tbuckley/cabot-search huggingface dataset:
Abstract 136: T-cell clonotype convergence in colorectal cancer driven by tumor-specific neoantigens
Authors: Jose C. Machado, Joana Reis, Margarida Fernandes, Rafaela Silva, Luis Cirnes, Fatima Carneiro, Jose L. Costa
Journal: Cancer Research (2018)

Abstract A cornerstone of the biological process which mediates response to immunotherapy in cancer patients is the expression of neoantigens resulting from somatic mutations in cancer cells. Little attention has been paid so far to the neoantigen's immune cell counterpart, the T-cell receptor (TCR). In this study, we aimed at characterizing the tumor infiltrating T-cell repertoire in colorectal cancer (CRC), and to evaluate evidence for neoantigen driven T-cell expansion within the tumor microenvironment. To characterize the T-cell repertoire, we used the Ion AmpliSeq Immune Repertoire Assay Plus with an Ion S5 XL system. This assay works with as little as 10ng of starting total RNA, allows 400bp read length, and offers complete characterization of the CDR1, CDR2 and CDR3 regions. A cohort of 20 CRC cases was used, including microsatellite instability (MSI) positive and MSI-negative cases. Our results show a higher T-cell richness in distal CRC samples compared with proximal samples (p=0.04), and lower T-cell richness in M1 as compared with M0 cases (p=0.0001). No association was observed with MSI status, inflammatory infiltrate, tumor grade or lymph node metastasis. We observed that the T-cell repertoire in CRC samples is highly convergent compared to the peripheral blood lymphocyte repertoire of healthy donors (p&amp;lt;0.0001). In CRC samples we observed evidence of selection of TCR clonotypes coding for the same CDR3 aminoacid sequence, suggesting neoantigen-driven TCR convergence. TCR clone overlap was observed only between pairs of samples (4 pairs of primary tumor and metastasis samples available) from the same patient, and not between samples from different patients, suggesting high tumor specificity of T-cell clonotype selection. A validation cohort of CRC cases, including additional pairs of primary tumor and metastasis samples, is currently being analyzed to validate our findings. In this study we provide evidence of T-cell clonotype selection in CRC driven by tumor-specific neoantigens. The specificity of this process is further reinforced by the T-cell clonotype overlap within patients. It remains to be seen whether it is possible to map convergent T-cell clonotypes to its respective tumor neoantigens. Citation Format: Jose C. Machado, Joana Reis, Margarida Fernandes, Rafaela Silva, Luis Cirnes, Fatima Carneiro, Jose L. Costa. T-cell clonotype convergence in colorectal cancer driven by tumor-specific neoantigens [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 136.
Abstract 13621: Integrating Metabolomics and Genomics Uncovers Novel Pathways and Genetic Signatures Influencing Hydrochlorothiazide Blood Pressure Response: A Genetic Response Score for Hydrochlorothiazide Use
Authors: Mohamed H Shahin, Daniel M Rotroff, Amy Webb, Yan Gong, Taimour Langaee, Caitrin W McDonough, Amber L Beitelshees, Timothy Garrett, John G Gums, Alison Motsinger-Reif, Arlene B Chapman, Stephen T Turner, Eric Boerwinkle, Reginald F Frye, Steven E Scherer, Wolfgang Sadee, Oliver Fiehn, Rhonda M Cooper-DeHoff, Rima Kaddurah-Daouk, Julie A Johnson
Journal: Circulation (2015)

Introduction: Hydrochlorothiazide (HCTZ) is among the most commonly prescribed antihypertensives in the US, yet &lt;50% of HCTZ treated patients achieve blood pressure (BP) control. Hypothesis: Integrating metabolomic and genomic profiles of HCTZ treated patients could identify novel pathways/biomarkers for optimizing the use of HCTZ. Methods: Primary analysis included 228 white hypertensives treated with HCTZ from the Pharmacogenomic Evaluation of Antihypertensive Response (PEAR) study. Genotyping was determined via Illumina Omni 1M-Quad Chip and untargeted metabolomics was performed on baseline fasting plasma samples using a GC-TOF MS platform. Pathway analysis was used to integrate metabolites significantly associated with HCTZ BP response (FDR&lt;.05) and genetic signals at p&lt;5x10-5 from HCTZ BP genome-wide analysis. Replication was conducted in another 212 white HCTZ treated patients. Replicated genetic signals were used to create a BP response score by summing their BP lowering alleles. We validated this score by testing it in 196 white HCTZ treated patients in the Genetic Epidemiology of Responses to Antihypertensives (GERA) study. Results: Thirteen metabolites were significantly associated with HCTZ systolic BP (SBP) and diastolic BP (DBP) responses (FDR&lt;.05). Metabolomics-genomics integration revealed significant metabolites along with rs2727563 PRKAG2, rs12604940 DCC, and rs13262930 EPHX2, in the netrin signalling pathway (p=1x10-5), as potential markers significantly influencing HCTZ BP response. We successfully replicated those 3 genetic signals and added their alleles to create a response score which explained 11.3% and 11.9% of the variability to HCTZ SBP and DBP responses, respectively. We found that patients carrying one “response” allele had a significantly worse response than carriers of six alleles (ΔSBP/ΔDBP: -1.5/1.2 vs -16.3/-10.4 mmHg, respectively, SBP score p=1x10-8 and DBP score p=3x10-9). We further validated this response score by testing it in the GERA (DBP score p=0.03, SBP score p=0.07). Conclusion: This study highlights the power of using different omics to identify novel pathways/biomarkers of drug response, and suggests that PRKAG2, DCC and EPHX2 might be important determinants of HCTZ BP response.
The role of fluorescence-guided surgical resection in the combined treatment of malignant glioma.
Authors: Carmine Maria Carapella, Piero Andrea Oppido, Antonello Vidiri, Fabio Cattani, Stefano Maria Telera, Alfredo Pompili, Andrea Pace
Journal: Journal of Clinical Oncology (2012)

2085 Background: Malignant glioma represents a relevant therapeutic issue and the value of extensive surgical resection remains debated; recent evidence suggests that radical removal is associated with better survival. An interesting tool for identifying tumor tissue and increasing the extent of surgery is represented by fluorescence-guided resection, taking advantage of metabolic and structural changes induced by a natural precursor of heme biosynthetic pathway, 5-amino-levulinic acid (ALA). Methods: The present experience is related to 32 patients affected by malignant glioma (18 newly diagnosed: 16 glioblastoma (GBM), 2 anaplastic oligodendroglioma; and 14 recurrent GBM) eligible for fluorescence-guided resection, operated on in our Institute since fall of 2009. All patients underwent preoperative and early postoperative MRI, showing contrast enhancing lesions. An oral dose of 20 mg 5-ALA /kg bw was administered to each patient. Microsurgical resection was performed by an operating microscope enabled to visualize the fluorescence. All the patients, as first line treatment, have been submitted to radiotherapy and chemotherapy; second and in some cases third line treatments were utilized in recurrent cases. The patients follow-up ranged from 2 years to 6 months. Results: In more than 90% of patients tumor tissue showed intraoperative red fluorescence; mainly in recurrent GBM, when MRI documented heterogeneous lesions with enhancing areas mixed with non enhancing gliotic scars, fluorescence-guided surgery allowed a better definition of active tumor, with net margins from perilesional “healthy” brain. Early postoperative MRI confirmed gross total resection without contrast enhancement in 80 % of patients. In the present experience the procedure did not determine any relevant additional neurological deficit. Considering overall survival of recurrent patients we obtained a median extension of at least 9.0 months (3 – 16+ months). Conclusions: Fluorescence-guided surgery improves tumor detection and allows extended resection of malignant glioma, without any relevant impact on neurological status, resulting helpful mainly in the recurrent setting with a consistent effect on overall survival.
Abstract 4845: Preclinical evaluation of HWH340, a novel PARP inhibitor
Authors: Wenjie Sun, Yang Yue, Hailiang Chen, Ronghua Tu, Jie Shen, Gang Li, Guoqiang Ma, Zhixiang Zhang, Charles Z. Ding, Shuhui Chen
Journal: Cancer Research (2018)

Abstract Objective: Poly-ADP-ribose polymerase (PARP) participates in DNA repair, replication and transcription, and is important to maintaining genome stability and integrity. PARP inhibitors have proven to be efficacious in the clinic to treat BRCA-deficient cancers. PARP inhibitors may also be used as sensitizing agent in combination with other antitumor agents. The purpose of this study is to investigate in preclinical models the antitumor activity of HWH340, a novel potent and selective PARP inhibitor currently undergoing clinical investigation. Method: HWH340 was evaluated for its PARP1/2 enzymatic activity in corresponding enzyme assays and its cellular PARylation inhibitory activity in HCC1937 cells. The anti-proliferative activity and the synergistic effect in combination with temozolamide (TMZ) were evaluated in vitro in a BRCA-deficient cell line MDA-MB-436 and BRCA proficient cell line MDA-MB-231. Antitumor activity was evaluated by daily oral administration of in xenograft tumor models. Synergistic effect in combination with TMZ was also determined. The animal models used were PARP highly expressed patient-derived xenograft (PDX) model of small cell lung cancer (SCLC) LU-01-0547 and BRCA1/2-deficient CDX models of breast cancer MDA-MB-436 and pancreatic cancer CAPAN-1. Result: HWH340 displayed potent PARP1/2 enzymatic inhibitory activity with IC50 1.14 nM and 1.72 nM respectively. It also potently inhibited cellular PARylation in HCC1937 cell with IC50 2.77 nM. In BRCA proficient cell line MDA-MB-231, HWH340 showed no synergistic effect when combined with TMZ and a weak anti-proliferative activity with IC50 5.83 uM and 4.86 uM. In contrast, it displayed potent anti-proliferative activity and a synergistic effect in combination with TMZ with IC50 of 71 nM and 7 nM in the BRCA1/2-deficient MDA-MB-436 cells, respectively. HWH340 showed excellent in vivo antitumor efficacy in PARP overexpressed SCLC LU-01-0547 PDX model (TGI=81.69%@50mpk, QD). In BRCA-deficient breast cancer MDA-MB-436 CDX model, HWH340 showed potent antitumor efficacy as single agent (TGI=122% @12.5mpk, QD). In BRCA-deficient pancreatic cancer CAPAN-1 CDX model, it showed potent antitumor efficacy in combination with TMZ (TGI=79.61% @25mpk+ TMZ 30mpk, QD). Conclusion: HWH340 is a potent PARP inhibitor. Its antitumor activity in the preclinical tumor models together with its excellent pharmaceutical properties provide confidence that HWH340 may have high potential in the clinic for treatment of BRCA deficient solid cancers. Citation Format: Wenjie Sun, Yang Yue, Hailiang Chen, Ronghua Tu, Jie Shen, Gang Li, Guoqiang Ma, Zhixiang Zhang, Charles Z. Ding, Shuhui Chen. Preclinical evaluation of HWH340, a novel PARP inhibitor [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 4845.
Abstract 15021: Pulse Wave Transit Time During Exercise Testing Reflects Severity of Heart Failure in Cardiac Patients
Authors: Yo Joon Pak, Akira Koike, Tomoko Terai, Yuta Takayanagi, Rujie Qin, Longmei Wu, Isao Nishi, Kazutaka Aonuma
Journal: Circulation (2017)

Background: The pulse wave transit time (PWTT) can be easily measured as the time from the R wave of electrocardiogram to the arrival of the pulse wave at fingertips using an O2 saturation monitor....
George E. Brown Memorial Lecture
Authors: Hughmontgomery
Journal: Circulation (1957)

It seems fair to say that prior to the use of the oxygen electrode there was a static concept of the oxygen tension of tissues. This was true in spite of the fact that Bazett and Sribyatta, with the gas bubble technic, had demonstrated one example of a labile oxygen tension, in the subcutaneous space of man.17 They of course could not show the rapidity with which the changes take place. Experiments with the polarographic technic have shown that profound changes in oxygen tension can take place very rapidly, all the way from values approaching that of arterial blood down to zero. In vasodilated skin oxygen tension approaches that of arterial blood. When different concentrations of oxygen are breathed, the changes in oxygen tension in such skin closely follow those of the arterial blood. When the circulation to skin is limited by peripheral arterial occlusion, oxygen is reduced and does not increase on vasodilatation as much as does that of normal skin. When a normal person breathes oxygen, the oxygen in th...
Lysophosphatidylcholine Enhances Cytokine-Induced Interferon Gamma Expression in Human T Lymphocytes
Authors: EiichiroNishi, NoriakiKume, YasushiUeno, HiroshiOchi, HideakiMoriwaki, ToruKita
Journal: Circulation Research (1998)

Abstract—Accumulation of substantial numbers of activated T lymphocytes, as well as monocyte/macrophages, in focal areas of arterial intima appears to be a hallmark of atherogenesis. Our previous report demonstrated that lysophosphatidylcholine (lyso-PC), a polar phospholipid component that is increased in atherogenic lipoproteins and atherosclerotic lesions, can upregulate the expression of heparin-binding epidermal growth factor–like growth factor and the interleukin (IL)-2 receptor in cultured human peripheral T lymphocytes. In this study, we show that lyso-PC can also enhance interferon gamma (IFN-γ) secretion and gene expression in human T lymphocytes. Lyso-PC–induced upregulation of IFN-γ depended on the presence of IL-2, IL-12, or phytohemagglutinin in culture media and was similarly observed in both CD4+ and CD8+ subsets. Actinomycin D chase by Northern blotting showed that lyso-PC significantly prolonged IFN-γ mRNA half-lives in human T cells. Transient transfection of IFN-γ promoter-reporter gen...
Italy suspends mandatory vaccination of nursery children after Senate vote
Authors: Marta Paterlini
Journal: BMJ (2018)

The Italian Senate has voted through an amendment to a law passed a year ago, to suspend that law’s requirement for parents to prove that their child has had a series of vaccinations when they enrol at nursery.

The bill now passes to the lower house, which is expected to vote on the amendment in mid-September, meaning that the bill would not be restored until 2019 at the earliest. Confused parents have been told that, for the time being, they can simply provide self signed certification that their child has been vaccinated.

Doctors, school principals, and the scientific community at large have criticised the U turn by the new government.

Italy’s National …
Abstract 15345: Prevalence of Abnormal Preparticipation Screening H&Ps in Collegiate Athletes as Compared to Focused Screening Echocardiography
Authors: DanielModaff, SheilaHegde, DennisHelwig, NancyBell, PeterRahko
Journal: Circulation (2014)

Introduction: For all competitive athletes, the American Heart Association preparticipation screening (AHA PPS) guidelines recommend a 12 element focused history and physical. Evaluation of an abnormal PPS finding is left to the clinician’s discretion. The correlation between an abnormal PPS finding and structural heart disease is not well documented. A murmur on physical exam is classically used as a tool to identify a multitude of structural heart abnormalities. We propose that the current AHA PPS and specifically, a murmur detected on exam, correlate poorly with true echocardiographic abnormalities in the collegiate athlete population. Methods: A PPS modeled after the AHA guidelines was conducted on all incoming athletes at a single university from 2007 to 2013. All athletes independently underwent a focused screening echo the same day of the exam. PPS examiners were blinded to results of the screening echoes. Data from both screening exams were compared. We report the prevalence of abnormal H&P findin...
Abstract 4794: Preclinical evaluation of WX-0593, a potent orally active ALK inhibitor
Authors: Liu Xile, Charles Z Ding, Weifeng Mao, Yuxin Qin, Shansong Zheng, Yingying Yang, Qingmei Zheng, Long Zhang, Shuyong Zhao
Journal: Cancer Research (2018)

Abstract Objective: ALK is a tyrosine kinase belonging to the insulin receptor super-family. The constitutively active ALK fusions are oncogenic and linked with multiple types of human cancer. The EML4-ALK fusion has been proven to be the driver of approximately 5% of NSCLC patients. We disclose here for the first time a novel ALK inhibitor WX-0593 and its preclinical evaluation data in preclinical models of ALK driven NSCLC. Method: The enzyme activities of WX-0593 for ALKWT, ALKL1196M, ALKC1156Y and EGFRL858R/T790M were measured with corresponding kinase assays. The anti-proliferative activity was evaluated in Karpas-299, Ba/F3, Ba/F3 (EML4-ALK-WT), Ba/F3 (EML4-ALK-L1196M), Ba/F3 (EML4-ALK-C1156Y), and NCI-H1975 cell lines. The specific effect (PD) of WX-0593 on ALK signaling was analyzed in NCI-H3122 cells. Antitumor activity of WX-0593 was evaluated in three patient-derived xenograft (PDX) models of NSCLC (LU-01-0015, LU-01-0319, and crizotinib resistant LU-01-0319R) and one cell-derived xenograft (CDX) model of NSCLC (NCI-H3122). PKPD was assessed by western blot analysis of the treated tumor tissues for p-ALK (Tyr1604), p-STAT3 (Tyr705), p-STAT5 (Tyr694), p-AKT, and p-ERK. Result: WX-0593 displayed potent enzymatic activities for ALKWT, ALKL1196M, ALKC1156Y and EGFRL858R/T790M with IC50 of 5.38, 9.26, 9.28, and 16.74 nM respectively. It also showed expected anti-proliferative activity in six cell lines, Karpas-299, Ba/F3, Ba/F3 (EML4-ALK-WT), Ba/F3 (EML4- ALK-L1196M), Ba/F3 (EML4-ALK-C1156Y), and NCI-H1975, with IC50 of 4.5, 2208, 4, 9.5, 9, and 508 nM, respectively. Western blot study in NCI-H3122 cells showed that WX-0593 could fully inhibit p-ALK, p-ERK,p-STAT5 at 11.1 nM and p-AKT at 100 nM. WX-0593 significantly inhibited tumor growth at all doses tested (P&amp;lt;0.001) in the LU-01-0015 (HIP1-ALK), LU-01-0319 (EML4-ALK), and LU-01-0319R NSCLC PDX models as well as in the NCI-H3122 CDX model. Western blot analysis of the tumor samples showed that WX-0593 inhibited p-ALK (Tyr1604), p-STAT3 (Tyr705), p-STAT5 (Tyr694), p-AKT, and p-ERK, indicating that the tumor growth inhibition was mediated by inhibition of ALK signaling. Conclusion: We have identified a potent orally active second generation ALK inhibitor, WX-0593. It can inhibit the activity of both wide type and crizotinib resistant ALK and showed strong antitumor activity in in vitro and in vivo preclinical models. These results are considered highly promising and warrant moving the compound forward to clinical investigation. Citation Format: Liu Xile, Charles Z Ding, Weifeng Mao, Yuxin Qin, Shansong Zheng, Yingying Yang, Qingmei Zheng, Long Zhang, Shuyong Zhao. Preclinical evaluation of WX-0593, a potent orally active ALK inhibitor [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 4794.
Abstract 4512: Doublecortin-like kinase 1 (DCLK1) correlates with Notch pathway signaling, controls metastatic characteristics in head and neck cancer
Authors: Esther Channah Broner, Tejaswini Subbannayya, Jayshree Advani, Alex Zhavoronkov, Artem Artemov, Ivan Ozerov, Ido Sloma, Harsha Gowda, David Sidransky, Eugene Izumchenko, Aditi Chatterjee
Journal: Cancer Research (2018)

Abstract Despite advancements in the field, the 5 year survival rate of Head and Neck Squamous Cell Carcinoma (HNSCC) still hovers at 60%. In a quest for novel therapy targets for this disease, we performed an extensive and comprehensive quantitative phosphoproteomics scan on 10 HNSCC patient derived xenografts (PDXs) in order to find dysregulated phosphoproteins. DCLK1 is hyperphosphorylated but not over expressed in most of the HNSCC derived PDXs. DCLK1 has been shown to regulate epithelial-to-mesenchymal transition (EMT) as well as serving as a cancer stem cell marker in colon and pancreas cancer. DCLK1 is also associated with bad prognosis in colon, renal and oropharyngeal cancers. We performed a comprehensive transcriptome-based computational analysis on hundreds of HNSCC patients from TCGA and GEO databases. While our results confirm the role of DCLK1 in regulating EMT and focal adhesion kinase (FAK) mediated integrin signaling, we found that high DCLK1 expression also correlates with NOTCH pathway signaling signatures in HNSCC. We have selected 5 cell HNSCC cell lines (JHU-011, JHU-022, JHU-029, FaDu and Cal29) that express DCLK1, and inhibited DCLK1 with LRRK2-in1 inhibitor and siRNA. DCLK1 inhibition resulted in substantially decreased proliferation, migration, and colony formation. Furthermore, these effects paralleled downregulation NOTCH1 signaling in all cell lines tested. Overall, our results demonstrate the novel role of DCLK1 in regulating the NOTCH signaling network and suggest its potential as a therapeutic target in HNSCC. Citation Format: Esther Channah Broner, Tejaswini Subbannayya, Jayshree Advani, Alex Zhavoronkov, Artem Artemov, Ivan Ozerov, Ido Sloma, Harsha Gowda, David Sidransky, Eugene Izumchenko, Aditi Chatterjee. Doublecortin-like kinase 1 (DCLK1) correlates with Notch pathway signaling, controls metastatic characteristics 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 4512.