tbuckley/cabot-search huggingface dataset:
Phase I and Pharmacokinetic Study of Vorinostat, A Histone Deacetylase Inhibitor, in Combination with Carboplatin and Paclitaxel for Advanced Solid Malignancies
Authors: Suresh S. Ramalingam, Robert A. Parise, Ramesh K. Ramananthan, Theodore F. Lagattuta, Lori A. Musguire, Ronald G. Stoller, Douglas M. Potter, Athanassios E. Argiris, James A. Zwiebel, Merrill J. Egorin, Chandra P. Belani
Journal: Clinical Cancer Research (2007)

The primary objective of this study was to determine the recommended phase II doses of the novel histone deacetylase inhibitor vorinostat when administered in combination with carboplatin and paclitaxel.Patients (N = 28) with advanced solid malignancies were treated with vorinostat, administered orally once daily for 2 weeks or twice daily for 1 week, every 3 weeks. Carboplatin and paclitaxel were administered i.v. once every 3 weeks. Doses of vorinostat and paclitaxel were escalated in sequential cohorts of three patients. The pharmacokinetics of vorinostat, its metabolites, and paclitaxel were characterized.Vorinostat was administered safely up to 400 mg qd or 300 mg bd with carboplatin and paclitaxel. Two of 12 patients at the 400 mg qd schedule experienced dose-limiting toxicities of grade 3 emesis and grade 4 neutropenia with fever. Non-dose-limiting toxicity included nausea, diarrhea, fatigue, neuropathy, thrombocytopenia, and anemia. Of 25 patients evaluable for response, partial responses occurred in 11 (10 non-small cell lung cancer and 1 head and neck cancer) and stable disease occurred in 7. Vorinostat pharmacokinetics were linear over the dose range studied. Vorinostat area under the concentration versus time curve and half-life increased when vorinostat was coadministered with carboplatin and paclitaxel, but vorinostat did not alter paclitaxel pharmacokinetics.Both schedules of vorinostat (400 mg oral qd x 14 days or 300 mg bd x 7 days) were tolerated well in combination with carboplatin (area under the concentration versus time curve = 6 mg/mL x min) and paclitaxel (200 mg/m(2)). Encouraging anticancer activity was noted in patients with previously untreated non-small cell lung cancer.
Systematic review of oocyte donation: investigating attitudes, motivations and experiences
Authors: S. Purewal, O.B.A. van den Akker
Journal: Human Reproduction Update (2009)

The social and psychological factors determining intentions to donate gametes are important for clinics, policy-makers and recruitment campaigns. The aims of this systematic review were therefore to integrate the research findings regarding the psychosocial determinants of oocyte donation and extrapolate women's experiences of donation. A bibliographic search of English language publications of four computerized databases was undertaken with no time restriction set for publications. A total of 64 studies met the inclusion criteria and were included in the review. The research syntheses revealed there were distinct differences between patient and non-patient (known, commercial, volunteer and potential) donors on demographic characteristics, motives for donation, and issues relating to disclosure and attitudes towards the resultant offspring. Further, studies have found that a significant proportion of oocyte donors and women from the general population were prepared to donate their oocytes as identifiable donors. Studies which have examined the experiences of donors report positive experiences of oocyte donation. However, a number of methodological limitations relating to the oocyte donation research literature have been identified in this systematic review. Differences between donor groups on a range of factors highlight the need for tailored psychosocial evaluation and counselling. The review has demonstrated that it is not useful to generalize across donor groups on various factors relating to oocyte donation.
Short- and Long-Term Prognosis of Syncope, Risk Factors, and Role of Hospital Admission
Authors: Giorgio Costantino, Francesca Perego, Franca Dipaola, Marta Borella, Andrea Galli, Giulia Cantoni, Simonetta Dell’Orto, Simonetta Dassi, Nicola Filardo, Pier Giorgio Duca, Nicola Montano, Raffaello Furlan
Journal: Journal of the American College of Cardiology (2008)
High Rate of Recent Intron Gain and Loss in Simultaneously Duplicated Arabidopsis Genes
Authors: David G. Knowles, Aoife McLysaght
Journal: Molecular Biology and Evolution (2006)

We examined the gene structure of a set of 2563 Arabidopsis thaliana paralogous pairs that were duplicated simultaneously 20–60 MYA by tetraploidy. Out of a total of 23,164 introns in these genes, we found that 10,004 pairs have been conserved and 578 introns have been inserted or deleted in the time since the duplication event. This intron insertion/deletion rate of 2.7 × 10−3 to 9.1 × 10−4 per site per million years is high in comparison to previous studies. At least 56 introns were gained and 39 lost based on parsimony analysis of the phylogenetic distribution of these introns. We found weak evidence that genes undergoing intron gain and loss are biased with respect to gene ontology terms. Gene pairs that experienced at least 2 intron insertions or deletions show evidence of enrichment for membrane location and transport and transporter activity function. We do not find any relationship of intron flux to expression level or G + C content of the gene. Detection of a bias in the location of intron gains and losses within a gene depends on the method of measurement: an intragene method indicates that events (specifically intron losses) are biased toward the 3′ end of the gene. Despite the relatively recent acquisition of these introns, we found only one case where we could identify the mechanism of intron origin—the TOUCH3 gene has experienced 2 tandem, partial, internal gene duplications that duplicated a preexisting intron and also created a novel, alternatively spliced intron that makes use of a duplicated pair of cryptic splice sites.
Topical photodynamic therapy for Bowen's disease of the digit in epidermolysis bullosa
Authors: C.S. Souza, L.B.A. Felício, M.V. Bentley, A.C. Tedesco, J. Ferreira, C. Kurachi, V.S. Bagnato
Journal: British Journal of Dermatology (2005)

Conflicts of interest: none declared. Sir, Dystrophic epidermolysis bullosa (DEB) is a heritable disorder characterized by subepidermal blistering, with a propensity to develop malignant skin conditions.1 Photodynamic therapy (PDT) uses a combination of a photosensitizer, light and cytotoxic oxygen species and free radicals to kill tumour cells. PDT with topically applied 5‐aminolaevulinic acid (5‐ALA), a precursor of the natural photosensitizer protoporphyrin IX (PpIX), has shown promising results in the treatment of a variety of premalignant and malignant skin conditions, including Bowen's disease (BD).2, 3 This is a squamous cell carcinoma (SCC) in situ with the potential to progress into invasive malignancy.4 When BD occurs on the finger, surgical treatment is limited by the potential scar contracture and loss of function of the finger. We report a patient with DEB and digital BD treated successfully with 5‐ALA–PDT with minimal scarring. A 51‐year‐old woman with a clinical and histopathological diagnosis of non‐Hallopeau–Siemens recessive DEB had developed blistering mainly on her hands and feet, moderate cutaneous involvement with scarring and nail dystrophy. She complained about a persistently scaly and eroded lesion that had involved the ventral and dorsal side of her right ring finger for 1 year (Fig. 1a). Skin biopsy revealed SCC in situ, compatible with BD. At this anatomical site, abnormal wound repair responses, scarring and deformities due to DEB offered obstacles to conventional treatments. Furthermore, she could not tolerate topical 5‐fluorouracil, so PDT was proposed as an alternative therapy. The tumour‐bearing area of the finger was covered with a topical application of 20% 5‐ALA (Alasens, Moscow, Russia) with 20% dimethylsulphoxide (Sigma, St Louis, MO, U.S.A.) in an oil–water emulsion. The area was then occluded with a 5‐ALA bandage for 6 h. Thirty minutes before exposure to light, the fluorescence spectra from tumour‐bearing and adjacent areas were assayed by fluorescence spectroscopy using a Fluorolog‐3 spectrofluorometer (Jobin Yvon, Longjumeau, France). A sharp peak of fluorescence intensity at 636 nm, characteristic of PpIX, was observed in the tumour‐bearing area, which was later subdivided into three fields of 6·15 cm2 and illuminated with two fractions of 50 J cm−2 (6·5 min), with one interruption of 15 min, at an intensity of 130 mW cm−2 using a diode laser at 630 nm wavelength (CeramOptec‐GmbH, Bonn, Germany).
More Cellular Signals for Atherogenesis?
Authors: Thomas Edgington
Journal: Circulation (1998)

he potential importance of the nuclear factor B (NF-B) system as a key player in control of transcription of genes for mediators of a variety of inflammatory responses, from those mediated by cytokine pathways to atherogenesis and thrombogenesis, has been a topic of broad interest.The proteins of the NF-B family that form the inactive heterodimeric complexes in the cytoplasm of cells, the inhibitors that prevent nuclear translocation, and the stimuli that lead to release and nuclear translocation of the active uninhibited NF-B complexes, commonly referred to as activation, have received great attention, as have the many genes subject to transcriptional activation by the various heterodimeric NF-B complexes once translocated to the nucleus.These details are central to the goal of mapping the cellular and molecular pathways of vascular injury, including atherosclerosis, restenosis, and other vascular pathobiology.The overall schema is growing richer in detail and interpretive hypotheses.However, the answers remain elusive.A valid schema is nevertheless critically important to discovery of molecular strategies for effective and safe intervention in acute and chronic diseases of the vasculature.
Diagnosis of Thin-Cap Fibroatheromas by a Self-Contained Intravascular Magnetic Resonance Imaging Probe in Ex Vivo Human Aortas and In Situ Coronary Arteries
Authors: Jacob Schneiderman, Robert L. Wilensky, Assaf Weiss, Eitzek Samouha, Lev Muchnik, Malca Chen-Zion, Mordechay Ilovitch, Erez Golan, Aharon Blank, Moshe Flugelman, Yosef Rozenman, Renu Virmani
Journal: Journal of the American College of Cardiology (2005)
THE RELATION OF ANTIBODY TO THE RATE OF DISAPPEARANCE OF CIRCULATING ANTIGEN
Authors: George M. Mackenzie
Journal: The Journal of Experimental Medicine (1923)

1. In rabbits previously immunized to horse serum the rate of disappearance of horse serum after reinjection is somewhat more rapid than in control animals not previously immunized. But when the average duration of the persistence of antigen in ten previously immunized rabbits is compared with the average duration of persistence in ten normal controls, the difference is not impressive. This holds true for animals previously immunized by repeated injections but having no free circulating antibody, as well as for animals having a high titer of antibody at the time of reinjection. The same animal may dispose of circulating antigen as rapidly at a time when the blood contains no precipitin as when there is a high titer of circulating precipitin. 2. The intravenous injection of large amounts of potent antihorse rabbit serum immediately after an injection of horse serum does not materially accelerate the rate of disappearance of the horse serum from the circulation. While the number of days that circulating antigen was demonstrable in two experiments of this type was less than the average of controls the duration of persistence was within the limits of variation of normal controls. 3. Under the condition of the experiments intravascular union of antigen and antibody is an unimportant factor in the mechanism for disposal of antigen. By exclusion it therefore seems probable that the rate of disappearance of antigen is largely dependent upon cell avidity for the antigen. 4. Rabbits show a wide range of individual variation in the rapidity with which foreign serum is appropriated by the tissue cells, and in their ability to form precipitins. There does not appear to be any close relation between the amount of precipitin set free in the circulation and the rate of disappearance of precipitinogen. 5. The type of interrelation between precipitin and precipitinogen—demonstrable not infrequently in patients with serum disease—in which the precipitinogen diminishes rapidly when the precipitin rises to the crest of its curve is sometimes reproduced in rabbits. The type of curve which has been observed in patients with little or no serum disease in which the precipitinogen persists steadily in the circulation for many weeks and little or no antibody is formed, has not been observed in the present series of rabbits.
Diminished Ca <sup>2+</sup> Sensitivity of Skinned Cardiac Muscle Contractility Coincident With Troponin T–Band Shifts in the Diabetic Rat
Authors: Árvind Babu Akella, Xiao-Ling Ding, Rendi Cheng, Jagdish Gulati
Journal: Circulation Research (1995)

Abstract We have measured the apparent Ca 2+ sensitivities of force development in skinned cardiac trabeculae at different sarcomere lengths together with shifts in troponin (Tn) T subunits on specimens from the same hearts and drawn insights into the pathogenesis of myocardial dysfunction in the diabetic rat. The Ca 2+ -force relations were measured at a long (2.4-μm) and a short (1.9-μm) sarcomere length. In disease, compared with the control condition, the apparent Ca 2+ sensitivity was greatly diminished at a sarcomere length of 1.9 μm but not affected at all at the long length (2.4 μm). We also examined the alterations in contractile regulatory proteins TnT and TnI by both sodium dodecyl sulfate–polyacrylamide gel electrophoresis and Western blots. The TnI band was largely unperturbed, but major changes were discerned in TnT. The normal rat heart indicated two major bands (TnT1 and TnT2) and a faint third band (TnT3); in the diabetic rat heart, there was a significant shift in intensity from TnT1 to TnT3. Since myosin isozyme shifts also accompany diabetes in the rat, we used a prototypical hypothyroid rat as well to evaluate the myosin influence in the length-induced effects on Ca 2+ sensitivity. Myosin shifts during hypothyroidism were unaccompanied by significant changes in TnT, and there were also no length-dependent modifications in Ca 2+ sensitivity. The findings raise the possibility that diabetic Ca 2+ -sensitivity changes in the myocardium are coupled with TnT alterations. A plausible explanation is offered whereby these TnT alterations modify the length dependence of Ca 2+ sensitivity.
Combined small-cell and non-small-cell lung cancer.
Authors: M D Mangum, F A Greco, J D Hainsworth, K R Hande, D H Johnson
Journal: Journal of Clinical Oncology (1989)

Nine (2%) of 429 small-cell lung cancer (SCLC) patients seen at Vanderbilt University between 1977 and 1983 had a combined subtype SCLC at diagnosis (ie, small-cell carcinoma plus squamous cell or adenocarcinoma). Staging procedures and chemotherapy treatment were uniform for all 429 patients. The diagnosis of combined histology was established via bronchoscopy (six patients), needle aspiration biopsy (one), lymph node biopsy (one), and thoracotomy (one). The clinical characteristics of the combined subtype patients were similar to patients with other subtypes of SCLC (ie, there were no differences in median age, sex, performance status, and stage of disease). However, patients with a combined subtype histology had a higher incidence of peripheral lesions on chest x-ray (56% v 14%, P less than .001) and a lower median lactate dehydrogenase (LDH) (301 IU/L v 341 IU/L, P = .0002) at diagnosis. The overall response to chemotherapy (57% v 78; P = .5) and the median survival (8 months v 10 months; P = .4) of the combined subtype patients were similar to patients with other subtypes of SCLC. Two (22%) combined histology patients survived greater than or equal to 5 years. Both had had surgical resection in addition to chemotherapy. These data suggest that the combined subtype of SCLC is clinically similar to pure SCLCs and that surgery may play a prominent role in the management of these tumors. The possibility of a combined histology tumor should be considered in patients thought to have SCLC on the basis of limited biopsy material, such as a needle aspiration or bronchial biopsy, and when the primary lesion is peripherally located on chest x-ray.
DNA Synthesis in Adult Feline Ventricular Myocytes
Authors: Patricia L. Kozlovskis, Marcel J.D. Smets, William L. Strauss, Robert J. Myerburg
Journal: Circulation Research (1996)

Abstract Adult mammalian ventricular myocytes are terminally differentiated cells, and the prevailing perception has been that DNA synthesis and repair are not active. We tested the hypothesis that there is potential for DNA synthesis and repair by studying the ability of whole-cell extracts from adult myocytes to incorporate [α- 32 P]dCTP into damaged plasmids. Left ventricular myocytes were isolated from adult cat hearts by collagenase dissociation. Cells were maintained in room air (control extract, CE) or made ischemic (IE) with N 2 displacement of O 2 and extracted for total protein. The nicked form of the plasmid was produced by exposure to an Fe 3+ /ascorbic acid free radical generating system. Both IE and CE degraded the supercoiled form of the plasmid and incorporated [α- 32 P]dCTP into the nicked ( 32 P/DNA mass; CE=2.2, IE=3.0) and linear forms ( 32 P/DNA mass; CE=28.7, IE=25.2). Exposure of plasmids to UV light did not inhibit incorporation of label. Inhibition studies with the cell extracts suggested a participation of polymerase δ in myocyte DNA repair/synthesis. Myocyte extract was as active as extract from rapidly growing COS cells at incorporating labeled nucleotides into plasmid DNA. The ability of intact myocytes to incorporate [α- 32 P]dCTP into endogenous DNA was measured in isolated cells made permeable with saponin. Studies were done in room air or N 2 . Permeable cells incorporated [α- 32 P]dCTP into nuclear DNA, but maximal specific activity of DNA was observed at 15 minutes with ischemia and at 60 minutes with room air control cells (ischemia, 1.34±0.5, 0.86±0.33, 0.60±0.04; air, 1.0, 1.28±0.20, 1.87±0.38, at 15, 30, and 60 minutes, respectively). These data indicate that mammalian adult ventricular myocytes can actively repair and/or synthesize both exogenous and endogenous DNA. A DNA synthetic response to cellular damage may have important pathological and clinical implications.
De-novo mutation in hereditary motor and sensory neuropathy type I
Authors: J.E. Hoogendijk, G.W. Hensels, E.A.M. Janssen, L.J. Valentijn, F. Baas, M. de Visser, P.A. Bolhuis, A.A.W.M. Gabreels-Festen, F.J.M. Gabreels, P. de onghe, J.-J. Martin, C. van Broeckhoven
Journal: The Lancet (1992)
Impaired GABA Neuronal Response to Acute Benzodiazepine Administration in Panic Disorder
Authors: Andrew W Goddard, Graeme F Mason, Michael Appel, Douglas L Rothman, Ralitza Gueorguieva, Kevin L Behar, John H Krystal
Journal: American Journal of Psychiatry (2004)

OBJECTIVE: Disturbances in the metabolism of the brain amino acid transmitter γ-aminobutyric acid (GABA) may contribute to the pathophysiology of human anxiety disorders. Animal studies indicate that deletions or reductions in the expression of the gene for the GABA synthetic enzyme, glutamate decarboxylase 65 (GAD65), reduce basal cortical GABA levels or stress-induced release of GABA in the cerebral cortex and increase fear behaviors. Complementing these findings, the authors recently observed lower than normal cortical GABA levels in patients with panic disorder. In the current study, the authors tested the hypothesis that panic disorder patients have a deficient GABA neuronal response to benzodiazepine (clonazepam) administration. METHOD: In a parallel-group, repeated-measures design, occipital cortex GABA responses to acute oral, open-label benzodiazepine administration were tested in 10 panic disorder patients and nine healthy comparison subjects. Occipital cortex total GABA levels were measured before and after medication administration by means of a novel proton magnetic resonance spectroscopic technique. RESULTS: Panic disorder patients had a deficient GABA neuronal response (blunted reduction of occipital cortex GABA level) to acute benzodiazepine administration, compared to the healthy subjects, who exhibited a significant decrease in occipital cortex GABA levels after this intervention. The patients also appeared to have persistently low occipital cortex GABA after chronic benzodiazepine treatment. CONCLUSIONS: Overall, these data are consistent with the hypothesis that a trait-like abnormality in GABA neuronal function contributes to the pathogenesis of human panic disorder. The data raise the possibility that GAD65 enzyme dysfunction could be a pathogenic factor in panic disorder.
Modeling Metabolic Adaptations and Energy Regulation in Humans
Authors: Kevin D. Hall
Journal: Annual Review of Nutrition (2012)

Mathematical modeling of human energy regulation and body weight change has recently reached the level of sophistication required for accurate predictions. Mathematical models are beginning to provide a quantitative framework for integrating experimental data in humans and thereby help us better understand the dynamic imbalances of energy and macronutrients that give rise to changes in body weight and composition. This review provides an overview of the various approaches that have been used to model body weight dynamics and energy regulation in humans, highlights several insights that these models have provided, and suggests how mathematical models can serve as a guide for future experimental research.
New Issues in Genetic Counseling of Hereditary Colon Cancer
Authors: Patrick M. Lynch
Journal: Clinical Cancer Research (2007)

Abstract Clinicians face significant challenges in the diagnosis and management of familial colorectal cancer predisposition. Many of the challenges concern the rarity of individual conditions and their unfamiliarity to most clinicians, even those in the subspecialty areas of gastroenterology, colorectal surgery, and medical oncology. Because the World Wide Web now offers a wealth of information, familiarity with available online resources should be a minimal expectation of clinicians. Notably, these same resources are available to the lay public, so a more informed group of patients can be expected and is already being encountered. The web sites noted throughout this article are merely early examples of what should become an opportunity for instant access to the most up-to-date knowledge of rare familial colorectal cancers and their clinical features, molecular diagnostics, and clinical management and prevention. Many professional organizations have produced guidelines (in print and online) for use by practitioners in various specialties. The consistency, growing evidence base, and ready availability of these guidelines to providers and patients alike will likely foster greater recognition of the need to be in compliance with them. Finally, as investigators make progress with the genetics of these rare diseases, one can anticipate a “cooperative group” approach to clinical trials.