tbuckley/cabot-search huggingface dataset:
Immune Inhibitory Molecules LAG-3 and PD-1 Synergistically Regulate T-cell Function to Promote Tumoral Immune Escape
Authors: Seng-Ryong Woo, Meghan E. Turnis, Monica V. Goldberg, Jaishree Bankoti, Mark Selby, Christopher J. Nirschl, Matthew L. Bettini, David M. Gravano, Peter Vogel, Chih Long Liu, Stephanie Tangsombatvisit, Joseph F. Grosso, George Netto, Matthew P. Smeltzer, Alcides Chaux, Paul J. Utz, Creg J. Workman, Drew M. Pardoll, Alan J. Korman, Charles G. Drake, Dario A.A. Vignali
Journal: Cancer Research (2011)

Inhibitory receptors on immune cells are pivotal regulators of immune escape in cancer. Among these inhibitory receptors, CTLA-4 (targeted clinically by ipilimumab) serves as a dominant off-switch while other receptors such as PD-1 and LAG-3 seem to serve more subtle rheostat functions. However, the extent of synergy and cooperative interactions between inhibitory pathways in cancer remain largely unexplored. Here, we reveal extensive coexpression of PD-1 and LAG-3 on tumor-infiltrating CD4(+) and CD8(+) T cells in three distinct transplantable tumors. Dual anti-LAG-3/anti-PD-1 antibody treatment cured most mice of established tumors that were largely resistant to single antibody treatment. Despite minimal immunopathologic sequelae in PD-1 and LAG-3 single knockout mice, dual knockout mice abrogated self-tolerance with resultant autoimmune infiltrates in multiple organs, leading to eventual lethality. However, Lag3(-/-)Pdcd1(-/-) mice showed markedly increased survival from and clearance of multiple transplantable tumors. Together, these results define a strong synergy between the PD-1 and LAG-3 inhibitory pathways in tolerance to both self and tumor antigens. In addition, they argue strongly that dual blockade of these molecules represents a promising combinatorial strategy for cancer.
Prediction of Reinforcing Responses to Psychostimulants in Humans by Brain Dopamine D<sub>2</sub> Receptor Levels
Authors: Nora D. Volkow, Gene-Jack Wang, Joanna S. Fowler, Jean Logan, Samuel J. Gatley, Andrew Gifford, Robert Hitzemann, Yu-Shin Ding, Naomi Pappas
Journal: American Journal of Psychiatry (1999)

This study assessed whether brain dopamine D2 receptor levels, which show significant intersubject variability, predict reinforcing responses to psychostimulants in humans.[11C]Raclopride and positron emission tomography were used to measure D2 receptor levels in 23 healthy men (mean age = 34 years, SD = 7) who had no drug abuse histories in order to assess if there were differences between the subjects who liked and those who disliked the effects of intravenous methylphenidate (0.5 mg/kg).Subjects who liked the effects of methylphenidate had significantly lower D2 receptor levels (mean = 2.72 Bmax/Kd, SD = 0.3) than subjects who disliked its effects (mean = 3.16, SD = 0.3). Moreover, the higher the D2 levels found, the more intense were methylphenidate's unpleasant effects.These results provide preliminary evidence that D2 receptor levels predict response to psychostimulants in humans and that low D2 receptors may contribute to psychostimulant abuse by favoring pleasant response.
Genetic Polymorphisms in MicroRNA-Related Genes as Predictors of Clinical Outcomes in Colorectal Adenocarcinoma Patients
Authors: Moubin Lin, Jian Gu, Cathy Eng, Lee M. Ellis, Michelle A. Hildebrandt, Jie Lin, Maosheng Huang, George A. Calin, Dingzhi Wang, Raymond N. DuBois, Ernest T. Hawk, Xifeng Wu
Journal: Clinical Cancer Research (2012)

To evaluate the effects of single-nucleotide polymorphisms (SNP) in microRNA-related genes on clinical outcomes in patients with colorectal cancer (CRC) receiving first-line fluoropyrimidine-based chemotherapy.Forty-one SNPs in 26 microRNA-related genes were genotyped in 1,097 patients with CRC recruited at the University of Texas MD Anderson Cancer Center (Houston, TX). Patients were enrolled between 1990 and 2008 and last follow-up was in 2010. The associations between genotypes and recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS) stratified by clinical stage were analyzed in 741 newly diagnosed patients (diagnosed within 1 year) and replicated the findings in an additional 356 patients.In patients with stage III disease, mir608: rs4919510 was associated with increased risk for both recurrence [HR, 2.72; 95% confidence interval (CI), 1.38-5.33] and death (HR, 3.53; 95%CI, 1.42-8.73). The associations were confirmed in the replication set, and the combined HRs for training and replication sets were 1.65 (95% CI, 1.13-2.41) for recurrence and 1.96 (95% CI, 1.19-3.21) for death, respectively. The mir219-1:rs213210 showed consistent association with death in the training set (HR, 3.86; 95% CI, 1.33-11.22), the replication set (HR, 3.33; 95% CI, 1.39-7.98), and combined data set (HR, 3.22; 95% CI, 1.70-6.10). In combined analysis of these two SNPs, patients carrying the variant genotypes at both sites exhibited a 5.6-fold increased risk of death.Genetic polymorphisms in the microRNA pathway may predict prognosis in patients with stage III CRC treated with fluoropyrimidine-based chemotherapy.
Functional Characterization of a Putative Serine Carboxypeptidase in Vascular Smooth Muscle Cells
Authors: Ting-Hein Lee, Jiyuan Chen, Joseph M. Miano
Journal: Circulation Research (2009)

We previously identified a novel serine carboxypeptidase, SCPEP1, that undergoes cleavage across all tissues where it is expressed. SCPEP1 bears the signature catalytic triad found in all serine carboxypeptidases, but its biological function is completely unknown.To begin elucidating the functions of SCPEP1 in vitro and in the vessel wall after injury.Cultured smooth muscle cells were transduced with adenovirus carrying wild-type Scpep1, a short hairpin RNA to Scpep1, or variants of Scpep1 with mutations that disrupt the catalytic triad domain or SCPEP1 cleavage. Western blotting of key growth regulators or growth and migratory responses were assessed following SCPEP1 gain- or loss-of-function in smooth muscle cells. Vascular injury-induced remodeling and cell proliferation were evaluated in wild-type or newly created Scpep1 knockout mice. Overexpression of wild-type or cleavage-defective SCPEP1, but not a catalytic triad mutant SCPEP1, promotes smooth muscle cell proliferation and migration in vitro. A short hairpin RNA to Scpep1 blunts endogenous growth, which is rescued on concurrent expression of Scpep1 carrying silent mutations that evade knockdown. SCPEP1 protein is highly expressed in the neointima of 2 models of vascular remodeling. Scpep1-null mice show decreases in medial and intimal cell proliferation as well as vessel remodeling following arterial injury.SCPEP1 promotes smooth muscle cell proliferation and migration in a catalytic triad-dependent, cleavage-independent manner. SCPEP1 represents a new mediator of vascular remodeling and a potential therapeutic target for the treatment of vascular occlusive diseases.
Cardiovascular Disease in Williams Syndrome
Authors: R. Thomas Collins
Journal: Circulation (2013)

W illiams syndrome (WS), also referred to as Williams- Beuren syndrome (Online Mendelian Inheritance in Man 194050), is a congenital, multisystem disorder involving the cardiovascular, connective tissue, and central nervous systems. 1 WS occurs in ≈1 in 10 000 live births 2 as a result of the de novo deletion of ≈1.55 to 1.83 Mb on chromosome 7q11.23. 3 Familial cases can occur but are far less common than de novo cases. 4The deletion involves 26 to 28 genes, including the ELN gene, which codes for the protein elastin. 5emizygosity of the ELN gene coding for elastin has been demonstrated to be responsible for the vascular pathology in WS. 6 The remaining 25 to 27 deleted genes contribute to the phenotypic findings in patients with WS and have recently been reviewed in detail elsewhere. 5n 1961, Williams et al 7 reported their experience with 4 patients with supravalvar aortic stenosis (SVAS), mental retardation, and abnormal facial features.The following year, Beuren and colleagues 8 reported similar findings in 5 patients, and they subsequently reported detailed cardiac and angiographic data from 10 such patients. 9Their findings, combined with other characteristic features, led both groups to theorize that a previously unrecognized syndrome was the likely origin, a theory that led to the eponym Williams-Beuren syndrome.
Deubiquitinase inhibition as a cancer therapeutic strategy
Authors: Padraig D'Arcy, Xin Wang, Stig Linder
Journal: Pharmacology & Therapeutics (2014)

The ubiquitin proteasome system (UPS) is the main system for controlled protein degradation and a key regulator of fundamental cellular processes. The dependency of cancer cells on a functioning UPS has made this an attractive target for development of drugs that show selectivity for tumor cells. Deubiquitinases (DUBs, ubiquitin isopeptidases) are components of the UPS that catalyze the removal of ubiquitin moieties from target proteins or polyubiquitin chains, resulting in altered signaling or changes in protein stability. A number of DUBs regulate processes associated with cell proliferation and apoptosis, and as such represent candidate targets for cancer therapeutics. The majority of DUBs are cysteine proteases and are likely to be more "druggable" than E3 ligases. Cysteine residues in the active sites of DUBs are expected to be reactive to various electrophiles. Various compounds containing α,β-unsaturated ketones have indeed been demonstrated to inhibit cellular DUB activity. Inhibition of proteasomal cysteine DUB enzymes (i.e. USP14 and UCHL5) can be predicted to be particularly cytotoxic to cancer cells as it leads to blocking of proteasome function and accumulation of proteasomal substrates. We here provide an overall review of DUBs relevant to cancer and of various small molecules which have been demonstrated to inhibit DUB activity.
Modern prostate brachytherapy
Authors: H. Ragde, G. L. Grado, B. Nadir, A. A. Elgamal
Journal: CA A Cancer Journal for Clinicians (2000)

Of all the treatment options available for men with organ-confined prostate cancer, brachytherapy—permament implantation of radioactive seeds into the prostate gland—is the least disruptive for the patient, both physiologically and practically. Early brachytherapy represents the oldest technique for delivering radiation to the prostate gland, preceding external beam therapy of the prostate by several decades. Although there have not been, and are not likely to be, any definitive randomized studies comparing radical prostatectomy, external beam radiotherapy, and brachytherapy, treatment decisions will continue to be made on the basis of patient and physician preferences in conjunction with clinical probabilities. Long-term results in this series show that monotherapy with seed implants achieved disease-free survival of 66%; moreover, 79% of patients with higher grade disease who were treated with a combination of brachytherapy and external beam radiation also experienced long-term disease-free survival. The following article provides a brief historical review of prostate brachytherapy, rationale for treatments, patient selection criteria, up-to-date implant techniques, and long-term (12-year) outcome results.
Delayed Gadolinium‐Enhanced Magnetic Resonance Imaging of Medial Tibiofemoral Cartilage and Its Relationship With Meniscal Pathology: A Longitudinal Study Using 3.0T Magnetic Resonance Imaging
Authors: Michel D. Crema, David J. Hunter, Deborah Burstein, Frank W. Roemer, Ling Li, Nitya Krishnan, Monica D. Marra, Marie‐Pierre Hellio Le‐Graverand, Ali Guermazi
Journal: Arthritis & Rheumatology (2014)

To evaluate the relationship between medial meniscal pathology and cartilage matrix status using delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) in medial tibiofemoral cartilage in a sample of middle-aged women.A total of 148 women ages ≥40 years were included, and 3.0T MRI of the knee was performed at baseline and at 1 year. T2-weighted, fat-suppressed and 3-dimensional inversion recovery-prepared spoiled gradient-recalled echo sequences were acquired 90 minutes after gadolinium injection. Baseline medial meniscal pathology was scored on a scale of 0-3, where 0 = normal, 1 = intrasubstance meniscal signal change, 2 = single tears, and 3 = complex tears/maceration. The central medial femur, the medial tibial plateau, and the posterior medial femur were subjected to dGEMRIC at baseline and at 1 year. Analysis of covariance was used to examine whether baseline and 1-year dGEMRIC indices in the same regions were related to the severity of meniscal damage at baseline, using normal medial menisci (grade 0) as the reference.Medial compartments with grade 3 lesions showed significantly lower dGEMRIC indices (less proteoglycan content) at the central medial femur region compared with compartments with normal menisci. Mean ± SEM differences in dGEMRIC indices between grade 3 and grade 0 menisci at the central medial femur were -119.1 ± 34.2 msec at baseline (P = 0.03) and -120.3 ± 35.2 msec at followup (P = 0.04).High-grade damage of the medial meniscus showed significant associations with lower dGEMRIC indices. The dGEMRIC technique may be a useful tool in detecting early degenerative changes of cartilage when meniscal function is lost.
Epidemiology of Type 2 Diabetes and Cardiovascular Disease: Translation From Population to Prevention
Authors: James B. Meigs
Journal: Diabetes Care (2010)

In the book Epidemiology of Diabetes and Its Vascular Lesions (1978), Kelly West summarized extant knowledge of the distribution and causes of diabetes. The 30 years of epidemiological research that followed have seen remarkable advances in the understanding of obesity as a risk factor for type 2 diabetes, and diabetes and pre-diabetes as risk factors for cardiovascular disease. Increasingly detailed understanding of these relationships has, unfortunately, been accompanied by an alarming increase in the prevalence of obesity, diabetes, and cardiovascular disease. West recognized that pre-diabetes is recognizable as what we now call metabolic syndrome. He predicted that novel insight into diabetes pathogenesis would come from biochemical and genetic epidemiology studies. He predicted that type 2 diabetes could be prevented by healthy lifestyle change. The challenge now is for us to translate these insights into effective strategies for the prevention of the modern epidemic of diabetes and vascular disease.
Tumour necrosis factor blockade increases lymphangiogenesis in murine and human arthritic joints
Authors: K Polzer, D Baeten, A Soleiman, J Distler, D M Gerlag, P P Tak, G Schett, J Zwerina
Journal: Annals of the Rheumatic Diseases (2008)

<h3>Objective:</h3> To investigate the presence and regulation of lymphatic vessels in inflamed joints of mice with experimental arthritis as well as patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA). <h3>Methods:</h3> Lymphatic vessels and blood vessels were assessed in synovial tissue of human tumour necrosis factor transgenic (TNFtg) mice and synovial biopsies from patients with RA and SpA by immunohistochemistry for podoplanin and CD31, respectively. Assessments were performed before and after TNF blockade in all biopsies. <h3>Results:</h3> Lymphatic vessels were abundantly present in the synovial tissue of hTNFtg mice as well as patients with RA and SpA. The number of lymphatic vessels was positively related to the severity of synovial inflammation. Treatment with infliximab led to an increase in the formation of lymphatic vessels in murine and human inflammatory tissue. <h3>Conclusions:</h3> This study shows that TNF blockade promotes the proliferation of lymphatic vessels in the inflamed synovium of RA and SpA. This finding leads to the assumption that promotion of lymphangiogenesis may play an important part in efflux of cells and fluid out of the inflamed tissue.
Platelets mediate lymphovenous hemostasis to maintain blood-lymphatic separation throughout life
Authors: Paul R. Hess, David R. Rawnsley, Zoltán Jakus, Yiqing Yang, Daniel T. Sweet, Jianxin Fu, Brett Herzog, MinMin Lu, Bernhard Nieswandt, Guillermo Oliver, Taija Makinen, Lijun Xia, Mark L. Kahn
Journal: Journal of Clinical Investigation (2013)

Mammals transport blood through a high-pressure, closed vascular network and lymph through a low-pressure, open vascular network. These vascular networks connect at the lymphovenous (LV) junction, where lymph drains into blood and an LV valve (LVV) prevents backflow of blood into lymphatic vessels. Here we describe an essential role for platelets in preventing blood from entering the lymphatic system at the LV junction. Loss of CLEC2, a receptor that activates platelets in response to lymphatic endothelial cells, resulted in backfilling of the lymphatic network with blood from the thoracic duct (TD) in both neonatal and mature mice. Fibrin-containing platelet thrombi were observed at the LVV and in the terminal TD in wild-type mice, but not Clec2-deficient mice. Analysis of mice lacking LVVs or lymphatic valves revealed that platelet-mediated thrombus formation limits LV backflow under conditions of impaired valve function. Examination of mice lacking integrin-mediated platelet aggregation indicated that platelet aggregation stabilizes thrombi that form in the lymphatic vascular environment to prevent retrograde blood flow. Collectively, these studies unveil a newly recognized form of hemostasis that functions with the LVV to safeguard the lymphatic vascular network throughout life.
The effects of aging and exercise training on endothelin-1 vasoconstrictor responses in rat skeletal muscle arterioles
Authors: A DONATO, L LESNIEWSKI, M DELP
Journal: Cardiovascular Research (2004)

Objectives: The incidence of cardiovascular disease increases with advancing age. Vascular dysfunction has been linked to cardiovascular disease and aging, although most research has focused on endothelium-dependent vasodilator dysfunction. Another possible mechanism for this vascular dysfunction with aging is enhanced vasoconstrictor responsiveness of the resistance vasculature, and in particular, reactivity of arterioles to endothelin-1 (ET-1). We hypothesized that vasoreactivity to ET-1 would be greater in skeletal muscle arterioles from old rats, and that endurance exercise training would abolish differences in ET-1 responsiveness between young and old animals.
Multicenter Collaborative Panic Disorder Severity Scale
Authors: M. Katherine Shear, Timothy A. Brown, David H. Barlow, Roy Money, Diane E. Sholomskas, Scott W. Woods, Jack M. Gorman, Laszlo A. Papp
Journal: American Journal of Psychiatry (1997)

To address the lack of a simple and standardized instrument to assess overall panic disorder severity, the authors developed a scale for the measurement of panic disorder severity.Ten independent evaluators used the seven-item Panic Disorder Severity Scale to assess 186 patients with principal DSM-III-R diagnoses of panic disorder (with no or mild agoraphobia) who were participating in the Multicenter Collaborative Treatment Study of Panic Disorder. In addition, 89 of these patients were reevaluated with the same scale after short-term treatment. A subset of 24 patients underwent two independent assessments to establish interrater reliability. Internal consistency, convergent and discriminant validity, and sensitivity to change were also determined.The Panic Disorder Severity Scale was associated with excellent interrater reliability, moderate internal consistency, and favorable levels of validity and sensitivity to change. Individual items showed good convergent and discriminant validity. Analysis suggested a two-factor model fit the data best.The Panic Disorder Severity Scale is a simple, efficient way for clinicians to rate severity in patients with established diagnoses of panic disorder. However, further research with more diverse groups of panic disorder patients and with a broader range of convergent and discriminant validity measures is needed.
The Metamorphosis of the Thrombus After Thrombolytic Therapy
Authors: Lukasz Chrzanowski, Marcin Fiutowski, Maria Krzeminska-Pakula, Karina Wierzbowska-Drabik, Jaroslaw Drozdz, Bartlomiej Wozniakowski, Ludomir Stefanczyk, Jaroslaw D. Kasprzak
Journal: Circulation (2007)
Observations on oesophageal length.
Authors: G J Kalloor, A H Deshpande, J L Collis
Journal: Thorax (1976)

The subject of oesophageal length is discussed. The great variations in the length of the oesophagus in individual patients is noted, and the practical use of its recognition in oesophageal surgery is stressed. An apprasial of the various methods available for this measurement is made; this includes the use of external chest measurement, endoscopic measurement, and the measurement of the level of the electrical mucosal potential change. Correlative studies of these various methods are made, and these show a very high degree of significance. These studies involved simultaneous measurement of external and internal oesophageal length in 26 patients without a hiatal hernia or gastro-oesophageal length in 26 patients without a hiatal hernia or gastro-oesophageal reflux symptoms, 42 patients with sliding type hiatal hernia, and 17 patients with a peptic stricture in association with hiatal hernia. The method of measuring oesophageal length by the use of the external chest measurement, that is, the distance between the lower incisor teeth and the xiphisternum, measured with the neck fully extended and the patient lying supine, is described in detail, its practical application in oesophageal surgery is illustrated, and its validity tested by internal measurements. The findings of this study demonstrate that the external chest measurement provides a mean of assessing the true static length of the oesophagus, corrected for the size of the individual.
Natural Androgens Inhibit Male Atherosclerosis
Authors: Peter Alexandersen, Jens Haarbo, Inger Byrjalsen, Henrik Lawaetz, Claus Christiansen
Journal: Circulation Research (1999)

Abstract —The effect of natural androgens on serum lipids and atherosclerosis is controversial. We therefore studied this important issue prospectively in an animal model of atherosclerosis. Eighty male rabbits were randomized to bilateral castration, and 20 animals were sham operated. The castrated rabbits were randomized to 500 mg oral dehydroepiandrosterone (DHEA) daily, 80 mg oral testosterone undecanoate (TU) daily, or 25-mg intramuscular injection of testosterone enanthate (TE) twice weekly, whereas the fourth castrated group (placebo) and the sham-operated rabbits did not receive any hormones. All animals were fed a cholesterol-rich diet during the 30-week treatment period. Average serum lipids and atherogenic lipoproteins were higher in the placebo group than in the other groups (ANOVA, P &lt;0.0001). Aortic atherosclerosis, as evaluated by the cholesterol content (nmol/mg protein), was also highest in the placebo group (308±39) and lowest in the TE group (61±12), but was intermediate in the DHEA (155±30), TU (191±43), and sham operation (162±29) groups (ANOVA, P &lt;0.0001). ANCOVA indicated that the androgen effect on aortic atherosclerosis was only in part explained by the changes in lipoproteins. Aortic estrogen receptor contents were significantly lower in the androgen-treated groups than in the control groups, whereas there was no difference in aortic androgen receptor contents between groups. Natural androgens inhibit aortic atherosclerosis in castrated male rabbits only partly through a lipid-mediated effect.
Evaluation of fat grafting safety in patients with intra epithelial neoplasia: a matched-cohort study
Authors: J.Y. Petit, M. Rietjens, E. Botteri, N. Rotmensz, F. Bertolini, G. Curigliano, P. Rey, C. Garusi, F. De Lorenzi, S. Martella, A. Manconi, B. Barbieri, P. Veronesi, M. Intra, T. Brambullo, A. Gottardi, M. Sommario, G. Lomeo, M. Iera, V. Giovinazzo, V. Lohsiriwat
Journal: Annals of Oncology (2013)