tbuckley/cabot-search huggingface dataset:
Ocular adverse events in PD-1 and PD-L1 inhibitors
Authors: LeAnne Young, Shanda Finnigan, Howard Streicher, Helen X Chen, James Murray, H Nida Sen, Elad Sharon
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors can cause unique immune-related adverse effects due to non-specific immunological activation. However, less is known about adverse effects of these drugs in the eye. Methods Two adverse event databases were retrospectively reviewed. The two databases consisted of a routine adverse event database and a serious adverse event database of expeditiously submitted reports. Patients with any malignancy who had ocular adverse events while on PD-1/PD-L1 inhibitor treatment were included. Patients received nivolumab, pembrolizumab, atezolizumab or durvalumab alone or in combination with other anticancer agents per each trial’s protocol. Databases were queried up to May 19, 2020. Results In the routine adverse event database, 272 adverse events from 213 patients were reported and in the serious adverse event reporting database, 59 ocular adverse events from 47 patients were reported. A lower estimate of the prevalance from the routine adverse event database showed 259/7727 patients on study treatment arms reporting ocular adverse events (3.3% prevalence). Excluding trials that do not report lower grade adverse events to the routine adverse event database results in a higher end estimate of 242/3255 patients on study treatment arms reporting ocular adverse events (7.4% prevalence). Ocular events occurred early after drug initiation (routine database: median 6 weeks, IQR 0–16, serious adverse events database: median 11 weeks, IQR 6–21). The median Common Terminology Criteria for Adverse Events grade was grade 1 (mild) (IQR 1–2) and grade 2 (moderate) (IQR 2–3) for the routine database and the serious adverse events database, respectively. In-depth analysis of the serious adverse event reports revealed varying degrees of clinical workup, with 30/47 patients (64%) receiving ophthalmological evaluation and 16/47 (34%) of patients having to delay or discontinue treatment. However, 16/47 (34%) patients experienced resolution and 14/47 (30%) patients experienced at least some improvement. Conclusions This is one of the largest analyses of ocular adverse events in patients treated with PD-1/PD-L1 inhibitors in the USA. We found ocular adverse events are rare complications of PD-1/PD-L1 inhibitor therapy, can be severe enough to cause treatment discontinuation/delay, and may not always be appropriately evaluated by eye specialists. Standardized plans for ophthalmology evaluation and management of ocular toxicities are needed in studies of patients treated with PD-1/PD-L1 inhibitors.
Abstract 1909: Pan-TGF-β inhibition with PD-1 blockade as a combination treatment strategy to augment anti-tumor immune response in hepatocellular carcinoma
Authors: Natalia Malkova, Joachim Theilhaber, Mikhail Levit, Tatiana Tolstykh, Andrew Hebert, Kevin Atchison, Adalis Maisonet, Sara Sara Sinicropi-Yao, Alexei Protopopov, Jack Pollard, Sukhvinder Sidhu, Tun Tun Lin, Lily Pao, Dmitri Wiederschain, Sharad K. Sharma
Journal: Cancer Research (2021)

Abstract Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide, accounting for more than 700,000 deaths per year. Although transforming growth factor beta (TGF-β) can function as a tumor-suppressor in premalignant cells, patient data suggest that it plays a role in the progression of HCC. Recently, immunotherapy targeting PD-1 has been approved for HCC, however, success is limited to only ~17% objective response rate in the treated HCC patients. Analysis of genomic data from two HCC patient cohorts revealed that TGF-β pathway is highly activated in patients with advanced HCC. Collectively, these findings indicate that targeting TGF-β in combination with PD-1 blockade may be a compelling therapeutic strategy. Therefore, using two syngeneic mouse models of HCC (Hepa1-6 and H22), we examined the effect of a pan-TGF-β neutralizing antibody (1D11) in combination with PD-1 blockade. Results from our study show that co-inhibiting TGF-β with PD-1 resulted in significant tumor growth inhibition in both HCC models. Flow cytometry analysis of the tumor revealed the combination treatment group exhibited a reduction in potentially suppressive tumor-associated-macrophages relative to either single agent groups. In addition, we show that combination therapy was associated with increase in the intra-tumoral levels of proinflammatory cytokines - IFNγ, IL-1β, TNF-α as well as enhanced expression of anti-tumor immune related genes. Based on these data, clinical testing of SAR439459 (TGF-β antibody) and Cemiplimab (anti-PD1) combination has recently been initiated in HCC patients (NCT03192345). Citation Format: Natalia Malkova, Joachim Theilhaber, Mikhail Levit, Tatiana Tolstykh, Andrew Hebert, Kevin Atchison, Adalis Maisonet, Sara Sara Sinicropi-Yao, Alexei Protopopov, Jack Pollard, Sukhvinder Sidhu, Tun Tun Lin, Lily Pao, Dmitri Wiederschain, Sharad K. Sharma. Pan-TGF-β inhibition with PD-1 blockade as a combination treatment strategy to augment anti-tumor immune response in hepatocellular carcinoma [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 1909.
Abstract 1966: Cell proliferation-related pathway scores (G2M Checkpoint, E2F Targets, MYC Targets V1 and V2, Mitotic Spindle, p53 pathway) as predictive and prognostic biomarkers in pancreatic cancer
Authors: Masanori Oshi, Lan Le, Yoshihisa Tokumaru, Li Yan, Ryusei Matsuyama, Itaru Endo, Kazuaki Takabe
Journal: Cancer Research (2021)

Abstract Background: Given the poor survival and severe side effects of treatments for pancreatic cancer, we need prognostic and predictive biomarkers to guide management. We hypothesized that the cell proliferation-related pathway is associated with drug response and survival in pancreatic cancer. Methods: We studied six hallmark cell proliferation-related gene sets (G2M Checkpoint, E2F Targets, MYC Targets V1 and V2, Mitotic Spindle, p53 pathway) defined by MSigDB in gene set variant analysis (GSVA) was evaluated in 3 independent cohorts, TCGA-PDAC (n = 176), GSE57495 (n = 63), and GSE62452 (n = 69). Results: We found that although G2M and E2F correlated strongly with each other (spearman's r = 0.976), Mitotic and p53 pathway scores correlated highly with the other cell function gene sets. All pathways were significantly associated with high expression of MKI67 and with proliferation score (all p &amp;gt; 0.001), but none with pathologically complete resection (R0). Mitotic Spindle pathway alone associated with high cytolytic activity (p = 0.020). All pathways were significantly associated with high expression of KRAS and TP53 genes and with high rate of KRAS gene alteration except for MYC v1. The G2M, E2F, and p53 pathway were significantly associated with a high rate of TP53 gene alteration (p = 0.026, 0.011, and 0.07, respectively). Interestingly, different pathway correlated with AUC of different agents, such as Gemcitabine (Mitotic: r=0.706 [p = 0.01]), Paclitaxel (MYC v2: r = -0.636 [p &amp;lt; 0.05]), Apatinib (Mitotic: r = -0.556 [p = 0.03]), Palbociclib (E2F: r =0.675 [p &amp;lt; 0.01]), and Sorafenib (G2M: r = -0.593 [p = 0.03]), for pancreatic cancer. Among all six pathways, only G2M was significantly associated with worse patient survival consistently in all 3 cohorts. Conclusion: Each proliferation-related pathway was predictive of unique agent, and G2M score predicts survival of pancreatic cancer. Citation Format: Masanori Oshi, Lan Le, Yoshihisa Tokumaru, Li Yan, Ryusei Matsuyama, Itaru Endo, Kazuaki Takabe. Cell proliferation-related pathway scores (G2M Checkpoint, E2F Targets, MYC Targets V1 and V2, Mitotic Spindle, p53 pathway) as predictive and prognostic biomarkers in pancreatic 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 1966.
Interalveolar Pores Increase in Aging and Severe Airway Obstruction
Authors: Arno Vanstapel, Birgit Weynand, Janne Kaes, Arne P. Neyrinck, Laurens J. Ceulemans, Bart M. Vanaudenaerde, Robin Vos, Geert M. Verleden, Maximilian Ackermann, Stijn E. Verleden
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

"Interalveolar Pores Increase in Aging and Severe Airway Obstruction." American Journal of Respiratory and Critical Care Medicine, 204(7), pp. 862–865
Abstract 1869: Novel TNFR2 antibodies to overcome T cell exhaustion and suppressive tumor microenvironment
Authors: Chi Shing Sum, Makenzie Danton, Qii hu, Alla Pritsker, Ray Lin, Raymond Yu, Kevin Chen, Fangqiang Tang, Thomas Pohl, Samantha Wallner, Ahmed Hassan, Huarui Lu, Haichun Huang, James Pei, Zhong Liu, Han Li, Ming Lei
Journal: Cancer Research (2021)

Abstract TNFR2 is highly expressed on the surface of activated T effector cells, T regulatory cells and myeloid cells, and it plays essential roles in modulating the tumor microenvironment. In most cancer types, higher TNFR2 expression correlates with increased immune cell infiltration. Furthermore, the TNFR2 gene is differentially expressed in various cancer types, including breast, lung, renal, liver and skin cancers. In cancers such as head and neck cancer and cutaneous melanoma, high TNFR2 expression correlates with better overall survival. The therapeutic potential of antibodies targeting TNFR2 has been demonstrated by agonist antibodies for the T effector cells, and antibodies that antagonize or deplete the T regulatory cells and suppressive myeloid cells. We discovered novel TNFR2 antibodies that demonstrate unique mechanisms to overcome T cell exhaustion and the suppressive tumor microenvironment for more effective immunotherapy. In vitro studies have shown that our antibodies block TNFα ligand binding and potently inhibit TNFR2 signaling in the monocytic cells. Moreover, these antibodies enhance CD8 T cell function to overcome the suppressive effect from the T regulatory cells and can invigorate exhausted CD8 T cells in an FcγR-dependent manner. In a humanized mouse model, our antibodies demonstrate strong anti-tumor efficacy as single agents or in combination with a PD-L1 inhibitor. Therefore, these antibodies offer potential advantages when the tumor microenvironment is enriched in the exhausted T cells, the suppressive myeloid cells, or the regulatory T cells, as found in anti-PD-1/PD-L1 resistant and PD-1 refractory patients. In conclusion, the data obtained indicate that our TNFR2 antibodies are a novel and promising class of drug candidates for cancer immunotherapeutics. Our lead antibody is currently at the IND-enabling stage with the target of entering clinical studies in early 2022. Citation Format: Chi Shing Sum, Makenzie Danton, Qii hu, Alla Pritsker, Ray Lin, Raymond Yu, Kevin Chen, Fangqiang Tang, Thomas Pohl, Samantha Wallner, Ahmed Hassan, Huarui Lu, Haichun Huang, James Pei, Zhong Liu, Han Li, Ming Lei. Novel TNFR2 antibodies to overcome T cell exhaustion and suppressive tumor microenvironment [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 1869.
Abstract 1108: A new mechanism of drug resistance in cancer: Extracellular ATP-induced resistance through ATP internalization and upregulation of ATP-binding cassette multidrug transporters
Authors: Haiyun Zhang, Xuan Wang, Xiaozhuo Chen
Journal: Cancer Research (2021)

Abstract Cancer is the second leading cause of death in the US. Multidrug resistance (MDR) and the resulting ineffectiveness of the drug treatment are responsible for most relapses of cancer and cancer-related death. One major mechanism of MDR is the efflux of multiple drugs mediated by ATP-binding Cassette (ABC) multidrug transporters. ABC transporters pump drugs with different structures and mechanisms of action out of cancer cells using ATP-provided energy. The opportunistic uptake of extracellular molecules has been named as a key emerging hallmark of cancer metabolism1. Intratumoral extracellular ATP levels of various cancer types are 103 to 104 times higher than those in their corresponding normal tissues2. Our previous studies have shown that extracellular ATP is internalized by cancer cell via macropinocytosis, and promotes cancer drug resistance by fueling ABC transporters and increase its efflux activities3. However, whether extracellular ATP can indeed enhance efflux of drugs, and the underlying mechanism besides providing energy remain unclear. Our current study results showed extracellular ATP decreased intracellular accumulation and thereby enhanced efflux of 3H-labeled chemotherapeutic drug and targeted drug in human cancer cells. The results of quantitative reverse transcription PCR, western blot and immunofluorescence microscopy demonstrated that extracellular ATP can also significantly upregulate ABC transporters at mRNA and protein levels, and change the intracellular localization of the latter. These results suggest that extracellular ATP has profound regulatory effects on ABC transporters and thus promotes drug resistance, linking the ATP-rich tumor microenvironment with cancer drug resistance. The completion of the study will expand our understanding of the roles of extracellular ATP in cancer, and reveal new therapeutic targets for reducing drug resistance and enhance anticancer efficacy of chemotherapeutics and targeted drugs. 1. Pavlova N, Thompson C. Cell Metab. (2016) 23:27-47 2. Falzoni S, et al., Interface Focus. (2013) 3: 20120101 3. Wang X, et al., Oncotarget. (2017) 8(50):87860-87877 Citation Format: Haiyun Zhang, Xuan Wang, Xiaozhuo Chen. A new mechanism of drug resistance in cancer: Extracellular ATP-induced resistance through ATP internalization and upregulation of ATP-binding cassette multidrug transporters [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 1108.
Additional Counseling Support for Mothers With Gestational Hypertensive Disorders Regarding Neurodevelopmental Outcomes in Their Children—Reply
Authors: Judith S. Brand, Deborah A. Lawlor, Scott Montgomery
Journal: JAMA Pediatrics (2021)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
ゲムシタビンを含む処方で以前に治療された進行膵癌患者におけるラロタキセルと5-FU(5-FUまたはカペシタビンの連続的血管内投与)を比較する第3相試験
Authors: Van Cutsem E, Macarulla T, Van Laethem J, Couture F, Peeters M, Gehn Hoff M, Roman L, Lequesne L, Charpentier E, Conroy T
Journal: Annals of Oncology (2010)
Abstract LB206: Simultaneous single cell profiling of open chromatin and gene expression in B cell lymphoma highlights tumor-specific regulatory networks
Authors: Shamoni Maheshwari, Li Wang, Vijay Gopalan, Joe Shuga, Sharmila Chatterjee, Kamila Belhocine
Journal: Cancer Research (2021)

Abstract Profiling multiple analytes from a single cell enables additional dimensions to characterize tumor biology. Simultaneous measurement of epigenetic information and gene expression in single cells provides a clearer readout of the links between regulatory elements and target genes, allowing a more mechanistic interpretation of cell clusters and better cell type distinctions based on a cell's history and its future potential. Here, we describe simultaneous measurement of gene expression and chromatin accessibility from thousands of single nuclei using the Chromium Single Cell Multiome ATAC + Gene Expression. We leverage a microfluidic platform to generate paired barcoded gene expression and ATAC-seq libraries, linking transcriptomic and open chromatin information at the single cell level. Using this method, we jointly profiled gene expression and chromatin accessibility from over 10,000 immune cells from healthy human PBMCs and over 14,000 cells from a human B cell lymphoma sample. In healthy immune cells, we leveraged chromatin information to better parse distinct cell states within a gene expression-defined cell type, showing that the addition of ATAC profiling to gene expression improves resolution of cell type specification. In B cell lymphoma, we used known markers of malignancy to segregate tumor B cells from normal B cells. We constructed regulatory networks in both cell states using the observed transcription factor motif enrichment in open chromatin regions combined with gene expression from the same cells. Comparing regulatory networks in healthy vs. tumor B cells highlighted the presence of unique regulatory networks in tumor B cells. Notably, the PAX5 tumor regulator was observed only in tumor B cells, and its impacts on the regulation of many downstream genes was characterized. Building this regulatory network analysis was only made possible through the joint profiling of open chromatin and gene expression at the single cell level. Our data demonstrate the power of simultaneous profiling of both epigenomic and transcriptomic data in characterizing cells in cancer state and extracting functional information from tumor samples. Citation Format: Shamoni Maheshwari, Li Wang, Vijay Gopalan, Joe Shuga, Sharmila Chatterjee, Kamila Belhocine. Simultaneous single cell profiling of open chromatin and gene expression in B cell lymphoma highlights tumor-specific regulatory networks [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 LB206.
Abstract 2850: Astrocyte-breast cancer interactions facilitate brain metastasis
Authors: Sahar Israeli Dangoor, Ori Hadad, Ronit Satchi-Fainaro
Journal: Cancer Research (2021)

Abstract Diagnosis and treatment of breast cancer patients have been considerably improved, including those at the metastatic stage. However, brain metastasis still presents a major clinical challenge, and it is a leading cause of death. Unfortunately, there are no targeted therapies specific for this secondary tumor, and the current treatment modalities present limited clinical outcomes. Thus, better understanding of the pathways involved in the metastatic cascade, which lead to brain metastases colonization and progression, is essential. To that end, we investigated the mutual effects of astrocytes and breast cancer cells, using the traditional 2-dimensional (2D) cell-culture and a newly-established 3-dimensional (3D) model of multicellular breast cancer brain metastases spheroids. We found that astrocytes enhance the proliferation, migration and invasion of breast cancer cells, suggesting a supportive role for astrocytes in the metastatic process of breast cancer in the brain. Using a protein array, we identified several cytokines which were elevated following the co-culturing of breast cancer cells with astrocytes, suggesting them as potential key candidates involved in breast cancer-brain stroma interactions. One of these cytokines was MCP-1, which is a chemokine that is associated with poor prognosis in breast cancer patients. When it was functionally neutralized, breast cancer cell proliferation and migration rates were decreased, in addition to reduced invasion shown in our 3D-spheroid model. Considering these results, MCP-1 is proposed as one of the key factors promoting breast cancer brain metastasis. Although further validation using in vivo models is still required, this study deepens our understanding of the contribution of the metastatic breast cancer cells-brain microenvironment crosstalk to brain colonization. Taken together, our findings may be utilized to provide a novel therapeutic approach for the prevention of breast cancer brain metastasis following resection of the primary lesion. Keywords: Breast Cancer, Brain Metastasis, Brain Microenvironment, Astrocytes, Cytokines, Chemokines, MCP-1, CCL2, 3D Tumor Spheroids. Citation Format: Sahar Israeli Dangoor, Ori Hadad, Ronit Satchi-Fainaro. Astrocyte-breast cancer interactions facilitate brain metastasis [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 2850.
Weakly unsupervised conditional generative adversarial network for image-based prognostic prediction for COVID-19 patients based on chest CT
Authors: Tomoki Uemura, Janne J. Näppi, Chinatsu Watari, Toru Hironaka, Tohru Kamiya, Hiroyuki Yoshida
Journal: Medical Image Analysis (2021)

Because of the rapid spread and wide range of the clinical manifestations of the coronavirus disease 2019 (COVID-19), fast and accurate estimation of the disease progression and mortality is vital for the management of the patients. Currently available image-based prognostic predictors for patients with COVID-19 are largely limited to semi-automated schemes with manually designed features and supervised learning, and the survival analysis is largely limited to logistic regression. We developed a weakly unsupervised conditional generative adversarial network, called pix2surv, which can be trained to estimate the time-to-event information for survival analysis directly from the chest computed tomography (CT) images of a patient. We show that the performance of pix2surv based on CT images significantly outperforms those of existing laboratory tests and image-based visual and quantitative predictors in estimating the disease progression and mortality of COVID-19 patients. Thus, pix2surv is a promising approach for performing image-based prognostic predictions.