tbuckley/cabot-search huggingface dataset:
Harmonizing acute and chronic kidney disease definition and classification: report of a Kidney Disease: Improving Global Outcomes (KDIGO) Consensus Conference
Authors: Norbert H. Lameire, Adeera Levin, John A. Kellum, Michael Cheung, Michel Jadoul, Wolfgang C. Winkelmayer, Paul E. Stevens, Fergus J. Caskey, Chris K.T. Farmer, Alejandro Ferreiro Fuentes, Masafumi Fukagawa, Stuart L. Goldstein, Grace Igiraneza, Andreas Kribben, Edgar V. Lerma, Andrew S. Levey, Kathleen D. Liu, Jolanta Małyszko, Marlies Ostermann, Neesh Pannu, Claudio Ronco, Simon Sawhney, Andrew D. Shaw, Nattachai Srisawat
Journal: Kidney International (2021)

Kidney disease is an important public health problem. Both acute kidney injury (AKI) and chronic kidney disease have been well defined and classified, leading to improved research efforts and subsequent management strategies and recommendations. For those patients with abnormalities in kidney function and/or structure who meet neither the definition of AKI nor chronic kidney disease, there remains a gap in research, care, and guidance. The term acute kidney diseases and disorders, abbreviated to acute kidney disease (AKD), has been introduced as an important construct to address this. To expand and harmonize existing definitions and to ultimately better inform research and clinical care, Kidney Disease: Improving Global Outcomes (KDIGO) organized a consensus workshop. Multiple invitees from around the globe, representing both acute and chronic kidney disease researchers and experts, met virtually to examine existing data, and discuss key concepts related to AKD. Despite some remaining unresolved questions, conference attendees reached general consensus on the definition and classification of AKD, management strategies, and research priorities. AKD is defined by abnormalities of kidney function and/or structure with implications for health and with a duration of ≤3 months. AKD may include AKI, but, more importantly, also includes abnormalities in kidney function that are not as severe as AKI or that develop over a period of >7 days. The cause(s) of AKD should be sought, and classification includes functional and structural parameters. Management of AKD is currently based on empirical considerations. A robust research agenda to enable refinement and validation of definitions and classification systems, and thus testing of interventions and strategies, is proposed.
Abstract 12326: Comparison of 8 Biomarkers to Predict Coronary Plaque Burden in Patients With and Without Chronic Kidney Disease: From the EXCEED-J Study
Authors: Hiromichi Wada, Tsuyoshi Shinozaki, Masahiro Suzuki, Satoru Sakagami, Yoichi Ajiro, Junichi Funada, Morihiro Matsuda, Masatoshi Shimizu, Takashi Takenaka, Yukiko Morita, Kazuya Yonezawa, Hiromi Matsubara, Yujiro Ono, Toshihiro Nakamura, Kazuteru Fujimoto, Kazuro Yoshida, Toru Kato, Takashi Unoki, Daisuke Takagi, Moritake Iguchi, Kazuhiko Kotani, Noriko Satoh-Asahara, Mitsuru Abe, Masaharu Akao, Koji Hasegawa
Journal: Circulation (2019)

Background: The biomarkers that represent coronary plaque burden in patients with and without chronic kidney disease (CKD) is unclear. A previous study found that increased soluble vascular endothe...
Abstract 1915: Novel synthetic DNA vaccines in prostate cancer immunotherapy
Authors: Devivasha Bordoloi, Peng Xiao, Hyeree Choi, Michelle Ho, Alfredo Perales-Puchalt, Makan Khoshnejad, J.Joseph Kim, Laurent Humeau, Alagarsamy Srinivasan, David B. Weiner, Kar Muthumani
Journal: Cancer Research (2021)

Abstract Prostate cancer (PCa) represents the most predominant cancer type among males with an estimated 191,930 cases diagnosed in 2020 with 33,330 deaths globally. Notably, different treatment modalities such as surgery, chemo, radiation and hormone therapy exhibited improved outcomes in early stage PCa patients; however, there exist high recurrence rate in the treated patients and leads to castration resistant prostate cancer, the treatment choices for which are highly restricted. This scenario has pressed us to consider synthetic DNA vaccine-based immunotherapy approach, with ability to induce antigen-specific tumor-killing immune cells. Considering the high heterogeneity of prostate cancer cells, we hypothesized that synthetic DNA vaccines targeting multiple prostate specific antigens would elicit improved immune responses in those who are at high risk as well as advanced stages of prostate cancer. Therefore, we generated synthetic enhanced DNA immunogens as DNA constructs (SEV) targeting STEAP1, PAP, PARM1, PSCA, PCTA and PSP94 through utilization of bioinformatics approaches. The SEVs for prostate cancer antigens elicited potent cellular immunity as well as polyfunctionality of antigen-specific T cells in mice. Further, they were capable of generating robust humoral immune responses to each antigen. The anti-tumor activities of the SEVs were studied in prostate tumor which showed that the induced immune responses delayed tumor progression and enhanced infiltration of anti-tumor CD8+ T cells in the tumor microenvironment in a mouse model challenge system. These data highlight further study of these novel immunogens as synthetic DNA immunogens for immunotherapy of PCa, and perhaps other human cancers. Citation Format: Devivasha Bordoloi, Peng Xiao, Hyeree Choi, Michelle Ho, Alfredo Perales-Puchalt, Makan Khoshnejad, J.Joseph Kim, Laurent Humeau, Alagarsamy Srinivasan, David B. Weiner, Kar Muthumani. Novel synthetic DNA vaccines in prostate cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1915.
Abstract 2968: Organoid based functional genomics approach to identify treatment options for patients with rare cancers
Authors: Benjamin David Hopkins, Julie-Ann Cavallo-Fleming, Sally Claridge, Lamberto De Boni, Chantal Pauli
Journal: Cancer Research (2021)

Abstract Rare cancers present a distinct challenge for the identification of effective therapeutic strategies. While these tumors make up 20% of total cancer cases in the United States, they are categorically defined as occurring in less than 6 of every 100,000 people, limiting the utility of traditional methods to study, and identify treatments for these cancers. Though there have been tremendous advances in cancer therapeutics, identification of treatments for rare tumors have lagged, leaving patients with rare tumors with worse 5 year survival rates than individuals diagnosed with common cancer types. The goal of precision oncology is to identify effective therapeutic strategies for each individual patient. With high throughput sequencing it is now possible to identify the genetic events that give rise to and sustain each individual tumor in clinically relevant time frames, however our capacity to leverage this information to identify effective therapeutic options remains limited. This gap in our capacity stems from a lack of clinically relevant approaches that would allow physicians to accurately gauge the impact of multiple therapeutic strategies and relate them to clinical responses. Through the establishment of an iterative Functional Genomics Pipeline which integrates the development and analysis of high-fidelity patient derived organoid models of rare cancers with personalized drug sensitivity testing, and comprehensive genomics our work suggests that personalized modeling could have clinical utility for the identification of treatment options for individual patients with rare cancers. Citation Format: Benjamin David Hopkins, Julie-Ann Cavallo-Fleming, Sally Claridge, Lamberto De Boni, Chantal Pauli. Organoid based functional genomics approach to identify treatment options for patients with rare cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2968.
Abstract 1914: Orally available oncolytic reovirus, RC402, effectively promotes anti-cancer immunity and synergizes with immune checkpoint blockade in colon cancer
Authors: Chan Kim, Hong Jae Chon, Hye Jin Lee, Won Suk Lee, Hannah Yang, Jeong Hun Kim, So Jung Kong, Yu Seong Lee, Seung Joon Lee, Enkhtaivan Gansukh, Ki-Hoon Song, Yeon-Sook Lee, Beodeul Kang
Journal: Cancer Research (2021)

Abstract Introduction: Reoviruses are replication-competent and selectively infect and destroy cancer cells. Although the most common route of oncolytic virotherapy is intratumoral or intravenous administration, these routes are often not clinically feasible because of tumor inaccessibility, tumor multiplicity, and systemic toxicities. Here, we developed an orally available oncolytic reovirus, RC402, to elicit potent anti-tumor immune responses without the above mentioned limitations and thereby maximize the efficacy of PD-1 immune checkpoint blockade in colon cancer. Method: MC38 or CT26 colon cancer-bearing immunocompetent mice were treated with RC402 and/or anti-PD-1 antibody. Tumor growth was monitored after treatment and comprehensively analyzed by flow cytometry and/or multiplex tissue imaging. Results: RC402 treatment effectively delayed tumor growth regardless of the route of administration (per os as well as intratumorally). In particular, orally administered RC402 was well tolerated without gross toxicity and interacted with intestinal immune cells, eliciting adaptive T cell responses within intestinal lymphoid organs such as Peyer's patch. Most of the RC402 was cleared in the gastrointestinal tract within 10 days of the first treatment, and it was not detectable in the blood stream or major organs after oral administration. However, RC402 selectively induced strong and durable anti-tumor immunity in distant tumor tissues. Oral RC402 monotherapy markedly increased CD8+ cytotoxic T cells and decreased CD4+CD25+Foxp3+ regulatory T cells in distant colon cancers, while there were no significant changes in tumor-associated myeloid cells. Finally, oral RC402 treatment cooperated with anti-PD-1 blockade to further suppress colon cancer growth and augment anti-tumor immunity within the tumor microenvironment, leading to complete regression of tumors and survival benefit of tumor-bearing mice. Conclusion: Our study demonstrates that orally available oncolytic reovirus, RC402, could induce potent anti-cancer immune responses and effectively suppress colon cancer progression in combination with anti-PD-1 blockade. Citation Format: Chan Kim, Hong Jae Chon, Hye Jin Lee, Won Suk Lee, Hannah Yang, Jeong Hun Kim, So Jung Kong, Yu Seong Lee, Seung Joon Lee, Enkhtaivan Gansukh, Ki-Hoon Song, Yeon-Sook Lee, Beodeul Kang. Orally available oncolytic reovirus, RC402, effectively promotes anti-cancer immunity and synergizes with immune checkpoint blockade in colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1914.
Abstract 3072: Clinically relevant MAPK pathway inhibition reverses stem cell fate defects and sensitize BRAF mutant glioma to immune modulatory therapies
Authors: Claudia K. Petritsch, Stefan Grossauer, Wei Wang, Anne Marie Barrette, Jongwhi Park
Journal: Cancer Research (2021)

Abstract Pediatric low-grade gliomas (pLGG) are the most common central nervous system (CNS) tumor in children. Although the majority of pLGG has unregulated MAPK pathway activity, and clinical MAPK pathway inhibitors are available, pLGG treatment remains challenging. Tumor progression, rebound, and therapy resistance limit the success of MAPK pathway inhibitors, especially in high risk subgroups, such as BRAF V600E mutant CDKN2A deleted gliomas.To define mechanisms for progression and overcome resistance, we generated BRAF V600E mutant, CDKN2A deleted murine glioma models of different grades and drug sensitivities. Here, we use genetically engineered mice to target expression of BRAF V600E and deletion of CDKN2A to various germinal and non-germinal areas, assessing neuro-anatomical aspects of oncogene sensitivity. Using neural stem cell (NSC)- and astrocyte-, and oligodendrocyte progenitor cell (OPC)-selective driver line, we investigate the likely origin for pLGG and therapy resistant glioma stem cells, developing models that faithfully recapitulate human tumor development. Our numerous immunocompetent, orthotopic BRAF V600E mutant glioma model derived from endogenous tumors exhibit a range of sensitivities to MAPK inhibitor therapies, allowing us to define mechanisms for therapy resistance. In syngeneic, orthotopic BRAF V600E mutant CDKN2A deleted gliomas, we define MAPK pathway inhibitor-induced-changes in the tumor microenvironment, including the immune infiltrate, and investigate immune modulatory therapy as novel treatment strategy for children with BRAF mutant gliomas. Our numerous models for BRAF mutant glioma will facilitate research on tumor development, progression and the tumor-immune interactions. Collectively, our results describe genetic alteration- and microenvironment-based mechanisms for BRAF mutant tumor initiation and progression, and suggest therapeutic combination therapies for glioma. Citation Format: Claudia K. Petritsch, Stefan Grossauer, Wei Wang, Anne Marie Barrette, Jongwhi Park. Clinically relevant MAPK pathway inhibition reverses stem cell fate defects and sensitize BRAF mutant glioma to immune modulatory therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3072.
Abstract 2261: A multimodal single-cell workflow to interrogate cellular responses to cancer therapy
Authors: Dalia Dhingra, Aik Ooi, Alex Li, Adam Sciambi, Shu Wang, Saurabh Gulati, David Ruff
Journal: Cancer Research (2021)

Abstract Understanding the genomic landscape of cancer in single cells can be valuable for the characterization of molecular events that drive evolution of tumorigenesis and fostering progress in identifying druggable regimens for patient treatment scenarios. We report a new approach to measure multiple modalities simultaneously from up to 10,000 individual cells using microfluidics paired with next generation sequencing. Our procedure determines targeted protein levels, mRNA transcript levels and somatic gDNA sequence variations including copy number variants. This approach can resolve over 20 proteins, 100s of targeted transcripts and DNA amplicons. We employ oligo-conjugated antibody panels to probe cell surface markers and targeted RNA and DNA amplification to resolve gene expression levels and genomic variants. Cell suspensions are first stained with the antibody panel then loaded onto the Mission Bio Tapestri for generation of a droplet. This droplet biochemistry allows for concurrent cell lysis and release of gDNA/mRNA. A second droplet formation event brings together a barcoded bead and multiplex PCR amplification reagents. After amplification, the combined libraries are sequenced yielding a multimodal readout. We applied this technique to several dynamic immunology and oncology in vitro models. As fusion gene detection has long been a focus of cancer research, we demonstrate this multi-modal workflow on cell lines containing variants of BCR-ABL transcripts with high sensitivities and specificities. We further explored the relationship between genotype-to-phenotype in imatinib impact on retinoblastoma and BCR-ABL driven leukemic cells. Our pilot studies demonstrate the utility of multimodal resolution in further illuminating cellular states and biological responses in cancer cells. Citation Format: Dalia Dhingra, Aik Ooi, Alex Li, Adam Sciambi, Shu Wang, Saurabh Gulati, David Ruff. A multimodal single-cell workflow to interrogate cellular responses to cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2261.
Phase 1 study of safety, tolerability and immunogenicity of the human telomerase (hTERT)-encoded DNA plasmids INO-1400 and INO-1401 with or without IL-12 DNA plasmid INO-9012 in adult patients with solid tumors
Authors: Robert H Vonderheide, Kimberly A Kraynyak, Anthony F Shields, Autumn J McRee, Jennifer M Johnson, Weijing Sun, Ashish V Chintakuntlawar, Jan Pawlicki, Albert J Sylvester, Trevor McMullan, Robert Samuels, Joseph J Kim, David Weiner, Jean D Boyer, Matthew P Morrow, Laurent Humeau, Jeffrey M Skolnik
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Human telomerase reverse transcriptase (hTERT) is frequently classified as a ‘universal’ tumor associated antigen due to its expression in a vast number of cancers. We evaluated plasmid DNA-encoded hTERT as an immunotherapy across nine cancer types. Methods A phase 1 clinical trial was conducted in adult patients with no evidence of disease following definitive surgery and standard therapy, who were at high risk of relapse. Plasmid DNA encoding one of two hTERT variants (INO-1400 or INO-1401) with or without plasmid DNA encoding interleukin 12 (IL-12) (INO-9012) was delivered intramuscularly concurrent with the application of the CELLECTRA constant-current electroporation device 4 times across 12 weeks. Safety assessments and immune monitoring against native (germline, non-mutated, non-plasmid matched) hTERT antigen were performed. The largest cohort of patients enrolled had pancreatic cancer, allowing for additional targeted assessments for this tumor type. Results Of the 93 enrolled patients who received at least one dose, 88 had at least one adverse event; the majority were grade 1 or 2, related to injection site. At 18 months, 54.8% (51/93) patients were disease-free, with median disease-free survival (DFS) not reached by end of study. For patients with pancreatic cancer, the median DFS was 9 months, with 41.4% of these patients remaining disease-free at 18 months. hTERT immunotherapy induced a de novo cellular immune response or enhanced pre-existing cellular responses to native hTERT in 96% (88/92) of patients with various cancer types. Treatment with INO-1400/INO-1401±INO-9012 drove hTERT-specific IFN-γ production, generated hTERT-specific CD4+ and CD8+ T cells expressing the activation marker CD38, and induced hTERT-specific activated CD8 +CTLs as defined by cells expressing perforin and granzymes. The addition of plasmid IL-12 adjuvant elicited higher magnitudes of cellular responses including IFN-γ production, activated CD4+ and CD8+ T cells, and activated CD8+CTLs. In a subset analysis of pancreatic cancer patients, the presence of immunotherapy-induced activated CD8+ T cells expressing PD-1, granzymes and perforin correlated with survival. Conclusions Plasmid DNA-encoded hTERT/IL-12 DNA immunotherapy was well-tolerated, immune responses were noted across all tumor types, and a specific CD8+ phenotype increased by the immunotherapy was significantly correlated with survival in patients with pancreatic cancer.
Assessment of physicians’ satisfaction with a virtual tumour board in a French academic centre during the COVID-19 pandemic
Authors: U. Pinar, A. Clerget, O. Perrot, N. Beaud, W. Akakpo, M. Ruggiero, J. Parra, C. Vaessen, C. Guillot-Tantay, P. Conort, L. Campedel, J. Girault, J.M. Simon, P. Maingon, R. Renard-Penna, P. Mozer, E. Chartier-Kastler, M. Roupret, T. Seisen
Journal: European Urology (2021)
Abstract 457: A comparison of IDH1 R132H [H09] and [IHC132] antibodies on diffuse gliomas
Authors: Sara Figueroa, Joseph Vargas, Jason Ramos
Journal: Cancer Research (2021)

Abstract Introduction In the 2016 World Health Organization Central Nervous System Tumor Classification, diffuse gliomas were reclassified to include astrocytic tumors (grade II and III), oligodendrogliomas (grade II and III), and grade IV glioblastomas with diffuse astrocytoma being distinct from the diffuse gliomas. This reclassification is due to the abundance of IDH1 mutations in many of these tumors. A much better outcome has been observed in these patients than those without this mutation. IDH1 mutation of the R132H type constitutes more than 90% of all IDH1 and IDH2 mutations. Further, IDH1 IHC is now widely applied for the differential diagnosis of these tumors. There are two distinct IDH1 R132H clones on the market, the H09 and IHC132. Comparing these markers for the IDH1 R132H mutations by IHC can help determine if one is superior for diagnostics. Materials and Methods IHC was performed on 3-5 um thick formalin-fixed, paraffin-embedded (FFPE) brain tissue arrays containing glioblastoma, astrocytoma, oligoastrocytoma, oligodendroglioma with adjacent normal tissue (US Biomax, Derwood, USA). These slides were deparaffinized, and peroxidase blocked in the usual manner. Slides were then subjected to HIER in a pressure cooker using a citrate-based buffer at 110°C for 15 minutes before being stained on a semi-automated instrument. The slides were stained with rabbit monoclonal IDH1 R132H antibody H09 (Dianova, Hamburg, Germany) and mouse monoclonal IDH1 R132H antibody IHC132 (GenomeMe, Richmond, Canada) at concentrations and protocols predetermined to match staining intensity. Results The mouse monoclonal anti-IDH1 R132H IHC132 has shown that it is analogous to the current IDH1 R132H [H09]. Upon review of the data, IHC132 marker stains a higher percentage of cases in glioblastoma compared to H09 (11%, n=36) and equal in astrocytoma (73%, n=15), oligoastrocytoma (75%, n=4), oligodendroglioma (100%, n=8). Neither clone stained normal brain tissue per negative controls. Conclusion Mouse monoclonal anti-IDH1 R132H [IHC132] compared with that of the rabbit monoclonal anti-IDH1 R132H [H09] showed equal sensitivity for astrocytoma, oligodendroglioma, and oligoastrocytomas with higher sensitivity for glioblastoma. The results provide evidence to support a higher percentage of positive staining and equal or greater intensity for clone IHC132 versus H09. Citation Format: Sara Figueroa, Joseph Vargas, Jason Ramos. A comparison of IDH1 R132H [H09] and [IHC132] antibodies on diffuse gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 457.