tbuckley/cabot-search huggingface dataset:
Identification of Metastasis-Associated Receptor Tyrosine Kinases in Non–Small Cell Lung Cancer
Authors: Carsten Müller-Tidow, Sven Diederichs, Etmar Bulk, Thorsten Pohle, Björn Steffen, Joachim Schwäble, Sylvia Plewka, Michael Thomas, Ralf Metzger, Paul M. Schneider, Christian H. Brandts, Wolfgang E. Berdel, Hubert Serve
Journal: Cancer Research (2005)

Abstract Development of distant metastasis after tumor resection is the leading cause of death in early-stage non–small cell lung cancer (NSCLC). Receptor tyrosine kinases (RTK) are involved in tumorigenesis but only few RTKs have been systematically studied in NSCLC. Here, we provide quantitative real-time reverse transcription-PCR expression data of all RTKs (n = 56) in primary tumors of 70 patients with early-stage (I-IIIA) NSCLC. Overall, 33 RTKs were expressed in at least 25% of the patients. Several RTKs were significantly expressed higher in tumors that ultimately metastasized. The hazard risk for metastasis development in stage I/II disease was increased at least 3-fold for tumors with high expression levels of insulin receptor, neurotrophic tyrosine receptor kinase 1, epidermal growth factor receptor, ERBB2, ERBB3, platelet-derived growth factor receptor β, fibroblast growth factor receptor 1, or leukocyte tyrosine kinase. Relative risks were reduced 3-fold by expression of EPHB6 or DKFZ1. Three members of the epidermal growth factor receptor family were associated with a high risk of metastasis, emphasizing the validity of our data. High ERBB3 expression was significantly associated with decreased survival. Taken together, our genome-wide RTK expression map uncovered the previously unknown value of several RTKs as potential markers for prognosis and metastasis prediction in early-stage NSCLC. The identified RTKs represent promising novel candidates for further functional analyses.
THE PRESENT STATE OF THE TEACHING AND PRACTICE OF SURGERY
Authors: G. L. Cheatle
Journal: BMJ (1925)

DURINGthe last year I had a heart-to-heart talk with a learned and thouglhtful provinicial surgeon.Allmong the things he said to inie werce the following: " Provincial surgeons Ino loniger look towvards the r'lurgeons of Lcndon for new niotionis or' leadership, and th,is is because there is little or no original reiearch work beinig done by Lotidon mzeni.Provinicial sur geons see as much surgery, operate on as many patienlts, and wc are technically as perfect as Lonidon men."Gentlemexi, although I would not lhear your eniemy say so, wxe have all hiad sonie such thoughts about ourselves.Research TVork.Let us begin witlh tlle first point he made-that London is losing its leadership, because so very few men are engaged in research work as well as practice.I think it miiust be admitted that, in these days, mere technical ability is nlot enough to maintain ascendancy of leadership, or to regain ascendancy if leadership be lost.I take it to be a fact all the world over that lie who is only a so-called clinical surgeon and nothing more is losing, or has lost, his position as a leader in his profession.He can add very little kniow- ledge, and except for acquiring skill in the technicality 6f his art he can acquire very little more of any value what- ever.His thouglhts cani never be profound, and without researchl work there is very little encouragement for him to think at all; instead of his teaching being inspired by the results of his ownl original research, it is limited in outlook, dull and conventional in type.It seems to me essenitial that every surgeon should be performing researclh work, however little, in a laboratory, however srDall, in conjuinctioni with his practice.I know many men will say that practice excludes the possibility of such a schleimie.I do not admit this.Time can always be found for thlings that a man wants to do.It will be said that some men are more fit for practice than investigation.I do not think that statement has been properly tested.But that is not so much my point.My point does not concern those men.
Reduced bone density in patients with inflammatory bowel disease.
Authors: I Bjarnason, A Macpherson, C Mackintosh, M Buxton-Thomas, I Forgacs, C Moniz
Journal: Gut (1997)

Reduced bone mineral density in patients with inflammatory bowel disease is thought to be due to disturbances in calcium homeostasis or the effects of corticosteroid treatment.To assess the prevalence and mechanism of reduced bone mineral density in 79 patients with inflammatory bowel disease (44 with Crohn's disease, 35 with ulcerative colitis) who did not have significant risk factors for low bone densities.Dual x ray absorptiometry was used to measure bone mineral density and serum and urinary markers of osteoblast (alkaline phosphatase, procollagen 1 carboxy terminal peptide and osteocalcin) and osteoclast (pyridinoline, deoxypyridinoline, and type 1 collagen carboxy terminal peptide) activities to assess bone turnover.There was a high prevalence of low bone mineral density (prevalence of T scores < -1.0 from 51%-77%; T scores < -2.5 (osteoporosis) from 17%-28%) with hips being more often affected than vertebrae (p < 0.001). Reduced bone mineral density did not relate to concurrent or past corticosteroid intake, or type, site, or severity of disease. Whereas calcium homeostasis was normal, bone markers showed increased bone resorption without a compensatory increase in bone formation.The greater prevalence of reduced hip bone mineral density, as opposed to vertebral, mineral density and the pattern of a selective increase in bone resorption contrasts with that found in other known causes of metabolic bone disease.
Ethical and practical considerations concerning perimortem sperm procurement in a severe neurologically damaged patient and the apparent discrepancy in validation of proxy consent in various postmortem procedures
Authors: J. L. Epker, Y. J. de Groot, E. J. O. Kompanje
Journal: Intensive Care Medicine (2012)

Although sperm procurement and preservation has been become commonplace in situations in which infertility can be easily foreseen, peri- or postmortem sperm procurement for reproductive use in unexpected coma or death is not generally accepted. There are no laws and regulations for this kind of intervention in all countries and they may also differ from country to country. Intensive care specialists can be confronted with a request for peri- or postmortem sperm procurement, while not being aware of the country-specific provisions. A young male patient who suffered 17 L blood loss and half an hour of cardiopulmonary resuscitation was admitted to a university hospital for an ill-understood unstoppable abdominal bleed. After rapid deterioration of the neurological situation, due to severe post-anoxic damage, the decision was made to withdraw life-sustaining treatment. At that moment the partner of the patient asked for perimortem sperm procurement, which was denied, on the basis of the ethical reasoning that consent of the man involved was lacking. Retrospectively the decision was right according to Dutch regulations; however, with more time for elaborate ethical reasoning, the decision outcome, without the awareness of an existing prohibition, also could have been different. Guidelines and laws for peri- or postmortem sperm procurement differ from country to country, so any intensive care specialist should have knowledge from the latest legislation for this specific subject in his/her country. An overview is provided. A decision based on ethical reasoning may appear satisfying, but can unfortunately be in full contrast with the existing laws.
FINANCE AND RESPONSIBILITY
Authors: L. Jas. Picton
Journal: BMJ (1930)

<h3>ABSTRACT</h3> Midbrain dopaminergic (mDA) neurons degenerate in Parkinson’s disease and are one of the main targets for cell replacement therapies. However, a comprehensive view of the signals and cell types contributing to mDA neurogenesis is not yet available. By analyzing the transcriptome of the mouse ventral midbrain at a tissue and single-cell level during mDA neurogenesis we found that three recently identified radial glia types 1-3 (Rgl1-3) contribute to different key aspects of mDA neurogenesis. While Rgl3 expressed most extracellular matrix components and multiple ligands for various pathways controlling mDA neuron development, such as Wnt and Shh, Rgl1-2 expressed most receptors. Moreover, we found that specific transcription factor networks explain the transcriptome and suggest a function for each individual radial glia. A network controlling neurogenesis was found in Rgl1, progenitor maintenance in Rgl2 and the secretion of factors forming the mDA niche by Rgl3. Our results thus uncover a broad repertoire of developmental signals expressed by each midbrain cell type during mDA neurogenesis. Cells identified for their emerging importance are Rgl3, a niche cell type, and Rgl1, a neurogenic progenitor that expresses <i>ARNTL,</i> a transcription factor that we find is required for mDA neurogenesis.
Phase II Study of Imatinib Mesylate Plus Hydroxyurea in Adults With Recurrent Glioblastoma Multiforme
Authors: David A. Reardon, Merrill J. Egorin, Jennifer A. Quinn, Jeremy N. Rich, Idharan Gururangan, James J. Vredenburgh, Annick Desjardins, Sith Sathornsumetee, James M. Provenzale, James E. Herndon, Jeannette M. Dowell, Michael A. Badruddoja, Roger E. McLendon, Theodore F. Lagattuta, Kimberly P. Kicielinski, Gregor Dresemann, John H. Sampson, Allan H. Friedman, August J. Salvado, Henry S. Friedman
Journal: Journal of Clinical Oncology (2005)

We performed a phase II study to evaluate the combination of imatinib mesylate, an adenosine triphosphate mimetic, tyrosine kinase inhibitor, plus hydroxyurea, a ribonucleotide reductase inhibitor, in patients with recurrent glioblastoma multiforme (GBM).Patients with GBM at any recurrence received imatinib mesylate plus hydroxyurea (500 mg twice a day) orally on a continuous, daily schedule. The imatinib mesylate dose was 500 mg twice a day for patients on enzyme-inducing antiepileptic drugs (EIAEDs) and 400 mg once a day for those not on EIAEDs. Assessments were performed every 28 days. The primary end point was 6-month progression-free survival (PFS).Thirty-three patients enrolled with progressive disease after prior radiotherapy and at least temozolomide-based chemotherapy. With a median follow-up of 58 weeks, 27% of patients were progression-free at 6 months, and the median PFS was 14.4 weeks. Three patients (9%) achieved radiographic response, and 14 (42%) achieved stable disease. Cox regression analysis identified concurrent EIAED use and no more than one prior progression as independent positive prognostic factors of PFS. The most common toxicities included grade 3 neutropenia (16%), thrombocytopenia (6%), and edema (6%). There were no grade 4 or 5 events. Concurrent EIAED use lowered imatinib mesylate exposure. Imatinib mesylate clearance was decreased at day 28 compared with day 1 in all patients, suggesting an effect of hydroxyurea.Imatinib mesylate plus hydroxyurea is well tolerated and associated with durable antitumor activity in some patients with recurrent GBM.
Correlations between Serum Monocyte Chemotactic Protein-1 Levels, Clinical Prognostic Factors, and HER-2/<i>neu</i> Vaccine-Related Immunity in Breast Cancer Patients
Authors: Zia A. Dehqanzada, Catherine E. Storrer, Matthew T. Hueman, Rebecca J. Foley, Katie A. Harris, Yusuf H. Jama, Tzu-Cheg Kao, Craig D. Shriver, Sathibalan Ponniah, George E. Peoples
Journal: Clinical Cancer Research (2006)

Abstract Purpose: We studied serum monocyte chemotactic protein-1 (MCP-1) levels in breast cancer patients in relationship to their clinicopathologic variables and immune response to a /neu E75 vaccine. Experimental Design: We measured MCP-1 levels in 32 /neu+ breast cancer patients before and after vaccination with a /neu E75 peptide + granulocyte macrophage colony-stimulating factor vaccine. Clinical prognostic variables were collected. Vaccine-specific immunologic responses were monitored. Results: Serum MCP-1 levels &amp;gt;250 pg/mL (MCP-high) correlated with favorable prognostic variables. MCP-high patients compared with MCP-low (&amp;lt;250 pg/mL) patients showed statistically significant later onset of disease, earlier stage of disease, fewer nodal metastasis, and less chemotherapy. MCP-high patients had increased levels of preexisting immunity when compared with MCP-low patients (69% versus 21%; P = 0.02). However, MCP-low patients showed higher inducible levels of MCP-1 compared with MCP-high patients (median increase, 41% versus 0%; P = 0.001) after vaccination. Moreover, MCP-low patients with &amp;gt;50% increase in MCP-1 levels (response-high) had worse clinical prognostic variables compared with patients with &amp;lt;50% increase (response-low). Response-high patients had statistically significant more poorly differentiated tumors, later stage of disease, and higher percentage of large tumors. Patients with &amp;gt;30% postvaccination MCP-1 increase also showed significant increases in E75-specific CD8+ T-cells (0.05% versus 0.38%; P = 0.03) in response to vaccination. Conclusions: High serum MCP-1 levels in breast cancer patients correlate with favorable prognostic variables and increased preexisting /neu immunity. E75 vaccination induces the largest MCP-1 response in patients with unfavorable clinicopathologic variables. Therefore, low serum MCP-1 levels may identify patients with worse prognosis and those most likely to benefit from this vaccination.
The Basic Principles of Chimeric Antigen Receptor Design
Authors: Michel Sadelain, Renier Brentjens, Isabelle Rivière
Journal: Cancer Discovery (2013)

Abstract Chimeric antigen receptors (CAR) are recombinant receptors that provide both antigen-binding and T-cell–activating functions. A multitude of CARs has been reported over the past decade, targeting an array of cell surface tumor antigens. Their biologic functions have dramatically changed following the introduction of tripartite receptors comprising a costimulatory domain, termed second-generation CARs. These have recently shown clinical benefit in patients treated with CD19-targeted autologous T cells. CARs may be combined with costimulatory ligands, chimeric costimulatory receptors, or cytokines to further enhance T-cell potency, specificity, and safety. CARs represent a new class of drugs with exciting potential for cancer immunotherapy. Significance: CARs are a new class of drugs with great potential for cancer immunotherapy. Upon their expression in T lymphocytes, CARs direct potent, targeted immune responses that have recently shown encouraging clinical outcomes in a subset of patients with B-cell malignancies. This review focuses on the design of CARs, including the requirements for optimal antigen recognition and different modalities to provide costimulatory support to targeted T cells, which include the use of second- and third-generation CARs, costimulatory ligands, chimeric costimulatory receptors, and cytokines. Cancer Discov; 3(4); 388–98. ©2013 AACR.
Rapid Mobilization of CD34+ Cells Following Administration of the CXCR4 Antagonist AMD3100 to Patients With Multiple Myeloma and Non-Hodgkin's Lymphoma
Authors: Steven M. Devine, Neal Flomenberg, David H. Vesole, Jane Liesveld, Daniel Weisdorf, Karin Badel, Gary Calandra, John F. DiPersio
Journal: Journal of Clinical Oncology (2004)

Interactions between the chemokine receptor CXCR4 and its ligand stromal derived factor-1 regulate hematopoietic stem-cell trafficking. AMD3100 is a CXCR4 antagonist that induces rapid mobilization of CD34+ cells in healthy volunteers. We performed a phase I study assessing the safety and clinical effects of AMD3100 in patients with multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL).Thirteen patients (MM, n=7; NHL, n=6) received AMD3100 at a dose of either 160 microg/kg (n=6) or 240 microg/kg (n=7). WBC and peripheral blood (PB) CD34+ cell counts were analyzed at 4 and 6 hours following injection.AMD3100 caused a rapid and statistically significant increase in the total WBC and PB CD34+ counts at both 4 and 6 hours following a single injection. The absolute CD34+ cell count increased from a baseline of 2.6 +/- 0.7/microL (mean +/- SE) to 15.6 +/- 3.9/microL and 16.2 +/- 4.3/microL at 4 hours (P=.002) and 6 hours after injection (P =.003), respectively. The absolute CD34+ cell counts observed at 4 and 6 hours following AMD3100 were higher in the 240 microg/kg group (19.3 +/- 6.9/microL and 20.4 +/- 7.6/microL, respectively) compared with the 160 microg/kg group (11.3 +/- 2.7/microL and 11.3 +/- 2.5/microL, respectively). The drug was well tolerated and only grade 1 toxicities were encountered.AMD3100 appears to be a safe and effective agent for the rapid mobilization of CD34+ cells in patients who have received prior chemotherapy. Further studies in combination with granulocyte colony-stimulating factor in patients with lymphoid malignancies are warranted.
Total bypass of the oesophagus for benign strictures using a reversed gastric tube.
Authors: P Yannopoulos, A Marselos
Journal: Thorax (1977)

Four cases of benign stricture of the oesophagus treated by reversed gastric tube oesophagoplasty are presented. The technique used is described in detail, and the advantages of this method over other ways of bypassing the oesophagus are discussed. The most important advantage is the restoration of normal deglutition with only one extrathoracic anasthomosis.
Therapeutic targeting of the MYC signal by inhibition of histone chaperone FACT in neuroblastoma
Authors: Daniel R. Carter, Jayne Murray, Belamy B. Cheung, Laura Gamble, Jessica Koach, Joanna Tsang, Selina Sutton, Heyam Kalla, Sarah Syed, Andrew J. Gifford, Natalia Issaeva, Asel Biktasova, Bernard Atmadibrata, Yuting Sun, Nicolas Sokolowski, Dora Ling, Patrick Y. Kim, Hannah Webber, Ashleigh Clark, Michelle Ruhle, Bing Liu, André Oberthuer, Matthias Fischer, Jennifer Byrne, Federica Saletta, Le Myo Thwe, Andrei Purmal, Gary Haderski, Catherine Burkhart, Frank Speleman, Katleen De Preter, Anneleen Beckers, David S. Ziegler, Tao Liu, Katerina V. Gurova, Andrei V. Gudkov, Murray D. Norris, Michelle Haber, Glenn M. Marshall
Journal: Science Translational Medicine (2015)

Histone chaperone FACT acts in a positive feedback loop with MYCN and is a therapeutic target in neuroblastoma.
The anti-inflammatory effects of sympathectomy in murine antigen-induced arthritis are associated with a reduction of Th1 and Th17 responses
Authors: Matthias Ebbinghaus, Mieczyslaw Gajda, Michael K Boettger, Hans-Georg Schaible, Rolf Bräuer
Journal: Annals of the Rheumatic Diseases (2011)

<b>Objective:</b> To determine if submaximal contractions used in contract-relax proprioceptive neuromuscular facilitation (CRPNF) stretching of the hamstrings yield comparable gains in hamstring flexibility to maximal voluntary isometric contractions (MVICs). <b>Method:</b> Randomised controlled trial. A convenience sample of 72 male subjects aged 18–27 was used. Subjects qualified by demonstrating tight hamstrings, defined as the inability to reach 70° of hip flexion during a straight leg raise. Sixty subjects were randomly assigned to one of three treatment groups: 1, 20% of MVIC; 2, 60% of MVIC; 3, 100% MVIC. Twelve subjects were randomly assigned to a control group (no stretching). Subjects in groups 1–3 performed three separate six second CRPNF stretches at the respective intensity with a 10 second rest between contractions, once a day for five days. Goniometric measurements of hamstring flexibility using a lying passive knee extension test were made before and after the stretching period to determine flexibility changes. <b>Results:</b> Paired <i>t</i> tests showed a significant change in flexibility for all treatment groups. A comparison of least squares means showed that there was no difference in flexibility gains between the treatment groups, but all treatment groups had significantly greater flexibility than the control group. <b>Conclusion:</b> CRPNF stretching using submaximal contractions is just as beneficial at improving hamstring flexibility as maximal contractions, and may reduce the risk of injury associated with PNF stretching.
How similar are fluid cognition and general intelligence? A developmental neuroscience perspective on fluid cognition as an aspect of human cognitive ability
Authors: Clancy Blair
Journal: Behavioral and Brain Sciences (2006)

This target article considers the relation of fluid cognitive functioning to general intelligence. A neurobiological model differentiating working memory/executive function cognitive processes of the prefrontal cortex from aspects of psychometrically defined general intelligence is presented. Work examining the rise in mean intelligence-test performance between normative cohorts, the neuropsychology and neuroscience of cognitive function in typically and atypically developing human populations, and stress, brain development, and corticolimbic connectivity in human and nonhuman animal models is reviewed and found to provide evidence of mechanisms through which early experience affects the development of an aspect of cognition closely related to, but distinct from, general intelligence. Particular emphasis is placed on the role of emotion in fluid cognition and on research indicating fluid cognitive deficits associated with early hippocampal pathology and with dysregulation of the hypothalamic-pituitary-adrenal axis stress-response system. Findings are seen to be consistent with the idea of an independent fluid cognitive construct and to assist with the interpretation of findings from the study of early compensatory education for children facing psychosocial adversity and from behavior genetic research on intelligence. It is concluded that ongoing development of neurobiologically grounded measures of fluid cognitive skills appropriate for young children will play a key role in understanding early mental development and the adaptive success to which it is related, particularly for young children facing social and economic disadvantage. Specifically, in the evaluation of the efficacy of compensatory education efforts such as Head Start and the readiness for school of children from diverse backgrounds, it is important to distinguish fluid cognition from psychometrically defined general intelligence.
Antibody-Drug Conjugates in Cancer Therapy
Authors: Eric L. Sievers, Peter D. Senter
Journal: Annual Review of Medicine (2012)

An antibody-drug conjugate (ADC) provides the possibility of selectively ablating cancer cells by combining the specificity of a monoclonal antibody (mAb) for a target antigen with the delivery of a highly potent cytotoxic agent. ADC target antigens are typically highly expressed on the surface of cancer cells compared to normal cells. The tumor target, the cytotoxic agent, and the manner in which the agent is attached to the antibody are key determinants of clinical activity and tolerability. Recently, several clinical trials have demonstrated that ADCs achieve higher clinical response rates than unconjugated mAbs targeting the same cell surface antigen. Brentuximab vedotin represents one such ADC that has recently been approved for the treatment of relapsed Hodgkin and systemic anaplastic large cell lymphomas—both characterized by high expression of the target antigen, CD30, on the surface of malignant cells. This review summarizes key characteristics of current, clinically active ADCs and highlights recent clinical data illustrating the benefit of antibody-targeted delivery of cytotoxic agents to cancer cells.