tbuckley/cabot-search huggingface dataset:
Proven bioequivalence of blood exposure between vinorelbine 80 mg/m<sup>2</sup> oral and 30 mg/m<sup>2</sup> IV doses in cancer patients
Authors: H. Bourgeois, J. Vermorken, G. Dark, A. Jones, P. Fumoleau, R. Stupp, J.-M. Tourani, E. Brain, F. Lefresne, L. Nguyen
Journal: Journal of Clinical Oncology (2005)

2028 Background: Patient’s preference is for oral chemotherapy when both oral and IV are available, provided that efficacy is equivalent. Reliable switch from oral to IV is possible if correspondence between respective doses has been established. Vinorelbine (VRL) oral was developed as a line extension of VRL IV on the basis that similar AUCs result in similar activities. From a first cross-over study on 24 patients receiving VRL 25 mg/m2 IV and 80 mg/m2 oral [Marty et al., Ann Oncol 12(11): 1643–1649, 2001] data extrapolation concluded on AUCs bioequivalence between VRL 30 mg/m2 IV and 80 mg/m2 oral. A new trial was performed to support this calculation. Methods: In a cross-over design study on patients (PS 0–1) with advanced solid tumours (44% breast carcinoma), VRL was administered (30 mg/m2 IV, 80 mg/m2 oral) with a standard meal and 5-HT3 antagonists, at 2 weeks interval. Pharmacokinetics (PK) was performed over 168 h and VRL was measured by LC-MS/MS. Statistics included bioequivalence tests. Results: 48 patients were evaluable for PK: median age 58 y [25 - 71], PS0/PS1: 20/28, M/F: 11/37. Mean AUCs were 1230 ± 290 and 1216 ± 521 ng/ml for IV and oral, respectively. The confidence interval of the AUC ratio [0.83 - 1.03] was within the required regulatory range [0.8 - 1.25] and proved the bioequivalence between the two doses. The absolute bioavailability was 37.8 ± 16.0%, and close to the value from the first study (40%). Patient tolerability was globally comparable between both forms with no significant difference on either haematological or non-haematological toxicities (grade 3–4). Conclusions: The dose correspondence between VRL 80 mg/m2 oral and 30 mg/m2 IV was confirmed in this new study on a larger population, a longer period of blood sampling, and a more sensitive analytical Method: No significant financial relationships to disclose.
Screening for mitochondrial dysfunction in chronic fatigue syndrome using Near Infrared Spectroscopy: a preliminary study
Authors: Els Tobback, Bert Celie, An Mariman, Jan Boone, Liesbeth Delesie, Tine De Backer, Dirk Vogelaers, Rudy Van Coster, Jan Bourgois
Journal: Psychotherapy and Psychosomatics (2015)
Diffuse Large B Cell Lymphoma: Role Of MYC, BCL2, BCL6 Protein Expressions and Translocations
Authors: Susmita Sakruti, Nabila Bennani, Swapna Thota, Rohan Garje, Adewale Fawole, Paul Elson, Abdo Haddad, Timothy Spiro, Hamed Daw
Journal: Blood (2013)
THE PARTICULATE HYDROLASES OF MACROPHAGES
Authors: Zanvil A. Cohn, Edith Wiener
Journal: The Journal of Experimental Medicine (1963)

The contents of selected hydrolytic enzymes of oil-induced peritoneal, normal alveolar, and BCG-induced alveolar macrophages have been studied. On a per cell or nitrogen basis the normal alveolar cells contained considerably more acid phosphatase, cathepsin, acid ribonuclease, lysozyme, and lipase than peritoneal cells. The BCG-induced alveolar macrophage exhibited increased levels of acid phosphatase, lysozyme, and lipase as compared to alveolar macrophages from unstimulated rabbits. The morphological differences between these cells was discussed and electron micrographs of the BCG-induced macrophage presented. Fractionation of the BCG-induced macrophage by differential centrifugation showed that 60 to 80 per cent of the total cell content of acid phosphatase, cathepsin, beta glucuronidase, acid ribonuclease, acid deoxyribonuclease, aryl sulfatase, lysozyme, and lipase were localized in a postnuclear fraction which sedimented at 15,000 g. This fraction also contained the majority of the mitochondria as evidenced by its content of cytochrome oxidase. Non-specific esterase was not localized to this fraction. A separation of the hydrolase-containing particles and mitochondria was achieved by isopycnic sucrose gradient centrifugation. Under the conditions employed, the mitochondria distributed at densities of 1.19 to 1.20, whereas the hydrolase particles sedimented to a density of 1.26 to 1.27. Each of the hydrolases including acid phosphatase, beta glucuronidase, cathepsin, lysozyme, and acid ribonuclease exhibited maximum activities in the same gradient fraction. The isolated granules exhibited enzymatic latency, and activation could be achieved by cycles of freezing and thawing or surface active agents. The majority of each of the hydrolytic enzymes could be liberated in a non-particulate form by mechanical trauma. Macrophages which had been stained supravitally with neutral red were fractionated by differential and gradient centrifugation. More than 70 per cent of the dye could be recovered in the particulate hydrolase fraction. The isolated, stained granules resembled those seen in the intact cell.
Pathophysiological significance and therapeutic targeting of germinal center kinase in diffuse large B-cell lymphoma
Authors: Julie Marie Matthews, Shruti Bhatt, Matthew P. Patricelli, Tyzoon K. Nomanbhoy, Xiaoyu Jiang, Yasodha Natkunam, Andrew J. Gentles, Ezequiel Martinez, Daxing Zhu, Jennifer Rose Chapman, Elena Cortizas, Ragini Shyam, Shideh Chinichian, Ranjana Advani, Li Tan, Jianming Zhang, Hwan Geun Choi, Robert Tibshirani, Sara J. Buhrlage, Dita Gratzinger, Ramiro Verdun, Nathanael S. Gray, Izidore S. Lossos
Journal: Blood (2016)
Capillary Rarefaction Associates with Albuminuria: The Maastricht Study
Authors: Remy J.H. Martens, Ronald M.A. Henry, Alfons J.H.M. Houben, Carla J.H. van der Kallen, Abraham A. Kroon, Casper G. Schalkwijk, Miranda T. Schram, Simone J.S. Sep, Nicolaas C. Schaper, Pieter C. Dagnelie, Dennis M.J. Muris, Ed H.B.M. Gronenschild, Frank M. van der Sande, Karel M.L. Leunissen, Jeroen P. Kooman, Coen D.A. Stehouwer
Journal: Journal of the American Society of Nephrology (2016)

Albuminuria may be a biomarker of generalized ( i.e. , microvascular and macrovascular) endothelial dysfunction. According to this concept, endothelial dysfunction of the renal microcirculation causes albuminuria by increasing glomerular capillary wall permeability and intraglomerular pressure, the latter eventually leading to glomerular capillary dropout (rarefaction) and further increases in intraglomerular pressure. However, direct evidence for an association between capillary rarefaction and albuminuria is lacking. Therefore, we examined the cross-sectional association between the recruitment of capillaries after arterial occlusion (capillary density during postocclusive peak reactive hyperemia) and during venous occlusion (venous congestion), as assessed with skin capillaroscopy, and albuminuria in 741 participants of the Maastricht Study, including 211 participants with type 2 diabetes. Overall, 57 participants had albuminuria, which was defined as a urinary albumin excretion ≥30 mg/24 h. After adjustment for potential confounders, participants in the lowest tertile of skin capillary recruitment during postocclusive peak reactive hyperemia had an odds ratio for albuminuria of 2.27 (95% confidence interval, 1.07 to 4.80) compared with those in the highest tertile. Similarly, a comparison between the lowest and the highest tertiles of capillary recruitment during venous congestion yielded an odds ratio of 2.89 (95% confidence interval, 1.27 to 6.61) for participants in the lowest tertile. In conclusion, lower capillary density of the skin microcirculation independently associated with albuminuria, providing direct support for a role of capillary rarefaction in the pathogenesis of albuminuria.
Psoriasis
Authors: Janet M. Torpy, Alison E. Burke, Robert M. Golub
Journal: JAMA (2011)

Caitriona Ryan, MB, BAO, BCh; Craig L. Leonardi, MD; James G. Krueger, MD, PhD; Alexa B. Kimball, MD, MPH; Bruce E. Strober, MD, PhD; Kenneth B. Gordon, MD; Richard G. Langley, MD; James A. de Lemos, MD; Yahya Daoud, MA; Derek Blankenship, PhD; Salahuddin Kazi, MD; Daniel H. Kaplan, MD, PhD; Vincent E. Friedewald, MD; Alan Menter, MD
Are doctors themselves responsible for delay in cancer management?
Authors: R. Karwasra, S. Bhanot, R. Goel
Journal: Journal of Clinical Oncology (2007)

17027 Background: In developing countries poor results of cancer management are believed to be due to late presentation of patients because of poverty, illiteracy and lack of cancer awareness. But the scenario changed little despite regular cancer awareness campaigns in last few decades. Methods: 1,006 cancer patients were assessed for time of onset of symptoms, time of presentation to physician, time taken in diagnosis &amp; initiation of anticancer treatment to identify the level of delay in cancer management and factors responsible. Results: 81.3% of the patients belonged to low socioeconomic group. 61.9% were illiterate &amp; 43.7% were laborers. Literacy level of 84.5% of patients was under metric level and 50.3% had no awareness about cancer. 55.4% patients presented to qualified medical practitioners, 38.9% to non-qualified medical practitioners &amp; 5.5% to qualified non-medical practitioners working as primary care physicians. Almost 80% of patients had delay in cancer management at various levels, the maximum being at diagnosis level. 67.3% patients presented to primary care physician within a month of onset of symptoms without delay. In 68.6% patients the diagnosis of cancer was delayed by more than one month once they presented, the physicians being responsible for this delay in 60.4 % cases. Though non-qualified physicians almost never diagnosed cancer but even 58% of the qualified medical physicians delayed the diagnosis of cancer in the symptomatic patients. In 77.1% patients, physicians did not suspect cancer and disposed off the patients on symptomatic treatment. Literacy of the patients affects awareness and has bearing on the pattern of consultation whereby most of the literates consulted qualified physicians while most of the illiterates consulted non-qualified physicians resulting in delay. Conclusions: Presentation of the cancer patient depends upon reaction to the symptom and therefore despite illiteracy and poverty, majority of symptomatic patients present without delay to their primary care physicians. Delay occurs at diagnosis level in most of the patients and physician is the most common factor responsible for this delay. Tendency to treat the symptoms rather than making diagnosis of the patient and poor oncology knowledge to differentiate symptoms of cancer may be the reasons for this. No significant financial relationships to disclose.
Formyl-Peptide Receptor 2/3/Lipoxin A <sub>4</sub> Receptor Regulates Neutrophil-Platelet Aggregation and Attenuates Cerebral Inflammation
Authors: Shantel A. Vital, Felix Becker, Paul M. Holloway, Janice Russell, Mauro Perretti, D. Neil Granger, Felicity N.E. Gavins
Journal: Circulation (2016)

Background— Platelet activation at sites of vascular injury is essential for hemostasis, but it is also a major pathomechanism underlying ischemic injury. Because anti-inflammatory therapies limit thrombosis and antithrombotic therapies reduce vascular inflammation, we tested the therapeutic potential of 2 proresolving endogenous mediators, annexin A1 N-terminal derived peptide (AnxA1 Ac2–26 ) and aspirin-triggered lipoxin A 4 (15-epi-lipoxin A 4 ), on the cerebral microcirculation after ischemia/reperfusion injury. Furthermore, we tested whether the lipoxin A 4 receptor formyl-peptide receptor 2/3 (Fpr2/3; ortholog to human FPR2/lipoxin A 4 receptor) evoked neuroprotective functions after cerebral ischemia/reperfusion injury. Methods and Results— Using intravital microscopy, we found that cerebral ischemia/reperfusion injury was accompanied by neutrophil and platelet activation and neutrophil-platelet aggregate formation within cerebral microvessels. Moreover, aspirin-triggered lipoxin A 4 activation of neutrophil Fpr2/3 regulated neutrophil-platelet aggregate formation in the brain and inhibited the reactivity of the cerebral microvasculature. The same results were obtained with AnxA1 Ac2–26 administration. Blocking Fpr2/lipoxin A 4 receptor with the antagonist Boc2 reversed this effect, and treatments were ineffective in Fpr2/3 knockout mice, which displayed an exacerbated disease severity, evidenced by increased infarct area, blood-brain barrier dysfunction, increased neurological score, and elevated levels of cytokines. Furthermore, aspirin treatment significantly reduced cerebral leukocyte recruitment and increased endogenous levels of aspirin-triggered lipoxin A 4 , effects again mediated by Fpr2/3. Conclusion— Fpr2/lipoxin A 4 receptor is a therapeutic target for initiating endogenous proresolving, anti-inflammatory pathways after cerebral ischemia/reperfusion injury.
Reevaluating PSA Testing Rates in the PLCO Trial
Authors: Jonathan E Shoag, Sameer Mittal, Jim C Hu
Journal: New England Journal of Medicine (2016)

tation. 1,3 Underreporting of jaw claudication may be a consequence of modern diets that require less mastication effort, particularly in the elderly population.The two cases reported here show that the chewing gum test (i.e., chewing gum at the rate of one chew per second) may be a simple and repeatable test for jaw claudication and allow for a better characterization of this symptom.In our patients, claudication of the jaw appeared after 2 to 3 minutes of chewing and resolved after prednisolone treatment.
Analysis of Ferritins in Lymphoblastoid Cell Lines and in the Lens of Subjects With Hereditary Hyperferritinemia-Cataract Syndrome
Authors: Sonia Levi, Domenico Girelli, Federica Perrone, Marcella Pasti, Carole Beaumont, Roberto Corrocher, Alberto Albertini, Paolo Arosio
Journal: Blood (1998)
Generic Medication Prescription Rates After Health System–Wide Redesign of Default Options Within the Electronic Health Record
Authors: Mitesh S. Patel, Susan C. Day, Scott D. Halpern, C. William Hanson, Joseph R. Martinez, Steven Honeywell, Kevin G. Volpp
Journal: JAMA Internal Medicine (2016)

This study examines prescription data from the University of Pennsylvania Health System outpatient clinics to compare generic medication prescription rates before and after a redesign of the electronic health record display defaults.
Contribution of IPSS-R Cytogenetics to Predict Outcome after Allogeneic Stem Cell Transplantation for Myelodysplastic Syndromes: A Study from the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC)
Authors: Jordan Gauthier, Damaj Gandhi, Carole Langlois, Marie Robin, Patrice Chevallier, Yves Beguin, Stephanie Nguyen, Pierre Bories, Didier Blaise, Jerome Cornillon, Aline Clavert, Mohamad Mohty, Anne Huynh, Anne Thiebaut, Stephane Vigouroux, Alain Duhamel, Ibrahim Yakoub-Agha
Journal: Blood (2014)
Keratin 23 is a stress-inducible marker of mouse and human ductular reaction in liver disease
Authors: Nurdan Guldiken, Gokce Kobazi Ensari, Pooja Lahiri, Gabrielle Couchy, Christian Preisinger, Christian Liedtke, Henning W. Zimmermann, Marianne Ziol, Peter Boor, Jessica Zucman-Rossi, Christian Trautwein, Pavel Strnad
Journal: Journal of Hepatology (2016)
General practice workload is unsustainable, real time data show
Authors: Nigel Hawkes
Journal: BMJ (2016)

Demand for primary care in the past five years in England has far outstripped the cash and staff available, leading to a crisis in general practice, the King’s Fund has found in a new report.1

Though this will come as little surprise to GPs who have been complaining about an unsustainable workload, the report provides concrete evidence to back their complaints. Despite being awash with paper, the NHS in England lacks real time information on primary care, and this report aims to fill the gap.

Its sources included data collected over five years from 177 general practices by TTP, a supplier of GP information systems, together with a one week snapshot survey of 43 practices and interviews with 318 GP trainees. Along with additional qualitative data, the report provides a solid basis for assessing the current state of primary care. The data were analysed before NHS England announced on 21 April that it would invest extra money in general practice each year, rising to …
SAT0446 Autologous Fat Transplantation Has a Long Term Efficacy on Scleroderma Skin Fibrosis: Results from a Controlled Study Versus Hyaluronic Acid Filler
Authors: N. Del Papa, D. Sambataro, E. Zaccara, W. Maglione, R. Andracco, F. Caviggioli, G. Di Luca, A. Parafioriti, C. Vitali
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> Autologous fat tissue grafting (AFTG) has been successfully used in the treatment of different sclerotic conditions, including scleroderma. <h3>Objectives</h3> We evaluated in patients with SSc who complained of a reduced mouth opening, the long-term efficacy of AFTG of the lips in improving mouth opening in comparison with hyaluronic acid (HA) filler. We also investigated whether these procedures may induce some changes in the microvascular architecture and dermal structure of the treated skin area. <h3>Methods</h3> We studied 30 patients with dcSSc, (median age 37±12 yrs, disease duration 11±8yrs): 15 were treated by topical perioral AFTG according to Coleman technique and 15 by HA filler. The filler was repeated after 3 months. Baseline and after treatment (at months 3, 6, and 12) mouth opening changes were assessed by measuring inter-incisal distance and oral perimeter. Pre- and post-treatment modifications of microvascular architecture were assessed by counting capillaries in the inferior lip videocapillaroscopy (VC) images. Similarly, histological sections of perioral skin biopsy were examined at baseline and 3 months to evaluate dermo-epidermic junction (DEJ), the collagen content (by Masson9s Trichrome staining) and microvessel density (MVD) (by anti-CD34/CD31staining). <h3>Results</h3> 3 months after treatment both the inter-incisal distance and oral perimeter significantly increased (p&lt;0.001). At the same time, a significant skin neovascularization became evident, both considering the VC images (p&lt;0.001) and MVD scores in IH sections (p&lt;0.0001). Finally, some skin histological aspects also improved, as shown by the significant changes in DEJ flattening scores (p&lt;0.0001) and collagen content with less abnormal and denser collagen bundles. At 6 and 12 months, despite the disappearance of filling effect, both the functional improvement in mouth opening and the increased number of capillaries were maintained. No effect either on the mouth opening, VC images and skin histological aspects was observed in SSc patients treated by HA filler. <h3>Conclusions</h3> The present study shows that, in patients with SSc, AFTG can improve mouth opening, induce a neovascularization, and partially restore the skin structure. All these effects were confirmed in the long-term observation. The lack of functional and biological effects in the control group treated by HA filler, suggests that the observed therapeutic effect of lipostructure may be specifically ascribed to the on site transplantation of fat tissue. Our study may open new perspectives for the local and general therapeutic approach to SSc. <h3>Disclosure of Interest</h3> None declared
Pattern of chemotherapy use at end-of-life (EOL) in patients with solid tumors (ST).
Authors: Thomas W. Burke, Yvette A DeJesus, Lee Cheng, Aman Buzdar, Maria Alma Rodriguez
Journal: Journal of Clinical Oncology (2013)

9539 Background: Quality performance measures for cancer care, including use of chemotherapy in the last two-weeks of life, will be required for reporting. In this study, we evaluated the pattern and frequency of chemotherapy use for ST patients in the last two-weeks of life, and whether such treatment included standard or investigational drugs. Methods: We conducted a retrospective study of 5,607 adult cancer patients (≥18 years) who received their care at The University of Texas MD Anderson Cancer Center and died between December 01, 2010 through May 31, 2012. Data on patients’ demographics, and chemotherapy agents dispensed (excluded: hormones) were obtained from the institution’s administrative databases. Type of treatment (research versus standard) was obtained from our chemotherapy dispensed database. Chi-square test and Fisher's exact test were used to determine the association between categorical variables.All statistically significant levels were determined with P values &lt; 0.05. Results: Only 3.9% (216/5,607) of ST patients who died had received chemotherapy within 14 days EOL. For those 216 patients who received chemothapy: median age 64 years; 48% female; 89% metastatic disease. The distribution by chemotherapy treatment route: intravenous (IV) 85%; IV plus oral 6%; oral 6%; other 3%. The distribution of patients by number of chemotherapy agents: one 56%; two 31%, and three or more 13%. Among those who received chemotherapy, 98.6% (213/216) of the chemotherapy administered were standard agents. There were no differences in frequency distribution for chemotherapy treatment route (p&gt;0.05), number of chemotherapy agents (p&gt;0.05) between patients with metastatic and non-metastatic disease, or between men and women (p&gt;0.05). Conclusions: Our results indicate EOL chemotherapy use was infrequent in our patients with STs, and most of those treated received standard chemotherapy, with simple one or two drug regimens. We need more research to determine factors that influence chemotherapy use at EOL, and if it palliates physical symptoms and/or emotional distress in advanced stages of disease.
The Nuanced Interplay of Intrinsic Disorder and Other Structural Properties Driving Protein Evolution
Authors: Joseph Ahrens, Helena G Dos Santos, Jessica Siltberg-Liberles
Journal: Molecular Biology and Evolution (2016)

Protein evolution often occurs at unequal rates in different sites along an amino acid chain. Site-specific evolutionary rates have been linked to several structural and functional properties of proteins. Previous analyses of this phenomenon have involved relatively small datasets and, in some cases, the interaction among multiple structural factors is not evaluated. Here, we present the results of a large-scale phylogenetic and statistical analysis, testing the effects and interactions of three structural properties on amino acid replacement rates. We used sequence-based computational methods to predict (i) intrinsic disorder propensity, (ii) secondary structure, and (iii) functional domain involvement across millions of amino acid sites in thousands of sequence alignments of metazoan proteins. Our results somewhat corroborate earlier findings that intrinsically disordered sites tend to be more variable than ordered sites, but there is considerable overlap among their rate distributions, and a significant confounding interaction exists between intrinsic disorder and secondary structure. Notably, protein sites that are consistently predicted to be both intrinsically disordered and involved in secondary structures tend to be the most conserved at the amino acid level, suggesting that they are highly constrained and functionally important. In addition, a significant interaction exists between functional domain involvement and secondary structure. These findings suggest that multiple structural drivers of protein evolution should be evaluated simultaneously in order to get a clear picture of their individual effects as well as any confounding interactions among them.