tbuckley/cabot-search huggingface dataset:
Capecitabine As First-Line Treatment for Patients Older Than 70 Years With Metastatic Colorectal Cancer: An Oncopaz Cooperative Group Study
Authors: Jaime Feliu, Pilar Escudero, Ferrán Llosa, Matilde Bolaños, Jose-Manuel Vicent, Alfonso Yubero, Jose-Javier Sanz-Lacalle, Rafael Lopez, Luis Lopez-Gómez, Enrique Casado, María-José Gómez-Reina, Manuel González-Baron
Journal: Journal of Clinical Oncology (2005)

To determine the tolerability of capecitabine in elderly patients with advanced colorectal cancer (CRC).Fifty-one patients with advanced CRC who were >/= 70 years and considered ineligible for combination chemotherapy received oral capecitabine 1,250 mg/m(2) twice daily on days 1 to 14 every 3 weeks. Patients with a creatinine clearance of 30 to 50 mL/min received a dose of 950 mg/m(2) twice daily.A total of 248 cycles of capecitabine were administered (median, five cycles; range, one to eight cycles). The overall response rate was 24% (95% CI, 15% to 41%), including two complete responses (CR; 4%) and 10 partial responses (PR; 20%). Disease control (CR + PR + stable disease) was achieved in 67% of patients. The median times to disease progression and overall survival were 7 months (95% CI, 6.4 to 9.5 months) and 11 months (95% CI, 8.6 to 13.3 months), respectively. Of the 35 patients evaluated for clinical benefit response, 14 (40%; 95% CI, 24% to 58%) showed clinical benefit. Capecitabine was well tolerated. Treatment-related grade 3 and 4 adverse events were observed in only six patients (12%), and the most common events were diarrhea, hand-foot syndrome, and thrombocytopenia. One patient (2%) had an episode of angina, but no treatment-related deaths were reported.Our findings suggest that capecitabine is effective and well tolerated in elderly patients with advanced CRC who are considered ineligible for combination chemotherapy.
Sarcoidosis: TB or not TB?
Authors: I Litinsky
Journal: Annals of the Rheumatic Diseases (2002)

A 37 year old man presented at another centre with a three week history of high grade fever, chills, and cervical lymphadenopathy. Routine laboratory tests as well as a purified protein derivative (PPD) test were within the normal ranges. Computed tomography of the chest and abdomen showed massive lymphadenopathy in the mediastinum and retroperitoneum. A cervical lymph node biopsy disclosed non-caseating granuloma negative for Mycobacterium tuberculosis by acid fast staining and culture. Sarcoidosis was diagnosed and the patient was treated with corticosteroids at a maximum dose of 60 mg/day for two months with complete resolution of the fever and lymphadenopathy.

Four months later, the patient developed right carpal tunnel syndrome, which was attributed to a lesion occupying space in the right radius; the tumour was removed and histology demonstrated non-caseating granuloma, interpreted as osseous sarcoidosis. A short course of corticosteroids was renewed and tapered off. He remained asymptomatic during the following six months when he developed oligoarthritis affecting the right ankle and wrist. Synovectomy of his right wrist showed non-caseating granuloma. Culture of the synovium was negative for Mycobacterium tuberculosis . Despite treatment with systemic and intra-articular steroids and addition of a three month course of weekly methotrexate, chronic and disabling monarthritis of the right ankle …
Protein Kinase C-α–Mediated Regulation of Low-Density Lipoprotein Receptor–Related Protein and Urokinase Increases Astrocytoma Invasion
Authors: Samson Amos, Melike Mut, Charles G. diPierro, Joan E. Carpenter, Aizhen Xiao, Zachary A. Kohutek, Gerard T. Redpath, Yunge Zhao, Jiahu Wang, Mark E. Shaffrey, Isa M. Hussaini
Journal: Cancer Research (2007)

Abstract Aggressive and infiltrative invasion is one of the hallmarks of glioblastoma. Low-density lipoprotein receptor–related protein (LRP) is expressed by glioblastoma, but the role of this receptor in astrocytic tumor invasion remains poorly understood. We show that activation of protein kinase C-α (PKC-α) phosphorylated and down-regulated LRP expression. Pretreatment of tumor cells with PKC inhibitors, phosphoinositide 3-kinase (PI3K) inhibitor, PKC-α small interfering RNA (siRNA), and short hairpin RNA abrogated phorbol 12-myristate 13-acetate–induced down-regulation of LRP and inhibited astrocytic tumor invasion in vitro. In xenograft glioblastoma mouse model and in vitro transmembrane invasion assay, LRP-deficient cells, which secreted high levels of urokinase-type plasminogen activator (uPA), invaded extensively the surrounding normal brain tissue, whereas the LRP-overexpressing and uPA-deficient cells did not invade into the surrounding normal brain. siRNA, targeted against uPA in LRP-deficient clones, attenuated their invasive potential. Taken together, our results strongly suggest the involvement of PKC-α/PI3K signaling pathways in the regulation of LRP-mediated astrocytoma invasion. Thus, a strategy of combining small molecule inhibitors of PKC-α and PI3K could provide a new treatment paradigm for glioblastomas. [Cancer Res 2007;67(21):10241–51]
Acute Coronary Syndrome in Patients With Atrial Fibrillation
Authors: Aldo Pietro Maggioni
Journal: Circulation (2012)

What We Know2][3][4] Several trials testing clopidogrel [5][6][7] or new antiplatelet agents 8,9 clearly showed that the addition of a thyenopiridine to aspirin is associated with a significant improvement of patients' outcomes.Furthermore, even in the case of elective percutaneous coronary procedures, the use of dual antiplatelet therapy is recommended for a medium-long period of time after the procedure. 2,4,10 Article see p 1185A similar level of good evidence is available for the prevention of ischemic stroke and peripheral thromboembolic events in patients with atrial fibrillation. 11,12In this clinical condition, appropriate use of vitamin K antagonists (VKAs) is associated with a significant reduction of thromboembolic events, in particular ischemic stroke. 13Specifically, in patients with nonvalvular atrial fibrillation, when the risk of stroke is relevantly high (CHA2DS2-VASc Ն2) 14 and the risk of bleeding is acceptable (HAS-BLED Ͻ3), 15 a favorable risk/benefit profile of VKAs, at a dosage that maintains the international normalized ratio between 2 and 3, has been clearly demonstrated.
Synergistic Cytotoxicity for L929 Cells of Polyriboinosinic-Polyribocytidylic Acid and Amphotericin B Methyl Ester: Brief Communication 2
Authors: Ernest C. Borden
Journal: JNCI Journal of the National Cancer Institute (1978)

A synergistic impairment in cell growth of L929 mouse fibroblasts resulted from treatment with a combination of amphotericin B methyl ester and polyriboinosinic-polyribocytidylic acid. This effect, which may result from the altered membrane permeability induced by polyenes, may augment the therapeutic efficacy of polyribonucleotides as antitumor compounds.
Lactate preserves neuronal metabolism and function following antecedent recurrent hypoglycemia
Authors: Raimund I. Herzog, Lihong Jiang, Peter Herman, Chen Zhao, Basavaraju G. Sanganahalli, Graeme F. Mason, Fahmeed Hyder, Douglas L. Rothman, Robert S. Sherwin, Kevin L. Behar
Journal: Journal of Clinical Investigation (2013)

Hypoglycemia occurs frequently during intensive insulin therapy in patients with both type 1 and type 2 diabetes and remains the single most important obstacle in achieving tight glycemic control. Using a rodent model of hypoglycemia, we demonstrated that exposure to antecedent recurrent hypoglycemia leads to adaptations of brain metabolism so that modest increments in circulating lactate allow the brain to function normally under acute hypoglycemic conditions. We characterized 3 major factors underlying this effect. First, we measured enhanced transport of lactate both into as well as out of the brain that resulted in only a small increase of its contribution to total brain oxidative capacity, suggesting that it was not the major fuel. Second, we observed a doubling of the glucose contribution to brain metabolism under hypoglycemic conditions that restored metabolic activity to levels otherwise only observed at euglycemia. Third, we determined that elevated lactate is critical for maintaining glucose metabolism under hypoglycemia, which preserves neuronal function. These unexpected findings suggest that while lactate uptake was enhanced, it is insufficient to support metabolism as an alternate substrate to replace glucose. Lactate is, however, able to modulate metabolic and neuronal activity, serving as a "metabolic regulator" instead.
Signal Transducer and Activator of Transcription 6 Is Essential in the Induction of Contact Hypersensitivity
Authors: Hiroo Yokozeki, Mehran Ghoreishi, Shinsuke Takagawa, Kaoru Takayama, Takahiro Satoh, Ichiro Katayama, Kiyoshi Takeda, Shizuo Akira, Kiyoshi Nishioka
Journal: The Journal of Experimental Medicine (2000)

Contact hypersensitivity (CHS) is thought to be mainly associated with the activation of T helper type 1 (Th1) cells. However, there is also evidence that Th2 cells or Th2 cytokines play a role in the development of CHS. To analyze the functional contribution of Th2 cytokines interleukin (IL)-4 and IL-13, signal transducer and activator of transcription 6 (STAT6)-deficient (STAT6(-/)-) and wild-type (wt) control C57BL/6 mice were contact sensitized with 5% 2,4,6-trinitrochlorobenzene (TNCB), 0.5% 2,4-dinitrofluorobenzene, or 5% 4-ethoxyl methylene-2-phenyl-2-oxazolin-5-one, and any skin reactions were examined. Ear swelling was significantly reduced with a delayed peak response in STAT6(-/)- mice compared with wt mice.A histological analysis revealed that the infiltration of both eosinophils and neutrophils in the skin challenged after 24 h in STAT6(-/)- mice decreased substantially compared with that in wt mice. The expression of Th2 cytokines (IL-4, IL-5) in TNCB-challenged skin tissues and the supernatants from T cells stimulated by 2,4,6-trinitrobenzene sulfonate-modified spleen cells, as well as the immunoglobulin (Ig)E and IgG1 response after challenge, were also profoundly reduced in STAT6(-/)- mice, whereas the expression of interferon gamma was the same in STAT6(-/)- and wt mice after challenge. Furthermore, adoptive transfer experiments revealed that STAT6(-/)- mice induced CHS after injection of lymph node cells obtained from sensitized wt mice. Our data suggest that the STAT6 signal plays a critical role in the induction phase of CHS.
The incongruous hip joint: a loading study.
Authors: N Y Afoke, P D Byers, W C Hutton
Journal: Annals of the Rheumatic Diseases (1984)

Hip incongruency was studied by load-displacement and casting methods. Twenty-five joints were loaded in 5 different positions of the walking cycle. Seventeen of them had a space at the apex in all positions, while 3 were congruent at low loads, and the remaining 5 had femoral heads smaller than their acetabula. No trends with age were apparent.
Grandparental investment and the epiphenomenon of menopause in recent human history
Authors: Douglas C. Broadfield
Journal: Behavioral and Brain Sciences (2010)

Abstract The effects of grandparental investment in relatives are apparent in human groups, suggesting that a postreproductive period in humans is selective. Although investment of relatives in kin produces obvious benefits for kin groups, selection for a postreproductive period in humans is not supported by evidence from chimpanzees. Instead, grandparental investment is likely a recent phenomenon of longevity, rather than an evolved feature.
THE INVESTIGATION OF PHOTOCONTACT DERMATITIS IN A DYE MANUFACTURING PROCESS
Authors: J. S. GARDINER, A. DICKSON, T. M. MACLEOD, W. FRAIN-BELL
Journal: British Journal of Dermatology (1972)

Summary.— An investigation of photocontact dermatitis occurring in a dye manufacturing process is described. Sixteen employees were studied by photopatch testing to the complete anthraquinone‐based dye: Disperse Blue 35 and to chromatographically separated bands. By irradiation of the skin with visible light between 400 and 700 nm evidence was obtained to show that the complete dye produced photo‐contact dermatitis in individuals, whether they had previously been exposed to it or not. Using the same technique, only 4 of the 10 constituent hands produced a similar photocontact reaction.
Evolution and modulation of age-related medial elastocalcinosis: Impact on large artery stiffness and isolated systolic hypertension
Authors: H DAO, R ESSALIHI, C BOUVET, P MOREAU
Journal: Cardiovascular Research (2005)

Arteriosclerosis, characterized by remodeling and stiffening of large elastic arteries is the most significant manifestation of vascular aging. The increased stiffening is believed to originate from a gradual mechanical senescence of the elastic network, alterations in cross-linking of extracellular matrix components, fibrosis and calcification of elastic fibers (medial elastocalcinosis). The stiffening of large arteries reduces their capacitance and accelerates pulse wave velocity, thus contributing to a widening of pulse pressure and to the increased prevalence of isolated systolic hypertension with age. Current antihypertensive drugs were mainly designed to reduce peripheral resistance and are not adequate to alter the pathological process of vascular stiffening or even to selectively reduce systolic blood pressure in isolated systolic hypertension. This review puts forward the concept that elastocalcinosis is a valuable therapeutic target and presents evidence that this process can be prevented and reversed pharmacologically.
Local Gene Transfer of phVEGF-2 Plasmid by Gene-Eluting Stents
Authors: Dirk H. Walter, Manfred Cejna, Larry Diaz-Sandoval, Sean Willis, Laura Kirkwood, Peter W. Stratford, Anne B. Tietz, Rudolf Kirchmair, Marcy Silver, Cindy Curry, Andrea Wecker, Young-Sup Yoon, Regina Heidenreich, Allison Hanley, Marianne Kearney, Fermin O. Tio, Patrik Kuenzler, Jeffrey M. Isner, Douglas W. Losordo
Journal: Circulation (2004)

Background— Drug-eluting stents represent a useful strategy for the prevention of restenosis using various antiproliferative drugs. These strategies share the liability of impairing endothelial recovery, thereby altering the natural biology of the vessel wall and increasing the associated risk of stent thrombosis. Accordingly, we tested the hypothesis that local delivery via gene-eluting stent of naked plasmid DNA encoding for human vascular endothelial growth factor (VEGF)-2 could achieve similar reductions in neointima formation while accelerating, rather than inhibiting, reendothelialization. Methods and Results— phVEGF 2-plasmid (100 or 200 μg per stent)–coated BiodivYsio phosphorylcholine polymer stents versus uncoated stents were deployed in a randomized, blinded fashion in iliac arteries of 40 normocholesterolemic and 16 hypercholesterolemic rabbits. Reendothelialization was nearly complete in the VEGF stent group after 10 days and was significantly greater than in control stents (98.7±1% versus 79.0±6%, P &lt;0.01). At 3 months, intravascular ultrasound analysis revealed that lumen cross-sectional area (4.2±0.4 versus 2.27±0.3 mm 2 , P &lt;0.001) was significantly greater and percent cross-sectional narrowing was significantly lower (23.4±6 versus 51.2±10, P &lt;0.001) in VEGF stents compared with control stents implanted in hypercholesterolemic rabbits. Transgene expression was detectable in the vessel wall along with improved functional recovery of stented segments, resulting in a 2.4-fold increase in NO production. Conclusions— Acceleration of reendothelialization via VEGF-2 gene–eluting stents provides an alternative treatment strategy for the prevention of restenosis. VEGF-2 gene–eluting stents may be considered as a stand-alone or combination therapy.
A history of luminal gastroenterology in Britain: the inside guide
Authors: Peter Cotton
Journal: Gut (2014)

Peter Down. Published by Watery Books, Dorset. ISBN: 978-0-9572504-0-6

Residing recently in the Sheila Sherlock room in the refurbished accommodations at the William Harvey house at the College of Physicians in London, I was reminded that it was she who first told me (at one of my unsuccessful Consultant interviews) that “Gastroenterologists help people to get square meals through round holes”. I have been at that task ever since, often with an endoscope in hand, as recounted in a recent memoir called The Tunnel at the End of the Light (www.peterbcotton.com).

I approached Peter Down's majestic history of the British contributions to ‘luminal gastroenterology’ with some trepidation. It is 780 pages long, with almost 1500 references, and looked like seriously heavy going. It is indeed heavy, but it took only a few pages for me to realise that Peter has married serious scholarship with a conversational style that makes easy, indeed enjoyable, reading.

Each of the 76 chapters in the seven sections (oesophagus, stomach and duodenum, small intestine, coeliac disease, IBD, functional bowel disorders and …
Diabetic Retinopathy
Authors: Jonathan Betz Brown, Kathryn L. Pedula, Kent H. Summers
Journal: Diabetes Care (2003)

OBJECTIVE—To measure the extent to which modern intensified risk factor control has lessened the duration-specific prevalence of diabetic retinopathy and, therefore, has decreased the risk of blindness in Americans with type 2 diabetes. RESEARCH DESIGN AND METHODS—Intensified control of blood glucose and blood pressure has prevented diabetic retinopathy in randomized controlled trials. There is as yet no confirmation that subsequent treatment intensification in the community has had the same result. We identified all 6,993 members of a health maintenance organization, Kaiser Permanente Northwest (KPNW), who, in 1997–1998, had dilated retinal examinations and verifiable data of diagnosis of type 2 diabetes. We plotted prevalence by time since diagnosis for background diabetic retinopathy (BDR) and proliferative diabetic retinopathy (PDR) and compared these results to identically derived 1980–1982 results from the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR). We estimated multivariate predictive models. RESULTS—Mean (± SD) HbA1c in KPNW was 7.84 ± 1.26% versus 10.37% (standardized) in the WESDR. KPNW blood pressure averaged 138.6 ± 13.8/79.5 ± 7.4 mmHg compared with 147.0/79.0 in the WESDR. BDR was much less prevalent in KPNW, but PDR prevalence appeared unchanged. BDR preceded diagnosis in 20.8% of the WESDR subjects but only 2.0% of KPNW subjects. However, in both populations, the first cases of PDR appeared similarly, soon after diagnosis. CONCLUSIONS—Earlier diagnosis and more aggressive control of blood glucose and blood pressure decreased the duration-adjusted prevalence of background, but not of sight-threatening proliferative retinopathy. More population-based research is needed to replicate and explain this unexpected finding. Detecting and treating PDR should not be neglected on the assumption that risk-factor control has minimized its prevalence.
Proapoptotic protein bim and its upstream activator Foxo3A are overexpressed in primary biliary cirrhosis but not in primary sclerosing cholangitis
Authors: J. A. Czyszek, M. Milkiewicz, E. Elias, P. Milkiewicz
Journal: Gut (2011)

<h3>Introduction</h3> Apoptosis, with subsequent aberrant expression of pyruvate dehydrogenase complex (PDC-E2) on cell surface has been postulated to play an important role in the pathogenesis of Primary Biliary Cirrhosis (PBC). More recently, a particular feature of cholangiocytes that leads to prolonged exposure of an intact immunoreactive PDC-E2 to the immune system within apoptotic blebs has been described. Whether this effect is related to specific for PBC, impaired regulation of apoptotic pathways remains to be established. The transcription factor FoxO3a is known to be an upstream activator of Bim (Bcl-2-interacting mediator of cell death) protein which is involved in cellular apoptosis. The aim of the study was to analyse gene expression of transcription factor FoxO3a and Bim in livers of patients with early PBC, end-stage PBC, end-stage Primary Sclerosing Cholangitis (PSC) and control liver tissue. <h3>Methods</h3> Total RNA was isolated from liver tissues obtained either during routine percutaneous liver biopsies (early PBC n=21) or from explanted livers from end-stage diseases (PBC n=19; PSC n=8). Liver tissues from large margin resections of HCC were used as controls (n=19). Gene expressions were evaluated using Quantitative Taq Man real time PCR analysis. Protein levels (not measured in early PBC) were assessed with Western Blot. <h3>Results</h3> As compared to controls, expression of FoxO3a mRNA showed statistically significant increase in both early PBC (2.2-fold increase; p=0.006) and end-stage PBC (4.3-fold increase; p=0.003). Expression of FoxO3a was significantly higher in patients with more advanced fibrosis (F0-2 vs F3-4, p=0.042). Also, a substantial upregulation of Bim mRNA was observed both in early PBC (eightfold increase vs controls; p=0.045). and end-stage PBC (8.2-fold increase vs controls; p=0.003). Correspondingly, levels of Foxo3a and Bim proteins were significantly enhanced in end-stage PBC. Levels of FoxO3a and Bim mRNAs in PSC were not significantly different from controls. <h3>Conclusion</h3> Upregulation of FoxO3a and Bim observed in PBC but not in PSC may support an involvement of apoptotic pathways in the pathogenesis of this condition.
Atrial gap junction remodeling: Looking for lost gaps and orphaned connexins in three dimensions
Authors: R MUSTERS
Journal: Cardiovascular Research (2006)

See article by Rucker-Martin et al.  [22]  (pages 69–79) in this issue. 

Gap junction channels are composed of members of a multi-gene family of proteins called connexins. These proteins are named by the abbreviation Cx followed by the molecular weight of the specific protein. Mammalian cardiac myocytes express Cx43, Cx45, and Cx40, the former being the major cardiac gap junction protein, which is expressed in atrial and ventricular myocytes as well as in selected regions of the atrioventricular conduction system [1,2]. Individual gap junction channels (also called connexons) formed by multiple connexin molecules exhibit distinct unitary conductance, pH and voltage dependence, and permeability to ions and small molecules as well as fluorescent dyes [3]. Regulation of the extent to which cardiac myocytes are electrically coupled by gap junction channels is complex and still not well understood [4,5]. In general, it appears that cells can rapidly (within minutes) change the number of functional channels at the cell surface through multiple mechanisms involving mobilization of intracellular connexin molecules to junctional plaques, internalization of junctional channels, changes in channel open probability and, potentially, changes in rates of … 

*Tel.: +31 20 444 1749; fax: +31 20 444 8255. Email address: r.musters{at}vumc.nl