tbuckley/cabot-search huggingface dataset:
Abstract 115: Neutrophil extracellular traps express PD-L1 which promotes T cell exhaustion in the tumor microenvironment
Authors: Christof Kaltenmeier, Hamza Yazdani, Samer Tohme
Journal: Cancer Research (2021)

Abstract Neutrophil extracellular traps (NETs) have recently been implicated in the growth of tumors, however their impact on immune cells within the tumor microenvironment (TME) remain incompletely understood. We hypothesize that NETs can directly interact with infiltrating T cells to promote an immunosuppressive TME. We performed liver Ischemia/Reperfusion (I/R) in an established colorectal cancer metastasis model to induce NET formation in the TME. In this NET-rich TME we discovered elevated levels of phenotypically and functionally exhausted T cells. We demonstrated that the majority of CD4 and CD8 T cells are not effector cells, but rather express multiple inhibitory receptors and are highly dysfunctional, with reduced cytokine production and proliferative capacity. This effect was limited to the T cells present the the NET-rich TME in comparison to T cells isolated from the spleen. In vitro, NETs contained the immunosuppressive ligand PD-L1 responsible for T cell exhaustion; an effect abrogated by using PD-L1 KO NETs. This exhausted state was directly linked to mitochondrial dysfunction in the T cells. Furthermore, NETs were targeted in vivo by treating mice with DNAse or anti-PD-L1 at time of I/R. Treatment caused decreased metastatic burden, decreased NET formation and higher levels of functioning non-exhausted T cells. Conversely, injecting NETs in tumors led to acceleration of tumor growth and T cell exhaustion in the TME. In addition, we measured sPDL-1 and MPO-DNA, a NET marker, in the serum of patients undergoing surgery for colorectal liver metastases resection. High levels of both markers were significantly associated with decreased disease free survival. Neutrophils isolated from patients after surgery were primed to form NETs that caused a similar exhaustion and dysfunction of human CD4 and CD8 T cells. Our data thus reveal that NETs have the capability of suppressing T cell responses and promoting tumor growth. This mechanism of T cell suppression by NETs represents a viable target for sustaining immune competence within the TME. Citation Format: Christof Kaltenmeier, Hamza Yazdani, Samer Tohme. Neutrophil extracellular traps express PD-L1 which promotes T cell exhaustion in the tumor microenvironment [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 115.
Biological significance of monoallelic and biallelic BIRC3 loss in del(11q) chronic lymphocytic leukemia progression
Authors: Miguel Quijada-Álamo, María Hernández-Sánchez, Ana-Eugenia Rodríguez-Vicente, Claudia Pérez-Carretero, Alberto Rodríguez-Sánchez, Marta Martín-Izquierdo, Verónica Alonso-Pérez, Ignacio García-Tuñón, José María Bastida, María Jesús Vidal-Manceñido, Josefina Galende, Carlos Aguilar, José Antonio Queizán, Isabel González-Gascón y Marín, José-Ángel Hernández-Rivas, Rocío Benito, José Luis Ordóñez, Jesús-María Hernández-Rivas
Journal: Blood Cancer Journal (2021)

BIRC3 is monoallelically deleted in up to 80% of chronic lymphocytic leukemia (CLL) cases harboring del(11q). In addition, truncating mutations in the remaining allele of this gene can lead to BIRC3 biallelic inactivation, which has been shown to be a marker for reduced survival in CLL. Nevertheless, the biological mechanisms by which these lesions could contribute to del(11q) CLL pathogenesis and progression are partially unexplored. We implemented the CRISPR/Cas9-editing system to generate isogenic CLL cell lines harboring del(11q) and/or BIRC3 mutations, modeling monoallelic and biallelic BIRC3 loss. Our results reveal that monoallelic BIRC3 deletion in del(11q) cells promotes non-canonical NF-κB signaling activation via RelB-p52 nuclear translocation, being these effects allelic dose-dependent and therefore further enhanced in del(11q) cells with biallelic BIRC3 loss. Moreover, we demonstrate ex vivo in primary cells that del(11q) cases including BIRC3 within their deleted region show evidence of non-canonical NF-κB activation which correlates with high BCL2 levels and enhanced sensitivity to venetoclax. Furthermore, our results show that BIRC3 mutations in del(11q) cells promote clonal advantage in vitro and accelerate leukemic progression in an in vivo xenograft model. Altogether, this work highlights the biological bases underlying disease progression of del(11q) CLL patients harboring BIRC3 deletion and mutation.
Abstract 1934: Modulation of protein homeostasis networks upon Hsp70 inhibition in cancer cells
Authors: Sara Sannino, Jeffrey L. Brodsky
Journal: Cancer Research (2021)

Abstract Cellular protein homeostasis is tightly regulated by balancing protein synthesis, folding, and degradation. Cancer cells constantly modulate protein folding and degradation efficiency to survive and proliferate without accumulating toxic misfolded proteins under acute stress conditions, such as low oxygen and energy, and exposure to chemotherapeutic agents. Many cancers rely on the unfolded protein response (UPR) to cope with stress, which increases the expression of molecular chaperones and mitigates the accumulation of misfolded proteins. Thus, it is unsurprising that the Hsp70 molecular chaperone, which serves as a master regulator of proteostasis, is upregulated in many cancers. Increased Hsp70 correlates with metastasis formation and poor patient prognosis in different cancers, like breast cancer. To define the role of Hsp70 in cancer survival and identify how cancer cells compensate for chaperone-mediated proteotoxicity, we investigated the response to a specific Hsp70 inhibitor, MAL3-101, in breast cancer cells. We discovered that breast cancer cells bin into distinct groups when subjected to Hsp70 inhibition based on their sensitivity to the compound. Moreover, we demonstrate that resistant cells have higher autophagy levels compared to more sensitive lines. Autophagy was further induced by MAL3-101 in resistant breast cancer cells, as evidenced by the accumulation of both autophagy related genes and proteins, as well as by autophagic-like structures detected by confocal microscopy. These data suggest that resistance to Hsp70 inhibition arises from autophagy induction. We then discovered that Hsp70 inhibition induces the UPR pathway, triggering apoptosis in sensitive cells. In particular, the activation of the UPR transducer, PERK, is required to induce apoptosis in sensitive cells when Hsp70 was inhibited. Overall, our work positions autophagy as a critical compensatory mechanism when molecular chaperone function is overwhelmed and misfolded proteins accumulate. Furthermore, our findings delineate a distinct role of PERK in apoptosis induction upon Hsp70 inhibition, highlighting the interplay between the PERK, Hsp70, and autophagy. Citation Format: Sara Sannino, Jeffrey L. Brodsky. Modulation of protein homeostasis networks upon Hsp70 inhibition in cancer cells [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 1934.
Impact of post-operative proteinuria on development of CKD: Analysis of functional outcomes post nephrectomy
Authors: M.F. Meagher, K. Hakimi, S. Soliman, J. Yuan, D. Patil, K. Saito, J. Javier-Desolges, Y. Yasuda, F. Wan, Y. Fujii, V. Master, I. Derweesh
Journal: European Urology (2021)
Characteristics of Registered Studies of Chimeric Antigen Receptor Therapies
Authors: Rahul Banerjee, Vinay Prasad
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Hundreds of chimeric antigen receptor (CAR) therapies are under investigation for hematologic malignant cancers and solid malignant tumors. As the field of modern CAR therapy enters its second decade, clinical trials that demonstrate the efficacy of CAR therapies using randomized clinical trials (RCTs) and/or investigate methods to optimize patient outcomes with commercially available CAR therapies are increasingly important. <h3>Objective</h3> To analyze the landscape of registered CAR-related trials with dual focuses on trial methods and intent. <h3>Evidence Review</h3> This systematic review identified 1304 ongoing or upcoming CAR-related trials registered at ClinicalTrials.gov as of December 22, 2020, and excluded 513 trials that did not pertain to cell-based therapy. Both CAR-related and trial-related variables, including target antigens and countries of origin, were recorded. Trials were categorized as non-RCTs that compared CAR with non-CAR therapies or RCTs in which every arm received CAR therapy. Trial intent was separately categorized as demonstrating the efficacy of a CAR therapy, optimizing patient outcomes with established CAR therapies using adjunctive non-CAR modalities, or miscellaneous. <h3>Findings</h3> Of 778 relevant trials, 587 (75%) involved blood cancers, whereas 182 (23%) involved solid tumor cancers; the remaining 9 (1%) involved nonmalignant diseases. A total of 433 trials (56%) were from China and 288 from the US (37%). Ten RCTs (1%) compared CAR therapies with non-CAR therapies, including phase 3 RCTs for 4 of 5 CAR therapies (80%) that are currently commercially available. Twenty-eight studies (4%) sought to optimize outcomes with established CAR therapies using non-CAR drugs or radiotherapy, whereas 3 studies (0.4%) sought to optimize supportive care during CAR therapy. <h3>Conclusions and Relevance</h3> This systematic review found that randomized and optimization-focused trials are comparatively rare within the landscape of ongoing and upcoming CAR-related trials. As the field of modern CAR therapy enters its second decade, additional studies of these characteristics are necessary to strengthen the evidence base for CAR therapy and improve patient outcomes.
Factors contributing to long-term adherence to pelvic floor muscle training in women suffering from stress urinary incontinence
Authors: A. Zachariou, M. Filiponi, F. Dimitriadis, C. Mamoulakis, A. Paliouras, A. Kaltsas, I. Chabilomatis, I. Giannakis, A. Karagiannis, A. Zikopoulos, P. Tsounapi, A. Takenaka, N. Sofikitis
Journal: European Urology (2021)
Concerns About Study on Fluoroquinolone Use and Risk of Development Of Aortic Aneurysm–Reply
Authors: Emily R. Newton, Paula D. Strassle, Melina R. Kibbe
Journal: JAMA Surgery (2021)

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Associations between smoke-free vehicle legislation and childhood admissions to hospital for asthma in Scotland: an interrupted time-series analysis of whole-population data
Authors: Daniel F Mackay, Stephen W Turner, Sean E Semple, Smita Dick, Jill P Pell
Journal: The Lancet Public Health (2021)

BackgroundIn Scotland, childhood admissions to hospital for asthma fell from March, 2006, after legislation was introduced to prohibit smoking in public places. In December, 2016, new Scottish legislation banned smoking in vehicles containing a child. We aimed to determine whether the introduction of this new legislation produced additional benefits.MethodsWe obtained data on all asthma emergency admissions to hospitals in Scotland between 2000 and 2018 for individuals younger than 16 years. We used interrupted time-series analyses to study changes in monthly incidence of asthma emergency admissions to hospital per 100 000 children after the introduction of smoke-free vehicle legislation, taking into account previous smoke-free interventions. We did subgroup analyses according to age and area deprivation, using the Scottish Index of Multiple Deprivation, and repeated the analyses for a control condition, gastroenteritis, and other respiratory conditions.FindingsOf the 32 342 emergency admissions to hospital for asthma among children younger than 16 years over the 19-year study period (Jan 1, 2000, to Dec 31, 2018), 13 954 (43%) were among children younger than 5 years and 18 388 (57%) were among children aged 5–15 years. After the introduction of smoke-free vehicle legislation, there was a non-significant decline in the slope for monthly emergency admissions to hospital for asthma among children younger than 16 years (−1·21%, 95% CI −2·64 to 0·23) relative to the underlying trend in hospital admissions for childhood asthma. However, children younger than 5 years had a significant decline in the slope for monthly asthma admissions (−1·49%, −2·69 to −0·27) over and above the underlying trend among children in this age group (equivalent to six fewer hospitalisations per year), but no such decline was seen in children aged 5–15 years. Monthly admissions to hospital for asthma fell significantly among children living in the most affluent areas (−2·27%, −4·41 to −0·07) but not among those living in the most deprived areas. We found no change in admissions to hospital for gastroenteritis or other respiratory conditions after the introduction of the smoke-free vehicle legislation.InterpretationAlthough legislation banning smoking in vehicles did not affect hospital admissions for severe asthma among children overall or in the older age group, this legislation was associated with a reduction in severe asthma exacerbations requiring hospital admission among preschool children, over and above the underlying trend and previous interventions designed to reduce exposure to second-hand smoke. Similar legislation prohibiting smoking in vehicles that contain children should be adopted in other countries.FundingNone.
A prospective study assessing the post-prostatectomy detection rate of a presumed local failure at mpMR with 18F-choline, 64Cu-Cl2 or 64Cu-PSMA PET/CT
Authors: G. Sanguineti, D. Giannarelli, A. Faiella, M. Bottero, A. Farneti, L. Bertini, S. Rea, V. Landoni, M.C. Ferriero, R. Sciuto
Journal: European Urology (2021)
Abstract 878: Contraceptive use and ovarian cancer risk in <i>BRCA1</i> and <i>BRCA2</i> mutation carriers: A prospective cohort study
Authors: Yue Yin Xia, Jan Lubinski, Barry Rosen, Pal Moller, Andrea Eisen, Peter Ainsworth, Leigha Senter, Louise Bordeleau, Susan L. Neuhausen, Christian F. Singer, Jennifer Brooks, Ping Sun, Steven A. Narod, Joanne Kotsopoulos
Journal: Cancer Research (2021)

Abstract Background: Oral contraceptive use is associated with a significantly reduced risk of ovarian cancer among BRCA1 and BRCA2 mutation carriers. To date, there have been no prospective analyses of this relationship, and the impact of other types of contraception (e.g. intrauterine device (IUD), implant, patch, injection) on BRCA-associated ovarian cancer risk is unknown. The goal of this study is to prospectively evaluate the relationship between types of contraception and ovarian cancer incidence in women with a BRCA1 or BRCA2 mutation. Methods: The longitudinal study included 3,298 eligible BRCA1/2 mutation carriers. Self-reported information regarding contraceptive use, including medication name, start year, end year, duration of use and method of administration were collected by biennial questionnaire. Women were classified according to history of contraceptive use (ever/never), duration of use, contraceptive method, calendar year of initiation and time since last use. Time-dependent Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) of ovarian cancer associated with each contraceptive method. Results: There were 84 incident ovarian cancer cases diagnosed over a mean follow-up period of 5.1 years. There was no significant association between ever use of an IUD (HR: 0.78; 95% CI: 0.28-2.14) and risk of ovarian cancer compared to IUD never users. Ongoing analyses will focus on the relationships between other contraceptive methods, formulations and duration of use on ovarian cancer risk, further stratified by histology and site of origin. Conclusions: Preliminary findings from this prospective analysis suggest that IUD use may not be protective among BRCA1/2 mutation carriers. Ongoing results will elucidate the impact of contraceptive formulation and method on ovarian cancer risk to inform clinical recommendations surrounding the use of contraceptive agents for chemoprevention in high risk women. Citation Format: Yue Yin Xia, Jan Lubinski, Barry Rosen, Pal Moller, Andrea Eisen, Peter Ainsworth, Leigha Senter, Louise Bordeleau, Susan L. Neuhausen, Christian F. Singer, Jennifer Brooks, Ping Sun, Steven A. Narod, Joanne Kotsopoulos. Contraceptive use and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers: A prospective cohort study [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 878.
Abstract 2116: Promoter enrichment of subnucleosomes using breast cancer cell-free DNA
Authors: Alexis Zukowski, Amy Han, Peter Kabos, Srinivas Ramachandran
Journal: Cancer Research (2021)

Abstract Breast cancer is the leading cancer diagnosis and the second major cause of cancer-related deaths in women worldwide. The use of non-invasive cell-free DNA (cfDNA) to detect and assess cancer dynamics has recently gained traction with a focus on targeted mutation panels. However, mutation panels have to contend with non-tumor origin of mutations like clonal hematopoiesis and the emergence of novel mutations in the tumor. A potential alternative is to harness the epigenomic, or non-genetic, features of cfDNA. In a healthy individual, blood cell turnover is the major contributor to the cfDNA pool. In cancer, tumor DNA adds to the cfDNA pool, which represents the end product of endogenous nucleases acting on accessible genomic DNA. Since genomic DNA is protected by histone proteins, cfDNA maps the chromatin structure of individual cells that turn over. Subnucleosomes (partially formed structures of nucleosomes that are the building blocks of chromatin) are by-products of transcription and thus reflect small protections enriched in active genes. The enrichment of subnucleosomes at promoters correlate with gene expression profiles of cfDNA tissues-of-origin and based on this knowledge, we hypothesized that we could reconstruct the transcriptional profiles of cancer cells by selectively targeting promoter regions. We first extracted cfDNA from 9 healthy female donors and 8 patient donors with various stages of breast cancer (Stage I, n=1; Stage III, n=1; Stage IV, n=4). We used a single-stranded DNA library protocol that robustly captures highly nicked cfDNA, enabling the genome-wide mapping of both nucleosomes and subnucleosomes. We performed targeted capture of promoter-proximal, nucleosome-protected sequences in cfDNA using non-overlapping tiling probes from transcription start sites to 300 bp downstream. After whole-genome sequencing of pooled libraries, we show that 76.4% (n=13/17) of samples exhibited &amp;gt;10X enrichment compared to unenriched samples, and 64.7% (n=11/17) of samples exhibited &amp;gt;100X enrichment. The enriched samples allowed us to profile &amp;gt;10,000 genes, whereas unenriched samples enabled profiling between 100-10,000 genes at an average sequencing depth of 40 million reads. Overall, we obtain higher depth per sequencing read after enrichment resulting in a high-resolution snapshot of promoter-nucleosome dynamics derived by probing only ~0.18% of the genome. We believe that this significant advancement will allow us not only to identify presence of cancer but also detect distinct tumor states. Citation Format: Alexis Zukowski, Amy Han, Peter Kabos, Srinivas Ramachandran. Promoter enrichment of subnucleosomes using breast cancer cell-free DNA [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 2116.
Abstract 2915: Synergistic, cytokine mediated stimulation (IL-1α/β + IL-6) of colon cancer cells reveals a novel mechanism of DNA damage facilitated by up-regulation of NOX1 and DUOX2
Authors: Jennifer L. Meitzler, Yongzhong Wu, Agnes Juhasz, Annamaria Rapisarda, Petreena Campbell, Becky A. Diebold, Smitha Antony, Guojian Jiang, Jiamo Lu, David J. Mallick, Mariam M. Konaté, Krishnendu Roy, James H. Doroshow
Journal: Cancer Research (2021)

Abstract Inflammatory bowel diseases are states of long-term inflammation of the colon resulting from an interplay of environmental factors and dysregulated immune responses. As inflammatory exposure increases over the time frame of active disease, patients with these chronic conditions are at risk of developing colorectal cancers. Chronic inflammation is thought to contribute to cancer initiation through persistent release of reactive oxygen species (ROS), leading to genome damage. Accumulating evidence suggests inflammatory cells contribute to this process, as the secretion of cytokines and growth factors in response to gut inflammation also supports cancer cell progression. Specifically, IL-1 family members play a pivotal role in the pathogenesis of acute and chronic intestinal inflammation, regulating both innate and adaptive immune responses. To elucidate a direct link between IL-1 family cytokines, ROS generation and colorectal cancer, we observed that treatment of HT29 or T84 cells with IL-1α or IL-1β, in cooperation with IL-6, resulted in oxidant production through up-regulation of both NOX1 and DUOX2 enzymes. Up-regulation of the hydrogen peroxide generating DUOX2/DUOXA2 enzyme complex was directly associated with enhanced histone H2AX phosphorylation (γH2AX), a marker of DNA double strand breaks. Interestingly, this concentration and time-dependent induction of expression and oxidative response was absent in Caco2 cells and was not mediated by other IL-1 family members (IL-18, IL-33 or IL-37). Prior studies from our group have demonstrated significant up-regulation of DUOX2 and DUOXA2 in surgically resected colon cancer specimens compared with adjacent normal colonic epithelium. Future studies will focus on cytokine stimulation of colon organoids derived from patient tumor and adjacent non-malignant tissues to evaluate enzymatic expression and oxidant level changes in a novel patient-derived colon model system. Citation Format: Jennifer L. Meitzler, Yongzhong Wu, Agnes Juhasz, Annamaria Rapisarda, Petreena Campbell, Becky A. Diebold, Smitha Antony, Guojian Jiang, Jiamo Lu, David J. Mallick, Mariam M. Konaté, Krishnendu Roy, James H. Doroshow. Synergistic, cytokine mediated stimulation (IL-1α/β + IL-6) of colon cancer cells reveals a novel mechanism of DNA damage facilitated by up-regulation of NOX1 and DUOX2 [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 2915.