tbuckley/cabot-search huggingface dataset:
Enhanced Growth of Primary Tumors in Cancer-Prone Mice after Immunization against the Mutant Region of an Inherited Oncoprotein
Authors: Christopher T. Siegel, Karin Schreiber, Stephen C. Meredith, Gabriele B. Beck-Engeser, David W. Lancki, Christopher A. Lazarski, Yang-Xin Fu, Donald A. Rowley, Hans Schreiber
Journal: The Journal of Experimental Medicine (1999)

One major objective of tumor immunologists is to prevent cancer development in individuals at high risk. (TG.AC × C57BL/6)F1 mice serve as a model for testing the feasibility of this objective. The mice carry in the germline a mutant ras oncogene that has an arginine at codon 12 instead of glycine present in the wild-type, and after physical (wounding) or chemical promotion, these mice have a high probability for developing papillomas that progress to cancer. Furthermore, F1 mice immunized with Arg12 mutant ras peptide in complete Freund's adjuvant (CFA) develop T cells within 10 d that proliferate in vitro on stimulation with the Arg12 mutant ras peptide. Within 14 d, these mice have delayed-type hypersensitivity to the peptide. Immunization with CFA alone or with a different Arg12 mutant ras peptide in CFA induced neither response. To determine the effect of immunization on development of tumors, mice immunized 3 wk earlier were painted on the back with phorbol 12-myristate 13-acetate every 3 d for 8 wk. The time of appearance and the number of papillomas were about the same in immunized and control mice, but the tumors grew faster and became much larger in the mice immunized with the Arg12 mutant ras peptide. Thus, the immunization failed to protect against growth of papillomas. The peptide-induced CD4+ T cells preferentially recognized the peptide but not the native mutant ras protein. On the other hand, mice immunized with Arg12 mutant ras peptide and bearing papillomas had serum antibodies that did bind native mutant ras protein. Together, these studies indicate that active immunization of cancer-prone individuals may result in immune responses that fail to eradicate mutant oncogene–expressing tumor cells, but rather induce a remarkable enhancement of tumor growth.
Impact of Cancer Research Bureaucracy on Innovation, Costs, and Patient Care
Authors: David P. Steensma, Hagop M. Kantarjian
Journal: Journal of Clinical Oncology (2014)

Batteredworkshoptablesandcrowdedchemicalbenchesbearsilentwitnesstothe thousands of failed prototypes that preceded development of theincandescentlightbulb,waxcylinderphonograph,andothertechni-cal advances described in Edison’s record 1,093 US patents. Edisonoftenwentseveraldayswithoutsleepingandmighthaveworkedevenlonger hours than a 1960s medical house ofﬁcer. He so detestedstoppingworktowaitforsuppliesfromvendorsthathekeptbinsandcupboards stocked with a broad range of exotic materials—anythinghisresearchteamsmightpossiblyneed.If Edison were an American cancer investigator working in theearly21stcentury,delaysinthesupplychainwouldbetheleastofhisperspiration-inducing problems. His shirt might be soaked withsweat, but his productivity would likely be meager and his nameunknown at the patent ofﬁce. Today, the inspirational idealism ofnewly minted medical faculty members with a driving ambition to“cure cancer”—oncology’s Edisons—is being smothered under amountain of red tape, their good intentions crushed by the logisticalrealityofwhatitactuallytakestoopenandexecuteaclinicalstudy.Trials of new drugs, especially in oncology, have become a longrow to hoe.
Polymyalgia Rheumatica: Pitfalls in Diagnosis
Authors: S Siebert, T M Lawson, M H Wheeler, J C Martin, B D Williams
Journal: Journal of the Royal Society of Medicine (2001)

The prevalence of polymyalgia rheumatica (PMR) in persons aged over 50 is about 700 per 100 0001,2. The diagnosis is based on a symptom complex of proximal myalgia and stiffness developing late in life usually associated with a raised erythrocyte sedimentation rate (ESR). A rapid response to low-dose oral steroids (10-20 mg prednisolone daily) is commonly thought to support the diagnosis3,4. PMR is, however, a diagnosis of exclusion.
Clinical significance of serum RCAS1 levels detected by monoclonal antibody 22-1-1 in patients with cholangiocellular carcinoma
Authors: Hironobu Watanabe, Munechika Enjoji, Manabu Nakashima, Ken-ichi Noguchi, Naoko Kinukawa, Rie Sugimoto, Kazuhiro Kotoh, Makoto Nakamuta, Hajime Nawata, Takeshi Watanabe
Journal: Journal of Hepatology (2003)
Loss of AngiomiR-126 and 130a in Angiogenic Early Outgrowth Cells From Patients With Chronic Heart Failure
Authors: Philipp Jakob, Carola Doerries, Sylvie Briand, Pavani Mocharla, Nicolle Kränkel, Christian Besler, Maja Mueller, Costantina Manes, Christian Templin, Christof Baltes, Markus Rudin, Heiner Adams, Mathias Wolfrum, Georg Noll, Frank Ruschitzka, Thomas F. Lüscher, Ulf Landmesser
Journal: Circulation (2012)

Background— MicroRNAs are key regulators of angiogenic processes. Administration of angiogenic early outgrowth cells (EOCs) or CD34 + cells has been suggested to improve cardiac function after ischemic injury, in particular by promoting neovascularization. The present study therefore examines regulation of angiomiRs, microRNAs involved in angiogenesis, in angiogenic EOCs and circulating CD34 + cells from patients with chronic heart failure (CHF) and the role for their cardiac repair capacity. Methods and Results— Angiogenic EOCs and CD34 + cells were isolated from patients with CHF caused by ischemic cardiomyopathy (n=45) and healthy subjects (n=35). In flow cytometry analyses, angiogenic EOCs were largely myeloid and positive for alternatively activated M2 macrophage markers. In vivo cardiac neovascularization and functional repair capacity were examined after transplantation into nude mice with myocardial infarction. Cardiac transplantation of angiogenic EOCs from healthy subjects markedly increased neovascularization and improved cardiac function, whereas no such effect was observed after transplantation of angiogenic EOCs from patients with CHF. Real-time polymerase chain reaction analysis of 14 candidate angiomiRs, expressed in angiogenic EOCs, revealed a pronounced loss of angiomiR-126 and -130a in angiogenic EOCs from patients with CHF that was also observed in circulating CD34 + cells. Anti–miR-126 transfection markedly impaired the capacity of angiogenic EOCs from healthy subjects to improve cardiac function. miR-126 mimic transfection increased the capacity of angiogenic EOCs from patients with CHF to improve cardiac neovascularization and function. Conclusions— The present study reveals a loss of angiomiR-126 and -130a in angiogenic EOCs and circulating CD34 + cells from patients with CHF. Reduced miR-126 expression was identified as a novel mechanism limiting their capacity to improve cardiac neovascularization and function that can be targeted by miR-126 mimic transfection.
The major component in schistosome eggs responsible for conditioning dendritic cells for Th2 polarization is a T2 ribonuclease (omega-1)
Authors: Svenja Steinfelder, John F. Andersen, Jennifer L. Cannons, Carl G. Feng, Manju Joshi, Dennis Dwyer, Pat Caspar, Pamela L. Schwartzberg, Alan Sher, Dragana Jankovic
Journal: The Journal of Experimental Medicine (2009)

Schistosoma mansoni eggs contain factors that trigger potent Th2 responses in vivo and condition mouse dendritic cells (DCs) to promote Th2 lymphocyte differentiation. Using an in vitro bystander polarization assay as the readout, we purified and identified the major Th2-inducing component from soluble egg extract (SEA) as the secreted T2 ribonuclease, omega-1. The Th2-promoting activity of omega-1 was found to be sensitive to ribonuclease inhibition and did not require MyD88/TRIF signaling in DCs. In common with unfractioned SEA, the purified native protein suppresses lipopolysaccharide-induced DC activation, but unlike SEA, it fails to trigger interleukin 4 production from basophils. Importantly, omega-1–exposed DCs displayed pronounced cytoskeletal changes and exhibited decreased antigen-dependent conjugate formation with CD4+ T cells. Based on this evidence, we hypothesize that S. mansoni omega-1 acts by limiting the interaction of DCs with CD4+ T lymphocytes, thereby lowering the strength of the activation signal delivered.
PSYCHIATRIC WORK THERAPY IN THE SOVIET UNION
Authors: JOSEPH WORTIS, DAVID FREUNDLICH
Journal: American Journal of Psychiatry (1964)

Work therapy in the Soviet Union, in both theory and practice, has its counterparts in this country, and cannot be regarded as unique. Its special features however are: 1. The great emphasis placed on its role in the treatment and rehabilitation of psychiatric patients. 2. The extensive investment of plant and equipment to promote its use. 3. The close relationship that is maintained between the sheltered work in a psychiatric setting and the normal work outside. 4. The emphasis on group work. 5. The extremely varied and individualized forms of work therapy that the state provides. 6. And finally there may well be a greater willingness among normal Russian workers to accept in their midst and to assist a convalescent or chronic psychiatric patient.
Tissue Renin-Angiotensin-Aldosterone Systems: Targets for Pharmacological Therapy
Authors: Michael Bader
Journal: The Annual Review of Pharmacology and Toxicology (2010)

The renin-angiotensin-aldosterone system is one of the most important systems in cardiovascular control and in the pathogenesis of cardiovascular diseases. Therefore, it is already a very successful drug target for the therapy of these diseases. However, angiotensins are generated not only in the plasma but also locally in tissues from precursors and substrates either locally expressed or imported from the circulation. In most areas of the brain, only locally generated angiotensins can exert effects on their receptors owing to the blood-brain barrier. Other tissue renin-angiotensin-aldosterone systems are found in cardiovascular organs such as kidney, heart, and vessels and play important roles in the function of these organs and in the deleterious actions of hypertension and diabetes on these tissues. Novel components with mostly opposite actions to the classical renin-angiotensin-aldosterone systems have been described and need functional characterization to evaluate their suitability as novel drug targets.
Limitation of myocardial infarct expansion by reperfusion independent of myocardial salvage.
Authors: J S Hochman, H Choo
Journal: Circulation (1987)

Very early reperfusion after coronary occlusion can reduce infarct size and preserve left ventricular function. Whether later reperfusion is of benefit is unclear. We studied the effect of very early reperfusion with myocardial salvage and "late" reperfusion without myocardial salvage on infarct expansion and aneurysm formation. Sixty-eight rats underwent left coronary artery ligation and were randomized to 30 min reperfusion, 2 hr reperfusion, or permanent coronary artery ligation. The animals were killed and the hearts examined at 2 weeks. Thirty minute reperfusion reduced infarct size, extent of transmurality, and infarct expansion. Two hour reperfusion reduced neither infarct size nor transmurality but inhibited infarct expansion. The results of this study in the rat preparation suggest a beneficial effect of "late" reperfusion on infarct expansion independent of myocardial salvage. If these results are confirmed in human beings, the period after myocardial infarction during which a patient can be considered for thrombolytic therapy or reperfusion by percutaneous transluminal coronary angioplasty could be greatly prolonged.
Mutational Landscape of Aggressive Cutaneous Squamous Cell Carcinoma
Authors: Curtis R. Pickering, Jane H. Zhou, J. Jack Lee, Jennifer A. Drummond, S. Andrew Peng, Rami E. Saade, Kenneth Y. Tsai, Jonathan L. Curry, Michael T. Tetzlaff, Stephen Y. Lai, Jun Yu, Donna M. Muzny, Harshavardhan Doddapaneni, Eve Shinbrot, Kyle R. Covington, Jianhua Zhang, Sahil Seth, Carlos Caulin, Gary L. Clayman, Adel K. El-Naggar, Richard A. Gibbs, Randal S. Weber, Jeffrey N. Myers, David A. Wheeler, Mitchell J. Frederick
Journal: Clinical Cancer Research (2014)

Abstract Purpose: Aggressive cutaneous squamous cell carcinoma (cSCC) is often a disfiguring and lethal disease. Very little is currently known about the mutations that drive aggressive cSCC. Experimental Design: Whole-exome sequencing was performed on 39 cases of aggressive cSCC to identify driver genes and novel therapeutic targets. Significantly, mutated genes were identified with MutSig or complementary methods developed to specifically identify candidate tumor suppressors based upon their inactivating mutation bias. Results: Despite the very high-mutational background caused by UV exposure, 23 candidate drivers were identified, including the well-known cancer-associated genes TP53, CDKN2A, NOTCH1, AJUBA, HRAS, CASP8, FAT1, and KMT2C (MLL3). Three novel candidate tumor suppressors with putative links to cancer or differentiation, NOTCH2, PARD3, and RASA1, were also identified as possible drivers in cSCC. KMT2C mutations were associated with poor outcome and increased bone invasion. Conclusions: The mutational spectrum of cSCC is similar to that of head and neck squamous cell carcinoma and dominated by tumor-suppressor genes. These results improve the foundation for understanding this disease and should aid in identifying and treating aggressive cSCC. Clin Cancer Res; 20(24); 6582–92. ©2014 AACR.
Atrial structure and fibres: morphologic bases of atrial conduction
Authors: S Ho
Journal: Cardiovascular Research (2002)

The relationship between anatomy and function has long been recognised. Understanding the gross structure, and the myoarchitecture, of the atriums is fundamental to investigations into the substrates and therapy of atrial fibrillation. Based primarily on our experience with normal human hearts, this review provides, firstly, a basis of comparison of gross structures as seen in the clinical situation, and in animals commonly used in experimental studies. Secondly, we discuss the general arrangement of myocardial fibres with respect to gross topography in the normal human heart. The right atrium is dominated by an extensive array of pectinate muscles within the extensive appendage, whereas the left atrium is relatively smooth-walled, with a much smaller tubular appendage. Myoarchitecture displays parallel alignment of fibres along distinct muscle bundles, such as the terminal crest and Bachmann's bundle. Within the smooth wall of the left atrium, there is a marked transmural change in the orientation of the muscular fibres. Abrupt changes in orientation, and mixed arrangements, are common between bundles. Other than Bachmann's bundle, the muscular bridges which provide interatrial connections, and connections between the left atrium and the coronary sinus and inferior caval vein, are highly variable. Inhomogeneities both in gross structure and myoarchitecture are common in the normal heart. These should be taken into account when investigating hearts from patients known to have had a history of arrhythmias, in devising computer models, or when refining diagnostic and therapeutic strategies.
Modulation of tumor growth by inhibitory Fcγ receptor expressed by human melanoma cells
Authors: Lydie Cassard, Joël F.G. Cohen-Solal, Annie Galinha, Xavier Sastre-Garau, Claire Mathiot, Jérôme Galon, Thierry Dorval, Alain Bernheim, Wolf H. Fridman, Catherine Sautès-Fridman
Journal: Journal of Clinical Investigation (2002)

The efficacy of anti-tumor IgG reflects the balance between opposing signals mediated by activating and inhibitory Fcγ receptors (FcγRs) expressed by effector cells. Here, we show that human malignant melanoma cells express the inhibitory low-affinity Fcγ receptor FcγRIIB1 in 40% of tested metastases. When melanoma cells were grafted in nude mice, a profound inhibition of FcγRIIB1 tumor growth that required the intracytoplasmic region of the receptor was observed. IgG immune complexes (ICs) may be required for this inhibition, since sera from nude mice bearing tumors contained IgG that decreased the proliferation of FcγRIIB1-positive cells in vitro, and tumor development of FcγRIIB1-positive melanoma lines was not inhibited in antibody-defective severe combined immunodeficiency (SCID) mice. Passive immunization of SCID mice with anti–ganglioside GD2 antibody resulted in significant inhibition of growth of FcγRIIB1-positive tumors in an intracytoplasmic-dependent manner. Altogether, these data suggest that human melanoma cells express biologically active inhibitory FcγRIIB1, which regulates their development upon direct interaction with anti-tumor antibodies. Therefore, FcγR expression on human tumors may be one component of the efficacy of antibody-mediated therapies, and FcγR-positive tumors could be the most sensitive candidates for such treatments.
Role of Sterol Regulatory Element Binding Proteins in the Regulation of Gα <sub>i2</sub> Expression in Cultured Atrial Cells
Authors: Ho-Jin Park, Ulrike Begley, Dequan Kong, Haiyan Yu, Liya Yin, F. Bradley Hillgartner, Timothy F. Osborne, Jonas B. Galper
Journal: Circulation Research (2002)

We have previously demonstrated that growth of embryonic chick atrial cells in medium supplemented with lipoprotein-depleted serum (LPDS) resulted in a coordinate increase in the expression of genes involved in the parasympathetic response of the heart (the M 2 muscarinic receptor; the α-subunit of the heterotrimeric G protein, Gα i2 ; and the inward rectifying K + channel protein, GIRK1) and a marked increase in the negative chronotropic response of atrial cells to muscarinic stimulation. In the present study, we demonstrate that regulation of Gα i2 promoter activity by LPDS is mediated by the binding of a sterol regulatory element binding protein (SREBP) to a sterol regulatory element (SRE) in the Gα i2 promoter. Deletion and point mutation of this putative SRE interfered with the regulation of the Gα i2 promoter by SREBP and LPDS. Furthermore gel shift assays demonstrated that point mutations in the putative Gα i2 SRE markedly inhibited the binding of purified SREBP to oligonucleotides containing the Gα i2 SRE sequence. The expression of a dominant-negative SREBP mutant interfered with LPDS stimulation of Gα i2 promoter activity. Finally, we demonstrate that SREBP-1 is markedly more potent than SREBP-2 for the stimulation of Gα i2 promoter activity, suggesting that SREBP1 may play a role in the regulation of Gα i2 expression. These are the first data to demonstrate SREBP regulation of a protein not involved in lipid homeostasis and suggest a new relationship between lipid metabolism and the parasympathetic response of the heart.
Cost-effectiveness of Cervical Total Disc Replacement vs Fusion for the Treatment of 2-Level Symptomatic Degenerative Disc Disease
Authors: Jared D. Ament, Zhuo Yang, Pierce Nunley, Marcus B. Stone, Kee D. Kim
Journal: JAMA Surgery (2014)

Cervical total disc replacement (CTDR) was developed to treat cervical spondylosis, while preserving motion. While anterior cervical discectomy and fusion (ACDF) has been the standard of care for 2-level disease, a randomized clinical trial (RCT) suggested similar outcomes. Cost-effectiveness of this intervention has never been elucidated.To determine the cost-effectiveness of CTDR compared with ACDF.Data were derived from an RCT that followed up 330 patients over 24 months. The original RCT consisted of multi-institutional data including private and academic institutions. Using linear regression for the current study, health states were constructed based on the stratification of the Neck Disability Index and a visual analog scale. Data from the 12-item Short-Form Health Survey questionnaires were transformed into utilities values using the SF-6D mapping algorithm. Costs were calculated by extracting Diagnosis-Related Group codes from institutional billing data and then applying 2012 Medicare reimbursement rates. The costs of complications and return-to-work data were also calculated. A Markov model was built to evaluate quality-adjusted life-years (QALYs) for both treatment groups. The model adopted a third-party payer perspective and applied a 3% annual discount rate. Patients included in the original RCT had to be diagnosed as having radiculopathy or myeloradiculopathy at 2 contiguous levels from C3-C7 that was unresponsive to conservative treatment for at least 6 weeks or demonstrated progressive symptoms.Incremental cost-effectiveness ratio of CTDR compared with ACDF.A strong correlation (R2 = 0.6864; P < .001) was found by projecting a visual analog scale onto the Neck Disability Index. Cervical total disc replacement had an average of 1.58 QALYs after 24 months compared with 1.50 QALYs for ACDF recipients. Cervical total disc replacement was associated with $2139 greater average cost. The incremental cost-effectiveness ratio of CTDR compared with ACDF was $24,594 per QALY at 2 years. Despite varying input parameters in the sensitivity analysis, the incremental cost-effectiveness ratio value stays below the threshold of $50,000 per QALY in most scenarios (range, -$58,194 to $147,862 per QALY).The incremental cost-effectiveness ratio of CTDR compared with traditional ACDF is lower than the commonly accepted threshold of $50,000 per QALY. This remains true with varying input parameters in a robust sensitivity analysis, reaffirming the stability of the model and the sustainability of this intervention.
Disseminated dermatophytic pseudomycetomas arising in an immunocompromised patient
Authors: I. Petrov, W. Kempf, D. Stoilova, V. Broshtilova, G. Mateev, M. Balabanova
Journal: British Journal of Dermatology (2006)

Conflicts of interest: none declared. Sir, Skin infections due to dermatophytes are common and are generally associated with a low degree of morbidity in normal hosts. However, in immunocompromised patients dermatophyte infections are more extensive and often present an atypical clinical picture. Dermatophytes frequently invade the dermis1–3 and even disseminate to internal organs.4 We report a case of disseminated dermatophytic pseudomycetomas, arising in an immunocompromised patient, as a result of an infection with a common dermatophyte –Trichophyton mentagrophytes. A 32‐year‐old woman presented with a 4‐year history of a widespread nodular cutaneous eruption. Her medical history was significant for a thymectomy and severe myasthenia gravis, controlled over the past 12 years with dexamethasone, azathioprine and cholinesterase inhibitors. Physical examination revealed multiple, sharply demarcated, erythematous to violaceous dermal nodules disseminated over the arms, trunk and lower extremities. Upon palpation, some of the nodules were firm, while others demonstrated anetoderma‐like herniation. None of them was draining or ulcerated (Fig. 1a). The second, third and fourth fingernails of the right hand were opaque and dystrophic. Side‐effects of prolonged therapy with potent systemic corticosteroids, such as cushingoid subcutaneous fat redistribution, hypertrichosis and marked striae distensae, were also observed.
FUNCTION OF THE RETICULOENDOTHELIAL SYSTEM
Authors: Sigurd J. Normann, Earl P. Benditt
Journal: The Journal of Experimental Medicine (1965)

The inhibitory effect of heat-aggregated albumin on carbon clearance has been studied with respect to the dose-dependent relationships involved. It has been found that the dose of aggregated albumin does not affect the degree of inhibition but does affect the duration of inhibition. Above a critical dose the duration increases exponentially with increasing albumin dose. The addition of gelatin to the carbon suspension was found to produce two effects: (a) it prolonged the inhibitory effect of a given aggregated albumin dose, and (b) it produced a slowing in the rate of carbon removal. The fact that foreign red cells inhibit carbon clearance in a manner similar to denatured albumin suggests that the relationships observed relative to denatured albumin may be generally applicable to carbon clearance and indeed may have application to phagocytic particles other than carbon.