tbuckley/cabot-search huggingface dataset:
Patient commentary: my experience of gestational diabetes
Authors: S. N. Finlay
Journal: BMJ (2014)

Aspartate (Asp) isomerization is a common post-translational modification of recombinant therapeutic proteins that can occur during manufacturing, storage, or administration. Asp isomerization in the complementarity-determining regions of a monoclonal antibody may affect the target binding and thus a sufficiently robust quality control method for routine monitoring is desirable. In this work, we utilized a liquid chromatography–mass spectrometry (LC/MS)-based approach to identify the Asp isomerization in the complementarity-determining regions of a therapeutic monoclonal antibody. To quantitate the site-specific Asp isomerization of the monoclonal antibody, a UV detection–based quantitation assay utilizing the same LC platform was developed. The assay was qualified and implemented for routine monitoring of this product-specific modification. Compared with existing methods, this analytical paradigm is applicable to identify Asp isomerization (or other modifications) and subsequently develop a rapid, sufficiently robust quality control method for routine site-specific monitoring and quantitation to ensure product quality. This approach first identifies and locates a product-related impurity (a critical quality attribute) caused by isomerization, deamidation, oxidation, or other post-translational modifications, and then utilizes synthetic peptides and MS to assist the development of a LC-UV–based chromatographic method that separates and quantifies the product-related impurities by UV peaks. The established LC-UV method has acceptable peak specificity, precision, linearity, and accuracy; it can be validated and used in a good manufacturing practice environment for lot release and stability testing. <i>LAY ABSTRACT:</i> Aspartate isomerization is a common post-translational modification of recombinant proteins during manufacture process and storage. Isomerization in the complementarity-determining regions (CDRs) of a monoclonal antibody A (mAb-A) has been detected and has been shown to have impact on the binding affinity to the antigen. In this work, we utilized a mass spectrometry–based peptide mapping approach to detect and quantitate the Asp isomerization in the CDRs of mAb-A. To routinely monitor the CDR isomerization of mAb-A, a focused peptide mapping method utilizing reversed phase chromatographic separation and UV detection has been developed and qualified. This approach is generally applicable to monitor isomerization and other post-translational modifications of proteins in a specific and high-throughput mode to ensure product quality.
Abstract 2654: 5-Fluorouracil increases and decreases proteins involved in oncogenic pathways
Authors: Sherry Y. Wu, Noriko Mori, Balaji Krishnamachary, Yelena Mironchik, Zaver M. Bhujwalla
Journal: Cancer Research (2011)

Abstract Cancer cells are remarkably adaptive to treatments. 5-Fluorouracil, 5-FU, is a pyrimidine analogue, that is widely used for treatment of solid tumors1. It interferes with nucleoside metabolism and is incorporated into RNA and DNA, leading to cell death1. Its use, however, has been associated with increased cyclooxygenase-2 (COX-2) levels in breast, ovarian, esophageal, and colon cancers2 that could lead to the emergence of a more aggressive phenotype3. Here we have determined the effect of 5-FU in the expression of oncogenic molecules that are involved in phospholipid metabolism (choline kinase (Chk) and phospholipase D1 (PLD1)), inflammation (cyclooxygenase (COX)-2), and hypoxia response (hypoxia inducible factor (HIF)-1α) in order to facilitate a rational therapeutic design. Two triple negative breast cancer cell lines, MDA-MB-231 and SUM-149, were investigated. Cells were treated with 5-FU at various concentrations (1-25 μg/mL) and protein levels were examined at 24 and 48 hrs post treatment. Both HIF-1α and PLD1 levels decreased in a dose dependent manner following 5-FU treatment. In contrast, COX-2 level increased in response to 5-FU treatment together with an increase in Chk. Increased expressions of HIF-1α, PLD1, COX-2, and Chk have been associated with increased invasion and metastasis3-6. Our data suggest that in addition to its ability to interfere with DNA/RNA synthesis, 5-FU inhibits HIF-1α and PLD1 but increases the expression of two enzymes associated with invasive metastatic cancers. Importantly, while the mechanism by which 5-FU elevates COX-2 and Chk levels in these cancer cells remains to be investigated, these results provide a molecular basis for the combinational treatment of 5-FU with COX-2 and/or Chk inhibitors in cancer therapy. References (1) Arias J. Molecules, 2008. (2) Mercer S.J., et al. Anticancer Drugs, 2005. (3) Stasinopoulos I, et al. Neoplasia, 2008. (4) Pai J.K., et al. Anticancer Drug Des, 1994. (5) Shah T., et al. NMR Biomed, 2010. (6) Lu X and Kang Y. Clin Cancer Res, 2010 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 2654. doi:10.1158/1538-7445.AM2011-2654
A welcome address for the new criteria
Authors: D. van Schaardenburg, B. A. C. Dijkmans
Journal: Annals of the Rheumatic Diseases (2010)

After lively presentations at the European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) meetings, the new criteria for rheumatoid arthritis (RA) now appear in print accompanied by methodological reports.1 2 The interested reader can thereby follow the entire process from beginning to end. It has been a huge task and the members of the ACR/EULAR joint taskforce deserve our warm congratulations for the result, which is easy to absorb because the reasoning is clear and the manuscripts are well written. Through the combination of a first phase with a data-driven approach followed by a second phase using new consensus methodology, we can be confident that a high-quality product has been delivered.

The main question is why the 1987 ACR criteria for the classification of RA should be revised. The 1987 criteria were derived from patients with RA with mostly longstanding disease and identified features that best discriminated these patients from those with a variety of other rheumatic disorders. In the meantime, the focus of the management of RA has shifted from alleviating the consequences of joint damage to early diagnosis and intervention. The old criteria were increasingly viewed as not helpful in achieving the new goal. The aim of the endeavour of experts leading to new classification criteria was to define the group of patients with a high risk of developing persistent and erosive disease who will likely benefit from the rapid initiation of antirheumatic treatment.

What these criteria actually attempt to do is to separate, at an early stage, patients with undifferentiated arthritis into two groups—one with a poor prognosis and one with a good prognosis. The underlying message could be to treat those with a poor prognosis (RA) aggressively and those with a good prognosis (not RA) symptomatically. Rheumatologists have already become used to …
Abstract 3252: A novel small molecule, LY5, selectively inhibits STAT3 phosphorylation and activities and exhibits potent growth suppressive activity in cancer cells.
Authors: Hui Xiao, Wenying Yu, Veronica R. Olson, Chenglong Li, Peter Houghton, Jiayuh Lin
Journal: Cancer Research (2013)

Abstract In response to cytokines and growth factors, Signal Transducers and Activators of Transcription 3 (STAT3) signaling is activated which plays a critical role in oncogenesis, proliferation, survival, and invasion of various human cancers and cancer cell lines. Numerous evidences have demonstrated that inhibition of STAT3 signaling pathway results in decreased growth and apoptosis in human cancer cells. This makes STAT3 an excellent molecular target for cancer therapy. In this study, we investigated a novel non-peptide, cell-permeable, small molecule, named as LY5, which selectively targets STAT3. LY5 inhibited constitutive STAT3 activation in various human pediatric sarcoma and medulloblastoma cell lines expressing elevated levels of STAT3 phosphorylation. LY5 also blocked STAT3 phosphorylation induced by Interleukin-6, IGF-1, and OSM in SJSA human osteosarcoma cells, but did not inhibit STAT1, STAT2, STAT4, and STAT6 phosphorylation stimulated by interferon (IFN)-γ,IFN-α, and IL-4, respectively. Furthermore, LY5 suppressed the induction of STAT3 nuclear localization by IL-6, which could prevent STAT3 function as a transcription factor, but not STAT1 nuclear localization induced by IFN-γ. In addition, LY5 induced apoptosis in sarcoma and medulloblastoma cells as indicated by the increases of cleaved caspase-3, but LY5 did not induce apoptosis in normal primary human cells. The inhibition of STAT3 signaling by LY5 was further confirmed by down-regulating the expression of the downstream targets of STAT3, including cyclin D1, Bcl-XL, and survivin. Taken together, these findings indicated LY5 selectively inhibited constitutive STAT3 activation and suggested that LY5 is a promising therapeutic candidate for pediatric sarcoma and medulloblastoma through inhibiting STAT3 signaling. Citation Format: Hui Xiao, Wenying Yu, Veronica R. Olson, Chenglong Li, Peter Houghton, Jiayuh Lin. A novel small molecule, LY5, selectively inhibits STAT3 phosphorylation and activities and exhibits potent growth suppressive activity in cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3252. doi:10.1158/1538-7445.AM2013-3252
Whole-Heart Modeling
Authors: Natalia A. Trayanova
Journal: Circulation Research (2011)

Recent developments in cardiac simulation have rendered the heart the most highly integrated example of a virtual organ. We are on the brink of a revolution in cardiac research, one in which computational modeling of proteins, cells, tissues, and the organ permit linking genomic and proteomic information to the integrated organ behavior, in the quest for a quantitative understanding of the functioning of the heart in health and disease. The goal of this review is to assess the existing state-of-the-art in whole-heart modeling and the plethora of its applications in cardiac research. General whole-heart modeling approaches are presented, and the applications of whole-heart models in cardiac electrophysiology and electromechanics research are reviewed. The article showcases the contributions that whole-heart modeling and simulation have made to our understanding of the functioning of the heart. A summary of the future developments envisioned for the field of cardiac simulation and modeling is also presented. Biophysically based computational modeling of the heart, applied to human heart physiology and the diagnosis and treatment of cardiac disease, has the potential to dramatically change 21st century cardiac research and the field of cardiology.
The mind unleashed
Authors: S. Spence
Journal: BMJ (1996)

“Outsider art”—the collective term for the art of “insane,” imprisoned, or handicapped people—is undergoing a mini-Renaissance at present with the reemergence of periodicals and monographs devoted to the subject. Historically, psychiatrists began to note their patients' works when they themselves became more humane. Thus, the first modern accounts belong to Pinel and Rush, the philanthropists of psychiatry: Pinel removed the chains from the inmates of La Salpetriere, while Rush championed the “moral treatment” of the mentally ill in America.

Hans Prinzhorn, born on 8 June 1886, assembled the collection that bears his name while …
The Immunological Genome Project: networks of gene expression in immune cells
Authors: Tracy S P Heng, Michio W Painter, Kutlu Elpek, Veronika Lukacs-Kornek, Nora Mauermann, Shannon J Turley, Daphne Koller, Francis S Kim, Amy J Wagers, Natasha Asinovski, Scott Davis, Marlys Fassett, Markus Feuerer, Daniel H D Gray, Sokol Haxhinasto, Jonathan A Hill, Gordon Hyatt, Catherine Laplace, Kristen Leatherbee, Diane Mathis, Christophe Benoist, Radu Jianu, David H Laidlaw, J Adam Best, Jamie Knell, Ananda W Goldrath, Jessica Jarjoura, Joseph C Sun, Yanan Zhu, Lewis L Lanier, Ayla Ergun, Zheng Li, James J Collins, Susan A Shinton, Richard R Hardy, Randall Friedline, Katelyn Sylvia, Joonsoo Kang
Journal: Nature Immunology (2008)
Teratogens and Litogens
Authors: James L. Mills, Duane Alexander
Journal: New England Journal of Medicine (1986)

In 1981, Katie Laurel Wells was born with a cleft lip, an optic-nerve defect, and limb abnormalities, including absence of the left arm. Her mother had used vaginal spermicides during the first four weeks after conception. In 1982, her parents brought suit against Ortho Pharmaceutical Corporation, alleging that the malformations were caused by the spermicidal jelly.1 The court awarded the plaintiffs $5.1 million. In May 1986, the ruling was upheld on appeal; the award was not substantially reduced.The Wells v. Ortho decision took the medical community by surprise, because the overwhelming body of evidence indicates that spermicides are not . . .
Scintigraphic Sequelae of Superior Vena Caval Obstruction
Authors: S GOLLUB, T HIROSE, J KLAUBER
Journal: Clinical Nuclear Medicine (1980)

The scintigraphic characteristics of superior vena caval obstruction are presented together with a discussion of the relevant vascular anatomy. Alterations in scintigraphic venous blood flow patterns of a patient who underwent two surgical bypass procedures for symptomatic relief of superior vena caval obstruction are shown.
Measurements of serum creatinine
Authors: S. E. Warren
Journal: JAMA (1977)

To the Editor.—  The advent of multiple analyzer systems has enabled physicians to screen a large variety of serum chemistries at a glance. The well-known SMA 12/60 offers one so much information that we have observed a natural tendency in ourselves and others to pattern-read the results.  It is disturbing that of all the SMA 12/60 values, the most visually diminutive is the serum creatinine. The lowly serum creatinine must attain values of 3 or 4 mg/100 ml before it really strikes the eye. It clearly would be possible to overlook a creatinine value that rose from. 5 to 1.5 mg/100 ml, even though this may represent a 50% reduction in renal function. Minor elevations in uric acid and alkaline phosphatase levels can attract disproportionate attention (Fig 1, A). We wonder how much prerenal azotemia or how much needless nephrotoxic pharmacotherapy has been abetted by the creatinine's low profile on the
Familial Hypokalemic Periodic Paralysis in Blacks
Authors: VICTOR A. CORBETT
Journal: Annals of Internal Medicine (1975)

Two cases of familial hypokalemic periodic paralysis in Negro brothers occurred, and—because this has been reported to be an unusual disease among blacks—the family pedigree was investigated. Histories were obtained on 79 family members in four generations. Twenty seven (34%) had symptoms of periodic paralysis or weakness. As far as we could determine, there were no Caucasian ancestors.
Different Patterns of Duplicate Publication
Authors: Erik von Elm, Greta Poglia, Bernhard Walder, Martin R. Tramèr
Journal: JAMA (2004)

Duplicate publication is publication of an article that overlaps substantially with an article published elsewhere. Patterns of duplication are not well understood.To investigate duplication patterns and propose a decision tree for classification.We searched a comprehensive list of systematic reviews (1989 through August 15, 2002) in anesthesia and analgesia that is accessible on the Internet. We selected published full articles of duplicates that had been identified in these systematic reviews. Abstracts, letters, or book chapters were excluded.Authors of 56 (40%) of 141 systematic reviews acknowledged identification of duplicates. Duplication patterns were identified independently by all investigators comparing samples and outcomes of pairs of duplicates and main articles. Information on cross-reference, sponsorship, authorship, and publication characteristics was extracted from the articles.The 56 systematic reviews included 1131 main articles (129 337 subjects) and excluded 103 duplicates (12 589 subjects) that originated from 78 main articles. Sixty articles were published twice, 13 three times, 3 four times, and 2 five times. We identified 6 duplication patterns: (1A) identical samples and identical outcomes (21 pairs); (1B) same as 1A but several duplicates assembled (n = 16); (2) identical samples and different outcomes (n = 24); (3A) increasing sample and identical outcomes (n = 11); (3B) decreasing sample and identical outcomes (n = 11); (4) different samples and different outcomes (n = 20). The prevalence of covert duplicate articles (without a cross-reference to the main article) was 5.3% (65/1234). Of the duplicates, 34 (33%) were sponsored by the pharmaceutical industry, and 66 (64%) had authorship that differed partly or completely from the main article. The median journal impact factor was 1.8 (range, 0.1-29.5) for duplicates and 2.0 (range, 0.4-29.5) for main articles (P =.13). The median annual citation rate was 1.7 (range, 0-27) for duplicates and 2.1 (range, 0-31) for main articles (P =.45). The median number of authors was 4 (range, 1-14) for duplicates and 4 (range, 1-15) for corresponding main articles (P =.02). The median delay in publication between main articles and duplicates was 1 year (range, 0-7 years).Duplication goes beyond simple copying. Six distinct duplication patterns were identified after comparing study samples and outcomes of duplicates and corresponding main articles. Authorship was an unreliable criterion. Duplicates were published in journals with similar impact factors and were cited as frequently as main articles.
Improved tumour localisation using indium-111 labelled antibodies.
Authors: D S Fairweather, A R Bradwell, P W Dykes, A T Vaughan, S F Watson-James, S Chandler
Journal: BMJ (1983)

Immunoglobulin G (IgG) antibodies to carcinoembryonic antigen (CEA) were labelled with radioactive indium (111In) or iodine (131I) and a comparison made of their value in locating CEA producing tumours. Eleven patients given 111In-anti-CEA had 31 tumours as judged by a combination of all techniques. Of these, 28 were detected by 111In-anti-CEA and 26 by conventional clinical techniques. Five of the patients also received 131I-anti-CEA. These patients had 15 tumour areas. Thirteen were detected by 111In and eight by 131I. 111In also produced a better signal to noise ratio in the scans and thereby showed lesions with greater certainty. In addition, the 111In isotope continued to accumulate in the tumour areas for considerably longer than 131I. Absorbed doses (whole body) were similar for both isotopes. The results show that antibody scanning is greatly improved by using 111In as the radiolabel in place of 131I and should allow the detection of smaller or deeper lesions.
Dobutamine stress echocardiography for detection of coronary artery stenosis in children with Kawasaki disease
Authors: Nobutaka Noto, Mamoru Ayusawa, Kensuke Karasawa, Hideo Yamaguchi, Naokata Sumitomo, Tomoo Okada, Kensuke Harada
Journal: Journal of the American College of Cardiology (1996)
Climate change experts need funds to research vital questions, conference hears
Authors: M. Limb
Journal: BMJ (2012)

Researchers and funding bodies have pledged to ramp up their response to harmful climate change at a UK summit on sustainable health and social care.

David Pencheon, director of the Sustainable Development Unit of the NHS in England, said that the meeting on Tuesday 6 November organised by the healthcare think tank the King’s Fund had achieved “breakthrough” commitments and had paved the way for developing a new research and development strategy on sustainable healthcare.

He said that a small task force comprising research experts, funders, commissioners, and patients’ representatives would now coordinate efforts to fill gaps in research and act on the evidence for sustainable practices in the NHS and public health systems.

Pencheon also said that funding bodies such as the National Institute for Health Research, Wellcome Trust, and Bupa Foundation had agreed to try to dismantle the “barriers” to funding research for interdisciplinary …
Abstract 5121: Omega-3 polyunsaturated fatty acids induce apoptotic and autophagic cell death through inhibition of Akt/mTOR pathway in human oral cancer cells
Authors: Kyu Lim, Soyeon Shin, Tae-Hwa Hong, Kaipeng Jing, Soyeon Jeong, Soyeon Kim, Gi-Ryang Kweon, Seung-Kiel Park, Jong-Il Park
Journal: Cancer Research (2014)

Abstract Omega-3 polyunsaturated fatty acids (ω3-PUFAs) have been found to possess anticancer properties in a variety of cancer cell lines and animal models, but their effect in oral cancer remains unclear. This study was designed to examine the impact of ω3-PUFAs on oral cancer and the molecular mechanism of their action using in vitro and in vivo models. Exposure SCC4 and SCC9 human oral cancer cells to the ω3-PUFA docosahexaenoic acid (DHA) reduced cell viability in a dose- and time-dependent manner. The increase in cell death was due in part to apoptosis, since cells incubated with DHA exhibited elevated levels of apoptotic markers including cleaved PARP expression, subG1 DNA portion and TUNEL-positive nuclei. DHA treatment also led to autophagic vesicle formation and an increase in autophagic flux, indicating the involvement of both apoptosis and autophagy in the cytotoxic effect of ω3-PUFAs on oral cancer cells. Further experiments revealed that the concurrent activation of apoptosis and autophagy induced by DHA was linked to reactive oxygen species (ROS) overproduction and inhibition of Akt/mTOR signaling molecules. Moreover, stable SCC9 cell lines expressing the ω3-desaturase gene (SCC9-fsc) or control vector (SCC9-csc) were generated, and the effect of endogenous high level of ω3-PUFAs was investigated. The growth rate and colony-forming capacity of SCC9-fsc were remarkably decreased compared to those of SCC9-csc. Likewise, tumor size and volume of SCC9-fsc implanted into nude mice were also significantly inhibited with increases in the cell death index. Taken together, these results indicate that ω3-PUFAs induce apoptosis- and autophagy-associated cell death through ROS and Akt/mTOR signaling pathways in oral cancer cells. Thus, utilization of ω3-PUFAs may represent a promising therapeutic approach for chemoprevention and treatment of human oral cancer. [This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. 2011-0013263 and 2007-0054932).] Citation Format: Kyu Lim, Soyeon Shin, Tae-Hwa Hong, Kaipeng Jing, Soyeon Jeong, Soyeon Kim, Gi-Ryang Kweon, Seung-Kiel Park, Jong-Il Park. Omega-3 polyunsaturated fatty acids induce apoptotic and autophagic cell death through inhibition of Akt/mTOR pathway in human oral cancer cells. [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 5121. doi:10.1158/1538-7445.AM2014-5121
The Management of Infertility
Authors: Egbert R. te Velde, Bernard J. Cohlen
Journal: New England Journal of Medicine (1999)

The proportion of women in the United States who think they have a fertility problem increased from 5.7 percent in 1988 to 7.7 percent in 1995.1 This growing perception of infertility is likely to be related to improvements in assisted reproductive technology, including the growing number of fertility services that compete for couples as clients, and the widespread availability of information about fertility issues. Assisted reproductive technology includes many options nowadays, and the marketing of it has created the public perception that fertility interventions can make all the difference between having a baby in a relatively short period and being . . .