tbuckley/cabot-search huggingface dataset:
Therapeutic Synergy Between Irinotecan and 5-Fluorouracil against Human Tumor Xenografts
Authors: Rami G. Azrak, Shousong Cao, Harry K. Slocum, Károly Tóth, Farukh A. Durrani, Ming-biao Yin, Lakshmi Pendyala, Wanghai Zhang, Howard L. McLeod, Youcef M. Rustum
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Although the combination of irinotecan and 5-Fluorouracil is clinically active, it is associated with significant toxicity and resistance. Studies were carried out to define the optimal dosage, sequence, and timing for the combination in mice bearing xenografted human tumors. Experimental Design: The maximum tolerated dose of irinotecan and 5-Fluorouracil in combination was determined in nude mice. Therapeutic efficacy against established human colon carcinoma xenografts, HCT-8 and HT-29, and human head and neck squamous cell carcinoma xenografts, FaDu and A253, was determined using the rugs individually, simultaneously, and in sequence with various intervals in between. Treatments were i.v. weekly × 4. Immunohistochemical and reverse transcription-PCR measurements of relevant drug-metabolizing enzymes, apoptosis-related proteins, cell cycle distribution, cyclin A, and S phase fraction expression were carried out and compared with the therapeutic outcome. Results: The maximum tolerated dose of irinotecan resulted in cure rates of 30% or less in all xenografts. No cures were achieved with FUra alone. Concurrent administration of irinotecan and FUra, or of FUra 24 h before irinotecan, resulted in cure rates of &amp;lt;20%, except for FaDu (60%). Administration of irinotecan 24 h before FUra resulted in the highest cure rates, 80% in HCT-8, 0% in HT-29, 100% in FaDu, and 10% in A253. Conclusions: The optimal therapeutic synergy was achieved when irinotecan was administered 24 h before 5-Flurouracil. Sensitivity to this combination was associated with poor differentiation status, higher cyclin A index, recruitment of cells into S phase, and induction of Bax expression and apoptosis.
Molecular Pathways: VCAM-1 as a Potential Therapeutic Target in Metastasis
Authors: Qing Chen, Joan Massagué
Journal: Clinical Cancer Research (2012)

Abstract Interactions between disseminated tumor cells (DTC) and stromal cells in the microenvironment are critical for tumor colonization of distal organs. Recent studies have shown that vascular cell adhesion molecule-1 (VCAM-1) is aberrantly expressed in breast cancer cells and mediates prometastatic tumor-stromal interactions. Moreover, the usefulness of VCAM-1 to DTCs in 2 different organs—lung and bone—is based on distinct mechanisms. In the lungs, VCAM-1 on the surface of cancer cells binds to its counterreceptor, the α4β1 integrin (also known as very-late antigen, VLA-4), on metastasis-associated macrophages, triggering VCAM-1–mediated activation of the phosphoinositide 3-kinase growth and survival pathway in the cancer cells. In the bone marrow, cancer cell VCAM-1 attracts and tethers α4 integrin–expressing osteoclast progenitors to facilitate their maturation into multinucleated osteoclasts that mediate osteolytic metastasis. These findings highlight the importance of direct interactions between DTCs and stromal cells during tumor dissemination and draw attention to the possibility of targeting the α4 integrin–VCAM-1 interactions in metastatic breast cancer. Anti-α4 integrin inhibitors have been developed to treat various diseases driven by massive leukocyte infiltrates and have gained U.S. Food and Drug Administration approval or are undergoing clinical trials. Testing these drugs against tumor-stromal leukocyte interactions may provide a new strategy to suppress lung and bone relapse of breast cancer. Clin Cancer Res; 18(20); 5520–5. ©2012 AACR.
Effect of nisoldipine on atherosclerosis in the cholesterol fed rabbit: endothelium dependent relaxation and aortic cholesterol content
Authors: C T. Kappagoda, A. B R Thomson, M. P J Senaratne
Journal: Cardiovascular Research (1991)

The aim was to determine the effect of the calcium channel blocker nisoldipine on the loss of endothelium dependent relaxation and the accumulation of cholesterol in the aorta produced by feeding a diet enriched with cholesterol.12 week old New Zealand white rabbits were assigned randomly to four groups with the following dietary and drug regimens: group A--standard diet + 2.5% cholesterol (n = 45); group B--standard diet + nisoldipine (n = 9); group C--standard diet + nisoldipine + 2.5% cholesterol (n = 9); group D--standard diet (n = 9). After 3 weeks the cholesterol supplements were stopped and all animals were given the standard rabbit diet. The animals in groups B and C were given nisoldipine (1 mg.kg-1.d-1) by mouth for the entire 7 week period.Aortic tissue was removed for measurement of cholesterol content, endothelium dependent relaxation to acetylcholine, contractile responses to noradrenaline, relaxant responses to sodium nitrite, and sudan staining. Serum was obtained for measurement of cholesterol and triglyceride concentration.At 7 weeks, endothelium dependent relaxation to acetylcholine was impaired in group A compared to group D, while that in group C was not. Aortic tissue cholesterol content in group A was significantly greater than in groups B, C, and D. At 15 weeks, ie, 12 weeks after reversal of the diet, endothelium dependent relaxation had recovered in the animals in group A. There was a significant reduction in the aortic cholesterol content at this stage. In two subgroups of A (groups A2 and A4) which were given nisoldipine immediately after and 4 weeks after cessation of cholesterol feeding respectively, the drug was found to have no influence upon restoration of endothelium dependent relaxation. However, the drug appeared to promote the retention of cholesterol within the aorta after cessation of cholesterol feeding.Nisoldipine protects against the accumulation of cholesterol and loss of endothelium dependent relaxation in the aorta of rabbits fed a diet supplemented with 2.5% cholesterol for three weeks. Administration of the drug after the lesions are established in the aorta also appears to retard the removal of cholesterol from the aorta.
Surfactant and Physiologic Responses of Preterm Lambs to Continuous Positive Airway Pressure
Authors: Neil Mulrooney, Zahra Champion, Timothy J. M. Moss, Ilias Nitsos, Machiko Ikegami, Alan H. Jobe
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

Although continuous positive airway pressure (CPAP) is used frequently for preterm infants, the relationships between the amount of surfactant and lung physiologic and injury responses to CPAP are unknown. Therefore, saturated phosphatidylcholine (Sat PC) was measured to quantify the surfactant necessary for preterm lambs to breathe successfully on a CPAP of 5 cm H(2)O (CPAP 5). Five of 21 lambs delivered at 130-136 days gestation failed to keep PCO(2) below 100 mm Hg by 2 hours. The lambs that failed had less than 1.9 micromol/kg Sat PC in bronchoalveolar fluid (approximately 3% the pool size at term), less surfactant secretion, and less large aggregate surfactant. Physiologic responses of other 132-day preterm lambs after 2 or 6 hours of CPAP 5, 8 cm H(2)O CPAP (CPAP 8), or mechanical ventilation were then characterized. At 6 hours, oxygenation and lung gas volumes were higher with CPAP 8 relative to the other groups and VE was decreased with CPAP 8 relative to CPAP 5. Lung dry/wet ratios were greater for the CPAP groups than for the mechanical ventilation group. A small amount of endogenous Sat PC is required for preterm lambs to breathe successfully with CPAP. CPAP 8 improves early newborn respiratory transition relative to CPAP 5.
Suppressors of Cytokine Signaling Abrogate Diabetic Nephropathy
Authors: Guadalupe Ortiz-Muñoz, Virginia Lopez-Parra, Oscar Lopez-Franco, Paula Fernandez-Vizarra, Beñat Mallavia, Claudio Flores, Ana Sanz, Julia Blanco, Sergio Mezzano, Alberto Ortiz, Jesus Egido, Carmen Gomez-Guerrero
Journal: Journal of the American Society of Nephrology (2010)

Activation of Janus kinase/signal transducers and activators of transcription (JAK/STAT) is an important mechanism by which hyperglycemia contributes to renal damage, suggesting that modulation of this pathway may prevent renal and vascular complications of diabetes. Here, we investigated the involvement of suppressors of cytokine signaling (SOCS) as intracellular negative regulators of JAK/STAT activation in diabetic nephropathy. In a rat model, inducing diabetes resulted in JAK/STAT activation and increased expression of SOCS1 and SOCS3. In humans, we observed increased expression of glomerular and tubulointerstitial SOCS proteins in biopsies of patients with diabetic nephropathy. In vitro, high concentrations of glucose activated JAK/STAT/SOCS in human mesangial and tubular cells. Overexpression of SOCS reversed the glucose-induced activation of the JAK/STAT pathway, expression of STAT-dependent genes (chemokines, growth factors, and extracellular matrix proteins), and cell proliferation. In vivo, intrarenal delivery of adenovirus expressing SOCS1 and SOCS3 to diabetic rats significantly improved renal function and reduced renal lesions associated with diabetes, such as mesangial expansion, fibrosis, and influx of macrophages. SOCS gene delivery also decreased the activation of STAT1 and STAT3 and the expression of proinflammatory and profibrotic proteins in the diabetic kidney. In summary, these results provide direct evidence for a link between the JAK/STAT/SOCS axis and hyperglycemia-induced cell responses in the kidney. Suppression of the JAK/STAT pathway by increasing intracellular SOCS proteins may have therapeutic potential in diabetic nephropathy.
Blood Pressure, Cardiac, and Renal Responses to Salt and Deoxycorticosterone Acetate in Mice
Authors: Qing Wang, Edith Hummler, Jürg Nussberger, Sophie Clément, Giulio Gabbiani, Hans R. Brunner, Michel Burnier
Journal: Journal of the American Society of Nephrology (2002)

Several studies have demonstrated that mice are polymorphic for the number of renin genes, with some inbred strains harboring one gene (Ren-1(c)) and other strains containing two genes (Ren-1(d) and Ren-2). In this study, the effects of 1% salt and deoxycorticosterone acetate (DOCA)/salt were investigated in one- and two-renin gene mice, for elucidation of the role of renin in the modulation of BP, cardiac, and renal responses to salt and DOCA. The results demonstrated that, under baseline conditions, mice with two renin genes exhibited 10-fold higher plasma renin activity, 100-fold higher plasma renin concentrations, elevated BP (which was angiotensin II-dependent), and an increased cardiac weight index, compared with one-renin gene mice (all P < 0.01). The presence of two renin genes markedly increased the BP, cardiac, and renal responses to salt. The number of renin genes also modulated the responses to DOCA/salt. In one-renin gene mice, DOCA/salt induced significant renal and cardiac hypertrophy (P < 0.01) even in the absence of any increase in BP. Treatment with losartan, an angiotensin II AT(1) receptor antagonist, decreased BP in two-renin gene mice but not in one-renin gene mice. However, losartan prevented the development of cardiac hypertrophy in both groups of mice. In conclusion, these data demonstrate that renin genes are important determinants of BP and of the responses to salt and DOCA in mice. The results confirm that the Ren-2 gene, which controls renin production mainly in the submaxillary gland, is physiologically active in mice and is not subject to the usual negative feedback control. Finally, these data provide further evidence that mineralocorticoids promote cardiac hypertrophy even in the absence of BP changes. This hypertrophic process is mediated in part by the activation of angiotensin II AT(1) receptors.
Intussusception in a 51-year-old male
Authors: R Persiani, A Biondi, L Luigi, A Grieco, S Rausei, D D'Ugo
Journal: Gut (2008)

Functional connectivity of neural oscillations (oscillation-based FC) is thought to afford dynamic information exchange across task-relevant neural ensembles. Although oscillation-based FC is classically defined relative to a prestimulus baseline, giving rise to rapid, context-dependent changes in individual connections, studies of distributed spatial patterns show that oscillation-based FC is omnipresent, occurring even in the absence of explicit cognitive demands. Thus, the issue of whether oscillation-based FC is primarily shaped by cognitive state or is intrinsic in nature remains open. Accordingly, we sought to reconcile these observations by interrogating the ECoG recordings of 18 presurgical human patients (8 females) for state dependence of oscillation-based FC in five canonical frequency bands across an array of six task states. FC analysis of phase and amplitude coupling revealed a highly similar, largely state-invariant (i.e., intrinsic) spatial component across cognitive states. This spatial organization was shared across all frequency bands. Crucially, however, each band also exhibited temporally independent FC dynamics capable of supporting frequency-specific information exchange. In conclusion, the spatial organization of oscillation-based FC is largely stable over cognitive states (i.e., primarily intrinsic in nature) and shared across frequency bands. Together, our findings converge with previous observations of spatially invariant patterns of FC derived from extremely slow and aperiodic fluctuations in fMRI signals. Our observations indicate that “background” FC should be accounted for in conceptual frameworks of oscillation-based FC targeting task-related changes. <b>Significance Statement</b> A fundamental property of neural activity is that it is periodic, enabling functional connectivity (FC) between distant regions through coupling of their oscillations. According to task-based studies, such oscillation-based FC is rapid and malleable to meet cognitive task demands. Studying distributed FC patterns instead of FC in a few individual connections, we found that oscillation-based FC is largely stable across various cognitive states and shares a common layout across oscillation frequencies. This stable spatial organization of FC in fast oscillatory brain signals parallels the known stability of fMRI-based intrinsic FC architecture. Despite the observed spatial state and frequency invariance, FC of individual connections was temporally independent between frequency bands, suggesting a putative mechanism for malleable frequency-specific FC to support cognitive tasks.
Cannulation of the papilla of Vater by endoscopy and retrograde cholangiopancreatography (ERCP).
Authors: P B Cotton
Journal: Gut (1972)

Progress reportCannulation ofthe papilla of Vater by endoscopy and retrograde cholangiopancreatography (ERCP) New fibreoptic duodenoscopes allow an experienced endoscopist to visualize and cannulate the papilla of Vater in conscious patients with at least an 80% chance of achieving retrograde cholangiopancreatography-a technique with obvious diagnostic potential.The historical aspects have already been ade- quately covered.'-4This review concerns the rapidly increasing world experience, with particular regard to technical problems, clinical relevance, and safety. InstrumentsCurrent forward-viewing panendoscopes, while excellent for routine oesophago-gastro-bulboscopy5, do not allow reliable views of the descending duodenum or papilla.To provide the face-on papillary views required for cannulation, the Olympus JFB2,6 and Machida FDS7 duodenoscopes view laterally rather than forwards, are even more flexible, and the distal tip cani be manoeuvred in four directions under control.Biopsy forceps or teflon cannulae (1 .6 mm diameter) may be passed through the instrument channel and out into the field of view over a small controllable bridge (Fig. 1).The cannula must be withdrawn to allow suction, which is frequently needed to remove bile and spilt contrast material.Machida instruments have been difficult to obtain and maintain outside Japan.The latest FDS duodenoscope closely resembles the Olympus instrument, but still lacks push-button control of air and suction.American Cystoscope Makers are developing a thicker lateral viewing gastroduodenoscope (model 5008) with a larger channel; this allows suction with the cannula in place.Preliminary experience with a * : . . .
587 DIAGNOSTIC YIELD AND STANDARDIZATION OF FINE NEEDLE BIOPSY IN THE CHARACTERIZATION OF LIVER NODULES IN CIRRHOTIC PATIENTS
Authors: A. Sangiovanni, M. Iavarone, S. Vavassori, C. Della Corte, M.A. Manini, M. Fraquelli, G. Ronchi, M. Colombo
Journal: Journal of Hepatology (2010)
Intravascular ultrasound of coronary arteries in children. Assessment of the wall morphology and the lumen after Kawasaki disease.
Authors: T Sugimura, H Kato, O Inoue, T Fukuda, N Sato, M Ishii, J Takagi, T Akagi, Y Maeno, T Kawano
Journal: Circulation (1994)

BACKGROUND The long-term clinical issue in Kawasaki disease (KD) concerns the coronary artery lesion. Two-dimensional echocardiography and coronary angiography are routine examinations to evaluate the coronary lesions; however, these are not adequate to assess the wall morphology of the coronary artery (CA). Intravascular ultrasound imaging (IVUS), a new technology for the evaluation of the coronary artery lumen and wall morphology in vivo, was performed for patients after KD in their long-term follow-up, and we examined the new insights it gave. METHODS AND RESULTS IVUS was performed during cardiac catheterization in 20 subjects (10 patients after KD who still had coronary aneurysms or regressed coronary aneurysms, 2 after KD who had no coronary abnormal lesion, and 8 control patients with congenital heart disease and normal CA). We evaluated the wall structure at 10 to 15 sites of the CA in each patient. IVUS was performed with a commercially available ultrasound imaging catheter. Four sites of a CA aneurysm in KD demonstrated a markedly dilated lumen without thickened intima. One site of a CA aneurysm with calcification demonstrated an asymmetrical lumen by a dense echo with acoustic shadows. Twenty-two sites of a regressed CA aneurysm demonstrated a marked symmetrical or asymmetrical thickening of the intima with a dense echo, in which the size of the lumen was similar to that at a site near a regressed aneurysm. The sites of angiographically normal CA revealed normal structures and a thin intima in many instances. Nine of 28 sites in KD with a CA abnormal lesion, particularly near a coronary aneurysm or regressed aneurysm, demonstrated a mild thickening of the intima. All the 10 sites in KD without a CA abnormal lesion and all the 25 sites in patients with congenital heart disease with normal CA demonstrated a smooth intima. CONCLUSIONS This study demonstrated that the site of a regressed coronary aneurysm has a markedly thickened but smooth intima. The sites of angiographically normal CA after KD with or without a coronary lesion demonstrated normal IVUS findings in most instances but in some cases revealed a mild intimal thickening. IVUS is useful to evaluate the CA wall morphology and may contribute to the assessment of long-term CA sequelae and the possible development of arteriosclerotic changes in KD.
Improving bioinformatic pipelines for exome variant calling
Authors: Hanlee P Ji
Journal: Genome Medicine (2012)

Exome sequencing analysis is a cost-effective approach for identifying variants in coding regions. However, recognizing the relevant single nucleotide variants, small insertions and deletions remains a challenge for many researchers and diagnostic laboratories typically do not have access to the bioinformatic analysis pipelines necessary for clinical application. The Atlas2 suite, recently released by Baylor Genome Center, is designed to be widely accessible, runs on desktop computers but is scalable to computational clusters, and performs comparably with other popular variant callers. Atlas2 may be an accessible alternative for data processing when a rapid solution for variant calling is required.See research article http://www.biomedcentral.com/1471-2105/13/8.
Deficiency or inhibition of Gas6 causes platelet dysfunction and protects mice against thrombosis
Authors: Anne Angelillo-Scherrer, Pablo Garcia de Frutos, Cristina Aparicio, Els Melis, Pierre Savi, Florea Lupu, Jef Arnout, Mieke Dewerchin, Marc F. Hoylaerts, Jean-Marc Herbert, Désiré Collen, Björn Dahlbäck, Peter Carmeliet
Journal: Nature Medicine (2001)
The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats.
Authors: J D Taurog, J A Richardson, J T Croft, W A Simmons, M Zhou, J L Fernández-Sueiro, E Balish, R E Hammer
Journal: The Journal of Experimental Medicine (1994)

A number of inflammatory disease states occur with greatly increased frequency in individuals inheriting the human major histocompatibility complex class I allele HLA-B27. In a minority of cases, namely those with B27-associated reactive arthritis, there is good evidence that the disease state is triggered by infection with an enteric or genitourinary bacterial pathogen. For the majority of B27-associated disease, no definite pathogenetic role for bacteria has been established. However, in these latter cases intestinal inflammation can often be demonstrated, and it sometimes occupies a major part of the clinical picture. Rats transgenic for B27 are known to develop a disorder resembling B27-associated human disease, with prominent intestinal, joint, skin, and male genital inflammatory lesions. We report here that B27 transgenic rats raised in a germfree environment do not develop inflammatory intestinal or peripheral joint disease, whereas the skin and genital inflammatory lesions are unaffected by the germfree state. These findings support the concept that gut and joint inflammation are pathogenetically closely related, and they provide direct evidence that the commensal gut flora play an important role in the pathogenesis of B27-associated gut and joint inflammation.
Still in the Game — Harnessing Employer Inventiveness in U.S. Health Care Reform
Authors: Robert S. Galvin
Journal: New England Journal of Medicine (2008)

The pressures employers face have worsened as health care costs have grown faster than wages. Dr. Robert Galvin writes that although the business community has been a reluctant actor in this arena, it remains skeptical that its interests will be served by solutions arising from the provider community or from increased government control.