tbuckley/cabot-search huggingface dataset:
In Pulmonary Arterial Hypertension, Reduced BMPR2 Promotes Endothelial-to-Mesenchymal Transition via HMGA1 and Its Target Slug
Authors: Rachel K. Hopper, Jan-Renier A.J. Moonen, Isabel Diebold, Aiqin Cao, Christopher J. Rhodes, Nancy F. Tojais, Jan K. Hennigs, Mingxia Gu, Lingli Wang, Marlene Rabinovitch
Journal: Circulation (2016)

We previously reported high-throughput RNA sequencing analyses that identified heightened expression of the chromatin architectural factor High Mobility Group AT-hook 1 (HMGA1) in pulmonary arterial endothelial cells (PAECs) from patients who had idiopathic pulmonary arterial hypertension (PAH) in comparison with controls. Because HMGA1 promotes epithelial-to-mesenchymal transition in cancer, we hypothesized that increased HMGA1 could induce transition of PAECs to a smooth muscle (SM)-like mesenchymal phenotype (endothelial-to-mesenchymal transition), explaining both dysregulation of PAEC function and possible cellular contribution to the occlusive remodeling that characterizes advanced idiopathic PAH.We documented increased HMGA1 in PAECs cultured from idiopathic PAH versus donor control lungs. Confocal microscopy of lung explants localized the increase in HMGA1 consistently to pulmonary arterial endothelium, and identified many cells double-positive for HMGA1 and SM22α in occlusive and plexogenic lesions. Because decreased expression and function of bone morphogenetic protein receptor 2 (BMPR2) is observed in PAH, we reduced BMPR2 by small interfering RNA in control PAECs and documented an increase in HMGA1 protein. Consistent with transition of PAECs by HMGA1, we detected reduced platelet endothelial cell adhesion molecule 1 (CD31) and increased endothelial-to-mesenchymal transition markers, αSM actin, SM22α, calponin, phospho-vimentin, and Slug. The transition was associated with spindle SM-like morphology, and the increase in αSM actin was largely reversed by joint knockdown of BMPR2 and HMGA1 or Slug. Pulmonary endothelial cells from mice with endothelial cell-specific loss of Bmpr2 showed similar gene and protein changes.Increased HMGA1 in PAECs resulting from dysfunctional BMPR2 signaling can transition endothelium to SM-like cells associated with PAH.
Relapsed Or Refractory Aggressive Non Hodgkin B-Cell Lymphomas Treated With Lenalidomide With/Without Rituximab Or Steroids: A Single Center Restrospective Study
Authors: Alessia Castellino, Annalisa Chiappella, Paola Ghione, Manuela Ceccarelli, Giulia Benevolo, Barbara Botto, Daniele Caracciolo, Chiara Ciochetto, Maura Nicolosi, Lorella Orsucci, Clara Pecoraro, Patrizia Pregno, Paola Riccomagno, Manuela Zanni, Marco Ladetto, Umberto Vitolo
Journal: Blood (2013)
OC-056 The utility of measuring adenoma detection rate as a key performance indicator at diagnostic colonoscopy: Abstract OC-056
Authors: S Gupta, A Murino, K Abeysekera, S Thomas-Gibson
Journal: Gut (2010)

<h3>Introduction</h3> Adenoma detection rate (ADR) is a key performance indicator for colonoscopy. Evidence suggests that various factors influence ADR. The BSG quality and safety indicators for endoscopy and the Global Rating Scale recommend ADR&gt;10%. <h3>Methods</h3> To assess how case mix affects ADR in a tertiary centre. We analysed 25 consecutive colonoscopies from each of the 15 non-trainee endoscopists at our institution. A further 50 cases each from six of the 15 endoscopists with low ADR, were assessed. Indications were divided into high (polyp follow-up, surveillance, familial cancer syndromes, rectal bleeding, anaemia) and low risk (IBD, diarrhoea, constipation, pain). <h3>Results</h3> Six endoscopists had a median ADR of 8% (0–16%). The other nine had a median ADR of 28% (24–40%) with significantly more high-risk indications (p&lt;0.0001). A further 50 cases from each of the six endoscopists with lower ADR were analysed. Median ADR was 12% (8–22%). <h3>Conclusion</h3> In the 50 cases analysed for each of the six colonoscopists with low ADR, there were significantly more low risk cases (p&lt;0.0001). The ADR was significantly lower for the low risk cases (2.6% vs 22.6%, p&lt;0.0001). ADR should be measured as a key performance indicator in the context of indication for colonoscopy.
The Early Rad Catches the Tumor?
Authors: Mitchell Machtay
Journal: Journal of Clinical Oncology (2002)

Article Tools EDITORIALS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2002.20.14.3045 Journal of Clinical Oncology - published online before print November 1, 2016 PMID: 12118015 The Early Rad Catches the Tumor? Mitchell MachtayxMitchell MachtaySearch for articles by this author Show More University of Pennsylvania Medical Center, Philadelphia, PA https://doi.org/10.1200/JCO.2002.20.14.3045 First Page Full Text PDF Figures and Tables © 2002 by American Society of Clinical Oncology
MTR-19A MACROPHAGE-/MICROGLIAL-RICH TUMOR MICROENVIRONMENT MIMICS PRONEURAL TO MESENCHYMAL TRANSITION IN GLIOBLASTOMA
Authors: Qiangu Wang, Xin Hu, Florian Muller, Hoon Kim, Tom Mikkelsen, Lisa Scarpace, Yu-Hsi Lin, Nikunj Satani, Edward Chang, Adriana Olar, Ana Decarvalho, Eskil Eskilsson, Raul Rabadan, Antonio Iavarone, Gaetano Finocchiaro, Do-Hyun Nam, Siyuan Zheng, Erik Sulman, Roel G.W. Verhaak
Journal: Neuro-Oncology (2015)

GBM have been classified into four transcriptional subtypes, termed proneural, neural, classical, and mesenchymal, which are characterized by distinct genomic properties but reports on how transcriptional classification relates to clinical outcome have been conflicting. Methods for classification of new GBMs according to these subtypes have shown poor concordance. We used robust classification methods to classify TCGA samples and found that 37% of GBM could be assigned to multiple expression subtypes, suggesting that mutually exclusive subtype classification may be too strict for deriving robust biologic correlates. We observed that the neural GBM class showed a significant reduction in tumor cellularity, which could be traced to the presence of normal brain tissue. Additionally, mesenchymal GBM were associated with decreased tumor cell fractions which we related to an increase in the microglia. Consequently, microglial marker genes such as ITGAM and AIF1 were found to be highly expressed in thirteen mesenchymal GBM but could not be detected in neurosphere GBM models derived from them. Immunostaining unequivocally identified microglial cells as the source for ITGAM and AIF1 protein, confirming the tumor microenvironment as a key component of the mesenchymal class. GBM was previously described to undergo proneural-to-mesenchymal transition which has been hypothesized as a contributor to therapy resistance. Analysis of 67 matched primary-recurrent GBM pairs showed that most (48 of 67) GBM tumors retained their expression subtype after treatment but cases that showed a transition towards the mesenchymal class at recurrence were specifically associated with a decrease in tumor purity relative to their primary counterparts. We did not find evidence for a tumor cell intrinsic increase in mesenchymal gene expression. Our study provides critical insights into the origin of the neural and mesenchymal subtypes, their transition from other subtypes upon recurrence, and place emphasis on the contribution of the microenvironment in glioma biology.
Interferon Alfa-2b Alone or in Combination with Ribavirin for the Treatment of Relapse of Chronic Hepatitis C
Authors: Gary L. Davis, Rafael Esteban-Mur, Vinod Rustgi, John Hoefs, Stuart C. Gordon, Christian Trepo, Mitchell L. Shiffman, Stefan Zeuzem, Antonio Craxi, Mei-Hsiu Ling, Janice Albrecht
Journal: New England Journal of Medicine (1998)

Interferon alfa is the only effective treatment for patients with chronic hepatitis C. Forty percent of patients have an initial response to this therapy, but most subsequently relapse. We compared the effect of interferon alone with that of interferon plus oral ribavirin for relapses of chronic hepatitis C.
<i>Notes from the Field</i>: Development of a Contact Tracing System for Ebola Virus Disease — Kambia District, Sierra Leone, January–February 2015
Authors: Rebecca Levine, Margherita Ghiselli, Agnes Conteh, Bobson Turay, Andrew Kemoh, Foday Sesay, Alfred Kamara, Aldo Gaeta, Clinton Davis, Sara Hersey
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

Kambia District is located in northwestern Sierra Leone along the international border with Guinea. The district is dominated by forest and swamp habitat and has a population of approximately 270,000 persons (approximately 5% of the nation's population) who live in rural villages and predominantly subsist on farming and trading. During 2014-2015, the remoteness of the area, a highly porous border with Guinea, and strong traditional beliefs about health care and sickness led to unique challenges in controlling the Ebola Virus Disease (Ebola) outbreak within the district.
Neuroendocrine Responses to Starvation and Weight Loss
Authors: Michael W. Schwartz, Randy J. Seeley
Journal: New England Journal of Medicine (1997)

The inability to consume enough calories to meet energy requirements is a common threat to survival. To meet this danger, animals retard their fuel depletion by lowering their metabolic rate and changing fuel substrates. They also stimulate their feeding behavior and defer the high energy cost of reproduction by suppressing gonadal function. We are now beginning to understand the physiologic basis of these responses.Historical BackgroundEarly investigators1,2 established that after the first few days of starvation, free fatty acids and ketone bodies, rather than glucose, become the predominant fuels. The adaptive value of this switch derives from the . . .
Late relapse associated with CEP 17 polysomic breast cancer
Authors: L. J. Theobald, S. Dobin, S. Beeran, D. Miltenburg, H. Rajab, J. Song, T. Boyle
Journal: Journal of Clinical Oncology (2006)

20011 Background: The clinicopathologic features associated with chromosome enumeration probe 17 (CEP 17) polysomy by fluorescence in situ hybridization (FISH) are not well defined. CEP 17 polysomy is frequently encountered in assessing Her-2neu amplification, which has become an important adjuvant therapeutic target. One mechanism to increase Her-2neu gene copy is polysomy. In this analysis the prognostic and predictive factors associated with CEP 17 polysomy are compared to similar factors in Her-2neu gene amplification. Methods: All cases of Her-2neu gene amplification and CEP 17 polysomic breast cancers from 2000 to present were abstracted. The polysomy group was defined as at least 3 gene copies and was further subdivided into two groups; 3–4 copies and ≥ 5 copies. This resulted in 193 cases of invasive breast cancer, which became the study cohort. Polysomic status and her-2neu gene amplification was compared to age, estrogen receptor (ER), progesterone receptor (PR), grade, tumor size, cell type, mitotic rate, nodal status, number of positive nodes and relapse. Descriptive statistics were used for categorical variables. The χ 2 test was used to compare each clinicopathologic factor. Results: Both the ER and PR status was significantly different in the 3 groups. For the Her-2neu amplified, the polysomic 3–4, and the polysomic ≥ 5, the ER positive status was 53%, 67% and 81%, respectively (p = .012). Histologic grade, tumor size and nodal status were not significantly different between groups. Lobular pathology was present in 15% of the polysomy ≥ 5 group, 8% of the polysomy 3–4 group and 1.7% of the amplified group and this difference was significant (p = .03). Relapse disease status was significantly more frequent in the polysomy ≥ 5 group (18.5%) compared to the amplified group (2.6%) (p = .007). Within the relapsed group the median time to relapse was 4 years for the amplified patients versus 12 years and 10 years for the polysomic patients. Conclusion: The incidence of CEP 17 polysomy varies in the literature from 10–50% depending on definitions. Our study is unique in that we divided the polysomic group into 3–4 copies which can be complicated by proliferative activity versus ≥ 5 copies. A significant association between relapse and polysomic breast cancer is described in our dataset. No significant financial relationships to disclose.
Observations on the Metabolism of &lt;italic&gt;N&lt;/italic&gt;-2-Fluorenylacetamide in Dogs and Rats,&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Helen M. Dyer, Barbara Ensfield Sherwin, Harold P. Morris
Journal: JNCI Journal of the National Cancer Institute (1965)

With colorimetric methods for comparison of the excretion of metabolites of N-2-fluorenylacetamide (2-FAA) by rats and dogs, less diazotizable material was recovered from the urine of dogs than from rats. Paper chromatography of ether extracts of β-glucuronidase and Taka-diastase-digested urine confirmed published observations that rats excrete numerous ring-hydroxylated metabolites of 2-FAA as well as N-hydroxy-2-FAA, chiefly as glucuronides. N-hydroxy-2-FAA, 7-hydroxy-2-FAA and 7-hydroxy-2-FA glucuronides, unconjugated 7-hydroxy-2-FAA, and small amounts of 2-FAA were identified in ether extracts of the urine of four dogs. Recoveries of diazotizable metabolites accounted for 55 percent of the average recovery of radioactivity from rats' urine after a single dose of 2-FAA-9-C 14. For dogs recoveries from urine by the colorimetric methods approximately equaled those reported elsewhere for radioactivity. This difference in recoveries of urinary metabolites from rats and dogs by the colorimetric methods compared with radioactivity recoveries may be explained by the fact that many of the ring-hydroxy metabolites in the rat are not measurable by the colorimetric methods, whereas the metabolites in the urine of dogs react more nearly quantitatively, provided the urine has not been subjected to hydrolysis. However, dogs' urine, unlike that of rats, after a dose of 2-FAA, contained a considerable amount of diazotizable R-salt-reacting free amines, including one or more that were unstable after digestion of the urine with ×-glucuronidase. It has been postulated that part, if not all of the unstable amine(s) may be N-hydroxy-2-FA. Acetylation of the urine or hydrochloric-acid-extracted free amines from dogs' urine revealed no metabolites of 2-FAA except N-hydroxy-2-FAA and 7-hydroxy-2-FAA.
Case 22-1963
Authors: Raymond D. Adams, Edward P. Richardson, Benjamin Castleman
Journal: New England Journal of Medicine (1963)

Presentation of Case First admission. A fifty-six-year-old stationary engineer was brought to the Emergency Ward because of collapse.On the day of admission the patient suddenly became weak while walking and collapsed to the floor, striking the right side of the head; there was no loss of consciousness, incontinence or biting of the tongue. A similar episode had occurred four days previously, when he sustained a laceration of the right eyebrow. He had had no recent headache, vertigo, paralysis or paresthesia.The patient had been in excellent health except for occasional episodes of excessive consumption of alcohol and was . . .
A 12-week DBPC dose-finding study with sublingual monomeric allergoid tablets in house dust mite-allergic patients
Authors: C. Hüser, P. Dieterich, J. Singh, K. Shah-Hosseini, S. Allekotte, W. Lehmacher, E. Compalati, R. Mösges
Journal: Allergy (2016)

Background In sublingual immunotherapy, optimal doses are a key factor for therapeutic outcomes. The aim of this study with tablets containing carbamylated monomeric house dust mite allergoids was to determine the most effective and safe dose. Methods In this double-blind, placebo-controlled dose-finding study, 131 patients with house dust mite-induced allergic rhinoconjunctivitis were randomized to 12-week treatments with 300 UA/day, 1000 UA/day, 2000 UA/day, 3000 UA/day or placebo. Conjunctival provocation tests (CPT) were performed before, during and after treatment. The change in mean allergic severity (primary endpoint), calculated from the severity of the CPT reaction, and the proportion of patients with an improved CPT threshold (secondary endpoint) determined the treatment effect. Results The mean allergic severity decreased in all groups, including the placebo group. It was lower in all active treatment groups (300 UA/day: 0.14, 1000 UA/day: 0.15, 2000 UA/day: 0.10, 3000 UA/day: 0.15) than in the placebo group (0.30). However, this difference was not statistically significant (P < 0.1). The percentage of patients with an improved CPT threshold was higher in the active treatment groups (300 UA/day: 73.9%; 1000 UA/day: 76.0%; 2000 UA/day: 88.5%; 3000 UA/day: 76.0%) than in the placebo group (64.3%). The difference between placebo and 2000 UA/day was statistically significant (P = 0.04). In 13 (10%) exposed patients, a total of 20 treatment-related adverse events of mild severity were observed. Conclusions The 12-week daily treatment using 2000 UA/day monomeric allergoid sublingual tablets is well tolerated and reduces the CPT reaction in house dust mite-allergic patients.
Congenital Protein C Deficiency and Venous Thromboembolism
Authors: André W. Broekmans, Jan J. Veltkamp, Rogier M. Bertina
Journal: New England Journal of Medicine (1983)

Protein C is the zymogen of a vitamin K-dependent serine protease involved in blood coagulation. In the absence of protein C the inactivation of activated factors V and VIIIC is impaired, and the fibrinolytic capacity of the circulating blood is reduced. These conditions promote excessive fibrin formation and thus constitute a risk factor for thrombosis. Using an immunologic assay for protein C, we identified 18 patients (11 male and 7 female) in three unrelated Dutch families as fulfilling the criteria for an isolated protein C deficiency. In 12 patients who were not receiving oral anticoagulant treatment the mean protein C antigen concentration was 0.48 +/- 0.09 U per milliliter (+/- S.D.), and in 6 patients who were receiving adjusted doses of oral anticoagulants and had stable anticoagulation, the mean value was 0.17 +/- 0.05 U per milliliter. (The value in healthy subjects is 0.98 +/- 0.19 U per milliliter.) Fourteen of the 18 patients had a history of venous thromboembolism, with superficial thrombophlebitis as the hallmark of this condition (in 13 patients). These data are consistent with an autosomal dominant trait with variable expressivity.
A phase I trial of gefitinib and sirolimus in adults with recurrent glioblastoma multiforme (GBM)
Authors: S. Phuphanich, J. Rudnick, R. Chu, J. S. Yu, K. L. Black
Journal: Journal of Clinical Oncology (2008)

2088 Background: Glioblastoma multiforme (GBM) overexpresses the epidermal growth factor receptor (EGFR) and gefitinib is an EGFR tyrosine kinase inhibitor (TKI). The protein mammalian target of rapamycin (mTOR) also promotes GBM growth and rapamycin blocks the interaction of mTOR with its target proteins. Therefore, the novel therapeutic approach by combination of gefitinib (iressa), and sirolimus (rapamycin) should have a synergistic effect in treating GBM. A possible mechanism of EGFR TKI resistance may be targeted by mTOR antagonists. The primary objective is to evaluate the safety, toxicity of gefitinib and sirolimus with a secondary end point of determining time to tumor progression, overall survival and quality of life in recurrent GBM. Methods: Eligible patients aged 18 years or older with recurrent GBM, who were treated previously with surgery, radiation, chemotherapy with or without immunotherapy (vaccine) and KPS > 40% are eligible. Gefitinib is dosed at 500 mg/day with those receiving dexamethasone or enzyme inducing anti-epileptic drugs (EIAED) escalated to 1,000 mg/day. Sirolimus is dosed at 2 mg/day and adjusted to levels of 4–12 nanograms/ml. They were co-administered on a continuous oral daily dosing. Neurological exam, KPS, laboratory parameters and NCI CTC are initially obtained every 2 weeks and then monthly. MRI scans of the brain and FACT-Br are performed every two months. Results: To date 21 patients have enrolled and 18 are evaluable. There are 13 male and 5 female with a median age of 51.6 years (range 23–72 years), a median KPS of 60% (range 50–80%) and 12 patients were on EIAED. Diarrhea, rash and mucositis were the most common toxicities as expected. There were 3 patients with grade 3/4 non-hematological toxicities with rash, renal failure, hypotension, dyspnea, coagulopathy, and elevated LFT. One patient developed wound infection which was not related to these drugs. There were 2 (11%) minor response and 6 (33%) stable disease (range 1–18 months) with a clinical benefit of 44%. Conclusions: Oral daily co-administration of getifinib and sirolimus is safe, tolerable in this heavy treated group of patients with modest antitumor activity. The median progressive free survival time and time to tumor progression is to be determined. No significant financial relationships to disclose.
Case 40-2006
Authors: Mandakolathur R. Murali, Alexander Kratz, Karin E. Finberg
Journal: New England Journal of Medicine (2006)

A 64-year-old man with a 3-year history of anemia was found to have a low serum level of high-density lipoprotein (HDL) on routine testing, with a cardiac risk ratio of 9.8. The level of HDL cholesterol had been normal 3 years earlier. A diagnostic procedure was performed.
BMET-20RTOG1119 PHASE II RANDOMIZED STUDY OF WHOLE BRAIN RADIOTHERAPY WITH CONCURRENT LAPATINIB IN PATIENTS WITH BRAIN METASTASIS FROM Her2-POSITIVE BREAST CANCER: A COLLABORATIVE STUDY OF NRG AND KROG (NCT01622868)
Authors: In Ah. Kim, Kathryn A. Winter, David M. Peereboom, Jennifer F. De Los Santos, Paul W. Sperduto, Julia R. White, Minesh P. Mehta
Journal: Neuro-Oncology (2015)

BACKGROUND: The addition of trastuzumab to cytotoxic chemotherapy has improved outcomes for patients with HER2 positive breast cancer. Increased survival coupled with limited blood-brain barrier (BBB) penetration of trastuzumab may contribute to the increased incidence of brain metastasis in these patients. Half of these patients die of intracranial disease progression rather than extracranial disease. Therefore, strategies to improve survival must include increased CNS disease control in these patients. Lapatinib crosses the BBB and demonstrates modest activity against intracranial metastases. Based upon preclinical data and results of a phase I study, it's hypothesized that lapatinib plus WBRT can improve the intracranial disease control compared to WBRT alone. METHODS: A randomized phase II trial of WBRT (37.5 Gy/3 weeks) plus or minus concurrent lapatinib (1000 mg qd x 21 during WBRT and for 21 days after) was initiated. Non-CNS penetrating HER2 targeted therapy is permitted throughout the study, but patients not on trastuzumab, pertuzumab or any other breast cancer therapy at study entry are not permitted to begin this therapy while on protocol treatment, but may begin it 24 hours after completion of protocol treatment. Eligibility includes HER2+ breast cancer with at least one measurable, unirradiated parenchymal brain metastasis. The two populations targeted for accrual include patients with 1) newly diagnosed, multiple brain metastases or 2) progressive brain metastases after stereotactic radiosurgery (SRS) or surgical resection of 1-3 metastases. Prior lapatinib is allowed. Patients are stratified by breast-specific graded prognostic assessment; use of non-CNS penetrating HER2 targeted therapy; and prior SRS or surgical resection. The primary endpoint is complete response rate in the brain 12 weeks after WBRT. Secondary endpoints include objective response rate, lesion-specific response rate, CNS progression-free survival, and overall survival. 52 of 143 target accrual have enrolled (6/1/2015). Supported by NCI grants U10CA21661, U10CA180868, U10CA180822, U10CA37422 and UG1CA189867.
Risk factors predictive of occult cancer detection in patients with unprovoked venous thromboembolism
Authors: Ryma Ihaddadene, Daniel J. Corsi, Alejandro Lazo-Langner, Sudeep Shivakumar, Ryan Zarychanski, Vicky Tagalakis, Susan Solymoss, Nathalie Routhier, James Douketis, Gregoire Le Gal, Marc Carrier
Journal: Blood (2016)