tbuckley/cabot-search huggingface dataset:
Materia Medica and Therapeutics.
Journal: JAMA (1891)

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Abstract 199: Blossom AI: A novel drug discovery app for the prediction of hotspots on multiplex protein protein interaction complexes using random forest algorithms
Authors: Stephanie Zhang, Minsoo Kang
Journal: Cancer Research (2021)

Abstract Protein protein interactions (PPIs) form the backbone of signal transduction pathways in diverse physiological processes, mediating the transmission and regulation of oncogenic signals essential to cellular proliferation and survival, thus representing a potential new class of drug targets for anticancer therapeutic discovery. However, several challenges face the targeting of PPIs, including large PPI interface areas, a lack of deep pockets, the presence of noncontiguous binding sites, and a general lack of natural ligands. The presence of hot spots (small subsets of amino acid residues that contribute significantly to free binding energy) makes PPIs amenable to small molecule perturbations, playing essential roles in the stability of protein binding. Effectively identifying which specific interface residues of protein protein complexes form the hot spots is critical for understanding the principles of protein interactions and has broad application prospects in protein design and drug development. This project presents Blossom AI, a novel, user friendly mobile app developed in XCode and CoreML that uses random forest decision tree algorithms (RF) to computationally predict the presence of hotspots on protein complexes within seconds, aiding the design of small molecule and peptide drugs that target protein-protein interactions, particularly for anticancer therapy. Leveraging features such as solvent accessible surface area (ASA), blocks substitution matrix, physicochemical properties (hydrophobicity, polarity, polarizability, propensities), position specific scoring matrix (PSSM) and solvent exposure, the RF is trained through a dataset of 313 mutated interface residues (133 hotspot residues and 180 non hotspot residues) from over 60 protein complexes to produce a training accuracy of 88.75%, validation accuracy of 92.86%, specificity of 87.18%, sensitivity of 75.38%, PPV 94.23%, NPV 86.61%. Blossom is high speed, low cost, and user friendly with significantly improved accuracy over the standard of alanine scanning mutagenesis. Citation Format: Stephanie Zhang, Minsoo Kang. Blossom AI: A novel drug discovery app for the prediction of hotspots on multiplex protein protein interaction complexes using random forest algorithms [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 199.
Abstract 1297: Synthesis and structural analysis on an ionic diphenyltin complex as a potential anticancer agent
Authors: Jade Witter, Xueqing Song, Tajera Henry, William Li
Journal: Cancer Research (2021)

Abstract Triorganotins are popular among chemists due to their potential biological properties against bacteria, fungi, and cancer cell lines. However, they have limited applications due to their poor water solubility. We hypothesize that solubility can be improved when the complex exhibits partial ionic characteristics. Therefore, it is our research goal to synthesize triphenyltin complexes that possess ionic characteristics. Syntheses of the ionic triphenyltin complex involved the reaction of a diprotic carboxylic acid, with triphenyltin chloride in the presence of di-isopropylamine. However, a tin-carbon cleavage reaction was observed, as IR/NMR spectroscopy and X-ray Crystallography studies showed that an ionic diphenyltin complex was successfully obtained in the reaction. The ionic complex consists of a diphenyltin anionic moiety, two oxalate ligands are observed coordinating to the tin atom in the bidentate mode, and two diisopropylammonium as the counterions. The anionic diphenyltin moieties has a distorted octohedral geometry with two carbons and two oxygens atom occupying the equatorial positions and two oxygen atoms occupying the axial positions. The ionic complex is essentially a 1-D polymer chain through an extensive hydrogen-bonding network between the oxalate groups (OCO) and the N atom from the ammonium cations. Compared to the similar reaction with triphenyltin hydroxide, which resulted in ionic triphenyltin complexes, cleavage of one phenyl group was observed for the first time in the reaction with triphenyltin chloride. Future studies will be focused on the mechanistic studies on the Sn-C cleavage. Citation Format: Jade Witter, Xueqing Song, Tajera Henry, William Li. Synthesis and structural analysis on an ionic diphenyltin complex as a potential anticancer agent [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 1297.
Timing of steroid initiation and response rates to immune checkpoint inhibitors in metastatic cancer
Authors: Diana V Maslov, Karine Tawagi, Madhav KC, Victoria Simenson, Helen Yuan, Cameron Parent, Adi Bamnolker, Richa Goel, Zoe Blake, Marc R Matrana, Daniel H Johnson
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Corticosteroids (CS) are the mainstay of immune-related adverse effect (irAE) management, as well as for other indications in cancer treatment. Previous studies evaluating whether CS affect immune checkpoint inhibitor (CPI) efficacy compared patients receiving CS versus no CS. However, there is a paucity of clinical data evaluating the timing of concomitant CS and CPI efficacy. Methods We retrospectively collected data from patients who received CS during CPI treatment at a single institution. Patients were in two cohorts based on timing of initiation of CS (≥2 months vs &lt;2 months after initiating CPI). Patient characteristics, irAEs, cancer type, treatment type, treatment response/progression per RECIST V.1.1, and survival data were collected. Kaplan-Meier and Cox proportional hazard regression methods estimated HRs for the primary endpoint of progression-free survival (PFS) along with overall survival (OS). Results We identified 247 patients with metastatic cancer who received CS concurrently with CPIs. The median time on CS was 1.8 months. After adjusting for treatment type, tumor type, brain metastases, and irAEs, those treated with CS ≥2 months after starting CPI had a statistically significant longer PFS (HR=0.30, p&lt;0.001), and OS (HR 0.34, p&lt;0.0001) than those who received CS &lt;2 months after starting CPI. Objective response rate (ORR) for patients on CS ≥2 months was 39.8%, versus ORR for patients &lt;2 months was 14.7% (p value =&lt;0.001) Conclusion Our results suggest that early use of CS during CPI treatment significantly hinders CPI efficacy. This data needs to be validated prospectively. Future studies should focus on the immune mechanisms by which CSs affect T-cell function early in the CPI treatment course.
Abstract 2837: NR2F1 is a barrier to early dissemination of pre-malignant mammary cells
Authors: Maria Soledad Sosa, Carolina Rodriguez-Tirado, Nupura Kale, Maria Carlini, Nitisha Shrivastava, Bassem Khalil, Javier Bravo-Cordero, Melissa Alexander, Jiayi Ji
Journal: Cancer Research (2021)

Abstract Cancer cells disseminate during very early and sometimes asymptomatic stages of tumor progression. Granted that biological barriers to tumorigenesis exist, there must also be limiting steps to early dissemination, all of which remain largely unknown. We report that the orphan nuclear receptor NR2F1/COUP-TF1 serves as a barrier to early dissemination. High-resolution intravital imaging revealed that loss of function of NR2F1 in HER2+ early cancer cells increased in vivo dissemination without accelerating mammary tumor formation. NR2F1 expression was positively regulated by the tumor suppressive MMK3/6-p38-MAPK pathway and downregulated by HER2 and Wnt4 oncogenic signaling. NR2F1 downregulation by HER2 in early cancer cells led to decreased E-cadherin expression and β-catenin membrane localization, disorganized laminin 5 deposition, and increased expression of CK14, TWIST1, ZEB1 and PRRX1. Our findings reveal the existence of an inhibitory mechanism of dissemination regulated by NR2F1 downstream of HER2 signaling. Citation Format: Maria Soledad Sosa, Carolina Rodriguez-Tirado, Nupura Kale, Maria Carlini, Nitisha Shrivastava, Bassem Khalil, Javier Bravo-Cordero, Melissa Alexander, Jiayi Ji. NR2F1 is a barrier to early dissemination of pre-malignant mammary 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 2837.
Abstract 69: A biological circuit involving Mef2c, Mef2d and Hdac9 controls the immunosuppressive functions of CD4+Foxp3+ T-regulatory cells and anti-cancer immunity
Authors: Eros Di Giorgio, Liqing Wang, Yan Xiong, Rongxiang Han, Arabinda Samanta, Matteo Trevisanut, Wayne W. Hancock
Journal: Cancer Research (2021)

Abstract The Mads/Mef2 (Mef2a/b/c/d) transcription factors (TFs) regulate differentiation of myocytes, neurons and hematopoietic cells. Mef2 TFs are subject to regulation by negative feedback in that they promote transcription of their strong repressor Hdac9, providing temporal control of Mef2-driven differentiative responses. Disruption of this feedback occurs within various sarcomas and leukemias. In addition, Mef2 TFs indirectly control tumor progression by regulating antitumor immunity. We recently reported that in CD4+CD25+Foxp3+ T-regulatory (Treg) cells, Mef2d is required for the acquisition of an effector Treg phenotype and the activation of an epigenetic program that in turn represses the anti-cancer responses of CD4, CD8 and B-cells. We now report that similarly to Mef2d, deletion of Mef2c in Tregs switches off expression of Il10 and Ctla4 and leads to enhanced antitumor immunity in syngeneic models of lung cancer. Mechanistically, Mef2c does not directly bind to the regulatory elements of Ctla4 and Il10, but rather, its loss-of-function in Tregs induces the expression of the transcriptional repressor Hdac9. As a consequence, Mef2d, the more abundant member of the Mef2 family, is displaced from p300 and is converted by Hdac9 into a transcriptional repressor at these loci. This leads to the impairment of Treg suppressive properties and to enhanced anti-cancer immunity. These data further highlight the central role played by Mef2/Hdac9 axis in the regulation of CD4+Foxp3+ Treg function and provide a rationale for the development of small molecules targeting Mef2 and/or Mef2-containing complexes. Citation Format: Eros Di Giorgio, Liqing Wang, Yan Xiong, Rongxiang Han, Arabinda Samanta, Matteo Trevisanut, Wayne W. Hancock. A biological circuit involving Mef2c, Mef2d and Hdac9 controls the immunosuppressive functions of CD4+Foxp3+ T-regulatory cells and anti-cancer immunity [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 69.
Association Between BNT162b2 Vaccination and Incidence of SARS-CoV-2 Infection in Pregnant Women
Authors: Inbal Goldshtein, Daniel Nevo, David M. Steinberg, Ran S. Rotem, Malka Gorfine, Gabriel Chodick, Yaakov Segal
Journal: JAMA (2021)

Data on BNT162b2 messenger RNA (mRNA) vaccine (Pfizer-BioNTech) effectiveness and safety in pregnancy are currently lacking because pregnant women were excluded from the phase 3 trial.To assess the association between receipt of BNT162b2 mRNA vaccine and risk of SARS-CoV-2 infection among pregnant women.This was a retrospective cohort study within the pregnancy registry of a large state-mandated health care organization in Israel. Pregnant women vaccinated with a first dose from December 19, 2020, through February 28, 2021, were 1:1 matched to unvaccinated women by age, gestational age, residential area, population subgroup, parity, and influenza immunization status. Follow-up ended on April 11, 2021.Exposure was defined by receipt of the BNT162b2 mRNA vaccine. To maintain comparability, nonexposed women who were subsequently vaccinated were censored 10 days after their exposure, along with their matched pair.The primary outcome was polymerase chain reaction-validated SARS-CoV-2 infection at 28 days or more after the first vaccine dose.The cohort included 7530 vaccinated and 7530 matched unvaccinated women, 46% and 33% in the second and third trimester, respectively, with a mean age of 31.1 years (SD, 4.9 years). The median follow-up for the primary outcome was 37 days (interquartile range, 21-54 days; range, 0-70). There were 118 SARS-CoV-2 infections in the vaccinated group and 202 in the unvaccinated group. Among infected women, 88 of 105 (83.8%) were symptomatic in the vaccinated group vs 149 of 179 (83.2%) in the unvaccinated group (P ≥ .99). During 28 to 70 days of follow-up, there were 10 infections in the vaccinated group and 46 in the unvaccinated group. The hazards of infection were 0.33% vs 1.64% in the vaccinated and unvaccinated groups, respectively, representing an absolute difference of 1.31% (95% CI, 0.89%-1.74%), with an adjusted hazard ratio of 0.22 (95% CI, 0.11-0.43). Vaccine-related adverse events were reported by 68 patients; none was severe. The most commonly reported symptoms were headache (n = 10, 0.1%), general weakness (n = 8, 0.1%), nonspecified pain (n = 6, <0.1%), and stomachache (n = 5, <0.1%).In this retrospective cohort study of pregnant women, BNT162b2 mRNA vaccination compared with no vaccination was associated with a significantly lower risk of SARS-CoV-2 infection. Interpretation of study findings is limited by the observational design.
Abstract 2604: Urinary microRNAs as biomarkers for early detection of urothelial cancer
Authors: Kazuya Takayama, Kohei Yamazaki, Hiroki Yamaguchi, Keishu Tsuda, Takao Yasui, Yuki Ichikawa
Journal: Cancer Research (2021)

Abstract microRNAs modulate gene expression in various cancer types, and their profiles differ in healthy and cancer groups of people and they represent a warning sign for various cancer scenarios. Identification of tumor-specific microRNAs presents a powerful opportunity to potentially reduce cancer mortality through early detection. In order to achieve early detection through population screening, noninvasive approaches are needed to complement and improve upon current strategies for urothelial cancer (UC) screening. Since all microRNAs in the blood cannot be transferred from donor to recipient cells during single blood circulation, kidney filtration could pass some untransferred microRNAs from blood to urine, therefore urinary microRNAs might be used as biomarkers for the diagnosis of cancer. We investigated whether urine levels of microRNA can differentiate patients with UC from healthy individuals. Here, we successfully identified UC-related microRNA ensembles in urine through a combination of microfluidic microRNA extraction device and machine learning-based analysis. We analyzed 93 urine samples from 27 UC patients and 66 healthy individuals (controls). An initial set of 74 microRNAs was selected by microarray microRNA profiling assay as biomarker candidates. Quantitative reverse-transcription PCR was used for further analysis to validate the expression of microRNAs. We selected a group of 6 microRNAs for validation; (miR-6089, miR-4488, miR-4784, miR-26a-5p, miR-148a-3p, and miR-143-3p) were confirmed to be significantly different in UC and controls. We adopted a logistic regression model and successfully developed a classifier based on these 6 microRNAs, which showed remarkably high sensitivity (94%) and specificity (85%). In summary, patients with UC have significantly different patterns of microRNA expression from healthy individuals. We identified a signature of 6 microRNAs as predictors that can differentiate patients with UC from those who are healthy. These microRNAs could be potentially developed as biomarkers for UC. Citation Format: Kazuya Takayama, Kohei Yamazaki, Hiroki Yamaguchi, Keishu Tsuda, Takao Yasui, Yuki Ichikawa. Urinary microRNAs as biomarkers for early detection of urothelial 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 2604.
Abstract LB134: The rexinoid MSU-42011 enhances dendritic-T cell cross talk in a HER2 positive model of breast cancer
Authors: Ana Sofia Leal, Sarah Carapellucci, Karen T. Liby
Journal: Cancer Research (2021)

Abstract Breast cancer (BC) was considered an immunologically silent tumor, however recent findings suggest that immune cells present in the tumor microenvironment play important roles in tumor growth. Retinoid X receptors (RXRs) are a subclass of nuclear receptors that act as ligand-dependent transcription factors that regulate a variety of cellular processes including proliferation and differentiation. Rexinoids are synthetic molecules that bind and activate RXRs. Bexarotene (Targretin®) is the only rexinoid approved by the FDA and is used for the treatment of refractory cutaneous T-cell lymphoma. Other more potent rexinoids have been synthesized, such as LG100268 and LG101506, which will not be tested in clinical trials because of intellectual property issues. Because recent studies have suggested that RXRs are involved in immune regulation, we synthesized novel rexinoids and selected MSU-42011 as a lead compound. MMTV-neu mice with tumors approximately 32 mm3 in volume were treated with control diet or MSU-42011 (100 mg/kg diet) for 10 days. Rexinoid treatment significantly (p=0.0069) reduced tumor fold change normalized to initial volume from 8.33 in controls to 4.80 on treatment. Analysis of the tumor by flow cytometry showed no significant differences in the major immune populations, such as T cells, macrophages and dendritic cells. However, expression of PDL1 was increased in CD11c+, MHC-II+ dendritic cells (5484 vs 7140 MFI, p=0.0456), suggesting engaged dendritic cells in activating cytotoxic T cells. To further elucidate the cross talk between dendritic and T cells, cytokines associated with T cell recruitment and activation were analyzed by RT-PCR. Tumor treated with MSU42011 had a 38.5 fold increase in IL12a expression (p=0.011, n=4), and a 20.8 fold increase in CCL9 (p=ns, n=4), suggesting that dendritic cells are actively recruiting and activating T cells. The activation of cytotoxic T cells was confirmed by a 75.5 fold increase in interferon gamma (p=0.0026, n=4) and a decrease of FOXP3 expression (p=ns, n=4). To test if the effects seen in tumor reduction were dependent on the presence of T cells, CD4 and CD8 were depleted. Depletion of CD4 alone, but not CD8, reversed the tumor reduction induced by MSU-42011. These results show that RXR agonists can be used to modulate immune cell populations in the tumor microenvironment, specifically by recruiting and activating dendritic cells that then activate cytotoxic T cells. We thank the Breast Cancer Research Foundation for support of these studies. Citation Format: Ana Sofia Leal, Sarah Carapellucci, Karen T. Liby. The rexinoid MSU-42011 enhances dendritic-T cell cross talk in a HER2 positive model of 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 LB134.
Validated Models to Estimate Probability of Dialysis After Nephrectomy and Partial Nephrectomy
Authors: Luke L. Wang, Kaeli K. Samson, Shawna L. Boyle
Journal: JAMA Surgery (2021)

Postoperative kidney failure requiring dialysis significantly increases in-hospital and long-term mortality. 1,2A major challenge in nephrectomy is estimating the probability of postoperative dialysis.Because of its rarity (0.5% to 2.1%), 3,4 to our knowledge, there are no validated models to estimate this probability.We developed externally validated nomograms to compute this probability after nephrectomy and partial nephrectomy (PN).Methods | We queried all 6 637 415 patients included in the National Surgical Quality Improvement Program (NSQIP) database between January 2005 and December 2017.We selected all patients who underwent open or minimally invasive radical nephrectomy, nephroureterectomy, simple nephrectomy, or PN for any indication.We excluded all patients who received dialysis preoperatively or had bilateral nephrectomies, kidney mass ablation, or traumatic nephrectomies.The NSQIP database excludes patients admitted for trauma or any transplant procedure(s).All remaining emergent nephrectomies were included.Because data were publicly available and deidentified, the University of Nebraska Medical Center Institutional Review Board waived the study.Using NSQIP data from 2005 to 2017, 2 models were generated: one for nephrectomy (including simple nephrectomy, radical nephrectomy, and nephroureterectomy) and one for PN.t Tests or χ 2 tests assessed associations between preoperative variables and postoperative dialysis within 30 days postoperatively, as appropriate.While race reported in the NSQIP database was incorporated to calculate glomerular filtration, caution should be used when doing this. 5,6Variables with univariable P values less than .10were included in multivariable logistic regression models.Backward selection with stay criteria of a P value less than .05selected variables for the nomograms.The nomograms were validated with 2018 NSQIP data.Data for 2018 postoperative dialysis probabilities were compared with known 2018 postoperative dialysis status to generate calibration plots and C statistics.Deciles of the log of these predicted probabilities were defined; the proportion of patients with postoperative dialysis were plotted against the midpoint of the predicted probability of each decile (eMethods in the Supplement).Statistical analysis was conducted using SAS version 9.4 (SAS Institute).Two-sided P values less than .05were considered statistically significant.Using the Shiny package in R version 4.0.3(R Core Team), we developed an online calculator for each nomogram.
The effect of BCG revaccination on all-cause mortality beyond infancy: 30-year follow-up of a population-based, double-blind, randomised placebo-controlled trial in Malawi
Authors: Judith R Glynn, Albert Dube, Katherine Fielding, Amelia C Crampin, Chifundo Kanjala, Paul E M Fine
Journal: The Lancet Infectious Diseases (2021)