tbuckley/cabot-search huggingface dataset:
A Pan-Cancer Proteogenomic Atlas of PI3K/AKT/mTOR Pathway Alterations
Authors: Yiqun Zhang, Patrick Kwok-Shing Ng, Melanie Kucherlapati, Fengju Chen, Yuexin Liu, Yiu Huen Tsang, Guillermo de Velasco, Kang Jin Jeong, Rehan Akbani, Angela Hadjipanayis, Angeliki Pantazi, Christopher A. Bristow, Eunjung Lee, Harshad S. Mahadeshwar, Jiabin Tang, Jianhua Zhang, Lixing Yang, Sahil Seth, Semin Lee, Xiaojia Ren, Xingzhi Song, Huandong Sun, Jonathan Seidman, Lovelace J. Luquette, Ruibin Xi, Lynda Chin, Alexei Protopopov, Thomas F. Westbrook, Carl Simon Shelley, Toni K. Choueiri, Michael Ittmann, Carter Van Waes, John N. Weinstein, Han Liang, Elizabeth P. Henske, Andrew K. Godwin, Peter J. Park, Raju Kucherlapati, Kenneth L. Scott, Gordon B. Mills, David J. Kwiatkowski, Chad J. Creighton
Journal: Cancer Cell (2017)
Randomized Clinical Trials
Authors: David P. Byar, Richard M. Simon, William T. Friedewald, James J. Schlesselman, David L. DeMets, Jonas H. Ellenberg, Mitchell H. Gail, James H. Ware
Journal: New England Journal of Medicine (1976)

In spite of the controversy over the role of randomized clinical trials in medical research, the rationale underlying such trials remains persuasive as compared to recent suggestions for alternative non-randomized studies such as those relying on the use of historical controls and adjustment technics. Others have suggested that recent statistical innovations for improving clinical trials, including adaptive allocation of treatment to patients and sequential stopping procedures, are underutilized. These innovations, though theoretically interesting, are not easily adapted to large-scale, complex medical trials in which there may be multiple end points and delayed response times. Ethical considerations suggest that randomized trials are more suitable than uncontrolled experimentation in protecting the interests of patients. Randomized clinical trials remain the most reliable method for evaluating the efficacy of therapies.
p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis
Authors: Hilaire C. Lam, Christian V. Baglini, Alicia Llorente Lope, Andrey A. Parkhitko, Heng-Jia Liu, Nicola Alesi, Izabela A. Malinowska, Darius Ebrahimi-Fakhari, Afshin Saffari, Jane J. Yu, Ana Pereira, Damir Khabibullin, Barbara Ogorek, Julie Nijmeh, Taylor Kavanagh, Adam Handen, Stephen Y. Chan, John M. Asara, William M. Oldham, Maria T. Diaz-Meco, Jorge Moscat, Mustafa Sahin, Carmen Priolo, Elizabeth P. Henske
Journal: Cancer Research (2017)

p62/sequestosome-1 (SQSTM1) is a multifunctional adaptor protein and autophagic substrate that accumulates in cells with hyperactive mTORC1, such as kidney cells with mutations in the tumor suppressor genes tuberous sclerosis complex (TSC)1 or TSC2. Here we report that p62 is a critical mediator of TSC2-driven tumorigenesis, as Tsc2
GPs demand full reimbursement of “crippling” indemnity fees
Authors: Gareth Iacobucci
Journal: BMJ (2017)

Grassroots GPs have unanimously demanded that the BMA negotiate with the government for the full reimbursement of medical indemnity costs for providing NHS services.

Delegates at the annual local medical committees conference in Edinburgh on 18 May backed a motion that welcomed the contribution towards rising costs recently negotiated in England between the BMA and the government. But in the context of the spiralling costs of medical indemnity, the motion also stated that the contractual uplift to practices in England had been “insufficient to cover the actual rise in indemnity costs.” …
Abstract 15573: Association of Concentric Left Ventricular Geometry With Acute Pulmonary Edema in Patients With Reduced Left Ventricular Ejection Fraction
Authors: Junichi Imanishi, Sachiko Yoshikawa, Makoto Nishimori, Naohiko Sone, Tomoyuki Honjo, Kenji Kaihotsu, Masanori Iwahashi
Journal: Circulation (2016)

Introduction:  Acute pulmonary edema (APE) caused by rapid elevation of filling pressure often occurs in patients with heart failure (HF) with preserved ejection fraction (EF), but the pathogenesis of APE in patients with HF with reduced EF (HFREF) is not completely understood. Changes in LV geometry have been reported to reflect the underlying hemodynamic alterations associated with blood pressure elevation.   Hypothesis:  The purpose of our study was therefore to explore the contributions of LV geometry to understand the difference between HFREF patients with or without APE.   Methods:  We studied 110 consecutive acute HF patients with HFREF (   Results:  Patients hospitalized with APE had a higher systolic blood pressure, RWT, EF, and lower end-diastolic dimension and volume index than that with non-APE. Of the echocardiographic variables, multivariate logistic regression analysis identified that RWT was the only independent determinant of APE (OR=2.89, p=0.001). The group of concentric geometry (n=28; RWT>0.42) had higher incidence of APE compared with the group of non-concentric geometry (Figure1). Among patients presenting APE, mortality was significantly greater in patients with concentric geometry compared with patients with non-concentric geometry (Figure2).   Conclusions:  Concentric geometry (increased RWT, not LV mass) has the strong association with the onset of APE in HFREF. An easily obtained echocardiographic index of RWT may enhance risk stratification of patients presenting APE in HFREF.
ACRIN 6684 assessment of tumor hypoxia in glioblastoma using 18F-fluoromisonidazole with PET and MRI.
Authors: Elizabeth Robins Gerstner, Zheng Zhang, James R Fink, Gregory A Sorensen, Darryl L'Heureux, Martha L. Heckel, Bernadine Dunning, Mark Muzi, David A. Mankoff, Daniel Barboriak
Journal: Journal of Clinical Oncology (2012)

TPS10635 Background: Glioblastoma (GBM) is an aggressive type of primary malignant brain tumor and despite treatment with surgery, radiation, and temozolomide (TMZ) chemotherapy, median overall survival (OS) remains poor. A pathologic hallmark of GBM is tumor necrosis, a suspected result from endogenous tumor hypoxia. Angiogenesis is stimulated by hypoxia-driven signaling cascades and is required for tumor proliferation. The inefficient blood supply of these hypoxic tumors also limits the efficacy of chemotherapy and radiotherapy. Surviving hypoxic tumor cells may be selected out and proliferate as a more aggressive tumor subtype, therefore hindering OS. 18 F-Fluoromisonidazole (FMISO) is a PET radiotracer whose uptake in hypoxic tissues can be measured radiographically. The degree of tumor hypoxia has been negatively associated with time to tumor progression and survival (Spence et al, 2008). Knowledge of the degree/distribution of tumor hypoxia by PET uptake and perfusion MRI parameters may provide prognostic information and help guide therapy for patients with GBM. Methods: In this phase II prospective single arm multi-institution study, patients will undergo baseline FMISO PET and MR imaging two weeks prior to chemoradiotherapy (CRT). A subset of patients will receive a second FMISO PET one week prior to CRT to assess reproducibility. Clinical outcomes of OS and 6-month progression-free survival (PFS-6) will be correlated to PET and MRI parameters. Eligibility: Pathologically confirmed GBM with residual tumor after surgery (including T2/FLAIR hyperintensity consistent with tumor) scheduled to receive standard fractionated radiation therapy and temozolomide alone or with an anti-VEGF agent or PARP inhibitor. Current enrollment: 22 patients of 50 sample size Contact information: Please contact the PI, Elizabeth R. Gerstner, MD ( egerstner@partners.org ) for additional information. Significance: With a better understanding of the extent of tumor hypoxia and changes in hypoxia levels from treatment, more effective therapies could be developed to inhibit GBM growth, target hypoxic areas and individualize patient care.
Preliminary focus on the mechanical and antibacterial activity of a PMMA-based bone cement loaded with gold nanoparticles
Authors: T. Russo, A. Gloria, R. De Santis, U. D'Amora, G. Balato, A. Vollaro, O. Oliviero, G. Improta, M. Triassi, L. Ambrosio
Journal: Bioactive Materials (2017)

In total knee arthroplasty (TKA) and total hip replacement (THR) the restoration of the normal joint function represents a fundamental feature. A prosthetic joint must be able to provide motions and to transmit functional loads. As reported in the literature, the stress distribution may be altered in bones after the implantation of a total joint prosthesis. Some scientific works have also correlated uncemented TKA to a progressive decrease of bone density below the tibial component. Antibiotic-loaded bone cements are commonly employed in conjunction with systemic antibiotics to treat infections. Furthermore, nanoparticles with antimicrobial activity have been widely analysed. Accordingly, the current research was focused on a preliminary analysis of the mechanical and antibacterial activity of a PMMA-based bone cement loaded with gold nanoparticles. The obtained results demonstrated that nanocomposite cements with a specific concentration of gold nanoparticles improved the punching performance and antibacterial activity. However, critical aspects were found in the optimization of the nanocomposite bone cement.
Craniosynostosis in transgenic mice overexpressing Nell-1
Authors: X. Zhang
Journal: Journal of Clinical Investigation (2002)

IntroductionCraniosynostosis (CS), the premature closure of cranial sutures, affects 1 in 3,000 infants and therefore is one of the most common human congenital craniofacial deformities (1).Premature suture closure, which results in cranial dysmorphism, can be either familial or sporadic in origin (1).Neither gender nor ethnicity can be used to predict which infants will be affected.Although genetic linkage analyses of CS-related syndromes have provided a wealth of new information about the molecular control of suture formation, the biology of local suture closure, especially in nonsyndromic, nonfamilial CS, is still largely unknown.Presently, more than 85 human mutations, which produce various familial CS syndromes, have been localized to the FGF receptor genes FGFR1, FGFR2, and FGFR3.All are "gain-of-function" mutations that result in increased receptor activity (1).No human CS syndromes have been linked to the FGF ligands; however, several animal models of CS have been associated with FGF overexpression (2, 3).The only described MSX2 mutation associated with CS (4) also results in increased MSX2 activity (5-7).While these candidate genes are known to play important roles in osteoblast proliferation and differentiation, they also have more generalized roles during embryogenesis.Thus, it is not surprising that transgenic mouse models with mutations in these genes often manifest extracranial abnormalities not observed in the majority of patients with CS (1, 2, 8).
Epidemiological Approach of Chronic Myeloid Leukemia. Algerian-Tunisian Study
Authors: K Djouadi, N Abdennebi, F Harieche, R Ahmed Nacer, RM Hamladji, A Bouchakour, S Taoussi, MT Abad, Fz Touil, S Hamdi, S Bougherira, F Grifi, C Kerrar, I Allam, O Djidjik, N Boudjerra, M Belhani, S Gherras, A Graine, H Ait Ali, B Entasoltane, M Brahimi, MA Bekadja, R Ben lakhal, B Meddeb, Z Ouchenane, N Sidi Mansour, F Kacha, F Tibermacine, M Saidi, N Mehalhal, Fz Brahimi, L Touati, N Lakhdari, D Saber Cherif, Y Meddour, S Chaib, Fz Ardjoun, H Bellaaj, K Taibi, H Touhami, HZ Manai, B Benzineb, N Mesli, A Maghraoui, S Hadjeb, Z Zouaoui, S Baghdad, A Bachiri, MA Laatiri, M Attari, D Lamara, B Bendjabellah, H Ghedira, Y Ben Youcef, A Trabzi, S Menif, T Ben Othman, M Benakli
Journal: Blood (2016)
Melanoma survivor treatment severity and correlates of psychosocial and physical health.
Authors: Kelly Bugos, Arianna Aldridge Gerry, Oxana Palesh, Susan M. Swetter, Katherine L. McGurk, Ralph Steven Greco
Journal: Journal of Clinical Oncology (2013)

e20026 Background: Melanoma survivors’ psychosocial needs and physical symptoms are not well understood, despite nearly 1 million melanoma survivors in the US. In addition, there is a paucity of support available as it is generally believed that cutaneous melanoma survivors don’t suffer long term health consequences. Methods: As part of the new Stanford Cancer Survivorship Program, melanoma survivors previously treated at Stanford Cancer Center were asked to complete a quality improvement survey to explore the value of a melanoma survivorship clinic. 21% of 893 invited survivors responded to the electronic survey. We compared survivors based on treatments received: surgical excision only (SX) vs. surgical excision plus (SX+) one or more of the following: sentinel lymph node biopsy, lymph node dissection, skin graft, interferon, chemotherapy, or radiation therapy. Results: 161 melanoma survivors (SX+: 32% vs. SX: 68%) completed the survey. Those who received surgery plus additional treatment were predominantly male (SX+: 68% vs. SX: 32%, p = 0.003) and slightly older (SX+: 67 years vs. SX: 60 years, p = 0.004). Survivors who received SX+ reported greater fatigue (p &lt; 0.001), weight loss (p &lt; 0.001), arm or leg swelling (p &lt; 0.001), weakness (p = 0.001), numbness/tingling (p = 0.009), pain (p = 0.015), and nausea and/or vomiting (p = 0.039) than SX survivors. Similarly, SX+ survivors reported reduced vitality (24% vs. 6%, p = 0.004), worse social functioning (12% vs. 5%, p = 0.032), and worse sexual functioning (20% vs. 6%, p = 0.017) following treatment. Related to patient care, health care providers were less likely to address these symptoms in SX survivors relative to SX+ survivors (75% vs. 57%, p = 0.019). More SX than SX+ survivors wanted education on how to protect their skin from further damage (24% vs. 8%, p= 0.016). Conclusions: Melanoma survivors receiving SX+ for more advanced disease experienced greater psychosocial and physical symptoms following treatment. However, survivors treated with excision alone for cutaneous melanoma wanted provider attention for their treatment-related symptoms and improved education on skin protection.
Abstract 331: Hdac5 Represses The Angiogenic Growth Factor Fgf2 And Guidance Molecules And Thereby Blocks Endothelial Cell Function
Authors: Lothar Roessig, Carmen Urbich, Michael Potente, Andreas M Zeiher, Stefanie Dimmeler
Journal: Circulation (2007)

Histone deacetylases (HDAC) modulate gene expression for cardiac hypertrophy and angiogenesis. HDAC7 is essentially required for vascular development and vessel integrity. We used specific siRNA to investigate the role of other HDAC isoenzymes for angiogenic endothelial cell activity. Consistent with previous reports, HDAC7 suppression inhibited migration and capillary-like sprouting of endothelial cells, whereas, in contrast, siRNA against HDAC5 surprisingly increased migration to 121 ± 4% (P
Infusion of Coagulation Factor VIII-Containing Induced Pluripotent Stem Cell (iPSC)-Derived Megakaryocytes (iMks) Shows Potential As Hemophilia a Treatment
Authors: Randolph B Lyde, Hyunsook Ahn, Karen K Vo, Danuta Jadwiga Jarocha, Li Zhai, Spencer K. Sullivan, Valder R Arruda, Denise E. Sabatino, Rodney M. Camire, Deborah French, Mortimer Poncz
Journal: Blood (2016)
Rabbit ATG Plus Cyclophosphamide with or without Fludarabine Is Superior Conditioning Regimen for Patients with Severe Aplastic Anemia Undergoing Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Parvez Ahmed, Tariq Mahmood Satti, Qamar Un Nisa Chaudhry, Kamran Mehmood, Nighat Shahbaz, Mehreen Ali Khan, Tariq Ghafoor, Raheel Iftikhar, Humayoon Satti, Andleeb Hanif
Journal: Blood (2016)
Abstract 208: Farnesylation-Dependent Fibrosis in the Aged Murine Heart
Authors: Katarzyna A Cieslik, Mark L Entman, JoAnn Trial, George E Taffet
Journal: Circulation Research (2012)

Mesenchymal stem cells (MSC) derived from the aged murine heart express reduced levels of the multipotency marker Nanog. These CD44 + CD45 - MSC inappropriately differentiate into fibroblasts characterized by markedly enhanced basal collagen expression. While collagen synthesis in cardiac fibroblasts derived from young mice is driven by TGF-β1, paradoxically, fibroblasts derived from the aged heart displayed reduced TGF-β1 responsiveness and decreased TGF-β receptor expression (ALK5). To resolve this apparent contradiction we looked for other pathways leading to collagen expression. We found that circulating insulin levels in aged mice were elevated ∼2.5 fold when compared to young animals. We hypothesized that increased circulating insulin levels drive MSC differentiation and caused upregulation of procollagen expression in cardiac fibroblasts. Our in vitro experiment confirmed that insulin at a pathophysiological concentration (1 nM) increased procollagen type I expression only in fibroblasts isolated from old hearts. As insulin can signal through substrate prenylation, cardiac fibroblasts isolated from aged mice had ∼2 fold greater basal activity of farnesyltransferase (FTase, enzyme that transfers the prenyl chain) than fibroblasts isolated from young mice. FTase activity was further increased when fibroblasts isolated from aged hearts were stimulated with insulin. Cells derived from 3 month old mice did not upregulate FTase activity in response to insulin. Basal expression of FTase regulatory subunit (FNTA) was also upregulated by 3 fold in aged fibroblasts and expression of catalytic subunit (FTNB) was increased with insulin stimulation. FTase inhibitor reduced procollagen synthesis in aged fibroblasts. Here we present new data linking insulin-dependent upregulation of collagen type I synthesis via increased farnesylation in the aging heart.
Overweight, obesity, and risk of cardiometabolic multimorbidity: pooled analysis of individual-level data for 120 813 adults from 16 cohort studies from the USA and Europe
Authors: Mika Kivimäki, Eeva Kuosma, Jane E Ferrie, Ritva Luukkonen, Solja T Nyberg, Lars Alfredsson, G David Batty, Eric J Brunner, Eleonor Fransson, Marcel Goldberg, Anders Knutsson, Markku Koskenvuo, Maria Nordin, Tuula Oksanen, Jaana Pentti, Reiner Rugulies, Martin J Shipley, Archana Singh-Manoux, Andrew Steptoe, Sakari B Suominen, Töres Theorell, Jussi Vahtera, Marianna Virtanen, Peter Westerholm, Hugo Westerlund, Marie Zins, Mark Hamer, Joshua A Bell, Adam G Tabak, Markus Jokela
Journal: The Lancet Public Health (2017)

Although overweight and obesity have been studied in relation to individual cardiometabolic diseases, their association with risk of cardiometabolic multimorbidity is poorly understood. Here we aimed to establish the risk of incident cardiometabolic multimorbidity (ie, at least two from: type 2 diabetes, coronary heart disease, and stroke) in adults who are overweight and obese compared with those who are a healthy weight.
A tumor-penetrating recombinant protein anti-EGFR-iRGD to enchance efficacy of paclitaxel in 3D multicellular spheroids and gastric cancer in vivo.
Authors: Huizi Sha, Zhengyun Zou, Baorui Liu
Journal: Journal of Clinical Oncology (2015)

e13526 Background: Human tumors, including gastric cancer, frequently express high levels of epidermal growth factor receptors (EGFRs), which are associated with a poor prognosis. Targeted delivery of anticancer drugs to cancerous tissues shows potential in sparing unaffected tissues. However, it has been a major challenge for drug penetration in solid tumor tissues due to the complicated tumor microenvironment. Chemotherapy employing paclitaxel (PTX) is widely used for treating various kinds of cancer including gastric cancer. Methods: Recombinant protein anti-EGFR-iRGD consisting of an anti-EGFR VHH (the variable domain from the heavy chain of the antibody) fused to iRGD, a tumor-specific binding peptide with high permeability were expressed in E. coli BL21 (DE3) and purified by nickel-nitrilotriacetic acid affinity chromatography. We use tumor cell lines (2D), multicellular spheroids (3D), and mice to analyze the antitumor activity of recombinant protein. To investigate the ability of anti-EGFR-iRGD to improve other drugs (e.g. PTX) penetrating into tumor, we used multicellular spheroids and mice. Results: We have successfully constructed a recombinant protein named anti-EGFR-iRGD, a dual targets of EGFR and integrin and high permeable protein. It could spread extensively throughout both the multicellular spheroids and the tumor mass. The recombinant protein anti-EGFR-iRGD also exhibited antitumor activity in tumor cell lines (2D), multicellular spheroids (3D), and mice. Moreover, we demonstrated the therapeutic efficacy of PTX combined with anti-EGFR-iRGD on monolayer cells (2D), multicellular spheroids (3D) and tumor-bearing mice for the first time. Conclusions: Our results provide impetus for further studies for potentially using iRGD based fusion protein anti-EGFR-iRGD with standard cytotoxic treatment regimens for enhancing therapy of gastric cancer patients.
Abstract 281: Long-Term Therapy with a Partial Adenosine A1-Receptor Agonist Upregulates mRNA and Protein Expression of Glucose Transporters in Left Ventricular Myocardium of Dogs with Chronic Heart Failure
Authors: Hani N Sabbah, Ramesh C Gupta, Sharad Rastogi, Mengjun Wang, Keife Zhang, Paula M Mohyi, Barbara Albrecht-Kupper
Journal: Circulation Research (2012)

Background: Recruitment of glucose transport proteins GLUT-1 and -4 is a mechanism by which the heart increases glucose transport for metabolism in response to increased energy demands. In the failing LV, mRNA and protein levels of GLUT-1 and -4 are down-regulated and the response to increased demands is met by increased dependence on fatty acid oxidation. We previously showed that treatment with the partial adenosine A1-receptor agonist capadenoson (CAP) improves LV systolic function in dogs with advanced heart failure (HF). This study examined the effects of CAP on the regulation of GLUT-1 and -4 in LV myocardium of dogs with chronic HF. Methods: Studies were performed in LV tissue from 12 HF dogs randomized to 3 months oral therapy with the CAP (7.5 mg twice daily, n=6) or to no therapy at all (Control, n=6). LV tissue from 6 normal (NL) dogs was used for comparison. mRNA expression of GLUT-1 and -4 was measured in LV tissue homogenate using real time polymerase chain reaction (RT-PCR). Protein levels of GLUT-1 and -4 and calsequestrin (CSQ), a sarcoplasmic reticulum protein that does not change in HF (internal control), were measured in SDS-extract using Western blotting coupled with chemiluminescent method. Band intensity was quantified in densitometric units (du). Results: Compared to NL dogs, Control HF dogs showed a 3.6 fold decrease in mRNA expression of GLUT-1 and a 2.7 fold decrease in the expression of GLUT-4. CAP-treatment in HF dogs improved mRNA expression of GLUT-1 (1.38 fold decrease) and GLUT-4 (0.8 fold decrease). Similarly, compared to NL dogs, Control HF dogs showed a significant decrease of protein levels of GLUT-1 (0.64 ± 0.04 vs. 0.26 ± 0.04 du, p&lt;0.05) and GLUT-4 (1.42 ± 0.06 vs. 0.40 ± 0.05 du, p&lt;0.05). CAP treatment significantly increased protein levels of both GLUT-1 (0.49 ± 0.03 du) and GLUT-4 (0.82 ± 0.03) compared to Control HF dogs (p&lt;0.05). CSQ levels were similar in all study groups. Conclusions: In dogs with chronic HF, long-term therapy with CAP improves mRNA and protein expression of GLUT-1 and -4. This improvement in expression of glucose transport proteins is likely to restore partial dependency of the failing heart to more efficient glucose metabolism, and therefore, lead to improved myocardial energetics and pump function.