tbuckley/cabot-search huggingface dataset:
In vivo expression of perforin by CD8+ lymphocytes during an acute viral infection.
Authors: L H Young, L S Klavinskis, M B Oldstone, J D Young
Journal: The Journal of Experimental Medicine (1989)

CTL and NK cells cultured in vitro have been shown to contain a cytolytic pore-forming protein (PFP/perforin/cytolysin). To date, it has not been determined whether perforin is expressed by CTL that have been primed in vivo. Here, we have infected mice with two strains of lymphocytic choriomeningitis virus (LCMV), one of which mainly produces choriomeningitis and, the other, hepatitis. Brain and liver cryostat sections obtained from LCMV-infected mice were stained for various lymphocyte markers, including perforin. We were able to detect a large accumulation of perforin antigen in CD8+/Thy-1+/asialo GM1+/CD4- lymphocytes, which in fact represent the main infiltrating cell type found in brain and liver sections obtained during the late acute stage of LCMV infection. Perforin was also detected in a smaller population of CD8-/asialo GM1+/NK 1.1+/F480- cells, presumably corresponding to NK cells. Perforin-positive cells were found to have the morphology of blasts or large granular lymphocytes (LGL). These observations, together with in vitro studies performed in the past, indicate that perforin may be associated exclusively with LGL-like CTL blasts and NK cells. Our results demonstrate for the first time the presence of perforin in CTL that have been primed in vivo and suggest that perforin-positive CTL may be directly involved in producing the immunopathology associated with the LCMV infection.
OC-040 Community-based Endoscopy In A Car Park. Fantasy Or Reality?
Authors: A Hitchen, B Kompo, P Phillips, E Price, G Deans, NK Ahluwalia
Journal: Gut (2014)

<h3>Introduction</h3> Owing to safety and quality concerns raised by BSG in 1990s, Community Based Endoscopy (CBE) rapidly declined. In 2014 CBE is back on the agenda with CCGs demanding a safe, high-quality, sub-tariff, 7 day endoscopy service close to the patient's home, at a time of the patient's choosing. We describe 5 years experience of a fully JAG accredited consultant-delivered completely mobile endoscopy service provided in shopping centre car parks throughout Greater Manchester (GM). <h3>Methods</h3> In 2007, concept emerged out of a tender from 10 PCTs demanding safe and high quality endoscopy in the community. A linked-3-trailer unit with spacious waiting area for patients/relatives, consent-counselling, preparation, examination, decontamination and recovery areas. with its own – water, electricity, waste disposal, e-communications and administration network was commissioned with integral office, staff kitchen/rest room and changing area. All staff undergo rigorous mandatory induction and regular updates, CPD, audits as per JAG. Emergency scenarios are regularly rehearsed and audited. Full complement of ALS certified staff support consultants 8 am–8 pm, 7/7 [360] days in diagnostic UGI and LGI endoscopies [including polypectomies] and deliver 36 units/day. All patients undergo JAG-standard monitoring of pulse, BP, O<sub>2</sub> saturation, sedation and pain scores. All records are paperless, live and e-MAXIM andUNISOFT-based. All patients are contacted within 24 h by an experienced nurse to record any untoward incident. Patient and family feedback and regular meetings with GP allows total quality management in service delivery. Though no age limit, patients with IDDM, BMI &gt;40, &gt;25st and ASA≥3+ are excluded. Quarterly audits are shared with commissioners. Unit relocates biweekly to 7 convenient locations with adjacent free parking. <h3>Results</h3> Of 26599 (10539 UGI, 10583 Flexi-Sig, 5477 Colonoscopy) procedures, 1 in 3 patients opted for out-of-hours or weekend as first choice. LGI- 93% good-bowel prep, 91% caecal intubation, 8.8% adenoma detection, 97% polyp recovery and 100% Bx for diarrhoea. UGI- 98% D2 intubation, 100% 6 week repeat for GU, 84% unsedated. Biannual JAG-GRS compliant audits showed 0% 30 day mortality, 0% UGI SAE and 5 (0.018%) unplanned hospital admissions 4 requiring surgery due to colon perforation [one post-flexi detected in the unit (diverticular disease), 1 from polypectomy, 2 diagnostic colonoscopy] and fifth due to hyponatremia (CitraFleet – now discontinued) requiring electrolyte correction. <h3>Conclusion</h3> CBE is ready for prime time, just at the right time, as commissioners are now seeking more care in the community wherever safely possible. We however, recommend caution as model for sub-tariff CBE endoscopy from static sites needs to be first piloted. <h3>Disclosure of Interest</h3> None Declared.
Liver X Receptor Activation Controls Intracellular Cholesterol Trafficking and Esterification in Human Macrophages
Authors: E. Rigamonti, L. Helin, S. Lestavel, A.L. Mutka, M. Lepore, C. Fontaine, M.A. Bouhlel, S. Bultel, J.C. Fruchart, E. Ikonen, V. Clavey, B. Staels, G. Chinetti-Gbaguidi
Journal: Circulation Research (2005)

Liver X receptors (LXRs) are nuclear receptors that regulate macrophage cholesterol efflux by inducing ATP-binding cassette transporter A1 (ABCA1) and ABCG1/ABCG4 gene expression. The Niemann-Pick C (NPC) proteins NPC1 and NPC2 are located in the late endosome, where they control cholesterol trafficking to the plasma membrane. The mobilization of cholesterol from intracellular pools to the plasma membrane is a determinant governing its availability for efflux to extracellular acceptors. Here we investigated the influence of LXR activation on intracellular cholesterol trafficking in primary human macrophages. Synthetic LXR activators increase the amount of free cholesterol in the plasma membrane by inducing NPC1 and NPC2 gene expression. Moreover, ABCA1-dependent cholesterol efflux induced by LXR activators was drastically decreased in the presence of progesterone, which blocks postlysosomal cholesterol trafficking, and reduced when NPC1 and NPC2 mRNA expression was depleted using small interfering RNA. The stimulation of cholesterol mobilization to the plasma membrane by LXRs led to a decrease in cholesteryl ester formation and Acyl–coenzyme A cholesterol acyltransferase-1 activity. These data indicate that LXR activation enhances cholesterol trafficking to the plasma membrane, where it becomes available for efflux, at the expense of esterification, thus contributing to the overall effects of LXR agonists in the control of macrophage cholesterol homeostasis.
Abstract 1643: AZD4547, a potent and selective inhibitor of FGF-receptor tyrosine kinases 1, 2 and 3, inhibits the growth of FGF-receptor 2 driven gastric cancer models <i>in vitro</i> and <i>in vivo</i>
Authors: Liang Xie, Xinying Su, David Zhang, Lily Tang, Jessie Xu, Maggie Wang, Lucy Yin, Jingchuan Zhang, Katherine Ye, Zengquan Wang, Elaine Kilgour, Qunsheng Ji
Journal: Cancer Research (2011)

Abstract Gastric cancer is the second most lethal cancer worldwide. We and others have shown that the FGFR2 gene is amplified in a subset of gastric cancers. To validate FGFR2 as a potential therapeutic target for gastric cancer, we employed an inducible shRNA system to specifically block expression of individual FGFRs, both in vitro and in vivo. When FGFR2 was specifically down regulated in an FGFR2-amplified gastric cancer cell line Snu-16, the activation of pFGFR2 and its downstream signaling effectors were blocked and there was significant inhibition of the cell growth and survival that further translated into tumor growth regression in vivo, demonstrating that in this model tumor growth/survival is dependent on the FGFR2 pathway. To further confirm this, AZD4547, a selective inhibitor of FGFR 1, 2 and 3 receptor tyrosine kinases was tested in a panel of gastric cancer cell lines for its anti-proliferative effect. In this panel the cell-lines that were most sensitive to AZD4547 were the Snu-16 and KATOIII, both of which are gene amplified for FGFR2. Exposure of the Snu-16 cells to AZD4547 resulted in cell-death and once daily oral dosing of AZD4547 resulted in tumor growth inhibition of the Snu-16 xenografts in a dose-dependent fashion, with significant tumor regression observed when AZD4547 was dosed once daily at 12.5 mg/kg. The anti-tumor efficacy of AZD4547 correlated with inhibition of pFGFR2 and modulation of other downstream markers of FGFR pathway activation, including pErk, pS6 protein and pPLCγ and efficacious doses of AZD4547 induced elevations of levels of plasma FGF23, a known marker of FGFR inhibition. In addition to the single-agent efficacy, combining of AZD4547 with cytotoxic agents, currently used for the treatment of gastric cancer patients, revealed enhanced growth inhibition of Snu-16 xenografts. Taken together, these data support clinical testing of AZD4547 in gastric cancer patients harboring FGFR2 gene amplification. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1643. doi:10.1158/1538-7445.AM2011-1643
Cancer Screening: The Clash of Science and Intuition
Authors: Barnett S. Kramer, Jennifer Miller Croswell
Journal: Annual Review of Medicine (2008)

The concept of early detection of cancer holds great promise and intuitive appeal. However, powerful biases can mislead clinicians when evaluating the efficacy of screening tests by clinical observation alone. Selection bias, lead-time bias, length-biased sampling, and overdiagnosis are counterintuitive concepts with critical implications for early-detection efforts. This article explains these biases and other common confounders in cancer screening. The most direct and reliable way to avoid being led astray by intuitions is through the use of randomized controlled trials.
Ceratamines, Structurally Simple Microtubule-Stabilizing Antimitotic Agents with Unusual Cellular Effects
Authors: Geoffrey Karjala, Queenie Chan, Emiliano Manzo, Raymond J. Andersen, Michel Roberge
Journal: Cancer Research (2005)

Abstract Ceratamine A and ceratamine B are heterocyclic alkaloids recently identified in a screen for compounds that arrest cells in mitosis. Treatment of breast carcinoma MCF-7 cells causes a concentration-dependent block of cell cycle progression exclusively at mitosis. In vitro studies with purified tubulin indicate that the ceratamines directly stimulate microtubule polymerization in the absence of microtubule-associated proteins. Cells treated with ceratamines show a dense perinuclear microtubule network in interphase and multiple pillar-like tubulin structures in mitotic cells. The ceratamines do not compete with paclitaxel for binding to microtubules in vitro. Unlike other microtubule-stabilizing agents, the ceratamines have simple structures with no chiral centers, making them attractive drug leads.
Adenomatous Polyposis Coli Determines Sensitivity to Histone Deacetylase Inhibitor–Induced Apoptosis in Colon Cancer Cells
Authors: Xiangwei Huang, Bin Guo
Journal: Cancer Research (2006)

Abstract Inhibitors of histone deacetylases (HDAC) inhibit malignant cell growth and induce apoptosis through unknown mechanisms. Here, we report that the expression status of adenomatous polyposis coli (APC) protein determines the relative sensitivity of colon cancer cells to HDAC inhibitor–induced apoptosis. HCA-7 cells (expressing wild-type β-catenin and APC proteins) are more sensitive to apoptosis induced by HDAC inhibitors valproic acid (VPA) and suberoylanilide hydroxamic acid than SW620 or HT-29 cells (both expressing mutant APC). When wild-type APC protein was expressed using an inducible expression system, HT-29 cells became sensitive to apoptosis in response to VPA. Conversely, knocking down of endogenous APC protein by small interfering RNA (siRNA) blocked VPA-induced apoptosis in HCA-7 cells. APC mediated VPA-induced apoptosis through down-regulation of survivin. The level of survivin protein decreased in HCA-7 and HT-29/APC cells, but not in SW620 and HT-29/β-Gal cells after VPA treatment. Whereas knocking down of survivin by siRNA sensitized SW620 cells to VPA-induced apoptosis, overexpression of survivin blocked VPA-induced apoptosis in HCA-7 cells. Down-regulation of survivin transcription occurred through changes in GSK-3β/β-catenin/Tcf-4 signaling molecules. VPA also induced proteasome-mediated degradation of survivin protein in HCA-7 cells. Furthermore, we have shown that APC mutation–mediated resistance to apoptosis can be overcome by cotreatment with Flavopiridol, which promotes survivin degradation. These results suggest that APC is a critical determinant of HDAC inhibitor–induced apoptosis in colon cancer cells and survivin is a potential target to enhance apoptotic response to HDAC inhibitors. (Cancer Res 2006; 66(18): 9245-51)
Ionizing Radiation and Tobacco Use Increases the Risk of a Subsequent Lung Carcinoma in Women With Breast Cancer: Case-Only Design
Authors: Michaela Prochazka, Per Hall, Giovanna Gagliardi, Fredrik Granath, Bo N. Nilsson, Peter G. Shields, Meredith Tennis, Kamila Czene
Journal: Journal of Clinical Oncology (2005)

To analyze the risk of lung cancer in women treated with radiotherapy for breast cancer. We accessed the lung dose in relation to different radiotherapy techniques, provided the excess relative risk (ERR) estimate for radiation-associated lung cancer, and evaluated the influence of tobacco use.The Swedish Cancer Registry was used to identify 182 women diagnosed with breast and subsequent lung cancers in Stockholm County during 1958 to 2000. Radiotherapy was administered to 116 patients. Radiation dose was estimated from the original treatment charts, and information on smoking history was searched for in case records and among relatives. The risk of lung cancer was assessed in a case-only approach, where each woman contributed a pair of lungs.The average mean lung dose to the ipsilateral lung was 17.2 Gy (range, 7.1 to 32.0 Gy). A significantly increased relative risk (RR) of a subsequent ipsilateral lung cancer was observed at > or = 10 years of follow-up (RR = 2.04; 95% CI, 1.24 to 3.36). Squamous cell carcinoma (RR = 4.00; 95% CI, 1.50 to 10.66) was the histopathologic subgroup most closely related to ionizing radiation. The effect of radiotherapy was restricted to smokers only (RR = 3.08; 95% CI, 1.61 to 5.91). The ERR/Gy for women with latency > or = 10 years after exposure was 0.11 (95% CI, 0.02 to 0.44).Radiotherapy for breast cancer significantly increases the risk of lung carcinoma more than 10 years after exposure in women who smoked at time of breast cancer.
Production of 1,25-dihydroxyvitamin D3 by human T cell lymphotrophic virus-I-transformed lymphocytes.
Authors: D A Fetchick, D R Bertolini, P S Sarin, S T Weintraub, G R Mundy, J F Dunn
Journal: Journal of Clinical Investigation (1986)

The human T cell lymphotrophic virus type I (HTLV-I) has recently been identified in a T cell lymphoma associated with hypercalcemia and increased bone turnover. Since increased serum concentrations of 1,25-dihydroxyvitamin D have been reported in this disease, we have examined the capacity of HTLV-I-infected cord blood lymphocytes to metabolize 25-hydroxyvitamin D3. Our results demonstrate that HTLV-I-infected cells have the capacity to metabolize 25-hydroxyvitamin D3 to a substance that co-migrates with 1,25-dihydroxyvitamin D3 by high performance liquid chromatography over a silica column using either 12% isopropanol in hexane or 5% isopropanol in dichloromethane. The metabolite binds to the 1,25-dihydroxyvitamin D3 receptor in rat osteosarcoma cells and stimulates bone resorption in cultures of fetal rat long bones. Mass spectrometric analysis of the metabolite confirmed the presence of 1,25-dihydroxyvitamin D3. Production of 1,25-dihydroxyvitamin D by lymphoma cells may contribute to the pathogenesis of the hypercalcemia seen in patients with HTLV-I-associated T cell lymphomas.
Mesenchymal Stem Cell-Derived Microvesicles Protect Against Acute Tubular Injury
Authors: Stefania Bruno, Cristina Grange, Maria Chiara Deregibus, Raffaele A. Calogero, Silvia Saviozzi, Federica Collino, Laura Morando, Alessandro Busca, Michele Falda, Benedetta Bussolati, Ciro Tetta, Giovanni Camussi
Journal: Journal of the American Society of Nephrology (2009)

Administration of mesenchymal stem cells (MSCs) improves the recovery from acute kidney injury (AKI). The mechanism may involve paracrine factors promoting proliferation of surviving intrinsic epithelial cells, but these factors remain unknown. In the current study, we found that microvesicles derived from human bone marrow MSCs stimulated proliferation <i>in vitro</i> and conferred resistance of tubular epithelial cells to apoptosis. The biologic action of microvesicles required their CD44- and β1-integrin-dependent incorporation into tubular cells. <i>In vivo</i>, microvesicles accelerated the morphologic and functional recovery of glycerol-induced AKI in SCID mice by inducing proliferation of tubular cells. The effect of microvesicles on the recovery of AKI was similar to the effect of human MSCs. RNase abolished the aforementioned effects of microvesicles <i>in vitro</i> and <i>in vivo</i>, suggesting RNA-dependent biologic effects. Microarray analysis and quantitative real time PCR of microvesicle-RNA extracts indicate that microvesicles shuttle a specific subset of cellular mRNA, such as mRNAs associated with the mesenchymal phenotype and with control of transcription, proliferation, and immunoregulation. These results suggest that microvesicles derived from MSCs may activate a proliferative program in surviving tubular cells after injury via a horizontal transfer of mRNA.
Medulloblastomas Derived from <i>Cxcr6</i> Mutant Mice Respond to Treatment with a Smoothened Inhibitor
Authors: Ken Sasai, Justyna T. Romer, Hiromichi Kimura, Derek E. Eberhart, Dennis S. Rice, Tom Curran
Journal: Cancer Research (2007)

The sonic hedgehog (Shh) pathway is activated in approximately 30% of human medulloblastoma resulting in increased expression of downstream target genes. In about half of these cases, this has been shown to be a consequence of mutations in regulatory genes within the pathway, including Ptc1, Smo, and Sufu. However, for some tumors, no mutations have been detected in known pathway genes. This suggests that either mutations in other genes promote tumorigenesis or that epigenetic alterations increase pathway activity in these tumors. Here, we report that 3% to 4% of mice lacking either one or both functional copies of Cxcr6 develop medulloblastoma. Although CXCR6 is not known to be involved in Shh signaling, tumors derived from Cxcr6 mutant mice expressed Shh pathway target genes including Gli1, Gli2, Ptc2, and Sfrp1, indicating elevated pathway activity. Interestingly, the level of Ptc1 expression was decreased in tumor cells although two normal copies of Ptc1 were retained. This implies that reduced CXCR6 function leads to suppression of Ptc1 thereby increasing Smoothened function and promoting tumorigenesis. We used a direct transplant model to test the sensitivity of medulloblastoma arising in Cxcr6 mutant mice to a small-molecule inhibitor of Smoothened (HhAntag). We found that transplanted tumors were dramatically inhibited in mice treated for only 4 days with HhAntag. These findings suggest that HhAntag may be effective against tumors lacking mutations in known Shh pathway genes.
Protective effects of the sickle cell gene against malaria morbidity and mortality
Authors: Michael Aidoo, Dianne J Terlouw, Margarette S Kolczak, Peter D McElroy, Feiko O ter Kuile, Simon Kariuki, Bernard L Nahlen, Altaf A Lal, Venkatachalam Udhayakumar
Journal: The Lancet (2002)
The Utility of Two Somatostatin Analog Radiopharmaceuticals in Assessment of Radiologically Indeterminate Pulmonary Lesions
Authors: Dragana P Sobic-Saranovic, Smiljana V Pavlovic, Vera M Artiko, Djordjije Z Saranovic, Emilija D Jaksic, Dragan Subotic, Ljudmila Nagorni-Obradovic, Nebojsa Kozarevic, Nebojsa Petrovic, Isidora T Grozdic, Vladimir B Obradovic
Journal: Clinical Nuclear Medicine (2011)

The aim of our study was to assess diagnostic accuracy of Tc-99m depreotide and Tc-99m-EDDA/HYNIC-TOC scintigraphy for evaluation of pulmonary lesions that appeared ambiguous on computed tomography (CT).Forty-nine consecutive patients (37 men and 12 women; mean age, 60 ± 11 years) with 60 pulmonary lesions on chest radiography and CT were referred for nuclear imaging. They were prospectively allocated to undergo whole-body scintigraphy (WBS) and single photon emission computed tomography (SPECT) using either Tc-99m depreotide (26 patients, group 1) or Tc-99m-EDDA/HYNIC-TOC imaging (23 patients, group 2). Histologic findings after tissue biopsy served as a gold standard for determining diagnostic accuracy of the 2 somatostatin analogs. Visual assessment was complemented by semiquantitative analysis based on target to background ratio.Among the 32 pulmonary lesions scanned with Tc-99m depreotide, focal uptake was increased in 22 of 25 malignancies, whereas no uptake was found in 6 of 7 benign lesions (88% sensitivity, 85% specificity, and 88% accuracy) on both WBS and SPECT. Imaging of 28 pulmonary lesions with Tc-99m-EDDA/HYNIC-TOC had a similar diagnostic yield (sensitivity 87%, specificity 84%, and accuracy 86%). Overall, target to background ratios were higher on SPECT than WBS but not significantly different between groups 1 and 2 (SPECT 2.72 ± 0.70 vs. 2.71 ± 0.50, WBS 1.61 ± 0.32 vs. 1.62 ± 0.28, respectively).This study demonstrates that Tc-99m depreotide and Tc-99m-EDDA/HYNIC-TOC have similar diagnostic value for characterizing pulmonary lesions that appear ambiguous on CT.
A New Model for Accreditation of Residency Programs in Internal Medicine
Authors: Allan H. Goroll, Carl Sirio, F. Daniel Duffy, Richard F. LeBlond, Patrick Alguire, Thomas A. Blackwell, William E. Rodak, Thomas Nasca
Journal: Annals of Internal Medicine (2004)

A renewed emphasis on clinical competence and its assessment has grown out of public concerns about the safety, efficacy, and accountability of health care in the United States. Medical schools and residency training programs are paying increased attention to teaching and evaluating basic clinical skills, stimulated in part by these concerns and the responding initiatives of accrediting, certifying, and licensing bodies. This paper, from the Residency Review Committee for Internal Medicine of the Accreditation Council for Graduate Medical Education, proposes a new outcomes-based accreditation strategy for residency training programs in internal medicine. It shifts residency program accreditation from external audit of educational process to continuous assessment and improvement of trainee clinical competence.