tbuckley/cabot-search huggingface dataset:
15. Trans-Splicing Adeno-Associated Viral Vector-Mediated Gene Therapy Is Limited by Transcription across the ITR Junction but Not by Dual Vector Co-Infection Efficiency
Authors: Zhuping Xu, Yongping Yue, Chaoyang Ye, Jianming Qiu, David J. Pintel, Dongsheng Duan
Journal: Molecular Therapy (2004)

Adeno-associated virus (AAV) is one of the smallest DNA viruses. Therapeutic application of recombinant AAV has been limited by its small carrying capacity. Many large genes, such as the 6 kb mini-dystrophin gene for Duchenne muscular dystrophy (DMD), are traditionally excluded from rAAV gene therapy. To overcome the size limitation, we have recently developed trans-splicing AAV vectors. This approach takes advantage of AAV inverted terminal repeat (ITR)-mediated intermolecular recombination and the eukaryotic splicing machinery. A large gene is split into two parts and engineered with splicing signals. Following packaging and co-infection, the transgene is expressed from the reconstituted genome. Despite the success of the proof-of-principle studies, the overall transduction efficiency of trans-splicing vectors is considerably lower than that of a single intact vector in skeletal muscle. To improve trans-splicing vectors for DMD gene therapy, we examined whether co-infection efficiency is a rate-limiting factor for skeletal muscle in a mouse model for DMD (mdx mouse). Two different AAV viruses carrying the gene either for alkaline phosphatase or nuclear-localized LacZ were delivered to mdx anterior tibialis muscle. Consistent with previous reports in normal muscle, co-infection efficiency reached 89.2±2.0% in the diseased muscle. This result suggests that co-infection efficiency is not a hurdle for trans-splicing vector-mediated gene therapy in dystrophic muscle.
Something to celebrate: The Bevan legacy
Authors: M. Portillo
Journal: BMJ (1998)

This paper is an edited extract from the Royal College of Nursing Kathleen A Raven Lecture given at the Royal College of Surgeons on 10 June 1998

At the conclusion of the second world war Britons wanted a new order of things. Medical care had made big advances in the war, and soldiers had been offered a higher standard of care than they were likely to encounter after demobilisation. Civil servants and politicians discerned these currents long before the war ended.

Following the war, therefore, Britain would almost certainly have created a national health service without Aneurin Bevan, and even without a Labour government. Bevan had to work with the conditions he inherited and he accepted much that had been planned during the wartime coalition government. He made relatively few big decisions, but those that he made have had a profound effect on the way the service has developed.

Bevan held fast to the principle of a service funded by the taxpayer, and essentially by no other source, and his resignation from the cabinet on the issue of health charges had the effect of raising that principle to the status of a dogma. That has been an important cause of the strain experienced by the health service ever since. It has been refused sufficient funds from the taxpayer, and has never had anywhere else to turn for money. Worse, sensible discussion of alternatives has been made almost impossible ever since Bevan turned the National Health Service into a party political battleground.

#### Summary points

After the war Britain would probably have created a national health service without Aneurin Bevan. He made relatively few big decisions, but those he did make had a profound effect on the way the NHS developed

His decision to nationalise the hospitals led to the government supplying virtually all …
Relationship between methotrexate dosing and clinical response in patients with moderate to severe psoriasis: subanalysis of the CHAMPION study
Authors: J.-H. Saurat, R.G. Langley, K. Reich, K. Unnebrink, E.H. Sasso, W. Kampman
Journal: British Journal of Dermatology (2011)

Background CHAMPION was a phase III trial that compared adalimumab with methotrexate and placebo for chronic plaque psoriasis. Objectives To determine the relationship between methotrexate dosing and improvement in psoriasis for patients in CHAMPION. Methods Methotrexate-treated patients in CHAMPION received step-up dosing to 15 mg per week during the first 8 weeks. At week 8, PASI 50 responders (early responders, ER) were to continue with 15 mg weekly for the next 8 weeks; PASI 50 nonresponders were to receive 20 mg weekly for the next 4 weeks, followed by 20 mg weekly if they achieved ≥ PASI 50 at week 12 (late responders, LR), or 25 mg weekly if not (late nonresponders, LN). Outcomes were assessed post hoc for patients in these groups who completed CHAMPION. Results One hundred and three methotrexate-treated patients were analysed: 40 ER, 22 LR and 41 LN. Week 16 mean percentage improvement from baseline in Psoriasis Area and Severity Index was greatest in the ER group, nearly as good in LR, and poor in LN; PASI 75/90/100 response rates were 70%/32%/18%, 41%/9%/5% and 5%/0%/0%, respectively. Among patients with a PASI 75 response at week 16, 72% were in the ER group (comprising 27% of patients overall) and 23% were in the LR group. Conclusions Nearly all week 16 PASI 75 responders in CHAMPION achieved a PASI 50 response at week 8 or 12, with maximum methotrexate dosages of 15 or 20 mg per week, respectively. Week 12 may be an appropriate time to discontinue methotrexate treatment in patients who are not achieving good responses.
Abstract 1489: Pri-let-7a-2 rs629367 associated with increased risk and poor survival of gastric cancer in Chinese by up-regulated let-7a expression
Authors: Qian Xu, Yuan Yuan
Journal: Cancer Research (2014)

Abstract Abstract:Aim:Variant in pri-miRNA could affect miRNA expression and mature process or splicing efficiency, thus altering the hereditary susceptibility and prognosis of cancer. We aimed to assess miRNA-let-7 single nucleotide polymorphisms (SNP) associated with the risk and prognosis of gastric cancer (GC) as predicting biomarkers, and furthermore, its possible mechanisms. Method:We designed a two-stage case-control study to screen four miRNA SNPs (pri-let-7a-2 rs629367 and rs1143770, pri-let-7a-1 rs10739971, pri-let-7f-2 rs17276588) in 107 GC patients, 107 atrophic gastritis (AG), and matched 124 controls using PCR-RFLP. Two promising SNPs (pri-let-7a-2 rs629367 and pri-let-7a-1 rs10739971) were validated in another independent 1949 samples (including 579 GC patients, 649 AG and 721 controls) using Sequenom MassARRAY platform and sequencing. Results: We found that pri-let-7a-2 rs629367 CC variant genotype was associated with increased risks of GC and AG by 1.83-fold and 1.86-fold, respectively. For GC prognosis, patients with rs629367 CC genotype had significantly poorer survival than patients with AA genotype (log-rank P=0.004). We further investigated the let-7a expression levels in serum and found that let-7a expression elevated gradually for rs629367 AA, CA, CC genotype in the AG group (P=0.043). Furthermore, we confirmed these findings in vitro study by overexpressing let-7a carrying pri-let-7a-2 wild-type A or polymorphic-type C allele (P&amp;lt;0.001). Conclusion: pri-let-7a-2 rs629367 CC genotype could increase the risks of GC as well as AG and was also associated with poor survival of GC, which possibly by affecting the mature let-7a expression, and could serve as a predicting biomarker for high-risk and poor prognosis of GC. Note: This abstract was not presented at the meeting. Citation Format: Qian Xu, Yuan Yuan. Pri-let-7a-2 rs629367 associated with increased risk and poor survival of gastric cancer in Chinese by up-regulated let-7a expression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1489. doi:10.1158/1538-7445.AM2014-1489
UN urges Nigeria to do more to prevent further cases of lead poisoning
Authors: John Zarocostas
Journal: BMJ (2011)

Nigerian authorities need to take more steps to prevent further cases of acute lead poisoning in the northern state of Zamfara, a United Nations report says. Already more than 18 000 people have been affected, and hundreds of children have died, it warns.

Investigations have shown that the cause of the high rates of death and illness among children since the beginning of 2010 was acute lead poisoning from the processing of rich lead ore for gold extraction inside houses and compounds. At least 2400 children, located in seven affected villages, needed immediate emergency treatment, the report says.

The problem was …
Eosinophil and neutrophil activity in blood in asthma in a one-year-double-blind trail with Theophylline and two doses of inhaled Budesonide. The impact of smoking
Authors: P Venge, R Dahl, R Karlstrom, B Pedersen, Cgb Peterson
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

Eosinophil and neutrophil activity in blood in asthma in a one-year-double-blind trail with Theophylline and two doses of inhaled Budesonide. The impact of smoking
Endocannabinoids acting at vascular CB1 receptors mediate the vasodilated state in advanced liver cirrhosis
Authors: Sándor Bátkai, Zoltán Járai, Jens A. Wagner, Sravan K. Goparaju, KÁroly Varga, Jie Liu, Lei Wang, Faridoddin Mirshahi, Atmaram D. Khanolkar, Alexandros Makriyannis, Renata Urbaschek, Nelson Garcia, Arun J. Sanyal, George Kunos
Journal: Nature Medicine (2001)
The lateralization of lichen simplex is independent of hand dominance
Authors: M. Murphy, A.J. Carmichael
Journal: British Journal of Dermatology (2000)

Journal Article The lateralization of lichen simplex is independent of hand dominance Get access M. Murphy, M. Murphy Department of Dermatology, South Cleveland Hospital, Middlesbrough TS4 3BW, U.K. Search for other works by this author on: Oxford Academic Google Scholar A.J. Carmichael A.J. Carmichael Department of Dermatology, South Cleveland Hospital, Middlesbrough TS4 3BW, U.K. Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 142, Issue 4, 1 April 2000, Page 844, https://doi.org/10.1046/j.1365-2133.2000.03456.x Published: 01 April 2000
Penile Kaposi’s sarcoma preceded by chronic penile lymphoedema
Authors: R.A. Schwartz, J.B. Cohen, R.A. Watson, P. Gascón, R.N. Ahkami, Z. Ruszczak, J. Halpern, W.C. Lambert
Journal: British Journal of Dermatology (2000)

Journal Article Penile Kaposi's sarcoma preceded by chronic penile lymphoedema Get access R.A. Schwartz, R.A. Schwartz Departments of Dermatology,Pathology, Search for other works by this author on: Oxford Academic Google Scholar J.B. Cohen, J.B. Cohen Departments of Dermatology, Search for other works by this author on: Oxford Academic Google Scholar R.A. Watson, R.A. Watson Urology, Search for other works by this author on: Oxford Academic Google Scholar P. Gascón, P. Gascón Hematology, Search for other works by this author on: Oxford Academic Google Scholar R.N. Ahkami, R.N. Ahkami Departments of Dermatology, Search for other works by this author on: Oxford Academic Google Scholar Z. Ruszczak, Z. Ruszczak Departments of Dermatology, Search for other works by this author on: Oxford Academic Google Scholar J. Halpern, J. Halpern Radiation Oncology, New Jersey Medical School, 185 South Orange Avenue, Newark, NJ, 07103‐2714, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar W.C. Lambert W.C. Lambert Departments of Dermatology,Pathology, Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 142, Issue 1, 1 January 2000, Pages 153–156, https://doi.org/10.1046/j.1365-2133.2000.03259.x Published: 01 January 2000
Expression of the Dermatomyositis Autoantigen Transcription Intermediary Factor 1γ in Regenerating Muscle
Authors: Payam Mohassel, Paul Rosen, Livia Casciola‐Rosen, Katherine Pak, Andrew L. Mammen
Journal: Arthritis & Rheumatology (2014)

Objective Autoantibodies against transcription intermediary factor 1γ (TIF1γ) are found in many patients with dermatomyositis (DM). Although TIF1γ is known to play a role in the differentiation of other tissues, its functional role in muscle regeneration has not been elucidated. This study was undertaken to explore the regulation and functional role of this protein during muscle differentiation and regeneration. Methods TIF1γ expression was analyzed in human muscle biopsy specimens using immunofluorescence microscopy. Immunofluorescence microscopy and immunoblotting analyses were used to study TIF1γ expression in a mouse model of muscle injury and repair. The effect of premature TIF1γ silencing on muscle differentiation was studied in cultured mouse myoblasts. Results In muscle biopsy specimens from DM patients, TIF1γ was expressed at low levels in the nuclei of histologically normal muscle cells but at high levels in the centralized nuclei of atrophic, perifascicular myofibers expressing markers of regeneration. TIF1γ levels were also increased in regenerating myonuclei following muscle injury in mice. Premature silencing of TIF1γ in vitro using small interfering RNA did not accelerate the expression of myogenin, a transcription factor that plays a central role in regulating relatively early stages of muscle differentiation. However, premature silencing of TIF1γ did accelerate myotube fusion and the expression of myosin heavy chain (MyHC), a later marker of muscle differentiation. Conclusion The DM autoantigen TIF1γ is markedly up‐regulated during muscle regeneration in human and mouse muscle cells. Premature silencing of this protein in cultured myoblasts accelerates MyHC expression and myoblast fusion. However, TIF1γ may function independently of, or downstream from, myogenin.
IKZF1 deletion is an independent prognostic marker in childhood B-cell precursor acute lymphoblastic leukemia, and distinguishes patients benefiting from pulses during maintenance therapy: results of the EORTC Children's Leukemia Group study 58951
Authors: E Clappier, N Grardel, M Bakkus, J Rapion, B De Moerloose, P Kastner, A Caye, J Vivent, V Costa, A Ferster, P Lutz, F Mazingue, F Millot, D Plantaz, G Plat, E Plouvier, M Poirée, N Sirvent, A Uyttebroeck, K Yakouben, S Girard, N Dastugue, S Suciu, Y Benoit, Y Bertrand, H Cavé
Journal: Leukemia (2015)
The Potter Syndrome of Renal Agenesis
Authors: R. G. Welch
Journal: BMJ (1958)

JUBRNALfive weeks after exposure, and good fluorescence was observed throughout both feet, even in toes which were already blackened.As an indication of expected tissue loss it was useless, but it certainly revealed the presence of a brisk circulation and in so doing gave strong support to Lewis's theory of direct thermal injury. SummaryAn account is given of two cases of trench-foot which occurred as a result of abnormal exposure in peacetime England.It appears likely that trench-foot, immersion foot, and frostbite are but variants of the same clinical condition, the most important aetiological factor being in all cases a direct noxious effect of cold.Recent experimental evidence favours early rapid warming to body temperature as the most effective form of treatment, and, provided suitable facilities are avail- able to avoid overheating, the clinical application of this principle is advocated.Our thanks are due to Dr. K. 0.
Selection of a highly metastatic subpopulation of colon cancer cells in an in vivo immunocompetent mouse model.
Authors: Fei Wu, Natasha G. Deane, Nipun B. Merchant, Robert J. Coffey, R. Daniel Beauchamp
Journal: Cancer Research (2006)

5144  Progression of cancer results in the development of cancer cells with a metastatic potential from either mutation or adaptive changes phenotype at the primary site where the cancer arises. To enrich for these metastatic cells in an immunocompetent in vivo mouse model, we stably transfected mouse colon cancer MC-38 cells derived from C57/B16 mice with a luciferase reporter under control of the CMV promoter. Selection of highly invasive cells was accomplished in vitro through matrigel-coated polycarbonate filters in Transwells using a modified Boyden chamber invasion assay with serial enrichment of invasive cell populations through replicate selections. Bioluminescent imaging was used to monitor both in vitro invasion through the matrigel-coated Transwell filters and in vivo metastasis in syngeneic C57/B16 mice. MC-38 cells selected for invasion demonstrated a 15.2-fold increase in the number of invasive cells as compared with parental MC-38 cells. Equal number of the MC-38 parental cells or the invasion-enriched cells (MC-38inv) was injected into the tail vein, and C57/B16 mice were analyzed for in vivo bioluminescence weekly for three weeks (10 mice per group). At necropsy the number of pulmonary metastases per mouse in the group injected with MC-38inv cells averaged 14.2-fold greater and lung weight per mouse 2.6-fold greater than the group of mice injected with parental MC-38 cells. A cell line (now called MC-38Lu) was then established from a lung metastasis that developed after MC-38inv injection. These MC-38Lu cells were injected into tail vein to test formation of pulmonary metastasis in comparison with the MC-38 parental cells. After three weeks, the metastatic number resulting from MC-38Lu injection was too many to count. Lung weight per mouse for the MC-38Lu group increased 4.3-fold over parental MC-38 injected mice. Additionally, after the MC-38Lu cells were injected into the spleen, the mice developed numerous liver metastases that were too many to count. The liver weight per mouse was 3.6-fold greater than that of mice injected with MC-38 parental cells. Thus, this study establishes a reproducible metastastic model of colon cancer in syngeneic mice without the need for immunosuppression, providing an excellent opportunity to identify metastatic biomarkers and to study metastatic mechanisms in colon cancer. We are currently conducting genomic and proteomic studies of these metastatic cells.
Statistics notes: The intracluster correlation coefficient in cluster randomisation
Authors: S. M Kerry, J M. Bland
Journal: BMJ (1998)

We have described the calculation of sample size when subjects are randomised in groups or clusters in terms of two variances—the variance of observations taken from individuals in the same cluster, sw 2, and the variance of true cluster means, s  c 2.1 We described how such a study could be analysed using the sample cluster means. The variance of such means would be s  c 2+ s  w 2/ m , where m is the number of subjects in a cluster. We used this to estimate the sample size needed for a cluster randomised trial.

This sum of two components of variance is analogous to what happens with measurement error, where we have the variance within the subject, also denoted by sw 2, and between subjects ( s  b …
Moral Wounds: Complicated Complications
Authors: S Munch, L deKryger
Journal: JAMA (2001)

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Abstract 69: Identification of rare and novel alleles in FFPE tumor samples using laser capture microdissection (LCM) and Ampliseq™ sequencing technologies
Authors: Stephen Jackson, Paul Choppa, Kulvinda Kulvar, Kristin Schmidt
Journal: Cancer Research (2015)

Abstract Tumors are becoming recognized as genetically heterogeneous masses of cells with different clonal histories. Identifying the mutations present in these heterogeneous masses can lead to important insights into the future behavior of the tumor and possible intervention mechanisms. However, the rarity of pathogenic mutations in small subsets of cells can make identification of such alleles difficult. In this study, we demonstrate a complete workflow that facilitates the identification of rare and novel alleles from FFPE tumor sections. We collected small regions with different cellular morphologies from lung tumor samples using laser capture microdissection, extracted both DNA and RNA from these regions, and characterized mutations present and transcript abundances by using Ampliseq™ targeted sequencing. We show that LCM facilitates the detection of alleles that are not detectable in macrodissected tissue scrapes. We also show that different regions of a tumor have very different patterns of alleles detectable and have a great deal of genetic diversity. Finally, we show that RNA expression patterns are also clearly different in the different regions. Interestingly, dissected regions with similar gross tissue morphologies display differences in alleles present and RNA expression patterns. These results suggest the best way to analyze mutations present in a tumor is to microdissect different subregions of the tumor, and using Ampliseq™ panels to identify the alleles present in those subregions. Citation Format: Stephen Jackson, Paul Choppa, Kulvinda Kulvar, Kristin Schmidt. Identification of rare and novel alleles in FFPE tumor samples using laser capture microdissection (LCM) and Ampliseq™ sequencing technologies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 69. doi:10.1158/1538-7445.AM2015-69
Expression of selected human HOX-2 genes in B/T acute lymphoid leukemia and interleukin-2/interleukin-1 beta-stimulated natural killer lymphocytes
Authors: M Petrini, MT Quaranta, U Testa, P Samoggia, E Tritarelli, A Care, L Cianetti, M Valtieri, C Barletta, C Peschle
Journal: Blood (1992)