tbuckley/cabot-search huggingface dataset:
Abstract 5457: Structural and functional assessment of mutations identified in different breast cancer genes
Authors: Neha Mishra, Mudassar Ali Khan, Ekaterina S. Kuligina, Syed Hasan, Ashok K. Varma
Journal: Cancer Research (2020)

Abstract Atomic protein structure helps in understanding the functions associated with protein molecule. Therefore, it is very important to correlate the structural information from the biological functions of proteins for translational research. So far, BRCA1 and BRCA2 (Breast Cancer Susceptibility genes 1 and 2) genes have been extensively studied genes for hereditary breast and ovarian cancers. BRCA1 comprises 1863 amino acids and is involved in the tumour suppressor function. It also plays an important role in cell cycle checkpoint control and DNA damage repair process. Germ-line mutations discovered in BRCA1 and BRCA2 genes are distributed all over gene coding regions. BRCA1 encompasses different functional domains like RING-domain at N- terminus, DNA binding domain at the centre and tandem repeats of BRCT at C-terminus. RING-domain of BRCA1 interacts with BARD1, BAP1 whereas C-terminal region of BRCA1 interacts with BACH1, CtIP, Abraxas and controls the cell -cycle checkpoint through the protein-protein interactions. Germ-line mutations identified from the larger cohort of patients is available in different databases. However, unreported mutations are also regularly detected in clinical settings. We have evaluated the folding pattern of mutations discovered in different domains of BRCA1 and BRCA2 using in-silico, in-vitro and biophysical approaches. Furthermore, studies of protein-protein interactions (PPIs) with the binding partners of BRCA1 such as RAP80, MERIT40, and ABRAXAS have been explored using isothermal titration calorimetry. The slight differences between wild-type and mutant proteins of BRCA1 and BRCA2 have been observed. The data obtained from Circular- Dichroism, protein-protein interactions and structural analysis confirm that an alterations in protein folding pattern although not able to serve as a sole tool for mutation pathogenicity assessment, could provide valuable information to aid the classification of uncertain, potentially disease-causing, variants in the human cancer-relevant genes. Grant number: DST (Grant DST/INT/RUS/RSF/11), Russian foundation for Basic research (grant number 19-515-25001) Citation Format: Neha Mishra, Mudassar Ali Khan, Ekaterina S. Kuligina, Syed Hasan, Ashok K. Varma. Structural and functional assessment of mutations identified in different breast cancer genes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5457.
Bacteria responsive polyoxometalates nanocluster strategy to regulate biofilm microenvironments for enhanced synergetic antibiofilm activity and wound healing
Authors: Yuetong Zhang, Yang Pi, Yusheng Hua, Jiani Xie, Chengyan Wang, Kun Guo, Zhigang Zhao, Yuan Yong
Journal: Theranostics (2020)

Backgroud: Nowadays, biofilms that are generated as a result of antibiotic abuse cause serious threats to global public health. Such films are the primary factor that contributes to the failure of antimicrobial treatment. This is due to the fact that the films prevent antibiotic infiltration, escape from innate immune attacks by phagocytes and consequently generate bacterial resistance. Therefore, exploiting novel antibacterial agents or strategies is extremely urgent. Methods: Herein, we report a rational construction of a novel biofilm microenvironment (BME)-responsive antibacterial platform that is based on tungsten (W)-polyoxometalate clusters (POMs) to achieve efficient bactericidal effects. Results: On one hand, the acidity and reducibility of a BME could lead to the self-assembly of POMs to produce large aggregates, which favor biofilm accumulation and enhance photothermal conversion under near-infrared (NIR) light irradiation. On the other hand, reduced POM aggregates with BME-induced photothermal-enhanced efficiency also exhibit surprisingly high peroxidase-like activity in the catalysis of bacterial endogenous hydrogen peroxide (H2O2) to produce abundant reactive oxygen species (ROS). This enhances biofilm elimination and favors antibacterial effects. Most importantly, reduced POMs exhibit the optimal peroxidase-like activity in an acidic BME. Conclusion: Therefore, in addition to providing a prospective antibacterial agent, intelligent acid/reductive dual-responsive POMs will establish a new representative paradigm for the areas of healthcare with minimal side effects.
Abstract 4441: CS3003, an HDAC6-selective inhibitor, improves anti-PD-1 immune checkpoint blockade therapy efficacy
Authors: Zhenhu Li, Zhaoxiang Ren, Jingshu Ma, Liang Tang, Liang Lu, Ying Zhu, Yunfei Wu, Tiancheng Liu, Juan Zhang, Yuanwu Bao, Kangyu Zhang, Changqing Wei, Shuhui Chen, Xinzhong Jon Wang
Journal: Cancer Research (2020)

Abstract Background: Histone deacetylases (HDACs) are involved in diverse cellular regulatory function including histone modification and non-histone modification. Several publications have demonstrated that selective HDAC inhibitors (HDACi) can influence tumor growth and immunogenicity. In particular, the selective inhibition of HDAC6 has function of inhibiting tumor growth in several malignancies. However, the mechanism of this effect is still not clear. Methods: In this study, we evaluated CS3003, a selective HDAC6 inhibitor, inhibition profile using cell-based free assays. In vivo anti-tumor efficacy was evaluated in MM.1S xenograft mouse model. CS3003 and PD-1 blockade combination effect was evaluated in CT26 syngeneic mouse model. RNA-seq method was used to explore the transcription regulation by CS3003 compared to other pan-HDAC, Class I HDAC inhibitor and selective HDAC6 inhibitors. Results: CS3003 has distinct inhibition profile in HDAC family members. Combination of CS3003 and proteasome inhibitor synergistically enhanced anti-tumor function in human multiple myeloma mouse model (coefficient of drug interaction, CDI=0.69). In addition, CS3003 improves the anti-tumor activity of anti-PD-1 immune checkpoint blockade in solid tumor model (CDI=0.62 and 0.88 when the dosage of CS3003 was 30 and 70mg/kg, respectively). Transcriptome analysis demonstrated a unique gene expression pattern of CS3003 from other pan-HDAC and selective HDAC6 inhibitors. Conclusions: These data provide a comprehensive pre-clinical characterization of CS3003 that supports its unique HDAC inhibition profile and its capability of improving anti-PD-1 immune checkpoint blockade therapy efficacy. Citation Format: Zhenhu Li, Zhaoxiang Ren, Jingshu Ma, Liang Tang, Liang Lu, Ying Zhu, Yunfei Wu, Tiancheng Liu, Juan Zhang, Yuanwu Bao, Kangyu Zhang, Changqing Wei, Shuhui Chen, Xinzhong Jon Wang. CS3003, an HDAC6-selective inhibitor, improves anti-PD-1 immune checkpoint blockade therapy efficacy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4441.
Abstract 539: Novel engineered toxin bodies targeting SLAMF7 (CS1)
Authors: Aimee Iberg, Garrett L. Cornelison, Caleigh Howard, Garrett L. Robinson, Jay Zhao, Hilario J. Ramos, Erin K. Willert
Journal: Cancer Research (2020)

Abstract Engineered toxin bodies (ETBs) are comprised of a proprietarily engineered form of Shiga-like Toxin A subunit (SLT-A) genetically fused to antibody-like binding domains. ETBs work through novel mechanisms of action and are capable of forcing internalization, self-routing through intracellular compartments to the cytosol, and inducing potent cell-kill via the enzymatic and permanent inactivation of ribosomes. Three ETBs are in clinical development (MT-3724 targeting CD20, MT-5111 targeting HER2, and TAK-169 targeting CD38). The novel mechanism of action has potential benefit in different indications including in the relapsed setting, when disease has progressed after chemotherapies and other targeted therapies, and additionally may be able to be combined with standard of care. Additional ETBs are being developed that target other cell surface receptors for solid and hematological malignancies, including SLAMF7 (CS1). SLAMF7 is a clinically validated target of monoclonal antibody therapy. Although clinical responses to the monotherapy were not observed, patients treated with combination therapy using standard of care agents that are known to stimulate immune effector cell activity have improved responses. Thus, a SLAMF7 targeted agent that can act independent of effector cells by directly killing tumor cells has the potential to provide broader benefit to patients. ETBs targeting SLAMF7 harbor the catalytic activity of the SLTA subunit and can effectively and specifically kill multiple myeloma cell lines expressing the target protein in vitro. The coupling of specific targeting to myeloma cells with potent and direct cell kill activity has the potential to deplete malignant cells without reliance on effector functions of the patient immune system, such as antibody or complement dependent cellular cytotoxicity or phagocytosis, and could be beneficial when disease progresses post antibody therapy. Additionally, the novel mechanism of action of an ETB also has potential to be combined with standard of care therapies and/ or to be effective in the relapsed or refractory setting. Citation Format: Aimee Iberg, Garrett L. Cornelison, Caleigh Howard, Garrett L. Robinson, Jay Zhao, Hilario J. Ramos, Erin K. Willert. Novel engineered toxin bodies targeting SLAMF7 (CS1) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 539.
Long Non Coding RNA BALR2-CDK6 Axis Influences Cell Differentiation and Metabolic Status of Acute Myeloid Leukemia
Authors: Valeria Bisio, Claudia Tregnago, Matteo Zampini, Giulia Borella, Thilini Fernando, Dinesh S. Rao, Andrea Pession, Franco Locatelli, Giuseppe Basso, Pigazzi Martina
Journal: Blood (2017)
COVID‐19 drug repurposing: A review of computational screening methods, clinical trials, and protein interaction assays
Authors: Xueqing Wang, Yuanfang Guan
Journal: Medicinal Research Reviews (2020)

Abstract The situation of coronavirus disease 2019 (COVID‐19) pandemic is rapidly evolving, and medical researchers around the globe are dedicated to finding cures for the disease. Drug repurposing, as an efficient way for drug development, has received a lot of attention. However, the huge amount of studies makes it challenging to keep up to date with the literature on COVID‐19 therapeutic development. This review addresses this challenge by grouping the COVID‐19 drug repurposing research into three large groups, including clinical trials, computational research, and in vitro protein‐binding experiments. Particularly, to facilitate future drug discovery and the creation of effective drug combinations, drugs are organized by their mechanisms of action and reviewed by their efficacy measured by clinical trials. Providing this subtyping information, we hope this review would serve the scientists, clinicians, and the pharmaceutical industry who are looking at the new therapeutics for COVID‐19 treatment.
Abstract 4809: Monoethanolamine stimulates calcium-induced metabolic stress leading to autophagic cell death in prostate cancer
Authors: Chakravarthy Garlapati
Journal: Cancer Research (2020)

Abstract Mitochondrial activity and metabolism are crucial to meet the energy demands of cancer cells. We have recently shown the efficacy of monoethanolamine (Etn), an orally deliverable lipid formulation, in reducing tumor growth in various xenograft models including prostate cancer (PCa). Etn increased the metabolic stress of PCa cells by depleting cellular glucose and glutamine levels. However, the precise mechanism of Etn-mediated metabolic stress in cancer cells remains elusive. Herein, we examined how Etn alters the activity and structure of the mitochondria to induce cell death. Etn treatment modulated phosphatidylethanolamine (PE) lipid and glycerophosphoethanolamine (GPE) levels in PCa cells. Altered PE lipids correlated with disruption of mitochondrial cristae and led to a concomitant accumulation of autophagosomes. Deregulated functional activity of mitochondria, as evidenced by reduced oxygen consumption rate (OCR), extracellular acidification rate (ECAR), were associated with structural distortions of the mitochondria and a transient increase in the intracellular calcium concentration. Etn treatment reduced the amount of cytosolic lipid droplets (LD) and caused a reduction in PE/GPE ratio. Further, we observed an increase in lipolysis and death-inducing autophagy activation in Etn-treated PCa cells. These data suggest that Etn is a promising anticancer agent for PCa and further studies to determine its efficacy in other cancer types are warranted. Citation Format: Chakravarthy Garlapati. Monoethanolamine stimulates calcium-induced metabolic stress leading to autophagic cell death in prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4809.
Early BCR-ABL1 kinetics are predictive of subsequent achievement of treatment-free remission in chronic myeloid leukemia
Authors: Naranie Shanmuganathan, Ilaria S. Pagani, David M. Ross, Sahee Park, Agnes S. M. Yong, Jodi A. Braley, Haley K. Altamura, Devendra K. Hiwase, David T. Yeung, Dong-Wook Kim, Susan Branford, Timothy P. Hughes
Journal: Blood (2020)
Abstract 6551: Novel leads from <i>Prosopis juliflora</i> (Sw.) arrest the growth of B16F10 melanoma cancer cells by inducing apoptosis and down regulating the cell proliferating signalling pathways
Authors: Raju Nivarti Gacche
Journal: Cancer Research (2020)

Abstract The evolving drug resistance and cancer heterogeneity is limiting the efficacy of current chemotherapy drugs. In the present state of the art, natural product and drug discovery has remained a significant hope for the identification of novel leads against series anti-cancer drug targets. The major issue is to convert the traditional knowledge into clinical reality by applying omics approaches. As a part of our continues efforts in exploring the efficacy of Prosopis juliflora as possible resource for the management of cancer, we have carried out the efficacy of P. juliflora against melanoma cancer using B16F10 as a melanoma model. The rational in selecting the melanoma lies in its aggressive metastatic phenotype and resistance to present chemotherapy drugs. Prosopis juliflora leaves methanol extract (PJLME) was assessed for its anticancer activity against B16F10 skin melanoma cancer cell line. Series of in vitro and in vivo experiments demonstrated that PJLME is cytotoxic (IC5017ug/ml), inhibited the migration ability of cells, inhibited the colony formation, arrested cell cycle at G0-G1 phase, induced apoptosis by up regulating the pro-apoptic markers like Bax &amp; Bad, along with successful cleavage of Caspase-9 and PARP-1 and down regulated the anti-apoptotic marker Bcl2. The PJLME also suppressed the expression of Akt, mTOR and ERK signalling pathways. The in vivo xenograft studies in BALB/c mice model demonstrated impressive activity against the melanoma cancer. As a part of understanding the possible mechanism of action, our studies indicate that, PJLME induces cell death via apoptosis mechanism and by down regulating the cell proliferation signalling pathways. The HPLC-MS analysis of PJLME indicates the diversity of compounds, few of them are known for their anticancer effects. Our studies unraveled the significance of PJLME as a novel natural source for the management of melanoma cancer. Citation Format: Raju Nivarti Gacche. Novel leads from Prosopis juliflora (Sw.) arrest the growth of B16F10 melanoma cancer cells by inducing apoptosis and down regulating the cell proliferating signalling pathways [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6551.
Abstract A04: Tumor development trajectories for exploring differences between cancer subtypes
Authors: Ignaty Leshchiner, Daniel Rosebrock, Oliver Spiro, Edmund Mroz, Dimitri Livitz, James W. Rocco, Gad Getz
Journal: Clinical Cancer Research (2020)

Abstract We have employed PhylogicNDT, our computational method for timing somatic events and subclonal architecture reconstruction, to explore the association of tumor development trajectory (from normal cell to malignant state) with cancer subtype and genetic landscape. Previous attempts to understand the order of somatic events that lead to the formation of cancers are mostly based on studies of premalignant samples, which are often hard or impossible to obtain due to small size or inaccessible location. Our approach allows us to use information from whole-exome and whole-genome data to computationally reconstruct the order of events preceding malignant transformation of the tissue. We show that this approach yields accurate reconstruction of premalignant events in lung, colorectal, and head and neck cancers based on previous exploration of premalignant lesions. We explored the association between the developmental trajectories, treatment outcome, and survival in several cancer types. PhylogicNDT can be used to infer the order of clonal driver events (including in precancerous stages), subclonal populations of cells and their phylogenetic relationships, and dynamics of cell populations. This methodology will enable a systematic study of tumor initiation and progression across cancer types and therapies. Citation Format: Ignaty Leshchiner, Daniel Rosebrock, Oliver Spiro, Edmund Mroz, Dimitri Livitz, James W. Rocco, Gad Getz. Tumor development trajectories for exploring differences between cancer subtypes [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr A04.
Evolocumab in Pediatric Heterozygous Familial Hypercholesterolemia
Authors: Raul D. Santos, Andrea Ruzza, G. Kees Hovingh, Albert Wiegman, François Mach, Christopher E. Kurtz, Andrew Hamer, Ian Bridges, Andrea Bartuli, Jean Bergeron, Tamás Szamosi, Saikat Santra, Claudia Stefanutti, Olivier S. Descamps, Susanne Greber-Platzer, Ilse Luirink, John J.P. Kastelein, Daniel Gaudet
Journal: New England Journal of Medicine (2020)

Evolocumab, a fully human monoclonal antibody directed against proprotein convertase subtilisin–kexin type 9, is widely used in adult patients to lower low-density lipoprotein (LDL) cholesterol levels. Its effects in pediatric patients with heterozygous familial hypercholesterolemia are not known.
Reduced repolarization reserve underlies calcium dependent early afterdepolarizations and consequent reentrant tachyarrhythmias in pathological hypertrophic cardiac tissue
Authors: B.O. Bingen, S.F.A. Askar, D.L. Ypey, A. van der Laarse, M.J. Schalij, D.A. Pijnappels
Journal: Cardiovascular Research (2012)
Corticosteroids in COVID-19 ARDS
Authors: Hallie C. Prescott, Todd W. Rice
Journal: JAMA (2020)

Pierre-François Dequin, MD, PhD; Nicholas Heming, MD, PhD; Ferhat Meziani, MD, PhD; Gaëtan Plantefève, MD; Guillaume Voiriot, MD, PhD; Julio Badié, MD; Bruno François, MD; Cécile Aubron, MD, PhD; Jean-Damien Ricard, MD, PhD; Stephan Ehrmann, MD, PhD; Youenn Jouan, MD, PhD; Antoine Guillon, MD, PhD; Marie Leclerc, MSc; Carine Coffre, MSc; Hélène Bourgoin, PharmD; Céline Lengellé, PharmD; Caroline Caille-Fénérol, MSc; Elsa Tavernier, PhD; Sarah Zohar, PhD; Bruno Giraudeau, PhD; Djillali Annane, MD, PhD; Amélie Le Gouge, MSc; CAPE COVID Trial Group and the CRICS-TriGGERSep Network
Association of the Psoriatic Microenvironment With Treatment Response
Authors: Gaofeng Wang, Yong Miao, Noori Kim, Evan Sweren, Sewon Kang, Zhiqi Hu, Luis A. Garza
Journal: JAMA Dermatology (2020)

The ability to predict the efficacy of systemic psoriasis therapy based on immune profiles in skin biopsies could reduce the use of inappropriate treatment and its associated costs and adverse events. It could considerably decrease drug development trial costs as well.To develop a bioinformatic gene signature score derived from skin mRNA to predict psoriasis treatment outcomes for a variety of therapies.In this decision analytical model using 1145 skin samples from different cohorts of 12 retrospective psoriasis studies, samples were analyzed using the CIBERSORT algorithm to define the immune landscape of psoriasis lesions and controls. Random forest classification and principal component analysis algorithms were used to estimate psoriatic microenvironment (PME) signature genes and construct a PME score. Overall, 85 and 421 psoriasis lesions from 1 and 4 independent cohorts were used as discovery and validation studies, respectively. Among them, 157, 71, 89, and 90 psoriasis lesions were treated with etanercept, tofacitinib, adalimumab, and methotrexate, respectively.Number of weeks after treatment initiation when responders and nonresponders could be predicted.Overall, 22 immune cell subtypes formed infiltration patterns that differentiated psoriasis lesions from healthy skin. In psoriasis lesions, the expression of 33 PME signature genes defined 2 immune phenotypes and in aggregate could be simplified to a numerical PME score. A high PME score, characterized by keratinocyte differentiation, correlated with a better treatment response (Psoriasis Area and Severity Index [PASI] reduction, 75.8%; 95% CI, 69.4% to 82.2%; P = .03), whereas a low PME score exhibited an immune activation signature and was associated with a worse response (PASI reduction, 53.5%; 95% CI, 45.3% to 61.7%; P = .03). The PME score at week 4 after treatment initiation correlated with future responder vs nonresponder to treatment status 8 to 12 weeks earlier than PASI reduction for etanercept, methotrexate plus adalimumab, and tofacitinib.The PME score is a biometric score that may predict clinical efficacy of systemic psoriasis therapy in advance of clinical responses. As an application of personalized medicine, it may reduce the exposure of patients with psoriasis to ineffective and expensive therapies.