tbuckley/cabot-search huggingface dataset:
Tolerance of Whole-Genome Doubling Propagates Chromosomal Instability and Accelerates Cancer Genome Evolution
Authors: Sally M. Dewhurst, Nicholas McGranahan, Rebecca A. Burrell, Andrew J. Rowan, Eva Grönroos, David Endesfelder, Tejal Joshi, Dmitri Mouradov, Peter Gibbs, Robyn L. Ward, Nicholas J. Hawkins, Zoltan Szallasi, Oliver M. Sieber, Charles Swanton
Journal: Cancer Discovery (2014)

The contribution of whole-genome doubling to chromosomal instability (CIN) and tumor evolution is unclear. We use long-term culture of isogenic tetraploid cells from a stable diploid colon cancer progenitor to investigate how a genome-doubling event affects genome stability over time. Rare cells that survive genome doubling demonstrate increased tolerance to chromosome aberrations. Tetraploid cells do not exhibit increased frequencies of structural or numerical CIN per chromosome. However, the tolerant phenotype in tetraploid cells, coupled with a doubling of chromosome aberrations per cell, allows chromosome abnormalities to evolve specifically in tetraploids, recapitulating chromosomal changes in genomically complex colorectal tumors. Finally, a genome-doubling event is independently predictive of poor relapse-free survival in early-stage disease in two independent cohorts in multivariate analyses [discovery data: hazard ratio (HR), 4.70, 95% confidence interval (CI), 1.04-21.37; validation data: HR, 1.59, 95% CI, 1.05-2.42]. These data highlight an important role for the tolerance of genome doubling in driving cancer genome evolution.Our work sheds light on the importance of whole-genome–doubling events in colorectal cancer evolution. We show that tetraploid cells undergo rapid genomic changes and recapitulate the genetic alterations seen in chromosomally unstable tumors. Furthermore, we demonstrate that a genome-doubling event is prognostic of poor relapse-free survival in this disease type.
Comparison of exercise capacity, pulmonary functions, respiratory and peripheral muscle strength between patients with idiopathic pulmonary arterial hypertension and Eisenmenger syndrome
Authors: Rengin Demir, Hulya Nilgun Gurses, Semiramis Ozyilmaz, Serdar Kucukoglu
Journal: European Respiratory Journal (2012)

This study was designed to compare exercise capacity, pulmonary functions, respiratory and peripheral muscle strength between patients with idiopathic pulmonary arterial hypertension (IPAH) and Eisenmenger syndrome.Thirty-three patients with PAH of either IPAH (mean age 45.31; 12 female and 4 male) or Eisenmenger syndrome (mean age 38.41;10 female and 7 male) were studied. Exercise capacity was determined by using six minute walk test. Also pulmonary functions, respiratory muscle strength (maximal inspiratory (MIP) and maximal expiratory (MEP) pressure) and handgrip strength were measured. Unpaired-t, Mann-Whitney and Fisher9s exact tests have been used for the statistical analysis of the data. There were no significant differences in exercise capacity, respiratory and peripheral muscle strength between the two groups. FVC% (p=0.0025), FEV 1 % (p=0.01) and PEF% (p=0.02) of patients with Eisenmenger syndrome were significantly lower than those of patients with IPAH. In conclusion; exercise capacity, respiratory and peripheral muscle strength were similar for patients with Eisenmenger syndrome compared to those IPAH. In addition, the present study provides evidence that pulmonary functions are reduced in patients with Eisenmenger syndrome compared with IPAH.
Cardioprotective growth factors
Authors: D. J. Hausenloy, D. M. Yellon
Journal: Cardiovascular Research (2009)

Many of the originally identified cardiovascular 'growth factors' have been demonstrated to exert a diverse variety of actions within the cardiovascular system, the majority of which are unrelated to their initially proposed mechanism of action. Interestingly, several of these growth factors have been demonstrated to protect the cardiomyocyte from the detrimental effects of acute ischaemia–reperfusion injury, through the activation of a variety of cell-surface receptors and the subsequent recruitment of a number of intracellular signal transduction pathways, which include components of the reperfusion injury salvage kinase pathway. This article will review several of these cardioprotective growth factors with respect to their ability to confer direct myocardial protection, focusing on the underlying signalling pathways involved and their potential for clinical application.
Etiology of Pruritic Papular Eruption With HIV Infection in Uganda
Authors: Jack S. Resneck
Journal: JAMA (2004)

A frequent cause of human immunodeficiency virus (HIV)-related morbidity in sub-Saharan Africa is a commonly occurring, intensely pruritic skin rash. The resulting scars are disfiguring and stigmatizing. Despite the substantial prevalence of pruritic papular eruption (PPE) among HIV-infected Africans, the cause has been elusive.To determine the etiology of PPE occurring in HIV-infected individuals.Cross-sectional study of HIV-infected patients with active PPE from clinics in Uganda conducted from May 19 through June 6, 2003. Enrollment occurred in the month preceding May 19. Each participant was clinically examined by 2 dermatologists, had laboratory studies performed, was administered an epidemiologic questionnaire, and had a skin biopsy of a new lesion evaluated by a dermatopathologist.Histological characteristics of new pruritic lesions. Other assessments included CD4 cell count, eosinophil count, and physician-assessed rash severity.Of 109 patients meeting inclusion criteria, 102 (93.6%) completed the study. The CD4 cell counts in this study population were generally low (median, 46/microL) and inversely related to increasing rash severity (median CD4 cell counts: 122 for mild, 41 for moderate, and 9 for severe; P<.001 for trend). Eighty-six patients (84%; 95% confidence interval, 77%-91%) had biopsy findings characteristic of arthropod bites. Patients with arthropod bites on biopsy had significantly higher peripheral eosinophil counts (median, 330 vs 180/microL; P = .02) and had a trend toward lower CD4 cell counts (median, 40 vs 99/microL; P = .07) than those without histological evidence of arthropod bites.Pruritic papular eruption occurring in HIV-infected individuals may be a reaction to arthropod bites. We hypothesize that this condition reflects an altered and exaggerated immune response to arthropod antigens in a subset of susceptible HIV-infected patients.
A SNP in the ABCC11 gene is the determinant of human earwax type
Authors: Koh-ichiro Yoshiura, Akira Kinoshita, Takafumi Ishida, Aya Ninokata, Toshihisa Ishikawa, Tadashi Kaname, Makoto Bannai, Katsushi Tokunaga, Shunro Sonoda, Ryoichi Komaki, Makoto Ihara, Vladimir A Saenko, Gabit K Alipov, Ichiro Sekine, Kazuki Komatsu, Haruo Takahashi, Mitsuko Nakashima, Nadiya Sosonkina, Christophe K Mapendano, Mohsen Ghadami, Masayo Nomura, De-Sheng Liang, Nobutomo Miwa, Dae-Kwang Kim, Ariuntuul Garidkhuu, Nagato Natsume, Tohru Ohta, Hiroaki Tomita, Akira Kaneko, Mihoko Kikuchi, Graciela Russomando, Kenji Hirayama, Minaka Ishibashi, Aya Takahashi, Naruya Saitou, Jeffery C Murray, Susumu Saito, Yusuke Nakamura, Norio Niikawa
Journal: Nature Genetics (2006)
Safety and Efficacy of Gene Transfer for Leber's Congenital Amaurosis
Authors: Albert M. Maguire, Francesca Simonelli, Eric A. Pierce, Edward N. Pugh, Federico Mingozzi, Jeannette Bennicelli, Sandro Banfi, Kathleen A. Marshall, Francesco Testa, Enrico M. Surace, Settimio Rossi, Arkady Lyubarsky, Valder R. Arruda, Barbara Konkle, Edwin Stone, Junwei Sun, Jonathan Jacobs, Lou Dell'Osso, Richard Hertle, Jian-xing Ma, T. Michael Redmond, Xiaosong Zhu, Bernd Hauck, Olga Zelenaia, Kenneth S. Shindler, Maureen G. Maguire, J. Fraser Wright, Nicholas J. Volpe, Jennifer Wellman McDonnell, Alberto Auricchio, Katherine A. High, Jean Bennett
Journal: New England Journal of Medicine (2008)

Leber's congenital amaurosis (LCA) is a group of inherited blinding diseases with onset during childhood. One form of the disease, LCA2, is caused by mutations in the retinal pigment epithelium-specific 65-kDa protein gene (RPE65). We investigated the safety of subretinal delivery of a recombinant adeno-associated virus (AAV) carrying RPE65 complementary DNA (cDNA) (ClinicalTrials.gov number, NCT00516477 [ClinicalTrials.gov]). Three patients with LCA2 had an acceptable local and systemic adverse-event profile after delivery of AAV2.hRPE65v2. Each patient had a modest improvement in measures of retinal function on subjective tests of visual acuity. In one patient, an asymptomatic macular hole developed, and although the occurrence was considered to be an adverse event, the patient had some return of retinal function. Although the follow-up was very short and normal vision was not achieved, this study provides the basis for further gene therapy studies in patients with LCA.
Herpesvirus Infections in the Acquired Immune Deficiency Syndrome
Authors: Gerald V. Quinnan, Henry Masur, Alain H. Rook, Gary Armstrong, Winston R. Frederick, Jay Epstein, Jody F. Manischewitz, Abe M. Macher, Lozannie Jackson, John Ames, Holly A. Smith, Margaret Parker, Gary R. Pearson, Joseph Parrillo, Charles Mitchell, Stephen E. Straus
Journal: JAMA (1984)

Herpesvirus infections were studied in persons with or at risk for the acquired immune deficiency syndrome (AIDS). The infections diagnosed were as follows: patients with AIDS, cytomegalovirus (CMV) in 34 of 34, Epstein-Barr virus (EBV) in 33 of 34, herpes simplex viruses (HSV) in eight of 34, and varicella zoster virus in four of 34; patients with chronic lymphadenopathy syndrome, CMV in eight of nine and EBV in nine of nine; in healthy homosexual men, CMV in five of 13 and EBV in seven of eight. Cytomegalovirus infections were frequently related to disease and death. Herpesvirus infections are frequent causes of serious diseases in AIDS. The prevalence of EBV and CMV infections in AIDS and the chronic lymphadenopathy syndrome may be the result of an important interaction between these viruses and the cause of AIDS.
The anti-angiogenic and cytotoxic effects of the boswellic acid analog BA145 are potentiated by autophagy inhibitors
Authors: Anup S Pathania, Zahoor A Wani, Santosh K Guru, Suresh Kumar, Shashi Bhushan, Hasan Korkaya, Darren F Seals, Ajay Kumar, Dilip M Mondhe, Zabeer Ahmed, Bal K Chandan, Fayaz Malik
Journal: Molecular Cancer (2015)

While angiogenesis inhibitors represent a viable cancer therapy, there is preclinical and clinical data to suggest that many tumors develop resistance to such treatments. Moreover, previous studies have revealed a complex association between autophagy and angiogenesis, and their collective influence on tumorigenesis. Autophagy has been implicated in cytoprotection and tumor promotion, and as such may represent an alternative way of targeting apoptosis-resistant cancer cells. This study explored the anti-cancer agent and boswellic acid analog BA145 as an inducer of autophagy and angiogenesis-mediated cytoprotection of tumor cells.Flow cytometry, western blotting, and confocal microscopy were used to investigate the role of BA145 mediated autophagy. ELISA, microvessel sprouting, capillary structure formation, aortic ring and wound healing assays were performed to determine the relationship between BA145 triggered autophagy and angiogenesis. Flow cytometery, western blotting, and microscopy were employed to examine the mechanism of BA145 induced cell death and apoptosis. Live imaging and tumor volume analysis were carried out to evaluate the effect of BA145 triggered autophagy on mouse tumor xenografts.BA145 induced autophagy in PC-3 cancer cells and HUVECs significantly impeded its negative regulation on cell proliferation, migration, invasion and tube formation. These effects of BA145 induced autophagy were observed under both normoxic and hypoxic conditions. However, inhibition of autophagy using either pharmacological inhibitors or RNA interference enhanced the BA145 mediated death of these cells. Similar observations were noticed with sunitinib, the anti-angiogenic properties of which were significantly enhanced during combination treatments with autophagy inhibitors. In mouse tumor xenografts, co-treatment with chloroquinone and BA145 led to a considerable reduction in tumor burden and angiogenesis compared to BA145 alone.These studies reveal the essential role of BA145 triggered autophagy in the regulation of angiogenesis and cytoprotection. It also suggests that the combination of the autophagy inhibitors with chemotherapy or anti-angiogenic agents may be an effective therapeutic approach against cancer.
Cloning and identification of human Sca as a novel inhibitor of osteoclast formation and bone resorption.
Authors: S J Choi, R D Devlin, C Menaa, H Chung, G D Roodman, S V Reddy
Journal: Journal of Clinical Investigation (1998)

Increased osteoclast activity is responsible for the enhanced bone destruction in postmenopausal osteoporosis, Paget's disease, bone metastasis, and hypercalcemia of malignancy. However, the number of known inhibitory factors that block osteoclast formation and bone resorption are limited. Therefore, we used an expression-cloning approach to identify novel factors produced by osteoclasts that inhibit osteoclast activity. A candidate clone was identified and isolated from a human osteoclast-like multinucleated cell (MNC) cDNA library, named osteoclast inhibitory peptide-1 (OIP-1), and the cDNA sequence was determined. This sequence matched that of the recently identified human stem cell antigen, was structurally similar to the mouse Ly-6 gene family, and the sequence predicted it was a glycosyl phosphatidyl inositol (GPI)-anchored protein that had a cleavable COOH-terminal peptide. Western blot analysis of conditioned media from 293 cells transfected with the OIP-1 cDNA clone confirmed that OIP-1 was released into the media as a membrane-bound GPI-linked protein. Interestingly, both recombinant OIP-1 expressed in Escherichia coli (which does not have GPI linker) and OIP-1 expressed by mammalian cells significantly reduced osteoclast-like MNC formation induced by 1,25-dihydroxyvitamin D3 or PTH-related protein in mouse and human bone marrow cultures, and inhibited 45Ca release from prelabeled bone in fetal rat organ cultures. In contrast, recombinant OIP-1 did not inhibit the growth of a variety of other cell types. These data indicate that OIP-1 is a novel, specific inhibitor of osteoclast formation and bone resorption.
Neurofibromatosis type 1: a multidisciplinary approach to care
Authors: Angela C Hirbe, David H Gutmann
Journal: The Lancet Neurology (2014)

Neurofibromatosis type 1 is a relatively common inherited disorder. Patients have a high predisposition to develop both benign and malignant tumours. Although many manifestations of neurofibromatosis type 1 affect the nervous system, other organs and tissues can also be affected. Because of the varying features and clinical heterogeneity inherent to this disorder, patients can present to different medical and surgical specialists and, therefore, the association of clinical symptoms with neurofibromatosis type 1 might not be appreciated. Thus, for prompt diagnosis and to provide optimum care for patients with neurofibromatosis type 1, clinicians must be aware of the diverse clinical features of this disorder. We advocate a multidisciplinary approach to care, entailing a dedicated team of specialists throughout the lifetime of the patient. As our understanding of this disorder deepens through basic laboratory and clinical investigations, swift implementation of new effective treatments becomes feasible.
Systems Biology Reveals New Strategies for Personalizing Cancer Medicine and Confirms the Role of PTEN in Resistance to Trastuzumab
Authors: Dana Faratian, Alexey Goltsov, Galina Lebedeva, Anatoly Sorokin, Stuart Moodie, Peter Mullen, Charlene Kay, In Hwa Um, Simon Langdon, Igor Goryanin, David J. Harrison
Journal: Cancer Research (2009)

Resistance to targeted cancer therapies such as trastuzumab is a frequent clinical problem not solely because of insufficient expression of HER2 receptor but also because of the overriding activation states of cell signaling pathways. Systems biology approaches lend themselves to rapid in silico testing of factors, which may confer resistance to targeted therapies. Inthis study, we aimed to develop a new kinetic model that could be interrogated to predict resistance to receptor tyrosine kinase (RTK) inhibitor therapies and directly test predictions in vitro and in clinical samples. The new mathematical model included RTK inhibitor antibody binding, HER2/HER3 dimerization and inhibition, AKT/mitogen-activated protein kinase cross-talk, and the regulatory properties of PTEN. The model was parameterized using quantitative phosphoprotein expression data from cancer cell lines using reverse-phase protein microarrays. Quantitative PTEN protein expression was found to be the key determinant of resistance to anti-HER2 therapy in silico, which was predictive of unseen experiments in vitro using the PTEN inhibitor bp(V). When measured in cancer cell lines, PTEN expression predicts sensitivity to anti-HER2 therapy; furthermore, this quantitative measurement is more predictive of response (relative risk, 3.0; 95% confidence interval, 1.6-5.5; P < 0.0001) than other pathway components taken in isolation and when tested by multivariate analysis in a cohort of 122 breast cancers treated with trastuzumab. For the first time, a systems biology approach has successfully been used to stratify patients for personalized therapy in cancer and is further compelling evidence that PTEN, appropriately measured in the clinical setting, refines clinical decision making in patients treated with anti-HER2 therapies.
International Union of Basic and Clinical Pharmacology. LXXXII: Nomenclature and Classification of Hydroxy-carboxylic Acid Receptors (GPR81, GPR109A, and GPR109B)
Authors: Stefan Offermanns, Steven L. Colletti, Timothy W. Lovenberg, Graeme Semple, Alan Wise, Adriaan P. IJzerman
Journal: Pharmacological Reviews (2011)

The G-protein-coupled receptors GPR81, GPR109A, and GPR109B share significant sequence homology and form a small group of receptors, each of which is encoded by clustered genes. In recent years, endogenous ligands for all three receptors have been described. These endogenous ligands have in common that they are hydroxy-carboxylic acid metabolites, and we therefore have proposed that this receptor family be named hydroxy-carboxylic acid (HCA) receptors. The HCA<sub>1</sub> receptor (GPR81) is activated by 2-hydroxy-propanoic acid (lactate), the HCA<sub>2</sub> receptor (GPR109A) is a receptor for the ketone body 3-hydroxy-butyric acid, and the HCA<sub>3</sub> receptor (GPR109B) is activated by the β-oxidation intermediate 3-hydroxy-octanoic acid. HCA<sub>1</sub> and HCA<sub>2</sub> receptors are found in most mammalian species, whereas the HCA<sub>3</sub> receptor is present only in higher primates. The three receptors have in common that they are expressed in adipocytes and are coupled to G<sub>i</sub>-type G-proteins mediating antilipolytic effects in fat cells. HCA<sub>2</sub> and HCA<sub>3</sub> receptors are also expressed in a variety of immune cells. HCA<sub>2</sub> is a receptor for the antidyslipidemic drug nicotinic acid (niacin) and related compounds, and there is an increasing number of synthetic ligands mainly targeted at HCA<sub>2</sub> and HCA<sub>3</sub> receptors. The aim of this article is to give an overview on the discovery and pharmacological characterization of HCAs, and to introduce an International Union of Basic and Clinical Pharmacology (IUPHAR)-recommended nomenclature. We will also discuss open questions regarding this receptor family as well as their physiological role and therapeutic potential.
Markers of oxidative stress are increased in exhaled breath condensates of children with atopic dermatitis
Authors: D.G. Peroni, A. Bodini, M. Corradi, A. Coghi, A.L. Boner, G.L. Piacentini
Journal: British Journal of Dermatology (2011)

Airway inflammation may be present in subjects affected by atopic dermatitis (AD) but still without asthma symptoms. Exhaled breath condensate (EBC) reflects the composition of bronchoalveolar extracellular lining fluid that contains a large number of mediators of airway inflammation and oxidative damage. We assessed inflammatory markers in the EBC of patients with AD. Fifty-six children (34 girls and 22 boys) were enrolled: 33 affected by AD and 23 healthy controls. EBC was collected using a condenser device. We measured EBC pH and concentrations of leukotriene B4 (LTB4), 8-isoprostane, H(2) O(2) , malondialdehyde and 4-hydroxynoneal. Respiratory resistance was also evaluated. EBC pH in patients with AD was significantly lower than in healthy children, median (range) being 8·02 (7·94-8·12) in AD vs. 8·11 (8·05-8·16) (P = 0·02). The values of exhaled 8-isoprostane and LTB4 were significantly increased in subjects with AD compared with normal controls (P < 0·01 and P < 0·001, respectively). There was increased 4-hydroxynoneal in patients with AD but this did not reach statistical significance. Evaluating respiratory resistance, no bronchoreversibility was demonstrated in the children with AD.pH, LTB4 and 8-isoprostane in EBC could be sensitive markers of airway inflammation in children with AD. Prospective studies would be of interest to evaluate if airway inflammation, not yet clinically evident, could predict the development of asthma later in life in children with AD.
Guantanamo force feeding trial: the US is wrong to medicalize hunger striking
Authors: W. J. Kalk
Journal: BMJ (2015)

Legal wrangles continue after a US judge demanded videos showing forced nasogastric feeding in Guantanamo be made public. Force feeding should play no part in the care of mentally competent patients, says <b>W John Kalk</b>, who treated hunger striking prisoners in South Africa during the apartheid era
Clinical Usefulness of Respiratory Variations in Arterial Pressure
Authors: Sheldon Magder
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

There is increasing interest in the use of respiratory variations in arterial pulse pressure to predict the Q response to a fluid challenge (1–4). This has likely evolved because of the appreciation that excess fluid infusion is harmful, as well as concerns over invasive monitoring (5). Thus, techniques that provide noninvasive assessment of volume status hold great promise. The major impetus for these tests came from the work of Perel and coworkers (6) who followed-up on a preliminary report by Coyle and coworkers (7). They defined the difference between maximum and minimum arterial systolic pressure during a respiratory cycle as systolic pressure variation (SPV) (6). The inspiratory increase in pressure relative to the value at end-expiration was called dUp, and the fall in pressure relative to the end-expiratory value was called dDown (Figures 1 and E1). The larger the dDown and SPV, the larger the predicted increase in Q with volume loading.