tbuckley/cabot-search huggingface dataset:
Influence of genetic variants of genes potentially associated with brain metastases on overall survival in 70 colorectal cancer patients.
Authors: Matthias Preusser, Stefan Stremitzer, Anna Sophie Berghoff, Nico Benjamin Volz, Wu Zhang, Dongyun Yang, Sebastian Stintzing, Yan Ning, Yu Sunakawa, Shinichi Yamauchi, Ana Sebio, Satoshi Matsusaka, Rita Elie El-Khoueiry, Peter Birner, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2014)

3565 Background: Brain metastases (BM) in colorectal cancer (CRC) are rare, developing in only 0.3-9% of the patients, and considered a late-stage manifestation of the disease. The aim of this study was to investigate whether genetic variants of genes from integrin, invasion- and adhesion-mediating, angiogenic and tumor suppressing pathways, involved in overcoming the blood-brain barrier are associated with outcome. Methods: Genomic DNA was extracted from formalin-fixed paraffin embedded resected BM from 70 patients with histologically proven CRC. Single nucleotide polymorphisms (SNP) in seven genes (CXCR4, MMP9, ST6GALNAC5, ITGAV, ITGB1, ITGB3, KLF4) were analyzed by direct Sanger DNA sequencing and evaluated for association with overall survival (OS) from resection of BM. Only SNPs with an allele frequency of ≥10% were analyzed. Results: In univariate analysis, rs17577 (MMP9) and rs4642 (ITGB3) showed a significant difference in OS [(G/G 7.4 months, G/A 5.1 months; HR (95% CI) 1.83 (0.95-3.53), P=0.044) and (A/A or A/G 8.0 months, G/G 4.3 months; HR (95% CI) 2.31 (1.08-4.93), P=0.014), respectively]. In multivariate analysis adjusted for baseline characteristics (primary tumor site, age at diagnosis of CRC, BM location, Karnofsky performance status), rs2236599 (KLF4), rs10171481 (ITGAV), rs1883778 (ST6GALNAC5), and rs2680880 (CXCR4) were significant in OS [(G/G 7.4 months, G/A or A/A 4.8 months; HR (95% CI) 2.12 (1.01-4.45), P=0.048), (A/A or A/G 5.3 months, G/G 15.5 months; HR (95% CI) 0.39 (0.18-0.85), P=0.018), (G/G 4.6 months, G/A or A/A 9.4 months; HR (95% CI) 0.53 (0.30-0.93), P=0.028) and (A/A 6.4 months, A/T 9.3 months, T/T 4.6 months; HR (95% CI) 0.45 (0.22-0.89) and 1.54 (0.75-3.15), P=0.005), respectively]. Recursive partitioning analyses revealed that rs4642 is the dominant SNP predicting OS. Conclusions: This study suggests for the first time a prognostic effect of the genetic variations within genes involved in the blood-brain barrier breach. Further analyses are needed to confirm these findings.
Cardiovascular Consequences of Prostanoid I Receptor Deletion in Microsomal Prostaglandin E Synthase-1–Deficient Hyperlipidemic Mice
Authors: Soon Yew Tang, James Monslow, Gregory R. Grant, Leslie Todd, Sven-Christian Pawelzik, Lihong Chen, John Lawson, Ellen Puré, Garret A. FitzGerald
Journal: Circulation (2016)

Inhibitors of cyclooxygenase-2 alleviate pain and reduce fever and inflammation by suppressing the biosynthesis of prostacyclin (PGI2) and prostaglandin E2. However, suppression of these prostaglandins, particularly PGI2, by cyclooxygenase-2 inhibition or deletion of its I prostanoid receptor also predisposes to accelerated atherogenesis and thrombosis in mice. By contrast, deletion of microsomal prostaglandin E synthase 1 (mPGES-1) confers analgesia, attenuates atherogenesis, and fails to accelerate thrombogenesis, while suppressing prostaglandin E2, but increasing biosynthesis of PGI2.To address the cardioprotective contribution of PGI2, we generated mice lacking the I prostanoid receptor together with mPges-1 on a hyperlipidemic background (low-density lipoprotein receptor knockouts).mPges-1 depletion modestly increased thrombogenesis, but this response was markedly further augmented by coincident deletion of the I prostanoid receptor (n=10-18). By contrast, deletion of the I prostanoid receptor had no effect on the attenuation of atherogenesis by mPGES-1 deletion in the low-density lipoprotein receptor knockout mice (n=17-21).Although suppression of prostaglandin E2 accounts for the protective effect of mPGES-1 deletion in atherosclerosis, augmentation of PGI2 is the dominant contributor to its favorable thrombogenic profile. The divergent effects on these prostaglandins suggest that inhibitors of mPGES-1 may be less likely to cause cardiovascular adverse effects than nonsteroidal anti-inflammatory drugs specific for inhibition of cyclooxygenase-2.
Toxic Alcohol Calculations and Misinterpretation of Laboratory Results
Authors: Mark K. Su, Robert S. Hoffman
Journal: JAMA Internal Medicine (2016)

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Abstract 1314: Evaluating payload delivery to the CNS from surface-modified nanoparticles
Authors: Kyle T. Householder, Danielle DiPerna, Layla Ghaffari, Rachael Sirianni
Journal: Cancer Research (2016)

Abstract The blood-brain barrier (BBB) remains a major obstacle to treatment of intracranial tumors. Most drugs are poorly bioavailable in the brain, and peripheral toxicity can severely limit administerable dose. Drug loaded nanoparticles are capable of accumulating preferentially in the core of angiogenic tumors by a mechanisms known as the enhanced permeation and retention (EPR) effect, which can improve therapeutic efficacy of encapsulated molecules compared to free form. However, to achieve complete tumor kill, chemotherapy must target both the leaky tumor core and cells that reside behind an intact blood-brain barrier. The goal of this work was to evaluate payload delivery to the CNS from nanoparticles modified with one of four targeting ligands: TAT, antennapedia (AP), angiopep2 (Ang2) or Tet-1. Poly(lactic acid)-co- poly(ethylene glycol) nanoparticles (NPs) encapsulating Nile Red, a small fluorescent dye, were produced by solvent-evaporation technique. Peptides were covalently attached to the nanoparticle surface by a maliemide-thiol reaction. The effect of targeting ligands on NP payload delivery to healthy brain and spinal cord compared to unmodified NPs was evaluated in mice at 2 and 6 hours post injection. Mice were perfused with saline, and the brains and spinal cord were removed, homogenized and payload delivery quantified by fluorescence. All targeting ligands evaluated significantly increased payload delivery to the brain at both 2 and 6 hours, with the cell-penetrating peptides, TAT and AP, producing the greatest effect of a 4-fold increase over control. Additionally, the cell-penetrating peptides significantly increased payload delivery to the spinal cord at 2 hours but had no significant effect on delivery at 6 hours. Interestingly, the receptor-mediated peptides, Ang2 and Tet-1, did not significantly change spinal cord delivery at 2 hours but significantly increased payload concentration at 6 hours. These data suggest both receptor and nonspecific targeting ligands affect payload delivery and kinetics in a regionally specific manner. Future work is focused on evaluating additional ligands to better understand how the type of cell-nanoparticle interactions affects payload distribution. Citation Format: Kyle T. Householder, Danielle DiPerna, Layla Ghaffari, Rachael Sirianni. Evaluating payload delivery to the CNS from surface-modified nanoparticles. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1314.
Abstract 4689: Successfully targeting triple negative breast cancer using combination therapy of Didox and Doxorubicin with reduced cardiotoxicity
Authors: Elizabeth A. Wilson, Howard L. Elford, Jesika S. Faridi
Journal: Cancer Research (2016)

Abstract Triple-negative breast cancer (TNBC) is an aggressive histological subtype that has limited treatment options with chemotherapy being the only systemic therapy for these patients. The most common chemotherapy regimen used includes the anthracycline Doxorubicin (DOXO). Although DOXO is a highly effective agent, its efficacy is limited due to acquired drug resistance and cardiotoxicity. We have previously identified that ribonucleotide reductase M2 (RRM2) is upregulated in TNBC cells and is a key contributor to acquired drug resistance. The ribonucleotide reductase inhibitor Didox has been shown to be a powerful free radical scavenger and iron chelator that provides the capabilities to alleviate the cytotoxic profile of DOXO especially the cardiotoxicity as well as enhance the DOXO efficacy. In this current study, MDA-MB-468 and MDA-MB-231 TNBC cells were treated with DOXO alone or DOXO plus Didox. Synergy assays were performed and IC50 values were determined. Here we report that Didox worked synergistically with DOXO and reduced the DOXO IC50 values by more than one-half in each cell line. In order to determine the in vivo benefit of adding Didox to DOXO therapy, ncr-nude mice implanted with MDA-MB-468 xenografts were treated with (1) vehicle, (2) daily Didox alone (425 mg/kg), (3) DOXO alone (10 mg/kg/week for 2 doses and 2 mg/kg/week for 3 additional doses), or (4) the combination of DOXO and Didox. Tumor volumes over time were determined for each of the treatment groups. At endpoint, we performed necropsy, collected serum, and dried and weighed the hearts. Treatment with DOXO alone prevented tumor growth and provided about a 70% lower tumor volume as compared to vehicle treatment. Treatment with Didox alone yielded about 50% lower tumor volume as compared to vehicle treatment. However, adding Didox in combination with DOXO significantly inhibited the tumor size and resulted in a 90% lower final tumor volume as compared to vehicle treatment. One indicator of DOXO cardiotoxicity is increased heart weight. We found that the heart weight of DOXO alone treated animals was significantly increased and the inclusion of Didox in the treatment prevented this increase. Collectively, these results identify that adding the ribonucleotide reductase inhibitor Didox in combination with DOXO may be used to treat TNBC by enhancing the efficacy on tumor inhibition and by alleviating the cardiotoxic effects of DOXO. Citation Format: Elizabeth A. Wilson, Howard L. Elford, Jesika S. Faridi. Successfully targeting triple negative breast cancer using combination therapy of Didox and Doxorubicin with reduced cardiotoxicity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4689.
Is Mutation Random or Targeted?: No Evidence for Hypermutability in Snail Toxin Genes
Authors: Scott W. Roy
Journal: Molecular Biology and Evolution (2016)

Ever since Luria and Delbruck, the notion that mutation is random with respect to fitness has been foundational to modern biology. However, various studies have claimed striking exceptions to this rule. One influential case involves toxin-encoding genes in snails of the genus Conus, termed conotoxins, a large gene family that undergoes rapid diversification of their protein-coding sequences by positive selection. Previous reconstructions of the sequence evolution of conotoxin genes claimed striking patterns: (1) elevated synonymous change, interpreted as being due to targeted "hypermutation" in this region; (2) elevated transversion-to-transition ratios, interpreted as reflective of the particular mechanism of hypermutation; and (3) much lower rates of synonymous change in the codons encoding several highly conserved cysteine residues, interpreted as strong position-specific codon bias. This work has spawned a variety of studies on the potential mechanisms of hypermutation and on causes for cysteine codon bias, and has inspired hypermutation hypotheses for various other fast-evolving genes. Here, I show that all three findings are likely to be artifacts of statistical reconstruction. First, by simulating nonsynonymous change I show that high rates of dN can lead to overestimation of dS. Second, I show that there is no evidence for any of these three patterns in comparisons of closely related conotoxin sequences, suggesting that the reported findings are due to breakdown of statistical methods at high levels of sequence divergence. The current findings suggest that mutation and codon bias in conotoxin genes may not be atypical, and that random mutation and selection can explain the evolution of even these exceptional loci.
Change in Pattern of <i>HER2</i> Fluorescent in Situ Hybridization (FISH) Results in Breast Cancers Submitted for FISH Testing: Experience of a Reference Laboratory Using US Food and Drug Administration Criteria and American Society of Clinical Oncology and College of American Pathologists Guidelines
Authors: Mithun Vinod Shah, Anne E. Wiktor, Reid G. Meyer, Kathleen S. Tenner, Karla V. Ballman, Stefan J. Green, William R. Sukov, Rhett P. Ketterling, Edith A. Perez, Robert B. Jenkins
Journal: Journal of Clinical Oncology (2016)

Purpose In 1998, the US Food and Drug Administration (FDA) approved human epidermal growth factor receptor 2 (HER2) testing guidelines to determine eligibility for HER2-directed therapy (HDT) in breast cancer. ASCO and the College of American Pathologists published immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) HER2 testing guidelines in 2007 (AC2007) and updated these guidelines in 2013 (AC2013). We compared the HER2 FISH amplification frequency using these three guidelines. Methods Patient samples that were sent to the Mayo Clinic cytogenetics laboratory for FISH testing (n = 2,851; from November 2013 to October 2014) were analyzed. Frequency of HER2 FISH amplification was examined and impact of AC2013 assessed. Results IHC results were available for 1,922 patient samples (67.4%), 137 of which were from Mayo Clinic. Distribution was 2.4% IHC 0, 7.9% IHC 1+, 84.8% IHC 2+, and 2.5% IHC 3+. Among IHC 2+ patients, HER2 FISH positivity was 11.8% (FDA), 9.4% (AC2007), and 24.1% (AC2013). Overall, 11.8% (n = 339) were positive with a FISH ratio ≥ 2.0, 1.3% (n = 35) with a FISH ratio ≥ 2.0 despite a HER2 signal < 4.0, and 3.0% (n = 86) with HER2 signal ≥ 6.0 despite FISH ratio < 2.0. Among 405 patients (14.2%) who were initially considered FISH-equivocal (ratio < 2.0 with HER2 signal ≥ 4.0, but < 6.0; AC2013), use of an alternative chromosome 17 probe reassigned 212 (7.4% overall) patients to FISH-positive and 36 (1.3% overall) patients to FISH-negative, whereas 157 (5.5% overall) patients remained equivocal. Final HER2 positivity with AC2013 (23.6%) was increased (P < .001) compared with FDA (13.1%) and AC2007 (11%) guidelines. Conclusion In a reference laboratory cohort that was highly enriched for IHC 2+ patient samples, AC2013 guidelines led to a larger number of FISH-equivocal patients. Approximately one half of these FISH-equivocal patients (7.4% overall) became HER2-positive upon alternative FISH probe testing. However, these patients would not have participated in the pivotal HDT trials. Clinical utility data on HDT benefit in these patients and other special subsets are needed.
Partially Matched Related Donor Transplantation Can Achieve Outcomes Comparable to Unrelated Donor Transplantation for Patients with Hematologic Malignancies.
Authors: Xiao Jun Huang, Lan-Ping Xu, Kai yan Liu, Dai-Hong Liu, Yu Wang, Huan Chen, Yu-Hong Chen, Wei Han, Jing-Zhi Wang, Yao Chen, Xiao-Hui Zhang, Hongxia Shi, Feng-Rong Wang, Fei-Fei Tang
Journal: Blood (2009)
Adolescent idiopathic scoliosis
Authors: Jack C. Cheng, René M. Castelein, Winnie C. Chu, Aina J. Danielsson, Matthew B. Dobbs, Theodoros B. Grivas, Christina A. Gurnett, Keith D. Luk, Alain Moreau, Peter O. Newton, Ian A. Stokes, Stuart L. Weinstein, R. Geoffrey Burwell
Journal: Nature Reviews Disease Primers (2015)
Obesity and Life Expectancy with and without Diabetes in Adults Aged 55 Years and Older in the Netherlands: A Prospective Cohort Study
Authors: Klodian Dhana, Jana Nano, Symen Ligthart, Anna Peeters, Albert Hofman, Wilma Nusselder, Abbas Dehghan, Oscar H. Franco
Journal: PLoS Medicine (2016)

Overweight and obesity are associated with increased risk of type 2 diabetes. Limited evidence exists regarding the effect of excess weight on years lived with and without diabetes. We aimed to determine the association of overweight and obesity with the number of years lived with and without diabetes in a middle-aged and elderly population.The study included 6,499 individuals (3,656 women) aged 55 y and older from the population-based Rotterdam Study. We developed a multistate life table to calculate life expectancy for individuals who were normal weight, overweight, and obese and the difference in years lived with and without diabetes. For life table calculations, we used prevalence, incidence rate, and hazard ratios (HRs) for three transitions (healthy to diabetes, healthy to death, and diabetes to death), stratifying by body mass index (BMI) at baseline and adjusting for confounders. During a median follow-up of 11.1 y, we observed 697 incident diabetes events and 2,192 overall deaths. Obesity was associated with an increased risk of developing diabetes (HR: 2.13 [p < 0.001] for men and 3.54 [p < 0.001] for women). Overweight and obesity were not associated with mortality in men and women with or without diabetes. Total life expectancy remained unaffected by overweight and obesity. Nevertheless, men with obesity aged 55 y and older lived 2.8 (95% CI -6.1 to -0.1) fewer y without diabetes than normal weight individuals, whereas, for women, the difference between obese and normal weight counterparts was 4.7 (95% CI -9.0 to -0.6) y. Men and women with obesity lived 2.8 (95% CI 0.6 to 6.2) and 5.3 (95% CI 1.6 to 9.3) y longer with diabetes, respectively, compared to their normal weight counterparts. Since the implications of these findings could be limited to middle-aged and older white European populations, our results need confirmation in other populations.Obesity in the middle aged and elderly is associated with a reduction in the number of years lived free of diabetes and an increase in the number of years lived with diabetes. Those extra years lived with morbidity might place a high toll on individuals and health care systems.
Stem Cell‐Based Therapies for Ischemic Stroke: Preclinical Results and the Potential of Imaging‐Assisted Evaluation of Donor Cell Fate and Mechanisms of Brain Regeneration
Authors: Pascal Gervois, Esther Wolfs, Jessica Ratajczak, Yörg Dillen, Tim Vangansewinkel, Petra Hilkens, Annelies Bronckaers, Ivo Lambrichts, Tom Struys
Journal: Medicinal Research Reviews (2016)

Abstract Stroke is the second most common cause of death and is a major cause of permanent disability. Given the current demographic trend of an ageing population and associated increased risk, the prevalence of and socioeconomic burden caused by stroke will continue to rise. Current therapies are unable to sufficiently ameliorate the disease outcome and are not applicable to all patients. Therefore, strategies such as cell‐based therapies with mesenchymal stem cell (MSC) or induced pluripotent stem cell (iPSC) pave the way for new treatment options for stroke. These cells showed great preclinical promise despite the fact that the precise mechanism of action and the optimal administration route are unknown. To gain dynamic insights into the underlying repair processes after stem cell engraftment, noninvasive imaging modalities were developed to provide detailed spatial and functional information on the donor cell fate and host microenvironment. This review will focus on MSCs and iPSCs as types of widely used stem cell sources in current (bio)medical research and compare their efficacy and potential to ameliorate the disease outcome in animal stroke models. In addition, novel noninvasive imaging strategies allowing temporospatial in vivo tracking of transplanted cells and coinciding evaluation of neuronal repair following stroke will be discussed.
The relationship between body fat and respiratory function in young adults
Authors: Tim J.T. Sutherland, Christene R. McLachlan, Malcolm R. Sears, Richie Poulton, Robert J. Hancox
Journal: European Respiratory Journal (2016)

The relationship between adiposity and respiratory function is poorly understood. Most studies investigating this have used indirect measures of body fat and few have assessed how changes in adiposity influence lung function. Body fat measured by bio-electrical impedance analysis, body mass index, waist circumference, spirometry, body plethysmography and transfer factor were measured at ages 32 and 38 years in 361 non-smoking, non-asthmatic participants from a population-based birth cohort. Higher percentage body fat was associated with lower spirometric and plethysmographic lung volumes, but not with airflow obstruction, or transfer factor at 32 years. Changes in adiposity between ages 32 and 38 years were inversely associated with changes in lung volumes. These associations were generally stronger in men than women, but an association between increasing adiposity and lower airway function (forced expiratory volume in 1 s/forced vital capacity) was only found in women. Similar associations were found for body mass index and waist circumference. Higher percentage body fat is associated with lower lung volumes. Direct and indirect measures of adiposity had similar associations with lung function. Adiposity had a greater effect on lung volumes in men than women but was associated with airway function only in women. There was little evidence that adiposity influenced transfer factor.
Understanding the burnout experience: recent research and its implications for psychiatry
Authors: Christina Maslach, Michael P. Leiter
Journal: World Psychiatry (2016)

The experience of burnout has been the focus of much research during the past few decades. Measures have been developed, as have various theoretical models, and research studies from many countries have contributed to a better understanding of the causes and consequences of this occupationally-specific dysphoria. The majority of this work has focused on human service occupations, and particularly health care. Research on the burnout experience for psychiatrists mirrors much of the broader literature, in terms of both sources and outcomes of burnout. But it has also identified some of the unique stressors that mental health professionals face when they are dealing with especially difficult or violent clients. Current issues of particular relevance for psychiatry include the links between burnout and mental illness, the attempts to redefine burnout as simply exhaustion, and the relative dearth of evaluative research on potential interventions to treat and/or prevent burnout. Given that the treatment goal for burnout is usually to enable people to return to their job, and to be successful in their work, psychiatry could make an important contribution by identifying the treatment strategies that would be most effective in achieving that goal.