tbuckley/cabot-search huggingface dataset:
P27 * DEVELOPMENT OF AN IMPLANTABLE CATHETER AND BONE-ANCHORED PORT FOR INTERMITTENT CONVECTION-ENHANCED DELIVERY OF CARBOPLATIN FOR RECURRENT HIGH GRADE GLIOMA
Authors: N. U. Barua, M. Woolley, K. Hopkins, A. S. Bienemann, D. Cronin, S. S. Gill
Journal: Neuro-Oncology (2014)

INTRODUCTION: The translational potential of convection-enhanced drug delivery (CED) for the treatment of high grade glioma (HGG) may be enhanced by the facility to perform repeated drug infusions. We report the development of an implantable catheter and transcutaneous bone-anchored port (TBAP) for intermittent CED, and its use for delivery of carboplatin in 2 patients with progressive HGG. METHOD: The feasibility of implanting the port and catheter system and performing intermittent infusions was tested in a large animal (porcine) model. Intermittent infusions of 0.2% Gadolinium-DTPA were performed at one month intervals with real-time MRI tracking by attaching a needle administration set to the port. Intermittent CED of carboplatin was performed in 2 patients with recurrent and progressive HGG (1 GBM, 1 AA). RESULTS: The porcine study confirmed the feasibility of performing intermittent CED through an implanted port and catheter system. All catheters were implanted with satisfactory accuracy, and without any haemorrhagic or infectious complications. Repeated delivery of carboplatin in a patient with recurrent GBM resulted in initial tumour regression. A second patient with progressive AA continues to show tumour control 8 months after commencing treatment. CONCLUSION: This study confirms the safety and feasibility of performing intermittent CED through a transcutaneous bone-anchored port. The use of a transcutaneous port has the potential to facilitate clinical translation of CED of therapeutics requiring intermittent delivery to achieve optimum efficacy.
Obesity and osteoarthritis: more complex than predicted!
Authors: P Pottie, N Presle, B Terlain, P Netter, D Mainard, F Berenbaum
Journal: Annals of the Rheumatic Diseases (2006)

Dysregulation of lipid homeostasis is one of the mechanisms leading to osteoarthritis

Osteoarthritis is usually considered to be a joint disorder the central pathological feature of which is cartilage destruction. However, this concept has evolved, and today osteoarthritis is generally regarded as a disease that may affect the whole joint (bone, muscles, ligaments and synovium). Although the aetiology of osteoarthritis is not established, the main risk factors are well known and commonly include mechanical, biochemical and genetic factors. Of these risk factors, obesity is beyond doubt considered a prominent one.

The overload effect on joint cartilage may explain part of the increased risk of osteoarthritis, at least for osteoarthritis of the knee, in overweight people. A recent discovery in the discipline of cartilage biology is the presence of mechanoreceptors at the surface of chondrocytes, which are sensitive to pressure and link extracellular environment to intracellular signalling cascades. Three types of mechanoreceptors have been described on chondrocytes: the stretch-activated channels, the α-5β1 integrin and CD44. Compression and stretch stimulate integrins and stretch-activated channels leading to the activation of signalling pathways (mitogen-activated protein kinase, NF-κB), as well as the release of second messengers (calcium, Inositol triphosphate and Adenosine monophosphate cyclic). 1 After mechanoreceptor activation, cytokines, growth factors and metalloproteinases may be expressed, and mediators such as prostaglandins or nitric oxide may be produced.2 As experimental studies have shown that under specific conditions overload may trigger both inhibition of matrix synthesis and cartilage degradation, we can speculate that obesity may induce cartilage damage through activation of these mechanoreceptors. In the same manner, the mechanoreceptors expressed on osteoblasts3,4 may also be involved in the impaired response of chondrocytes to the obesity-induced overload.

Even if it is usually accepted that mechanical loading contributes to joint cartilage destruction in overweight patients, recent advances …
Johns Hopkins faces further criticism over experiments
Authors: D. Josefson
Journal: BMJ (2001)

The right of terminally ill patients for assistance to end their life moved a step closer last week when a woman with motor neurone disease won the battle to have her case reviewed in the high court.Diane Pretty was diagnosed as having the disease in 1999.Now aged 42, she is paralysed from the neck down but is fully mentally competent.She wants to die at home when she chooses but is physically unable to take her own life.On 31 August she won the right to a full judicial review of the director of public prosecution's refusal to guarantee that Mr Pretty would not be prosecuted under the 1961 Suicide Act if he helped to end his wife's life.Her case could be heard within the next month.Under section 2.1 of the act, Mr Pretty could be imprisoned for up to 14 years if he helped his wife to die.Liberty, the human rights organisation that is representing the Prettys, and the Voluntary
Evidence for superoxide radical-dependent coronary vasospasm after angioplasty in intact dogs.
Authors: F R Laurindo, P L da Luz, L Uint, T F Rocha, R G Jaeger, E A Lopes
Journal: Circulation (1991)

BACKGROUND Active oxygen species can influence vascular tone and platelet activation through a variety of mechanisms. This study assessed the role of the superoxide anion, the hydroxyl radical, and hydrogen peroxide in vasoconstriction and mural thrombosis after coronary artery angioplasty in intact dogs. METHODS AND RESULTS Injury was induced by inflation of a balloon catheter 50 +/- 6% above baseline arterial diameter; dogs were followed for 2 hours before death. Epicardial coronary diameters at arteriography and extent of thrombus deposition at serial histological sections were analyzed in controls (n = 20) and in dogs pretreated with superoxide dismutase (SOD, a superoxide radical scavenger, n = 10); other dogs were pretreated with the hydrogen peroxide scavenger catalase (n = 8), the iron chelator deferoxamine (n = 6), or the hydroxyl radical scavenger 1,3-dimethyl-2-thiourea (n = 9). Angioplasty-induced injury was similar among groups. After angioplasty, control dogs exhibited localized and persistent vessel constriction, which was maximal at the initial 5 minutes (28.9 +/- 6.3% diameter decrease versus baseline). Corresponding arterial diameters of SOD-treated dogs were 24-69% larger (95% confidence interval, p less than 0.001) than controls at 5 minutes and, on average, 32% larger than controls thereafter (p less than 0.01). Vasoconstriction was not prevented by the other treatments. The SOD dose used accounted for inhibition of zymosan-stimulated blood cytochrome c reduction versus baseline (7 +/- 3 versus 30 +/- 6 nmol/min/10(6) cells, respectively, p = 0.003); such inhibition occurred in no other group. Prevalence of mural thrombosis was similar among all groups, but large thrombi (greater than 15% of lumen area) were absent in SOD-treated dogs, contrary to control group (p = 0.028); other groups were similar to control. In the absence of injury, SOD alone induced no change in coronary diameter, coronary blood flow, or platelet aggregation. CONCLUSIONS These data provide evidence implicating the superoxide radical in the genesis of vasoconstriction after coronary angioplasty in vivo. Such effects seem to be independent of its conversion to hydroxyl radicals and availability of hydrogen peroxide or catalytic iron complexes.
Detection of Achalasia on Thyroid Scintigraphy and MRI
Authors: Christian Grieser, Juri Ruf
Journal: Clinical Nuclear Medicine (2008)

Although mediastinal tracer accumulation on thyroid scintigraphy is usually characteristic for a retrosternal goiter, areas of specific (eg, teratoma) or nonspecific uptake (inflammatory and/or tumorous masses) have to be taken into consideration. Moreover, it has also been sporadically reported that achalasia may present with increased mediastinal tracer accumulation. The pathomechanism of this uptake is, however, not yet fully understood. We report the case of a 28-year-old female medicinal student in whom a thyroid nodule was incidentally detected by ultrasound during a student teaching session and who therefore underwent thyroid scintigraphy.
The Citric, Acetic, and Carbolic Acids in Cancer
Authors: J. Barclay
Journal: BMJ (1866)

tion which is sometimes entertained, I will quote the words of the last writer on the subject, Paul Broca.In the first volume of his new work on Tumours, he recites two cases in which the growth of cancer is alleged to have followed an injury.In one ease, the disease was first noticed soon after a severe blow on the heel; in the other, after prolonged fric- tion, combined with an injury, of the pubes.The
Therapeutic Vaccination against Murine Lymphoma by Intratumoral Injection of Recombinant Fowlpox Virus Encoding CD40 Ligand
Authors: Aichun Liu, Alice Guardino, Lek Chinsangaram, Matthew J. Goldstein, Dennis Panicali, Ronald Levy
Journal: Cancer Research (2007)

Abstract The interaction between CD40 ligand (CD40L, CD154) and its receptor CD40 on antigen-presenting cells is essential for the initiation of cell-mediated and humoral immune responses. Malignant B cells also express CD40 and respond to CD40L by enhancing expression of costimulatory molecules. In this study, we investigated the therapeutic antitumor effect of intratumoral administration of recombinant fowlpox virus encoding murine CD40L (rF-mCD40L) in a murine B-cell lymphoma model. BALB/c mice with established s.c. and widely metastatic A20 lymphoma tumors were treated with intratumoral injections of rF-mCD40L together with systemic chemotherapy. This combined chemoimmunotherapy resulted in complete tumor regression and long-term survival of the mice. Some tumor cells in the injected sites expressed the CD40L transgene and had increased expression of the CD80 and CD86 costimulatory molecules. The therapeutic effect was dependent on CD8 but not on CD4 T cells. Moreover, there was a requirement that the recombinant CD40L virus be injected directly into the tumor, as opposed to peritumoral or distant sites. Thus, rF-mCD40L injected directly into the tumor microenvironment enhances the immunogenicity of tumor B cells. The results support future plans for intratumoral injection of rF-mCD40L in patients with lymphoma. [Cancer Res 2007;67(14):7037–44]
Phase II study of the histone deacetylase inhibitor panobinostat (LBH589) in patients with low or intermediate‐1 risk myelodysplastic syndrome
Authors: Sophie Dimicoli, Elias Jabbour, Gautam Borthakur, Tapan Kadia, Zeev Estrov, Hui Yang, Mary Kelly, Sherry Pierce, Hagop Kantarjian, Guillermo Garcia‐Manero
Journal: American Journal of Hematology (2011)

Abstract A phase II non‐randomized single arm trial of oral panobinostat (LBH589) was conducted in patients with low or intermediate‐1 risk myelodysplastic syndrome (MDS). The objective of this study was to determine the clinical efficacy, safety, and tolerability of panobinostat in this patient population. The study would stop early if there was a chance &gt;99% that the average overall response rate was &lt;15%. Thirteen patients were treated: Median age was 70 years (range 47–84), 70% were transfusion dependent, 70% had intermediate‐1 risk MDS. Most patients were diploid but one patient with del(5q), one with trisomy 8, one with complex cytogenetics, and two with deletion of 20q were included. Approximately 40% had previous therapy for MDS. Of the 13 patients, 1 (8%) achieved hematological improvement (HI‐E and HI‐P, duration 3 months) and 6 (46%) had stable disease for a median duration of 6 months (range 1.7–13.6). Treatment was withheld in one patient because of QTc prolongation but no other serious adverse effects were otherwise observed. Panobinostat did not consistently induce histone acetylation as measured with Western blot. This data indicates that panobinostat at the dose and schedule studied here has limited activity in lower risk MDS. Am. J. Hematol., 2012. © 2011 Wiley Periodicals, Inc.
DNA bound to polypyrrole films: high-resolution imaging, DNA binding kinetics and internal migration
Authors: Rajiv Pande, George C. Ruben, Jeong Ok Lim, Sukant Tripathy, Kenneth A. Marx
Journal: Biomaterials (1998)

We have studied the time-dependent uptake of 35S radiolabeled DNA with electrochemically prepared polypyrrole films. The two distinct polypyrrole film surfaces, a rough (solution polymeric growth face, R) and a smooth surface (electrode face, S) were characterized by low-resolution AFM and high-resolution transmission electron microscopy (TEM). These studies showed the presence of steep contours and defects in the form of large and small surface holes and valleys on the rough surface of polypyrrole. The void dimensions ranged from the nanoscale to micron size. By contrast, the smooth surface was flatter and largely devoid of significant structural defects and exhibited closer packing of the polypyrrole chains over large areas. Both surfaces were comprised largely of chains whose average diameters were 1.0–1.2±0.3 nm. The surface characterization studies were complemented by time-dependent DNA uptake studies which showed a t1/2-dependent total uptake of 35S DNA at higher levels on the rough surface compared to the smooth surface. This is consistent with the apparent higher effective surface area of the rough surface compared to the smooth. Using a proportional counter the time-dependent ratio (R/S) of the 35S DNA detected from the rough surface of the polypyrrole disk to that detected from the smooth surface suggested that DNA was migrating into the disk interior from its uptake surface. The rough side defect dimensions measured by TEM were more than sufficient to allow for the penetration and migration of DNA into the disk interior. Both R/S ratios were extrapolated and found to intersect at an R/S value close to 1.0, suggesting a kinetic process leading ultimately towards a nearly uniform radiolabeled DNA distribution in the disk. These kinetic results were in agreement with the surface characterization studies and suggest a model in which sizeable internal pores exist throughout the electrochemically prepared polypyrrole, that could account for the DNA migration effect. This was confirmed by TEM of the interior of a polypyrrole disk produced by Argon ion milling.
β-Catenin Activation in a Novel Liver Progenitor Cell Type Is Sufficient to Cause Hepatocellular Carcinoma and Hepatoblastoma
Authors: Sharada Mokkapati, Katharina Niopek, Le Huang, Kegan J. Cunniff, E. Cristy Ruteshouser, Mark deCaestecker, Milton J. Finegold, Vicki Huff
Journal: Cancer Research (2014)

Abstract Hepatocellular carcinoma (HCC) was thought historically to arise from hepatocytes, but gene expression studies have suggested that it can also arise from fetal progenitor cells or their adult progenitor progeny. Here, we report the identification of a unique population of fetal liver progenitor cells in mice that can serve as a cell of origin in HCC development. In the transgenic model used, mice carry the Cited1-CreERTM-GFP BAC transgene in which a tamoxifen-inducible Cre (CreERTM) and GFP are controlled by a 190-kb 5′ genomic region of Cited1, a transcriptional coactivator protein for CBP/p300. Wnt signaling is critical for regulating self-renewal of progenitor/stem cells and has been implicated in the etiology of cancers of rapidly self-renewing tissues, so we hypothesized that Wnt pathway activation in CreERTM-GFP+ progenitors would result in HCC. In livers from the mouse model, transgene-expressing cells represented 4% of liver cells at E11.5 when other markers were expressed, characteristic of the hepatic stem/progenitor cells that give rise to adult hepatocytes, cholangiocytes, and SOX9+ periductal cells. By 26 weeks of age, more than 90% of Cited1-CreERTM-GFP;Ctnnb1ex3(fl) mice with Wnt pathway activation developed HCC and, in some cases, hepatoblastomas and lung metastases. HCC and hepatoblastomas resembled their human counterparts histologically, showing activation of Wnt, Ras/Raf/MAPK, and PI3K/AKT/mTOR pathways and expressing relevant stem/progenitor cell markers. Our results show that Wnt pathway activation is sufficient for malignant transformation of these unique liver progenitor cells, offering functional support for a fetal/adult progenitor origin of some human HCC. We believe this model may offer a valuable new tool to improve understanding of the cellular etiology and biology of HCC and hepatoblastomas and the development of improved therapeutics for these diseases. Cancer Res; 74(16); 4515–25. ©2014 AACR.
False-Positive Parathyroid Thallium-Pertechnetate Subtraction Imaging of the Mediastinum
Authors: PETER W. BLUE, ARNOLD A. ASP, GERALD S. KIDD
Journal: Clinical Nuclear Medicine (1988)

Thallium-pertechnetate subtraction images are presented that suggest the diagnosis of a mediastinal parathyroid adenoma in which only adenomatous thyroid tissue was found surgically. Because of the possibility of a thallium avid, pertechnetate negative retrosternal goiter, care should be exercised in the diagnosis of mediastinal parathyroid adenoma.
A CRITICISM OF THE CONCEPT OF NEUROTIC DEPRESSION
Authors: EDUARD ASCHER
Journal: American Journal of Psychiatry (1952)

There appears to be a good deal of confusion in the literature as well as in psychiatric practice about depressive illness, which is a left-over from the era of descriptive psychiatry. Concepts of psychogenesis, endogeny, reactivity, neurosis, psychosis, and others had been introduced to clarify the issue through more specific characterization, however, without producing the desired result. Neither the course of the illness nor the therapeutic success of various procedures, nor the danger of suicide are consistently enough dependent on the factors mentioned to justify their continued use. The concept of considering a "neurotic" depressive reaction to be merely a milder condition than the psychotic variety only supports the view of those who look upon the differentiation of neurosis from psychosis as being superfluous and misleading. The danger of suicide is independent of the presence of overtly psychotic behavior and is likely to be overlooked by the inexperienced person who considers neurosis and suicide incompatible. Dynamic features in depressive illness do not show differentiating characteristics specific enough to permit the distinction between a neurotic and psychotic group. The apparently different response of various depressive reactions to electroshock therapy is more dependent on the relative prominence of depressive mood in the total picture than on the neurotic or psychotic nature of the condition. It is suggested that in evaluating depressive disorders more emphasis be put on suicidal dangers and problems of management rather than on adjectival characterization of "neurotic" or "psychotic."
PERSONAL EXPERIENCE IN SPINAL INJURIES.
Authors: J. F. PRITCHARD
Journal: JAMA (1896)

The question of spinal injuries has been so much discussed that one feels like apologizing for presenting anything more on the subject, but as it is yet vital in some measure, we must continue our investigation until we have an approximation to the truth. In going over my records, carefully kept for many years, involving every case of injury on one line of road, I find that an average of injuries to the back was thirteen per thousand. These include all classes of injuries, and are noted on my reports as contusions, sprains, twists, and injuries which are popularly called concussions, also dislocations, fractures and serious injuries of like nature to the spinal column. But what is remarkable is that of these injuries caused by falls, blows, or other like causes incident to railway life there was but one in which recovery was not complete and permanent. My experience would
Characterization of an Akt Kinase Inhibitor with Potent Pharmacodynamic and Antitumor Activity
Authors: Nelson Rhodes, Dirk A. Heerding, Derek R. Duckett, Derek J. Eberwein, Victoria B. Knick, Timothy J. Lansing, Randy T. McConnell, Tona M. Gilmer, Shu-Yun Zhang, Kimberly Robell, Jason A. Kahana, Robert S. Geske, Elena V. Kleymenova, Anthony E. Choudhry, Zhihong Lai, Jack D. Leber, Elisabeth A. Minthorn, Susan L. Strum, Edgar R. Wood, Pearl S. Huang, Robert A. Copeland, Rakesh Kumar
Journal: Cancer Research (2008)

Akt kinases 1, 2, and 3 are important regulators of cell survival and have been shown to be constitutively active in a variety of human tumors. GSK690693 is a novel ATP-competitive, low-nanomolar pan-Akt kinase inhibitor. It is selective for the Akt isoforms versus the majority of kinases in other families; however, it does inhibit additional members of the AGC kinase family. It causes dose-dependent reductions in the phosphorylation state of multiple proteins downstream of Akt, including GSK3 beta, PRAS40, and Forkhead. GSK690693 inhibited proliferation and induced apoptosis in a subset of tumor cells with potency consistent with intracellular inhibition of Akt kinase activity. In immune-compromised mice implanted with human BT474 breast carcinoma xenografts, a single i.p. administration of GSK690693 inhibited GSK3 beta phosphorylation in a dose- and time-dependent manner. After a single dose of GSK690693, >3 micromol/L drug concentration in BT474 tumor xenografts correlated with a sustained decrease in GSK3 beta phosphorylation. Consistent with the role of Akt in insulin signaling, treatment with GSK690693 resulted in acute and transient increases in blood glucose level. Daily administration of GSK690693 produced significant antitumor activity in mice bearing established human SKOV-3 ovarian, LNCaP prostate, and BT474 and HCC-1954 breast carcinoma xenografts. Immunohistochemical analysis of tumor xenografts after repeat dosing with GSK690693 showed reductions in phosphorylated Akt substrates in vivo. These results support further evaluation of GSK690693 as an anticancer agent.
West Yorkshire has most casualties from road traffic incidents
Authors: Roger Dobson
Journal: BMJ (2007)

An analysis of deaths and injuries from road traffic incidents has identified West Yorkshire and the West Midlands as the counties with highest risk of injury and the Isle of Wight and parts of Wales as the safest ( Health and Place 2007 doi: 10.1016/j.healthplace.2007.10.001).⇓





Between 1995 and 2000 there were 15 797 deaths, 191 870 serious injuries that needed hospital treatment, and 1 282 563 minor injuries from road traffic incidents in England and Wales.

For the NHS funded study researchers looked at geographical variations in mortality and morbidity throughout England and Wales using a number of different datasets.

The results were presented in two ways for each county. The first, …