tbuckley/cabot-search huggingface dataset:
Abstract 1969: Role of the CXCL17-CXCR8 (GPR35) axis in cutaneous squamous cell carcinoma
Authors: Alok R. Khandelwal, Md Maksud Alam, Tara Moore-Medlin, Hillary A. Savage, Cherie-Ann O. Nathan
Journal: Cancer Research (2019)

Abstract Cutaneous squamous cell carcinoma (cSCC) is a keratinocyte-derived invasive and metastatic tumor of the skin and is the second-most commonly diagnosed form of skin cancer (16%) striking 200,000 Americans annually. Increased exposure to Ultraviolet-B (UVB) from solar radiation as a result of the depletion of the ozone layer and the widespread use of tanning beds are the primary reasons for the increased incidence of cSCC. Novel mechanism-based therapeutics are needed to prevent UVB-induced cSCC. Chemokines are a group of small chemotactic cytokines that can exert extensive and complex effects on cancer via interaction with their receptors. Chemokine (C-X-C motif) ligand 17 (CXCL17) is the latest member of the chemokine family, and recent studies have identified both a causative and suppressive role of CXCL17 and its cognate receptor GPR35 in tumorigenesis. The purpose of this study was to determine the role of CXCL17 and GPR35 in the pathogenesis of cSCC. CXCL17 and GPR35 were significantly overexpressed in cSCC cells (SCC12A and SCC118) compared to HaCaT cells. Stimulation with CXCL17 significantly induced cSCC cell proliferation, migration, and motility suggesting an essential role in tumor growth, invasion, and metastasis. Tumor-specific overexpression of CXCL17 was detected in human cSCC and UVB-induced mouse cSCCs that further bolsters our in vitro findings. Recent studies have also identified the role of CXCL17 in tumor cell infiltration and immune invasion leading to tumor progression. In our preliminary studies, increased expression of CXCL17 in cSCC correlated with an augmented number of CD3+, CD4+ and CD8+ T-cells infiltrates. Our data suggest that CXCL17 could potentially exert differential effects based on cell types in the tumor microenvironment. Our studies underscore the importance of CXCL17/GPR35 signaling in cSCC and provide a novel target for the treatment of non-melanoma skin cancer. Citation Format: Alok R. Khandelwal, Md Maksud Alam, Tara Moore-Medlin, Hillary A. Savage, Cherie-Ann O. Nathan. Role of the CXCL17-CXCR8 (GPR35) axis in cutaneous squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1969.
Abstract PL04-01: Screening for nasopharyngeal carcinoma using plasma Epstein-Barr virus DNA: Technological and clinical insights
Authors: Yuk Ming Dennis Lo
Journal: Cancer Research (2019)

Abstract Epstein-Barr virus (EBV) DNA is released by a number of EBV-associated malignancies into the plasma. Examples of such malignancies include nasopharyngeal carcinoma (NPC), certain lymphomas and EBV-associated gastric carcinoma. Plasma EBV DNA in such malignancies exhibits a strong correlation with tumor stage, clinical progress and prognosis; and is thus an archetypal circulating tumor DNA species. Our group is interested in exploring the use of plasma EBV DNA to screen for NPC. We have recently completed a prospective population screening project involving over 20,000 middle aged men in Hong Kong. Using plasma EBV DNA as a screening tool, NPC could be found at a much earlier stage than was normally possible. Furthermore, the prognosis of the NPC patients identified through such screening was much more favorable than those diagnosed without such screening. The positive predictive value of this approach was 11%. False-positive results were observed a proportion of subjects without NPC. Factors that contributed to increased false-positive results included advancing age and surprisingly, the ambient temperature of the day when samples were collected. Hence, a higher percentage of false-positive results were observed when samples were collected in colder weather. We hypothesized that such results might be related to the fluctuations in the effectiveness of the immune system in certain individuals due to ambient temperature. Since the reporting of the above-mentioned results, we have been exploring approaches for further enhancing the positive predictive value. Through the use of targeted massively parallel paired-end sequencing, we found that the size profiles of plasma EBV DNA in subjects with NPC and those without were different. Indeed, by combining such size profile and the concentration of plasma EBV DNA as measured by sequencing, the positive predictive value could be further enhanced. Very recently, we investigated the epigenetic profile of plasma EBV DNA in subjects with NPC and those without cancer, in an attempt to further enhance the positive predictive value of the approach. We believe that the development of a robust approach for NPC screening using circulating EBV DNA would have major public health impact, allowing the earlier detection and treatment of NPC in high prevalence areas. We also believe that such developments would also guide the development of other circulating tumor DNA markers for early cancer detection. Citation Format: Yuk Ming Dennis Lo. Screening for nasopharyngeal carcinoma using plasma Epstein-Barr virus DNA: Technological and clinical insights [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr PL04-01.
Abstract 36: Cardiac Progenitor Cell Lineage Tracing During Embryonic Cardiomyogenesis
Authors: Bingyan J Wang, Alvin Muliono, Roberto Alvarez, Mark A Sussman
Journal: Circulation Research (2017)

Introduction: Stem cell therapy represents great promises to myocardium regeneration. Multipotent c-Kit pos cardiac progenitor cells (CPCs) are able to differentiate into endothelial cells, smooth muscle cells, and cardiomyocytes. However, fundamental knowledge of CPC biology remains incomplete. Studies in rodent myocardial infarction model revealed that CPCs have poor long-term survival and engraftment after adoptive transfer, perhaps due to the severely damaged host environment. Therefore, it is critical to understand how CPCs interface with the recipient environment following transfer in order to enhance their true regenerative potentials. Hypothesis: Adoptively transferred stem cells are thought to survive and engraft best in an environment closely resembling their original habitat. Thus, we hypothesized that the embryonic environment provides the optimal spatiotemporal conditions to promote CPCs engraftment and commitment to cardiac fate. Methods: CPCs isolated from adult mouse hearts were expanded, fluorescence-tagged, and injected into blastocysts at E3.75 and in utero at E15.5. Embryos were analyzed following cardiogenesis by immunofluorescence for presence of CPC-derived tissues. Additionally, CPCs were injected intramyocardially at various stages from P0 to P7, to follow long-term adoptive transfer and assess CPCs lineage commitment. Results and Conclusions: At 48 hours post injection, donor CPCs were found anchoring in blastocoel and trophoblasts at E5.5, and were detected within the host myocardium at E17.5 predominantly at perivascular regions (n=4). Interestingly, CPCs also integrated into aminochorionic sac, indicating a novel non-cardiogenic fate of CPCs (n=5). CPCs injected at P3 stably engrafted into left ventricular myocardium by 14 days post injection (n=4), sharing gap junction proteins (ZO-1, Connexin-43) with neighboring cells. In conclusion, this study provides vivid evidence for the first time of CPC engraftment and survival in vivo under homeostasis during cardiogenesis. Future studies will assess the permissive environmental conditions, which may optimize their use in therapeutic applications, and the cardiogenic potential of CPCs in order to provide fundamental insights on CPCs biology.
Concurrent chemoradiotherapy with weekly docetaxel versus cisplatin in the treatment of locoregionally advanced nasopharyngeal carcinoma: a propensity score-matched analysis
Authors: Jun‐Fang Liao, Qun Zhang, Xiao‐Jing Du, Mei Lan, Shan Liu, Yun‐Fei Xia, Xiu‐Yu Cai, Wei Luo
Journal: Cancer Communications (2019)

Promising efficacy and manageable toxicity of docetaxel-based concurrent chemoradiotherapy (CCRT) were reported in head and neck cancer. In addition, the effect of CCRT in combination with cisplatin and/or 5-fluorouracil on both locoregionally advanced and metastatic/recurrent nasopharyngeal carcinoma (NPC) was verified. However, CCRT with docetaxel for locoregionally advanced NPC are not well studied. This study aimed to compare effectiveness and toxicities of CCRT with weekly docetaxel versus tri-weekly cisplatin for locoregionally advanced NPC.Clinical data of patients with locoregionally advanced NPC newly diagnosed between January 2010 and December 2014 receiving CCRT with either weekly docetaxel (15 mg/m2) or tri-weekly cisplatin (80-100 mg/m2) were reviewed. Propensity score matching at a 1:1 ratio was performed to balance baseline characteristics. Adverse events and survival were compared between the two groups.A total of 962 patients were included as the whole cohort, and 448 patients were matched and were regarded as the matched cohort. The median follow-up duration was 48 months for the whole cohort. The 3-year nodal recurrence-free survival rate was significantly increased for patients treated with docetaxel in both the whole (hazard ratio [HR] = 0.37, 95% confidence interval [CI] 0.19-0.72, P = 0.030) and matched cohorts (HR = 0.33, 95% CI 0.14-0.79, P = 0.023). However, no significant differences were observed in overall survival, local recurrence-free survival, and distant metastasis-free survival between the two groups in both cohorts. Significantly higher rates of grade 3 radiodermatitis (6.7% vs. 1.8%, P = 0.001), mucositis (74.5% vs. 37.9%, P < 0.001), and leucopenia (2.2% vs. 11.6%, P < 0.001) were observed in the docetaxel group, but any grade of renal injury (1.8% vs. 15.1%, P < 0.001), vomiting (18.8% vs. 88.3%, P < 0.001), and ALT elevation (19.2% vs. 31.3%, P = 0.027) were more common in the cisplatin group.CCRT with weekly low-dose docetaxel is an effective and tolerable therapeutic regimen for locally advanced NPC. It provides a survival benefit mainly by improving the control of regional lymph node metastases, especially for patients with low pretreatment EBV DNA levels.
Abstract 2849: Axl: A promising therapeutic target that leads to multimodal inhibition of the metastatic pathway
Authors: Mai Tanaka, Dietmar W. Siemann
Journal: Cancer Research (2019)

Abstract Cancer is the second leading cause of death in the United States and approximately 90% of cancer-related deaths result from metastasis, the spread of cancer cells to secondary sites. In tumors, the upregulation of certain signaling pathways promotes the metastatic phenotypes of cancer cells characterized by enhanced invasion, migration, survival, proliferation and induction of angiogenesis. A key pathway involved in metastasis is the receptor tyrosine kinase Axl. Axl is expressed in a variety of tumor types and is associated with poor prognosis, metastasis, and outcome. The purpose of the current study was to evaluate the efficacy of genetic and pharmacologic inhibitions of Axl on the metastatic phenotypes, specifically cell migration, invasion and angiogenesis. Human breast and prostate cancer cell lines (MDA-MB-231 and PC3-ML, respectively), and human lung microvascular endothelial cell (HMVEC-L) were used in this study. Stable Axl short hairpin RNA (shRNA) knockdown MDA-MB-231 and PC3-ML cell lines were generated by Mission Lentiviral transduction particles (Sigma). The efficacy of genetic and pharmacologic inhibition of Axl on tumor cell migration and invasion was evaluated by transwell migration and invasion assays. The effect of Axl knockdown on prostate cancer cell metastasis in vivo was evaluated by an intracardiac bone metastasis model. Conditioned media of Axl knockdown or control MDA-MB-231 cells were analyzed for angiogenic factors using the human angiogenesis array. The effect of Axl knockdown conditioned medium on angiogenic properties in vitro were assessed by endothelial cell tube formation and sprouting. Induction of angiogenesis in vivo was measured by performing intradermal assay. Genetic and pharmacologic inhibition of Axl decreases tumor cell migration and invasion. Axl knockdown inhibits metastatic disease burden of prostate cancer. Axl knockdown conditioned medium secretes less pro-angiogenic factors compared to its scramble control cells, suggesting that tumor cells utilize Axl pathway to promote the induction of angiogenesis. Axl knockdown conditioned medium impairs angiogenic properties, including endothelial cell tube formation and sprouting. Axl knockdown of tumor cells suppress tumor cell-induced angiogenesis in vivo. Collectively, these data indicate that Axl is involved in multiple steps of the metastatic pathway and that Axl is a promising anti-metastatic agent to inhibit tumor cell dissemination and initiation of angiogenesis. Further studies are ongoing to understand the downstream molecular signaling of Axl. Citation Format: Mai Tanaka, Dietmar W. Siemann. Axl: A promising therapeutic target that leads to multimodal inhibition of the metastatic pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2849.
VEGFR1+ Metastasis–Associated Macrophages Contribute to Metastatic Angiogenesis and Influence Colorectal Cancer Patient Outcome
Authors: Aida Freire Valls, Karl Knipper, Evangelia Giannakouri, Víctor Sarachaga, Sascha Hinterkopf, Michael Wuehrl, Ying Shen, Praveenkumar Radhakrishnan, Johannes Klose, Alexis Ulrich, Martin Schneider, Hellmut G. Augustin, Carmen Ruiz de Almodovar, Thomas Schmidt
Journal: Clinical Cancer Research (2019)

To investigate the clinical relevance of macrophages in liver metastasis of colorectal cancer and their influence on angiogenesis and patient survival. Moreover to evaluate specific blood monocytes as markers of disease recurrence.Experimental design: In a mouse model with spontaneous liver metastasis, the angiogenic characteristics of tumor- and metastasis (MAM)-associated macrophages were evaluated. Macrophages and the vasculature from 130 primary tumor (pTU) and 123 patients with liver metastasis were assessed. In vivo and in human samples, the clinical relevance of macrophage VEGFR1 expression was analyzed. Blood samples from patients (n = 157, 80 pTU and 77 liver metastasis) were analyzed for assessing VEGFR1-positive (VEGFR1+) cells as suitable biomarkers of disease recurrence.The number of macrophages positively correlated with vascularization in metastasis. Both in the murine model as well as in primary isolated human cells, a subpopulation of MAMs expressing VEGFR1 were found highly angiogenic. While VEGFR1 expression in pTU patients did not predict prognosis; high percentage of VEGFR1+ cells in liver metastasis was associated with worse patient outcome. Interestingly, VEGFR1+-circulating monocytes in blood samples from patients with liver metastasis not only predicted progression but also site of recurrence.Our findings identify a new subset of proangiogenic VEGFR1+ MAMs in colorectal cancer that support metastatic growth and may become a liquid biomarker to predict disease recurrence in the liver.
Abstract 18520: Novel Tissue-specific Cyclooxygenase-1 Knockout Mice Demonstrate a Dominant Role for Endothelial Cyclooxygenase-1 in Prostacyclin Production
Authors: Jane A Mitchell, Fisnik Shala, Blerina Ahmetaj-Shala, Jing Jiao, Paul C Armstrong, Melissa V Chan, Marilena Crescente, Timothy D Warner, Harvey R Herschman, Nicholas S Kirkby
Journal: Circulation (2017)

Introduction: Prostacyclin is a ubiquitous cardioprotective hormone with vasodilator and anti-platelet activity, produced via cyclooxygenase (COX)-1 and -2 enzymes. Reduced prostacyclin in vessels ...
Abstract 2697: YPN005, an oral CDK7 inhibitor, exhibits a significant antitumor activity in Myc-driven cancers
Authors: Kwang-Ok Lee, Jakyung Yoo, Mi Jung Lee, Kang Woo Lee, Ji Eun Min, Jinhwan Kim, Ki-Nam Min, Tae Chul Roh, Kang-Sik Seo, Hae In Rhee, Jun Hee Lee, Da-Hye Jeon, Dae Seong Lim
Journal: Cancer Research (2019)

Abstract Background: CDK7 plays an important role in regulating cell cycle progression and gene via activation of cell cycle kinases (CDK1, CDK2, CDK4 and CDK6) and RNA polymerase II (PolII). Recent studies indicate that the inhibition of CDK7 is an attractive strategy for the treatment of cancer by down-regulation of c-Myc expression. (Wang et al 2018) We have investigated the therapeutic efficacy of YPN005, a novel oral CDK7 inhibitor, in triple negative breast cancer (TNBC) and hepatocellular carcinoma (HCC). Methods: We evaluated antiproliferative activity of YPN005 on TNBC and HCC cells and the expression of RNA PolII and c-Myc was studied by Western Blot analyses to investigate the mechanism of action. To identify a biomarker, we examined the correlation between the level of c-Myc expression and anticancer activity of YPN005 in vitro using HCC cells. The therapeutic efficacy of YPN005 was evaluated in TNBC xenograft mouse model. Results: YPN005 significantly inhibited the proliferation of TNBC and HCC cells and IC50s was determined as 10-20 nM and 5-30 nM range, respectively. Inhibition of cell proliferation was accompanied by a decrease in the levels of RNA PolII phosphorylation and c-Myc expression. Western Blot analyses revealed that the sensitivity of HCC cells to YPN005 was correlated with the level of c-Myc expression. In vivo xenograft model of TNBC showed that oral daily administration of YPN005 for 21 days (once, and 10mg/kg) efficiently inhibited the growth of tumor. All mice survived during the dosing period without significant changes of the hematologic profiles. Conclusion: We propose that oral administration of YPN005, an orally available CDK7 inhibitor, could be a potent and attractive approach to treat the Myc overexpressing cancers. Citation Format: Kwang-Ok Lee, Jakyung Yoo, Mi Jung Lee, Kang Woo Lee, Ji Eun Min, Jinhwan Kim, Ki-Nam Min, Tae Chul Roh, Kang-Sik Seo, Hae In Rhee, Jun Hee Lee, Da-Hye Jeon, Dae Seong Lim. YPN005, an oral CDK7 inhibitor, exhibits a significant antitumor activity in Myc-driven cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2697.
Effectiveness of a Bundled Intervention Including Adjunctive Corticosteroids on Outcomes of Hospitalized Patients With Community-Acquired Pneumonia
Authors: Melanie Lloyd, Amalia Karahalios, Edward Janus, Elizabeth H. Skinner, Terry Haines, Anurika De Silva, Stephanie Lowe, Melina Shackell, Soe Ko, Lucy Desmond, Harin Karunajeewa
Journal: JAMA Internal Medicine (2019)

Community-acquired pneumonia remains a leading cause of hospitalization, mortality, and health care costs worldwide. Randomized clinical trials support the use of adjunctive corticosteroids, early progressive mobilization, antibiotic switching rules, and dietary interventions in improving outcomes. However, it is uncertain whether implementing these interventions will translate into effectiveness under routine health care conditions.To evaluate the effectiveness of a bundle of evidence-supported treatments under conditions of routine care in a representative population hospitalized for community-acquired pneumonia.A double-blind, stepped-wedge, cluster-randomized clinical trial with 90-day follow-up was conducted between August 1, 2016, and October 29, 2017, in the general internal medicine service at 2 tertiary hospitals in Melbourne, Australia, among a consecutive sample of patients with community-acquired pneumonia. The primary analysis and preparation of results took place between May 14 and November 25, 2018.Treating clinical teams were advised to prescribe prednisolone acetate, 50 mg/d, for 7 days (in the absence of any contraindication) and de-escalate from parenteral to oral antibiotics according to standardized criteria. Algorithm-guided early mobilization and malnutrition screening and treatment were also implemented.Hospital length of stay, mortality, readmission, and intervention-associated adverse events (eg, gastrointestinal bleeding and hyperglycemia).A total of 917 patients were screened, and 816 (351 women and 465 men; mean [SD] age, 76 [13] years) were included in the intention-to-treat analysis, with 401 patients receiving the intervention and 415 patients in the control group. An unadjusted geometric mean ratio of 0.95 (95% CI, 0.78-1.16) was observed for the difference in length of stay (days) between the intervention and control groups. Similarly, no significant differences were observed for the secondary outcomes of mortality and readmission, and the results remained unchanged after further adjustment for sex and age. The study reported higher proportions of gastrointestinal bleeding in the intervention group (9 [2.2%]) compared with the controls (3 [0.7%]), with an unadjusted estimated difference in mean proportions of 0.008 (95% CI, 0.005-0.010).This bundled intervention including adjunctive corticosteroids demonstrated no evidence of effectiveness and resulted in a higher incidence of gastrointestinal bleeding. Efficacy of individual interventions demonstrated in clinical trials may not necessarily translate into effectiveness when implemented in combination and may even result in net harm.ClinicalTrials.gov identifier: NCT02835040.
Phase 3 multicenter, open-label, randomized study of infigratinib versus gemcitabine plus cisplatin in the first-line treatment of patients with advanced cholangiocarcinoma with FGFR2 gene fusions/translocations: the PROOF trial
Authors: M. Javle, I. Borbath, S. Clarke, E. Hitre, C. Louvet, T. Macarulla, D. Oh, J. Spratlin, J. Valle, K. Weiss, C. Berman, M. Howland, Y. Ye, T. Cho, S. Moran, G. Abou-Alfa
Journal: Annals of Oncology (2019)