tbuckley/cabot-search huggingface dataset:
Phosphotyrosine Signaling Analysis in Human Tumors Is Confounded by Systemic Ischemia-Driven Artifacts and Intra-Specimen Heterogeneity
Authors: Aaron S. Gajadhar, Hannah Johnson, Robbert J.C. Slebos, Kent Shaddox, Kerry Wiles, Mary Kay Washington, Alan J. Herline, Douglas A. Levine, Daniel C. Liebler, Forest M. White
Journal: Cancer Research (2015)

Abstract Tumor protein phosphorylation analysis may provide insight into intracellular signaling networks underlying tumor behavior, revealing diagnostic, prognostic or therapeutic information. Human tumors collected by The Cancer Genome Atlas program potentially offer the opportunity to characterize activated networks driving tumor progression, in parallel with the genetic and transcriptional landscape already documented for these tumors. However, a critical question is whether cellular signaling networks can be reliably analyzed in surgical specimens, where freezing delays and spatial sampling disparities may potentially obscure physiologic signaling. To quantify the extent of these effects, we analyzed the stability of phosphotyrosine (pTyr) sites in ovarian and colon tumors collected under conditions of controlled ischemia and in the context of defined intratumoral sampling. Cold-ischemia produced a rapid, unpredictable, and widespread impact on tumor pTyr networks within 5 minutes of resection, altering up to 50% of pTyr sites by more than 2-fold. Effects on adhesion and migration, inflammatory response, proliferation, and stress response pathways were recapitulated in both ovarian and colon tumors. In addition, sampling of spatially distinct colon tumor biopsies revealed pTyr differences as dramatic as those associated with ischemic times, despite uniform protein expression profiles. Moreover, intratumoral spatial heterogeneity and pTyr dynamic response to ischemia varied dramatically between tumors collected from different patients. Overall, these findings reveal unforeseen phosphorylation complexity, thereby increasing the difficulty of extracting physiologically relevant pTyr signaling networks from archived tissue specimens. In light of this data, prospective tumor pTyr analysis will require appropriate sampling and collection protocols to preserve in vivo signaling features. Cancer Res; 75(7); 1495–503. ©2015 AACR.
A Panel of Four miRNAs Accurately Differentiates Malignant from Benign Indeterminate Thyroid Lesions on Fine Needle Aspiration
Authors: Xavier M. Keutgen, Filippo Filicori, Michael J. Crowley, Yongchun Wang, Theresa Scognamiglio, Rana Hoda, Daniel Buitrago, David Cooper, Martha A. Zeiger, Rasa Zarnegar, Olivier Elemento, Thomas J. Fahey
Journal: Clinical Cancer Research (2012)

Indeterminate thyroid lesions on fine needle aspiration (FNA) harbor malignancy in about 25% of cases. Hemi- or total thyroidectomy has, therefore, been routinely advocated for definitive diagnosis. In this study, we analyzed miRNA expression in indeterminate FNA samples and determined its prognostic effects on final pathologic diagnosis.A predictive model was derived using 29 ex vivo indeterminate thyroid lesions on FNA to differentiate malignant from benign tumors at a tertiary referral center and validated on an independent set of 72 prospectively collected in vivo FNA samples. Expression levels of miR-222, miR-328, miR-197, miR-21, miR-181a, and miR-146b were determined using reverse transcriptase PCR. A statistical model was developed using the support vector machine (SVM) approach.A SVM model with four miRNAs (miR-222, miR-328, miR-197, and miR-21) was initially estimated to have 86% predictive accuracy using cross-validation. When applied to the 72 independent in vivo validation samples, performance was actually better than predicted with a sensitivity of 100% and specificity of 86%, for a predictive accuracy of 90% in differentiating malignant from benign indeterminate lesions. When Hurthle cell lesions were excluded, overall accuracy improved to 97% with 100% sensitivity and 95% specificity.This study shows that that the expression of miR-222, miR-328, miR-197, and miR-21 combined in a predictive model is accurate at differentiating malignant from benign indeterminate thyroid lesions on FNA. These findings suggest that FNA miRNA analysis could be a useful adjunct in the management algorithm of patients with thyroid nodules.
Constant Mean Viral Copy Number per Infected Cell in Tissues Regardless of High, Low, or Undetectable Plasma HIV RNA
Authors: Richard D. Hockett, J. Michael Kilby, Cynthia A. Derdeyn, Michael S. Saag, Michael Sillers, Kathleen Squires, Scott Chiz, Martin A. Nowak, George M. Shaw, R. Pat Bucy
Journal: The Journal of Experimental Medicine (1999)

Quantitative analysis of the relationship between virus expression and disease outcome has been critical for understanding HIV-1 pathogenesis. Yet the amount of viral RNA contained within an HIV-expressing cell and the relationship between the number of virus-producing cells and plasma virus load has not been established or reflected in models of viral dynamics. We report here a novel strategy for the coordinated analysis of virus expression in lymph node specimens. The results obtained for patients with a broad range of plasma viral loads before and after antiretroviral therapy reveal a constant mean viral (v)RNA copy number (3.6 log10 copies) per infected cell, regardless of plasma virus load or treatment status. In addition, there was a significant but nonlinear direct correlation between the frequency of vRNA+ lymph node cells and plasma vRNA. As predicted from this relationship, residual cells expressing this same mean copy number are detectable (frequency &amp;lt;2/106 cells) in tissues of treated patients who have plasma vRNA levels below the current detectable threshold (&amp;lt;50 copies/ml). These data suggest that fully replication-active cells are responsible for sustaining viremia after initiation of potent antiretroviral therapy and that plasma virus titers correlate, albeit in a nonlinear fashion, with the number of virus-expressing cells in lymphoid tissue.
Extending the Convergence of Canonical WNT Signaling and Classic Cancer Pathways for Treatment of Malignant Peripheral Nerve Sheath Tumors
Authors: Karlyne M. Reilly
Journal: Cancer Discovery (2013)

Malignant peripheral nerve sheath tumors (MPNST) are incurable tumors of the Schwann cell lineage that progress unpredictably from benign plexiform neurofibromas. In this issue of Cancer Discovery, Watson and colleagues use an insertional mutagenesis screen combined with network analysis to identify the canonical WNT signaling pathway as an important potential biomarker of tumor progression and target for combination therapy in MPNSTs.
Intracellular localisation of galectin-3 has a protective role in chondrocyte survival
Authors: C Boileau, F Poirier, J-P Pelletier, M Guévremont, N Duval, J Martel-Pelletier, P Reboul
Journal: Annals of the Rheumatic Diseases (2007)

Objective: Although galectin-3 (gal-3) is expressed during arthritic disorders, the part it plays has never been described. The aim of the study was to determine the intracellular roles of gal-3 in chondrocytes and cartilage. Methods: Following treatment with sodium nitroprusside, a cell death inducer, intracellular levels of total and phosphorylated gal-3 were measured by immunoblots in human osteoarthritic (OA) chondrocytes. Cell viability was also assessed by the lactate dehydrogenase activity in conditioned media from OA chondrocytes or from ATDC5 cells transfected with a gal-3-expressing vector. After generating an OA model by intra-articular injection of 0.5% mono-iodoacetate (MIA), histological evaluation of articular cartilage and subchondral bone was performed in wild-type (WT) and gal-3 knockout (KO) mice aged 6 weeks and 4 months. Results: In vitro experiments demonstrated that intracellular gal-3 had a protective role in chondrocyte survival, which involved its phosphorylation. In contrast to 6-week-old mice, 4-month-old gal-3 KO mice, compared with WT mice, presented OA-like cartilage modifications. OA induction via MIA injection in WT mice generated cartilage lesions similar to those found in gal-3 KO animals. Moreover, OA induction showed a significant decrease in subchondral bone surface in the gal-3 KO mice in contrast to the WT group. Conclusions: Altogether these findings indicate that intracellular gal-3 has a beneficial effect in articular cells, as its absence in KO mice led to cartilage lesions.
Cubilin and Amnionless Mediate Protein Reabsorption in Drosophila Nephrocytes
Authors: Fujian Zhang, Ying Zhao, Yufang Chao, Katherine Muir, Zhe Han
Journal: Journal of the American Society of Nephrology (2012)

The insect nephrocyte and the mammalian glomerular podocyte are similar with regard to filtration, but it remains unclear whether there is an organ or cell type in flies that reabsorbs proteins. Here, we show that the Drosophila nephrocyte has molecular, structural, and functional similarities to the renal proximal tubule cell. We screened for genes required for nephrocyte function and identified two Drosophila genes encoding orthologs of mammalian cubilin and amnionless (AMN), two major receptors for protein reabsorption in the proximal tubule. In Drosophila, expression of dCubilin and dAMN is specific to nephrocytes, where they function as co-receptors for protein uptake. Targeted expression of human AMN in Drosophila nephrocytes was sufficient to rescue defective protein uptake induced by dAMN knockdown, suggesting evolutionary conservation of Cubilin/AMN co-receptors function from flies to humans. Furthermore, we found that Cubilin/AMN-mediated protein reabsorption is required for the maintenance of nephrocyte ultrastructure and fly survival under conditions of toxic stress. In conclusion, the insect nephrocyte combines filtration with protein reabsorption, using evolutionarily conserved genes and subcellular structures, suggesting that it can serve as a simplified model for both podocytes and the renal proximal tubule.
Erlotinib as second-line treatment in patients with advanced non-small-cell lung cancer and asymptomatic brain metastases: a phase II study (CTONG–0803)
Authors: Y.-L. Wu, C. Zhou, Y. Cheng, S. Lu, G.-Y. Chen, C. Huang, Y.-S. Huang, H.-H. Yan, S. Ren, Y. Liu, J.-J. Yang
Journal: Annals of Oncology (2012)
Live imaging of effector cell trafficking and autoantigen recognition within the unfolding autoimmune encephalomyelitis lesion
Authors: Naoto Kawakami, U. Valentin Nägerl, Francesca Odoardi, Tobias Bonhoeffer, Hartmut Wekerle, Alexander Flügel
Journal: The Journal of Experimental Medicine (2005)

We tracked pathogenic myelin basic protein-specific CD4+ effector T cells in early central nervous system (CNS) lesions of experimental autoimmune encephalomyelitis (EAE) by combining two-photon imaging and fluorescence video microscopy. We made two key observations: (a) the majority of the cells (65%) moved fast (maximal speed 25 μm/min) and apparently nondirected through the compact tissue; and (b) a second group of effector T cells (35%) appeared tethered to a fixed point. Polarization of T cell receptor and adhesion molecules (lymphocyte function-associated antigen 1) towards this fixed point suggests the formation of immune synapses. Nonpathogenic, ovalbumin-specific T cells were not tethered in the CNS and did not form synapse-like contacts, but moved through the tissue. After intrathecal injection of antigen, 40% of ovalbumin-specific T cells became tethered. Conversely, injection of anti–major histocompatibility complex class II antibodies profoundly reduced the number of stationary pathogenic T cells within the CNS (to 15%). We propose that rapid penetration of the CNS parenchyma by numerous autoimmune effector T cells along with multiple autoantigen-presentation events are responsible for the fulminate development of clinical EAE.
REGARDING SODIUM AMYTAL AS A PROGNOSTIC AID IN INSULIN AND METRAZOL SHOCK THERAPY OF MENTAL PATIENTS. (DEMENTIA PRÆCOX.)
Authors: M. M. HARRIS, WM. A. HORWITZ, E. A. MILCH
Journal: American Journal of Psychiatry (1939)

1. A total of 55 cases of dementia præcox were tested by the intravenous injection of prenarcotic doses of sodium amytal prior to treatment with insulin hypoglycemic therapy. 2. An ameliorating response to the injection of sodium amytal was obtained in 30 patients and of these 23 or 77 per cent had a favorable therapeutic response to insulin hypoglycemic treatment. 3. No ameliorating response to sodium amytal was obtained in 25 cases and of these 16 or 64 per cent failed to respond to insulin treatment. 4. The results of metrazol convulsant therapy in cases that failed to respond to insulin treatments are also compared with the sodium amytal test. 5. The response to the sodium amytal test appears to be of prognostic value in insulin hypoglycemic shock therapy. 6. Plans for further studies are indicated.
Factors influencing the incidence and prevalence of food allergy
Authors: S. Cochrane, K. Beyer, M. Clausen, M. Wjst, R. Hiller, C. Nicoletti, Z. Szepfalusi, H. Savelkoul, H. Breiteneder, Y. Manios, R. Crittenden, P. Burney
Journal: Allergy (2009)

Food allergy is an increasing problem in Europe and elsewhere and severe reactions to food are also becoming more common. As food allergy is usually associated with other forms of allergic sensitisation it is likely that many risk factors are common to all forms of allergy. However the potential severity of the disease and the specific public heath measures required for food allergy make it important to identify the specific risk factors for this condition. Food allergy is unusual in that it often manifests itself very early in life and commonly remits with the development of tolerance. Hypotheses that explain the distribution of food allergy include specific genetic polymorphisms, the nature of the allergens involved and the unique exposure to large quantities of allergen through the gut. Progress has been made in developing more specific and testable hypotheses but the evidence for any of these is still only preliminary. Further collaborative research is required to develop an appropriate public health response to this growing problem.
Premenopausal Advantages in Postprandial Lipid Metabolism Are Lost in Women With Type 2 Diabetes
Authors: Michael G. Masding, Anna J. Stears, Graham C. Burdge, Stephen A. Wootton, Derek D. Sandeman
Journal: Diabetes Care (2003)

OBJECTIVE—Women with type 2 diabetes appear to lose the protection against cardiovascular disease afforded by estrogens. We examined the effects of menopausal status on postprandial clearance of dietary fat in healthy and diabetic women. RESEARCH DESIGN AND METHODS—Fasting subjects (premenopausal and postmenopausal control subjects, premenopausal and postmenopausal diabetic women, all n = 8) were given a meal containing the stable isotope 1,1,1-13C-tripalmitin, with blood and breath sampled for 6 and 24 h, respectively, in the postprandial period. Lower levels of 13C-palmitic acid (13C-PA) in the triglyceride fraction implies more efficient chylomicron clearance, lower levels of 13C-PA in the nonesterified fatty acid (NEFA) fraction implies improved dietary NEFA entrapment, and higher levels of 13CO2 in the breath denote more efficient of oxidation of dietary-derived lipid. RESULTS—In diabetic women, there were no differences between the pre- and postmenopausal groups for any of these parameters. In contrast, premenopausal control subjects, compared with postmenopausal control subjects, had lower 13C-PA in the triglyceride fraction area under the curve (AUC) (premenopausal median [range] 25.2 [12.1–49.4 mmol/l] per 6 h, postmenopausal 48.5 [15.5–77.2 mmol/l] per 6 h; P &amp;lt; 0.01) and higher 13CO2 levels in the breath AUC (premenopausal 22.5 [18.0–31.5%] of administered dose, postmenopausal 17.2 [11.2–31.5%] of administered dose; P &amp;lt; 0.01) with no difference between groups in levels of 13C-PA in the NEFA fraction AUC. CONCLUSIONS—The premenopausal advantage in clearance of dietary lipid is not seen in premenopausal diabetic women. This is likely to promote an atherogenic lipoprotein profile and may contribute to the loss of cardiovascular disease protection seen in diabetic women.
Public at risk: a survey of sunbed parlour operating practices in Northern Ireland
Authors: A. Gavin, C. Donnelly, A. Devlin, C. Devereux, G. O’Callaghan, G. McElwee, S. Gordon, T. Crossan, N. McMahon, P. Loan, S. Martin, L. McPeak, J. Caughey, A.H. O’Hagan
Journal: British Journal of Dermatology (2009)

Background The International Agency for Research on Cancer has identified artificial ultraviolet (UV) radiation as a class 1 carcinogen. The contribution of sunbeds to malignant melanoma has been estimated at 100 deaths per year in the U.K. The sunbed industry is growing and claims self-regulation. Objectives To explore the standards of operation and client protection for sunbed users. Methods An observational study of tanning parlour practices was conducted by Environmental Health Practitioners who made unannounced visits to the majority of known commercial tanning parlours in Northern Ireland (population 1·77 million) during July/August 2007. Descriptive statistics were produced and comparisons between groups were made using χ2 analysis. Results All 332 premises visited cooperated with the survey. The UV type in machines was unknown in 71·2% of premises while 15·6% reported using type 4, high-dose UV devices; 36·2% of premises did not regularly service sunbeds or were unsure. Unsupervised use of sunbeds was reported in 8·6% of parlours and 3·4% provided a home sunbed service. Eye protection was available in 97·6% of premises but 34·6% charged for the service and only 79·6% sanitized these between use. Of the responders 15·9% were members of the Sunbed Association. These were more likely to have maintenance records and operating manuals but were also more likely to provide a home sunbed service. Conclusions This study highlights the need for improved standards of regulation of the sunbed industry to protect clients from excessive and dangerous levels of UV radiation in a population where the numbers of melanomas continue to rise.
A novel lentiviral vector targets gene transfer into human hematopoietic stem cells in marrow from patients with bone marrow failure syndrome and in vivo in humanized mice
Authors: Cecilia Frecha, Caroline Costa, Didier Nègre, Fouzia Amirache, Didier Trono, Paula Rio, Juan Bueren, François-Loïc Cosset, Els Verhoeyen
Journal: Blood (2011)
Macular degeneration needs longer lasting treatments
Authors: S. J. Talks
Journal: BMJ (2014)

Clinical trials show that bevacizumab can work as well as ranibizumab for the treatment of age related macular degeneration.1 For patients to gain the full visual benefit they need four weekly review and possible treatment. This has proved difficult for patients, relatives, and healthcare providers. Real world outcome data have failed to show the same visual …
Lactic dehydrogenase isoenzyme determination in the diagnosis of acute myocardial infarction.
Authors: G Vasudevan, D W Mercer, M A Varat
Journal: Circulation (1978)

Lactic dehydrogenase (LD) isoenzymes were determined by a rapid, simple technique and their utility in the diagnosis of acute myocardial infarction (AMI) was evaluated. LD isoenzymes were separated by ion-exchange column chromatography using DEAE-Sephadex. The cardiac fractions (LD-1 and LD-2) were measured separately on an Abbott ABA-100 analyzer and ratio of LD isoenzyme 1 to LD isoenzyme 2 (LD1:2) calculated. Daily serum samples were obtained from 100 patients selected only for a history of chest pain of abrupt onset. In 47 patients whose diagnosis was acute myocardial infarction (AMI), confirmed by typical clinical presentation and typical rise in cardiac-specific creatine kinase isoenzyme (MB(, peak LD1:2 ranged from 0.77 to 2.26. In 44 patients without AMI, peak LD1:2 ranged from 0.25 to 0.76. In two patients with electrocardiographic changes chest pain occurred two and five days previously; there was no rise in MB, but LD1:2 was elevated. Four patients with small AMI had no rise in LD1:2. Three more patients (one with active hemolysis) had false positive results. Thus, there was a sensitivity of 96% and a specificity of 97% when the cut-off point was LD1:2 = 0.76. LD1:2 is not quite as sensitive or specific as MD, but the ratio allows for the diagnosis of infarction in cases where MB has already returned to normal.
RIBBON-2: A Randomized, Double-Blind, Placebo-Controlled, Phase III Trial Evaluating the Efficacy and Safety of Bevacizumab in Combination With Chemotherapy for Second-Line Treatment of Human Epidermal Growth Factor Receptor 2–Negative Metastatic Breast Cancer
Authors: Adam M. Brufsky, Sara Hurvitz, Edith Perez, Raji Swamy, Vicente Valero, Vincent O'Neill, Hope S. Rugo
Journal: Journal of Clinical Oncology (2011)

This phase III study compared the efficacy and safety of bevacizumab combined with standard chemotherapy regimens versus chemotherapy alone as second-line treatment of patients with human epidermal growth factor receptor 2 (HER2) -negative metastatic breast cancer.Patients were randomly assigned 2:1 to chemotherapy + bevacizumab or to chemotherapy + placebo. Before random assignment, investigators chose capecitabine, a taxane (paclitaxel, nab-paclitaxel, or docetaxel), gemcitabine, or vinorelbine. Dosing for bevacizumab or placebo was 15 mg/kg every 3 weeks or 10 mg/kg every 2 weeks, depending on chemotherapy regimen. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, PFS by chemotherapy cohort, objective response rate (ORR), duration of objective response, 1-year survival rate, and safety.RIBBON-2 enrolled 684 patients (225, chemotherapy + placebo; 459, chemotherapy + bevacizumab). The combination of bevacizumab with chemotherapy demonstrated a statistically significant benefit. Median PFS increased from 5.1 to 7.2 months (stratified hazard ratio for PFS, 0.78; 95% CI, 0.64 to 0.93; P = .0072). The 10% improvement in ORR between the placebo- and bevacizumab-containing arms (39.5% v 29.6%; P = .0193), although not statistically significant, was consistent with previous trials. There was no statistically significant difference in overall survival. The most common grade ≥ 3 adverse events (AEs) related to bevacizumab treatment were hypertension (9.0%) and proteinuria (3.1%). There was an increased number of AEs leading to study discontinuation in the chemotherapy + bevacizumab arm compared with the chemotherapy + placebo arm (13.3% v 7.2%).The combination of bevacizumab with commonly used chemotherapies improved PFS in the second-line treatment of patients with HER2-negative metastatic breast cancer, with a safety profile comparable with that in prior phase III studies.