tbuckley/cabot-search huggingface dataset:
ET-26 * COMBINED TREATMENT WITH ABT263 AND GX15-070 YIELDS A SYNERGISTIC ANTIPROLIFERATIVE EFFECT IN GLIOBLASTOMA
Authors: G. Karpel-Massler, M.-E. Halatsch, M.-A. Westhoff, M. D. Siegelin
Journal: Neuro-Oncology (2014)

BACKGROUND: Glioblastoma represents the most common primary brain tumor in adults and still remains to be among those human diseases that are related to the worst prognosis despite major effort in refining current treatment modalities. Multi-targeting is one of the current approaches that are undertaken to overcome this desperate situation. The members of the Bcl-2 family are commonly upregulated in glioblastoma. Unfortunately, inhibition of these proteins by existing inhibitors such as BH3-mimetics fall short of expectations due to high intrinsic levels of Mcl-1 in glioblastoma urging novel combination therapies involving Mcl-1 inhibitors such as GX15-070 to overcome this problem. METHODS: The IC50 was determined for GX15-070 and ABT263 in U87MG, U87-EGFRvIII, LN229 and T98G established glioblastoma cell lines as well as glioma stem-like cells GS9-6 and NCH644 after 72 h of continuous drug exposure. The antiproliferative effect of combining both agents was determined by 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide (MTT) assays. Moreover, cell death and specific induction of apoptosis were analyzed by staining for annexin V or propidium iodide prior to flow cytometric analysis. Soft agar assays were performed to examine antitumorigenic effects. RESULTS: Combined treatment with GX15-070 and ABT263 resulted in at least additive antiproliferative effects on all examined cell lines. On the cellular level we confirmed that this effect is due to induction of apoptosis. Moreover, we showed that combined treatment with both agents inhibited anchorage-independent growth in a cooperative manner. CONCLUSIONS: In conclusion, we present that combined treatment with the Bcl-2 inhibitor ABT263 and the Mcl-1 inhibitor GX15-070 results in a synergistic antiproliferative effect on established and glioma stem-like cells and therefore may represent a novel and promising therapeutic approach in this disease.
869. Infectious Titer Assay for Recombinant Adeno-Associated Virus Vectors Using Direct Cell Lysis and Endpoint Taqman PCR
Authors: Simon M. Grainger, Richard Peluso, Christopher J. Gerard
Journal: Molecular Therapy (2005)

TCID50-based test methods are widely used to determine infectious titers for viral test articles such as recombinant adeno-associated virus (AAV). These in vitro cell culture based methods use replicates of an endpoint dilution series in order to back calculate the infectious titer (50% tissue culture infectious doses/mL) of the original test article. Previously, these test methods used dot blot and real-time PCR readout methods in order to determine if viral replication had occurred in the infected cells. However effective these techniques were, issues such as lack of sensitivity, background caused by non-specific probe binding, requirements for DNA processing, and the need for costly reagents and equipment (e.g., a real-time thermal cycler) limited their universal applicability. In order to resolve such issues, an endpoint Taqman PCR-based readout was developed for use with a rAAV TCID50 infectivity method. The highly sensitive endpoint PCR readout eliminates the need for costly real-time PCR equipment, but still takes advantage of a Taqman probe to allow for the specific targeting of the rAAV vector product being tested. The method also incorporates the use of a direct cell lysis technique and an endogenous cellular DNA control. The direct lysis method eliminates the need for extensive sample processing (e.g., DNA isolation), while the endogenous control protects against the possibility of scoring false negatives. The rAAV TCID50 infectivity method described not only increases the sensitivity and robustness of the technique, but also increases its versatility in the titering of many different recombinant viral vectors.
Comparison of Various Envelope Proteins for Their Ability to Pseudotype Lentiviral Vectors and Transduce Primitive Hematopoietic Cells from Human Blood
Authors: Hideki Hanawa, Patrick F Kelly, Amit C Nathwani, Derek A Persons, Jody A Vandergriff, Phillip Hargrove, Elio F Vanin, Arthur W Nienhuis
Journal: Molecular Therapy (2002)

Substantial effort has been invested in developing methodologies for efficient gene transfer into human, repopulating, hematopoietic stem cells. Oncoretroviral vectors are limited by the lack of nuclear mitosis in quiescent stem cells during ex vivo transduction, whereas the preintegration complex of lentiviral vectors contains nuclear-localizing signals that permit genome integration without mitosis. We have developed a flexible and versatile system for generating lentiviral vector particles and have pseudotyped such particles with amphotropic, ecotropic, feline endogenous virus (RD114) or vesicular stomatitis virus (VSV-G) envelope proteins. Particles of all four types could be concentrated ∼100-fold by ultracentrifugation or ultrafiltration. RD114 or amphotropic particles were more efficient than VSV-G-pseudotyped particles at transducing human cord blood CD34+ cells and clonogenic progenitors within that population. Amphotropic particles transduced cytokine-mobilized, human peripheral blood CD34+ cells capable of establishing hematopoiesis in immunodeficient mice more efficiently than the other two types of particles. We conclude that the use of amphotropic pseudotyped lentiviral vector particles rather than the commonly used VSV-G-pseudotyped particles should be considered in potential applications of lentiviral vectors for gene transfer into this therapeutically relevant target cell population.
Glycosidic Tn-based vaccines targeting dermal dendritic cells favor germinal center B-cell development and potent antibody response in the absence of adjuvant
Authors: Teresa Freire, Xiaoming Zhang, Edith Dériaud, Christelle Ganneau, Sophie Vichier-Guerre, Elie Azria, Odile Launay, Richard Lo-Man, Sylvie Bay, Claude Leclerc
Journal: Blood (2010)
Doctor in the House
Authors: James Owen Drife
Journal: BMJ (2007)

Everyone has heard of Doctor in the House . It has been a film, a play, and a television series, but it started as a novel by “Richard Gordon,” the pseudonym of a BMJ assistant editor. The book, published in 1952, has acquired the reputation of being a collection of old medical jokes. It is in fact a picture of medical student life in London in the late 1940s—comical, yes, but also full of what one reviewer called “shrewd, sympathetic understanding.” 

It was the …
Cytomegalovirus reactivation following allogeneic stem cell transplantation is associated with the presence of dysfunctional antigen-specific CD8+ T cells
Authors: Evren Özdemir, Lisa S. St. John, Geraldine Gillespie, Sarah Rowland-Jones, Richard E. Champlin, Jeffrey J. Molldrem, Krishna V. Komanduri
Journal: Blood (2002)
THE CALCITONIN GENE-RELATED PEPTIDE RECEPTOR ANTAGONIST TELCAGEPANT DOES NOT REDUCE EXERCISE TOLERANCE IN PATIENTS WITH EXERCISE INDUCED MYOCARDIAL ISCHEMIA
Authors: Bernard R. Chaitman, Andrew P. Ho, Martin O. Behm, Janice F. Rowe, John S. Palcza, Tine Laethem, Ingeborg Heirman, Deborah L. Panebianco, Valentin S. Moiseev, Sergey Y. Martsevich, Almena L. Free, Neville Bittar, Steven G. Chrysant, Tony W. Ho, Jeffrey A. Chodakewitz, M. Gail Murphy, Rebecca L. Blanchard
Journal: Journal of the American College of Cardiology (2010)
Autonomic Function in Neuropathic Diabetic Patients With Foot Ulceration
Authors: James E Gilmore, Judith A Allen, John R Hayes
Journal: Diabetes Care (1993)

Objective— The aim of this study was to compare peripheral autonomic function in neuropathic diabetic subjects with and without foot ulceration. Research Design and Methods— Measurements were made on 57 diabetic subjects; 35 subjects had evidence of peripheral neuropathy, 14 of these had a history of foot ulceration, and 22 subjects had no evidence of peripheral neuropathy. No patient had peripheral vascular disease. Measurements were made of motor and sensory nerve conduction. Autonomic function was investigated by using standard cardiovascular reflex tests and by measuring blood flow variability in the foot. The vasoconstrictor responses to deep breathing and body cooling were measured by using venous occlusion plethysmography. Results— Peripheral sympathetic function was significantly worse in the DU group. The vasoconstrictor response to deep breathing in the DU group was significantly smaller than the response in the DN group (15.3 ± 2.7 vs. 38 ± 4%, P &amp;lt; 0.001). The response to body cooling in the DU group was significantly smaller than the response in the DN group (6.2 ± 3.1 vs. 20.8 ± 3.5%, P &amp;lt; 0.01). Tests of cardiac autonomic function and measurements of motor and sensory nerve conduction were similar in both neuropathic groups. Conclusions— Peripheral autonomic neuropathy is associated with the development of foot ulceration in diabetic subjects.
Protean manifestations of human papillomavirus type 60 infection on the extremities
Authors: M. Ashida, M. Ueda, M. Kunisada, M. Ichihashi, M. Terai, T. Sata, T. Matsukura
Journal: British Journal of Dermatology (2002)

Human papillomavirus type 60 (HPV-60) induces a ridged wart or an epidermal cyst on the sole of the foot, exhibiting identical pathological changes, with a single refractile eosinophilic intracytoplasmic inclusion body in infected cells. However, there is no information on the role of HPV-60 in the development of cutaneous lesions on other anatomical sites.To perform the clinicopathological analysis of various cutaneous lesions of a patient in relation to HPV genotype.A 50-year-old male patient developed multiple papules, plaques and nodules on his hand, arm and legs.Clinicopathologically, the lesions were classified into three categories. A common wart on the finger showed papillomatosis and acanthosis characterized by numerous keratohyalin granules. Plane warts on the arm showed perinuclear vacuolization of the cells in the upper Malpighian layer. On the other hand, a pigmented papillomatous nodule on the finger, and the other lesions on the hands and legs exhibited similar histological features with a unique cytoplasmic eosinophilic inclusion body. All the three categorized lesions were equally positive for HPV capsid antigen by immunohistochemistry. By blot hybridization analysis for HPV sequences, it was revealed that a common wart on the finger and plane warts on the arm harboured HPV-27 and HPV-3, respectively, while all the other lesions harboured HPV-60. The histological localization of each viral DNA was confirmed in the corresponding lesions by in situ hybridization.HPV-60 is able to induce papular and nodular lesions on the extremities.
Michael Gerald Askew
Authors: Donald McNutt, Roz Reid
Journal: BMJ (2007)

After St George's house jobs, Mike joined the navy, serving at Dartmouth College, the Dartmouth Squadron, and Royal Naval Hospital Haslar.

Later he became a singlehanded practitioner caring particularly for British and overseas naval families. Mike routinely worked 15-16 hours a day. He was a natural enthusiast who soon attracted a …
Self-Mutilation and Malingering among Cuban Migrants Detained at Guantanamo Bay
Authors: T C Andrews, D L Cull, J J Pelton, S O Massey, J M Bostwick
Journal: New England Journal of Medicine (1997)

In the late summer of 1994, thousands of Cubans tried to flee to the United States, using crude rafts to make the trip across the Caribbean to the Florida coast.1 The reason for this exodus was their increasing frustration with deteriorating economic conditions in Cuba, brought on by a dramatic decline in Russian economic support and a tightening of economic sanctions by the United States.2,3 In contrast to previous U.S. policy, which allowed relatively free immigration, the U.S. Coast Guard intercepted most of the Cubans and transported them to hastily assembled tent camps at the U.S. naval base at . . .
Expression of an idiotype (Id-460) during in vivo anti-dinitrophenyl antibody responses. III. Detection of Id-460 in normal serum that does not bind dinitrophenyl.
Authors: E A Dzierzak, C A Janeway
Journal: The Journal of Experimental Medicine (1981)

Using an anti-idiotypic antibody previously characterized as specific for the hapten binding site of the 2,4-dinitrophenyl (DNP)-binding BALB/c myeloma protein MOPC-460, we have detected substantial amounts of this idiotype (Id-460) in the serum of normal mice. Whereas the idiotypic material in DNP-immune serum binds to DNP, the Id-460-positive material in normal mouse serum is not specific for DNP. The material in normal serum appears to be immunoglobulin. Furthermore, Id-460-positive, non-DNP-binding monoclonal immunoglobulins that completely inhibit our assay for Id-460 are repeatedly isolated when hybridomas are prepared from LPS-activated normal spleen cells. These data are interpreted in the context of Jerne's network hypothesis. It is our conclusion that the non-DNP-binding form of Id-460 is the inherited form and that this form establishes an idiotypic network favoring the production of anti-DNP bearing Id-460. Thus, the paradox of finding an inherited idiotype in the antibody response to the nonpathogen DNP may be resolved by proposing that the true form of Id-460 is specific for an environmental pathogen and that Id-460 dominance in the anti-DNP response is simply a consequence of idiotype-specific regulatory events preconditioned by Id-460-bearing immunoglobulin specific for antigenic determinants unrelated to DNP.
On the detection of emotional facial expressions: Are girls really better than boys?
Authors: Vanessa LoBue, Judy S. DeLoache
Journal: Behavioral and Brain Sciences (2009)

Abstract One facet of Vigil's socio-relational framework of expressive behaviors (SRFB) suggests that females are more sensitive to facial expressions than are males, and should detect facial expressions more quickly. A re-examination of recent research with children demonstrates that girls do detect various facial expressions more quickly than do boys. Although this provides support for SRFB, further examination of SRFB in children would lend important support this evolutionary-based theory.
Bone densitometry Is a valuable investigation
Authors: J E Compston, W E Duncan, D M Stott, K D Burman, A S Change, D M Reid, C Cooper, I Fogelman, R Eastell, A Woolf
Journal: BMJ (1994)

EDITOR, - Susan M Ott draws attention to some of the potential pitfalls associated with the use of bone densitometry in clinical practice.1 Though I acknowledge that caution is needed in interpreting measurements of bone density, their value should not be understated. In particular, distinction should be made between the assessment of risk in an individual person and that in population screening. Because of the gaussian distribution of bone density and the gradient of the risk of fracture over its whole range, the proportional contribution to the total incidence of fracture of those with the lowest bone density is small; a major impact on the incidence can be achieved only by increasing bone density across the whole population. In clinical practice, however, the risk in an individual person is an important factor in decisions about treatment, based on analysis of the risk of disease on the one hand and the ratio of risk to benefit associated with treatment on the other. The present lack of strict densitometric criteria for treatment does not invalidate this approach, particularly for those at high risk.

The figure of around 6% quoted for the precision of bone densitometry is misleading since it applies only to Ward's triangle; for other regions of the femur, such as the femoral neck and trochanter, precision of 3% …
Acute otitis media: a new treatment strategy.
Authors: F L van Buchem, M F Peeters, M A van 't Hof
Journal: BMJ (1985)

The incidence of acute otitis media and its response to treatment only with nose drops and analgesics (but without antibiotics or myringotomy) were assessed over three months by 45 doctors in and around Tilburg. In addition, over 17 months 60 general practitioners assessed the effects of this limited treatment in children aged 2 to 12 years and referred all those in whom the condition took an unsatisfactory course (either a severe course--illness continuing beyond three to four days with high temperature or pain, or both--or persistent discharge after 14 days) to an ear, nose, and throat specialist. Those referred because of appreciable illness continuing beyond three or four days were entered into a further study, comparing the effects of myringotomy alone, antibiotics alone, and myringotomy and antibiotics combined. Bacteriology was assessed in all children in whom the course of the condition was unsatisfactory. More than 90% of an estimated 4860 children seen over 17 months (estimation based on incidence of severe course in the three month study) recovered within a few days. The course of the condition was severe in only 126 (2.7%) patients; haemolytic streptococci group A were identified in 30 of these 126 patients but Haemophilus influenzae in only one. One hundred of these patients with a severe course entered the trial of treatment, which showed antimicrobial treatment either alone or in combination to be more effective than myringotomy alone. Whether combined treatment was more effective than antibiotics alone remained unconfirmed. Acute otitis media in children can be treated with nose drops and analgesics alone for the first three to four days. Patients in whom this regimen is not accompanied by satisfactory recovery can be recognised within a short time and treated by the general practitioner.
Colchicine antimitosis abolishes resiliency of postnatally developing rats to chlordecone-amplified carbon tetrachloride hepatotoxicity and lethality.
Authors: A Dalu, P S Rao, H M Mehendale
Journal: Environmental Health Perspectives (1998)

We have previously reported that rats are resilient to the hepatotoxic and lethal combination of chlordecone (CD) and carbon tetrachloride (CCl4) during early postnatal development. The overall findings pointed to stimulated cell division and tissue repair mechanisms as the underlying cause of resistance. The objective of the current study was to investigate if the antimitotic effect of colchicine (CLC) abolishes this resiliency to CD + CCl4 by inhibiting ongoing and stimulated cell division. We used 45-day-old rats in this study because this age group exhibited partial sensitivity to CD + CCl4 in our previous studies. Male Sprague-Dawley rats were treated with a single low intraperitoneal dose of CCl4 (100 microl/kg) or corn oil after exposure to either 10 ppm CD in the diet or a normal diet (ND) for 15 days. CLC (1 mg/kg) was administered 6 or 30 hr after CCl4 to ND or CD rats, respectively. Administration of CLC resulted in increased CCl4-induced mortality from 25% to 85% in rats pretreated with CD, in contrast to 100% survival in ND rats. Liver injury was assessed by plasma alanine transaminase (ALT) and sorbitol dehydrogenase (SDH) elevations as well as by histopathology. Hepatocellular regeneration was assessed by 3H-thymidine (3H-T) incorporation into hepatonuclear DNA and proliferating cell nuclear antigen (PCNA) studies during 0-96 hr after CCl4. Administration of CLC to ND + CCl4 rats resulted in a slight delay in cell division and tissue repair, as indicated by 3H-T incorporation and PCNA, thereby leading to prolonged liver injury as revealed by elevations in plasma ALT, SDH, and histopathological lesions. In contrast, CLC administration to CD + CCl4-treated rats further delayed and diminished cell division by 80%, which led to unrestrained progression of CCl4-induced liver injury, resulting in 85% mortality. These findings underscore the importance of ongoing and toxicant-stimulated cell division and tissue repair mechanisms in hepatotoxicity, and the need for the inclusion of age factors in risk assessment of exposure to environmental and other chemicals.
Clinical and research implications of new concepts in the assessment of cardiac pumping performance in heart failure
Authors: L B TAN
Journal: Cardiovascular Research (1987)

Every cardiac pump has its own maximum performance, which denotes its pumping capability. The difference between the performance in the resting state and that at maximum is called pumping reserve. Cardiac pumping performance is therefore best quantified by its hydraulic power output. Cardiac pumping capability is predictive of the ultimate prognosis of patients in severe heart failure whereas pumping reserve is a major determinant of exercise capacity. The therapeutic efficacy of cardiotonic drugs used in the treatment of ambulant heart failure patients should be evaluated with reference to the way they alter the relation between cardiac pumping reserve and exercise capacity.
Harvey and the Scientific Method
Authors: H. Cohen
Journal: BMJ (1950)

We can, however, study the mind of the man and its working in his writings. It is this which conveys to us a due sense of his greatness ; it is this which helps us to assess his contribution to that irrepressible insurgence of the human spirit which reveals itself in the advancing frontiers of knowledge. It explains why we place Harvey amongst the greatest physicians of all times, not because he discovered that the blood circulates but because he demonstrated beyond all reasonable doubt that the blood circulates. It is with the Harveian method that I pro pose to concern myself in this lecture, and with why after he had demonstrated  the passage of the blood from the veins into the arteries and of the manner in which it is transmitted and distributed by the action of the heart  he was constrained to write :  But what remains to be said upon the quantity and source of the blood which thus passes, is of a character so novel and unheard-of that I not 'only fear injury to myself from the envy of a few, but I tremble lest I have mankind at large for my enemies, so much doth wont and custom become a second nature. Doctrine once sown strikes deep its root, and respect for antiquity influences all men. Still the die is cast, and my trust is in my love of truth, and the candour of cultivated minds.
Bilateral Blue Toe Syndrome
Authors: Michael W. Rosenberg
Journal: JAMA (1980)

IN 1945, Flory<sup>1</sup>described episodes of multiple emboli of atheromatous material to small arteries. Although these arteries perfused visceral organs, Flory speculated that emboli of cholesterol crystals not only may produce infarcts of visceral organs, but also may be implicated in the production of gangrenous toes or limbs. In 1959, Hoyle et al<sup>2</sup>confirmed this concept clinically when they reported the first case of distal extremity embolization originating from an eroded atherosclerotic plaque. As late as 1976, however, Mehigan and Stoney<sup>3</sup>noted that acute focal ischemia secondary to embolization from nonocclusive atherosclerotic lesions from the arterial tree is frequently overlooked. This article illustrates that repeated attacks of acute ischemic changes evenly distributed to both lower extremities should alert one to consider microemboli as a cause of the problem. <h3>Report of a Case</h3> A 48-year-old man had been admitted to the hospital in 1962 with a long history