tbuckley/cabot-search huggingface dataset:
Prognostic value of PD-L1<sup>+</sup>CD4<sup>+</sup> T cells in non-small cell lung cancer (NSCLC) patients treated with a PD-1 inhibitor.
Authors: Kiriaki E. Vetsika, Despoina Aggouraki, Zacharoula Lyristi, Filippos Koinis, Vassilis Georgoulias, Athanasios Kotsakis
Journal: Journal of Clinical Oncology (2017)

58 Background: One of the tumour escape mechanisms is the expression of programmed cell death-1 (PD-1) receptor on immune cells. Clinical trials have demonstrated that antibodies against PD-L1 or PD-1 molecules induce objective clinical responses in pre-treated patients with NSCLC. In this study, we evaluated the levels of PD-1 + and PD-L1 + expressing- immune cells and their association with the clinical outcome in NSCLC patients. Methods: Peripheral blood was collected from 32 advanced/metastatic pre-treated NSCLC patients before anti-PD-1 therapy (Nivolumab). Flow cytometry was performed to identify and quantify PD-1 and PD-L1 expression on circulating immune cells with anti-tumor function (CD4 + and CD8 + T cells, B cells, Dendritic cells) , as well as on immunosuppressivecells [(CD4 + and CD8 + Treg cells, Bregs, Myeloid-derived Suppressor cells (MDSC)]. Correlation between the levels of PD-1 + and PD-L1 + -expressing immune cells, as well as their association with overall (OS) and progression-free survival (PFS) was evaluated; high expression of immune cells was defined as the percentage of the cells above the mean value. Results: PD-1 and PD-L1 expression was detected on all tested immune cells with anti-tumor activity. PD-1 expression was found on all immunosuppressive cells, whereas only CD4 + and CD8 + Treg cells and Granulocytic -MDSCs expressed PD-L1. No PD-L1 expression was observed on Bregs and monocytic-MDSCs. There was no correlation of PD-1 or PD-L1-expressing cells with response to anti-PD1 treatment. A significantly decreased PFS was observed in the low CD4 + PD-L1 + T cells group compared with the high CD4 + PD-L1 + group (3.4 months vs. 5.2 months, p=0.03). Univariate analysis for PFS revealed that the low percentages of CD4 + PDL-1 + T cells were prognostic for shorter PFS (HR= 3.1, p=0.04). On the multivariate analysis, low PD-L1 + CD4 + T cells were independently associated with decreased PFS (HR: 3.3, p=0.03). Conclusions: These data provide evidence that PD-L1 + expression on peripheral CD4 + T cells was a significant predictor of better PFS in NSCLC patients. Therefore, PD-L1 expression could be used for the selection of patients who might benefit from PD-1/PD-L1 inhibitors.
Progression from latent infection to active disease in dynamic tuberculosis transmission models: a systematic review of the validity of modelling assumptions
Authors: Nicolas A Menzies, Emory Wolf, David Connors, Meghan Bellerose, Alyssa N Sbarra, Ted Cohen, Andrew N Hill, Reza Yaesoubi, Kara Galer, Peter J White, Ibrahim Abubakar, Joshua A Salomon
Journal: The Lancet Infectious Diseases (2018)
Oncolytic viruses: New era in cancer therapy.
Authors: A. Rasmy, Amal A.
Journal: Journal of Clinical Oncology (2017)

161 Background: Modern technology has afforded the human race with a new treatment for cancer using immunotherapy, and the Oncolytic Viruses (OVs) represent a new class of this type of therapeutic agent. Targeted therapy of cancer using OVs has generated much interest over the past few years in light of the limited efficacy and side effects of standard cancer therapeutics for advanced disease. Methods: By definition, OVs are a type of virus that infect and lyse cancer cells, but healthy cells are left intact. OVs can occur naturally or can be synthesized in the laboratory through the alteration of other viruses. The OVs immunotherapy treats cancer patients by using native or genetically modified viruses that selectively replicate within tumor cells. The mechanisms of action are not entirely understood but are likely dependent on viral replication within transformed cells, induction of primary cell death, interaction with tumor cell antiviral elements, and initiation of innate and adaptive anti-tumor immunity. Results: On 27 October 2016, the FDA approved the first genetically engineered virus called talimogene laherparepvec (T-VEC or Imlygic) to treat advanced melanoma. A treatment course with Imlygic consists of injections into the melanoma lesions. After the first injection, a second one is administered after three weeks, then additional doses every two weeks for at least six months. Conclusions: The OVs immunotherapy is a highly promising approach and introduces a new class of drugs for treating cancer patients particularly in combination approach. Additional studies are required to learn more about the mechanism of action and to understand how this new class of drug can improve the prognosis of cancer patients. As continuing work is being done to improve the OVs that are currently available, new viral species are also emerging and are worth exploring.
Rapid Biophysical Analysis of Host Immune Cell Variations Associated with Sepsis
Authors: Katherine Crawford, Aaron DeWitt, Stephen Brierre, Terrell Caffery, Tonya Jagneaux, Christopher Thomas, Mara Macdonald, Henry Tse, Ajay Shah, Dino Di Carlo, Hollis R. O’Neal
Journal: American Journal of Respiratory and Critical Care Medicine (2018)
i-GONAD: a robust method for in situ germline genome engineering using CRISPR nucleases
Authors: Masato Ohtsuka, Masahiro Sato, Hiromi Miura, Shuji Takabayashi, Makoto Matsuyama, Takayuki Koyano, Naomi Arifin, Shingo Nakamura, Kenta Wada, Channabasavaiah B. Gurumurthy
Journal: Genome biology (2018)

We present a robust method called improved-Genome editing via Oviductal Nucleic Acids Delivery (i-GONAD) that delivers CRISPR ribonucleoproteins to E0.7 embryos via in situ electroporation. The method generates mouse models containing single-base changes, kilobase-sized deletions, and knock-ins. The efficiency of i-GONAD is comparable to that of traditional microinjection methods, which rely on ex vivo handling of zygotes and require recipient animals for embryo transfer. In contrast, i-GONAD avoids these technically difficult steps, and it can be performed at any laboratory with simple equipment and technical expertise. Further, i-GONAD-treated females retain reproductive function, suggesting future use of the method for germline gene therapy.
Gastric Peroral Endoscopic Pyloromyotomy Reduces Symptoms, Increases Quality of Life, and Reduces Health Care Use For Patients With Gastroparesis
Authors: Parit Mekaroonkamol, Sunil Dacha, Lei Wang, Xiaoyu Li, Yueping Jiang, Lianyong Li, Tian Li, Nikrad Shahnavaz, Sonali Sakaria, Francis E. LeVert, Steven Keilin, Field Willingham, Jennifer Christie, Qiang Cai
Journal: Clinical Gastroenterology and Hepatology (2018)
Abstract 13924: Four-Tier Classification of Pulmonary Artery Metric Severity for Diagnosis and Prognosis of Pulmonary Hypertension
Authors: Harpreet S Bhatia, Jackie Szymonifka, Qing Zhou, Zachary R Lavender, Aaron B Waxman, Marc J Semigran, Rajeev Malhotra, Quynh A Truong
Journal: Circulation (2016)

Introduction: Increased main pulmonary artery diameter (mPA) and ratio of mPA to ascending aortic diameter (ratio PA) on computed tomography (CT) are associated with pulmonary hypertension (PH). We aimed to develop a four-tier severity classification of mPA and ratio PA for diagnosis of PH. Methods: In 228 patients (136 with PH) undergoing right heart catheterization (RHC) and CT for dyspnea, we measured mPA and ratio PA. Using a derivation cohort (n=114), we determined cutpoints for four tiers of mPA and ratio PA severity to maximize sensitivity and specificity, and confirmed these values in a validation cohort (n=114). Results: Figure A shows the 4-tier cutpoints for mPA and ratio PA as Framingham sex-specific normal, mild, moderate, and severe. The 4-tier classification of mPA and ratio PA successfully predicted PH (derivation: both c-stats 0.90; validation: both c-stats 0.85). The sensitivity of the normal tier was 99% for mPA and 93% for ratio PA, while the specificity of the severe tier was 98% for mPA and 100% for ratio PA. With increasing severity of mPA and ratio PA tiers, there was a corresponding increase in the proportion of patients with elevated RHC Mean Pulmonary Artery Pressure (Figure A) and Echo Right Ventricular Systolic Pressure (both p&lt;0.001). Patients with moderate to severely enlarged mPA had worse survival than those with normal or mildly enlarged mPA (Figure B). Similar results were seen with ratio PA. Conclusions: Non-invasive CT four-tier classification of mPA and ratio PA has high diagnostic accuracy for PH and can easily be used clinically. Higher severity of mPA and ratio PA are also associated with worse prognosis.
Lung Ultrasound and Microbubbles Enhance Aminoglycoside Efficacy and Delivery to the Lung in <i>Escherichia coli</i>–induced Pneumonia and Acute Respiratory Distress Syndrome
Authors: Michael G. Sugiyama, Victoria Mintsopoulos, Hira Raheel, Neil M. Goldenberg, Jane E. Batt, Laurent Brochard, Wolfgang M. Kuebler, Howard Leong-Poi, Raffi Karshafian, Warren L. Lee
Journal: American Journal of Respiratory and Critical Care Medicine (2018)
135O A phase 1b study of necitumumab in combination with abemaciclib in patients with stage IV non-small cell lung cancer
Authors: B. Besse, F. Barlesi, I. Demedts, J. Fuentes Pradera, A. Renault, G. Robinet, B. Frimodt-Moller, M. Gil, J. Vansteenkiste
Journal: Journal of Thoracic Oncology (2018)
HER3-Mediated Resistance to Hsp90 Inhibition Detected in Breast Cancer Xenografts by Affibody-Based PET Imaging
Authors: Carlos D. Martins, Chiara Da Pieve, Thomas A. Burley, Rhodri Smith, Daniela M. Ciobota, Louis Allott, Kevin J. Harrington, Wim J.G. Oyen, Graham Smith, Gabriela Kramer-Marek
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Recent studies have highlighted a role of HER3 in HER2-driven cancers (e.g., breast cancer), implicating the upregulation of the receptor in resistance to HER-targeted therapies and Hsp90 inhibitors (e.g., AUY922). Therefore, we have developed an affibody-based PET radioconjugate that quantitatively assesses HER3 changes induced by Hsp90 inhibition in vivo. Experimental Design: ZHER3:8698 affibody molecules were conjugated via the C-terminus cysteine to DFO-maleimide for 89Zr radiolabeling. The probe was characterized in vitro and in vivo in a panel of human breast cell lines and xenograft models with varying HER3 receptor levels. In addition, the radioconjugate was investigated as a tool to monitor the outcome of AUY922, an Hsp90 inhibitor, in an MCF-7 xenograft model. Results: We demonstrated that 89Zr-DFO-ZHER3:8698 can track changes in receptor expression in HER3-positive xenograft models and monitor the outcome of AUY922 treatment. Our in vitro findings showed that MCF-7 cells, which are phenotypically different from BT474, develop resistance to treatment with AUY922 through HER3/IGF-1Rβ–mediated signaling. Of note, the lack of response in vitro due to HER3 recovery was confirmed in vivo using 89Zr-DFO-ZHER3:8698–based imaging. Upon AUY922 treatment, higher radioconjugate uptake was detected in treated MCF-7 xenografts, correlating with an AUY922-induced HER3 upregulation concomitant with an increase in IGF-1Rβ expression. Conclusions: These data underline the potential of HER3-based PET imaging to noninvasively provide information about HER3 expression and to identify patients not responding to targeted therapies due to HER3 recovery. Clin Cancer Res; 24(8); 1853–65. ©2018 AACR.
Radical Prostatectomy in Metastatic Castration-resistant Prostate Cancer: Feasibility, Safety, and Quality of Life Outcomes
Authors: Chad A. Reichard, Justin R. Gregg, Mary F. Achim, Ana M. Aparicio, Curtis A. Pettaway, Louis L. Pisters, John F. Ward, John W. Davis, Brian F. Chapin
Journal: European Urology (2018)
Combining PD-1 blockade with T-cell redirecting bispecific antibodies for solid cancer therapy.
Authors: Chien-Hsing Chang, Yang Wang, Diane L Rossi, Rongxiu Li, Edmund A. Rossi, Thomas M. Cardillo, David M. Goldenberg
Journal: Journal of Clinical Oncology (2017)

98 Background: Bispecific antibodies (bsAbs) for redirecting T cells to cancers have shown promise in both preclinical and clinical studies. However, clinical results have been disappointing in solid cancers. We have applied the DOCK-AND-LOCK method to generate a novel class of trivalent bsAbs, each comprising an anti-CD3 scFv covalently conjugated to a stabilized dimer of different anti-tumor Fabs. Herein we report the characterization of two such constructs, (E1)-3s and (14)-3s, which activate T cells and target Trop-2- and CEACAM5-expressing cancer cells, respectively. Methods: Human breast and colonic cancer cell lines were grown in monolayer cultures or as 3D spheroids for in vitro evaluation. NOD/SCID mice carrying xenografts of MDA-MB-231 (a TNBC line constitutively expressing Trop-2 and PD-L1) were used for in vivo studies. A human PD-1 antagonistic murine hybridoma antibody was subsequently converted to its chimeric form (IMMU-cPD-1). Human PBMCs, or T cells isolated from buffy coats by negative selection, were used as effector cells in cytotoxicity assays. The effect of IMMU-cPD-1 on cancer cells pretreated with IFN-γ to induce the expression of PD-L1 was compared with those not pretreated. Results: (E1)-3s and (14)-3s, in the presence of human T cells, killed target cells grown as monolayers at low picomolar concentrations, with similar potency observed for drug-resistant cells. The antitumor efficacy was demonstrated for (E1)-3s plus human PBMCs in NOD/SCID mice bearing MDA-MB-231, and for human PBMCs combined with (E1)-3s or (14)-3s in 3D spheroids generated from target cell lines to mimic the in vivo behavior and microenvironment of these tumors. Moreover, with the addition of IMMU-cPD-1, the benefit of PD-1 blockade was indicated by increased cell death in 3D spheroids and longer survival of MDA-MB-231-bearing mice. Conclusions: These results highlight the potency of (E1)-3s and (14)-3s as T-cell redirecting bsAbs, emphasize the potential of combining such bsAbs with immune checkpoint inhibitors to improve the therapeutic activity in the immunotherapy of solid cancers, and provide a basis for using 3D spheroids as an alternative to in vivo models for evaluating T-cell functions.
Heritability and genome-wide association study of diffusing capacity of the lung
Authors: Natalie Terzikhan, Fangui Sun, Fien M. Verhamme, Hieab H.H. Adams, Daan Loth, Ken R. Bracke, Bruno H.C. Stricker, Lies Lahousse, Josée Dupuis, Guy G. Brusselle, George T. O'Connor
Journal: European Respiratory Journal (2018)

Although several genome-wide association studies (GWAS) have investigated the genetics of pulmonary ventilatory function, little is known about the genetic factors that influence gas exchange. The aim of the study was to investigate the heritability of, and genetic variants associated with the diffusing capacity of the lung.GWAS was performed on diffusing capacity of the lung measured by carbon monoxide uptake (DLCO) and per alveolar volume (VA) using the single-breath technique, in 8372 individuals from two population-based cohort studies, the Rotterdam Study and the Framingham Heart Study. Heritability was estimated in related (n=6246) and unrelated (n=3286) individuals.Heritability of DLCO and DLCO/VA ranged between 23% and 28% in unrelated individuals and between 45% and 49% in related individuals. Meta-analysis identified a genetic variant in ADGRG6 that is significantly associated with DLCO/VA Gene expression analysis of ADGRG6 in human lung tissue revealed a decreased expression in patients with chronic obstructive pulmonary disease (COPD) and subjects with decreased DLCO/VADLCO and DLCO/VA are heritable traits, with a considerable proportion of variance explained by genetics. A functional variant in ADGRG6 gene region was significantly associated with DLCO/VA Pulmonary ADGRG6 expression was decreased in patients with COPD.
Analysis of hybridoma and CHO-derived pritumumab for therapeutic applications.
Authors: Ivan Babic, Rajesh Mukthavaram, Pengfei Jiang, Natsuko Nomura, Eric Glassy, Mark Charles Glassy, Santosh Kesari
Journal: Journal of Clinical Oncology (2017)

71 Background: Pritumumab, a natural huma IgG1 kappa antibody was obtained from a regional draining lymph node of a patient with cervical carcinoma through traditional hybridoma technology. Methods: Both cell lines and tissues were processed and analyzed for FACS analysis, Western blots, and immunohistochemistry. Results: Specificity analysis of the target antigen, an altered form of vimentin (ecto-domain vimentin (EDV)) shows it to be limited to cell surface expression on cancer cells. Clinically, 249 Japanese brain cancer patients were treated with a low dose pritumumab regimen, either at 1mg once a week or 1mg twice a week, and overall response rates of between 25-30% were seen with several complete and partial responses. A recombinant version of the mAb was made using the GPEx system in CHO cells. In a series of comparable studies the CHO mAb was compared with the original hybridoma. Binding specificity with both flow cytometry and immunohistochemical (IHC) analysis, Western blot analysis, and Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) activity confirms the comparability of the two versions. IHC analysis suggests restricted binding to tumor cells and not normal cells and tissues. Further studies include establishing a xenograft model with both SCID and athymic nude mice in which pritumumab was effective in preventing tumor growth in nude mice but not in SCID mice. Analysis of a blood brain barrier model suggests pritumumab shows minimal distribution in normal brain tissues and significant binding in tumor areas of brain tissues indicating the mAb crosses the tumor brain barrier. Conclusions: Overall, these data together suggest pritumumab is suitable for development as an anti-tumor therapeutic.
Mutation burden as a biomarker of response to immune checkpoint therapy in nine solid cancers.
Authors: Shridar Ganesan, Gyan Bhanot, Janice M. Mehnert, Ann W. Silk, Jeffrey S. Ross, Dean Pavlick, Siraj Mahamed Ali, Paul Markowski, Howard L. Kaufman, Ryan J. Sullivan, Christine Marie Lovly, Jeffrey Alan Sosman, Douglas Buckner Johnson, Anil Betigeri, Kalyanasundaram Subramanian, Anshuman Panda
Journal: Journal of Clinical Oncology (2017)

35 Background: A high mutation burden a biomarker of response to immune checkpoint therapy in melanoma, non-small cell lung cancer, and colorectal cancer. It is unknown whether mutation burden is predictive of response in other cancer types, and whether it is identifiable using available clinical assays. Methods: Using data for 10,745 tumors from 33 solid cancer types in TCGA, we looked for a mutation burden threshold (iCAM) in each cancer type associated with gene expression signatures of a blocked immune response of robust CD8 + T cell response and up-regulation of immune checkpoint genes. Results: A unique iCAM threshold was identified in nine cancers: melanoma and lung, colon, endometrial, and gastric adenocarcinoma; serous ovarian, bladder urothelial, cervical, and ER+ HER2− breast cancer. iCAM thresholds applied to published clinical data for patients treated with immune checkpoint therapy showed that iCAM+ patients had significantly better response. iCAM+ tumors can be identified from clinical-grade NGS assays with high accuracy . In a prospective melanoma cohort of patients treated with anti- PD-1 patients with iCAM+ tumors had significantly better objective response rates, progression free survival, and overall survival compared patients to iCAM− tumors. Pattern of somatic mutations were different in iCAM+ and iCAM− tumors, suggesting different mechanism of carcinogenesis in iCAM+ versus iCAM− tumors. Higher fractions of leukocytes were NK (Natural Killer) cells and macrophages were M1 polarized, and a lower fraction of T cells were regulatory T cells in iCAM+ tumors compared to iCAM− tumors. Over 75% of the genes significantly up-regulated in iCAM+ tumors in every cancer types were in the immune response pathway, confirming immune response to be the main differentiator in iCAM+ veruss iCAM− tumors. Conclusions: In nine cancer types, a clinically useful mutation burden threshold (iCAM) associated with gene expression signatures of blocked immune response can identify likely responders to immune checkpoint therapy, and iCAM status is identifiable using currently available clinical NGS assays.
A randomized phase II study of continuous versus intermittent S-1 plus oxaliplatin in first-line treatment of patients with metastatic gastric carcinoma.
Authors: Sook Ryun Park, Young-Iee Park, Jiyoung Rhee, Byung-Ho Nam, Sun-Young Kong, Sung Hyun Kim, Mihee Choi, Il Ju Choi, Chan Gyoo Kim, Jong Yeul Lee, Soo-Jeong Cho, Young Woo Kim, Keun Won Ryu, Jun Ho Lee, Noe Kyeong Kim
Journal: Journal of Clinical Oncology (2012)

4028 Background: We conducted a randomized phase II study to compare continuous vs. intermittent S-1 + oxaliplatin (SOX) after induction of 6 cycles of SOX in patients (pts) with metastatic gastric cancer (MGC). Methods: Pts &gt;18 yrs with chemo-naive MGC, normal organ function, ECOG PS 0-2, and measurable or evaluable lesion(s) were initially given an induction treatment of 6 cycles of SOX (S-1 40 mg/m 2 bid on D1-14 + oxaliplatin 130 mg/m 2 on D1 q 3 wks). Pts with CR/PR or SD were randomized to continue SOX (arm A) until progression/intolerable toxicity or discontinue until progression when SOX was re-administered (arm B). The primary endpoint was overall survival (OS), and secondary endpoints included progression-free survival (PFS), response rate, safety, quality of life, and biomarker correlative studies. Results: From July 2007 to Dec 2010, a total of 250 pts entered into the study. Median age was 53 yrs (range, 24-69); PS 0/1/2=13/219/18; M/F=162/88. Three pts did not receive treatment and 126 (50.4%) discontinued treatment before or at the completion of 6 cycles of SOX due to progression (45.6%), pt refusal (2.8%), or adverse events (2.0%). A total of 121 pts were randomized: 59 (48.8%) to arm A and 62 (51.2%) to arm B. Clinical characteristics were well balanced between arms. SOX continuation resulted in a significant reduction in the risk of progression (median PFS, 10.5 months for arm A vs. 7.2 months for arm B; HR=0.57, 95% CI 0.39-0.84, p=0.005). With a median follow-up of 34.0 months (range, 10.5-53.3 months), there was no significant difference in OS (median OS, 22.6 months for arm A vs. 22.7 months for arm B; HR, 0.79, 95% CI 0.51-1.25, p=0.31). Arm A had higher rates of grade 3/4 fatigue (28.8% vs. 8.1%, p=0.004) and neuropathy (25.4% vs. 8.1%, p=0.014) but other grade 3/4 hematologic (neutropenia, 35.6% vs. 32.3%; thrombocytopenia, 23.7% vs. 21.0%; anemia, 15.3% vs. 6.5%) or non-hematologic toxicity rates were not significantly different. Conclusions: Continuous chemotherapy with SOX after induction therapy improved PFS but not OS. Supported by NCC Grant 1010180 (S-1 and oxaliplatin was provided by JEIL Pharm. Co., Ltd. and sanofi-aventis Korea Co., Ltd., respectively).