tbuckley/cabot-search huggingface dataset:
Abstract 585: A robust method for expanding patient-derived circulating tumor cells <i>ex vivo</i>
Authors: Jerry Xiao, Joshua D. Kassner, Kelly Stanton, Richard Schlegel, Paula R. Pohlmann, Seema Agarwal
Journal: Cancer Research (2021)

Abstract In the United States, an estimated 280,000 people will be diagnosed with invasive breast cancer, which has a 5-year survival rate of 27% and 22% in females and males, respectively. Despite the clinical burden of metastasis, the underlying machinery of metastasis remains unclear. This is largely due to a lack of available technologies that can robustly expand patient-derived metastatic cell populations for study ex vivo. One such population is circulating tumor cells (CTCs), which are cells that escape from the primary tumor, intravasate through blood vessel endothelium, and circulate throughout the body. Eventually, CTCs will extravasate at the metastatic site and become the seeds for metastatic colonization. Based on their role in metastasis, CTCs yield great promise for identifying key mechanistic drivers of metastasis. Unfortunately, CTCs exist in low levels within the blood (typically &amp;lt; 100 cells/10mL of blood). Previous methods for culturing CTCs ex vivo have reported low success rates (~ 20%), and often depend on the presence of a high number of CTCs for success. To better interrogate the mechanisms of metastasis, robust methods to propagate CTCs for study are needed. Recently, our lab developed a method using an unbiased selection criterion for isolating and propagating CTCs derived from metastatic breast cancer, yielding 100% success in twelve distinct individuals. This method, based on a density gradient centrifugation, extracts not only CTCs from blood plasma, but also includes potential cancer-associated neutrophils and macrophages. All cultures under our conditions demonstrated growth for &amp;gt; 30 days and were confirmed to have an epithelial and breast phenotype. Notably, 6/12 samples grew longer and were associated with increased CD45 expression using qRT-PCR. We have also recently demonstrated further success in culturing CTCs derived from a variety of other cancers, including colorectal, lung, and pancreatic cancers. This study therefore not only defines a novel technology for expanding CTCs, but also suggests a deficiency in modern isolation methods, which rely on CD45 exclusion, that is limiting culture success in previous methods. Citation Format: Jerry Xiao, Joshua D. Kassner, Kelly Stanton, Richard Schlegel, Paula R. Pohlmann, Seema Agarwal. A robust method for expanding patient-derived circulating tumor cells ex vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 585.
Abstract 3170: Targeting tumor-associated astrocyte dependence in glioblastoma treatment
Authors: Joseph S. Domino, Anthony Alvarado, Levi Arnold, Sumedha Gunewardena, David Akhavan, Sufi M. Thomas
Journal: Cancer Research (2021)

Abstract Glioblastoma (GBM) is the most common malignant primary brain tumor and remains challenging to treat due to its aggressive nature with high rate of recurrence. Despite advances in therapy, prognosis is poor with median survival of 19 months with maximal therapy. The normal astrocytes within the GBM TME undergo a phenotypic shift, promoting alterations supportive of tumor growth. There is increasing attention on the role of tumor-associated astrocytes (TAA) in GBM progression and resistance to therapy. Previous studies assessing astrocyte support of GBM employ astrocytes derived from murine or fetal sources. We have isolated TAAs from patients with GBM as well as normal human astrocytes (NHA) from cancer-free patients undergoing surgical treatment of epilepsy. The cells are maintained at a low passage number (&amp;lt;10 passes). Our data emphasize the supportive role these cells in GBM progression and resistance to GBM therapy. Briefly, conditioned media (CM) from non-malignant, GFAP positive TAAs, demonstrate a propensity to induce invasion and migration of U87 GBM cells compared to the NHA CM. In addition, TAA CM significantly increased the IC50 dose of U87 cells treated with temozolomide from 536 μM to 1351 μM demonstrating treatment resistance (p&amp;lt;0.001). TAA CM induced temozolomide resistance of the GBM cells can be abolished with supra-therapeutic dosing. RNA sequencing (RNAseq) of two TAA and three NHA samples revealed 399 differentially expressed genes identified with 38 of those upregulated genes coding extracellular products. Expression data was verified by quantitative polymerase chain reaction (qPCR), thus validating the differential expression profile generated by RNAseq. The differential expression data was explored further using Ingenuity Pathway Analysis (IPA) and gene set enrichment analysis (GSEA). Attention was focused on genes with excreted factors as products or involved in the regulation of critical excreted products. We identified and validated high expression of IL1β in TAAs compared to NHAs. RNAseq data revealed multiple potential pathways for targeted therapies aimed at modulating the effect of TAAs in the tumor microenvironment. In ongoing studies, we will determine the efficacy of IL1β in attenuating the TAA-induced temozolomide resistance in GBM. These studies reveal for the first time a highly clinically relevant approach to attenuate TAA-facilitated GBM progression and therapy resistance. Citation Format: Joseph S. Domino, Anthony Alvarado, Levi Arnold, Sumedha Gunewardena, David Akhavan, Sufi M. Thomas. Targeting tumor-associated astrocyte dependence in glioblastoma treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3170.
Preference and perception of treatment choices between radiologists and urologists for treatment for urgent urinary obstruction – nephrostomy versus retrograde ureteric stent: European survey from YAU and ESUT Endourology groups
Authors: A. Pietropaolo, L. Mosquera Seoane, A. Abu-Suboh Abadia, R.M. Geraghty, P. Kallidonis, T. Tailly, S. Modi, A. Skolarikos, K. Sarica, A. Gozen, E. Emiliani, E. Sener, B.P. Rai, Z.B. Hameed, E. Liatsikos, B.K. Somani
Journal: European Urology (2021)
Multifunctional barcoding with ClonMapper enables high-resolution study of clonal dynamics during tumor evolution and treatment
Authors: Catherine Gutierrez, Aziz M. Al’Khafaji, Eric Brenner, Kaitlyn E. Johnson, Satyen H. Gohil, Ziao Lin, Binyamin A. Knisbacher, Russell E. Durrett, Shuqiang Li, Salma Parvin, Anat Biran, Wandi Zhang, Laura Rassenti, Thomas J. Kipps, Kenneth J. Livak, Donna Neuberg, Anthony Letai, Gad Getz, Catherine J. Wu, Amy Brock
Journal: Nature Cancer (2021)
Predictive Immune-Checkpoint Blockade Classifiers Identify Tumors Responding to Inhibition of PD-1 and/or CTLA-4
Authors: Oscar Krijgsman, Kristel Kemper, Julia Boshuizen, David W. Vredevoogd, Elisa A. Rozeman, Sofia Ibanez Molero, Beaunelle de Bruijn, Paulien Cornelissen-Steijger, Aida Shahrabi, Martin Del Castillo Velasco-Herrera, Ji-Ying Song, Maarten A. Ligtenberg, Roelof J.C. Kluin, Thomas Kuilman, Petra Ross-Macdonald, John B.A.G. Haanen, David J. Adams, Christian U. Blank, Daniel S. Peeper
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Combining anti–PD-1 + anti–CTLA-4 immune-checkpoint blockade (ICB) shows improved patient benefit, but it is associated with severe immune-related adverse events and exceedingly high cost. Therefore, there is a dire need to predict which patients respond to monotherapy and which require combination ICB treatment. Experimental Design: In patient-derived melanoma xenografts (PDX), human tumor microenvironment (TME) cells were swiftly replaced by murine cells upon transplantation. Using our XenofilteR deconvolution algorithm we curated human tumor cell RNA reads, which were subsequently subtracted in silico from bulk (tumor cell + TME) patients' melanoma RNA. This produced a purely tumor cell–intrinsic signature (“InTumor”) and a signature comprising tumor cell–extrinsic RNA reads (“ExTumor”). Results: We show that whereas the InTumor signature predicts response to anti–PD-1, the ExTumor predicts anti–CTLA-4 benefit. In PDX, InTumorLO, but not InTumorHI, tumors are effectively eliminated by cytotoxic T cells. When used in conjunction, the InTumor and ExTumor signatures identify not only patients who have a substantially higher chance of responding to combination treatment than to either monotherapy, but also those who are likely to benefit little from anti–CTLA-4 on top of anti–PD-1. Conclusions: These signatures may be exploited to distinguish melanoma patients who need combination ICB blockade from those who likely benefit from either monotherapy.
Association of Travel Distance to Nearest Abortion Facility With Rates of Abortion
Authors: Kirsten M. J. Thompson, Hugh J. W. Sturrock, Diana Greene Foster, Ushma D. Upadhyay
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Travel distance to abortion services varies widely in the US. Some evidence shows travel distance affects use of abortion care, but there is no national analysis of how abortion rate changes with travel distance. <h3>Objective</h3> To examine the association between travel distance to the nearest abortion care facility and the abortion rate and to model the effect of reduced travel distance. <h3>Design, Setting, and Participants</h3> This cross-sectional geographic analysis used 2015 data on abortions by county of residence from 1948 counties in 27 states. Abortion rates were modeled using a spatial Poisson model adjusted for age, race/ethnicity, marital status, educational attainment, household poverty, nativity, and state abortion policies. Abortion rates for 3107 counties in the 48 contiguous states that were home to 62.5 million female residents of reproductive age (15-44 years) and changes under travel distance scenarios, including integration into primary care (&lt;30 miles) and availability of telemedicine care (&lt;5 miles), were estimated. Data were collected from April 2018 to October 2019 and analyzed from December 2019 to July 2020. <h3>Exposures</h3> Median travel distance by car to the nearest abortion facility. <h3>Main Outcomes and Measures</h3> US county abortion rate per 1000 female residents of reproductive age. <h3>Results</h3> Among the 1948 counties included in the analysis, greater travel distances were associated with lower abortion rates in a dose-response manner. Compared with a median travel distance of less than 5 miles (median rate, 21.1 [range, 1.2-63.6] per 1000 female residents of reproductive age), distances of 5 to 15 miles (median rate, 12.2 [range, 0.5-23.4] per 1000 female residents of reproductive age; adjusted coefficient, −0.05 [95% CI, −0.07 to −0.03]) and 120 miles or more (median rate, 3.9 [range, 0-12.9] per 1000 female residents of reproductive age; coefficient, −0.73 [95% CI, −0.80 to −0.65]) were associated with lower rates. In a model of 3107 counties with 62.5 million female residents of reproductive age, 696 760 abortions were estimated (mean rate, 11.1 [range, 1.0-45.5] per 1000 female residents of reproductive age). If abortion were integrated into primary care, an additional 18 190 abortions (mean rate, 11.4 [range, 1.1-45.5] per 1000 female residents of reproductive age) were estimated. If telemedicine were widely available, an additional 70 920 abortions were estimated (mean rate, 12.3 [range, 1.4-45.5] per 1000 female residents of reproductive age). <h3>Conclusions and Relevance</h3> These findings suggest that greater travel distances to abortion services are associated with lower abortion rates. The results indicate which geographic areas have insufficient access to abortion care. Modeling suggests that integrating abortion into primary care or making medication abortion care available by telemedicine may decrease unmet need.
Abstract 70: Obesity-induced impairment of antitumor immunity is associated with an immunosuppressive tumor immune landscape
Authors: Barbara Pazdrak, Duncan Mak, William Damsky, Marcus Bosenberg, Brooklyn Lochmann, Matthew Gubin, Jennifer McQuade
Journal: Cancer Research (2021)

Abstract Obesity is associated with an increased risk and progression in a variety of cancers. In melanoma, obesity is associated with an increased risk of recurrence following surgical resection which may reflect immune escape of cancer surveillance. We sought to examine the impact of obesity on antitumor immunity in an immunogenic preclinical melanoma model.Male C57/Bl6 mice were fed a 45% fat diet or 10% fat diet for 12 months resulting in obese (body weight 52.8g ±1.3) vs control mice (body weight 38.8g ±2.2). For these studies, we utilized the YUMMER cell line, a C57BL/6J syngeneic melanoma cell line with three driver mutation/deletions (BrafV600E, Pten-/-, Cdkn2a-/-), irradiated to mimic the high mutation burden of human melanoma. 0.5x106 YUMMER cells were subcutaneously injected into the flank of aged (13 month old) control and obese mice. After 14 days post injection, tumors in control mice either had growth arrest or regression. In contrast, all obese mice exhibited progressively growing tumors with 6-fold greater tumor weights after 21 days as compared to control (1.3g ±0.4 vs 0.23g ±0.06). CyTOF analysis of tumor-infiltrating immune cells at day 21 showed 2-fold decrease in the percentage of CD4 T cells in tumors from obese mice (9.8% vs 21.1% of CD45). In addition, obesity resulted in 4-fold increase in the frequency of intratumoral Treg (26.1% vs 8.3% of CD3CD4 cells) and CD8/Treg ratio was 2-fold reduced in obese mice. In contrast to prior findings in obese mice bearing B16 melanomas, the percentage of CD8 T cells expressing PD1 was similar (80.4% vs 74.3%), but we found 2-fold higher frequency of CD8PD1 T cells co-expressing TIM3 and LAG3 in tumors from obese mice (43.3% vs 23.0%). Moreover, obesity also attenuated the frequency of tumor-infiltrating cDC2 (1.4% vs 3.5% of CD45) but did not affect NK cells or B cell proportions. Furthermore, the ratio of tumor infiltrating myeloid cells to T cells was higher in obese mice (1.94:1 vs 0.82:1). Moreover, myeloid cells from obese mouse tumors had higher expression of PDL1, CD206, and CD38 markers.Our findings provide evidence that obesity impairs antitumor immunity by modulating the relative abundance of intratumoral immune cell populations and their phenotypes to promote immunosuppressive microenvironment. These findings will be validated in subsequent studies and examined in human specimens. Citation Format: Barbara Pazdrak, Duncan Mak, William Damsky, Marcus Bosenberg, Brooklyn Lochmann, Matthew Gubin, Jennifer McQuade. Obesity-induced impairment of antitumor immunity is associated with an immunosuppressive tumor immune landscape [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 70.
Abstract 788: Differences in somatic <i>TP53</i> mutation type in breast tumors by race and receptor status
Authors: Nijole Pollock, Johnny Ramroop, Joseph McElroy, Amanda E. Toland
Journal: Cancer Research (2021)

Abstract Somatic driver mutations in TP53 are associated with triple negative breast cancer (TNBC) and poorer outcomes. African American women with breast cancer are more likely to have TNBC and TP53 driver mutations. Missense driver mutations in TP53 can be loss-of function (LOF) or gain-of-function (GOF). Additionally, some variants show dominant negative (DNE) activity. There are a number of hot-spot TP53 mutations, many occurring at CpG sites. Given the differences in TNBC status and TP53 driver mutation frequency by race, we wanted to determine if there are differences in TP53 mutation type by race. From multiple databases and a literature review, we identified 98 studies with patient race and TP53 mutation details. We compiled TP53 mutations from 2964 breast tumors from these 98 studies. The cohort included 715 (24.1%) Asian, 258 (8.7%) African (AA), and 1931 (65.1%) European (EA) ancestry individuals. Additionally, 60 patients (2%) had Hispanic or Latina ethnicity. Of the somatic TP53 mutations, 939 (31.7%) were GOF, 1739 (58.7%) were LOF, while the remaining 286 (9.6%) were not able to be classified by existing literature. With respect to DNE activity, 1246 (42%) showed DNE, 1190 (40.1%) showed no DNE, and 528 (17.8%) were unknown DNE status. CpG hotspots accounted for 613 (20.6%) mutations. Using Fisher's Exact test, we did not identify significant associations between any of the functional categories and overall race. However, 35.8% of tumors from EA individuals had GOF mutations compared to 29% in AA individuals (p=0.04). Mutations with DNE activity were positively associated with TNBC (OR=1.37, p=0.03) and negative estrogen receptor (ER) status (OR=1.38; p=0.005). Patients with hotspot mutations were slightly younger (mean age 53.61) compared to those with non-hotspot mutations (mean age 55.04), and this association neared significance (p=0.065). Larger cohorts are needed, in particular the AA cohort, to further elucidate some of these borderline findings. In summary, ER negative and TNBC breast tumors are more likely to have DNE TP53 mutations which could reflect biological processes. Citation Format: Nijole Pollock, Johnny Ramroop, Joseph McElroy, Amanda E. Toland. Differences in somatic TP53 mutation type in breast tumors by race and receptor status [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 788.
Abstract 475: Improving liposarcoma diagnosis through cross-flow microfiltration
Authors: Lucia Casadei, Patricia Sarchet, Adarsh Choudhury, Shaurya Prakash, Raphael Pollock
Journal: Cancer Research (2021)

Abstract Introduction: Dedifferentiated liposarcoma (DDLPS) is frequently diagnosed late and patients typically respondpoorly to treatments bringing to an overall survival rate of only 10% at 10 years. Prognosis isenhanced by early detection of recurrent lesions, but current diagnostic methods rely on invasivetissue biopsies combined with whole or part-body imaging. These diagnostic and prognosticchallenges prompted us to explore the use of circulating biomolecules as potential biomarkersaccessible through bodily fluids. Extracellular Vesicles (EVs) are membrane vesicles containingproteins and nucleic acids that circulate in the blood, so they are an emerging class of easilyaccessible blood biomarkers. We recently identified extracellular vesicle EV-MDM2 as liquidbiopsy biomarker for disease identification in DDLPS. Unfortunately, due to these challenges forisolation and capture of EVs, despite the potential diagnostic and prognostic utility, the practicalrelevance of using EVs for routine analysis remains limited. Methods: A microfluidic device was fabricated via standard soft lithography in PDMS(polydimethylsiloxane). A 5 x 5 mm2 nanocapillary array membrane (nominal capillary diameterof 0.2 µm) was sandwiched between two microchannels for a vertically aligned configuration withan injection and separation channel (each 500 µm wide and 150 µm high) perpendicular to eachother. The separation channel surface was functionalized with the anti-CD63 antibody forcapturing EVs. Results: We present here a facile approach to fabricate and operate a micro-nanofluidic device that usescross-flow filtration to isolate and capture liposarcoma derived EVs. Our methodology integratesthe unit operations of size based separation with immunoaffinity-based capture of extracellularvesicles in the same device. The eluted media collected showed ~84% extracellular vesiclerecovery from the liposarcoma cell conditioned media and ~38% extracellular vesicle recoveryfrom dedifferentiated liposarcoma patient serum when compared to extracellular vesicle isolationand subsequent quantification by ultracentrifugation. The results reported here also show a five-fold increase in amount of critical liposarcoma relevant extracellular vesicle cargo obtained in30 minutes presenting a significant advance over existing state-of-art. Conclusion: In conclusion we developed a cross-flow filtration micro-nanofluidic device for isolation, selectivecapture and release of liposarcoma EVs. Citation Format: Lucia Casadei, Patricia Sarchet, Adarsh Choudhury, Shaurya Prakash, Raphael Pollock. Improving liposarcoma diagnosis through cross-flow microfiltration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 475.
Diabetes and COVID-19: Population Impact 18 Months Into the Pandemic
Authors: Edward W. Gregg, Marisa K. Sophiea, Misghina Weldegiorgis
Journal: Diabetes Care (2021)

Eighteen months into the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (coronavirus disease 2019 [COVID-19]) pandemic, epidemiologic studies indicate that diabetes is a central contributor to severe COVID-19 morbidity, and, conversely, COVID-19 has had a devastating effect on the population with diabetes. In this literature synthesis, we summarize the relationship of diabetes to COVID-19-related morbidity and mortality, discuss the predictors of severe adverse outcomes and implications of the overall pandemic, and critique the current status of and identify needs for epidemiologic studies for the next phase of the pandemic. Case series show that ∼30-40% of people with COVID-19-related hospitalization, severe morbidity requiring intensive care, and/or death have type 2 or type 1 diabetes. Among hospitalized individuals with diabetes, ∼21-43% required intensive care and case fatality is ∼25%. Risk of severe morbidity and mortality is 100-250% higher among people with diabetes than those without, even after adjustment for sociodemographic factors and comorbid conditions. Impact on the general population with diabetes has been similarly dire, as overall mortality rates were 50% higher than historical trends, a net increase more than twice that of the general population. Of the excess deaths, ∼75-80% are not officially attributed to COVID-19, which raises unanswered questions about missed attribution or collateral impact. Many predictors of poor outcomes have been identified, particularly comorbid conditions (chronic kidney disease, coronary heart disease, and heart failure), concurrent obesity, and acute and chronic poor HbA1c control, that point to the potential to reduce severe morbidity and mortality in its next stages. However, response to the continuing pandemic will benefit from population-wide studies with broader examination of the risks of exposure, infection, and hospitalization, for which few data currently exist. The indirect impact of the pandemic's effects on health services, health behaviors, disease management, care, control, and complications has not been well quantified; determining this impact will be essential to lessen the future impact. Expanding epidemiologic studies of the relationship of diabetes to COVID-19 beyond few high-income countries will also be essential to limit the burden in low- and middle-income countries where 80% of individuals with diabetes reside and where the COVID-19 pandemic has been so damaging.
Abstract 14413: Epsin-Mimetic UPI Peptide Delivery Strategies From Electrospun Meshes Improve Endothelial Cell Attachment for Vascular Tissue Engineering
Authors: Mahyar Sameti, Ana R Martinez-Dehesa, Hong Chen, Chris A Bashur
Journal: Circulation (2019)

Tissue engineered vascular grafts (TEVGs) are a promising alternative to overcome challenges with current graft options. However, viability of small diameter TEVGs is limited by the lack of a funct...