tbuckley/cabot-search huggingface dataset:
Reovirus as a Viable Therapeutic Option for the Treatment of Multiple Myeloma
Authors: Chandini M. Thirukkumaran, Zhong Qiao Shi, Joanne Luider, Karen Kopciuk, He Gao, Nizar Bahlis, Paola Neri, Mark Pho, Douglas Stewart, Adnan Mansoor, Don G. Morris
Journal: Clinical Cancer Research (2012)

Despite the recent advances made in the treatment of multiple myeloma, the disease still remains incurable. The oncolytic potential of reovirus has previously been shown and is currently in phase III clinical trials for solid tumors. We tested the hypothesis that reovirus can successfully target human multiple myeloma in vitro, ex vivo, and in vivo without affecting human hematopoietic stem cell (HHSC) re-population/differentiation in a murine model that partially recapitulates human multiple myeloma.Human myeloma cell lines and ex vivo tumor specimens were exposed to reovirus and oncolysis and mechanisms of cell death were assessed. RPMI 8226(GFP+) cells were injected intravenously to non-obese diabetic/severe combined immune deficient (NOD/SCID) mice and treated with live reovirus (LV) or dead virus (DV). Multiple myeloma disease progression was evaluated via whole-body fluorescence and bone marrow infiltration. HHSCs exposed to LV/DV were injected to NOD/SCID mice and re-population/differentiation was monitored.A total of six of seven myeloma cell lines and five of seven patient tumor specimens exposed to reovirus showed significant in vitro sensitivity. Tumor response of multiple myeloma by LV, but not DV, was confirmed by comparison of total tumor weights (P = 0.05), and bone marrow infiltration (1/6, LV; 5/6, DV). Mice injected with LV- or DV-exposed HHSCs maintained in vivo re-population/lineage differentiation showing a lack of viral effect on the stem cell compartment. Reovirus oncolysis was mediated primarily by activation of the apoptotic pathways.The unique ability of reovirus to selectively kill multiple myeloma while sparing HHSCs places it as a promising systemic multiple myeloma therapeutic for clinical testing.
TUMOR DORMANCY IN VIVO BY PREVENTION OF NEOVASCULARIZATION
Authors: Michael A. Gimbrone, Stephen B. Leapman, Ramzi S. Cotran, Judah Folkman
Journal: The Journal of Experimental Medicine (1972)

Dormant solid tumors were produced in vivo by prevention of neovascularization. When small fragments of anaplastic Brown-Pearce carcinoma were implanted directly on the iris in susceptible rabbits, they always vascularized. A characteristic growth pattern, consisting of prevascular, vascular, and late phases, was observed, which terminated with destruction of the eye within 2 wk. The beginning of exponential volume increase was shown to coincide with vascularization of the implant, as demonstrated by perfusion with intravenous fluorescein and by histologic sections. In contrast, implants placed in the anterior chamber, at a distance from the iris, did not become vascularized. After initial growth into spheroids, they remained arrested at a small size comparable to prevascular iris implants, for periods as long as 6 wk. Although dormant in terms of expansion, these avascular tumors contained a population of viable and mitotically active tumor cells. When reimplanted on the iris, vascularization was followed by rapid, invasive growth. These observations suggest that neovascularization is a necessary condition for malignant growth of a solid tumor. When a small mass of tumor cells is prevented from eliciting new vessel ingrowth from surrounding host tissues, population dormancy results. These data suggest that the specific blockade of tumor-induced angiogenesis may be an effective means of controlling neoplastic growth.
GROUP THERAPY FOR MOTHERS WITH INFANTICIDAL IMPULSES
Authors: HOWARD M. FEINSTEIN, NORMAN PAUL, PATTISON ESMIOL
Journal: American Journal of Psychiatry (1964)

This study reports on the clinical experience with a group of mothers with were unique. 2. The patients encouraged infanticidal impulses. The 4 shared, biographical characteristics found were: 1. They have strong feelings of resentment toward their parents for not fulfilling their dependency needs during childhood. 2. One or both of the parents or a significant parental figure was subject to uncontrolled temper outbursts during which the patient was the object of or witness to acts of violence. 3. They had lifelong feelings of rivalry with and hatred for men. Many trace this feeling to intense sibling rivalry with their brothers during childhood. 4. They seek motherly type men for husbands. Clinically they range from obsessional neurotics to borderline psychotics. Though there is this wide variation in diagnosis, there are a number of symptoms held in common: 1. They have disturbing thoughts about harming their children. The major focus of this aggression is a male child. The gap between the impulse and the act is on a continuum which parallels the diagnostic range. At the obsessional end of the scale the gap is wide and the impulse is alien to the concept of self. At the other end the impulse is felt in full intensity and primitive defenses are used to keep from committing infanticide. 2. They have multiple phobias. Here, too, the adequacy of the phobia as a defense varies on a scale parallel with the diagnostic range. At one extreme, the phobias, like the obsessional thoughts, effectively screen the rejected impulse from consciousness. At the other end of the scale the phobia is related in consciousness to the impulse which it is used to defend against. Throughout the entire range the phobias were crippling symptoms which encouraged progressive withdrawal from social contact. 3. They were depressed. Here too there is a range from vague feelings of hopelessness with unexplained episodes of tearfulness to psychotic depression with marked feelings of guilt, selfdepreciatory ideas and retardation. 4. They were disturbed by suicidal impulses. 5. They were intermittently or chronically frigid. Group psychotherapy offered a number of therapeutic advantages. 1. The group situation corrected the impression that the murderous impulses that they experienced and supported each other in their efforts to overcome common symptoms such as phobias about riding public transportation. 3. Consensual validation by the group members was helpful in correcting transference distortions. Such observations by group members were less likely to be interpreted as criticisms to be defended against than were observations by the therapist. 4. A mixing of defenses took place. The group members were able to learn different methods of adaptation from each other and to try them out in the group setting. 5. The group meetings provided a meaningful social experience for otherwise isolated people.
Sphingosine-1-phosphate is increased in patients with idiopathic pulmonary fibrosis and mediates epithelial to mesenchymal transition
Authors: Javier Milara, Rafael Navarro, Gustavo Juan, Teresa Peiró, Adela Serrano, Mercedes Ramón, Esteban Morcillo, Julio Cortijo
Journal: Thorax (2011)

<h3>Background</h3> Idiopathic pulmonary fibrosis (IPF) is characterised by the aberrant epithelial to mesenchymal transition (EMT) and myofibroblast accumulation. Sphingosine-1-phosphate (S1P) and sphingosine kinase 1 (SPHK1) have been implicated in lung myofibroblast transition, but their role in EMT and their expression in patients with IPF is unknown. <h3>Methods and results</h3> S1P levels were measured in serum (n=27) and bronchoalveolar lavage (BAL; n=15) from patients with IPF and controls (n=30 for serum and n=15 for BAL studies). SPHK1 expression was measured in lung tissue from patients with IPF (n=12) and controls (n=15). Alveolar type II transformation into mesenchymal cells was studied in response to S1P (10<sup>−9</sup>–10<sup>−5</sup> M). The median (IQR) of S1P serum levels was increased in patients with IPF (1.4 (0.4) μM) versus controls (1 (0.26) μM; p&lt;0.0001). BAL S1P levels were increased in patients with IPF (1.12 (0.53) μM) versus controls (0.2 (0.5); p&lt;0.0001) and correlated with diffusion capacity of the lung for carbon monoxide, forced expiratory volume in 1 s and forced vital capacity (Spearman9s r=−0.87, −0.72 and −0.68, respectively) in patients with IPF. SPHK1 was upregulated in lung tissue from patients with IPF and correlated with α-smooth muscle actin, vimentin and collagen type I (Spearman9s r=0.82, 0.85 and 0.72, respectively). S1P induced EMT in alveolar type II cells by interacting with S1P<sub>2</sub> and S1P<sub>3</sub>, as well as by the activation of p-Smad3, RhoA-GTP, oxidative stress and transforming growth factor-β1 (TGF-β1) release. Furthermore, TGF-β1-induced EMT was partially conducted by the S1P/SPHK1 activation, suggesting crosstalk between TGF-β1 and the S1P/SPHK1 axis. <h3>Conclusions</h3> S1P is elevated in patients with IPF, correlates with the lung function and mediates EMT.
Dysglycemia and a History of Reproductive Risk Factors
Authors: Sarah D. McDonald, Salim Yusuf, Patrick Sheridan, Sonia S. Anand, Hertzel C. Gerstein
Journal: Diabetes Care (2008)

The purpose of this study was to identify reproductive risk factors associated with dysglycemia (diabetes, impaired glucose tolerance, and impaired fasting glucose) in a contemporary multiethnic population.We studied 14,661 women screened with an oral glucose tolerance test for the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial. Reproductive risk factors were compared in normoglycemic and dysglycemic women.Dysglycemia was significantly associated with the number of children born (odds ratio 1.03 per child [95% CI 1.01-1.05]), age (1.05 per year [1.04-1.05]), non-European ancestry (1.09 [1.01-1.17]), preeclampsia/eclampsia (1.14 [1.02-1.27]), irregular periods (1.21 [1.07-1.36]), and gestational diabetes mellitus (GDM) (1.53 [1.35-1.74]). The relationship between GDM and dysglycemia did not differ across BMI tertiles (P = 0.84) nor did the relationships of other risk factors.Reproductive factors, particularly GDM, are associated with dysglycemia in middle-aged women from many ethnicities. Reproductive factors can be used to counsel young women about their future risk of dysglycemia, whereas in middle age they may help screen for dysglycemia.
A new surgical approach to myocardial revascularization--internal mammary artery to coronary vein anastomosis
Authors: I. A. Sallam, W. J. Kolff
Journal: Thorax (1973)

<b>Sallam, I. A., and Kolff, W. J. (1973).</b><i>Thorax</i>, <b>28</b>, 613-616. <b>A new surgical approach to myocardial revascularization—internal mammary artery to coronary vein anastomosis.</b> Myocardial ischaemia was established in anaesthetized animals (five dogs and five sheep) by ligating the anterior descending interventricular branch of the left coronary artery. Once the ischaemic changes became evident electrocardiographically, retrograde perfusion of the coronary vein draining the ischaemic area was established by connecting the internal mammary artery to the coronary vein. The vein was ligated proximally. When retrograde perfusion of the coronary vein was begun, the signs of ischaemia gradually disappeared but could be reproduced by clamping the internal mammary artery. This indicated the effectiveness of the anastomosis in establishing an efficient new blood supply to the ischaemic area. The present approach offers a new prospect to patients in whom the coronary artery is not suitable for coronary vein bypass grafting due to extensive diffuse narrowing. Further application may be found in patients with cardiogenic shock after myocardial infarction. Direct immediate revascularization by this approach may prove of value in such cases.
Asthma Associated with Decreased Hypoxic Ventilatory Drive
Authors: DAVID W. HUDGEL
Journal: Annals of Internal Medicine (1974)

Hypoxic and hypercapnic ventilatory drives were measured in a 17-year-old asthmatic because of an unusual degree of hypoxemia and hypoventilation that developed during bronchospasm. A severely depressed hypoxic ventilatory drive and a normal hypercapnic ventilatory drive were found. This decrease in responsiveness to hypoxia probably contributed to the occurrence of chronic hypoxemia, CO2 retention, cor pulmonale, and polycythemia in this asthmatic patient. Ventilatory drives of all four healthy members of his immediate family were also studied. Three had a depressed hypoxic drive, and one had a depressed hypercapnic drive. This clustering suggested that hereditary factors might have played a role in the patient's low hypoxic drive. Thus, antecedent, possibly hereditary, deficiencies in ventilatory drive may detrimentally influence the clinical course of persons who develop a mechanical impediment to breathing.
IRF9 and STAT1 are required for IgG autoantibody production and B cell expression of TLR7 in mice
Authors: Donna L. Thibault, Alvina D. Chu, Kareem L. Graham, Imelda Balboni, Lowen Y. Lee, Cassidy Kohlmoos, Angela Landrigan, John P. Higgins, Robert Tibshirani, Paul J. Utz
Journal: Journal of Clinical Investigation (2008)

A hallmark of SLE is the production of high-titer, high-affinity, isotype-switched IgG autoantibodies directed against nucleic acid-associated antigens. Several studies have established a role for both type I IFN (IFN-I) and the activation of TLRs by nucleic acid-associated autoantigens in the pathogenesis of this disease. Here, we demonstrate that 2 IFN-I signaling molecules, IFN regulatory factor 9 (IRF9) and STAT1, were required for the production of IgG autoantibodies in the pristane-induced mouse model of SLE. In addition, levels of IgM autoantibodies were increased in pristane-treated Irf9 -/- mice, suggesting that IRF9 plays a role in isotype switching in response to self antigens. Upregulation of TLR7 by IFN-alpha was greatly reduced in Irf9 -/- and Stat1 -/- B cells. Irf9 -/- B cells were incapable of being activated through TLR7, and Stat1 -/- B cells were impaired in activation through both TLR7 and TLR9. These data may reveal a novel role for IFN-I signaling molecules in both TLR-specific B cell responses and production of IgG autoantibodies directed against nucleic acid-associated autoantigens. Our results suggest that IFN-I is upstream of TLR signaling in the activation of autoreactive B cells in SLE.
Quality of Life in Patients With Colorectal Cancer 1 Year After Diagnosis Compared With the General Population: A Population-Based Study
Authors: Volker Arndt, Henrike Merx, Christa Stegmaier, Hartwig Ziegler, Hermann Brenner
Journal: Journal of Clinical Oncology (2004)

Purpose Quality of life (QOL) has become an important outcome measure for patients with cancer, but long-term results from population-based studies are rare. The objective of our study was to identify specific limitations of QOL in survivors of colorectal cancer in comparison with men and women from the general population 1 year after diagnosis when acute treatment effects are expected to have declined. Patients and Methods QOL was assessed 1 year after diagnosis in a population-based cohort of 439 patients with colorectal cancer from Saarland (Germany) using the EORTC-QLC30 questionnaire. Specific functional and symptom QOL scores were compared with published reference data from the general population. Results Of 439 patients, 378 of them survived the first year after tumor diagnosis (86.1%). Of these, 309 returned the questionnaire (response rate, 81.7%). Compared with the general population, colorectal cancer patients scored their physical, role, cognitive, and global health functioning only slightly worse. More severe limitations were observed for the emotional and social functioning scales and for the symptom subscales of fatigue, dyspnea, insomnia, constipation, diarrhea, and financial difficulties. The differences regarding functional and symptom scores were predominantly found in younger age groups whereas older cancer patients and controls rated their health and QOL similarly. Conclusion Deficits in emotional and social functioning and specific limitations like fatigue, dyspnea, insomnia, constipation, diarrhea, and financial difficulties are main factors hampering the QOL among colorectal cancer patients and seem to affect predominantly younger patients.
Apical Lumen Formation in Renal Epithelia
Authors: Marc A. Schlüter, Ben Margolis
Journal: Journal of the American Society of Nephrology (2009)

The ability to form epithelial lumina is a central architectural characteristic of virtually all organs and indispensable for their function. Ontogenetically, the kidney is one of the best-characterized organs, but concepts of the regulated formation of its hollow epithelial structures are still emerging. Epithelial cell lines provide the opportunity to study molecular mechanisms in simplified assays modeling cyst and tube formation. In these systems, several groups have identified molecules implicated in lumen formation, and their downregulation results in either multiple-lumen or no-lumen phenotypes. On the basis of these phenotypes, we propose a working model, assigning proteins to groups with similar functions. Defects within these specific protein groups lead to distinct epithelial phenotypes. Studies of mesenchymal-to-epithelial transition underline the importance of these protein groups, but converting these basic models of lumen formation to an understanding of the mesenchymal to tubule formation during kidney development is still challenging.
Upregulation of insulin receptor substrate-2 in pancreatic β cells prevents diabetes
Authors: Anita M. Hennige, Deborah J. Burks, Umut Ozcan, Rohit N. Kulkarni, Jing Ye, Sunmin Park, Markus Schubert, Tracey L. Fisher, Matt A. Dow, Rebecca Leshan, Mark Zakaria, Mahmud Mossa-Basha, Morris F. White
Journal: Journal of Clinical Investigation (2003)

The insulin receptor substrate-2 (Irs2) branch of the insulin/IGF signaling system coordinates peripheral insulin action and pancreatic beta cell function, so mice lacking Irs2 display similarities to humans with type 2 diabetes. Here we show that beta cell-specific expression of Irs2 at a low or a high level delivered a graded physiologic response that promoted beta cell growth, survival, and insulin secretion that prevented diabetes in Irs2-/- mice, obese mice, and streptozotocin-treated mice; and that upon transplantation, the transgenic islets cured diabetes more effectively than WT islets. Thus, pharmacological approaches that promote Irs2 expression in beta cells, especially specific cAMP agonists, could be rational treatments for beta cell failure and diabetes.
Sports drinks hazard to teeth.
Authors: A Milosevic
Journal: British Journal of Sports Medicine (1997)

To determine the dental hazards associated with sports supplement drinks by investigating the chemicophysical properties of eight brands of sports drinks.The pH and titratable acidity against 0.1 M NaOH was measured. Calcium, phosphate, and fluoride concentrations and viscosities of Carbolode, Gatorade, High Five, Isostar, Lucozade Sport Lemon, Lucozade Sport Orange, Maxim, and PSP22 were determined.The pH values of the drinks ranged from 4.46 (Maxim) to 2.38 (Isostar) and therefore were below the critical pH value (5.5) for enamel demineralisation. Both Lucozade varieties had high titratable acidities (16.30 ml 0.1M NaOH to neutrality) with Gatorade, High Five, and Isostar displaying intermediate titratable acidity, although Isostar had 74.5 ppm calcium and 63.6 ppm phosphate. The fluoride concentration of all drinks was low, and none of the drinks was particularly viscous (range 3.1-1.4 mPa.s).The chemicophysical analyses indicate that all the sports drinks in this study have erosive potential. However, drinks with higher pH, lower titratable acidity, and higher concentrations of calcium, phosphate, and fluoride will reduce this erosive potential.
A genome-wide RNAi screen in mouse embryonic stem cells identifies Mp1 as a key mediator of differentiation
Authors: Bart A. Westerman, A. Koen Braat, Nicole Taub, Marko Potman, Joseph H.A. Vissers, Marleen Blom, Els Verhoeven, Hans Stoop, Ad Gillis, Arno Velds, Wouter Nijkamp, Roderick Beijersbergen, Lukas A. Huber, Leendert H.J. Looijenga, Maarten van Lohuizen
Journal: The Journal of Experimental Medicine (2011)

Despite intense investigation of intrinsic and extrinsic factors that regulate pluripotency, the process of initial fate commitment of embryonic stem (ES) cells is still poorly understood. We used a genome-wide short hairpin RNA screen in mouse ES cells to identify genes that are essential for initiation of differentiation. Knockdown of the scaffolding protein Mek binding protein 1 (Mp1, also known as Lamtor3 or Map2k1ip1) stimulated self-renewal of ES cells, blocked differentiation, and promoted proliferation. Fibroblast growth factor 4 (FGF4) signaling is required for initial fate commitment of ES cells. Knockdown of Mp1 inhibited FGF4-induced differentiation but did not alter FGF4-driven proliferation. This uncoupling of differentiation and proliferation was also observed when oncogenic Ras isoforms were overexpressed in ES cells. Knockdown of Mp1 redirected FGF4 signaling from differentiation toward pluripotency and up-regulated the pluripotency-related genes Esrrb, Rex1, Tcl1, and Sox2. We also found that human germ cell tumors (GCTs) express low amounts of Mp1 in the invasive embryonic carcinoma and seminoma histologies and higher amounts of Mp1 in the noninvasive carcinoma in situ precursor and differentiated components. Knockdown of Mp1 in invasive GCT cells resulted in resistance to differentiation, thereby showing a functional role for Mp1 both in normal differentiation of ES cells and in germ cell cancer.
Synuclein-γ Targeting Peptide Inhibitor that Enhances Sensitivity of Breast Cancer Cells to Antimicrotubule Drugs
Authors: Vinay K. Singh, Yue Zhou, Joseph A. Marsh, Vladimir N. Uversky, Julie D. Forman-Kay, Jingwen Liu, Zongchao Jia
Journal: Cancer Research (2007)

Abstract Synuclein-γ (SNCG) plays oncogenic roles in breast carcinogenesis. Although the expression of SNCG is abnormally high in advanced and metastatic breast carcinomas, SNCG is not expressed in normal or benign breast tissues. SNCG is an intrinsically disordered protein known to interact with BubR1, a mitotic checkpoint kinase. The SNCG-BubR1 interaction inhibits mitotic checkpoint control upon spindle damage caused by anticancer drugs, such as nocodazole and taxol. Antimicrotubule drugs that cause mitotic arrest and subsequent apoptosis of cancer cells are frequently used to treat breast cancer patients with advanced or metastatic diseases. However, patient response rates to this class of chemotherapeutic agents vary significantly. In this study, we have designed a novel peptide (ANK) and shown its interaction with SNCG using fluorometry, surface plasmon resonance, and isothermal titration calorimetry. Binding of the ANK peptide did not induce folding of SNCG, suggesting that SNCG can function biologically in its intrinsically disordered state. Microinjection of the ANK peptide in breast cancer cell line overexpressing SNCG (MCF7-SNCG) exhibited a similar cell killing response by nocodazole as in the SNCG-negative MCF7 cells. Overexpression of enhanced green fluorescent protein–tagged ANK reduces SNCG-mediated resistance to paclitaxel treatment by ∼3.5-fold. Our coimmunoprecipitation and colocalization results confirmed the intracellular association of the ANK peptide with SNCG. This is likely due to the disruption of the interaction of SNCG with BubR1 interaction. Our findings shed light on the molecular mechanism of the ANK peptide in releasing SNCG-mediated drug resistance. [Cancer Res 2007;67(2):626–33]