tbuckley/cabot-search huggingface dataset:
Critical Reevaluation of Endothelial Progenitor Cell Phenotypes for Therapeutic and Diagnostic Use
Authors: Gian PaoloFadini, DouglasLosordo, StefanieDimmeler
Journal: Circulation Research (2012)

Diverse subsets of endothelial progenitor cells (EPCs) are used for the treatment of ischemic diseases in clinical trials, and circulating EPCs levels are considered as biomarkers for coronary and peripheral artery disease. However, despite significant steps forward in defining their potential for both therapeutic and diagnostic purposes, further progress has been mired by unresolved questions around the definition and the mechanism of action of EPCs. Diverse culturing methods and detection of various combinations of different surface antigens were used to enrich and identify EPCs. These attempts were particularly challenged by the close relationship and overlapping markers of the endothelial and hematopoietic lineages. This article will critically review the most commonly used protocols to define EPCs by culture assays or by fluorescence-activated cell sorter in the context of their therapeutic or diagnostic use. We also delineate new research avenues to move forward our knowledge on EPC biology.
Abstract 5732: Zinc transporter, ZIP14, as a mediator of systemic muscle wasting in metastatic cancers
Authors: Anup Biswas, Gang Wang, Wanchao Ma, Courtney Coker, Kurenai Tanji, Manoj Kandpal, Ramana Davuluri, Swarnali Acharyya
Journal: Cancer Research (2018)

Abstract Metastasis contributes to the vast majority of cancer-related mortalities. Metastatic tumors secrete factors that systemically affect various organs leading to dysfunction and accelerated death. More than 80% of metastatic cancer patients experience a progressive and debilitating loss of muscle mass and function by a process known as cachexia. Cachectic patients suffer deterioration of diaphragm and cardiac muscles and often die prematurely due to respiratory and cardiac failure. The prognosis for these patients is further diminished by the fact that they are often too weak to tolerate standard doses of anti-cancer treatments. Cachexia is therefore an important determinant of therapeutic response, outcome and patient survival in advanced cancer patients. Although systemic metabolic derangements and chronic inflammation predominate in cachexia, the underlying molecular mechanisms driving its development are not well understood. Therefore, insights into the specific interventions that could either reverse or prevent cachexia are expected to improve treatment outcome, survival and quality of life in cancer patients. In this study, we identified a metal ion transporter, ZIP14 that was upregulated in cachectic muscles from five independent metastatic models, as well as in metastatic cancer patients. We find that TNF-alpha and TGF-beta cytokines upregulate ZIP14 in muscles, which in turn results in the accumulation of intracellular zinc. Increased zinc influx in muscle cells is associated with the degradation of myofibrillar proteins that contributes to muscle atrophy and muscle mass loss. Importantly, germline ablation or muscle-specific depletion of Zip14 markedly inhibits cancer-induced muscle wasting. Our study demonstrates a novel function of ZIP14 in muscles as a mediator of cachexia in advanced cancers. Insights from this study can be used to develop therapeutic strategies to prevent cachexia, and improve the survival and quality of life in metastatic cancer patients. Citation Format: Anup Biswas, Gang Wang, Wanchao Ma, Courtney Coker, Kurenai Tanji, Manoj Kandpal, Ramana Davuluri, Swarnali Acharyya. Zinc transporter, ZIP14, as a mediator of systemic muscle wasting in metastatic cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5732.
Abstract 14447: Novel Metrics for High Sensitivity-Cardiac Troponin T Improves Diagnosis of Missed Perioperative Myocardial Infarction Events
Authors: Jamie CBrown, SrikarRao, EslamSamaha, Mohammad AHelwani, FrankBrown, Fred SApple, Mitchell GScott, Allan SJaffe, PeterNagele
Journal: Circulation (2016)

Introduction: High-sensitivity cardiac troponin (hscTn) assays can detect baseline values in perioperative patients, allowing comparison of relative and absolute changes. Change metrics for hscTn have been advocated for the diagnosis of acute MI, however, there is no evidence for the diagnosis of perioperative myocardial injury or infarction (MI). Hypothesis: Methods: We retrospectively compared several hscTnT metrics for diagnosing perioperative MI, according to the Third Universal Definition, in 607 high cardiovascular risk, non-cardiac surgery patients from the Vitamins in Nitrous Oxide study. Serial 12-lead ECGs, standard cTnI, and hscTnT were obtained preoperatively and up to postoperative day 3 for each patient. The ECGs were read by blinded clinicians and adjudicated by the PI for ischemic changes. All charts, for patients diagnosed with MI by these novel metrics, were further reviewed by the PI to identify real vs. missed events. Adjusted Cox regression was performed to assess association of morta...
Abstract CT089: The Dutch Oncology Research Platform (DORP), a national infrastructure for investigator-initiated multicenter clinical cancer research
Authors: Cornelis J. Punt
Journal: Cancer Research (2018)

Abstract Background Investigator-initiated clinical cancer research (IICCR) contributes in a major way to improved prognosis of cancer patients. However, increased complexity of legislation and regulation, lack of uniformity in local procedures among participating hospitals, and increasing demands on monitoring seriously endanger IICCR, since insufficient staff/funding is available to meet these requirements. In addition, better characterization of patient subgroups requiring specific treatments hamper the feasibility of randomized studies with classic design, and calls for innovative study designs. In The Netherlands, tumor-specific research groups exist for almost every tumor type, which however have different levels of professionalization, but which all face the same problems. This seriously hampers future development of IICCR. Methods A national infrastructure (DORP) has been developed to facilitate IICCR. DORP has 3 pillars: statistical support, monitoring, and project management. DORP provides statistical and logistic support in protocol development according to up-to-date standards, and, once financial support for the conduct of the study (i.e. datamanagement) has been obtained, provides support for monitoring and project management. The latter includes implementation of the study in participating hospitals, and administrative/financial management of the study. DORP statisticians will develop innovative trial designs that provide more feasible alternatives to classic phase 3 studies in small subgroups of patients, and DORP project managers will aim to harmonize local study procedures in hospitals in order to speed up study initiation. Results The DORP initiative has been received with great enthousiasm among stakeholders (i.e. research groups, patient advocacy groups, large trial offices, professional and hospital organisations, insurance companies). DORP has recently received a 6.5 million euro starting grant from the Dutch Cancer Society (KWF Kankerbestrijding), which has allowed to established DORP as a cooperation in which all stakeholders participate. A total of approx. 30 statisticians, monitors and project managers will be recruited and will be employed at institutions with established expertise in the respective fields. A director has been commissioned by the board. Trial development with DORP support has been initiated in January 2018. Conclusion The objective of DORP is more trials, for more patients, of better quality, that are timely completed. DORP may internationally provide an example for IICCR support. Citation Format: Cornelis J. Punt. The Dutch Oncology Research Platform (DORP), a national infrastructure for investigator-initiated multicenter clinical cancer research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT089.
Abstract 214: Genetic and transcriptional instability alters cell line drug response
Authors: Uri Ben-David, Ben Siranosian, Gavin Ha, Helen Tang, Nicholas J. Lyons, Robert Burns, Anwesha Nag, Beth Cimini, Peter Tsvetkov, Andrew A. Tubelli, Bang Wong, Aaron R. Thorner, Joshua Bittker, Matthew Meyerson, Rameen Beroukhim, Todd R. Golub
Journal: Cancer Research (2018)

Abstract Inconsistencies in cell line-based studies jeopardize reproducibility of cancer research. Natural evolution leading to genetic and transcriptional heterogeneity within cancer cell lines may contribute to such inconsistencies. To systematically test this hypothesis, we performed comprehensive genetic and transcriptomic characterization of 27 strains of the common breast cancer cell line MCF7, and then assessed the response of those strains to 321 anti-cancer compounds. We found extensive variation in genomic profiles and responses to small molecules across strains. Genetic variation occurred at all levels – point mutations, rearrangements, and copy number changes – and affected multiple oncogenes and tumor suppressor genes. Similar findings were obtained across 23 strains of the lung cancer cell line A549, indicating that such variation is a general property of cancer cell lines. These changes resulted in substantial differences in gene expression programs, cell morphology and proliferation, and strikingly high variability in drug response. Over 75% of the compounds that exhibited strong activity in some of the strains, were completely inactive in other strains. These results indicate that genomic variation within commonly used cancer cell lines is extensive, resulting in disparate drug responses. Such variation may contribute to difficulties in conducting reproducible cell line-based studies. Citation Format: Uri Ben-David, Ben Siranosian, Gavin Ha, Helen Tang, Nicholas J. Lyons, Robert Burns, Anwesha Nag, Beth Cimini, Peter Tsvetkov, Andrew A. Tubelli, Bang Wong, Aaron R. Thorner, Joshua Bittker, Matthew Meyerson, Rameen Beroukhim, Todd R. Golub. Genetic and transcriptional instability alters cell line drug response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 214.
CD28<sup>null</sup> pro-atherogenic CD4 T-cells explain the link between CMV infection and an increased risk of cardiovascular death
Authors: Alejandra Pera, Stefano Caserta, Fabio Albanese, Pinar Blowers, George Morrow, Nadia Terrazzini, Helen E Smith, Chakravarthi Rajkumar, Bernhard Reus, James R Msonda, Murielle Verboom, Michael Hallensleben, Rainer Blasczyk, Kevin A Davies, Florian Kern
Journal: Theranostics (2018)

An increased risk of cardiovascular death in Cytomegalovirus (CMV)-infected individuals remains unexplained, although it might partly result from the fact that CMV infection is closely associated with the accumulation of CD28null T-cells, in particular CD28null CD4 T-cells. These cells can directly damage endothelium and precipitate cardiovascular events. However, the current paradigm holds that the accumulation of CD28null T-cells is a normal consequence of aging, whereas the link between these T-cell populations and CMV infection is explained by the increased prevalence of this infection in older people. Resolving whether CMV infection or aging triggers CD28null T-cell expansions is of critical importance because, unlike aging, CMV infection can be treated. Methods: We used multi-color flow-cytometry, antigen-specific activation assays, and HLA-typing to dissect the contributions of CMV infection and aging to the accumulation of CD28null CD4 and CD8 T-cells in CMV+ and CMV- individuals aged 19 to 94 years. Linear/logistic regression was used to test the effect of sex, age, CMV infection, and HLA-type on CD28null T-cell frequencies. Results: The median frequencies of CD28null CD4 T-cells and CD28null CD8 T-cells were >12-fold (p=0.000) but only approximately 2-fold higher (p=0.000), respectively, in CMV+ (n=136) compared with CMV- individuals (n=106). The effect of CMV infection on these T-cell subsets was confirmed by linear regression. Unexpectedly, aging contributed only marginally to an increase in CD28null T-cell frequencies, and only in CMV+ individuals. Interestingly, the presence of HLA-DRB1*0301 led to an approximately 9-fold reduction of the risk of having CD28null CD4 T-cell expansions (OR=0.108, p=0.003). Over 75% of CMV-reactive CD4 T-cells were CD28null. Conclusion: CMV infection and HLA type are major risk factors for CD28null CD4 T-cell-associated cardiovascular pathology. Increased numbers of CD28null CD8 T-cells are also associated with CMV infection, but to a lesser extent. Aging, however, makes only a negligible contribution to the expansion of these T-cell subsets, and only in the presence of CMV infection. Our results open up new avenues for risk assessment, prevention, and treatment.
Abstract 2634: Predictive value of18F-FDG PET/CT scanning in combination with clinical parameters in patients with newly diagnosed multiple myeloma
Authors: Honglei Tu, Fuling Zhou, Yunbao Pan, Francois X Claret
Journal: Cancer Research (2018)

Abstract Objective: To evaluate the association of 18F-2`-deoxy 2`-fluorodeoxyglucose (18F-FDG) PET/CT with clinical parameters in predicting patients with newly diagnosed multiple myeloma (MM). Methods: One hundred and twenty MM patients undergoing 18F-FDG PET/CT scanning were analyzed in a retrospective cohort study. Results: Based on multivariate analysis, β2M, LDH, number of focal lesions (FLs) and SUVmax were significantly correlated with overall survival (OS). These 4 variables were used to construct a new staging system (NSS) based on the number of risk factors. NSS provided a better discrimination of risk between stages III and II than International staging system (ISS) (p &amp;lt; 0.001 vs. p = 0.086). For OS, there was no significant difference among risk groups in Durie-Salmon (DS) stage (p &amp;gt; 0.05). Based on Spearman correlation analysis, presence of lesions in appendicular skeleton, number of FLs and SUVmax appeared to indicate advanced stage of MM. ROC curves which showed the combination of β2M with Calcium got a specificity of 96.3% for the presence of lesions in appendicular skeleton, and LDH alone had 100% specificity in predicting the number of FLs, although the sensitivity was only 50%. Conclusions: 18F-FDG PET/CT in combination with clinical parameters provided an accurate and simple method for risk stratification of patients with newly diagnosed MM. Citation Format: Honglei Tu, Fuling Zhou, Yunbao Pan, Francois X Claret. Predictive value of 18F-FDG PET/CT scanning in combination with clinical parameters in patients with newly diagnosed multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2634.
Abstract 2157: Chemotherapeutic tolerability and estrogen dose response in the B6;129-Rag2tm1FwaIL2rgtm1Rsky/DwlHsd (R2G2) mouse model
Authors: Jamie L. Naden, Michele Melton, Athena Bast, Jermaine Gardner
Journal: Cancer Research (2018)

Abstract The B6;129-Rag2tm1FwaIL2rgtm1Rsky/DwlHsd (R2G2) knockout mouse was developed by backcrossing an IL2rg (common gamma) knockout model to a RAG2 (recombinase activating gene) knockout model. The resulting mouse lacks various cytokines including IL-2, IL-4, IL-7, IL-9 and IL-15. In addition, this model lacks B cells, T cells, NK cells and has a deficit in lymphocyte development. This model was developed to provide another immunodeficient option for the oncology and immunology fields. The literature supports better tolerability of DNA-damaging oncology treatments for models that do not carry the SCID mutation. We have already reported in a white paper that the R2G2 mouse model is more tolerant of whole-body radiation than a model with the SCID mutation. Herein we describe a study examining chemotherapeutic tolerability of common DNA-damaging oncology drugs including 5-fluorouracil (5-FU), doxorubicin (Doxo), and cyclophosphamide (CTX) (n = 10 per group). 5-FU was given at 30, 60 or 100 mg/kg, intraperitoneally, twice weekly for five weeks. Doxo was given at 2 or 5 mg/kg, intraperitoneally, once weekly for three weeks. CTX was given at 100 or 140 mg/kg intraperitoneally, once weekly for three weeks. The low dose was chosen based on the average dose used in immunodeficient mouse models and the high dose was chosen based on the average dose used in immunocompetent mouse models. This was done to determine if the R2G2 mouse model can tolerate higher doses of these chemotherapeutic agents compared to other immunodeficient mouse models. Results show that the R2G2 mouse model tolerates higher doses of these chemotherapeutic drugs than doses found in the literature for SCID models. Exogenous estrogen tolerance is another common concern in oncology research as some immunodeficient mouse models cannot tolerate the subcutaneous estrogen pellets, developing negative secondary effects resulting in removal from study. We performed an estrogen pellet dose-response study using four doses of 60-day release 17-β estradiol pellets at 0.18, 0.36, 0.72, and 1.7 mg/pellet (n = 10 per group). R2G2 mice show dose-dependent effects of estrogen on morbidity. These data will allow researchers to determine the optimal dose for use in the R2G2 model. In conclusion, these data support that the R2G2 mouse model may be a good alternative to SCID models when administering DNA-damaging chemotherapies or when estrogen supplementation is required for xenograft growth. Citation Format: Jamie L. Naden, Michele Melton, Athena Bast, Jermaine Gardner. Chemotherapeutic tolerability and estrogen dose response in the B6;129-Rag2tm1FwaIL2rgtm1Rsky/DwlHsd (R2G2) mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2157.
Blood Coagulation After a Fat Meal
Authors: Ratkobuzina, Ancelkeys
Journal: Circulation (1956)

The influence of meals on the coagulability of blood was studied in experiments on 20 men with parallel nonfed controls. The whole blood clotting time in siliconized tubes was not altered by a low-fat meal or by continued absence of a meal, but it was significantly shortened after a meal containing 100 Gm. of butterfat. The degree of lipemia did not determine the degree of shortening. There was no important effect on prothrombin time of the fatty meal as contrasted with the nonfatty meal or with no meal. Heparin tolerance results were difficult to interpret.
Abstract 3944: Blockage of EGFR signaling repurposes tumor metabolism through suppression of glycolysis and Kreb cycle in head and neck cancer
Authors: Ching-Chuan Kuo, Jang-Yang Chang, Hsing-Pang Hsieh, Hsing-Jien Kung, Hsih-Huei Chang, Chih-Hsiang Huang, Cheng-Chin Kuo, Yi-Yu Ke
Journal: Cancer Research (2018)

Abstract Head and neck squamous cell carcinoma (HNSCC), the most common malignant neoplasm arising in the mucosa of the upper aerodigestive tract, remains a significant cause of morbidity worldwide. With respect to the cancer treatment, HNSCC has a moderately good survival rate, however, the disease often recurs, leading to a poor prognostic disease course and tends to fail in treatment. The metabolic properties of cancer cells diverge significantly from those of normal cells. Emerging evidence suggests these metabolic alterations are also linked to therapeutic resistance in cancer treatment. EGFR targeted agents currently approved or under investigation for HNSCC. We recently identified a novel EGFR tyrosine kinase inhibitor (EGFR-TKI), BPR3K007S0, and found that this compound significantly inhibited EGFR phosphorylation in EGFR-overexpressing HNSCC cells in vitro and in vivo than that of gefitinib. BPR3K007S0 significantly suppressed the expression of a wide range of metabolic genes, including metabolic-related transcription factors, glycolysis, TCA cycle, and pentose phosphate pathway genes. Collectively, we also found that BPR3K007S0 significantly decreased glycolytic and mitochondria respiratory capacity. Pharmacological and genetic manipulation demonstrated that c-Myc/hexokinase 2 axis was one of downstream effector in response to EGFR inhibition. Furthermore, we found that EGFR-TKIs were able to suppress succinate dehydrogenase A leading to reduce fumarate, an oncometabolite generates from Kreb cycle, and contributed to EGFR-TKIs mediated antitumor effect. Taken together, these results revealed that blockage of EGFR signaling repurposes tumor metabolism through suppression of hexokinase 2 and succinate dehydrogenase A, in glycolysis and Kreb cycle, respectively, and demonstrated added benefits to treatment of HNSCCs. Citation Format: Ching-Chuan Kuo, Jang-Yang Chang, Hsing-Pang Hsieh, Hsing-Jien Kung, Hsih-Huei Chang, Chih-Hsiang Huang, Cheng-Chin Kuo, Yi-Yu Ke. Blockage of EGFR signaling repurposes tumor metabolism through suppression of glycolysis and Kreb cycle in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3944.
Can Adenosine 5′-Triphosphate Be Used to Select Treatment in Severe Vasovagal Syndrome?
Authors: DanielFlammang, TimothyChurch, MarcWaynberger, AnnickChassing, MarkAntiel
Journal: Circulation (1997)

Background Selection of treatment in vasovagal syndrome should be guided by the mechanism of symptoms. This study determined whether a simple drug test may assess one mechanism. Methods and Results To identify patients at risk of severe cardioinhibitory response of vagal origin, we infused 20 mg ATP into 316 patients hospitalized for recurrent syncope (n=195) or presyncope (n=121) of unknown origin and into normal subjects (n=51). We then assessed the ECG and clinical responses to the drug, recommended therapy, and followed up the subjects chronically. A cardiac pause >10 seconds was seen in only 3 normal subjects (6%). Therefore, a pause ≤10 seconds yielded the ≈95th percentile of the normal range. ATP provoked a pause >10 seconds in 130 symptomatic patients (41%) and a pause ≤10 seconds in 186 symptomatic patients (59%). Thus, symptomatic patients with pauses >10 seconds were proposed for pacemaker implantation; all other patients and normal subjects were simply monitored. Among long-pause patients with...