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Groth, Paul, Helena Cousijn, Tim Clark, and Carole Goble. "FAIR Data Reuse – the Path through Data Citation." Data Intelligence 2, no. 1-2 (January 2020): 78–86. http://dx.doi.org/10.1162/dint_a_00030.
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One of the key goals of the FAIR guiding principles is defined by its final principle – to optimize data sets for reuse by both humans and machines. To do so, data providers need to implement and support consistent machine readable metadata to describe their data sets. This can seem like a daunting task for data providers, whether it is determining what level of detail should be provided in the provenance metadata or figuring out what common shared vocabularies should be used. Additionally, for existing data sets it is often unclear what steps should be taken to enable maximal, appropriate reuse. Data citation already plays an important role in making data findable and accessible, providing persistent and unique identifiers plus metadata on over 16 million data sets. In this paper, we discuss how data citation and its underlying infrastructures, in particular associated metadata, provide an important pathway for enabling FAIR data reuse.
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Kalugin, Vasilij V. "VERSES BY DIMITRY OF ROSTOV IN THE MANUSCRIPT COLOPHON BY THE OLD BELIEVER MAXIM FROM AROUND 1820s." Texts and History Journal of Philological Historical and Cultural Texts and History Studies 2 (2022): 55–61. http://dx.doi.org/10.31860/2712-7591-2022-2-55-61.
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There are three unique Old Believer manuscript books written on canvas. It is established that all of them were written around the 1820s by Maxim, an adherent of the sect of the beglopopovtsy (“runaway priests”). Two books are anonymous; the third, a prayer book of the “kanonnik” type, contains a colophon in the beginning of which Maxim almost verbatim cited syllabic verses with a mesostic from the Menologium ( Cheti Minei) of Dimitry of Rostov, a renowned critic of Old Believers. Maxim added his own name to the citation. Certain features of the ornament in the canvas codices suggest that Maxim was acquainted with both the Synodal and the Ukrainian-Belarusian book tradition. The citation from Dimitry of Rostov proves this supposition. Maxim’s colophon represents new evidence of Dmitry of Rostov’s literary influence on Old Believers, which has yet received little attention.
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Rabb, Intisar. "Islamic Legal Maxims as Substantive Canons of Construction: Hudūd-Avoidance in Cases of Doubt." Islamic Law and Society 17, no. 1 (2010): 63–125. http://dx.doi.org/10.1163/092893809x12472107043920.
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AbstractLegal maxims reflect settled principles of law to which jurists appeal when confronting new legal cases. One such maxim of Islamic criminal law stipulates that judges are to avoid imposing hudūd and other sanctions when beset by doubts as to the scope of the law or the sufficiency of the evidence (idra'ū'l-hudūd bi'l-shubahāt): the "hudūd maxim." Jurists of all periods reference this maxim widely. But whereas developed juristic works attribute it to Muhammad in the form of a prophetic report (hadīth), early jurists do not. Instead, they cite the maxim as an anonymous saying of nonspecific provenance in a form unknown to hadīth collectors of the first three centuries after Islam's advent. This difference in the jurists' citations of the maxim signals a significant shift in claims to legal authority and the asserted scope of judicial discretion, as jurists debated whether and how to resolve legal and factual doubt. While political authorities exercised increasingly wide discretion over criminal matters and used it to benefit the elite, most jurists promoted an egalitarian "jurisprudence of doubt" through insisting on criminal liability for high-status offenders and heightening claims of the authoritativeness and scope of the hudūd maxim as a hadīth.
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Murchison, Claire C., Avery Ironside, Lila M. A. Hedayat, and Heather J. A. Foulds. "A Systematic Review of Musculoskeletal Fitness Among Indigenous Populations in North America and Circumpolar Inuit Populations." Journal of Physical Activity and Health 17, no. 3 (March 1, 2020): 384–95. http://dx.doi.org/10.1123/jpah.2018-0702.
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Background: North American indigenous populations experience higher rates of obesity and chronic disease compared with nonindigenous populations. Improvements in musculoskeletal fitness can mitigate negative health outcomes, but is not well understood among indigenous populations. This review examines musculoskeletal fitness measures among North American indigenous populations. Methods: A total of 1632 citations were evaluated and 18 studies were included. Results: Comparisons of musculoskeletal fitness measures between North American indigenous men and boys and women and girls were generally not reported. The greatest left and right combined maximal grip strength and maximal leg strength among Inuit boys and men and girls and women were observed among 20–29 years age group. Maximal combined right and left grip strength declined from 1970 to 1990, by an average of 15% among adults and 10% among youth. Maximal leg extension among Inuit has declined even further, averaging 38% among adults and 27% among youth from 1970 to 1990. Inuit men demonstrate greater grip strength and lower leg strength than Russian indigenous men, whereas Inuit women demonstrate greater leg strength. Conclusions: Further research is needed to better understand physical fitness among indigenous peoples and the potential for improving health and reducing chronic disease risk for indigenous peoples through physical fitness.
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Hamar, Imre. "Syncretism in Exegesis: The Integration of Confucian Texts in Chengguan’s Huayan Commentary." Religions 15, no. 4 (March 25, 2024): 400. http://dx.doi.org/10.3390/rel15040400.
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Commentarial literature constitutes a cornerstone in the edifice of Chinese Buddhism, providing critical exegesis of Indian Buddhist texts. This paper examines the pivotal role of Chengguan (738–839), the fourth patriarch of the Huayan school, revered for his extensive commentarial work on the Chinese translations of the Buddhāvataṃsaka-sūtra. Chengguan not only composed a written commentary but also engaged in discourses with the monastic and lay communities at Wutaishan, prompting the creation of a sub-commentary derived from these oral elucidations. The study posits that the composition of Chengguan’s audiences, comprising Confucian-educated scholars and Buddhist monks, necessitated a pedagogical strategy that integrated Chinese intellectual traditions into the Buddhist narrative to enhance comprehension. This analysis focuses on Chengguan’s citations of the Analects, showcasing how he interweaves Confucian maxims into the fabric of his commentary to illuminate Buddhist doctrines. The research articulates the method he employed to make the Buddhist texts resonate with a Chinese audience.
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Ladyawati, Erlin, Prayogo, Restu Ria Wantika, and Annida Dwi Sulistyaningtyas. "CITATION WRITING WORKSHOP AND SCIENTIFIC ARTICLE REFERENCE FOR SMA/MA SE-MGMP TEACHERS, MOJOKERTO DISTRICT." PANCASONA 2, no. 1 (January 31, 2023): 55–62. http://dx.doi.org/10.36456/pancasona.v2i1.6620.
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The purpose of the 2022-2023 Odd Semester Program Pengabdian kepada Masyarakat (PPM) activities is to improve teachers' ability to make citations and references in writing scientific articles which they will publish either manually or by using computer application programs, especially Mendeley. The target of this PPM activity is all SMA/MA Mathematics MGMP Teachers in Mojokerto Regency. There are three stages in this activity, namely the planning stage. at the socialization stage, the implementation stage. This PPM was held from 1 to 30 November 2022 which was attended by 47 MGMP mathematics teachers in Mojokerto Regency. The implementation of the Community Service Program activities by the Mathematics Education Lecturer team at PGRI Adi Buana University, Surabaya, went smoothly. The participants were very enthusiastic about participating in every activity that had been scheduled. There are three activities in this PPM, namely the Basic Concepts of PTK and Writing of PTK as well as how to cite and make references in writing PTK Scientific Articles. The implementation of the Program Pengabdian kepada Masyarakat (PPM) activities by the Mathematics Education Lecturer team at PGRI Adi Buana University, Surabaya, went smoothly. The participants were very enthusiastic about participating in every activity that had been scheduled. The obstacle faced during the implementation of the Program Pengabdian kepada Masyarakat (PPM) by the Lecturer Team of the Mathematics Education Study Program at PGRI Adi Buana University Surabaya was that the room provided was not comfortable because the room was hot so the participants were less comfortable and maximal in participating in the delivery of the material. However, this did not affect the enthusiasm of the participants during the discussion session. Many questions were submitted to the resource person related to the material presented, especially during the mentoring session.
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Boyce, John M., Philip M. Polgreen, Mauricio Monsalve, David R. Macinga, and James W. Arbogast. "Frequency of Use of Alcohol-Based Hand Rubs by Nurses: A Systematic Review." Infection Control & Hospital Epidemiology 38, no. 2 (November 7, 2016): 189–95. http://dx.doi.org/10.1017/ice.2016.247.
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BACKGROUNDRecently, the US Food and Drug Administration requested that a “maximal use” trial be conducted to ensure the safety of frequent use of alcohol-based hand rubs (ABHRs) by healthcare workers.OBJECTIVETo establish how frequently volunteers should be exposed to ABHR during a maximal use trial.DESIGNRetrospective review of literature and analysis of 2 recent studies that utilized hand hygiene electronic compliance monitoring (ECM) systems.METHODSWe reviewed PubMed for articles published between 1970 and December 31, 2015, containing the terms hand washing, hand hygiene, hand hygiene compliance, and alcohol-based hand rubs. Article titles, abstracts, or text were reviewed to determine whether the frequency of ABHR use by healthcare workers was reported. Two studies using hand hygiene ECM systems were reviewed to determine how frequently nurses used ABHR per shift and per hour.RESULTSOf 3,487 citations reviewed, only 10 reported how frequently individual healthcare workers used ABHR per shift or per hour. Very conservative estimates of the frequency of ABHR use were reported owing to shortcomings of the methods utilized. The greatest frequency of ABHR use was recorded by an ECM system in a medical intensive care unit. In 95% of nursing shifts, individual nurses used ABHR 141 times or less per shift, and 15 times or less per hour.CONCLUSIONSHand hygiene ECM systems established that the frequency of exposure to ABHRs varies substantially among nurses. Our findings should be useful in designing how frequently individuals should be exposed to ABHR during a maximal use trial.Infect Control Hosp Epidemiol 2017;38:189–195
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Kurpad, Shekar, Allan R. Martin, Lindsay A. Tetreault, Dena J. Fischer, Andrea C. Skelly, David Mikulis, Adam Flanders, et al. "Impact of Baseline Magnetic Resonance Imaging on Neurologic, Functional, and Safety Outcomes in Patients With Acute Traumatic Spinal Cord Injury." Global Spine Journal 7, no. 3_suppl (September 2017): 151S—174S. http://dx.doi.org/10.1177/2192568217703666.
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Study Design: Systematic review. Objective: To perform a systematic review to evaluate the utility of magnetic resonance imaging (MRI) in patients with acute spinal cord injury (SCI). Methods: An electronic search of Medline, EMBASE, the Cochrane Collaboration Library, and Google Scholar was conducted for literature published through May 12, 2015, to answer key questions associated with the use of MRI in patients with acute SCI. Results: The literature search yielded 796 potentially relevant citations, 8 of which were included in this review. One study used MRI in a protocol to decide on early surgical decompression. The MRI-protocol group showed improved outcomes; however, the quality of evidence was deemed very low due to selection bias. Seven studies reported MRI predictors of neurologic or functional outcomes. There was moderate-quality evidence that longer intramedullary hemorrhage (2 studies) and low-quality evidence that smaller spinal canal diameter at the location of maximal spinal cord compression and the presence of cord swelling are associated with poor neurologic recovery. There was moderate-quality evidence that clinical outcomes are not predicted by SCI lesion length and the presence of cord edema. Conclusions: Certain MRI characteristics appear to be predictive of outcomes in acute SCI, including length of intramedullary hemorrhage (moderate-quality evidence), canal diameter at maximal spinal cord compression (low-quality evidence), and spinal cord swelling (low-quality evidence). Other imaging features were either inconsistently (presence of hemorrhage, maximal canal compromise, and edema length) or not associated with outcomes. The paucity of literature highlights the need for well-designed prospective studies.
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Bourque, Bernard J. "Abbé d’Aubignac : prétendant au trône du goût." Oeuvres et Critiques XLVI, no. 1 (April 25, 2022): 69–84. http://dx.doi.org/10.24053/oec-2021-0005.
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L’abbé d’Aubignac déclare comme maxime incontestable « que jamais personne ne sera savant dans la Poésie Dramatique, que par le secours des Anciens, et que dans le seul examen de leurs Pièces »1. Les nombreuses citations des auteurs antiques dans La Pratique du théâtre constituent une tentative de la part de d’Aubignac de démontrer ses vastes connaissances dans sa quête de s’imposer comme l’autorité du monde théâtral de son temps. Comme l’affirme Hélène Baby, « l’abbé réserve une place d’honneur à la pratique antique »2. Plaute, Sophocle, Euripide, Térence, Eschyle et Aristophane sont cités plus de trois cents fois dans La Pratique. Des dramaturges contemporains, seul Pierre Corneille attire une attention particulière dans la version non corrigée de l’ouvrage3. À l’égard des théoriciens, les auteurs qui sont le plus souvent cités sont Horace et Aristote. Clairement épris de ce dernier, l’abbé se place toutefois moins comme un disciple que comme une version évoluée de l’auteur de La Poétique. La présente étude vise à examiner l’attitude ambivalente de d’Aubignac à l’égard de l’Antiquité et à démontrer comment l’abbé essaie de s’imposer comme monarque incontesté sur le trône du goût.
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Chevallier, Max-Alain. "Sur un Silence du Nouveau Testament: l'Esprit de Dieu a l'Oeuvre dans le Cosmos et l'Humanite." New Testament Studies 33, no. 3 (July 1987): 344–69. http://dx.doi.org/10.1017/s0028688500014326.
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‘L'Esprit du Seigneur a rempli l'Univers et lui qui maintient tout dans l'unité, il connaît toute parole.’ Tel est l'introït de la fête de la Pentecôte dans la liturgie de l'Eglise catholique latine; c'est une citation du livre de la Sagesse (1. 7). La thèse d'une omniprésence de l'Esprit saint s'est trouvée, au cours des siècles, développée dans différentes directions. Sensible à la question de la vérité, le Moyen-Age aimait commenter une maxime datant du 4e siècle: ‘Toute vérité, quel que soit celui qui la dise, vient du Saint-Esprit.’ Préoccupé de la sécularisation contemporaine, le Concile Vatican II disait: ‘L'homme, sans cesse sollicité par l'Esprit de Dieu, ne sera jamais tout à fait indifférent au problème religieux.’ Et, soucieux comme toute notre génération de la justice dans la société, il affirmait: ‘L'Esprit de Dieu qui, par une providence admirable, conduit le cours des temps et rénove la face de la terre, est présent à [l'] évolution [des mentalités dans le sens du progrès social].’
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Dexheimer, Judith, Eric Kirkendall, Michal Kouril, Philip Hagedorn, Thomas Minich, Leo Duan, Monifa Mahdi, Rhonda Szczesniak, and S. Andrew Spooner. "The Effects of Medication Alerts on Prescriber Response in a Pediatric Hospital." Applied Clinical Informatics 08, no. 02 (April 2017): 491–501. http://dx.doi.org/10.4338/aci-2016-10-ra-0168.
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Summary Objective: More than 70% of hospitals in the United States have electronic health records (EHRs). Clinical decision support (CDS) presents clinicians with electronic alerts during the course of patient care; however, alert fatigue can influence a provider’s response to any EHR alert. The primary goal was to evaluate the effects of alert burden on user response to the alerts. Methods: We performed a retrospective study of medication alerts over a 24-month period (1/2013–12/2014) in a large pediatric academic medical center. The institutional review board approved this study. The primary outcome measure was alert salience, a measure of whether or not the prescriber took any corrective action on the order that generated an alert. We estimated the ideal number of alerts to maximize salience. Salience rates were examined for providers at each training level, by day of week, and time of day through logistic regressions. Results: While salience never exceeded 38%, 49 alerts/day were associated with maximal salience in our dataset. The time of day an order was placed was associated with alert salience (maximal salience 2am). The day of the week was also associated with alert salience (maximal salience on Wednesday). Provider role did not have an impact on salience. Conclusion: Alert burden plays a role in influencing provider response to medication alerts. An increased number of alerts a provider saw during a one-day period did not directly lead to decreased response to alerts. Given the multiple factors influencing the response to alerts, efforts focused solely on burden are not likely to be effective. Citation: Dexheimer JW, Kirkendall ES, Kouril M, Hagedorn PA, Minich T, Duan LL, Mahdi M, Szczesniak R, Spooner SA. The effects of medication alerts on prescriber response in a pediatric hospital. Appl Clin Inform 2017; 8: 491–501 https://doi.org/10.4338/ACI-2016-10-RA-0168
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Trinh, Kien Vinh, Dion Diep, Kevin Jia Qi Chen, Le Huang, and Oleksiy Gulenko. "Effect of erythropoietin on athletic performance: a systematic review and meta-analysis." BMJ Open Sport & Exercise Medicine 6, no. 1 (April 2020): e000716. http://dx.doi.org/10.1136/bmjsem-2019-000716.
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IntroductionAthletes have attempted to glean the ergogenic benefits of recombinant human erythropoietin (rHuEPO) since it became available in the 1980s. However, there is limited consensus in the literature regarding its true performance-enhancing effects. In fact, some studies suggest there is no conclusive evidence; therefore, it is necessary to evaluate and quantify the strength of the evidence.ObjectiveTo determine the effects of erythropoietin on enhancing athletic performance.DesignAt least two independent reviewers conducted citation identification through abstract and full-text screening, and study selection, and extracted raw data on demographics, descriptions of interventions and all outcomes to predesigned abstraction forms. Outcomes were stratified by treatment periods and dosages. Study quality was assessed using the Cochrane Risk of Bias Tool and Cochrane Grading of Recommendations Assessment Development and Education (GRADE) scale. Where appropriate, quantitative analysis was performed.Data sourcesEMBASE, MEDLINE and SPORTDiscus were searched from their inception to January 2020.Eligibility criteriaTrials that examined any enhancement in sport in healthy participants aged 18–65 using rHuEPO compared with placebo were included.ResultsOverall, there is low-to-moderate quality evidence suggesting rHuEPO may be more beneficial than placebo in enhancing haematological parameters, pulmonary measures, maximal power output and time to exhaustion independent of dosage. However, these improvements are almost exclusively seen during maximal exercise intensities, which may be less relevant to athletic competition conditions.ConclusionDue to heterogeneity among trials, more high-quality randomised controlled trials with larger sample sizes in conditions that mirror actual competition are needed to further elucidate these effects.
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Khundaqji, Hamzeh, Wayne Hing, James Furness, and Mike Climstein. "Smart Shirts for Monitoring Physiological Parameters: Scoping Review." JMIR mHealth and uHealth 8, no. 5 (May 27, 2020): e18092. http://dx.doi.org/10.2196/18092.
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Background The recent trends of technological innovation and widescale digitization as potential solutions to challenges in health care, sports, and emergency service operations have led to the conception of smart textile technology. In health care, these smart textile systems present the potential to aid preventative medicine and early diagnosis through continuous, noninvasive tracking of physical and mental health while promoting proactive involvement of patients in their medical management. In areas such as sports and emergency response, the potential to provide comprehensive and simultaneous physiological insights across multiple body systems is promising. However, it is currently unclear what type of evidence exists surrounding the use of smart textiles for the monitoring of physiological outcome measures across different settings. Objective This scoping review aimed to systematically survey the existing body of scientific literature surrounding smart textiles in their most prevalent form, the smart shirt, for monitoring physiological outcome measures. Methods A total of 5 electronic bibliographic databases were systematically searched (Ovid Medical Literature Analysis and Retrieval System Online, Excerpta Medica database, Scopus, Cumulative Index to Nursing and Allied Health Literature, and SPORTDiscus). Publications from the inception of the database to June 24, 2019 were reviewed. Nonindexed literature relevant to this review was also systematically searched. The results were then collated, summarized, and reported. Results Following the removal of duplicates, 7871 citations were identified. On the basis of title and abstract screening, 7632 citations were excluded, whereas 239 were retrieved and assessed for eligibility. Of these, 101 citations were included in the final analysis. Included studies were categorized into four themes: (1) prototype design, (2) validation, (3) observational, and (4) reviews. Among the 101 analyzed studies, prototype design was the most prevalent theme (50/101, 49.5%), followed by validation (29/101, 28.7%), observational studies (21/101, 20.8%), and reviews (1/101, 0.1%). Presented prototype designs ranged from those capable of monitoring one physiological metric to those capable of monitoring several simultaneously. In 29 validation studies, 16 distinct smart shirts were validated against reference technology under various conditions and work rates, including rest, submaximal exercise, and maximal exercise. The identified observational studies used smart shirts in clinical, healthy, and occupational populations for aims such as early diagnosis and stress detection. One scoping review was identified, investigating the use of smart shirts for electrocardiograph signal monitoring in cardiac patients. Conclusions Although smart shirts have been found to be valid and reliable in the monitoring of specific physiological metrics, results were variable for others, demonstrating the need for further systematic validation. Analysis of the results has also demonstrated gaps in knowledge, such as a considerable lag of validation and observational studies in comparison with prototype design and limited investigation using smart shirts in pediatric, elite sports, and emergency service populations.
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Garbisu-Hualde, Arkaitz, and Jordan Santos-Concejero. "What are the Limiting Factors During an Ultra‐Marathon? A Systematic Review of the Scientific Literature." Journal of Human Kinetics 72, no. 1 (March 31, 2020): 129–39. http://dx.doi.org/10.2478/hukin-2019-0102.
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AbstractThis review aimed to analyse factors that limited performance in ultra-marathons and mountain ultra-marathons. A literature search in one database (PubMed) was conducted in February 2019. Quality of information of the articles was evaluated using the Oxford´s level of evidence and the Physiotherapy Evidence Database (PEDro) scale. The search strategy yielded 111 total citations from which 23 met the inclusion criteria. Twenty one of the 23 included studies had a level of evidence 2b (individual cohort study), while the 2 remaining studies had a level of evidence of 5 (expert opinion). Also, the mean score in the PEDro scale was 3.65 ± 1.61, with values ranging from 0 to 7. Participants were characterised as experienced or well-trained athletes in all of the studies. The total number of participants was 1002 (893 men, 86 women and 23 unknown). The findings of this review suggest that fatigue in ultra-endurance events is a multifactorial phenomenon that includes physiological, neuromuscular, biomechanical and cognitive factors. Improved exercise performance during ultra-endurance events seems to be related to higher VO2max values and maximal aerobic speed (especially during submaximal efforts sustained over a long time), lower oxygen cost of transport and greater running experience.
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Salma, Umme, Min Xue, Ali Sheikh Md Sayed, and Dabao Xu. "Efficacy of Intrauterine Device in the Treatment of Intrauterine Adhesions." BioMed Research International 2014 (2014): 1–15. http://dx.doi.org/10.1155/2014/589296.
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The primary purpose of this paper is to assess the efficacy of the use of the intrauterine device (IUD) as an adjunctive treatment modality, for intrauterine adhesions (IUAs). All eligible literatures were identified by electronic databases including PubMed, Scopus, and Web of Science. Additional relevant articles were identified from citations in these publications. There were 28 studies included for a systematic review. Of these, 5 studies were eligible for meta-analysis and 23 for qualitative assessment only. Twenty-eight studies related to the use of IUDs as ancillary treatment following adhesiolysis were identified. Of these studies, 25 studies at least one of the following methods were carried out as ancillary treatment: Foley catheter, hyaluronic acid gel, hormonal therapy, or amnion graft in addition to the IUD. There was one study that used IUD therapy as a single ancillary treatment. In 2 studies, no adjunctive therapy was used after adhesiolysis. There was a wide range of reported menstrual and fertility outcomes which were associated with the use of IUD combined with other ancillary treatments. At present, the IUD is beneficial in patients with IUA, regardless of stage of adhesions. However, IUD needs to be combined with other ancillary treatments to obtain maximal outcomes, in particular in patients with moderate to severe IUA.
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Lee, Jihyun, Nam-Hoon Kim, Jeong Su Park, Jihyun Noh, Sowon Bae, and Hun-Taek Kim. "Abstract 4038: TU2218 (TGFβRI/VEGFR2 dual inhibitor) maximizes the benefit of cancer immunotherapies." Cancer Research 84, no. 6_Supplement (March 22, 2024): 4038. http://dx.doi.org/10.1158/1538-7445.am2024-4038.
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Abstract Approved anti-PD-1 antibodies play a pivotal role in driving innovative clinical outcomes through combination with cytotoxic agents, targeted therapies, or other immune checkpoint inhibitors in various cancers. Anti-PD-1 antibody-based combination therapies have led to a paradigm shift in cancer treatment from cytotoxic agents or targeted therapy to immunotherapy. Considering this change in the regimen, the clinical development of TU2218 aims to accelerate approval and clinical application by improving the efficacy and safety of clinically proven combination therapies. TU2218 is characterized by the following four mechanisms of action: 1) improvement of T lymphocyte activity, 2) suppression of Treg, 3) improvement of costimulatory signal defects, and 4) overcoming endothelial cell anergy. Based on the mechanisms of action, TU2218 is expected to show significant clinical effects when combined with immune checkpoint inhibitors by lowering the intensity of immune evasion and changing more favorably to immune checkpoint inhibitors. To test the feasibility of various combination options based on TU2218, in vivo efficacy studies were conducted in 4T1, MC38, and CT26 syngeneic tumor models. In the 4T1 of TNBC type, a level of tumor reduction was significant to p<0.001 on TU2218 and anti-PD-1 antibody combination group compared to vehicle, whereas anti-PD-1 antibody alone or anti-PD-1 antibody and paclitaxel combination group was not significant. Combination therapy with anti-CTLA4 antibody and anti-PD-1 antibody has been approved for some cancers but has therapeutic limitations due to safety issues such as immune-related toxicity and needs improvement. In the MC38, the effectiveness of a dose-sparing strategy of anti-CTLA4 antibody was evaluated by adding TU2218 to the anti-CTLA4 antibody and anti-PD-1 antibody combination regimen to improve safety concerns. In the anti-CTLA4 antibody sparing group, co-administration of TU2218 maintained the anti-tumor activity despite reducing 90% or 60% of the original anti-CTLA4 antibody dose. In effect, the difference in anti-tumor activity between the group with a reduced dose of anti-CTLA4 antibody and the group without was not statistically significant. In CT26, the efficacy of Lenvatinib and anti-PD-1 antibody combination therapy was compared with the combination of Lenvatinib, anti-PD-1 antibody, and TU2218. The efficacy of the Lenvatinib anti-PD-1 antibody, and TU2218 combination group was superior to that of TGI 99% and CR 67% than the Lenvatinib and anti-PD-1 antibody combination group of TGI 76% and CR 17%. Moreover, a statistical difference in anti-tumor activity between the two groups was significant at p<0.001. Collectively, the combination therapies using TU2218 not only improved efficacy but also showed high safety profiles without weight loss or any toxicity signs, supporting the feasibility of the combination strategy of TU2218. Citation Format: Jihyun Lee, Nam-Hoon Kim, Jeong Su Park, Jihyun Noh, Sowon Bae, Hun-Taek Kim. TU2218 (TGFβRI/VEGFR2 dual inhibitor) maximizes the benefit of cancer immunotherapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4038.
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Fahad Alkhamees, Bader, Mogeeb A. A. Mosleh, Hussain AlSalman, and Muhammad Azeem Akbar. "An Effective Approach for Modular Community Detection in Bipartite Network Based on Integrating Rider with Harris Hawks Optimization Algorithms." Journal of Mathematics 2021 (November 16, 2021): 1–16. http://dx.doi.org/10.1155/2021/9511425.
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The strenuous mining and arduous discovery of the concealed community structure in complex networks has received tremendous attention by the research community and is a trending domain in the multifaceted network as it not only reveals details about the hierarchical structure of multifaceted network but also assists in better understanding of the core functions of the network and subsequently information recommendation. The bipartite networks belong to the multifaceted network whose nodes can be divided into a dissimilar node-set so that no edges assist between the vertices. Even though the discovery of communities in one-mode network is briefly studied, community detection in bipartite networks is not studied. In this paper, we propose a novel Rider-Harris Hawks Optimization (RHHO) algorithm for community detection in a bipartite network through node similarity. The proposed RHHO is developed by the integration of the Rider Optimization (RO) algorithm with the Harris Hawks Optimization (HHO) algorithm. Moreover, a new evaluation metric, i.e., h-Tversky Index (h-TI), is also proposed for computing node similarity and fitness is newly devised considering modularity. The goal of modularity is to quantify the goodness of a specific division of network to evaluate the accuracy of the proposed community detection. The quantitative assessment of the proposed approach, as well as thorough comparative evaluation, was meticulously conducted in terms of fitness and modularity over the citation networks datasets (cit-HepPh and cit-HepTh) and bipartite network datasets (Movie Lens 100 K and American Revolution datasets). The performance was analyzed for 250 iterations of the simulation experiments. Experimental results have shown that the proposed method demonstrated a maximal fitness of 0.74353 and maximal modularity of 0.77433, outperforming the state-of-the-art approaches, including h-index-based link prediction, such as Multiagent Genetic Algorithm (MAGA), Genetic Algorithm (GA), Memetic Algorithm for Community Detection in Bipartite Networks (MATMCD-BN), and HHO.
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Evans, Jeffery D., Tibb F. Jacobs, and Emily W. Evans. "Role of Acetyl-L-Carnitine in the Treatment of Diabetic Peripheral Neuropathy." Annals of Pharmacotherapy 42, no. 11 (October 28, 2008): 1686–91. http://dx.doi.org/10.1345/aph.1l201.
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Objective: To examine the role of acetyl-L-carnitine (ALC) in the treatment of diabetic peripheral neuropathy (DPN). Data Sources: A MEDLINE search (1966–April 2008) of the English-language literature was performed using the search terms carnitine, diabetes, nerve, and neuropathy. Studies identified were then cross-referenced for their citations. Study Selection and Data Extraction: The search was limited to clinical trials, meta-analyses, and reviews addressing the use of ALC for the treatment of DPN. Studies that included other disease states that could cause peripheral neuropathy were excluded. Two large clinical studies that used ALC for the treatment of DPN were identified. No case studies were identified. Data Synthesis: The results from 2 published clinical trials Involving 1679 subjects were included. Subjects who received at least 2 g daily of ALC showed decreases in pain scores. One study showed improvements in electrophysiologic factors such as nerve conduction velocities, while the other did not. Patients who had neuropathic pain reported reductions in pain using a visual analog scale. Nerve regeneration was documented in one trial. The supplement was well tolerated, A proprietary form of ALC was used in both studies. Conclusions: Data on treatment of DPN with ALC support its use. It should be recommended to patients early in the disease process to provide maximal benefit. Further studies should be conducted to determine the effectiveness of ALC in the treatment and prevention of the worsening symptoms of DPN.
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Yanik, Andrey Aleksandrovich. "Digital depersonalization of scientific results as an unaccounted risk of modernization of the system of scientific management in the Russian Federation." Тренды и управление, no. 4 (April 2019): 17–30. http://dx.doi.org/10.7256/2454-0730.2019.4.31916.
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This work explores number of unaccounted risks that immerge in the course of modernization of state management of scientific development in Russia, under the influence of a complex of circumstances of various origin. It is demonstrated that stimulation of transfer of scientific results into international citation systems, allowing solution of the current tasks of measurement and assessment of the efficiency of scientific work, is one of the links in the chain of greater process – annexation of countries to the global added value chains in the area of production and use of knowledge. Broader context reveals that digital depersonalization of scientific results in combination with the impossibility of legal protection of the ideas, theories and discoveries contained in the articles, can potentially establish a country in within the less profitable segment of the chain with maximal transaction costs. Objective downside to the multidimensional view of the global context, in which the reform of Russian science is taking place, is that it does not allow forecasting full spectrum of possible consequences at the early stages. It would seem that constant analysis of the multilevel effects, caused by the current management practice, is necessary not only for improving the quality of local solutions, but also for correction of strategies.
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Yu, Qing, Zhaoyi Liu, Xiaohan Xu, and Hongxiao Liu. "B cells intervention in inflammatory mechanism of ankylosing spondylitis: A visualization analysis for the past 20 years." Medicine 102, no. 46 (November 17, 2023): e35904. http://dx.doi.org/10.1097/md.0000000000035904.
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Ankylosing spondylitis (AS) is an autoimmune disease with complex inflammatory mechanism. The aim of this study is to apply the methods of bibliometrics and knowledge mapping to analyze the research trends and hot spots of B cells intervention in inflammatory mechanism of AS. Global published articles on B-cells intervention in inflammatory mechanism of AS were retrieved from the Web of Science (WOS) database from 2004 to 2023. CiteSpace 6.1.R6 software was used to conduct the visualization analysis of countries, authors, institutions, references and keywords in this field. A total of 359 related articles were collected. Since 2004, the number of articles published in the field of B cells intervention in inflammatory mechanism of AS has shown a fluctuating upward trend. The 29 core authors are part of a research group centered on Bowness, Paul and Breban, Maxime. The main research institutions are Anhui Med Univ and Charite. Co-citation analysis reveals that research in this field is currently focused on “intergenic region” and “bone mineral density.” Keyword analysis shows that the current research hotspots and trends in this field mainly focus on the cellular immune mechanism, humoral immune mechanism and clinical application value of B cells intervention in inflammatory mechanism of AS. In the past 20 years, the research on the mechanism of B cells intervention in AS inflammation has focused on B cells intervention in AS inflammation through humoral and cellular immune mechanisms. The future research focus may tend to use B cells as a new therapeutic target for AS.
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Li, Chenyang, Thinh T. Nguyen, Jian-Rong Li, Xingzhi Song, Ignacio I. Wistuba, Andy Futureal, Jianhua Zhang, et al. "Abstract 97: Multiregional profiling revealed intra-tumor transcriptomic heterogeneity associated with the prognosis in non-small cell lung cancer." Cancer Research 83, no. 7_Supplement (April 4, 2023): 97. http://dx.doi.org/10.1158/1538-7445.am2023-97.
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Abstract Introduction: Intratumor heterogeneity (ITH) describes the distinct tumor cell populations and microenvironments within the same tumor, which may profoundly impact cancer evolution and clinical outcomes. Non-small cell lung cancer (NSCLC) is not only a genetically diverse disease but also has high transcriptomic heterogeneity (RNA-ITH). The RNA-ITH limits the reproducibility of expression-based prognostic models, which is poorly understood. Methods: To address the issue, we investigated the effect of RNA-ITH on prognosis at both gene and signature levels using multiregional RNA-seq data from 45 NSCLC patients (145 regions) in the TRACERx study. We also performed multiregional RNA-seq of 25 NSCLC tumors (64 regions) for independent validation. Results: At the gene level, we found that the maximal expression of hazardous genes (Hazard Ration (HR) > 1) and the minimal expression of protective (HR < 1) genes across different regions within a tumor are more prognostic than their average expression. As for prognostic signatures, we first designed five different functions to transform the multiregional expression of signature genes into patient-level values. To calculate individual risk scores, we applied them to assist two existing prognostic gene signatures, ORACLE (Outcome Risk Associated Clonal Lung Expression) and WTGS (whole-transcriptomic gene signature). As a result, the best performance was achieved using the combination of maximal hazardous signature expressions and minimal protective signature expressions. We next developed a new signature called PACEG (Prognosis-Associated Clonally Expressed Genes) and proposed a multiregional assay for higher prognostic accuracy in NSCLC. We demonstrated significant improvement in PACEG performance by leveraging RNA-ITH captured by multiregional expression of signature genes. Finally, we utilized the same strategy to study the impact of tumor immune microenvironment ITH on patient prognosis. Consistently, the minimal/maximal infiltration of protective/hazardous immune cells across tumor regions was the best measurement associated with prognosis in NSCLC. These results were independently validated by our local datasets. Conclusions: The prognosis of NSCLC patients is often driven by the most aggressive tumor subclones. Our study proposed a novel strategy to incorporate RNA-ITH with expression-based prognostic models. Multiple distinct tumor regions should be considered to overcome the ITH issue for better prognostic evaluation, e.g., using the minimal/maximal expression of protective/hazardous signature genes across all regions to calculate the risk score in individuals. We also developed the PACEG panel composed of 26 genes that could be potentially applied in clinical specimens to identify high-risk NSCLC patients who may benefit from intensified adjuvant therapy. Citation Format: Chenyang Li, Thinh T. Nguyen, Jian-Rong Li, Xingzhi Song, Ignacio I. Wistuba, Andy Futureal, Jianhua Zhang, Shawna M. Hubert, Jia Wu, Jianjun Zhang, Chao Cheng. Multiregional profiling revealed intra-tumor transcriptomic heterogeneity associated with the prognosis in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 97.
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Nzuki Bakwaye, Flavien, Céline Termote, A. O. Kibungu Kembelo, and Patrick Van Damme. "Identification et importance locale des plantes médicinales utilisées dans la région de Mbanza-Ngungu, République démocratique du Congo." BOIS & FORETS DES TROPIQUES 316, no. 316 (June 1, 2013): 63. http://dx.doi.org/10.19182/bft2013.316.a20531.
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Une enquête ethnobotanique a été menée sur les plantes médicinales dans la région de Mbanza-Ngungu, province du Bas- Congo, en République démocratique du Congo. Des interviews semi-structurées et des observations participatives ont été effectuées entre février 2009 et mai 2012 auprès de 51 tradipraticiens échantillonnés par la méthode " boule de neige ". Un herbier de référence a été constitué et les échantillons ont été identifiés à l'herbarium du Jardin botanique de Kisantu et de l'Université de Kinshasa. Le but était d'identifier les plantes médicinales populaires en médecine traditionnelle, de documenter leur importance relative et de comparer l'usage alimentaire et non alimentaire de ces plantes. Pendant l'interview, 195 plantes médicinales ont été enregistrées, dont 165 espèces botaniques identifiées appartenant à 138 genres et 56 familles. Les feuilles et les racines constituent les parties de plantes les plus utilisées (63 % des citations) et la décoction représente le mode de préparation le plus fréquent (46 %). L'administration des remèdes se fait le plus souvent par voie orale (71 %). L'importance locale des plantes médicinales et le degré de consensus des informateurs ont respectivement été déterminés sur la base des paramètres medicinal Use Value (med.UVs) et Informant Agreement Ratio (med.IARs). Elaeis guineensis (0,71), Brillantaisia patula (0,39), Zingiber officinale (0,35) et Mondia whitei (0,35) présentent les med.UVs les plus élevés. Par ailleurs, Catharanthus roseus, Lannea antiscorbutica, Palisota ambigua, Raphia gentiliana, Sansevieria trifasciata se distinguent par un med.IARs maximal de 1. Parmi les les plantes médicinales aux med.UVs les plus élevés, M. whitei et Dorstenia laurentii sont présentement très menacées dans le milieu d'étude. Quant aux études plus approfondies, Senna occidentalis serait prioritaire. Il faudrait lui associer les plantes médicinales avec un med.IARs de 1.
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John, Evit, Tom Lesluyes, Toby Baker, Maxime Tarabichi, Peter Van Loo, and Xiao Zhao. "Abstract 1765: The genetic landscape of head and neck cancer using brush biopsy." Cancer Research 84, no. 6_Supplement (March 22, 2024): 1765. http://dx.doi.org/10.1158/1538-7445.am2024-1765.
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Abstract Oral premalignant lesions (OPLs) with genomic alterations have a heightened risk of evolving into oral squamous cell carcinoma (OSCC). Currently, genomic data are obtained through invasive tissue biopsy. Brush biopsy has been utilized for diagnosing dysplasia but its effectiveness in reflecting the complete genomic landscape of OPLs remains uncertain. This study investigates the potential of brush biopsy samples in accurately reconstructing the genomic profile of OPLs. The evolution and heterogeneity were assessed by assessing SNVs, copy number analysis, and subclonal architecture reconstruction of paired tissue-brush biopsy samples of oral epithelium, dysplastic lesion, and OSCC lesion. We found that brush biopsy accurately reflects the genomic landscape of oral lesions, mirroring about 90% of SNVs and comparable CNA profiles found in tissue biopsies. Genomic profiling with brush biopsy was tissue-specific, as SNVs identified in OPL or OSCC lesions were not found in adjacent normal mucosa. Shared SNVs and CNAs were observed between OPL and OSCC samples. This suggested a common ancestor giving rise to these lesions. Subclonal architecture reconstruction confirmed that both lesion types shared a common ancestor clone and then diverged evolutionarily. These findings underscore the potential of brush biopsies in accurately reconstructing the genomic profile of OPL and OSCC, highlighting their usefulness in understanding the biological processes involved in tumor evolution. Citation Format: Evit John, Tom Lesluyes, Toby Baker, Maxime Tarabichi, Peter Van Loo, Xiao Zhao. The genetic landscape of head and neck cancer using brush biopsy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1765.
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Discher, Dennis E. "Abstract 417: Chromosomal instability leads to durable tumor suppression upon macrophage-checkpoint disruption, with induction of anti-tumor IgG." Cancer Research 84, no. 6_Supplement (March 22, 2024): 417. http://dx.doi.org/10.1158/1538-7445.am2024-417.
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Abstract Solid tumors generally exhibit chromosome copy number variation caused by chromosomal instability (CIN) in mitosis, and the resulting aneuploidy associates with poor prognosis in various cancer types and poor Tcell checkpoint blockade response in melanoma. In such contexts, however, macrophages and the SIRPa-CD47 checkpoint are understudied. Here, CIN is induced pharmacologically in poorly immunogenic B16F10 mouse melanoma cells, generating micronuclei plus diverse aneuploidy and skewing macrophages towards an anti-cancer phenotype based on markers and short-term tumor studies. Mice bearing CIN-afflicted tumors with wild-type CD47 levels survive only slightly longer compared to chromosomally stable controls, but long-term survival can be maximized when anti-tumor IgG opsonization is combined with adoptive transfer of macrophages with SIRPa blockade or with CD47 knockout of the B16F10. Multi-epitope, de novo anti-cancer IgG in survivors promote phagocytosis of CD47 knockout B16F10 cells by macrophages and suppress tumoroids in vitro and growth of tumors in vivo. An unexpected benefit of pairing CIN with maximal macrophage anti-cancer activity is thus an anti-cancer vaccination-like response that can lead to durable cures and potentiate cell-mediated acquired immunity. Citation Format: Dennis E. Discher. Chromosomal instability leads to durable tumor suppression upon macrophage-checkpoint disruption, with induction of anti-tumor IgG [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 417.
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Doiar, Larуsa. "Cossack roots of our independence: we think about the past for the future of the future." Вісник Книжкової палати, no. 8 (August 26, 2021): 40–45. http://dx.doi.org/10.36273/2076-9555.2021.8(301).40-45.
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The presented article raises the problem of Ukrainian statehood, which is always relevant and emphasized on the eve of the 30th anniversary, in the context of its initial — Cossack — segment. The article is devoted to the history of state formation, initiated and generated by the Zaporozhian (Sich) and Ukrainian urban (Hetmanate) Cossacks. The author's classification of the Cossack period of national history according to such features as chronology of liberation struggles, character of confrontation and struggle, attributive registration of statehood (in particular, institutionalization of branches of state power and their documentary fixation in legislative (constitutional) acts is noted in the work. The author captures the stages of Cossack statehood (Christian republic-protostate, monarchical hetman state, autonomous Hetmanate as part of tsarist Russia), arguing the obvious regression in its development. Avoiding the possible politicization of the scientific problem, the author deliberately chose retrocontent as the primary source for this study, namely, the works of the most authoritative, without exaggeration, legendary Ukrainian historians of the end of the XIX — first third of the last century, such as: M. Hrushevsky, M. Drahomanov, B. Grinchenko, G. Khotkevych, L. Tsehelsky, G. Kovalenko (Hetmanets), P. Klepatsky, V. Riznychenko and others. The latter cannot be suspected of "treacherous" sentiments, although they cite harsh critical maxims, presenting the past and its participants comprehensively and objectively, while not hiding their personal feelings. An interesting circumstance of their mutual view is the extremely negative attitude towards I. Mazepa, a figure glorified in modern Ukraine, who became the foundation of the education of Ukrainian society. The highlight of the study is the citation of the "Constitution of Kostya Gordienko", older than the legal document of P. Orlyk and quoted in the work of L. Tsegelsky "Russia-Ukraine and Moscow-Russia".
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Leuzzi, Giuseppe, Alessandro Vasciaveo, Angelo Taglialatela, Xiao Chen, Tessa M. Firestone, Allison R. Hickman, Wendy Mao, et al. "Abstract PR009: SMARCAL1 is a dual regulator of innate immune signaling and PD-L1 expression that promotes tumor immune evasion." Cancer Research 84, no. 1_Supplement (January 9, 2024): PR009. http://dx.doi.org/10.1158/1538-7445.dnarepair24-pr009.
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Abstract Genomic instability can trigger cancer-intrinsic innate immune responses that promote tumor rejection. However, cancer cells often evade these responses by overexpressing immune checkpoint regulators, such as PD-L1. Here, we identify the SNF2-family DNA translocase SMARCAL1 as a factor that favors tumor immune evasion by a dual mechanism involving both the suppression of innate immune signaling and the induction of PD-L1-mediated immune checkpoint responses. Mechanistically, SMARCAL1 relieves endogenous DNA damage and suppresses cGAS-STING-dependent immune signaling during cancer cell growth. Simultaneously, it cooperates with the AP-1 family member JUN to maintain chromatin accessibility at a transcriptional regulatory element in the PD-L1 gene, thereby promoting PD-L1 expression in cancer cells. Loss of SMARCAL1 enhances anti-tumor immune responses and sensitizes tumors to immune checkpoint blockade in a mouse melanoma model. Collectively, these studies uncover SMARCAL1 as a valuable target for cancer immunotherapy. Citation Format: Giuseppe Leuzzi, Alessandro Vasciaveo, Angelo Taglialatela, Xiao Chen, Tessa M. Firestone, Allison R. Hickman, Wendy Mao, Tanay Thakar, Alina Vaitsiankova, Jen-Wei Huang, Raquel Cuella-Martin, Samuel B. Hayward, Jordan S. Kesner, Ali Ghasemzadeh, Tarun S. Nambiar, Patricia Ho, Alexander Rialdi, Maxime Hebrard, Yinglu Li, Jinmei Gao, Saarang Gopinath, Oluwatobi A. Adeleke, Bryan Venters, Charles G. Drake, Richard Baer, Benjamin Izar, Ernesto Guccione, Michael-Christopher Keogh, Raphael Guerois, Lu Sun, Chao Lu, Andrea Califano, Alberto Ciccia. SMARCAL1 is a dual regulator of innate immune signaling and PD-L1 expression that promotes tumor immune evasion [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr PR009.
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Bosso-Lefèvre, Célia, Erica Cirri, Eric Mennesson, Dimitri Szymczak, Flavien Carpentier, Alexandra Foucher, Alzbeta Komarkova, Maxime Rochet, Armelle Vindrios, and Romain Goulay. "Abstract 6756: Our RNA production platform and the associated tools facilitate the development of RNA-based vaccine." Cancer Research 84, no. 6_Supplement (March 22, 2024): 6756. http://dx.doi.org/10.1158/1538-7445.am2024-6756.
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Abstract mRNA vaccines have shown their full potential in the Covid-19 pandemic. The application of these technologies for the treatment of cancers represents significant hope, but clinical effectiveness remains to be demonstrated. For this purpose, researchers require high quality production of vaccine mRNA and accurate and cost-saving test tools that are adapted to oncology research. Since 2021, Tebubio has developed a miniscale RNA production platform for providing RNAs (from 100 µg to 1 mg) to researchers around the world. This service is completed by offers on RNA delivery solutions using lipid nanoparticles (LNPs) and cellular tests with biomarker analysis. Through an ingenious design, our DNA matrix for mRNA is easily transferable for GMP production for clinical studies. Recently, Tebubio has developed DNA matrices for circular RNA production. Indeed, circular RNA has many advantages by being less immunogenic and more stable than linear RNA. We compared the quality and the quantity of CAP1 capped linear RNA and circular RNA produced from our DNA templates. We also assessed the stability of both RNAs expressing GFP and the typical tumor antigen, p53, and their relative expression into antigen-presenting cells (APCs). Finally, we quantified the response of the APCs expressing p53 by using our biomarker multiplex analysis system. This new type of RNA and its efficiency testing in APCs will constitute a new addition to our pipeline of RNA production and testing for preclinical studies. Citation Format: Célia Bosso-Lefèvre, Erica Cirri, Eric Mennesson, Dimitri Szymczak, Flavien Carpentier, Alexandra Foucher, Alzbeta Komarkova, Maxime Rochet, Armelle Vindrios, Romain Goulay. Our RNA production platform and the associated tools facilitate the development of RNA-based vaccine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6756.
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Zhu, Jiawei, Bo Li, Zhenshi Zhang, Ling Zhao, and Haifeng Li. "High-Order Topology-Enhanced Graph Convolutional Networks for Dynamic Graphs." Symmetry 14, no. 10 (October 21, 2022): 2218. http://dx.doi.org/10.3390/sym14102218.
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Understanding the evolutionary mechanisms of dynamic graphs is crucial since dynamic is a basic characteristic of real-world networks. The challenges of modeling dynamic graphs are as follows: (1) Real-world dynamics are frequently characterized by group effects, which essentially emerge from high-order interactions involving groups of entities. Therefore, the pairwise interactions revealed by the edges of graphs are insufficient to describe complex systems. (2) The graph data obtained from real systems are often noisy, and the spurious edges can interfere with the stability and efficiency of models. To address these issues, we propose a high-order topology-enhanced graph convolutional network for modeling dynamic graphs. The rationale behind it is that the symmetric substructure in a graph, called the maximal clique, can reflect group impacts from high-order interactions on the one hand, while not being readily disturbed by spurious links on the other hand. Then, we utilize two independent branches to model the distinct influence mechanisms of the two effects. Learnable parameters are used to tune the relative importance of the two effects during the process. We conduct link predictions on real-world datasets, including one social network and two citation networks. Results show that the average improvements of the high-order enhanced methods are 68%, 15%, and 280% over the corresponding backbones across datasets. The ablation study and perturbation analysis validate the effectiveness and robustness of the proposed method. Our research reveals that high-order structures provide new perspectives for studying the dynamics of graphs and highlight the necessity of employing higher-order topologies in the future.
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Quereda, Victor, Shane W. O'Brien, Tony C. Della Pietra, James J. Foley, and Andy Fedoriw. "Abstract B021: CFLAR targeting selectively exploits extrinsic apoptosis signaling in triple-negative breast cancer." Molecular Cancer Therapeutics 23, no. 6_Supplement (June 10, 2024): B021. http://dx.doi.org/10.1158/1538-8514.synthleth24-b021.
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Abstract The extrinsic apoptotic pathway activates programmed cell death through the binding of extracellular death ligands, such as TNFα, to their cognate receptors. Although some death ligands are often upregulated in the tumor microenvironment, this pathway is subverted in cancer cells to instead favor growth and survival rather than the induction of apoptosis. Reflecting the strict control cancer cells exert over this pathway, functional genomics screens, such as DepMap, have identified several of the extrinsic apoptotic components as essential targets, with selective dependency in a subset of cancer cell lines. We have genetically validated that downregulation of CFLAR, a negative regulator of the extrinsic apoptosis pathway, causes apoptosis and cell growth inhibition alone, but specially in combination with TNFα signaling, across multiple cancer types, with increase prevalence in Triple-negative breast cancer. Furthermore, we have shown that in order to have maximal activity most cell lines require targeting of CFLAR short isoform splicing variant. Importantly, CFLAR downregulation in non-tumoral models presented much less activity than the observed in the sensitive cancer models supporting the selective activity of CFLAR in a subset of cancer cells. Citation Format: Victor Quereda, Shane W. O'Brien, Tony C. Della Pietra, James J. Foley, Andy Fedoriw. CFLAR targeting selectively exploits extrinsic apoptosis signaling in triple-negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr B021.
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Chai, Annie Wai Yeeng, Yee Hua Tan, Shiyin Ooi, Pei San Yee, Shi Mun Yee, Howard Lightfoot, Syd Bathorpe, Mathew J. Garnett, and Sok Ching Cheong. "Abstract C042: Integrative analyses of CRISPR and drug screens identify a selective and potent compound for oral squamous cell carcinoma." Molecular Cancer Therapeutics 22, no. 12_Supplement (December 1, 2023): C042. http://dx.doi.org/10.1158/1535-7163.targ-23-c042.
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Abstract Mechanism-guided drug repurposing can accelerate the development of therapeutic strategies for oral squamous cell carcinoma (OSCC), which has an unmet clinical need. We integrated cell line sensitivity data for 339 anti-cancer drugs with genome-wide CRISPR-Cas9 screen gene essentiality data for 21 unique OSCC cell lines, derived primarily from Asian patients. We identified a significant correlation between AZD5582 sensitivity (an antagonist of the inhibitor of apoptosis (IAP) family proteins), and dependency on several members of the NF kappa-B pathway (RNF31, MAP3K7 and IKBKG). Dependent OSCC lines are more sensitive to AZD5582, with nanomolar range half-maximal inhibitory drug concentrations (IC50). We confirmed the on-target specificity and potency of AZD5582 in vitro and in vivo. Furthermore, AZD5582 sensitivity was associated with high levels of tumor necrosis factor (TNF) and either functional apoptotic or necroptotic pathways. In summary, our approach of integrating pharmacological and CRISPR screen data in a unique cohort of OSCC cell lines data has enabled the identification of specific dependencies and drug repurposing candidates. Citation Format: Annie Wai Yeeng Chai, Yee Hua Tan, Shiyin Ooi, Pei San Yee, Shi Mun Yee, Howard Lightfoot, Syd Bathorpe, Mathew J Garnett, Sok Ching Cheong. Integrative analyses of CRISPR and drug screens identify a selective and potent compound for oral squamous cell carcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C042.
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Reddy, Joshua P., Ziqi Yu, Ryan M. Shepard, Tami Von Schalscha, Stephen J. McCormack, Sara M. Weis, David A. Cheresh, and Hiromi I. Wettersten. "Abstract 6358: Arming tumor-associated macrophages to inhibit cancer progression." Cancer Research 84, no. 6_Supplement (March 22, 2024): 6358. http://dx.doi.org/10.1158/1538-7445.am2024-6358.
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Abstract Integrin αvβ3 is a marker of cancer progression in a range of epithelial cancers. In the 1990s, a humanized anti-αvβ3 antibody (Etaracizumab) was developed to target αvβ3+ cancer cells via NK cell-mediated cytotoxicity. While it demonstrated safety and some efficacy in clinical trials, our recent study of the immune microenvironment in αvβ3+ human epithelial tumors revealed increased tumor-associated macrophages (TAMs) but minimal NK cell accumulation. Accordingly, we re-engineered Etaracizumab to favor TAM engagement over NK cells and compared the efficacy of this antibody (ABT101) to that of Etaracizumab in various αvβ3+ epithelial cancer models. While ABT101 and Etaracizumab exhibited identical affinity for αvβ3, ABT 101 showed superior anti-tumor activity in vivo. Notably, depleting NK cells in mice had no impact on ABT101’s effectiveness, while macrophage depletion completely abolished its anti-tumor activity. Interestingly, tumors in mice treated with ABT101 displayed a significant increase in TAMs. Here we define an “antigen-effector cell matching” strategy that allows for maximal anti-tumor activity for various drug resistant epithelial cancers. ABT101 will enter clinical trials for patients with drug resistant lung cancer in the first quarter of 2024. Citation Format: Joshua P. Reddy, Ziqi Yu, Ryan M. Shepard, Tami Von Schalscha, Stephen J. McCormack, Sara M. Weis, David A. Cheresh, Hiromi I. Wettersten. Arming tumor-associated macrophages to inhibit cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6358.
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Rozendal, Pim, Paul van der Leest, Elise M. van der Logt, Naomi Rifaela, Inge Platteel, Frank J. Scherpen, Harry J. Groen, Léon C. van Kempen, and Ed M. Schuuring. "Abstract 1299: Cost-effectiveness analysis of circulating tumor DNA-based molecular profiling platforms for the detection of EGFR mutations in lung cancer." Cancer Research 84, no. 6_Supplement (March 22, 2024): 1299. http://dx.doi.org/10.1158/1538-7445.am2024-1299.
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Abstract Background The detection of mutations in circulating tumor DNA (ctDNA) in blood plasma of lung cancer patients can be used to monitor the tumor-response to therapy and for the early detection of resistance mechanisms. In 2017, the Roche Cobas® EGFR Mutation Test v2 for the detection of the EGFR c.2369C>T p.(T790M) mutation in plasma-derived ctDNA was FDA-approved to identify patients eligible for osimertinib treatment. Today, different platforms are available for EGFR mutation testing in plasma-derived cell-free DNA (cfDNA). In this study we compared the clinical utility of five platforms for the detection of EGFR mutations in cfDNA offering insights into their operational costs, target coverage, hands-on-time and turn-around-time. Methods Four PCR-based platforms and one NGS-based approach for the detection of EGFR mutations were compared. Operational, maintenance, material and personnel costs were calculated for each platform and used as input variables for our recently developed ctDNA micro-costing framework (doi.org/10.1016/j.jmoldx.2022.10.004). This was compared to target coverage and turn-around-time of each platform in the context of therapy resistance. Results Per sample costs decreased for all platforms at maximal weekly throughput. The BioCartis Idylla™ demonstrated the shortest turn-around-time while the Roche Cobas® was the least expensive. Despite being the most expensive and time-consuming, the AVENIO ctDNA Expanded kit covered the most known resistance mechanisms to EGFR inhibitors, many of which are targetable with other TKIs. Conclusion EGFR ctDNA mutation analysis is only cost-effective when the throughput is high. This implies that centralization of cfDNA-testing is necessary to optimize cost-efficiency. With the advent of ctDNA analysis beyond EGFR in the context of targeted therapies for lung cancer, multigene detection assays will become more cost-effective with high throughput. Overview of results Platform Turn-around time at maximal weekly throughput Per sample cost at maximal weekly throughput Coverage of resistance mutations in EGFR 1Additional testing necessary Coverage of genome-wide resistance mutations to EGFR-TKI 1Additional testing necessary BioCartis Idylla™ ctEGFR Mutation Assay 2,5 hours €571 33% 12%1 Roche Cobas® EGFR Mutation Test v2 4 hours €497 33% 6% Bio-Rad QX200 droplet digital PCR (ddPCR) 7,5 hours €766 100%1 24%1 Agena MassARRAY® UltraSEEK® Lung Panel 2 days €613 53% 12% Roche AVENIO ctDNA Expanded kit 1 week €1551 100% 65% Citation Format: Pim Rozendal, Paul van der Leest, Elise M. van der Logt, Naomi Rifaela, Inge Platteel, Frank J. Scherpen, Harry J. Groen, Léon C. van Kempen, Ed M. Schuuring. Cost-effectiveness analysis of circulating tumor DNA-based molecular profiling platforms for the detection of EGFR mutations in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1299.
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Zaplatnikov, A. L., A. A. Girina, E. I. Burtseva, I. V. Lepiseva, I. D. Maykova, V. I. Svintsitskaya, M. V. Leshik, N. V. Koroid, and N. F. Dubovets. "Acute, recurrent and repeat respiratory infections in children: the issues of immunoprophylaxis and immunotherapy." Russian Journal of Woman and Child Health 6, no. 1 (2023): 59. http://dx.doi.org/10.32364/2618-8430-2023-6-1-50-59.
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The article is focused on the issues of immunoprophylaxis and immunotherapy of acute, recurrent and repeat respiratory infections in children. The authors underscore the high efficacy of active specific immunoprophylaxis against influenza virus, pneumococcal and Hib-infections. They emphasize that the use of combined immunoprophylaxis (vaccine + non-specific immunoprophylactic agents) is effective for achieving the maximal preventive effect, especially in children with recurrent and repeat respiratory infections. The article elucidates such issues as the mode of action and the efficacy of therapy and prevention, as well as the tolerability and safety of topical bacterial lysates in pediatric practice. It also reviews the pathogenetic rationale of using topical bacterial lysate IRS 19 in the prevention and treatment of acute, recurrent and repeat respiratory infections in children. The authors highlight the beneficial therapeutic effects of topical bacterial lysate Imudon on the clinical course of infectious and inflammatory oropharyngeal diseases and its preventive action. The authors outline the good tolerability of topical bacterial lysates used in pediatric practice. Taking into consideration that achievement of the most effective prevention of acute respiratory infections (ARI) in children with recurrent and repeat respiratory infections is possible via combination of immunizations, whereas topical bacterial lysates can be applied successfully as non-specific immunoprophylactic agents. KEYWORDS: vaccination, influenza, children, immunity, immunotherapy, immunoprophylaxis, acute respiratory infections, recurrent respiratory infections, repeat respiratory infections, topical bacterial lysates, trained immunity, frequently ill children. FOR CITATION: Zaplatnikov A.L., Girina A.A., Burtseva E.I. et al. Acute, recurrent and repeat respiratory infections in children: the issues of immunoprophylaxis and immunotherapy. Russian Journal of Woman and Child Health. 2023;6(1):50–59 (in Russ.). DOI: 10.32364/2618- 8430-2023-6-1-50-59.
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Zhang, Yuxiang, Saidi Wang, Haiyan Hu, and Xiaoman Li. "Abstract LB066: Machine learning algorithm for drug discovery targeting new co-transcription factors of HIF1A." Cancer Research 83, no. 8_Supplement (April 14, 2023): LB066. http://dx.doi.org/10.1158/1538-7445.am2023-lb066.
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Abstract Hypoxia-inducible factor 1 alpha (HIF1A) activation drives cellular adaption to low oxygen stress in malignant and non-malignant cells. HIF1A transcriptionally regulates many genes in key processes like angiogenesis and metastasis, facilitating the cell’s survival. Interestingly, HIF1A is able to carry out its regulatory functions by forming protein-protein interactions with its co-transcription factors. Since low oxygen conditions are frequently present in cancerous cells, we predict that these co-transcription factors could serve as new cancer therapeutic targets. Our recent work has thus focused on identifying motifs in HIF1A ChIP-Seq sequences and discovering novel HIF1A co-transcription factors. In this study, we leveraged cutting-edge deep learning methods, including a hybrid convolutional neural network (CNN) and recurrent neural network (RNN) based motif-discovery model, and discovered several novel motifs. We also look to predict potential therapeutic drugs against the identified co-transcription factors using a machine-learning drug discovery model that evaluates therapies based on their half-maximal inhibitory concentration (IC50). We have so far found several small molecules that could adequately modulate the activity of the identified co-transcription factors. Our results could lead to new therapeutic approaches against HIF1A-dependent cancers such as colon, breast, gastric, lung, brain, and prostate. Citation Format: Yuxiang Zhang, Saidi Wang, Haiyan Hu, Xiaoman Li. Machine learning algorithm for drug discovery targeting new co-transcription factors of HIF1A [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB066.
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Harwood, Dylan, Vilde Pedersen, Nicolai S. Bager, Ane Y. Schmidt, Tobias O. Stannius, Ausrine Areskeviciute, Knud Josefsen, et al. "Abstract 1144: Glioblastoma cells increase expression of neurodevelopmental programs and synaptic connectivity in the tumor periphery." Cancer Research 84, no. 6_Supplement (March 22, 2024): 1144. http://dx.doi.org/10.1158/1538-7445.am2024-1144.
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Abstract Glioblastoma remains one of the deadliest brain malignancies. First-line therapy consists of maximal surgical tumor resection, accompanied by concomitant and adjuvant temozolomide chemotherapy and radiotherapy. Malignant cells escape surgical resection by migrating into the brain parenchyma, where they give rise to the recurrent tumor. Based on gene expression, the tumor core can be subtyped into mesenchymal, proneural and classical areas, each being associated with differences in genetic alterations and cellular composition. In contrast, the tumor periphery where migrating tumor cells infiltrate brain parenchyma is less characterized in patients. Using spatial transcriptomics (n = 11), we show that specific malignant states colocalize in tumor core areas with necrosis and microvascular proliferation. Malignant cells within proneural or mesenchymal subtyped cores displayed, as expected, many differences in genetic expression, although such differences disappeared in the tumor periphery. Malignant cells residing in the tumor periphery had increased expression of genes related to neurodevelopmental pathways and synaptic connectivity. Our findings show similarities in cellular states across tumor subtypes with implications for post-operative treatment and provide an updated view of the spatial landscape of glioblastomas. Citation Format: Dylan Harwood, Vilde Pedersen, Nicolai S. Bager, Ane Y. Schmidt, Tobias O. Stannius, Ausrine Areskeviciute, Knud Josefsen, Dorte S. Nørøxe, David Scheie, Hannah E. Rostalski, Ulrik Lassen, Frederik O. Bagger, Joachim Weischenfeldt, Dieter H. Heiland, Kristoffer Vitting-Seerup, Signe R. Michaelsen, Bjarne W. Kristensen. Glioblastoma cells increase expression of neurodevelopmental programs and synaptic connectivity in the tumor periphery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1144.
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Jones, Daniel A., Deshan Weeraman, Martina Colicchia, Mohsin A. Hussain, Devanayegi Veerapen, Mervyn Andiapen, Krishnaraj S. Rathod, Andreas Baumbach, and Anthony Mathur. "The Impact of Cell Therapy on Cardiovascular Outcomes in Patients With Refractory Angina." Circulation Research 124, no. 12 (June 7, 2019): 1786–95. http://dx.doi.org/10.1161/circresaha.118.314118.
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Rationale: Cell-based therapies are a novel potential treatment for refractory angina and have been found to improve markers of angina. However, the effects on mortality and major adverse cardiac events (MACE) have not been definitively investigated. Objective: To investigate the efficacy and safety of stem cell treatment compared with optimal medical treatment for refractory angina by conducting an updated meta-analysis, looking at clinical outcomes. Methods and Results: We performed a systematic review and meta-analysis of randomized controlled trials using the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. A comprehensive search was performed of PubMed, EMBASE (Excerpta Medica database), Cochrane, ClinicalTrials.gov , Google Scholar databases of randomized controlled trials, and scientific session abstracts. Studies were deemed eligible if they met the following criteria: (1) full-length publications in peer-reviewed journals; (2) evaluated cell therapy use in patients with no further revascularisation options while on optimal medical treatment; (3) patients had ongoing angina, Canadian Cardiovascular Society class II—IV; and (4) included a placebo/control arm. We calculated risk ratios for all-cause mortality, combined MACE events. We assessed heterogeneity using χ 2 and I 2 tests. We identified 1191 citations with 8 randomized controlled trials meeting inclusion criteria involving 526 patients. Outcomes pooled were MACE, mortality, and indices of angina (angina episodes, Canadian Cardiovascular Society angina class, exercise tolerance, and antianginal medications). Our analysis showed a decreased risk of both MACE (odds ratio, 0.41; CI, 0.25−0.70) and mortality (odds ratio, 0.24; 95% CI, 0.10−0.60) in cell-treated patients compared with patients on maximal medical therapy. This was supported by improvements in surrogate end points of anginal episodes, use of antianginal medications, Canadian Cardiovascular Society class, and exercise tolerance. Conclusions: In addition to improvements in indices of angina, cell-based therapies improve cardiovascular outcomes (mortality/MACE) in patients with refractory angina. Given the premature termination of the phase III study, this supports the need for further definitive trials. Prospero Registration : URL: https://www.crd.york.ac.uk/prospero/ . Unique identifier: CRD42018084257.
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Moorthy, Ganesh, Veronika Voronova, Cesar Pichardo, Kirill Peskov, Giuditta Illuzzi, Anna Staniszewska, Mark Albertella, and Holly Kimko. "Abstract 2794: A Quantitative Systems Pharmacology (QSP) model to characterize dose-dependent antitumor activity of AZD5305, PARP1 selective inhibitor, across multiple xenograft models." Cancer Research 83, no. 7_Supplement (April 4, 2023): 2794. http://dx.doi.org/10.1158/1538-7445.am2023-2794.
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Abstract AZD5305 is a potent and selective PARP1 inhibitor and trapper which is hypothesized to improve therapeutic index over first generation nonselective PARP inhibitors. AZD5305 demonstrated significant and sustained antitumor activity in multiple BRCA1/2 mutant xenograft models. Here we present a mechanistic Quantitative Systems Pharmacology (QSP) model to analyze dose-dependent antitumor activity of AZD5305 (0.01-10 mg/kg) across a selection of xenograft models with different homologous recombination repair (HRR) status (Capan-1, DLD-1 BRCA2 KO, HBCx-9, HBCx-17, MDA-MB-436 and SUM149PT). A QSP model was developed based on a system of ordinary differential equations (ODEs) to address formation and repair of trapped PARP-DNA fragments and longitudinal changes in tumor size as a function of pharmacokinetic (PK) profiles in individual animals. Tumor growth data as well as intratumoral PARylation inhibition from xenograft models were utilized for model development and qualification. Model parameters characterizing intrinsic tumor growth and cancer cell sensitivity to accumulated DNA damage, were set to be different across xenograft models, to provide unbiased data reproduction. Sensitivity analyses were performed to identify model parameters which have the most impact on differential antitumor activity observed across various xenograft models. Maximal antitumor efficacy was seen at 0.1 to 1 mg/kg AZD5305, depending on the tumor model. Exposures at 1 mg/kg were similar to those causing peak PARP1 trapping in vitro. The QSP model adequately captures antitumor activity across different xenograft models. Simulations indicate antitumor activity of AZD5305 was driven mainly by differences in the HRR status-related model parameter (khrr). Xenograft models with HRR deficiency such as HBCx-17, DLD-1 BRCA2 KO and MDA-MB-436 (with a very low khrr) were the most sensitive to AZD5305 and treatment led to tumor regressions. In contrast, tumor models with partial sensitivity, such as HBCx-9, Capan-1, SUM149PT (with khrr up to 1000-fold higher than in the sensitive tumors), AZD5305 only achieved tumor growth inhibition. Dosing AZD5305 at 0.03 mg/kg daily was associated with tumor regression in HBCx-17 and MDA-MB-436 xenografts, whereas 1 mg/kg daily dosing was required to achieve tumor regression in the DLD-1 BRCA2 KO model, and maximal tumor growth inhibition in less sensitive models. Further biomarker analyses to assess functional HRR status (e.g. via RAD51 foci score) in these xenograft models is ongoing to validate model estimated khrr parameters. The calibrated model was used to predict antitumor activity of AZD5305 at clinically relevant exposures observed in the phase I clinical study PETRA. Model-based simulations indicated near maximal efficacy at clinical doses equivalent to 1 mg/kg AZD5305 exposure in xenograft models. Citation Format: Ganesh Moorthy, Veronika Voronova, Cesar Pichardo, Kirill Peskov, Giuditta Illuzzi, Anna Staniszewska, Mark Albertella, Holly Kimko. A Quantitative Systems Pharmacology (QSP) model to characterize dose-dependent antitumor activity of AZD5305, PARP1 selective inhibitor, across multiple xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2794.
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Zheng, Suilan, Bo Huang, Yashapal Singh, Haiyan Chu, Suresh K. Bowroju, Md Sazzadul Bari, Madduri Srinivasarao, et al. "Abstract 1787: Design of bispecific adapters for universal CAR T cell therapies of solid tumors." Cancer Research 83, no. 7_Supplement (April 4, 2023): 1787. http://dx.doi.org/10.1158/1538-7445.am2023-1787.
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Abstract Recent success in the use of chimeric antigen receptor (CAR) T cell therapies to treat hematologic cancers has encouraged the exploration of CAR T cell technologies to treat solid tumors. For establishment of a productive immunologic synapse between the CAR T cell and cancer cell, multiple CARs on the T cell surface must engage multiple tumor antigens on the cancer cell surface. Whereas these binding interactions are mediated in classical CAR T cells by direct recognition of the tumor antigen by the scFv on the CAR, in the case of universal CAR T cells this recognition must be created by a bispecific adapter that can bridge between the tumor antigen and the CAR. While a diversity of bispecific adapters have been explored in the literature, the bispecific adapter used here is comprised of a low molecular weight ligand that binds avidly to the desired tumor antigen, the yellow dye fluorescein (FL) that binds tightly to an anti-fluorescein scFv on the CAR, and a polyethylene glycol (PEG) spacer that spans between the two. The length of this PEG spacer appears to be critical to ensure that 1) the bispecific adapter is long enough to mediate engagement of the universal CAR T cell with the cancer cell, and 2) the resulting intercellular distance is optimal for activating the necessary co-receptor interactions.In our study, we have utilized protein structure data and molecular modeling to estimate the optimal adapter spacer lengths for bridging between our CAR T cell and two important target cells, namely PSMA positive prostate cancer cells and fibroblast activation protein (FAP) expressing cancer associated fibroblasts. We then synthesized the desired bispecific adapters with a variety lengths of PEG spacer and evaluated their effects in mediating the cytotoxicity of our universal anti-FL CAR T cells both in vitro and in vivo. Our results reveal that the optimal spacer lengths in the bispecific adapters for targeting PSMA (DUPA-FL) and FAP (FAPL-FL) are different and depend on the locations of the adapter binding pockets on their respective protein targets, as predicted by molecular modeling. Specifically, a shorter PEG spacer is required for maximal cytoxicity when employing the PSMA-targeted adapter, whereas a much longer PEG spacer is needed to achieve maximal cell killing with the FAP-targeted adapter. In addition, spacer length can also be adjusted to avoid overactivation-induced T cell exhaustion. Taken together, our studies demonstrate that instead of optimizing the hinge length of a CAR for each antigen epitope, our bispecific adapter/universal CAR platform provides a highly flexible strategy for optimizing the intermembrane distance between the universal CAR T cell and cancer cell to achieve maximal target cell killing with minimal CAR T cell exhaustion. Citation Format: Suilan Zheng, Bo Huang, Yashapal Singh, Haiyan Chu, Suresh K. Bowroju, Md Sazzadul Bari, Madduri Srinivasarao, Sudarsan R. Kasireddy, Ramesh Mukkamala, Laurie Beitz, Byoung Ryu, Andrew M. Scharenberg, Michael Jensen, Philip S. Low. Design of bispecific adapters for universal CAR T cell therapies of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1787.
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Zegzouti, Hicham, Laurie Engel, Matthew Swiatnicki, Juliano Alves, and Said A. Goueli. "Abstract 2977: Profiling oncogenic Ras mutant drugs with homogeneous bioluminescent immunoassays." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2977. http://dx.doi.org/10.1158/1538-7445.am2022-2977.
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Abstract Activating KRAS mutations present in many cancers are difficult to target with drugs until recently with the FDA approval of sotorasib (AMG-510), a KRAS G12C selective inhibitor. In an effort to study Ras inhibitors in cells and identify new compounds that inhibit Ras and its downstream signaling, assays such as western or ELISA are commonly used. These traditional immunoassays can be tedious, require multiple washing steps, and are not easily adaptable to a high throughput screening (HTS) format. To overcome these limitations, we developed Lumit, a novel immunoassay approach that combines bioluminescent enzyme subunit complementation technology and immunodetection. We applied this bioluminescent and homogeneous “Add and Read” assay to analyze Ras signaling pathway activation and inhibition through multiple nodes of the pathway including detection of phosphorylated ERK. The assay was used to profile different allele specific inhibitors with cell lines harboring different activating KRAS mutations and obtained the predicted pharmacology and selectivity. The potency of PROTAC compound targeting selective degradation of KRAS G12C was also tested using Lumit and the result showed that maximal decrease in RAS signaling was achieved. Unlike current assays that require lengthy sample preparation and multiple washing steps, the Lumit immunoassay provides an alternative platform because it is homogeneous and allows to decipher signaling pathways activities in a fast and simple manner. Our results demonstrate that this bioluminescent technology can be adapted to any signaling pathway node, allowing scientists to streamline the analysis of signaling pathways of interest such as Ras, and identify much needed inhibitors of its mutants. Citation Format: Hicham Zegzouti, Laurie Engel, Matthew Swiatnicki, Juliano Alves, Said A. Goueli. Profiling oncogenic Ras mutant drugs with homogeneous bioluminescent immunoassays [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 2977.
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Ha, Nguyen Cam, Hoang Thi Minh Hien, Le Thi Thom, Hoang Thi Huong Quynh, and Dang Diem Hong. "Optimization of fermentation conditions for squalene production by heterotrophic marine microalgae Schizochytrium mangrovei PQ6." TAP CHI SINH HOC 39, no. 3 (November 7, 2017): 349–58. http://dx.doi.org/10.15625/0866-7160/v39n3.9130.
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Squalene is currently known as chemopreventive agents in reducing the incident of coronary heart disease and cancer. It is also a strong antioxidant used extensively in the food and cosmetic industries. Microbial sources of squalene are being explored in recent years. The objective of this study was to investigate fermentation conditions of Schizochytrium mangrovei PQ6 for high squalene production in 30L bioreactor. Squalene production was influenced by various nutritional factors such as glucose, nitrogen, vitamins etc. and physical factors such as batch and fed-batch fermentation. Our study established that fed-batch fermentation with nitrogen source of 1.2% yeast extract and 6.4% monosodium glutamate and 0.4% mixture of vitamin B1, 6 and 12 as optimal culture condition for maximal production of squalene by S. mangrovei PQ6. In fed-batch culture, the glucose concentration feeding was added up to 22% into the culture at 36 h of fermentation. The maximum squalene production was achieved 6.9 ± 0.1 g/L at 48 h of fed-batch fermentation, respectively. The values were 2-3 times more than that in fed-batch cultivation without adding mixture of vitamins and 4-6 times more than that in batch cultivation. Our obtained results are a breakthrough for the development of alternative squalene source from heterotrophic marine microalgae of Schizochytrium mangrovei PQ6 species for health-promoting functional foods. Citation: Nguyen Cam Ha, Hoang Thi Minh Hien, Le Thi Thom, Hoang Thi Huong Quynh, Dang Diem Hong, 2017. Optimization of fermentation conditions for squalene production by heterotrophic marine microalgae Schizochytrium mangrovei PQ6. Tap chi Sinh hoc, 39(3): 349-358. DOI: 10.15625/0866-7160/v39n3.9130. *Corresponding author: hoangminhhien@yahoo.com; ddhong60vn@yahoo.com Received 6 January 2017, accepted 20 August 2017
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Dada, Hannah, Kun Do, Alexander Cartagena-Rivera, and Grégoire Altan-Bonnet. "Abstract 4132: Effect of mechanical cues on T cell killing of cancer cells." Cancer Research 83, no. 7_Supplement (April 4, 2023): 4132. http://dx.doi.org/10.1158/1538-7445.am2023-4132.
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Abstract Cancer immunotherapies have focused on strategies to strengthen immune cell activation and effector function. These treatment strategies enhance the effector function of immune cells, particularly cytotoxic T cells (CTL), driving tumor eradication. Methods to improve the killing mechanisms of CTLs are not well studied and largely focused on assessing/strengthening the antigenic responses of T cells. We hypothesize that the mechanical landscape of CTL-tumor interactions can also drastically impact CTL cytotoxicity. By altering the physical context for T cell recognition of tumors, we measured cytotoxicity changes and subsequently used these changes in killing capacities to train and generate a quantitative parametrization of T cell killing. CTLs utilize cytokine expression to kill and shape the inflammatory milieu. Taking advantage of a robotic platform that enables the automatic collection of cytokines, we assembled datasets of T cell attacks of tumor cells grown on substrates with varying stiffness levels. The stiffness levels were altered using polyacrylamide (PAA) gels and ranged from 0.2kPa to approximately 113 kPa. Preliminary results from two different models (i.e., mouse and human TCR-transgenic T cells) suggest that there exists an optimal stiffness value for maximal response by T cells. These results suggest that CTLs utilize biophysical cues in addition to molecular cues (antigen) to properly elicit an immune response—modeling and fine-tuning these mechanical cues can be a novel and effective approach to improving cancer immunotherapies. Citation Format: Hannah Dada, Kun Do, Alexander Cartagena-Rivera, Grégoire Altan-Bonnet. Effect of mechanical cues on T cell killing of cancer cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4132.
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Subham, Siddharth, John D. Jeppson, Bryan Schatmeyer, Stephen J. Forman, Christine E. Brown, and David Akhavan. "Abstract 3235: Protein kinase C is an upstream regulator of IL13Ra2 and small molecular activator enhances CAR T mediated killing." Cancer Research 83, no. 7_Supplement (April 4, 2023): 3235. http://dx.doi.org/10.1158/1538-7445.am2023-3235.
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Abstract Glioblastoma multiforme (GBM) is the most aggressive primary malignant brain cancer with a median survival of 16-20 months. Maximal safe resection and adjuvant chemotherapy improve survival but there is no cure and hence improved therapies are urgently needed. CAR T cell therapy has been FDA approved for hematologic malignancies but there are some barriers to their application for solid tumors in the clinic such as heterogenous tumor antigen expression. Chimeric Antigen Receptor (CAR) T Cells combine the cytolytic potency of T cells with the tumor specificity of an antibody. The interleukin 13 receptor alpha 2 (IL13Rα2) is an important target of CAR T cell therapy in ongoing GBM clinical trials. However, regulation of IL13Ra2 expression in GBM is unclear. Identifying upstream regulators of IL13Rα2 will not only help delineate IL13Rα2 carcinogenesis but also may help improve CAR T cell therapy. Utilizing knockout and overexpression constructs, we have identified protein kinase C family as an upstream regulator of IL13Rα2 transcription and translation in GBM cell lines. We have also identified a small molecule regulator of IL13Rα2, Ingenol-3-Angelate (I3A), that inhibits U87 tumor cell proliferation. Furthermore, I3A enhances IL13Rα2 re-directed CAR T cell mediated tumor cytolysis in vitro. Importantly, I3A treatment increases interferon gamma secretion by T cells. Taken together, our data implicates PKC isoforms as an upstream regulator of IL13Rα2. I3A treatment may serve as a therapeutic strategy to enhance CAR T mediated killing. Citation Format: Siddharth Subham, John D. Jeppson, Bryan Schatmeyer, Stephen J. Forman, Christine E. Brown, David Akhavan. Protein kinase C is an upstream regulator of IL13Ra2 and small molecular activator enhances CAR T mediated killing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3235.
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Efstathiou, Jason A. "Abstract IA013: Current state of the art: Bladder-preserving trimodality therapy for muscle-invasive bladder cancer." Clinical Cancer Research 30, no. 10_Supplement (May 17, 2024): IA013. http://dx.doi.org/10.1158/1557-3265.bladder24-ia013.
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Abstract Many muscle-invasive bladder cancer (MIBC) patients are not getting curative treatment, there remains an undertreated/underserved population and a huge unmet need. Some are not good surgical candidates and others decline a radical cystectomy given concerns regarding its morbidity. Trimodality therapy (TMT), comprising of a maximal transurethral resection of bladder tumor (TURBT) followed by chemoradiation (with salvage cystectomy reserved for those that incur a muscle-invasive recurrence), has emerged as a viable bladder-preserving alternative to radical cystectomy for selected patients. In clinically-matched cohorts, survival is comparable to radical cystectomy in the modern era. More than 85% of contemporary patients keep their own native bladder and long-term quality of life after bladder preservation is good. Salvage cystectomy is feasible and can be curative for those with MIBC recurrences. TMT is now supported by numerous clinical guidelines, including NCCN (category 1 recommendation for stage II and IIIA). There are opportunities to continue to optimize clinical staging of disease (e.g. MRI), delivery of RT (e.g. image guidance, adaptive delivery, dose escalation, hypofractionation, field design) and systemic therapies (e.g. concurrent, neoadjuvant and adjuvant, including possibly immunotherapy) to improve outcomes. Ongoing trials (such as SWOG/NRG 1806 which recently closed to accrual) will inform the addition of immunotherapy to TMT. Validation of biomarkers in independent cohorts and in prospective trials is necessary to further guide bladder preservation therapy for MIBC and for personalized treatment selection. Ultimately, MIBC patients should be seen in a multidisciplinary environment where informed decision making by the patient is key. Citation Format: Jason A. Efstathiou. Current state of the art: Bladder-preserving trimodality therapy for muscle-invasive bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr IA013.
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Smith, Aaron C., Ben Arwood-Levine, Alexandra Born, Richard Brizendine, Payal Chatterjee, Mark J. Chicarelli, Michael L. Conner, et al. "Abstract PO3-26-01: Preclinical in vitro and in vivo characterization of a novel, wild-type-sparing, PI3Kα H1047R mutant-selective inhibitor." Cancer Research 84, no. 9_Supplement (May 2, 2024): PO3–26–01—PO3–26–01. http://dx.doi.org/10.1158/1538-7445.sabcs23-po3-26-01.
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Abstract The PI3K pathway is a key cell cycle regulating pathway that has an established role in tumor growth and development. Specifically, the H1047R and helical domain mutations E542K/E545K of the p110α subunit of PI3K are known activating mutations that are targeted by inhibitors under clinical investigation as well as by approved drugs. PI3Kα mutations are prevalent in patients with breast, colorectal, lung, endometrial, and numerous other cancers. The approved PI3Kα inhibitor, alpelisib, shows promise for this targeted class with improvements in progression-free survival in HR+/Her2- breast cancer in combination with fulvestrant. However, tolerability concerns such as hyperglycemia, gastrointestinal issues, and skin reactions have emerged related to on-target inhibition of wild type PI3Kα. These issues likely limit dose administration leading to exposure which is suboptimal for maximal efficacy and creates an opportunity to identify an inhibitor with an improved tolerability profile that targets oncogenic mutations while sparing wild type PI3Kα. Herein, we present preclinical in vitro and in vivo activity of a novel, wild type sparing PI3Kα inhibitor which is potent against the oncogenic H1047R mutation. Citation Format: Aaron C. Smith, Ben Arwood-Levine, Alexandra Born, Richard Brizendine, Payal Chatterjee, Mark J. Chicarelli, Michael L. Conner, Brad Fell, Jennifer Fulton, Anna Guarnieri, Ravi Jalluri, Hailey Knox, Keith Koch, Daniel Krischlunas, Vijay Kumar, Colin McHugh, Brent Mclean, Kelsey Nassar, Brad Newhouse, Rob Rieger, John Robinson, Marelí Rodriguez, Leah Salituro, Lee Stunkard, Francis Sullivan, Roy Turton, Shannon Winski, Yeyun Zhou. Preclinical in vitro and in vivo characterization of a novel, wild-type-sparing, PI3Kα H1047R mutant-selective inhibitor [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-26-01.
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Gallagher, Kit, Maximilian Strobl, Robert Gatenby, Philip Maini, and Alexander Anderson. "Abstract PR001: Learning to adapt: Rational personalization of adaptive therapy using deep reinforcement learning." Cancer Research 84, no. 3_Supplement_2 (February 1, 2024): PR001. http://dx.doi.org/10.1158/1538-7445.canevol23-pr001.
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Abstract Standard-of-care treatment regimens have long been designed for maximal cell kill, yet these strategies often fail when applied to metastatic cancers due to the emergence of drug resistance. Adaptive treatment strategies have been developed as an alternative approach, dynamically adjusting treatment to suppress the growth of treatment-resistant populations, delaying, or even preventing, tumor progression. Promising clinical results in prostate cancer indicate the potential to optimize adaptive treatment protocols. We propose the application of deep reinforcement learning (DRL) to guide adaptive drug scheduling, and demonstrate that these treatment schedules can outperform the current adaptive protocols in a mathematical model calibrated to prostate cancer dynamics, more than doubling the time to progression. We show that the DRL strategies are robust to patient variability, including both tumor dynamics and clinical monitoring schedules. We demonstrate that the DRL framework can produce interpretable, adaptive strategies based on a single tumor burden threshold, replicating and informing optimal treatment strategies. Given the DRL framework has no knowledge of the underlying mathematical tumor model, this demonstrates the capability of DRL to help develop treatment strategies in novel or complex settings. Finally, we propose a five-step pathway combining mechanistic modeling with the DRL framework to translate this approach to the clinic with limited information for a given patient. Integrating conventional tools to ensure the interpretability of traditionally `black-box' DRL models, we generate personalized treatment schedules that consistently outperform clinical standard-of-care protocols. Citation Format: Kit Gallagher, Maximilian Strobl, Robert Gatenby, Philip Maini, Alexander Anderson. Learning to adapt: Rational personalization of adaptive therapy using deep reinforcement learning [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr PR001.
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McDonough, Alaina C., Jeffery Y. Cheng, Shabber Mohammed, Pui-Kai Li, and Yangzom Bhutia. "Abstract 4479: Design, synthesis, and evaluation of amino acid conjugated niclosamide prodrugs as a PepT1 substrate." Cancer Research 84, no. 6_Supplement (March 22, 2024): 4479. http://dx.doi.org/10.1158/1538-7445.am2024-4479.
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Abstract The anthelmintic drug, Niclosamide, has a multitude of promising anticancer properties including inhibition of key signaling pathways involved in tumorigenesis, disruption of mitochondrial function, degradation of the overexpressed androgen receptor, and more. However, a key limitation of the clinical use of Niclosamide in cancer treatment is its low solubility and cellular uptake, which result in poor pharmacokinetic properties and dose-limiting GI toxicities at concentrations lower than the therapeutic threshold of the drug. To overcome this, we hypothesized that we could use amino acid conjugated niclosamide prodrugs to improve cellular uptake by creating a substrate of the PepT1 transport protein. The overexpression of the PepT1 transport protein that is involved in many hormonal cancers is being used to our advantage. Our study involved first synthesizing a group of niclosamide and niclosamide analogs conjugated with polar or nonpolar amino acids. Next, we conducted a Glycine-Sarcosine assay measuring changes in the uptake of the dipeptide glycyl-sarcosine (Gly-Sar). Our initial step was to examine if our conjugates could disrupt the absorption of Gly-Sar. The active conjugate will be tested whether they are substrates or inhibitors of the transporter. For the future, we have plans to determine the half-maximal inhibitory concentration (IC50) of niclosamide conjugates in various cancer cell lines and to quantify cleavage of the prodrugs intracellularly. Citation Format: Alaina C. McDonough, Jeffery Y. Cheng, Shabber Mohammed, Pui-Kai Li, Yangzom Bhutia. Design, synthesis, and evaluation of amino acid conjugated niclosamide prodrugs as a PepT1 substrate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4479.
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Choi, Sung Hee, Jay Myers, Suzanne Tomchuck, Melissa Bonner, Saada Eid, Daniel Kingsley, Kristen VanHeyst, Seong-Jin Kim, Byung-Gyu Kim, and Alex Y. Huang. "Abstract 728: Oral TGF-beta receptor1 inhibitor vactosertib promotes osteosarcoma regression by targeting tumor proliferation and enhancing anti-tumor immunity." Cancer Research 84, no. 6_Supplement (March 22, 2024): 728. http://dx.doi.org/10.1158/1538-7445.am2024-728.
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Abstract Osteosarcoma (OS) is an aggressive malignant bone cancer, with the lung as the most frequent site of metastasis. Unresectable pulmonary metastasis remains a significant challenge with a survival rate of less than 20%. Identification of novel therapeutic strategies are desperately needed. Transforming growth factor-β1 (TGF-β) is a potent immune suppressive cytokine in OS tumor microenvironment (TME). TGF-β1 expression is increased in the sera and tumor tissues of OS patients and this increase is associated with high-grade OS and lung metastases. Therefore, blocking TGF-β1 signaling may be a novel therapy for OS treatment. In this study, we show that blocking TGF-β1 signaling using the orally bioavailable small molecule TGF-βR1 inhibitor, Vactosertib, significantly inhibited OS proliferation in vitro and in vivo. Notably, Vactosertib inhibits c-Myc expression in the OS cells and oral administration of Vactosertib significantly reduces OS growth in vivo. Vactosertib increased immune effectors (e.g., IFNγ+CD8+ cells and NK cells) and inhibited immune suppressors (e.g., M2-like TAM, MDSC) in the OS TME. Our results suggest that inhibition of TGF-β1 signaling is an effective therapeutic strategy against OS through a multi-pronged approach that targets tumor intrinsic and extrinsic factors to achieve optimal immune-effector functions and maximal clinical response. Citation Format: Sung Hee Choi, Jay Myers, Suzanne Tomchuck, Melissa Bonner, Saada Eid, Daniel Kingsley, Kristen VanHeyst, Seong-Jin Kim, Byung-Gyu Kim, Alex Y. Huang. Oral TGF-beta receptor1 inhibitor vactosertib promotes osteosarcoma regression by targeting tumor proliferation and enhancing anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 728.
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Koltun, Bella, Tali Voloshin, Tal Kan, Lilach Koren, Yaara Porat, Alexandra Volodin, Noa Kaynan, et al. "Abstract 1801: Application of Tumor Treating Fields (TTFields) to cancer cells enhances their membrane permeability." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1801. http://dx.doi.org/10.1158/1538-7445.am2022-1801.
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Abstract INTRODUCTION: Tumor Treating Fields (TTFields) are alternating electric fields at intermediate frequencies that exert anti-mitotic effects on cancerous cells. TTFields therapy is approved in several territories for treatment of glioblastoma (GBM) and unresectable malignant pleural mesothelioma. Recently, membrane permeability of GBM cells has been found to be increased in response to TTFields application. The current study aimed to further explore this effect, testing the potential of TTFields to facilitate cellular accumulation of the anticancer agent doxorubicin (DOX) in breast carcinoma cells. METHODS: 4T1 breast mammary carcinoma cells were treated with TTFields (1.7 V/cm RMS) for 72 h across a frequency range (50-500 kHz). Cytotoxicity was examined by cell counts, and permeability determined by 7-aminoactinomycin D (7-AAD) intracellular accumulation, both measured by flow cytometry. Next, TTFields at the frequency inducing highest permeability was applied to chemotherapy-sensitive and matched chemotherapy-resistant cells. Intracellular accumulation of DOX and drug-induced cytotoxicity were measured by flow cytometry. In vivo validation was performed by 72 h delivery of TTFields at the frequency of maximal permeability to mice orthotopically inoculated with 4T1 cells and injected with DOX 24 h before treatment cessation. DOX florescence was measured using in vivo imaging system (IVIS) for whole tumor assessment and flow cytometry for detection at the single-cell level. RESULTS: While highest TTFields-induced cytotoxicity was observed at 150 kHz, 7-AAD intracellular accumulation was maximal at 300 kHz. When TTFields were delivered concomitant with DOX, the drug accumulated to the same extent in chemotherapy-resistant cells as in chemotherapy-sensitive cells. Application of TTFields also sensitized both cell types to DOX, with cytotoxicity observed at low drug concentrations. Furthermore, 2- to 3-fold higher DOX accumulation was seen in tumors isolated from mice treated with TTFields relative to control. CONCLUSIONS: Permeability of 4T1 breast cancer cells was elevated by TTFields, allowing enhanced intracellular accumulation of DOX and improving drug efficacy, even in chemotherapy-resistant cells. Increased cellular accumulation of DOX was also demonstrated in vivo. Citation Format: Bella Koltun, Tali Voloshin, Tal Kan, Lilach Koren, Yaara Porat, Alexandra Volodin, Noa Kaynan, Anat Klein-Goldberg, Rom Paz, Boris Brant, Yiftah Barsheshet, Efrat Zemer-Tov, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti. Application of Tumor Treating Fields (TTFields) to cancer cells enhances their membrane permeability [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 1801.
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Hsieh, Kang Lin, Tanjida Kabir, Luis Nunez-Rubiano, Yu-Chun Hsu, Yu Cai, Juan Rodriguez Quintero, Octavio Arevalo, et al. "Abstract LB067: A confident and operator-independent deep segmentation model to measure residual tumor volume in the follow-up MRIs for glioblastoma." Cancer Research 83, no. 8_Supplement (April 14, 2023): LB067. http://dx.doi.org/10.1158/1538-7445.am2023-lb067.
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Abstract Introduction: Magnetic resonance imaging (MRI) is the most common tool to examine glioblastoma. Preoperative MRI can be used to initial diagnosis, and surgery planning, while follow-up MRIs can be used to evaluate treatment responses, identify recurrency, and detect side effects. The follow-up MRIs are usually taken after the first-line therapy, such as maximal safe resection. In the past, radiologists manually segment the tumor regions from normal brain tissue on follow-up MRIs, which is time-consuming, error-prone, and challenging. Several deep-learning (DL) models have been developed utilizing preoperative images, but their performance has yet to be evaluated on follow-up MRIs. In this research, we built the largest follow-up MRI cohort (311 patients) to assess these DL models and their generalizability and performance on independent preoperative and follow-up images. We also made the first follow-up-based deep learning models for this specific task. Methods: All evaluation deep learning models (10 models) were trained by the Brain Tumor Segmentation challenge 2020 (BraTS’20) and evaluated by fifty pairs of preoperative and follow-up scans from our institution. The segmentation form our institution is evaluated by board certified radiologist. MRIs in the BraTS’20 dataset were all preoperative scans. After the evaluation, we randomly assigned 264 patients’ scans from our institution to the training dataset and 47 patients’ scans to the testing dataset. We compared three types of models in our follow-up deep learning model, including 1) UNet-3D, 2) UNet-3D+transfer-learning, and 3) UNet-3D+transfer-learning+baysian-learning. The benchmark for all models was the Dice similarity coefficient (DSC). DSC can measure the spatial overlap between model prediction and ground truth. The value of DSC is between zero to one. Zero means no overlap and one indicates complete overlap. Results: Our study demonstrates that the BraTS'20 trained models' performance decreased by 13.05% in independent preoperative MRI scans and 19.04% in follow-up MRI scans. The most significant mismatch regions were FLAIR hyperintense regions (3.68% drop in independent preoperative scans and 10.61% drop in independent follow-up scans) and Non-enhancing core (5.20% drop in independent preoperative scans and 11.99% drop in independent follow-up scans). Our best model can achieve the best DSC among three tumor regions compared to all evaluation models (FLAIR hyperintense regions: DSC 0.77 V.S. DSC 0.58; Enhancing tumor region: DSC 0.87 V.S. DSC 0.68; Non-enhancing tumor region: DSC 0.92 V.S. DSC 0.55). Conclusion: Maximal safe resection induced brain structure change, decreasing the performance of the preoperative-based DL model. Implementing a follow-up MRI-based segmentation model is essential to make accurate and generalizable results to address structural changes after maximal safe resection. Our follow-up DL model demonstrates the DSC score can be recovered. We commit to further developing the tool to assist radiologists in handling follow-up MRIs for glioblastoma patients. Citation Format: Kang Lin Hsieh, Tanjida Kabir, Luis Nunez-Rubiano, Yu-Chun Hsu, Yu Cai, Juan Rodriguez Quintero, Octavio Arevalo, Kangyi Zhao, Jackie Zhang, Jiguang Zhu Zhu, Roy Riascos, Xioaqian Jiang, Shayan Shams. A confident and operator-independent deep segmentation model to measure residual tumor volume in the follow-up MRIs for glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB067.
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Walbert, Tobias, and Muhib Alam Khan. "End-of-life care in patients with primary malignant brain tumors: A systematic literature review and analysis." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e20703-e20703. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e20703.
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e20703 Background: 80–85% of all adult brain tumors are high-grade glioma (HGG). HGG are typically treated with maximal surgical resection, followed by radiotherapy with concurrent and adjuvant chemotherapy. The median survival for anaplastic glioma is estimated to be 2-5 years and 15 months for patients with glioblastoma. Quality of life (QoL) has become an increasing important outcome assessed in clinical trials as well as in the standard care of brain tumor patients. Despite the inevitable disease trajectory, not much is known about symptoms and needs of brain tumor patients and their caretakers at the end of life. There appears to be a lack of published literature on this important aspect of neuro-oncology. Methods: A systematic literature search was conducted in PubMed and Cochrane covering the years between 1946 through 2012. In total, 7146 article citations were found. After first review 942 abstracts were obtained. Based on content 82 articles were examined separately by both authors and it was agreed to eliminate 67 of them because they did not include a significant number of primary brain tumor patients or the focus was not on end of life care and symptoms. Results: Only 7 of the retained articles contained specific patient data and did not just reflect opinions of authors or reviews of the topic. Only one study was performed prospectively. Three studies assessed symptom management in inpatients, 2 in outpatients and 2 in a combined setting. Studies included between 29 and 169 patients. Drowsiness and loss of consciousness was the most common symptom (85%–90%). Poor communication (64% and 90%), focal deficits (29%– 62%), seizures (3%–67%), dysphagia (10%–85%), headache (4%–62%), and fatigue (25%–67%) were also frequent. Interventions included hydration (87%-93%), urinary catheter (89%), steroids (62%-80%), anti-epileptic drugs (45%-76%), oxygen (48%), tube feeding (13%) and palliative sedation (13%). Conclusions: There is 1 prospective study and only a total of 7 studies describing detailed end of life symptoms. None of the studies addressed caregiver quality of life. More research is needed to develop purposeful interventions to address end of life symptoms and QoL in patients with HGG.