tbuckley/cabot-search huggingface dataset:
Inspiratory pressure during noninvasive ventilation in stable COPD: help the lungs, but do not forget the heart
Authors: Antonio M. Esquinas, Raffaele Scala, Jacek Nasiłowski
Journal: European Respiratory Journal (2013)

To the Editor :

The disappointing results of the randomised trials on the use of noninvasive ventilation (NIV) in stable hypercapnic chronic obstructive pulmonary disease (COPD) patients [1] necessitates a search for the reasons for NIV inefficiency in long term treatment. Windisch et al. [2] suggested that NIV aimed at increasing maximum-tolerated inspiratory positive airway pressure and taking over patients breathing rhythm by a ventilator is a key factor in the success of NIV. The new idea proposed by Windisch et al. [3], called high intensity noninvasive positive pressure ventilation (Hi-NPPV), seems to be attractive, but requires verification. Therefore, we would like to congratulate Lukacsovits et al. [4] on their excellent physiological study of the short-term effects of Hi-NPPV published in the April 2012 issue of the European Respiratory Journal . However, we believe that some aspects of this study need to be critically discussed.

Firstly, Lukacsovits et al. [4] …
Thymic output generates a new and diverse TCR repertoire after autologous stem cell transplantation in multiple sclerosis patients
Authors: Paolo A. Muraro, Daniel C. Douek, Amy Packer, Katherine Chung, Francisco J. Guenaga, Riccardo Cassiani-Ingoni, Catherine Campbell, Sarfraz Memon, James W. Nagle, Frances T. Hakim, Ronald E. Gress, Henry F. McFarland, Richard K. Burt, Roland Martin
Journal: The Journal of Experimental Medicine (2005)

Clinical trials have indicated that autologous hematopoietic stem cell transplantation (HSCT) can persistently suppress inflammatory disease activity in a subset of patients with severe multiple sclerosis (MS), but the mechanism has remained unclear. To understand whether the beneficial effects on the course of disease are mediated by lympho-depletive effects alone or are sustained by a regeneration of the immune repertoire, we examined the long-term immune reconstitution in patients with MS who received HSCT. After numeric recovery of leukocytes, at 2-yr follow-up there was on average a doubling of the frequency of naive CD4+ T cells at the expense of memory T cells. Phenotypic and T cell receptor excision circle (TREC) analysis confirmed a recent thymic origin of the expanded naive T cell subset. Analysis of the T cell receptor repertoire showed the reconstitution of an overall broader clonal diversity and an extensive renewal of clonal specificities compared with pretherapy. These data are the first to demonstrate that long-term suppression of inflammatory activity in MS patients who received HSCT does not depend on persisting lymphopenia and is associated with profound qualitative immunological changes that demonstrate a de novo regeneration of the T cell compartment.
Biochemistry and Biomechanics of Cell Motility
Authors: Song Li, Jun-Lin Guan, Shu Chien
Journal: Annual Review of Biomedical Engineering (2005)

Cell motility is an essential cellular process for a variety of biological events. The process of cell migration requires the integration and coordination of complex biochemical and biomechanical signals. The protrusion force at the leading edge of a cell is generated by the cytoskeleton, and this force generation is controlled by multiple signaling cascades. The formation of new adhesions at the front and the release of adhesions at the rear involve the outside-in and inside-out signaling mediated by integrins and other adhesion receptors. The traction force generated by the cell on the extracellular matrix (ECM) regulates cell-ECM adhesions, and the counter force exerted by ECM on the cell drives the migration. The polarity of cell migration can be amplified and maintained by the feedback loop between the cytoskeleton and cell-ECM adhesions. Cell migration in three-dimensional ECM has characteristics distinct from that on two-dimensional ECM. The migration of cells is initiated and modulated by external chemical and mechanical factors, such as chemoattractants and the mechanical forces acting on the cells and ECM, as well as the surface density, distribution, topography, and rigidity of the ECM.
Antitumor Efficacy of Oblimersen Bcl-2 Antisense Oligonucleotide Alone and in Combination with Vinorelbine in Xenograft Models of Human Non–Small Cell Lung Cancer
Authors: YanPing Hu, Gwyn Bebb, Sophia Tan, Rebecca Ng, Hong Yan, Jason R. Sartor, Lawrence D. Mayer, Marcel B. Bally
Journal: Clinical Cancer Research (2004)

Abstract Overexpression of Bcl-2 protein in cancer cells can inhibit programmed cell death and engender chemoresistance. Reducing Bcl-2 protein levels by using antisense oligonucleotides targeting the gene message can increase the sensitivity of cancer cells to cytotoxic agents. The objective of this work was to investigate the antitumor efficacy of the Bcl-2 antisense oligonucleotide oblimersen (Genasense; G3139), alone and in combination with vinorelbine (VNB), in an ectopic and orthotopic xenograft model of NCI-H460 human non–small-cell lung cancer. In addition to assessing therapeutic effect, Bcl-2 protein expression in tumor tissue isolated from lung and heart was measured. In the ectopic xenograft model, oblimersen at 5 and 10 mg/kg significantly inhibited tumor growth compared with saline-treated control groups, and furthermore, the antitumor effect of oblimersen was associated with down-regulation of Bcl-2 protein in isolated tumor tissue. Moreover, the combination of oblimersen with VNB was more active in inhibiting tumor growth than either drug used alone. In the orthotopic model, oblimersen treatment (5 mg/kg) increased the median survival time of mice to 33 days in comparison with a median survival time of 21 days in the control animals. With this model, the anticancer effect was demonstrated by assessing tumor growth in lung and heart tissues by hematoxylin and eosin staining and Bcl-2 expression by immunohistochemistry. When VNB at 5 mg/kg was combined with oblimersen administered at 5 mg/kg, 33% of mice survived more than 90 days. These data suggest that the combination of oblimersen and VNB may provide enhanced antitumor activities against non–small-cell lung cancer.
Effectiveness and cost-effectiveness of first BCG vaccination against tuberculosis in school-age children without previous tuberculin test (BCG-REVAC trial): a cluster-randomised trial
Authors: Susan M Pereira, Mauricio L Barreto, Daniel Pilger, Alvaro A Cruz, Clemax Sant'Anna, Miguel A Hijjar, Maria Y Ichihara, Andreia C Santos, Bernd Genser, Laura C Rodrigues
Journal: The Lancet Infectious Diseases (2011)
FLIPping the Balance between Apoptosis and Proliferation in Thyroid Cancer
Authors: Robin Mathew, Eileen White
Journal: Clinical Cancer Research (2006)

In an article in this issue of Clinical Cancer Research , Mitsiades et al. ([1][1]) suggest that molecular alterations in thyroid cancer can divert a death receptor–mediated apoptotic pathway into a proliferative response, which poses a serious challenge to treating this cancer effectively by
Prognostic Significance of Progesterone Receptor–Positive Tumor Cells Within Immunohistochemically Defined Luminal A Breast Cancer
Authors: Aleix Prat, Maggie Chon U. Cheang, Miguel Martín, Joel S. Parker, Eva Carrasco, Rosalía Caballero, Scott Tyldesley, Karen Gelmon, Philip S. Bernard, Torsten O. Nielsen, Charles M. Perou
Journal: Journal of Clinical Oncology (2012)

Purpose Current immunohistochemical (IHC)-based definitions of luminal A and B breast cancers are imperfect when compared with multigene expression-based assays. In this study, we sought to improve the IHC subtyping by examining the pathologic and gene expression characteristics of genomically defined luminal A and B subtypes. Patients and Methods Gene expression and pathologic features were collected from primary tumors across five independent cohorts: British Columbia Cancer Agency (BCCA) tamoxifen-treated only, Grupo Español de Investigación en Cáncer de Mama 9906 trial, BCCA no systemic treatment cohort, PAM50 microarray training data set, and a combined publicly available microarray data set. Optimal cutoffs of percentage of progesterone receptor (PR) –positive tumor cells to predict survival were derived and independently tested. Multivariable Cox models were used to test the prognostic significance. Results Clinicopathologic comparisons among luminal A and B subtypes consistently identified higher rates of PR positivity, human epidermal growth factor receptor 2 (HER2) negativity, and histologic grade 1 in luminal A tumors. Quantitative PR gene and protein expression were also found to be significantly higher in luminal A tumors. An empiric cutoff of more than 20% of PR-positive tumor cells was statistically chosen and proved significant for predicting survival differences within IHC-defined luminal A tumors independently of endocrine therapy administration. Finally, no additional prognostic value within hormonal receptor (HR) –positive/HER2-negative disease was observed with the use of the IHC4 score when intrinsic IHC-based subtypes were used that included the more than 20% PR-positive tumor cells and vice versa. Conclusion Semiquantitative IHC expression of PR adds prognostic value within the current IHC-based luminal A definition by improving the identification of good outcome breast cancers. The new proposed IHC-based definition of luminal A tumors is HR positive/HER2 negative/Ki-67 less than 14%, and PR more than 20%.
Integrating RAS Status into Prognostic Signatures for Adenocarcinomas of the Lung
Authors: Maud HW. Starmans, Melania Pintilie, Michelle Chan-Seng-Yue, Nathalie C. Moon, Syed Haider, Francis Nguyen, Suzanne K. Lau, Ni Liu, Arek Kasprzyk, Bradly G. Wouters, Sandy D. Der, Frances A. Shepherd, Igor Jurisica, Linda Z. Penn, Ming-Sound Tsao, Philippe Lambin, Paul C. Boutros
Journal: Clinical Cancer Research (2015)

While the dysregulation of specific pathways in cancer influences both treatment response and outcome, few current prognostic markers explicitly consider differential pathway activation. Here we explore this concept, focusing on K-Ras mutations in lung adenocarcinoma (present in 25%-35% of patients).The effect of K-Ras mutation status on prognostic accuracy of existing signatures was evaluated in 404 patients. Genes associated with K-Ras mutation status were identified and used to create a RAS pathway activation classifier to provide a more accurate measure of RAS pathway status. Next, 8 million random signatures were evaluated to assess differences in prognosing patients with or without RAS activation. Finally, a prognostic signature was created to target patients with RAS pathway activation.We first show that K-Ras status influences the accuracy of existing prognostic signatures, which are effective in K-Ras-wild-type patients but fail in patients with K-Ras mutations. Next, we show that it is fundamentally more difficult to predict the outcome of patients with RAS activation (RAS(mt)) than that of those without (RAS(wt)). More importantly, we demonstrate that different signatures are prognostic in RAS(wt) and RAS(mt). Finally, to exploit this discovery, we create separate prognostic signatures for RAS(wt) and RAS(mt) patients and show that combining them significantly improves predictions of patient outcome.We present a nested model for integrated genomic and transcriptomic data. This model is general and is not limited to lung adenocarcinomas but can be expanded to other tumor types and oncogenes.
Percutaneous Coronary Angioplasty Compared With Exercise Training in Patients With Stable Coronary Artery Disease
Authors: Rainer Hambrecht, Claudia Walther, Sven Möbius-Winkler, Stephan Gielen, Axel Linke, Katrin Conradi, Sandra Erbs, Regine Kluge, Kai Kendziorra, Osama Sabri, Peter Sick, Gerhard Schuler
Journal: Circulation (2004)

Background— Regular exercise in patients with stable coronary artery disease has been shown to improve myocardial perfusion and to retard disease progression. We therefore conducted a randomized study to compare the effects of exercise training versus standard percutaneous coronary intervention (PCI) with stenting on clinical symptoms, angina-free exercise capacity, myocardial perfusion, cost-effectiveness, and frequency of a combined clinical end point (death of cardiac cause, stroke, CABG, angioplasty, acute myocardial infarction, and worsening angina with objective evidence resulting in hospitalization). Methods and Results— A total of 101 male patients aged ≤70 years were recruited after routine coronary angiography and randomized to 12 months of exercise training (20 minutes of bicycle ergometry per day) or to PCI. Cost efficiency was calculated as the average expense (in US dollars) needed to improve the Canadian Cardiovascular Society class by 1 class. Exercise training was associated with a higher event-free survival (88% versus 70% in the PCI group, P =0.023) and increased maximal oxygen uptake (+16%, from 22.7±0.7 to 26.2±0.8 mL O 2 /kg, P &lt;0.001 versus baseline, P &lt;0.001 versus PCI group after 12 months). To gain 1 Canadian Cardiovascular Society class, $6956 was spent in the PCI group versus $3429 in the training group ( P &lt;0.001). Conclusions— Compared with PCI, a 12-month program of regular physical exercise in selected patients with stable coronary artery disease resulted in superior event-free survival and exercise capacity at lower costs, notably owing to reduced rehospitalizations and repeat revascularizations.
Upper gastrointestinal surgeons comment on NICE dyspepsia guidelines
Authors: S M Griffin, D J Bowrey, W H Allum
Journal: BMJ (2005)

Save the FDAEditor-Abbasi asks whether drug regulation is failing. 1 The US Food and Drug Administration (FDA) performs a thankless task.Patients want new drugs available immediately and agitate to accomplish this.Patients also wish medicines to be guaranteed safe, and blame the FDA when toxicity leads to a drug's withdrawal.Clinical scientists complain that the FDA obstructs their investigations.Pharmaceutical companies see the FDA as an adversary, not a protector.Practising in the USA for 20 years, I encountered many FDA agents.A few revered regulations for their own sake.Such people are irksome, but without strict oversight valueless and toxic agents would be marketed.A prime example is Laetrile (laevo-mandelonitrile-beta-glucuronoside), a useless and poisonous drug promoted for cancer treatment.The FDA, supported by the National Cancer Institute, successfully resisted extreme public pressure to allow its marketing, saving many lives and a multimillion dollar fraud.The FDA faces serious accusations.Attempting to suppress David Graham's whistleblowing on rofecoxib assaults scientific honesty. 2 3 The FDA's refusal to allow non-prescription sales of emergency contraception indicates unacceptable political pressure from the religious right.Unduly close relations between the FDA and pharmaceutical companies may lead to premature marketing approvals.How should the FDA be saved?Firstly, officials ordering withdrawal of a drug should be independent of those who approve marketing.Secondly, making the FDA a quango would protect from political pressures.Thirdly, conflicts of interest involving FDA employees and consultants must be rigorously scrutinised, even more severely than editors scrutinise the interests of contributors.The UK's Medicines and Healthcare products Regulatory Agency is accused of proindustry bias.Housecleaning there and at the FDA will benefit patients, doctors, and the pharmaceutical industry itself.
Plasma nitrate concentration in infective gastroenteritis and inflammatory bowel disease.
Authors: R S Dykhuizen, J Masson, G McKnight, A N Mowat, C C Smith, L M Smith, N Benjamin
Journal: Gut (1996)

In subjects on a low nitrate diet, plasma nitrate concentration and urinary nitrate excretion are thought to reflect endogenous nitric oxide (NO) production, and have been reported to increase during infective and inflammatory bowel disease.To compare the extent of NO production in patients with infective versus non-infective forms of bowel dysfunction.Four groups: 20 healthy, volunteer clerical and laboratory staff, 12 patients with irritable bowel syndrome, 19 patients with inflammatory bowel disease, and 20 patients with infective gastroenteritis.The plasma nitrate concentration was determined with a copper coated cadmium column and spectrophotometry. Mean and median plasma nitrate concentrations were calculated and compared within the four groups. Mann-Whitney distribution free rank testing was used to compare the median values.Median plasma nitrate concentrations in the four groups were: controls 32.7 mumol/l; irritable bowel syndrome 35.5 mumol/l; inflammatory bowel disease 35.1 mumol/l; and gastroenteritis 117.9 mumol/l (p < 0.001 gastroenteritis v all other groups).Plasma nitrate concentration could serve as a discriminant between infective and inflammatory or functional bowel disease in patients presenting with diarrhoea. It is not clear why there is considerable difference in endogenous nitrate synthesis in these two conditions, which are both characterised by severe gut inflammation.
Endothelin-1/endothelin-B receptor–mediated increases in NHE3 activity in chronic metabolic acidosis
Authors: Kamel Laghmani, Patricia A. Preisig, Orson W. Moe, Masashi Yanagisawa, Robert J. Alpern
Journal: Journal of Clinical Investigation (2001)

Decreases in blood pH activate NHE3, the proximal tubular apical membrane Na/H antiporter. In cultured renal epithelial cells, activation of the endothelin-B (ETB) receptor increases NHE3 activity. To examine the role of the ETB receptor in the response to acidosis in vivo, the present studies examined ETB receptor–deficient mice, rescued from neonatal lethality by expression of a dopamine β-hydroxylase promoter/ETB receptor transgene (Tg/Tg:ETB–/– mice). In proximal tubule suspensions from Tg/Tg:ETB+/– mice, 10–8 M endothelin-1 (ET-1) increased NHE3 activity, but this treatment had no effect on tubules from Tg/Tg:ETB–/– mice. Acid ingestion for 7 days caused a greater decrease in blood HCO3– concentration in Tg/Tg:ETB–/– mice compared with Tg/Tg:ETB+/+ and Tg/Tg:ETB+/– mice. Whereas acid ingestion increased apical membrane NHE3 by 42–46% in Tg/Tg:ETB+/+ and Tg/Tg:ETB+/– mice, it had no effect on NHE3 in Tg/Tg:ETB–/– mice. In C57BL/6 mice, excess acid ingestion increased renal cortical preproET-1 mRNA expression 2.4-fold and decreased preproET-3 mRNA expression by 37%. On a control diet, Tg/Tg:ETB–/– mice had low rates of ammonium excretion, which could not be attributed to an inability to acidify the urine, as well as hypercitraturia, with increased titratable acid excretion. Acid ingestion increased ammonium excretion, citrate absorption, and titratable acid excretion to the same levels in Tg/Tg:ETB–/– and Tg/Tg:ETB+/+ mice. In conclusion, metabolic acidosis increases ET-1 expression, which increases NHE3 activity via the ETB receptor.
Association of Serum Phosphate with Vascular and Valvular Calcification in Moderate CKD
Authors: Kathryn L. Adeney, David S. Siscovick, Joachim H. Ix, Stephen L. Seliger, Michael G. Shlipak, Nancy S. Jenny, Bryan R. Kestenbaum
Journal: Journal of the American Society of Nephrology (2008)

Within the normal range, higher serum phosphate concentrations are associated with cardiovascular events and mortality in individuals with chronic kidney disease (CKD) and in those with normal kidney function. Experimental models suggest that phosphate has a direct calcifying effect on vascular smooth muscle. We examined associations of serum phosphate concentrations with vascular and valvular calcification in 439 participants from the Multi-Ethnic Study of Atherosclerosis who had moderate CKD and no clinical cardiovascular disease. Serum phosphate concentrations were within the normal range (2.5 to 4.5 mg/dl) in 95% of study participants. The prevalence of calcification in the coronary arteries, descending thoracic aorta, aortic valve, and mitral valve was 67, 49, 25, and 20%, respectively, measured by electron-beam or multi-detector row computed tomography. After adjustment for demographics and estimated GFR, each 1-mg/dl increment in serum phosphate concentration was associated with a 21% (P = 0.002), 33% (P = 0.001), 25% (P = 0.16), and 62% (P = 0.007) greater prevalence of coronary artery, thoracic, aortic valve, and mitral valve calcification, respectively. Adjustment for traditional risk factors for atherosclerosis, parathyroid hormone, or 1,25-dihydroxyvitamin D levels did not alter these associations. In conclusion, higher serum phosphate concentrations, although still within the normal range, are associated with a greater prevalence of vascular and valvular calcification in people with moderate CKD. It remains to be determined whether lowering phosphate concentrations will impact calcification risk in the setting of kidney disease.
Metastatic extramedullary plasmacytoma: A case report and review of the literature of a rare pseudocarcinoma
Authors: Hideki Akiyama, Robert L. Krigel
Journal: American Journal of Hematology (1988)

Abstract Extramedullary plasmacytomas are unusual plasma cell tumors arising outside the bone marrow. Most extramedullary plasmacytomas are solitary, but occasionally they disseminate, usually in conjunction with systemic myelomatosis. The authors report a case of disseminated extramedullary plasmacytoma with a picture suggestive of metastatic pancreatic carcinoma. This unusual presentation reconfirms the need for tissue diagnosis in all suspected cases of pancreatic carcinoma and demonstrates that extramedullary plasmacytoma can be an aggressive cancer without any sign of osseous or systemic disease.
Neuregulin-1 Enhances Depolarization-Induced GABA Release
Authors: Ran-Sook Woo, Xiao-Ming Li, Yanmei Tao, Ezekiel Carpenter-Hyland, Yang Z. Huang, Janet Weber, Hannah Neiswender, Xian-Ping Dong, Jiong Wu, Martin Gassmann, Cary Lai, Wen-Cheng Xiong, Tian-Ming Gao, Lin Mei
Journal: Neuron (2007)