tbuckley/cabot-search huggingface dataset:
The host transcriptional response to Candidemia is dominated by neutrophil activation and heme biosynthesis and supports novel diagnostic approaches
Authors: Julie M. Steinbrink, Rachel A. Myers, Kaiyuan Hua, Melissa D. Johnson, Jessica L. Seidelman, Ephraim L. Tsalik, Ricardo Henao, Geoffrey S. Ginsburg, Christopher W. Woods, Barbara D. Alexander, Micah T. McClain
Journal: Genome Medicine (2021)

Abstract Background Candidemia is one of the most common nosocomial bloodstream infections in the United States, causing significant morbidity and mortality in hospitalized patients, but the breadth of the host response to Candida infections in human patients remains poorly defined. Methods In order to better define the host response to Candida infection at the transcriptional level, we performed RNA sequencing on serial peripheral blood samples from 48 hospitalized patients with blood cultures positive for Candida species and compared them to patients with other acute viral, bacterial, and non-infectious illnesses. Regularized multinomial regression was utilized to develop pathogen class-specific gene expression classifiers. Results Candidemia triggers a unique, robust, and conserved transcriptomic response in human hosts with 1641 genes differentially upregulated compared to healthy controls. Many of these genes corresponded to components of the immune response to fungal infection, heavily weighted toward neutrophil activation, heme biosynthesis, and T cell signaling. We developed pathogen class-specific classifiers from these unique signals capable of identifying and differentiating candidemia, viral, or bacterial infection across a variety of hosts with a high degree of accuracy (auROC 0.98 for candidemia, 0.99 for viral and bacterial infection). This classifier was validated on two separate human cohorts (auROC 0.88 for viral infection and 0.87 for bacterial infection in one cohort; auROC 0.97 in another cohort) and an in vitro model (auROC 0.94 for fungal infection, 0.96 for bacterial, and 0.90 for viral infection). Conclusions Transcriptional analysis of circulating leukocytes in patients with acute Candida infections defines novel aspects of the breadth of the human immune response during candidemia and suggests promising diagnostic approaches for simultaneously differentiating multiple types of clinical illnesses in at-risk, acutely ill patients.
Effects of preoperative immunonutrition on surgical site infections for bladder cancer patients undergoing cystectomy and ileal conduit
Authors: H. Takeuchi, W. Nakata, M. Matsuse, M. Ishii, Y. Horibe, G. Tsujimura, Y. Tsujimoto, M. Nin, T. Saijo, M. Ohashi, M. Tsujihata
Journal: European Urology (2021)
Abstract 1486: Inhibition of host PI3K-gamma modulates anti-tumor immunity in poorly immunogenic HNSCC
Authors: Kelvin Anderson, Nathan Ryan, Anastasia Alkhimovitch, Arham Siddiqui, Steve Oghumu
Journal: Cancer Research (2021)

Abstract HNSCC is the 6th most common cancer, with around 650,000 new cases yearly. Gain of function mutations in the PI3K pathway are common in HNSCC, and inhibition of the PI3K p110γ subunit has shown promise in HNSCC treatment. However, given that PI3K p110γ plays an important role in myeloid and lymphoid immune cell function, it is essential to understand how PI3K p110γ inhibition affects the anti-tumor immune response independent of tumor cells. To elucidate PI3K p110γ function in HNSCC, we employed an orthotopic mouse model using poorly immunogenic and aggressive cell line MOC2 on Pik3cg-/- mice. We observed that wild-type and Pik3cg-/- mice displayed similar rates of HNSCC tumor growth and metastasis after 20 days post tumor injection. T cell infiltration and intrinsic T cell responses to MOC2 oral tumors were comparable between wild-type and Pik3cg-/- mice. Interestingly, the immune response of tumor-bearing Pik3cg-/- mice was marked by increased anti-tumor cytotoxic molecules (IFN-γ, IL-17, PD-1) by T cells, and immune checkpoint marker (PD-L1) expression by myeloid cells compared to tumor bearing wild type mice. Taken together, our findings demonstrate that inhibition of PI3K p110γ modulates tumor associated immune cells, which likely potentiates HNSCC treatment when used in combination with selective PD-L1 inhibitors. Citation Format: Kelvin Anderson, Nathan Ryan, Anastasia Alkhimovitch, Arham Siddiqui, Steve Oghumu. Inhibition of host PI3K-gamma modulates anti-tumor immunity in poorly immunogenic HNSCC [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 1486.
Mandatory covid-19 vaccination for care home workers
Authors: Lydia Hayes, Allyson M Pollock
Journal: BMJ (2021)

There is a need for clinical trial end-points to better assess how patients feel and function, so that interventions can be developed which alleviate symptoms and improve quality of life. Use of 6-min walk test (6MWT) outcomes as a primary end-point in interstitial lung disease (ILD) trials is growing, particularly for drugs targeting concurrent pulmonary hypertension. However, 6MWT outcomes may be influenced differentially by interstitial lung and pulmonary vascular components of ILD, making interpretation complicated. We propose that using 6MWT outcomes, including 6-min walk distance or oxygen desaturation, as primary end-points should depend upon the study population (how advanced the ILD is; whether vasculopathy is significant), the degree of disease progression, and, importantly, the effect of study treatment expected. We argue that the 6MWT as a single outcome measure is suitable as a primary end-point if the treatment goal is to improve functional performance or prevent disease progression within a study population of patients with advanced ILD or those with ILD and co-existent vasculopathy. In addition, we discuss the potential of composite primary end-points incorporating 6MWT outcomes, outlining important considerations to ensure that they are appropriate for the study population and treatment goals.
Tofacitinib as treatment for refractory dermatomyositis: A retrospective study from 2 academic medical centers
Authors: Michelle S. Min, Abeer Alsarheed, Bina Kassamali, Daniel R. Mazori, Morgan Schaefer, Joseph F. Merola, Gabriela Cobos, Avery H. LaChance, Ruth Ann Vleugels
Journal: Journal of the American Academy of Dermatology (2021)
Abstract 1949: Caspase 3 plays a requisite role in regulating survival of human breast cancer cells
Authors: Ebrahim Eskandari, Connie J. Eaves, Susanna Tan
Journal: Cancer Research (2021)

Abstract Caspase-3 has long been recognized for its key role as a protease that mediates the degradation of cellular components during the late stages of apoptosis. However, there is also a growing body of evidence that caspase-3 has essential intrinsic functions in regulating normal and malignant cell properties that are distinct from its apoptotic functions. In a previous study, we showed that a readily detectable but low proportion of freshly isolated normal human mammary cells with a luminal phenotype and a capacity to divide in vitro display a reversible expression of activated caspase-3, and subsequently it was found that suppression of caspase-3 expression in the MDA-MB-231 human breast cancer cell line contributes to its radiation-induced loss of proliferative activity in vitro. To further investigate the role of caspase-3 in normal and malignant human mammary cells, we constructed shRNA-caspase-3 and control lentiviral vectors to examine the effect of decreasing caspase-3 expression (2-fold determined by Western blot) in normal and transformed human mammary cell types. Knockdown (KD) of caspase-3 expression in 2 breast cancer cell lines (MDA-MB-231 and MCF7 cells) showed that caspase-3 KD suppressed their growth in vitro 5-fold within 8 days and inhibited formation of tumors in highly immunodeficient (NRG) adult female mice transplanted subcutaneously with shCaspase-3-transduced cells in contrast to controls in which 1cm diameter tumors appeared within 6 weeks. The shCaspase-3-transduced cells also showed a complete loss of lung metastasizing activity in intravenously injected mice. A similar anti-tumorigenic effect was also obtained in freshly isolated normal human mammary cells that were co-transduced with the shCaspase-3 vector as well as KRASG12D which otherwise causes the normal cells to produce invasive ductal carcinomas in subcutaneously transplanted immunodeficient mice. Annex V and propidium iodide staining of single-cell, as well as bulk cultures of the MDA-MB-231cells, showed that Caspase-3 is required for their survival as well as their growth. Surprisingly, initial parallel experiments with purified basal and luminal progenitor subsets of normal human mammary cells and the immortalized but non-tumorigenic MCF-10A cell line also indicates a significant suppression of cell growth in vitro within 10 days. These findings highlight the multiplicity of pro- as well as anti-survival activities that Caspase-3 exerts on normal and malignant human mammary cells raising important considerations of any therapy designed to augment their activity. Keywords: Breast cancer, Caspase-3, Cell survival Citation Format: Ebrahim Eskandari, Connie J. Eaves, Susanna Tan. Caspase 3 plays a requisite role in regulating survival of human breast 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 1949.
Abstract 2497: Inositol Polyphosphate 4-Phosphatase Type-II B protects mice from benign prostatic hyperplasia
Authors: Yasemin Ceyhan, Manqi Zhang, Irina U. Agoulnik
Journal: Cancer Research (2021)

Abstract BPH is the most common tumor-like condition that afflicts more than 50% of men between the ages of 51-60 and over 90% in men older than 80. While connection between obesity and BPH is well established, the driving signaling pathways are not clear. BPH is a nonmalignant enlargement of prostate epithelium that requires androgen receptor (AR) signaling. INPP4B and EZH2 are highly expressed in prostate epithelium where they regulate AR signaling and play an important role in prostate cancer etiology. EZH2 is an epigenetic silencer that methylates histone H3 on K9 and K27 residues and INPP4B is a dual specificity phosphatase that dephosphorylates PI(3,4)P2 and PI(4,5)P2, membrane lipids that activate Akt and PKC signaling pathways respectively. We discovered that Inpp4b-/- male mice develop BPH at 3 months old of age and subsequently prostate intraepithelial neoplasia (PIN) when fed high fat diet. While expression of AR in the prostates of these mice is similar, AR activity is reduced. The loss of INPP4B caused reduction in EZH2 protein levels in prostate cancer cell lines and in mouse prostate. Inhibition of Akt and PKC signaling reduced EZH2 levels in ventral and dorsolateral prostate lobes of Inpp4b-/- males, suggesting that INPP4B upregulates EZH2 levels by suppressing Akt and PKC signaling pathways. Consistent with decline in EZH2 levels, Inpp4b-/- males have reduced levels of H3K27me3 and H3K9me2 in the ventral prostate, and high fat diet exacerbated this phenotype. Our data suggests that INPP4B modulates epigenetic profile of prostate epithelium by stabilizing EZH2 levels. Both loss of INPP4B and high fat diet treatment lead to decline in EZH2 levels and activity and contribute to development of BPH in mouse model. Citation Format: Yasemin Ceyhan, Manqi Zhang, Irina U. Agoulnik. Inositol Polyphosphate 4-Phosphatase Type-II B protects mice from benign prostatic hyperplasia [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 2497.
Loss of Hepatic Angiotensinogen Attenuates Sepsis-Induced Myocardial Dysfunction
Authors: Jiabing Rong, Xinran Tao, Yao Lin, Haiqiong Zheng, Le Ning, Hong S. Lu, Alan Daugherty, Peng Shi, Adam E. Mullick, Sicong Chen, Zhaocai Zhang, Yinchuan Xu, Jian’an Wang
Journal: Circulation Research (2021)

[Figure: see text].
Comparison of salvage radiation therapy delivered for PSA persistence versus PSA relapse after radical prostatectomy: How is the outcome changing?
Authors: N. Fossati, R.J. Karnes, S.A. Boorjian, G. Motterle, A. Bossi, T. Kumar, N. Di Muzio, C. Cozzarini, B. Noris Chiorda, G. Gandaglia, E. Mazzone, D. Robesti, S. Scuderi, C. Bravi, A. Stabile, D. Bartkowiak, S. Shariat, G. Goldner, S. Joniau, H. Van Poppel, C. Berghen, G. De Meerleer, F. Montorsi, T. Wiegel, A. Briganti
Journal: European Urology (2021)
Trans-arterial ICG delivery before purely off-clamp robot-assisted partial nephrectomy for totally endophytic renal tumors: Mid-term outcomes
Authors: G. Tuderti, R. Mastroianni, U. Anceschi, S. D’Annunzio, L. Misuraca, M. Ferriero, A.M. Bove, A. Brassetti, M. Costantini, S. Guaglianone, M. Gallucci, G. Simone
Journal: European Urology (2021)
Abstract 2112: Epigenetic control of heparanase expression using CRISPR/dCas9
Authors: Zixin Chen, Guihua Zeng, Xiaogang Li, Fu-Sen Liang, Lina Cui
Journal: Cancer Research (2021)

Abstract Heparanase (HPSE) is the only known enzyme that cleaves the polymeric heparan sulfate (HS), a key component of the extracellular matrix (ECM). Heparanase has been implicated in various pathophysiological conditions involving ECM remodeling, such as tumor progression, metastasis angiogenesis, and inflammation. To study the role of heparanase in diseases, we developed a strategy to epigenetically modulate its expression in cells based on the clustered regularly interspaced short palindromic repeats (CRISPR) system. A fusion protein of dCAS9 can be directed to the HPSE gene via one or a combination of single guide RNAs. By linking dCas9 with different histone modification enzymes (eg. P300, hHDAC3, LSD1), the expression of heparanase can be up- or down-regulated through histone acetylation, deacetylation and demethylation. This approach allows us to tune heparanase expression in various cell lines on demand, enabling the study of heparanase activity in real-time. This work will also lead to novel therapeutics targeting heparanase. Citation Format: Zixin Chen, Guihua Zeng, Xiaogang Li, Fu-Sen Liang, Lina Cui. Epigenetic control of heparanase expression using CRISPR/dCas9 [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 2112.
Ureteroscopy (URS) video consensus: A simple and effective way to improve awareness of patients undergoing URS
Authors: F. Esperto, F. Prata, A. Civitella, P. Tuzzolo, L. Romei, V.G. Crimi, F. Tedesco, T. Bach, Y. Tanidir, R.M. Scarpa, R. Papalia
Journal: European Urology (2021)
PSA density and clinical outcome in MRI-based active surveillance for prostate cancer: A joint longitudinal-survival analysis
Authors: V. Stavrinides, G. Papageorgiou, D. Danks, F. Giganti, N. Pashayan, B. Trock, A. Freeman, H. Whitaker, C. Allen, A. Kirkham, G. Sonn, S. Punwani, D. Barratt, M. Emberton, C. Moore
Journal: European Urology (2021)
Abstract 1985: Activation of EGFR/IGF1R - beta catenin - CD44 pathway in periampullary cancer
Authors: Suvendu Maji, Biswabandhu Bankura, Chinmay Kumar Panda, Neyaz Alam
Journal: Cancer Research (2021)

Abstract Background: Periampullary cancer (PC) is a global medical burden, although infrequent but less than 5% of patients experience an overall survival of five years or more. The study aims to analyze the importance of Epidermal Growth Factor Receptor (EGFR)/Insulin-Like Growth Factor 1 Receptor (IGF1R) - Beta-catenin (β-catenin)- CD44 pathway in the development of periampullary cancer of Indian patients. Materials and Methods: Expression profile of EGFR, IGF1R, β-catenin, and CD44 was verified by immunohistochemical analysis in primary tumor samples (N=14) and respective adjacent normal tissues. Results: In periampullary carcinoma patients, a high level of EGFR expression was seen in 64% of the samples along with co-expression of IGF1-R in 77.8% samples. Furthermore, the high expression of EGFR and IGF1R significantly correlated with the increased expression of β-catenin along with CD44 expression of the tumors. Conclusion: The EGFR/IGF1R - β-catenin- CD44 pathway seems to be important in the development of PC with clinical importance. Key-words: Periampullary cancer; EGFR; IGF1R; β-catenin; CD44 Key Messages: Interplay of EGFR, IGF1R, β-Catenin and CD44 expressions is important phenomena in the development of PC. Citation Format: Suvendu Maji, Biswabandhu Bankura, Chinmay Kumar Panda, Neyaz Alam. Activation of EGFR/IGF1R - beta catenin - CD44 pathway in periampullary 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 1985.
Abstract 1650: MoA-based reporter bioassays enable quantitative potency determination for therapeutic biologics targeting co-stimulatory and co-inhibitory immune checkpoint receptors
Authors: Jamison Grailer, Julia Gilden, Pete Stecha, Denise Garvin, Jun Wang, michael Beck, Jim Hartnett, Frank Fan, mei cong, Zhi-Jie Jey Cheng
Journal: Cancer Research (2021)

Abstract Immune checkpoint (IC) receptors play critical roles in maintaining immune homeostasis and are emerged as promising drug targets for the treatment of various cancers and autoimmune disorders. Monoclonal antibodies designed to block immune inhibitory receptors PD-1 and CTLA-4 have been approved and showed unprecedented efficacy in cancer treatment. This led to rapid expansion of drug development to many more IC receptors targeted individually or in combination. However, due to the novelty and fast speed, one of the bottleneck during immunotherapy drug development is the lack of quantitative and reproducible functional assays for potency determination when existing methods heavily rely on primary immune cells and the process are labor intensive and highly variable. To address this need, we developed a panel of cell-based reporter bioassays that can quantitatively measure the potencies of biologics targeting individual IC receptor (e.g. PD-1, LAG-3, BTLA, CTLA-4, TIGIT, TIM-3, ICOS, 4-1BB, CD40), or bispecific molecules targeting two IC receptors spontaneously (e.g. PD-1xTIGIT, PD-1xLAG-3, PD-1xCTLA-4, PD1x4-1BB). These bioassays each consist of an engineered T effector cell line that expresses T cell receptors and IC receptors of interest, and an engineered artificial antigen presenting cells (aAPC) expressing the corresponding ligands for the IC receptors. The T effector cell line also expresses a luciferase reporter driven by response elements/promoter specifically responding to TCR activation which can be co-stimulated or inhibited by the signal from the IC receptors. These bioassays are designed to reflect the mechanisms of action for the drug candidates designed for each IC receptor and the assay signals are specific. They are prequalified according to ICH guidelines and show the precision, accuracy and linearity required for relative potency determination and product stability study under cGMP environments. Therefore, these MoA-based bioassays can serve as value tools for early drug discovery, potency determination and stability study throughout immunotherapy drug development. Citation Format: Jamison Grailer, Julia Gilden, Pete Stecha, Denise Garvin, Jun Wang, michael Beck, Jim Hartnett, Frank Fan, mei cong, Zhi-Jie Jey Cheng. MoA-based reporter bioassays enable quantitative potency determination for therapeutic biologics targeting co-stimulatory and co-inhibitory immune checkpoint receptors [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 1650.
Prostate cancer detection, tolerability and safety of transperineal prostate biopsy under local-anaesthesia versus standard transrectal biopsy in biopsy-naïve men: A pragmatic, parallel group, randomized-controlled study
Authors: W. Lam, A.H.G. Wong, S. Chun, T. Wong, W.P.L. Hung, H. Lie, C.F. Tsang, B.S. Ho, A.T.L. Ng, J.H.L. Tsu
Journal: European Urology (2021)
Abstract 2318: EP300 selectively controls the enhancer landscape of high risk neuroblastoma
Authors: Adam D. Durbin, Tingjian Wang, Virangika K. Wimalasena, Mark W. Zimmerman, Deyao Li, Neekesh V. Dharia, Luca Mariani, Paul M. Park, Logan H. Sigua, Ken Morita, Amy S. Conway, Amanda L. Robichaud, Antonio Perez-Atayde, Melissa Bikowitz, Taylor Quinn, Olaf Wiest, Ernst Schonbrunn, Martha Bulyk, Brian J. Abraham, Kimberly Stegmaier, A. Thomas Look, Jun Qi
Journal: Cancer Research (2021)

Abstract Gene expression is regulated by promoters and enhancers marked by histone H3-lysine-27 acetylation (H3K27ac) and established by the paralogous histone acetyltransferases (HATs), EP300 and CBP. These enzymes display overlapping regulatory roles in untransformed cells, but less characterized roles in cancer cells. We demonstrate that the majority of high-risk pediatric neuroblastoma depend on EP300, while CBP has a limited role. EP300 controls enhancer acetylation by interacting with TFAP2β, a transcription factor member of the lineage-defining core-regulatory transcriptional circuitry (CRC). To disrupt EP300, we developed a proteolysis-targeted-chimaera (PROTAC) compound “JQAD1” that selectively targets EP300 for degradation. This results in loss of H3K27ac at CRC enhancers and neuroblastoma apoptosis, with limited toxicity to untransformed cells where CBP compensates. EP300 physically interacts with the MYCN oncoprotein, promoting its chromatin localization in neuroblastoma. EP300 degradation therefore capitalizes on EP300 dependency in neuroblastoma by controlling MYCN localization and preventing MYCN from sustaining the malignant cell state. Citation Format: Adam D. Durbin, Tingjian Wang, Virangika K. Wimalasena, Mark W. Zimmerman, Deyao Li, Neekesh V. Dharia, Luca Mariani, Paul M. Park, Logan H. Sigua, Ken Morita, Amy S. Conway, Amanda L. Robichaud, Antonio Perez-Atayde, Melissa Bikowitz, Taylor Quinn, Olaf Wiest, Ernst Schonbrunn, Martha Bulyk, Brian J. Abraham, Kimberly Stegmaier, A. Thomas Look, Jun Qi. EP300 selectively controls the enhancer landscape of high risk neuroblastoma [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 2318.