tbuckley/cabot-search huggingface dataset:
Cabazitaxel Versus Docetaxel As First-Line Therapy for Patients With Metastatic Castration-Resistant Prostate Cancer: A Randomized Phase III Trial—FIRSTANA
Authors: Stéphane Oudard, Karim Fizazi, Lisa Sengeløv, Gedske Daugaard, Fred Saad, Steinbjørn Hansen, Marie Hjälm-Eriksson, Jacek Jassem, Antoine Thiery-Vuillemin, Orazio Caffo, Daniel Castellano, Paul N. Mainwaring, John Bernard, Liji Shen, Mustapha Chadjaa, Oliver Sartor
Journal: Journal of Clinical Oncology (2017)

Purpose In patients with metastatic castration-resistant prostate cancer (mCRPC), overall survival (OS) is significantly improved with cabazitaxel versus mitoxantrone after prior docetaxel treatment. FIRSTANA ( ClinicalTrials.gov identifier: NCT01308567) assessed whether cabazitaxel 20 mg/m2 (C20) or 25 mg/m2 (C25) is superior to docetaxel 75 mg/m2 (D75) in terms of OS in patients with chemotherapy-naïve mCRPC. Patients and Methods Patients with mCRPC and Eastern Cooperative Oncology Group performance status of 0 to 2 were randomly assigned 1:1:1 to receive C20, C25, or D75 intravenously every 3 weeks plus daily prednisone. The primary end point was OS. Secondary end points included safety; progression-free survival (PFS); tumor, prostate-specific antigen, and pain response; pharmacokinetics; and health-related quality of life. Results Between May 2011 and April 2013, 1,168 patients were randomly assigned. Baseline characteristics were similar across cohorts. Median OS was 24.5 months with C20, 25.2 months with C25, and 24.3 months with D75. Hazard ratio for C20 versus D75 was 1.01 (95% CI, 0.85 to 1.20; P = .997), and hazard ratio for C25 versus D75 was 0.97 (95% CI, 0.82 to 1.16; P = .757). Median PFS was 4.4 months with C20, 5.1 months with C25, and 5.3 months with D75, with no significant differences between treatment arms. Radiographic tumor responses were numerically higher for C25 (41.6%) versus D75 (30.9%; nominal P = .037, without multiplicity test adjustment). Rates of grade 3 or 4 treatment-emergent adverse events were 41.2%, 60.1%, and 46.0% for C20, C25, and D75, respectively. Febrile neutropenia, diarrhea, and hematuria were more frequent with C25; peripheral neuropathy, peripheral edema, alopecia, and nail disorders were more frequent with D75. Conclusion C20 and C25 did not demonstrate superiority for OS versus D75 in patients with chemotherapy-naïve mCRPC. Tumor response was numerically higher with C25 versus D75; pain PFS was numerically improved with D75 versus C25. Cabazitaxel and docetaxel demonstrated different toxicity profiles, with overall less toxicity with C20.
Evaluation of a widely used culture-based method for detection of livestock-associated meticillin-resistant Staphylococcus aureus (MRSA), Denmark and Norway, 2014 to 2016
Authors: Jesper Larsen, Marianne Sunde, Md Zohorul Islam, Anne Margrete Urdahl, Aina Steihaug Barstad, Anders Rhod Larsen, Carl Andreas Grøntvedt, Øystein Angen
Journal: Eurosurveillance (2017)

We evaluated a widely used culture-based method for detection of livestock-associated meticillin-resistant Staphylococcus aureus (LA-MRSA) in samples collected from pigs and the environment inside pig stables in Denmark and Norway. Selective enrichment in tryptic soy broth containing cefoxitin and aztreonam led to a high ratio of false-negative results (26%; 57/221). On this basis, we recommend reconsidering the use of selective enrichment for detection of LA-MRSA in animal and environmental samples.
Abstract 5777: Translation of HPV mediated immortalization to cancer precision medicine
Authors: Aleksandra Dakic, Nancy Palechor-Ceron, Ewa Krawczyk, Hang Yuan, Frank Suprynowicz, Seema Agarwal, Richard Schlegel, Vera Simic, Praathibha Sripadhan, Chen Chen, Jie Lu, Tung-Wei Hou, Sujata Choudhury, Xuefeng Liu
Journal: Cancer Research (2017)

Abstract The E6/E7 oncogenes of the high-risk HPVs are both necessary and sufficient to immortalize HFKs and their presence and expression is required for the continued proliferation of HPV-positive cervical cancer cells. We and others have shown previously that hTERT induced by E6 and cytoskeleton alteration by E7 are critical. Both E6 and feeder cells activate telomerase, while both E7 and Rock inhibitor (Y-27632) disrupt the actin cytoskeleton and inactivate Rho. Feeders and Y-27632 to induce unlimited cell proliferation of human keratinocytes. Unexpectedly, we observed that feeders and Y-27632 could be used to establish both normal and tumor cell cultures from non-keratinocyte tissues. This culture has been termed as “conditional reprogramming”, since CR cultures stop proliferating or terminally differentiate after its removal, depending on culture conditions. The Combination of CR and Organoids ( (Matrigel, air-liquid interface (ALI)) cultures represents next generation human cancer models and functional diagnostics for cancer precision medicine as described in August 2015 in the NCI precision medicine initiative and three nature review articles (Nat Rev Cancer. 2015 Dec; Nat Rev Genet. 2015 Jul; Nat Rev Clin Oncol. 2014 Nov.). The technique is relatively simple and has been reproduced in more than 50 laboratories (including an original and independent article in Science from Massachusetts General Hospital) (Science. 2014, 346(6216):1480-6.). Importantly, the CR technology can generate 2x10&amp;lt;6cells in a week from small biopsies, and can generate cultures from cryopreserved tissue and small biopsies. We therefore initiated studies to examine whether CR cultures reflected the biology and genotype of the original tumor and whether cultures might be used to predict clinical responses. Moreover, the epithelial cells can be propagated indefinitely in vitro, yet retain the capacity to become fully differentiated when placed into conditions that mimic their natural environment. Thus, the CR method significantly advances applications for regenerative medicine. Citation Format: Aleksandra Dakic, Nancy Palechor-Ceron, Ewa Krawczyk, Hang Yuan, Frank Suprynowicz, Seema Agarwal, Richard Schlegel, Vera Simic, Praathibha Sripadhan, Chen Chen, Jie Lu, Tung-Wei Hou, Sujata Choudhury, Xuefeng Liu. Translation of HPV mediated immortalization to cancer precision medicine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5777. doi:10.1158/1538-7445.AM2017-5777
Phase 1 Dose Escalation Study of MDM2 Inhibitor DS-3032b in Patients with Hematological Malignancies - Preliminary Results
Authors: Courtney D DiNardo, Joseph Rosenthal, Michael Andreeff, Oleg Zernovak, Prasanna Kumar, Roohi Gajee, Shuquan Chen, Michael Rosen, Saeheum Song, Jarema Kochan, Tharin Limsakun, Rebecca Olin
Journal: Blood (2016)
Abstract 3919: Isolation and characterization of viable pancreatic cancer circulating tumor cells using size-based filtration system
Authors: Kenneth H. Yu, Benjamin D. Krempley, Brian McCarthy
Journal: Cancer Research (2017)

Abstract Introduction: Circulating tumor cells (CTCs) are important actors in metastasis, a key feature of pancreatic ductal adenocarcinoma (PDAC). The ability to isolate, characterize and culture viable CTCs holds promise for understanding biology, treatment response and resistance. Methods: Peripheral blood samples from healthy donors and patients with advanced PDAC were processed using an innovative size filtration system (Viatar LLC, Lowell MA). Normal human blood samples were spiked with varying numbers of human PDAC organoid cells. The impact of buffy coat separation was studied. Isolated CTCs were cultured in Matrigel to generate organoids as previously described. Cells were imaged with fluorescently labeled antibody to EpCAM. Data: Using spiked normal human blood samples, viable CTCs can be isolated and expanded reliably in 3D organoid culture from as few as 10 CTCs/mL. Separation and processing of the buffy coat enriched for the number of viable CTCs isolated. EpCAM positive CTCs were isolated from 6/6 blood samples from patients with advanced PDAC. Updated results will be presented. Conclusions: The current size-based filtration system allows for collection of viable CTCs from human PDAC blood samples. Current work will use this system to grow, expand and characterize human PDAC CTCs in organoid culture. Genetic, transcriptional, and epigenetic characteristics will be compared with the primary tumor. CTC characteristics will be studied as biomarker of treatment response and resistance. Citation Format: Kenneth H. Yu, Benjamin D. Krempley, Brian McCarthy. Isolation and characterization of viable pancreatic cancer circulating tumor cells using size-based filtration system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3919. doi:10.1158/1538-7445.AM2017-3919
Abstract 3168: Overcoming acquired drug resistance by TPX-0005, an ALK, ROS1 and pan-TRK inhibitor
Authors: Wei Deng, John Huang, Dayong Zhai, Evan Rogers, Jean Cui
Journal: Cancer Research (2017)

Abstract The inevitable development of clinical drug resistance presents a common challenge for targeted cancer therapy. In non-small cell lung cancer (NSCLC) patients with ALK and ROS1 rearrangements, the emergence of mutations in the targeted oncogenes was identified as one of the mechanisms that confer drug resistance. In particular, a group of mutations known as solvent front mutations, such as ALKG1202R and ROS1G2032R, render common resistance to ALK and ROS1 inhibitors. Similar solvent front mutations, such as TRKAG595R and TRKCG623R, have also been identified in cancer patients with rearrangement of NTRK family genes who developed resistance to TRK-targeted therapies. TPX-0005, a compact three-dimensional macrocyclic molecule, was designed to completely locate at the adenine binding site of ATP in order to efficiently target the active kinase conformation and systematically circumvent the steric interference from various clinical resistant mutations, especially the solvent front mutations. TPX-0005 is an orally available and potent ATP-competitive inhibitor against ALK, ROS1, TRKA, TRKB and TRKC recombinant kinases and their corresponding clinical resistant mutants. TPX-0005 demonstrated potent anti-proliferative activity in the range of sub-nanomolar to low nanomolar in a number of human cancer cell lines and engineered stable cell lines expressing the targeted oncogenes or their solvent front mutants, accompanied by inhibition of target phosphorylation and concomitant inactivation of downstream effectors such as ERK, AKT and STAT3. In patient derived xenograft tumor models, TPX-0005 treatment resulted in significant regression of tumors harboring the oncogenic ALK, ROS1 and TRKC fusions. Moreover, in a series of mouse xenograft tumor models, TPX-0005 exhibited marked anti-tumor activity not only in tumors harboring the wildtype oncogenic targets but also in tumors harboring the oncogenes with the solvent front mutations via inhibition of the target phosphorylation. Taken together, these pre-clinical studies have demonstrated the potent activities of TPX-0005 against not only wild type oncogenic ALK, ROS1, TRK fusions but also their corresponding solvent front mutations, which will bring in a new therapy for cancer patients resistant to currently available ALK, ROS1, and TRK inhibitors in clinic. Citation Format: Wei Deng, John Huang, Dayong Zhai, Evan Rogers, Jean Cui. Overcoming acquired drug resistance by TPX-0005, an ALK, ROS1 and pan-TRK inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3168. doi:10.1158/1538-7445.AM2017-3168
Abstract 3451: Depletion of Mastl kinase inhibits cancer growth by induction of mitotic catastrophe in breast cancer
Authors: Yoon Yina, Jae Sung Kim
Journal: Cancer Research (2017)

Abstract Targeting mitotic kinase is an emerging anticancer strategy with promising pre-clinical results. Mastl is an essential mitotic kinase regulating mitotic progression by inactivation of a tumor suppressor protein phosphatase 2A (PP2A). However, it is unclear whether inhibition of Mastl kinase can kills tumor cells. Here, we show that Mastl inhibition selectively kills cancer cells by induction of mitotic catastrophe in breast cancer cells. We found that Mastl overexpression was tightly associated with tumor progression and poor prognosis in breast cancer. Mastl depletion with specific siRNAs induced cell death in Mastl high breast cancer cells, but not in Mastl low breast cancer cells. Interestingly, Mastl depletion did not affect the viability of normal cells. In addition, Mastl depletion reduced the oncogenic properties of breast cancer cells. Furthermore, we found that Mastl depletion caused mitotic catastrophe. Therefore, our data indicate that inhibition of Mastl can selectively kill breast cancer cells by induction of mitotic catastrophe, providing that targeting Mastl kinase is a very useful approach for breast cancer treatment. Citation Format: Yoon Yina, Jae Sung Kim. Depletion of Mastl kinase inhibits cancer growth by induction of mitotic catastrophe in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3451. doi:10.1158/1538-7445.AM2017-3451
Abstract 260: Time Course Observation of Left Ventricular Hypertrophy and Regression Induced by an Improved Technique
Authors: Xiu Zhang, Ling Li, Amanda Szucsik, Hadi Javan, Yubin Deng, Ren Zhang, Craig Selzman
Journal: Circulation Research (2012)

In order to study the left ventricular hypertrophy (LVH) and its regression, we improved the surgical technique for producing LV pressure overload and its reversing mouse model using the titanium clip placement for transverse aortic banding (AB) and removal for debanding (DB). A time course study on heart function and histology proved the importance of the regression time. Materials and methods: The technique was applying titanium clip for AB and removing for DB with minimal invasion. A total of 95 male C57BL6 mice weighing 20-30 g were used in this study. Experimental groups included: control (n=11), AB 3 (11), 4 (12), and 6 (12) wks, DB at 3 (12), 4 (11), and 6 (12) wks of AB for 1 wk. Carotid arteries velocity were measured to evaluate the constrictive level. Heart/body weight ratio, cardiac wall thickness from echocardiography, LV pressure from catheterization and heart histology studies were used to evaluate the pressure overload and hypertrophy. Results: The echocardiographic and histology results indicated that AB induce significent LVH which was a concentric hypertrophy at AB 3 wks and then progressively become a dilated hypertrophy at AB 6 wks. The cardiac function also indicated a stable ejection fraction before 3 wks of AB and then gradually declined at AB 6 wks. After 6 wks AB, the enlargement in LV dimensions becomes significant. When deband at 3 and 4 wks for one week, there were significant regression of hypertrophy but the regression is limited after AB 6 wks and the evidences of lung congestion were apparent. In catheterizaiton, the LV systolic pressure were markedly elevated in AB mice but these pressure elevations became less at AB 6 wks and the LV end-diastolic pressure (LVEDP) at AB 6 wks was elevated significantly. After DB at AB 3 and 4 wks, the pressure parameters retriced close to normal but LVEPD elevation retreat is limited in the DB 6 wks group. Conclusion: With applying and removing titanium clip to induce pressure overload and reversing can provide a relatively simple, effecive, consistent and minimal invasive methods to establish the mouse model for studying LVH and its regression. Our data indicate that AB induced mouse LVH could be retriced close to normal when remove the constriction at the concentric LVH phase but the regression is limited in dilated LVH.
68Ga-PSMA Uptake in Neurofibromas Demonstrated on PET/CT in a Patient With Neurofibromatosis Type 1
Authors: Brook Gulhane, Stuart Ramsay, William Fong
Journal: Clinical Nuclear Medicine (2017)

We present a case of 68Ga-PSMA PET/CT imaging of PSMA expression in neurofibromas in a patient with neurofibromatosis type 1 (or von Recklinghausen disease). PSMA uptake has previously been demonstrated in schwannomas both with PET and histological staining. The presented images confirm that PSMA expression in cutaneous neurofibromas can be well imaged with PET, with uptake mostly at relatively low levels. Interestingly, some lesions demonstrated significantly higher PSMA expression, although the clinical significance of these differences remains to be determined. The images raise the possibility of a potential role for 68Ga-PSMA PET/CT in neurofibromatosis type 1 monitoring.
Abstract 4350: Cell-of-origin differentiation stages define methylation-based subtypes of human colorectal cancer
Authors: Felix Bormann, Manuel Rodríguez-Paredes, Yehudit Bergman, Heinz G. Linhart, Frank Lyko
Journal: Cancer Research (2017)

Abstract Introduction: Colorectal cancer accounts for a significant fraction of cancer-related mortalities, but has proven to be surprisingly refractory to consensus pathological and molecular subclassification. Similarly, little is known about the molecular profiles of colorectal cancer cells-of-origin. DNA methylation is an important epigenomic marker of cellular identity and can therefore be used to infer cancer cells-of-origin. Methods: Infinium 450k data from colorectal cancer samples provided by “The Cancer Genome Atlas” was applied to a consensus clustering algorithm. The identified epigenetic subgroups were tested for features including well established clinical parameters or subgroup specific gene expression. Additionally, the subgroups were compared with Infinium 450k data of non-malignant colorectal adenomas. Finally, clinical significance was addressed by testing for subgroup specific overall survival rates. Results: Analysis of the TCGA dataset defined 5 distinct epigenetic subtypes of human colorectal cancer. These subgroups showed an overlap to the microsatellite instability phenotype and the CpG island methylator phenotype. Gene expression based analysis revealed that the subtypes also form a continuum of epigenetic programs reflecting various intestinal crypt cell differentiation stages. Patient survival correlated with the differentiation stage, with a particular poor prognosis for patients with stem cell-related signatures. Interestingly, its prognostic potential outperformed a recently established gene expression-based classifier. Finally, non-malignant colorectal adenomas could be classified into the same methylation subtypes, reflecting their shared cell-types of origin with carcinomas Conclusion: Our results establish a novel and clinically relevant approach for colorectal cancer classification and illustrate how differences in the cell-type of origin shape the tumor methylome. Citation Format: Felix Bormann, Manuel Rodríguez-Paredes, Yehudit Bergman, Heinz G. Linhart, Frank Lyko. Cell-of-origin differentiation stages define methylation-based subtypes of human colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4350. doi:10.1158/1538-7445.AM2017-4350
Abstract LB-334: xCT promotes malignant phenotypes in EGFR-expressing glioma
Authors: Kenji Tsuchihashi, Shogo Okazaki, Momoko Yoshikawa, Ryo Seishima, Oltea Sampetrean, Nobuyuki Onishi, Hiroaki Wakimoto, Frank Furnari, Eishi Baba, Koichi Akashi, Hideyuki Saya, Osamu Nagano
Journal: Cancer Research (2017)

Abstract Malignant glioma such as glioblastoma is a cancer still difficult to treat. System xc(-) is composed of xCT and CD98hc subunits and functions as a plasma membrane antiporter for the uptake of extracellular cystine in exchange for intracellular glutamate, which has been reported to be involved in malignant phenotypes of glioma cells. However, the underlying mechanism of xCT regulation in glioma is not elucidated. Here we show that the epidermal growth factor receptor (EGFR) interacts with xCT and thereby promotes its cell surface expression and function in human glioma cells. EGFR-expressing glioma cells manifested both enhanced antioxidant capacity as a result of increased cystine uptake as well as increased extracellular glutamate which promotes glioma matrix invasion. Imaging mass spectrometry also revealed that brain tumors formed in mice by human glioma cells stably overexpressing EGFR contained higher levels of reduced glutathione compared with those formed by parental cells. Targeted inhibition of xCT suppressed the EGFR-dependent enhancement of antioxidant capacity in glioma cells as well as tumor growth and invasiveness. Our findings propose that xCT is a promising therapeutic target in EGFR-overexpressing malignant glioma. Citation Format: Kenji Tsuchihashi, Shogo Okazaki, Momoko Yoshikawa, Ryo Seishima, Oltea Sampetrean, Nobuyuki Onishi, Hiroaki Wakimoto, Frank Furnari, Eishi Baba, Koichi Akashi, Hideyuki Saya, Osamu Nagano. xCT promotes malignant phenotypes in EGFR-expressing glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-334. doi:10.1158/1538-7445.AM2017-LB-334