tbuckley/cabot-search huggingface dataset:
Abstract 2709: CD44 inhibits DCIS progression to invasive carcinoma
Authors: Fang Liu, Jun Zhou, Tanima Kundu-Roy, Joseph Wahler, Jae Young So, Yong Lin, You-Rong Lou, Nicola J. Barnard, Isao Matsuura, Nanjoo Suh
Journal: Cancer Research (2021)

Abstract Ductal carcinoma in situ (DCIS) transition to invasive tumor is an important issue for breast cancer. The human MCF10DCIS.com cell line (abbreviated as MCF10DCIS) is derived from the spontaneously immortalized human MCF10A breast epithelial cell line. The MCF10DCIS xenografts are similar to human high grade comedo DCIS. In the xenograft assay, MCF10DCIS cells form DCIS-like lesion, remain as DCIS-like lesion in the first several weeks, and then progress into invasive carcinoma. Thus, it is an excellent model to study human breast cancer transition from DCIS to invasive carcinoma. To the best of our knowledge, it is the most commonly used model for DCIS transition to invasive carcinoma. We investigated the role of CD44 in breast cancer transition from DCIS to invasive carcinoma by knockdown the expression of CD44 in the MCF10DCIS xenograft model. Our results show that knockdown of CD44 expression in the MCF10DCIS cells enhances DCIS transition to invasive carcinoma. Our finding is supported by a previous study which showed that CD44 expression was lower in invasive human breast carcinomas than in DCIS, especially in the luminal A subtype. Our study uncovered an unexpected role of CD44 in the inhibition of DCIS transition to invasive carcinoma. We will also present a model for the underlying mechanisms for the protective role of CD44 in the inhibition of transition from DCIS to invasive carcinoma. Our findings have important implications for breast cancer. Citation Format: Fang Liu, Jun Zhou, Tanima Kundu-Roy, Joseph Wahler, Jae Young So, Yong Lin, You-Rong Lou, Nicola J. Barnard, Isao Matsuura, Nanjoo Suh. CD44 inhibits DCIS progression to invasive carcinoma [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 2709.
Sequential Chemoradiotherapy vs Concurrent Chemoradiotherapy or Radiotherapy Alone in Adjuvant Treatment for Patients With Cervical Cancer—Reply
Authors: He Huang, Yan-Ling Feng, Ji-Hong Liu
Journal: JAMA Oncology (2021)

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Abstract 2684: Single cell transcriptomics reveals the effect of PD-L1 and TGF-B blockade on the tumor microenvironment
Authors: Erica L. Stone, Yoong Wearn Lim, Garry L. Coles, Savreet K. Sandhu, David S. Johnson, Adam S. Adler
Journal: Cancer Research (2021)

Abstract Background: The anti-tumor activity of anti-PD-1/PD-L1 therapies correlates with T cell infiltration in tumors. Thus, a major goal in oncology is to find strategies that enhance T cell infiltration and efficacy of anti-PD-1/PD-L1 therapy. TGF-β has been shown to contribute to T cell exclusion and anti-TGF-β improves anti-PD-L1 efficacy in vivo. However, TGF-β inhibition has frequently been shown to induce toxicity in the clinic, and the clinical efficacy of combination PD-L1 and TGF-β blockade has not yet been proven. To identify strategies to overcome resistance to PD-L1 blockade, the transcriptional programs associated with PD-L1 and/or TGF-β blockade in the tumor microenvironment should be further elucidated. Results: We used single-cell RNA sequencing to characterize the transcriptomic effects of PD-L1 and/or TGF-β blockade on cells in the tumor and surrounding microenvironment. Combination treatment led to upregulation of immune response genes, including multiple chemokine genes such as CCL5, in CD45+ cells, and down-regulation of extracellular matrix genes in CD45- cells. Analysis of publicly available tumor transcriptome profiles showed that the chemokine CCL5 was strongly associated with immune cell infiltration in various human cancers. Further investigation with in vivo models showed that intratumorally administered CCL5 enhanced cytotoxic lymphocytes and the anti-tumor activity of anti-PD-L1. Conclusions: Taken together, our data could be leveraged translationally to improve anti-PD-L1 plus anti-TGF-β combination therapy, for example through companion biomarkers, and/or to identify novel targets that could be modulated to overcome resistance. Citation Format: Erica L. Stone, Yoong Wearn Lim, Garry L. Coles, Savreet K. Sandhu, David S. Johnson, Adam S. Adler. Single cell transcriptomics reveals the effect of PD-L1 and TGF-B blockade on the tumor microenvironment [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 2684.
Integrating solutions to adapt cities for climate change
Authors: Brenda B Lin, Alessandro Ossola, Marina Alberti, Erik Andersson, Xuemei Bai, Cynnamon Dobbs, Thomas Elmqvist, Karl L Evans, Niki Frantzeskaki, Richard A Fuller, Kevin J Gaston, Dagmar Haase, Chi Yung Jim, Cecil Konijnendijk, Harini Nagendra, Jari Niemelä, Timon McPhearson, William R Moomaw, Susan Parnell, Diane Pataki, William J Ripple, Puay Yok Tan
Journal: The Lancet Planetary Health (2021)

Record climate extremes are reducing urban liveability, compounding inequality, and threatening infrastructure. Adaptation measures that integrate technological, nature-based, and social solutions can provide multiple co-benefits to address complex socioecological issues in cities while increasing resilience to potential impacts. However, there remain many challenges to developing and implementing integrated solutions. In this Viewpoint, we consider the value of integrating across the three solution sets, the challenges and potential enablers for integrating solution sets, and present examples of challenges and adopted solutions in three cities with different urban contexts and climates (Freiburg, Germany; Durban, South Africa; and Singapore). We conclude with a discussion of research directions and provide a road map to identify the actions that enable successful implementation of integrated climate solutions. We highlight the need for more systematic research that targets enabling environments for integration; achieving integrated solutions in different contexts to avoid maladaptation; simultaneously improving liveability, sustainability, and equality; and replicating via transfer and scale-up of local solutions. Cities in systematically disadvantaged countries (sometimes referred to as the Global South) are central to future urban development and must be prioritised. Helping decision makers and communities understand the potential opportunities associated with integrated solutions for climate change will encourage urgent and deliberate strides towards adapting cities to the dynamic climate reality.
Exosomes: Advances, development and potential therapeutic strategies in diabetic nephropathy
Authors: Jingfang Chen, Qing Zhang, Dongwei Liu, Zhangsuo Liu
Journal: Metabolism (2021)

Exosomes, a major type of extracellular vesicles (EVs), are nanoscale vesicles excreted by almost all cell types via invagination of the endosomal membrane pathway. Exosomes play a crucial role in the mediation of intercellular communication both in health and disease, which can be ascribed to their capacity to be transported to neighboring or distant cells, thus regulating the biological function of recipient cells through cargos such as DNA, mRNA, proteins and microRNA. Diabetic nephropathy (DN) is a serious microvascular complication associated with diabetes mellitus as well as a significant cause of end-stage renal disease worldwide, which has resulted in a substantial economic burden on individuals and society. However, despite extensive efforts, therapeutic approaches that prevent the progression of DN do not exist, which implies new approaches are required. An increasing number of studies suggest that exosomes are involved in the pathophysiological processes associated with DN, which may potentially provide novel biomarkers and therapeutic targets for DN. Hence, this review summarizes recent advances involving exosome mechanisms in DN and their potential as biomarkers and therapeutic targets.
Abstract 2312: Identification of tumor associated genes using transcriptome analysis
Authors: Guoqiang Liang, Jinqiu Sun, Yiwei Liu, Dongxue Liu, Shengxian Liang, Rui Guo, Li Zhong
Journal: Cancer Research (2021)

Abstract Background: Lung cancer is the leading cause of cancer death worldwide. Identification of tumor associated genes is an effective approach for early cancer detection, prognosis prediction and target therapy development. With the rapid growth in high-throughput sequencing techniques, big data regarding gene expression of lung cancer has been generated and deposited in public data banks. In this study, we used bioinformatic and statistic techniques to analyze big data from public data banks in identifying novel genes in association with prognosis of non-small cell lung cancer. Methods: Transcriptome data and clinical information of 1020 non-small cell lung cancer (NSCLC) cases were downloaded from The Cancer Genome Atlas (TCGA). After removing the incomplete data, we obtained 1008 NSCLC cases. All the gene expression data was normalized using differential analysis software DESeq2 in R language. The normalized data was further analyzed using weighted gene co-expression network to screen out the differentially expressed tumor associated genes. After applying Protein-Protein Interaction Networks (PPI) analysis in combination with clinical information, we have identified some hub genes. Using univariate/multivariate Cox regression analysis we identified several genes associated with NSCLC prognosis. Results: After DESeq2 analysis, we obtained 2873 differentially expressed genes when the threshold padj &amp;lt; 0.01 and Fold change &amp;gt; 4. Among them, 1955 were upregulated and downregulated genes. When the weighted gene co-expression network analysis was applied, we achieved 50 blocks after data clustering (7 cases were outliers and removed). After linked with the clinical information, we identified that the yellow block contained the most NSCLC related genes. This block contains a total of 2803 genes, and 417 of them were differentially expressed tumor genes. Further analysis using univariate/multivariate Cox regression, we identified SPP1, PKMYT1, PRB11, LINC0116 and PTPRM 5 genes that were associated with poor prognosis of NSCLC. After combined analysis, we found that the 5-year survival rate is 31.3% for early stages of NSCLC and 4.1% with late stages of NSCLC. Conclusion: transcriptome analysis is a good approach in identifying disease associated genes, which can lead to a quick and reliable approach in developing clinical applications. Citation Format: Guoqiang Liang, Jinqiu Sun, Yiwei Liu, Dongxue Liu, Shengxian Liang, Rui Guo, Li Zhong. Identification of tumor associated genes using transcriptome analysis [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 2312.
A novel prognostic model for patients undergoing salvage radiotherapy for biochemical recurrence after radical prostatectomy
Authors: T. Van Den Broeck, M. Daimantas, N. Fossati, A. Briganti, J.R. Karnes, A. Bossi, C. Berghen, G. De Meerleer, P. Ost, H. Van Poppel, I. Van Oort, S. Joniau
Journal: European Urology (2021)
Minimally invasive percutaneous nephrolithotomy with SuperPulsed Thulium-fiber laser
Authors: A. Shpikina, M. Taratkin, D. Korolev, G. Akopyan, D. Tsarichenko, S. Ali, D. Chinenov, M. Corrales, O. Traxer, D. Enikeev
Journal: European Urology (2021)
FDA Seeks Improvements in Labeling Medical Device Materials
Authors: Bridget M. Kuehn
Journal: JAMA (2021)

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Abstract 3095: Targeting ALDH1A1 and regulatory networks that support stemness in ovarian cancer cells
Authors: Vaishnavi Muralikrishnan, Kenneth P. Nephew, Thomas D. Hurley
Journal: Cancer Research (2021)

Abstract Epithelial ovarian cancer (OC) is the deadliest amongst gynecologic cancers with the majority of deaths caused by cancer recurrence. A new paradigm explaining tumor relapse involves the persistence of cancer stem cells after chemotherapy. OC stem cells (OCSCs) are hypothesized to be largely responsible for the emergence of chemoresistant tumors, and we have previously shown that OCSCs contribute to recurrent, drug resistant high-grade serous OC (HGSOC) using ALDH (aldehyde dehydrogenase) activity as a robust functional marker to identify OCSCs. Of the ALDH isoforms, ALDH1A1 is an intracellular enzyme that oxidizes toxic aldehydes to carboxylic acids and plays a role in controlling cell differentiation pathways. High levels of ALDH1A1 expression have been associated with poor outcome in OC patients. Our group and others have demonstrated that OCSCs with high expression of ALDH1A1 have a greater ability to initiate ovarian tumors in vivo. However, the mechanism by which ALDH1A1 maintains stemness phenotype remains poorly understood. In the current study, we hypothesized that ALDH1A1 upregulation in OCSCs was associated with genetic changes that mediate the cellular signals needed for survival. To test this hypothesis, we used a novel ALDH1A1-specific small molecule inhibitor named compound 974. Treatment of HGSOC cell lines with compound 974 reduced ALDH enzyme activity (p&amp;lt;0.01) and inhibited stem-like properties including spheroid formation (p&amp;lt;0.01) and clonogenic survival (p&amp;lt;0.05). To further examine the effect of compound 974 to inhibit ALDH1A1 and consequently tumor initiation, mice were injected with 106, 105 and 104 OVCAR3 cells treated in vitro with compound 974 (5µM for 48h). Tumor initiation was delayed by 974 treatment compared to vehicle-treated group. Extreme limiting dilution analysis revealed that compound 974 reduced CSC frequency compared to control. Transcriptomic sequencing of ovarian cancer cells treated with compound 974 revealed significant inhibition of genes and pathways associated with stemness (NF-κB, KLF4, FZD7), chemoresistance (ABCB1) and senescence pathway genes (p15, p21). Furthermore, key genes associated with senescence associated secretory phenotype (SASP) such as IL6, IL8 and IL1α were significantly inhibited. Taken together, these data warrant further investigation into the mechanism of ALDH1A1 inhibition and loss of stemness in HGSOC. Citation Format: Vaishnavi Muralikrishnan, Kenneth P. Nephew, Thomas D. Hurley. Targeting ALDH1A1 and regulatory networks that support stemness in ovarian cancer cells [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 3095.
Effect of Particle Size and Surface Chemistry of Photon‐Upconversion Nanoparticles on Analog and Digital Immunoassays for Cardiac Troponin
Authors: Julian C. Brandmeier, Kirsti Raiko, Zdeněk Farka, Riikka Peltomaa, Matthias J. Mickert, Antonín Hlaváček, Petr Skládal, Tero Soukka, Hans H. Gorris
Journal: Advanced Healthcare Materials (2021)

Abstract Sensitive immunoassays are required for troponin, a low‐abundance cardiac biomarker in blood. In contrast to conventional (analog) assays that measure the integrated signal of thousands of molecules, digital assays are based on counting individual biomarker molecules. Photon‐upconversion nanoparticles (UCNP) are an excellent nanomaterial for labeling and detecting single biomarker molecules because their unique anti‐Stokes emission avoids optical interference, and single nanoparticles can be reliably distinguished from the background signal. Here, the effect of the surface architecture and size of UCNP labels on the performance of upconversion‐linked immunosorbent assays (ULISA) is critically assessed. The size, brightness, and surface architecture of UCNP labels are more important for measuring low troponin concentrations in human plasma than changing from an analog to a digital detection mode. Both detection modes result approximately in the same assay sensitivity, reaching a limit of detection (LOD) of 10 pg mL −1 in plasma, which is in the range of troponin concentrations found in the blood of healthy individuals.
Abstract 328: Selective fluorogenic probe for rapid detection of cathepsin L activity
Authors: Kelton A. Schleyer, Ben Fetrow, Peter Fatland, Jun Liu, Maya Chaaban, Biwu Ma, Lina Cui
Journal: Cancer Research (2021)

Abstract Cathepsin L (CTL) is a cysteine protease that demonstrates upregulated activity and altered trafficking in various cancers. Its upregulation in many cancers correlates positively with tumor grade while its excessive secretion makes elevated serum levels a possible biomarker for aggressive cancer types. The overlapping substrate specificity of cathepsin family members makes selective detection of activity from a single cathepsin difficult, and CTL activity is particularly difficult to parse from its close homologue CTV and the ubiquitous CTB. This complicates clinical sample assays for CTL activity, which generally rely on simple fluorescent probes lacking specificity for CTL over other cathepsins. We have developed a fluorogenic probe, CTLAP, that is rapidly activated by CTL and displays good selectivity over CTB and CTV, the closest competing analytes for CTL. The novel chemical structure of CTLAP facilitates markedly higher signal generation and improved selectivity for CTL when compared to Z-FR-AMC, the commercial probe commonly used to detect CTL activity in mixed samples. Optimum selectivity for CTL is achieved within 10 min of incubation, suggesting that CTLAP is amenable for rapid detection of CTL, even in the presence of competing cathepsins. Citation Format: Kelton A. Schleyer, Ben Fetrow, Peter Fatland, Jun Liu, Maya Chaaban, Biwu Ma, Lina Cui. Selective fluorogenic probe for rapid detection of cathepsin L activity [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 328.
Abstract 11254: Double Product Privilege in Predicting All-cause and Cardiovascular Disease Mortality Compare to Heart Rate and Blood Pressure Separately, the Nippon-data 80 Study
Authors: Yiwei Liu, Daisuke Sugiyama, Aya Hirata, Katsuyuki Miura, Hirotsugu Ueshima, Aya Kadota, Takayoshi Ohkubo, Akita Okayama, Keiko Kondo, Tomonori Okamura
Journal: Circulation (2019)

Background: To clarify whether the double product (DP) (systolic blood pressure (SBP) * resting heart rate (HR)/100) measurement has prognostic value for mortality. Method: We followed up 8,307 par...
Abstract 1388: ATM inhibitor AZD1390 sensitizes breast cancer brain metastasis to radiation therapy
Authors: Ben Yi Tew, Stephen Durant, Bodour Salhia
Journal: Cancer Research (2021)

Abstract Metastasis to the central nervous system (CNS) has remained a major source of morbidity and mortality for patients with breast cancer. This is mainly driven by the lack of therapeutic options, as traditional chemotherapy and targeted therapies have been shown to have limited efficacy in the brain. Ataxia-telangiectasia mutated (ATM) protein orchestrates the cellular DNA damage response (DDR) to cytotoxic DNA double-strand breaks induced by ionizing radiation (IR). ATM genetic ablation or pharmacological inhibition results in tumor cell hypersensitivity to IR.AZD1390 is a potent orally bioavailable ATM inhibitor, specifically optimized for blood brain barrier penetration and has shown to be an effective radiosensitizer in gliomas. We have shown that there are frequent alterations in DNA damage response (DDR) pathways in CNS metastasis (CM), which include frequent mutations in TP53. Incorrect repair of DNA lesions often leads to genomic instability. ATM, a core component of the DNA repair system, is activated to enhance the homologous recombination (HR) repair pathway upon DNA double-strand breaks. Here we show that AZD1390, when used in combination with radiation therapy, can inhibit the growth of breast cancer CM in patient derived xenograft (PDX) tumors. Three PDX models (2 Her2+ and one triple negative), all of which harbor TP53 mutations and other DDR alterations, were implanted into the flank or brain of immunocompromised mice. Pre-treatment with AZD1390 followed by a fractionated regime of radiation therapy (2Gy/day for 5 days) significantly inhibited growth of flank PDX tumors by an average of 81% (85% and 80% in the HER2+ and 77% in the triple negative PDX, p-value &amp;lt; 0.05). This is compared to an average of 7% (8%, 13% and 0% respectively) for tumors treated with AZD1390 alone or 40% (39%, 21% and 58% respectively) for radiation therapy alone in all PDX models. Growth inhibition was sustained until the experiment endpoint at 90 days in 75% of the tumors, and 25% of the tumors regressed below their size at the beginning of treatment. About 31% of tumors across three models started to grow back and gene expression analysis comparing these tumors with complete responders demonstrated changes in oxidative phosphorylation, sirtuin signaling, and ERK/MAPK signaling. Adjuvant therapy of AZD1390 did not further decrease tumor growth. Our results demonstrate that AZD1390 can sensitize breast cancer CM with DDR pathway alterations to radiation therapy. This points to the potential of AZD1390 as a potential novel therapeutic agent for patients with breast cancer CM. Citation Format: Ben Yi Tew, Stephen Durant, Bodour Salhia. ATM inhibitor AZD1390 sensitizes breast cancer brain metastasis to radiation therapy [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 1388.