tbuckley/cabot-search huggingface dataset:
Abstract 3082: Synergistic inhibition of TNBC cell growth by novel doxorubicin/salinomycin-encapsulated dual drug-nanoparticles
Authors: Anees Mohammad, Sachchidanand Tiwari, Neha Mehrotra, Bozena Korczak, Sireesh Appajosyula, Steve Laumas, Surender M. Kharbanda, Harpal Singh
Journal: Cancer Research (2021)

Abstract Triple negative breast cancer (TNBC) is an aggressive subtype with limited treatment options and a worse clinical outcome as compared with other breast cancer subtypes. Doxorubicin (DOX) is considered to be one of the most effective agents in the treatment. Unfortunately, resistance to DOX is very common due to drug efflux mediated by overexpression of ABC transporter. Recent studies suggest that cancer stem cells (CSCs) play an important role in tumorigenesis and biology of TNBC. Targeting CSCs may be a promising, novel strategy for the treatment of this aggressive disease. Recent studies have shown that salinomycin (SAL) preferentially targets the viability of CSCs. In the present study, SAL and DOX were co-encapsulated in polylactic acid (PLA)-based block copolymeric nanoparticles (NPs) (novel Quatramer Technology) to efficiently co-deliver these agents to treat TNBC cells. Generated SAL-DOX co-encapsulated dual drug NPs showed an average diameter of 91 ± 2 nm, zeta potential of -9.4 ± 1.1mV and PDI of less than 0.1. Both of these anti-cancer agents showed slow and sustained release profile in non-physiological buffer (PBS, pH 7.4) from these dual drug-encapsulated NPs. Additionally, multiple ratios (DOX:SAL = 3:1, 1:1, 1:3) were encapsulated to generate diverse dual drug NPs. The results demonstrate that, in contrast to 1:1 and 1:3, treatment of TNBC cells with 3:1 ratio of DOX:SAL dual drug NPs, was associated with significant inhibition of growth in vitro and more interestingly, was synergistic as compared to either agent alone. The IC50 of DOX and SAL in single drug-encapsulated NPs is 0.56 uM and 3.56 uM respectively. Importantly, the IC50 of DOX and SAL in dual drug-encapsulated NPs is 0.13 uM and 0.034 uM respectively. Furthermore, bi-weekly treatment of BALB/c wild-type mice harboring EAT cells (as syngeneic mouse model) with DOX-SAL (3:1) dual drug NPs at a dose of 3 mg/kg i.v. resulted in significant tumor growth inhibition (TGI). The TGI effect was synergistic with dual-NPs as compared to either agent alone. The TGI by dual drug NPs was without any significant effect on the body weights of the mice. These results demonstrate that a novel dual drug NP formulation of DOX and SAL in a unique ratio (3:1) represents an approach for successful targeting of CSCs and bulk tumor cells in TNBC and potentially other cancer types. Citation Format: Anees Mohammad, Sachchidanand Tiwari, Neha Mehrotra, Bozena Korczak, Sireesh Appajosyula, Steve Laumas, Surender M. Kharbanda, Harpal Singh. Synergistic inhibition of TNBC cell growth by novel doxorubicin/salinomycin-encapsulated dual drug-nanoparticles [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 3082.
Abstract 374: NGS based profiling of homologous recombination genes to predict response to platinum-based chemotherapy in NSCLC
Authors: Linlin Zhang, Xin Wang, Hui Song, Fanlu Meng, Guowei Yu, Diansheng Zhong
Journal: Cancer Research (2021)

Abstract Background: In the era of precision medicine, better response of anti-tumor therapies attribute to detection of specific molecular markers. However, up to the present no validated biomarker for platinum-based chemotherapy could be used in clinic. Next-generation sequencing (NGS) technology has been applied for non-small cell lung cancer (NSCLC) molecular typing for years. Whether analysis of homologous recombination (HR) gene mutations based on NGS results could predict the efficiency of platinum-based therapy in NSCLC is still obscure. Methods: NGS has been performed for screening homologous recombination (HR) gene mutations, as well as common driver genes in NSCLC, with tumor samples. Advanced or metastatic NSCLC patients receiving platinum-based chemotherapy were included for efficacy analysis. Results: 129 patients with HR genes information were included for analysis. Among the 129 patients, 55 patients were received platinum-based chemotherapy. The efficiency results showed the objective response rates (ORR) of patients with BRCA1/2 and without BRCA1/2 mutations were 71.4% and 31.3%; and the median progression free survival (PFS) were 7.5 and 5.6 months(p=0.161), respectively. The ORR of patients with and without HR genes mutations were 57.9% and 25.0%; and the median PFS were 8.0 and 5.3 months (p=0.039), respectively. Conclusions: NGS based profiling of BRCA1/2 and other gene mutations in HR pathways have a promising predictive value for efficacy of platinum-based chemotherapy in advance and metastatic NSCLC. Citation Format: Linlin Zhang, Xin Wang, Hui Song, Fanlu Meng, Guowei Yu, Diansheng Zhong. NGS based profiling of homologous recombination genes to predict response to platinum-based chemotherapy in NSCLC [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 374.
Abstract 2019: Drug repositioning to induce the synthetic lethality in cancer cells with GSH-depleting therapy
Authors: Yuji Otsuki, Osamu Nagano, Hideyuki Saya
Journal: Cancer Research (2021)

Abstract The major cellular antioxidant glutathione (GSH) protects cancer cells from oxidative damage that can lead to the induction of ferroptosis. Inhibitor of the GSH synthesis including buthionine sulfoximine (BSO) and cystine-glutamate antiporter subunit xCT, which mediates the uptake of extracellular cystine and thereby promotes GSH synthesis, thus potential anticancer agents. However, the efficacy of xCT or GSH synthesis-targeted therapy has been found to be diminished by metabolic reprogramming that affects redox status in cancer cells. In this study, we performed a synthetic lethal screen of a drug library to identify agents that sensitize the GSH deficiency-resistant cancer cells to the xCT inhibitor sulfasalazine (SSZ). This screen identified the oral anesthetic dyclonine (DYC) which act as a covalent inhibitor for aldehyde dehydrogenases (ALDHs). Treatment with DYC induced intracellular accumulation of the toxic aldehyde 4-hydroxynonenal (4-HNE) in a cooperative manner with SSZ. The combination of DYC and SSZ cooperatively suppressed the growth of SSZ-resistant tumors. Furthermore, we recently found that a vasodilator oxyfedrine (OXY) also possess the similar structure with dyclonine and induce cell death in BSO-resistant cancer cells both in vitro and in vivo. Microarray analysis of tumor xenograft tissue showed cyclooxygenase-2 expression as a potential biomarker for the efficacy of such combination therapy. Moreover, OXY-mediated ALDH inhibition was found to sensitize cancer cells to GSH depletion induced by radiation therapy in vitro. Our findings thus establish a rationale for repurposing of OXY as a sensitizing drug for cancer treatment with agents that induce GSH depletion. Citation Format: Yuji Otsuki, Osamu Nagano, Hideyuki Saya. Drug repositioning to induce the synthetic lethality in cancer cells with GSH-depleting 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 2019.
Correspondence on ‘Efficacy of a tight-control and treat-to-target strategy in axial spondyloarthritis: results of the open-label, pragmatic, cluster-randomised TICOSPA trial’
Authors: Weijie Wang, Yung-Heng Lee, James Cheng Chung Wei
Journal: Annals of the Rheumatic Diseases (2021)

Correspondence on 'Efficacy of a tight-control and treat-to-target strategy in axial spondyloarthritis: results of the open-label, pragmatic, cluster-randomised TICOSPA trial'We have read with great interest the work of Anna Molto et al studying on comparing the benefits of TICOSPA (a tight control/ treat-to-target strategy (TC/T2T) in axial spondyloarthritis (axSpA)) trial with those of usual care (UC). 1 They concluded that TC/T2T approach was not significantly superior to UC for the primary outcome, while it might be beneficial in axSpA and had a favourable outcome from a societal health economic perspective.However, we believe that some concerns should be discussed in this important study.First of all, although the primary endpoint Assessmnet of SpondyloArthritis international Society Healthy Index (ASAS-HI) was not met due to relatively small sample size and treatment duration, the EQ5D of TC/T2T arm was significantly superior to UC (p=0.02).We understand that ASAS-HI was a newly validated instrument to measure quality of life in ankylosing spondylitis.However, the selection of this tool as primary endpoint in patients with axSpA might not be suitable.3][4] The difference and sensitivity to detect changes between ASAS-HI and 5-level version of the EuroQol five dimensions (EQ-5D-5L) in axSpA should be also considered in this study.Second, it is a pity that radiographic evaluation was not available in this study.We suggested that future T2T study in SpA should include Modified Stoke AS Spine Score (mSASSS) which is the most important treatment goal of axSpA by experts' consensus. 5 6 We also suggest that the study duration should be extended to at least 2 years to observe the benefit on mSASSS. 5inally, the mean age of study population is 37.9, but mean disease duration is only 3.7.This is not reasonable because that average age of onset in axSpA should be 20-30. 7We wonder that there might be measurement inaccuracy in the disease duration.The relative old age of study subjects might also lead to negative result.In conclusion, although the primary endpoint was not met, we still see some benefits in the T2T strategy in axSpA in this study.We believe that more T2T studies in SpA should be done before drawing the conclusion.
Trends in cancer mortality in China from 2004 to 2018: A nationwide longitudinal study
Authors: Dongming Jiang, Lijuan Zhang, Wenbin Liu, Yibo Ding, Jianhua Yin, Rongbing Ren, Qi Li, Yifan Chen, Jiaying Shen, Xiaojie Tan, Hongwei Zhang, Guangwen Cao
Journal: Cancer Communications (2021)

The long-term trend in cancer death in a rapidly developing country provides information for cancer prophylaxis. Here, we aimed to identify the trends in cancer mortality in China during the 2004-2018 period.Using raw data from the national mortality surveillance system of China, we assessed the mortalities of all cancer and site-specific cancers during the 2004-2018 period. The participants were divided into three age groups: ≥65 years, 40-64 years, and ≤39 years. Changing trends in cancer death by gender, residency, and tumor location were estimated using fitting joinpoint models to log-transformed crude mortality rates (CMRs) and age-standardized mortality rates (ASMRs).Cancer death accounted for 24% of all-cause of death in China during 2014-2018. The CMR of all cancer was 150.0 per 100,000 persons. Cancer was the leading cause of death in the population <65 years. The six major cancer types (lung/bronchus cancer, liver cancer, stomach cancer, esophagus cancer, colorectal cancer, and pancreas cancer) accounted for 75.85% of all cancer deaths. The CMR of all cancer increased while the ASMR decreased during 2014-2018 (P < 0.001). Lung/bronchus cancer and liver cancer were the leading causes of cancer death in the population <65 years, accounting for 45.31% (CMR) and 44.35% (ASMR) of all cancer death, respectively. The ASMR of liver cancer was higher in the 40-64 years population than in the ≥65 years population, in contrast to the other five major cancers. The ASMRs of liver cancer, stomach cancer, and esophagus cancer decreased although they were higher in rural residents than in urban residents; the ASMRs of lung/bronchus cancer, colorectal cancer, and pancreas cancer increased in rural residents although they were higher in urban residents than in rural residents during 2014-2018.Although the ASMR of all cancer decreased in China during 2004-2018, lung/bronchus cancer and liver cancer remained the leading causes of cancer-related premature death. Lung/bronchus cancer, colorectal cancer, and pancreas cancer increased in rural residents.
Abstract 2720: Perivascular accumulation of immunosuppressive cells in the stroma of human triple negative breast carcinomas: implications for immunotherapy
Authors: Mohammed Ridha Moamin, Richard J. Allen, Nicholas Stavrou, Mate Nagy, Anna Juncker-Jensen, Claire E. Lewis
Journal: Cancer Research (2021)

Abstract A distinct subset of tumor-associated macrophages (TAMs) accumulate around blood vessels in mouse tumors where they stimulate tumor angiogenesis and various steps in the metastatic pathway. They also limit tumor responses to frontline anti-cancer therapies like irradiation and chemotherapy, and dampen anti-tumor immunity by recruiting regulatory T cells and suppressing the proliferation of T cells. However, the presence and phenotype of such perivascular (PV) TAMs have yet to be investigated in human tumors. In this study we have used MultiOmyx multiplex immunofluorescence coupled to advanced analytics to compare the distribution and phenotype of TAMs, CD4+ and CD8+ T cells, and CD4+FOXP3+ regulatory T cells (Tregs) in PV vs non-PV areas in the stroma and tumor cell islands (TCIs) of 40 human triple negative breast carcinomas (TNBCs) - and whether this was altered after neoadjuvant chemotherapy. Tregs along with distinct subsets of TAMs and CD4+ and CD8+ T cells were found to preferentially accumulate in PV areas (ie. within 50um of CD31+ blood vessels), especially in the tumor stroma. CD163+ TIM3+ TAMs often made direct contact with the abluminal surface of blood vessels in these sites, and at increased numbers in in chemotherapy-treated TNBCs. This suggests they may regulate the formation/function of blood vessels in relapsing tumors. In both untreated and chemotherapy-treated tumors, a major subset of CD163+ TAMs lacked PDL1 expression and also accumulated preferentially in stromal PV areas, where many made direct contact with PD1- CD4+ or PD1- CD8+ T cells as well as FOXP3+CD4+ Tregs. We are currently investigating whether such close contact of these subsets of T cells with two immunosuppressive cell types (ie. CD163+ TAMs and Tregs) inhibits their subsequent anti-tumor functions. Taken together, our study shows that, as T cells cross blood vessels into TNBCs, they encounter a high density of at least two immunosuppressive cell types in the perivascular niche. This could lead to the inactivation of T cells before they migrate further into tumors, thereby reducing anti-tumor immunity. It could also limit the efficacy of cancer immunotherapies mediated by activated T cells. Identifying and targeting the mechanism causing these suppressive cells to accumulate and interact in such sites could remove this inhibition. Citation Format: Mohammed Ridha Moamin, Richard J. Allen, Nicholas Stavrou, Mate Nagy, Anna Juncker-Jensen, Claire E. Lewis. Perivascular accumulation of immunosuppressive cells in the stroma of human triple negative breast carcinomas: implications for immunotherapy [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 2720.
Abstract 2119: Genome-wide epigenetic alterations in T-cell prolymphocytic leukemia
Authors: Shulan Tian, Henan Zhang, Eric Klee, Huihuang Yan, Wei Ding
Journal: Cancer Research (2021)

Abstract T-cell prolymphocytic leukemia (T-PLL) is a rare disease showing a rapid clinical course, with a median survival of &amp;lt;1 year. Whole-genome and whole-exome sequencing have identified key genetic lesions in T-PLL, including structural alterations such as inversions, translocations, and large copy number variants, as well as recurrent somatic mutations of genes encoding chromatin regulators and of those in the JAK-STAT signaling pathway. Epigenetic alteration is implicated in the susceptibility and progression of both cancer and non-cancerous diseases. However, genome-wide epigenetic data has not been generated for T-PLL, which prohibits the mechanistic studies of transcriptional misregulation in T-PLL. This study used micrococcal nuclease digestion and sequencing (MNase-seq) to profile the chromatin accessible regions, i.e., gene regulatory regions such as promoters, enhancers and insulators, in both T-PLL patients and healthy individuals. Our analysis revealed the prevalence of lost open chromatin regions in T-PLL. We also generated histone H3 lysine 4 monomethylation (H3K4me1) and lysine 27 acetylation (H3K27ac) chromatin immunoprecipitation and sequencing (ChIP-seq) data from the same samples. We identified 5,462 and 2,833 active enhancers (&amp;gt;=2.5 kb away from transcription start sites) that are lost and gained in T-PLL, respectively, compared to normal. The differential H3K27ac peaks are preferentially associated with the nearest genes differentially expressed between T-PLL and normal (chi-square test p &amp;lt;2.2e-16), indicating a role of epigenetic alteration in transcriptional misregulation. In addition, we identified alterations of active enhancers that target oncogenes with key roles in T-PLL, such as TCL1Aand MYC. Together, our analysis has provided insights into the epigenetic mechanisms that drive oncogenic activation in T-PLL. Citation Format: Shulan Tian, Henan Zhang, Eric Klee, Huihuang Yan, Wei Ding. Genome-wide epigenetic alterations in T-cell prolymphocytic leukemia [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 2119.
Abstract 2215: Landscape of <i>RET</i> fusion identified by next-generation sequencing in a Chinese multi-cancer retrospective analysis
Authors: Ting Lei, Weiran Wang, Danhua Wang, Junfeng Fu, Yu Wang, Ze Wang, Zhe Fan, Zhenyang Lv, Tonghui Ma
Journal: Cancer Research (2021)

Abstract Background: Fusion of RET with several partner genes has been detected in papillary thyroid, lung, colorectal, pancreatic and breast cancers. FDA has approved Retevmo (Selpercatinib) for lung and thyroid cancers with RET gene mutations or fusions. Here we focused on the prevalence of RET fusions in a Multi-cancer cohort (besides lung and thyroid cancers) for patients (pts) whom might benefit from RET inhibitors in clinical development. Methods: Genomic profiling was performed on 12,888 lung cancer pts, 2,848 colorectal cancer pts, 1,785 liver cancer pts, 1,169 Gastric cancer pts and 232 thyroid cancer pts from Jan. 2017 to Dec. 2019 using next-generation sequencing (NGS), which covers all exons of RET and specific intron 7-11 containing the break points of fusions. The fusion patterns of RET were analyzed. Results: A total of 165 RET fusions were identified in approximately 0.86% (163/18,922) of this Chinese multi-cancer cohort. The RET fusion-positive rates were 1.05% (135/12,888) in lung cancer pts, 0.39% (11/2,848) in the colorectal cancer pts, 0.06% (1/1,785) in liver cancer pts, 0.09% (1/1,169) in the 1169 Gastric cancer pts and 6.03% (15/232) in the 232 thyroid cancer pts tested. The most common partners were KIF5B (62.04%) and CCDC6 (21.17%) in lung cancer, NCOA4 (45.45%) and CCDC6 (27.27%) in colorectal cancer, and CCDC6 (93.33%) and NCOA4 (6.67%) in thyroid cancer. The most frequent regions of RET fusions were intron 11 (140/165) and intron 10 (15/165). The common fusion partners detected in different cancers are variable, indicating that the same oncogene has different carcinogenic mechanisms in cancers, and the sensitivity of these fusions to RET inhibitors in different cancers needs to be further studied. Conclusions: This study revealed the molecular features of RET rearrangement in Chinese cancer pts, which might result in more effective personalized diagnoses and therapies. Citation Format: Ting Lei, Weiran Wang, Danhua Wang, Junfeng Fu, Yu Wang, Ze Wang, Zhe Fan, Zhenyang Lv, Tonghui Ma. Landscape of RET fusion identified by next-generation sequencing in a Chinese multi-cancer retrospective 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 2215.
Abstract 2484: Detection of loss of heterozygosity in GBM revealed the role of a tumor suppressive gene in regulating glioma progression and tumor recurrence
Authors: Mei-Yee Kiang, Stella Sun, Gilberto Ka-Kit Leung
Journal: Cancer Research (2021)

Abstract Adducin 3 (ADD3) is a major cytoskeleton protein in glioma cells. Our previous studies demonstrated a significant downregulation of ADD3 in GBM when compared with lower-grade gliomas, and that ADD3 knockdown promoted malignant phenotypes. GBMs are usually characterized by high levels of genomic instability, including frequent loss of heterozygosity (LOH) of chromosome 10q, whilst ADD3 is also located in chromosome 10q25.1-25.2 where it is known to be a tumor-suppressor region. However, it is not known whether ADD3 downregulation in malignant gliomas is associated with allelic loss in 10q. To determine 10q LOH on different polymorphic DNA loci (covering ADD3 locus) on glioma tissues, specimens of Normal, Grade II, Grade III, Grade IV GBM and recurrent GBM tissue were included. DNA fragments were evaluated by using a PCR-based microsatellite capillary electrophoresis and analyzed by a fragment analyzer. LOH status were correlated with patient survival for potential prognostic and diagnostic implications. LOH on ADD3 locus was detected in high grade and recurrent GBMs. It is revealed that downregulation of ADD3 level in GBM is associated with genetic instability of LOH in 10q and associated with recurrence disease. This study would provide significant implications, particularly for understanding pathogenesis of GBM and add valuable credits on the diagnostic as well as prognostic implications. Citation Format: Mei-Yee Kiang, Stella Sun, Gilberto Ka-Kit Leung. Detection of loss of heterozygosity in GBM revealed the role of a tumor suppressive gene in regulating glioma progression and tumor recurrence [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 2484.
In adults and children in the ED with COVID-19 symptoms or a confirmed contact, a rapid POC antigen test had ≥72% sensitivity and ≥99% specificity vs. RT-PCR
Authors: Thomas Fekete
Journal: Annals of Internal Medicine (2021)

Source CitationMöckel M, Corman VM, Stegemann MS, et al. SARS-CoV-2 antigen rapid immunoassay for diagnosis of COVID-19 in the emergency department. Biomarkers. 2021;26:213-20. https://pubmed.ncbi.nlm.nih.gov/33455451/AbstractClinical Impact RatingsEmergency Med: Hospitalists: Infectious Disease: