bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PO-064: Predicting molecular phenotypes with scRNAseq: An assessment of unsupervised machine learning methods
Authors: Dunca Anastasia , Adler Frederick R. , Smithson Mark W. 
Published: April 2021

Abstract
We evaluated the performance of machine learning models in predicting cell state based on single cell RNA sequencing data (scRNAseq) analysis. scRNAseq quantifies the number of mRNA molecules in individual cells providing information on regulatory relationships between genes and the trajectories of distinct cell lineages in development. Different cells may express different genes at different levels which is key to analyzing the molecular phenotypes of cells. We tested nine machine learning models for their ability to distinguish subclonal cell populations in scRNAseq data by making predictions of cell state. Two scRNAseq datasets were examined: one with cells separated by cell phase: S, G1, or G2/M and one with distinct tumor and non-tumor cells. The pipeline consisted of data filtering, dimensionality reduction with Principal Component Analysis, naive projection with Uniform Manifold Approximation and Projection, and cluster analysis using Ward, BIRCH, Gaussian Mixture Model, DBSCAN, Spectral, Affinity Propagation, Average Linkage Agglomerative Clustering, Mean Shift, and K-Means models. These represent centroid, density, hierarchical, distribution, and graph-based clustering. Models failing to generate the true number of cells of each type were eliminated from further evaluation. The rest were evaluated on accuracy on a true cell type versus predicted cell type basis with a mapping algorithm. The true molecular phenotypes of the plotted cells were annotated onto the data points for a biological examination of the clusters. Six models divided G2 vs. S cells; Spectral and Ward clustering performed best with ~60% accuracy on average. Parallel to that result, seven models divided the total population into the tumorous and non-tumorous subclonal cell populations; Ward and BIRCH clustering performed best with ~80% accuracy on average. Overall, unsupervised machine learning models were effective in predicting molecular phenotypes of cells by accurately identifying subclonal cell populations and analyzing the relationship between gene expression levels and cell state. BIRCH, Ward, and Spectral clustering showed the highest performance.
Citation Format: Anastasia Dunca, Frederick R. Adler, Mark W. Smithson. Predicting molecular phenotypes with scRNAseq: An assessment of unsupervised machine learning methods [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-064.
Abstract PO-077: Study evaluating metastatic castrate resistant prostate cancer (mCRPC) treatment using 177Lu-PNT2002 PSMA therapy after second-line hormonal treatment (SPLASH) - Trial in progress
Authors: Chi Kim N. , Metser Ur , Czernin Johannes , Calais Jeremie , Prasad Vikas , Eiber Matthias , Shore Neal , Jensen Jessica , Fleshner Neil , Tagawa Scott , Sartor Oliver 
Published: April 2021

Abstract
Background: Treatment options with minimal toxicity and novel mechanisms of action are urgently needed to improve clinical outcomes from mCRPC. Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) represents a new treatment for patients with PSMA-avid mCRPC. 177Lu-PNT2002 (also known as [Lu-177]-PSMA-I&T) is a PSMA-targeting agent and studies have shown demonstrable promising initial data. This trial seeks to prospectively evaluate the efficacy of 177Lu-PNT2002 for men with progressive mCRPC after androgen receptor axis-targeted (ARAT) therapy. Methods: This is a multi-center, open-label, phase III study. All patients must be at least 18 years of age, have documented progressive mCRPC at time of screening, high PSMA expression by PSMA PET/CT per blinded independent central review (BICR), chemotherapy naïve for CRPC and unfit or unwilling to receive chemotherapy. The study will commence with a 25-patient dosimetry lead-in. In the dosimetry phase, patients will receive up to four cycles of 177Lu-PNT2002 at 6.8 GBq every 8 weeks. In the randomization phase, approximately 390 patients will be randomized in a 2:1 ratio to receive 177Lu-PNT2002 (Arm A) versus enzalutamide or abiraterone (with prednisone or dexamethasone) (Arm B). Patients randomized to Arm B have an option to crossover to 177Lu-PNT2002 treatment after BICR-assessed radiologic progression. The primary endpoint is Radiological progression-free survival (rPFS) assessed by BICR using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (soft tissue) and Prostate Cancer Working Group 3 (PCWG3) (bone) criteria. Key secondary endpoints include objective response rate, duration of response, PSA response, and overall survival. The study is powered at 90% to test the alternative hypothesis of a hazard ratio (HR) ≤ 0.66 at an α of 0.025. ClinicalTrials.gov identifier: NCT04647526.
Citation Format: Kim N. Chi, Ur Metser, Johannes Czernin, Jeremie Calais, Vikas Prasad, Matthias Eiber, Neal Shore, Jessica Jensen, Neil Fleshner, Scott Tagawa, Oliver Sartor. Study evaluating metastatic castrate resistant prostate cancer (mCRPC) treatment using 177Lu-PNT2002 PSMA therapy after second-line hormonal treatment (SPLASH) - Trial in progress [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-077.
Abstract PO-082: Radiation therapy enhances the potential of the oncolytic virus in the treatment of osteosarcoma
Authors: Hossain Elora , Higashino Fumihiro 
Published: April 2021

Abstract
Background: Combination of neoadjuvant chemotherapy and surgery is the standard treatment approach for osteosarcoma. Despite aggressive treatment protocol, ~40% of patients do not respond and relapse, the survival rate is poor for these patients. Conditionally replicative adenovirus (CRAds) destroying cancer cell while sparing normal cells is a new treatment approach for cancers. We developed a new oncolytic adenovirus which grows using mRNA stabilization system found in many cancer cells. Our recent report showed that this virus replicated in cancer cells where AU-rich element (ARE) containing mRNA is stabilized. ARE-mRNA is stabilized in the majority types of cancers mediate by binding with HuR (Human antigen R), which exports target ARE-mRNA to the cytoplasm. Radiotherapy (RT) is not a first-line treatment option for osteosarcoma as osteosarcoma cells are not killed by radiation easily. But in certain conditions radiotherapy can be used where surgical resection is not technically possible without undue morbidity or when surgery is refused. In response to ionizing radiation and UV radiation DNA damage response (DDR) can influence HuR action either by the increasing cytoplasmic HuR abundance or affecting the binding affinity to target ARE-mRNA. The purpose of the present study was to analyze the efficacy of the combination treatment of RT and oncolytic adenovirus for osteosarcoma. Materials and Methods: E4rof6-deleted adenovirus (dl355) and human osteosarcoma cell lines U2OS and Saos2 were used in this study. Cell viability assays were carried out to evaluate the cytotoxicity and synergism of dl355 and RT combination. Chou and Talalay’s median-effect method was used to calculate the combination index. CPE assay was used to assess the cytopathic effect of the combination. Viral replication with or without radiation combination was investigated by hexon staining. Western blot analysis was performed to examine viral protein expression. Results: We found that RT treatment enhanced the cytoplasmic relocalization of HuR; thus irradiation up-regulated the propagations of dl355. Also, radiation-induced upregulation of viral protein expression was observed by western blotting. The RT and dl355 combination treatment increased the cytolysis of U2OS, and Saos2 cells in a synergistic manner compared to RT or virus only. Conclusion: Radiotherapy up-regulated of oncolytic adenovirus, which grows using the ARE-mRNA stabilization system, and this cytolytic effect provides a rationale for this combination. This combination approach has the possibility of a promising strategy for osteosarcoma.
Citation Format: Elora Hossain, Fumihiro Higashino. Radiation therapy enhances the potential of the oncolytic virus in the treatment of osteosarcoma [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-082.
Abstract PO-095: Intrinsic and acquired resistance to RIG-I induced anti-tumor responses
Authors: Anand Sudarshan , Fraile-Bethencourt Eugenia , Khou Sokchea 
Published: April 2021

Abstract
The immune microenvironment plays a critical role in cancer orchestrating tumor progression and response to therapeutics. Strategies to manipulate the tumor immune microenvironment are invaluable to complement current standard of care treatments. Recently, approaches to target Pattern Recognition Receptors (PRRs) that recognize intracellular and extracellular pathogens have emerged as a promising strategy to enhance immune recognition of tumors. Among the PRRs, intracellular receptors that recognize DNA and RNA in the cells are unique in their ability to respond to both pathogenic and ‘self’ nucleic acids that are generated as a result of aberrant cell division/transcription. We previously showed that targeting a cytosolic DNA sensor three prime exonuclease 1 (TREX1) enhanced immune responses in mouse tumor models including colorectal carcinomas (CRCs). Here we show that a cytosolic RNA sensing pathway, Retinoic acid Induced Gene 1 (RIG-I) acts as a robust immune activator across cancer types by enhancing the cellular and molecular correlates of anti-tumor immune responses. Using a stem loop hairpin RNA structure derived from a H1N1 sequence we elicited a potent RIG-1 response in CRC and breast cancers. Interestingly, activation of RIG also increased expression of TREX1 revealing potential cross-talk between the two pathways. We show that activation of tumor cell RIG-I alone is sufficient to decrease tumor burden with a concomitant broad cellular and molecular anti-tumor response. We observed a group of negative regulators of immune responses, including the NKG2a ligand - HLA-E, mono PARPs and the inhibitory checkpoint protein LAG3, are upregulated in RIG high tumors in cell culture, mouse and human tumors indicating how RIG-I high tumors may develop resistance to immune killing. Combination of RIG-I agonists synergized with inhibition of these resistance mechanisms in a tumor and context dependent manner. To understand intrinsic resistance to RIG signaling, we performed a focused RNAi screen and identified critical positive and negative modulators of RIG-I function in tumor cells. Taken together, our findings illustrate how tumor cell RIG-I is a potent inducer of cellular and molecular immune responses. Our work also highlights tumor cell intrinsic and extrinsic pathways that confer resistance to RIG-I induced anti-tumor responses and provide strategies to mitigate such resistance.
Citation Format: Sudarshan Anand, Eugenia Fraile-Bethencourt, Sokchea Khou. Intrinsic and acquired resistance to RIG-I induced anti-tumor responses [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-095.
Abstract PO-097: Selective targeting and imaging of orthotopic glioblastoma after a single systemic dose of a novel hydoxyl dendrimer radionuclide
Authors: Sharma Rishi , Sun Minghao , Appiani Santiago , Coelho Richard , McConville Patrick , Alters Susan , Cleland Jeffrey L. 
Published: April 2021

Abstract
Previous studies have demonstrated hydroxyl dendrimers (HDs) are selectively taken up by tumor associated macrophages (TAMs) after a single administration. HDs have also been observed to cross the blood brain barrier in six animal species including dogs and monkeys. The treatment of brain tumors and metastases is hampered by the inability to deliver radiotherapy or cancer agents selectively to the tumor. HDs of two different generations were prepared (HD4 and HD6; both smaller than antibodies) and DOTA was conjugated to the HD through linker arms attached to the hydroxyls on the dendrimer surface. 111In radiolabeling of HD4- and HD6-DOTA resulted in &gt;95% radiochemical purity in both cases and specific activities of 0.621 mCi/mg and 0.638 mCi/mg, respectively. GL-261-luc cells, a syngeneic glioblastoma, were implanted intracranially in 8 female albino C57.bl/6 mice. Tumors were 15-60 mm3 at time of dosing. Mice received a single administration of HD4-DOTA-111In or HD6-DOTA-111In at a dose of approximately 0.5 mg/mouse and 0.3 mCi/mouse. Whole body SPECT/CT imaging was done over time up to 6 days post-dose in 3 animals per compound. The biodistribution and uptake in the brain tumor and other tissues was quantitatively measured using VivoQuant 4.0 (Invicro, Boston). Both HDs rapidly distributed in the systemic circulation after administration. Clearance appeared to be primarily via the kidneys based upon the fraction of injected dose observed in the bladder over time. The % injected dose (%ID)/g in the brain tumor was 2.67 ± 0.45 and 7.05 ± 0.53 at 24 h post-dose for the HD4 and HD6 compounds, respectively. The %ID/g in the contralateral brain section was 0.37 ± 0.17 and 0.90 ± 0.20 at 24 h post-dose for the HD4 and HD6 compounds, respectively. Tumor associated radioactivity persisted for the duration of the study (last time points: HD4, 96 h, 5.27 ± 2.04 %ID/g; HD6, 144 h, 3.20 ± 1.02 %ID/g). These results confirm previous studies in this model demonstrating selective tumor uptake and persistence with 58 fold greater radioactivity at the last time point in brain tumor compared to contralateral brain. The selectivity and prolonged duration of HDs in TAMs will enable the use of the same HD-DOTA constructs to deliver radiotherapeutic 90Y to brain tumors. The HD radiotherapy approach may eliminate the off-target toxicity of current ligand-based approaches.
Citation Format: Rishi Sharma, Minghao Sun, Santiago Appiani, Richard Coelho, Patrick McConville, Susan Alters, Jeffrey L. Cleland. Selective targeting and imaging of orthotopic glioblastoma after a single systemic dose of a novel hydoxyl dendrimer radionuclide [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-097.
Abstract PR-008: Identification and characterization of the molecular mechanisms of SCLC chemo-radiation resistance
Authors: Carrieri Francesca Anna , Connis Nick , Grasset Eloise , Luidy-Imada Eddie , Ewald Andrew , Marchionni Luigi , Hann Christine , Tran Phuoc T. 
Published: April 2021

Abstract
Small cell lung cancer (SCLC) is among the most aggressive form of lung malignancies and accounts for 15-20% of all lung cancers. It has the tendency to metastasize early, thus limited-stage SCLC patients still receive systemic treatment with chemo-radiotherapy (chemoXRT) for their localized disease. SCLC is exceptionally sensitive to chemoXRT and exhibits high response rates; however, the recurrence rate is almost 100% and patients relapse with tumors that resist further treatments. Elucidating mechanisms of chemoXRT resistance in SCLC is needed to develop improved therapies and positively impact patient outcomes. To better interrogate mechanisms of chemoXRT resistance, we developed a SCLC patient-derived xenograft (PDX) in vivo system for the major molecular subtypes of SCLC (classic and variant). Briefly, PDX tumor bearing mice were treated with: 1) vehicle control; 2) cisplatin plus etoposide (EP); 3) radiotherapy (XRT); and 4) both EP/XRT. A major response was observed within the EP/XRT arm compared to vehicle or single therapy arms. Whole transcriptome profiling among all treatment arms revealed molecular pathways and biological processes associated with chemoXRT resistance. Also, by comparing our data with two previous SCLC patient cohort studies, we identified gene candidates for functional validation of chemoXRT resistance (i.e. ST6GAL1, TNIK and SOHLH2). To enable real-time cellular and molecular analysis of PDX behavior ex vivo and to validate SCLC chemoXRT resistance candidate genes, we established a novel PDX organoid (PDO) model to study the molecular underpinnings of XRT resistance in SCLC. Classic and variant SCLC PDOs still retained the cellular, DNA and RNA markers consistent with their parental PDX molecular subtype classification using array comparative genomic hybridization and RNA-sequencing. We aim to utilize our novel SCLC PDX/PDO models as a tool to identify and validate candidates for chemoXRT resistance to be used as biomarkers and targets to combat chemoXRT resistance in SCLC.
Citation Format: Francesca Anna Carrieri, Nick Connis, Eloise Grasset, Eddie Luidy-Imada, Andrew Ewald, Luigi Marchionni, Christine Hann, Phuoc T. Tran. Identification and characterization of the molecular mechanisms of SCLC chemo-radiation resistance [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PR-008.
РОЗДУМИ СТОСОВНО ЛІКУВАЛЬНОЇ ТА ПРОФІЛАКТИЧНОЇ ПЕРСПЕКТИВНОСТІ РІЗНИХ ЗАСОБІВ ПРИ COVID-19
Authors: Bondarenko A. M. , Kopcha V. S. 
Published: April 2021

Мета роботи – на підставі зіставлення особливостей попередніх епідемій коронавірусних інфекцій та аналізу патогістології, патогенезу COVID-19 і досвіду емпірично апробованого лікування таких хворих виділити перспективні напрямки подальших засобів терапії та профілактики.
Наведено інформацію про зворотну залежність у ряді SARS→MERS→COVID-19 географічної поширеності з інкубаційним періодом і летальністю.
У патогенезі COVID-19 виділено два основні патогенетичні механізми: пряме вірусне пошкодження епітелію легень, ендотеліоцитів капілярів і тканинних легеневих фібробластів, а також прогресуюча запальна реакція, що супроводжується «цитокіновою бурею», яка спочатку може призводити до «гострого респіраторного дистрес-синдрому» (ГРДС), а потім – й до так званого синдрому гострої запальної відповіді. Таким чином, патогенез COVID-19 схожий з грипозними «геморагічними пневмоніями» або грипозним геморагічним набряком легень. Це дає змогу припускати першорядне значення не етіотропної, а патогенетичної протинабрякової, протизапальної та ангіопротекторної терапії хворих на COVID-19.
Перспективними профілактичними стосовно COVID-19 засобами видаються готові інтерферони або індуктори інтерфероногенезу.
КЛІНІЧНІ ПРОЯВИ ВІЛ-АСОЦІЙОВАНОГО УРАЖЕННЯ ЦЕНТРАЛЬНОЇ НЕРВОВОЇ СИСТЕМИ ТА ВПЛИВ НА НИХ АНТИРЕТРОВІРУСНОЇ ТЕРАПІЇ
Authors: Moskaliuk V. D. , Boyko Yu. I. , Randiuk Yu. O. , Andrushchak M. O. 
Published: April 2021

Симптоматика ураження нервової системи проявляється в різних випадках по-різному: переважним залученням у процес речовини головного мозку; спинного мозку; оболонок; периферичних відділів нервової системи. Спектр порушень широкий і не є специфічним тільки для ВІЛ-інфекції. Реєструють порушення когнітивних функцій (пам’ять, інтелект, навчання), розлади свідомості та уваги, емоційні й поведінкові розлади аж до тяжкого ураження центральної нервової системи (ЦНС) – ВІЛ-асоційованої деменції. Можуть виявлятися симптоми ураження периферичної нервової системи. Неврологічні прояви СНІДу поділяються на первинні та вторинні. Первинні пов’язані з прямою шкідливою дією вірусу, автоімунними процесами, нейротоксичною дією антиретровірусної терапії, а вторинні – зумовлені прогресуючим імунним дефектом і приєднанням опортуністичних інфекцій. Первинні ураження поділяють на ранні: СНІД-деменція (ВІЛ-асоційована енцефалопатія з наступною деменцією, або СНІД-дементний комплекс); гострий ранній ВІЛ-енцефаліт; менінгіт або менінгоенцефаліт; васкулярний нейроСНІД; та пізні: мієлопатії вакуолярні на кшталт висхідного або поперечного мієліту; ураження периферичної нервової системи у вигляді симетричної сенсорної дистальної полінейропатії, хронічної запальної демілієнізуючої полінейропатії, гострої запальної демієлінізуючої полінейропатії за типом синдрому Гійєна-Барре, енцефаломієлополінейропатії, БАС-подібний синдром. Нині всі ВІЛ-обумовлені ураження ЦНС об’єднують під загальною назвою «ВІЛ-асоційовані нейрокогнітивні розлади».
Раннє призначення противірусної терапії є стримуючим чинником для патогенного впливу ВІЛ на функції ЦНС. Та для оптимізації схеми терапії доцільно визначати медикаментозну стійкість вірусу у спинно-мозковій рідині (СМР) і вірусне навантаження у лікворі. Та результати вивчення кореляційних стосунків між кількістю ВІЛ у СМР і плазмі крові розрізняються: одні дослідники виявляють взаємозв’язок, інші не знаходять статистично значущого зв’язку між цими показниками. Та очевидно, що необхідно підбирати схеми антиретровірусної терапії (АРТ) з добрим проникненням крізь гемато-енцефалічний бар’єр (ГЕБ) для забезпечення достатньої концентрації препаратів і припинення вірусної реплікації в клітинах ЦНС.
Таким чином, вимагають додаткових досліджень клініко-лабораторні аспекти ураження нервової системи при ВІЛ-інфекції. Клінічна інформативність вірусологічних досліджень СМР для оцінки ступеня тяжкості ВІЛ-асоційованого ураження ЦНС досі не доведена. У світі немає зареєстрованих тест-систем для оцінки навантаження ВІЛ у лікворі, й ці методи діагностики не застосовуються у клінічній практиці.
КІР У ДІТЕЙ, ПОЄДНАНИЙ З ІНШИМИ ІНФЕКЦІЙНИМИ ЗАХВОРЮВАННЯМИ
Authors: Ivanova L. A. , Haras M. N. , Horbatiuk I. B. , Bileychuk R. Yu. , Ruda T. D. 
Published: April 2021

Метою роботи був аналіз особливостей кору у поєднанні з іншими інфекційними захворюваннями у дітей на прикладі клінічних випадків.
Наведено динаміку кору у пацієнтів з кліщовим бореліозом та ВІЛ-інфекцією під час стаціонарного лікування в інфекційному боксованому відділенні крапельних інфекцій обласної дитячої клінічної лікарні м. Чернівці.
Установлено, що при поєднаному перебігу кору та кліщового бореліозу спостерігалися типові клінічні симптоми обох захворювань із посиленням мігруючої еритеми на тлі макулопапульозного висипу. Перебіг кору, ускладненого пневмонією в імуноскомпрометованої ВІЛ-інфікованої дитини на тлі агресивної комбінованої антибіотикотерапії при лікуванні антиретровірусними препаратами характеризувався сприятливим прогнозом.
Materialisation of the Good Life in the New House
Authors: Wei Lan 
Published: April 2021

Abstract
Over the past two decades, Chinese rural architecture has experienced dramatic changes through the Building the Chinese Socialist New Village movement. Thousands of new houses, particularly in the model of the New Village, have risen abruptly out of the ground. These Western-style new houses with a garden (huayuan yangfang), which often appear in the media as typical family houses in Western society, largely represent the image of the good life of the state and the peasant in contemporary China. In this article, I focus on how the family house is produced and consumed in Baikou New Village in south China. By presenting the materiality of the dwelling space, this paper probes the intertwined processes of the materialisation of the blueprint of the good life and how the new houses influence family life (especially intergenerational relationships) in post-socialist Baikou New Village.
Targumic Parallels to Variant Readings of the Book of Samuel amongst the Cairo Geniza Manuscripts
Authors: Rendsburg Gary A. 
Published: April 2021

Abstract
The Cairo Geniza has yielded 650+ manuscripts (all fragmentary, of course) of the book of Samuel. A survey of those documents reveals a number of places with variant readings, especially when compared to the great medieval codices: Aleppo (A) and St Petersburg (L). The present article demonstrates that many of these variant readings are reflected in Targum Jonathan and in the Peshitta.