tbuckley/cabot-search huggingface dataset:
Paget's Disease of Bone
Authors: K J Simcic, A J Moreno
Journal: New England Journal of Medicine (1996)

Figure 1. A 67-year-old man had Paget's disease involving the right tibia and the first lumbar vertebrae. The patient initially presented with bone pain and bowing of his right lower leg, but the vertebral lesion was not symptomatic. An x-ray film of the right tibia (Panel A) and a bone scan obtained after the administration of technetium-99m–labeled methylene diphosphonate (Panel B) show a marked expansion of bone and a bowing deformity in the right tibia. In addition, the x-ray film shows mixed lytic and sclerotic changes typical of chronic Paget's disease. The accumulation of radionuclide in the right kidney on . . .
Expression of the Butyrate/Niacin Receptor, GPR109a on T Cells Plays an Important Role in a Mouse Model of Graft Versus Host Disease
Authors: Melissa D Docampo, Christoph K. Stein-Thoeringer, Amina Lazrak, Marina D Burgos da Silva, Justin Cross, Marcel R.M. van den Brink
Journal: Blood (2018)
Abstract 19178: Cardiac Rehabilitation in the Elderly: An Under Referred Population That Does Not Attend
Authors: Billie-Jean Martin, Mark Haykowsky, Trina Hauer, Danielle A Southern, Merill L Knudtson, Ross Arena, James A Stone, Sandeep Aggarwal
Journal: Circulation (2012)

Introduction: Elderly subjects have been shown in recent years to derive benefit from attending cardiac rehabilitation (CR). However, they are less likely to attend. Further, the dependency of CR referral on patient age has not been explored. Methods: The Alberta Provincial Project for Outcomes Assessment in Coronary Heart Disease (APPROACH) database was used to obtain information on all patients. Subjects with at least one vessel CAD were considered as the pool of subjects to be referred. Patients were categorized according to age, &lt;50 years, 50-60 years, 60-70 years, 70-80 years, and over 80 years of age. Rates of referral to and subsequent attendance at CR were compared across age categories. Logistic regression models were constructed to assess whether age predicted referral or attendance. Results: A total of 25,958 (24.6% female) subjects were included; of those, 3,266 (12.6%) were under 50 years of age, 6,330 (24.4%) were 50-60, 7,618 (29.4%) were 60-70, 6,798 (26.2%) were 70-80, and 1946 (7.5%) were over 80 years of age. Subjects in the higher age ranges had a greater prevalence of congestive heart failure and chronic obstructive pulmonary disease but lower prevalence of diabetes than their younger counterparts (all p&lt;0.0001). Advanced age was associated with both decreased attendance and referral, though the association was stronger with referral (both p&lt;0.0001, Figure 1). Relative to the youngest group, each age category had reduced referral in unadjusted and adjusted models (adjusted OR (95%CI): age 50-60: 0.86 (0.79, 0.95); age 60-70: 0.57 (0.52, 0.63); age 70-80: 0.34 (0.31, 0.38); age&gt;80: 0.15 (0.13, 0.17)). Only the two oldest groups were less likely to attend. Conclusions: Advanced age represents a barrier to CR in two ways: one, elderly subjects are less likely to be referred, and subsequently less likely to attend. As elderly subjects have been shown to derive similar benefits from CR as their younger counterparts, age as a barrier to CR needs to be addressed.
Novel first-in-class small molecule targeting APE1/Ref-1 to prevent and treat chemotherapy-induced peripheral neuropathy (CIPN).
Authors: Mark R. Kelley, Richard Adam Messmann, Jill Fehrenbacher
Journal: Journal of Clinical Oncology (2018)

229 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is an acute and chronic debilitating side effect of a number of chemotherapeutic agents lacking FDA-approved interventions or strategies resulting in dose-limiting neurotoxicity. CIPN can persist following discontinuation of the drug with up to 40% of patients having continued CIPN five years after treatment ends. Thus, CIPN directly affects cancer survivorship, quality of life, and may limit future treatment options if cancer recurs. Although the cellular mechanisms mediating CIPN remain to be determined, several lines of evidence support the notion that DNA damage caused by anticancer therapies could contribute to the neuropathy. Methods: Using an experimental model of isolated sensory neurons in culture, we established a causal relationship between cancer-therapy-induced neurotoxicity and DNA damage and repair. Results: Genetically reducing the activity of APE1 increased the neurotoxicity produced by platin treatment, whereas augmenting the activity of APE1 lessened neurotoxicity. Furthermore, using a targeted small-molecule, APX3330, which increases DNA repair of APE1 in neurons, it lessened neurotoxicity using a variety of endpoints ex vivo; e.g. DNA damage, CGRP release. We will present data using animal models of CIPN demonstrating a protective effect of APX3330 using either cis- or oxaliplatin without diminishing the anti-tumor effect of the platins. A Phase 1 clinical trial for safety/RF2D for APX3330 has completed (NCT03375086). Conclusions: Effective prevention and management of CIPN hinges on understanding its pathophysiology. While multiple causal mechanisms may be at work, we believe that the induction of oxidative DNA damage in sensory neurons is a major cause of CIPN. Thus, enhancement of oxidative DNA damage repair by APX3330 results in reduction of CIPN.
Spatial-Temporal Cellular Bioeffects from Acoustic Droplet Vaporization
Authors: Ching-Hsiang Fan, Yi-Ting Lin, Yi-Ju Ho, Chih-Kuang Yeh
Journal: Theranostics (2018)

One of the major challenges in developing acoustic droplet vaporization (ADV)-associated therapy as an effective and safe strategy is the precise determination of the spatial cellular bioeffects after ADV (cell death or cell membrane permeabilization).In this study, we combined high-speed camera imaging and live-cell microscopic imaging to observe the transient dynamics of droplets during ADV and to evaluate the mechanical force on cells.Methods: C6 glioma cells were co-incubated with DiI-labeled droplets (radius: 1.5, 2.25, and 3.0 μm).We used an acousto-optical system for high-speed bright-field (500 kfps) and fluorescence (40 kfps) microscopic imaging in order to visualize the dynamics of droplets under ultrasound excitation (frequency = 5 MHz, pressure = 5-8 MPa, cycle number = 3, pulse number = 1).Live-cell microscopic imaging was used to monitor the cell morphology, cell membrane permeabilization, and cell viability by membrane-anchored Lyn-yellow fluorescence protein, propidium Iodide staining, and calcein blue AM staining, respectively.Results: We discovered that the spatial distribution of ADV-induced bioeffects could be mapped to the physical dynamics of droplet vaporization.For droplets with a 1.5 μm radius, the distance threshold for ADV-induced cell death (5.5±1.9 μm) and reversible membrane permeabilization (11.3±3.5 μm) was well correlated with the distance of ADV-bubble pressing downward to the floor (5.7±1.3 μm) and maximum distance of droplet expansion (11.5±2.6 μm), respectively.These distances were enlarged by increasing the droplet sizes and insonation acoustic pressures.The live-cell imaging results show that ADV-bubbles can directly disrupt the cell membrane layer and induce intensive intracellular substance leakage.Further, the droplets shed the payload onto nearby cells during ADV, suggesting ADV could directly induce adjacent cell death by physical force and enhancement of chemotherapy to distant cells. Conclusion:This study provide new insights into the ADV-mediated physicochemical synergic effect for medical applications.
Relationship Between the Efficacy of Cardiac Cell Therapy and the Inhibition of Differentiation of Human iPSC-Derived Nonmyocyte Cardiac Cells Into Myofibroblast-Like Cells
Authors: Ling Gao, Libang Yang, Lu Wang, Zhaohui Geng, Yuhua Wei, Glenn Gourley, Jianyi Zhang
Journal: Circulation Research (2018)

Myofibroblasts are believed to evolve from precursor cells; however, whether noncardiomyocyte cardiac cells (NMCCs; ie, endothelial cells, smooth muscle cells, pericytes, and fibroblasts) that have been derived from human-induced pluripotent stem cells (hiPSCs) can transdifferentiate into myofibroblast-like cells, and if so, whether this process reduces the efficacy of hiPSC-NMCC therapy, is unknown.To determine whether hiPSC-NMCCs can differentiate to myofibroblast-like cells and whether limiting the transdifferentiation of hiPSC-NMCCs can improve their effectiveness for myocardial repair.When endothelial cells, smooth muscle cells, pericytes, and fibroblasts that had been generated from hiPSCs were cultured with TGF-β (transforming growth factor-β), the expression of myofibroblast markers increased, whereas endothelial cell, smooth muscle cell, pericyte, and fibroblast marker expression declined. TGF-β-associated myofibroblast differentiation was accompanied by increases in the signaling activity of Smad, Snail, and mTOR (mammalian target of rapamycin). However, measures of pathway activation, proliferation, apoptosis, migration, and protein expression in hiPSC-endothelial cell-derived, smooth muscle cell-derived, pericyte-derived, and fibroblast-derived myofibroblast-like cells differed. Furthermore, when hiPSC-NMCCs were transplanted into the hearts of mice after myocardial infarction, ≈21% to 35% of the transplanted hiPSC-NMCCs expressed myofibroblast markers 1 week later, compared with <7% of transplanted cells ( P<0.01, each cell type) in animals that were treated with both hiPSC-NMCCs and the TGF-β inhibitor galunisertib. Galunisertib coadministration was also associated with significant improvements in fibrotic area, left ventricular dilatation, vascular density, and cardiac function.hiPSC-NMCCs differentiate into myofibroblast-like cells when cultured with TGF-β or when transplanted into infarcted mouse hearts, and the phenotypes of the myofibroblast-like cells can differ depending on the lineage of origin. TGF-β inhibition significantly improved the efficacy of transplanted hiPSC-NMCCs for cardiac repair, perhaps by limiting the differentiation of hiPSC-NMCCs into myofibroblast-like cells.
Correlation of demographic factors with length of treatment and survival in a palliative radiation oncology population.
Authors: Lauren Michelle Hertan, Alexandra Nichipor, Yaseer Mohammed Khouj, Cierra Zaslowe-Dude, Tracy A. Balboni, Monica Shalini Krishnan
Journal: Journal of Clinical Oncology (2018)

123 Background: Radiation is often used to palliate symptoms in patients with advanced cancer and the number of fractions used can vary significantly from as short as a single fraction (SF) to up to a multiple week course. No data currently exists regarding demographic factors and their influence on survival and fractionation decisions. The aim of this project is to investigate the association of demographic factors with survival, likelihood of SF use in patients (pts) receiving RT for bone metastases, and likelihood of hypofractionation (HF) (≤ 5 fx) in pts being treated for any palliative reason, excluding those receiving partial brain RT (PBRT) which includes stereotactic radiosurgery, and stereotactic radiation therapy. Methods: We retrospectively reviewed charts of pts treated with palliative RT between 1/2015 – 5/2017 at 2 tertiary centers and 4 community satellite practices. Demographic factors analyzed are included in table 1. Logistic regression was used to evaluate the associations between the factors and outcomes. Results: A total of 928 pts were included in the survival analysis. In the two subset analyses, 373 pts were included in the bone metastasis analysis and 745 were included in the analysis of all patients excluding pts receiving PBRT. In pts treated for bone metastases, consult type (inpatient vs. outpatient) was the only significant factor on multivariate analysis, with inpatient consults being more likely to get SF (HR = 2.169, =.025). In the pts receiving palliative RT (excluding PBRT), race and consult location (tertiary vs. community) were significant. Non-white pts (HR=0.527, p=.012) and pts treated in the community (HR=.778, p&lt;.001) were less likely to get HF. Gender (male vs. female), consult location (tertiary vs. community), and consult type (inpatient vs. outpatient) were significant on multivariate analysis for survival (HR=1.243, p=.028; HR=1.602, p&lt;.001; HR=2.301, p&lt;.001, respectively). Conclusions: This analysis suggests that demographic factors may affect both survival and decision making regarding fractionation in patients receiving palliative radiation. Further investigation into the reasons for these differences is needed.
To absorb fat — supersize my lipid droplets
Authors: Ira J. Goldberg, M. Mahmood Hussain
Journal: Journal of Clinical Investigation (2018)

Lipins play important roles in adipogenesis, insulin sensitivity, and gene regulation, and mutations in these genes cause lipodystrophy, myoglobinuria, and inflammatory disorders. While all lipins (lipin 1, 2, and 3) act as phosphatidic acid phosphatase (PAP) enzymes, which are required for triacylglycerol (TAG) synthesis from glycerol 3-phosphate, lipin 1 has been the focus of most of the lipin-related research. In the current issue of the JCI, Zhang et al. show that while lipin 2 and 3 are expendable for the incorporation of dietary fatty acids into triglycerides, lipin 2/3 PAP activity has a critical role in phospholipid homeostasis and chylomicron assembly in enterocytes.
<scp>CCR</scp>10<sup>+</sup><scp>ILC</scp>2s with <scp>ILC</scp>1‐like properties exhibit a protective function in severe allergic asthma
Authors: Chloé Beuraud, Vincent Lombardi, Sonia Luce, Stéphane Horiot, Emmanuel Naline, Catherine Neukirch, Sabi Airouche, Thibaut Perchet, Rachel Golub, Philippe Devillier, Sylvie Chollet‐Martin, Véronique Baron‐Bodo, Emmanuel Nony, Michel Aubier, Laurent Mascarell, Philippe Moingeon
Journal: Allergy (2018)

We previously showed that patients with severe allergic asthma have high numbers of circulating ILC2s expressing CCR10.Herein, CCR10+ ILC2s were further analyzed in the blood of healthy individuals or patients with allergic and non-allergic asthma. Characteristics of human CCR10+ and CCR10- ILC2s were assessed by flow cytometry as well as single-cell multiplex RT-qPCR. The role of CCR10+ ILC2s in asthma pathophysiology was studied in allergen-treated mice.When compared to healthy controls, CCR10+ ILC2s are enriched in the blood of both allergic and non-allergic severe asthmatic patients, and these cells are recruited to the lungs. Plasma concentrations of the CCR10 ligand CCL27 are significantly increased in severe asthmatics when compared to non-asthmatic patients. CCR10+ ILC2s secrete little TH 2 cytokines, but exhibit ILC1-like properties, including a capacity to produce IFN-γ. Also, single-cell analysis reveals that the CCR10+ ILC2 subset is enriched in cells expressing amphiregulin. CCR10+ ILC2 depletion, as well as blocking of IFN-γ activity, exacerbates airway hyperreactivity in allergen-challenged mice, providing evidence for a protective role of these cells in allergic inflammation.Frequencies of circulating CCR10+ ILC2s and CCL27 plasma concentrations represent candidate markers of asthma severity. The characterization of CCR10+ ILC2s in human samples and in mouse asthma models suggests that these cells downregulate allergic inflammation through IFN-γ production.
Unleashing Blocked Apoptosis in Cancer Cells: New MCL1 Inhibitors Find Their Groove
Authors: Brian Leber, Justin Kale, David W. Andrews
Journal: Cancer Discovery (2018)

Abstract Summary: Unleashing blocked apoptosis has emerged as an important tool in treating cancer as shown by the recent success of the BCL2 inhibitor venetoclax. However, MCL1 represents another important target as it is the predominant survival signal in many types of cancers and functions as a resistance mechanism to BCL2 inhibition. Caenepeel and colleagues and Ramsey and colleagues have developed two novel, potent, and selective MCL1 inhibitors that are effective against many hematologic malignancies, and Nangia and colleagues describe how one of these inhibitors can be successfully combined with BCL-xL and MEK inhibition to treat KRAS-mutated lung cancer. See related article by Ramsey et al., p. 1566. See related article by Caenepeel et al., p. 1582. See related article by Nangia et al., p. 1598.
Abstract #3890: The role of CXCR4 in the switch from E-cadherin to cadherin 11 during epithelial to mesenchymal transition in breast carcinoma cells
Authors: Tammy Sobolik-Delmaire, Yukiko Ueda, Ann Richmond
Journal: Cancer Research (2009)

Chemokines activate a family of seven-transmembrane G-protein-coupled receptors known as chemokine receptors to promote mitosis, survival and angiogenesis. The CXC chemokine receptor-4 (CXCR4) is the receptor for the chemokine ligand CXCL12 or stromal cell-derived factor-1 (SDF-1). Studies have demonstrated that aberrant expression of CXCR4 in metastatic breast cancer results in invasion of tumor cells into the extracellular matrix and subsequent entry into the circulatory system. To understand the mechanisms involved in CXCR4 related metastasis during breast carcinoma, our lab previously generated a constitutively active CXCR4 mutant receptor that is missing a portion of the carboxyl-terminal domain (CXCR4-\#916;CTD) and expressed this mutant receptor or wild-type CXCR4 in MCF-7 breast carcinoma cells. We demonstrated that expression of CXCR4-\#916;CTD but not wild type CXCR4 in MCF-7 breast carcinoma cells results in down regulation of E-cadherin and cell contacts, and enhanced motility and proliferation. During cancer progression there is a down regulation of E-cadherin and an up regulation of mesenchymal cadherins such as N-cadherin or cadherin 11 leading to an epithelial-to-mesenchymal-transition (EMT) and a loss of epithelial characteristics and a migratory phenotype. Several proteins involved in the down regulation of E-cadherin are transcription factors Snail, SIP-1, and Twist. Microarray data from our previous studies demonstrated an up regulation in genes responsible for the EMT phenotype such as vimentin and Snail in MCF-7 cells expressing CXCR4-\#916;CTD but not wild-type CXCR4. Our unpublished studies described here utilize immunofluorescence and western blot analysis to demonstrate increased expression and nuclear localization of Snail, SIP1, and Twist in CXCR4-\#916;CTD MCF-7 cells as compared to wild-type CXCR4 cells. Utilizing western blot analysis and immunofluorescence, we show that the mesenchymal cadherin, cadherin 11, but not N-cadherin, is upregulated in both CXCR4-\#916;CTD and CXCR4 wild-type cells. To understand the up regulation of cadherin 11 in both cell lines, we sought to determine if the binding partners of E-cadherin such as \#914;-catenin and p120 change during the switch from E-cadherin to cadherin 11. We show that both \#914;-catenin and p120 are bound to E-cadherin in wild-type cells. However, in CXCR4-\#916;CTD cells, \#914;-catenin expression is lost while p120 localization is cytoplasmic and a small fraction is localized to junctions where it may interact with cadherin 11 to promote up regulation of cadherin 11, which is essential for increased cell motility and a more invasive phenotype. This work was supported by grants from the NIH (HL07751) and CA34590.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3890.
Clare Gerada: Dissecting resilience
Authors: Clare Gerada
Journal: BMJ (2018)

The traditional structures that have helped doctors prepare themselves psychologically for a career in medicine are changing rapidly or disappearing altogether.

I started medical school over 40 years ago. In my first week I joined my first medical group—for dissection. The groups were allocated alphabetically, and mine was made up of students with surnames beginning with E-K. For the next two years we met over the cadaver for three hours a day, four days a week.

Decades later we still meet, though usually without a dead body in sight. We’ve become lifelong friends and borne …
Random versus targeted urine drug testing among cancer patients receiving opioid therapy at a supportive care clinic.
Authors: Joseph Anthony Arthur, Zhanni Lu, David Hui, Kristy Nguyen, Bernard Lobato Prado, Tonya Edwards, Sriram J. Yennu, Suresh Reddy, Diane D. Liu, Eduardo Bruera
Journal: Journal of Clinical Oncology (2018)

221 Background: Although urine drug testing (UDT) is an effective risk monitoring tool for patients on chronic opioid therapy, there is currently no evidence to guide physicians in identifying who should have UDT, or when and how often it should be ordered. The main objective of our study was to describe the characteristics of patients who underwent random UDT and a similar cohort who underwent targeted UDT. Methods: Demographic and clinical information of 212 patients who underwent random UDT was retrospectively reviewed and compared with 88 patients who underwent targeted UDT. Targeted UDT was ordered based on the physician’s estimation of patient risk for nonmedical opioid use. All patients were eligible for random UDT regardless of their risk potential for nonmedical opioid use. Results: 212/231 (92%) eligible patients underwent random UDT. Of these 59 (28%) had abnormal results. Among 64 abnormalities detected, 14 (20%) were prescribed opioids that were absent from the urine, 19 (30%) were unprescribed opioids that were present, and 32 (50%) were illicit drugs (91% marijuana). 38/88(43%) of targeted patients had abnormal results. Among 49 abnormalities detected, 13 (27%) were prescribed opioids that were absent from the urine, 15 (31%) were unprescribed opioids that were absent, and 21 (43%) were illicit drugs (71% marijuana). UDT abnormalities were significantly higher in the targeted group than the random group (43.2% vs. 27.8%, p=0.01). There were no significant differences in demographic and clinical characteristics between random and targeted patients with abnormal UDT findings. UDT abnormality was independently associated with age (OR= 0.97 per year, 95% CI: 0.95-0.99, p=0.012), female gender (OR=0.47, 95% CI: 0.28-0.81, p=0.006), anxiety (OR=1.11per point, 95% CI: 1.01-1.22, p=0.039), and appetite (OR= 1.14 per point, 95% CI: 1.04-1.26, p=0.006). Conclusions: More than 1 in 4 cancer patients who underwent random UDT had abnormal results. UDT abnormality in randomly selected patients were no different from targeted patients. Further studies are needed to guide clinical practice regarding standardization of UDT ordering among patients with cancer.
Ischemic Complications After High-Grade Glioma Resection Could Interfere With Residual Tumor Detection With 18F-Fluorocholine PET/CT
Authors: Ana María García Vicente, María José Rodriguez Muñoz, Francisco José Pena Pardo, Milton Miguel Martinez Madrigal, Angel Soriano Castrejón
Journal: Clinical Nuclear Medicine (2018)

Ischemic complications after resection of high-grade glioma are frequent and may constitute potential cause of false-positive results in postsurgical evaluation using F-fluorocholine PET/CT. On the other hand, hypoxia caused by ischemia promotes invasive glioma growth. We present 3 cases of patients with different grades of ischemic injury after resection of high-grade glioma. The combined interpretation of diffusion-weighted imaging and apparent diffusion coefficient map on MRI, in this clinical setting, is mandatory to avoid PET/CT misinterpretations.