tbuckley/cabot-search huggingface dataset:
Abstract 416: Toripalimab plus paclitaxel and carboplatin as neoadjuvant therapy in patients with locally advanced resectable esophageal squamous carcinoma: An open-label, single arm phase 2 trial
Authors: Wenwu He, Lin Peng, Yu Bao, Wenguang Xiao, Qiang Fang, Xuefeng Leng, Jiaxin Yan, Tianqin Mao, Xudong Shen, Depei Huang, Hushan Zhang, Xueke She, Yongtao Han
Journal: Cancer Research (2021)

Abstract Background: Immune checkpoint inhibitors (ICIs) have shown promising results in patients with advanced esophageal squamous carcinoma (ESCC), while their efficacy for locally advanced patients is unclear. We conducted a neoadjuvant immunotherapy trial, investigating the safety and feasibility of toripalimab, a PD-1 inhibitor, combined with paclitaxel and carboplatin in patients with resectable ESCC (ClinicalTrials.gov identifier: NCT04177797). Methods: Between May 2020 and June 2020, 18 patients with histopathologically diagnosed ESCC, clinically staged as T3N1-3M0, ECOG PS 0, received toripalimab 240 mg IV, D1, Q3W and paclitaxel 135 mg/m2, IV, D1, Q3W and carboplatin AUC 5 mg/mL per min, IV, D1, Q3W for two cycles, followed by McKeown esophagectomy 4-6 weeks later. The primary endpoint were safety and major pathological response (MPR) rate, and the secondary point were pathological complete response (pCR) rate, DFS and OS. Results: Sixteen patients received surgery with no treatment-related surgical delay, and the R0 resection rate was 87.5% (14/16). Two patients refused surgery due to the clinical assessment as complete response. Among 16 patients undergoing surgery, 3 (16.6%) were pCR and 7 (43.8%) were MPR. Treatment-related adverse events occurred in all patients (100%), and 4 patients (22.2%) experienced grade 3 or higher treatment-related adverse events including neutropenia (2, 12.5%), leukopenia (1, 6.2%), diarrhea (1, 6.2%), fatigue (1, 6.2%). No surgery-related adverse events or treatment-related death occurred. Conclusions: The combination of toripalimab, paclitaxel and carboplatin for patients with locally advanced resectable ESCC is well tolerated and shows antitumor activity, which might be a potential neoadjuvant therapy regimen. Citation Format: Wenwu He, Lin Peng, Yu Bao, Wenguang Xiao, Qiang Fang, Xuefeng Leng, Jiaxin Yan, Tianqin Mao, Xudong Shen, Depei Huang, Hushan Zhang, Xueke She, Yongtao Han. Toripalimab plus paclitaxel and carboplatin as neoadjuvant therapy in patients with locally advanced resectable esophageal squamous carcinoma: An open-label, single arm phase 2 trial [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 416.
Safety, pharmacokinetics, and antiviral activity of RO7049389, a core protein allosteric modulator, in patients with chronic hepatitis B virus infection: a multicentre, randomised, placebo-controlled, phase 1 trial
Authors: Man-Fung Yuen, Xue Zhou, Edward Gane, Christian Schwabe, Tawesak Tanwandee, Sheng Feng, Yuyan Jin, Miriam Triyatni, Annabelle Lemenuel-Diot, Valerie Cosson, Zenghui Xue, Remi Kazma, Qingyan Bo
Journal: The Lancet. Gastroenterology & hepatology (2021)
Abstract 386: Evaluation of CPa9-HNE - a peripheral biomarker based on neutrophil extracellular traps (NETs) - for predicting outcome in patients with metastatic melanoma treated with anti-PD-1 therapy
Authors: Christina Jensen, Anders Kverneland, Marco Donia, Joachim H. Mortensen, Morten A. Karsdal, Inge Marie Svane, Nicholas Willumsen
Journal: Cancer Research (2021)

Abstract Background: Peripheral biomarkers associated with response and resistance to anti-PD-1 therapy in metastatic melanoma patients represent an unmet medical need. High neutrophil activity is associated with immune checkpoint inhibitor failure, amongst others due to release of neutrophil extracellular traps (NETs) that have been shown to protect tumor cells against cytotoxic attacks. Human neutrophil elastase (HNE) and calprotectin are the major NETs constituents. We hypothesized that HNE mediated degradation of calprotectin (CPa9-HNE), when measured in serum, has peripheral biomarker potential in metastatic melanoma patients treated with anti-PD-1 therapy. Methods: A monoclonal antibody was raised against a specific HNE mediated degradation fragment of calprotectin (CPa9-HNE) and used to develop an ELISA for quantifying CPa9-HNE in serum. CPa9-HNE was then measured in pre-treatment serum from metastatic melanoma patients treated with anti-PD-1 therapy (pembrolizumab) (n=35). The biomarker levels were associated with progression-free survival (PFS) and overall survival (OS) by univariate and multivariate Cox regression analyses adjusting for PDL1 expression (≥1%), lactate dehydrogenase (LDH), BRAF mutational status, and c-reactive protein (CRP). Results: High pre-treatment CPa9-HNE levels predicted worse PFS (HR=3.32, 95%CI=1.25-8.82, p=0.016) and OS (HR=11.31, 95%CI=2.27-56.33, p=0.003) when compared to low CPa9-HNE levels by univariate Cox regression. By multivariate Cox regression, high CPa9-HNE was found to be independently predictive of poor PFS (HR=8.22, 95%CI=1.30-52.14, p=0.025) and OS (HR=76.87, 95%CI=4.73-1248.57, p=0.002) when adjusted for PDL1 expression, LDH, BRAF mutations, and CRP. Conclusions: A non-invasive biomarker of HNE mediated degradation of calprotectin (CPa9-HNE) was associated with poor PFS and OS in metastatic melanoma patients treated with anti-PD-1 therapy. These findings support a link between neutrophil activity/NETs and response to anti-PD-1 and indicate promising non-invasive biomarker potential to stratify melanoma patients for anti-PD-1 therapy in future clinical studies. Citation Format: Christina Jensen, Anders Kverneland, Marco Donia, Joachim H. Mortensen, Morten A. Karsdal, Inge Marie Svane, Nicholas Willumsen. Evaluation of CPa9-HNE - a peripheral biomarker based on neutrophil extracellular traps (NETs) - for predicting outcome in patients with metastatic melanoma treated with anti-PD-1 therapy [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 386.
Reassessment of Glycemic Goals in Older Patients With Dementia—More Work Is Needed to Do Less
Authors: Jennifer D. Claytor, Richard W. Grant
Journal: JAMA Internal Medicine (2021)

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Abstract 173: Efficient representations of tumor diversity with paired DNA-RNA aberrations
Authors: Qian Ke, Wikum Dinalankara, Laurent Younes, Donald Geman, Luigi Marchionni
Journal: Cancer Research (2021)

Abstract In this work we develop a framework which allows for a systematic analysis of joint DNA and putative downstream RNA effects in cancer data cohorts. Using the Reactome database, we extract gene pairs that are linked by known mechanistic connections. Such pairs, which we refer to as 'Source Target Pairs' or STPs, consist of a source gene for which we examine aberrant activity in the DNA profile, and a target gene that is affected by said source gene, for which we examine aberrant activity in the RNA profile. Using TCGA data for six different cancer types (breast, colon, kidney, liver, lung and prostate), we use mutation and copy number variation information to compile DNA aberrant activity data. For the same cancer cohorts, we use RNASeq gene expression data to quantify RNA aberrant activity via the previous 'divergence' method we have developed. In the divergence framework, normal samples from the same cancer are used to estimate a normal range of expression for target genes of interest and deviation from the normal range is assumed to indicate aberrant activity which may result from upstream DNA aberrations. Then for a given sample, an STP can be represented as a binary variable, indicating presence or absence of joint DNA-RNA aberrant activity. We utilize integer programming to discover a small set of such STPs for each cancer type such that every sample displays aberrant activity in at least one STP. We refer to these reduced STP configurations as 'minimal coverings' of that cancer. These configurations then allow for the quantification of heterogeneity for that cancer type, as well as for phenotypical groups of interest. This is made possible due to the fact that sample to sample variability can be compared via the entropy of the distribution of the minimal covering, where the small number of STPs in such a configuration makes the computation more tractable. Our results reveal many known putative drivers of cancer, as well as identify some novel genes of interest for further consideration. Comparison of heterogeneity across phenotypes of interest show higher entropy in more pathological phenotypes, indicating increasing heterogeneity with severity of disease. Citation Format: Qian Ke, Wikum Dinalankara, Laurent Younes, Donald Geman, Luigi Marchionni. Efficient representations of tumor diversity with paired DNA-RNA aberrations [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 173.
Abstract 2790: Temporal immune changes of murine breast and melanoma tumor microenvironments following pulsed focused ultrasound
Authors: Gadi Cohen, Parwathy Chandran, Rebecca M. Lorsung, Lauren E. Tomlinson, Robert B. Rosenblatt, Scott R. Burks, Joseph A. Frank
Journal: Cancer Research (2021)

Abstract Various cellular and biological immunotherapies have revolutionized the treatment of human malignancies by augmenting endogenous immune responses within the tumor microenvironment (TME). Although non-ablative pulsed-FUS (pFUS) has received less attention, it has been successfully used as a noninvasive treatment of solid malignancies by stimulating a pro-inflammatory immune response within the TME. Such an approach could be useful to treat peripheral micro-metastases in normal-appearing tissues. In the present study, we interrogated the immune-modulatory changes that occur within the TME following pFUS exposure. Murine B16 melanoma and 4T1 mammary carcinoma cells were subcutaneously implanted into both mice flanks (n=10 tumors/group/time point). The natural histories cytokine, chemokine, trophic factor (CCTF), and cell adhesion molecule (CAM) expression was evaluated within the TME of untreated flank tumors over 11 days. Ultrasound-guided pFUS at 1 MHz and peak negative pressures of 6 MPa was administered to tumors after reaching ~5 mm in diameter. Temporal immune-related changes in tumors were assessed following sonication using using proteomic, transcriptomic and histological analyses. Natural history growth characteristics showed a progressive increase in size for both tumors, and proteomic analysis revealed a shift toward an immunosuppressive TME. An anti-tumor TME was detected following pFUS treatment with increased expression of various pro-inflammatory CCTF and CAM as well as reduced tumor growth rates. Transcriptomic analyses following sonication identified inverted gene expression patterns in the two tumor types. Functional analysis of B16 tumors revealed increased intracellular signaling pathways associated with immune response regulations, while 4T1 tumors demonstrated reduced expression of proliferation genes. This study provides a macroscopic overview on the temporal dynamics of the TME and underline the profound magnitude of tumoral heterogeneity between tumor types as well as through progressive stages of similar primary tumors. Nevertheless, the induced immune-modulation changes suggest that pFUS may alter the expression of pro-inflammatory CCTF, CAM, towards an anti-tumoral TME, and supports the potential use of pFUS as a neoadjuvant treatment approach. Citation Format: Gadi Cohen, Parwathy Chandran, Rebecca M. Lorsung, Lauren E. Tomlinson, Robert B. Rosenblatt, Scott R. Burks, Joseph A. Frank. Temporal immune changes of murine breast and melanoma tumor microenvironments following pulsed focused ultrasound [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 2790.
Perineuronal net degradation rescues CA2 plasticity in a mouse model of Rett syndrome
Authors: Kelly E. Carstens, Daniel J. Lustberg, Emma K. Shaughnessy, Katharine E. McCann, Georgia M. Alexander, Serena M. Dudek
Journal: Journal of Clinical Investigation (2021)

Perineuronal nets (PNNs), a specialized form of extracellular matrix, are abnormal in the brains of people with Rett syndrome (RTT). We previously reported that PNNs function to restrict synaptic plasticity in hippocampal area CA2, which is unusually resistant to long-term potentiation (LTP) and has been linked to social learning in mice. Here we report that PNNs appear elevated in area CA2 of the hippocampus of an individual with RTT and that PNNs develop precociously and remain elevated in area CA2 of a mouse model of RTT (Mecp2-null). Further, we provide evidence that LTP could be induced at CA2 synapses prior to PNN maturation (postnatal day 8-11) in wild-type mice and that this window of plasticity was prematurely restricted at CA2 synapses in Mecp2-null mice. Degrading PNNs in Mecp2-null hippocampus was sufficient to rescue the premature disruption of CA2 plasticity. We identified several molecular targets that were altered in the developing Mecp2-null hippocampus that may explain aberrant PNNs and CA2 plasticity, and we discovered that CA2 PNNs are negatively regulated by neuronal activity. Collectively, our findings demonstrate that CA2 PNN development is regulated by Mecp2 and identify a window of hippocampal plasticity that is disrupted in a mouse model of RTT.
Assessment of the lower ureteric excision technique associated oncological outcomes for upper urinary tract urothelial carcinoma: Retrospective, updated interim analysis from the Scottish Renal Cancer Network
Authors: J.P. Blackmur, E. Chew, M. Trail, K. Brodie, N. Santoni, F. Rodger, D. Hamilton, F. Gaba, S. Randall, A. Chapman, A. Laird
Journal: European Urology (2021)
Abstract 265: Evaluating variation in drug efficacy endpoints in a syngeneic mouse model (CT26.WT) under immune checkpoint blockade
Authors: Binchen Mao, Sheng Guo, Davy Ouyang, Henry Li
Journal: Cancer Research (2021)

Abstract INTRODUCTION: Preclinical research into immune checkpoint blockade (ICB) requires in vivo models with fully functional immunity. Syngeneic mouse models are homografts derived by transplanting immortalized mouse cancer cell lines or tumor tissues into strain-matched mouse hosts, and are well suited for evaluating the efficacy of new immunotherapies due to retaining an intact mouse immune system. Tumor growth inhibition (TGI) is widely used to characterize drug efficacy, however, a considerable amount of heterogeneity among TGI is often observed for a given ICB treatment in the same syngeneic mouse model. It is of vital importance to understand the source of such variation. The present study sets out to systematically investigate the variation of TGI for ICB treatment in syngeneic mouse models, using tumor growth data of anti-PD-1 treatment in the CT26.WT syngeneic mouse model for 27 independent studies. METHODS: For each study, we calculated TGI and median area under curve (AUC) ratio on the corresponding study day when tumor volume data was collected. We utilized standard deviation and inter quantile range to quantify the variation. We evaluated the relationship between TGI and the corresponding day, and also compared the variation between TGI and median AUC ratio. Furthermore, to better understand the source of drug efficacy variation, we utilized a Bayesian multilevel model to quantify the amount of tumor growth variation at both the study and mouse level. RESULTS: We found that TGI variation was much higher at earlier stages of studies. In contrast, the median AUC ratio showed smaller variation across the duration of each study than TGI for the majority of studies. Additionally, we found neither TGI nor median AUC ratio had significant correlation with the number of mice used in the study. Based on a Bayesian multilevel model, we observed that drug efficacy had larger variation on the mouse level (i.e. within a study), than variation on the study level (i.e. observed between studies), which could indicate heterogeneity of the tumor microenvironment (e.g. TILs) among mice play a major role in the variation of ICB treatment efficacy among studies. CONCLUSIONS: Response to ICB treatment among mice of the same syngeneic model is inherently heterogeneous. TGI of later time points should be favored to reduce variation, and generally median AUC Ratio is more stable than TGI. Citation Format: Binchen Mao, Sheng Guo, Davy Ouyang, Henry Li. Evaluating variation in drug efficacy endpoints in a syngeneic mouse model (CT26.WT) under immune checkpoint blockade [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 265.
Expression of KLRG1 and CD127 defines distinct CD8<sup>+</sup>subsets that differentially impact patient outcome in follicular lymphoma
Authors: Hongyan Wu, Xinyi Tang, Hyo Jin Kim, Shahrzad Jalali, Joshua C Pritchett, Jose C Villasboas, Anne J Novak, Zhi-Zhang Yang, Stephen M Ansell
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background CD8 + T-lymphocyte subsets defined by killer lectin-like receptor G1 (KLRG1) and CD127 expression have been reported to have an important role in infection, but their role in the setting of lymphoid malignancies, specifically follicular lymphoma (FL), has not been studied. Methods To characterize the phenotype of KLRG1/CD127-defined CD8 + subsets, surface and intracellular markers were measured by flow cytometry and Cytometry by time of flight (CyTOF), and the transcriptional profile of these cells was determined by CITE-Seq (Cellular Indexing of Transcriptomes and Epitopes by Sequencing). The functional capacity of each subset was determined, as was their impact on overall survival (OS) and event-free survival (EFS) of patients with FL. Results We found that intratumoral CD8 + cells in FL are skewed toward effector cell subsets, particularly KLRG + CD127 - and KLRG1 - CD127 - cells over memory cell subsets, such as KLRG1 - CD127 + and KLRG1 + CD127 + cells. While effector subsets exhibited increased capacity to produce cytokines/granules when compared with memory subsets, their proliferative capacity and viability were found to be substantially inferior. Clinically, a skewed distribution of intratumoral CD8 + T cells favoring effector subtypes was associated with an inferior outcome in patients with FL. Increased numbers of CD127 + KLRG1 - and CD127 + KLRG1 + were significantly associated with a favorable OS and EFS, while CD127 - KLRG1 - correlated with a poor EFS and OS in patients with FL. Furthermore, we demonstrated that interleukin (IL)-15 promotes CD127 - KLRG1 + cell development in the presence of dendritic cells via a phosphoinositide 3-kinase (PI3K)-dependent mechanism, and treatment of CD8 + T cells with a PI3K inhibitor downregulated the transcription factors responsible for CD127 - KLRG1 + differentiation. Conclusions Taken together, these results reveal not only a biological and prognostic role for KLRG1/CD127-defined CD8 + subsets in FL but also a potential role for PI3K inhibitors to manipulate the differentiation of CD8 + T cells, thereby promoting a more effective antitumor immune response.
Abstract 1988: Association between CEACAMs and hypoxia defines gastric cancer progression
Authors: Indrajit Poirah, Debashish Chakraborty, Pragyesh Dixit, Supriya Samal, Pratyush Kumar Padhan, Alok Barik, Shivaram Prasad Singh, Bernhard B. Singer, Asima Bhattacharyya
Journal: Cancer Research (2021)

Abstract Background: Gastric cancer is one of the most prevalent cancers. As in many other solid tumors, hypoxia is a notable feature in gastric cancer as well. The hypoxic microenvironment promotes cancer by modulating expression of several master regulator oncoproteins. Carcinoembryonic antigen-related cell adhesion molecules or (CEACAMs) are adhesion proteins that have been associated with many epithelial tumors but their expression pattern in hypoxic gastric epithelial cells are not known. Since these membrane proteins have widespread roles in the intracellular and intercellular signaling, inflammation, angiogenesis and metastasis, we examined hypoxia-mediated regulation of CEACAM proteins. Methods: AGS, MKN45 and primary gastric epithelial cells were subjected to hypoxia of varying degrees and the changes in the CEACAM protein profile were evaluated by immunoblotting, FACS assay and immunofluorescence microscopy. In vitro DNA-binding assay and luciferase assays were performed to assess the transcriptional regulation of CEACAMs. Overexpression and suppression studies were also performed to elucidate upstream regulations of CEACAM proteins. Gastric cancer biopsy tissues were examined from consenting patients by performing fluorescence and confocal microscopy. Results: We found that varying degrees of hypoxia differentially modulate CEACAM expression in gastric cancer epithelial cells which in turn leads to altered proliferation and invasiveness of cancer cells. Interestingly, gastric adenocarcinoma and metastatic gastric cancer biopsies show distinct CEACAM signatures. These findings unfold further avenues highlighting the importance of CEACAM proteins as biomarkers of gastric cancer and as therapeutic targets to treat gastric cancer. Funding: Department of Atomic Energy (DAE). Citation Format: Indrajit Poirah, Debashish Chakraborty, Pragyesh Dixit, Supriya Samal, Pratyush Kumar Padhan, Alok Barik, Shivaram Prasad Singh, Bernhard B. Singer, Asima Bhattacharyya. Association between CEACAMs and hypoxia defines gastric cancer progression [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 1988.
Four-year experience with robotic kidney transplantation from deceased donors: Overcoming logistical and technical challenges to broaden the indications of robotic kidney transplantation
Authors: R. Campi, G. Vignolini, A. Pecoraro, S. Morselli, R. Nicoletti, A. Rivetti, A. Berni, D. Paganelli, F. Sessa, I. Greco, F. Corti, N. Mormile, P. Barzaghi, J. Gianassi, R. Cutruzzullà, P. Spatafora, A. Sebastianelli, S. Giancane, V. Li Marzi, M. Gacci, C. Cirami, S. Serni
Journal: European Urology (2021)