tbuckley/cabot-search huggingface dataset:
Leukotriene B4-Neutrophil Elastase Axis Drives Neutrophil Reverse Transendothelial Cell Migration In Vivo
Authors: Bartomeu Colom, Jennifer V Bodkin, Martina Beyrau, Abigail Woodfin, Christiane Ody, Claire Rourke, Triantafyllos Chavakis, Karim Brohi, Beat A Imhof, Sussan Nourshargh
Journal: Immunity (2015)

Breaching endothelial cells (ECs) is a decisive step in the migration of leukocytes from the vascular lumen to the extravascular tissue, but fundamental aspects of this response remain largely unknown. We have previously shown that neutrophils can exhibit abluminal-to-luminal migration through EC junctions within mouse cremasteric venules and that this response is elicited following reduced expression and/or functionality of the EC junctional adhesion molecule-C (JAM-C). Here we demonstrate that the lipid chemoattractant leukotriene B4 (LTB4) was efficacious at causing loss of venular JAM-C and promoting neutrophil reverse transendothelial cell migration (rTEM) in vivo. Local proteolytic cleavage of EC JAM-C by neutrophil elastase (NE) drove this cascade of events as supported by presentation of NE to JAM-C via the neutrophil adhesion molecule Mac-1. The results identify local LTB4-NE axis as a promoter of neutrophil rTEM and provide evidence that this pathway can propagate a local sterile inflammatory response to become systemic.
Role of TWEAK in coregulating liver progenitor cell and fibrogenic responses
Authors: Janina E.E. Tirnitz-Parker, John K. Olynyk, Grant A. Ramm
Journal: Hepatology (2013)

Failure of fibrotic liver to regenerate after resection limits therapeutic options and increases demand for liver transplantation, representing a significant clinical problem. The mechanism underlying regenerative failure in fibrosis is poorly understood. Seventy percent partial hepatectomy (PHx) was performed in C57Bl/6 mice with or without carbon tetrachloride (CCl4)-induced liver fibrosis. Liver function and regeneration was monitored at 1 to 14 days thereafter by assessing liver mass, alanine aminotransferase (ALT), mRNA expression, and histology. Progenitor (oval) cell mitogen tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and TWEAK-neutralizing antibody were used to manipulate progenitor cell proliferation in vivo. In fibrotic liver, hepatocytes failed to replicate efficiently after PHx. Fibrotic livers showed late (day 5) peak of serum ALT (3542 ± 355 IU/L compared to 93 ± 65 IU/L in nonfibrotic livers), which coincided with progenitor cell expansion, increase in profibrogenic gene expression and de novo collagen deposition. In fibrotic mice, inhibition of progenitor activation using TWEAK-neutralizing antibody after PHx resulted in strongly down-regulated profibrogenic mRNA, reduced serum ALT levels and improved regeneration. Failure of hepatocyte-mediated regeneration in fibrotic liver triggers activation of the progenitor (oval) cell compartment and a severe fibrogenic response. Inhibition of progenitor cell proliferation using anti-TWEAK antibody prevents fibrogenic response and augments fibrotic liver regeneration. Targeting the fibrogenic progenitor response represents a promising strategy to improve hepatectomy outcomes in patients with liver fibrosis.
Coronary Computed Tomographic Angiography as a Gatekeeper to Invasive Diagnostic and Surgical Procedures
Authors: Leslee J. Shaw, Jörg Hausleiter, Stephan Achenbach, Mouaz Al-Mallah, Daniel S. Berman, Matthew J. Budoff, Fillippo Cademartiri, Tracy Q. Callister, Hyuk-Jae Chang, Yong-Jin Kim, Victor Y. Cheng, Benjamin J.W. Chow, Ricardo C. Cury, Augustin J. Delago, Allison L. Dunning, Gudrun M. Feuchtner, Martin Hadamitzky, Ronald P. Karlsberg, Philipp A. Kaufmann, Jonathon Leipsic, Fay Y. Lin, Kavitha M. Chinnaiyan, Erica Maffei, Gilbert L. Raff, Todd C. Villines, Troy LaBounty, Millie J. Gomez, James K. Min
Journal: Journal of the American College of Cardiology (2012)
High-Flow Nasal Cannulae in Very Preterm Infants after Extubation
Authors: Stephen A Roberts, Simon Mitchell, Suresh Victor
Journal: New England Journal of Medicine (2014)

n engl j med 370;4 nejm.org january 23, 2014 384 ment. We believe that the most likely explanation for our trial results is that dabigatran is less effective than warfarin in suppressing coagulation activation resulting from exposure of the blood to the artificial surface of a mechanical valve. Gasparovic and colleagues are concerned about a lack of concomitant antiplatelet therapy in our trial. The 2012 Guidelines on the Management of Valvular Heart Disease published by the European Society of Cardiology and the European Association for Cardio-Thoracic Surgery suggest that antiplatelet therapy should not be routinely prescribed for all patients who have a mechanical valve but instead should be reserved for specific indications.1 Approximately one third of the patients in our trial received concomitant antiplatelet therapy, and there is no evidence that this concomitant therapy explains the results of the trial. John W. Eikelboom, M.D.
Genomic Profiling of Cancers of Unknown Primary Site
Authors: Erin F. Cobain, Arul M. Chinnaiyan, Razelle Kurzrock, Laurence H. Baker
Journal: JAMA Oncology (2015)

A recent article by Ross et al 1 reported the results of comprehensive genomic profiling of cancers of unknown primary (CUPs) and documents frequent occurrence of clinically relevant genomic alterations.We describe herein the outcome of a case of CUP, which may serve to illustrate both the benefit of personalized therapy and potential pitfalls.A man in his 60s presented with CUP involving bones and lymph nodes.He had a history of stage II testicular seminoma, treated with orchiectomy and radiation therapy, and this disease had been in remission for 5 years.Bone pain led to the diagnosis of multiple lytic bone metastases.Excisional biopsy of a supraclavicular node demonstrated poorly differentiated adenocarcinoma.Immunohistochemistry and gene expression profiling and positron emission tomography were inconclusive for the primary site.The patient was empirically treated with carboplatin and paclitaxel with a good clinical and radiographic response.After initiation of chemotherapy, results of tumor genomic profiling became available.ErbB2 amplification and a BRCA1 mutation were found.Therefore, trastuzumab was added to the last 2 cycles of chemotherapy and continued as maintenance therapy.After completion of chemotherapy, lapatinib was prescribed in addition to trastuzumab.Two years after diagnosis of CUP, the patient remained free of disease progression or symptoms.Although this patient's disease responded well to chemotherapy, durable remission after chemotherapy is rare in CUP.Bone metastasis is associated with poor survival in CUP. 2 Therefore, it is tempting to attribute the unusually long progressionfree interval to ErbB2-directed maintenance therapy with trastuzumab and lapatinib.The tumor also harbored a mutant BRCA1 allele, which was independently detected by our institutional research study of tumor genome sequencing (UNCSeq: NCT01457196). 3 The patient was referred to genetic counseling, and standard genetic testing confirmed him to be a germline carrier of a common BRCA1 founder mutation, 5385insC (formerly 5382insC). 4 The wild-type allele of BRCA1 was retained in the tumor, and it is unclear whether the tumor is predisposed to respond to therapy targeting BRCA1 loss of function.Tumor profiling led to the diagnosis of his germline BRCA1 mutation, which raised serious implications for his children's risk of cancer and their decisions regarding genetic testing.Tumor genomic profiling may yield additional treatment options with long-term clinical benefit.However, clinicians and patients should be made aware that there may be unanticipated consequences for patients and their families from detection of germline variants.
Abstract 2635: The Relation Between Axis Deviation On An Ecg And Left Ventricular Dyssynchrony
Authors: Kazuyoshi Ogura, Osamu igawa, Masamitsu Adachi, Akio Yano, Yoshiaki Inoue, Masaru Kato, Kazuhiko Iitsuka, Ichiro Hisatome
Journal: Circulation (2007)

Background: Patients with end-stage left ventricular (LV) dysfunction and a wide QRS complex are considered prime candidates for cardiac resynchronization therapy (CRT). However, 18% to 30% of pati...
Ageing: The Facts.
Authors: Nicholas Coni, William Davison, Stephen Webster
Journal: Annals of Internal Medicine (1985)

The world grows grey the benefits of an ageing society retirement - the opportunity of age living arrangements physical disability servicing an ageing society the biology of ageing normal ageing the body's chemical and physical composition the ageing brain age-related psychological problems stroke, Parkinson's disease and motor neurone disease mobility nutrition and digestion the bladder and its control heart, blood vessels and lungs eyes, ears, teeth, skin and feet cancer medicines caring for an infirm elderly person at home death bereavement.
Is radiologic evidence of interstitial infiltrate enough to predict FEV1 and DLCO disparity in lung cancer patients
Authors: Frederico Fernandes, Gustavo Prado, Juliana Puka, Salge João Marcos, André Albuquerque, Mariana Araujo, Paula Chaves Sampaio, Milena Suesada, Teresa Takagaki
Journal: European Respiratory Journal (2011)

Guidelines have been established for the physiological evaluation of lung cancer patients considered for surgery. While some recommend routine measurement of DLCO, others require this measure if there is evidence of interstitial disease, relying on FEV1 alone in most cases. Our objective in this study was to evaluate if radiologic evidence of interstitial disease is a good predictor of disparities between FEV1 and DLCO.

We studied a sample of 50 patients with NSCLC referred to perform lung function measurement. Based on chest CT, patients were divided into two groups according to presence of interstitial disease. The correlation between FEV1 and DLCO was tested.

48 individuals completed the study. 11 patients had diffuse interstitial disease in CT (Group ICT) while 37 patients had no signs of interstitial pattern (Group NCT). Both groups were similar in terms of age, gender and BMI. Mean DLCO% predicted was lower in ICT group 42 x 61% (p<0.01). VEF1 and TLC were also significantly lower in ICT. 7 patients in ICT and 32 in NCT had an obstructive pattern on spirometry (p=NS).

FEV1 and DLCO had a significant correlation (R=0,376 p=0,009). The same analysis for both groups showed that FEV1 and DLCO correlated better in ICT (R=0,630 p=0,03) than in NCT (R=0,249 p=NS). In NCT group, 10 from 14 patients with normal FEV1 had impaired diffusion capacity.

Interstitial infiltrate predicts impaired lung function and diffusion capacity but disparities between FEV1 and DLCO are more frequent in lung cancer patients without diffuse interstitial pattern. These findings support the routine assessment of DLCO in patients who are candidates for surgical treatment of NSCLC.
Abstract 13703: Patients With Familial Hypercholesterolemia Are Protected Against Type II Diabetes - a Cross-sectional Study in 63,000 Individuals Tested for the Presence of LDL Receptor Mutations
Authors: Joost Besseling, Joep Defesche, John J Kastelein, Barbara A Hutten, Gerard K Hovingh
Journal: Circulation (2014)

Introduction: Familial Hypercholesterolemia (FH) is a prevalent single gene disorder characterized by decreased transmembrane cholesterol transport (TCT). In clinical practice, it was noticed that FH patients are less prone to develop type 2 diabetes mellitus (T2DM). In contrast, statin use increases TCT and, intriguingly, increases risk for T2DM. Hypothesis: Hence, we hypothesized that perturbations in TCT contribute to the development of T2DM, and we investigated whether T2DM prevalence is indeed lower in FH. Methods: All Dutch individuals who underwent DNA testing for FH between 1994 and 2014 were enrolled. We compared T2DM prevalence between FH patients and unaffected relatives. Additionally, we tested whether more severe FH mutations were associated with an even lower risk for T2DM; i.e. LDLR vs. APOB, and receptor-negative vs. receptor-deficient LDLR mutations, with unaffected relatives as reference, after adjustment for potential confounders. Results: Unadjusted, the prevalence of T2DM proved to be 1.8% in 25,137 FH patients (n=440) (adjusted: 1.4%) versus 2.9% in 38,183 unaffected relatives (n=1,119) (p&lt;0.001). The adjusted odds ratios for T2DM in LDLR vs. APOB, and in receptor-negative vs. receptor-deficient LDLR mutation carriers were 0.44 (95% CI: 0.37 - 0.52) vs. 0.63 (95% CI: 0.47 - 0.85), and 0.37 (95% CI: 0.28 - 0.47) vs. 0.48 (95% CI: 0.39 - 0.58), respectively, compared to unaffected relatives (p-for-trend&lt;0.001 in both associations). Conclusions: The prevalence of T2DM in FH patients is 50% lower than in unaffected relatives. Moreover, the more severe the FH mutation, the lower the prevalence of T2DM. Together with the observed association between statin use and T2DM, our findings suggest a role for cholesterol metabolism in the pathogenesis of T2DM and point to novel targets for disease modification.
Antileukemia activity of the novel peptidic CXCR4 antagonist LY2510924 as monotherapy and in combination with chemotherapy
Authors: Byung-Sik Cho, Zhihong Zeng, Hong Mu, Zhiqiang Wang, Sergej Konoplev, Teresa McQueen, Marina Protopopova, Jorge Cortes, Joseph R. Marszalek, Sheng-Bin Peng, Wencai Ma, R. Eric Davis, Donald E. Thornton, Michael Andreeff, Marina Konopleva
Journal: Blood (2015)
Abstract 40: Association of Interferon-induced protein with tetratricopeptide repeats 1 and 3 expression with regional metastasis and drug resistance in oral squamous cell carcinoma
Authors: Ai-Hsin Yen, Ying-Chen Chen, Vijaya Kumar Pidugu, Chung-Ji Liu, Te-Chang Lee
Journal: Cancer Research (2014)

Abstract Interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) gene family, consisting of 4 members (IFIT1, IFIT2, IFIT3, and IFIT5) in humans, is one of most responsive interferon-stimulated gene families. We have previously demonstrated that IFIT2 silencing activates atypical PKC signaling and induces epithelial-mescenchymal transition, cell migration, invasion, and metastasis of oral squamous cell carcinoma (OSCC) cells in cultured or animal models. These results implicate that IFIT2 is potentially a prognosis biomarker of patients with OSCC. In the present study, we further explore the roles of other IFIT1 family proteins involved in the regulatory mechanism of metastasis and drug resistance in OSCC cells. We determined the expression levels of IFIT1 gene family proteins in 82 patients with OSCC by immunohistochemical technique. Our present results revealed a close association between IFIT1 and IFIT3 protein expression in OSCC patient-derived tumor specimens (p &amp;lt; 0.001). However, the expression levels of IFIT1 or IFIT3 did not have a correlation with that of IFIT2 in tumor tissues. Intriguingly, IFIT5 was the only member of IFIT1 family displayed a well correlation with HPV E6 protein expression. Furthermore, we found that the expression levels of IFIT1 and IFIT3 were positively associated with age as well as regional lymph node metastasis status, whereas they were marginally and inversely associated with the differentiation features. We further demonstrated that IFIT1 and IFIT3 protein expression-induced by pre-treatment or co-treatment with IFN-β in Ca9-22 cells increased their resistance to Cisplatin and 5-flurouracil (5-FU). Silencing of IFIT1 and IFIT3 protein expression in SCC-25 cells by its specific shRNA, respectively, increased their susceptibility to Cisplatin and 5-FU. Since our present studies reveal that enhanced IFIT1 and IFIT3 expression associate with regional lymph node metastasis and drug resistance to Cisplatin and 5-FU, the roles of IFIT1 and IFIT3 expression associated with the clinicopathologic development in OSCC patients warrant our further investigation. Citation Format: Ai-Hsin Yen, Ying-Chen Chen, Vijaya Kumar Pidugu, Chung-Ji Liu, Te-Chang Lee. Association of Interferon-induced protein with tetratricopeptide repeats 1 and 3 expression with regional metastasis and drug resistance in oral squamous cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 40. doi:10.1158/1538-7445.AM2014-40
Abstract 9906: Endothelial Function is Impaired in Peripheral Arterial Disease With Borderline Ankle-Brachial Index
Authors: Masato Kajikawa, Yukihito Higashi, Tatsuya Maruhashi, Yumiko Iwamoto, Akimichi Iwamoto, Takeshi Matsumoto, Nozomu Oda, Takayuki Hidaka, Ayumu Nakashima, Kensuke Noma, Yasuki Kihara
Journal: Circulation (2014)

Introduction:  Ankle-brachial index (ABI) measurement is useful for detecting peripheral arterial disease (PAD). Recently, several investigators have reported that an ABI value of 0.91 to 0.99 should be considered borderline and is associated with an increasing risk of cardiovascular disease. However, there is no information on the relationship between borderline ABI and endothelial function. The purpose of this study was to evaluate the relationship between ABI value and vascular function.   Methods and Results:  We measured ABI and assessed vascular function by measurement of flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation in 389 subjects who underwent health examinations (mean age, 58±18 years). Subjects were divided into 3 groups according to ABI (normal group: 1.00-1.40, borderline group: 0.91-0.99, abnormal group: ≤0.90 or >1.40). FMD were significantly smaller in the borderline group and abnormal group than in the normal group (3.6±1.9% and 3.1±2.8% vs. 5.1±2.7%, P=0.003 and P   Conclusion:  ABI value of 0.91-0.99 is associated with endothelial dysfunction, while vascular smooth muscle function is maintained in normal ranges. ABI examination is a simple and cost-effective method for obtaining the additional information on the grade of atherosclerosis beyond the assessment of PAD.
Efficacy and Tolerability of Pegloticase for the Treatment of Chronic Gout in Patients Refractory to Conventional Treatment
Authors: John S Sundy, Herbert S B Baraf, Robert A Yood, N Lawrence Edwards, Sergio R Gutierrez-Urena, Edward L Treadwell, Janitzia Vázquez-Mellado, William B White, Peter E Lipsky, Zeb Horowitz, William Huang, Allan N Maroli, Royce W Waltrip, Steven A Hamburger, Michael A Becker
Journal: JAMA (2011)

Patients with chronic disabling gout refractory to conventional urate-lowering therapy need timely treatment to control disease manifestations related to tissue urate crystal deposition. Pegloticase, monomethoxypoly(ethylene glycol)-conjugated mammalian recombinant uricase, was developed to fulfill this need.To assess the efficacy and tolerability of pegloticase in managing refractory chronic gout.Two replicate, randomized, double-blind, placebo-controlled trials (C0405 and C0406) were conducted between June 2006 and October 2007 at 56 rheumatology practices in the United States, Canada, and Mexico in patients with severe gout, allopurinol intolerance or refractoriness, and serum uric acid concentration of 8.0 mg/dL or greater. A total of 225 patients participated: 109 in trial C0405 and 116 in trial C0406.Twelve biweekly intravenous infusions containing either pegloticase 8 mg at each infusion (biweekly treatment group), pegloticase alternating with placebo at successive infusions (monthly treatment group), or placebo (placebo group).Primary end point was plasma uric acid levels of less than 6.0 mg/dL in months 3 and 6.In trial C0405 the primary end point was reached in 20 of 43 patients in the biweekly group (47%; 95% CI, 31%-62%), 8 of 41 patients in the monthly group (20%; 95% CI, 9%-35%), and in 0 patients treated with placebo (0/20; 95% CI, 0%-17%; P < .001 and <.04 for comparisons between biweekly and monthly groups vs placebo, respectively). Among patients treated with pegloticase in trial C0406, 16 of 42 in the biweekly group (38%; 95% CI, 24%-54%) and 21 of 43 in the monthly group (49%; 95% CI, 33%-65%) achieved the primary end point; no placebo-treated patients reached the primary end point (0/23; 95% CI, 0%-15%; P = .001 and < .001, respectively). When data in the 2 trials were pooled, the primary end point was achieved in 36 of 85 patients in the biweekly group (42%; 95% CI, 32%-54%), 29 of 84 patients in the monthly group (35%; 95% CI, 24%-46%), and 0 of 43 patients in the placebo group (0%; 95% CI, 0%-8%; P < .001 for each comparison). Seven deaths (4 in patients receiving pegloticase and 3 in the placebo group) occurred between randomization and closure of the study database (February 15, 2008).Among patients with chronic gout, elevated serum uric acid level, and allopurinol intolerance or refractoriness, the use of pegloticase 8 mg either every 2 weeks or every 4 weeks for 6 months resulted in lower uric acid levels compared with placebo.clinicaltrials.gov Identifier: NCT00325195.
Some Factors Involved in the Induction or Growth of Testicular Tumors in BALB/c Mice
Authors: Howard B. Andervont, Michael B. Shimkin, Harry Y. Canter
Journal: JNCI Journal of the National Cancer Institute (1960)

The effects of interruption of estrogen after second exposure to estrogenic stimulation, age of the animals, and treatment with progesterone were studied on the development and growth of interstitial-cell tumors of the testes in BALB/c mice implanted subcutaneously with diethylstilbestrol-cholesterol pellets. (1) Estrogenic stimulation for 8 weeks, removal of the pellet for 24 weeks, and reimplantation of a second pellet delayed the occurrence of tumors by approximately the intervening nonestrogen period, which indicated that the process was interrupted, but did not progress or regress to any appreciable extent during that period. (2) Diethylstilbestrol pellets implanted in mice from 2 weeks to 12 months of age showed that all age groups responded with the appearance of testicular tumors. The tumors appeared later and reached a lower cumulative frequency in the 2-week-old mice, and a smaller proportion grew progressively after removal of diethylstilbestrol from the 12-month-old mice. (3) Progesterone retarded but did not prevent the occurrence of estrogen-induced tumors under the conditions of the experiment.