tbuckley/cabot-search huggingface dataset:
Novel Combinations Based on Epidermal Growth Factor Receptor Inhibition
Authors: Alex A. Adjei
Journal: Clinical Cancer Research (2006)

Abstract In spite of recent advances in molecular biology leading to the introduction of clinically active novel agents, such as imatinib, erlotinib, and bevacizumab, therapy of the most common epithelial tumors, such as lung cancer, remains unsuccessful. The diversity of molecular abnormalities in these tumors is felt to partly contribute to their resistance to therapy. It is, therefore, widely accepted that one approach to improving the efficacy of cancer therapy is the development of rational, hypothesis-based combinations of anticancer agents that may exhibit synergistic cytotoxic interactions. A number of empirical combination studies with the epidermal growth factor receptor and classic cytotoxic agents were undertaken in clinical trials, with disappointing results. It is, therefore, felt that preclinical combinations of epidermal growth factor receptor inhibitors and other novel agents, based on sound knowledge of complementary signaling pathways whose concerted inhibition would be hypothesized to inhibit growth, is the reasonable approach in the future. A brief overview of some of these pathways (mammalian target of rapamycin, vascular endothelial growth factor receptor, and ras/mitogen-activated protein kinase signaling) is provided in this review.
Angiotensin-induced myocardial necrosis and renal failure in the rabbit: distribution of lesions and severity in relation to plasma angiotensin II concentration and arterial pressure
Authors: D KREMER, G LINDOP, W C B BROWN, J J MORTON, J I S ROBERTSON
Journal: Cardiovascular Research (1981)

Angiotensin II was infused into conscious rabbits at various doses from 0.001 to 0.5 microgram . kg-1 . min-1 for 24 h, and caused multifocal myocardial necrosis, renal tubular necrosis and acute renal failure. The myocardial necroses were found principally in the left ventricle; only at the highest doses of angiotensin II were right ventricular lesions present. The endocardium was not involved and no arterial or arteriolar lesions were seen. Mean arterial plasma angiotensin II concentration during angiotensin infusion was closely correlated with the increase in arterial pressure, the height of the plasma urea at the end of the infusion and the severity of the induced myocardial lesions. The myocardial necroses could be a consequence of the induced hypertension, or a direct effect of angiotensin II, or a combination of effects, although their predominance in the left ventricle suggests high systemic arterial pressure is an important factor. Cardiac lesions were observed with plasma angiotensin II concentrations only some 2 to 3 fold normal values; it is therefore possible that similar myocardial abnormalities might occur as a result of rises in endogenous renin, for example, in experimental or clinical renovascular hypertension.
Uremic Cardiomyopathy—An Endogenous Digitalis Intoxication?
Authors: DJ Kennedy, S Vetteth, SM Periyasamy, M Kanj, L Fedorova, S Khouri, MB Kahaleh, Z Xie, D Malhotra, NI Kolodkin, EG Lakatta, OV Fedorova, AY Bagrov, JI Shapiro
Journal: Journal of the American Society of Nephrology (2006)

Since the days of Richard Bright ([1][1]), it has been common knowledge that the heart is a target organ in uremia, and by the beginning of the 20th century it had been recognized that heart failure and cardiac death were frequent in renal patients ([2][2]). Despite the common occurrence of failing
The New Immunology — The End of Immunosuppressive Drug Therapy?
Authors: Robert S. Schwartz
Journal: New England Journal of Medicine (1999)

In 1970, almost a decade before molecular biology began to make its mark on immunology, Bretscher and Cohn1 advanced a novel theory to explain how the immune system responds to foreign proteins. Stripped to its core and recast in modern terms, their model holds that the initiation of an immune response requires two signals: signal 1 and signal 2. The effect of these signals is to activate lymphocytes of the helper type, which, when activated, can induce B cells to produce antibodies or prepare cytotoxic T cells for cell killing. The necessary activating signals arise when the helper T cell . . .
Mediators of Pulmonary Inflammation
Authors: G. J Laurent
Journal: Thorax (1992)

Letters to the Editor sequestration (not true "margination") in the pulmonary microvasculature.We would, however, suggest that such a rapid retention and subsequent release is much more likely to be due to changes in cell deformability, which is now generally believed to be the initiating factor in leucocyte sequestration before an increase in adherence.The importance of cell deformability as a determinant of neutrophil sequestration within human lungs has been demonstrated.'We2 and others' have shown that the effect of this tripeptide in vitro is to increase neutrophil rigidity within seconds by assembly of F-actin.Such a change is much more rapid than any up regulation of either leucocyte or endothelial adhesion ligands, which require minutes to hours.It is attractive to speculate that the inhala- tion of FMLP, either by a direct effect across the alveolar capillary cellular barrier or by indirect action via mediators released from macrophages or mesenchymal cells, impairs the deformability and hence transit ofneutro- phils through the pulmonary vascular bed.
Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2
Authors: D. B. Savage
Journal: Journal of Clinical Investigation (2006)

Hepatic steatosis is a core feature of the metabolic syndrome and type 2 diabetes and leads to hepatic insulin resistance. Malonyl-CoA, generated by acetyl-CoA carboxylases 1 and 2 (Acc1 and Acc2), is a key regulator of both mitochondrial fatty acid oxidation and fat synthesis. We used a diet-induced rat model of nonalcoholic fatty liver disease (NAFLD) and hepatic insulin resistance to explore the impact of suppressing Acc1, Acc2, or both Acc1 and Acc2 on hepatic lipid levels and insulin sensitivity. While suppression of Acc1 or Acc2 expression with antisense oligonucleotides (ASOs) increased fat oxidation in rat hepatocytes, suppression of both enzymes with a single ASO was significantly more effective in promoting fat oxidation. Suppression of Acc1 also inhibited lipogenesis whereas Acc2 reduction had no effect on lipogenesis. In rats with NAFLD, suppression of both enzymes with a single ASO was required to significantly reduce hepatic malonyl-CoA levels in vivo, lower hepatic lipids (long-chain acyl-CoAs, diacylglycerol, and triglycerides), and improve hepatic insulin sensitivity. Plasma ketones were significantly elevated compared with controls in the fed state but not in the fasting state, indicating that lowering Acc1 and -2 expression increases hepatic fat oxidation specifically in the fed state. These studies suggest that pharmacological inhibition of Acc1 and -2 may be a novel approach in the treatment of NAFLD and hepatic insulin resistance.
Heterochronic Meiotic Misexpression in an Interspecific Yeast Hybrid
Authors: Devjanee Swain Lenz, Linda Riles, Justin C. Fay
Journal: Molecular Biology and Evolution (2014)

Regulatory changes rapidly accumulate between species, and interspecific hybrids often misexpress genes. Hybrid misexpression, expression levels outside the range of both parental species, can result from cis- and trans-acting regulatory changes that interact abnormally in hybrids. Thus, misexpressed genes may contribute to hybrid sterility. However, in the context of a whole organism, misexpression may not result directly from cis-trans interactions but rather indirectly from differences between hybrid and parental abundance of cell types. Here we eliminate the confounding effects of cell types by examining gene expression in a sterile interspecific yeast hybrid during meiosis. We investigated gene expression of the yeasts Saccharomyces cerevisiae, S. paradoxus, and their hybrid at multiple meiotic stages. Although the hybrid and parents exhibit similar changes in expression levels across meiosis, the hybrid meiotic program occurs earlier than either parent. The timing change produces a heterochronic pattern of misexpression during midmeiosis. Coincident with the timing of misexpression, we find a transition from predominantly trans-acting to cis-acting expression divergence and an increase in the number of opposing cis-trans changes. However, we find no direct relationship between opposing cis-trans changes and misexpression. Contrary to the notion that cis-trans interactions cause misexpression, a heterochronic shift in the normal meiotic gene expression program produces patterns of misexpression in an yeast hybrid. Our results imply that temporal dynamics of single cell types is important to understanding hybrid misexpression and its relationship to cis-trans interactions.
Clinical significance of serum high-mobility group box 1 level in alopecia areata
Authors: Young Lee, Hae-Eul Lee, Jung-Min Shin, Kyung-Cheol Sohn, Myung Im, Chang-Deok Kim, Young-Joon Seo, Young-Ho Lee, Jeung-Hoon Lee
Journal: Journal of the American Academy of Dermatology (2013)
A clinicopathological study of human liver allograft recipients harboring preformed IgG lymphocytotoxic antibodies
Authors: Anthony J. Demetris, Kenjiro Nakamura, Atsuhito Yagihashi, Yuichi Iwaki, Shunichi Takaya, Grace G. Hartman, Noriko Murase, Oscar Bronsther, Rafael Manez, John J. Fung, Shunzaburo Iwatsuki, Thomas E. Starzl
Journal: Hepatology (1992)

Twenty–six adult patients with preformed IgG donor lymphocytotoxic antibodies received primary liver allografts under FK 506 immunosuppression. The effect of the crossmatch–positive state on early graft function and on the immunopathological and histopathological findings was compared with that of 52 crossmatch–negative control recipients. The presensitized (crossmatch–positive) patients had prolongation of early graft dysfunction, underwent more clinically indicated biopsies and had a higher incidence of cellular rejection, both overall (p &lt; 0.05) and within 10 days of transplantation (p &lt; 0.01). They also had a higher incidence of graft failure in the first 180 days (p &lt; 0.01). Hyperacute rejection with necrotizing or neutrophilic arteritis was not seen in the crossmatchpositive grafts. However, histological findings associated with presensitization included platelet margination in central veins and sinusoids in biopsy specimens 60 to 90 min after graft revascularization. Later biopsy specimens had neutrophilic portal venulitis followed by cholangiolar proliferation, acute cholangiolitis and centrilobular hepatocyte swelling that mimicked preservation injury, endothelial activation of arteries with medial changes and relapsing episodes of acute cellular rejection. These clinicopathological observations suggest that lymphocytotoxic antibodies can have a deleterious effect on liver allograft function and survival, even if they do not precipitate immediate or hyperacute rejection. (Hepatology 1992;16:671-681.)
Identification and characterization of Dicer1e, a Dicer1 protein variant, in oral cancer cells
Authors: Liliana P Cantini, Lourdes M Andino, Christopher C Attaway, Betsy Butler, Anca Dumitriu, Aaron Blackshaw, Andrew Jakymiw
Journal: Molecular Cancer (2014)

The human dicer1 gene has been predicted to produce several mRNA variants that encode truncated Dicer1 proteins of varying lengths. One of these Dicer1 variants, Dicer1e, was recently found to be differentially expressed in breast cancer cells. Because the expression and function of the Dicer1e protein variant has not been well characterized and the underlying molecular mechanisms for the development of oral squamous cell carcinomas (OSCCs) are poorly understood, the present study sought to characterize the biological role of Dicer1e and determine its relationship, if any, to OSCC pathogenesis. Western blot analyses were used to examine Dicer1e expression levels in a panel of oral cancer cells/tissues and during epithelial-mesenchymal transition (EMT), followed by 5′/3′-RACE analyses to obtain the full-length Dicer1e transcript. Biochemical fractionation and indirect immunofluorescent studies were performed to determine the cellular localization of Dicer1e and the effects of Dicer1e silencing on cancer cell proliferation, clonogenicity, and drug sensitivity were also assessed. Dicer1e protein levels were found to be overexpressed in OSCC cell lines of epithelial phenotype and in OSCC tissues with its levels downregulated during EMT. Moreover, the Dicer1e protein was observed to predominantly localize in the nucleus. 5′/3′-RACE analyses confirmed the presence of the Dicer1e transcript and silencing of Dicer1e impaired both cancer cell proliferation and clonogenicity by inducing either apoptosis and/or G2/M cell cycle arrest. Lastly, Dicer1e knockdown enhanced the chemosensitivity of oral cancer cells to cisplatin. The expression levels of Dicer1e influence the pathogenesis of oral cancer cells and alter their response to chemosensitivity, thus supporting the importance of Dicer1e as a therapeutic target for OSCCs.
Role of microRNA in IBS with increased gut permeability
Authors: M. Vicario, C. Martinez, J. Santos
Journal: Gut (2010)

Paradoxically, irritable bowel syndrome (IBS), a leading reason for medical consultation, is presently lacking sensitive and specific biological markers, and hence its diagnosis still relies on clinical symptom-based criteria. Luckily, and in close liaison with the progressive advent of innovative and ultrasensitive technologies and their rapid incorporation into research protocols, our mechanistic understanding of the origin of IBS may be undergoing a giant leap forward. One such remarkable advance could be the identification of a pathophysiological substrate common to the intestine of some patients with IBS—that is, a combined process of low-grade mucosal inflammation and immune activation, and disruption of the epithelial barrier.1–4 Physical and functional disintegrity of the intestinal barrier, reflected by distorted expression patterns of key selective transporters and structural proteins, and enhanced permeability, also characterises a number of inflammatory conditions including coeliac disease, inflammatory bowel disease, food allergy or type 1 diabetes, suggesting a role in disease pathogenesis.5 As for IBS, this may also be clinically relevant because the grade of barrier dysfunction has been related to the onset and severity of abdominal pain and visceral hypersensitivity.6 Interestingly, the above observations, although not unique to patients with diarrhoea-predominant IBS (d-IBS), tend to predominate in this IBS subtype.

MicroRNAs (miRNAs) are 18–25 nucleotide long RNAs serving as master endogenous fine-tuners of gene expression commonly operating via partial binding complementarity to target mRNAs. Indeed, the stability and functional expression of at least 30% of all protein-coding human genes are governed by miRNAs, acting primarily but not exclusively at the post-transcriptional level.7 In humans, the low grade repression induced by miRNAs, rarely exceeding twofold,8 mainly affects protein translation and infrequently causes degradation or cleavage of the cognate mRNA. In mammals, miRNAs comprise 2–3% of genes, found spread throughout the genome, with the exception of the …
Role of Akt Signaling in Vascular Homeostasis and Angiogenesis
Authors: Ichiro Shiojima, Kenneth Walsh
Journal: Circulation Research (2002)

Akt is a serine/threonine protein kinase that is activated by a number of growth factors and cytokines in a phosphatidylinositol-3 kinase-dependent manner. Although antiapoptotic activity of Akt is well known, it also regulates other aspects of cellular functions, including migration, glucose metabolism, and protein synthesis. In this review, Akt signaling in endothelial cells and its critical roles in the regulation of vascular homeostasis and angiogenesis will be discussed.
The kinetics of reduction of minimal residual disease impacts on duration of response and survival of patients with acute myeloid leukemia
Authors: F Buccisano, L Maurillo, V Gattei, G Del Poeta, M I Del Principe, M C Cox, P Panetta, M Irno Consalvo, C Mazzone, B Neri, L Ottaviani, D Fraboni, A Tamburini, F Lo-Coco, S Amadori, A Venditti
Journal: Leukemia (2006)
Target-Seeking Behavior of Plasma Glucose With Exercise in Type 1 Diabetes
Authors: Sandra A. Biankin, Arthur B. Jenkins, Lesley V. Campbell, Kin Lam Choi, Quentin G. Forrest, Donald J. Chisholm
Journal: Diabetes Care (2003)

OBJECTIVE—To investigate the reproducibility of the plasma glucose (PG) response to exercise in subjects with type 1 diabetes on a nonintensive insulin regimen. RESEARCH DESIGN AND METHODS—Subjects cycled for 45 min at 50% Vo2max on two occasions (studies 1 and 2) either 1 h after lunch and usual insulin (protocol A) or after overnight fasting without morning insulin (protocol B). Identical diet, activity, and insulin (twice daily neutral and intermediate) were maintained before and during each study day. A total of 13 type 1 diabetic subjects (6 men and 7 women, BMI 24.0 ± 0.9 kg/m2 [means ± SE], age 42.6 ± 2.7 years, diabetes duration 14.1 ± 2.8 years) completed protocol A, and 7 (3 men and 4 women, BMI 25.8 ± 1.3 kg/m2, age 39.7 ± 1.3 years, diabetes duration 14 ± 4.4 years) completed protocol B. RESULTS—In protocol A (fed), the fall in PG during exercise was 4.5 ± 1.0 and 5.0 ± 0.8 mmol/l in studies 1 and 2, respectively, whereas in protocol B (fasted), it was 0.6 ± 0.8 and 3.4 ± 1.6 mmol/l. Regression analysis of the change in PG in protocol A in study 1 versus study 2 showed poor reproducibility (r2 = 0.12, P = 0.25) despite uniform conditions. In protocol B, the fall in PG was more reproducible (r2 = 0.81, P = 0.006). In fed subjects, there was better (P = 0.01) and clinically useful reproducibility of the PG at exercise completion (r2 = 0.77, P = 0.0001) compared with preexercise. CONCLUSIONS—These results indicate poor reproducibility of the change in PG during exercise after feeding in type 1 diabetes on nonintensive insulin regimens but reasonable reproducibility when fasting. Exercise apparently decreases the glycemic variability after feeding, so that PG concentrations after exercise seek a reproducible “target.” Thus, the absolute PG level after a typical bout of exercise in the fed state should be a good guide to carbohydrate or insulin adjustment on subsequent occasions.
Two-Year Statin Therapy Does Not Alter the Progression of Intima-Media Thickness in Patients With Type 2 Diabetes Without Manifest Cardiovascular Disease
Authors: Edith D. Beishuizen, Marcel A. van de Ree, J. Wouter Jukema, Jouke T. Tamsma, J. Carel M. van der Vijver, A. Edo Meinders, Hein Putter, Menno V. Huisman
Journal: Diabetes Care (2004)

OBJECTIVE—Cardiovascular disease (CVD) is the most important cause of mortality in patients with type 2 diabetes. We aimed to determine the effect of statin therapy versus placebo on the progression of carotid intima-media thickness (IMT) in type 2 diabetic patients without manifest CVD. RESEARCH DESIGN AND METHODS—A randomized, placebo-controlled, double-blind clinical trial was performed in 250 patients with type 2 diabetes. Patients were given either 0.4 mg cerivastatin or placebo daily. In August 2001, when cerivastatin was withdrawn from the market, 0.4 mg cerivastatin was replaced by 20 mg simvastatin without deblinding the study. The primary end point was the change of mean common carotid IMT, as measured by B-mode ultrasound, over 2 years. RESULTS—Common carotid IMT at baseline was 0.780 mm in the placebo group and 0.763 mm in the statin group and did not change significantly after 2 years. There was no significant difference in IMT change in any carotid segment between the groups. LDL cholesterol was reduced by 25% in the statin group and increased by 8% in the placebo group (P &amp;lt; 0.001). Cardiovascular events occurred in 12 patients in the placebo group and two patients in the statin group (P = 0.006). CONCLUSIONS—There was no effect of 2 years’ statin therapy on carotid IMT in type 2 diabetic subjects. The natural history of IMT in our patients was milder than anticipated. In contrast, we observed a significantly lower cardiovascular event rate on statin therapy. Prognostic tools other than IMT should be explored in this patient group.
Prognostic Impact of Germinal Center–Associated Proteins and Chromosomal Breakpoints in Poor-Risk Diffuse Large B-Cell Lymphoma
Authors: Gustaaf W. van Imhoff, Evert-Jan G. Boerma, Bronno van der Holt, Ed Schuuring, Leo F. Verdonck, Hanneke C. Kluin-Nelemans, Philip M. Kluin
Journal: Journal of Clinical Oncology (2006)

Outcome of diffuse large B-cell lymphoma (DLBCL) with a germinal center B-cell (GCB) expression profile is superior to that of non-GCB DLBCL. This conclusion is mainly derived from patients with mixed international prognostic index (IPI) risk profiles treated with CHOP-like therapy (cyclophosphamide, doxorubicin, vincristine, and prednisone). We wondered whether the prognostic impact of the expression profile would hold out in a homogeneous cohort of poor-risk DLBCL patients treated with high-dose sequential therapy (HDT) and autologous stem-cell transplantation (ASCT) as first-line therapy.DLBCL from 66 newly diagnosed poor-risk patients, treated in two sequential prospective Dutch Hemato-Oncology Association (HOVON) trials, were studied retrospectively for expression of CD10, bcl6, MUM1/IRF4, bcl2, Ki67, and CD21+ follicular dendritic cells (FDC) by immunohistochemistry, and for the breakpoints of BCL2, BCL6, and MYC by fluorescent in situ hybridization (FISH). Lymphomas with any follicular component were excluded.A GCB immunophenotype profile was found in 58% and non-GCB immunophenotype profile in 42% of the tumors. Clinical characteristics of both groups were similar. Complete response (CR) rate was higher in patients with CD10+ tumors (58% v 30%; P = .03). A GCB immunophenotype profile, its constituting markers CD10 more than 30% and MUM1 less than 70%, and bcl2 less than 10% were each associated with a better overall survival (OS). FDC networks, equally present in GCB and non-GCB tumors, had superior CR (73% v 31%; P = .01), but disease-free survival rates were lower and there was no difference in OS rates. None of the breakpoints had a prognostic impact on outcome.Also in patients with poor-risk DLBCL treated with HDT and ASCT, the GCB immunophenotype and bcl2 expression retained a major impact on survival.