bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PO-052: Radiation regimen and timing of PD1 blockade critically influence response to combination therapy in head and neck squamous cell carcinoma
Authors: Verma Aparajita , Habitzruther Michael , Attwood Kristopher , Seshadri Mukund 
Published: April 2021

Abstract
Head and neck squamous cell carcinoma (HNSCC) constitute the sixth most common cancer worldwide, with a 5-year survival of less than 50% for advanced HNSCC patients. Radiation therapy (RT) is widely used in the treatment of HNSCC patients. Preclinical studies have shown that RT can trigger immune mediated response that potentiates tumor regression. However, the use of RT in combination with immune checkpoint inhibitor, specifically programmed death protein-1 blockade (αPD-1), has not been extensively examined in HNSCC. In vitro studies in our laboratory revealed that radiation increased PD-L1 expression in HNSCC tumor cells in a dose-dependent manner. Based on this observation, we hypothesized that the efficacy of RT and αPD-1 therapy would be critically influenced by the timing of αPD-1 of administration. To test this hypothesis, we conducted a preclinical study using a novel orthotopic immunocompetent mouse model of HNSCC (RPMOC1). Tumor bearing mice were randomized into the following arms: RT (single dose 10 Gy), fractionated RT (fRT- 2Gy x 5), RT prior to αPD-1(200 μg), RT post αPD-1, fRT prior to αPD-1 and fRT post αPD-1. Non-invasive magnetic resonance imaging (MRI) was used to monitor tumor response to therapy. All treatment regimens were well tolerated and did not result in weight loss during the experiment. The most potent tumor growth inhibition was observed in the RT (10 Gy) and αPD-1 combination therapy group. RT given either before or after αPD-1 therapy resulted in a significant decrease in tumor volumes (p&lt;0.05) compared to other groups. Combination therapy with fractionated radiation did not show improved response compared to monotherapy. Overall, our observations indicate that tumor response to combined radiation and immunotherapy is critically influenced by the radiation regimen and timing of PD1 blockade in HNSCC.
Citation Format: Aparajita Verma, Michael Habitzruther, Kristopher Attwood, Mukund Seshadri. Radiation regimen and timing of PD1 blockade critically influence response to combination therapy in head and neck squamous cell carcinoma [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-052.
Abstract PO-061: Deciphering radiation resistance in head and neck cancer using patient derived organoids
Authors: Vincent-Chong Vui King , Gluck Christian , Hershberger Pamela A. , Sinha Satrajit , Seshadri Mukund 
Published: April 2021

Abstract
Radiation therapy (RT) is an integral component of the standard of care for patients with head and neck squamous cell carcinoma (HNSCC). While advances in radiation delivery methods have led to improved outcomes, radioresistance poses a significant therapeutic challenge and a major cause of poor prognosis in this patient population. To date, a majority of studies investigating mechanisms of radioresistance have employed in vitro monolayer cell culture models that lack the heterogeneity and cell-extracellular matrix interactions. To overcome this limitation, we established and credentialed a panel of 3D patient-derived organoid (PDO) models of HNSCC to identify molecular signatures and signaling pathways that contribute to radiation resistance. A total of 7 PDOs were established from surgical HNSCC specimens and credentialed using a combination of histologic/immunohistochemical evaluation (H&E, cytokeratin, p16), genotyping (HPV), whole exome sequencing (WES) and RNA sequencing analysis. Radiation response of the PDO panel was also examined and assessed for concordance with patient response and PDOs were ranked based on their radiosensitivity and bioinformatic analysis was performed on radiosensitive and radioresistance PDOs to identify molecular pathways associated with resistance. All PDOs retained the histology, p16/HPV status and mutational landscape (p53, HLA-A) of donor patient tissues. Radiation response of PDOs showed excellent (100%) concordance with patient responses (n=5 with history of radiation treatment). RNA-seq revealed identified pathways associated with epithelial mesenchymal transition (IGFBP2, TIMP1, TIMP2, LAMA3, LOXL1), NOTCH signaling (NOTCH1, HES1, FZD1, FZD5, DTX1, NOTCH3, FZD7), E2F targets and G2M checkpoint signaling (MCM2, MCM7, MCM4, PCNA) and the p53 pathway (SFN, NDRG1, ALOX15B). Collectively, our findings illustrate the translational utility of PDOs as a robust platform in identifying potential therapeutic targets that could overcome radiation resistance in HNSCC. Ongoing studies are evaluating the potential of PDOs to serve as a screening platform to identify radiosensitizers through repurposing of FDA-approved drugs to facilitate rapid clinical translation.
Citation Format: Vui King Vincent-Chong, Christian Gluck, Pamela A. Hershberger, Satrajit Sinha, Mukund Seshadri. Deciphering radiation resistance in head and neck cancer using patient derived organoids [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-061.
Abstract PO-065: ATRXLoss and IDH1R132H impair self-renewal of glioma stem cells after proton radiotherapy
Authors: Garces Angel A. , Bronk Lawrence , Bhat Krishna P.L. , Grosshans David R. 
Published: April 2021

Abstract
Background: Glioblastoma Multiforme (GBM-Grade IV) is the most aggressive form of glioma in the USA carrying only a 15-month median survival time. IDH1R132H is an early onset mutation present in 70-80% of low grade gliomas (LGG-Grade I and II) and secondary GBM patients that causes intracellular oxidative stress and impairment of post-radiation DNA damage repair (DDR) via Homologous Recombination (HR). Although IDH1R132H is associated with improved patient survival and clinical response to chemotherapy, astrocytoma (LGG) patients specifically also harbor ATRXLoss, a genetic alteration that inactivates the ATRX chromatin remodeling protein and impairs DDR via non-homologous end joining (NHEJ). Importantly, the recent discovery of glioma stem cells (GSCs), a subpopulation of chemoradioresistant, self-renewable, tumor initiating cells known to promote tumor recurrence, presents a new target for therapeutic intervention. However, the mechanisms by which IDH1R132H and ATRXLoss contribute to GSC sensitivity to proton radiotherapy (PRT), a more tumor specific and cytotoxic form of radiation therapy than conventional X-rays (XRT), is not well understood. We hypothesize that both IDH1R132H and ATRXLoss contribute to the impairment of GSC self-renewal after PRT, but not after XRT. Methods: Isogenic MGG18-IDH1WT, MGG18-IDH1R132H, TS543-ATRXWT, and TS543-ATRXLoss patient derived glioma cells were cultured as neurospheres and treated with 3-6 Gy of XRT or PRT. GSC self-renewal, based on neurosphere formation frequency, was quantified using extreme limiting dilution analysis (ELDA). Results: TS543-ATRXLoss significantly inhibited GSC self-renewal over TS543-ATRXWT when subject to PRT (Pairwise Testing Pr(&gt;χ2)&lt;0.01). However, TS543-ATRXWT displayed lower GSC self-renewal compared to TS543-ATRXLoss when subject to XRT (Pr(&gt;χ2)&lt;0.0001). Interestingly, similar results were found in the isogenic MGG18 cell lines. MGG18-IDH1R132H displayed higher radiosensitivity to PRT (Pr(&gt;χ2)&lt;0.05) while MGG18-IDH1WT displayed higher radiosensitivity to XRT (Pr(&gt;χ2)&lt;0.01), as defined by GSC self-renewal. Conclusions: We conclude that ATRXLoss and IDH1R132H both substantially contribute to PRT sensitivity in GSCs, thereby supporting the benefits of PRT for astrocytoma patients. Our future experiments will further elucidate the biological mechanisms by which ATRXLoss and IDH1R132H confer PRT sensitivity, especially via dsDNA damage and apoptosis.
Citation Format: Angel A. Garces, Lawrence Bronk, Krishna P.L. Bhat, David R. Grosshans. ATRXLoss and IDH1R132H impair self-renewal of glioma stem cells after proton radiotherapy [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-065.
Abstract PR-002: SIRT2 promotes BRCA1-BARD1 heterodimerization through deacetylation
Authors: Minten Elizabeth V. , Kappor-Vazirani Priya , Li Chunyang , Zhang Hui , Balakrishnan Kamakshi , Yu David S. 
Published: April 2021

Abstract
The breast cancer type I susceptibility protein (BRCA1) and BRCA1-associated RING domain protein I (BARD1) heterodimer promotes genome integrity through pleiotropic functions, including DNA double-strand break (DSB) repair by homologous recombination (HR). BRCA1-BARD1 heterodimerization is required for their mutual stability, HR function, and role in tumor suppression; however, the upstream signaling events governing BRCA1-BARD1 heterodimerization are unclear. Here, we show that SIRT2, a sirtuin deacetylase and breast tumor suppressor, promotes BRCA1-BARD1 heterodimerization through deacetylation. SIRT2 complexes with BRCA1-BARD1 and deacetylates conserved lysines in the BARD1 RING domain, interfacing BRCA1, which promotes BRCA1-BARD1 heterodimerization and consequently BRCA1-BARD1 stability, nuclear retention, and localization to DNA damage sites, as well as efficient HR. Our findings define a mechanism for regulation of BRCA1-BARD1 heterodimerization through SIRT2 deacetylation, elucidating a critical upstream signaling event directing BRCA1-BARD1 heterodimerization, which facilitates HR and tumor suppression, and delineating a role for SIRT2 in directing DSB repair by HR.
Citation Format: Elizabeth V. Minten, Priya Kappor-Vazirani, Chunyang Li, Hui Zhang, Kamakshi Balakrishnan, David S. Yu. SIRT2 promotes BRCA1-BARD1 heterodimerization through deacetylation [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-002.
Abstract PR-004: Radiation modulates hepatic siphoning of T cells to improve immunotherapy efficacy
Authors: Green Michael , Yu Jiali , Li Shasha , Lawrence Theodore S. , Zou Weiping 
Published: April 2021

Abstract
It is not well established which site(s) in a metastatic patients should be targeted with radiotherapy to elicit responses to immunotherapy. While cancer frequently metastasizes to the liver, it is unknown if liver immune tolerance mechanisms contribute to cancer outcomes. We have found that that liver metastases diminish immunotherapy efficacy systemically in patients and preclinical models. We and others have shown that patients with liver metastases derive limited benefit from immune checkpoint inhibitors. In preclinical models, we show that liver metastases siphon activated CD8+ T cells from systemic circulation and induce their apoptosis within the liver. Consequently, liver metastases create a systemic immune desert. Similarly, patients with liver metastases have reduced adaptive immune responses. In preclinical models, liver-directed radiotherapy eliminates hepatic siphoning of T cells. Thus, liver metastases cause acquired immunotherapy resistance through CD8+ T cell deletion, and the combination of liver-directed radiotherapy and immunotherapy could promote systemic anti-tumor immunity.
Citation Format: Michael Green, Jiali Yu, Shasha Li, Theodore S. Lawrence, Weiping Zou. Radiation modulates hepatic siphoning of T cells to improve immunotherapy efficacy [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-004.
The Influence of Vitamin D on Mammographic Density: Results from CALGB 70806 (Alliance) a Randomized Clinical Trial
Authors: Wood Marie E. , Liu Heshan , Storrick Elizabeth , Zahrieh David , Le-Petross H. Carisa , Jung Sin-Ho , Zekan Patricia , Kemeny M. Margaret , Charlamb Jayne R. , Wang Lili X. , Unzeitig Gary W. , Johnson Candace S. , Garber Judy E. , Marshall James R. , Bedrosian Isabelle 
Published: April 2021

Abstract

Current therapies for breast cancer prevention only prevent estrogen receptor positive (ER+) disease and toxicity limits use of these agents. Vitamin D is a potential prevention therapy for both ER+ and ER− disease and is safe with few side effects. This study evaluates the effect of 1-year of vitamin D supplementation on mammographic density (MD), a biomarker of breast cancer risk in a multicenter randomized controlled trial. Premenopausal women with ≥25% MD and no history of cancer were randomly assigned to 2,000 international units (IU) of vitamin D or placebo orally daily for 1 year. Change in percent MD was evaluated using Cumulus software after all participants completed treatment. Three hundred women enrolled between January 2011 and December 2013 with a mean age of 43 and diverse ethnicity [14% Hispanic, 12% African American (AA)]. Supplementation significantly increased vitamin D levels compared with placebo (14.5 ng/mL vs. −1.6 ng/mL; P &lt; 0.0001) with all participants on the vitamin D arm achieving vitamin D sufficiency at 12 months. Vitamin D was safe and well tolerated. After adjustment for baseline MD, the mean between-arm difference (vitamin D vs. placebo) at 1 year was −0.75 (−0.26, 1.76; P = 0.56). A greater effect was seen for women with ≥50% MD and AA women, although neither reached significance. This randomized controlled trial demonstrated significant improvement in vitamin D levels with 2,000 IU for 1 year, with 100% of supplemented women achieving sufficiency. However, a null effect was seen regarding change in MD for premenopausal women (the primary outcome of the study).

Prevention Relevance:
Current therapies for breast cancer prevention only prevent estrogen receptor positive (ER+) disease and are underutilized due to toxicity and side effects. Vitamin D is a potential prevention therapy for both ER+ and ER− disease and is safe with few side effects.
ОПТИМІЗАЦІЯ ПРОТИЕПІДЕМІЧНОГО ЗАБЕЗПЕЧЕННЯ У ДИНАМІЦІ ПАНДЕМІЇ COVID-19
Authors: Vynohrad N. O. , Vasylyshyn Z. P. , Kozak L. P. , Shul U. A. , Yurchenko O. O. , Dubyna D. O. 
Published: April 2021

Новий коронавірус SARS-Cov-2, який виявили в м. Ухань у грудні 2019 р., спричинив пандемію COVID-19. Протиепідемічний захист у різних уражених країнах відрізняється за обсягами режимно-обмежувальних заходів і регламентами реагування. Найефективнішим виявився комплекс карантинних заходів у поєднанні з раннім виявленням епідемічних осередків та їх блокуванням.
Масовість ураження населення в більшості країнах світу зумовила неефективність діяльності усіх трьох основних медичних ланок системи реагування на біологічні загрози: клінічної, епідеміологічної та лабораторної, – які є визначальними у ліквідації пандемії. Відсутність засобів лікування і профілактики вимагає постійного моніторингу епідемічної ситуації та своєчасної корекції заходів стримання її негативних тенденцій розвитку. Медичні заклади стали об’єктами високого ризику зараження як медичного персоналу, так і усіх, хто звертається за медичною допомогою, що вимагає тотального запровадження специфічних заходів інфекційного контролю щодо COVID-19 на всіх рівнях надання медичної допомоги, включно на етапах евакуації та сортування хворих.
Швидке прогресування розвитку епідемічного процесу COVID-19 на планеті на фоні даних про низьке репродуктивне число свідчить про недостатність знань з основних проявів і закономірностей епідемічного процесу цього особливо небезпечного інфекційного захворювання, що може бути основною причиною неефективності протиепідемічних заходів.
Еволюція SARS-Cov-2 з формуванням трьох підтипів і п’яти генотипів збудника, особливо поява варіанту вірусу D614G з підвищеною контагіозністю і вірулентністю, вимагає ефективного вірусологічного моніторингу для створення валідних діагностичних тест-систем і оцінювання перспективності застосування специфічної активної імунопрофілактики на момент появи вакцин проти COVID-19.
Відсутність даних про інфікувальну дозу SARS-Cov-2 із врахуванням механізмів передачі збудника інфекції, наявність високої частки асимптомних форм хвороби, обмежені дані щодо «суперрозповсюджувачів» патогена, великі втрати серед медичного персоналу, відмінності в системах реагування на біологічні небезпеки на уражених територіях та низка інших обставин ускладнюють можливості ефективного протиепідемічного реагування на COVID-19. Відсутність контролю дотримання рекомендованого обсягу протиепідемічних заходів інтенсифікує розвиток епідемічного процесу в період запровадження адаптивного карантину.
An updated Checklist of the Mediterranean fishes of Israel, with illustrations of recently recorded species and delineation of Lessepsian migrants
Authors: GOLANI DANIEL 
Published: April 2021

This checklist of the Mediterranean fishes of Israel enumerates 469 species which is an addition of 62 species since the previous checklist of 2005. This new checklist includes 58 Condrichthys and 411 Osteicthys species. Most newly-recorded species are of Red Sea origin (Lessepsian migrants)—38 species, 25 species are from previously poorly investigated habitats, mainly deep water, while two species reached the Mediterranean most likely by ballast water and two are aquaculture escapees. The dramatic increase in the number of Lessepsian migrants (an average of 2.5 species per year) is most likely due to the increased water influx between the Red Sea and the Mediterranean, following the recent opening of the new parallel, 72 km, “new canal” and the enlargement of other parts of the Suez Canal.
Toward a Theory of the Evolution of Drop Morphology and Splintering by Freezing
Authors: Staroselsky Alexander , Acharya Ranadip , Khain Alexander 
Published: April 2021

AbstractThe drop freezing process is described by a phase-field model. Two cases are considered: when the freezing is triggered by central nucleation and when nucleation occurs on the drop surface. Depending on the environmental temperature and drop size, different morphological structures develop. Detailed dendritic growth was simulated at the first stage of drop freezing. Independent of the nucleation location, a decrease in temperature within the range from ~−5° to −25°C led to an increase in the number of dendrites and a decrease in their width and the interdendritic space. At temperatures lower than about −25°C, a planar front developed following surface nucleation, while dendrites formed a granular-like structure with small interdendritic distances following bulk nucleation. An ice shell grew in at the same time (but slower) as dendrites following surface nucleation, while it started forming once the dendrites have reached the drop surface in the case of central nucleation. The formed ice morphology at the first freezing stage predefined the splintering probability. We assume that stresses needed to break the ice shell arose from freezing of the water in the interdendritic spaces. Under this assumption, the number of possible splinters/fragments was proportional to the number of dendrites, and the maximum rate of splintering/fragmentation occurred within a temperature range of about −10° to −20°C, is in agreement with available laboratory and in situ measurements. At temperatures < −25°C, freezing did not lead to the formation of significant stresses, making splintering unlikely. The number of dendrites increased with drop size, causing a corresponding increase in the number of splinters. Examples of morphology that favors drop cracking are presented, and the duration of the freezing stages is evaluated. Sensitivity of the freezing process to the surface fluxes is discussed.
A Neural Network-Based Observation Operator for Coupled Ocean-Acoustic Variational Data Assimilation
Authors: Storto Andrea , De Magistris Giovanni , Falchetti Silvia , Oddo Paolo 
Published: April 2021

AbstractVariational data assimilation requires implementing the tangent-linear and adjoint (TA/AD) version of any operator. This intrinsically hampers the use of complicated observations. Here, we assess a new data-driven approach to assimilate acoustic underwater propagation measurements (Transmission Loss, TL) into a regional ocean forecasting system. TL measurements depend on the underlying sound speed fields, mostly temperature, and their inversion would require heavy coding of the TA/AD of an acoustic underwater propagation model. In this study, the non-linear version of the acoustic model is applied to an ensemble of perturbed oceanic conditions. TL outputs are used to formulate both a statistical linear operator based on canonical correlation analysis (CCA), and a neural network-based (NN) operator. For the latter, two linearization strategies are compared, the best-performing one relying on reverse-mode automatic differentiation. The new observation operator is applied in data assimilation experiments over the Ligurian Sea (Mediterranean Sea), using the Observing System Simulation Experiments (OSSE) methodology to assess the impact of TL observations onto oceanic fields. TL observations are extracted from a nature run with perturbed surface boundary conditions and stochastic ocean physics. Sensitivity analyses indicate that the NN reconstruction of TL is significantly better than CCA. Both CCA and NN are able to improve the upper ocean skill scores in forecast experiments, with NN outperforming CCA on the average. The use of the NN observation operator is computationally affordable, and its general formulation appears promising for the adjoint-free assimilation of any remote sensing observing network.
Government choice between contract termination and contract expiration in re-municipalization: a case of historical recurrence?
Authors: Albalate Daniel , Bel Germà , Reeves Eoin 
Published: April 2021

Since the early 2000s, the terms ‘re-municipalization’ and ‘reverse privatization’ entered the lexicon as several examples emerged of governments taking ownership of assets and services that had previously been privatized or outsourced. Various methods are used to implement re-municipalization decisions and differences are observed across countries and sectors. The approaches most frequently adopted are re-municipalization through contract termination and contract expiration. We utilize a wide database of re-municipalizations worldwide to analyse the factors that influence governments’ choice between these two approaches. The results from our multivariate analysis find a pattern of historical recurrence in the characteristics of the current re-municipalization process. Points for practitioners Most governments wait for contracts to expire but the number of contract terminations is sizeable. Re-municipalization in larger cities, network sectors (particularly water) and implemented by municipal governments have a positive association with termination. Re-municipalization of energy utilities and conducted in countries of French legal origin is positively associated with contract expiration. Patterns of contemporary re-municipalization closely resemble those witnessed in the ‘Progressive Era’.