tbuckley/cabot-search huggingface dataset:
Abstract SY17-03: Tumor-associated antigen MUC1 vaccine for colon cancer prevention
Authors: Olivera (Olja) J. Finn
Journal: Cancer Research (2021)

Abstract For most human cancers, infectious etiology is unknown and preventative vaccines based on viral antigens, such as HPV for cervical cancer, are not a possibility. However, non-viral cancer-associated antigens, self-antigens abnormally expressed on tumors, have been identified as candidates for vaccines. In patients diagnosed with cancer, preexisting immunity to some of these antigens correlates with better disease outcome or reduced risk of recurrence. In transgenic mice or other animal models where they are expressed as self-antigens, immune responses induced to their tumor forms protect from tumor challenge without causing autoimmunity. Therapeutic vaccines that have utilized these antigens have had only marginal efficacy, which extensive research has now attributed to the presence of many immunosuppressive influences in the tumor microenvironment. MUC1 is one such antigen that has been shown effective as a vaccine in preclinical animal models but has had limited immunogenicity and little efficacy as a therapeutic vaccine in numerous clinical trials in many epithelial tumors, including cancer. Hypothesizing that the major difference between the outcome of the vaccine in preclinical models and in clinical trials is likely to be the high level of immune suppression in cancer patients, we began to develop models and MUC1 vaccines for cancer prevention in patients at risk, before immune suppression develops. We determined first that the tumor form of MUC1 was expressed on early premalignant lesions as well and chose premalignant colonic polyps as the first setting for testing the preventative vaccine. Data will be reviewed from a published feasibility study confirming immunogenicity and safety of the MUC1 vaccine in healthy individuals at risk for colon cancer. Data will then be presented from a recently completed unpublished randomized, double blind placebo controlled multi-center prophylactic MUC1 vaccine trial in the same patient population, those with a history of advanced colonic polyps and therefore at increased risk of developing colon cancer. Citation Format: Olivera (Olja) J. Finn. Tumor-associated antigen MUC1 vaccine for colon cancer prevention [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 SY17-03.
FcRn expression in cancer: Mechanistic basis and therapeutic opportunities
Authors: Imke Rudnik-Jansen, Kenneth A. Howard
Journal: Journal of Controlled Release (2021)

There is an urgent need to identify new cellular targets to expand the repertoire, potency and safety of cancer therapeutics. Neonatal Fc Receptor (FcRn)-driven cellular recycling plays a predominant role in the prolonged serum half-life of human serum albumin (HSA) and immunoglobulin G (IgG) exploited in long-acting cancer drug designs. FcRn-mediated HSA and IgG uptake in epithelial cells and dendritic cell antigen presentation offers new therapeutic opportunities beyond half-life extension. Altered FcRn expression in solid tumours accounting for HSA catabolism or recycling supports a role for FcRn in tumour metabolism and growth. This review addresses the mechanistic basis for different FcRn expression profiles observed in cancer and exploitation for targeted drug delivery. Furthermore, the review highlights FcRn-mediated immunosurveillance and immune therapy. FcRn offers a potential attractive cancer target but in-depth understanding of role and expression profiles during cancer pathogenesis is required for tailoring targeted drug designs.
An unusual cause of acute cholangitis
Authors: Guillaume Perrod, Enrique Pérez-Cuadrado-Robles, Hedi Benosman, Hadrien Alric, Christophe Cellier, Gabriel Rahmi
Journal: Endoscopy (2021)

Endoscopic treatment can be challenging in patients presenting with biliary adverse events and a biliodigestive diversion. Multiples approaches have been described. In the past decade, an overall technical success of 80–86 % [1] [2] [3] of enteroscopy-assisted endoscopic retrograde cholangiopancreatography (ERCP) has been described.
PGC1α Driven Mitochondrial Biogenesis within the Bone Marrow Stromal Cells of the Acute Myeloid Leukemia Micro-Environment Is a Pre-Requisite for Mitochondrial Transfer to Leukemic Blasts
Authors: Christopher Marlein, Lyubov Zaitseva, Rachel Piddock, Manar Shafat, Angela Collins, Kristian Bowles, Stuart Rushworth
Journal: Blood (2017)
Abstract 2836: Effect of autophagy inhibition on epithelial mesenchymal transition in breast cancer cell lines
Authors: Guadalupe Rojas, Nidia Pazos, Paola Maycotte
Journal: Cancer Research (2021)

Abstract The aim of our work is to evaluate potential undesirable effects of autophagy inhibition in breast cancer subtypes which are not sensitive to the inhibition of autophagy. Worldwide, BC is the most frequent cancer in women. Despite recent advances in diagnosis, molecular stratification and targeted therapy, BC is still the leading cause of cancer-related death in women. Thus, it is a public health issue that must be attended. In cancer, autophagy has a pro-tumorigenic role that helps tumor cells survive metabolic stress and growth factor deprivation, hypoxia, maintain tumor initiating cells, confer therapy resistance and modulate epithelial mesenchymal transition (EMT). Because tumor cells benefit from autophagy, it has been proposed that autophagy inhibition could be beneficial for cancer treatment. Nowadays, there are clinical trials where autophagy is being inhibited with promising results that encourage this approach. However, in these clinical trials, cancer types are not been stratified and autophagy is being inhibited in many solid tumor types. In this regard, there is also in vitro evidence in which autophagy inhibition in some cancer types induces EMT, which in the clinic could be detrimental for patients. This highlights the urgency for stratifying patients that will benefit the most from autophagy inhibition. In this work, autophagy inhibition in MCF7 ER+ cell line increased secretion, inflammation and EMT related pathways suggesting induction of malignancy. Autophagy inhibition induced changes in cell morphology in ER+ breast cancer cell lines (MCF7 and T47D) when evaluated by aspect ratio estimation changing from a cobblestone -like epithelial morphology to a fibroblast-like morphology. No changes in cell morphology were found in MCF10A and MDAMB231 cell lines. Changes in morphology were accompanied by a decrease in E-cadherin protein levels suggesting induction of EMT. Our results suggest that CQ treatment in ER+ BC cells could induce a malignant process related to EMT. Thus, ER+ BC patients may not benefit from autophagy inhibition. Nowadays, there are clinical trials where autophagy is being inhibited and no subtype stratification is being done, so we encourage to stratify patients to determine who will be benefited the most from autophagy inhibition and who will not. Citation Format: Guadalupe Rojas, Nidia Pazos, Paola Maycotte. Effect of autophagy inhibition on epithelial mesenchymal transition in breast cancer cell lines [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 2836.
Abstract 830: Validity and reproducibility of immunohistochemical scoring by trained non-pathologists on Tissue MicroArrays
Authors: Kelly Offermans, Josien C. Jenniskens, Iryna Samarska, Gregorio E. Fazzi, Colinda C. Simons, Kim M. Smits, Leo J. Schouten, Matty P. Weijenberg, Piet A. van den Brandt, Heike I. Grabsch
Journal: Cancer Research (2021)

Abstract Aims: Scoring of immunohistochemical (IHC) staining is often done by non-pathologists, especially in large-scale Tissue MicroArray (TMA)-based studies. Studies on the validity of scoring results from non-pathologists are very limited. Therefore, our main aim was to assess inter-observer agreement between trained non-pathologists and an experienced histopathologist for three IHC markers with different subcellular localisation (nucleus/membrane/cytoplasm). Methods and results: Three non-pathologists were trained in recognizing adenocarcinoma and IHC scoring by a senior histopathologist. Kappa statistics were used to analyse inter- and intra-observer agreement for 6249 TMA cores from a colorectal cancer (CRC) series. Inter-observer agreement between non-pathologists (independently scored) and the histopathologist was “substantial” for nuclear and membranous IHC markers (κrange=0.67-0.75 and κrange=0.61-0.69, respectively), and “moderate” for the cytoplasmic IHC marker (κrange=0.43-0.57). Scores of the three non-pathologists were also combined into a combination score (if at least two non-pathologists independently assigned the same score to a core, this was the combination score). This increased agreement with the pathologist (κnuclear=0.74; κmembranous=0.73; κcytopasmic=0.56). Inter-observer agreement between non-pathologists was “substantial” (κnuclear=0.78; κmembranous=0.72; κcytopasmic=0.61). Intra-observer agreement of non-pathologists was “substantial” to “almost perfect” (κnuclear,range=0.83-0.87; κmembranous,range=0.75-0.82; κcytopasmic,range=0.69-0.69). Overall, agreement was lowest for the cytoplasmic IHC marker. Conclusions: This study shows that adequately trained non-pathologists are able to produce similar IHC scoring results as an experienced histopathologist. Considering the histopathologist's score as the golden standard, we can conclude that trained non-pathologists can produce valid IHC results on TMA sections. A combination score of at least two non-pathologists yielded optimal results. Citation Format: Kelly Offermans, Josien C. Jenniskens, Iryna Samarska, Gregorio E. Fazzi, Colinda C. Simons, Kim M. Smits, Leo J. Schouten, Matty P. Weijenberg, Piet A. van den Brandt, Heike I. Grabsch. Validity and reproducibility of immunohistochemical scoring by trained non-pathologists on Tissue MicroArrays [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 830.
Novel antimicrobial strategies for catheter infection prevention in muscle invasive bladder cancer patients after radical cystectomy and ureterocutaneostomy
Authors: R. Gaglione, A. Arciello, M. De Luca, K. Pane, M. Franzese, M. Salvatore, S. Brancorsini, E. Illiano, F. Trama, E. Costantini
Journal: European Urology (2021)
Robert Angus Harkness
Authors: Anne Harkness, Sally Harkness
Journal: BMJ (2021)

Robert Angus Harkness (“Angus”) was born in Stockton on Tees, the eldest son of Robert Harkness, who was a founder member of the Royal College of General Practitioners. He had a long scientific career in clinical biochemistry, explained to others as trying to understand how we all function and helping those for whom things go wrong. He held posts at the Medical Research Council’s Clinical Endocrinology Research Unit, Edinburgh; the Royal Hospital for Sick Children, Edinburgh; the MRC Clinical Research Centre, Northwick …
Treatment of Donors with Liposomal Alpha-Galactosylceramide Results in the In Vivo Expansion of Invariant Natural Killer T Cells and Reduced Incidence of Acute Graft Versus Host Disease
Authors: Toshihito Hirai, Federico Simonetta, Jeanette Baker, Kristina Maas-Bauer, Musutafa Turkoz, Maite Alvarez, Melissa Mavers, Robert S. Negrin
Journal: Blood (2017)
Abstract 2256: A population-based mouse model for an experimental basal-like mammary cancer
Authors: John Edgar French, William Pressel, Jody Albright, Melissa VerHague, Stephen D. Hursting
Journal: Cancer Research (2021)

Abstract The prevalence of obesity, an established risk and prognostic factor for basal-like breast cancer (BLBC), has risen dramatically in the US and many other countries over the past 4 decades. Obesity is also associated with increased resistance to several classes of cancer chemotherapeutic agents used for advanced BLBC. Unfortunately the mechanisms underlying chemotherapy resistance, and the inter-individual differences driving resistance, are poorly understood. Population-based experimental mouse models for determining inter-individual genetic differences in chemotherapy pharmacokinetics and treatment-related efficacy or resistance in mammary gland cancer are not well-defined. Our aim is to develop a population-based experimental model based on outcrosses between 30 different Collaborative Cross line females and hemizygous male B6.FVB-Tg(C3-1-TAg) (greater than N15) congenic mice to produce 30 Collaborative Cross (CC) recombinant inbred line intercross (CC RIX) mouse lines to investigate the interactive effects between diet-induced obesity (DIO) and genetic susceptibility to chemotherapy in a genetically heterogeneous mouse model of BLBC. We report here that thirty genetically-different CCRIL X hemizygous B6.FVB-Tg(C3-1-TAg) congenic female and male CC RIX mice observed longitudinally for occurrence of basal-like mammary tumors showed significant differences in both age at first mammary tumor observation and the fraction of females and males in each RIX bearing tumors. Litter size and the number of females and males of each RIX varied across the 30 CC RIX line. The study was well-powered, with at least X males and Y females for each CC RIX line evaluated longitudinally. We observed that 25 of 30 female CC RIX lines presented with BLMC, with distinct times-to-tumor with each CC RIX. The penetrance of the fraction of each CC RIX line (birth cohort) presenting with BLMC varied greatly in females (25-100%). Surprisingly, 11 of 30 male CC RIX lines presented with BLMC, with penetrance of BLMC varying in males between 10-75%. In conclusion, we present preliminary data to support development of an experimental mouse model for BLBC based on the random mating of 8 genetically-diverse homozygous inbred founder lines followed by in-breeding to greater than 95% homozygosity carrying 45 million single-nucleotide and structural variants. Studies are underway using these CC RIX lines to evaluate the genetic underpinnings of obesity-associated resistance to carboplatin in C3-TAg-driven mammary tumors. Citation Format: John Edgar French, William Pressel, Jody Albright, Melissa VerHague, Stephen D. Hursting. A population-based mouse model for an experimental basal-like mammary 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 2256.
Elucidating Exposure-Response (Safety and Efficacy) of ADCT-402 (Loncastuximab Tesirine), a Novel Pyrrolobenzodiazepine-Containing Antibody Drug Conjugate, for Recommended Phase 2 Dose Determination in Patients with Relapsed or Refractory Non-Hodgkin Lymphoma
Authors: Owen Anthony O'Connor, Brad S Kahl, Mehdi Hamadani, Paolo Caimi, Erin Reid, Jay Feingold, Karin Havenith, Shui He, Diane R Mould, Immanuel Freedman, Joseph Boni
Journal: Blood (2017)
Inhibition of Angiopoietin-Like Protein 3 With Evinacumab in Subjects With High and Severe Hypertriglyceridemia
Authors: Zahid Ahmad, Robert Pordy, Daniel J. Rader, Daniel Gaudet, Shazia Ali, Claudia Gonzaga-Jauregui, Manish P. Ponda, Brad Shumel, Poulabi Banerjee, Richard L. Dunbar
Journal: Journal of the American College of Cardiology (2021)
Abstract 2410: The mutant p53 C-terminal domain assists in DNA interactions and cell cycle promotion
Authors: Devon Lundine, Zafar Syed, Viola Ellison, George Annor, Gu Xiao, Jill Bargonetti
Journal: Cancer Research (2021)

Abstract Introduction: Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer and has the worst prognosis of any breast cancer sub-type. More than 80% of TNBC patients harbor mutated TP53. Some mutant p53 proteins (mtp53) exhibit gain-of function (GOF) oncogenic characteristics, contributing to the decreased prognosis for TNBC patients, but also providing a potential therapeutic target for this aggressive disease. Our group previously found mtp53 R273H interacts with replicating DNA, and increases chromatin-bound replication proteins MCM2-7, PCNA, and PARP1. Mutant p53 retains an intact C-terminal domain (CTD), the domain which facilitates non-specific DNA binding. We hypothesize that the CTD of mtp53 facilitates increased DNA replication processivity. Methods: To test this hypothesis, we have transiently transfected human cells to compare wild-type p53, and R273H mtp53 full-length and CTD-truncated variants. We used CRISPR/Cas9 to generate endogenous CTD truncations of mtp53 R273H in the breast cancer cell line MDA-MB-468. Specifically, clones were used which have mtp53 CTD truncations (R273HΔ381-388 and R273HΔ347-393) and one clone with a frameshift resulting in no detectable mtp53 protein (R273Hfs387). Various western blotting techniques were used to assess protein level and sub-cellular localization, including the iPOND (isolation of proteins on nascent DNA) assay. Several microscopy techniques were used to visualize protein-protein interactions in cells including immunofluorescence, proximity ligation, and DNA fiber assays. Results: Our data show mtp53 R273H and wild-type p53 proteins with CTD truncations tether less to chromatin than their full-length counterparts. Also, our data shows that the truncated R273HΔ381-388 mtp53 is in close proximity to PARylated proteins (and potentially even PARylated itself), but the R273HΔ347-393 truncation is not in close proximity to PARylated proteins. Additionally, R273HΔ381-388 and R273HΔ347-393 demonstrate delayed cell cycle progression and reduced proliferation compared to MDA-MB-468 cells. We observe DNA replication processivity is decreased in 468 R273HΔ381-388 and R273Hfs387 cells. Processivity, but not proliferation rate, is rescued in 468 R273HΔ347-393 cells. Conclusions: The combination of reduced cell proliferation in all CTD-truncated cells, and reduced DNA replication processivity in R273HΔ381-388 and R273Hfs387 cells, but not in R273HΔ347-393 indicates a nuanced role for the CTD in DNA replication and S-phase progression. Citation Format: Devon Lundine, Zafar Syed, Viola Ellison, George Annor, Gu Xiao, Jill Bargonetti. The mutant p53 C-terminal domain assists in DNA interactions and cell cycle promotion [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 2410.
The molecular chaperone TRAP1 in cancer: From the basics of biology to pharmacological targeting
Authors: Ionica Masgras, Claudio Laquatra, Giuseppe Cannino, Stefano A. Serapian, Giorgio Colombo, Andrea Rasola
Journal: Seminars in Cancer Biology (2021)

TRAP1, the mitochondrial component of the Hsp90 family of molecular chaperones, displays important bioenergetic and proteostatic functions. In tumor cells, TRAP1 contributes to shape metabolism, dynamically tuning it with the changing environmental conditions, and to shield from noxious insults. Hence, TRAP1 activity has profound effects on the capability of neoplastic cells to evolve towards more malignant phenotypes. Here, we discuss our knowledge on the biochemical functions of TRAP1 in the context of a growing tumor mass, and we analyze the possibility of targeting its chaperone functions for developing novel anti-neoplastic approaches.
Persistence of anti-SARS-CoV-2 antibodies: immunoassay heterogeneity and implications for serosurveillance
Authors: Javier Perez-Saez, María-Eugenia Zaballa, Sabine Yerly, Diego O. Andrey, Benjamin Meyer, Isabella Eckerle, Jean-François Balavoine, François Chappuis, Didier Pittet, Didier Trono, Omar Kherad, Nicolas Vuilleumier, Laurent Kaiser, Idris Guessous, Silvia Stringhini, Andrew S. Azman
Journal: Clinical Microbiology and Infection (2021)
Secondary treatment for men with localized prostate cancer: A pooled analysis of PRIAS and ERSPC-Rotterdam datasets within the PIONEER data platform
Authors: K. Beyer, S. Remmers, V. Straten, S. Maclennan, S.J. Maclennan, P.P. Willemse, R. Herrera, M.I. Omar, B. Russell, J. Huber, M. Kreuz, T. Abbott, A. Asiimwe, A. Briganti, M. Van Hemelrijck, M.J. Roobol
Journal: European Urology (2021)
Abstract 297: Innovation in delivering synthetically challenging bicyclic arginase inhibitors to enhance immunotherapy
Authors: Derun Li, Hongjun Zhang, Thomas W. Lyons, Theodore A. Martinot, Abdelghani Achab, Min lu, Lisa M. Nogle, Spencer McMinn, Matthew J. Mitcheltree, Matthew Childers, Qinglin Pu, Symon Gathiaka, Anand Palani, Kalyan Chakravarthy, Amy D. DeCastro, Jennifer O'Neil, Roshi Afshar, Nicole C. Walsh, Peter W. Fan, Mangeng Cheng, Richard Miller, Amy Doty, Rachel Palte, Hai-Young Kim, Josep Saurí, Adam Beard, Christopher Brynczka, Christian Fischer
Journal: Cancer Research (2021)

Abstract Arginase overexpression has been associated with poor survival rates in advanced cancer patients treated with Keytruda. High levels of Arginase may lead to a depletion of arginine within the tumor microenvironment, inhibiting the immune response. Thus, arginase inhibition has the potential to greatly enhance immunotherapy treatment. Discovering novel arginase inhibitors was met with several challenges including analyzing/purifying extremely polar chemical matter without chromophores, synthetically challenging space, and poor bioavailability of compounds with ClogP less than minus two. Cross-functional collaborations and innovations rapidly overcame these challenges. Structural chemistry and modeling guided the design of novel arginase inhibitors. Analytical and purification groups developed innovative analytical/purification methods. Novel technologies including ReatIR and Vapourtec flow system, provided key intermediates to enable chartering into synthetically challenging space. Through creative cyclization strategies and active transport strategy to improve bioavailability, the team ultimately delivered a diverse set of potent and extremely synthetically challenging arginase inhibitors to study the potential of arginase inhibition. Preliminary in vivo evaluation showed single agent efficacy in an EMT6 model. These arginase inhibitors have the potential to enhance immunotherapy. Citation Format: Derun Li, Hongjun Zhang, Thomas W. Lyons, Theodore A. Martinot, Abdelghani Achab, Min lu, Lisa M. Nogle, Spencer McMinn, Matthew J. Mitcheltree, Matthew Childers, Qinglin Pu, Symon Gathiaka, Anand Palani, Kalyan Chakravarthy, Amy D. DeCastro, Jennifer O'Neil, Roshi Afshar, Nicole C. Walsh, Peter W. Fan, Mangeng Cheng, Richard Miller, Amy Doty, Rachel Palte, Hai-Young Kim, Josep Saurí, Adam Beard, Christopher Brynczka, Christian Fischer. Innovation in delivering synthetically challenging bicyclic arginase inhibitors to enhance 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 297.