tbuckley/cabot-search huggingface dataset:
Utilization of single-fraction radiotherapy for the treatment of bone metastases before and after the “Choosing Wisely” campaign.
Authors: Heather A Curry, Arlene A. Forastiere, William A. Flood, Elaine Whyler, Lauren Michelle Hertan, Sonam Sharma, Joshua Adam Jones
Journal: Journal of Clinical Oncology (2014)

245 Background: Multiple studies have demonstrated equivalence of single vs. multi-fraction regimens for palliation of uncomplicated bone metastases, but single fraction (SF) radiotherapy (RT) remains under-utilized in the United States. To increase physician and patient awareness of RT options for bone metastases, both AAHPM and ASTRO participated in the “Choosing Wisely” campaign. AAHPM recommended 8 Gy X 1 for uncomplicated bone metastases. ASTRO recommended against routine use of courses &gt; 10 fractions and supported strong consideration for the use of SF RT for patients with limited prognosis or transportation difficulties. To identify possible changes in prescribing patterns following “Choosing Wisely”, we evaluated utilization rates of SF (8 Gy x 1) for treatment of bone metastases via treatment requests submitted for preauthorization over a 3 year period. Methods: A proprietary web-based application (eviti Connect ) enables oncology providers to obtain real time automated precertification for patients insured by payers across the U.S. that utilize the platform. All preauthorization requests for RT of bone metastases were evaluated for the prescription of 8 Gy X 1. The overall rate of SF use was calculated as were quarterly rates within the study period. Results: From 6/1/11-6/30/14 7,524 requests were submitted; 658 were for bone metastases. Overall SF was used in 7.6 % of cases. Prior to Q4 of 2012 no prescriptions for 8 Gy X 1 were used. In 2013 SF was prescribed in 9.6% of cases (30/314): 2.8%, 7.3%, 7% and 20% for Q1, Q2, Q3, and Q4 respectively. During 2014 use of 8 Gy X 1 was 23.9% in Q1 and 19.5% in Q2. Protracted schedules &gt; 10 treatments were prescribed in 31% of cases, but decreased over the study period (from 40% prior to Q4 2012, to 28% in 2013, and to 23% in the first half of 2014). Conclusions: Within this unique dataset of working aged insured patients, utilization of 8 Gy X 1 for treatment of bone metastases has increased. Increases were most pronounced in 2013. This coincides with the announcement and dissemination of the “Choosing Wisely” initiatives. Longer follow-up is needed to determine if increased provider uptake of SF RT as a componant of patient-centered quality care persists.
The Ad Hoc Committee report on estimating the future workforce and training requirements for nephrology. The Ad Hoc Committee on Nephrology Manpower Needs.
Authors: E G Neilson, A R Hull, J B Wish, J F Neylan, D Sherman, W N Suki
Journal: Journal of the American Society of Nephrology (1997)

Neilson, E G; Hull, A R; Wish, J B; Neylan, J F; Sherman, D; Suki, W N Author Information
Significant lung damage revealed at early chest computed tomography is related to subsequent pseudomonas (PsA) colonization in children with cystic fibrosis
Authors: Carla Federica Bortoluzzi, Sonia Volpi, Ciro D'Orazio, Martine Loeve, Harm A. Tiddens, Baroukh M. Assael
Journal: European Respiratory Journal (2013)

Background : Chest computed tomography (CT) has been recognized to be superior to FEV 1  in monitoring progression of lung disease in children with cystic fibrosis (CF). To our knowledge, it has never been investigated if CT can predict a subsequent PsA colonization.   Objective : to investigate if abnormalities on CT in CF schoolchildren PsA free is related to the risk of PsA infection in the following 6 years.   Methods : CT scans routinely performed in 80 pediatric CF patients in a single center were scored using CF-CT scoring system. All patients had ≥4 sputum cultures/year for 6 years. Chronic PsA colonization was defined as ≥3 positive sputum cultures in the same year. One-way ANOVA was used to determine mean difference in CF-CT score according to PsA status at baseline and after 6 years.   Results : mean age and FEV 1  at time of CT were respectively 8.2 years and 83.3% predicted. At baseline, 66.3% patients were PsA free, 23.7% had episodic PsA, 10% had chronic PsA. Six years later, 13 of patients PsA free or episodically colonized at baseline became chronically infected with PsA (group A) and 59 patients remained PsA free or had occasional positive sputum (group B). Children in group A had a significantly worse CF-CT score at baseline (Mean 19, SD 9.1) than patients in group B (Mean 10, SD 9.1), F = 12.1, p   Conclusions : Early lung structural damage is associated with later chronic PsA infection in children with CF. CT can potentially be used to personalize monitoring based on risk profile.
Jagged1 heterozygosity in mice results in a congenital cholangiopathy which is reversed by concomitant deletion of one copy of Poglut1 (Rumi)
Authors: Shakeel M. Thakurdas, Mario F. Lopez, Shinako Kakuda, Rodrigo Fernandez‐Valdivia, Neda Zarrin‐Khameh, Robert S. Haltiwanger, Hamed Jafar‐Nejad
Journal: Hepatology (2015)

Haploinsufficiency for the Notch ligand JAG1 in humans results in an autosomal‐dominant, multisystem disorder known as Alagille syndrome, which is characterized by a congenital cholangiopathy of variable severity. Here, we show that on a C57BL/6 background, jagged1 heterozygous mice ( Jag1+/− ) exhibit impaired intrahepatic bile duct (IHBD) development, decreased SOX9 expression, and thinning of the periportal vascular smooth muscle cell (VSMC) layer, which are apparent at embryonic day 18 and the first postnatal week. In contrast, mice double heterozygous for Jag1 and the glycosyltransferase, Poglut1 ( Rumi ), start showing a significant improvement in IHBD development and VSMC differentiation during the first week. At P30, Jag1+/− mice show widespread ductular reactions and ductopenia in liver and a mild, but statistically, significant bilirubinemia. In contrast, P30 Jag1/Rumi double‐heterozygous mice show well‐developed portal triads around most portal veins, with no elevation of serum bilirubin. Conditional deletion of Rumi in VSMCs results in progressive arborization of the IHBD tree, whereas deletion of Rumi in hepatoblasts frequently results in an increase in the number of hepatic arteries without affecting bile duct formation. Nevertheless, removing one copy of Rumi from either VSMCs or hepatoblasts is sufficient to partially suppress the Jag1+/− bile duct defects. Finally, all Rumi target sites of the human JAG1 are efficiently glucosylated, and loss of Rumi in VSMCs results in increased levels of full‐length JAG1 and a shorter fragment of JAG1 without affecting Jag1 messenger RNA levels. Conclusions : On a C57BL/6 background, Jag1 haploinsufficiency results in bile duct paucity in mice. Removing one copy of Rumi suppresses the Jag1+/− bile duct phenotype, indicating that Rumi opposes JAG1 function in the liver. (H epatology 2016;63:550–565)
The response of the CCQ in unselected respiratory patients attending PR
Authors: Jane Canavan, Deniz Dilaver, Jones Sarah, Nolan Claire, Amy Clark, Kon Samantha, William Man
Journal: European Respiratory Journal (2014)

The Clinical Chronic Obstructive Pulmonary Disease Questionnaire (CCQ) is a health status instrument that is responsive to PR, in patients with COPD. Changes in CCQ correlate with well-established health related quality of life tools used in COPD. More non-COPD chronic respiratory patients are now referred to PR but it is not known whether the CCQ is responsive in these groups. We wanted to determine if the CCQ is responsive to PR in non-COPD patients.  The CCQ, CAT, St George9s Respiratory Questionnaire (SGRQ), Chronic Respiratory Questionnaire (CRQ), Incremental Shuttle Walk (ISW) were measured in patients with a chronic respiratory disorder other than COPD. Pearson9s correlation was used to assess change in CCQ with CRQ, CAT, SGRQ. The response to PR was determined using paired t-tests or non-parametric equivalent.  CCQ was significantly correlated pre-PR with CAT and CRQ (r=0.53,r=-0.76 respectively, both p th , 75 th  percentiles) 50 (20, 100)m, p  The CCQ appears to be a useful outcome measure to assess health status in all respiratory patients referred for PR.
Vimentin Is a Dominant Target of In Situ Humoral Immunity in Human Lupus Tubulointerstitial Nephritis
Authors: Andrew J. Kinloch, Anthony Chang, Kichul Ko, Carole J. Henry Dunand, Scott Henderson, Mark Maienschein‐Cline, Natalya Kaverina, Brad H. Rovin, Marlene Salgado Ferrer, Don Wolfgeher, Vladimir Liarski, D. James Haddon, Paul J. Utz, Patrick C. Wilson, Marcus R. Clark
Journal: Arthritis & Rheumatology (2014)

Objective In lupus nephritis (LN), severe tubulointerstitial inflammation (TII) predicts progression to renal failure. Severe TII is associated with tertiary lymphoid neogenesis and in situ antigen‐driven clonal B cell selection. The autoantigen(s) driving in situ B cell selection in TII are not known. This study was undertaken to identify the dominant driving autoantigen(s). Methods Single CD38+ or Ki‐67+ B cells were laser captured from 7 biopsy specimens that were diagnostic for LN. Eighteen clonally expanded immunoglobulin heavy‐ and light‐chain variable region pairs were cloned and expressed as monoclonal antibodies. Seven more antibodies were cloned from flow‐sorted CD38+ cells from an eighth biopsy specimen. Antigen characterization was performed using a combination of confocal microscopy, enzyme‐linked immunosorbent assay, screening protoarrays, immunoprecipitation, and mass spectrometry. Serum IgG titers to the dominant antigen in 48 LN and 35 non‐nephritic lupus samples were determined using purified antigen‐coated arrays. Autoantigen expression on normal and LN kidney was localized by immunohistochemistry and immunofluorescence. Results Eleven of 25 antibodies reacted with cytoplasmic structures, 4 reacted with nuclei, and none reacted with double‐stranded DNA. Vimentin was the only autoantigen identified by both mass spectrometry and protoarray. Ten of the 11 anticytoplasmic TII antibodies directly bound vimentin. Vimentin was highly expressed by tubulointerstitial inflammatory cells, and the TII antibodies tested preferentially bound inflamed tubulointerstitium. Finally, high titers of serum antivimentin antibodies were associated with severe TII ( P = 0.0001). Conclusion Vimentin, an antigenic feature of inflammation, is a dominant autoantigen targeted in situ in LN TII. This adaptive autoimmune response likely feeds forward to worsen TII and renal damage.
Dosing Recommendations for New Oral Anticoagulants—Reply
Authors: J. Robert Powell
Journal: JAMA (2015)

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Case 29-2013: An HIV-Positive Man with Dyspnea and Skin Lesions
Authors: Gustavo Reyes-Terán, Karla Romero-Mora
Journal: New England Journal of Medicine (2014)

In the Case Record of the man with Kaposi's sarcoma and inflammatory symptoms, we think it worthwhile to point out another possible diagnosis -multicentric Castleman's disease (MCD) related to Kaposi's sarcoma herpesvirus (KSHV), or KSHV-MCD.This lymphoproliferative disorder, which is often fatal if untreated, may occur concurrently with Kaposi's sarcoma and could account for the fever, cachexia, anemia, adenopathy, hypoalbuminemia, and splenomegaly in this case.1 KSHV-MCD should be included in the differential diagnosis of inflammatory symptoms in patients with Kaposi's sarcoma, because it is often missed if not specifically considered.Diagnosis requires pathological evaluation of an affected node.KSHV replication and dysregulation of human and viral interleukin-6 have been implicated in its pathogenesis.2To date, few cases have been reported from Africa, but given the high prevalence of KSHV in the region, it may be underappreciated.Kaposi's sarcoma-associated IRIS is currently defined according to various clinical case definitions.3Its pathogenesis may differ from that of other forms of IRIS, and the clinical and pathophysiological relationship between it and other KSHV-associated inflammatory syndromes is worthy of further study.4,
A staphylococcus aureus pore-forming toxin subverts the activity of ADAM10 to cause lethal infection in mice
Authors: Ichiro Inoshima, Juliane Bubeck Wardenburg, Naoko Inoshima, Georgia Wilke, Micheal Powers, Karen Frank, Hironori Mikumo, Yuichi Mizuta, Yoichi Nakanishi
Journal: European Respiratory Journal (2014)

Staphylococcus aureus  secretes α-hemolysin, a pore-forming cytotoxin that contributes to the pathogenesis of pneumonia. α-hemolysin injures epithelial cells by interacting with the zinc-dependent metalloprotease ADAM10 as its receptor 5 . We show that conditional knock out mice of  Adam10  in the lung epithelium are highly resistant to lethal pneumonia.  Investigation of the molecular mechanism of toxin-receptor function revealed that α-hemolysin upregulates ADAM10 metalloprotease activity in alveolar epithelial cells, resulting in cleavage of the adherens junction protein E-cadherin. Cleavage causes a disruption of epithelial barrier function, contributing to the pathogenesis of acute lung injury.  A specific metalloprotease inhibitor of ADAM10 prevents toxin-induced E-cadherin cleavage; similarly, E- cadherin proteolysis and barrier disruption is attenuated in ADAM10 knockout mice.  The observation that Hla can usurp the metalloprotease activity of its receptor reveals a novel mechanism of pore-forming cytotoxin action in which pathologic insults are not solely the result of irreversible membrane injury, and defines inhibition of ADAM10 activity as a strategy for disease modification.
Abstract 19384: Direct Thrombin Inhibition by Dabigatran Protects against Severe Atherosclerosis Progression in Prothrombotic Mice
Authors: Julian I Borissoff, Sarah T Loubele, Peter Leenders, Oliver Soehnlein, Rory R Koenen, René van Oerle, Karly Hamulyák, Sylvia Heeneman, Mat J Daemen, Hartmut Weiler, Joanne van Ryn, Henri M Spronk, Hugo ten Cate
Journal: Circulation (2010)

Introduction: Thrombin (FIIa) plays a key role in thrombus formation. Increased FIIa levels may also influence the onset and progression of atherosclerosis by inducing diverse cellular functions related to inflammation, apoptosis, and angiogenesis. Hypothesis: 1. To determine the effects of hypercoagulability on atherogenesis and atherothrombotic phenotype; 2. To assess the potential of direct oral thrombin inhibition (dabigatran) to attenuate atherothrombosis. Methods: Mice (TMPRO/PRO:ApoE−/−) with a pro-coagulant phenotype, based on a 90% impaired FIIa mediated protein C activation, were generated and compared to littermate control ApoE−/− mice. Atherosclerosis was studied by two different models: a spontaneous course and a carotid cuff model. In a separate cuff-induced atherosclerosis experiment, we established the effects of direct thrombin inhibition by treating TMPRO/PRO:ApoE−/− mice with dabigatran etexilate-supplemented high-fat diet or placebo for 6 weeks. Furthermore, we investigated arterial th...
Phase I dose escalating study of PEG-PGA and DON (GlutaDON): A new amino acid depleting anti cancer drug approach
Authors: C. Unger, F. Baas, S. Wiessner, S. Steinbild, M. Medinger, J. Drevs, R. Harzmann, J. Roberts, K. Mross
Journal: Journal of Clinical Oncology (2004)

3175 Background: Tumor cells are avid glutamine consumers due to their decreased expression of glutamine synthase and the need for glutamine as a substrate in nucleotide and protein biosynthesis, for energy production and for the generation of key metabolic intermediates. The rationale for using an glutamine antimetabolite 6-diazo-5-oxo-L-norleucine (DON) in combination with PEGylated Glutaminase (PEG-PGA) is based on the premise that the effectiveness of the antimetabolite will be enhanced when the available pool of glutamine is depleted by the enzyme. This clinical trial will test PEG-PGA and DON for treatment of patients with advanced solid tumors. The trial is conducted in two steps: First step involves dose escalation of PEG-PGA until the glutamine level is below 10% of the baseline level and glutamate level has increased 5–25 fold. Second step is the escalation of DON with PEG-PGA at the optimized dose. Methods: PEG-PGA was administered twice a week for 3 weeks as a 15 min i.v. infusion. 7 cohorts of pts recieved 10 (n=3), 20 (n=3), 33 (n=3), 50 (n=3), 70 (n=3), 90 (n=4) and 120 (n=4) I.U./m2/d PEG-PGA at day 1, 4, 8, 11, 15 and 18 qd22. Study treatment was finished after 6 weeks of treatment. A close clinical, laboratory and toxicity monitoring of all pts was performed. Toxicity was graded according to NCI-CTC. Glutamine, glutamate, ammonium and bicarbonate was measured before and 4 hrs after application of PEG-PGA. Results: 23 patients, 13 female and 10 male, were included. Median age was 59.2 years (41–80). We found a depletion of glutamine below 10% of baseline and an increase of glutamate up to 5–25 fold compared to baseline level at a dose of 120 I.U./m2 in all 4 pts. Toxicities observed possibly related to the drug were fatigue (grade 1–3), sleeplessness (g.1), neuropathic pain (g.1–2), pain (g.1–2), dyspnea (g.2) and allergic reaction (g.3–4). Conclusions: At 120 I.U./m2 all patients showed a sufficient level of glutamine depletion and increase of glutamate. The second step is currently ongoing using PEG-PGA combined with DON. DON will be escalated to the MTD. DON itself should force the tumor cell into apoptotic death. An update of the study will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Medical Enzymes AG Medical Enzymes AG
Protein Phosphatase 2A (PP2A) regulates estrogen receptor alpha (ER) expression through interaction with the ER promoter.
Authors: Judith C. Keen, Catherine Pettit, Kelly M. Mack, Nancy E. Davidson
Journal: Cancer Research (2004)

2399  Protein Phosphatase 2A (PP2A) is a ubiquitously expressed member of the serine-threonine phosphatase family that is involved in regulation of many cellular processes including transcription, translation, cellular metabolism and apoptosis. We confirmed by Real Time PCR the recent finding of Gopalakrishna et al (Cancer Letters 136:145, 1999) demonstrating a correlation between PP2A expression and ER expression in several human breast cancer cell lines. Therefore, we investigated if a potential molecular pathway involving PP2A could contribute to regulation of ER expression in the human breast cancer cell line, MCF7. Through the use of Okadaic Acid (OA), a specific PP2A inhibitor, at 250 nM for 24 hours, we were able to significantly inhibit PP2A protein expression by Western analysis and detected a 40% reduction in PP2A activity in MCF7 cells. This inhibition of PP2A also resulted in 75% reduction in ER mRNA expression by Real Time PCR and a significant decrease in protein expression. Inhibition of ER mRNA and protein expression following PP2A inhibition was further confirmed using siRNA probes specifically targeting expression of PP2A. siRNA inhibition of PP2A resulted in 77% decrease in ER mRNA expression by Real Time PCR and a similar decrease in protein expression. Taken together, these data suggest a role for PP2A in the transcriptional regulation of ER. Because the transcription factor Sp1 is activated by PP2A and binds to the ER P1 promoter, we evaluated a region within the P1 promoter that contains two putative Sp1 binding sites by electrophoretic mobility shift assay (EMSA). We have identified a region of the P1 promoter with decreased transcription factor complex formation following inhibition of PP2A in MCF7 cells. These data suggest a novel pathway controlling ER expression resulting from the activation of PP2A and could potentially provide a novel therapeutic target. Supported by NIH CA88843, T32 CA09110, and K14 GM063673.
Psychological autopsy of completed suicide in children and adolescents
Authors: M Shafii, S Carrigan, J R Whittinghill, A Derrick
Journal: American Journal of Psychiatry (1985)

A psychological autopsy of 20 children and adolescents aged 12-19 years who had committed suicide and a matched-pair control group revealed that 85% of the victims and 18% of the control subjects had expressed suicidal ideation. A statistically significant number of the victims had a history of suicide threats (55%), suicide attempts (40%), drug or alcohol abuse (70%), antisocial behavior (70%), or inhibited personality (65%). Suicidal behavior of parents, relatives, or friends and a parental history of emotional problems and absence or abusiveness were also significant factors for the victims.
Utility of SAPS II and SAPS 3 in predicting noninvasive positive pressure ventilation success in intermediate care
Authors: Diego Martinez-Urbistondo, Francisco Carmona-Torre, Felix Alegre, Ana Huerta, Manuel Fortun Landecho, Juan Felipe Lucena
Journal: European Respiratory Journal (2013)

OBJECTIVE  To assess the performance of SAPS II and SAPS 3 as predictors of response to noninvasive positive pressure ventilation (NPPV) in an Intermediate Care Unit (ImCU).  BACKGROUND  Different scores have been tested to predict NPPV success. SAPS 3 still need to be studied in this context. The population difference between ImCU and ICUs might deserve the validation of these indexes in this scenario.  MATERIALS AND METHODS  A prospective study was conducted in an ImCU between 2006 and 2012. We analyzed a cohort of 192 patients with respiratory failure due to COPD reagudization (16.7%), acute pulmonary edema (9.4%), hypoxemia secondary to pneumonia or sepsis related ALI (66.7%) and neuromuscular diseases (7.3%). Indication of NPPV was set according to published criteria. NPPV failure was considered when a patient was transferred to ICU for intubation and when patients with do-not-resucitate orders died.  RESULTS  The overall success ratio was 63.5 %. 24 patients (34.3%) were intubated and 46 (65.7%) died in ImCU. A logistic regression analysis was carried out for SAPS II and SAPS 3, including pH and PaO2/FiO2 at admission as well as NPPV indication. Both SAPS II and SAPS 3 were independent significant predictors of NPPV success (p=0.007 and p=0.015 respectively). They showed poor discrimination (AUROC 0.654 and 0.662, respectively), with better calibration perfomance for SAPS II, based on Hosmer-Lemeshow C test.  CONCLUSION  SAPS II and 3 are significant predictors of success for NPPV in ImCU patients. Both scores lack discrimination power with better calibration performance for SAPS II. Severity indexes need to be customized for NPPV aplication in ImCU.