tbuckley/cabot-search huggingface dataset:
Immune tolerance of allogeneic haematopoietic cell transplantation supports donor epidermal grafting of recessive dystrophic epidermolysis bullosa chronic wounds*
Authors: C.L. Ebens, J.A. McGrath, J.A. Riedl, A.R. Keith, G. Lilja, S. Rusch, D.R. Keene, S.F. Tufa, M.J. Riddle, R. Shanley, A.E. Van Heest, J. Tolar
Journal: British Journal of Dermatology (2020)

Chronic wounds, a common morbidity in recessive dystrophic epidermolysis bullosa (RDEB), lack definitive therapies.To assess allogeneic epidermal skin grafts in terms of wound healing and durability over time.In a prospective, open-label clinical trial for postallogeneic haematopoietic cell transplantation (post-alloHCT) patients with RDEB, up to nine chronic wounds per patient were grafted over 1 year. Epidermal grafts measuring 5 cm2 were obtained from related alloHCT donors in the outpatient setting using the CELLUTOMETM Epidermal Harvesting System. Wounds were photographed and symptom inventories completed at baseline and 6, 12 and 52 weeks after grafting. The trial was registered at ClinicalTrials.gov (NCT02670837).Between August 2016 and January 2019, eight patients with RDEB received a total of 35 epidermal allografts at a median of 1157 days (range 548-2884) post-alloHCT. The median (interquartile range) percentage reductions in wound surface area were 75% (52-94), 95% (72-100) and 100% (97-100) at 6, 12 and 52 weeks postgraft, respectively, each significantly reduced from baseline (P < 0·001). Donor harvest sites healed quickly without scarring. Biopsy evaluation at 1 year of an epidermal allograft site revealed wildtype type VII collagen (immunofluorescence), anchoring fibrils (electron microscopy), and full-thickness skin whole-DNA donor chimerism of 42% (compared with 16% in concurrently biopsied native skin). This strategy subsequently supported release of RDEB pseudosyndactyly.The immune tolerance established by alloHCT supports successful adoptive transfer of donor epidermal grafts. Persistence of donor grafts in a single patient beyond 1 year and observed migration of donor-grafted cells into adjacent wound suggest that epidermal allografts include nonterminally differentiated cells and/or trigger recruitment of donor bone-marrow-derived cells to mediate wound healing.
Abstract B52: Inhibition of ovarian cancer spheroid adhesion using graphene oxide nanomaterials
Authors: Hak Rae Lee, Melissa A. Geller, Samira M. Azarin
Journal: Clinical Cancer Research (2020)

Abstract There is an urgent need for development of alternative treatment strategies for advanced-stage ovarian cancer. During metastatic spread, single cells or spheroids detach from the primary tumor and are carried by the peritoneal fluid until attaching to the mesothelial cells lining the abdominal cavity. While attachment of ovarian tumor cells and spheroids to the mesothelial layer is known to be mediated by β-integrins and CD44, efforts to block these receptors with antibodies have been insufficient to inhibit disease progression. As graphene oxide nanosheets have previously been shown bind to β-integrins on the surface of mesenchymal stem cells, we hypothesized that they would be able to attach to ovarian cancer spheroids, forming a physical barrier around the spheroids and thus inhibiting their adhesion to the mesothelium. SKOV-3 human ovarian cancer cells were used in this study, as this cell line was derived from ascites fluid. SKOV-3 cells were placed in poly(hydroxyethyl methacrylate) (polyHEMA)-coated plates for 24 hours to form spheroids, followed by 48-hour treatment with the nanosheets. The graphene oxide nanosheets were functionalized with 4-arm polyethylene glycol (PEG) to enhance biocompatibility and provide additional steric hindrance to prevent spheroid adhesion. Scanning electron microscopy confirmed that the nanosheets were able to bind to the tumor spheroids. Association of the nanosheets with the SKOV-3 spheroids reduced their adhesion to extracellular matrix proteins collagen and fibronectin as well as LP-9 human mesothelial cells over a 7-day time period, with the PEG-functionalized nanosheets showing the greatest reduction in adhesion. The nanomaterials did not exhibit cytotoxicity to LP-9 cells at the range of concentrations used to prevent adhesion. Receptor blocking studies confirmed that the nanosheets were predominantly engaging with the tumor spheroids via β-integrins. Finally, for tumor spheroids that did bind to the mesothelial cells, the presence of nanosheets on the surface of the spheroids decreased the rate of mesothelial layer clearance by the tumor cells. Taken together, these results demonstrate that graphene oxide nanomaterials can bind to ovarian tumor spheroids and inhibit their attachment to matrix proteins and mesothelial cells, while also reducing their ability to clear mesothelial cells once bound. Future efforts are focused on testing these materials with human ascites fluid and further modifying the nanosheets to enable ablation of tumor cells bound to the nanosheets to enhance their therapeutic potential. Citation Format: Hak Rae Lee, Melissa A. Geller, Samira M. Azarin. Inhibition of ovarian cancer spheroid adhesion using graphene oxide nanomaterials [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B52.
Prasugrel-based de-escalation of dual antiplatelet therapy after percutaneous coronary intervention in patients with acute coronary syndrome (HOST-REDUCE-POLYTECH-ACS): an open-label, multicentre, non-inferiority randomised trial
Authors: Hyo-Soo Kim, Jeehoon Kang, Doyeon Hwang, Jung-Kyu Han, Han-Mo Yang, Hyun-Jae Kang, Bon-Kwon Koo, Jay Young Rhew, Kook-Jin Chun, Young-Hyo Lim, Jung Min Bong, Jang-Whan Bae, Bong Ki Lee, Kyung Woo Park
Journal: The Lancet (2020)
Abstract 4966: MyD88 in myofibroblasts enhances colitis-associated tumorigenesis via promoting macrophage M2 polarization in mice
Authors: Jinhua Zhang, Tian Tian, Qi Yuan
Journal: Cancer Research (2020)

Abstract Background &amp; Aims: The signal adapter MyD88, an essential component of TLR signaling, plays an important role in gut-microbiome interactions. However, its contribution to colitis-associated cancer (CAC) is still controversial. We investigated whether MyD88 signaling in myofibroblasts contributes to an environment that promotes CAC development. Methods: C57BL/6J mice (control) and mice with myofibroblasts-specific deletion of MyD88 (Fib-MyD88 KO) were performed azoxymethane (AOM)/dextran sodium sulfate (DSS) model or DSS model. Colon tissue was collected and analyzed for inflammation, cell proliferation and macrophage polarization. Primary normal fibroblasts (NFs) were isolated and measured for mechanisms that induced macrophage polarization. Results: Myofibroblasts MyD88-deficient mice were resistant to AOM/DSS-induced tumorigenesis, as evidence by the decrease in the number and sizes of tumors. MyD88 deficiency in myofibroblasts did not affect the inflammatory response but attenuated intestinal epithelial cell (IEC) proliferation after acute DSS-induced colitis. Furthermore, MyD88 signaling in myofibroblasts increased the secretion of osteopontin (OPN), which promoted macrophage M2 polarization through binding to αvβ3 and CD44, leading to activation of the STAT3 and PPARγ pathways. Conclusions: MyD88 signaling in myofibroblasts crucially contributes to colorectal cancer development and provides a promising therapeutic target for the prevention of colitis-associated carcinogenesis. Citation Format: Jinhua Zhang, Tian Tian, Qi Yuan. MyD88 in myofibroblasts enhances colitis-associated tumorigenesis via promoting macrophage M2 polarization in mice [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 4966.
Abstract 6289: Phenotypic screening of small molecules for novel immuno-oncology potential using BioMAP® Early Screening Services
Authors: Alison O'Mahony, Sheryl P. Denker, Sharlene Velichko
Journal: Cancer Research (2020)

Abstract Approved immuno-oncology (IO) drugs that have expanded the arsenal of available treatment options for recalcitrant cancers include antibodies to PD-(L)1 checkpoints–a relatively new class of immunotherapies. While the clinical success reported for these drugs is compelling, efficacy is limited to a small cohort of patients. The need for more IO therapeutic options has prompted the pursuit of next-generation candidates that can achieve better patient outcomes. One approach is to screen compounds for novel targets that elicit an immunorestorative response within the tumor microenvironment (TME), consistent with approved IO drugs. Ideally, a small molecule therapeutic would represent a distinct advantage over existing biologics, both in terms of administration as well as ability to optimize chemistry. In order to efficiently identify molecules with IO potential, a high throughput, physiologically relevant screening approach that recapitulates the complexity of the TME is needed. BioMAP Oncology systems are co-cultures of human primary cell types (endothelial cells, fibroblasts, and PBMCs) and cancer cells that model immune suppressed TME biology. Compounds can be screened in these in vitro TME models to look for impacts on protein biomarkers relevant for immune responses, inflammation, matrix modulation and for impacts on cancer cells. These systems were validated for immune restorative activities using anti PD-(L)1 therapeutics such as pembrolizumab, nivolumab, and durvalumab. Specifically, increased pro-inflammatory cytokine levels served as hallmark activities indicating a reversal of the immune suppressive influence of the cancer cell. In one of the BioMAP Oncology systems, we screened a library of 72 compounds targeting different molecules, the vast majority of which had not previously been identified as potential immuno-oncology candidates. Several small molecules that increased one or more cytokines were identified, indicating immune restorative potential. Other small molecules inhibited immune responses and/or demonstrated anti-inflammatory activities. Additionally, modulation of matrix biomarkers on tissue and tumor cells indicate impacts on distinct compartments of the TME. This approach using human cell-based in vitro TME models represents a rapid and cost-effective manner to rapidly screen libraries of small molecules (both novel and repurposed) for immuno-oncology potential. Citation Format: Alison O'Mahony, Sheryl P. Denker, Sharlene Velichko. Phenotypic screening of small molecules for novel immuno-oncology potential using BioMAP® Early Screening Services [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 6289.
Intermittent regimens for tuberculosis treatment: Back to the Future?
Authors: Jan-Willem C. Alffenaar, Simon Tiberi, Daniela M. Cirillo, Giovanni Battista Migliori
Journal: European Respiratory Journal (2020)

<b>Once weekly bedaquiline, rifapentine and pyrazinamide has sterilising activity and is ready for further exploration in a clinical trial, including appropriate safety and pharmacokinetic assessment</b>https://bit.ly/3ivrY4m
Phosphorylation Control of p53 DNA-Binding Cooperativity Balances Tumorigenesis and Aging
Authors: Oleg Timofeev, Lukas Koch, Constantin Niederau, Alina Tscherne, Jean Schneikert, Maria Klimovich, Sabrina Elmshäuser, Marie Zeitlinger, Marco Mernberger, Andrea Nist, Christian Osterburg, Volker Dötsch, Martin Hrabé de Angelis, Thorsten Stiewe
Journal: Cancer Research (2020)

Abstract Posttranslational modifications are essential for regulating the transcription factor p53, which binds DNA in a highly cooperative manner to control expression of a plethora of tumor-suppressive programs. Here we show at the biochemical, cellular, and organismal level that the cooperative nature of DNA binding is reduced by phosphorylation of highly conserved serine residues (human S183/S185, mouse S180) in the DNA-binding domain. To explore the role of this inhibitory phosphorylation in vivo, new phosphorylation-deficient p53-S180A knock-in mice were generated. Chromatin immunoprecipitation sequencing and RNA sequencing studies of S180A knock-in cells demonstrated enhanced DNA binding and increased target gene expression. In vivo, this translated into a tissue-specific vulnerability of the bone marrow that caused depletion of hematopoietic stem cells and impaired proper regeneration of hematopoiesis after DNA damage. Median lifespan was significantly reduced by 20% from 709 days in wild type to only 568 days in S180A littermates. Importantly, lifespan was reduced by a loss of general fitness and increased susceptibility to age-related diseases, not by increased cancer incidence as often seen in other p53-mutant mouse models. For example, S180A knock-in mice showed markedly reduced spontaneous tumorigenesis and increased resistance to Myc-driven lymphoma and Eml4–Alk-driven lung cancer. Preventing phosphorylation of S183/S185 in human cells boosted p53 activity and allowed tumor cells to be killed more efficiently. Together, our data identify p53 DNA-binding domain phosphorylation as a druggable mechanism that balances tumorigenesis and aging. Significance: These findings demonstrate that p53 tumor suppressor activity is reduced by DNA-binding domain phosphorylation to prevent aging and identify this phosphorylation as a potential target for cancer therapy. See related commentary by Horikawa, p. 5164
Broaden sources and reduce expenditure: Tumor-specific transformable oxidative stress nanoamplifier enabling economized photodynamic therapy for reinforced oxidation therapy
Authors: Xiaoyu Xu, Binyao Huang, Zishan Zeng, Jie Chen, Zeqian Huang, Zilin Guan, Meixu Chen, Yanjuan Huang, Chunshun Zhao
Journal: Theranostics (2020)

Cancer cells immersed in inherent oxidative stress are more vulnerable to exogenous oxidative damages than normal cells. Reactive oxygen species (ROS)-mediated oxidation therapy preferentially aggravating tumor oxidative stress to disrupt redox homeostasis, has emerged as an effective and specific anticancer treatment. Herein, following an ingenious strategy of "broaden sources and reduce expenditure", we designed a versatile tumor-specific oxidative stress nanoamplifier enabling economized photodynamic therapy (PDT), to achieve synergistic oxidative stress explosion for superior oxidation therapy. Methods: Cinnamaldehyde (CA) as a therapeutic ROS generator was first conjugated to hyaluronic acid (HA) through acid-labile hydrazone bond to synthesize tailored amphiphilic HA@CA conjugates, which could surprisingly self-assemble into uniform nanofibers in aqueous media. Photosensitizer protoporphyrin (PpIX) was efficiently encapsulated into HA@CA nanofibers and transformed HA@CA nanofibers to final spherical HA@CAP. Results: With beneficial pH-responsiveness and morphology transformation, improved bioavailability and selective tumor accumulation, HA@CAP combining ROS-based dual chemo/photodynamic treatment modalities could induce cytotoxic ROS generation in a two-pronged approach to amplify tumor oxidative stress, termed "broaden sources". Moreover, utilizing CA-induced H2O2 production and cascaded Fenton reaction in mitochondria to consume intracellular overloaded Fe(II), HA@CAP could skillfully block endogenic heme biosynthesis pathway on site to restrain undesired elimination of PpIX for economized PDT, termed "reduce expenditure". Both in vitro and in vivo results demonstrated the superior antitumor performance of HA@CAP. Conclusion: This study offered an inspiring strategy of "broaden sources and reduce expenditure" to specifically boost tumor oxidative stress for reinforced oxidation therapy.
Recognition of G-quadruplex topology through hybrid binding with implications in cancer theranostics
Authors: Yelisetty Venkata Suseela, Pardhasaradhi Satha, N. Arul Murugan, Thimmaiah Govindaraju
Journal: Theranostics (2020)

The selective recognition and imaging of oncogene specific G-quadruplex (GQ) structures holds great promise in the development of diagnostic therapy (theranostics) for cancer and has been challenging due to their structural dynamics and diversity. We report selective recognition of GQ by a small molecule through unique hybrid loop stacking and groove binding mode with turn on far-red fluorescence response and anticancer activity demonstrating the potential implications for GQ-targeted cancer theranostics. Methods: Biophysical investigation reveal the turn on far-red emission property of TGP18 for selective recognition of GQ. In cellulo studies including DNA damage and oxidative stress evaluation guided us to perform in vitro (3D spheroid) and in vivo (xenograft mice model) anti-cancer activity, and tumor tissue imaging to assess the theranostic potential of TGP18. Results: Neocuproine-based far-red turn on fluorescence probe TGP18 shows GQ-to-duplex selectivity and specifically recognizes BCL-2 GQ with high affinity through a unique hybrid binding mode involving loop-stacking and groove interactions. Our study reveals that the selective recognition originating from the distinct loop structure of GQ that alters the overall probe interaction and binding affinity. TGP18 binding to anti-apoptotic BCL-2 GQ ablates the pro-survival function and elicit anti-cancer activity by inducing apoptosis in cancer cells. We deciphered that inhibition of BCL-2 transcription synergized with signaling cascade of nucleolar stress, DNA damage and oxidative stress in triggering apoptosis signaling pathway. Conclusion: Intervention of GQ mediated lethality by TGP18 has translated into anti-cancer activity in both in vitro 3D spheroid culture and in vivo xenograft models of lung and breast cancer with superior efficacy for the former. In vivo therapeutic efficacy supplemented with tumor 3D spheroid and tissue imaging potential define the role of TGP18 in GQ-targeted cancer theranostics.
Abstract 739: A disintegrin and metalloproteinase 8 as a potential blood biomarker for early diagnosis of gastric cancer
Authors: Jae-Il Choi, Joon Seong Park, Hye Won Chung, Jong-Baeck Lim
Journal: Cancer Research (2020)

Abstract Purpose: We evaluate the clinical significance of A Disintegrin and Metalloproteinase 8 (ADAM 8) as a potential blood biomarker for gastric cancer (GC). Materials &amp; Methods: Blood ADAM 8 was measured by ELISA and CEA, Cytokines/chemokines (IL-23, SDF-1α/CXCL12, IL-8, and sCD40L) were measured by chemiluminescent immunoassay. They were compared among 5 groups; normal/gastritis, high-risk, early GC (EGC), advanced GC (AGC) without distant metastasis and AGC with distant metastasis by one-way analysis of variance in both training (n=80) and validation dataset (n=241). Clinicopathological features of GC and GC-associated cytokines were evaluated for their correlations with blood ADAM 8. To evaluate the diagnostic accuracy to predict GC, receiver operating characteristic (ROC) curve and logistic regression were used. Results: In both training and validation dataset, blood ADAM 8 increased along the GC carcinogenesis (ANOVA, all of p&amp;lt;0.01). Blood ADAM 8 were significantly higher in EGC and AGC compared with high-risk and normal (post-hoc Bonferroni, all of p&amp;lt;0.01). However, there was no significant difference among cancer groups. Blood ADAM 8 was correlated with N-stage (Spearman's correlation, γs,=0.320, p=0.011), but not correlated with T-stage or M-stage. Pearson's correlations showed blood ADAM 8 was closely correlated with pre-inflammatory cytokines (IL-23, SDF-1α/CXCL12, all of p&amp;lt;0.05), but not correlated with pro-angiogenic cytokines (IL-8, sCD40L). ROC curve and logistic regression demonstrated serum ADAM 8 showed higher diagnostic accuracy (sensitivity, 73.7%; specificity, 86.2%) than CEA (sensitivity, 23.1%; specificity, 91.4%). Combination of ADAM 8 and CEA more increased the diagnostic accuracy to predict GC (sensitivity, 81.8%; specificity, 84.0%). Conclusion: Blood ADAM 8 is a promising biomarker for early detection of GC. Citation Format: Jae-Il Choi, Joon Seong Park, Hye Won Chung, Jong-Baeck Lim. A disintegrin and metalloproteinase 8 as a potential blood biomarker for early diagnosis of gastric 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 739.
Abstract 6461: HER2 positive DCIS increases short term risk of ipsilateral invasive ductal carcinoma in breast conserving surgery patients
Authors: Thomas O'Keefe, Sarah Blair, Ava Hosseini, Olivier Harismendy, Anne Wallace
Journal: Cancer Research (2020)

Abstract Purpose: The impact of HER2 status in ductal carcinoma in situ (DCIS) lesions on the risk of progression to invasive ductal carcinoma (IDC) has been debated with reports of both increased and decreased risk of development of invasive breast cancer in HER2 positive patients. We aim to use a large national database to elucidate the effect of HER2 positivity on ipsilateral IDC (iIDC) development. Methods: We performed survival analyses on patient-level data using the US National Cancer Institute's Surveillance, Epidemiology, and End Results program to identify patients diagnosed with DCIS who underwent lumpectomy and had known HER2, estrogen and progesterone receptor statuses, grade, comedonecrosis, age, tumor size, and radiation therapy (RT). Competing risks analysis was performed. Results: 1,540 patients meeting inclusion criteria were identified. Median age at diagnosis was 60 with median follow-up time of 44.5 months. 22 (1.4%) patients developed iIDC and 27 (1.8%) developed ipsilateral in situ or contralateral disease. 1,035 (67.2%) patients were HER2 negative and 417 (27.1%) were HER2 positive. The estimated cumulative incidence of iIDC at 5 years was 1.9% for all patients, 1.2% (95% CI 0.6-2.1%) for HER2 negative patients, and 4.0% (95% CI 2.9-5.4%) for HER2 positive patients. On competing risks regression, two factors were significant for iIDC: RT within 20 months (HR=0.02, p=0.0002) and HER2 positivity (HR=2.81, p=0.046). Conclusions: HER2 may serve as a prognostic factor for consideration in decision making in patients for whom it is available, and in our analysis was the only lesion-related factor to significantly relate to iIDC development. Citation Format: Thomas O'Keefe, Sarah Blair, Ava Hosseini, Olivier Harismendy, Anne Wallace. HER2 positive DCIS increases short term risk of ipsilateral invasive ductal carcinoma in breast conserving surgery patients [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 6461.