tbuckley/cabot-search huggingface dataset:
Abstract 752: Neutrophil-to-lymphocyte ratio and subsequent cancer risk in the UK Biobank
Authors: Minkyo Song, Eric A. Engels
Journal: Cancer Research (2021)

Abstract Background: The neutrophil-to-lymphocyte ratio (NLR), a ratio between neutrophil and lymphocyte counts in peripheral blood, is a measure of the balance between systemic levels of inflammation and immunity. NLR has been associated with cancer prognosis, but the role of NLR as a biomarker in carcinogenesis is not well established. Methods: We evaluated 445,443 adults in the UK Biobank, who were aged 37-73 years at baseline, had measured differential blood counts, and were cancer-free and under follow-up 1 year after baseline. NLR was categorized into quartiles. Incident cancers were ascertained from cancer registries. Multivariable Cox regression was used to estimate the per quartile hazard ratio (HR), separately for 69 cancer sites. Models were adjusted for age (quartile), sex, ethnicity (white vs non-white), total WBC (quartile), smoking (never, past, current), alcohol drinking (never, past, current), and BMI (&amp;lt;25, 25-30, ≥30 kg/m2). We present nominally significant results (p&amp;lt;0.05) and also accounting for multiple comparison using a Bonferroni cutoff (p=0.00072). Results: 26,294 incident cancers were diagnosed during a median of 3.3 years of follow-up. The mean NLR in the population was 2.3 (standard deviation 1.2). Increasing NLR quartile was associated with increased risk of cancers in esophagus, colon, lung, soft tissue including heart, uterus, and kidney, but decreased risk of myeloma and chronic lymphocytic leukemia [CLL] (ptrend&amp;lt;0.05). Compared with the lowest NLR quartile, the highest NLR quartile was significantly associated with risk of cancers of the soft tissue including heart (HR 1.98, 95%CI 1.15-3.42), kidney (1.54, 1.22-1.94), uterus (1.39, 1.11-1.73), esophagus (1.27, 0.96-1.69), colon (1.22, 1.06-1.41), myeloma (0.63, 0.47-0.86) and CLL (0.11, 0.02-0.48). After Bonferroni correction, NLR associations remained significant for kidney cancer and CLL. Conclusion: In a comprehensive analysis in a large population-based cohort, NLR was associated with subsequent risk of several cancer types. NLR may reflect the excessive inflammatory status of an individual, even in a subclinical condition, which may promote the development of cancer. On the other hand, low NLR represents a relative rise in the lymphocytes, which may be an indication of circulating premalignant cells for lymphoid malignancies. Citation Format: Minkyo Song, Eric A. Engels. Neutrophil-to-lymphocyte ratio and subsequent cancer risk in the UK Biobank [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 752.
Abstract LB117: Identification of novel SOS1-K-Ras disruptors for NSCLC and colon cancers with K-Ras mutation
Authors: Sanjita Sasmal, Anuradha Ramanathan, Venkatesham Boorgu
Journal: Cancer Research (2021)

Abstract KRAS along with other RAS genes represents the most prevalent oncogene in human cancers. Atypical Ras signaling has been identified in more than 30% of all human cancers with the most common being lung, colon, and pancreatic cancers. In particular, K-Ras has been identified as the most important Ras protein in cancer research, implicated in over 21% of human cancers. Current strategies drug only specific K-Ras mutants, leaving open an unmet need for new agents that can address a broader patient population. A new opportunity is emerging for the development of a therapeutic Pan Ras inhibitor by targeting the upstream guanine nucleotide exchange factor (GEF) protein SOS (Son of sevenless). Disruption of SOS1- K-Ras mutant interaction is a good strategy to inhibit activation of mutant K-Ras. SOS1 inhibition through the protein-protein interaction (PPI) disruption assists in keeping K-Ras in the GDP inactive, rather than its active GTP-bound state. Inhibition of SOS1 results in blockade of the RAS-MEK-ERK pathway and lowering proliferation, in both WT and all mutant Ras forms. Here we discuss our approach to target SOS1 to control aberrant Ras signaling in NSCLC and colon cancers. We report the identification of novel potent SOS1-K-Ras disruptors using the SOS1-K-Ras PPI TR-FRET assay. Multiple series have been identified, with a good SAR trend. We have identified low nanomolar potent compounds that translate to modulation of p-ERK in cell based assays in K-Ras mutant cell lines. These compounds exhibited good ADME properties like solubility and metabolic stability. Further profiling of these compounds is ongoing. Citation Format: Sanjita Sasmal, Anuradha Ramanathan, Venkatesham Boorgu. Identification of novel SOS1-K-Ras disruptors for NSCLC and colon cancers with K-Ras 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 LB117.
DeepProg: an ensemble of deep-learning and machine-learning models for prognosis prediction using multi-omics data
Authors: Olivier B. Poirion, Zheng Jing, Kumardeep Chaudhary, Sijia Huang, Lana X. Garmire
Journal: Genome Medicine (2021)

Abstract Multi-omics data are good resources for prognosis and survival prediction; however, these are difficult to integrate computationally. We introduce DeepProg, a novel ensemble framework of deep-learning and machine-learning approaches that robustly predicts patient survival subtypes using multi-omics data. It identifies two optimal survival subtypes in most cancers and yields significantly better risk-stratification than other multi-omics integration methods. DeepProg is highly predictive, exemplified by two liver cancer (C-index 0.73–0.80) and five breast cancer datasets (C-index 0.68–0.73). Pan-cancer analysis associates common genomic signatures in poor survival subtypes with extracellular matrix modeling, immune deregulation, and mitosis processes. DeepProg is freely available at https://github.com/lanagarmire/DeepProg
Monoprophylaxis with cephalosporins for transrectal prostate biopsy after the fluoroquinolone-era: A multi-institutional comparison of infectious complications
Authors: M. Wenzel, J. Von Hardenberg, M.N. Welte, B. Hoeh, C. Wittler, T. Höfner, M.C. Kriegmair, M.S. Michel, F.K.H. Chun, J. Herrmann, P. Mandel, N. Westhoff
Journal: European Urology (2021)
The selective PARP inhibitor, CEP-8983 exhibits significant chemosensitization in combination with TMZ and SN38 against chemoresistant tumor cell lines and xenografts
Authors: Sheila J. Miknyoczki, Sonya Pritchard, Natalie McGann, Jennifer Grobelny, Candace Burns, James Diebold, Allison Zulli, Mark Ator, Jean Husten, Robert Hudkins, Ralph Parchment, Bruce Ruggeri
Journal: Cancer Research (2005)

5109  Poly (ADP-ribose) polymerase 1 (PARP-1) a nuclear zinc finger DNA binding protein, is activated by and implicated in DNA repair. Inhibition of PARP by small molecules and through knockouts causes cells to become hypersensitive to various chemotherapeutic agents. The ability of CEP-8983, a potent and selective PARP-1 and 2 inhibitor (enzyme IC50 19 nM and 6 nM, respectively; cell assay for attenuation of H2O2-induced NAD+ depletion IC50 300 nM), to enhance the anti-tumor efficacy of temozolomide (TMZ), SN38 and/or camptothecin (CPT) against chemo-resistant tumor cell lines was evaluated in vitro. We also evaluated the ability of CEP-8983 delivered as a prodrug to potentiate the anti-tumor efficacy of TMZ against TMZ-resistant RG2 rat glioblastoma xenografts in nude mice. Co-incubation of CEP-8983 with TMZ or SN38 significantly potentiated tumor cell growth inhibition as compared to treatment with TMZ or SN38 alone in NB1691 human neuroblastoma or HT29 human colon carcinoma cells, respectively. CEP-8983 (1 μM) potentiated the fraction of and/or duration of time RH18 rhabdomyosarcoma or HT29 cells accumulated in TMZ and SN38-induced G2/M arrest, respectively. In addition, CEP-8983 (1 μM) potentiated CPT-induced DNA damage in HT29 cells over 72 hours. CEP-8983 was evaluated in a validated in vitro CFU-GM colony formation assay to determine if it potentiated the myelotoxicity associated with TMZ or TPT treatment2. Co-incubation of human peripheral blood mononuclear cells with CEP-8983 (1 or 3 μM) and TMZ or TPT did not result in potentiation of chemotherapy-associated toxicity, nor did CEP-8983 have intrinsic hematotoxic effects. Administration of a prodrug of CEP-8983 (100 mg/kg/dose s.c., QD x 5 days) one hour after administration of TMZ (68 mg/kg/dose p.o., QD x 5 days) inhibited significantly the growth of RG2 tumors compared to TMZ monotherapy with a maximum inhibition of tumor growth of 60% relative to TMZ monotherapy. Plasma analysis revealed sustained levels of CEP-8983 (40 μM) substantially above the cell-based IC50 throughout the dosing period. The combination of TMZ and CEP-8983 prodrug was well tolerated with only transient and reversible body weight loss observed. An ELISA using PAR-specific antibodies demonstrated CEP-8983 prodrug dose dependently attenuated in vivo TMZ-induced PAR accumulation in glioma xenografts. These combined data indicate that the selective PARP inhibitor, CEP-8983 prodrug, attenuates in vivo TMZ-induced PARP activity and results in sustained and significant chemosensitization of TMZ and SN38 in chemotherapy-resistant human and rodent tumor cell lines and xenografts. 2 Parchment R, et al. Annals of Oncology 9:357-364, 1998.
Abstract 2277: <i>HER2</i> copy number variation detected by next-generation sequencing reveals HER2 expression heterogeneity in gastric cancer
Authors: Xiaotian Zhang, Hui Chen, Xiaochen Zhao, Jie Wang, Yuezong Bai
Journal: Cancer Research (2021)

Abstract Purpose: Human epidermal growth factor receptor 2 (HER2) is an effective therapeutic target in gastric cancer (GC). Both HER2-positive and HER2-low GC could benefit from HER2 inhibitors including trastuzumab and trastuzumab deruxtecan. However, it is difficult to accurately evaluate HER2 status by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), owing to intra-tumor heterogeneity and the experience of the pathologist. Herein, we investigated whether HER2 copy number variation (CNV) detected by next-generation sequencing (NGS) could assist in accurately determining the HER2 status. Methods: We analyzed HER2 CNV on tumor specimens from 212 GC patients using NGS in a CLIA-certified laboratory. The log ratio of HER2 &amp;gt;0.7 was defined as amplification and log ratio of 0.4 to 0.7 was defined as low amplification. HER2 expression was examined in all 212 GC patients by IHC and HER2 amplification was assessed in 22 patients by FISH. Results: Of 212 patients, three had HER2 amplification and three had low HER2 amplification. Among three patients with HER2 amplification, all were found to have strong positive HER2 expression (IHC 3+). Among three patients with HER2 low amplification, two patients had HER2 IHC 2+ (including one HER2 FISH-negative and one HER2 FISH-unknown) and one patient had HER2 IHC 1+. Moreover, two patients were found HER2 IHC 3+ in whom without HER2 amplification. Of the two, one was most HER2 IHC 2+ with focal tumor IHC 3+, and the HER2 CNV was close to the threshold (log ratio of HER2: 0.2882). The reason for the discordance may be related to intra-tumor heterogeneity. HER2 copy number will be diluted in samples with focal 3+ and NGS reflects the relative global nature of the tumor specimens. No HER2 IHC-negative cases (N=99) showed HER2 CNV, suggesting that HER2 CNV detected by NGS has specificity of 100%. Conclusions: HER2 CNV detected by NGS could predicts HER2 status in GC and more accurately stratified GC patients with either HER2-positive or HER2-low. Thus, we can screen out those who can truly benefit from trastuzumab and trastuzumab deruxtecan (eg. DS-8201). Prospective cohorts are needed to validate HER2 CNV detected by NGS for predicting response to anti-HER2 therapy. Citation Format: Xiaotian Zhang, Hui Chen, Xiaochen Zhao, Jie Wang, Yuezong Bai. HER2 copy number variation detected by next-generation sequencing reveals HER2 expression heterogeneity in gastric 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 2277.
Development and Validation of Image-Based Deep Learning Models to Predict Surgical Complexity and Complications in Abdominal Wall Reconstruction
Authors: Sharbel Adib Elhage, Eva Barbara Deerenberg, Sullivan Armando Ayuso, Keith Joseph Murphy, Jenny Meng Shao, Kent Williams Kercher, Neil James Smart, John Patrick Fischer, Vedra Abdomerovic Augenstein, Paul Dominick Colavita, B. Todd Heniford
Journal: JAMA Surgery (2021)

Image-based deep learning models (DLMs) have been used in other disciplines, but this method has yet to be used to predict surgical outcomes.To apply image-based deep learning to predict complexity, defined as need for component separation, and pulmonary and wound complications after abdominal wall reconstruction (AWR).This quality improvement study was performed at an 874-bed hospital and tertiary hernia referral center from September 2019 to January 2020. A prospective database was queried for patients with ventral hernias who underwent open AWR by experienced surgeons and had preoperative computed tomography images containing the entire hernia defect. An 8-layer convolutional neural network was generated to analyze image characteristics. Images were batched into training (approximately 80%) or test sets (approximately 20%) to analyze model output. Test sets were blinded from the convolutional neural network until training was completed. For the surgical complexity model, a separate validation set of computed tomography images was evaluated by a blinded panel of 6 expert AWR surgeons and the surgical complexity DLM. Analysis started February 2020.Image-based DLM.The primary outcome was model performance as measured by area under the curve in the receiver operating curve (ROC) calculated for each model; accuracy with accompanying sensitivity and specificity were also calculated. Measures were DLM prediction of surgical complexity using need for component separation techniques as a surrogate and prediction of postoperative surgical site infection and pulmonary failure. The DLM for predicting surgical complexity was compared against the prediction of 6 expert AWR surgeons.A total of 369 patients and 9303 computed tomography images were used. The mean (SD) age of patients was 57.9 (12.6) years, 232 (62.9%) were female, and 323 (87.5%) were White. The surgical complexity DLM performed well (ROC = 0.744; P < .001) and, when compared with surgeon prediction on the validation set, performed better with an accuracy of 81.3% compared with 65.0% (P < .001). Surgical site infection was predicted successfully with an ROC of 0.898 (P < .001). However, the DLM for predicting pulmonary failure was less effective with an ROC of 0.545 (P = .03).Image-based DLM using routine, preoperative computed tomography images was successful in predicting surgical complexity and more accurate than expert surgeon judgment. An additional DLM accurately predicted the development of surgical site infection.
Safety and side effects after perineal prostate biopsy without antibiotic prophylaxis: Results of a multicenter trial with 30 days follow-up
Authors: A. Sigle, T. Kohl, T. Kuru, J. Salem, H. Rolfs, T. Kowalke, R. Suarez-Ibarrola, N. Binder, C.A. Jilg, M.T. Grabbert, D. Porres, C. Gratzke
Journal: European Urology (2021)
Abstract 1231: Identification of selective Brd4 degrader for cancer treatment
Authors: Biao Hu, Jiantao Hu, fuming Xu, Liyue Huang, Mi Wang, Shaomeng Wang
Journal: Cancer Research (2021)

Abstract Human BET family proteins consist of four members, termed Brd2, Brd3, Brd4 and testis-specific BrdT. They all contain two highly conserved tandem N-terminal bromodomains (BD1 and BD2) and a C-terminal extra-terminal (ET) domain. One of the major functions of the BET proteins is to recognize the acetylated lysine residues on histone proteins and transcriptional factors, thereby regulating the gene expression. Recent studies have implicated the BET proteins as a valid pharmaceutical target for treating cancers. Disrupting the interactions by pan-BET inhibitors have displayed beneficial prognosis in both the preclinical animal models and the clinic trials. Nevertheless, dose limiting adverse effects including mild to moderate gastrointestinal toxicity and fatigue, as well as reversible grade 3 thrombocytopenia, have been observed for some pan-BET inhibitors clinically. While the three BET proteins BRD2, BRD3 and BRD4 exhibit redundant and dynamic patterns in regulating gene transcription, the individual protein may have distinct functions. Thus developing of isoform-selective regulatory reagents is of interest to elucidate the biological function of the BET proteins and their applications in pharmaceutical development. Here, we describe our efforts for the development of selective Brd4 degraders with proteolysis-targeting chimera approaches. Our medicinal chemistry campaign led to the discovery of a series of highly potent Brd4 selective degraders. Treat the tumor cells with these selective Brd4 degraders resulted in rapid, sustained and selective degradation of Brd4. RNA-seq and real time RT-PCR analysis indicates the selective Brd4 degrader exhibits distinct regulation of gene expression in tumor cells comparing to pan-BET degraders and inhibitors. Further tests with flow cytometry analysis and WST-8 assays indicates that selective Brd4 degraders strongly suppress the tumor cells growth and induces the cell death through induction of apoptosis. Strong tumor suppression was also observed with treatment of selective Brd4 degrader in mouse xenograft models. These results suggest that the selective Brd4 degraders are strong candidates for potential tumor treatment. Citation Format: Biao Hu, Jiantao Hu, fuming Xu, Liyue Huang, Mi Wang, Shaomeng Wang. Identification of selective Brd4 degrader for cancer treatment [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 1231.
Bone Tissue Engineering: A Biphasic Osteovascular Biomimetic Scaffold for Rapid and Self‐Sustained Endochondral Ossification (Adv. Healthcare Mater. 13/2021)
Authors: Hwan D. Kim, Xuechong Hong, Young‐Hyeon An, Mihn Jeong Park, Do‐Gyoon Kim, Arin K. Greene, Bonnie L. Padwa, Nathaniel S. Hwang, Ruei‐Zeng Lin, Juan M. Melero‐Martin
Journal: Advanced Healthcare Materials (2021)

In article number 2100070, Juan M. Melero-Martin, Ruei-Zeng Lin, and co-workers present a biphasic scaffold that allows self-sustained endochondral ossification. Following seeding with human vascular and mesenchymal stem cells, this biomimetic material enables the rapid generation of osteovascular niches and ossification centers, leading to the formation of vascularized bone tissue in vivo.
Abstract 1204: SO-N102, a novel CLDN18.2-targeting antibody-drug conjugate with strong anti-tumor effect in various solid tumors expressing low target levels
Authors: Lenka Kyrych Sadilkova, Iva Valentova, Simona Hoskova, Pavel Vopalensky, Lukas Bammert, Roger Beerli, Ulrich Moebius, Radek Spisek
Journal: Cancer Research (2021)

Abstract Claudin (CLDN) 18.2, a member of a large family of transmembrane proteins with distinct functions, has been shown to have a high prevalence, predominantly in gastric and pancreatic cancer. In addition, ectopic expression of CLDN18.2 was described for other cancer types including ovarian, lung, liver and colon, whereas healthy tissue expression is restricted to the stomach. SO-N102 represents a CLDN18.2 targeting antibody-drug conjugate based on a novel proprietary highly specific monoclonal antibody conjugated to a derivative of PNU-159682 using SMACTM technology for the therapy of patients with various CLDN18.2-positive solid tumors, mainly of gastric and pancreatic origin. The CLDN18.2 protein sequence is highly conserved in mammalians with 100% identity in the targeted extracellular loop among rodents, cynomolgus monkey and human. SO-N102 showed excellent specificity for CLDN18.2, strong binding to the target followed by efficient tumor cell killing. Preferential binding to selected patient-derived tumor tissues was observed ex vivo when compared to healthy stomach tissues from mice and cynomolgus monkey. Single-agent therapeutic activity of SO-N102 was demonstrated in 10 patient-derived mouse xenografts models (gastric, pancreatic, liver, colon and lung adenocarcinomas). Complete responses were observed in all models, independent of CLDN18.2 expression levels, ranging from low (IHC1+) to high (IHC3+), with minimum efficacious doses between 0.2 mg/kg and 0.6 mg/kg. An acceptable tolerability profile was observed in preliminary toxicity studies at 10 mg/kg (mouse), 6 mg/kg (rat) and 1 mg/kg (cynomolgus monkey). SO-N102 demonstrated favorable pharmacokinetic properties with half-lives in the range of 8 days and 13 days in cynomolgus monkey and rat, respectively. Stability of SO-N102 without any significant loss of the payload was demonstrated in vitro and in animals. Further toxicology studies in rats and cynomolgus monkeys were initiated, paralleled by process development and manufacturing activities with the plan to initiate the first clinical study with SO-N102 in patients in the first half of 2022. Citation Format: Lenka Kyrych Sadilkova, Iva Valentova, Simona Hoskova, Pavel Vopalensky, Lukas Bammert, Roger Beerli, Ulrich Moebius, Radek Spisek. SO-N102, a novel CLDN18.2-targeting antibody-drug conjugate with strong anti-tumor effect in various solid tumors expressing low target levels [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 1204.
Potential for inhibition of checkpoint kinases 1/2 in pulmonary fibrosis and secondary pulmonary hypertension
Authors: Wen-Hui Wu, Sébastien Bonnet, Tsukasa Shimauchi, Victoria Toro, Yann Grobs, Charlotte Romanet, Alice Bourgeois, Geraldine Vitry, Junichi Omura, Eve Tremblay, Valerie Nadeau, Mark Orcholski, Sandra Breuils-Bonnet, Sandra Martineau, Pasquale Ferraro, Francois Potus, Roxane Paulin, Steeve Provencher, Olivier Boucherat
Journal: Thorax (2021)

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterised by exuberant tissue remodelling and associated with high unmet medical needs. Outcomes are even worse when IPF results in secondary pulmonary hypertension (PH). Importantly, exaggerated resistance to cell death, excessive proliferation and enhanced synthetic capacity are key endophenotypes of both fibroblasts and pulmonary artery smooth muscle cells, suggesting shared molecular pathways. Under persistent injury, sustained activation of the DNA damage response (DDR) is integral to the preservation of cells survival and their capacity to proliferate. Checkpoint kinases 1 and 2 (CHK1/2) are key components of the DDR. The objective of this study was to assess the role of CHK1/2 in the development and progression of IPF and IPF+PH.Increased expression of DNA damage markers and CHK1/2 were observed in lungs, remodelled pulmonary arteries and isolated fibroblasts from IPF patients and animal models. Blockade of CHK1/2 expression or activity-induced DNA damage overload and reverted the apoptosis-resistant and fibroproliferative phenotype of disease cells. Moreover, inhibition of CHK1/2 was sufficient to interfere with transforming growth factor beta 1-mediated fibroblast activation. Importantly, pharmacological inhibition of CHK1/2 using LY2606368 attenuated fibrosis and pulmonary vascular remodelling leading to improvement in respiratory mechanics and haemodynamic parameters in two animal models mimicking IPF and IPF+PH.This study identifies CHK1/2 as key regulators of lung fibrosis and provides a proof of principle for CHK1/2 inhibition as a potential novel therapeutic option for IPF and IPF+PH.