tbuckley/cabot-search huggingface dataset:
A Phase I/IIa Trial Using CD19-Targeted Third-Generation CAR T Cells for Lymphoma and Leukemia
Authors: Gunilla Enblad, Hannah Karlsson, Gustav Gammelgård, Jessica Wenthe, Tanja Lövgren, Rose Marie Amini, Kristina I. Wikstrom, Magnus Essand, Barbara Savoldo, Helene Hallböök, Martin Höglund, Gianpietro Dotti, Malcolm K. Brenner, Hans Hagberg, Angelica Loskog
Journal: Clinical Cancer Research (2018)

Abstract Purpose: The chimeric antigen receptor (CAR) T-cell therapy has been effective for patients with CD19+ B-cell malignancies. Most studies have investigated the second-generation CARs with either CD28 or 4-1BB costimulatory domains in the CAR receptor. Here, we describe the first clinical phase I/IIa trial using third-generation CAR T cells targeting CD19 to evaluate safety and efficacy. Patients and Methods: Fifteen patients with B-cell lymphoma or leukemia were treated with CAR T cells. The patients with lymphoma received chemotherapy during CAR manufacture and 11 of 15 were given low-dose cyclophosphamide and fludarabine conditioning prior to CAR infusion. Peripheral blood was sampled before and at multiple time points after CAR infusion to evaluate the persistence of CAR T cells and for immune profiling, using quantitative PCR, flow cytometry, and a proteomic array. Results: Treatment with third-generation CAR T cells was generally safe with 4 patients requiring hospitalization due to adverse reactions. Six of the 15 patients had initial complete responses [4/11 lymphoma and 2/4 acute lymphoblastic leukemia (ALL)], and 3 of the patients with lymphoma were in remission at 3 months. Two patients are still alive. Best predictor of response was a good immune status prior to CAR infusion with high IL12, DC-Lamp, Fas ligand, and TRAIL. Responding patients had low monocytic myeloid-derived suppressor cells (MDSCs; CD14+CD33+HLA−DR−) and low levels of IL6, IL8, NAP3, sPDL1, and sPDL2. Conclusions: Third-generation CARs may be efficient in patients with advanced B-cell lymphoproliferative malignancy with only modest toxicity. Immune profiling pre- and posttreatment can be used to find response biomarkers.
Abstract 3743: Translational regulation by ERα in hormone-dependent cancers
Authors: Julie Lorent, Vincent van Hoef, Richard Rebello, Mitchell Lawrence, Ivan Topisirovic, Ola Larsson, Luc Furic
Journal: Cancer Research (2018)

Abstract The estrogen receptor α (ERα) activities are complex: in the cytoplasm ERα can directly stimulate survival signalling at the cell membrane, while in the nucleus ERα activates and represses the transcription of target genes. We recently showed that in prostate cancer ERα expression is associated with increased proliferation and higher clinical grade. Here we explore the role of ERα in coordinating transcription and mRNA translation. Unexpectedly, loss of ERα expression leads to decoupling of transcription and translation events. Namely, mRNAs whose levels are induced by ERα loss exhibit reduced translation efficiency and, vice versa, mRNAs whose levels are reduced by ERα loss exhibit enhanced translation efficiency. Such regulation is manifested at the protein level and targets a range of key cellular functions including translation and metabolism. Our detailed mechanistic assessment reveal that while ERα-regulated microRNA levels contribute to global changes in mRNA levels, translational buffering is explained by changes in ribosome processivity and elongation rate. Overall, we have recently identified a process by which ERα drastically impacts the translation of a subset of mRNAs in cancer cells. We propose that this new regulatory pathway plays a major role in mediating biological effects of ERα in neoplastic tissues. Moreover, our findings have important implications in understanding alterations in gene expression programs following treatment with ERα antagonists. Citation Format: Julie Lorent, Vincent van Hoef, Richard Rebello, Mitchell Lawrence, Ivan Topisirovic, Ola Larsson, Luc Furic. Translational regulation by ERα in hormone-dependent 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 3743.
Abstract 14146: Brain-derived Neurotrophic Factor Plays an Important Role of Exercise Capacity and Mitochondrial Function in the Skeletal Muscle in Mice With Post-infarct Heart Failure
Authors: TakayukiNakajima, ShintaroKinugawa, JunichiMatsumoto, ShingoTakada, TakaakiFurihata, MasayaTsuda, TakashiKatayama, HideoNanbu, RyosukeShirakawa, SatoshiMaekawa, NaoyaKakutani, WataruMizushima, TakashiYokota, KoichiOkita, HiroyukiTsutsui
Journal: Circulation (2016)

Background: Exercise intolerance is an independent prognostic factor in patients with heart failure (HF), which is involved in the dysfunction of skeletal muscle. We previously reported that serum brain-derived neurotrophic factor (BDNF) was reduced in HF patients and related to exercise capacity and prognosis. BDNF is known to be produced not only in the brain but also in the skeletal muscle in response to exercise. We thus examined the role of BDNF in the regulation of mitochondrial function in the skeletal muscle from mice with HF. Methods and Results: Myocardial infarction (MI) was created in male C57BL/6J mice by ligating the left coronary artery, and sham operation was also performed. At two weeks after operation, exercise capacity was significantly decreased in MI compared to sham mice (n=7 for each group). BDNF protein levels examined by western blot analysis were significantly decreased by 62% in the skeletal muscle from MI compared to sham mice (p<0.05). Mitochondrial complex I and II-linked res...
Role of Akt Signaling in Vascular Homeostasis and Angiogenesis
Authors: IchiroShiojima, KennethWalsh
Journal: Circulation Research (2002)

Akt is a serine/threonine protein kinase that is activated by a number of growth factors and cytokines in a phosphatidylinositol-3 kinase–dependent manner. Although antiapoptotic activity of Akt is well known, it also regulates other aspects of cellular functions, including migration, glucose metabolism, and protein synthesis. In this review, Akt signaling in endothelial cells and its critical roles in the regulation of vascular homeostasis and angiogenesis will be discussed.
Abstract B71: New directions in gynecologic cancer research utilizing Text Information Extraction System (TIES) Cancer Research Network
Authors: Faina Y. Linkov, Melissa Schwenk, Michael Davis, Robert Edwards, Michael Becich
Journal: Clinical Cancer Research (2018)

Abstract Gynecologic cancers pose significant morbidity and mortality burden for US women. Endometrial cancer is the most common gynecologic malignancy in the US, while ovarian cancer is one of the deadliest. Since research funding for some of the gynecologic malignancies has been limited, novel research on the existing datasets needs to be harnessed to improve the health of the women affected by these conditions. We aim to evaluate if Text Information Extraction System (TIES) Cancer Research Network, a federated network that facilitates data and biospecimen sharing among member institutions, has capabilities for conducting research in the area of gynecologic cancers. TIES system provides effective tools for searching deidentified structured and unstructured data for gynecologic cancers with capabilities to explore pathology and radiology records. We used TIES system to identify records of patients with ovarian, endometrial, and cervical cancers. We used temporal search features to identify patients who developed ovarian tumors after being diagnosed with endometrial tumors. We examined records for completeness of information on diagnosis, age, and procedure year. We found that TIES system has 13,762 records for endometrial cancer, 7,692 records for ovarian cancer, and 10,826 records for cervical cancer for Pittsburgh site. 306 records have been identified for patients who had both ovarian and endometrial malignancies. Nearly 100% of the records had information on age of the patient, year of the procedure, and exact diagnosis. TIES is a promising tool for conducting research in the area of gynecologic malignancies, especially for rare diseases such as concurrent endometrial and ovarian cancers. Existing data repositories like TIES need to be further explored for novel research questions in the area of gynecologic cancer. Citation Format: Faina Y. Linkov, Melissa Schwenk, Michael Davis, Robert Edwards, Michael Becich. New directions in gynecologic cancer research utilizing Text Information Extraction System (TIES) Cancer Research Network. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B71.
Abstract 2889: Aitongxiao (ATX) induces apoptosis and blocks exosomes release in human liver carcinoma cells
Authors: Ming B. Huang, Jiang Leng
Journal: Cancer Research (2018)

Abstract Background: The role of exosomes in cancer development has become the focus of much research, due to the many emerging roles possessed by exosomes. These contents of exosomes could contribute to tumorigenesis. We discovered Aitongxiao (ATX), a group of 80% alcohol extracts from 15 plants, has been shown to have an anti-tumor effect on liver carcinoma; however, the mechanism for the anti-cancer effect of ATX on human liver carcinoma cells is still unclear. Objective: Due its inhibitory effects on chemical carcinogenesis and inflammation, Aitongxiao (ATX) has been proposed as an effective agent for the prevention or treatment of human carcinoma. In this study, we aimed to explore the effect of ATX on human liver carcinoma cells. Methods: The inhibitory effect of Aitongxiao (ATX) on proliferation of HepG2 and HKCL-C3 cells was assessed by CCK-8 assay. The cell cycle distribution and cell apoptosis were determined by flow cytometry. The expression of Alix and CD63 exosomes marker proteins, were detected by Western Blotting. The exosomes protein concentration was measured by and fluorescent antibody assays. Exosomes size and particle number were measured by NanoSight analysis. Results: Aitongxiao (TAX) inhibited the growth of human liver carcinoma cells in a dose and time- dependent manner. Flow cytometry analysis showed that ATX induced G2/M phase arrest and cell apoptosis. ATX treatment promoted the cleavage of caspase 3. In addition, the ATX reduced exosomes release from HepG2 cells, and lose-dose ATX significantly enhanced the growth inhibition induced by 5-Fu. Conclusions: Aitongxiao (ATX) could inhibit the growth of human liver carcinoma cells in vitro. ATX induced both apoptosis and cell cycle arrest and blocked exosomes release, probably through the inhibition of STAT3 function. Lose-dose ATX significantly enhanced the growth inhibitory effect of 5-FU on breast cancer cells, further indicating the potential clinical values of ATX for the prevention or treatment of human liver carcinoma. Keywords: Aitongxiao, liver carcinoma, HepG2 cells, apoptosis, exosomes Citation Format: Ming B. Huang, Jiang Leng. Aitongxiao (ATX) induces apoptosis and blocks exosomes release in human liver carcinoma 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 2889.
Abstract 917: Defects in multiple DNA damage repair pathways render endocrine treatment resistance in ER+ breast cancer patients
Authors: Meenakshi Anurag, Nindo Punturi, Jeremy Hoog, Matthew N. Bainbridge, Matthew J. Ellis, Svasti Haricharan
Journal: Cancer Research (2018)

Abstract Endocrine therapy resistance results in the death of majority of women diagnosed with breast cancer in the USA every year. Although a few markers can predict endocrine treatment failure, comprehensive understanding of the underlying cause and early detection of resistant population remains biggest challenge in the field. Recently, deficient expression or mutation in MutL mismatch repair components was found to cause 20% of intrinsic resistance in primary ER+ HER2- breast cancers. The role of other DNA damage repair (DDR) defects in inducing endocrine resistance therefore requires exploration. To address this question, a systematic study of associations between DDR dysregulation at DNA and RNA level and response to endocrine therapy was conducted using aggregated data from patient tumors from several neoadjuvant aromatase inhibitor (NeoAI) clinical trials. METABRIC, TCGA and Loi et al. datasets were used as validation datasets. Statistically significant correlations between endocrine therapy resistance and mutations in two single strand break repair (SSBR) pathways, i.e. nucleotide excision repair (NER; p=0.04) and base excision repair (BER; p=0.03), and one double strand break repair (DSBR) pathway, i.e. non-homologous end joining (NHEJ; p=0.004) were identified. A second set of analyses identified loss of expression of three genes: CETN2 and ERCC1 from the NER pathway and NEIL2 from BER as specifically associating with poor outcome despite endocrine treatment, emphasizing potential connections between NER and BER defects and endocrine treatment response. The functional role of CETN2, NEIL2 and ERCC1 loss in inducing intrinsic endocrine therapy resistance was experimentally validated in two breast cancer cell lines, and in ER+ PDX models. Finally, a DDR signature score was devised from baseline expression levels of candidate genes and was able to predict endocrine treatment failure in &amp;gt;30% of patients.In conclusion, this study describes a screening strategy for identifying novel predictive markers of endocrine therapy resistance in primary patient tumors. Three DDR pathways, NER, BER and NHEJ, were identified in clinical data as associating with endocrine resistance and validated using experimental model systems. Results reveal an understudied but impactful role for DDR pathways that may explain up to half of all endocrine therapy failure and open new avenues for early screening, predictive diagnostics and personalized medicine. Citation Format: Meenakshi Anurag, Nindo Punturi, Jeremy Hoog, Matthew N. Bainbridge, Matthew J. Ellis, Svasti Haricharan. Defects in multiple DNA damage repair pathways render endocrine treatment resistance in ER+ breast cancer patients [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 917.
Tumor Necrosis Factor Receptor–Associated Factor 1 (TRAF1) Deficiency Attenuates Atherosclerosis in Mice by Impairing Monocyte Recruitment to the Vessel Wall
Authors: AnnaMissiou, NataschaKöstlin, NereaVaro, PhilippRudolf, PeterAichele, SandraErnst, ChristianMünkel, CarinaWalter, PeterStachon, BenjaminSommer, DietmarPfeifer, KatjaZirlik, LindseyMacFarlane, DennisWolf, ErdyniTsitsikov, ChristophBode, PeterLibby, AndreasZirlik
Journal: Circulation (2010)

Background— Members of the tumor necrosis factor superfamily, such as tumor necrosis factor-α, potently promote atherogenesis in mice and humans. Tumor necrosis factor receptor–associated factors (TRAFs) are cytoplasmic adaptor proteins for this group of cytokines. Methods and Results— This study tested the hypothesis that TRAF1 modulates atherogenesis in vivo. TRAF1−/−/LDLR−/− mice that consumed a high-cholesterol diet for 18 weeks developed significantly smaller atherosclerotic lesions than LDLR−/− (LDL receptor–deficient) control animals. As the most prominent change in histological composition, plaques of TRAF1-deficient animals contained significantly fewer macrophages. Bone marrow transplantations revealed that TRAF1 deficiency in both hematopoietic and vascular resident cells contributed to the reduction in atherogenesis observed. Mechanistic studies showed that deficiency of TRAF1 in endothelial cells and monocytes reduced adhesion of inflammatory cells to the endothelium in static and dynamic ass...
Abstract CT138: Open-label personalized targeted intervention to maximize TTFields intensity in recurrent GBM (OptimalTTF Trial)
Authors: Nikola Mikic, Anders Rosendal Korshøj
Journal: Cancer Research (2018)

Abstract Introduction Tumor Treating Fields (TTFields) is approved for the treatment of recurrent glioblastoma (rGBM). Skull remodeling surgery involves formation of strategically placed craniectomies, burr holes or skull thinning, in order to facilitate electric current flow into the tumor region. Preclinical studies have indicated that these procedures provide a marked and focal enhancement (~100%) of TTFields intensity without significantly compromising patient safety. In this open-label phase 1 investigator-initiated interventional trial, we test the safety, feasibility and efficacy of TTfields plus personalized targeted skull remodeling surgery and best choice chemotherapy. We believe this study has high-impact potential at a low clinical risk and may advance current state-of-the-art therapy of GBM therapy. Methods The trial will include fifteen patients. Major eligibility criteria include age &amp;gt; 18 years, first recurrence of supratentorial GBM, Karnofsky performance score (KPS) &amp;gt; 60, focal tumor &amp;lt; 2 cm to cortical surface, and lack of uncontrollable epilepsy or significant co-morbidity. Upon inclusion, personalized field calculations will be performed to validate TTFields enhancement &amp;gt; 25% due by skull remodeling surgery. The primary endpoint is toxicity assessed by CTCAEv4.0. Secondary endpoints include overall survival, progression free survival (PFS), PFS at six months (PFS6), objective response rate, quality of life (EORTC QLQ-C30 and BN20), KPS, and steroid dose. Follow-up is 18 months and includes regular toxicity assessment (6-week intervals) as well as quality of life and response assessments (3-month intervals). Endpoint data will be collected at the end of scheduled follow-up, occurrence of suspected unexpected serious adverse reactions (SUSARs) or unacceptable serious adverse events (SAEs), withdrawal of consent, or loss to follow-up. Interim analysis will be performed upon endpoint registration for the first five-10 patients. Citation Format: Nikola Mikic, Anders Rosendal Korshøj. Open-label personalized targeted intervention to maximize TTFields intensity in recurrent GBM (OptimalTTF Trial) [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 CT138.
Abstract 3643: Utility of peritoneal and pleural lavages for detection of somatic alterations: A proof-of-concept study
Authors: Núria Jordana Ariza, Mónica Garzón Ibañez, Alejandro Martinez-Bueno, Sonia Gatius Caldero, Clara Mayo de las casas, Ana Velasco, Maria Ruiz, Berta Roman Canal, Jordi Bertran Alamillo, Sonia Rodríguez Muñoz, Raquel Campos Fuentes, Beatriz García, Ariadna Balada Bel, Sergi Villatoro, Miguel Ángel Molina-Vila, Xavier Matias-Guiu
Journal: Cancer Research (2018)

Abstract Background: Surgical resection remains the best treatment option for early-stage endometrial (CE), colorectal (CRC) and lung cancer (LC) patients. However, a proportion of patients (p) develop tumor recurrence, even after curative resection. Peritoneal or pleural lavages may be performed during surgery but little data is available about their potential as liquid biopsies with predictive value for recurrence. This proof-of concept study aimed to determine if somatic mutations can be detected in these lavages. Methods: We analyzed mutations in paired surgical biopsies, blood and peritoneal or pleural lavages supernatants in an early-stage cohort of 25 EC, 12 CRC and 19 LC p. Molecular characterization of surgical biopsies was performed using the GeneReader NGS platform (Qiagen) and the Actionable Insight Tumor Panel, which includes 12 genes (KRAS, NRAS, KIT, BRAF, PDGFRA, ALK, EGFR, ERBB2, PIK3CA, ERBB3, ESR1, and RAF1). cfDNA was purified from blood and lavages using an automatic extractor and the hotspot mutations identified in tumor tissue were tested using a sensitive Taqman assay for codons 12, 13, and 61 in KRAS, codons 542, 545 and 1047 in PIK3CA and codon 600 in BRAF. Results: NGS of tumor biopsies revealed hotspot KRAS, PIK3CA or BRAF mutations in a total of 11/25 (44%) early-stage EC p, 7/12 (58%) early-stage CRC p and 6/19 (32%) early-stage LC p. In peritoneal lavages, hotspot mutations were found in 6/11 (55%) EC p and 2/7 (29%) CRC p and, in pleural lavages, hotspot mutations appeared in 2/6 (33%) LC p. Furthermore, 2/11 (18%) blood samples from EC p, 1/7 (14%) blood samples from CRC p and 1/6 (17%) blood samples from LC p were positive. Conclusions: Our study reveals that mutational analysis in peritoneal or pleural lavages from early stage tumors is feasible and that mutations are more frequently detected in lavages than in blood. Further research will determine if positivity in blood or lavages is associated with early relapse. Citation Format: Núria Jordana Ariza, Mónica Garzón Ibañez, Alejandro Martinez-Bueno, Sonia Gatius Caldero, Clara Mayo de las casas, Ana Velasco, Maria Ruiz, Berta Roman Canal, Jordi Bertran Alamillo, Sonia Rodríguez Muñoz, Raquel Campos Fuentes, Beatriz García, Ariadna Balada Bel, Sergi Villatoro, Miguel Ángel Molina-Vila, Xavier Matias-Guiu. Utility of peritoneal and pleural lavages for detection of somatic alterations: A proof-of-concept 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 3643.
Trust in GPs remains high but patients report more difficulties getting an appointment
Authors: Gareth Iacobucci
Journal: BMJ (2018)

Patients’ confidence and trust in their GP remains high despite people finding it increasingly difficult to obtain an appointment, the latest national GP patient survey has shown.1

The annual poll by NHS England and Ipsos MORI found that 96% of people in England had confidence and trust in their GP, up from 92% the previous year. Eight in 10 people (84%) rated their overall experience of their GP surgery as good, compared with 85% the previous year.

But four in 10 patients (38%) were not …
Involvement of Glycoprotein VI in Platelet Thrombus Formation on Both Collagen and von Willebrand Factor Surfaces Under Flow Conditions
Authors: ShinyaGoto, NorikoTamura, ShunnosukeHanda, MorioArai, KumiKodama, HiroshiTakayama
Journal: Circulation (2002)

Background— We studied the role of glycoprotein (GP) VI in platelet adhesion and thrombus formation on the immobilized collagen and von Willebrand factor (vWF) surface under flow conditions. Methods and Results— Whole blood obtained from 2 patients with GP VI–deficient platelets and the effects of the Fab of anti–GP VI antibody (Fab/anti–GP VI) were tested. Blood containing platelets rendered fluorescent by mepacrine was perfused on immobilized type I collagen or vWF under controlled wall shear rate. Platelet adhesion and thrombus formation were detected by epifluorescent videomicroscopy. The percentage of surface coverage by the platelets was calculated. Fc receptor γ-chain and spleen tyrosine kinase (Syk) were immunoprecipitated from the lysate of platelets stimulated by vWF plus ristocetin and then analyzed by antiphosphotyrosine immunoblotting. No platelet attachment was seen on the surface of collagen even after 9 minutes of perfusion of blood at relatively low (100 s−1) or high (1500 s−1) wall shear...