tbuckley/cabot-search huggingface dataset:
Breast cancer histology and non-sentinel lymph node involvement following a positive sentinel lymph node biopsy: A multi-institutional cohort study.
Authors: Alana Hosein, Dominique LeBlanc, Amanda Roberts, Erin Cordeiro, Sharon Nofech-Mozes, Bruce Youngson, David R. McCready, Manar Al-Assi, Stephanie Ramkumar, Tulin Cil
Journal: Journal of Clinical Oncology (2016)

1043 Background: Management of the axilla in early breast cancer has shifted towards a more conservative surgical approach. The omission of a completion axillary lymph node dissection (cALND) in the context of a positive sentinel lymph node (SLN) has become common, even though this practice may result in residual non-sentinel positive nodes left behind. Furthermore, the axillary management of both invasive ductal and invasive lobular carcinomas (IDCs and ILCs) has traditionally been the same despite the different pattern of invasion and metastases in ILCs. The objective of this study was to determine if lobular histology is an independent predictor of non-sentinel lymph node (NSLN) involvement following a positive SLN biopsy (SLNB). Methods: A multi-institutional cohort study was completed. Patients with node positive IDC or ILC who were treated with both a SLNB followed by cALND from November 1997 to June 2009 were included. The primary outcome was NSLN involvement, defined as having at least one positive lymph node within the cALND specimen. Univariate analysis was performed to determine baseline differences between the IDC and ILC subgroups. A multivariable logistic regression analysis was performed to determine the independent effect of lobular histology on NSLN involvement. Results: A total of 261 cALNDs from 259 patients were included. The primary histology was ductal for 200 (77%) of the tumors. Overall, 35.6% of all cALNDs had NSLNs involved. The presence of lymphovascular invasion (LVI) within the primary tumor (OR 3.28, p = 0.0009) and the absolute number of SLNs involved (OR 2.54, p < 0.0001) were both found to be independent predictors of NSLN involvement. Lobular histology was not an independent predictor (OR 1.42, p = 0.42). Conclusions: Within our cohort, lobular histology is not an independent predictor of residual disease in NSLNs. Predictors of nodal involvement included presence of LVI and the absolute number of positive SLNs. Overall, the clinical practice changes to axillary management following a positive SLN biopsy appear to be generalizable to both ductal and lobular breast cancers.
Abstract 217: Hexokinase II Binding to Mitochondria Suppresses Irreversible Ischemia Reperfusion Injury in the Beating Heart by Respiratory Inhibition and Reduced ROS Levels
Authors: Rianne Nederlof, Chaoqin Xie, Ebru Gúrel, Anneke Koeman, Markus W Hollmann, Rick Southworth, Fadi G Akar, Coert J Zuurbier
Journal: Circulation Research (2012)

Introduction: The glycolytic enzyme hexokinase II (HKII) can be mitochondrial-bound (mtHK) or free in the cytosol. Increased mtHKII protects the heart against ischemia-reperfusion (I/R) injury. The mechanism of protection is not yet elucidated. Hypothesis: We hypothesized that mtHKII protects the heart against I/R injury by respiratory inhibition and reducing reactive oxygen species (ROS). Methods: Langendorff perfused rat hearts were exposed for 20min to 1 μ M TAT-only, 1 μ M TAT-HK or 200 nM TAT-HK, followed by 15 min ischemia and 30 min reperfusion. TAT-HK contains the binding motif of HKII and dislodges HKII from mitochondria. ROS was measured using DHE fluorescence (n=6/group). Lactate was measured after peptide treatment, necrosis (LDH release) was determined during reperfusion and oxygen consumption (MVO 2 ) and heart function (rate pressure product (RPP)) were monitored (n=12-15/group). Results: Disruption of mtHKII binding resulted in increased MVO 2 /RPP values during both baseline and reperfusion in the 1 μ M TAT-HK group. Effluent lactate increased from (mean±SEM) 0.024±0.0041 μ mol/ml effluent in the TAT-only group to 0.042±0.0072 and 0.091±0.016 μ mol/ml effluent in the 200 nM and 1 μ M TAT-HK treated hearts, respectively. TAT-HK treatment had no effect on ROS production during baseline conditions. However, during both ischemia (normalized values (mean±SEM) 1.14±0.05 and 1.17±0.08 versus 1.09±0.06) and reperfusion (1.58±0.24 and 1.84±0.15 versus 1.30±0.17) TAT-HK significantly and dose dependently increased ROS when compared to TAT-only treatment. This was accompanied by an increased LDH release during reperfusion of (mean±SEM) 27.1±4.1 and 42.9±4.2 μ mol/30min/g heart for the 200 nM and 1 μ M TAT-HK treated hearts, respectively. There was no cell necrosis in the TAT-only group. Conclusion: &gt;Our results show for the first time that disruption of the mtHK binding affects cardiac MVO 2 and causes an increase in ROS production during ischemia and reperfusion in the intact heart. These data indicate that mtHKII is a master switch turning reversible ischemia into irreversible ischemia. Our data also suggest that mtHKII is a determinant of glycolysis/glucose oxidation coupling. Supported by the Dutch Heart Foundation (NHS 2010B011)
FRI0106 Results of a systematic literature review of prognostic factors in rheumatoid arthritis as a basis for a prospective rheumatologists survey
Authors: L Carmona, T Otόn, A Royo, JL Baquero, S Luján, S Muñoz-Fernández
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Selecting the most appropriate therapy for each patient with rheumatoid arthritis (RA) is crucial in order to prevent joint damage, particularly in patients with rapidly progressing disease. The literature on prognostic factors is tremendous, being practical to summarize which factors are most strongly associated with a particular outcome and what is the utility that rheumatologists assign to these factors. <h3>Objectives</h3> To identify well established factors predicting long-term outcomes in RA, as the basis for a survey. <h3>Methods</h3> The identification of the factors was performed via an overview of systematic reviews studying prognostic factors in RA, followed by scoping reviews for individual factors. All searches were conducted in PubMed. In order to be included in the overview, the study had to be a systematic review of prognostic factors of any of the following outcomes: disability, mortality, remission, response to treatment, or radiological damage. All factors identified, in positive or negative association with the selected outcomes, were compiled in a matrix of factors * outcomes. Subsequent scoping literature reviews were performed for each combination of the matrix. <h3>Results</h3> The overview of systematic reviews allowed the identification of 36 prognostic factors (see Table 1). After a round of discussions, we decided to remove all factors depending on treatment or study methodology for the scoping reviews, considering that they could not properly be considered prognostic factors but modifiers. Following the scoping reviews, we obtained a list of studies of prognostic factors, with methodological characteristics and 27 reviews of specific prognostic factors and outcomes. With this information, a survey addressed to practicing rheumatologists was developed to test how often they use the various factors to make long-term predictions, and how strong they think the association with outcome is. <h3>Conclusions</h3> We have analyzed and compiled a summary of prognostic factors published in RA and their predictability of long-term outcomes. This may act as a reference for cross-factor comparison and evidence-based risk assimilation and serve as a basis of surveying the value of such factors. <h3>Acknowledgements</h3> This study was funded by Bristol-Myers Squibb. <h3>Disclosure of Interest</h3> L. Carmona Grant/research support from: BMS, T. Otόn Grant/research support from: BMS, A. Royo Employee of: BMS, J. L. Baquero Grant/research support from: BMS, S. Luján: None declared, S. Muñoz-Fernández Grant/research support from: BMS
Abstract 303: Detrimental Effects of Prolonged AKT Activation in Hearts from Ozone-Exposed Healthy Adult Rats
Authors: Shubham Manchanda, Magdalena Ramirez, Pranjal Manchanda, Vishal Sethi, David Dostal, Rajat Sethi
Journal: Circulation Research (2012)

Tropospheric ozone (O3) is one of six major air pollutants regulated by National Ambient Air Quality Standards (NAAQS) under the U.S. Clean Air Act. In the current study, we are trying to understand the effects of survival proteins, such as AKT and BCl-2, subsequent to chronic exposure of ozone in healthy adult rats. Twenty age/weight matched male Sprague Dawley rats were randomly divided into two groups that were exposed to air (0 ppm O3) or 0.8 ppm O3 for 8 hours/day for 28 days. Four rats were sacrificed, their hearts and lungs were extracted, and left ventricular tissue was used for various estimations. Western blot analysis was performed on lung and heart tissue from filtered air and O3-exposed rats to quantify the differential levels of P-p38 (activity) in the cytosolic fraction, Akt (expression) in the cytosolic fraction, p-Akt-Thr (activity) and p-Akt-Ser (activity) in the cytosolic fraction, Bcl-2 (expression) in the cytosolic fraction, and p-Bcl-2 (activity) in the cytosolic fraction. As a consequence of chronic O3 exposure, the significant findings of the current work are: 1) cytosolic fraction from 28 days O3-exposed group showed no significant change in P-p38MAPKα activity, but 56 days O3-exposed group showed increased P-p38MAPKα activity, 2) cytosolic fraction from 28 days and 56 days O3-exposed group showed increased expression of Akt, 3) cytosolic fraction from 28 days O3-exposed group showed decreased p-Akt-Ser activity, but 56 days O3-exposed group showed increased p-Akt-Ser activity, 4) cytosolic fraction from 28 days O3-exposed group showed increased p-Akt-Thr activity, but 56 days O3-exposed group showed decreased p-Akt-Thr activity, 5) cytosolic fraction from 28 days O3-exposed group showed decreased expression of Bcl-2, but 56 days O3-exposed group showed increased expression of Bcl-2, 6) cytosolic fraction from 28 days O3-exposed group showed increased p-Bcl-2 activity, but 56 days O3-exposed group showed decreased p-Bcl-2 activity. Based on these results we can conclude that prolonged Akt activation subsequent to chronic ozone exposure may be detrimental to hearts and have adverse effects over time. Roles of Bcl-2 and Bax in this injury are not yet clear and are being currently investigated in our laboratory.
General intelligence is a source of individual differences <i>between</i> species: Solving an anomaly
Authors: Michael A. Woodley of Menie, Heitor B. F. Fernandes, Jan te Nijenhuis, Mateo Peñaherrera-Aguirre, Aurelio José Figueredo
Journal: Behavioral and Brain Sciences (2017)

Abstract Burkart et al. present a paradox – general factors of intelligence exist among individual differences ( g ) in performance in several species, and also at the aggregate level ( G ); however, there is ambiguous evidence for the existence of g when analyzing data using a mixed approach, that is, when comparing individuals of different species using the same cognitive ability battery. Here, we present an empirical solution to this paradox.
PCI Versus CABG in Patients With Type 1 Diabetes and Multivessel Disease
Authors: Thomas Nyström, Ulrik Sartipy, Stefan Franzén, Björn Eliasson, Soffia Gudbjörnsdottir, Mervete Miftaraj, Bo Lagerqvist, Ann-Marie Svensson, Martin J. Holzmann
Journal: Journal of the American College of Cardiology (2017)

It is unknown if coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) may offer a survival benefit in patients with type 1 diabetes (T1D) in need of multivessel revascularization. This study sought to determine if patients with T1D and multivessel disease may benefit from CABG compared with PCI. In an observational cohort study, the authors included all patients with T1D who underwent a first multivessel revascularization in Sweden from 1995 to 2013. The authors used the SWEDEHEART (Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies) register, the Swedish National Diabetes Register, and the Swedish National Patient Register to retrieve information about patient characteristics and outcomes. They estimated hazard ratios (HRs) adjusted for confounders with 95% confidence intervals (CIs) for all-cause and coronary heart disease mortality, myocardial infarction, repeat revascularization, stroke, and heart failure using inverse probability of treatment weighting based on propensity scores. In total, 683 patients who underwent CABG and 1,863 patients who underwent PCI were included. During a mean follow-up of 10.6 years, 53% of patients in the CABG group and 45% in the PCI group died. PCI, compared with CABG, was associated with a similar risk of all-cause mortality (HR: 1.14; 95% CI: 0.99 to 1.32), but higher risks of death from coronary heart disease (HR: 1.45; 95% CI: 1.21 to 1.74), myocardial infarction (HR: 1.47; 95% CI: 1.23 to 1.78), and repeat revascularization (HR: 5.64; 95% CI: 4.67 to 6.82). No differences in risks of stroke or heart failure were found. Notwithstanding the inclusion of patients with T1D who might not have been able to undergo CABG in the PCI group we found that PCI, compared with CABG, was associated with higher rates and risks of coronary heart disease mortality, myocardial infarction, and repeat revascularizations. Our findings indicate that CABG may be the preferred strategy in patients with T1D in need of multivessel revascularization.
Comment on “esophageal balloon tamponade vs. esophageal stent in controlling acute refractory variceal bleeding: A multicenter RCT”
Authors: Felix Gundling, Maximilian Tiller, Wolfgang Schepp
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. TO THE EDITOR: We read with great interest the prospective study by Escorsell et al. demonstrating that self‐expandable, covered, esophageal metal stents (SX‐ELLA Danis; Ella‐CS, Hradec Kralove, Czech Republic) have greater efficacy and fewer serious adverse events in controlling acute esophageal variceal bleeding compared with balloon tamponade.1 However, an important problem of this procedure was not addressed by the investigators: Whereas a recent meta‐analysis published by Shao et al. (which already included the study of Escorsell et al.) described migration after stent deployment in 21.6%,2 Escorsell et al. did not observe a single case of stent migration. In our clinic, we used the SX‐Ella Danis stent several times (n = 3). Although the acute bleeding was stopped successfully, we observed stent migration into the stomach in all cases within 4 days after endoscopic deployment (Fig. 1A,B).Figure 1: Endoscopy showing stent migration into the stomach (A, proximal end; B, distal end of the stent).This seems to be a frequent problem (as indicated by Shao et al. in their meta‐analysis) given that the esophageal diameter in patients with esophageal variceal bleeding tends to be broader than usual, enabling the covered stent to slip downward into the stomach. However, repositioning seems to be risky due to the danger of causing acute variceal bleeding after manipulation. Therefore, we removed the stent immediately upon diagnosing migration. Interestingly, neither Shao et al. nor our group observed a dramatic bleed following stent migration. Possibly, this can be explained by an accelerated obliteration of the esophageal varices, but this, of course, remains hypothetical. To conclude, migration after deployment of covered stents represents a frequent complication in the treatment of esophageal varices. Therefore, clear guidance on what to do—reposition or subsequent removal—needs to be developed.
Quantitative Experiments on the Production of Subcutaneous Tumors in Strain A Mice with Marginal Doses of 3, 4-Benzpyrene&lt;xref ref-type="fn" rid="fn1"&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/xref&gt;
Authors: Joseph Leiter, M. J. Shear
Journal: JNCI Journal of the National Cancer Institute (1943)

Quantitative Experiments on the Production of Subcutaneous Tumors in Strain A Mice with Marginal Doses of 3, 4-Benzpyrene Get access Joseph Leiter, Joseph Leiter assistant chemist Search for other works by this author on: Oxford Academic PubMed Google Scholar M. J. Shear M. J. Shear principal biochemist National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 3, Issue 5, June 1943, Pages 455–477, https://doi.org/10.1093/jnci/3.5.455 Published: 01 June 1943
Treatment of Low Back Pain
Authors: Hannah C. Wenger, Adam S. Cifu
Journal: JAMA (2017)

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Role of cardiac inflammation in right ventricular failure
Authors: Xiao-Qing Sun, Antonio Abbate, Harm-Jan Bogaard
Journal: Cardiovascular Research (2017)

Right ventricular failure (RVF) is the main determinant of mortality in patients with pulmonary arterial hypertension (PAH). Although the exact pathophysiology underlying RVF remains unclear, inflammation may play an important role, as it does in left heart failure. Perivascular pulmonary artery and systemic inflammation is relatively well studied and known to contribute to the initiation and maintenance of the pulmonary vascular insult in PAH. However, less attention has been paid to the role of cardiac inflammation in RVF and PAH. Consistent with many other types of heart failure, cardiac inflammation, triggered by systemic and local stressors, has been shown in RVF patients as well as in RVF animal models. RV inflammation likely contributes to impaired RV contractility, maladaptive remodelling and a vicious circle between RV and pulmonary vascular injury. Although the potential to improve RV function through anti-inflammatory therapy has not been tested, this approach has been applied clinically in left ventricular failure patients, with variable success. Because inflammation plays a dual role in the development of both pulmonary vascular pathology and RVF, anti-inflammatory therapies may have a potential double benefit in patients with PAH and associated RVF.
A phase I study of SRA737 (formerly known as CCT245737) administered orally in patients with advanced cancer.
Authors: Maxime Chenard-Poirier, Alvaro Henrique Ingles Garces, Robert Hugh Jones, Amy Quinton, Elizabeth R. Plummer, Yvette Drew, Mark Marion Kowalski, Barbara J. Klencke, Udai Banerji
Journal: Journal of Clinical Oncology (2017)

TPS2607 Background: SRA737 is a highly selective, orally bioavailable small molecule inhibitor of Checkpoint kinase 1 (Chk1), a key cell cycle checkpoint and central regulator of the DNA Damage Response (DDR) network. In cancer cells, replication stress induced by genomic alterations in oncogenes (eg, MYC and RAS) combined with loss of function in tumor suppressors (eg, TP53 and ATM) results in persistent DNA damage and genomic instability. Targeted inhibition of components of the DDR network such as Chk1 by SRA737 may be synthetically lethal to cancer cells and have utility as a monotherapy in a range of tumor indications. SRA737 is currently being investigated in two Phase 1 trials in patients with advanced cancer. We now describe the Phase 1 multicenter, dose-escalation, monotherapy study of SRA737 (NCT02797964). Methods: Up to 40 patients with advanced cancer will receive oral SRA737 administered daily on a 28-day schedule. For dose-escalation, an accelerated titration design with 100% dose escalation and single patient cohorts is allowed until Grade 2 related toxicity is observed, followed by a rolling-6 design. Dose expansion will include 6 patients with any solid tumor treated at the recommended Phase 2 dose (RP2D). Eligibility criteria include WHO performance status of 0-1 and ≤ 3 prior lines of cytotoxic chemotherapy for metastatic disease. Primary objectives are to assess the safety profile of monotherapy SRA737 and to establish a RP2D. The PK profile and PD biomarkers will be investigated. The study was opened to enrollment in mid-2016. An amendment, which includes the addition of indication specific expansion cohorts of subjects with genetically-defined tumors known to have Chk1-sensitizing aberrations such as gene mutations and amplifications/deletions, has been submitted and is pending regulatory review while enrollment continues. At the Annual Meeting, the amended design will be described. The dose and schedule identified in this trial will inform the design and conduct of Phase 2 studies of SRA737 as a single agent and in combination with other targeted or immunomodulatory agents. Clinical trial information: NCT02797964.
3D Bioprinting for Cartilage and Osteochondral Tissue Engineering
Authors: Andrew C. Daly, Fiona E. Freeman, Tomas Gonzalez‐Fernandez, Susan E. Critchley, Jessica Nulty, Daniel J. Kelly
Journal: Advanced Healthcare Materials (2017)

Abstract Significant progress has been made in the field of cartilage and bone tissue engineering over the last two decades. As a result, there is real promise that strategies to regenerate rather than replace damaged or diseased bones and joints will one day reach the clinic however, a number of major challenges must still be addressed before this becomes a reality. These include vascularization in the context of large bone defect repair, engineering complex gradients for bone‐soft tissue interface regeneration and recapitulating the stratified zonal architecture present in many adult tissues such as articular cartilage. Tissue engineered constructs typically lack such spatial complexity in cell types and tissue organization, which may explain their relatively limited success to date. This has led to increased interest in bioprinting technologies in the field of musculoskeletal tissue engineering. The additive, layer by layer nature of such biofabrication strategies makes it possible to generate zonal distributions of cells, matrix and bioactive cues in 3D. The adoption of biofabrication technology in musculoskeletal tissue engineering may therefore make it possible to produce the next generation of biological implants capable of treating a range of conditions. Here, advances in bioprinting for cartilage and osteochondral tissue engineering are reviewed.
Optimal Treatment of Stage IIIA-N2 Non–Small Cell Lung Cancer: A Neverending Story?
Authors: Paul E Van Schil
Journal: Journal of Thoracic Oncology (2017)

Stage IIIA-N2 NSCLC remains the Achilles' heel in thoracic surgery, with diagnostic and therapeutic strategies being hotly debated at plenary sessions of major oncological conferences.1 This results from many uncertainties and imprecise definitions surrounding the specific category of NSCLC lying between clearly resectable disease (with complete resection offering the best chance of long-term survival) and unresectable disease (which is treated mainly by concurrent or sequential chemoradiation in patients with good performance status).