tbuckley/cabot-search huggingface dataset:
Abstract LB-264: Biodynamic chemotherapy selection in breast cancer patients
Authors: Ran An, John Turek, David Nolte, David Loesch, Travis Morgan
Journal: Cancer Research (2020)

Abstract Purpose: Biodynamic signatures (temporal patterns of microscopic motion within a three-dimensional tumor explant) offer a phenomic biomarker that is highly predictive for therapeutic response. The purpose of this study is to evaluate predictive accuracy of a biodynamic drug response classifier in breast cancer patients receiving neoadjuvant chemotherapy (NAC). Methods: Consecutive breast cancer patients from 4 institutions were screened for enrollment in a prospective observational study (NCT03164863). Treatment-naïve needle biopsies were delivered to a central laboratory where biodynamic signatures were measured in living tumor fragments challenged by standard-of-care cytotoxins. Patients received NAC per institutional guidelines and were followed through surgical intervention. A four-point classifier was trained to predict pathologic complete response (CR) then prospectively validated. Results: Among patients completing neoadjuvant treatment and surgical intervention, 33% (24 of 72) achieved CR. The biodynamic classifier predicted CR with 96% sensitivity and 97% negative predictive value. Biodynamically “favored” (scoring ≥ 3) and “strongly favored” (scoring 4) regimens produced CR at rates of 56% (23 of 41) and 73% (19 of 26), respectively. Only 3% of patients (1 of 31) achieved CR from regimens scoring 1 or 2. Area under the receiver operating curve (AUC) was 87% (95% CI: 75% to 93%, p &amp;lt;.0001), with similar performance across all subtypes and therapy cohorts (range: 84% to 89%). Performance of the classifier on training and validation patients was statistically equivalent. Conclusion: Biodynamic scoring accurately predicts response in breast cancer patients receiving NAC and holds promise to substantially improve management of these patients. Chemotherapy response distribution by biodynamic scoreBiodynamic ScoreNo ResponsePartial ResponseComplete ResponseTotal111 (58%)7 (37%)1 (5%)1922 (17%)10 (83%)0 (0%)1231 (7%)10 (67%)4 (27%)1540 (0%)7 (27%)19 (73%)26Totals14 (19%)34 (47%)24 (33%)72 Citation Format: Ran An, John Turek, David Nolte, David Loesch, Travis Morgan. Biodynamic chemotherapy selection in breast cancer patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-264.
Improved Time in Range Over 1 Year Is Associated With Reduced Albuminuria in Individuals With Sensor-Augmented Insulin Pump–Treated Type 1 Diabetes
Authors: Ajenthen G. Ranjan, Signe V. Rosenlund, Tine W. Hansen, Peter Rossing, Steen Andersen, Kirsten Nørgaard
Journal: Diabetes Care (2020)

To investigate the association between treatment-induced change in continuous glucose monitoring (CGM) time in range (TIR) and albuminuria in persons with type 1 diabetes (T1D) treated with sensor-augmented insulin pumps (SAP).Twenty-six out of 55 participants with albuminuria and multiple daily injection therapy (25% females; median 51 [interquartile range 46-63] years of age; glycated hemoglobin A1c (HbA1c) 75 [68-88] mmol/mol [9.0% (8.4-10.4%)]; and urinary albumin-to-creatinine ratio (UACR) 89 [37-250] mg/g) were in a randomized controlled trial assigned to SAP therapy for 1 year. Anthropometrics, CGM data, and blood and urine samples were collected every 3 months.Mean change (95% CI) in percentage of TIR (%TIR) was 13.2% (6.2; 20.2), in HbA1c was -14.4 (-17.4; -10.5) mmol/mol (-1.3% [-1.6; -1.0]), and in UACR was -15% (-38; 17) (all P < 0.05). UACR decreased by 19% (10; 28) per 10% increase in %TIR (P = 0.04), 18% (1; 30) per 10 mmol/mol decrease in HbA1c (P = 0.07), and 31% per 10-mmHg decrease in mean arterial pressure (P < 0.001).In this longitudinal study, treatment-induced increase in %TIR was significantly associated with decrease in albuminuria in T1D.
Abstract LB-352: CD4+ follicular helper-like T cells are key players in anti-tumor immunity
Authors: Anusha Preethi Ganesan
Journal: Cancer Research (2020)

Abstract CD4+ T helper cells (TH) are central orchestrators of an efficient immune response. However, within the tumor microenvironment (TME), it is unknown what type of CD4+ TH cells or CD4 helper-derived signals are essential to generate robust CD8+ CTL and TRM anti-tumor immune responses, which are positively associated with patient prognosis. To determine the nature of CD4+ T cells that provide ‘help' for generating robust anti-tumor CD8+ CTL responses, we profiled the transcriptomes of patient-matched CD4+ and CD8+ T cells present in the TME of treatment-naïve patients with lung cancer and analyzed them jointly using a novel approach, integrated weighted gene correlation network analysis. We found that the follicular helper T cell (TFH) program in CD4+ T cells was strongly associated with proliferation and tissue-residency in CD8+ CTLs. Single-cell transcriptomic analysis demonstrated the presence of tumor-infiltrating TFH-like cells, a subset of which lacked CXCR5 expression but displayed superior functional properties such as provision of CD8+ ‘help', cytotoxicity and proliferation. Because these anti-tumor functions were not previously ascribed to TFH cells which are known to support B cell responses, we validated our findings using independent in vitro and in vivo approaches. Multi-parametric immunohistochemistry showed co-localization of TFH cells with CD8+ TRM cells within tumors, the density of which was positively correlated with that of TFH cells. Adoptive transfer or induction of TFH cells in mouse tumor models resulted in augmented CD8+ CTL responses and impairment of tumor growth, indicating an important role of TFH-like CD4+ T cells in anti-tumor immunity. Furthermore, tumor-infiltrating TFH-like cells expressed PD-1 and were enriched in tumors following checkpoint blockade, suggesting that they may respond to anti-PD-1 therapy in addition to CD8+ CTLs. Our findings provide insights into the molecular identity and functional status of CD4+ T cells within tumors that mount robust CTL responses and uncover potential targets for tumor immunotherapy. Citation Format: Anusha Preethi Ganesan. CD4+ follicular helper-like T cells are key players in anti-tumor immunity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-352.
Abstract 5272: Molecular analysis of Sunitinib resistant renal cell carcinoma after sequential application of Cabozantinib
Authors: Angela Zaccagnino, Bozhena Vynnytska-Myronovska, Michael Stockle, Kerstin Junker
Journal: Cancer Research (2020)

Abstract Introduction: The tyrosine kinase inhibitors Sunitinib and Pazopanib have been established in firstline treatment of metastatic renal cell carcinoma (mRCC) patients especially in the good prognosis group. Despite the primary response many patients become resistant. Resistance mechanisms include activation of MET and AXL - downstream pathways have been reported. Cabozantinib (Cbz), a MET/AXL/VEGFR inhibitor, showed clinical benefits as second-line agent. However, why the therapy becomes ineffective and how the long-term administration with Sunitinib influences sensitivity of tumor cells towards Cbz remain to be answered. Methods: We referred to previously generated Sunitinib -resistant cells (786-O/S) and their untreated counterpart (786-O/WT) to test effect of Cbz in vitro. Drug sensitivity was determined via WST-1 cell proliferation assay, whereas cell pathways analysis in response to Cbz was evaluated at different time points by means of immunoblotting. Results: By challenging the two cell phenotypes with different concentrations of Cbz we found that the 786-O/WT cells were more sensitive to the drug in comparison to 786-O/S (IC50 value of 9.9 µM versus 12.2 µM, respectively). The 786-O/WT cells responded to short-term incubation with Cbz by decreasing the expression of the receptor MET and its downstream intracellular pathways: the activated Src (pSrc) and p38 MAPK (p-p38 MAPK). Besides, Erk protein showed a slight increased activity (pErk) after 8 and 24h drug exposure. In contrast, no significant regulation of MET, nor pSrc and p-p38 MAPK kinase expression was reported in the 786-O/S cells. Remarkably, pErk level was induced after Cbz incubation in a time-dependent manner. Finally, phosphorylated S6 (pS6) was used as a marker of PI3K/Akt/mTOR pathway. Cbz decreased the level of pS6 in 786-O/WT, while enhancing it in the 786-O/S cells. Conclusions: Our work provides a preclinical model for sequential therapy in mRCC. The initial in vitro data confirmed Cbz as a potent tool to contrast the progress of RCC in the first-line setting. Still, switching to Cbz after Sunitinb resistance resulted in Erk and mTOR pathways activation and might be interpreted as overlapping survival mechanism. This ongoing work will provide a better knowledge of the protein expression patterns of possible cross-resistance in RCC by analyzing additional cell lines including Pazopanib-resistant ones. Citation Format: Angela Zaccagnino, Bozhena Vynnytska-Myronovska, Michael Stockle, Kerstin Junker. Molecular analysis of Sunitinib resistant renal cell carcinoma after sequential application of Cabozantinib [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5272.
Abstract 2321: Validating breast cancer risk prediction models in the Korean Cancer Prevention Study-II Biobank
Authors: Yon Ho Jee, Chi Gao, Jihye Kim, Seho Park, Sun Ha Jee, Peter Kraft
Journal: Cancer Research (2020)

Abstract Background: Informative and well-calibrated risk prediction models may be useful for precision breast-cancer screening. However, these models often have not been validated across diverse populations. Validation in East Asian populations is particularly lacking. Objective: To evaluate the performance of breast cancer risk models developed in European-ancestry studies in a Korean population, both directly and after recalibration. Methods: We compared discrimination and calibration of three multivariable risk models in a cohort of 77,457 women from the Korean Cancer Prevention Study-II. The first incorporated US breast-cancer incidence and mortality rates, US risk-factor distributions, and relative risk (RR) estimates from European-ancestry studies. The second recalibrated the first by using Korean incidence and mortality rates and Korean risk factor distributions, while retaining the European-ancestry RR estimates. Finally, we derived a Korea-specific model incorporating the RR estimates from Korean Cancer Prevention Study. The Individualized Coherent Absolute Risk Estimation (iCARE) software package was used to calculate 5 year predicted absolute risks of breast cancer and assess model performance. Results: The US European-ancestry breast cancer risk model was well calibrated among Korean women &amp;lt;50 years (E/O=1.124 (0.989, 1.278)) but markedly overestimated the risk for those ≥50 years (E/O=2.472 (2.005, 3.049)). Recalibrating absolute risk estimates using Korean breast cancer rates and risk distributions markedly improved the calibration in women ≥50 (E/O=1.018 (0.825, 1.255)). The model incorporating Korean-based RRs had similar but not clearly improved performance relative to the recalibrated model; this may reflect at most modest differences in the RRs between European and Korean populations and the relatively small sample used to estimate RRs among Korean women. Conclusions: The poor performance of the US European-ancestry breast cancer risk model among older Korean women highlights the importance of tailoring absolute risk models to specific populations. Recalibrating the model using Korean incidence and mortality rates and risk factor distributions greatly improved performance; we anticipate the performance could be further improved by incorporating multivariable risk-factor RRs from large Korea-based studies. Citation Format: Yon Ho Jee, Chi Gao, Jihye Kim, Seho Park, Sun Ha Jee, Peter Kraft. Validating breast cancer risk prediction models in the Korean Cancer Prevention Study-II Biobank [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2321.
Abstract 5827: Alterations of telomere and SOX9 play key roles on pancreatic carcinogenesis
Authors: Yoko Matsuda, Keiko Yamakawa, Yuko Narusawa
Journal: Cancer Research (2020)

Abstract The morbidity of pancreatic cancer is predicted to increase because of the growing elderly population. In this study, we analyzed alterations of telomere length and SOX9 expression to clarify the relationship between precancerous lesions (pancreatic intraepithelial neoplasia; PanIN), pancreatic cancer and aging. The incidence of PanIN in the elderly patients was 60%. The telomere, which can protect the chromosome ends, was shortened in the following order; pancreatic duct&amp;gt;PanIN-1&amp;gt;PanIN-2&amp;gt;PanIN-3&amp;gt;pancreatic cancer. The telomeres in normal duct epithelium became shorter with aging, and those in cancers were shorter than in controls, suggesting that telomere shortening occurs when histological changes are absent. SOX9, which regulates pancreatic progenitor cells, was the highest in carcinomas, followed by PanIN-3, PanIN-2, PanIN-1, and duct epithelium. SOX9 expression was positively correlated with telomere length in cancer cells. Inhibition of SOX9 using siRNA showed decrease of human telomerase reverse transcriptase (hTERT) expression and decrease of sphere formation in human pancreatic cancer cell lines. In conclusion, upregulation of SOX9 in the duct epithelium, which harbors shortened telomeres, may give rise to PanINs and pancreatic cancers. Citation Format: Yoko Matsuda, Keiko Yamakawa, Yuko Narusawa. Alterations of telomere and SOX9 play key roles on pancreatic carcinogenesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5827.
Sequential Protein Capture in Multiplex Single Molecule Arrays: A Strategy for Eliminating Assay Cross‐Reactivity
Authors: Tal Gilboa, Adam M. Maley, Alana F. Ogata, Connie Wu, David R. Walt
Journal: Advanced Healthcare Materials (2020)

Measurements of multiple biomolecules within the same biological sample are important for many clinical applications to enable accurate disease diagnosis or classification. These disease-related biomarkers often exist at very low levels in biological fluids, necessitating ultrasensitive measurement methods. Single-molecule arrays (Simoa), a bead-based digital enzyme-linked immunosorbent assay, is the current state of the art for ultrasensitive protein detection and can detect sub-femtomolar protein concentrations, but its ability to achieve high-order multiplexing without cross-reactivity remains a challenge. Here, a sequential protein capture approach for multiplex Simoa assays is implemented to eliminate cross-reactivity between binding reagents by sequentially capturing each protein analyte and then incubating each capture bead with only its corresponding detection antibody. This strategy not only reduces cross-reactivity to background levels and significantly improves measurement accuracies, but also enables higher-order multiplexing. As a proof of concept, the sequential multiplex Simoa assay is used to measure five different cytokines in plasma samples from Coronavirus Disease 2019 (COVID-19) patients. The ultrasensitive sequential multiplex Simoa assays will enable the simultaneous measurements of multiple low-abundance analytes in a time- and cost-effective manner and will prove especially critical in many cases where sample volumes are limited.
Abstract 5420: Multiomics approach identifies the SP8-FGF8 axis as an important promoter of metastatic features in hepatoblastoma
Authors: Alexandra Wagner, Beate Häberle, Irene Schmid, Christian Vokuhl, Dietrich von Schweinitz, Roland Kappler
Journal: Cancer Research (2020)

Abstract Introduction Hepatoblastoma (HB) is the most common pediatric liver tumor with a general good prognosis, but if associated with multifocal growth, vessel invasion or metastasis, outcome is still poor. The molecular mechanisms causing this high-risk profile are still unknown. The aim of our study was to gain insight into the neoplastic continuation towards more aggressive tumor phenotypes and to aid identification of biomarkers for high-risk patients. Experimental procedures Tumor specimens of seven non-metastasized and four metastasized HB patients were analyzed by RNA-sequencing and the Human Methylation 450 BeadChip microarray to assess global expression and methylation levels. Integration of both datasets identified new candidate genes, which were further verified in a cohort of 34 HB patients using real-time PCR. Gain and loss of function experiments of SP8 were conducted in five HB cell lines to evaluate its effects on proliferation, mobility, self renewal, migration and invasion. Chromatin-immunoprecipitation was used to assess binding of SP8 to the FGF8 promoter. Kaplan-Meier estimates of specific survival time in various groups were compared using the log-rank Mantel-Cox test. Results Global integration of expression and methylation levels identified the transcription factor SP8 and the fibroblast growth factor FGF8 as significantly upregulated genes accompanied with strong methylation changes in metastatic HB. In an independent cohort of 34 HB patients expression of both candidates was highly correlated (R² = 0.74, P &amp;lt; 0.0001) and could be positively associated with metastasis, the aggressive C2 subtype of the 16-gene signature and poor overall survival. Chromatin-immunoprecipitation identified binding of SP8 to the FGF8 promoter. Following SP8 overexpression in liver tumor cells, we found a significant increase in cell motility, self renewal and invasive growth together with the acquisition of a mesenchymal phenotype. In turn, CRISPRi-mediated knockdown of FGF8 rescued the phenotype. Conclusions We showed that elevated levels of SP8 induced cell motility, self renewal and mesenchymal characteristics by targeting FGF8, thereby implicating an important functional role of the SP8-FGF8 axis for the progression and metastasis of malignant childhood liver tumors. Moreover, SP8 might serve as a new biomarker in metastatic HB with poor prognosis. Citation Format: Alexandra Wagner, Beate Häberle, Irene Schmid, Christian Vokuhl, Dietrich von Schweinitz, Roland Kappler. Multiomics approach identifies the SP8-FGF8 axis as an important promoter of metastatic features in hepatoblastoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5420.
Abstract 1432: TORC2 dependent control of cell growth and size in cancer cells
Authors: Jerry T. DeWitt, Douglas Kellogg
Journal: Cancer Research (2020)

Abstract Severe defects in cell growth and size are a nearly universal feature of cancer cells and have provided a basis for cancer pathology for over 100 years; however, the underlying mechanisms remain largely unknown. Recent work in budding yeast has shown that a highly conserved signaling network surrounding Tor complex 2 (TORC2) controls cell growth and size. A key component of the network is the yeast homolog of serum and glucocorticoid-regulated kinase (SGK), which controls production of ceramide signaling lipids that control cell growth and size. Here, we present evidence that a similar TORC2 network controls cell growth and size in mammalian cells. In addition, we show that expression of oncogenic drivers in NIH3T3 cells causes defects in cell size, as well as defects in TORC2-dependent control of cell size. Cancer cells also show severe defects in TORC2-dependent control of cell size. Our working hypothesis is that the TORC2 network is downstream of multiple oncogenes, and that aberrant TORC2 signaling is a major cause of the nearly universal size defects observed in cancer cells. A better understanding of the mechanisms that control cell growth and size in normal cells, and how they go awry in cancer, could identify new targets for drugs to improve cancer therapies. Citation Format: Jerry T. DeWitt, Douglas Kellogg. TORC2 dependent control of cell growth and size in cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1432.
Abstract 1495: A transcriptional lineage tracing approach to unravel crucial gene expression patterns in breast cancer progression
Authors: Niccolò Roda, Roman Hillje, Valentina Gambino, Stefano Cheloni, Paolo Falvo, Andrea Tirelli, Francesco Bertolini, Pier Giuseppe Pelicci
Journal: Cancer Research (2020)

Abstract Breast cancer represents a major clinical hurdle, with intra-tumor heterogeneity and metastatic outcome accounting both for poor prognosis and therapeutic failure. Traditionally, its poly-clonal structure has been investigated through the genetic barcoding of cells followed by the tracing of the offspring. However, this analysis does not allow a solid investigation of the transcriptional profile associated to clones throughout tumor progression. In this work, we exploited a recently published library of expressed barcodes to perform both clonal and trancriptional tracing in breast cancer by single-cell RNA sequencing. To this aim, human breast cancer cell line MDA-MB-231 was transduced with the above mentioned library and orthotopically transplanted in immune-deficient mice. To analyze our data we generated a pipeline aimed at identifying the barcodes at single-cell level and subsequently sequenced more than 20000 cells.Our clonal distribution analysis strongly suggested that clones within the same tumor possess different proliferative potential. Additionally, we found that breast tumors show transcriptional intra-clonal heterogeneity, since cells within the same clone display multiple transcriptional patterns. Notably, clones similar in terms of proliferative potential show profound differences in the transcriptomic profile and in the upregulated pathways. All these results represent a launching pad for further experiments aimed at identifying the transcriptional determinants involved in the spreading of breast cancer clones and in the metastatic progression. Citation Format: Niccolò Roda, Roman Hillje, Valentina Gambino, Stefano Cheloni, Paolo Falvo, Andrea Tirelli, Francesco Bertolini, Pier Giuseppe Pelicci. A transcriptional lineage tracing approach to unravel crucial gene expression patterns in breast cancer progression [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1495.