tbuckley/cabot-search huggingface dataset:
Overcoming resistance to immune checkpoint blockade with RNA-loaded nanoparticles.
Authors: Elias Joseph Sayour, Adam Grippin, Duane Anthony Mitchell
Journal: Journal of Clinical Oncology (2017)

117 Background: While checkpoint blockade has shown promising survival benefits in patients with solid tumors, immune escape through loss of MHCI expression juxtaposed to an immunoregulatory milieu remain significant hurdles. To overcome these limitations, we developed a novel treatment platform, which leverages the use of commercially available and clinically translatable nanoparticles (NPs) that can be combined with tumor-derived RNA to activate systemic immunity and re-program the intratumoral microenvironment from a regulatory into an immune activated locale. Methods: Since local vaccination strategies are mired with poor immunogenicity, we assessed if i.v. delivery of tumor-derived RNA encapsulated in lipophilic NPs could activate peripheral and intratumoral antigen presenting cells (APCs) for induction of therapeutic anti-tumor immunity in pre-clinical murine melanoma models. Results: We identified a clinically translatable NP formulation that when administered intravenously, mediates release of inflammatory cytokines (i.e. CCL2, IFN-alpha) into serum, systemically activates host APCs in reticuloendothelial organs, and induces precipitous upregulation of MHCI and immune activation markers (i.e. CD86) within the tumor microenvironment. Both model-antigen encoding RNA and physiologically-relevant tumor-derived RNA, when encapsulated in NPs, could expand potent anti-tumor T-cell immunity. We demonstrated that RNA-NPs harness the anti-viral defense mechanism against tumor antigens in a type I interferon dependent manner, and can be further engineered to deliver combinatorial therapies by co-encapsulating mRNAs encoding for immunomodulatory molecules (i.e. HCV PAMPs, GM-CSF). In a pre-clinical melanoma model, RNA-NPs mediate anti-tumor efficacy and significantly enhance activity of immune checkpoint mAbs when used in combination. Conclusions: By employing a systemic RNA-NP formulation encoding for both tumor RNAs and immunomodulatory molecules, as an innovative and versatile platform for delivering combinatorial therapeutics via a single treatment modality, this platform can be harnessed to simultaneously target tumor antigens and re-program the intratumoral microenvironment
Grazoprevir, ruzasvir, and uprifosbuvir for hepatitis C virus after NS5A treatment failure
Authors: David Wyles, Heiner Wedemeyer, Ziv Ben‐Ari, Edward J. Gane, Jesper Bach Hansen, Ira M. Jacobson, Alex L. Laursen, Annie Luetkemeyer, Ronald Nahass, Stephen Pianko, Stefan Zeuzem, Patricia Jumes, Hsueh‐Cheng Huang, Joan Butterton, Michael Robertson, Janice Wahl, Eliav Barr, Hee‐Koung Joeng, Elizabeth Martin, Lawrence Serfaty
Journal: Hepatology (2017)

People with hepatitis C virus (HCV) infection who have failed treatment with an all-oral regimen represent a challenging treatment population. The present studies evaluated the safety and efficacy of grazoprevir, ruzasvir, and uprifosbuvir, with or without ribavirin, in participants who had failed an NS5A inhibitor-containing regimen. C-SURGE (PN-3682-021) and C-CREST Part C (PN-3682-011 and -012) were open-label, multicenter studies. Participants who had previously relapsed following an NS5A inhibitor-containing all-oral regimen were retreated with grazoprevir 100 mg, ruzasvir 60 mg, and uprifosbuvir 450 mg alone for 24 weeks or with ribavirin for 16 weeks. The primary efficacy endpoint was sustained virologic response (HCV RNA below the limit of quantitation [<15 IU/mL]) 12 weeks after treatment completion (SVR12). In C-SURGE, SVR12 was achieved by 49/49 (100%) and 43/44 (98%) genotype (GT)1 participants in the 24-week no ribavirin arm and the 16-week plus ribavirin arm (lost to follow-up, n = 1), respectively. In C-CREST Part C, SVR12 was achieved by 23/24 (96%) participants treated for 16 weeks with ribavirin (GT1, 2/2 [100%]; GT2, 13/14 [93%]; GT3, 8/8 [100%]). One participant with GT2 infection discontinued study medication after a single dose of grazoprevir, ruzasvir, and uprifosbuvir plus ribavirin due to serious adverse events of vomiting and tachycardia. The presence of baseline resistance-associated substitutions had no impact on SVR12. No participant who completed treatment in either study experienced virologic failure.Grazoprevir, ruzasvir, and uprifosbuvir, with or without ribavirin, for 16 or 24 weeks was safe and highly effective in participants with HCV infection who had previously failed NS5A inhibitor-containing therapy. (Hepatology 2017;66:1794-1804).
Characterization of a humanized PD-L1 blocking antibody with pH-dependent antigen binding in a humanized syngenic tumor model.
Authors: Xueming Qian, Fei Teng, Huanhuan Guo, Zhen Li, Xiao-Feng Qin
Journal: Journal of Clinical Oncology (2017)

81 Background: Checkpoint inhibition is a promising approach for cancer treatment with durable responses and survival benefits. Currently, immune-checkpoint inhibitors are delivered at maximally tolerated doses, resulting in significant toxicities and cost burden. There is significant need to develop more efficacious and safer immune checkpoint inhibitor. Towards this goal, we have developed a next-generation humanized PD-L1 antibody with pH-dependent antigen binding and evaluated its biological activities in vitro and in vivo. Methods: Hybridoma approach was employed to generate anti-PD-L1 antibodies. A cell-based receptor-ligand blocking assay was employed to identify neutralizing antibodies. Antibodies with pH-dependent antigen binding property were identified and characterized further with those without using PD-L1/PD-1 binding assay, mixed lymphocyte reaction assay, and in vivo tumor growth inhibition assay in syngeneic MC38 tumor model expressing human PD-L1 protein. Results: A panel of neutralizing antibodies blocking PD-L1/PD-L1 binding was isolated. Among them we identified antibodies with or without pH-dependent binding property. While the in vitro activities of these antibodies are similar, their tumor growth inhibition activities differ significantly. The in vivo activity of 23F11, an antibody with ph-dependent binding, is maximized at 1mg/kg in MC38/hPD-L1 model. At 1 mg/kg, 23F11 induced complete tumor regression in 7/12 of the mice treated, more potent than antibodies without pH-dependent binding. Imaging study revealed that significantly higher drug concentration in the tumor for 23F11 and correlated with extended period of target occupancy. Furthermore 23F11 treatment is correlated with sustained up-regulation of plasma mIL-18, a potential pharmacodynamics response marker. Conclusions: We have identified antibodies with pH-dependent PD-L1 binding property. These antibodies can maintain high antibody level in PD-L1 expressing tumor and have potent tumor inhibition activity at low dose. Current work will evaluate whether humanized 23F11 can be at least as efficacious as benchmark antibodies yet with improved safety profile in patients.
Hodgkin lymphoma: 2018 update on diagnosis, risk‐stratification, and management
Authors: Stephen M. Ansell
Journal: American Journal of Hematology (2018)

Abstract Disease Overview Hodgkin lymphoma (HL) is an uncommon B‐cell lymphoid malignancy affecting 8500 new patients annually and representing approximately 10.2% of all lymphomas in the United States. Diagnosis HL is composed of two distinct disease entities: classical HL and nodular lymphocyte predominant HL. Nodular sclerosis, mixed cellularity, lymphocyte depletion, and lymphocyte‐rich HL are subgroups of classical HL. Risk Stratification An accurate assessment of the stage of disease in patients with HL is critical for the selection of the appropriate therapy. Prognostic models that identify patients at low or high risk for recurrence, as well as the response to therapy as determined by positron emission tomography scan, are used to optimize therapy. Risk‐Adapted Therapy Initial therapy for HL patients is based on the histology of the disease, the anatomical stage and the presence of poor prognostic features. Patients with early stage disease are typically treated with combined modality strategies utilizing abbreviated courses of combination chemotherapy followed by involved‐field radiation therapy, while those with advanced stage disease receive a longer course of chemotherapy often without radiation therapy. Newer agents including brentuximab vedotin are now being incorporated into frontline therapy and these new combinations are becoming a standard of care. Management of Relapsed/Refractory Disease High‐dose chemotherapy (HDCT) followed by an autologous stem cell transplant (ASCT) is the standard of care for most patients who relapse following initial therapy. For patients who fail HDCT with ASCT, brentuximab vedotin, PD‐1 blockade, nonmyeloablative allogeneic transplant or participation in a clinical trial should be considered.
54P Epidermal growth factor receptor expression (EGFR) in serum as a marker of treatment response and survival in advanced squamous cell lung cancer
Authors: A. Mohan, A. Ansari, M. Masroor, A. Saxena, K. Luthra, R.M. Pandey, D. Jain, R. Kumar, G.C. Khilnani, R. Guleria
Journal: Journal of Thoracic Oncology (2018)
Abstract 19113: Cardiac Repair With Human-Induced Pluripotent Stem Cells-Derived Tri-Lineage Cardiac Cells in a Swine Myocardial Infarction Model
Authors: Ling Gao, Wuqiang Zhu, Jianyi Zhang
Journal: Circulation (2016)

Introduction: Human induced pluripotent stem cells (hiPSC) derived cardiovascular cells hold great promise for cell-based therapy of heart diseases. However, efficiency of differentiation procedure...
A Nonsynonymous Variant in the GOLM1 Gene in Cutaneous Malignant Melanoma
Authors: Craig C Teerlink, Chad Huff, Jeff Stevens, Yao Yu, Sheri L Holmen, Mark R Silvis, Kirby Trombetti, Hua Zhao, Douglas Grossman, James M Farnham, Jingran Wen, Julio C Facelli, Alun Thomas, Markus Babst, Scott R Florell, Laurence Meyer, John J Zone, Sancy Leachman, Lisa A Cannon-Albright
Journal: JNCI Journal of the National Cancer Institute (2018)

Statistically significant linkage of melanoma to chromosome 9q21 was previously reported in a Danish pedigree resource and independently confirmed in Utah high-risk pedigrees, indicating strong evidence that this region contains a melanoma predisposition gene.Whole-exome sequencing of pairs of related melanoma case subjects from two pedigrees with evidence of 9q21 linkage was performed to identify the responsible predisposition gene. Candidate variants were tested for association with melanoma in an independent set of 454 unrelated familial melanoma case subjects and 396 unrelated cancer-free control subjects from Utah, and 1534 melanoma case subjects and 1146 noncancer control subjects from Texas (MD Anderson) via a two-sided Fisher exact test.A rare nonsynonymous variant in Golgi Membrane Protein 1 (GOLM1), rs149739829, shared in two hypothesized predisposition carriers in one linked pedigree was observed. Segregation of this variant in additional affected relatives of the index carriers was confirmed. A statistically significant excess of carriers of the variant was observed among Utah case subjects and control subjects (odds ratio [OR] = 9.81, 95% confidence interval [CI] = 8.35 to 11.26, P < .001) and statistically significantly confirmed in Texas case subjects and control subjects (OR = 2.45, 95% CI = 1.65 to 3.25, P = .02).These findings support GOLM1 as a candidate melanoma predisposition gene.
Abstract 18933: Extracorporeal Life Support and Survival of Patients With Cardiac Arrest Developed During or After Office-Based Cosmetic Surgery
Authors: Duk Won Bang, Byoung Won Park, Min Ho Lee, Min Su Hyon, Won Ho Chang, Young Woo Park
Journal: Circulation (2016)

Introduction:  Cardiac arrest during or after office-based cosmetic surgery has been reported rarely. Little is known about the prognosis after cardiac arrest developed during or after cosmetic surgery at clinics.   Hypothesis:  Our aim is to assess the clinical outcomes of patients who occurred cardiac arrest during or after cosmetic surgery in office-based clinics.   Methods:  From May 2009 to March 2016, thirty-two patients developed cardiac arrest during or after cosmetic surgery at clinics were collected consecutively. The hospital was located nearby over 200 office-based cosmetic surgery clinics, usually its distance within 15-20 minutes by ambulance. We compared clinical outcomes including complications between the survivor (n=19) and the deceased (n=13) and accessed prognostic factors for mortality.   Results:  All 32 patients were female and mean age was 30.40 ± 11.87 years. Of 32 patients, extracorporeal life support (ECLS) was utilized more in the deceased than in the survivor (92.3% vs 47.4%, p=0.009). Cardiopulmonary resuscitation (CPR) duration at hospital was longer in the deceased than in the survivor (31.55±33.87 min vs 7.59±9.07, p=0.01). APACHE score was also higher in the deceased than in the survivor (23.85±6.68 vs 16.79±7.44, p=0.01). Of 19 the survivor, 9 patients (47.4%) had serious complications (8 hypoxic brain damage and 1 lower leg ischemia). In a logistic regression analysis, there was no important prognostic factor predicting the mortality.   Conclusion:  Patients with cardiac arrest developed at cosmetic surgery clinics showed poor prognosis despite of support of ECLS. Survivors also had serious complications. Careful monitoring and active cardiopulmonary resuscitation at cosmetic surgery clinics during or after surgery might be crucial.
Germline alterations in a consecutive series of acute myeloid leukemia
Authors: Ulla Wartiovaara-Kautto, Elina A. M. Hirvonen, Esa Pitkänen, Caroline Heckman, Janna Saarela, Kaisa Kettunen, Kimmo Porkka, Outi Kilpivaara
Journal: Leukemia (2018)
Markov decision analysis of neoadjuvant treatment pathway versus surgery first pathway for resectable pancreatic cancer.
Authors: Alison Bradley, Colin McKay, Nigel Jamieson, Euan Dickson, Ross Carter, Robert Van der Meer
Journal: Journal of Clinical Oncology (2018)

456 Background: Surgery first (SF) versus neoadjuvant approach (NAT) to management of potentially resectable pancreatic ductal adenocarcinoma (PDAC) is controversial. This study is unique in utilizing institutional data to offer Markov decision-analysis of overall treatment pathways for resectable PDAC. Methods: An advanced Markov decision analysis model was constructed and populated with data from a retrospective institutional database. Patients presenting with resectable PDAC from 2008-2012 were included in the SF arm. Those presenting with resectable PDAC from 2012-2016 and treated within NAT pathway populated the NAT arm. Model uncertainties were tested with one and two-way deterministic sensitivity analysis and probabilistic Monte Carlo sensitivity analysis set to 1000 cycles with variables altered between highest and lowest observed values. Results: NAT pathway gave an additional 0.58 QALMs (22.43 vs. 21.85 QALMs). Monte Carlo analysis reported indifference between treatment strategies. One-way deterministic sensitivity analysis showed that probability of resection in the SF pathway must be greater than 0.82, or below 0.72 in NAT pathway, and probability of receiving adjuvant therapy above 0.6 to alter pathway superiority. Two-way deterministic sensitivity analysis demonstrated treatment superiority depended on resection rate in each pathway and receiving adjuvant therapy in SF pathway. Markov cohort analysis demonstrated superiority of neoadjuvant pathway (Table). Conclusions: Optimal treatment pathway remains debatable on an intention-to-treat Markov decision analysis. Markov cohort analysis of treatment received demonstrated benefit with NAT pathway. [Table: see text]
Role of Non Receptor Tyrosine Kinases in Hematological Malignances and its Targeting by Natural Products
Authors: Kodappully S. Siveen, Kirti S. Prabhu, Iman W. Achkar, Shilpa Kuttikrishnan, Sunitha Shyam, Abdul Q. Khan, Maysaloun Merhi, Said Dermime, Shahab Uddin
Journal: Molecular Cancer (2018)

Tyrosine kinases belong to a family of enzymes that mediate the movement of the phosphate group to tyrosine residues of target protein, thus transmitting signals from the cell surface to cytoplasmic proteins and the nucleus to regulate physiological processes. Non-receptor tyrosine kinases (NRTK) are a sub-group of tyrosine kinases, which can relay intracellular signals originating from extracellular receptor. NRTKs can regulate a huge array of cellular functions such as cell survival, division/propagation and adhesion, gene expression, immune response, etc. NRTKs exhibit considerable variability in their structural make up, having a shared kinase domain and commonly possessing many other domains such as SH2, SH3 which are protein-protein interacting domains. Recent studies show that NRTKs are mutated in several hematological malignancies, including lymphomas, leukemias and myelomas, leading to aberrant activation. It can be due to point mutations which are intragenic changes or by fusion of genes leading to chromosome translocation. Mutations that lead to constitutive kinase activity result in the formation of oncogenes, such as Abl, Fes, Src, etc. Therefore, specific kinase inhibitors have been sought after to target mutated kinases. A number of compounds have since been discovered, which have shown to inhibit the activity of NRTKs, which are remarkably well tolerated. This review covers the role of various NRTKs in the development of hematological cancers, including their deregulation, genetic alterations, aberrant activation and associated mutations. In addition, it also looks at the recent advances in the development of novel natural compounds that can target NRTKs and perhaps in combination with other forms of therapy can show great promise for the treatment of hematological malignancies.
Characterization of cross-tissue genetic-epigenetic effects and their patterns in schizophrenia
Authors: Dongdong Lin, Jiayu Chen, Nora Perrone-Bizzozero, Juan R. Bustillo, Yuhui Du, Vince D. Calhoun, Jingyu Liu
Journal: Genome Medicine (2018)

One of the major challenges in current psychiatric epigenetic studies is the tissue specificity of epigenetic changes since access to brain samples is limited. Peripheral tissues have been studied as surrogates but the knowledge of cross-tissue genetic-epigenetic characteristics remains largely unknown. In this work, we conducted a comprehensive investigation of genetic influence on DNA methylation across brain and peripheral tissues with the aim to characterize cross-tissue genetic-epigenetic effects and their roles in the pathophysiology of psychiatric disorders. Genome-wide methylation quantitative trait loci (meQTLs) from brain prefrontal cortex, whole blood, and saliva were identified separately and compared. Focusing on cis-acting effects, we tested the enrichment of cross-tissue meQTLs among cross-tissue expression QTLs and genetic risk loci of various diseases, including major psychiatric disorders. CpGs targeted by cross-tissue meQTLs were also tested for genomic distribution and functional enrichment as well as their contribution to methylation correlation across tissues. Finally, a consensus co-methylation network analysis on the cross-tissue meQTL targeted CpGs was performed on data of the three tissues collected from schizophrenia patients and controls. We found a significant overlap of cis meQTLs (45–73 %) and targeted CpG sites (31–68 %) among tissues. The majority of cross-tissue meQTLs showed consistent signs of cis-acting effects across tissues. They were significantly enriched in genetic risk loci of various diseases, especially schizophrenia, and also enriched in cross-tissue expression QTLs. Compared to CpG sites not targeted by any meQTLs, cross-tissue targeted CpGs were more distributed in CpG island shores and enhancer regions, and more likely had strong correlation with methylation levels across tissues. The targeted CpGs were also annotated to genes enriched in multiple psychiatric disorders and neurodevelopment-related pathways. Finally, we identified one co-methylation network shared between brain and blood showing significant schizophrenia association (p = 5.5 × 10−6). Our results demonstrate prevalent cross-tissue meQTL effects and their contribution to the correlation of CpG methylation across tissues, while at the same time a large portion of meQTLs show tissue-specific characteristics, especially in brain. Significant enrichment of cross-tissue meQTLs in expression QTLs and genetic risk loci of schizophrenia suggests the potential of these cross-tissue meQTLs for studying the genetic effect on schizophrenia. The study provides compelling motivation for a well-designed experiment to further validate the use of surrogate tissues in the study of psychiatric disorders.
Initial therapy with FOLFOXIRI plus bevacizumab (bev) for RAS mutant metastatic colorectal cancer (mCRC) and gene mutations in circulating tumor DNA (ctDNA) as a predictive marker for the efficacy: JACCRO CC-11.
Authors: Yu Sunakawa, Hironaga Satake, Joshua L. Usher, Yolanda S Jaimes, Yuji Miyamoto, Masato Nakamura, Hiroshi Nakayama, Nobuhiro Sugano, Akinori Takagane, Masahiro Gotoh, Takanori Watanabe, Kiyoshi Ishigure, Chihiro Tanaka, Masahiro Takeuchi, Masashi Fujii, KATHLEEN DANENBERG, Heinz-Josef Lenz, Takashi Sekikawa, Wataru Ichikawa
Journal: Journal of Clinical Oncology (2018)

635 Background: We have reported that modified (m)-FOLFOXIRI plus bev was feasible and had a good objective response rate (ORR) for Japanese patients (pts) in a phase II trial of the JACCRO CC-11 (ESMO 2017 #543P). In addition, a pre-planned research was performed to investigate if the change of gene mutations in ctDNA during therapy can serve as a predictor for clinical outcomes in RAS mutant mCRC. Methods: The efficacy of m-FOLFOXIRI (irinotecan 150 mg/m², oxaliplatin 85 mg/m², levofolinate 200 mg/m², and fluorouracil 2400 mg/m² repeated biweekly) plus bev was evaluated prospectively in 62 pts (median age 63, 55% male, 92% PS0, and 27% right-sided tumors) with mCRC harboring RAS mutation (mt). The primary endpoint was ORR. Progression-free survival (PFS), overall survival, early tumor shrinkage (ETS), depth of response (DpR), and safety were secondary endpoints. Plasma samples for extraction of ctDNA were collected at 3 points (pre-, 8w, and progression) and analyzed for specific KRAS, NRAS, BRAF, and PIK3CA variants with real-time PCR assays. Results: Updated median follow-up time was 10.2 months. ORR and disease control rate were 75.8% and 96.8%, respectively. ETS was 73.8%, and median DpR was 49.6%. Median PFS was 11.5 months (95%CI 9.5-14.0). KRAS/ NRAS mt from pre-treatment plasma was confirmed in 79% of pts. In 41 pts with RAS mt at pre-treatment, mt status at 8 weeks predicted clinical outcomes (Table). Moreover, combined assessment of mt in ctDNA and ETS served as a refined predictor for efficacy. Pts with PIK3CA mt at pre-treatment had a poor outcome (ORR, 43%; median PFS, 8.8 months). Conclusions: FOLFOXIRI plus bev regimen is active for RAS mutant mCRC. RAS mt in ctDNA and ETS evaluation might potentially be a useful on-treatment biomarker in mCRC pts with RAS mt. Clinical trial information: UMIN000015152. [Table: see text]