tbuckley/cabot-search huggingface dataset:
Plasma fibronectin supports neuronal survival and reduces brain injury following transient focal cerebral ischemia but is not essential for skin-wound healing and hemostasis.
Authors: Takao Sakai, Kamin J. Johnson, Michihiro Murozono, Keiko Sakai, Marc A. Magnuson, Tadeuz Wieloch, Tobias Cronberg, Atsushi Isshiki, Harold P. Erickson, Reinhard Fässler
Journal: Nature Medicine (2001)
MKK3 is expressed in cells from patients with allergic asthma
Authors: Tatjana Holand, Yanira Riffo-Vasquez, Domenico Spina, Brian O'Connor, Francis Woisin, Mike Barber, Kevin Bacon, Christian Rohlff, Clive Page
Journal: European Respiratory Journal (2011)

MKK3 is a member of the p38 MAPK signalling pathway. Studies have shown that MKK3 is an important factor in non allergic inflammatory and Th1 responses. Less is known about the role of MKK3 in allergic inflammation and allergic diseases. Proteomic analysis was performed on peripheral blood cells obtained from 22 healthy and 18 allergic asthmatic patients. Lysates from purified lymphocytes were separated by SDS-PAGE and the protein inventories of each sample were identified using mass spectrometry. A 3.65 fold increase in the expression of MKK3 was observed in CD8 +  T lymphocytes from asthmatic in relation to healthy volunteers, (% vol protein abundance). Western blot (WB) analysis showed MKK3 expression in human CD4 +  lymphocytes, human endothelial cells (HUVECs) and human epithelial cells (HBECs) but not in neutrophils or eosinophils. However, using densitometric analysis we found no differences between healthy and asthmatic subjects (n=10) in any of the cell types analysed. Real time PCR studies showed no expression of MKK3 isoform C in any tissue or cell type. However, large quantities of isoform B gene expression were found in neutrophils and lung tissue from patients with COPD (isoform A: 450 vs Isoform B: 1500 relative expression (ACT)). MKK3 expression was also measured in lung samples from mice treated with lipopolysacharide (LPS) or saline. Densitometric analysis of WB data showed that LPS treated mice developed an increased total MKK3 protein expression compared to saline-treated mice (sham: 49  vs  LPS: 60 A.U. p≥0.05). No significant increase in expression in these tissues was observed in mice allergic to ovalbumin. In conclusion, MKK3 is differentially expressed under non-allergic and allergic conditions.
Cognitive impairment in schizophrenia
Authors: M A Taylor, R Abrams
Journal: American Journal of Psychiatry (1984)

The cognitive functioning of 62 schizophrenic subjects was compared with that of 42 normal controls using neuropsychological tasks that included assessment of soft neurological signs, an aphasia screening test, tachistoscopic stimulation, auditory threshold determinations, and items from the Mini-Mental State, Halstead-Reitan, and Luria-Nebraska batteries. Performance was rated blindly for hemispheric, regional cortical, and global impairment. No control showed more than a mild deficit, whereas three-quarters of the schizophrenic patients exhibited moderate to severe dysfunction. Schizophrenic subjects differed significantly from controls on all measures and showed bilateral impairment that was comparatively worse in the dominant frontotemporal regions. These differences were not a function of age, sex, handedness, or drug administration.
The histopathologic damage and glycation injury of C57BL/6 mouse lung due to titanium dioxide particles
Authors: Sung Hwan Jeong, Sun Young Kyung, Yu Jin Kim, Jeong-Woong Park, S.M. Kang, J.Y. Yoon, Hoik Lee
Journal: European Respiratory Journal (2013)

Background: 

In this study, we examined the associations between TiO2 particle and glycated products associated lung injury. To evaluate the relationship of inflammation and glycation injuries during TiO2 exposures, we examined the content of Advanced glycation end products(AGEs) and related proteins to glycation injuries on the lung tissue specimens and mice serum.

Methods: 

Titanium dioxide particles (TiO2) were administered intratracheally to C57BL/6 mice. The mice were exposed to saline and saline suspensions of 20 mg/ kg of TiO2particles twice a week for 12 weeks. Following exposure with these particles, the lungs were analyzed histopathologically by hematoxylin and eosin (H&E)stain, Glycation injuries were determined by immunohistochemistry (IHC) for AGE, HMGB1 and RAGE in the lung tissues. The serum of mice exposed to TiO2 particles was analysised for evaluating expression of proteins related to Glycation injuries by western blot.

Results: 

The lung tissue specimens of mice exposed to TiO2 showed significantly increased inflammatory changes and AGE expressions compared to the control group but didn’t show significant change in RAGE and HMGB1 expressions compared to the control group. The serum of mice exposed to TiO2 showed there was no significant changes for AGE, HMGB1, S100A12 and CML(carboxy methyl lysine) expressions compared to the control group.

Conclusion: 

Our results showed that 12 weeks exposure to TiO2 particle induced inflammatory changes and increased AGE expression in the lung tissue but not in serum of C57BL/6 mice. After TiO2 particles exposure in mice, Increased AGE expressions might have induce lung parenchymal inflammation.
Growth Attenuation of Cutaneous Angiosarcoma With Propranolol-Mediated β-Blockade
Authors: William Chow, Clarissa N. Amaya, Steven Rains, Michael Chow, Erin B. Dickerson, Brad A. Bryan
Journal: JAMA Dermatology (2015)

Patients with stage T2 multilesion angiosarcomas of the scalp and face that are larger than 10 cm demonstrate a 2-year survival rate of 0%. To our knowledge, major therapeutic advances against this disease have not been reported for decades. Preclinical data indicate that blocking β-adrenergic signaling with propranolol hydrochloride disrupts angiosarcoma cell survival and xenograft angiosarcoma progression.A patient presented with a β-adrenergic-positive multifocal stage T2 cutaneous angiosarcoma (≥20 cm) involving 80% of the scalp, left forehead, and left cheek, with no evidence of metastasis. The patient was immediately administered propranolol hydrochloride, 40 mg twice a day, as his workup progressed and treatment options were elucidated. Evaluation of the proliferative index of the tumor before and after only 1 week of propranolol monotherapy revealed a reduction in the proliferative index of the tumor by approximately 34%. A combination of propranolol hydrochloride, 40 mg 3 times a day, paclitaxel poliglumex, 2 mg/m2 infused weekly, and radiotherapy during the subsequent 8 months resulted in extensive tumor regression with no detectable metastases.Our data suggest that β-blockade alone substantially reduced angiosarcoma proliferation and, in combination with standard therapy, is effective for reducing the size of the tumor and preventing metastases. If successful, β-blockade could be the first major advancement in the treatment of angiosarcoma in decades.
Cause of Death Analysis in the NHLBI PTCA Registry: Results and Considerations for Evaluating Long-Term Survival After Coronary Interventions fn1fn1This study was supported by Grant HL-33292 from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland.
Authors: David R. Holmes, Kevin E. Kip, Sheryl F. Kelsey, Katherine M. Detre, Allan D. Rosen
Journal: Journal of the American College of Cardiology (1997)
C-kit protein expression in tumor specimens as a predictor of sensitivity to imatinib mesylate in patients with small cell lung cancer (SCLC): A phase II clinical trial
Authors: L. M. Krug, J. P. Crapanzano, V. A. Miller, C. G. Azzoli, N. Rizvi, J. Gomez, B. Pizzo, L. Tyson, M. Dunne, M. G. Kris
Journal: Journal of Clinical Oncology (2004)

7218 Background: Imatinib (Gleevec) inhibits the tyrosine kinase c-kit which accounts for its activity in GI stromal tumors. The high rate of c-kit protein expression in SCLC provided a rationale for studying imatinib in this disease. We conducted this phase II single-institution study of imatinib in patients with relapsed SCLC that expressed c-kit protein. Methods: Patients with progressive SCLC after one or two prior chemotherapy regimens consented to have their pathology screened by immunohistochemistry (CD117, DAKO) for c-kit protein expression. If present, patients were then eligible for treatment. Imatinib was dosed at 400 mg po twice daily (total 800 mg/day). Patients had a CT scan after 4 weeks of treatment and then every 8 weeks. Sample size was based on a Simon two-stage design with 12 patients in the first stage (p0=0.05, p1=0.20). Results: Pathology: 25/32 (78%) samples were c-kit positive, 3 samples were not evaluable. To date, 10 patients have received treatment. 6 patients had one prior regimen, 4 patients had 2 prior regimens. 6 patients had refractory disease (progression < 90 days after first-line therapy). The response rate was 0%. No patient stayed on treatment more than 4 weeks. 7 patients experienced edema, grade 1–2 patients, grade 2–3, grade 3–2. Other toxicities included electrolyte abnormalities and lymphopenia. One patient had grade 3 transaminitis which did not resolve with discontinuation of drug and was likely due to progression of liver metastases. Conclusions: 91% of tumor samples were adequate for c-kit testing. Even with the presence of c-kit protein (which was not prospectively assessed in the prior phase II trial reported by Johnson et al, ASCO 2002), no patient with SCLC responded to imatinib. The absence of c-kit mutations in SCLC may explain the lack of response. This study was supported by Novartis. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline Aventis; GlaxoSmithKline; Lilly Oncology Genentech
Reducing antibiotic use in children with acute otitis media
Authors: R W Clarke, C. Cates
Journal: BMJ (1999)

Editor—Cates’s paper made the point that children with acute otitis media who are not particularly ill often get better quickly; they may be managed with analgesics and a deferred prescription for an antibiotic, which is not always redeemed.1 Unfortunately, the content of the paper did little to justify its title. Nowhere does Cates make any reference to the diagnostic criteria for otitis media in children or specify whether the same diagnostic criteria were used in both his practice and the control practice—surely the essence of a control group. We are not even told the age range of the children.

The notion of reducing antibiotic use in children with acute otitis media is not at all evidence based; indeed, the evidence is highly controversial if strict criteria for the diagnosis are upheld. This has been the subject of several meta-analyses, which have universally shown a positive if marginal advantage for the use of antibiotics in the primary management of children with acute otitis media.2,3 How children with acute viral upper respiratory tract infections with some associated otalgia should be managed is an entirely different issue.

Any attempt to improve diagnostic accuracy in childhood middle ear infections is to be welcomed, but it is singularly unhelpful if journal editors publish papers alleging to deal with acute otitis media when the meaning of that term is not specified. I would quibble with the use of the terms “acute otitis media,” “evidence based approach,” and “controlled” in Cates’s paper.

I have a niggling feeling that this (admittedly worthwhile) audit would not have been published in the Papers section of the journal. It seems a shame that less rigorous scientific criteria should be applied to the peer review process for a general practice paper as would be the case with laboratory based or hospital research. If this is editorial practice then it does no credit to research endeavours in general practice and should be declared. I would be interested to see the reviewer’s comments as to whether the entry criteria for this study were sufficiently rigorous to justify the term acute otitis media; I would also be interested to know whether the paper was reviewed by somebody who deals daily with pyogenic middle ear infections in children and with the often catastrophic consequences of such infections. The view that acute suppurative middle ear disease is a benign self limiting condition seems to be taking hold; often it is not.

Both acute otitis media and unexplained otalgia in children are important entities, and confusing the two simply muddies the waters.
Driving after a Stroke
Authors: J Legh-Smith, D T Wade, R Langton Hewer
Journal: Journal of the Royal Society of Medicine (1986)

Four hundred and thirty-eight stroke patients from a community register covering a period of 28 months were interviewed at one year post-stroke. Of 144 (34%) living at home who had been driving prior to their stroke, 82 (58%) did not resume post-stroke. Assessments of arm function, walking, functional ability and IQ showed ex-drivers to be significantly more disabled than drivers. Stopping driving was associated with a loss of social activities and with a higher frequency of depression amongst ex-drivers when compared with drivers. This was despite 79% of ex-drivers having easy access to alternative car transport. Extending mobility allowance to the 49 (60%) ex-drivers over 65 years old at the time of their stroke might ease their situation. More appropriate assessments would be needed to establish whether ex-drivers would benefit from retraining or car adaptations to enable them to return to driving.
Phase I/II trial of the combination of midostaurin (PKC412) and 5‐azacytidine for patients with acute myeloid leukemia and myelodysplastic syndrome
Authors: Paolo Strati, Hagop Kantarjian, Farhad Ravandi, Aziz Nazha, Gautam Borthakur, Naval Daver, Tapan Kadia, Zeev Estrov, Guillermo Garcia‐Manero, Marina Konopleva, Trivikram Rajkhowa, Menda Durand, Michael Andreeff, Mark Levis, Jorge Cortes
Journal: American Journal of Hematology (2014)

We investigated the combination of midostaurin and azacitidine (AZA) in patients with acute myeloid leukemia (AML) and high risk myelodysplastic syndrome (MDS). Patients received AZA 75 mg m(-2) on days 1-7 and midostaurin 25 mg bid (in cohort 1 of phase I) or 50 mg bid (in cohort 2 of Phase I and in Phase II) orally on day 8-21 during the first cycle and continuously thereafter. Fourteen patients were enrolled in the phase I and 40 in the phase II. Overall response rate was 26%. The median remission duration (RD) was 20 weeks and was significantly longer in patients with FLT3 mutations not previously exposed to other FLT3 inhibitors (P = 0.05) and in patients not previously transplanted (P = 0.01). Thirty-two (59%) patients have died, all of complications related to disease progression. G3-4 nonhematological toxicity was reported in 38 (70%) patients, most frequently infections (56%), ejection fraction reduction (11%), and diarrhea or nausea/vomiting (9% each). The combination of midostaurin and AZA is an effective and safe regimen in patients with AML and high-risk MDS. Patients with FLT3 mutations but not previously exposed to other FLT3 inhibitors and patients not previously transplanted derived the greatest benefit. Further studies with this combination are warranted.
Beyond the sensory/functional dichotomy
Authors: George S. Cree, Ken McRae
Journal: Behavioral and Brain Sciences (2001)

Most current theories of category-specific semantic deficits appeal to the role of sensory and functional knowledge types in explaining patients' impairments. We discuss why this binary classification is inadequate, point to a more detailed knowledge type taxonomy, and suggest how it may provide insight into the relationships between category-specific semantic deficits and impairments of specific aspects of knowledge.
NRF2-regulated genes SLC7A11 and NQO1 confer chemoresistance in mesotheliomas
Authors: Chau Nguyen, Hanlin Gao, Arezoo Campbell, Anh-Nhan Pham, Xiaoning Bi, Guanghong Liao, Zhongting Hu, Joseph Abad
Journal: Cancer Research (2008)

3250   Mesothelioma is an aggressive and treatment-resistant tumor with increasing prevalence throughout the world. Expression of genes encoding antioxidants ( e.g ., glutathione) and xenobiotic detoxification enzymes has been shown to increase in mesothelioma cells, which may play an important role in anticancer drug resistance. SLC7A11 (xCT) is an amino acid transporter designated as system  x  c  - , responsible for the cystine entry in exchange for intracellular glutamate. Once inside the cell, cystine is rapidly reduced to cysteine, the rate limiting amino acid for glutathione biosynthesis. Our previous studies showed that SLC7A11 overexpression in lung and ovarian cancers maintained a high intracellular glutathione level and conferred chemoresistance to multiple anticancer agents. The present study investigated the expression and activity of SLC7A11 and related gene NADP[H] quinine oxidoreductase 1 (NQO1), both of which are positively regulated by the transcriptional factor NRF2 and negatively regulated by the NRF2 suppressor gene KEAP1. We examined the mRNA and protein levels of SLC7A11, NQO1, NRF2 and KEAP1 in eight mesothelioma cell lines using real-time RT-PCR, dot blot, Western blot and immunocytochemistry techniques. We also inhibited the transport activity of SLC7A11 using glutamate or (S)-4-carboxyphenylglycine and examined the effects of SLC7A11 inhibition on the sensitivity of tumor cells to anticancer drugs geldanamycin and L-alanosine. Our results indicated that SLC7A11 and NQO1 are expressed at different levels in mesothelioma cell lines and their expression levels correlated with the degree of drug resistance in these cells. In cell lines with high levels of SLC7A11 expression (e.g., H2461), SLC7A11 inhibition significantly increased the growth inhibitory potency of geldanamycin, while the potency of L-alanosine, an amino acid analog and potential substrate of SLC7A11, was reduced. Although we hypothesized that constitutive activation of NRF2-regulated SLC7A11 and NQO1 may be due to the loss of function of KEAP1, no somatic mutation(s) in exon-coding regions of the KEAP1 gene have been detected in the eight cell lines by sequencing analysis of the tumor genomic DNA. These findings suggest a potential role of NRF2-regulated genes such as SLC7A11 and NQO1 in chemoresistance of mesothelioma. The mechanisms for overexpression of SLC7A11 and NQO1 in the subset of mesotheliomas need further investigation. Understanding the function of these genes and their regulatory pathways may lead to effective pharmacological treatment for this malignancy.
A Phase 2 Randomized, Double-Blind, Placebo-Controlled Trial Demonstrating Reversal Of Rivaroxaban-Induced Anticoagulation In Healthy Subjects By Andexanet Alfa (PRT064445), An Antidote For Fxa Inhibitors
Authors: Crowther Mark, Mathur Vandana, Kitt Michael, Lu Genmin, Pamela B. Conley, Hollenbach Stanley, Janice Castillo, Athiwat Hutchaleelaha, Mark Karbarz, Joyce P. Lin, Lee Barron, Sandra Russell, Gallia G. Levy, Stuart Connolly, John T. Curnutte
Journal: Blood (2013)
Abstract 5872: Argatroban And Bivalirudin Compared To Unfractionated Heparin In Preventing Thrombus Formation On Mechanical Heart Valves, Results Of An <i>In Vitro</i> <b>Study</b>
Authors: Lars Maegdefessel, Torsten Linde, Thomas Michel, Ulrich Steinseifer, Uwe Raaz, Ivar Friedrich, Karl Werdan, Michael Buerke, Axel Schlitt
Journal: Circulation (2008)

Introduction Argatroban and bivalirudin both selectively inhibit thrombin at its active site. In patients with heparin-induced thrombocytopenia, and HIT complicated by thrombosis (HIT II), argatroban and bivalirudin are recommended due to their ability to significantly decrease the risk of thrombembolic complications in comparison to other treatments. The aim of the present study was to investigate the efficacy of argatroban and bivalirudin in comparison to unfractionated heparin (UFH) in preventing thrombus formation on mechanical heart valves using an in vitro system. Materials and Methods Blood (220 ml) from young and healthy male volunteers was anticoagulated either by UFH, argatroban bolus, argatroban bolus + continuous infusion, bivalirudin bolus, or bivalirudin bolus + continuous infusion. St. Jude Medical 27 mm prosthesis were placed in a newly constructed in vitro thrombosis tester, and exposed to a continuous circulation rate of 80 beats per minute to anticoagulated blood samples. The total exposure time was 60 minutes. To quantify the thrombi that developed, electron microscopy was performed. Using a Data Acquisition Unit (DAQ), flow- and pressure differences, before and after the heart valve, could be measured and compared between the five groups. And finally each valve was weighed before and after the experiment. Results The mean thrombus weight in group 1 (UFH) was 117 ± 93 mg, in group 2 (argatroban bolus) 722 ± 428 mg, in group 3 (argatroban bolus + continuous infusion) 162 ± 98 mg, in group 4 (bivalirudin bolus) 758 ± 323 mg, and in group 5 (bivalirudin bolus + continuous) 166 ± 141 mg (p-value: &lt;0,00 for comparison between groups 2 and 4 to the other 3 groups). Electron microscopy showed higher rates of thrombus formation in groups 2 and 4. Conclusion Argatroban and bivalirudin were as efficient as UFH in preventing thrombus formation on mechanical heart valves in our in vitro experiments, when they were administered continuously. We hypothesize that either the continuous infusion of argatroban or bivalirudin are an optimal treatment option for patients with HIT after mechanical heart valve replacement for adapting oral to parenteral anticoagulation or vice versa .
Abstract 2402: Matrix Metalloproteinases and their Tissue Inhibitors in Cardiac Amyloidosis: Relationship to Structural and Functional Changes and to Light Chain Amyloid Deposition in the Heart
Authors: Sujata Ramamurthy, Andreia Biolo, Lawreen H Connors, Carl J O’Hara, Hans K Meier-Ewert, Pamela T Soo Hoo, Douglas B Sawyer, David S Seldin, Flora Sam
Journal: Circulation (2008)

Cardiac amyloidosis is characterized by amyloid infiltration resulting in extracellular matrix disruption. Systemic deposition of immunoglobulin light chain (LC) fibrils (AL or “primary”) amyloidosis can lead to cardiac amyloidosis with heart failure. AL cardiomyopathy (AL-CMP) has an accelerated clinical course and a worse prognosis compared to non-LC cardiac amyloidoses. We therefore tested the hypothesis that determinants of proteolytic activity of the extracellular matrix, the matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), would have distinct patterns and contribute to the pathogenesis of AL-CMP. We studied 40 patients with systemic amyloidosis: 10 AL-CMP patients, 20 patients with non-LC cardiac amyloidosis: i.e. amyloidosis associated with either wild-type transthyretin (TTR), senile systemic amyloidois (SSA) or a mutant TTR (ATTR), and 10 patients with AL amyloidosis without cardiac involvement. Plasma MMP-2, MMP-9, TIMP-1, TIMP-2 and TIMP-4, brain natriuretic peptide (BNP) values and echocardiographic parameters were determined. AL-CMP and non-LC groups had similar degrees of increased left ventricular wall thickness (LVWT) and mass index (LVMI). However, BNP, MMP-9 and TIMP-1 levels were distinctly elevated and accompanied by marked diastolic dysfunction in the AL-CMP group vs. no or minimal increases in the non-LC group. BNP, MMPs and TIMPs were not associated with the degree of LVWT but were to each other and to measures of diastolic dysfunction. Immunostaining of human endomyocardial biopsies showed diffuse expression of MMP-9 and TIMP-1 in AL-CMP and limited expression in non-LC hearts. Despite comparable LVWT and LVMI with non-LC cardiac amyloidosis, AL-CMP patients have higher BNP, MMP-9 and TIMP-1, which correlated with diastolic dysfunction. These findings suggest a relationship between LC and extracellular matrix proteolytic activation that may play an important role in the functional and clinical manifestations of AL-CMP.