tbuckley/cabot-search huggingface dataset:
Heme oxygenase-1 via transcriptional activation of Nrf2 attenuates apoptosis in A549 cells
Authors: Hak Ryul Kim, Sei-Hoon Yang, Jong-Hoon Jung, Eun-Taik Jeong, Du-Young Choi, Raekil Park
Journal: Cancer Research (2006)

3056  Heme oxygenase-1 (HO-1) is an inducible enzyme that catalyzes oxidative degradation of heme to form biliverdin, carbon monoxide, and free iron. Increasing evidences have indicated the critical role of HO-1 in cytoprotection and more diverse biological functions. HO-1 has been reported to stimulate tumor cell growth and proliferation. And several tumors, including renal cell carcinoma, prostate tumor, hepatoma, and sarcoma, express a high level of HO-1. We previously demonstrated that HO-1 was expressed highly in A549 cells than other lung cancer cell lines. We aimed to investigate whether inhibition of HO-1 may induce apoptosis in A549 lung cancer cells. ZnPP, specific HO inhibitor, significantly decreased the viability of A549 cells than other lung cancer cells in a dose-dependant fashion. Consistent with viability, HO enzymatic activity also decreased. Moreover, ZnPP induced the generation of intracellular H2O2 in a dose-dependent manner. A549 cells, next, were transfected by HO-1 small interfering RNA (siRNA) induced apoptosis, and Nrf2 siRNA resulted in a decrease of HO-1 expression. However, NFkB siRNA had no influence on the expression of HO-1. These finding suggest that increasing HO-1 expression in A549 cells may be resulted from the transcriptional activation of Nrf2, and inhibition of Nrf2-HO-1 pathway induces apoptosis. Therefore it provides new important insights into the possible molecular mechanism of the antitumor therapy. Key word : Heme oxygenase-1, Nrf2, Lung Cancer
Low expression and tumor suppressor activities of the hormone Klotho in breast cancer
Authors: Tamar Rubinek, Shikha Bose, Smadar Levanon, Bella Kaufman, H. Koeffler, Ido Wolf
Journal: Cancer Research (2007)

3680   Klotho (KL) is a single-pass transmembrane protein, which is predominantly expressed in the kidneys and brain but is secreted to the blood and acts as a hormone. In mice, KL overexpression expands life span and is associated with insulin resistance and reduced fertility. KL activities are mediated through several mechanisms, including inhibition of the insulin/insulin-like growth factor (IGF) signaling pathway and upregulation of transcription factors such as CCAAT/enhancer-binding protein (C/EBP) alpha and C/EBP beta. As these mechanisms are also implicated in breast cancer tumorigenesis, we aimed to elucidate KL expression and activities in breast cancer.  KL expression was analyzed in breast cancer cell lines using Real-time RT-PCR. High KL expression was found in the non-malignant breast cell line MCF-12A and the well-differentiated MCF-7 cells, but low KL levels were found in the less differentiated cell lines MDA-MB-231, SK-BR3, T-47D. Immunohistochemical staining of KL was conducted on breast tissue arrays, containing 58 invasive ductal carcinomas (IDC) and 47 pure ductal carcinomas in situ (DCIS) samples. High KL expression was noted in only 15% and 17% of the IDC and DCIS samples, respectively but in 87% of the normal breast adjacent to the tumors (P  KL activity was analyzed in depth using the MCF-7 and MDA-MB-231 breast cancer cell lines using transfection assays. Transient KL upregulation decreased clonal growth of these cells, as measured by colony assays, and stable overexpression of it significantly reduced cell proliferation. Protein levels of the insulin/IGF pathway components were not changed following KL overexpression. However, KL overexpression reduced IGF-induced phosphorylation of the IGF receptor, insulin receptor substrate 1 (IRS 1), AKT, and the extracellular signal-regulated kinase (ERK). Moreover, KL overexpression increased the expression of the tumor suppressor gene C/EBPβ.  In order to reveal additional genes, which are associated with KL activity in breast cancer, we transfected MDA-MB-231 breast cancer cells with either KL or an empty vector. RNA was extracted and total cRNA was used to survey global gene expression in these cells, using HG-U133A (Affymetrix) microarray chips. The analysis revealed attenuation of genes associated with cell cycle, apoptosis and metabolism.  In summary, our data suggest, for the first time, reduced expression and growth inhibitory activities of KL in breast cancer. KL-induced growth inhibition may be mediated by inhibition of the insulin/IGF pathway. The roles of KL as a potential prognostic factor and as a novel therapeutic agent should be explored.
Lineage-specific dynamic and pre-established enhancer–promoter contacts cooperate in terminal differentiation
Authors: Adam J Rubin, Brook C Barajas, Mayra Furlan-Magaril, Vanessa Lopez-Pajares, Maxwell R Mumbach, Imani Howard, Daniel S Kim, Lisa D Boxer, Jonathan Cairns, Mikhail Spivakov, Steven W Wingett, Minyi Shi, Zhixin Zhao, William J Greenleaf, Anshul Kundaje, Michael Snyder, Howard Y Chang, Peter Fraser, Paul A Khavari
Journal: Nature Genetics (2017)
レドックス応答性薬物放出と併用化学療法のためのセレンに富むナノ粒子の可視光誘起架橋と生理学的安定化【Powered by NICT】
Authors: Zhai Shaodong, Hu Xianglong, Hu Yongjun, Wu Baoyan, Xing Da
Journal: Biomaterials (2017)
Optimal Duration of Extended Adjuvant Endocrine Therapy for Early Breast Cancer; Results of the IDEAL Trial (BOOG 2006-05)
Authors: Erik J Blok, Judith R Kroep, Elma Meershoek-Klein Kranenbarg, Marjolijn Duijm-de Carpentier, Hein Putter, Joan van den Bosch, Eduard Maartense, A Elise van Leeuwen-Stok, Gerrit-Jan Liefers, Johan W R Nortier, Emiel J Th Rutgers, Cornelis J H van de Velde
Journal: JNCI Journal of the National Cancer Institute (2017)

The optimal duration of extended endocrine therapy beyond five years after initial aromatase inhibitor-based adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer is still unknown. Therefore, we conducted a clinical trial to compare two different extended endocrine therapy durations.In the randomized phase III IDEAL trial, postmenopausal patients with hormone receptor-positive breast cancer were randomly allocated to either 2.5 or five years of letrozole after the initial five years of any endocrine therapy. The primary end point was disease free survival (DFS), and secondary end points were overall survival (OS), distant metastasis-free interval (DMFi), new primary breast cancer, and safety. Hazard ratios (HRs) were determined using Cox regression analysis. All analyses were by intention-to-treat principle.A total of 1824 patients were assigned to either 2.5 years (n = 909) or five years (n = 915) of letrozole, with a median follow-up of 6.6 years. A DFS event occurred in 152 patients in the five-year group, compared with 163 patients in the 2.5-year group (HR = 0.92, 95% confidence interval [CI] = 0.74 to 1.16). OS (HR = 1.04, 95% CI = 0.78 to 1.38) and DMFi (HR = 1.06, 95% CI = 0.78 to 1.45) were not different between both groups. A reduction in occurrence of second primary breast cancer was observed with five years of treatment (HR = 0.39, 95% CI = 0.19 to 0.81). Subgroup analysis did not identify patients who benefit from five-year extended therapy.This study showed no superiority of five years over 2.5 years of extended adjuvant letrozole after an initial five years of adjuvant endocrine therapy.
Efficacy and Safety of a Pharmaco-Invasive Strategy With Half-Dose Alteplase Versus Primary Angioplasty in ST-Segment–Elevation Myocardial Infarction
Authors: Jun Pu, Song Ding, Heng Ge, Yaling Han, Jinchen Guo, Rong Lin, Xi Su, Heng Zhang, Lianglong Chen, Ben He
Journal: Circulation (2017)

Timely primary percutaneous coronary intervention (PPCI) cannot be offered to all patients with ST-segment-elevation myocardial infarction (STEMI). Pharmaco-invasive (PhI) strategy has been proposed as a valuable alternative for eligible patients with STEMI. We conducted a randomized study to compare the efficacy and safety of a PhI strategy with half-dose fibrinolytic regimen versus PPCI in patients with STEMI.The EARLY-MYO trial (Early Routine Catheterization After Alteplase Fibrinolysis Versus Primary PCI in Acute ST-Segment-Elevation Myocardial Infarction) was an investigator-initiated, prospective, multicenter, randomized, noninferiority trial comparing a PhI strategy with half-dose alteplase versus PPCI in patients with STEMI 18 to 75 years of age presenting ≤6 hours after symptom onset but with an expected PCI-related delay. The primary end point of the study was complete epicardial and myocardial reperfusion after PCI, defined as thrombolysis in myocardial infarction flow grade 3, thrombolysis in myocardial infarction myocardial perfusion grade 3, and ST-segment resolution ≥70%. We also measured infarct size and left ventricular ejection fraction with cardiac magnetic resonance and recorded 30-day clinical and safety outcomes.A total of 344 patients from 7 centers were randomized to PhI (n=171) or PPCI (n=173). PhI was noninferior (and even superior) to PPCI for the primary end point (34.2% versus 22.8%, Pnoninferiority<0.05, Psuperiority=0.022), with no significant differences in the frequency of the individual components of the combined end point: thrombolysis in myocardial infarction flow 3 (91.3% versus 89.2%, P=0.580), thrombolysis in myocardial infarction myocardial perfusion grade 3 (65.8% versus 62.9%, P=0.730), and ST-segment resolution ≥70% (50.9% versus 45.5%, P=0.377). Infarct size (23.3%±11.3% versus 25.8%±13.7%, P=0.101) and left ventricular ejection fraction (52.2%±11.0% versus 51.4%±12.0%, P=0.562) were similar in both groups. No significant differences occurred in 30-day rates of total death (0.6% versus 1.2%, P=1.0), reinfarction (0.6% versus 0.6%, P=1.0), heart failure (13.5% versus 16.2%, P=0.545), major bleeding events (0.6% versus 0%, P=0.497), or intracranial hemorrhage (0% versus 0%), but minor bleeding (26.9% versus 11.0%, P<0.001) was observed more often in the PhI group.For patients with STEMI presenting ≤6 hours after symptom onset and with an expected PCI-related delay, a PhI strategy with half-dose alteplase and timely PCI offers more complete epicardial and myocardial reperfusion when compared with PPCI. Adequately powered trials with this reperfusion strategy to assess clinical and safety outcomes are warranted.URL: https://www.clinicaltrials.gov. Unique identifier: NCT01930682.
Review: A single hs-cTnT with a cutpoint < limit of detection plus a nonischemic ECG can rule out acute MI
Authors: Jennifer A. Rymer, Christopher B. Granger
Journal: Annals of Internal Medicine (2017)

Source Citation Pickering JW, Than MP, Cullen L, et al. Rapid rule-out of acute myocardial infarction with a single high-sensitivity cardiac troponin T measurement below the limit of detection: a collaborative meta-analysis. Ann Intern Med. 2017;166:715-24. 28418520
GMC appeals decision not to strike off doctor convicted of manslaughter
Authors: Clare Dyer
Journal: BMJ (2017)

The General Medical Council is appealing against the decision by a medical practitioners tribunal to suspend for 12 months a doctor who was convicted of gross negligence manslaughter. The GMC argues that Hadiza Bawa-Garba should have been struck off the UK medical register.

Bawa-Garba, who worked as a senior specialist registrar in paediatrics for University Hospitals of Leicester NHS Trust, was convicted along with a nurse, Isabel Amaro, after the death of …
Pregnant and breastfeeding women: A priority population for HIV viral load monitoring
Authors: Landon Myer, Shaffiq Essajee, Laura N. Broyles, D. Heather Watts, Maia Lesosky, Wafaa M. El-Sadr, Elaine J. Abrams
Journal: PLoS Medicine (2017)

Landon Myer and colleagues discuss viral load monitoring for pregnant HIV-positive women and those breastfeeding; ART treatments can suppress viral load and are key to preventing transmission to the child.
Optoacoustic Detection of Early Therapy-Induced Tumor Cell Death Using a Targeted Imaging Agent
Authors: Bangwen Xie, Michal R. Tomaszewski, André A. Neves, Susana Ros, De-En Hu, Sarah McGuire, Stefanie R. Mullins, David Tice, Richard C.A. Sainson, Sarah E. Bohndiek, Robert W. Wilkinson, Kevin M. Brindle
Journal: Clinical Cancer Research (2017)

Abstract Purpose: The development of new treatments and their deployment in the clinic may be assisted by imaging methods that allow an early assessment of treatment response in individual patients. The C2A domain of Synaptotagmin-I (C2Am), which binds to the phosphatidylserine (PS) exposed by apoptotic and necrotic cells, has been developed as an imaging probe for detecting cell death. Multispectral optoacoustic tomography (MSOT) is a real-time and clinically applicable imaging modality that was used here with a near infrared (NIR) fluorophore-labeled C2Am to image tumor cell death in mice treated with a TNF-related apoptosis-inducing ligand receptor 2 (TRAILR2) agonist and with 5-fluorouracil (5-FU). Experimental Design: C2Am was labeled with a NIR fluorophore and injected intravenously into mice bearing human colorectal TRAIL-sensitive Colo205 and TRAIL-resistant HT-29 xenografts that had been treated with a potent agonist of TRAILR2 and in Colo205 tumors treated with 5-FU. Results: Three-dimensional (3D) MSOT images of probe distribution showed development of tumor contrast within 3 hours of probe administration and a signal-to-background ratio in regions containing dead cells of &amp;gt;10 after 24 hours. A site-directed mutant of C2Am that is inactive in PS binding showed negligible binding. Tumor retention of the active probe was strongly correlated (R2 = 0.97, P value &amp;lt; 0.01) with a marker of apoptotic cell death measured in histologic sections obtained post mortem. Conclusions: The rapid development of relatively high levels of contrast suggests that NIR fluorophore-labeled C2Am could be a useful optoacoustic imaging probe for detecting early therapy-induced tumor cell death in the clinic. Clin Cancer Res; 23(22); 6893–903. ©2017 AACR.
A glucagon-like peptide-1 receptor agonist reduces intracranial pressure in a rat model of hydrocephalus
Authors: Hannah F. Botfield, Maria S. Uldall, Connar S. J. Westgate, James L. Mitchell, Snorre M. Hagen, Ana Maria Gonzalez, David J. Hodson, Rigmor H. Jensen, Alexandra J. Sinclair
Journal: Science Translational Medicine (2017)

GLP-1R agonists show promise as a therapeutic agent to lower intracranial pressure in rodents.
The Hereditary Paraganglioma-Pheochromocytoma Syndrome: No Time to Waste
Authors: Michael J. Hall, Andrea D. Forman, Elias Obeid
Journal: JAMA Oncology (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Trastuzumab Increases HER2 Uptake and Cross-Presentation by Dendritic Cells
Authors: Victor A. Gall, Anne V. Philips, Na Qiao, Karen Clise-Dwyer, Alexander A. Perakis, Mao Zhang, Guy T. Clifton, Pariya Sukhumalchandra, Qing Ma, Sangeetha M. Reddy, Dihua Yu, Jeffrey J. Molldrem, George E. Peoples, Gheath Alatrash, Elizabeth A. Mittendorf
Journal: Cancer Research (2017)

Abstract Early-phase clinical trials evaluating CD8+ T cell–eliciting, HER2-derived peptide vaccines administered to HER2+ breast cancer patients in the adjuvant setting suggest synergy between the vaccines and trastuzumab, the mAb targeting the HER2 protein. Among 60 patients enrolled in clinical trials evaluating the E75 + GM-CSF and GP2 + GM-CSF vaccines, there have been no recurrences in patients vaccinated after receiving trastuzumab as part of standard therapy in the per treatment analyses conducted after a median follow-up of greater than 34 months. Here, we describe a mechanism by which this synergy may occur. Flow cytometry showed that trastuzumab facilitated uptake of HER2 by dendritic cells (DC), which was mediated by the Fc receptor and was specific to trastuzumab. In vitro, increased HER2 uptake by DC increased cross-presentation of E75, the immunodominant epitope derived from the HER2 protein, an observation confirmed in two in vivo mouse models. This increased E75 cross-presentation, mediated by trastuzumab treatment, enabled more efficient expansion of E75-specific cytotoxic T cells (E75-CTL). These results demonstrate a mechanism by which trastuzumab links innate and adaptive immunity by facilitating activation of antigen-specific T cells. On the basis of these data, we conclude that HER2-positive breast cancer patients that have been treated with trastuzumab may experience a more robust antitumor immune response by restimulation of T cells with the E75 peptide vaccine, thereby accounting for the improved disease-free survival observed with combination therapy. Cancer Res; 77(19); 5374–83. ©2017 AACR.
SAT0577 Musculoskeletal manifestations of tuberculosis: an observational study
Authors: N Gupta, A Bhatnagar
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Data of musculoskeletal manifestations of tuberculosis is limited to case reports, series or retrospective study. To our knowledge there is no prospective study which has addressed this issue. So, we conducted this study to create awareness among the doctors about musculoskeletal manifestations of tuberculosis. <h3>Objectives</h3> To study the musculoskeletal manifestations of tuberculosis. <h3>Methods</h3> It was a prospective observational study which was conducted at a referral Tuberculosis Hospital in North India in the month of September &amp; October 2016. Patients from outpatient and inpatient department of pulmonology were recruited irrespective of the duration of anti tubercular therapy. We included patients who had active tuberculosis as per World Health Organization (WHO) 2010 criteria. Patients with other chronic illnesses were excluded. A detailed history, examination and appropriate investigations (blood, urine, serological and radiological) of the 100 consecutive patients fulfilling the inclusion criteria was recorded <h3>Results</h3> Mean age of patients was 32.16±12.93 years. Male to female ratio was 43:57. Mean duration of disease was 6.85±8.83 months. Of the 100 patients, 60 (60%) had pulmonary tuberculosis. Pleural tuberculosis presenting as pleural effusion was seen in 17 (17%) patients. Abdominal tuberculosis was seen in 9 (9%), tuberculous lymphadenopathy in 8 (8%) and pott9s spine in 4 (7%). Eye tuberculosis and tubercular breast lump was seen in 1 patient each. 83 (83%) patients had first episode of tuberculosis while the other 17 (17%) patients had second episode of tuberculosis. 74 (74%) patients were on category 1 anti tuberculosis treatment (ATT), while 23 (23%) were on category 2 ATT and 3 (3%) were on modified ATT. Mean duration of ATT was 1.79±1.34 months. Fibromyalgia was classified in 21 (21%) patients, polyarthralgia9s were seen in 9 (9%), pott9s spine in 7 (7%), osteomyelitis in 4 (4%) and scleritis in 2 (2%) patients. Uveitis, tenosynovitis, erythema induratum, subcutaneous abscess and dactylitis was seen in 1 (1%) each. Rheumatological manifestations as septic arthritis, DILE, poncet9s arthritis, tendinopathy, amyloidosis, gout, erythema nodosum and myositis were not seen in any patient. In 21 patients who had fibromyalgia, 11 patients developed fibromyalgia with 2nd episode of tuberculosis amounting to 60.75% patients. <h3>Conclusions</h3> This is the first prospective study to look at the musculoskeletal manifestations of tuberculosis. Patients with active tuberculosis were found to have various rheumatological manifestations. <h3>Acknowledgements</h3> I acknowledge Dr Sushil Gupta, director of the Rajan Babu TB Hspital for allowing me to conduct this study <h3>Disclosure of Interest</h3> None declared
FRI0080 CD11B+GR1DIM tolerogenic dendritic cell-like cells are expanded in interstitial lung disease in SKG mice
Authors: S Sendo, J Saegusa, Y Ichise, H Yamada, I Naka, T Okano, S Takahashi, Y Ueda, K Akashi, A Onishi, A Morinobu
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> SKG mice develop interstitial lung disease (ILD) resembling human rheumatoid arthritis (RA)–associated ILD. We identified a unique cell population of CD11b<sup>+</sup>Gr1<sup>dim</sup> cells in the severely inflamed lungs in SKG mice. <h3>Objectives</h3> The aims of this study are to clarify the mechanism behind the lung pathology, and to elucidate the phenotype and function of CD11b<sup>+</sup>Gr1<sup>dim</sup> cells in ILD-induced SKG mice. <h3>Methods</h3> We assessed the severity of zymosan A-induced ILD in SKG mice histologically, and examined lung-infiltrating cells by Giemsa stain and flow cytometry. Total lung cells and isolated monocytic myeloid-derived suppressor cells (M-MDSCs) were cultured in vitro with GM-CSF (and IL-4). The proliferation of CSFE-labeled naïve T cells co-cultured with isolated CD11b<sup>+</sup>Gr1<sup>dim</sup> cells and MDSCs was evaluated by flow cytometry. <h3>Results</h3> MDSCs, Th17 cells, and group 1 and 3 innate lymphoid cells (ILC1s and ILC3s) were increased in the lungs; the proportion of these cells varied with ILD severity. In this process, we found that a unique cell population, CD11b<sup>+</sup>Gr1<sup>dim</sup> cells, were expanded in the severely inflamed lungs (Figure). About half of the CD11b<sup>+</sup>Gr1<sup>dim</sup> cells expressed CD11c and Giemsa stain revealed that they were morphologically dendritic cell (DC)-like. The CD11b<sup>+</sup>Gr1<sup>dim</sup> cells were induced from M-MDSCs with GM-CSF in vitro and were considered tolerogenic because they expressed high levels of PD-L1 and suppressed T-cell proliferation. The CD11b<sup>+</sup>Gr1<sup>dim</sup> cells have never described previously and termed CD11b<sup>+</sup>Gr1<sup>dim</sup> tolerogenic DC-like cells (CD11b<sup>+</sup>Gr1<sup>dim</sup>tolDC-LCs). Th17 cells, ILC1s and ILC3s in the inflamed lung produced GM-CSF, which in turn could induce CD11b<sup>+</sup>Gr1<sup>dim</sup>tolDC-LCs to reduce inflammation. <h3>Conclusions</h3> We identified a unique cell population, termed CD11b<sup>+</sup>Gr1<sup>dim</sup>tolDC-LCs, in ILD-induced lungs in SKG mice. <h3>References</h3> Nishimura K, Saegusa J, Matsuki F, Akashi K, Kageyama G, Morinobu A. Tofacitinib facilitates the expansion of myeloid-derived suppressor cells and ameliorates arthritis in SKG mice. Arthritis Rheumatol 2015;67:893–902. Shiomi A, Usui T, Ishikawa Y, Shimuzu M, Murakami K, Mimori T. GM-CSF but not IL-17 is critical for the development of severe interstitial lung disease in SKG mice. J. Immunol 2014;193:849–59. Takenaka MC, Quintana FJ. Tolerogenic dendritic cells. Semin. Immunopahol 2016. doi:10.1007/s00281–016–0587–8. <h3>Acknowledgements</h3> The authors thank Shino Tanaka (Department Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine) for providing technical assistance. <h3>Disclosure of Interest</h3> None declared