tbuckley/cabot-search huggingface dataset:
Utility of 68Ga-PSMA-11 PET/CT in Imaging of Glioma—A Pilot Study
Authors: Arun Sasikumar, Raghava Kashyap, Ajith Joy, Kanhu Charan Patro, Parthasarathy Bhattacharya, Venkata Krishna Reddy Pilaka, Karuna Elza Oommen, Maroor Raghavan Ambikalmajan Pillai
Journal: Clinical Nuclear Medicine (2018)

Imaging of gliomas remains challenging. The aim of the study was to assess the feasibility of using Ga-PSMA-11 PET/CT for imaging gliomas.Fifteen patients with glioma from 2 centers were included in the study. Ten patients were treated cases of glioblastoma with suspected recurrence. Two patients were sent for assessing the nature (primary lesion/metastasis) of space-occupying lesion in the brain; 3 patients were imaged immediately after surgery and before radiotherapy. Target-to-background ratios (TBR) for the brain lesions were calculated using contralateral cerebellar uptake as background.Among the 10 cases with suspected recurrence, scan was positive in 9, subsequent surgery was done, and histopathology proved it to be true recurrence. In the scan-negative case on follow-up, no evidence of disease could be made clinically or radiologically. Among the other cases the presence or absence of disease could be unequivocally identified on the Ga-PSMA-11 brain scan and correlated with the histopathology or other imaging. Apart from the visual assessment quantitative assessment of the lesions with TBR also showed a significantly high TBR value for those with true disease compared with those with no disease.In the evaluation of gliomas, Ga-PSMA-11 PET/CT brain imaging is a potentially useful imaging tool. The use of Ga-PSMA-11 brain PET/CT in evaluation of recurrent glioma seems promising. Absence of physiological uptake of Ga-PSMA-11 in the normal brain parenchyma results in high TBR values and consequently better visualization of glioma lesions.
Abstract 1724: Evaluation of niraparib in combination with anti-PD1/anti-PD-L1 in preclinical models
Authors: Sarah Wang, Kaiming Sun, Yonghong Xiao, Bin Feng, Keith Mikule, Sridhar Ramaswamy, Jeffrey Hanke, Jing Wang
Journal: Cancer Research (2018)

Abstract Niraparib is an orally available and selective poly(ADP-ribose) polymerase (PARP)-1/-2 inhibitor approved for maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. PARP inhibition may enhance the immune response in tumors treated with anti-PD-1 therapy via generation of cytosolic DNA that activates T cells through the stimulator of interferon gene (STING) pathway, rendering tumors immunologically “hot” with an increase in infiltrating lymphocytes. In this study, we explored the responses and mechanism of action of niraparib and anti-PD-1/anti-PD-L1 combination therapy in preclinical models. Out of a cohort of 14 immune-competent mouse tumor models, the combination treatment demonstrated enhanced anti-tumor activity in eight tumor models derived from BRCA-proficient and BRCA-deficient genetic backgrounds. Substantial increases compared to monotherapies in anti-tumor activity was observed in 5 models, indicative of synergy between niraparib and anti-PD-1/anti-PD-L1 therapy. The combination triggered durable responses that were coincident with induction of immune memories in a BRCA-deficient ovarian syngeneic model. Mechanistically, niraparib treatment increased the number of infiltrating CD8+ and CD4+ cells within the intratumoral region. The enhanced immune cell infiltration was accompanied by elevated interferon-stimulated gene expression. Pathway analyses using transcriptome profiling identified interferon response gene signatures as the significantly differentially-upregulated gene sets following niraparib treatment. Consistently, niraparib treatment activated the STING pathway in vitro in BRCA-deficient MDA-MB-436 human triple negative breast cancer cells. STING pathway markers including p-STING(Ser366), p-TBK1(Ser172) and p-NFκB p65 were elevated following niraparib treatment and was accompanied by an increase in IFNB mRNA expression. In summary, our data suggested that niraparib treatment in combination with anti-PD-1/anti-PD-L1 therapy enhanced immune cell infiltration, interferon-stimulated gene expression and tumor responses. Citation Format: Sarah Wang, Kaiming Sun, Yonghong Xiao, Bin Feng, Keith Mikule, Sridhar Ramaswamy, Jeffrey Hanke, Jing Wang. Evaluation of niraparib in combination with anti-PD1/anti-PD-L1 in preclinical models [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 1724.
Abstract 858: Enzalutamide versus abiraterone as a radiosensitizer in hormone-sensitive prostate cancer cells
Authors: Maryam Ghashghaei, Thierry Muanza, Moulay Alaoui-Jamali, Miltiadis Paliouras, Mohammad Tamim Niazi
Journal: Cancer Research (2018)

Abstract Prostate cancer treatment is based on the estimated risk of recurrence in the U.S. Combined androgen deprivation therapy (ADT) with radiation therapy (XRT) is the standard of care for high-risk localized PCa. However, a large percentage of tumors are resistance to ADT due to continued AR signaling. Abiraterone (ABI), an androgen synthesis inhibitor, and Enzalutamide (ENZA), a potent AR antagonist, are new treatment options for metastatic castration resistance prostate cancer (mCRPC) patients. The aim of this study is to compare the efficacy of ENZA or ABI as a radiosensitizer in XRT therapy on PCa cells. Methods: The effect of ENZA or ABI alone or in combination with XRT was assessed on hormone-sensitive (LNCaP, PC3-AR-T877A) and insensitive (PC3, PC3-AR V7) PCa cells using cell viability (MTT) and also clonogenic assays in different scheduling regimens: A- drug 24 h before XRT, B-drug 2h before XRT, or C- XRT followed by 24h later drug. Results: We first determined the effect of ENZA or ABI on MTT assays in androgen-dependent (AD) and androgen-independent (AI) PCa cell lines. The results of MTT assay showed that ENZA inhibited the growth of the four different cell lines, LNCaP, PC3-T877A, PC3 and PC3 AR-V7 with IC50 values of 20, 22, 50, and 45μmol/L, respectively, after 24 hours of treatment. The same effect was observed on ABI treated cell lines. Radiosensitivity was not significantly increased in AD and AI PCa cell lines by ABI (DEF=1.00, in all cases) while there was a supra-additive dose enhancement factor (DEF= 1.75±0.08) for hormone-sensitive cells treated with ENZA (Table 1). Conclusion: Our data indicates that ENZA acts as a much stronger radiosensitizer compared to ABI through different probable mechanisms of radiosensitivity. Table 1. Dose Enhancement Factors calculations by scheduling ProtocolABCENZAABIENZAABIENZAABIADLNCaP1.35±0.021.05±0.011.75±0.081.001.30±0.051.00PC3-AR T877A1.30±0.031.001.65±0.011.001.35±0.061.05±0.02AIPC31.001.001.001.001.001.00PC3-AR V71.001.001.001.001.001.00 Citation Format: Maryam Ghashghaei, Thierry Muanza, Moulay Alaoui-Jamali, Miltiadis Paliouras, Mohammad Tamim Niazi. Enzalutamide versus abiraterone as a radiosensitizer in hormone-sensitive prostate cancer cells [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 858.
Rare Variants in Known Susceptibility Loci and Their Contribution to Risk of Lung Cancer
Authors: Yanhong Liu, Christine M. Lusk, Michael H. Cho, Edwin K. Silverman, Dandi Qiao, Ruyang Zhang, Michael E. Scheurer, Farrah Kheradmand, David A. Wheeler, Spiridon Tsavachidis, Georgina Armstrong, Dakai Zhu, Ignacio I. Wistuba, Chi-Wan B. Chow, Carmen Behrens, Claudio W. Pikielny, Christine Neslund-Dudas, Susan M. Pinney, Marshall Anderson, Elena Kupert, Joan Bailey-Wilson, Colette Gaba, Diptasri Mandal, Ming You, Mariza de Andrade, Ping Yang, John K. Field, Triantafillos Liloglou, Michael Davies, Jolanta Lissowska, Beata Swiatkowska, David Zaridze, Anush Mukeriya, Vladimir Janout, Ivana Holcatova, Dana Mates, Sasa Milosavljevic, Ghislaine Scelo, Paul Brennan, James McKay, Geoffrey Liu, Rayjean J. Hung, David C. Christiani, Ann G. Schwartz, Christopher I. Amos, Margaret R. Spitz
Journal: Journal of Thoracic Oncology (2018)
Aspirin-free strategies in cardiovascular disease and cardioembolic stroke prevention
Authors: Davide Capodanno, Roxana Mehran, Marco Valgimigli, Usman Baber, Stephan Windecker, Pascal Vranckx, George Dangas, Fabiana Rollini, Takeshi Kimura, Jean-Philippe Collet, C. Michael Gibson, Philippe Gabriel Steg, Renato D. Lopes, Hyeon-Cheol Gwon, Robert F. Storey, Francesco Franchi, Deepak L. Bhatt, Patrick W. Serruys, Dominick J. Angiolillo
Journal: Nature Reviews Cardiology (2018)
Abstract CT070: Innovative design for a phase I trial with intra-patient dose escalation: The Crotoxin study
Authors: Jacques Medioni, Mara Brizard, Reza Elaidi, Paul F. Reid, Benlhassan5 Khadija, Dorothy Bray
Journal: Cancer Research (2018)

Abstract INTRODUCTION. Crotoxin is a bipartite South America rattle snake neurotoxin. It has broad spectrum antitumor activity in vivo in addition to exerting analgesic effects. Prior clinical reports using i.m. injections resulted in local immune reactions with erythema, itching or pain, in addition to anaphylaxis though encouraging responses were recorded. A clinical study was designed incorporating i.v. administration, dose escalation and pre-treatment antihistamine use, aimed at improving dose limiting toxicity (DLT) and local tolerance. METHOD. This trial was performed in patients with stage IV cancer with the primary endpoints to assess safety and tolerability, measured by Dose-Limiting Toxicity (DLT) and to define the Maximum Tolerated Dose (MTD). The secondary objectives were to document anti-tumor efficacy, evaluated according to radiological RECIST criteria 1.0 and analgesia. Baseline pain assessments were completed for each patient. Cohort I included 6 patients with advanced solid tumors (no further therapy options), with dose escalation from 0.04 to 0.32 mg/m2/day administered IV by saline drip over 2h daily (Mon to Fri) over 54 days. RESULTS.One male and 5 females (pts) with prior heavily-treated advanced tumors were enrolled: colorectal adenocarcinoma, epithelioid mesothelioma, non-small-cell lung cancer, carcinoma of unknown primary site, invasive breast ductal carcinoma and ovarian papillary adenocarcinoma. Three patients reached the highest target dose level. DLT or MTD were not attained. In Cohort I grade 1 to 2 drug-related events occurred in 3/6 patients: anorexia, diplopia and nystagmus. There were no drug-related serious adverse events. Tumor assessment was performed after 8 weeks of dose escalation (day 54) and all subjects were determined to have progressive disease. At baseline, pain was reported for 5/6 subjects, surveys revealed a diminution of analgesic scores. CONCLUSION: Crotoxin i.v. dose escalation protocol allowed administering 0.32 mg/m2/day without unexpected toxicity. Lack of anti-cancer benefit might be related to the long period of 6-8 weeks to reach this dose. A redesign of the protocol to escalate faster and to higher doses, without weekend breaks, is required. Citation Format: Jacques Medioni, Mara Brizard, Reza Elaidi, Paul F. Reid, Benlhassan5 Khadija, Dorothy Bray. Innovative design for a phase I trial with intra-patient dose escalation: The Crotoxin study [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 CT070.
Double-sided effect of tumor microenvironment on platelets targeting nanoparticles
Authors: Xinli Chen, Qingbing Wang, Lisha Liu, Tao Sun, Wenxi Zhou, Qinjun Chen, Yifei Lu, Xi He, Yu Zhang, Yujie Zhang, Chunhui Ruan, Qin Guo, Chao Li, Chen Jiang
Journal: Biomaterials (2018)
Abstract 15027: Left Ventricular Mass is Associated with Orthostatic Leg Blood Pressure in Normotensive Subjects
Authors: Tiago Gemignani, Jose Roberto Matos-Souza, Kleber Franchini, Wilson Nadruz JUnior
Journal: Circulation (2012)

Changing from supine to orthostatic posture leads to substantial increments in leg blood pressure (BP) levels, which could ultimately influence the hemodynamic burden imposed to the heart. This study investigated the relationship between brachial and leg BP and left cardiac chambers structure and further assessed the role of body posture changes in this regard.   Methods:  One hundred thirty normotensive, non-diabetic, non-smoking, normolipemic subjects (59% women) were evaluated by clinical history, anthropometry, analysis of metabolic parameters, echocardiography, and had their BP measured in the arm and calf in supine and orthostatic positions.   Results:  Changing from supine to standing substantially increased BP levels in the legs (p p    Conclusion:  Orthostatic leg BP is independently associated with cardiac structure in normotensive subjects.
Abstract 1360: A PARylation biosensor genetic screen to identify novel PARylation targets
Authors: Dragomir B. Krastev, Stephen J. Pettitt, James Campbell, Alan Ashworth, Christopher J. Lord
Journal: Cancer Research (2018)

Abstract Poly(ADP-ribosylation) (PARylation) is a reversible post-translational protein modification that regulates a number of cellular processes. It is generated by a family of PAR polymerases (PARP), of which PARP1 has recently been exploited as a target in ovarian cancer carrying BRCA1/2 mutations. In addition, tankyrase (PARP5A and B), with its regulation of Wnt signalling, telomeres and the mitotic apparatus, has attracted much effort in the development of targeted therapies. All this necessitates the identification of PARylation targets and their mode of regulation by the modification. Genetically encoded fluorescent biosensor that can report the PARylation state of a target protein has the potential to report the modulation of the PARylation target in living cells. We used PAR-binding PBZ domains fused to a non-fluorescent fragment of a GFP molecule in combination with a protein of interest fused to the complementing fragment of GFP. When this protein is PARylated, it is recognized by the PBZ domain, which brings in proximity the two GFP fragments, and restores the GFP fluorescence. Known targets of PARylation, e.g. TERF1 and AXIN1, showed specific spatial patterns of PARylation validating our approach. In order to identify novel PARylation targets, we have designed a genetic screen based on the biosensor. We introduced the GFP fragment in a transposon, which was randomly integrated in cellular genome, thus generating cellular libraries of thousands of tagged genes. The introduction of the PAR binding probe lead to GFP fluorescence in clones that harbour putative PARylation targets. We developed a next generation sequencing approach to isolate the transposon integration sites and annotated the target genes. Reassuringly, we have identified NPM1, a well-known PARylation target, as a strongly scoring gene. We focused on one of novel identified hits (CTIF). We showed that CTIF is PARylated in vivo in a tankyrase-dependent manner. Furthermore, the biosensor revealed that this PARylation is predominant in a specific cellular compartment surrounding the centrosome. Functional studies have implicated this protein the regulation of the centrosomal satellites. Collectively, we are presenting a new approach to identify PARylated proteins and study their patterns of PARylation and regulation in vivo. Citation Format: Dragomir B. Krastev, Stephen J. Pettitt, James Campbell, Alan Ashworth, Christopher J. Lord. A PARylation biosensor genetic screen to identify novel PARylation targets [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 1360.
Diagnostic algorithm for lower-risk myelodysplastic syndromes
Authors: Ghulam J. Mufti, Donal P. McLornan, Arjan A. van de Loosdrecht, Ulrich Germing, Robert P. Hasserjian
Journal: Leukemia (2018)

Rapid advances over the past decade have uncovered the heterogeneous genomic and immunologic landscape of myelodysplastic syndromes (MDS). This has led to notable improvements in the accuracy and timing of diagnosis and prognostication of MDS, as well as the identification of possible novel targets for therapeutic intervention. For the practicing clinician, however, this increase in genomic, epigenomic, and immunologic knowledge needs consideration in a "real-world" context to aid diagnostic specificity. Although the 2016 revision to the World Health Organization classification for MDS is comprehensive and timely, certain limitations still exist for day-to-day clinical practice. In this review, we describe an up-to-date diagnostic approach to patients with suspected lower-risk MDS, including hypoplastic MDS, and demonstrate the requirement for an "integrated" diagnostic approach. Moreover, in the era of rapid access to massive parallel sequencing platforms for mutational screening, we suggest which patients should undergo such analyses, when such screening should be performed, and how those data should be interpreted. This is particularly relevant given the recent findings describing age-related clonal hematopoiesis.
Tongue Necrosis in Giant-Cell Arteritis
Authors: Laurent Truffaut, Philippe Lefebvre
Journal: New England Journal of Medicine (2018)

An 86-year-old woman presented with fatigue and headache. Temporal-artery biopsy confirmed a diagnosis of giant-cell arteritis. Several days later, she returned with tongue necrosis. Computed tomography revealed thrombosis of the right lingual artery.
Abstract 2734: Novel CTLA4 antibodies demonstrate potent antitumor activity in a humanized mouse model
Authors: Jie Xiang, Yanan Guo, Yuelei Shen, Benny Yang
Journal: Cancer Research (2018)

Abstract CTLA4 (cytotoxic T-lymphocyte-associated protein 4), is a member of the immunoglobulin superfamily. It is expressed in T cells upon activation and transmits an inhibitor signal to T cells. Also, it is constitutively expressed in regulatory T cells (Tregs) which is associated with their immunosuppressive phenotype. CTLA4 is homologous to the co-stimulatory protein CD28, and both receptor binds to CD80 and CD86. Cancer cells can be recognized and destructed by the host's immune system. In this setting, CTLA4 functions as a brake to dampen anti-tumor T cell responses, which promote cancer progression. Antibodies targeting CTLA4 was expected to subvert T cell inhibition. Moreover, regulatory T cells residing in the tumor microenvironment can be killed by anti-CTLA4 antibody since these cells have higher expression level of CTLA4 comparing with the activated T cells. Yervoy, an anti-CTLA4 antibody, was the first FDA-approved antibody targeting the immune checkpointfamily, and it protects a fraction of cancer patients when either used alone or in combination with other drugs. We asked whether the efficacy of anti-CTLA4 antibodies could be evaluated in humanized mouse models. And if so, whether we can use in vivo assay to guide the development of potent antibodies targeting CTLA4. Here, we describe that using the platform established at Biocytogen, we successfully discovered two antibodies whose efficacy is equivalent or exceed that of Yervoy. The clinical evaluation of these new entities are wanted. Citation Format: Jie Xiang, Yanan Guo, Yuelei Shen, Benny Yang. Novel CTLA4 antibodies demonstrate potent antitumor activity in a humanized 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 2734.
Increasing evidence-based interventions in patients with acute infections in a resource-limited setting: a before-and-after feasibility trial in Gitwe, Rwanda
Authors: Olivier Urayeneza, Pierre Mujyarugamba, Zacharie Rukemba, Vincent Nyiringabo, Polyphile Ntihinyurwa, John I. Baelani, Arthur Kwizera, Danstan Bagenda, Mervyn Mer, Ndidiamaka Musa, Julia T. Hoffman, Ashok Mudgapalli, Austin M. Porter, Niranjan Kissoon, Hanno Ulmer, Lori A. Harmon, Joseph C. Farmer, Martin W. Dünser, Andrew J. Patterson
Journal: Intensive Care Medicine (2018)
Abstract 1979: HQP1351, a novel multikinase inhibitor in clinical development, overcomes drug resistance for the treatment of gastrointestinal stromal tumors in preclinical models
Authors: Guangfeng Wang, Haibo Qiu, Ping Min, Miaoyi Wu, Shuo Dang, Chunyang Yang, Fei Zhang, Wei Zhuang, Zhiwei Zhou, Douglas D. Fang, Dajun Yang, Yifan Zhai
Journal: Cancer Research (2018)

Abstract Gastrointestinal stromal tumors (GIST) harbor driver mutations of signal transduction kinases such as KIT. Besides surgical resection for primary localized tumors, imatinib remains the first-line treatment for advanced and metastatic GISTs. Imatinib targets a few kinases including KIT that often carries the primary driver mutations commonly located on exon 11 and exon 9. Unfortunately, a large proportion of the patients ultimately develop progressive disease owing to the secondary resistance mutations in KIT gene. We have developed an orally bioavailable multikinase inhibitor HQP1351, which is currently in clinical trials for the treatment of T315I mutant CML. Here, we demonstrated that HQP1351 inhibited both wild type and mutant (i.e., KITL576P, KITV559D, and KITV559D/T670I) KIT in biochemical assays. Using a panel of imatinib-resistant and sensitive GIST cancer cell lines derived from patient samples, we showed that HQP1351 exhibited more potent anti-proliferative activities than ponatinib (range of IC50 values: 0.027-0.133 µM vs. 0.021-0.730 µM), the latter of which is currently in clinical development in GIST to overcome the resistance to imatinib (NCT03171389). In addition, the treatment of GIST cancer cells with HQP1351 in vitro led to more profound inhibition of pharmacodynamic markers, including p-c-KIT, p-AKT, p-ERK1/2, and p-AKT, in comparison with ponatinib. Correspondingly, in multiple xenograft tumor models derived from these GIST cancer cell lines carrying the secondary mutations of KIT, HQP1351 exhibited superior antitumor activities to ponatinib. Collectively, considering that HQP1351 has already been in clinical trials, the above results suggest that therapeutic application of HQP1351 in imatinib-resistant GIST patients deserves further investigation in human. Citation Format: Guangfeng Wang, Haibo Qiu, Ping Min, Miaoyi Wu, Shuo Dang, Chunyang Yang, Fei Zhang, Wei Zhuang, Zhiwei Zhou, Douglas D. Fang, Dajun Yang, Yifan Zhai. HQP1351, a novel multikinase inhibitor in clinical development, overcomes drug resistance for the treatment of gastrointestinal stromal tumors in preclinical models [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 1979.
Trophoblast Glycoprotein is Associated With a Favorable Outcome for Mesothelioma and a Target for Antibody Drug Conjugates
Authors: Laurel M. Schunselaar, Kim Monkhorst, Vincent van der Noort, Ruud Wijdeven, Dennis Peters, Wilbert Zwart, Jacques Neefjes, Paul Baas
Journal: Journal of Thoracic Oncology (2018)