tbuckley/cabot-search huggingface dataset:
Selective DNA-PKcs inhibition extends the therapeutic index of localized radiotherapy and chemotherapy
Authors: Catherine E. Willoughby, Yanyan Jiang, Huw D. Thomas, Elaine Willmore, Suzanne Kyle, Anita Wittner, Nicole Phillips, Yan Zhao, Susan J. Tudhope, Lisa Prendergast, Gesa Junge, Luiza Madia Lourenco, M. Raymond V. Finlay, Paul Turner, Joanne M. Munck, Roger J. Griffin, Tommy Rennison, James Pickles, Celine Cano, David R. Newell, Helen L. Reeves, Anderson J. Ryan, Stephen R. Wedge
Journal: Journal of Clinical Investigation (2019)

Potentiating radiotherapy and chemotherapy by inhibiting DNA damage repair is proposed as a therapeutic strategy to improve outcomes for patients with solid tumors. However, this approach risks enhancing normal tissue toxicity as much as tumor toxicity, thereby limiting its translational impact. Using NU5455, a newly identified highly selective oral inhibitor of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) activity, we found that it was indeed possible to preferentially augment the effect of targeted radiotherapy on human orthotopic lung tumors without influencing acute DNA damage or a late radiation-induced toxicity (fibrosis) to normal mouse lung. Furthermore, while NU5455 administration increased both the efficacy and the toxicity of a parenterally administered topoisomerase inhibitor, it enhanced the activity of doxorubicin released locally in liver tumor xenografts without inducing any adverse effect. This strategy is particularly relevant to hepatocellular cancer, which is treated clinically with localized drug-eluting beads and for which DNA-PKcs activity is reported to confer resistance to treatment. We conclude that transient pharmacological inhibition of DNA-PKcs activity is effective and tolerable when combined with localized DNA-damaging therapies and thus has promising clinical potential.
Dietary fiber, folate, and vitamin E with coronary risk : A pooled analysis of cohort studies
Authors: M A Pereira, E O'Reilly, Katarina Bälter, G E Fraser, U Goldbourt, B L Heitmann, G Hallmans, P Knekt, S M Liu, P Pietinen, J Virtamo, D Spiegelman, J Stevens, W C Willett, A Ascherio
Journal: Circulation (2006)

Dietary fiber, folate, and vitamin E with coronary risk : A pooled analysis of cohort studies
Highlights and recent developments in airway diseases in EAACI journals (2018)
Authors: Jean Bousquet, Cezmi A. Akdis, Clive Grattan, Philippe A. Eigenmann, Karin Hoffmann‐Sommergruber, Ioana Agache, Marek Jutel
Journal: Allergy (2019)

The European Academy of Allergy and Clinical Immunology (EAACI) supports three journals: Allergy, Pediatric Allergy and Immunology, and Clinical and Translational Allergy. EAACI's major goals include supporting the promotion of health, in which the prevention of allergy and asthma plays a critical role, and disseminating the knowledge of allergic disease to all stakeholders. In 2018, the remarkable progress in the identification of basic mechanisms of allergic and respiratory diseases as well as the translation of these findings into clinical practice were observed. Last year's highlights include publication of EAACI guidelines for allergen immunotherapy, many EAACI Position Papers covering important aspects for the specialty, better understanding of molecular and cellular mechanisms, identification of biomarkers for disease prediction and progress monitoring, novel prevention and intervention studies, elucidation of mechanisms of multimorbidities, introduction of new drugs to the clinics, recently completed phase three clinical studies, and publication of a large number of allergen immunotherapy studies and meta-analyses.
Quality of informed consent in clinical trials patients
Authors: G. Catania, A. Dal Molin, N. Diaz, A. Bagnasco, M. Zanini, G. Aleo, D. Grosso, S. Montalti, C. Caldara, R. Sperlinga, A. Lacamera, A. Zeneli, L. Sasso
Journal: Annals of Oncology (2019)
Morphology of tumour-associated macrophages dictates the prognosis of patients with colorectal liver metastases
Authors: M. Donadon, L Di Tommaso, N. Cortese, C. Soldani, B. Franceschini, R. Carriero, M. Barbagallo, A. Rigamonti, A. Anselmo, F. Colombo, G. Maggi, M. Roncalli, G. Torzilli, A. Mantovani, F. Marchesi
Journal: Annals of Oncology (2019)
A phase I study of HMPL-689, a selective oral phosphoinositide 3-kinase-delta inhibitor, in patients with relapsed or refractory lymphoma
Authors: J. Cohen, R. Cordoba Mascunano, A.J.M. Ferreri, C. Yang, M. Kania, J. Kauh, N. Ghosh
Journal: Annals of Oncology (2019)
A phase Ib study of pembrolizumab following trans-arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): PETAL
Authors: D.J. Pinato, T. Cole, B. Bengsch, P. Tait, A.A. Sayed, F. Abomeli, D. Gramenitskaya, E. Allara, R. Thomas, C. Ward, C.N. Wong, A.U. Akarca, J. Miguens Blanco, T. Marafioti, J. Marchesi, R. Sharma
Journal: Annals of Oncology (2019)
Different roles of Rac1 in the acquisition and extinction of methamphetamine-associated contextual memory in the nucleus accumbens
Authors: Jinlan Zhao, Li Ying, Yutong Liu, N Liu, Genghong Tu, Mengjuan Zhu, Yue Wu, Bin Xiao, Liuzhen Ye, Juan Li, Fukun Guo, Lin Zhang, Huijun Wang, Lu Zhang
Journal: Theranostics (2019)

Rationale: Repeated methamphetamine (METH) exposure induces long-term cognitive deficits and pathological drug-associated memory that can be disrupted by manipulating memory reconsolidation and extinction. The nucleus accumbens (NAc) is the key region of the brain reward system and predominantly consists of two subtypes of medium spiny neurons (MSNs) based on the expression of D1 or D2 dopamine receptors (D1-MSNs or D2-MSNs). Spine structural plasticity in the NAc is critical for the acquisition, reconsolidation and extinction of drug-associated memory. However, the molecular mechanisms underlying METH-associated memory and spine remodelling in each type of MSNs in the NAc remain unknown. Here, we explored whether Rac1 in the NAc mediates METH-associated contextual memory and spine remodelling. Methods: Pharmacological and genetic manipulations of Rac1 were used to investigate its role during the acquisition, reconsolidation and extinction of METH-associated contextual memory. Recombinant adeno-associated viruses expressing mCherry under the control of the dopamine D1 receptor gene promoter (Drd1-mCherry) or dopamine D2 receptor gene promoter (Drd2-mCherry) were used to specifically label D1-MSNs or D2-MSNs. Results: Using viral-mediated gene transfer, we demonstrated that decreased Rac1 activity was required for the acquisition of METH-associated contextual memory and the METH-induced increase in thin spine density, whereas increased Rac1 signalling was important for the extinction of METH-associated contextual memory and the related elimination of thin spines. Moreover, the increase of dendritic spines was both found in D1-MSNs and D2-MSNs during the acquisition process, but extinction training selectively decreased the spine density in D1-MSNs. Interestingly, Rac1 was responsible for METH-induced spine plasticity in D1-MSNs but not in D2-MSNs. Additionally, we found that microinjection of a Rac1 inhibitor or activator into the NAc was not sufficient to disrupt reconsolidation, and the pharmacological activation of Rac1 in the NAc facilitated the extinction of METH-associated contextual memory. Regarding cognitive memory, decreased Rac1 activity improved the METH-induced impairment in object recognition memory. Conclusion: Our findings indicate that Rac1 plays opposing roles in the acquisition and extinction of METH-associated contextual memory and reveal the cell-specific role of Rac1 in METH-associated spine remodelling, suggesting that Rac1 is a potential therapeutic target for reducing relapse in METH addiction and remediating METH-induced recognition memory impairment.
Safety, antitumor activity, and pharmacokinetics (PK) of pamiparib (BGB-290), a PARP1/2 inhibitor, in patients (pts) with advanced solid tumours: Updated phase I dose-escalation/expansion results
Authors: M. Voskoboynik, L. Mileshkin, H. Gan, M. Millward, G. Au-Yeung, T.M. Meniawy, G. Kichenadasse, K. Zhang, M. Zhang, S. Mu, J.D. Lickliter
Journal: Annals of Oncology (2019)
Anti-mullerian hormone (AMH) levels and antral follicle counts (AFC) may predict ovarian reserves before systemic chemotherapy (SC) in women with breast cancer (BC): A prospective clinical study
Authors: C. Ordu, F. Gachayev, F. Elbuken, B. Baysal, K.N. Pilanci, G. Alco, A.S. Ilgun, M. Ucuncu, A. Ozturk, Z. Erdogan, F. Agacayak, G. Ozdem, T. Kayan, T. Uyar, E. Hocaoğlu, G. Soybir, F. Aktepe, V. Ozmen
Journal: Annals of Oncology (2019)
Clinical significance of immune-related creatine phosphokinase increase associated with anti PD1/PD-L1 immunotherapies
Authors: S.S. Hajem, C. Baldini, S. Ederhy, M. Berhoune, F. Troalen, P. Romano-Martin, P. Vuagnat, S. Champiat, A. Varga, A. Hollebecque, C. Cauquil, C. Mateus, C. Robert, C. Massard, O. Lambotte, J.-M. Michot
Journal: Annals of Oncology (2019)
Abstract 2556: Understanding Spatial Location of ‘Glagov-Significant’ Coronary Plaque Accumulation as Measured with Angiography-IVUS Fusion: Is Significant Cross-Sectional Area Narrowing More Likely to Occur at Proximal Vessel Clinical ‘Hot Spots’?
Authors: Andreas Wahle, Richard W Downe, Kyungmoo Lee, Soydan Cinar, Theresa M Brennan, Ajanta De, Marlon Everett, Sandeep Nathan, James D Rossen, Milan Sonka, John J Lopez
Journal: Circulation (2008)

Background: Angiographic and IVUS studies demonstrated that acute clinical events (Myocardial Infarction) tend to cluster in the proximal third of the coronary vasculature. Mechanisms for arterial ...
Oncogenic mutations at the dimer interface of EGFR lead to formation of covalent homo-dimers and allosteric activation of the kinase domain: A mechanism which alters the selectivity profile of oncogenic EGFR
Authors: E. Buck, M. O’Connor, A. Flohr, R. Iacone, T. Nicolaides, J. Zhang, A.V. Mayweg, D.M. Epstein
Journal: Annals of Oncology (2019)
β2 adrenergic receptor–mediated signaling regulates the immunosuppressive potential of myeloid-derived suppressor cells
Authors: Hemn Mohammadpour, Cameron R. MacDonald, Guanxi Qiao, Minhui Chen, Bowen Dong, Bonnie L. Hylander, Philip L. McCarthy, Scott I. Abrams, Elizabeth A. Repasky
Journal: Journal of Clinical Investigation (2019)

Catecholamines released by sympathetic nerves can activate adrenergic receptors present on nearly every cell type, including myeloid-derived suppressor cells (MDSCs). Using in vitro systems, murine tumor models in wild-type and genetically modified (β2-AR–/–) mice, and adoptive transfer approaches, we found that the degree of β2-AR signaling significantly influences MDSC frequency and survival in tumors and other tissues. It also modulates their expression of immunosuppressive molecules such as arginase-I and PD-L1 and alters their ability to suppress the proliferation of T cells. The regulatory functions of β2-AR signaling in MDSCs were also found to be dependent upon STAT3 phosphorylation. Moreover, we observed that the β2-AR–mediated increase in MDSC survival is dependent upon Fas-FasL interactions, and this is consistent with gene expression analyses, which reveal a greater expression of apoptosis-related genes in β2-AR–/– MDSCs. Our data reveal the potential of β2-AR signaling to increase the generation of MDSCs from both murine and human peripheral blood cells and that the immunosuppressive function of MDSCs can be mitigated by treatment with β-AR antagonists, or enhanced by β-AR agonists. This strongly supports the possibility that reducing stress-induced activation of β2-ARs could help to overcome immune suppression and enhance the efficacy of immunotherapy and other cancer therapies.
Preferential expression of the affected MET allele in lung carcinomas with heterozygous MET exon 14 skipping mutations: Implications for clinical testing
Authors: E. Imyanitov, N. Mitiushkina, M. Kholmatov, V. Tiurin, A. Romanko, T. Strelkova, A. Ivantsov, E. Kuligina, A. Togo
Journal: Annals of Oncology (2019)
HPV16 E6-specific TCR-T armored with checkpoint blockade in the treatment of cervical cancer
Authors: P. Bryson, Q. Jia, G. Chen, S. li, J. Fang, L. Zhao, B. Wolff, R. Chen, Y. Wan, Q.-J. Li, B. Zhu
Journal: Annals of Oncology (2019)

Abstract   Background  Human papillomavirus 16 (HPV16) elicits cervical cancers and provides an ideal target for T cell-based immunotherapy. Although engineered T cell therapies delivered unprecedented successes in hematological cancers, treating solid cancers has been suboptimal. One key mechanism of tumor-elicited suppression is the PDL1-PD1 checkpoint which blocks T cell activation. Therefore, TCR-T cells armored with checkpoint blockades may further enhance the efficacy of TCR-T in solid cancers.    Methods  HPV16+HLA-A2+ Stage IV cervical cancer patients were consented and enrolled to a two-arm study: Arm 1 is a mono-treatment with HPV16 TCR-T, and, Arm 2 is a treatment with anti-PD1 scFv expressing HPV16 TCR-T cells. PBMCs were collected from patient by lymphocyte apheresis and a TCR targeting HLA-A2-presented E6 epitope was retrovirally transduced. This study is designed for dose escalation at three levels: 5 × 106/kg, 1 × 107/kg, and 5 × 107/kg. Initial safety and efficacy were monitored at day 7, 14, 28 post treatment, followed by long-term monthly monitoring for up to two years.    Results  By the date of submission, five patients have been treated in Arm 1: two were infused with 5 × 106/kg dose, and three were infused with 1 × 107/kg dose. Adverse effects include leukocytopenia (100%), anemia (100%), fatigue (60%), fever (40%) and thrombocytopenia (40%). One patient (20%) had Grade 4 leukocytopenia. No CRS was observed. For all five patients, TCR-T cells were engrafted, and expanded with peak responses during day 7 to 14 post-infusion. At 28 days post-infusion, three patients (60%) were assessed as SD, one patient (20%) was assessed as PD, and one patient was absent for follow-up. Two patients have been recruited for arm 2. One patient received 5 × 106/kg and one received 1 × 107/kg of anti-PD1 armored TCR-T cells. The low dose patient was assessed as SD at both day 28 and month 2 post treatment.    Conclusions  With mild and manageable sides effects, both mono and anti-PD1-armored E6-TCR-T therapies demonstrated to be safe at up to 1 × 107/kg dosage. T cells were stimulated in patients and clinical responses can be identified. These results warrant further evaluation of the safety and efficacy at higher doses.    Clinical trial identification  NCT03578406.    Legal entity responsible for the study  Xinqiao Hospital, Third Militrary Medical University and TCRCure Biopharma Corp.    Funding  TCRCure Biopharma Corp.    Disclosure  All authors have declared no conflicts of interest.
The Adrenal Cortex in Adaptation to Altitude, Climate, and Cancer By Edward S. Sundstroem and George Michaels [formerly Giragossintz]. Memoirs of the University of California. Vol. 12. University of California Press, Berkeley and Los Angeles. 1942. VIII + 410 pages; 125 illustrations. Price $4.00
Authors: William H. Woglom
Journal: Cancer Research (1943)
Beyond THC and Endocannabinoids
Authors: Pal Pacher, Natalya M. Kogan, Raphael Mechoulam
Journal: The Annual Review of Pharmacology and Toxicology (2019)

Research in the cannabinoid field, namely on phytocannabinoids, the endogenous cannabinoids anandamide and 2-arachidonoyl glycerol and their metabolizing and synthetic enzymes, the cannabinoid receptors, and anandamide-like cannabinoid compounds, has expanded tremendously over the last few years. Numerous endocannabinoid-like compounds have been discovered. The Cannabis plant constituent cannabidiol (CBD) was found to exert beneficial effects in many preclinical disease models ranging from epilepsy, cardiovascular disease, inflammation, and autoimmunity to neurodegenerative and kidney diseases and cancer. CBD was recently approved in the United States for the treatment of rare forms of childhood epilepsy. This has triggered the development of many CBD-based products for human use, often with overstated claims regarding their therapeutic effects. In this article, the recently published research on the chemistry and biological effects of plant cannabinoids (specifically CBD), endocannabinoids, certain long-chain fatty acid amides, and the variety of relevant receptors is critically reviewed.
The tyrosine kinase inhibitor dasatinib blocks tumour growth, invasion and recurrence potential by interrupting the communication between cancer cells and their surrounding microenvironment in triple negative breast cancer
Authors: M. Nuncia-Cantarero, C. Nieto-Jiménez, M. Burgos, J.C. Montero, A. Ocaña, E.M. Galán-Moya
Journal: Annals of Oncology (2019)
Exploratory analysis based on tumour location and early metabolic tumour response of REACHIN, a randomized double-blinded placebo-controlled phase II trial of regorafenib after failure of gemcitabine/platinum-based chemotherapy for advanced and metastatic biliary tract tumours
Authors: A. Demols, I. Borbath, L. Guillaume, J.L. Van Laethem, S. Goldman, R. Lhommel
Journal: Annals of Oncology (2019)
Ribociclib (RIB) + letrozole (LET) in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor-2–negative (HER2–) advanced breast cancer (ABC) and central nervous system (CNS) metastases: Subgroup analysis from the phase IIIb CompLEEment-1 trial
Authors: P.H. Cottu, M. De Laurentiis, P. Marchetti, L. Coltelli, N. Califaretti, M. Debled, S. Patil, E. Evron, F.P. Duhoux, L. Menon-Singh, J. Wu, K. Zhou, J. Salvador Bofill
Journal: Annals of Oncology (2019)
Reply to M. Schlumbrecht et al
Authors: Megan A. Clarke, Susan S. Devesa, Nicolas Wentzensen
Journal: Journal of Clinical Oncology (2019)

In their correspondence, Schlumbrecht et al 1 raise important issues related to the complexity of analyses focusing on racial and ethnic diversity and health outcomes.The authors make several wide-ranging points and give specific examples, from the diversity of nativities within larger racial groups to the importance of birthplace and acculturation and the impact on incidence of and survival from various female cancers.Although these points are important, their applicability to a registry-based surveillance study such as ours is currently very limited.
Survival trends in critically ill oncology patients: Impact of patient’s eligibility to post-ICU chemotherapy
Authors: E. Borcoman, V. Lemiale, A. Dupont, E. Mariotte, C. Pichereau, L. Doucet, A. Joseph, A. Chermak, S. Valade, M. Resche-Rigon, E. Azoulay
Journal: Annals of Oncology (2019)
A Dose Escalation Trial of Imatinib for Steroid Dependent Chronic Graft-Versus-Host Disease with Anti-PDGFRA Antibody Analysis.
Authors: George L. Chen, Sally Arai, Mary E.D. Flowers, Joanne Otani, Ethan C. Cheng, Alex McMillan, Wen-Kai Weng, Judith Shizuru, Laura Johnston, David Miklos
Journal: Blood (2009)
Efficacy and safety of FOLFIRI/Aflibercept (FA) in elderly population with mCRC after failure of oxaliplatin-based chemotherapy
Authors: N. Martinez Lago, M. Carmona Campos, P. Gonzalez Villarroel, M. Salgado Fernandez, J. De laCamara Gomez, C. Romero Reinoso, A. Cousillas Castiñeiras, Y. Vidal Insua, J.C. Mendez Mendez, C. Reboredo Rendo, M. Covela Rua, G. Quintero Aldana, B. Graña Suarez, A. Carral Maseda, M. Jorge Fernandez, M.L. Pellon Augusto, C. Grande Ventura, M.E. Gallardo Martin, A. Fernández Montes, M. Reboredo Lopez
Journal: Annals of Oncology (2019)
Limited Chemical Structural Diversity Found to Modulate Thyroid Hormone Receptor in the Tox21 Chemical Library
Authors: Katie Paul-Friedman, Matt Martin, Kevin M. Crofton, Chia-Wen Hsu, Srilatha Sakamuru, Jinghua Zhao, Menghang Xia, Ruili Huang, Diana A. Stavreva, Vikas Soni, Lyuba Varticovski, Razi Raziuddin, Gordon L. Hager, Keith A. Houck
Journal: Environmental Health Perspectives (2019)

Background: Thyroid hormone receptors (TRs) are critical endocrine receptors that regulate a multitude of processes in adult and developing organisms, and thyroid hormone disruption is of high concern for neurodevelopmental and reproductive toxicities in particular. To date, only a small number of chemical classes have been identified as possible TR modulators, and the receptors appear highly selective with respect to the ligand structural diversity. Thus, the question of whether TRs are an important screening target for protection of human and wildlife health remains. Objective: Our goal was to evaluate the hypothesis that there is limited structural diversity among environmentally relevant chemicals capable of modulating TR activity via the collaborative interagency Tox21 project. Methods: We screened the Tox21 chemical library (8,305 unique structures) in a quantitative high-throughput, cell-based reporter gene assay for TR agonist or antagonist activity. Active compounds were further characterized using additional orthogonal assays, including mammalian one-hybrid assays, coactivator recruitment assays, and a high-throughput, fluorescent imaging, nuclear receptor translocation assay. Results: Known agonist reference chemicals were readily identified in the TR transactivation assay, but only a single novel, direct agonist was found, the pharmaceutical betamipron. Indirect activation of TR through activation of its heterodimer partner, the retinoid-X-receptor (RXR), was also readily detected by confirmation in an RXR agonist assay. Identifying antagonists with high confidence was a challenge with the presence of significant confounding cytotoxicity and other, non-TR-specific mechanisms common to the transactivation assays. Only three pharmaceuticals—mefenamic acid, diclazuril, and risarestat—were confirmed as antagonists. Discussion: The results support limited structural diversity for direct ligand effects on TR and imply that other potential target sites in the thyroid hormone axis should be a greater priority for bioactivity screening for thyroid axis disruptors. https://doi.org/10.1289/EHP5314
Bioinspired Self-assembling Peptide Hydrogel with Proteoglycan-assisted Growth Factor Delivery for Therapeutic Angiogenesis
Authors: Lu-Chieh Huang, Huan-Chih Wang, Liang-Hsin Chen, Chia-Yu Ho, Pei-Hsuan Hsieh, Ming-Yuan Huang, Hsi-Chin Wu, Tzu-Wei Wang
Journal: Theranostics (2019)

Critical challenges still exist in surgical theaters and emergency rooms to stop bleeding effectively and facilitate wound healing efficiently. In circumstances of tissue ischemia, it is essential to induce proper angiogenesis to provide adequate vascular supply to the injury site. Methods: In view of these clinical unmet needs, we propose an applicable approach by designing functionalized self-assembling peptide (SAP) hydrogel with two sequences of RADA16-GGQQLK (QLK) and RADA16-GGLRKKLGKA (LRK) in this study. The SAP hydrogel conjugated with QLK functional motif could be crosslinked by endogenous transglutaminase, one of the intrinsic factors secreted during the coagulation process, the mechanical property of the hydrogel can then be enhanced without the need of external support. On the other hand, the LRK sequence exhibited a good binding affinity with the proteoglycan heparan sulfate and could act as a cofactor by sustaining the release of embedded growth factors. Results: The results showed that this SAP solution underwent self-assembling process in a physiological environment, formed hydrogel in situ, and possessed good shear thinning property with injectability. After pH adjustment, the SAP developed densely-compacted fiber entanglement that closely mimicked the three-dimensional fibrous framework of natural extracellular matrix. Such scaffold could not only support the survival of encapsulating cells but also promote the capillary-like tubular structure formation by dual angiogenic growth factors. The ex ovo chicken chorioallantoic membrane assay demonstrated that the growth factor-loaded hydrogel promoted the sprout of surrounding vessels in a spoke-wheel pattern compared to growth factor-free counterparts. Conclusion: The designer bioinspired SAP hydrogel may be an attractive and promising therapeutic modality for minimally-invasive surgery, ischemic tissue disorders and chronic wound healing.