tbuckley/cabot-search huggingface dataset:
Abstract LB-149: Serum thymidine kinase 1 levels predict prostate cancer-specific survival
Authors: Teemu J. Murtola, Paavo Raittinen, Teuvo Tammela
Journal: Cancer Research (2020)

Abstract Background: Thymidine kinase 1 (TK1) is an enzyme involved in DNA synthesis. Thymidine kinases phosphorylate thymidine as part of the DNA synthetic pathway. TK1 expression is a marker of active cellular proliferation; intracellular concentrations are low during the G0/G1 phases of the cell cycle, increasing during the S/G2 phases. Previous studies have suggested that serum TK1 levels could be used as marker for presence of prostate cancer (PCa). Here, we evaluated whether serum TK1 levels could predict risk of PCa prognosis. Materials and Methods: The study population included 40 men with clinically defined T1/T2NxM0 PCa and 43 men with de novo metastatic cancer (M1) at diagnosis confirmed by bone scan imaging. All men were diagnosed and treated at the Tampere University Hospital between 2000-2010. All men provided a serum sample at the time of diagnosis. Information on deaths and causes of death were obtained from national causes of death registry. Serum TK1 concentrations were determined using the AroCell TK210 ELISA kit. Cox regression and Kaplan-Meier Curves with adjustment for tumor risk group (Gleason-grade, TNM stage and PSA level) were used to evaluate the risk of PCa death in relation to TK1 levels (median or below vs. above median). ROC analyses were used to evaluate the predictive accuracy of PSA, TK1 and their combination. Results: M1 cases were older than M0 cases; median age 72 vs 62 years, respectively. M1 cases were mainly managed with androgen deprivation therapy, whereas M0 cases were most often managed with radical prostatectomy. Median serum TK1 levels were significantly higher among M1 cases compared to M0 cases (p for difference 0.001). In the combined study population, serum TK1 levels were a significant predictor of PCa-specific (HR 8.33, 95% CI 2.05-33.88) and overall mortality (HR 5.53, 95% CI 1.93-15.85) after adjustment for established prognostic factors including tumor risk group. Kaplan-Meier survival curves defined by TK1 level started to differ within 24 months from PCa diagnosis. In ROC analyses TK1 alone or in combination with PSA was no more accurate than PSA alone in predicting PCa death. Conclusion: The proliferation biomarker TK1 in serum predicted survival after PCa diagnosis, demonstrating independent predictive value over established clinical risk factors. If confirmed in further and larger studies, this biomarker could be incorporated in PCa risk stratification when selecting optimal treatment and surveillance schedule. Citation Format: Teemu J. Murtola, Paavo Raittinen, Teuvo Tammela. Serum thymidine kinase 1 levels predict prostate cancer-specific survival [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-149.
Abstract 917: Functional blocking of CD5 on T cells to enhance the efficacy of therapeutic PD-1 blockade in treatment of mouse 4T1 breast tumors
Authors: Faizah Alotaibi, Mateusz Rytelewski, Rene Figueredo, Ronak Zareardalan1, Saman Maleki Vareki, Xiufen Zheng, Meng Zhang, Peter Ferguson, Mikal El-Hajjar, Yousef Najajreh, Wei-ping Min, James Koropatnick
Journal: Cancer Research (2020)

Abstract Blockade of programmed cell death protein 1 (PD-1) is approved for treatment of multiple human cancers and is the focus of multiple studies due to its key role in T cell function. However, only patients with ‘'hot'' tumors (i.e. those with increased numbers of tumor-infiltrating CD8+ T cells) respond well to the blockade. This suggests that new strategies to increase infiltration of CD8+ T cells into tumors will increase the number of tumor types and patients benefiting from anti-PD-1 therapy. CD5, a member of the scavenger receptor cysteine-rich (SRCR) superfamily, is expressed on T cells and a subset of B cells (B1a). It can attenuate TCR signaling and impair cytotoxic T lymphocyte (CTL) activation. CD5 knockout mice have increased anti-tumor immunity and reduced homograft tumor growth: reducing CD5 on CTLs may be therapeutically beneficial to enhance the anti-tumor response and increase tumor-infiltrating CD8+ T cells. We report that in vivo administration of anti-CD5 blocking MAb treatment increased primary T cell activation in response to 4T1 tumor cell homografts and ex vivo activation as measured by increased CD69, Fas, Fas ligand, IFNγ, PD-1, and apoptosis. Further, anti-CD5 treatment enhanced the capacity of primary T cells to kill 4T1 tumor cells ex vivo. Mice receiving anti-CD5 and anti-PD-1 in combination exhibited increased overall survival compared to mice treated with either agent alone. These data support the potential of blockade of CD5 function to enhance T cell-mediated anti-tumor immunity and PD-1 blockade treatment. Citation Format: Faizah Alotaibi, Mateusz Rytelewski, Rene Figueredo, Ronak Zareardalan1, Saman Maleki Vareki, Xiufen Zheng, Meng Zhang, Peter Ferguson, Mikal El-Hajjar, Yousef Najajreh, Wei-ping Min, James Koropatnick. Functional blocking of CD5 on T cells to enhance the efficacy of therapeutic PD-1 blockade in treatment of mouse 4T1 breast tumors [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 917.
Abstract LB-130: Suppression of tumor immune activity in adrenocortical carcinoma with excess glucocorticoid
Authors: Andrew E. Greenstein, Mouhammed Amir Habra, Marzena Mura, Paweł Biernat, Marek J. Piatek, Andreas Grauer, Stacie Peacock Shepherd
Journal: Cancer Research (2020)

Abstract Introduction: Elevated glucocorticoid (GC) activity, while difficult to accurately quantify, has been implicated in the pathophysiology of multiple cancer types. Approximately half of adrenocortical carcinoma (ACC) patients exhibit excess GC (GC+), which provides a unique test case to assess correlates of GC activity. The broad immunosuppressive effects of GC may limit tumor immune response and immune checkpoint inhibitor (ICI) efficacy. ACC multi-omics were analyzed to identify the molecular consequences of GC activity and assess the rationale for combining relacorilant, a glucocorticoid receptor (GR) antagonist, with an ICI in GC+ ACC. Methods: GC status, mRNA expression, DNA mutation, and DNA methylation data from distinct adrenal resections (n=71) were accessed via The Cancer Genome Atlas (TCGA). To deconvolute immune cell type abundance, xCell was applied to the mRNA data. Random forest was used to derive gene signatures. Results: The expression of 858 genes differed significantly between GC- and GC+ ACC cases. KEGG pathway analysis showed higher gene expression of 7 pathways involved in steroid synthesis and secretion in GC+ cases. Nineteen pathways showed lower expression, most of which were related to natural killer cells, T-cells, and immune activity. Hypomethylation was primarily observed in the steroid synthesis pathways. Tumor-infiltrating CD4+ memory (P=.003), CD8+ memory (P&amp;lt;.001), and NKT-cells (P=.014) were depleted in GC+ cases, while tumor-associated neutrophils were enriched (P&amp;lt;.001). Higher tumor mutation burden (TMB) was observed in the GC+ cases (P=.029). A gene signature predictive of GC status in ACC was derived and applied to other cancer types to identify tumors with GC+-like transcriptional profiles. Conclusions: Reduced abundance of immune cells and immune-related transcripts in GC+ ACC provides insight into the mechanisms by which GC may limit response to ICI therapy. GR antagonism may increase immune related transcripts, thus promoting tumor immune response in GC+ ACC and other malignancies with elevated GC activity. This hypothesis will be tested in a Phase 1 trial of relacorilant + ICI. Citation Format: Andrew E. Greenstein, Mouhammed Amir Habra, Marzena Mura, Paweł Biernat, Marek J. Piatek, Andreas Grauer, Stacie Peacock Shepherd. Suppression of tumor immune activity in adrenocortical carcinoma with excess glucocorticoid [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-130.
Abstract 4437: Anti-tumor immunotherapeutic strategy for uveal melanoma by combining photodynamic therapy with ROCK inhibitor
Authors: Seohyun Kim, In-San Kim
Journal: Cancer Research (2020)

Abstract Uveal melanoma (UM) is the most frequent intraocular malignant tumor among adults. Although UM is a rare disease, the prognosis of patients with UM is poor since nearly 50% of patients develop metastatic disease, and the overall survival outcome is dismal. Here, we suggest a novel and optimal treatment regime for UM not only offering lower burden to patients with high applicability but also preventing lethal metastatic disease by empowering the immune system through the combination of local Photodynamic therapy (PDT) and ROCK inhibitor. PDT is a topical treatment modality with the minimally invasive therapeutic method and now broadly used in a treatment option for the eyes. PDT with chlorin e6 based formulated FIC elicits immunogenic cell death (ICD) of cancer cells, and hallmarks of ICD stimulate antigen-presenting cells (APCs). Furthermore, ripasudil, one of the ROCK inhibitors, is clinically approved for the treatment of glaucoma and ocular hypertension in the form of an eye drop solution. Ripasudil is repurposed as an anticancer compound based on the immuno-stimulatory effect of ROCK inhibition. A combination of FIC-PDT with ripasudil mediated stimulation of APCs leads primed cytotoxic T cell infiltration into the tumor microenvironment (TME) and eventually augment anti-tumor immunity. Moreover, the combinational strategy sensitizes PD-1/PD-L1 immune checkpoint blockade (ICB) therapy to improve survival rates over time and inhibit tumor growth of the distant tumor by generating a systemic anti-tumor immune response. Collectively, our therapeutic strategy may lead to a new treatment option for UM by suppressing the primary tumor effectively and preventing the metastatic disease. Citation Format: Seohyun Kim, In-San Kim. Anti-tumor immunotherapeutic strategy for uveal melanoma by combining photodynamic therapy with ROCK inhibitor [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 4437.
Abstract 2057: Delivering on the Vision of Bench to Bedside: A Rare Disease Funding Community Collaboration to Develop Effective Therapies for Neurofibromatosis Type 1 Tumors
Authors: Salvatore La Rosa, Annette C. Bakker, Vidya Browder, Jaishri O. Blakeley, Sharad K. Verma, Ling M. Wong, Jill Morris, Naba Bora
Journal: Cancer Research (2020)

Abstract The time from identifying a drug target to a new drug approval is often measured in decades and can take even longer for therapies to treat rare diseases. In fact, 95% of rare diseases do not have a specific therapy approved at all. Coordinated efforts to augment the drug development pipeline along with long-term and comprehensive support that enable scientific breakthroughs for rare diseases is possible, but it requires integration across multiple stakeholders. With the recently announced granted acceptance from the FDA to file status of the AstraZeneca and MSD (Merck) application for the MEK inhibitor selumetinib to treat plexiform neurofibromas in children, a major milestone towards the first-ever approved treatment for people with Neurofibromatosis Type 1 (NF1) associated tumors is closer than ever. This study analyzes the coordinated funding efforts of four federal and philanthropic organizations to advance drug development for NF1 associated tumors and discusses how these organizations collaborated and evolved practices to optimize funding and research support. This model could be replicated for other rare diseases if funders are able to take an active, coordinated approach to identify gaps, tools, and infrastructures most needed for that specific disease area. Citation Format: Salvatore La Rosa, Annette C. Bakker, Vidya Browder, Jaishri O. Blakeley, Sharad K. Verma, Ling M. Wong, Jill Morris, Naba Bora. Delivering on the Vision of Bench to Bedside: A Rare Disease Funding Community Collaboration to Develop Effective Therapies for Neurofibromatosis Type 1 Tumors [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 2057.
Abstract #5416: Loss of epithelial markers on CTC triggered by TWIST1 and SNAIL1 may lead to recurrent disease in breast cancer patients
Authors: Michal Mego, Changping Li, Sendurai Mani, Naoto Ueno, Evan Cohen, Hui Gao, Sanda Tin, Ugo De Giorgi, Richard Champlin, Gabriel Hortobagyi, Massino Cristofanilli, James Reuben
Journal: Cancer Research (2009)

Background: Circulating tumor cells (CTCs) are an independent predictor of survival in metastatic breast cancer (MBC) patients. We hypothesize that tumor breast cancer (BC) cells that normally accumulate in the bone marrow will be released during mobilization of hematopoietic stem cells (HSC) with G-CSF and can be recovered by aphaeresis. However, due to epithelial mesenchymal transition (EMT) BC cells lose epithelial markers and may not be detected by conventional detection methods. Methods: This study included 11 MBC patients treated with autologous HSC transplantation. Patient underwent aphaeresis to collect CD34+ HSC prior to receiving high dose chemotherapy. Mononuclear cells (MNC) were isolated from aphaeresis samples depleted of CD34+ HSC. Next, the MNC were depleted of CD45+ cells by magnetic bead separation technique. MNC and CD45-depleted (CD45-) MNC populations were interrogated for expression of TWIST1, SNAIL1 and SLUG by quantitative reverse transcription-PCR. Expression gene transcripts in MNC and CD45- MNC from patients are represented as a quotient of gene transcripts in peripheral blood mononuclear cells (PBMC) and CD45- PBMC of healthy donors (HD), respectively. At time of aphaeresis, a peripheral blood sample was collected for determination of CTC by the CellSearch System (Veridex, LLC). Results:Only 3 patients had detectable CTC; 2 had 2 CTC while the other had 115 CTC per 7.5 mL of blood.Median CTC count was 0 (range; 0-115) per 7.5 mL of peripheral blood. Compared with HD PBMC, MNC of patients had higher mean (± SEM) expression of TWIST1 (1.26 ± 0.22) and SNAIL1 (4.78 ± 1.10), but lower mean (± SEM) expression of SLUG (0.29 ± 0.12). Conclusions: Expression of TWIST1 is found in MNC depleted of CD45. Our study suggests that the loss of epithelial antigen due to EMT on CTC, triggered by high TWIST1 and SNAIl1 expression, may elude detection by convention methods and this development may lead to recurrence of disease.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5416.
Abstract 1637: ATP-citrate lyase transgenic mice frequently develop lymphoma/leukemia spontaneously
Authors: Hiroaki Kanda, Kimie Nomura, Toshihiko Iizuka, Mutsunori Fujiwara, Yuichi Ishikawa, Toshiro Migita
Journal: Cancer Research (2020)

Abstract ATP-citrate lyase (ACLY) catalyzes the generation of acetyl-CoA from citrate. ACLY expression is upregulated and/or ACLY is phosphorylated in several types of cancer. We generated ACLY transgenic mice (Tg) to examine the role of ACLY in carcinogenesis. (Materials and methods) Using human ACLY cDNA under the ROSA26 promoter, Tg with a C57BL background was established. We observed the Tg without treatment. Statistical analyses were performed using the Chi-square and Fisher's exact test. (Results) Of 24 male (M) Tg, aged 24–30 months, 14 (58%), 7 (29%), and 1 (4%) spontaneously developed lymphoma/leukemia (LL), lung carcinoma (LC), and small intestinal carcinoma (SIC), respectively. Since some C57BL mouse colonies are genetically susceptible to LL, and we have previously examined human cases of carcinoma, the Tg were back-crossed with C3H mice, which are resistant to LL and susceptible to carcinoma, especially hepatocellular carcinoma (HCC). A total of 129 (M: 67, female (F): 62) Tg were observed for 18 months. Forty-nine C3H mice (M: 19, F: 30) from the same colony were used as controls. Multiple tumors were counted individually. Seventy-three Tg (57%; M: 41, 61%; F: 32, 52%) and 8 controls (16%; M: 4, 21%; F: 4, 13%) developed cancer. The Tg developed significantly more tumors (total (T), M, F: all p&amp;lt;0.05), including 33 HCC (26%; M: 22, 33%; F: 11, 18%), 28 LL (22%; M: 12, 18%; F: 16, 26%), 7 LC (5%; M: 6, 9%; F: 1, 2%), 4 sarcomas (Sa)(3%; M: 2, 3%; F: 2, 3%), 2 SIC (2%; M: 2, 3%; F: 0), 2 skin appendage carcinomas (SAC) (2%; M: 0; F: 2, 3%), and 1 ovarian cancer (Ov) (1%; F: 1, 2%), than the control mice, which developed 7 HCC (14%; M: 4, 21%; F: 3, 10%), 1 LC (2%; M: 1, 5%; F: 0), and 1 Ov (2%; F: 1, 3%). No LL was seen in the controls. The frequency of HCC did not differ significantly between the Tg and controls (T, M, F: all p&amp;gt;0.05). (Discussion) ACLY was reported to be related to the carcinogenesis of anaplastic large cell lymphoma (Basappa J. et al. Blood 2015 126:465). This study suggests that ACLY might contribute to LL development. Table:Summary of developed cancersNumberTotal cancerHCCLLLCSICSaSACOvACLY12973(57%)*33(26%)28(22%)7(5%)2(2%)4(3%)2(2%)1(1%)Male6741(61%)**22(33%)12(18%)6(9%)2(3%)2(3%)0-Female6232(52%)***11(18%)16(26%)1(2%)02(3%)2(3%)1(2%)Control498(16%)*7(14%)01(2%)0001(2%)Male194(21%)**4(21%)01(5%)000-Female304(13%)***3(10%)000001(3%)*, **, ***; p&amp;lt;0.05 Citation Format: Hiroaki Kanda, Kimie Nomura, Toshihiko Iizuka, Mutsunori Fujiwara, Yuichi Ishikawa, Toshiro Migita. ATP-citrate lyase transgenic mice frequently develop lymphoma/leukemia spontaneously [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 1637.
Sarcoidosis in a time of pandemic
Authors: Praveen Govender, Yvette C. Cozier
Journal: European Respiratory Journal (2020)

<b>Sarcoidosis patients treated with immunosuppressants have a higher risk of serious, recurrent infection. The high morbidity and mortality associated with COVID-19 require a cautious re-evaluation of short- and long-term sarcoidosis treatments.</b>https://bit.ly/2YwZ9wb
Abstract 1755: Prodigiosin inhibits the proliferation and migration of mcf-7 breast cancer cells through the demethylation of mir-200c gene
Authors: Fengqin Shi, Lingeng Lu, Peng LV, Ya Li, Hou Li, Xinyi Chen, Yong Zhu
Journal: Cancer Research (2020)

Abstract Background: DNA methylation in microRNA (miRNA) host genes is associated with the down-regulation of gene expression in tumorigenesis and progression. Accumulating evidence shows that low levels of miR-200c were correlated with a worse prognosis in breast cancer. MiRNA promoter methylation has been reported as a major cause of miR-200c downregulation. Prodigiosin (PG), red bacterial pigment with a pyrrolylpyrromethene skeleton, has significant antibacterial, antifungal, antimalarial and antitumor activity via the modulation of multiple cell signaling pathways against a variety of human cancer cells. However, there is little information regarding the epigenetic-based effects of Prodigiosin in breast cancer. In this study, we hypothesize that Prodigiosin has anti-proliferative and anti-migration effects on breast cancer cells through the demethylation of miR-200c. Material and Methods: MCF-10A breast epithelial cells and MCF-7 breast cancer cells were used to investigate the effects of Prodigiosin on the expression and methylation of miR-200c using real time-PCR (RT-qPCR) and methylation-specific PCR (qMSP), respectively. MTS proliferation assay, cell scratch assay and three-dimensional (3D) formation assay were performed to assess the effect of Prodigiosin on the proliferation and migration of MCF-7 breast cancer cells. Result: MCF-7 breast cancer cells showed significant hypermethylation of miR-200c, and significantly down-regulated miR-200c expression compared to MCF-10A breast epithelial cells. Prodigiosin treatment led to significant inhibition of proliferation and migration, and significantly up-regulated miR-200c expression, whereas the methylation level of miR-200c significantly decreased in MCF-7 breast cancer cells. Conclusion: Prodigiosin, a secondary metabolite of bacteria, inhibits the proliferation and migration of breast cancer cells, and restores the demethylation status and expression of miR-200c. These findings elucidate that the demethylation of miR-200c may be a molecular mechanism underlying the anti-tumor of Prodigiosin in breast cancer. Citation Format: Fengqin Shi, Lingeng Lu, Peng LV, Ya Li, Hou Li, Xinyi Chen, Yong Zhu. Prodigiosin inhibits the proliferation and migration of mcf-7 breast cancer cells through the demethylation of mir-200c gene [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 1755.
Abstract 4827: <i>N6</i>-Methyladenosine modification of LINC00901 promotes pancreatic cancer progression
Authors: Wan-Xin Peng, Liu Yang, Yin-Yuan Mo
Journal: Cancer Research (2020)

Abstract N6-methyladenosine (m6A) is one of the most prevalent modifications of mRNAs in eukaryotes. Numerous recent studies have indicated that m6A plays the critical role in multiple physiologic functions and disease processes by regulation of mRNA processing, splicing, translation, and stability. Although the majority of RNA methylation studies focus on mRNAs, little is known whether long-coding RNAs (lncRNAs) are also subject to m6A modification. Therefore, this study aims to identify m6A modified lncRNAs and their functional role in pancreatic cancer. We performed methylated RNA immunoprecipitation (MeRIP) profiling against a focused group of lncRNAs and identified five lncRNA candidates, among which the highly enriched lncRNA was LINC00901. RNA dot blot, m6A RNA methylation quantification detection and in vivo RNA pulldown combined with m6A RNA methylation Western Blot confirmed the m6A modification of LINC00901. Of note, the analysis of TCGA datasets indicated that the high level of LINC00901 is associated with the poor overall survival (OS) of pancreatic ductal adenocarcinoma (PDAC) patients. Consistent with this result, we showed that LINC00901 promotes pancreatic cancer cell growth. Importantly, we identified that YTHDF1 serves as a “reader” of the m6A modified LINC00901 and furthermore, ectopic expression of YTHDF1 causes downregulation of LINC00901, suggesting a role for m6A modification in regulation of LINC00901 expression. Experiments are underway to determine how LINC00901 promotes pancreatic cancer cell growth. Citation Format: Wan-Xin Peng, Liu Yang, Yin-Yuan Mo. N6-Methyladenosine modification of LINC00901 promotes pancreatic 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 4827.