 shDDR2 cells compared to media from ES2 shSCRM cells (P​​&lt;0.0001). DDR2 WT mice bearing ID8 Trp53-/- BRCA2-/- tumors have 53% more CD31+ microvessels than DDR2 KO mice (P​​&lt;0.0001). We also identified that DDR2’s role in angiogenesis is mediated by the Hsp70/90 chaperone machinery. In summary, we have identified that DDR2 regulates angiogenesis in ovarian cancer.
Citation Format: Favour A. Akinjiyan, Ritu M. Dave, Gregory Longmore, Katherine C. Fuh. DDR2 regulates angiogenesis via HSP-90 modulation in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 168.