tbuckley/cabot-search huggingface dataset:
Phase I Study of Anti–Epidermal Growth Factor Receptor Antibody Cetuximab in Combination With Radiation Therapy in Patients With Advanced Head and Neck Cancer
Authors: Francisco Robert, Mark P. Ezekiel, Sharon A. Spencer, Ruby F. Meredith, James A. Bonner, M. B. Khazaeli, Mansoor N. Saleh, Delicia Carey, Albert F. LoBuglio, Richard H. Wheeler, Michael R. Cooper, Harlan W. Waksal
Journal: Journal of Clinical Oncology (2001)

PURPOSE: To evaluate the safety, pharmacokinetics, and efficacy of a chimeric anti–epidermal growth factor receptor monoclonal antibody, cetuximab, in combination with radiation therapy (RT) in patients with advanced squamous cell carcinoma of the head and neck. PATIENTS AND METHODS: We treated 16 patients in five successive treatment schedules. A standard dose escalation procedure was used; three patients entered onto the study at each dose level of cetuximab received conventional RT (70 Gy, 2 Gy/d), and the final three patients received hyperfractionated RT (76.8 Gy, 1.2 Gy bid). Cetuximab was delivered as a loading dose of 100 to 500 mg/m 2 , followed by weekly infusions of 100 to 250 mg/m 2 for 7 to 8 weeks. Circulating levels of cetuximab during therapy were determined using a biomolecular interaction analysis core instrument. Human antichimeric antibody response was evaluated with a double-antigen radiometric assay. The recommended phase II/III dose was defined as the optimal cetuximab dose level based on the pharmacologic parameters and adverse events. RESULTS: The most commonly reported adverse events were fever, asthenia, transaminase elevation, nausea, and skin toxicities (grade 1 to 2 in most patients). Skin toxicity outside of the RT field was not strictly dose-dependent; however, grade 2 or higher events were observed in patients treated with higher dose regimens. There was one grade 4 allergic reaction. Most acute adverse effects were associated with RT (xerostomia, mucositis, and local skin toxicity). No antibodies against cetuximab were detected. All patients achieved an objective response (13 complete and two partial remissions). CONCLUSION: Cetuximab can be safely administered with RT. The recommended dose for phase II/III studies is a loading dose of 400 to 500 mg/m 2 and a maintenance weekly dose of 250 mg/m 2 .
T cell responses affected by aminopeptidase N (CD13)-mediated trimming of major histocompatibility complex class II-bound peptides.
Authors: S L Larsen, L O Pedersen, S Buus, A Stryhn
Journal: The Journal of Experimental Medicine (1996)

Endocytosed protein antigens are believed to be fragmented in what appears to be a balance between proteolysis and MHC-mediated epitope protection, and the resulting peptide-MHC complexes are transported to the surface of the antigen-presenting cells (APC) and presented to T cells. The events that lead to antigenic peptide generation and the compartments where antigen processing takes place remains somewhat enigmatic. The importance of intracellular antigen processing has been well established; however, it is unclear whether additional processing occurs at the APC surface. To follow antigen processing, we have identified a pair of T cell hybridomas that recognize a long vs. a short version of the same epitope. We have used prefixed APC and various protease inhibitors to demonstrate that the APC surface has a considerable potential for antigen processing. Specific antibodies further identified the exopeptidase Aminopeptidase N (APN, CD13) as one of the enzymes involved in the observed cell-surface antigen processing. The NH2-terminal end of the longer peptide could, even while bound to major histocompatibility complex (MHC) class II molecules, be digested by APN with dramatic consequences for T cell antigen recognition. This could be demonstrated both in cell-free systems using purified reagents and in cellular systems. Thus, MHC class II and APN may act in concert to generate the final T cell epitopes.
miR-153 Supports Colorectal Cancer Progression via Pleiotropic Effects That Enhance Invasion and Chemotherapeutic Resistance
Authors: Lei Zhang, Karen Pickard, Veronika Jenei, Marc D. Bullock, Amanda Bruce, Richard Mitter, Gavin Kelly, Christos Paraskeva, John Strefford, John Primrose, Gareth J. Thomas, Graham Packham, Alex H. Mirnezami
Journal: Cancer Research (2013)

Abstract Although microRNAs (miRNA) have been broadly studied in cancer, comparatively less is understood about their role in progression. Here we report that miR-153 has a dual role during progression of colorectal cancer by enhancing cellular invasiveness and platinum-based chemotherapy resistance. miRNA profiling revealed that miR-153 was highly expressed in a cellular model of advanced stage colorectal cancer. Its upregulation was also noted in primary human colorectal cancer compared with normal colonic epithelium and in more advanced colorectal cancer stages compared with early stage disease. In colorectal cancer patients followed for 50 months, 21 of 30 patients with high levels of miR-153 had disease progression compared with others in this group with low levels of miR-153. Functional studies revealed that miR-153 upregulation increased colorectal cancer invasiveness and resistance to oxaliplatin and cisplatin both in vitro and in vivo. Mechanistic investigations indicated that miR-153 promoted invasiveness indirectly by inducing matrix metalloprotease enzyme 9 production, whereas drug resistance was mediated directly by inhibiting the Forkhead transcription factor Forkhead box O3a (FOXO3a). In support of the latter finding, we found that levels of miR-153 and FOXO3a were inversely correlated in matched human colorectal cancer specimens. Our findings establish key roles for miR-153 overexpression in colorectal cancer progression, rationalizing therapeutic strategies to target expression of this miRNA for colorectal cancer treatment. Cancer Res; 73(21); 6435–47. ©2013 AACR.
Cell Surface Expression of LDL Receptor Is Decreased in Type 2 Diabetic Patients and Is Normalized by Insulin Therapy
Authors: Laurence Duvillard, Emmanuel Florentin, Gérard Lizard, Jean-Michel Petit, Françoise Galland, Serge Monier, Philippe Gambert, Bruno Vergès
Journal: Diabetes Care (2003)

In type 2 diabetic patients with poor metabolic control, kinetic studies have demonstrated that LDL fractional catabolic rate (FCR) is slowed down, whereas it is normalized on insulin therapy. This study was designed to analyze whether variations in the expression of LDL receptors at the cell surface could explain the results observed in kinetic studies.LDL receptors were quantified at the surface of mononuclear cells in fresh fasting blood samples by a flow cytometry method in 21 control subjects and 21 type 2 diabetic patients before and 3 months after the introduction of insulin therapy and concomitant removal of oral antidiabetic drugs.Before insulin treatment, monocyte LDL receptor expression was reduced by 41% (6,439 +/- 2,310 vs. 10,846 +/- 2,764 receptors per monocyte, P < 0.001) in type 2 diabetic patients compared with control subjects. It increased by 57% after 3 months of insulin therapy (10,096 +/- 5,657 vs. 6,439 +/- 2,310, P < 0.01) and was similar to that observed in control subjects.Our results suggest that insulin plays an important role in the in vivo expression of LDL receptors. Moreover, modulations in the expression of LDL receptors in type 2 diabetic patients either with poor metabolic control or on insulin therapy are likely to contribute to the variations of LDL FCR demonstrated by kinetic studies under those circumstances.
Hypoglycemia During Sleep Impairs Consolidation of Declarative Memory in Type 1 Diabetic and Healthy Humans
Authors: Kamila Jauch-Chara, Manfred Hallschmid, Steffen Gais, Sebastian M. Schmid, Kerstin M. Oltmanns, Caterina Colmorgen, Jan Born, Bernd Schultes
Journal: Diabetes Care (2007)

OBJECTIVE—Early nocturnal sleep enhances the consolidation of declarative memories acquired during prior wakefulness. Patients with type 1 diabetes frequently experience hypoglycemic episodes during sleep. We investigated whether short-lasting hypoglycemia during early nocturnal sleep affects the sleep-associated consolidation of declarative memories. RESEARCH DESIGN AND METHODS—Sixteen type 1 diabetic patients and 16 healthy subjects matched for age and BMI were tested. On one condition, a linear fall of plasma glucose to 2.2 mmol/l was induced within 60 min by infusing insulin during early sleep. On the control condition, euglycemia (&amp;gt;3.86 mmol/l) was maintained throughout the night. In the morning, subjects recalled word pairs learned in the preceding evening. To assess mood and attention, a symptom questionnaire, an adjective check list, and the Stroop test were applied. Also, auditory event-related brain potentials were recorded. RESULTS—After euglycemia, subjects recalled 1.5 ± 0.5 more word pairs than after hypoglycemia (P &amp;lt; 0.01), remembering 2.0 ± 0.6 more word pairs than at immediate recall before sleep (P = 0.002). Across the hypoglycemic night, no such gain occurred (+0.5 ± 0.6 words; P = 0.41). Hypoglycemia during sleep also impaired mood (P &amp;lt; 0.05) but did not affect attention. Effects compared well between type 1 diabetic patients and healthy control subjects. CONCLUSIONS—Our findings indicate specific sensitivity of declarative memory consolidation during sleep to rather short episodes of mild hypoglycemia. This effect may disable memory processing in type 1 diabetic patients prone to nocturnal hypoglycemic episodes and underlines the importance of considering sleep as a critical period in the treatment of these patients.
Medicine and Chiropractic
Authors: H. Thomas Ballantine
Journal: JAMA (1967)

For the past 53 years a well-organized and determined band of practitioners has importuned the state legislatures of this country for permission to administer to the health needs of the people. Their efforts have been so successful in the political arena that 48 states license them. These individuals call themselves chiropractors. Their aggregate number is variously estimated at from 15,000 to 25,000, and it is claimed that about 4 million people consult them in any one year. In 1966, the American Chiropractic Association published a brochure entitled<i>What Medicine Really Thinks About Chiropractic</i>.<sup>1</sup>The authors were C. W. Weiant "dean emeritus of the Chiropractic Institute of New York" and S. Goldschmidt, "member Special Committee on Political Education, American Chiropractic Association." Two statements in their introduction to a defense of chiropractic present the salient points to be dealt with here. The first reads as follows: In this brochure we present
B Cell Development Is Arrested at the Immature B Cell Stage in Mice Carrying a Mutation in the Cytoplasmic Domain of Immunoglobulin β
Authors: Amy Reichlin, Yun Hu, Eric Meffre, Hitoshi Nagaoka, Shiaoching Gong, Manfred Kraus, Klaus Rajewsky, Michel C. Nussenzweig
Journal: The Journal of Experimental Medicine (2000)

The B cell receptor (BCR) regulates B cell development and function through immunoglobulin (Ig)α and Igβ, a pair of membrane-bound Ig superfamily proteins, each of which contains a single cytoplasmic immunoreceptor tyrosine activation motif (ITAM). To determine the function of Igβ, we produced mice that carry a deletion of the cytoplasmic domain of Igβ (IgβΔC mice) and compared them to mice that carry a similar mutation in Igα (MB1ΔC, herein referred to as IgαΔC mice). IgβΔC mice differ from IgαΔC mice in that they show little impairment in early B cell development and they produce immature B cells that respond normally to BCR cross-linking as determined by Ca2+ flux. However, IgβΔC B cells are arrested at the immature stage of B cell development in the bone marrow and die by apoptosis. We conclude that the cytoplasmic domain Igβ is required for B cell development beyond the immature B cell stage and that Igα and Igβ have distinct biologic activities in vivo.
The correlation of protein structure and evolution of a protein-coding gene: phylogenetic inference using cytochrome oxidase III
Authors: C. S. Griffiths
Journal: Molecular Biology and Evolution (1998)

Discriminating phylogenetic signal from noise in DNA sequence data is a difficult problem in phylogenetic inference at higher systematic levels. For protein-coding genes, noise at synonymous (silent) positions can be filtered by deleting entire codon positions or types of change at a codon position. This method is not appropriate for replacement sites, because changes at each site within a codon may not be independent. This research presents a method using information from protein structure to evaluate variation in replacement sites. Analysis of the correlation of amino acid variation with protein structure identified rapidly evolving codons in the COIII gene. In a series of phylogenetic analyses attempting to recover a known set of vertebrate relationships, downweighting these labile codons produced the most accurate results. Structural correlates of variable and invariant residues identified in this study can be used to increase the accuracy of models used for phylogenetic inference. Viewing amino acid variation within a phylogenetic framework provided insight into residue changes important in the secondary and tertiary structures of the molecule, changes that were correlated between pairs of neighboring residues or between residues in neighboring helices.
Low carbohydrate diet is vindicated
Authors: J. Hopkins Tanne
Journal: BMJ (2003)

For years authorities such as the American Heart Association and the US Department of Agriculture have recommended a high carbohydrate, low fat diet for cardiovascular health and weight loss, while Americans have grown ever fatter. Meanwhile Dr Robert Atkins' low carbohydrate “steak and eggs” diet books have sold 10 million copies and led to anecdotal reports of successful weight loss.

No prospective, randomised trials have shown the Atkins diet to be safe and effective—and it might actually be harmful, according to some doctors. But two studies published last week indicate that Dr Atkins, who died in April (17 May, p 1090), was right ( New England Journal of Medicine 2003;348:2074-81 and 348:2082-90). …
Excess Early Mortality in Schizophrenia
Authors: Thomas Munk Laursen, Merete Nordentoft, Preben Bo Mortensen
Journal: Annual Review of Clinical Psychology (2013)

Schizophrenia is often referred to as one of the most severe mental disorders, primarily because of the very high mortality rates of those with the disorder. This article reviews the literature on excess early mortality in persons with schizophrenia and suggests reasons for the high mortality as well as possible ways to reduce it. Persons with schizophrenia have an exceptionally short life expectancy. High mortality is found in all age groups, resulting in a life expectancy of approximately 20 years below that of the general population. Evidence suggests that persons with schizophrenia may not have seen the same improvement in life expectancy as the general population during the past decades. Thus, the mortality gap not only persists but may actually have increased. The most urgent research agenda concerns primary candidates for modifiable risk factors contributing to this excess mortality, i.e., side effects of treatment and lifestyle factors, as well as sufficient prevention and treatment of physical comorbidity.
Cardiac Efficiency Is Improved After Ischemia by Altering Both the Source and Fate of Protons
Authors: Bin Liu, Alexander S. Clanachan, Richard Schulz, Gary D. Lopaschuk
Journal: Circulation Research (1996)

Cardiac efficiency is decreased in hearts after severe ischemia. We determined whether reducing the production of H+ from glucose metabolism or inhibiting the clearance of H+ via Na(+)-H+ exchange could increase cardiac efficiency during reperfusion. This was achieved using dichloroacetate (DCA) to stimulate glucose oxidation and 5-(N,N-dimethyl)-amiloride (DMA) to inhibit Na(+)-H+ exchange, respectively. Isolated working rat hearts were subjected to 30 minutes of global ischemia and 60 minutes of reperfusion. Glycolysis and oxidation rates of glucose, lactate, and palmitate were measured. Recovery of cardiac work, O2 consumption (MVO2), and rates of acetyl-coenzyme A and ATP production during reperfusion were determined. After ischemia, cardiac work recovered to 35 +/- 5% of preischemic values in control hearts (n = 23), although MVO2, tricarboxylic acid (TCA) cycle activity, and ATP production from glycolysis and oxidative metabolism rapidly recovered to preischemic levels. This decrease in cardiac efficiency was accompanied by a substantial production of H+ from glucose metabolism DCA caused a 2.2-fold increase in glucose oxidation, a 46 +/- 17% decrease in H+ production, a 1.6-fold increase in cardiac efficiency, and a 2.0-fold increase in cardiac work during reperfusion (n = 17). Inhibition of Na(+)-H+ exchange with DMA did not alter TCA cycle activity and ATP production rates but did result in a 1.8-fold increase in cardiac efficiency and a 1.7-fold increase in cardiac work (n = 12). These data show that cardiac efficiency and the contractile function after ischemia can be improved by either reducing the rate of H+ production from glucose metabolism during reperfusion or inhibiting the clearance of H+ via Na(+)-H+ exchange. Our data suggest that an increased requirement for ATP to restore ischemia-reperfusion-induced alterations in ion homeostasis contributes to the decrease in cardiac efficiency and contractile function after ischemia.
Prevalence of Age-Related Macular Degeneration in 4 Racial/Ethnic Groups in the Multi-ethnic Study of Atherosclerosis
Authors: Ronald Klein, Barbara E.K. Klein, Michael D. Knudtson, Tien Yin Wong, Mary Frances Cotch, Kiang Liu, Gregory Burke, Mohammed F. Saad, David R. Jacobs
Journal: Ophthalmology (2006)
Oesophageal adenocarcinoma and prior diagnosis of Barrett's oesophagus: a population-based study
Authors: Shivaram K Bhat, Damian T McManus, Helen G Coleman, Brian T Johnston, Christopher R Cardwell, Úna McMenamin, Finian Bannon, Blanaid Hicks, Grace Kennedy, Anna T Gavin, Liam J Murray
Journal: Gut (2014)

<h3>Objective</h3> Endoscopic surveillance of Barrett9s oesophagus (BO) provides an opportunity to detect early stage oesophageal adenocarcinoma (OAC). We sought to determine the proportion of OAC patients with a prior diagnosis of BO on a population basis and to evaluate the influence of a prior diagnosis of BO on survival, taking into account lead and length time biases. <h3>Design</h3> A retrospective population-based study of all OAC patients in Northern Ireland between 2003 and 2008. A prior BO diagnosis was determined by linkage to the Northern Ireland BO register. Stage distribution at diagnosis and histological grade were compared between patients with and without a prior BO diagnosis. Overall survival, using Cox models, was compared between patients with and without a prior BO diagnosis. The effect of adjusting the survival differences for histological grade and estimates of lead and length time bias was assessed. <h3>Results</h3> There were 716 OAC cases, 52 (7.3%) of whom had a prior BO diagnosis. Patients with a prior BO diagnosis had significantly lower tumour stage (44.2% vs 11.1% had stage 1 or 2 disease; p&lt;0.001), a higher rate of surgical resection (50.0% vs 25.5%; p&lt;0.001) and had a higher proportion of low/intermediate grade tumours (46.2% vs 26.5%; p=0.011). A prior BO diagnosis was associated with significantly better survival (HR for death 0.39; 95% CI 0.27 to 0.58), which was minimally influenced by adjustment for age, sex and tumour grade (adjusted HR 0.44; 95% CI 0.30 to 0.64). Correction for lead time bias attenuated but did not abolish the survival benefit (HR 0.65; 95% CI 0.45 to 0.95) and further adjustment for length time bias had little effect. <h3>Conclusions</h3> The proportion of OAC patients with a prior diagnosis of BO is low; however, prior identification of BO is associated with an improvement in survival in OAC patients.
Treatment of Minor Burns by Salicyl Esters
Authors: R. L. Stewart
Journal: BMJ (1937)

gut and not from its excessively rapid utilization by the tissues.In three children with tabes mesenterica Ross (1936b) also found oral curves of a flat type associated with intravdnous curves of high type, and concluded that defective ab §orption of carbohydrate was responsible for the decreased glucose tolerance manifested by these patients.In the present series of cases the glucose tolerance following the intravenous injection of glucose was not determined, but in the steatorrhoeas flat oral glucose curves are often found in association with high faecal fat, and it is evident that defective absorption of both glucose and fat frequently occur together.Verzair (1936) has recently shown that phosphorylation controls the absorption of both fatty acids and glucose in the cells of the intestinal mucosa.Perhaps under the conditions of intestinal lymph stasis described in this paper the phos- phorylation process is defective, and lowering of the absorption gradient for both these substances results.Conclusions 1.A sprue-like syndrome associated with lymphoma, lymphadenoma, and lymphosarcoma of the mesenteric lymph glands is recorded in adults.2. Steatorrhoea was present in all four patients, one of whom died with severe tetany and hypocalcaemia.3. Flat oral glucose tolerance curves similar to those encountered in sprue were found in both cases investigated from this viewpoint.4. It is suggested that defective intestinal absorption resulting from lymphatic obstruction is responsible for the biochemical and clinical findings recorded above.
IDEAL framework for surgical innovation 2: observational studies in the exploration and assessment stages
Authors: P. L. Ergina, J. S. Barkun, P. McCulloch, J. A. Cook, D. G. Altman
Journal: BMJ (2013)

The IDEAL framework describes the stages of evaluation for surgical innovations. This paper considers the role of observational studies in the exploration and assessment stages. At the exploration stage, the surgical intervention is usually more widely used, and observational studies should collect prospective data from multiple surgeons, deal with factors such as case mix and learning, and prepare for a definitive evaluation at the next stage of assessment. Although a randomised controlled trial is preferable, a high quality observational study would be acceptable if a randomised trial is not feasible or, on rare occasions, deemed unnecessary.