tbuckley/cabot-search huggingface dataset:
Role of the IL-33/ST2 axis in cigarette smoke-induced airways remodelling in chronic obstructive pulmonary disease
Authors: Qiong Huang, Chen Duo Li, Yi Ran Yang, Xiao Feng Qin, Jing Jing Wang, Xin Zhang, Xiao Nan Du, Xia Yang, Ying Wang, Lun Li, Mi Mu, Zhe Lv, Ye Cui, Kewu Huang, Chris J Corrigan, Wei Wang, Sun Ying
Journal: Thorax (2021)

Background Efficient therapy and potential prophylaxis are confounded by current ignorance of the pathogenesis of airway remodelling and blockade in COPD. Objective To explore the role of the IL-33/ST2 axis in cigarette smoke (CS) exposure-induced airways remodelling. Methods C57BL/6, BALB/c and IL-1RL1 -/- mice exposed to CS were used to establish an animal surrogate of COPD (air-exposed=5~8, CS-exposed=6~12). Hallmarks of remodelling were measured in mice. Cigarette smoke extract (CSE)-induced proliferation and protein production in vitro by fibroblasts in the presence of anti-interleukin-33 (anti-IL-33) or hST2 antibodies were measured. Expression of IL-33 and ST2 and other remodelling hallmarks were measured, respectively, in bronchoalveolar lavage fluid (BALF) (controls=20, COPD=20), serum (controls=59, COPD=90) and lung tissue sections (controls=11, COPD=7) from patients with COPD and controls. Results Wild-type mice exposed to CS elevated expression of hallmarks of tissue remodelling in the lungs and also in the heart, spleen and kidneys, which were significantly abrogated in the IL-1RL1 -/- mice. Fibroblasts exposed to CSE, compared with control, exhibited early cellular translocation of IL-33, accompanied by proliferation and elevated protein synthesis, all inhabitable by blockade of IL-33/ST2 signalling. Expression of IL-33 and ST2 and hallmarks of tissue remodelling were significantly and proportionally elevated in BALF, serum and tissue samples from patients with COPD. Conclusions Exposure to CS induces remodelling changes in multiple organs. The data support the hypothesis that CS-induced lung collagen deposition is at least partly a result of CS-induced IL-33 translocation and release from local fibroblasts.
Abstract 482: Rapid highly multiplexed immunoprofiling of human fixed tissues by Orion imaging
Authors: Jia-Ren Lin, Daniel E. Campton, Jeremy Cooper, Yu-An Chen, Erin F. McCarty, Keith L. Ligon, Eric P. Kaldjian, Kyla Teplitz, Steve Reese, Sandro Santagata, Peter K. Sorger
Journal: Cancer Research (2021)

Abstract The dramatic impact of immune checkpoint inhibitors (ICIs) has focused interest in investigating immune-tumor cell interactions to understand mechanisms of ICI sensitivity and resistance, to identify patients that are responsive to specific treatments, and to develop new therapies. Multiplexed tissue imaging is a highly promising approach to immunoprofile tumors; it can assess many cell types and states within the context of preserved tumor architecture. However, the promise of highly multiplexed tissue imaging remains largely unfulfilled by current methods which are not compatible with pathology workflows. Here we present the development and implementation of Orion™ technology that permits whole-slide rapid single-pass imaging of up to 21 markers from formalin fixed paraffin embedded (FFPE) tissues. This method measures spectra for specific fluorophores to optimally sample the emitted light spectrum and distinguish multiple fluorescence excitation and emission channels across the spectral range of optical microscopes (~400-900 nm). To establish the utility of the Orion™ platform for immuno-phenotyping and immune checkpoint protein detection, we created an immunoprofiling panel of 21 qualified antibodies and labelled with fluorophores to subdivide the available emission spectrum in the 438-893 nm range. The panel includes markers that define subsets of T cells and macrophages. FFPE sections of human tonsil and matched primary and brain metastatic lung adenocarcinoma were stained and imaged in a single pass demonstrating staining patterns consistent with known micro-anatomic compartments and cell types in tonsil and identifying immune cell subtypes and heterogeneous checkpoint protein expression in tumor samples. An unexpected benefit of imaging with the Orion platform is the reduction of autofluorescence which is highly advantageous for the detection of proteins, like PD-L1, that function at very low levels. Orion imaging promises to accelerate discovery of predictive and prognostic biomarkers, enable pharmacodynamics study of immuno-oncology drugs undergoing clinical trials and ultimately provide clinically actionable diagnostic tests. Citation Format: Jia-Ren Lin, Daniel E. Campton, Jeremy Cooper, Yu-An Chen, Erin F. McCarty, Keith L. Ligon, Eric P. Kaldjian, Kyla Teplitz, Steve Reese, Sandro Santagata, Peter K. Sorger. Rapid highly multiplexed immunoprofiling of human fixed tissues by Orion imaging [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 482.
Continuing professional development (CPD) points do not always make prizes
Authors: Ashley Reece
Journal: BMJ (2021)

Fugh-Berman makes an astute observation about the sneaky way companies dress up marketing as medical education.1 Long gone are the lunch visits laid on by pharmaceutical companies peddling their drugs and gifting pens, post-its, mugs, calendars, towels, tie clips, letter openers, key rings, glasses’ cleaning cloths, and car fresheners. It is a different …
Anti-Leukemic Properties of Histamine in Monocytic Leukemia: Role of NOX2
Authors: Roberta Kiffin, Hanna Grauers Wiktorin, Malin Nilsson, Johan Aurelius, Ebru Aydin, Brianna Lenox, Jonas Nilsson, Anders Ståhlberg, Fredrik B Thoren, Kristoffer Hellstrand, Anna Martner
Journal: Blood (2017)
Targeting Lymphoplasmacytic Lymphoma through a Novel Anti-FGF-Based Therapeutical Strategy
Authors: Antonio Sacco, Loredana Affò, Gaia C Ghedini, Gaetana Lanzi, Arianna Giacomini, Marina Motta, Antonella Anastasia, Claudia Ghidini, Marco Chiarini, Silvia Giliani, Roberto Ronca, Luisa Imberti, Alessandro Montanelli, Nicole Bozza, Riccardo Castelli, Giuseppe Rossi, Marco Mor, Marco Presta, Aldo M. Roccaro
Journal: Blood (2017)
Abstract 2219: Analysis of gene landscape of small cell lung cancer of Chinese through next-generation sequencing
Authors: Jing Zhang, Hushan Zhang, Feng Ling, Yuanhan Wang, Long Li, Song Yang
Journal: Cancer Research (2021)

Abstract Background: As the more malignant subtype of lung cancer, small cell lung cancer (SCLC) displayed more aggressive and worse prognosis. Standard treatments have rarely changed in decades, therefore, in recent years, there have been attempts to explore targeted therapy and even immunotherapy. However, SCLC has more challenging targets. It was reported that almost 100% of SCLC has p53 and Rb mutations, and also has functional changes in Myc. Here we report some data about gene mutation of SCLC of Chinese patients. Methods: Tumor samples of 410 SCLC patients were consecutively collected in China from July 2018 to May 2020, next generation sequencing (NGS) was performed to detect gene mutation, and tumor mutational burden (TMB) measured by a 733 gene panel. PD-L1 expression detected by using Dako PD-L1 IHC 22C3 pharmDx, Tumor Proportion Score (TPS) was used to determine expression of PD-L1. TPS was arranged into the following intervals: strong positive ≥50%, moderate positive ≥5% and &amp;lt;50%, weak positive ≥1% and &amp;lt;5%, and negative &amp;lt;1%. All these were performed by 3D Medicines, a laboratory accredited by College of American Pathologists (CAP) and Clinical Laboratory Improvement Amendments (CLIA). Results: NGS results showed that the top gene mutation in these 410 Chinese SCLC patients were TP53 (88.0%,361/410), RB1(63.9%,262/410), BRCA1/2(34.0%,139/410), LRP1B(28.3%,116/410), FAM135B(24.1%,99/410), PIK3CA(23.9%,98/410), CYP2D6(21.0%,86/410), POLA1(20.2%,83/410), NTRK1(19.5%,80/410), MSH2(19.3%,79/410), ATM(19.3%,79/410), AKT2(18.8%,77/410), VEGFA(18.8%,77/410). Furthermore, 159 samples available for TMB analysis, and results showed that the average TMB level was 11.7 mutants/Mb, and 49.7%(79/159) were higher than 10 mutants/Mb, and 50.3%(80/159) were under 10mutants/Mb. In addition, 167 samples available for PD-L1 analysis, and results showed that 86.8% (145/167) with PD-L1 negative, 7.8(13/167) moderate positive, none with PD-L1 strong positive. Conclusion: Chinese patients with SCLC have rich spectrum of gene mutations, it suggests that targeted therapy should also have certain potential. In addition, about half of SCLCs have a TMB level above 10mutants/Mb, and immunotherapy should been considered more in the future treatment for Chinese SCLC patients. Citation Format: Jing Zhang, Hushan Zhang, Feng Ling, Yuanhan Wang, Long Li, Song Yang. Analysis of gene landscape of small cell lung cancer of Chinese through next-generation sequencing [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 2219.
The covid-19 lab leak hypothesis: did the media fall victim to a misinformation campaign?
Authors: Paul D Thacker
Journal: BMJ (2021)

The theory that SARS-CoV-2 may have originated in a lab was considered a debunked conspiracy theory, but some experts are revisiting it amid calls for a new, more thorough investigation. <b>Paul Thacker</b> explains the dramatic U turn and the role of contemporary science journalism
Abstract 2207: Genomic associations of biological sex and survival in head and neck squamous cell carcinoma
Authors: Alexandria G. Yao, Nadia Mezghani, Alison M. Taylor, Fatemeh Momen-Heravi
Journal: Cancer Research (2021)

Abstract Approximately half of all head and neck squamous cell carcinoma patients die within five years of diagnosis despite treatment. Recent studies revealed that females have a worse overall prognosis; however, the genetic and molecular underpinnings have not yet been identified. We investigated the genetic characteristics of head and neck squamous cell carcinomas stratified by HPV status and biological sex. Within the HPV-negative cohort, female patients have worse survival outcomes compared to male patients, although tumors in female patients show lower levels of aneuploidy alterations and copy number changes. Specifically, chromosomes 4, 5, 6, and 20 were amplified at higher frequency in the tumors of male patients compared to female patients. Analysis of mRNA expression found that genes most highly expressed in females compared to males included sex-chromosome genes XIST and TISX. Interestingly, along with y chromosome gene PRKY, Notch signaling gene HES7 was also up-regulated in the tumors of male patients. In addition, tumors of female patients showed higher expression of immune pathway genes, even when potential confounding factors of age and tumor location are considered. This study provides new insight into possible gene expression biomarkers for HNSCC in female patients. Future research will incorporate these findings to better assess therapeutic response in women with HNSCC. Citation Format: Alexandria G. Yao, Nadia Mezghani, Alison M. Taylor, Fatemeh Momen-Heravi. Genomic associations of biological sex and survival in head and neck squamous cell carcinoma [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 2207.
Abstract 2125: Roles of KAT6A and KAT6B in the biology of estrogen positive breast cancer
Authors: Isabelle Meaux, Dimitri Gorge-Bernat, Angele Paz, Catherine Geslin, Laurent Debussche, Jürgen Moll, Christophe Henry
Journal: Cancer Research (2021)

Abstract KAT6A and KAT6B are histone acetyl transferase (HAT) that are controlling gene expression by transferring acetyl groups to histones. Yu et al (Oncogene, 2017 36, 2910-2918) have shown that KAT6A has a role in breast cancer development by activating the ERα promoter and was found frequently amplified in 11% and is overexpressed in 15% of breast cancers. Altogether, these data support KAT6A as an attractive target in estrogen receptor driven breast cancer. KAT6B is a close homolog that shares 91% identity in the acetyl coA binding site. While the prevalence of gene amplification for KAT6B in breast cancer is only 1-2%, it is often overexpressed. In this study, we are exploring how KAT6A and KAT6B are contributing to ERα expression and the growth of KAT6A amplified breast cancer cell lines. To decipher each protein's role, we have designed specific siRNA against KAT6A and KAT6B and we tested their action either individually or in combination in the KAT6A gene amplified breast cancer cell lines T-47D, CAM-1 and ZR-75. Following treatment of T-47D, CAMA-1 and ZR75 cell lines with KAT6A or B siRNA we observed a decrease of ERα gene and protein expression for all siRNAs. The effect was more pronounced when using KAT6A over KAT6B and the effect of both siRNA A/B were additive. Phenotypically, the impact on cell line proliferation by applying clonogenic and incucyte assays, mirrors what is observed on ERα gene and protein expression. The effect on cellular proliferation of KAT6A is more prominent than KAT6B silencing, while the combined KAT6A + KAT6B silencing being more impactful than KAT6A silencing alone. In conclusion, our data show that KAT6A and KAT6B share similar function in the control of ER gene and protein expression. This study suggests that KAT6A and KAT6B may be paralogs, one compensating for the loss of the other. This translates into a more pronounced antiproliferative effect when both genes are silenced concomitantly. Citation Format: Isabelle Meaux, Dimitri Gorge-Bernat, Angele Paz, Catherine Geslin, Laurent Debussche, Jürgen Moll, Christophe Henry. Roles of KAT6A and KAT6B in the biology of estrogen positive breast 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 2125.
Abstract 2487: disrupting binding of p53 mutants to PEPD unleashes their tumor suppressor activities
Authors: Lu Yang
Journal: Cancer Research (2021)

Abstract Background &amp; Goals: The p53 tumor suppressor is one of the most important determinants of cell fate and is critical for tumor suppression. It functions by regulating the expression of a plethora of genes via sequence-specific DNA binding and also by transcription-independent, mitochondria-mediated mechanisms. Not surprisingly, the TP53 gene, which encodes p53, is frequently mutated in human cancer. For example, TP53 is mutated in about 75% of HER2-positive breast cancer and about 85% of triple negative breast cancer. The majority of TP53 mutations are missense mutations, changing one amino acid per mutant, most of which occur in its DNA-binding domain. p53 mutants show loss of tumor suppressor functions or gain of oncogenic functions. We recently found that peptidase D (PEPD), also known as prolidase, binds via its C-terminal sequence to the proline-rich domain (PRD) of wild type p53 and that disrupting the binding activates p53. The enzymatic activity of PEPD is not required for this function. Our objective in the present study is to determine whether PEPD also regulates p53 mutants. We focused on some of the most common oncogenic p53 mutants, including R175H, R248Q, R273H and R280K. Results: Our study shows that 1) each p53 mutant binds directly to PEPD and binds to PEPD in cells in a significant quantity, 2) disrupting their binding in cells by PEPD knockdown reactivates each p53 mutant, unleashing both transcription-dependent and -independent tumor suppressing activities, 3) after leaving PEPD, p53 mutants undergo acetylation, mono-ubiquitination and phosphorylation, which drive their refolding and reactivation, 4) Lysine 373 acetylation is essential for their reactivation, and 5) p53 mutants and p53WT show almost no difference in PEPD-binding and response to PEPD KD. Conclusions &amp; Therapeutic Relevance: In conclusion, we have identified a cellular mechanism by which the tumor suppressor functions of p53 mutants are strongly reactivated, which is neither cell-specific nor mutant-specific. Mainly, p53 mutants bind to PEPD in cancer cells, and disrupting the complex causes posttranslational modifications of mutants freed from PEPD, which drive their refolding and unleash their tumor suppressor activities. This discovery advances our understanding of the function and regulation of p53 mutants and breaks new ground for developing novel cancer treatment strategies. Citation Format: Lu Yang. disrupting binding of p53 mutants to PEPD unleashes their tumor suppressor activities [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 2487.
Health-related quality of life with adjuvant nivolumab vs. placebo after radical resection for high-risk muscle-invasive urothelial carcinoma: Results from the phase 3 checkmate 274 trial
Authors: J.E. Gschwend, D. Bajorin, M. Galsky, E. Broughton, J. Braverman, H. Koon, M. Maira-Arce, M. Hamilton, L. Shi, S. Guo, J.A. Witjes
Journal: European Urology (2021)
Abstract 2919: Novel pre-clinical model to identify genetic modifiers of triple negative breast cancer
Authors: Laura M. Sipe, Emily B. Korba, Lu Lu, Robert W. Williams, David G. Ashbrook, Liza Makowski
Journal: Cancer Research (2021)

Abstract Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype with poor outcomes. This is a grave clinical challenge for the ~30,000 patients diagnosed with this disease every year. Discovering genetic modifiers of differential TNBC vulnerability and disease progression is critical to improving predictive and personalized treatments. We hypothesized that using a well-established recombinant inbred strain, novel genetic modifiers of TNBC risk and aggression will be identified. The C3(1)-T antigen (C3Tag) genetically engineered mouse model (GEMM) recapitulates many facets of human basal-like TNBC to demonstrate promoting effects of exposures on tumor phenotypes. However, GEMM are highly constrained by their inbred genotype and do not allow a robust interrogation of the manner in which individual genetic variation might impact tumor initiation, progression, and response to therapy. Therefore, we developed a novel murine model of TNBC in the background of the largest and best characterized genetic reference population. Systems genetics is used to identify gene candidates. Cross-species comparison of our findings with publicly available human GWAS and genomic databases is an effective approach to validate conserved biologically relevant and targetable pathways. To our knowledge, this is the first study to explore modifier genes for TNBC phenotypes using a systems genetics approach in a GEMM for TNBC. Our results will contribute to significant advances in understanding risk and improving outcomes for breast cancer. Citation Format: Laura M. Sipe, Emily B. Korba, Lu Lu, Robert W. Williams, David G. Ashbrook, Liza Makowski. Novel pre-clinical model to identify genetic modifiers of triple negative breast 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 2919.
Deletion of Calr By CRISPR/Cas9 Genome-Editing Mimics Abnormalities of Megakaryocytopoiesis Induced By Calr Del52 Mutation
Authors: Niccolò Bartalucci, Laura Calabresi, Manjola Balliu, Matteo Lulli, Giuditta Corbizi Fattori, Paola Guglielmelli, Alessandro M. Vannucchi
Journal: Blood (2017)
Abstract 1925: Effect of <i>Averrhoa carambola</i> extract on the antineoplastic and apoptotic activities in mice
Authors: Md. Zahid Hasan, Ayesha Siddika
Journal: Cancer Research (2021)

Abstract Medicinal plants play significant roles in the treatment of different diseases. Averrhoa carambola has important clinical values in the treatment of cancer. However, its antineoplastic and apoptotic activities are still obscure. In this study, we were aimed to investigate those potentials of Averrhoa carambola in mice. For this, first the powder, prepared from the leaf and flower of Averrhoa carambola, were suspended with methanol to yield methanol extract of leaf and flower. Antineoplastic effect of leaf (25 and 50 mg/kg) against Ehrlich Ascites Carcinoma (EAC) was assessed by evaluating the viable tumor cell count, survival time, body weight and hematological parameters of EAC cell bearing mice. The result showed that the treatment with leaf significantly (p&amp;lt;0.05) decreased viable EAC cells and body weight gain thereby increasing the life span of EAC bearing mice and also revive the altered hematological (Hb, total RBC and WBC) parameters compare to those with normal values. Fluorescence microscopic view of 4,6-diamino-2-phenylindole (DAPI) staining demonstrated that leaf induced the alterations (i.e., nuclear condensation, fragmentation, membrane blabbing and apoptosis of cells) in the morphology of EAC cells. And, the quantitative analysis of p53 mRNA level by RT-PCR showed that p53 gene expression in leaf treated EAC cell was upregulated in respect to untreated control. These findings indicate that the induction of apoptosis in leaf-treated EAC cell was probably mediated through p53-dependent pathway. From this study, it can be concluded that the leaf of Averrhoa carambola exhibited potent antineoplastic and apoptotic activities that might be a potential agent for prevention of cancer in mice. Citation Format: Md. Zahid Hasan, Ayesha Siddika. Effect of Averrhoa carambola extract on the antineoplastic and apoptotic activities in mice [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 1925.
Development and validation of the fingertip unit for assessing Facial Vitiligo Area Scoring Index
Authors: Jung Min Bae, Raheel Zubair, Hyun Jeong Ju, Indermeet Kohli, Han Na Lee, Sung Hye Eun, Alexis B. Lyons, Gautham Vellaichamy, Tae Young Han, Henry W. Lim, Iltefat H. Hamzavi
Journal: Journal of the American Academy of Dermatology (2021)