tbuckley/cabot-search huggingface dataset:
Evaluation of CD73 in lung cancer.
Authors: Hui Yu, Maya Amar, Christopher J Rivard, Kim Ellison, Leslie Rozeboom, Kenichi Suda, Kristine Brovsky, Fred R. Hirsch
Journal: Journal of Clinical Oncology (2017)

e14525 Background: Immunotherapy has shown promising results in multiple forms of cancer including lung cancer patients. Treatment targeting alternative immune checkpoints may demonstrate value for specific cancers or in combination therapy with other immunotherapies or chemotherapeutic agents. While adenosine has physiological importance in preventing excess inflammatory reactions and inhibiting autoimmunity, it is generated through an enzymatic cascade in the tumor microenvironment whereby AMP is ultimately dephosphorylated to adenosine by CD73 on tumor cells. Previous studies have shown that increased tumor CD73 expression correlated with increased metastasis, worse prognosis and chemotherapy resistance. Methods: Genomic data from the CCLE and TCGA database were evaluated for CD73 expression in lung cancer. The specificity of an anti-CD73 antibody (Cell Signaling) was confirmed by Western blotting in lung cancer cell lines. Immunohistochemistry (IHC) was performed for FFPE lung cancer cell lines and a NSCLC patient cohort. CD73 expression data was correlated with patient demographic data including outcomes. Results: CD73 mRNA was expressed in lung cancer cell lines (70/126, 55.6%) and did not correlate with other immune checkpoint ligands including PD-L1, GAL-9, and B7H4 in NSCLC. Review of the TCGA database identified CD73 expression is highest in thyroid carcinoma and significant in lung cancer. The prevalence of CD73 protein expression by IHC in NSCLC cell lines was 84.8% (39/46) and 15.4% (6/39) in SCLC cell lines. We also evaluated CD73 protein expression in a NSCLC cohort with a prevalence of 32.1% (36/112), with no significant correlation to patient clinical characteristics or outcomes. Conclusions: We evaluated the expression of the immune checkpoint, CD73, in lung cancer cell lines and tissues. Both genomic data and protein expression by IHC demonstrated CD73 was significantly expressed. However, there was no correlation with other immune biomarkers or patient demographics or outcomes. CD73 is a new target for immunotherapy and current clinical studies with CD73 inhibitors may prove beneficial to lung cancer patients.
Remnant Liver Ischemia as a Prognostic Factor for Cancer-Specific Survival After Resection of Colorectal Liver Metastases
Authors: Suguru Yamashita, Aradhana M. Venkatesan, Takashi Mizuno, Thomas A. Aloia, Yun S. Chun, Jeffrey E. Lee, Jean-Nicolas Vauthey, Claudius Conrad
Journal: JAMA Surgery (2017)

Ischemia-reperfusion injury during hepatic resection has been shown to accelerate progression of liver cancer. However, the prognostic relevance of remnant liver ischemia (RLI) after resection of colorectal liver metastases (CLMs) is unknown to date.
左房内巨大球状血栓を生じ,その後浮遊血栓となり,突如消失した僧帽弁狭窄症の一例
Authors: 諏訪賢一郎, 俵原敬, 間遠文貴, 浮海洋史, 尾関真理子, 野中大史
Journal: Circulation (2008)
Treatment of HIV-associated Kaposi's sarcoma with aldoxorubicin.
Authors: Christopher Parsons, Shanta Chawla, Hillary Dinh, Scott Wieland, Jim Outland, Om Prakash, Daniel J. Levitt
Journal: Journal of Clinical Oncology (2016)

11038 Background: In the past Kaposi's sarcoma (KS) was a major cause of morbidity and mortality in HIV-infected individuals. Risk factors are defined by the TIS scoring system (tumor extent, immune status, symptom score, 0 or 1 each) with scores > / = 1 = increased risk. Current treatments for KS involve either liposomal doxorubicin(LD) or paclitaxel (P), each with up to 50% grade 3/4 AEs. Aldoxorubicin (A) is doxorubicin attached to a pH sensitive linker that binds covalently and specifically to albumin. We have treated 15 patients with KS with low dose A and monitored tumor response, adverse events and accumulation of A in the tumor and peritumor tissue. Methods: Of the 15 patients entered in the study 4 had received prior D, 1 prior LD and 1 prior P. Patients were administered either 50 mg/m2A (1), 100 mg/m2 A (7) or 150 mg/m2A (7) every 3 weeks by IV infusion. Tumor response and adverse events were recorded. Presence of KS human herpes virus (KS HHV-8; LANA+ cells) in biopsies was detected by immunofluorescence. Uptake of A in into biopsies of tumor and peritumoral tissue was assessed via a validated HPLC method. Results: 7 patients had a maximum TIS score of 3, 4 had a TIS score of 2, and 4 had a TIS score of 1. All were males. Average age was 35 years (23-57); 8 black and 7 white. Median number of cycles administered was 6 (1-9). Median exposure for the 100 mg/m2 dose was 614 mg/m2 Dequivalents (Deq), (range 130-1261 mg/m2 Deq); for 150 mg/m2 dose it was 1094 mg/m2 Deq (range 234-1787 mg/m2Deq). 4 subjects experienced grade 3/4 neutropenia; other grade 3/4 AEs were rare. 2 SAEs were treatment related (neutropenia, paresthesia). Best responses included 10 PRs, 1 SD and 1 PD of 12 evaluable patients. Average concentration of A in tumors was 31.4 +/- 4.6 ng/mg tissue and in the peritumoral tissue 23.5 +/- 7.2 ng/mg tissue. 5 patients were evaluated for LANA+ cells had either complete or partial disappearance of infected cells. All patients with extensive pulmonary lesions had either a CR or PR. Conclusions: A is an active drug for the treatment of HIV-associated KS even in patients with extensive disease and who had received prior doxorubicin therapy. It is detected in tumor tissue and is associated with marked improvement in pulmonary symptoms and decreases in HHV-8 infected KS cells. Clinical trial information: NCT02029430.
Abstract P230: Orchestration of Cardiac Mitochondrial Biogenesis by Mitofusin2
Authors: Yun Chen, Scot Matkovich, Yan Zhang, Yingqiu Liu, Gerald Dorn
Journal: Circulation Research (2011)

Mitochondria generate energy and play central roles governing cell signaling and programmed death. As an energy dependant tissue, the heart is more affected by mitochondrial dysfunction than other tissues. Mitochondrial fusion and fission are essential for normal morphology and function. Mitofusins Mfn1 and Mfn2 are the key components to process mitochondrial fusion. Previous data shows that Mfn1 and Mfn2 are functional redundant in skeletal muscle and the drosophila heart tube. But the role for the mitochondrial fusion proteins in mammalian cardiac myocytes is unknown. The functional role of mitofusins in the mammalian heart was investigated by conditional gene deletion of Mfn1 and Mfn2 in mice. Mice with myh6Cre-directed inactivation of Mfn1 exhibited normal cardiac structure and function. In contrast, ablation of Mfn2 in mouse heart caused progressive dilated cardiomyopathy. At 6 weeks old, the cardiac structure and function were normal, but at 16 weeks old, Mfn2 null mice developed severe cardiac dilation and impaired contractile performance at baseline and in response to β-adrenergic stimulation without induction of programmed cell death. Cardiomyocytes from young Mfn2 null mice had normal excitation-contraction coupling, whereas older cardiomyocytes showed decreased fractional shortening with normal calcium cycling. mRNA resequencing of Mfn2 null hearts revealed that cardiac dysfunction was associated with induction of nuclear-encoded mitochondrial genes. Mfn2 deficient cardiac mitochondria displayed normal function of the mitochondrial permeability transition, respiration and expression of respiration chain complexes, but increased mitochondrial oxidant stress. Remarkably, the development of cardiomyopathy paralleled dramatic (60-80%) loss of mitochondria, measured both as the ratio of mitochondrial DNA to nuclear DNA, and as μg protein/mg cardiac protein. Conclusion: 1. Mfn1 and Mfn2 are not redundant in the heart.Mfn1 is dispensable for normal cardiac development and function. 2. Mfn2 deficiency reacts in a dilated cariomyopathy caused not by a failure of mitochondrial function, but by a crisis of mitochondrial biogenesis.
高浸潤性乳癌の治療のための血管新生と循環腫瘍細胞二重標的ナノ粒子【Powered by NICT】
Authors: Yao Jianhui, Feng Jingxian, Gao Xiaoling, Wei Dan, Kang Ting, Zhu Qianqian, Jiang Tianze, Wei Xunbin, Chen Jun
Journal: Biomaterials (2017)
Treat-and-Extend versus Monthly Regimen in Neovascular Age-Related Macular Degeneration
Authors: Rufino Silva, András Berta, Michael Larsen, Wayne Macfadden, Chrystel Feller, Jordi Monés
Journal: Ophthalmology (2017)

To evaluate the efficacy and safety of ranibizumab 0.5 mg treat-and-extend (T&E) versus monthly regimens in patients with neovascular age-related macular degeneration (nAMD) from the TReat and extEND (TREND) study.A 12-month phase 3b visual acuity (VA) assessor-masked, multicenter, randomized, interventional study.Six hundred fifty patients.Treatment-naïve nAMD patients (age, ≥50 years) were randomized 1:1 to receive either a ranibizumab 0.5 mg T&E (n = 323) or monthly (n = 327) regimen.The primary objective was to show noninferiority of ranibizumab 0.5 mg T&E versus monthly regimen, as assessed by the change in best-corrected VA (BCVA) from baseline to the end of the study. Secondary objectives included change in retinal central subfield thickness (CSFT) from baseline to the end of study, treatment exposure, and safety.Overall, 89.8% (T&E) and 90.2% (monthly) of patients completed the study. Patient demographic and baseline characteristics were well balanced between the 2 treatment groups. The T&E regimen was noninferior (P < 0.001) to the monthly regimen, with a least squares mean BCVA change from baseline of 6.2 versus 8.1 letters to the end of study, respectively. In both treatment groups, most BCVA improvements occurred during the first 6 months and were maintained until the end of the study. The mean change in CSFT from baseline to the end of study was -169.2 μm and -173.3 μm in the T&E and monthly groups, respectively. Fewer injections were required in patients receiving the T&E (8.7) versus monthly (11.1) regimen, with mean number of postbaseline visits of 8.9 and 11.2, respectively. Types and rates of adverse events were comparable between the treatment groups.Ranibizumab 0.5 mg administered according to a T&E regimen was statistically noninferior and clinically comparable with a monthly regimen in improving VA from baseline to the end of study. No new safety signals for ranibizumab were identified.
MSF criticises India’s decision to grant pneumococcal vaccine patent to Pfizer
Authors: Sumi S Dutta
Journal: BMJ (2017)

India’s decision to grant a patent on the pneumococcal conjugate vaccine (PCV, sold as Prevnar 13) to the drug company Pfizer has been criticised by the international humanitarian agency Medecins Sans Frontieres (MSF).

Last month India’s patent office ruled that PCV, designed to protect against 13 strains of Streptococcus pneumoniae , met criteria for “novelty and inventiveness,” dismissing independent oppositions filed by MSF and Panacea Biotec, an Indian manufacturer.

Pfizer will now have the right to exclusively sell the vaccine in India until 2026. MSF—which has procured antituberculosis and antiretroviral drugs, antibiotics, and vaccines from Indian generic manufacturers for over a decade—had been hoping to use an inexpensive Indian version of the PCV to expand immunisation services in Asian and African countries.

MSF opposed Pfizer’s application …
Abstract 17301: Functional Characterization of KCNK3 Mutants Associated With Pulmonary Arterial Hypertension Under Physiologically Relevant Heterozygous Conditions
Authors: Michael S Bohnen, Danilo Roman-Campos, Cecile Terrenoire, Jack Jnani, Lei Chen, Kevin S Sampson, Wendy K Chung, Robert S Kass
Journal: Circulation (2015)

KCNK3 encodes a two-pore domain K+ channel, TASK-1, which is inhibited by extracellular acidity and hypoxia. Expressed in a variety of tissues, including human pulmonary artery smooth muscle cells (hPASMCs), the central nervous system, pancreas, and adrenal glands, TASK-1 contributes to the resting membrane potential of cells in which it is expressed. Recently, our group reported mutations in KCNK3 underlying idiopathic pulmonary arterial hypertension (PAH), resulting from loss of TASK-1 function, partially pharmacologically rescuable with ONO-RS-082. TASK-1 dimerizes in vivo, forming functional channels with another TASK-1 subunit or with the related TASK-3 channel. TASK-1 and TASK-3 often are expressed in the same cells, although it has been reported that TASK-1 alone is expressed in the lung. Our initial study examined mutant and wildtype (WT) homodimeric TASK-1 channels expressed heterologously in COS-7 cells. Here we further characterize PAH-linked TASK-1 mutations in physiologically relevant heterozygous conditions in COS-7 and hPASMC cell lines. We engineered heterodimeric channels consisting of one mutant and one WT subunit; compared this with co-expression of mutant and WT channels; and measured channel activity with whole cell patch clamp procedures. We found a mutation specific impact of heterozygosity on channel activity. One mutation, V221L, produces a shift in pH dependence accounting for loss of function at physiological pH 7.4, partially rescued by dimerization with a WT subunit, while another, G203D, produces near complete loss of function as a homo- or hetero-dimer. The presence of TASK-3 results in greater rescue of V221L TASK-1 activity at pH 7.4 than does WT TASK-1. Additionally, under current clamp we found that ONO-RS-082 hyperpolarizes the membrane potential in hPASMCs expressing WT or V221L TASK-1, reversible by selective block of TASK-1 with ML365. Together, our results suggest (a) TASK-1 mutant heterodimers exhibit loss of function with mutation specific severity; (b) TASK-3 may rescue mutant TASK-1 and underlie a tissue specific impact of the TASK-1 mutations observed clinically; and (c) PAH TASK-1 mutants can be pharmacologically modulated in hPASMCs and alter the critically important resting membrane potential.
Epigenetics in pediatric acute lymphoblastic leukemia
Authors: Jessica Nordlund, Ann-Christine Syvänen
Journal: Seminars in Cancer Biology (2017)

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. ALL arises from the malignant transformation of progenitor B- and T-cells in the bone marrow into leukemic cells, but the mechanisms underlying this transformation are not well understood. Recent technical advances and decreasing costs of methods for high-throughput DNA sequencing and SNP genotyping have stimulated systematic studies of the epigenetic changes in leukemic cells from pediatric ALL patients. The results emerging from these studies are increasing our understanding of the epigenetic component of leukemogenesis and have demonstrated the potential of DNA methylation as a biomarker for lineage and subtype classification, prognostication, and disease progression in ALL. In this review, we provide a concise examination of the epigenetic studies in ALL, with a focus on DNA methylation and mutations perturbing genes involved in chromatin modification, and discuss the future role of epigenetic analyses in research and clinical management of ALL.
Chronic Obstructive Pulmonary Disease in Hispanics. A 9-Year Update
Authors: Alejandro A. Díaz, Bartolomé Celli, Juan C. Celedón
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Until recently, spirometry reference equations were available for Mexican Americans but not for other U.S. Hispanic subgroups.Using data from more than 16,000 subjects, the HCHS/SOL (Hispanic Community Health Study/Study of Latinos) generated spirometry reference equations for specific Hispanic subgroups (9), including Mexicans, Puerto Ricans, Cubans,
Effects of a Telephone- and Web-based Coping Skills Training Program Compared with an Education Program for Survivors of Critical Illness and Their Family Members. A Randomized Clinical Trial
Authors: Christopher E. Cox, Catherine L. Hough, Shannon S. Carson, Douglas B. White, Jeremy M. Kahn, Maren K. Olsen, Derek M. Jones, Tamara J. Somers, Sarah A. Kelleher, Laura S. Porter
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Many survivors of critical illness and their family members experience significant psychological distress after patient discharge.To compare the effects of a coping skills training (CST) program with an education program on patient and family psychological distress.In this five-center clinical trial, adult patients who received mechanical ventilation for more than 48 hours and one family member of each patient were randomized to six weekly CST telephone sessions plus access to a study website or a critical illness education program.The primary outcome was the patient Hospital Anxiety and Depression Scale (HADS) score at 3 months. Secondary outcomes included 3- and 6-month HADS subscales and the Impact of Events Scale-Revised. Among the 175 patients randomized to CST (n = 86) or education (n = 89), there was no significant difference between CST and education in either 3-month HADS scores (difference, 1.3; 95% confidence interval [CI], -0.9 to 3.4; P = 0.24) or secondary patient and family outcomes. In prespecified analyses, among patients with high baseline distress (n = 60), CST recipients had greater improvement in 6-month HADS score (difference, -4.6; 95% CI, -8.6 to -0.6; P = 0.02) than the education group. Among patients ventilated longer than 7 days (n = 47), education recipients had greater improvement in 3-month HADS score (difference, -4.0; 95% CI, -8.1 to -0.05; P = 0.047) than the CST group.CST did not improve psychological distress symptoms compared with an education program. However, CST improved symptoms of distress at 6 months among patients with high baseline distress, whereas the education program improved distress at 3 months among those ventilated for more than 7 days. Future efforts to address psychological distress among critical illness survivors should target high-risk populations. Clinical trial registered with www.clinicaltrials.gov (NCT01983254).
Hypoplastic Left Heart Syndrome With Intact or Restrictive Atrial Septum
Authors: David W. Jantzen, Anita J. Moon-Grady, Shaine A. Morris, Aimee K. Armstrong, Christoph Berg, Joanna Dangel, Carlen G. Fifer, Michele Frommelt, Ulrich Gembruch, Ulrike Herberg, Edgar Jaeggi, Eftichia V. Kontopoulos, Audrey C. Marshall, Owen Miller, Renate Oberhoffer, Dick Oepkes, Carlos A. Pedra, Simone R. Pedra, Fabio Peralta, Ruben A. Quintero, Greg Ryan, Sarah K. Gelehrter
Journal: Circulation (2017)
蛋白質コロナ形成を経て調製された合成ウイルス様粒子はコロナウイルス感染の鳥類モデルにおける効果的なワクチン接種を可能にする【Powered by NICT】
Authors: Chen Hui-Wen, Huang Chen-Yu, Lin Shu-Yi, Fang Zih-Syun, Hsu Chen-Hsuan, Lin Jung-Chen, Chen Yuan-I, Yao Bing-Yu, J Hu Che-Ming
Journal: Biomaterials (2016)
Abstract 211: Intercellular Adhesion Molecule 1 Regulates Cardiac Remodeling and Function and T Cell Recruitment to the Heart in Pressure Overload Induced Heart Failure
Authors: Ane Miren Salvador, Tania Nevers, Mark Aronovitz, Robert Blanton, Pilar Alcaide
Journal: Circulation Research (2015)

Background: Left ventricular (LV) dysfunction and Heart Failure (HF) are associated in humans with systemic inflammation, including increased circulating levels of pro-inflammatory cytokines and soluble intercellular cell adhesion molecule-1 (ICAM-1). Endothelial ICAM-1 regulates leukocyte recruitment into tissues, which in the heart can result in altered cardiac function. We hypothesize that ICAM-1 regulates cardiac remodeling by mediating leukocyte recruitment to the LV and thus contributing to worsening of cardiac function during pressure overload induced HF. Methods and results: We used the mouse model of Thoracic Aortic Constriction (TAC) to induce LV remodeling and HF in WT and ICAM-1 deficient mice (ICAM-1 -/- ). Immunohistochemistry, flow cytometry, qPCR, echocardiography and hemodynamics were used to investigate leukocyte infiltration into the LV, cardiac function, hypertrophy and fibrosis mechanisms taking place in response to TAC. Endothelial ICAM-1 was upregulated in WT mice in response to TAC as compared to Sham, correlating with LV T cell infiltration. In contrast, CD3+ and CD4+ T cell recruitment into the LV was significantly reduced in response to TAC in ICAM-1 -/- mice as compared to WT mice. Further, indices of sistolic and diastolic function were preserved in ICAM-1 -/- mice (dP/dt max = WT TAC 5,627±549 vs. ICAM-1 -/- TAC 8,396±1,495 ; dP/dt min = WT TAC -5,614±1,195 vs. ICAM- 1-/- TAC -8,832±2,274) and the End Diastolic Pressure was significantly lower than in WT TAC mice (31.0±7.0mmHg in WT TAC vs 8.1±7.8mmHg in ICAM-1 -/- TAC). Despite increased LV weight, ICAM-1 -/- did not develop fibrosis in response to TAC, with blunted collagen deposition and lack of mRNA upregulation of fibrotic markers Collagen-I, TGFβ and SMAα four and ten weeks after TAC when dilated cardiomiopathy is established in WT mice. Conclusion: Our data indicate that ICAM-1 regulates LV T cell infiltration, cardiac function and fibrosis in HF induced by TAC. Further studies will determine whether ICAM-1 contributes to HF pathogenesis exclusively by regulating T cell interactions with the LV endothelium or participating in novel mechanisms regulating cardiac cell function, which could represent new targets for the treatment of this deadly syndrome.
AB0035 Angiopoietins: the missing link in poems syndrome?
Authors: F Coutant, Z Tatar, P Rouzaire, B Evrard, A Dosgilbert, O Tournilhac, G Le Guenno, R Lemal, M Soubrier
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy and Skin changes) is a rare multiorgan disease related to plasma cell dyscrasia. The pathogenesis of the POEMS syndrome is currently unknown, but microangiopathy involving neoangiogenesis and increased vascular permeability may explain some of the features of the disorder. Although vascular endothelial growth factor (VEGF) is constantly highly abundant in the serum of patients with POEMS syndrome, therapeutic approaches targeting the VEGF have led to conflicting results, suggesting that other mediators sharing functional similarities with the VEGF contribute to the pathogenesis. Angiopoietins are known to be involved in the development, remodeling and stability of blood vessels. It is thus tempting to speculate that altered expression of angiopoietins might contribute to the pathogenesis. <h3>Objectives</h3> The aim of this study was to evaluate the circulating levels of three major angiogenic cytokines in patients before and after treatment: VEGF, angiopoietin-1, which plays an essential role in the stabilization and the maturation of blood vessels, and angiopoietin-2 that facilitates angiogenesis in the presence of VEGF. <h3>Methods</h3> Circulating levels of VEGF, Angiopoietin-1 and angiopoietin-2 were determined by ELISA in the serum of 3 patients with POEMS syndrome, before and after therapy. All patients had polyneuropathy, organomegaly, a monoclonal gammopathy (2 IgAl, 1 IgGk) and osteosclerotic lesions. Two patients had typical skin lesions, oedema and one patient had a Castleman disease. <h3>Results</h3> As expected, the serum of patients before treatment exhibited high levels of VEGF (2901±920 pg/mL). Strikingly, angiopoietin-1 levels were highly abundant before treatment (67286±20395 pg/mL) and successful treatment led to a strong reduction in both VEGF and angiopoietin-1. Angiopoietin-1 levels strongly correlated with levels of VEGF (r=0.83). By contrast, angiopoietin-2 levels did not differ significantly before and after treatment. <h3>Conclusions</h3> Thus, angiopoietin-1 seems to be a crucial proangiogenic cytokine overproduced in patients with POEMS syndrome that might explain some of the features of the pathology. The overproduction of VEGF and angiopoietin-1 is likely to promote manifestations encountered in POEMS syndrome such as organomegaly, osteosclerotic lesions or glomeruloid hemangioma. Restoring the balance between angiopoitein-1, angiopoietin-2 and VEGF could constitute a very promising therapeutic strategy in this disease. <h3>Disclosure of Interest</h3> None declared