tbuckley/cabot-search huggingface dataset:
Magnetic Resonance Imaging–Assessed Subchondral Cysts and Incident Knee Pain and Knee Osteoarthritis: Data From the Multicenter Osteoarthritis Study
Authors: Thomas A. Perry, Terence W. O'Neill, Irina Tolstykh, John Lynch, David T. Felson, Nigel K. Arden, Michael C. Nevitt
Journal: Arthritis & Rheumatology (2021)

To examine whether knee subchondral cysts, measured on magnetic resonance imaging (MRI), are associated with incident knee osteoarthritis (OA) outcomes.We used longitudinal data from the Multicenter Osteoarthritis Study, a community-based cohort of subjects with risk factors for knee OA. Participants without a history of knee surgery and/or inflammatory arthritis (i.e., rheumatoid arthritis and gout) were followed up for 84 months for the following incident outcomes: 1) radiographic knee OA (Kellgren/Lawrence grade ≥2), 2) symptomatic radiographic knee OA (radiographic knee OA and frequent knee pain), and 3) frequent knee pain (with or without radiographic knee OA). In a subset of participants, subchondral cysts were scored on baseline MRIs of 1 knee. Multiple logistic regression, with adjustment for participant characteristics and other baseline knee MRI findings, was used to assess whether subchondral cysts were predictive of incident outcomes.Among the participants with knees eligible for analyses of outcomes over 84 months, incident radiographic knee OA occurred in 22.8% of knees with no baseline radiographic knee OA, symptomatic radiographic knee OA occurred in 17.0% of knees with no baseline symptomatic radiographic knee OA, and frequent knee pain (with or without radiographic knee OA) occurred in 28.8% of knees with no baseline radiographic knee OA and 43.7% of knees with baseline radiographic knee OA. With adjustment for age, sex, and body mass index, the presence of subchondral cysts was not associated with incident radiographic knee OA but was associated with increased odds of incident symptomatic radiographic knee OA (odds ratio 1.92 [95% confidence interval 1.16-3.19]) and increased odds of incident frequent knee pain in those who had radiographic knee OA at baseline (odds ratio 2.11 [95% confidence interval 0.87-5.12]). Stronger and significant associations were observed for outcomes based on consistent reports of frequent knee pain within ~1 month of the study visit.Subchondral cysts are likely to be a secondary phenomenon, rather than a primary trigger, of radiographic knee OA, and may predict symptoms in knees with existing disease.
Multi-institutional TSA-amplified Multiplexed Immunofluorescence Reproducibility Evaluation (MITRE) Study
Authors: Janis M Taube, Kristin Roman, Elizabeth L Engle, Chichung Wang, Carmen Ballesteros-Merino, Shawn M Jensen, John McGuire, Mei Jiang, Carla Coltharp, Bethany Remeniuk, Ignacio Wistuba, Darren Locke, Edwin R Parra, Bernard A Fox, David L Rimm, Cliff Hoyt
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Emerging data suggest predictive biomarkers based on the spatial arrangement of cells or coexpression patterns in tissue sections will play an important role in precision immuno-oncology. Multiplexed immunofluorescence (mIF) is ideally suited to such assessments. Standardization and validation of an end-to-end workflow that supports multisite trials and clinical laboratory processes are vital. Six institutions collaborated to: (1) optimize an automated six-plex assay focused on the PD-1/PD-L1 axis, (2) assess intersite and intrasite reproducibility of staining using a locked down image analysis algorithm to measure tumor cell and immune cell (IC) subset densities, %PD-L1 expression on tumor cells (TCs) and ICs, and PD-1/PD-L1 proximity assessments. Methods A six-plex mIF panel (PD-L1, PD-1, CD8, CD68, FOXP3, and CK) was rigorously optimized as determined by quantitative equivalence to immunohistochemistry (IHC) chromogenic assays. Serial sections from tonsil and breast carcinoma and non-small cell lung cancer (NSCLC) tissue microarrays (TMAs), TSA-Opal fluorescent detection reagents, and antibodies were distributed to the six sites equipped with a Leica Bond Rx autostainer and a Vectra Polaris multispectral imaging platform. Tissue sections were stained and imaged at each site and delivered to a single site for analysis. Intersite and intrasite reproducibility were assessed by linear fits to plots of cell densities, including %PDL1 expression by TCs and ICs in the breast and NSCLC TMAs. Results Comparison of the percent positive cells for each marker between mIF and IHC revealed that enhanced amplification in the mIF assay was required to detect low-level expression of PD-1, PD-L1, FoxP3 and CD68. Following optimization, an average equivalence of 90% was achieved between mIF and IHC across all six assay markers. Intersite and intrasite cell density assessments showed an average concordance of R 2 =0.75 (slope=0.92) and R 2 =0.88 (slope=0.93) for breast carcinoma, respectively, and an average concordance of R 2 =0.72 (slope=0.86) and R 2 =0.81 (slope=0.68) for NSCLC. Intersite concordance for %PD-L1+ICs had an average R 2 value of 0.88 and slope of 0.92. Assessments of PD-1/PD-L1 proximity also showed strong concordance (R 2 =0.82; slope=0.75). Conclusions Assay optimization yielded highly sensitive, reproducible mIF characterization of the PD-1/PD-L1 axis across multiple sites. High concordance was observed across sites for measures of density of specific IC subsets, measures of coexpression and proximity with single-cell resolution.
Abstract 494: Novel human B7-H3 knock-in mice demonstrate efficacy of anti-B7-H3 immunotherapy <i>in vivo</i>
Authors: Lei Zhao, Huilin Li, Yujie Liu, Zhaoxue Yu, Eugene Lin
Journal: Cancer Research (2021)

Abstract In recent years, immune checkpoint inhibitors (ICIs), particularly against PD-1/PD-L1, have revolutionized cancer treatment. However, ICI monotherapy only benefits a portion of cancer patients, while co-blockade of PD-1/PD-L1 and CTLA-4 is associated with increased IrAEs. Combined targeting of other immune checkpoints with PD-1/PD-L1 rather than CTLA-4 may be safer. B7-H3, also known as CD276, is a newer member of the same B7/CD28 superfamily as PD-1 and PD-L1. Its transcripts are ubiquitously expressed in normal tissues and solid tumors, but the protein is expressed in tumor tissues and by antigen-presenting cells, such as DC or macrophages, where it inhibits T cells and contributes to tumor immune evasion. Importantly, B7-H3 is overexpressed on a wide range of human solid cancers and correlates with negative prognosis and poor clinical outcome in patients. Recent studies have shown that B7-H3 also drives tumor growth, invasion, migration, angiogenesis, and metastasis beyond its immune regulatory roles. Thus, B7-H3 is an interesting new target for immunotherapy. To investigate B7-H3 function in vitro and evaluate in vivo efficacy of B7-H3 antibodies, Biocytogen generated a B7-H3 humanized mouse (B-hB7-H3) and B7-H3-expressing MC38 cell line (MC38-hB7-H3). In the mice, exons 3-4 of the mouse B7-H3 gene, which encode the extracellular domain, are replaced by human B7-H3 exons 3-6. Human B7-H3 mRNA was detectable in spleen and bone marrow of only B-hB7-H3 mice, and B7-H3 antibodies bound well to hB7-H3+ MC38 cells. Furthermore, using the MC38-hB7-H3 and EL4 tumor models, we showed robust efficacy of anti-human B7-H3 antibodies in inhibiting tumor growth in vivo, which was amplified in mice receiving combined human B7-H3 and mouse PD-1 blockade. Taken together, B7-H3 humanized mice are a useful tool for in vivo efficacy evaluation and selection of candidate human B7-H3 antibodies for advancement to clinical trials. In addition, Biocytogen has generated B7-H3/PD-1 and B7-H3/PD-1/PD-L1 multi-gene humanized mice to evaluate B7-H3/PD-1/PD-L1 combination therapies in vivo. Citation Format: Lei Zhao, Huilin Li, Yujie Liu, Zhaoxue Yu, Eugene Lin. Novel human B7-H3 knock-in mice demonstrate efficacy of anti-B7-H3 immunotherapy in vivo [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 494.
Rational integration of defense and repair synergy on PEEK osteoimplants via biomimetic peptide clicking strategy
Authors: Meng Li, Jiaxiang Bai, Huaqiang Tao, Li Hao, Weiling Yin, Xiaoxue Ren, Ang Gao, Ning Li, Miao Wang, Shiyuan Fang, Yaozeng Xu, Liang Chen, Huilin Yang, Huaiyu Wang, Guoqing Pan, Dechun Geng
Journal: Bioactive Materials (2021)

Polyetheretherketone (PEEK) has been widely used as orthopedic and dental materials due to excellent mechanical and physicochemical tolerance. However, its biological inertness, poor osteoinduction, and weak antibacterial activity make the clinical applications in a dilemma. Inspired by the mussel adhesion mechanism, here we reported a biomimetic surface strategy for rational integration and optimization of anti-infectivity and osteo-inductivity onto PEEK surfaces using a mussel foot proteins (Mfps)-mimic peptide with clickable azido terminal. The peptide enables mussel-like adhesion on PEEK biomaterial surfaces, leaving azido groups for the further steps of biofunctionalizations. In this study, antimicrobial peptide (AMP) and osteogenic growth peptide (OGP) were bioorthogonally clicked on the azido-modified PEEK biomaterials to obtain a dual-effect of host defense and tissue repair. Since bioorthogonal clicking allows precise collocation between AMP and OGP through changing their feeding molar ratios, an optimal PEEK surface was finally obtained in this research, which could long-term inhibit bacterial growth, stabilize bone homeostasis and facilitate interfacial bone regeneration. In a word, this upgraded mussel surface strategy proposed in this study is promising for the surface bioengineering of inert medical implants, in particular, achieving rational integration of multiple biofunctions to match clinical requirements.
Abstract 14489: Inhibition of NO-Mediated GABA Release by Reactive Oxygen Species in the Rostral Ventrolateral Medulla Results in Sympathoexcitation in Hypertensive Rats
Authors: Keisuke Shinohara, Yoshitaka Hirooka, Takuya Kishi, Kenji Sunagawa
Journal: Circulation (2011)

Background: The rostral ventrolateral medulla (RVLM) in the brainstem is known to regulate the activity of sympathetic nervous system (SNS). In the RVLM, increased reactive oxygen species (ROS) act...
Abstract 3190: PD-L1 protein expression in Middle Eastern breast cancer predicts favorable outcome in triple negative breast cancer
Authors: Khawla S. Al-Kuraya, Abdul K. Siraj, Sandeep K. Parvathareddy, Saeeda Ahmed, Allianah Benito, Kaleem Iqbal
Journal: Cancer Research (2021)

Abstract Programmed cell death ligand 1 (PD-L1) has been shown to induce potent T-cell mediated anti-tumoral immunity. The significance of PD-L1 expression on prognosis of breast cancer remains controversial and its prevalence and prognostic value in breast cancer from Middle Eastern ethnicity is lacking. A total of 1003 unselected Middle Eastern breast cancers were analyzed for PD-L1 expression using immunohistochemistry. The association with clinico-pathological markers and impact on overall survival as well as recurrence free survival was determined. PD-L1 expression was seen in 32.8% (329/1003) cases. PD-L1 positivity was significantly associated with poor prognostic indicators such as younger patients (p = 0.0499), high grade tumors (p = 0025), ER negative (p &amp;lt; 0.0001) and PR negative (p = 0.0001) status as well as high Ki-67 index (p &amp;lt; 0.0001). We also found a significant association between PD-L1 expression and deficient mismatch repair protein expression (p = 0.0009). No association was found between PD-L1 expression and clinical outcome. However, on further subgroup analysis, PD-L1 expression was found to be an independent marker for favorable prognosis in triple negative breast cancer (TNBC) (Hazard ratio = 0.27; 95% confidence interval = 0.10 - 0.63; p = 0.0018). In conclusion, we demonstrated strong association between PD-L1 and MSI in Middle Eastern BC patients and showed that PD-L1 overexpression on tumor cells was an independent favorable prognostic factor in TNBCs from this ethnicity. Overall, these findings might help in the development of more appropriate treatment strategies for BC in Middle Eastern population. Citation Format: Khawla S. Al-Kuraya, Abdul K. Siraj, Sandeep K. Parvathareddy, Saeeda Ahmed, Allianah Benito, Kaleem Iqbal. PD-L1 protein expression in Middle Eastern breast cancer predicts favorable outcome in 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 3190.
Abstract 2865: Repurposing potassium channel blockers to target metastasis in triple negative breast cancer
Authors: Priyanka Ram, Samantha L. Payne, Madeleine J. Oudin
Journal: Cancer Research (2021)

Abstract Despite the identification of pro-metastatic markers and signaling pathways that drive the invasion of triple negative breast cancer (TNBC), there are currently no treatments that directly target invading cells. Recent evidence suggests that the bioelectric state of cancer cells can drive cell proliferation and invasion, creating an opportunity to investigate new therapies that target the bioelectric state of a cell. Our previous data suggests that of the most abundant ions present in the body, potassium (K+) is most important for controlling the bioelectric state of TNBC cells, and that K+ flux affects the invasive properties of TNBC cells. Therefore, we hypothesized that blocking K+ channels would disrupt the bioelectric state and reduce 2D migration and 3D invasion. Four FDA-approved K+ channel blockers (amiodarone, carvedilol, imipramine, and thioridazine) were selected from the Repurposing Drugs in Oncology database based on inhibition target channels and mechanisms of action. Cell viability in human TNBC MDA-MB-231 and MDA-MB-468 cells was investigated and IC50 dose response curves were generated to determine that 5 µM and 10µM were the optimal doses to study further. Interestingly, while we determined that all four drugs reduced cell viability, amiodarone and carvedilol significantly changed the bioelectric state and reduced proliferation of TNBC cells compared to negative controls. Experiments are ongoing to evaluate the effects of these inhibitors on 2D migration, 3D invasion, and in an in vivo mouse xenograft study. Understanding the mechanism behind K+ channel inhibition in TNBC could give rise to new pharmacologic targets. In addition, supplementing existing metastatic TNBC regimens with a repurposed K+ channel blocker could potentially reduce development costs, decrease time to market, and provide a new treatment option to patients. Citation Format: Priyanka Ram, Samantha L. Payne, Madeleine J. Oudin. Repurposing potassium channel blockers to target metastasis in 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 2865.
P-70 First-in-human study of highly selective FGFR2 inhibitor, RLY-4008, in patients with intrahepatic cholangiocarcinoma and other advanced solid tumors
Authors: L. Goyal, V. Subbiah, A. Mahipal, S. Kamath, K. Mody, M. Borad, A. El-Khoueiry, V. Sahai, R. Kim, R. Kelley, O. Schmidt-Kittler, J. Shen, K. Jen, A. Deary, M. Padval, C. Sherwin, B. Wolf, A. Schram
Journal: Annals of Oncology (2021)
Accuracy and clinical utility of the tumor grade- and stage-centered predictive model in upper tract urothelial carcinoma
Authors: S. Katayama, K. Mori, V.M. Schuettfort, B. Pradere, H. Mostafaei, F. Quhal, P. Rajwa, R. Sari Motlagh, E. Laukhtina, M. Moschini, N.C. Grossmann, M. Araki, J.Y.C. Teoh, M. Rouprêt, V. Mragulis, D. Enikeev, P.I. Karakiewicz, M. Abufaraj, E. Compérat, Y. Nasu, S.F. Shariat
Journal: European Urology (2021)
PTH Infusion for Seizures in Autosomal Dominant Hypocalcemia Type 1
Authors: Ana Sastre, Kevin Valentino, Fadil M Hannan, Kate E Lines, Anna K Gluck, Mark Stevenson, Michael Ryalls, Rebecca J Gorrigan, Debbie Pullen, Jackie Buck, Sailesh Sankaranarayanan, Jeremy Allgrove, Rajesh V Thakker, Evelien F Gevers
Journal: New England Journal of Medicine (2021)

first dose and two after the second dose.Nevertheless, the reduced protection against infection with the B.1.351variant did not seem to translate into poor protection against the most severe forms of infection (i.e., those resulting in hospitalization or death), which was robust, at greater than 90%.
Abstract 3075: Effect of reducing AXIN2 levels in CRC cells with <i>APC</i> mutation and activated WNT signaling
Authors: Chi Zhang, Caroline O. Facey, Katherine Funk, Lynn M. Opdenaker, Bruce M. Boman
Journal: Cancer Research (2021)

Abstract Regulation of the WNT/beta-catenin signaling pathway occurs by a negative feedback loop that keeps beta-catenin levels in check in normal cells. Dysregulation of this feedback mechanism due to APC mutation is well known. However, the role of AXIN2, another component of this negative feedback loop is less known, particularly in APC mutant tissues. Our goal is to study how AXIN2 functions as part of the negative WNT/beta-catenin signaling feedback loop and understand of how it contributes to CRC development. Our bioinformatics analysis suggests that CRC cells carrying APC-truncating mutations still retain residual function of the destruction complex, but there are significant changes between AXIN2 and APC expression levels. Therefore, we hypothesize that the interaction between truncated-APC and AXIN2 is responsible for the dysregulation of the feedback loop. We found, using a TCF/LEF reporter assay, that siRNA-mediated knockdown of AXIN2 leads to increased WNT/beta-catenin signaling. This result confirmed the functional integrity of the downstream part of the WNT pathway from destruction complex to transcription activation by TCF/beta-catenin complex. It also narrowed down the dysregulated component(s) to within the destruction complex. Protein analysis further demonstrated that AXIN2 siRNA-mediated knockdown changed expression of several WNT/beta-catenin target genes. Surprisingly, siRNA-mediated knockdown led to decreased cell proliferation of HT29 cells. We surmise that AXIN2 knockdown in the setting of mutant APC leads to a high level of WNT signaling that reduces the self-renewal capacity of colonic cancer stem cells and lowers the rate of cell proliferation. Overall, our results indicate that it is important to understand how WNT signaling levels play a role in SC self-renewal and stemness. We conjecture that if WNT signaling is not strictly controlled in CSCs, high WNT levels can be detrimental to CSC proliferation and/or survival, which could have important clinical implications. Citation Format: Chi Zhang, Caroline O. Facey, Katherine Funk, Lynn M. Opdenaker, Bruce M. Boman. Effect of reducing AXIN2 levels in CRC cells with APC mutation and activated WNT signaling [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 3075.
The impact of COVID-19 on the medium-term outcomes of urological cancer - International prospective 3 year follow up study
Authors: C. Gao, A. Nathan, A. Light, C. Alexander, V.W-S. Chan, K. Gallagher, E. Harrison, R. Barod, S. Bromage, T. Klatte, K. Narahari, B. Lamb, A. Mcneill, J. Mcgrath, A. Colquhoun, S. Treece, S. Khadhouri, L. Magill, R. Perry, M. Waters, T. Pinkney, G. Stewart, V. Kasivisvanathan
Journal: European Urology (2021)
Association between Oncotype DX Genomic Prostate Score (GPS) and adverse tumor pathology after radical prostatectomy
Authors: M. Covas Moschovas, C. Chew, S. Bhat, M. Sandri, T. Rogers, P. Dell’oglio, S. Roof, S. Reddy, M. Chiara Sighinolfi, B. Rocco, V. Patel
Journal: European Urology (2021)
Innate-like Gene Expression of Lung-Resident Memory CD8<sup>+</sup> T Cells during Experimental Human Influenza: A Clinical Study
Authors: Suzanna Paterson, Satwik Kar, Seng Kuong Ung, Zoe Gardener, Emma Bergstrom, Stephanie Ascough, Mohini Kalyan, Joanna Zyla, Jeroen Maertzdorf, Hans-Joachim Mollenkopf, January Weiner, Agnieszka Jozwik, Hannah Jarvis, Akhilesh Jha, Bradly P. Nicholson, Timothy Veldman, Chris W. Woods, Patrick Mallia, Onn Min Kon, Stefan H. E. Kaufmann, Peter J. Openshaw, Christopher Chiu
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: Suboptimal vaccine immunogenicity and antigenic mismatch, compounded by poor uptake, means that influenza remains a major global disease. T cells recognizing peptides derived from conserved viral proteins could enhance vaccine-induced cross-strain protection. Objectives: To investigate the kinetics, phenotypes, and function of influenza virus-specific CD8+ resident memory T (Trm) cells in the lower airway and infer the molecular pathways associated with their response to infection in vivo. Methods: Healthy volunteers, aged 18-55, were inoculated intranasally with influenza A/California/4/09(H1N1). Blood, upper airway, and (in a subgroup) lower airway samples were obtained throughout infection. Symptoms were assessed by using self-reported diaries, and the nasal viral load was assessed by using quantitative PCR. T-cell responses were analyzed by using a three-color FluoroSpot assay, flow cytometry with MHC I-peptide tetramers, and RNA sequencing, with candidate markers being confirmed by using the immunohistochemistry results for endobronchial biopsy specimens. Measurements and Main Results: After challenge, 57% of participants became infected. Preexisting influenza-specific CD8+ T cells in blood correlated strongly with a reduced viral load, which peaked at Day 3. Influenza-specific CD8+ T cells in BAL fluid were highly enriched and predominantly expressed the Trm markers CD69 and CD103. Comparison between preinfection CD8+ T cells in BAL fluid and blood by using RNA sequencing revealed 3,928 differentially expressed genes, including all major Trm-cell markers. However, gene set enrichment analysis of BAL-fluid CD8+ T cells showed primarily innate cell-related pathways and, during infection, included upregulation of innate chemokines (Cxcl1, Cxcl10, and Cxcl16) that were also expressed by CD8+ cells in bronchial tissues. Conclusions: CD8+ Trm cells in the human lung display innate-like gene and protein expression that demonstrates blurred divisions between innate and adaptive immunity. Clinical study registered with www.clinicaltrials.gov (NCT02755948).
Vascular Mechanobiology: Homeostasis, Adaptation, and Disease
Authors: Jay D. Humphrey, Martin A. Schwartz
Journal: Annual Review of Biomedical Engineering (2021)

Cells of the vascular wall are exquisitely sensitive to changes in their mechanical environment. In healthy vessels, mechanical forces regulate signaling and gene expression to direct the remodeling needed for the vessel wall to maintain optimal function. Major diseases of arteries involve maladaptive remodeling with compromised or lost homeostatic mechanisms. Whereas homeostasis invokes negative feedback loops at multiple scales to mediate mechanobiological stability, disease progression often occurs via positive feedback that generates mechanobiological instabilities. In this review, we focus on the cell biology, wall mechanics, and regulatory pathways associated with arterial health and how changes in these processes lead to disease. We discuss how positive feedback loops arise via biomechanical and biochemical means. We conclude that inflammation plays a central role in overriding homeostatic pathways and suggest future directions for addressing therapeutic needs.