tbuckley/cabot-search huggingface dataset:
Abstract 19659: Early Detection of Right Ventricular Dysfunction Using Speckle-Tracking Echocardiography in Systemic Sclerosis Patients
Authors: Monica Mukherjee, Shang-En Chung, Laura K Hummers, Frederick M Wigley, Theodore P Abraham, Ami A Shah
Journal: Circulation (2014)

Background: Cardiac involvement in systemic sclerosis (SSc) adversely affects long-term prognosis, remaining undetectable despite frequent echocardiographic monitoring. Speckle tracking derived strain of the RV free wall was utilized to detect early changes in regional and global contractility in SSc patients. Methods: 138 SSc patients who had technically adequate, clinically indicated 2D echocardiograms were studied, and compared with a cohort of 40 age-matched non-scleroderma controls (C). Conventional 2D and off-line strain analysis were performed using commercially available software. RV longitudinal systolic strain (RVLSS) was assessed in the basal, mid and apical free wall. RVLSS in each segment was compared between SSc and C using a Student’s t test. We modeled RVLSS as a function of segment and disease group (SSc vs. C). T-test was used to compare the group difference, and GEE to account for clustering of RV strain values across the 3 RV segments. Results: Global RVLSS was diminished in SSc compared to C (β 1.5, p=0.045). Regional differences in RVLSS were also noted: decreased in the apex (SSc -8.5 vs C -17.2, p&lt;0.0001) and mid (SSc -12.4 vs. -17.8, p&lt;0.0001) segments and increased in the base (SSc -32.2 vs. C -22.5, p&lt;0.0001) in SSc vs C. Among C, regional differences in RVLSS were detected in the basal segment relative to the apex (base-apex β -5.4; p&lt;0.0001) but not in the mid-apex comparison. In contrast, SSc had significant regional differences throughout (base-apex β -23.6, mid-apex β -3.9, both p&lt;0.0001), especially when comparing the basal to apical segments. The base-apex difference was significantly greater in SSc compared to C (p&lt;0.0001 for interaction). While SSc had a higher mean PASP than C (SSc 31.4 vs C 22.7 mmHg, p=0.0001), the differences observed in regional strain between SSc and C were unchanged when restricting our analyses to those with a PASP&lt;35 mmHg. Conclusion: In SSc patients, basal segments of the RV free wall had increased RVLSS, in comparison to mid and apical segments, and the base-apex difference with significantly higher than that seen in non-scleroderma controls. This heterogenous pattern of regional strain in SSc patients, regardless of PASP, suggests regional remodeling of the RV prior to the onset of overt RV dysfunction.
CD52 as a new marker for osteogenic tumors and its potential implication in therapy
Authors: Raphaela Guenther, Christine Sers, Lars Morawietz, Manfred Dietel, Veit Krenn
Journal: Cancer Research (2005)

4203  Introduction. CD52 is a GPI-anchored glycoprotein which is expressed abundantely on all lymphocytes, monocytes, macrophages and eosinophils as well as in the epithelial cells of the distal epididymis and vas deferens. The protein core of the lymphocyte CD52 (L-CD52) and the sperm CD52 (S-CD52) is identical, but the GPI anchor structure and the N-linked carbohydrate side chains are different. To date, the physiologocal role of CD52 on lymphocytes is not clear. However, an antibody directed to CD52 called CAMPATH-1H is capable of complement activation as well as antibody-mediated cellular cytotoxity leading to a depletion of lymphocytes. Recently, we detected CD52 on giant cell tumors of the bone (GCT). The aim of the current study is the analysis of CD52-expression on different osteogenic tumors to evaluate the potential for a treatment of CD52 expressing solid tumours. Material and methods. Immunohistochemical analysis of CD52 was performed on 31 GCTs, 17 Osteosarcomas (OSs), 7 Chondrosarcomas (CSs) and 15 other bone-related tumors. In addition, we analyzed GCT, OS and CS cell lines for expression of CD52. All tumors were semiquantitatively scored using a combined immunoreactive score modified according to Remmele and Stegner. Furthermore, we used RT-PCR and Western blot analysis to investigate the presence and the type of CD52 both in cell lines and tissue. Results. Imunohistochemical staining confirmed that especially GCTs, OSs and CSs express the cellular antigen CD52 in the tumor cells. In the cartilage-forming tumors CS, Chondroma and Osteochondroma we could detect the strongest CD52 expression with an immunoreactive score of 4.6, 7.0 and 5.0, respectively when compared to the other osteogenic tumors. The amount of CD52-positive cells varies between 51% to 75%, whereas the staining intensities are moderate to strong. CD52-specific bands detected by western blot analysis in osteogenic tumors were different from bands detected in lymphocytes. This suggested a cell type specific modification of CD52. Discussion. These data demonstrated CD52 expression in osteogenic tumors. It confirms, that L-CD52 is distinct from the osteogenic form of CD52. In future, we want to evaluate the potential of the CAMPATH 1H antibody to recognize CD52 on osteogenic tumor cells and to activate the complement cascade for specific lysis.
Remodeling of breast cancer microenvironment visualized using second harmonic generation microscopy
Authors: Anju Mythreyi Raja, Dean Tai, Chien-Shing Chen, Hanry Yu
Journal: Clinical Cancer Research (2008)

B6    Background:  Breast cancer is the leading killer amongst cancer in women all over the world and it9s the second largest death causing cancer in Singapore. There are several treatment options available but still the incidence numbers have been increasing over several decades. Cancer is not a standalone disease where it9s sufficient to treat the diseased cells and cure the disease. It9s a multi-component disease with tumor cells and the environment cells involved. The cancer cells recruit host derived cells like the endothelial cells and fibroblasts to remodel the microenvironment and establish a tumor.   Methodology:  In our project we propose to study the disease in relationship to its environment by using advanced imaging techniques. Second harmonic generation (SHG) imaging detects changes in collagen, which is the most abundant of the ECM components. Mouse models of human breast cancer were developed by subcutaneous injections of human cancer cell line MX-1. Animals were anesthetized for whole animal imaging using the Olympus OV100 system to monitor tumor size changes. Animals were sacrificed to extract tumors for SHG imaging. SHG images were obtained for different stages of tumor progression and collagen amounts were quantified using image processing techniques.   Results:  We have visualized collagen changes as the tumor progresses and have correlated it to the tumor growth rate. The spatial and morphological information of the collagen fibers within the tumor as well as in the tumor boundary are easily visualized using this technique without the need for staining. We are capable of performing three dimensional imaging due to increased penetration depth of the SHG technique (250 um). The collagen quantity changes are drastic in the tumor boundary in comparison to the tumor interior.   Conclusion:  The study of tumor and its relationship to the environment will help us set up benchmark techniques to study drug efficacy in pre-clinical studies, where effects of the drug on not only the tumor but also on the environment can be observed. We might be able to design cures to cancer by using a dual pronged approach where we not only target the cancer cells but also the surrounding microenvironment.
1043. Spontaneous Transfection of B Lymphocytes
Authors: Mara Gerloni, Marta Rizzi, Paola Castiglioni, Matthew Wheeler, Maurizio Zanetti
Journal: Molecular Therapy (2004)

Genomic and plasmid DNA can cross the cell membrane by natural means, but the characteristics and functional relevance of this phenomenon have not been fully elucidated. We discovered that human and murine B lymphocytes internalize plasmid DNA in a totally spontaneous manner. To characterize this type of spontaneous transfection we used plasmid DNA coding for a functional immunoglobulin (Ig) heavy chain gene under the control of a B cell-specific promoter. Spontaneous transfection was effective in Burkitt's lymphoma cell lines, Epstein Barr Virus- (EBV) transformed cell lines, and peripheral blood B lymphocytes of the mature naive phenotype (IgM+/IgD+/CD27-). Transcription and expression of the transgene product were documented by reverse transcriptase-polymerase chain reaction (RT-PCR) and flow cytometry. With a reproducibility of 100% the efficiency of spontaneous transfection is on average 1.3% of the total unseparated PBMC population or ~13% of B lymphocytes in circulating blood.
Abstract 12752: Mortality Risk for Ruptured Abdominal Aortic Aneurysm After Endovascular and Open Intervention in Women
Authors: Paola De Rango, Gioele Simonte, Antonella Biello, Alessandra Manzone, Enrico Cieri, Fabio Verzini, Giovanbattista Parlani, Massimo Lenti
Journal: Circulation (2014)

Hypothesis: There may be sex differences in presentation and outcomes of abdominal aortic aneurysms (AAA) with increased mortality rates in women. Aim of this study was to assess mortality risk after repair of ruptured AAA (rAAA) in women in the endovascular repair (EVAR) era. Methods: All patients treated in 2006-2014 for rAAA were reviewed. Characteristics at presentation and outcomes were compared between women and men. Multivariable logistic regression and Cox proportional hazards modeling were performed to identify the effect of sex adjusted for other predictors on mortality. Results: One-hundred and four patients were identified: 16.3% (17/104) were women. Forty-one procedures (39.4%) were by EVAR, with comparable rates in women (47.1%) and men (37.9%;P=0.59). On admission women and men shared similar comorbidities and presentation (shock rates 43.8% vs. 45.9%; P=1; free rupture rates 58.8% vs. 67.8%; P=0.58 ) and comparable mean aneurysm diameter (76.2mm vs.77.7mm;P=0.8) but women were older (mean age 86.2+5.8 vs. 75.5 +10.3 years; P&lt;0.0001) and octogenarian women were twice as likely as men (88% vs. 40% P&lt;0.0001). Sex-related age difference was more evident within the open surgery group. Perioperative mortality was not different between women and men (35.3% vs. 35.6%) either after EVAR [25.0% vs. 33% in women and men respectively;Odds Ratio(OR) 0.7; 95%Confidence Interval (CI) 0.12-3.9] or after open surgery (44.4% vs. 37.0%; OR 4.7;95%CI 0.98-24.8), even though there was a trend for lower mortality in women with EVAR. In adjusted analyses, female sex was not associated with perioperative mortality as it was for old age (OR 5.5;95%CI 1.7-18.3) and free rupture (OR 3.5;95%CI 1.06- 11.7). At a mean follow-up of 22.3 months late survival was worse in women than in men but only for patients undergoing open surgery and the difference did not attain statistical relevance. After controlling for age, surgical repair, free rupture, cardiac disease, female sex was not predictor of late mortality. Conclusions: Despite AAA repair is often delayed in women and applied at older age, women might not show increased perioperative mortality risks from rAAA treatment after the introduction of EVAR. Larger data are required to confirm this hypothesis.
In Vivo Imaging of Matrix Metalloproteinase 12 and Matrix Metalloproteinase 13 Activities in the Mouse Model of Collagen-Induced Arthritis
Authors: Ngee Han Lim, Ernst Meinjohanns, George Bou‐Gharios, Luke L. Gompels, Elisa Nuti, Armando Rossello, Laurent Devel, Vincent Dive, Morten Meldal, Hideaki Nagase
Journal: Arthritis & Rheumatology (2013)

To develop enzyme-activatable Förster resonance energy transfer (FRET) substrate probes to detect matrix metalloproteinase 12 (MMP-12) and MMP-13 activities in vivo in mouse models of inflammatory arthritis.Peptidic FRET probes activated by MMP-12 and MMP-13 were reverse designed from inhibitors selected from a phosphinic peptide inhibitor library. Selectivity of the probes was demonstrated in vitro using MMP-1, MMP-2, MMP-3, MMP-12, and MMP-13. In vivo activation of the probes was tested in the zymosan-induced mouse model of inflammation, and probe specificity was evaluated by the MMP inhibitor GM6001 and specific synthetic inhibitors of MMP-12 and MMP-13. The probes were used to monitor these enzyme activities in the collagen-induced arthritis (CIA) model in vivo.The MMP-12 and MMP-13 activity probes (MMP12ap and MMP13ap, respectively) discriminated between the activities of the 2 enzymes. The in vivo activation of these probes was inhibited by GM6001 and by their respective specific inhibitors. In the CIA model, MMP12ap activation peaked 5 days after disease onset and showed strong correlation with disease severity during this time (r = 0.85, P < 0.0001). MMP13ap activation increased gradually after disease onset and correlated with disease severity over a longer period of 15 days (r = 0.58, P < 0.0001).We generated two selective FRET probes that can be used to monitor MMP-12 and MMP-13 activities in live animals. MMP12ap follows the initial stage of inflammation in CIA, while MMP13ap follows the progression of the disease. The specificity of these probes is useful in monitoring the efficacy of MMP inhibitors.
The Rectal Exam
Authors: Daniela Lamas
Journal: Annals of Internal Medicine (2015)

On Being a Doctor16 June 2015The Rectal ExamDaniela Lamas, MDDaniela Lamas, MDFrom Brigham and Women's Hospital, Beth Israel Deaconess Medical Center, and Massachusetts General Hospital, Boston, Massachusetts.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M14-2911 Audio Reading - “The Rectal Exam” Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads "The Rectal Exam," by D. Lamas. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail One early morning some years ago, I traded my patient a bagel for a rectal exam.It had been a hard night, and my pager hadn't stopped beeping with messages about patients I barely knew. I was finally settling down to write my admission notes when I realized that I hadn't given my anemic patient a rectal exam.The way I remember it now, I spent much of my medical internship doing things to people—uncomfortable, even unnecessary things—at odd hours to seem thorough on rounds. This patient was a 70-year-old man who had come into the hospital for pneumonia, but ... Author, Article, and Disclosure InformationAffiliations: From Brigham and Women's Hospital, Beth Israel Deaconess Medical Center, and Massachusetts General Hospital, Boston, Massachusetts.Corresponding Author: Daniela Lamas, MD, Massachusetts General Hospital, 55 Fruit Street, BUL-148, Boston, MA 02114; e-mail, [email protected]org. PreviousarticleNextarticle Advertisement Audio Reading - “The Rectal Exam” Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads "The Rectal Exam," by D. Lamas. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics Cited byDigital Rectal Examination Reduces Hospital Admissions, Endoscopies, and Medical Therapy in Patients with Acute Gastrointestinal Bleeding 16 June 2015Volume 162, Issue 12Page: 873KeywordsBloodCheesesEatingEmergency departmentGastric ulcersHemorrhagePneumoniaSleepStomachThorax ePublished: 16 June 2015 Issue Published: 16 June 2015 Copyright & PermissionsCopyright © 2015 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Acute Lower Gastrointestinal Bleeding
Authors: Irun Bhan, Dmitriy Kedrin, James M Richter
Journal: New England Journal of Medicine (2017)

1 Severe hematochezia is the most common presentation of acute lower gastrointestinal bleeding. 2 15–20% of patients hospitalized with severe hematochezia have a forgut source of the bleeding. 3 After initial resuscitation, urgent colonoscopy is the diagnostic test of choice. 4 The most common colonic cause of hemorrhage is diverticulosis, followed by internal hemorrhoids, ischemic colitis, rectal ulcers, post-polypectomy ulcers, polyps or cancer, and angiomas. 5 Therapeutic hemostasis of focal lesions includes epinephrine-saline injection, hemoclips and multipolar electrocoagulation. 6 Effective management results in improved patient outcomes such as decreased rebleeding rates as well as reduced transfusion requirements, median hospital stays and direct costs of medical care.
Abstract 4406: Role of KRAS in modulating the metabolomic profile and the response of NSCLC cells to PI3K/mTOR and AMPK interfering agents
Authors: Elisa Caiola, Laura Brunelli, Mirko Marabese, Marina Chiara Garassino, Gabriella Farina, Massimo Broggini, Roberta Pastorelli
Journal: Cancer Research (2014)

Abstract Background: Non-small-cell lung cancers (NSCLC) constitute the majority of lung cancer cases, whose risk is associated with environmental factors, such as air pollution, and smoking habits. KRAS mutations are present in about 20% of NSCLC patients, mostly at codon 12 and have been associated to tumor progression and resistance to chemotherapy in many types of cancer. Increasingly evidences seem to highlight that the definition of KRAS status is not sufficient to determine its predictive and/or prognostic role in NSCLC, and indicate that different KRAS mutations could differently impact on crucial cellular processes. An issue still to be addressed is whether different KRAS mutations may modulate cellular metabolism with possible implications on different response to anticancer treatments which specifically inhibit metabolism modulating pathways, such as the PI3K/AKT/mTOR axis. Methods: We generated from the human NSCLC cell line NCI-H1299 clones overexpressing WT KRAS, and the three most common NSCLC KRAS mutations (G12C, G12V and G12D). The clones were used to determine in vitro response to PI3K, mTOR and AMPK interfering agents. We applied an explorative mass spectrometry-based untargeted metabolomics strategy to characterize the largest possible number of metabolites that might distinguish the different KRAS mutated clones. Results: KRAS overexpressing clones resulted sensitive to the PI3K inhibitors BKM-120 and PIK-75 and to the PI3K/mTOR dual inhibitor BEZ-235. Metformin (acting on AMPK) did not display a cytotoxic activity on the clones at concentrations below or equal to 1mM. Metabolomics analyses revealed that clones harboring different KRAS mutations at codon 12 had different metabolic remodellings such as different redox buffering system and different glutamine-dependency. Conclusion: The preliminary findings reported herein indicate that specific KRAS mutations at codon 12 are associated to different metabolomics profiles that might have an impact to the response to anticancer treatments. Combination studies including metformin and PI3K/mTOR interfering agents and more detailed metabolomics analyses are ongoing in order to clarify whether metabolic adaptations dependent on KRAS mutants might account for the behaviour of KRAS overexpressing clones treated with different drugs. Citation Format: Elisa Caiola, Laura Brunelli, Mirko Marabese, Marina Chiara Garassino, Gabriella Farina, Massimo Broggini, Roberta Pastorelli. Role of KRAS in modulating the metabolomic profile and the response of NSCLC cells to PI3K/mTOR and AMPK interfering agents. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4406. doi:10.1158/1538-7445.AM2014-4406
Abstract 2532: Vemurafenib prodrugs suitable for oral and IV administration
Authors: Ning Xi, Yingjun Zhang, Zhaohe Wang, Taoxi Lin, Qian Wang
Journal: Cancer Research (2014)

Abstract Background: The oral therapy vemurafenib was approved by the U.S. FDA in 2011 for first-line treatment of metastatic melanomas. Patients whose tumors carry the BRAF(V600E) mutation are treated with vemurafenib at recommended dose of 960mg twice daily. One reason for such a high dose is due to the poor oral bioavailability of vemurafenib. It was reported that the crystalline formulation of vemurafenib provided only modest drug exposures in animals and human (solubility limited absorption). To increase its oral bioavailability, vemurafenib was subsequently formulated as a micro-precipitated bulk powder (MBP). Despite this special formulation, vemurafenib displayed marked accumulation after repeat dosing at 960 mg BID with high inter-patient variability. Methods and Results: To address the limitation of MBP formulation (e.g., high cost to manufacture and high doses to reach desired drug exposure), we developed prodrugs of vemurafenib, CT207 and CT317, with choices for both oral and i.v. administration. The prodrugs are homologues and freely soluble (&amp;gt;1g/mL) in water as their sodium salts. Both drugs are well-absorbed in dogs and monkeys when dosed in 100% saline solution or in capsule. For example, CT317 reached AUC(0-24) = 256 µMh and 429 µMh (calculated in vemurafenib form) when dosed to dogs at 30 and 50 mg/kg QD (equivalent to 1120 and 1890 mg/day adult dosage). The absolute oral bioavailability of CT207 and CT317 in dogs was consistent at ∼80% in dosing range of 10 to 100 mg/kg, which was approximately 4-times higher than vemurafenib (formulated as MBP). Excellent drug exposure was also observed when CT207 was given to monkeys orally at doses of 50 and 100 mg/kg QD (equivalent to 1120 and 2240 mg/day adult dosage), providing AUC(0-24) = 506 µMh and 955 µMh, respectively. Both CT207 and CT317 showed the same potent antitumor activity as vemurafenib in COLO205 xenograft tumor model, demonstrating the equivalency of tumoricidal effects of the prodrugs to vemurafenib. Conclusions: The consistent high oral bioavailability across wide dosing range and great aqueous solubility of CT207 and CT317 render them to have many advantages over vemurafenib: choices for oral or intravenous administration, reduced daily dose and frequency, and minimized inter-patient variability, among others. Therefore, the prodrugs described here have the potential to complement the clinic use of vemurafenib. Citation Format: Ning Xi, Yingjun Zhang, Zhaohe Wang, Taoxi Lin, Qian Wang. Vemurafenib prodrugs suitable for oral and IV administration. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2532. doi:10.1158/1538-7445.AM2014-2532
The receptor tyrosine kinase p185HER2 is expressed on a subset of B- lymphoid blasts from patients with acute lymphoblastic leukemia and chronic myelogenous leukemia
Authors: HJ Buhring, I Sures, B Jallal, FU Weiss, FW Busch, WD Ludwig, R Handgretinger, HD Waller, A Ullrich
Journal: Blood (1995)