tbuckley/cabot-search huggingface dataset:
Partial efficacy of a broadly neutralizing antibody against cell-associated SHIV infection
Authors: Matthew S. Parsons, Sarah B. Lloyd, Wen Shi Lee, Anne B. Kristensen, Thakshila Amarasena, Rob J. Center, Brandon F. Keele, Jeffrey D. Lifson, Celia C. LaBranche, David Montefiori, Bruce D. Wines, P. Mark Hogarth, Kristine M. Swiderek, Vanessa Venturi, Miles P. Davenport, Stephen J. Kent
Journal: Science Translational Medicine (2017)

Broadly neutralizing antibodies (BnAbs) protect macaques from cell-free simian/human immunodeficiency virus (SHIV) challenge, but their efficacy against cell-associated SHIV is unclear. Virus in cell-associated format is highly infectious, present in transmission-competent bodily fluids, and potentially capable of evading antibody-mediated neutralization. The PGT121 BnAb, which recognizes an epitope consisting of the V3 loop and envelope glycans, mediates antibody-dependent cellular cytotoxicity and neutralization of cell-to-cell HIV-1 transmission. To evaluate whether a BnAb can prevent infection after cell-associated viral challenge, we infused pigtail macaques with PGT121 or an isotype control and challenged animals 1 hour later intravenously with SHIVSF162P3-infected splenocytes. All five controls had high viremia 1 week after challenge. Three of six PGT121-infused animals were completely protected, two of six animals had a 1-week delay in onset of high viremia, and one animal had a 7-week delay in onset of viremia. The infused antibody had decayed on average to 2.0 μg/ml by 1 week after infusion and was well below 1 μg/ml (range, <0.1 to 0.8 μg/ml) by 8 weeks. The animals with a 1-week delay before high viremia had relatively lower plasma concentrations of PGT121. Transfer of 22 million peripheral blood mononuclear cells (PBMCs) stored at weeks 1 to 4 from the animal with the 7-week delayed onset of viremia into uninfected macaques did not initiate infection. Our results show that HIV-1-specific neutralizing antibodies have partial efficacy against cell-associated virus exposure in macaques. We conclude that sustaining high concentrations of bioavailable BnAb is important for protecting against cell-associated virus.
02.23 Translationally controlled tumour protein is a critical therapeutic target for rheumatoid arthritis
Authors: Sang-Il Lee, Min-Gyu Jeon, Jung-Yoon Choe, Jinseok Kim, Heewon Lee, Kyunglim Lee
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Rheumatoid arthritis (RA) is an invasive inflammatory disease leading to severe joint destruction. Fibroblast-like synoviocytes of rheumatoid arthritis (RA-FLS) are key players in RA, and have tumor-like characteristics such as abnormal proliferation and invasion. Translationally Controlled Tumour Protein (TCTP) has been known as a multifunctional protein in cancer progression and allergic response. However, there has been no study to assess the potential roles of TCTP in RA. <h3>Materials and methods</h3> The levels of TCTP were checked in the synovial tissue, serum, and synovial fluid of RA patients.The pathologic roles of TCTP were investigated in RA-FLS and TCTP knockdown (kdTCTP) mice with collagen-induced arthritis (CIA). The preventive and therapeutic effects of inhibitor of TCTP were evaluated in CIA mice on the basis of clinical, radiographic, and pathologic scores. <h3>Results</h3> TCTP expression was higher in the synovial tissue, serum, and synovial fluid of RA patients than control groups. Dimerized TCTP (dTCTP), as an active form of TCTP, exhibits pro-inflammatory cytokine-like activity, thus dTCTP induced cell proliferation, cytokine secretion, migration, and invasion of RA-FLS. Based on these <i>in vitro</i> observations, <i>in vivo</i> experiment using CIA was performed in kdTCTP and wild type (WT) mice. The results showed that inflammatory response and bone destruction were significantly decreased in kdTCTP mice than WT by investigating clinical score, micro-CT, histological, and biochemical analysis. Finally, we confirmed that dTBP2, as an inhibitor of dTCTP, suppressed tumor-like characteristics of RA-FLS, and had protective and therapeutic effects in CIA mice. <h3>Conclusions</h3> Collectively, we suggest that TCTP is a critical therapeutic target and the use of dTBP2 may be a beneficial strategy for the RA treatment.
Clinical outcome of EGFR-mutant NSCLC patients continuing TKIs beyond progression in combination with local ablative radiotherapy.
Authors: Sabrina Rossi, Giovanna Finocchiaro, Ettore D'Argento, Vincenzo Pio Di Noia, Alessandra Cassano, Maria Bonomi, Eleonora Cerchiaro, Giovanni Luca Ceresoli, Giordano D. Beretta, Carlo Barone, Armando Santoro, Luca Toschi
Journal: Journal of Clinical Oncology (2017)

e20662 Background: Continuation of EGFR TKIs with or without local ablative treatments in patients with metastatic EGFR-mutant NSCLC experiencing disease progression under TKIs is feasible and may be associated with improved outcomes. Methods: The retrospective analysis includes 130 patients with advanced EGFR-mutant NSCLC experiencing RECIST disease progression under first-line gefitinib or afatinib, treated in 3 Italian centers between 2011 and 2016. In group 1 (n = 99, 76.2%) patients stopped TKI treatment at first RECIST-confirmed progression while in group 2 (n = 31, 23.8%) TKIs were continued and sites of progression were irradiated. The primary endpoint was overall survival (OS). Progression-free survival (PFS) and time to treatment failure (TTF) were calculated from the start of first-line TKIs. Kaplan-Meier method, the log-rank test and multivariate Cox regression models were used to estimate outcome endpoints. Median follow-up time was 40 months. Results: Median OS, PFS and TTF in the whole cohort were 22.4, 11.1 and 13.0 months, respectively. The two groups resulted well balanced in terms of patients’ characteristics and TKI administered. Median OS was significantly longer in group 2 (37.3 vs 15.6 months; HR 0.33; 95%CI 0.22-0.50; p &lt; 0.0001), as well as median PFS (13.8 vs 8.9 months; HR 0.60; 95%CI 0.42-0.86; p = 0.01) and median TTF (29.3 vs 10.4 months; HR 0.30; 95%CI 0.21-0.44; p &lt; 0.0001). Ten out of 31 (32.3%) patients underwent radiotherapy in ≥2 sites of progressive disease; the most frequently irradiated site was bone (n = 16), followed by brain (n = 9), lung (n = 8) and lymph nodes (n = 6). On multivariate analysis including age, sex, smoking history, mutant exon, presence of brain metastases, TKI administered and treatment strategy at progression, only TKI continuation with radiotherapy was independently associated with all outcome endpoints (OS: p = 0.0007, PFS: p = 0.004; TTF: p &lt; 0.0001). Conclusions: In EGFR-mutant NSCLC progressing under first-line TKIs continuation of TKI in association with local ablative radiotherapy is associated with prolonged OS, PFS and TTF. Whether the improved outcome is a result of treatment strategy or more indolent disease remains unclear.
CT-Detected Growth of Coronary Artery Calcification in Asymptomatic Middle-Aged Subjects and Association With 15 Biomarkers
Authors: Søren Zöga Diederichsen, Mette Hjortdal Grønhøj, Hans Mickley, Oke Gerke, Flemming Hald Steffensen, Jess Lambrechtsen, Niels Peter Rønnow Sand, Lars Melholt Rasmussen, Michael Hecht Olsen, Axel Diederichsen
Journal: JACC. Cardiovascular imaging (2017)
Improving iron supplements: cooking with GOS
Authors: Hal Drakesmith, Stephen J Allen
Journal: Gut (2017)

Iron is essential for oxygen transport, generation of energy, synthesis of DNA and multiple enzymatic systems. Iron deficiency impairs these functions and a familiar and important manifestation of advanced iron deficiency is anaemia. Around a quarter of a billion children worldwide are anaemic, and at least half of childhood anaemia is caused in part by a lack of iron; a heavy burden of anaemia is especially present in sub-Saharan Africa and South Asia.1 Iron replenishments, including iron-containing multiple micronutrient powders (MNPs) can be effective treatments to increase haemoglobin. However, despite the use of such agents for many years, the estimated prevalence of anaemia worldwide in preschool children only decreased from 47% to 43% between 1993 and 2011.2 Furthermore, iron replenishments have been associated with adverse events, including infections, intestinal inflammation and diarrhoea in some (but not all) trials. There is a need to make iron treatments both safer and more effective especially in the developing world, and the study in Kenya by Zimmermann and colleagues3 in this issue of Gut addresses these issues.

Iron is needed for growth by humans, and the microbes that colonise and infect us. In particular, pathogenic bacteria in the gut require iron for their virulence, while conversely beneficial …
In Vivo Genome Editing Restores Dystrophin Expression and Cardiac Function in Dystrophic Mice
Authors: Mona El Refaey, Li Xu, Yandi Gao, Benjamin D. Canan, T.M. Ayodele Adesanya, Sarah C. Warner, Keiko Akagi, David E. Symer, Peter J. Mohler, Jianjie Ma, Paul M.L. Janssen, Renzhi Han
Journal: Circulation Research (2017)

Rationale: Duchenne muscular dystrophy is a severe inherited form of muscular dystrophy caused by mutations in the reading frame of the dystrophin gene disrupting its protein expression. Dystrophic cardiomyopathy is a leading cause of death in Duchenne muscular dystrophy patients, and currently no effective treatment exists to halt its progression. Recent advancement in genome editing technologies offers a promising therapeutic approach in restoring dystrophin protein expression. However, the impact of this approach on Duchenne muscular dystrophy cardiac function has yet to be evaluated. Therefore, we assessed the therapeutic efficacy of CRISPR (clustered regularly interspaced short palindromic repeats)-mediated genome editing on dystrophin expression and cardiac function in mdx/Utr +/− mice after a single systemic delivery of recombinant adeno-associated virus. Objective: To examine the efficiency and physiological impact of CRISPR-mediated genome editing on cardiac dystrophin expression and function in dystrophic mice. Methods and Results: Here, we packaged SaCas9 (clustered regularly interspaced short palindromic repeat–associated 9 from Staphylococcus aureus ) and guide RNA constructs into an adeno-associated virus vector and systemically delivered them to mdx/Utr +/− neonates. We showed that CRIPSR-mediated genome editing efficiently excised the mutant exon 23 in dystrophic mice, and immunofluorescence data supported the restoration of dystrophin protein expression in dystrophic cardiac muscles to a level approaching 40%. Moreover, there was a noted restoration in the architecture of cardiac muscle fibers and a reduction in the extent of fibrosis in dystrophin-deficient hearts. The contractility of cardiac papillary muscles was also restored in CRISPR-edited cardiac muscles compared with untreated controls. Furthermore, our targeted deep sequencing results confirmed that our adeno-associated virus-CRISPR/Cas9 strategy was very efficient in deleting the ≈23 kb of intervening genomic sequences. Conclusions: This study provides evidence for using CRISPR-based genome editing as a potential therapeutic approach for restoring dystrophic cardiomyopathy structurally and functionally.
C-Terminal Fibroblast Growth Factor 23, Iron Deficiency, and Mortality in Renal Transplant Recipients
Authors: Michele F. Eisenga, Marco van Londen, David E. Leaf, Ilja M. Nolte, Gerjan Navis, Stephan J.L. Bakker, Martin H. de Borst, Carlo A.J.M. Gaillard
Journal: Journal of the American Society of Nephrology (2017)

Iron deficiency (ID) is independently associated with an increased risk of death in renal transplant recipients (RTRs). ID promotes production and cleavage of intact fibroblast growth factor 23 (iFGF23) into C-terminal fibroblast growth factor 23 (cFGF23), elevated levels of which are also prospectively associated with adverse outcomes. We hypothesized that in RTRs, the relationship between ID and mortality is mediated by FGF23. We measured plasma iFGF23 and cFGF23 levels in 700 stable RTRs at a median of 5.4 years after transplant. RTRs with ID had median (interquartile range) cFGF23 concentrations higher than those of RTRs without ID (223 [131-361] versus 124 [88-180] RU/ml; P<0.001), whereas iFGF23 concentrations were similar between groups. In multivariable-adjusted Cox regression analyses, ID associated with increased mortality (81 events; hazard ratio, 1.95; 95% confidence interval, 1.22 to 3.10; P<0.01). However, this association lost significance after additional adjustment for cFGF23 levels (hazard ratio, 1.45; 95% confidence interval, 0.87 to 2.51; P=0.15). In further mediation analysis, cFGF23 explained 46% of the association between ID and mortality, whereas iFGF23 did not mediate this association. In conclusion, we found that cFGF23 levels are increased in iron-deficient RTRs and that the underlying biologic process driving production and cleavage of iFGF23, or alternatively the increased level of cFGF23 fragments, probably is an important mediator of the association between ID and mortality. Our results underline the strong relationship between iron and FGF23 physiology, and provide a potential mechanism explaining the relationship between ID and adverse outcome in RTRs.
12回ラジオ波焼灼療法施行後,食道胃接合部癌肝転移局所再発に対し,右肝切除を施行した1症例
Authors: 伊藤大介, 河口義邦, 長谷川潔, 山下裕玄, 阿部浩幸, 五ノ井渉, 有田淳一, 赤松延久, 金子順一, 阪本良弘, 瀬戸泰之, 國土典宏
Journal: Liver Cancer (2016)
Tubulointerstitial Nephritis with IgM-Positive Plasma Cells
Authors: Naoki Takahashi, Takako Saeki, Atsushi Komatsuda, Chishio Munemura, Takeaki Fukui, Naofumi Imai, Noriyuki Homma, Tsuguru Hatta, Ken-ichi Samejima, Takashi Fujimoto, Hiroki Omori, Yumi Ito, Yudai Nishikawa, Mamiko Kobayashi, Yukie Morikawa, Sachiko Fukushima, Seiji Yokoi, Daisuke Mikami, Kenji Kasuno, Hideki Kimura, Tomoyuki Nemoto, Yasunari Nakamoto, Kiyonao Sada, Manabu Sugai, Hironobu Naiki, Haruyoshi Yoshida, Ichiei Narita, Yoshihiko Saito, Masayuki Iwano
Journal: Journal of the American Society of Nephrology (2017)

Infiltration by IgG-positive plasma cells is a common finding in tubulointerstitial nephritis. Indeed, it has been thought that CD138-positive mature plasma cells secrete mainly IgG, and the occurrence of tubulointerstitial nephritis with CD138-positive plasma cells secreting IgM has rarely been reported. Routine immunofluorescence of fresh frozen sections is considered the gold standard for detection of immune deposits. However, the immunoenzyme method with formalin-fixed, paraffin-embedded sections is superior for detecting IgM- or IgG-positive cells within the renal interstitium, thus histologic variants may often go undetected. We recently discovered a case of tubulointerstitial nephritis showing IgM-positive plasma cell accumulation within the interstitium. To further explore the morphologic and clinical features of such cases, we performed a nationwide search for patients with biopsy-proven tubulointerstitial nephritis and high serum IgM levels. We identified 13 patients with tubulointerstitial nephritis and IgM-positive plasma cell infiltration confirmed with the immunoenzyme method. The clinical findings for these patients included a high prevalence of distal renal tubular acidosis (100%), Fanconi syndrome (92%), and anti-mitochondrial antibodies (82%). The pathologic findings were interstitial nephritis with diffusely distributed CD3-positive T lymphocytes and colocalized IgM-positive plasma cells, as well as tubulitis with CD3-positive T lymphocytes in the proximal tubules and collecting ducts. Additionally, levels of H+-ATPase, H+, K+-ATPase, and the HCO3--Cl- anion exchanger were markedly decreased in the collecting ducts. We propose to designate this group of cases, which have a common histologic and clinical form, as IgM-positive plasma cell-tubulointerstitial nephritis.
Defining Haemostatic Safety Zones for the Practice of Sport in Patients with Severe Haemophilia By Thromboelastography
Authors: Ihosvany Fernandez-Bello, MT Alvarez-Román, H de la Corte-Rodríguez, N Butta, AL Hernández-Moreno, S Rivas Muñoz, M Martín-Salces, EC Rodriguez-Merchan, Miguel Canales Albendea, V Jiménez-Yuste
Journal: Blood (2016)
Modelling future trends in cystic fibrosis demography using the French Cystic Fibrosis Registry: update and sensitivity analysis
Authors: Pierre-Régis Burgel, Gil Bellis, J. Stuart Elborn
Journal: European Respiratory Journal (2017)

Working with a group of investigators from the European Respiratory Society (ERS)/European Cystic Fibrosis Society (ECFS) task force for the "Provision of care in adults with cystic fibrosis (CF)" [1], we have previously modelled future trends in CF demography in European countries by calculating flows of patients entering and exiting CF cohorts in each country [2]. In that report, we used individual country data contained in the ECFS Patient Registry and were able to calculate demographic forecasts for several European Countries, including France [2]. These forecasts, which were based on the assumption that major demographic trends remained stable over time, suggested that a major increase in the number of CF adults was expected in western European countries by 2025 [1, 2]. In France, our forecast predicted an increase by 45.5% in the CF population between 2010 and 2025, corresponding to an increase by 18.4% in the paediatric population and an increase by 75.7% in the adult population [2]. Data confirm that a major increase in the adult cystic fibrosis population is expected within 10 years in France <http://ow.ly/8LhD30cKvO7> The authors thanks Lydie Lemonnier and Clémence Dehilotte from Vaincre la Mucoviscidose for help with the French Cystic Fibrosis Registry data.
GDF11: a fountain of youth for the ageing COPD lung?
Authors: Ma’en Obeidat, Don D Sin
Journal: Thorax (2017)

Smoking is the single most important causal risk factor for COPD. The public health campaigns and policies have worked to reduce smoking rates by over 50% since those of the 1970s and are now at an all-time low in the UK,1 Canada and throughout most of the western world. Yet, curiously and paradoxically, the burden of COPD (as measured by its prevalence, hospitalisation and mortality rate) is at an all-time high in these countries, and over the next 20 years, the burden of COPD is expected to more than double.2 Why? 

The answer is a simple math issue related to ageing. Most industrialised countries of the world are getting older and, unquestionably, COPD is an age-related disorder. Whereas COPD is almost unheard of in individuals less than 40 years of age (even among heavy smokers), 1 in 10 lifetime never-smokers and 1 in 3 develop COPD by age 75.3 This notion of accelerated ageing of COPD is supported by animal models, which demonstrate premature appearance of emphysematous lungs in mice, which have genetically altered age-related pathways (eg, Klotho mice).4

Physiologically, ageing can be defined as the progressive decline in homeostasis and loss of tissue and organ functions over time.5 Ageing is a risk factor for many (non-communicable) chronic conditions beyond COPD including cancer, congestive heart failure, dementia, diabetes and osteoarthritis.5 The aetiology of ageing is unknown, but the most popular theory involves accumulation of reactive oxygen species (ROS) related to excess oxidative stress.6 At a cellular level, ageing manifests as an irreversible loss of proliferative capacity of viable mitotic cells, termed cellular senescence. Unlike apoptotic cells, senescent cells remain metabolically active and display a senescence-associated secretory phenotype characterised by the production of proinflammatory cytokines such as interleukin (IL)-6, IL-8 and matrix metalloproteinases (MMPs).7 …
Chen Gao
Authors: Pam Goldberg-Smith
Journal: Circulation Research (2017)

What Can You Say About Your Background, and What BroughtYou to California?As college professors, my parents greatly influenced me by encouraging me to read.They cared not only about my education but the pursuit of my dreams.I was very much inspired by my mother when visiting her lab and watching her students perform experiments in very detailed and rigorous ways.I
Abstract 036: The Role Of Spinal Modulation On The Ventricular Electrophysiology In A Porcine Model
Authors: Wei Zhou, Kentaro Yamakawa, Olujimi Ajijola, Daigo Yagishita, Mariko Takemoto, Eileen So, Peyman Beharash, Marmar Vaseghi, Kalyanam Shivkumar, Aman Mahajan
Journal: Circulation Research (2013)

Background: Enhanced cardiac sympathetic tone has been associated with ventricular arrhythmias and sudden cardiac death. The spinal cord is an important integrative region of afferent and efferent pathways that participate in cardiovascular regulation. The purpose of this study is to investigate the role of spinal processing of cardiac afferent information on ventricular electrophysiology during cardiac sympathoexcitation. Methods: Female Yorkshire pigs (n=5) underwent surgical exposure of the heart and left stellate ganglion (LSG) through thoractomy as well as the dorsal and ventral roots of the spinal cord through laminectomy. A 56-electrode sock was placed over the ventricles to record epicardial electrograms. Animals underwent LSG stimulation in intact, after dorsal root transaction (DRTx), and followed by ventral root transaction (DVRTx). Activation recovery intervals (ARIs) were measured at each electrode before and during LSG stimulation. Results: With intact roots LSG stimulation resulted in significant global ARI shortening by 12.9% (p&lt;0.05). After DRTx, mean global ARI shortened by 7.2%. LSG stimulation after DRTx and DVRTx resulted in greater ARI shortening compared to LSG stimulation with intact roots (21.5 and 18.4 vs 12.9%, p&lt;0.05, see figure 1 below). ARI shortened more during LSG stimulation after DRTx than that after DVRTx (21.5 vs. 18.4%, p&lt;0.05). Conclusion: Spinal afferent pathways play an inhibitory role in sympathoexcitation of ventricle induced by LSG stimulation. This finding provides insight into the mechanism underlying the beneficial effects of thoracic epidural anesthesia in reducing ventricular arrhythmias.
血管内氷温液体を用いた低体温の早期の導入が神経学的結果を改善し(J‐PULSE‐Hypoレジストリー)中心部体温の最適監視を改善する
Authors: Matsuzaki Masakazu, Nagao Ken, Nonogi Hiroshi, Yokoyama Hiroyuki, Yonemoto Naohiro, Kikushima Kimio, Watanabe Kazuhiro, Tominaga Yoshiteru, Tada Katsushige, Ishii Mitsuru, Nishikawa Kei, Soga Taketomo, Tateda Yutaka, Ikeda Harumi, Yagi Tsukasa
Journal: Circulation (2010)
Activation of COX-2 mediates growth arrest and apoptosis induced by perifosine in human lung cancer cells
Authors: Heath Elrod, Ping Yue, Fadlo Khuri, Shi-Yong Sun
Journal: Clinical Cancer Research (2007)

B41   Perifosine is an orally bioavailable alkylphospholipid currently being tested in Phase II clinical trials and has shown efficacy in a number of human tumor types in preclinical studies. In this study, we have revealed a novel mechanism by which perifosine exerts a cyclooxygenase 2 (COX-2) activation-dependent anticancer activity in human non-small cell lung cancer cells. Perifosine induced apoptosis and/or cell cycle arrest in NSCLC cell lines. Unexpectedly, the combination of perifosine with low concentrations of celecoxib, a COX-2 inhibitor, rendered cells less sensitive to apoptosis or cell cycle arrest induced by perifosine. Subsequently, we examined the effects of perifosine on COX-2 expression and activity in a set of lung cancer cell lines and found that perifosine rapidly and potently increased COX-2 levels and activity, the degrees of which correlated to perifosine’s abilities to inhibit the growth of lung cancer cells. Moreover, blockage of COX-2 induction by both antisense and siRNA approaches decreased cell sensitivity to perifosine-induced growth inhibition. Collectively, these data indicate that the induction and activation of COX-2 contribute to perifosine-induced apoptosis and growth arrest in human lung cancer cells. These data are clinically relevant as they suggest that patients who are administered perifosine should not also take COX-2 inhibitors such as celecoxib, so as to avoid potential drug contradiction.