bluuebunny/crossref_metadata_2025 huggingface dataset:
Strategies to integrate oral health into primary care: a systematic review
Authors: Christian Bradley , George Ajesh , Veginadu Prabhakar , Villarosa Amy , Makino Yuka , Kim Warrick Junsuk , Masood Mohd , Martin Rachel , Harada Yuriko , Mijares-Majini Maria Carmela
Published: July 2023

Objectives

Integration of oral health into primary care has been proposed as a primary healthcare approach for efficient and sustainable delivery of oral health services, and the effective management of oral diseases. This paper aimed to synthesise evidence on the effectiveness of strategies to integrate oral health into primary care.

Design

Systematic review.

Data sources

MEDLINE, CINAHL, Embase, Scopus, ProQuest, Cochrane and Google Scholar were searched without date limits until the third week of June 2022. Reference lists of eligible studies were also searched. Experts in the field and existing professional networks were consulted.

Eligibility criteria

Only studies that evaluated integration strategies were included in the review. Eligibility was restricted to English language studies published in academic peer-reviewed journals.

Data extraction and synthesis

Two reviewers independently extracted data and performed the risk of bias assessments. A narrative synthesis approach was used to report review findings. Heterogeneity among included studies precluded a meta-analysis.

Results

The search identified 8731 unique articles, of which 49 were included in the review. Majority of the studies explored provision of oral healthcare by primary care professionals in primary care settings, where integration was primarily via training/education and/or policy changes. Most studies reported results favouring the integration strategy, such as improvements in referral pathways, documentation processes, operating efficiencies, number of available health staff, number of visits to non-dental primary care professionals for oral health issues, proportion of children receiving fluoride varnish applications/other preventive treatment, proportion of visits to an oral health professional and dental caries estimates.

Conclusion

The findings from this review demonstrate that the majority of identified strategies were associated with improved outcomes and can be used to inform decision-making on strategy selection. However, more research and evaluation are required to identify best practice models of service integration.

PROSPERO registration number

CRD42020203111.
Social support and psychosocial well-being among older adults in Europe during the COVID-19 pandemic: a cross-sectional study
Authors: Lu Ji , Xiong Juyang , Tang Shangfeng , Bishwajit Ghose , Guo Shuyan
Published: July 2023

The objective of the study was to identify the association between social support and psychosocial well-being among men and women aged over 65 years in Europe during the COVID-19 pandemic.

Methods

Cross-sectional data on 36 621 men (n=15 719) and women (n=20,902) aged 65 years or higher were obtained from the ninth round of the Survey of Health, Ageing and Retirement in Europe. The outcomes were measured by psychosocial well-being reflected with self-reported depression, nervousness, loneliness and sleep disturbances. Social support was measured in terms of receiving help from own children, relatives and neighbours/friends/colleagues since the pandemic outbreak.

Result

About one-third of the participants reported depression (31.03%), nervousness (32.85%), loneliness (32.23%) and sleep trouble (33.01%). The results of multivariable regression analysis revealed that social support was a protective factor to psychological well-being. For instance, receiving help from own children (RD=−0.13, 95% CI=−0.14 to –0.12), relatives (RD=−0.08, 95% CI=−0.11 to –0.06), neighbours/friends/colleagues (RD=−0.11, 95% CI=−0.13 to –0.09) and receiving home care (RD=−0.20, 95% CI=−0.22 to –0.18) showed significantly lower risk difference for depression. Similar findings were noted for loneliness, nervousness, and sleep trouble as well, with the risk difference being slightly different for men and women in the gender-stratified analysis. For instance, the risk difference in depression for receiving help from own children was −0.10 (95% CI=−0.12 to –0.08) among men compared with −0.12 (95% CI=−0.14 to –0.11) among women. The risk differences in the outcome measures were calculated using generalised linear model for binomial family.

Conclusion

Findings of the present study highlight a protective role of social support on psychological well-being among both men and women. Developing strategies to promote social support, especially among older adults, may mitigate the rising burden of psychological illness during the COVID-19 pandemic.
Emerging uses of glucagon-like peptide 1 (GLP-1) receptor agonists following ileal resection: literature review and case examples
Authors: Conley Thomas Edward , White Katherine Lynsey , Bond Ashley , Harrison Simon , McLaughlin John , Lal Simon
Published: July 2023

Following ileal resection, the combination of severe bile acid (BA) malabsorption, rapid small bowel transit and unrestricted upper gastrointestinal (GI) secretion results in severe diarrhoea that can prove refractory to pharmacological therapies. While established therapies, including BA sequestrants and antidiarrhoeal drugs seek to ameliorate symptoms, they do not target the underlying pathophysiological mechanisms in this patient group. Their use can also be limited by both intolerance and adverse effects. The novel use of glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) in these patients may allow restoration of the physiological negative feedback mechanisms lost in ileal resection and reduce diarrhoea by prolonging small bowel transit time, limiting upper GI secretions and perhaps by inhibiting hepatic BA synthesis. While recent evidence supports the use of GLP-1 RAs as a safe and effective therapy for bile acid diarrhoea (BAD), it remains uncertain whether those with severe BAD and subsequent short bowel syndrome secondary to extensive ileal resection will benefit. Here, we present three cases of severe diarrhoea secondary to extensive ileal resection in which the use of the GLP-1 RA, liraglutide, was well tolerated and resulted in an objective improvement in diarrhoeal symptoms. We further provide a narrative review of the emerging evidence base supporting the use of GLP therapies in this challenging condition.
Origin of gases and waters from a hypersaline, carbonate spring on Anticosti Island, Québec, Canada
Authors: Daoust Pascale , Clark Ian D. , Desrochers André
Published: July 2023

Hypersaline spring water (TDS ∼ 85 g/L) and gas are escaping from the top of a calcite travertine mound on Anticosti Island. This mound is located in the Chaloupe River area above the Jupiter Fault which cuts through the Ordovician formations in the subsurface, including the oil and gas-rich Macasty Shale Formation. The Cl content is approximately 3 times that of seawater, but the geochemical profile indicates it to be a Paleozoic basin brine (geogenic He = 2E–7 cc/cc) evaporatively enriched beyond halite saturation (Br:Cl molar ratio = 0.0022 ± 0.00013) that has been diluted by some 73 ± 6% with meteoric waters. Measurable tritium (3.4 TU) indicates this to be a mixture of modern and Holocene recharge. The radioiodine (129I < 10 million atoms/L) is a three-component mixture of geogenic and post-nuclear contributions with low levels in pre-nuclear Holocene recharge. Degassing at the vent (1% to 2% CO2,PCO2 = 0.02 atm, >90% CH4) provokes calcite precipitation and travertine mound formation. Methane comprises a thermo-catalytic component and a biogenic component produced at depth in the organic-rich Macasty Formation by reduction of surface-derived dissolved inorganic carbon (DIC; a14C = 3.5 pMC), producing enriched δ13CDICvalues recorded in the travertine. The occurrence of basin-derived brine and gas discharging in association with the surface expression of the Jupiter fault implies that this fault provides a pathway for deep circulation of meteoric waters, likely driven by the relief on the island.
Static de-Sitter black holes abhor charged scalar hair
Authors: An Yu-Ping , Li Li
Published: July 2023

We prove a no charged scalar hair theorem for static black holes in de-Sitter spacetime in the region between the event horizon and the cosmological horizon. The proof does not depend on the assumption of spherical symmetry. It allows for general non-minimal coupling functions of the scalar field to gravity and electromagnetic fields, and for higher curvature term corrections to Einstein gravity. The extension to other asympitotic spacetimes is applicable by requiring appropriate boundary conditions. Our result excludes the possibility for spontaneous scalarization of charged scalar around static charged de-Sitter black holes.
Investigating axial ligand impact on pinch-porphyrin peroxidase activity with [bis(o-methylpyridino) (dimethylesterprotoporphyrinato)Fe(III)] chloride
Authors: Romero-Morán Alejandra , Hernández-Anzaldo Samuel , Vazquez-Lima Hugo , Reyes-Ortega Yasmi
Published: July 2023

The synthesis and characterization of a novel hexacoordinated compound as a product of the reaction between chlorodimethylesterprotoprphyrin–Fe(III) 1 and 2–methylpiridine (2–CH3Py) was performed. The [bis(o–methylpyridino)(dimethylesterprotoporphyrinato)Fe(III)] chloride 2 is a compound of the family of the pinch–porphyrins, a model of peroxidase enzymes. We analyzed 2 using UV-Vis, 1H NMR, and EPR spectroscopies, as well as kinetic quantifications of its peroxidase activity and computational analysis, to evaluate the presence of the pinch-ligand coordinated to 1 in a series of pinch-ironprotoporphyrin complexes, as previously reported. Our investigation revealed that the oxidant activity of Compound I derived from peroxidase activity determination of 1 and 2, respectively, is better controlled when a heterohydrocarbonated chain is attached to the pyridyl groups that coordinate axially to 1; an effect evidenced by a decrease of the activation energy value associated with Compound 0 formation during the reaction performed by pinch–porphyrin, with the picdien axial ligand and hydrogen peroxide. When correlating the contribution of [Formula: see text]3/2 in the quantum mixed-spin state (qms), [Formula: see text]3/2, [Formula: see text]5/2, of iron(III)-based complexes with their peroxidase activity, we found that when the qms [Formula: see text]3/2, [Formula: see text]5/2, of iron(III) had 80% character [Formula: see text]3/2, the peroxide activity increased significantly. This could be a fundamental trait that could affect the peroxidase activity owing to the distortion of the iron geometry associated with its coordination number when o−methylpyridine is used as an axial ligand.
TIME AND TIMING IN ENTREPRENEURSHIP RESEARCH: INSIGHTS FROM A SYSTEMATIC LITERATURE REVIEW
Authors: LICHTINGER YASMINA , ENGELEN ANDREAS , TEUBNER TIMM
Published: July 2023

The factor of time has drawn considerable attention in entrepreneurship research for the past decades. There is widespread agreement among scholars that time plays a significant role in the development of new ventures: research on life cycle theory, timing of activities, and individual time perspectives had a lasting impact on the academic field. However, the broad interpretation of temporality extends the field of research to various disciplines and leads to a strong fragmentation. Therefore, even in recent work, scholars still call for the adoption of a dynamic view in entrepreneurship research and encourage the use of time-conscious methodologies. This paper conducts a systematic literature review to provide an overview on the thematic foci, methods, main findings, sample specifics, and open questions in this area. We perform co-citation analyses to quantify the extent of bibliographic fragmentation and thereby identify potential knowledge and research gaps that need to be addressed by future research.
The Facets of Intangible Heritage in Southern Chinese Martial Arts: Applying a Knowledge-driven Cultural Contact Detection Approach
Authors: Adamou Alessandro , Picca Davide , Hou Yumeng , Loreto Granados-García Paula
Published: July 2023

Investigating the intangible nature of a cultural domain can take multiple forms, addressing, for example, the aesthetic, epistemic, and social dimensions of its phenomenology. The context of Southern Chinese martial arts is of particular significance, as it carries immaterial components of all these aspects: The technical and stylistic framework of a martial art system; the imagery associated to movements; and the transmission of knowledge orally, practically, or through influence, are but examples of intangible characteristics that can and should be captured, not unlike cultural artifacts. The latter case—the one of formalizing cultural influence through its various forms of evidenceis emblematic as well as largely untrodden ground. A previous attempt at detecting cultural influence computationally was made in the context of Roman archaeology, though the binding of that early effort with the domain model was tight; also, there has hardly been any prior dedicated effort to model the martial arts domain through ontologies.

In this article, we present the realization of the full cycle of a computational approach to investigating cultural contact in Southern Chinese martial arts. The entire approach is predicated upon the usage of standards and techniques of the Semantic Web and formal knowledge. Starting from a modular domain ontology, which models martial arts independently of the goal of capturing cultural influence, we perform knowledge extraction from archival material from the
Hong Kong Martial Arts Living Archive
and generate a dataset of the results modeled after said ontology. Then, we combine the resulting knowledge base with a rule model that represents ways to infer knowledge of potential contact between cultures based on the evidence present in the knowledge base. The results offer an insight into how an inference-based computational model can be applied to detect interesting facts even in the as-yet underexplored domain of intangible cultural heritage. The implemented workflow shows that the full-cycle employment of semantic technologies can offer the ground truth required for largely different approaches, such as statistical and machine learning ones, to operate.
Describing Inscriptions of Ancient Italy. The ItAnt Project and Its Information Encoding Process
Authors: Murano Francesca , Quochi Valeria , Del Grosso Angelo Mario , Rigobianco Luca , Zinzi Mariarosaria
Published: July 2023

This article discusses the challenges addressed in the digital scholarly encoding of the fragmentary texts of the languages of Ancient Italy according to the TEI/EpiDoc Guidelines in XML format. It describes the solutions and customisations that have been adopted for dealing with the peculiarities of our epigraphical documentation and with the formalisation of epigraphical information deemed interesting for data retrieval in a historical linguistic perspective. The making of a digital corpus consisting of new critical editions of selected inscriptions is a work carried out in the context of the project “Languages and Cultures of Ancient Italy. Historical Linguistics and Digital Models”, which aims to investigate the languages of Ancient Italy by combining the traditional methods, proper to historical linguistics, with methods and technology proper to the digital humanities and computational lexicography. More specifically, the purpose of the project is to create a set of interrelated digital language resources which comprise: (1) a digital corpus of texts editions; (2) a computational lexicon compliant with the Web Semantic requirements; (3) a relevant bibliographic reference dataset encoded according to the FRBRoo/LRMoo specifications. Additionally, selected textual data and scientific interpretations will be encoded using CIDOC CRM and its extensions, namely CRMtex and CRMinf. The present contribution thus tackles one of the main aspects of the project, and proposes significant innovations in the encoding of critical editions for epigraphic texts of fragmentary languages, which will hopefully foster future interoperability and integration with other external datasets, a paramount concern of the project.
Scalable Binary Neural Network Applications in Oblivious Inference
Authors: Zhang Xinqiao , Samragh Mohammad , Hussain Siam , Huang Ke , Koushanfar Farinaz
Published: July 2023

Binary neural network (BNN) delivers increased compute intensity and reduces memory/data requirements for computation. Scalable BNN enables inference in a limited time due to different constraints. This paper explores the application of Scalable BNN in oblivious inference, a service provided by a server to mistrusting clients. Using this service, a client can obtain the inference result on his/her data by a trained model held by the server without disclosing the data or learning the model parameters. Two contributions of this paper are: (1) we devise lightweight cryptographic protocols explicitly designed to exploit the unique characteristics of BNNs. (2) we present an advanced dynamic exploration of the runtime-accuracy tradeoff of scalable BNNs in a single-shot training process. While previous works trained multiple BNNs with different computational complexities (which is cumbersome due to the slow convergence of BNNs), we train a single BNN that can perform inference under various computational budgets. Compared to CryptFlow2, the state-of-the-art technique in the oblivious inference of non-binary DNNs, our approach reaches 3× faster inference while keeping the same accuracy. Compared to XONN, the state-of-the-art technique in the oblivious inference of binary networks, we achieve 2× to 12× faster inference while obtaining higher accuracy.
RBG Motif Bridge-Like Lipid Transport Proteins: Structure, Functions, and Open Questions
Authors: Hanna Michael , Guillén-Samander Andrés , De Camilli Pietro
Published: July 2023

The life of eukaryotic cells requires the transport of lipids between membranes, which are separated by the aqueous environment of the cytosol. Vesicle-mediated traffic along the secretory and endocytic pathways and lipid transfer proteins (LTPs) cooperate in this transport. Until recently, known LTPs were shown to carry one or a few lipids at a time and were thought to mediate transport by shuttle-like mechanisms. Over the last few years, a new family of LTPs has been discovered that is defined by a repeating β-groove (RBG) rod-like structure with a hydrophobic channel running along their entire length. This structure and the localization of these proteins at membrane contact sites suggest a bridge-like mechanism of lipid transport. Mutations in some of these proteins result in neurodegenerative and developmental disorders. Here we review the known properties and well-established or putative physiological roles of these proteins, and we highlight the many questions that remain open about their functions.
Motor unit tracking using blind source separation filters and waveform cross-correlations: reliability under physiological and pharmacological conditions
Authors: Goodlich Benjamin I. , Del Vecchio Alessandro , Kavanagh Justin J.
Published: July 2023

The most direct way to validate longitudinal tracking of motor unit data extracted from high-density surface electromyography is to contrast findings with intramuscular electromyography. We used pharmacology to induce changes in motor unit discharge properties as a noninvasive alternative to validate the reliability of tracking motor units. This study confirmed that the specific tracking method may not impact interpretation of motor unit data at lower contraction intensities; however, caution should be used when tracking units during higher intensities.
The conducted vasomotor response and the principles of electrical communication in resistance arteries
Authors: Mironova Galina Yu , Kowalewska Paulina M. , El-Lakany Mohammed , Tran Cam Ha T. , Sancho Maria , Zechariah Anil , Jackson William F. , Welsh Donald G.
Published: July 2023

Biological tissues are fed by arterial networks whose task is to set blood flow delivery in accordance with energetic demand. Coordinating vasomotor activity among hundreds of neighboring segments is an essential process, one dependent upon electrical information spreading among smooth muscle and endothelial cells. The “conducted vasomotor response” is a functional expression of electrical spread, and it is this process that lies at the heart of this critical review. Written in a narrative format, this review first highlights historical manuscripts and then characterizes the conducted response across a range of preparations. Trends are highlighted and used to guide subsequent sections, focused on cellular foundations, biophysical underpinnings, and regulation in health and disease. Key information has been tabulated; figures reinforce grounding concepts and reveal a framework within which theoretical and experimental work can be rationalized. This summative review highlights that despite 30 years of concerted experimentation, key aspects of the conducted response remain ill defined. Of note is the need to rationalize the regulation and deterioration of conduction in pathobiological settings. New quantitative tools, along with transgenic technology, are discussed as a means of propelling this investigative field forward.
A New Graphical Representation of the Old Algebraic Structure
Authors: Nadeem Muhammad , Siddique Imran , Alam Md. Ashraful , Ali Waqas
Published: July 2023

The most recent advancements in algebra and graph theory enable us to ask a straightforward question: what practical use does this graph connected with a mathematical system have in the real world? With the use of algebraic approaches, we may now tackle a wide range of graph theory-related problems. We compute loop-involutions and nonself-loop-involutions of flexible weak inverse property loops. Importantly, diameter, radius, and eccentricity of this loop structure’s inverse graph have all been calculated in a broad manner. Some topological indices, as an application of inverse graph, are also given at the end of the paper.
The Effects of Lactobacillus farciminis and Lactobacillus rhamnosus on Growth, Blood Biochemical, and Meat Quality Indicators of Specific Pathogen‐Free Broiler Chickens
Authors: Eglite Sabine , Ilgaza Aija , Mancevica Lauma , Zolovs Maksims
Published: July 2023

The aim of our study was to evaluate the effects of Lactobacillus farciminis and Lactobacillus rhamnosus on live weight gain, feed consumption indicators, and some metabolic blood biochemical and meat quality indicators of specific pathogen‐free Ross 308 broiler chickens. We carried out the study in three trials and included a total of 780 unsexed Ross 308 chickens, which we randomly divided into two groups: the control group (Con, n = 390, basal diet) and the probiotic group (ProL, n = 390, basal diet + a powder consisting of L. farciminis and L. rhamnosus 4 g/10 kg of feed). We raised broilers until day 35. We determined the amount of feed consumed, the average daily weight gain, the feed conversion ratio, the average daily feed intake, and the cumulative feed intake once a week. We collected blood samples from 45 broilers from each group at the end of the study. In addition, we slaughtered 30 broilers from each group by cervical dislocation to obtain a breast muscle sample (without skin) to determine meat quality in these chickens (cholesterol and unsaturated, omega‐3, omega‐6, omega‐9, and saturated fatty acids). Feeding a probiotic mixture containing L. farciminis and L. rhamnosus did not significantly affect the growth and feed intake indicators. Feeding these probiotics significantly lowered the blood serum cholesterol levels but did not provide the expected reduction in meat cholesterol levels. However, feeding a probiotic mixture increased the levels of polyunsaturated fatty acids (omega‐3 and omega‐6 fatty acids) in the breast meat and decreased saturated fatty acids. To better explain the effect of the combination of lactic acid bacteria (L. farciminis and L. rhamnosus) on the growth and development of broiler chickens in our study, histological and immunohistochemical examinations should be performed.
Data from Periostin+ Stromal Cells Guide Lymphovascular Invasion by Cancer Cells
Authors: Null Jamie L. , Kim Dae Joong , McCann James V. , Pramoonjago Patcharin , Fox Jay W. , Zeng Jianhao , Kumar Pankaj , Edatt Lincy , Pecot Chad V. , Dudley Andrew C.
Published: July 2023

Abstract
Cancer cell dissemination to sentinel lymph nodes is associated with poor patient outcomes, particularly in breast cancer. The process by which cancer cells egress from the primary tumor upon interfacing with the lymphatic vasculature is complex and driven by dynamic interactions between cancer cells and stromal cells, including cancer-associated fibroblasts (CAF). The matricellular protein periostin can distinguish CAF subtypes in breast cancer and is associated with increased desmoplasia and disease recurrence in patients. However, as periostin is secreted, periostin-expressing CAFs are difficult to characterize in situ, limiting our understanding of their specific contribution to cancer progression. Here, we used in vivo genetic labeling and ablation to lineage trace periostin+ cells and characterize their functions during tumor growth and metastasis. Periostin-expressing CAFs were spatially found at periductal and perivascular margins, were enriched at lymphatic vessel peripheries, and were differentially activated by highly metastatic cancer cells versus poorly metastatic counterparts. Surprisingly, genetically depleting periostin+ CAFs slightly accelerated primary tumor growth but impaired intratumoral collagen organization and inhibited lymphatic, but not lung, metastases. Periostin ablation in CAFs impaired their ability to deposit aligned collagen matrices and inhibited cancer cell invasion through collagen and across lymphatic endothelial cell monolayers. Thus, highly metastatic cancer cells mobilize periostin-expressing CAFs in the primary tumor site that promote collagen remodeling and collective cell invasion within lymphatic vessels and ultimately to sentinel lymph nodes.
Significance:
Highly metastatic breast cancer cells activate a population of periostin-expressing CAFs that remodel the extracellular matrix to promote escape of cancer cells into lymphatic vessels and drive colonization of proximal lymph nodes.
Data from Bavituximab Decreases Immunosuppressive Myeloid-Derived Suppressor Cells in Newly Diagnosed Glioblastoma Patients
Authors: Ly K. Ina , Richardson Leland G. , Liu Mofei , Muzikansky Alona , Cardona Jonathan , Lou Kevin , Beers Andrew L. , Chang Ken , Brown James M. , Ma Xiaoyue , Reardon David A. , Arrillaga-Romany Isabel C. , Forst Deborah A. , Jordan Justin T. , Lee Eudocia Q. , Dietrich Jorg , Nayak Lakshmi , Wen Patrick Y. , Chukwueke Ugonma , Giobbie-Hurder Anita , Choi Bryan D. , Batchelor Tracy T. , Kalpathy-Cramer Jayashree , Curry William T. , Gerstner Elizabeth R.
Published: July 2023

AbstractPurpose:
We evaluated the efficacy of bavituximab—a mAb with anti-angiogenic and immunomodulatory properties—in newly diagnosed patients with glioblastoma (GBM) who also received radiotherapy and temozolomide. Perfusion MRI and myeloid-related gene transcription and inflammatory infiltrates in pre-and post-treatment tumor specimens were studied to evaluate on-target effects (NCT03139916).
Experimental design:
Thirty-three adults with IDH--wild-type GBM received 6 weeks of concurrent chemoradiotherapy, followed by 6 cycles of temozolomide (C1-C6). Bavituximab was given weekly, starting week 1 of chemoradiotherapy, for at least 18 weeks. The primary endpoint was proportion of patients alive at 12 months (OS-12). The null hypothesis would be rejected if OS-12 was ≥72%. Relative cerebral blood flow (rCBF) and vascular permeability (Ktrans) were calculated from perfusion MRIs. Peripheral blood mononuclear cells and tumor tissue were analyzed pre-treatment and at disease progression using RNA transcriptomics and multispectral immunofluorescence for myeloid-derived suppressor cells (MDSC) and macrophages.
Results:
The study met its primary endpoint with an OS-12 of 73% (95% confidence interval, 59%–90%). Decreased pre-C1 rCBF (HR, 4.63; P = 0.029) and increased pre-C1 Ktrans were associated with improved overall survival (HR, 0.09; P = 0.005). Pre-treatment overexpression of myeloid-related genes in tumor tissue was associated with longer survival. Post-treatment tumor specimens contained fewer immunosuppressive MDSCs (P = 0.01).
Conclusions:
Bavituximab has activity in newly diagnosed GBM and resulted in on-target depletion of intratumoral immunosuppressive MDSCs. Elevated pre-treatment expression of myeloid-related transcripts in GBM may predict response to bavituximab.
Determinants of Survival with Combined HER2 and PD-1 Blockade in Metastatic Esophagogastric Cancer
Authors: Maron Steven B. , Chatila Walid , Walch Henry , Chou Joanne F. , Ceglia Nicholas , Ptashkin Ryan , Do Richard Kinh Gian , Paroder Viktoriya , Pandit-Taskar Neeta , Lewis Jason S. , Biachi De Castria Tiago , Sabwa Shalom , Socolow Fiona , Feder Lara , Thomas Jasmine , Schulze Isabell , Kim Kwanghee , Elzein Arijh , Bojilova Viktoria , Zatzman Matthew , Bhanot Umesh , Nagy Rebecca J. , Lee Jeeyun , Simmons Marc , Segal Michal , Ku Geoffrey Yuyat , Ilson David H. , Capanu Marinela , Hechtman Jaclyn F. , Merghoub Taha , Shah Sohrab , Schultz Nikolaus , Solit David B. , Janjigian Yelena Y.
Published: July 2023

Purpose:

We report updated clinical outcomes from a phase II study of pembrolizumab, trastuzumab, and chemotherapy (PTC) in metastatic esophagogastric cancer in conjunction with outcomes from an independent Memorial Sloan Kettering (MSK) cohort.

Patients and Methods:

The significance of pretreatment 89Zr-trastuzumab PET, plasma circulating tumor DNA (ctDNA) dynamics, and tumor HER2 expression and whole exome sequencing was evaluated to identify prognostic biomarkers and mechanisms of resistance in patients treated on-protocol with PTC. Additional prognostic features were evaluated using a multivariable Cox regression model of trastuzumab-treated MSK patients (n = 226). Single-cell RNA sequencing (scRNA-seq) data from MSK and Samsung were evaluated for mechanisms of therapy resistance.

Results:

89Zr-trastuzumab PET, scRNA-seq, and serial ctDNA with CT imaging identified how pre-treatment intrapatient genomic heterogeneity contributes to inferior progression-free survival (PFS). We demonstrated that the presence of intensely avid lesions by 89Zr-trastuzumab PET declines in tumor-matched ctDNA by 3 weeks, and clearance of tumor-matched ctDNA by 9 weeks were minimally invasive biomarkers of durable PFS. Paired pre- and on-treatment scRNA-seq identified rapid clearance of HER2-expressing tumor clones with expansion of clones expressing a transcriptional resistance program, which was associated with MT1H, MT1E, MT2A, and MSMB expression. Among trastuzumab-treated patients at MSK, ERBB2 amplification was associated with improved PFS, while alterations in MYC and CDKN2A/B were associated with inferior PFS.

Conclusions:

These findings highlight the clinical relevance of identifying baseline intrapatient heterogeneity and serial ctDNA monitoring of HER2-positive esophagogastric cancer patients to identify early evidence of treatment resistance, which could guide proactive therapy escalation or deescalation.
Data from Selective Inhibition of ATM-dependent Double-strand Break Repair and Checkpoint Control Synergistically Enhances the Efficacy of ATR Inhibitors
Authors: Turchick Audrey , Zimmermann Astrid , Chiu Li-Ya , Dahmen Heike , Elenbaas Brian , Zenke Frank T. , Blaukat Andree , Vassilev Lyubomir T.
Published: July 2023

Abstract
Ataxia telangiectasia and Rad3-related protein (ATR) kinase regulate a key cell regulatory node for maintaining genomic integrity by preventing replication fork collapse. ATR inhibition has been shown to increase replication stress resulting in DNA double-strand breaks (DSBs) and cancer cell death, and several inhibitors are under clinical investigation for cancer therapy. However, activation of cell-cycle checkpoints controlled by ataxia telangiectasia–mutated (ATM) kinase could minimize the lethal consequences of ATR inhibition and protect cancer cells. Here, we investigate ATR-ATM functional relationship and potential therapeutic implications. In cancer cells with functional ATM and p53 signaling, selective suppression of ATR catalytic activity by M6620 induced G1-phase arrest to prevent S-phase entry with unrepaired DSBs. The selective ATM inhibitors, M3541 and M4076, suppressed both ATM-dependent cell-cycle checkpoints, and DSB repair lowered the p53 protective barrier and extended the life of ATR inhibitor–induced DSBs. Combination treatment amplified the fraction of cells with structural chromosomal defects and enhanced cancer cell death. ATM inhibitor synergistically potentiated the ATR inhibitor efficacy in cancer cells in vitro and increased ATR inhibitor efficacy in vivo at doses that did not show overt toxicities. Furthermore, a combination study in 26 patient-derived xenograft models of triple-negative breast cancer with the newer generation ATR inhibitor M4344 and ATM inhibitor M4076 demonstrated substantial improvement in efficacy and survival compared with single-agent M4344, suggesting a novel and potentially broad combination approach to cancer therapy.
Data from Tyrosine Kinase Inhibitors Diminish Renal Neoplasms in a Tuberous Sclerosis Model Via Induction of Apoptosis
Authors: Unachukwu Uchenna , Sonett Jarrod , Woode Denzel , Shiomi Takayuki , Chada Kiran , D'Armiento Jeanine M.
Published: July 2023

Abstract
Tuberous sclerosis complex (TSC) tumors are presently incurable despite a cytostatic response to mTOR pathway inhibition because recurrence of disease occurs after treatment is discontinued. Here, we explored the hypothesis that inhibiting tyrosine kinase activity in mesenchymal lineage-specific platelet-derived growth factor receptor β (PDGFRβ) signaling in TSC tumors is cytocidal and attenuates tumorigenesis at significantly higher levels than treatment with an mTOR inhibitor. Rapamycin-induced versus tyrosine kinase inhibitor (TKI)–induced renal angiomyolipoma (AML) and pulmonary lymphangioleiomyomatosis (LAM) tumor cells were comparatively analyzed using cell survival assays, RNA sequencing, and bioinformatics to distinguish tumoricidal mechanisms adopted by each drug type. The efficacy of imatinib therapy was validated against spontaneously developing renal cystadenomas in tuberous sclerosis Tsc2+/− mouse models (C57BL/6J mice; N = 6; 400 mg/kg/d; oral gavage) compared with Tsc2+/− mice treated with PBS (C57BL/6J mice; N = 6). Our study revealed that TKIs imatinib and nilotinib were cytocidal to both pulmonary LAM and renal AML cell cultures through the downregulation of the glycoprotein GPVI pathway and resultant disruption in mitochondrial permeability, increased cytosolic cytochrome C, and caspase 3 activation. Importantly, renal tumor growth was significantly attenuated in imatinib-treated Tsc2+/− mice compared with PBS treatment. The preclinical studies reported here provide evidence documenting the effectiveness of TKIs in limiting LAM and AML cell growth and viability with important clinical potential. Furthermore, these drugs elicit their effects by targeting a PDGF pathway-dependent apoptotic mechanism supporting the investigation of these drugs as a novel class of TSC therapeutics.
Data from Efficacy and Imaging-Enabled Pharmacodynamic Profiling of KRAS G12C Inhibitors in Xenograft and Genetically Engineered Mouse Models of Cancer
Authors: Lee Catherine , Jiang Ziyue Karen , Planken Simon , Manzuk Lisa K. , Ortiz Roberto , Hall Michael , Noorbehesht Kavon , Ram Sripad , Affolter Timothy , Troche Gabriel E. , Ihle Nathan T. , Johnson Theodore , Ahn Youngwook , Kraus Manfred , Giddabasappa Anand
Published: July 2023

Abstract
KRAS is one of the most commonly mutated oncogenes in lung, colorectal, and pancreatic cancers. Recent clinical trials directly targeting KRAS G12C presented encouraging results for a large population of non–small cell lung cancer (NSCLC), but resistance to treatment is a concern. Continued exploration of new inhibitors and preclinical models is needed to address resistance mechanisms and improve duration of patient responses. To further enable the development of KRAS G12C inhibitors, we present a preclinical framework involving translational, non-invasive imaging modalities (CT and PET) and histopathology in a conventional xenograft model and a novel KRAS G12C knock-in mouse model of NSCLC. We utilized an in-house developed KRAS G12C inhibitor (Compound A) as a tool to demonstrate the value of this framework in studying in vivo pharmacokinetic/pharmacodynamic (PK/PD) relationship and anti-tumor efficacy. We characterized the Kras G12C-driven genetically engineered mouse model (GEMM) and identify tumor growth and signaling differences compared to its Kras G12D-driven counterpart. We also find that Compound A has comparable efficacy to sotorasib in the Kras G12C-driven lung tumors arising in the GEMM, but like observations in the clinic, some tumors inevitably progress on treatment. These findings establish a foundation for evaluating future KRAS G12C inhibitors that is not limited to xenograft studies and can be applied in a translationally relevant mouse model that mirrors human disease progression and resistance.
Data from MACdb: A Curated Knowledgebase for Metabolic Associations across Human Cancers
Authors: Sun Yanling , Zheng Xinchang , Wang Guoliang , Wang Yibo , Chen Xiaoning , Sun Jiani , Xiong Zhuang , Zhang Sisi , Wang Tianyi , Fan Zhuojing , Bu Congfan , Bao Yiming , Zhao Wenming
Published: July 2023

Abstract
Cancer is one of the leading causes of human death. As metabolomics techniques become more and more widely used in cancer research, metabolites are increasingly recognized as crucial factors in both cancer diagnosis and treatment. In this study, we developed MACdb (https://ngdc.cncb.ac.cn/macdb), a curated knowledgebase to recruit the metabolic associations between metabolites and cancers. Unlike conventional data-driven resources, MACdb integrates cancer-metabolic knowledge from extensive publications, providing high quality metabolite associations and tools to support multiple research purposes. In the current implementation, MACdb has integrated 40,710 cancer-metabolite associations, covering 267 traits from 17 categories of cancers with high incidence or mortality, based entirely on manual curation from 1,127 studies reported in 462 publications (screened from 5,153 research papers). MACdb offers intuitive browsing functions to explore associations at multi-dimensions (metabolite, trait, study, and publication), and constructs knowledge graph to provide overall landscape among cancer, trait, and metabolite. Furthermore, NameToCid (map metabolite name to PubChem Cid) and Enrichment tools are developed to help users enrich the association of metabolites with various cancer types and traits.
Implication:
MACdb paves an informative and practical way to evaluate cancer-metabolite associations and has a great potential to help researchers identify key predictive metabolic markers in cancers.
Data from Triple-Negative Breast Cancer-Derived Extracellular Vesicles Promote a Hepatic Premetastatic Niche via a Cascade of Microenvironment Remodeling
Authors: Heo Woohang , Lee Woochan , Cheun Jong Ho , Lee Eun-Shin , Li Songbin , Kim Hoe suk , Son Hye-Youn , Kim Ju Hee , Woo Yeon Duk , Chung Doo Hyun , Yun Jihui , Jung Ji Gwang , Lee Han-Byoel , Han Wonshik , Kim Hong-Kyu , Kim Jong-Il , Moon Hyeong-Gon
Published: July 2023

Abstract
Patients with triple-negative breast cancer (TNBC) often develop metastases in visceral organs including the liver, but the detailed molecular mechanisms of TNBC liver metastasis is not clearly understood. In this study, we tried to dissect the process of premetastatic niche formation in the liver by using patient-derived xenograft (PDX) models of TNBC with different metastatic propensity. RNA sequencing of TNBC PDX models that successfully metastasized to liver showed upregulation of the Cx3cr1 gene in the liver microenvironment. In syngeneic breast cancer models, the Cx3cr1 upregulation in liver preceded the development of cancer cell metastasis and was the result of recruitment of CX3CR1-expressing macrophages. The recruitment was induced by the CX3CL1 production from the liver endothelial cells and this CX3CL1–CX3CR1 signaling in the premetastatic niche resulted in upregulation of MMP9 that promoted macrophage migration and cancer cell invasion. In addition, our data suggest that the extracellular vesicles derived from the breast cancer cells induced the TNFα expression in liver, which leads to the CX3CL1 upregulation. Lastly, the plasma CX3CL1 levels in 155 patients with breast cancer were significantly associated with development of liver metastasis.
Implications:
Our data provides previously unknown cascades regarding the molecular education of premetastatic niche in liver for TNBC.
Data from MYC Induces Immunotherapy and IFNγ Resistance Through Downregulation of JAK2
Authors: Markovits Ettai , Harush Ortal , Baruch Erez N. , Shulman Eldad D. , Debby Assaf , Itzhaki Orit , Anafi Liat , Danilevsky Artem , Shomron Noam , Ben-Betzalel Guy , Asher Nethanel , Shapira-Frommer Ronnie , Schachter Jacob , Barshack Iris , Geiger Tamar , Elkon Ran , Besser Michal J. , Markel Gal
Published: July 2023

Abstract
Immunotherapy has revolutionized the treatment of advanced melanoma. Because the pathways mediating resistance to immunotherapy are largely unknown, we conducted transcriptome profiling of preimmunotherapy tumor biopsies from patients with melanoma that received PD-1 blockade or adoptive cell therapy with tumor-infiltrating lymphocytes. We identified two melanoma-intrinsic, mutually exclusive gene programs, which were controlled by IFNγ and MYC, and the association with immunotherapy outcome. MYC-overexpressing melanoma cells exhibited lower IFNγ responsiveness, which was linked with JAK2 downregulation. Luciferase activity assays, under the control of JAK2 promoter, demonstrated reduced activity in MYC-overexpressing cells, which was partly reversible upon mutagenesis of a MYC E-box binding site in the JAK2 promoter. Moreover, silencing of MYC or its cofactor MAX with siRNA increased JAK2 expression and IFNγ responsiveness of melanomas, while concomitantly enhancing the effector functions of T cells coincubated with MYC-overexpressing cells. Thus, we propose that MYC plays a pivotal role in immunotherapy resistance through downregulation of JAK2.
Data from NL-201 Upregulates MHC-I Expression and Intratumoral T-cell Receptor Diversity, and Demonstrates Robust Antitumor Activity as Monotherapy and in Combination with PD-1 Blockade
Authors: Mortales Christie , Dutzar Benjamin , Chen Jerry , Chen Alex , Huard Justin , Walkey Carl , Swanson Ryan
Published: July 2023

Abstract
Cytokine engineering has shown promise as a means to create novel immunomodulatory agents or to improve upon the therapeutic potential of natural cytokines. NL-201, a de novo, hyperstable, IL2 receptor alpha (IL2Rα)–independent agonist of the receptors for IL2 and IL15, elicits robust preclinical activity in syngeneic murine cancer models, including those resistant to immune checkpoint inhibitors (ICI). Here, we report that NL-201 monotherapy converts ‘cold’ tumor microenvironments (TME) to immunologically ‘hot’ states by driving pro-inflammatory gene expression, enhancing IFNγ-dependent MHC-I expression, and expanding both T-cell number and clonal diversity. In addition, the combination of NL-201 and anti–PD-1 resulted in complementary antitumor activity in the immunologically ‘cold’ and ICI resistant B16F10, EMT6, and Renca syngeneic models. In the B16F10 model, treatment with NL-201 plus anti–PD-1 increased the abundance of CD4+ and CD8+ effector T cells in the TME. These findings reveal an important mechanistic basis for the antitumor activity of NL-201 both as a monotherapy and in combination with PD-1 antagonists, and provide further context for the role of IL2Rα-based signaling in ICI-resistant tumors.
The Effectiveness of Butterfly Hug in Reducing Anxiety Long-Distance Relationship (LDR) with Parents in Nursing Students
Authors: Caturini Endang , Safitri Nastiti Dyah , Sugi Sugiyarto
Published: July 2023

Introduction: Anxiety related to a long-distance relationship with parents is an unpleasant emotional reaction when away from parents that can cognitively interfere with feelings and emotions caused by feelings of loneliness and longing for home. One of the ways to reduce anxiety is a butterfly hug.

Methods Using quasi-experimental with the control group and pre-posttest design. The sampling technique used purposive sampling. The sample consisted of 60 respondents divided into a control group of 30 respondents and an intervention group of 30 respondents. Using the Zung Self-Anxiety Rating Scale for the instrument. The intervention group received a butterfly hug for 6 days in 8 sessions every day, and the control group received music therapy for 6 days. Bivariate analysis used the parametric test paired sample t-test to see the difference between the prepost-test intervention group and to see the difference between the prepost-test control group on the anxiety level using the nonparametric Wilcoxon test. Analysis of bivariate test to see the difference between groups using the independent sample t-test.

Result: The results of the Wilcoxon test of the anxiety level control group p=0,274 (p=>0,05), meanwhile the results of the intervention group of the paired sample t-test intervention group there was a significant effect (p=0,000). The results of the independent sample t-test between the control and intervention groups were p=0,001 (p=<0,05).

Conclusions: Butterfly hug therapy is an effective therapy to reduce anxiety in LDR with parents in nursing students. This therapy is expected to be applied and used as an intervention to reduce anxiety.