tbuckley/cabot-search huggingface dataset:
Transcriptomic Profiling of Sequential Tumors from Breast Cancer Patients Provides a Global View of Metastatic Expression Changes Following Endocrine Therapy
Authors: Jean McBryan, Ailís Fagan, Damian McCartan, Fiona T. Bane, Damir Varešlija, Sinéad Cocchiglia, Christopher Byrne, Jarlath Bolger, Marie McIlroy, Lance Hudson, Paul Tibbitts, Peadar Ó Gaora, Arnold D. Hill, Leonie S. Young
Journal: Clinical Cancer Research (2015)

Disease recurrence is a common problem in breast cancer and yet the mechanisms enabling tumor cells to evade therapy and colonize distant organs remain unclear. We sought to characterize global expression changes occurring with metastatic disease progression in the endocrine-resistant setting.Here, for the first time, RNAsequencing has been performed on matched primary, nodal, and liver metastatic tumors from tamoxifen-treated patients following disease progression. Expression of genes commonly elevated in the metastases of sequenced patients was subsequently examined in an extended matched patient cohort with metastatic disease from multiple sites. The impact of tamoxifen treatment on endocrine-resistant tumors in vivo was investigated in a xenograft model.The extent of patient heterogeneity at the gene level was striking. Less than 3% of the genes differentially expressed between sequential tumors were common to all patients. Larger divergence was observed between primary and liver tumors than between primary and nodal tumors, reflecting both the latency to disease progression and the genetic impact of intervening therapy. Furthermore, an endocrine-resistant in vivo mouse model demonstrated that tamoxifen treatment has the potential to drive disease progression and establish distant metastatic disease. Common functional pathways altered during metastatic, endocrine-resistant progression included extracellular matrix receptor interactions and focal adhesions.This novel global analysis highlights the influence of primary tumor biology in determining the transcriptomic profile of metastatic tumors, as well as the need for adaptations in cell-cell communications to facilitate successful tumor cell colonization of distant host organs.
Interferon therapy for atopic dermatitis reduces basophil histamine release, but does not reduce serum IgE or eosinophilic proteins
Authors: B. Windelborg Nielsen, C. M. Reimert, R. Hammer, P.O. Schiøtz, K. Thestrup‐Pedersen
Journal: Allergy (1994)

Nine adult patients suffering from severe atopic dermatitis (AD) and increased total serum IgE were treated with recombinant human interferon‐alpha 2A (Roferon‐A R ; IFN‐α‐2A) 3 × 10 6 units daily for 21 d to study the effect upon serum IgE, basophil histamine release (HR), eosinophil‐derived proteins in serum, and clinical symptoms. The skin disease was so severe that all patients needed topical treatment with glucocorticosteroid cream. Changes were not observed in total serum IgE or in eosinophil‐derived proteins, the latter being increased in six of nine patients. A significant reduction in basophil HR was found in six of nine patients after anti‐IgE and concanavalin A (Con A) stimulation, but not after A23187 stimulation. The clinical skin score was reduced in eight of nine patients at the end of therapy, but disease activity returned to pretreatment levels within 3 weeks despite continued topical treatment. rIFN‐α‐2A was well tolerated with few clinical side‐effects, and all patients completed the study. The short‐term therapy using IFN‐α‐2A neither brought a sustained clinical remission nor reduced total serum IgE or eosinophil‐derived proteins. However, a significant reduction in IgE‐receptor‐mediated basophil HR was observed in six of nine patients.
Pulse Wave Velocity as an Indicator of Atherosclerosis in Impaired Fasting Glucose
Authors: Hirofumi Ohnishi, Shigeyuki Saitoh, Satoru Takagi, Jun-ichi Ohata, Takeshi Isobe, Yuka Kikuchi, Hiroshi Takeuchi, Kazuaki Shimamoto
Journal: Diabetes Care (2003)

Brachial-ankle pulse wave velocity (baPWV), as an indicator of atherosclerosis in impaired fasting glucose (IFG), was studied in 232 subjects randomly selected from inhabitants of two rural communities in Japan.BMI, systolic blood pressure (SBP), fasting blood glucose (FBS), lipid parameters, ankle brachial pressure index (ABI), and baPWV were measured in each subject. ABI and baPWV were measured using the recently developed device, form ABI/PWV. The subjects were divided into three groups according FBS level: a normal group consisting of subjects with FBS <110 mg/dl, an IFG group consisting of subjects with FBS 110-125 mg/dl, and a diabetic group consisting of subjects with FBS > or =126 mg/dl and subjects taking hypoglycemic agents. The parameters in the three groups were compared. RESULTS-It was found that the baPWV value increased with increasing plasma glucose level. Significant differences were found between the baPWV values in the normal and IFG groups (1,518 vs. 1,673 cm/s, P = 0.01) and in the normal and diabetic groups (1,518 vs. 1,771 cm/s, P < 0.0001). The results of multiple regression analysis showed that FBS was closely related to baPWV as well as to age and SBP.The relationship between IFG and atherosclerosis remains controversial. Further studies are needed to evaluate whether strict control of blood glucose level in patients with IFG will result in the prevention of atherosclerosis progression.
Evidence for a Direct Action of Cholecalciferol and 25-Hydroxycholecalciferol on the Renal Transport of Phosphate, Sodium, and Calcium
Authors: Jules B. Puschett, Joel Moranz, Warren S. Kurnick
Journal: Journal of Clinical Investigation (1972)

Acute clearance studies were performed in stable thyroparathyroidectomized dogs to evaluate the possibility of a direct renal action of vitamin D and its biologically active 25-hydroxylated metabolite. Alterations in renal hemodynamics and serum calcium concentration were minimized and attempts at vitamin D depletion were not undertaken. Steady-state volume expansion of modest degree was employed as the control experimental situation so that an effect of the vitamin to enhance phosphate reabsorption would not go undetected because of an already maximal phosphate reabsorptive rate secondary to parathyroidectomy. Under these experimental circumstances, 10,000 U of cholecalciferol and 25-120 U of 25-hydroxycholecalciferol (25-HCC) produced significant depressions in the percentage of filtered phosphate excreted (mean declines of 39 and 47%, respectively), which were not attributable to alterations in renal hemodynamics or to changes in the levels of serum calcium or phosphate. There was an accompanying decline in sodium and calcium excretion; mean percentage excretion rates for sodium fell by 38% with vitamin D and 26% with 25HCC, and for calcium this measurement declined by 46 and 23%, respectively. Furthermore, parathyroid hormone and 25HCC produced antagonistic effects on phosphate excretion. These observations provide the first conclusive evidence for a direct (proximal) tubular action of vitamin D to promote phosphate (as well as sodium and calcium) transport.
Role of AMP-activated protein kinase in mechanism of metformin action
Authors: Gaochao Zhou, Robert Myers, Ying Li, Yuli Chen, Xiaolan Shen, Judy Fenyk-Melody, Margaret Wu, John Ventre, Thomas Doebber, Nobuharu Fujii, Nicolas Musi, Michael F. Hirshman, Laurie J. Goodyear, David E. Moller
Journal: Journal of Clinical Investigation (2001)

Metformin is a widely used drug for treatment of type 2 diabetes with no defined cellular mechanism of action. Its glucose-lowering effect results from decreased hepatic glucose production and increased glucose utilization. Metformin’s beneficial effects on circulating lipids have been linked to reduced fatty liver. AMP-activated protein kinase (AMPK) is a major cellular regulator of lipid and glucose metabolism. Here we report that metformin activates AMPK in hepatocytes; as a result, acetyl-CoA carboxylase (ACC) activity is reduced, fatty acid oxidation is induced, and expression of lipogenic enzymes is suppressed. Activation of AMPK by metformin or an adenosine analogue suppresses expression of SREBP-1, a key lipogenic transcription factor. In metformin-treated rats, hepatic expression of SREBP-1 (and other lipogenic) mRNAs and protein is reduced; activity of the AMPK target, ACC, is also reduced. Using a novel AMPK inhibitor, we find that AMPK activation is required for metformin’s inhibitory effect on glucose production by hepatocytes. In isolated rat skeletal muscles, metformin stimulates glucose uptake coincident with AMPK activation. Activation of AMPK provides a unified explanation for the pleiotropic beneficial effects of this drug; these results also suggest that alternative means of modulating AMPK should be useful for the treatment of metabolic disorders.
Selective Accumulation of Mature DC-Lamp+ Dendritic Cells in Tumor Sites Is Associated with Efficient T-Cell-Mediated Antitumor Response and Control of Metastatic Dissemination in Melanoma
Authors: Mojgan Movassagh, Alain Spatz, Jean Davoust, Serge Lebecque, Pedro Romero, Mikaël Pittet, Donata Rimoldi, Danièle Liénard, Oliver Gugerli, Laurent Ferradini, Caroline Robert, Marie-Françoise Avril, Laurence Zitvogel, Eric Angevin
Journal: Cancer Research (2004)

The clinical relevance of dendritic cells (DCs) at the tumor site remains a matter of debate concerning their role in the generation of effective antitumor immunity in human cancers. We performed a comprehensive immunohistochemical analysis using a panel of DC-specific antibodies on regressing tumor lesions and sentinel lymph nodes (SLNs) in melanoma patients. Here we show in a case report involving spontaneous regression of metastatic melanoma that the accumulation of DC-Lamp+ DCs, clustered with tumor cells and lymphocytes, is associated with local expansion of antigen-specific memory effector CTLs. These findings were extended in a series of 19 melanoma-positive SLNs and demonstrated a significant correlation between the density of DC-Lamp+ DC infiltrates in SLNs with the absence of metastasis in downstream lymph nodes. This study, albeit performed in a limited series of patients, points to a pivotal role of mature DCs in the local expansion of efficient antitumor T-cell-mediated immune responses at the initial sites of metastasis and may have important implications regarding the prognosis, staging, and immunotherapy of melanoma patients.
Gamma secretase–mediated Notch signaling worsens brain damage and functional outcome in ischemic stroke
Authors: Thiruma V Arumugam, Sic L Chan, Dong-Gyu Jo, Gokhan Yilmaz, Sung-Chun Tang, Aiwu Cheng, Marc Gleichmann, Eitan Okun, Vishwa D Dixit, Srinivasulu Chigurupati, Mohamed R Mughal, Xin Ouyang, Lucio Miele, Tim Magnus, Suresh Poosala, D Neil Granger, Mark P Mattson
Journal: Nature Medicine (2006)
Is the International Prognostic Index for aggressive lymphomas useful for low-grade lymphoma patients? Applicability to stage 111-IV patients
Authors: C. Foussard, B. Desablens, L. Sensebe, S. François, N. Milpied, E. Deconinck, V. Delwail, J. Dugay, T. Lamy, C. Ghandour, A. Le Mevel, H. Maisonneuve, P. Casassus, P. Colombat
Journal: Annals of Oncology (1997)
System-Level Analysis of Neuroblastoma Tumor–Initiating Cells Implicates AURKB as a Novel Drug Target for Neuroblastoma
Authors: Olena Morozova, Milijana Vojvodic, Natalie Grinshtein, Loen M. Hansford, Kim M. Blakely, Alexandra Maslova, Martin Hirst, Timothee Cezard, Ryan D. Morin, Richard Moore, Kristen M. Smith, Freda Miller, Paul Taylor, Nina Thiessen, Richard Varhol, Yongjun Zhao, Steven Jones, Jason Moffat, Thomas Kislinger, Michael F. Moran, David R. Kaplan, Marco A. Marra
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Neuroblastoma (NB) is an aggressive tumor of the developing peripheral nervous system that remains difficult to cure in the advanced stages. The poor prognosis for high-risk NB patients is associated with common disease recurrences that fail to respond to available therapies. NB tumor-initiating cells (TICs), isolated from metastases and primary tumors, may escape treatment and contribute to tumor relapse. New therapies that target the TICs may therefore prevent or treat tumor recurrences. Experimental Design: We undertook a system-level characterization of NB TICs to identify potential drug targets against recurrent NB. We used next-generation RNA sequencing and/or human exon arrays to profile the transcriptomes of 11 NB TIC lines from six NB patients, revealing genes that are highly expressed in the TICs compared with normal neural crest-like cells and unrelated cancer tissues. We used gel-free two-dimensional liquid chromatography coupled to shotgun tandem mass spectrometry to confirm the presence of proteins corresponding to the most abundant TIC-enriched transcripts, thereby providing validation to the gene expression result. Results: Our study revealed that genes in the BRCA1 signaling pathway are frequently misexpressed in NB TICs and implicated Aurora B kinase as a potential drug target for NB therapy. Treatment with a selective AURKB inhibitor was cytotoxic to NB TICs but not to the normal neural crest-like cells. Conclusion: This work provides the first high-resolution system-level analysis of the transcriptomes of 11 primary human NB TICs and identifies a set of candidate NB TIC-enriched transcripts for further development as therapeutic targets. Clin Cancer Res; 16(18); 4572–82. ©2010 AACR.
Are patients with rheumatoid arthritis still at an increased risk of tuberculosis and what is the role of biological treatments?
Authors: Elizabeth V Arkema, Jerker Jonsson, Eva Baecklund, Judith Bruchfeld, Nils Feltelius, Johan Askling
Journal: Annals of the Rheumatic Diseases (2014)

Objective To estimate the risk of tuberculosis (TB) in patients with rheumatoid arthritis (RA) both with and without exposure to biological therapy and to directly compare the risks between therapies. Methods Data from the Swedish National Population Registers, Tuberculosis Register and the Swedish Biologics Register were used to conduct a prospective population-based national cohort study (2002–2011). We estimated the rate of incident TB in the general population and in a cohort of biological-naïve and biological-exposed patients diagnosed with RA. Cox models were used to estimate HRs with particular attention to risks by calendar and follow-up time and individual biologics. Results Compared to the general population, RA patients not exposed to biologicals had a fourfold increased risk of TB (HR 4.2; 95% CI 2.7 to 6.7), which did not decline over calendar time. In contrast, the risk of TB in the biological-exposed RA population decreased since 2002 compared with biological-naïve; from HR=7.9 (95% CI 3.3 to 18.9) in 2002–2006 to HR=2.4 (95% CI 0.9 to 6.1) in 2007–2011. The HRs for most recent exposure to adalimumab and infliximab compared with etanercept were 3.1 (95% CI 0.8 to 12.5) and 2.7 (95% CI 0.7 to 10.9), respectively, and the HR for etanercept compared with biological-naïve RA was 1.7 (95% CI 0.6 to 4.6). Conclusions In the past decade, the risk of TB has decreased among biological-exposed RA patients but remains higher than in biological-naïve RA patients. Most cases of TB in RA occur in biological-naïve RA patients, underscoring the elevated risk also in these patients.
Nitric oxide synthesis in patients with infective gastroenteritis
Authors: P Forte, R S Dykhuizen, E Milne, A McKenzie, C C Smith, N Benjamin
Journal: Gut (1999)

BACKGROUND There is evidence that endogenous nitrate synthesis is notably increased in patients with infective gastroenteritis. AIMS To determine whether this is due to nitric oxide (NO) production via the l -arginine/NO pathway. METHODS Seven male patients with community acquired bacterial gastroenteritis and 15 healthy male volunteers participated in this study. All patients had stool culture positive infective gastroenteritis. A bolus of 200 mg l -[ 15 N] 2 -arginine was administered intravenously after an overnight fast. Urine was collected for the next 36 hours. Urinary [ 15 N: 14 N]nitrate ratio was assessed by dry combustion in an isotope ratio mass spectrometer. RESULTS Mean 36 hour total urinary nitrate excretion in the gastroenteritis group was 5157 (577) μmol compared with 2594 (234) μmol in the control group (p&lt;0.001). Thirty six hour urinary [ 15 N]nitrate excretion was considerably higher in the gastroenteritis group compared with the control group (13782 (1665) versus 1698 (98) ηmol; p&lt;0.001). These values represent 1.129 (0.139)% and 0.138 (0.007)% of [ 15 N]nitrogen administered (p&lt;0.001), respectively. Corrected 36 hour urinary [ 15 N]nitrate excretion for urinary creatinine was also significantly higher in the patient compared with the control group (1934 (221) versus 303 (35) ηmol/mmol; p&lt;0.001). CONCLUSION Results show notably enhanced nitrate synthesis due to increased activity of the l -arginine/NO pathway in patients with infective gastroenteritis.
Positive Positron Emission Tomography Scan in Sarcoidosis and Two Challenging Cases of Metastatic Cancer
Authors: Ji-Young Rhee, Joon Oh Park, Ghee Young Kwon, SeokJin Nam, Byung Chul Yoo, Young Suk Park, Young-hyuk Im, Won Ki Kang, Keunchil Park
Journal: Journal of Clinical Oncology (2005)
Respiratory bronchiolitis interstitial lung disease - What is the natural history?
Authors: Andrew Low, Jason Viner, Anthony Edey, Ann Millar
Journal: European Respiratory Journal (2012)

The natural history of RBILD remains uncertain with contradictory views based on current data. In order to investigate the effect of smoking cessation on the long term physiological and radiological outcome of RBILD we have retrospectively identified patients with this diagnosis between 2003-2011 (CT and pathological diagnosis). 12 patients with biopsies consistent with RBILD were included with follow up ranging from 8 months to 8 years. All patients were active smokers at diagnosis with a median 36 pack year history. 4 patients successfully quit smoking (Quitters) while 8 either continued to smoke or were inconsistent in their cessation attempts (Smokers). Baseline lung function at diagnosis was compared to current values of FEV1, FVC, TLCO and KCO between Quitters and Smokers:  and rate of decline:  There was a significant difference in median rate of decline of TLCO (p=0.036) and KCO (p=0.014) between Quitters and Smokers, with a trend towards a difference for FEV1 (p=0.141) and FVC (p=0.285).  This case series confirms previous findings supporting the importance of smoking cessation which can have a positive impact on lung function. Continued smoking however can result in continued decline at a rate faster than that reported in healthy normals and patients with COPD.
Impaired Turnover of Prolactin Receptor Contributes to Transformation of Human Breast Cells
Authors: Alexandr Plotnikov, Bentley Varghese, Thai H. Tran, Chengbao Liu, Hallgeir Rui, Serge Y. Fuchs
Journal: Cancer Research (2009)

Abstract Signaling by polypeptide hormone prolactin (PRL) is mediated by its cognate receptor (PRLr). PRLr is commonly stabilized in human breast cancer due to decreased phosphorylation of residue Ser349, which when phosphorylated recruits the βTrcp E3 ubiquitin ligase and facilitates PRLr degradation. Here, we show that an impaired PRLr turnover results in an augmented PRL signaling and PRL-induced transcription. Human mammary epithelial cells harboring degradation-resistant PRLr display accelerated proliferation and increased invasive growth. Conversely, a decrease in PRLr levels achieved by either pharmacologic or genetic means in human breast cancer cells dramatically reduced transformation and tumorigenic properties of these cells. Consequences of alteration of PRLr turnover for homeostasis of mammary cells and development of breast cancers, as well as the utility of therapies that target PRLr function in these malignancies, are discussed. [Cancer Res 2009;69(7):3165–72]
Biology and the Future of Psychoanalysis: A New Intellectual Framework for Psychiatry Revisited
Authors: Eric R. Kandel
Journal: American Journal of Psychiatry (1999)

The American Journal of Psychiatry has received a number of letters in response to my earlier "Framework" article (1). Some of these are reprinted elsewhere in this issue, and I have answered them briefly there. However, one issue raised by some letters deserves a more detailed answer, and that relates to whether biology is at all relevant to psychoanalysis. To my mind, this issue is so central to the future of psychoanalysis that it cannot be addressed with a brief comment. I therefore have written this article in an attempt to outline the importance of biology for the future of psychoanalysis.
A tertiary centre experience of vulval crohn's disease
Authors: J. Landy, S. T. Peake, A. Akbar, A. L. Hart
Journal: Gut (2011)

<h3>Introduction</h3> Crohn9s disease affecting the vulva is rarely described and often difficult to treat. The authors describe their experience of 20 patients with vulval Crohn9s disease, which to their knowledge is the largest series described in the literature to date. <h3>Methods</h3> The IBD database from 2006 to 2010 was searched for the terms ‘vulva’, ‘vulval’ and ‘Crohn9s’. The case notes identified by this search were reviewed. <h3>Results</h3> <i>Demographics.</i> The median age of Crohn9s disease diagnosis was 19 years (range 11–40 years). Vulval disease was the primary presentation of Crohn9s disease in 2 patients. All the patients were premenopausal. The median age of vulval involvement was 27.5 years (range 19–50 years) and the median interval from Crohn9s disease diagnosis to vulval disease was 9 years (range 0–32 years). 7 patients were smokers and 2 had a family history of inflammatory bowel disease. <i>Distribution.</i> 3 patients had metastatic disease (arising independently from other areas of Crohn9s disease) while 17 had vulval involvement contiguous with perianal disease. Of the 3 patients with metastatic disease, 2 had colonic involvement and 1 ileocolonic disease distribution. <i>Disease Severity</i>. 11 patients had previously undergone at least 1 surgery for their Crohn9s diseases. 1 patient had concomitant upper GI involvement and 3 had stricturing or penetrating disease. 4 patients had other extraintestinal manifestations (all arthropathy). <i>Diagnosis.</i> 5 patients were biopsied to confirm the diagnosis of vulval Crohn9s. Presenting symptoms included vulval swelling (n=9), discharge (n=7), pruritus (n=1), pain (n=6), erythema (n=8), vulval ulceration (n=2) and vulval abscess (n=7). <i>Treatment.</i> 10 patients received antibiotics, 2 topical steroids, 12 thiopurines, 3 methotrexate, 3 topical tacrolimus and 9 biologic therapy. Of those receiving an anti-TNF treatment, 8 received Infliximab first and 1 adalimumab. 1 patient had an infusion reaction, 3 had no response. Of the 5 primary responders, 3 lost response. 1 regained response with increased frequency of Infliximab, 2 patients were switched to adalimumab. <h3>Conclusion</h3> In this group with vulval Crohn9s disease, patients predominantly had contiguous disease from perianal or rectal concurrent disease. Metastatic disease was uncommon. The majority of patients with vulval Crohn9s had a severe course of their disease. Presentation was varied. There was a limited response with topical tacrolimus and 5 patients responded to anti-TNF therapy. Vulval Crohn9s disease is associated with severe disease and should be suspected with patients with Crohn9s disease and vulval symptoms. In keeping with previous case reports, anti-TNF therapy may be of benefit for some patients with vulval Crohn9s disease.
Angiotensin converting enzyme inhibitor therapy promotes remodeling in patients with left ventricular ejection fraction ⪢ 40% after acute transmural myocardial infarction
Authors: David B. Johnson, Robert E. Foster, Gilbert J. Perry, Gerald G. Blackwell, Francesco Barilla, Mary Ann Roney, Roger A. Orr, Alfred W.H. Stanley, Gerald M. Pohost, Louis J. Dell'Italia
Journal: Journal of the American College of Cardiology (1996)