tbuckley/cabot-search huggingface dataset:
In-vitro characterization of ranibizumab release from the Port Delivery System
Authors: Stefan Yohe, Katie F. Maass, Judit Horvath, Jennifer Rea, Giulio Barteselli, Shrirang V. Ranade
Journal: Journal of Controlled Release (2022)

The Port Delivery System with ranibizumab (PDS) consists of an implant that is a permanent, indwelling drug delivery device that can be refilled through a self-sealing septum and is designed to continuously release a customized formulation of ranibizumab into the vitreous by passive diffusion through a porous titanium release control element. Target release rates of ranibizumab via the implant used in studies of the PDS in patients with neovascular age-related macular degeneration were selected based on clinical and pharmacokinetic (PK) data from previously conducted intravitreal ranibizumab injection studies. In-vitro testing was performed to verify release rates with a range of ranibizumab concentrations before the phase II Ladder (NCT02510794) and phase III Archway (NCT03677934) trials of the PDS. Implants were filled with ranibizumab and were regularly transferred to new buffer-containing tubes to represent ocular ranibizumab clearance and release kinetics. Ranibizumab concentrations were measured and release rates calculated. Release rate data were fit to an exponential model and compared with expected release kinetics of diffusion. Release profiles of the implant releasing ranibizumab at concentrations of 10 mg/mL, 40 mg/mL, and 100 mg/mL were determined in the pre–phase II in-vitro studies. At day 3.5, mean (SD) ranibizumab release rates were 1.75 (0.07), 6.42 (0.35), and 16.69 (0.67) μg/d for PDS 10 mg/mL, 40 mg/mL, and 100 mg/mL, respectively. At month 6, mean (SD) release rates were 1.68 (0.05) and 4.16 (0.05) μg/d for PDS 40 mg/mL and 100 mg/mL, respectively. Measured release rates were within 90% of theoretical release rates during the course of drug release. PDS 100 mg/mL released 73% (SD, 1.92) of drug by month 6. In the pre–phase III in-vitro studies, mean (SD) release rates with PDS 100 mg/mL were 17.97 (0.90), 4.44 (0.11), and 2.45 (0.08) μg/d at 3.5 days, 6 months, and 9 months, respectively. Cumulative release (SD) was 73% (1.92) by month 6 and 87% (1.88) by month 9. The sustained, continuous, and reproducible release from the PDS observed in the in-vitro studies was also observed in Ladder and Archway. In conclusion, in-vitro studies were a powerful tool for characterizing and verifying ranibizumab release from the PDS implant and supported clinical evaluation of the PDS. PDS 100 mg/mL, which was associated with the longest therapeutic-level delivery of ranibizumab among the concentrations tested, was selected for evaluation in the pivotal phase III Archway trial.
Abstract 10607: Deficiency of Phospholipase A2 Receptor Exacerbates Autoimmune Myocarditis in Mice
Authors: Hiroki Kishi, Yousuke Watanabe, Kazuhiro Watanabe, Daisuke Fujioka, Kazuto Nakamura, Ken-ichi Kawabata, Kiyotaka Kugiyama
Journal: Circulation (2019)

Secretory phospholipase A2 (sPLA2) plays a critical role in the genesis of various inflammatory diseases through production of pro-inflammatory eicosanoids. PLA2 receptor 1 (PLA2R), a so-called M-t...
Abstract 3140: Tumor evolution selectively inactivates microRNA machinery for immune evasion
Authors: Haixin Zhao, Tian-yu Song, Min Long, Hong-Jie Fan, Yang Liu, Chen-Lu Geng, Xiaoxiao Xie, Dawei Huang, Zhengang Peng, Bo Peng, Yong Cang
Journal: Cancer Research (2021)

Abstract Cancer arises after somatic mutations override cellular and immunological control of cell proliferation1. Mutations in oncogenes and tumor suppressor genes endow cancer cells intrinsic growth advantage over neighboring cells. Mutations can also enable cancer cells to escape from immune surveillance during cancer evolution, but a targeted approach to uncover such mutations is lacking. We hypothesized that genetic heterogeneity intrinsic to cancer cells affects the cell fitness to T cell-mediated cytotoxicity. By deep sequencing of murine tumors grown under different conditions of immune editing, we identified 59 genetic mutations in clonal populations that were specifically enriched under host immune pressure. To differentiate driver from passenger mutations against immune selection, we performed in vivo and T cell co-culture CRISPR screens with a guide RNA library targeting the corresponding genes. We identified ANKRD52 as required for PD-1-independent T cell-mediated cytotoxicity, which enhanced the JAK-STAT-interferon-γ signaling and antigen presentation in cancer cells. ANKRD52, in complex with PPP6C, dephosphorylates AGO26 and promoted microRNA (miRNA)-targeted silencing of suppressor of cytokine signaling 1 (SOCS1), and deletion of SOCS1 reinstalled the sensitivity of the mutant cells to T cell killing. Introduction of patient hotspot ANKRD52 mutations, or deletion of AGO2, DICER1 or XPO5 in cancer cells compromised the interferon-γ and T cell response. Remarkably, expression of the core miRNA biogenesis and targeting machinery strongly correlates with intratumoral T cell abundance across nearly all human cancer types. Our data indicate that the evolutionarily conserved miRNA pathway is exploited by cancer cells for immune escape. Citation Format: Haixin Zhao, Tian-yu Song, Min Long, Hong-Jie Fan, Yang Liu, Chen-Lu Geng, Xiaoxiao Xie, Dawei Huang, Zhengang Peng, Bo Peng, Yong Cang. Tumor evolution selectively inactivates microRNA machinery for immune evasion [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 3140.
Lineage Deconvolution Using Chromatin Accessibility and DNA Methylation Shows a Spectrum of Lineage Characteristics and Differentiation States across Acute Leukemias
Authors: Jacob L Glass, Alyson J Palia, Francine E. Garrett-Bakelman, Richard Koche, Ross L. Levine, Martin S. Tallman, Richard James Dillon, David Grimwade, Adolfo A. Ferrando, Peter J.M. Valk, Ruud Delwel, Maria E. Figueroa, Ari Melnick, Olivier Elemento
Journal: Blood (2017)
Development and Validation of Computerized Adaptive Assessment Tools for the Measurement of Posttraumatic Stress Disorder Among US Military Veterans
Authors: Lisa A. Brenner, Lisa M. Betthauser, Molly Penzenik, Anne Germain, Jin Jun Li, Ishanu Chattopadhyay, Ellen Frank, David J. Kupfer, Robert D. Gibbons
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Veterans from recent and past conflicts have high rates of posttraumatic stress disorder (PTSD). Adaptive testing strategies can increase accuracy of diagnostic screening and symptom severity measurement while decreasing patient and clinician burden. <h3>Objective</h3> To develop and validate a computerized adaptive diagnostic (CAD) screener and computerized adaptive test (CAT) for PTSD symptom severity. <h3>Design, Setting, and Participants</h3> A diagnostic study of measure development and validation was conducted at a Veterans Health Administration facility. A total of 713 US military veterans were included. The study was conducted from April 25, 2017, to November 10, 2019. <h3>Main Outcomes and Measures</h3> The participants completed a PTSD-symptom questionnaire from the item bank and provided responses on the PTSD Checklist for<i>Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition</i>(<i>DSM-5</i>) (PCL-5). A subsample of 304 participants were interviewed using the Clinician-Administered Scale for PTSD for<i>DSM-5</i>. <h3>Results</h3> Of the 713 participants, 585 were men; mean (SD) age was 52.8 (15.0) years. The CAD-PTSD reproduced the Clinician-Administered Scale for PTSD for<i>DSM-5</i>PTSD diagnosis with high sensitivity and specificity as evidenced by an area under the curve of 0.91 (95% CI, 0.87-0.95). The CAT-PTSD demonstrated convergent validity with the PCL-5 (<i>r</i> = 0.88) and also tracked PTSD diagnosis (area under the curve = 0.85; 95% CI, 0.79-0.89). The CAT-PTSD reproduced the final 203-item bank score with a correlation of<i>r</i> = 0.95 with a mean of only 10 adaptively administered items, a 95% reduction in patient burden. <h3>Conclusions and Relevance</h3> Using a maximum of only 6 items, the CAD-PTSD developed in this study was shown to have excellent diagnostic screening accuracy. Similarly, using a mean of 10 items, the CAT-PTSD provided valid severity ratings with excellent convergent validity with an extant scale containing twice the number of items. The 10-item CAT-PTSD also outperformed the 20-item PCL-5 in terms of diagnostic accuracy. The results suggest that scalable, valid, and rapid PTSD diagnostic screening and severity measurement are possible.
Clofarabine/Busulfan-Based Reduced Intensity Conditioning Regimens Provides Very Good Survivals in Patients Allografted in Remission for Acute Myeloid Leukemia: A Retrospective Study on Behalf of the SFGM-TC
Authors: Amandine Le Bourgeois, Myriam Labopin, Sebastien Maury, Regis Peffault De Latour, Jean-Henri Bourhis, Patrice Ceballos, Sylvie François, Karin Bilger, Didier Blaise, Thierry Guillaume, Mohamad Mohty, Patrice Chevallier
Journal: Blood (2017)
Ductal Variant of Prostate Cancer
Authors: Yazan Z. Alabed
Journal: Clinical Nuclear Medicine (2021)

Abstract A 51-year-old man with high-grade ductal variant of prostate cancer with normal prostate-specific antigen (PSA) levels underwent radical prostatectomy. Follow-up 18 F–prostate-specific membrane antigen-targeted ligand 1007 (PSMA-1007) PET/CT revealed enlarged PSMA-expressing left common iliac node. Patient was placed on androgen deprivation therapy and was lost to follow-up. Repeat 18 F-PSMA PET/CT scan after 16 months showed disease progression. PSA levels were still within normal limits. This case highlights the utility of 18 F-PSMA PET/CT for staging and follow-up of patients with this rare ductal variant prostate cancer with normal PSA levels.
Abstract 3192: PD-L1 is an independent prognostic marker in Middle Eastern PTC and its expression is upregulated by <i>BRAFV600E</i> mutation
Authors: Tariq Masoodi, Abdul K. Siraj, Sandeep Kumar Parvathareddy, Poyil Pratheeshkumar, Sasidharan Padmaja Divya, Rafia Begum, Roxanne Diaz, Thangavel Saravanan, Khadija Al-Obaisi, Sarah Siraj, Saud Azam, Zeeshan Qadri, Khawla S. Al-Kuraya
Journal: Cancer Research (2021)

Abstract Background: PD-L1 inhibition is a promising therapeutic target whose efficacy has been demonstrated in several cancers. This study was conducted to evaluate the prognostic significance of PD-L1 expression in a large cohort of Middle Eastern PTC patients and to explore correlation of PD-L1 and BRAFV600E mutations in PTC tumors and cell lines. Methods: Immunohistochemistry was performed to assess PD-L1 protein expression in PTC. We further conducted in vitro analysis to investigate the role of PD-L1 in regulating BRAFV600E in PTC cell lines. Results: PD-L1 over-expression was noted in 32.4% (473/1458) of cases and significantly associated with adverse clinico-pathological parameters such as tall cell variant, extra-thyroidal extension and lymph node metastasis. Importantly, PD-L1 was found to be an independent poorer prognostic marker. We also found PD-L1 to be significantly associated with BRAF mutation and patients with co-existing PD-L1 over-expression and BRAF mutation had a poor disease-free survival compared to patients with BRAF mutation alone. In vitro analysis showed high expression of PD-L1 in BRAF mutated PTC cell lines compared to BRAF wild-type cell line. Inhibition of BRAF using vemurafenib induced PD-L1 expression in BRAF mutated cell lines without affecting cell growth. Knockdown of PD-L1 in BRAF mutated cell lines significantly decreased the cell growth and induced apoptosis. Conclusion: Our data suggests that PD-L1 might represent a useful prognostic marker in Middle Eastern PTC and PD-L1 inhibition could be a potential therapeutic option for aggressive PTC cancers, such as tall cell variant, BRAF mutation positive patients that are unresponsive to standard treatment. Citation Format: Tariq Masoodi, Abdul K. Siraj, Sandeep Kumar Parvathareddy, Poyil Pratheeshkumar, Sasidharan Padmaja Divya, Rafia Begum, Roxanne Diaz, Thangavel Saravanan, Khadija Al-Obaisi, Sarah Siraj, Saud Azam, Zeeshan Qadri, Khawla S. Al-Kuraya. PD-L1 is an independent prognostic marker in Middle Eastern PTC and its expression is upregulated by BRAFV600E mutation [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 3192.
O-10 ANCHOR CRC: Results from a single-arm, phase 2 study of encorafenib, binimetinib plus cetuximab in previously untreated BRAF V600E–mutant metastatic colorectal cancer
Authors: E. Van Cutsem, J. Taieb, R. Yaeger, T. Yoshino, E. Maiello, E. Elez, J. Dekervel, P. Ross, A. Ruiz Casado, J. Graham, T. Kato, J. Ruffinelli, T. André, E. Carriere Roussel, I. Klauck, M. Groc, A. Grothey, J. Vedovato, J. Tabernero
Journal: Annals of Oncology (2021)
Abstract 880: Development and validation of an electronic health record-based absolute risk prediction model for esophageal cancer in the primary care setting in China
Authors: Yuting Han, Canqing Yu, Yu Guo, Pei Pei, Ling Yang, Yiping Chen, Huaidong Du, Junshi Chen, Zhengming Chen, Dezheng Huo, Jun Lv, Liming Li
Journal: Cancer Research (2021)

Abstract Background This study aims to develop a set of electronic health record (EHR)-based absolute risk prediction models for esophageal cancer (EC), which are nationally applicable and easily integrated into the EHR system in China. Methods The study used data from China Kadoorie Biobank (CKB), a large nationwide prospective cohort recruited during 2004-2008 in ten regions. In a random two-thirds of the 510,145 participants with no prior cancer diagnoses, we developed four nested models, according to the availability of predictors in EHRs. A flexible parametric survival model was fitted to calculate a 10-year absolute risk of EC accounting for the competing risk of mortality from other diseases. Besides discrimination and calibration, we estimated a range of performance indices (e.g. sensitivity and specificity) and compared the model performance with current screening criteria in the remaining one-third. Results During a median of 11.1 years of follow-up, we observed 2,550 EC incident cases. The most sophisticated model included EHR variable (age, sex, region risk level [of ten regions: Hui county in Henan province and Pengzhou in Sichuan province], education level, family history of cancer, smoking, alcohol drinking, body mass index), and physical activity, hot tea consumption, and fresh fruit consumption. In the validation dataset, as more predictors included, the area under the receiver-operating characteristic curve statistically increased from 0.748 (0.732-0.763) to 0.883 (0.867-0.895). We observed a great agreement between predicted and observed risk, except for a slight underestimation in the top deciles. Taking 0.40% as the 10-year risk cut-off, models had sensitivities and specificities of around 80% and largely outperformed the current screening criteria. Conclusions Based only on non-invasive predictors, even the model including only five predictors in the EHRs exhibited excellent calibration and discrimination. Utilizing limited predictors in EHRs, our models are useful to develop nationwide risk-stratified screening strategies for esophageal cancer. Citation Format: Yuting Han, Canqing Yu, Yu Guo, Pei Pei, Ling Yang, Yiping Chen, Huaidong Du, Junshi Chen, Zhengming Chen, Dezheng Huo, Jun Lv, Liming Li. Development and validation of an electronic health record-based absolute risk prediction model for esophageal cancer in the primary care setting in China [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 880.
Abstract LB191: Downregulation of Stem-loop binding protein by nicotine and its role in nicotine-induced cell transformation in human lung epithelial cells
Authors: Qi Sun, Danqi Chen, Chunyuan Jin
Journal: Cancer Research (2021)

Abstract The use of electronic-cigarettes has increased substantially in recent years among the younger population in particular. The liquid nicotine is the main component of the e-cigarette. Mice exposed to e-cigarette smoke (ECS) generated by heating the liquid nicotine developed lung adenocarcinoma and bladder hyperplasia. This implicated a potential role for ECS/nicotine in cancer development, while the underlying mechanisms remain unclear. Here we report that nicotine reduces the protein level of Stem-loop binding protein (SLBP), a critical factor for the stability, processing and translation of canonical histone pre-mRNAs, in human lung epithelial BEAS-2B cells. It has been known that canonical histone mRNAs typically do not end in a poly(A) tail and that depletion of SLBP results in polyadenylation of canonical histone mRNAs that appeared to be carcinogenic. Indeed, nicotine exposure induced polyadenylation of mRNAs for histones H2A, H2B, H3.1, H3.2, and H4. Interestingly, the inhibitor for nAChRs (nicotinic acetylcholine receptors) reversed nicotine-induced SLBP depletion. Moreover, the depletion of SLBP was attenuated not only by both the inhibitors and siRNAs specific for CDK1/2 and CK2, but also by inhibition of AKT signal pathway. Importantly, nicotine-induced anchorage-independent cell growth was rescued by overexpression of SLBP. These results suggest that activation of nAChR and a series of signal transduction pathways are involved in nicotine-mediated SLBP reduction and they may play an important role in nicotine-induced cell transformation and carcinogenesis.Keywords: Nicotine, Stem-loop binding protein, Cell transformation, nAChR Citation Format: Qi Sun, Danqi Chen, Chunyuan Jin. Downregulation of Stem-loop binding protein by nicotine and its role in nicotine-induced cell transformation in human lung epithelial 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 LB191.
Abstract 1619: A prognostic score for advanced non-small cell lung cancer with PD-1/L1 inhibitors
Authors: Qianyu Yuan, Mulong Du, David Christiani
Journal: Cancer Research (2021)

Abstract Background: Programmed death 1 (PD-1)/programmed death-legend 1(PD-L1) inhibitors have shown clinical benefits for a proportion of advanced lung cancer patients. This study aimed to develop a prognostic store with routinely available variables to identify non-small cell lung cancer (NSCLC) patients who likely benefit from PD-1/L1 inhibitors. Methods: 412 patients who received PD-1/L1 inhibitors were retrospectively collected from Massachusetts General Hospital (MGH) and Brigham and Women's Hospital (BWH) between Nov 2013 and Jan 2018. Demographic, clinical, and common laboratory tests were collected. Penalized Cox proportional hazard model with group minimax concave penalty (MCP) penalty was applied for variable section and coefficient estimation. Model performance was assessed by calculating area under the receiver operating curves (AUC). A prognostic score was developed to categorize advanced NSCLC patients into good, intermediate and poor groups. Results: Median PFS was 3.6 (95% CI: 2.9 - 4.3) months, median OS was 18.4 (95% CI: 14.2-24.9) months. A prognostic scoring model incorporating the weighted coefficients of PD-L1 expression level, EGFR mutation status, ECOG performance status, and albumin level was developed. Median PFS were 1.7 (95% CI: 1.5-2.1) vs 3.2 (95% CI: 2.7-6.3) vs 6.2 (95% CI: 4.9-9.7) months for the poor, intermediate and good groups, respectively. Median OS were 8.2 (95% CI: 4.5-14.1) vs 14.9 (95% CI: 11.8-30.0) vs 34.7 (95% CI: 26.2 -NE) months for the poor, intermediate and good groups, respectively. Conclusions: a prognostic score combining PD-L1 expression level, EGFR mutation status, ECOG performance status, and albumin level may help to identify advanced NSCLC patients who likely benefit from PD-1/L1 inhibitors. Citation Format: Qianyu Yuan, Mulong Du, David Christiani. A prognostic score for advanced non-small cell lung cancer with PD-1/L1 inhibitors [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 1619.
Abstract 2826: BAG2 promotes tumorigenesis and metastasis by regulating the Cathepsin B cleavage in triple-negative breast cancer cells
Authors: Kyung-Min Yang, Kyoungwha Pang, Akira Ooshima, Jihee Lee, Seong-jin Kim
Journal: Cancer Research (2021)

Abstract Breast cancer is classified into clinical subtypes based upon receptor expression (ER, PR, Her2). Among the breast cancer subtypes, triple-negative breast cancer (TNBC) refers to a form of breast cancer which lacks expression of ER, PR and HER2. Most of breast cancer treatments can be targeted for cancers that express hormonal receptors or HER2, whereas traditional chemotherapy does not work in TNBCs. Therefore, TNBC remains a clinical challenge for discovery novel specific target biomarker because of no targeted therapies for TNBC. In this study, we show that BAG2 promotes cancer progression by regulating the dual function of Cathepsin B in TNBC cells. We found that BAG2 is highly expressed in basal-like breast cancer cells, where it was associated with recurrence or distant metastasis-free survival in patients. In loss-of-function experiment, BAG2 knockdown strongly decreased the ability of tumor formation and lung metastasis in vivo in TNBC cells. Mechanistically, BAG2 induces metastasis through regulation of secretion of pro-form Cathepsin B and prevents lysosome-mediated cell death through decrease of intracellular single-chain form of Cathepsin B into cytoplasm. Thus, our results suggest that BAG2 promotes tumorigenesis and metastasis through regulation of Cathepsin B cleavage in TNBC cells and may be possible as a novel specific target for treatment of TNBC. [This work was supported by National R&amp;D Program for Cancer Control, Ministry for Health and Welfare, Republic of Korea (HA17C0037).] Citation Format: Kyung-Min Yang, Kyoungwha Pang, Akira Ooshima, Jihee Lee, Seong-jin Kim. BAG2 promotes tumorigenesis and metastasis by regulating the Cathepsin B cleavage in triple-negative 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 2826.