tbuckley/cabot-search huggingface dataset:
Novel Strategies for Granulocyte Colony-Stimulating Factor Treatment of Severe Prolonged Neutropenia Suggested by Mathematical Modeling
Authors: Eliezer Shochat, Vered Rom-Kedar
Journal: Clinical Cancer Research (2008)

Abstract Purpose: To improve the effectiveness of granulocyte colony-stimulating factor (G-CSF) treatment in high-risk neutropenic patients. Experimental Design: We study G-CSF effects on chemotherapy-induced neutropenia by expanding a simple mathematical model of neutrophil dynamics in the blood. The final model is fitted and validated using published clinical data of neutrophil response to chemotherapy and standard s.c. G-CSF protocol (SG; filgrastim 5 μg/kg/d), single pegylated (pegG; pegfilgrastim 100 μg/kg), and continuous infusion (CG; filgrastim 10 μg/kg/d). The interpatient variability is studied by Monte-Carlo simulation of pegG compared with SG and placebo. Results: The effect G-CSF support on neutropenia depends on the neutrophil count at the nadir. Three distinct neutropenia grades are identified: G1 (300 × 103−500 × 103 cells/mL), G2 (50 × 103−300 × 103 cells/mL), and G3 (≤50 × 103 cells/mL). For many G2 patients, the G-CSF levels required for recovery are not attainable by the standard regimen, whereas the sustained pegG and CG seem to be significantly more effective. For G3 patients, G-CSF support alone is not sufficient and additional clinical approaches should be considered. The results presented here are robust and are only slightly affected by population variability. Conclusions: The model captures the G-CSF-neutrophil dynamics of severe chemotherapy-induced neutropenia. Our results clarify and complement the current American Society of Clinical Oncology recommendations for G-CSF administration in neutropenia: High sustained G-CSF levels are needed to treat severe neutropenia and may be achieved by either CG or pegG. The potential effect of sustained G-CSF on severe neutropenia should be studied within a framework of a prospective randomized clinical trial.
Tuberculosis in the Homeless
Authors: ANDREW R. MOSS, JUDITH A. HAHN, JACQUELINE P. TULSKY, CHARLES L. DALEY, PETER M. SMALL, PHILLIP C. HOPEWELL
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

We set out to determine tuberculosis incidence and risk factors in the homeless population in San Francisco. We also examined the transmission of tuberculosis by molecular methods. We followed a cohort of 2,774 of the homeless first seen between 1990 and 1994. There were 25 incident cases during the period 1992 to 1996, or 270 per 100,000 per year (350/100,000 in African Americans, 450/100,000 in other nonwhites, 60/100,000 in whites). Ten cases were persons with seropositive HIV. Independent risk factors for tuberculosis were HIV infection, African American or other nonwhite ethnicity, positive tuberculin skin test (TST) results, age, and education; 60% of the cases had clustered patterns of restriction fragment length polymorphism, thought to represent recent transmission of infection with rapid progression to disease. Seventy-seven percent of African-American cases were clustered, and 88% of HIV-seropositive cases. The high rate of tuberculosis in the homeless was due to recent transmission in those HIV-positive and nonwhite. African Americans and other nonwhites may be at high risk for infection or rapid progression. Control measures in the homeless should include directly observed therapy and incentive approaches, treatment of latent tuberculous infection in those HIV-seropositive, and screening in hotels and shelters.
HTLV-III IN SYMPTOM-FREE SERONEGATIVE PERSONS
Authors: S.Zaki Salahuddin, PhillipD. Markham, RobertR. Redfield, M. Essex, JeromeE. Groopman, M.G. Sarngadharan, MaryF. Mclane, Ann Sliski, RobertC. Gallo
Journal: The Lancet (1984)
Drug sensitivity in cancer cell lines is not tissue-specific
Authors: Samira Jaeger, Miquel Duran-Frigola, Patrick Aloy
Journal: Molecular Cancer (2015)

Cancer cell lines have a prominent role in the initial stages of drug discovery, facilitating high-throughput screening of potential drugs. However, their clinical relevance remains controversial. We assess whether drug sensitivity in cancer cell lines is able to discriminate tissue specificity. We find that cancer-specific drugs do not show higher efficacies in cell lines representing the respective tissues. Even when considering distinct cancer subtypes and targeted therapies, most drugs are evenly effective/ineffective throughout all cell lines. To get the most out of cell line panels, it will be necessary to look into their molecular characteristics, and integrate them into systems biology frameworks.
Genetically Distinct Subsets within ANCA-Associated Vasculitis
Authors: Paul A Lyons, Tim F Rayner, Sapna Trivedi, Julia U Holle, Richard A Watts, David R W Jayne, Bo Baslund, Paul Brenchley, Annette Bruchfeld, Afzal N Chaudhry, Jan Willem Cohen Tervaert, Panos Deloukas, Conleth Feighery, Wolfgang L Gross, Loic Guillevin, Iva Gunnarsson, Lorraine Harper, Zdenka Hrušková, Mark A Little, Davide Martorana, Thomas Neumann, Sophie Ohlsson, Sandosh Padmanabhan, Charles D Pusey, Alan D Salama, Jan-Stephan F Sanders, Caroline O Savage, Mårten Segelmark, Coen A Stegeman, Vladimir Tesař, Augusto Vaglio, Stefan Wieczorek, Benjamin Wilde, Jochen Zwerina, Andrew J Rees, David G Clayton, Kenneth G C Smith
Journal: New England Journal of Medicine (2012)

Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis is a severe condition encompassing two major syndromes: granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis) and microscopic polyangiitis. Its cause is unknown, and there is debate about whether it is a single disease entity and what role ANCA plays in its pathogenesis. We investigated its genetic basis.
Upregulation of FOXM1 induces genomic instability in human epidermal keratinocytes
Authors: Muy-Teck Teh, Emilios Gemenetzidis, Tracy Chaplin, Bryan D Young, Michael P Philpott
Journal: Molecular Cancer (2010)

The human cell cycle transcription factor FOXM1 is known to play a key role in regulating timely mitotic progression and accurate chromosomal segregation during cell division. Deregulation of FOXM1 has been linked to a majority of human cancers. We previously showed that FOXM1 was upregulated in basal cell carcinoma and recently reported that upregulation of FOXM1 precedes malignancy in a number of solid human cancer types including oral, oesophagus, lung, breast, kidney, bladder and uterus. This indicates that upregulation of FOXM1 may be an early molecular signal required for aberrant cell cycle and cancer initiation. The present study investigated the putative early mechanism of UVB and FOXM1 in skin cancer initiation. We have demonstrated that UVB dose-dependently increased FOXM1 protein levels through protein stabilisation and accumulation rather than de novo mRNA expression in human epidermal keratinocytes. FOXM1 upregulation in primary human keratinocytes triggered pro-apoptotic/DNA-damage checkpoint response genes such as p21, p38 MAPK, p53 and PARP, however, without causing significant cell cycle arrest or cell death. Using a high-resolution Affymetrix genome-wide single nucleotide polymorphism (SNP) mapping technique, we provided the evidence that FOXM1 upregulation in epidermal keratinocytes is sufficient to induce genomic instability, in the form of loss of heterozygosity (LOH) and copy number variations (CNV). FOXM1-induced genomic instability was significantly enhanced and accumulated with increasing cell passage and this instability was increased even further upon exposure to UVB resulting in whole chromosomal gain (7p21.3-7q36.3) and segmental LOH (6q25.1-6q25.3). We hypothesise that prolonged and repeated UVB exposure selects for skin cells bearing stable FOXM1 protein causes aberrant cell cycle checkpoint thereby allowing ectopic cell cycle entry and subsequent genomic instability. The aberrant upregulation of FOXM1 serves as a 'first hit' where cells acquire genomic instability which in turn predisposes cells to a 'second hit' whereby DNA-damage checkpoint response (eg. p53 or p16) is abolished to allow damaged cells to proliferate and accumulate genetic aberrations/mutations required for cancer initiation.
CD4+ T cells that enter the draining lymph nodes after antigen injection participate in the primary response and become central–memory cells
Authors: Drew M. Catron, Lori K. Rusch, Jason Hataye, Andrea A. Itano, Marc K. Jenkins
Journal: The Journal of Experimental Medicine (2006)

We explored the relationship between the time of naive CD4+ T cell exposure to antigen in the primary immune response and the quality of the memory cells produced. Naive CD4+ T cells that migrated into the skin-draining lymph nodes after subcutaneous antigen injection accounted for about half of the antigen-specific population present at the peak of clonal expansion. These late-arriving T cells divided less and more retained the central–memory marker CD62L than the T cells that resided in the draining lymph nodes at the time of antigen injection. The fewer cell divisions were related to competition with resident T cells that expanded earlier in the response and a reduction in the number of dendritic cells displaying peptide–major histocompatibility complex (MHC) II complexes at later times after antigen injection. The progeny of late-arriving T cells possessed the phenotype of central–memory cells, and proliferated more extensively during the secondary response than the progeny of the resident T cells. The results suggest that late arrival into lymph nodes and exposure to antigen-presenting cells displaying lower numbers of peptide–MHC II complexes in the presence of competing T cells ensures that some antigen-specific CD4+ T cells divide less in the primary response and become central–memory cells.
Mass Spectrometry–based Proteomic Analysis: A Good Diagnostic Tool for Cystic Lung Light Chain Deposition Disease
Authors: Magali Colombat, Sonia Holifanjaniaina, François Guillonneau, Herve Mal, Sandrine Hirschi, Martine Reynaud-Gaubert, Marc Stern
Journal: American Journal of Respiratory and Critical Care Medicine (2013)
Subacute Massive Pulmonary Embolism Diagnosed by Transesophageal Echocardiography
Authors: Rajinder S. Bilku, Peter E. Glennon, Martin Been
Journal: Circulation (2007)

A 78-year-old man presented with a 1 week history of breathlessness.He had no chest pain, cough, hemoptysis or any other symptoms.Past medical history was unremarkable.Initial examination revealed normal blood pressure, resting tachycardia of 140 beats per minute and type I respiratory failure requiring oxygen (FiO2 of 0.35) to maintain normal oxygen saturation.His chest x-ray showed no evidence of pneumonia or pulmonary edema.Admission ECGs showed ST depression and T wave inversion in the precordial leads V1-V5 and also a short run of paroxysmal atrial flutter.His troponin T measured 0.09 g/L (normal range Ͻ0.1 g/L).It was assumed that he suffered from an acute coronary syndrome, and therefore he was initially treated with low-molecular weight heparin and antiplatelet therapy using aspirin and clopidogrel.Transthoracic echocardiography was performed, but views were suboptimal and showed good left ventricular function, reasonable right ventricular function, and no significant valvular abnormalities.There was, however, an echogenic mass at the base of the right atrium attached to the atrial septum, which did not appear to be freely mobile.A transesophageal echocardiogram was subsequently performed (Figure and online-only Data Supplement Movies I through V).Transesophageal echocardiogram showed an intact atrial septum with no atrial masses, no significant valvular abnormalities, moderate right ventricular hypokinesia, and good left ventricular function, and no filling defects were seen in the inferior vena cava or superior vena cava.However, there was evidence of a large "saddle" pulmonary embolus, measuring approximately 7 cm, at the bifurcation of the main pulmonary artery.An urgent computed tomography pulmonary angiogram scan confirmed this saddle pulmonary embolus and further pulmonary emboli in the more distal pulmonary arteries.He received thrombolysis with tissue plasminogen activator, made a good recovery, and later began taking warfarin.
Accidental Poisoning From Pet Medicines in Children
Authors: Walter Silver
Journal: JAMA (1971)

<h3>To the Editor.—</h3> Recommendations and warnings by the American Academy of Pediatrics regarding accidental drug ingestion by children point out the dangers and complications that may result from carelessness.<sup>1</sup>In fact, warnings pertaining to medications left where children can reach them, or to the improper closing of containers are constantly being published.<sup>2-4</sup> Diseases transmitted from pets to humans are also well documented and include salmonella from turtles,<sup>5,6</sup>psittacosis from parakeets,<sup>7</sup>worms from dogs,<sup>8</sup>and allergic reactions.<sup>9</sup> Recently we admitted to our service a 20-month-old child who combined the problem of accidental drug ingestion with a disease re-resulting from one's pet by ingesting approximately ten digitoxin tablets (0.25 mg) that had been prescribed by a veterinarian for the family's dog. The current large number of house pets and the good medical care they get will often result in medications that are potentially toxic being around
Cetuximab Every 2 Weeks with First-Line Chemotherapy in APEC Study Patients with Metastatic Colorectal Cancer Grouped According to EGFR Expression
Authors: A.L. Cheng, G. Cornelio, L. Shen, T. Price, T.S. Yang, I.J. Chung, G.H. Dai, J.K. Lin, A. Sharma, K.H. Yeh, B. Ma, A. Zaatar, Z.Z. Guan, N. Masood, V. Srimuninnimit, T. Yau, F. Beier, S. Chatterjee, R. Lim
Journal: Annals of Oncology (2014)
ALKALOSIS AND LOW PLASMA POTASSIUM IN A CASE OF CUSHING'S SYNDROME: A METABOLIC STUDY
Authors: Donald M. Willson, Marschelle H. Power, Edwin J. Kepler
Journal: Journal of Clinical Investigation (1940)

Addison's disease is characterized to a large de- gree by pathologic changes in the metabolismii of electrolytes, but changes in the sexual organs and sexual clharacteristics either do not occur or are inconspicuous.In cases of Cuslhing's syndrome,.oni the other hand, demonstrable abnormalities in the mietabolismii of electrolytes occur only excep- tionally, but changes in the sexual organs and sexual characteristics are the rule.In both dis- eases, amenorrlhea or impotence may occur, al- thouglh neither symptom occurs with regularity in cases of Addison's disease.In view of the fact that lhyperplastic or neoplastic changes occur in the adrenal cortex with considerable regularity among cases of Cushing's syndrome, it is indeedl remarkable that abnormalities of electrolyte me- tabolism occur so infrequently.In a series of more than thirty cases, thirteen of which were adrenal cortical tumor, we found only three cases in which there were marked changes in the elec- trolyte pattern of the blood.2The first case of this type was reported by one of us in 1933 (1), I The term " Cutshinig's synidrom)ie " is used here in the
A critical review of the role of Fc gamma receptor polymorphisms in the response to monoclonal antibodies in cancer
Authors: James D Mellor, Michael P Brown, Helen R Irving, John R Zalcberg, Alexander Dobrovic
Journal: Journal of Hematology & Oncology (2013)

Antibody-dependent cellular cytotoxicity (ADCC) is a major mechanism of action of therapeutic monoclonal antibodies (mAbs) such as cetuximab, rituximab and trastuzumab. Fc gamma receptors (FcgR) on human white blood cells are an integral part of the ADCC pathway. Differential response to therapeutic mAbs has been reported to correlate with specific polymorphisms in two of these genes: FCGR2A (H131R) and FCGR3A (V158F). These polymorphisms are associated with differential affinity of the receptors for mAbs. This review critically examines the current evidence for genotyping the corresponding single nucleotide polymorphisms (SNPs) to predict response to mAbs in patients with cancer.
A Random Effects Branch-Site Model for Detecting Episodic Diversifying Selection
Authors: Sergei L. Kosakovsky Pond, Ben Murrell, Mathieu Fourment, Simon D.W. Frost, Wayne Delport, Konrad Scheffler
Journal: Molecular Biology and Evolution (2011)

Adaptive evolution frequently occurs in episodic bursts, localized to a few sites in a gene, and to a small number of lineages in a phylogenetic tree. A popular class of "branch-site" evolutionary models provides a statistical framework to search for evidence of such episodic selection. For computational tractability, current branch-site models unrealistically assume that all branches in the tree can be partitioned a priori into two rigid classes—"foreground" branches that are allowed to undergo diversifying selective bursts and "background" branches that are negatively selected or neutral. We demonstrate that this assumption leads to unacceptably high rates of false positives or false negatives when the evolutionary process along background branches strongly deviates from modeling assumptions. To address this problem, we extend Felsenstein's pruning algorithm to allow efficient likelihood computations for models in which variation over branches (and not just sites) is described in the random effects likelihood framework. This enables us to model the process at every branch-site combination as a mixture of three Markov substitution models—our model treats the selective class of every branch at a particular site as an unobserved state that is chosen independently of that at any other branch. When benchmarked on a previously published set of simulated sequences, our method consistently matched or outperformed existing branch-site tests in terms of power and error rates. Using three empirical data sets, previously analyzed for episodic selection, we discuss how modeling assumptions can influence inference in practical situations.
ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: executive summary
Authors: Valentin Fuster, Lars E Rydén, Richard W Asinger, David S Cannom, Harry J Crijns, Robert L Frye, Jonathan L Halperin, G.Neal Kay, Werner W Klein, Samuel Lévy, Robert L McNamara, Eric N Prystowsky, L.Samuel Wann, D.George Wyse, Raymond J Gibbons, Elliott M Antman, Joseph S Alpert, David P Faxon, Valentin Fuster, Gabriel Gregoratos, Loren F Hiratzka, Alice K Jacobs, Richard O Russell, Sidney C Smith, Werner W Klein, Angeles Alonso-Garcia, Carina Blomström-Lundqvist, Guy De Backer, Marcus Flather, Jaromir Hradec, Ali Oto, Alexander Parkhomenko, Sigmund Silber, Adam Torbicki
Journal: Journal of the American College of Cardiology (2001)
Association between fatigue and decreased survival in primary biliary cirrhosis.
Authors: Claudia O Zein, Arthur J McCullough
Journal: Gut (2007)

We read with interest the article by Jones and colleagues on the stability of fatigue severity in patients with primary biliary cirrhosis (PBC) over 4 years of follow-up ( Gut 2006; 55 :536–41). The authors reported that, in their patient cohort, a high fatigue score predicted subsequent decreased survival.

Fatigue is frequent in patients with PBC, and it is known to have a negative impact on quality of life in this population.1–3 An established association between the presence of a high fatigue score at presentation and a significantly higher likelihood of death would have important implications. To date, recognised variables associated with prognosis in patients with PBC include age, certain markers of liver function and scores based on these.3 A lack of association between fatigue and markers of liver disease severity in PBC has been demonstrated.4

We have investigated the relationship between the presence of fatigue at presentation and subsequent survival in PBC. A cohort of 241 patients with PBC seen at four major teaching hospitals in the city of Cleveland between 1990 and 2005 who had not undergone liver transplantation were identified. Data obtained at the time of the first evaluation leading to the diagnosis of PBC were collected. Self-reported fatigue at the time of initial evaluation was recorded. Medical records were reviewed to determine outcomes up to 2006. Mean (SD) follow-up time was 5.4 (0.3) years (range 1–16). The log rank test was used to compare survival following diagnosis in patients who reported fatigue at presentation compared with those who did not. Laboratory, clinical and histological characteristics at presentation were compared between patients who survived and those who died …
Targeting EGFR with photodynamic therapy in combination with Erbitux enhances in vivo bladder tumor response
Authors: Ramaswamy Bhuvaneswari, Yik Yuen Gan, Khee Chee Soo, Malini Olivo
Journal: Molecular Cancer (2009)

Abstract Background Photodynamic therapy (PDT) is a promising cancer treatment modality that involves the interaction of the photosensitizer, molecular oxygen and light of specific wavelength to destroy tumor cells. Treatment induced hypoxia is one of the main side effects of PDT and efforts are underway to optimize PDT protocols for improved efficacy. The aim of this study was to investigate the anti-tumor effects of PDT plus Erbitux, an angiogenesis inhibitor that targets epidermal growth factor receptor (EGFR), on human bladder cancer model. Tumor-bearing nude mice were assigned to four groups that included control, PDT, Erbitux and PDT plus Erbitux and tumor volume was charted over 90-day period. Results Our results demonstrate that combination of Erbitux with PDT strongly inhibits tumor growth in the bladder tumor xenograft model when compared to the other groups. Downregulation of EGFR was detected using immunohistochemistry, immunofluorescence and western blotting. Increased apoptosis was associated with tumor inhibition in the combination therapy group. In addition, we identified the dephosphorylation of ErbB4 at tyrosine 1284 site to play a major role in tumor inhibition. Also, at the RNA level downregulation of EGFR target genes cyclin D1 and c-myc was observed in tumors treated with PDT plus Erbitux. Conclusion The combination therapy of PDT and Erbitux effectively inhibits tumor growth and is a promising therapeutic approach in the treatment of bladder tumors.
Membrane Type 1 Matrix Metalloproteinase Regulates Collagen-Dependent Mitogen-Activated Protein/Extracellular Signal-Related Kinase Activation and Cell Migration
Authors: Takahisa Takino, Hisashi Miyamori, Yumi Watanabe, Katsuji Yoshioka, Motoharu Seiki, Hiroshi Sato
Journal: Cancer Research (2004)

Abstract Mitogen-activated protein kinase-extracellular signal-related kinase (ERK) kinase 1 (MEK1)/ERK signaling has been implicated in the regulation of tumor cell invasion and metastasis. Migration of HT1080 cells on type I collagen was suppressed by the matrix metalloproteinase (MMP) inhibitors BB94 and tissue inhibitor of metalloproteinase (TIMP)-2 but not by TIMP-1. TIMP-2-specific inhibition suggests that membrane type 1 MMP (MT1-MMP) is likely involved in this process. Activation of ERK was induced in HT1080 cells adhered on dishes coated with type I collagen, and this was inhibited by BB94. MMP-2 processing in HT1080 cells, which also was stimulated by cultivation on type I collagen, was inhibited by MEK inhibitor PD98059. Expression of a constitutively active form of MEK1 promoted MMP-2 processing concomitant with the increase of MT1-MMP levels, suggesting that MT1-MMP is regulated by MEK/ERK signaling. In addition, expression of the hemopexin-like domain of MT1-MMP in HT1080 cells interfered with MMP-2 processing, ERK activation, and cell migration, implying that the enzymatic activity of MT1-MMP is involved in collagen-induced ERK activation, which results in enhanced cell migration. Thus, adhesion of HT1080 cells to type I collagen induces MT1-MMP-dependent ERK activation, which in turn causes an increase in MT1-MMP levels and subsequent cell migration.