tbuckley/cabot-search huggingface dataset:
Shrinkage of the Heart in Anesthetized, Thoracotomized Dogs
Authors: ROBERT F. RUSHMER
Journal: Circulation Research (1954)

Changes in heart size have been studied by means of intraventricular gages, serial roentgenography and cinefluorographic angiocardiography. Evidence is presented that the area of the cardiac silhouette and the area and diameter of the left ventricle all diminish in response to thoracotomy and during recovery return toward the pre-operative dimensions. Since fundamental concepts of cardiac function and control are based largely on investigation of exposed hearts, these concepts must be re-examined in intact, unanesthetized animals and man.
Tumor Cell and Tumor Vasculature Expression of B7-H3 Predict Survival in Clear Cell Renal Cell Carcinoma
Authors: Paul L. Crispen, Yuri Sheinin, Timothy J. Roth, Christine M. Lohse, Susan M. Kuntz, Xavier Frigola, R. Houston Thompson, Stephen A. Boorjian, Haidong Dong, Bradley C. Leibovich, Michael L. Blute, Eugene D. Kwon
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Although the prognostic value of B7-H1 and B7-H4 expression by tumor cells in clear cell renal cell carcinoma (ccRCC) has been established, the role of B7-H3 is unknown. As such, we evaluated the association of B7-H3 expression with clinicopathologic outcomes in patients treated for ccRCC. Experimental Design: Nephrectomy specimens from 743 consecutive patients treated for ccRCC at our institution from 1990 to 1999 were evaluated for B7-H3 expression by immunohistochemical staining. Associations of B7-H3 expression with clinical and pathologic features were evaluated using χ2 and Fisher's exact tests. Associations of B7-H3 expression with death from RCC were evaluated using Cox proportional hazards regression models. Results: B7-H3 expression by tumor cells or tumor vasculature was noted in 17% and 95% of specimens, respectively. The presence of either tumor cell or diffuse tumor vasculature expression of B7-H3 was present in 46% of specimens and was associated with multiple adverse clinical and pathologic features. After multivariable adjustment, the presence of either tumor cell or diffuse tumor vasculature B7-H3 expression was significantly associated with an increased risk of death from RCC (risk ratio, 1.38; 95% confidence interval, 1.03-1.84; P = 0.029). Conclusions: Both tumor cell and tumor vasculature B7-H3 expression convey important information to predict ccRCC outcomes. Collectively, our past and present studies pertaining to B7-H ligand expression indicate that ccRCC may use redundant mechanisms to compromise host antitumoral immunity. Future studies will focus on the effect of combined B7-H ligand expression in RCC.
Survival signalling and apoptosis resistance in glioblastomas: opportunities for targeted therapeutics
Authors: Camilla Krakstad, Martha Chekenya
Journal: Molecular Cancer (2010)

Glioblastoma multiforme (GBM) is the most common primary brain tumour in adults and one of the most aggressive cancers in man. Despite technological advances in surgical management, combined regimens of radiotherapy with new generation chemotherapy, the median survival for these patients is 14.6 months. This is largely due to a highly deregulated tumour genome with opportunistic deletion of tumour suppressor genes, amplification and/or mutational hyper-activation of receptor tyrosine kinase receptors. The net result of these genetic changes is augmented survival pathways and systematic defects in the apoptosis signalling machinery. The only randomised, controlled phase II trial conducted targeting the epidermal growth factor receptor (EGFR) signalling with the small molecule inhibitor, erlotinib, has showed no therapeutic benefit. Survival signalling and apoptosis resistance in GBMs can be viewed as two sides of the same coin. Targeting increased survival is unlikely to be efficacious without at the same time targeting apoptosis resistance. We have critically reviewed the literature regarding survival and apoptosis signalling in GBM, and highlighted experimental, preclinical and recent clinical trials attempting to target these pathways. Combined therapies simultaneously targeting apoptosis and survival signalling defects might shift the balance from tumour growth stasis to cytotoxic therapeutic responses that might be associated with greater therapeutic benefits.
Immediate early detection of urokinase receptor after partial hepatectomy and its implications for initiation of liver regeneration
Authors: Wendy M. Mars, Meng-Lun Liu, Richard P. Kitson, Ronald H. Goldfarb, Megan K. Gabauer, George K. Michalopoulos
Journal: Hepatology (1995)

Hepatocyte growth factor (HGF), also known as scatter factor, is believed to play a primary role in liver regeneration. HGF is produced in an inactive single-chain form that can be cleaved in vitro to the active two-chain form by tissue-type and urokinase-type plasminogen (PLG) activators (tPA and uPA). We have now documented the de novo appearance of active uPA in livers from male Fischer F344 rats that underwent 70% partial hepatectomy (PHx) as early as 1 minute after surgery. Western blot analyses of protein extracts from liver remnants that were obtained immediately after surgery and periodically until 24 hours after PHx indicate that the quantity of uPA remains fairly constant in PHx samples. In contrast, the uPA receptor (uPAR) dramatically increases, beginning within 1 minute after PHx. This results in enhanced activity of uPA, as seen by direct zymography on cryostat sections. The uPA present in remnant liver homogenates from rats that underwent PHx is the primary agent that cleaves single-chain HGF to its two-chain form, because cleavage can be prevented when antibody against uPA is included in the liver homogenates. Furthermore, heterodimeric HGF, which is not present in normal liver, increases in the liver remnants from rats that underwent PHx, correlative to uPAR. The presence of active uPA is one of the earliest responses yet documented after PHx. These findings imply that both uPA and uPAR are involved in activating endogenous HGF in the regenerating livers of animals that underwent PHx.
Effect of meal induced splanchnic arterial vasodilatation on renal arterial haemodynamics in normal subjects and patients with cirrhosis
Authors: T Iwao, K Oho, R Nakano, M Yamawaki, T Sakai, M Sato, Y Miyamoto, A Toyonaga, K Tanikawa
Journal: Gut (1998)

To investigate the relation between changes in splanchnic arterial haemodynamics and renal arterial haemodynamics in controls and patients with cirrhosis.Superior mesenteric artery pulsatility index (SMA-PI) and renal artery pulsatility index (R-PI) were measured using Doppler ultrasonography in 24 controls and 36 patients with cirrhosis. These measurements were repeated 30 minutes after ingestion of a liquid meal or placebo. Sixteen controls and 24 patients received the meal, and eight controls and 12 patients received placebo.In the fasting condition, patients with cirrhosis had a lower SMA-PI (p<0.01) and a greater R-PI (p<0.01) compared with controls. Placebo ingestion had no effect on splanchnic and renal haemodynamics. In contrast, ingestion of the meal caused a notable reduction in SMA-PI (p<0.01, p<0.01) and an increase in R-PI (p<0.01, p<0.01) in controls and patients with cirrhosis. The meal induced haemodynamic change in SMA-PI was inversely correlated with that in R-PI in controls (t=-0.42, p<0.05) and in patients with cirrhosis (t=-0.29, p<0.05).Results support the hypothesis that renal arterial vasoconstriction seen in patients with cirrhosis is one of the kidney's homoeostatic responses to underfilling of the splanchnic arterial circulation.
Plasma Glucagon in Nonketotic Hyperosmolar Coma
Authors: C. A. Lindsey, G. R. Faloona, Roger H Unger
Journal: JAMA (1974)

To determine if hyperglucagonemia is present in the nonketotic hyperglycemic hyperosmolar syndrome as it is in diabetic ketoacidosis, we measured plasma glucagon in seven patients hospitalized with the former diagnosis. Despite blood glucose levels ranging from 812 to 1,224 mg/100 ml, plasma glucagon averaged 689 pg/ml (SEM±215), and ranged from 130 to 1,825 pg/ml. Hyperglucagonemia is a common finding in this form of poorly controlled diabetes. (<i>JAMA</i>229:1771-1773, 1974)
Laminin β2 Gene Missense Mutation Produces Endoplasmic Reticulum Stress in Podocytes
Authors: Ying Maggie Chen, Yuefang Zhou, Gloriosa Go, Joseph T. Marmerstein, Yamato Kikkawa, Jeffrey H. Miner
Journal: Journal of the American Society of Nephrology (2013)

Mutations in the laminin β2 gene (LAMB2) cause Pierson syndrome, a severe congenital nephrotic syndrome with ocular and neurologic defects. LAMB2 is a component of the laminin-521 (α5β2γ1) trimer, an important constituent of the glomerular basement membrane (GBM). The C321R-LAMB2 missense mutation leads to congenital nephrotic syndrome but only mild extrarenal symptoms; the mechanisms underlying the development of proteinuria with this mutation are unclear. We generated three transgenic mouse lines, in which rat C321R-LAMB2 replaced mouse LAMB2 in the GBM. During the first postnatal month, expression of C321R-LAMB2 attenuated the severe proteinuria exhibited by Lamb2−/− mice in a dose-dependent fashion; proteinuria eventually increased, however, leading to renal failure. The C321R mutation caused defective secretion of laminin-521 from podocytes to the GBM accompanied by podocyte endoplasmic reticulum (ER) stress, likely resulting from protein misfolding. Moreover, ER stress preceded the onset of significant proteinuria and was manifested by induction of the ER-initiated apoptotic signal C/EBP homologous protein (CHOP), ER distention, and podocyte injury. Treatment of cells expressing C321R-LAMB2 with the chemical chaperone taurodeoxycholic acid (TUDCA), which can facilitate protein folding and trafficking, greatly increased the secretion of the mutant LAMB2. Taken together, these results suggest that the mild variant of Pierson syndrome caused by the C321R-LAMB2 mutation may be a prototypical ER storage disease, which may benefit from treatment approaches that target the handling of misfolded proteins.
Inflammation and Progressive Nephropathy in Type 1 Diabetes in the Diabetes Control and Complications Trial
Authors: Julie Lin, Robert J. Glynn, Nader Rifai, JoAnn E. Manson, Paul M. Ridker, David M. Nathan, Debra A. Schaumberg
Journal: Diabetes Care (2008)

OBJECTIVE—Progressive nephropathy represents a substantial source of morbidity and mortality in type 1 diabetes. Increasing albuminuria is a strong predictor of progressive renal dysfunction and heightened cardiovascular risk. Early albuminuria probably reflects vascular endothelial dysfunction, which may be mediated in part by chronic inflammation. RESEARCH DESIGN AND METHODS—We measured baseline levels of four inflammatory biomarkers (high-sensitivity C-reactive protein, soluble intercellular adhesion molecule-1 [sICAM-1], soluble vascular cell adhesion molecule-1, and soluble tumor necrosis factor-α receptor-1) in stored blood samples from the 1,441 participants of the Diabetes Control and Complication Trial (DCCT). We used mixed-effects regression models to determine the average annual change in urinary albumin excretion rate (AER) by tertiles of each biomarker. We also used Cox proportional hazards models to estimate the relative risk of incident sustained microalbuminuria according to levels of each biomarker. RESULTS—After adjustment for baseline age, sex, duration of diabetes, A1C, and randomized treatment assignment, we observed a significantly higher 5.9 μg · min−1 · year−1 increase in AER among those in the highest compared with the lowest tertile of baseline sICAM-1 (P = 0.04). Those in the highest tertile of sICAM-1 had an adjusted relative risk of 1.67 (95% CI 0.96–2.92) of developing incident sustained microalbuminuria (Ptrend = 0.03). CONCLUSIONS—Higher baseline sICAM-1 levels predicted an increased risk of progressive nephropathy in type 1 diabetes and may represent an early risk marker that reflects the important role of vascular endothelial dysfunction in this long-term complication.
Durable Clinical, Cytogenetic, and Molecular Remissions After Allogeneic Hematopoietic Cell Transplantation for Refractory Sezary Syndrome and Mycosis Fungoides
Authors: Arturo Molina, Jasmine Zain, Daniel A. Arber, Maria Angelopolou, Margaret O’Donnell, Joyce Murata-Collins, Stephen J. Forman, Auayporn Nademanee
Journal: Journal of Clinical Oncology (2005)

Sezary syndrome (SS) and tumor-stage mycosis fungoides (MF) are generally incurable with currently available treatments. We conducted a retrospective study to evaluate the outcome of allogeneic hematopoietic stem-cell transplantation (HSCT) in this patient population.From August 1996 through October 2002, eight patients with advanced MF/SS underwent allogeneic HSCT at our institution. All patients were heavily pretreated, having failed a median number of seven prior therapies (range, five to 12). Clonal T-cell populations in peripheral blood or bone marrow were detectable by polymerase chain reaction analyses of T-cell receptor gamma-chain gene rearrangements in six patients and cytogenetics in three patients. The conditioning regimen included total-body irradiation and cyclophosphamide (n = 3), busulfan and cyclophosphamide (n = 1), and the reduced-intensity regimen of fludarabine and melphalan (n = 4). Allogeneic hematopoietic stem cells were obtained from HLA-matched siblings (n = 4) and unrelated donors (n = 4).All patients achieved complete clinical remission and resolution of molecular and cytogenetic markers of disease within 30 to 60 days after HSCT. Two patients died from transplantation-related complications; graft-versus-host disease (GVHD; n = 1) and respiratory syncytial virus pneumonia (n = 1). With a median follow-up of 56 months, six patients remain alive and without evidence of lymphoma.Our results suggest that allogeneic HSCT from both HLA-matched sibling and unrelated donors can induce durable clinical, molecular, and cytogenetic remissions in patients with advanced cutaneous T-cell lymphoma that is refractory to standard therapies.
Selective Manipulation of the Immune Response In Vivo by Monoclonal Antibodies
Authors: W. E. Seaman, D. Wofsy
Journal: Annual Review of Medicine (1988)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), emerged in China in December 2019 and quickly spread around the globe, killing more than 4 million people and causing a severe economic crisis. ...Read More
The Effects of a Mediterranean Diet on the Need for Diabetes Drugs and Remission of Newly Diagnosed Type 2 Diabetes: Follow-up of a Randomized Trial
Authors: Katherine Esposito, Maria Ida Maiorino, Michela Petrizzo, Giuseppe Bellastella, Dario Giugliano
Journal: Diabetes Care (2014)

OBJECTIVE To assess the long-term effects of dietary interventions on glycemic control, need for diabetes medications, and remission of type 2 diabetes. RESEARCH DESIGN AND METHODS Originally, in a two-arm trial design, overweight, middle-aged men and women with newly diagnosed type 2 diabetes were randomized to a low-carbohydrate Mediterranean diet (LCMD; n = 108) or a low-fat diet (n = 107). After 4 years, participants who were still free of diabetes medications were further followed up until the primary end point (need of a diabetic drug); remission of diabetes (partial or complete) and changes in weight, glycemic control, and cardiovascular risk factors were also evaluated. RESULTS The primary end point was reached in all participants after a total follow-up of 6.1 years in the low-fat group and 8.1 years in the LCMD group; median survival time was 2.8 years (95% CI 2.4–3.2) and 4.8 years (4.3–5.2), respectively. The unadjusted hazard ratio for the overall follow-up was 0.68 (0.50–0.89; P &amp;lt; 0.001). LCMD participants were more likely to experience any remission (partial or complete), with a prevalence of 14.7% (13.0–16.5%) during the first year and 5.0% (4.4–5.6%) during year 6 compared with 4.1% (3.1–5.0%) at year 1 and 0% at year 6 in the low-fat diet group. CONCLUSIONS In patients with newly diagnosed type 2 diabetes, an LCMD resulted in a greater reduction of HbA1c levels, higher rate of diabetes remission, and delayed need for diabetes medication compared with a low-fat diet.
Genetic lesions associated with chronic lymphocytic leukemia transformation to Richter syndrome
Authors: Giulia Fabbri, Hossein Khiabanian, Antony B. Holmes, Jiguang Wang, Monica Messina, Charles G. Mullighan, Laura Pasqualucci, Raul Rabadan, Riccardo Dalla-Favera
Journal: The Journal of Experimental Medicine (2013)

Richter syndrome (RS) derives from the rare transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma, most commonly of the diffuse large B cell lymphoma (DLBCL) type. The molecular pathogenesis of RS is only partially understood. By combining whole-exome sequencing and copy-number analysis of 9 CLL-RS pairs and of an extended panel of 43 RS cases, we show that this aggressive disease typically arises from the predominant CLL clone by acquiring an average of ∼20 genetic lesions/case. RS lesions are heterogeneous in terms of load and spectrum among patients, and include those involved in CLL progression and chemorefractoriness (TP53 disruption and NOTCH1 activation) as well as some not previously implicated in CLL or RS pathogenesis. In particular, disruption of the CDKN2A/B cell cycle regulator is associated with ∼30% of RS cases. Finally, we report that the genomic landscape of RS is significantly different from that of de novo DLBCL, suggesting that they represent distinct disease entities. These results provide insights into RS pathogenesis, and identify dysregulated pathways of potential diagnostic and therapeutic relevance.
Cirrhosis and bleeding: the need for very early management
Authors: Delphine Nidegger, Stéphanie Ragot, Philippe Berthelémy, Claude Masliah, Christophe Pilette, Thierry Martin, Alain Bianchi, Thierry Paupard, Christine Silvain, Michel Beauchant, A Multicenter Group
Journal: Journal of Hepatology (2003)
MOLECULAR BIOLOGY OF ODORANT RECEPTORS IN VERTEBRATES
Authors: Peter Mombaerts
Journal: Annual Review of Neuroscience (1999)

The initial step in olfactory discrimination involves the interaction of odorous ligands with specific receptors on the surface of olfactory sensory neurons. The foundation for a molecular understanding of odor recognition in vertebrates was provided by the identification of a family of genes encoding putative odorant receptors, by Buck & Axel in 1991. Odorant receptor (OR) genes from the largest gene family in the vertebrate genome. This review summarizes progress over the past seven years. Major new insights are: Olfaction is accomplished in vertebrates by a very large number of receptors; olfactory sensory neurons express a small subset of the OR repertoire; in rat and mouse, axons of neurons expressing the same OR converge onto defined glomeruli in the olfactory bulb.
AF10 Regulates Progressive H3K79 Methylation and HOX Gene Expression in Diverse AML Subtypes
Authors: Aniruddha J Deshpande, Anagha Deshpande, Amit U Sinha, Liying Chen, Jenny Chang, Ali Cihan, Maurizio Fazio, Chun-Wei Chen, Nan Zhu, Richard Koche, Liuda Dzhekieva, Gloria Ibáñez, Stuart Dias, Deepti Banka, Andrei Krivtsov, Minkui Luo, Robert G Roeder, James E Bradner, Kathrin M Bernt, Scott A Armstrong
Journal: Cancer Cell (2014)
A Specific Antagonist of the p110δ Catalytic Component of Phosphatidylinositol 3′-Kinase, IC486068, Enhances Radiation-Induced Tumor Vascular Destruction
Authors: Ling Geng, Jiahuai Tan, Eric Himmelfarb, Aaron Schueneman, Ken Niermann, Allie Fu, Kyle Cuneo, Edward A. Kesicki, Jennifer Treiberg, Joel S. Hayflick, Dennis E. Hallahan
Journal: Cancer Research (2004)

Abstract The phosphatidylinositol 3′-kinase (PI3k)/protein kinase B (PKB/Akt) signal transduction pathway plays a critical role in mediating endothelial cell survival and function during oxidative stress. The role of the PI3k/Akt signaling pathway in promoting cell viability was studied in vascular endothelial cells treated with ionizing radiation. Western blot analysis showed that Akt was rapidly phosphorylated in response to radiation in primary culture endothelial cells (human umbilical vascular endothelial cells) in the absence of serum or growth factors. PI3k consists of p85 and p110 subunits, which play a central upstream role in Akt activation in response to exogenous stimuli. The δ isoform of the p110 subunit is expressed in endothelial cells. We studied the effects of the p110δ specific inhibitor IC486068, which abrogated radiation-induced phosphorylation of Akt. IC486068 enhanced radiation-induced apoptosis in endothelial cells and reduced cell migration and tubule formation of endothelial cells in Matrigel following irradiation. In vivo tumor growth delay was studied in mice with Lewis lung carcinoma and GL261 hind limb tumors. Mice were treated with daily i.p. injections (25 mg/kg) of IC486068 during 6 days of radiation treatment (18 Gy). Combined treatment with IC486068 and radiation significantly reduced tumor volume as compared with either treatment alone. Reduction in vasculature was confirmed using the dorsal skinfold vascular window model. The vascular length density was measured by use of the tumor vascular window model and showed IC486068 significantly enhanced radiation-induced destruction of tumor vasculature as compared with either treatment alone. IC486068 enhances radiation-induced endothelial cytotoxicity, resulting in tumor vascular destruction and tumor control when combined with fractionated radiotherapy in murine tumor models. These findings suggest that p110δ is a therapeutic target to enhance radiation-induced tumor control.
The importance of the definition of early virological response for predicting treatment efficacy for chronic hepatitis C
Authors: Ming-Lung Yu
Journal: Hepatology (2010)

I read with interest Lam et al.'s report1 published in a recent issue of HEPATOLOGY. The sustained virological response (SVR) rates of hepatitis C virus genotype 6 (HCV-6) patients treated with peginterferon-α2a/ribavirin were similar in the 24-week arm (70%) and the 48-week arm (79%). However, an early virological response (EVR) was not a negative predictor of SVR in HCV-6 patients, as observed in Fung et al.'s study.2 These findings confused the 12-week stopping rule by EVR in HCV-1 patients.3 Nevertheless, the definition of EVR should be clarified. These two HCV-6 studies1, 2 defined EVR as seronegativity for HCV RNA in week 12. In contrast, almost all other reports have defined EVR as seronegativity for HCV RNA or a ≥2 log10 decline from the baseline in week 12.4, 5 With the consensus EVR definition, the negative predictive value for achieving SVR is ≥97% with the current standard of care4 in both HCV-13, 5 and HCV-2 patients.6 Recently, the consensus EVR definition has been further divided into rapid virological response (HCV RNA seronegativity in treatment week 4), complete EVR (no rapid virological response but HCV RNA seronegativity in week 12), and partial EVR (HCV RNA seropositivity in weeks 4 and 12 but a ≥2 log10 drop in HCV RNA in week 12) to improve the prediction of SVR.7 The SVR rates could reach 90% in both HCV-1 and HCV-2 patients who achieve complete EVR with the standard of care but only approximately 20% in those achieving partial EVR.8 Therefore, the clarification of a universal definition of EVR is very important for reporting data on the on-treatment and off-treatment efficacy for chronic hepatitis C. Ming-Lung Yu M.D., Ph.D.* , * Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan, Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.