tbuckley/cabot-search huggingface dataset:
Recombinant DNA Technology in the Treatment of Diabetes: Insulin Analogs
Authors: Zoltan Vajo, Janet Fawcett, William C. Duckworth
Journal: Endocrine Reviews (2001)

After more than half a century of treating diabetics with animal insulins, recombinant DNA technologies and advanced protein chemistry made human insulin preparations available in the early 1980s. As the next step, over the last decade, insulin analogs were constructed by changing the structure of the native protein with the goal of improving the therapeutic properties of it, because the pharmacokinetic characteristics of rapid-, intermediate-, and long-acting preparations of human insulin make it almost impossible to achieve sustained normoglycemia. The first clinically available insulin analog, lispro, confirmed the hopes by showing that improved glycemic control can be achieved without an increase in hypoglycemic events. Two new insulin analogs, insulin glargine and insulin aspart, have recently been approved for clinical use in the United States, and several other analogs are being intensively tested. Thus, it appears that a rapid acceleration of basic and clinical research in this arena will be seen, which will have direct significance to both patients and their physicians. The introduction of new short-acting analogs and the development of the first truly long-acting analogs and the development of analogs with increased stability, less variability, and perhaps selective action, will help to develop more individualized treatment strategies targeted to specific patient characteristics and to achieve further improvements in glycemic control. Data on the currently available and tested analogs, as well as data on those currently being developed, are reviewed.
Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A
Authors: Corien L. Eckhardt, Alice S. van Velzen, Marjolein Peters, Jan Astermark, Paul P. Brons, Giancarlo Castaman, Marjon H. Cnossen, Natasja Dors, Carmen Escuriola-Ettingshausen, Karly Hamulyak, Daniel P. Hart, Charles R. M. Hay, Saturnino Haya, Waander L. van Heerde, Cedric Hermans, Margareta Holmström, Victor Jimenez-Yuste, Russell D. Keenan, Robert Klamroth, Britta A. P. Laros-van Gorkom, Frank W. G. Leebeek, Ri Liesner, Anne Mäkipernaa, Christoph Male, Evelien Mauser-Bunschoten, Maria G. Mazzucconi, Simon McRae, Karina Meijer, Michael Mitchell, Massimo Morfini, Marten Nijziel, Johannes Oldenburg, Kathelijne Peerlinck, Pia Petrini, Helena Platokouki, Sylvia E. Reitter-Pfoertner, Elena Santagostino, Piercarla Schinco, Frans J. Smiers, Berthold Siegmund, Annarita Tagliaferri, Thynn T. Yee, Pieter Willem Kamphuisen, Johanna G. van der Bom, Karin Fijnvandraat
Journal: Blood (2013)
Power Doppler sonography monitoring of synovial perfusion at the wrist joints in patients with rheumatoid arthritis treated with adalimumab
Authors: E Filippucci, A Iagnocco, F Salaffi, A Cerioni, G Valesini, W Grassi
Journal: Annals of the Rheumatic Diseases (2006)

<b>Objective:</b> To use power Doppler sonography (PDS) to evaluate changes in synovial perfusion induced by adalimumab in the wrist joints of patients with rheumatoid arthritis. <b>Methods:</b> 48 wrists of 24 patients (18 women and 6 men) were examined. Despite prior treatment with disease-modifying antirheumatic drugs, including methotrexate, patients with clinically active rheumatoid arthritis were recruited in two rheumatological centres to receive 40 mg adalimumab subcutaneously every other week. Clinical, laboratory and PDS assessments were carried out at 0, 2, 6 and 12 weeks. Clinical and laboratory measurements of disease activity included physician's global assessment of disease activity, erythrocyte sedimentation rate and serum levels of C reactive protein. The Disease Activity Score for 28 joints (DAS28) was calculated. PDS signal was scored from 0 to 3 according to the overall expression of PDS findings at the wrists. <b>Results:</b> A significant reduction in both clinical (p&lt;0.001) and PDS findings (p&lt;0.001) was found at all follow-up examinations. A tendency to positive correlation (Spearman's r = 0.382; p = 0.067) was shown between reduction in PDS score and improvement in DAS28 at week 2 examination. <b>Conclusion:</b> PDS detected a rapid and significant reduction in synovial perfusion at the wrist joints of patients with rheumatoid arthritis receiving adalimumab. Ongoing follow-up will provide further information regarding the persistence of considerable reduction in PDS signal score and its correlation with DAS28.
Lack of Muc1-Regulated β-Catenin Stability Results in Aberrant Expansion of CD11b+Gr1+ Myeloid-Derived Suppressor Cells from the Bone Marrow
Authors: Tze Wei Poh, Judy M. Bradley, Pinku Mukherjee, Sandra J. Gendler
Journal: Cancer Research (2009)

Abstract Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of myeloid cells that inhibit T-cell activity and contribute to the immune suppression characteristic of most tumors. We discovered that bone marrow (BM) progenitor cells from the Muc1 knockout (KO) mice differentiated into CD11b+Gr1+ MDSCs in vitro under granulocyte macrophage colony-stimulating factor and interleukin-4 signaling. MUC1 is a tumor-associated mucin and its cytoplasmic tail (MUC1-CT) can regulate β-catenin to promote oncogenesis. Given the importance of β-catenin in hematopoiesis, we hypothesized that the MUC1 regulation of β-catenin is important for MDSC development. Our current study shows that the aberrant development of BM progenitors into CD11b+Gr1+ MDSCs is dependent on the down-regulation of β-catenin levels that occurs in the absence of Muc1. In light of this, KO mice showed enhanced EL4 tumor growth and were able to better tolerate allogeneic BM185 tumor growth, with an accumulation of CD11b+Gr1+ cells in the blood and tumor-draining lymph nodes. WT mice were able to similarly tolerate allogeneic tumor growth when they were injected with CD11b+Gr1+ cells from tumor-bearing KO mice, suggesting that tolerance of allogeneic tumors is dependent on MDSC-mediated immune suppression. This further delineates the ability of Muc1 to control MDSC development, which could directly affect tumorigenesis. Knowledge of the biology by which Muc1 regulates the development of myeloid progenitors into MDSCs would also be very useful in enhancing the efficacy of cancer vaccines in the face of tumor immune suppression. [Cancer Res 2009;69(8):3554–62]
Randomized Trial of Lenalidomide Alone Versus Lenalidomide Plus Rituximab in Patients With Recurrent Follicular Lymphoma: CALGB 50401 (Alliance)
Authors: John P. Leonard, Sin-Ho Jung, Jeffrey Johnson, Brandelyn N. Pitcher, Nancy L. Bartlett, Kristie A. Blum, Myron Czuczman, Jeffrey K. Giguere, Bruce D. Cheson
Journal: Journal of Clinical Oncology (2015)

Purpose Lenalidomide and rituximab (LR) are active agents in follicular lymphoma (FL). Combination regimens have not been previously assessed in randomized studies. Patients and Methods The Cancer and Leukemia Group B (Alliance) 50401 trial is a randomized phase II trial studying rituximab (375 mg/m 2 weekly for 4 weeks), lenalidomide (15 mg per day on days 1 to 21, followed by 7 days of rest, in cycle 1 and then 20 mg per day on days 1 to 21, followed by 7 days of rest, in cycles 2 to 12), or LR. The rituximab-alone arm was discontinued as a result of poor accrual. Eligibility included recurrent FL and prior rituximab with time to progression of ≥ 6 months from last dose. Aspirin or heparin was recommended for patients at high thrombosis risk. Results Ninety-one patients (lenalidomide, n = 45; LR, n = 46) received treatment; median age was 63 years (range, 34 to 89 years), and 58% were intermediate or high risk according to the Follicular Lymphoma International Prognostic Index. In the lenalidomide and LR arms, grade 3 to 4 adverse events occurred in 58% and 53% of patients, with 9% and 11% of patients experiencing grade 4 toxicity, respectively; grade 3 to 4 adverse events included neutropenia (16% v 20%, respectively), fatigue (9% v 13%, respectively), and thrombosis (16% [n = 7] v 4% [n = 2], respectively; P = .157). Thirty-six percent of lenalidomide patients and 63% of LR patients completed 12 cycles. Lenalidomide alone was associated with more treatment failures, with 22% of patients discontinuing treatment as a result of adverse events. Dose-intensity exceeded 80% in both arms. Overall response rate was 53% (20% complete response) and 76% (39% complete response) for lenalidomide alone and LR, respectively (P = .029). At the median follow-up of 2.5 years, median time to progression was 1.1 year for lenalidomide alone and 2 years for LR (P = .0023). Conclusion LR is more active than lenalidomide alone in recurrent FL with similar toxicity, warranting further study in B-cell non-Hodgkin lymphoma as a platform for addition of novel agents.
Histological findings of the computed tomography halo in pulmonary sarcoidosis
Authors: T. Harada, K. Nabeshima, T. Matsumoto, T. Akagi, M. Fujita, K. Watanabe
Journal: European Respiratory Journal (2009)

In 1974, Sahn et al. 1 described a patient with sarcoidosis who presented with a fine acinar rosette pattern of infiltrate on chest radiograph and alveolar filling with mononuclear cells in the biopsied specimen. In 1978, Shigematsu et al. 2 reported the presence of noncaseating epithelioid granulomas in the alveolar spaces in patients with radiographic findings similar to the previous report. They considered these lesions to represent the early stage of sarcoidosis. Although there seems to be no definite relationship between the stage of sarcoidosis and the anatomical extent of the granulomas, sarcoid granulomas in the alveoli are rarely found. Nowadays, in the era of high-resolution computed tomography (HRCT), ground-glass attenuations are sometimes found in sarcoidosis that could fit the “acinar pattern” proposed by Sahn et al. 1 and Shigematsu et al. 2.

In 2004, Marten et al. 3 described the presence of ground-glass attenuation around solid nodules, the halo sign, on computed tomography (CT) of a patient with sarcoidosis.

Herein, we report a case of sarcoidosis presenting a CT halo sign that was surgically biopsied. The pathological/radiological correlation of sarcoidosis with the halo sign is discussed.

A 69-yr-old female noticed general fatigue. She had a past history of left lower lobectomy due to adenocarcinoma of the lung 8 yrs prior to admission. She was admitted to our hospital (Fukuoka University School of Medicine, Fukuoka, Japan) …
Interpretations. The aftermath of a pill scare: regression to reassurance
Authors: W O Spitzer
Journal: Human Reproduction Update (1999)

In October 1995, following confidential exchanges of findings among investigators in several epidemiological studies, the UK Medicines Control Agency sent a 'Dear Doctor' letter to all clinical practitioners in the country. The letter alerted them to the possibility of an excess risk of venous thromboembolism among women taking combined oral contraceptives (OC) with the 'newer' progestins, notably desogestrel and gestodene. The communication provoked a major pill scare, not just in the United Kingdom but in other countries. The preliminary and unpublished findings from the four initial 1995-96 studies reported odds ratios (OR) ranging from 1.5 to 2.3 in the point estimates. These are very low relative risks but were communicated in a way that the public perceived as a 'doubling of the risks'. In the 3 years since the pill scare, additional research has been done. First, deliberate and careful analysis of some of the studies and replication of others have shown that the epidemiological investigations were affected by unavoidable systematic error. Three types of bias were demonstrated empirically, namely, prescription bias, referral bias and healthy user effect or attrition of susceptibles. All those biases would tend to drive OR spuriously upwards. Additional epidemiological studies have progressively shown lower ORs, some of them under the threshold of 1.0, i.e. 'no association'. Two major consensus assessments, one carried out by a World Health Organization Scientific Group and another undertaken by the International Federation of Fertility Societies, both attach little importance to differences between older (second generation) combined OC and newer ones (third generation). This paper is a synthesis of all published evidence since October 1995, at the time of the pill scare and in the 3 years since. In conclusion, all combined oral contraceptive pills are equally safe.
Paradoxical Relationship between Chromosomal Instability and Survival Outcome in Cancer
Authors: Nicolai J. Birkbak, Aron C. Eklund, Qiyuan Li, Sarah E. McClelland, David Endesfelder, Patrick Tan, Iain B. Tan, Andrea L. Richardson, Zoltan Szallasi, Charles Swanton
Journal: Cancer Research (2011)

Chromosomal instability (CIN) is associated with poor prognosis in human cancer. However, in certain animal tumor models elevated CIN negatively impacts upon organism fitness, and is poorly tolerated by cancer cells. To better understand this seemingly contradictory relationship between CIN and cancer cell biological fitness and its relationship with clinical outcome, we applied the CIN70 expression signature, which correlates with DNA-based measures of structural chromosomal complexity and numerical CIN in vivo, to gene expression profiles of 2,125 breast tumors from 13 published cohorts. Tumors with extreme CIN, defined as the highest quartile CIN70 score, were predominantly of the estrogen receptor negative (ER(-)), basal-like phenotype and displayed the highest chromosomal structural complexity and chromosomal numerical instability. We found that the extreme CIN/ER(-) tumors were associated with improved prognosis relative to tumors with intermediate CIN70 scores in the third quartile. We also observed this paradoxical relationship between CIN and prognosis in ovarian, gastric, and non-small cell lung cancer, with poorest outcome in tumors with intermediate, rather than extreme, CIN70 scores. These results suggest a nonmonotonic relationship between gene signature expression and HR for survival outcome, which may explain the difficulties encountered in the identification of prognostic expression signatures in ER(-) breast cancer. Furthermore, the data are consistent with the intolerance of excessive CIN in carcinomas and provide a plausible strategy to define distinct prognostic patient cohorts with ER(-) breast cancer. Inclusion of a surrogate measurement of CIN may improve cancer risk stratification and future therapeutic approaches.
Weekly 5-fluorouracil and leucovorin: achieving lower toxicity with higher dose-intensity in adjuvant chemotherapy after colorectal cancer resection
Authors: K. Patel, D.A. Anthoney, A.M. Crellin, D. Sebag-Montefiore, J. Messruther, M.T. Seymour
Journal: Annals of Oncology (2004)
Combined Targeting of STAT3/NF-κB/COX-2/EP4 for Effective Management of Pancreatic Cancer
Authors: Jingjing Gong, Jianping Xie, Roble Bedolla, Paul Rivas, Divya Chakravarthy, James W. Freeman, Robert Reddick, Scott Kopetz, Amanda Peterson, Huamin Wang, Susan M. Fischer, Addanki P. Kumar
Journal: Clinical Cancer Research (2014)

Near equal rates of incidence and mortality emphasize the need for novel targeted approaches for better management of patients with pancreatic cancer. Inflammatory molecules NF-κB and STAT3 are overexpressed in pancreatic tumors. Inhibition of one protein allows cancer cells to survive using the other. The goal of this study is to determine whether targeting STAT3/NF-κB crosstalk with a natural product Nexrutine can inhibit inflammatory signaling in pancreatic cancer.HPNE, HPNE-Ras, BxPC3, Capan-2, MIA PaCa-2, and AsPC-1 cells were tested for growth, apoptosis, cyclooxygenase-2 (COX-2), NF-κB, and STAT3 level in response to Nexrutine treatment. Transient expression, gel shift, chromatin immunoprecipitation assay was used to examine transcriptional regulation of COX-2. STAT3 knockdown was used to decipher STAT3/NF-κB crosstalk. Histopathologic and immunoblotting evaluation was performed on BK5-COX-2 transgenic mice treated with Nexrutine. In vivo expression of prostaglandin receptor E-prostanoid 4 (EP4) was analyzed in a retrospective cohort of pancreatic tumors using a tissue microarray.Nexrutine treatment inhibited growth of pancreatic cancer cells through induction of apoptosis. Reduced levels and activity of STAT3, NF-κB, and their crosstalk led to transcriptional suppression of COX-2 and subsequent decreased levels of prostaglandin E2 (PGE2) and PGF2. STAT3 knockdown studies suggest STAT3 as negative regulator of NF-κB activation. Nexrutine intervention reduced the levels of NF-κB, STAT3, and fibrosis in vivo. Expression of prostaglandin receptor EP4 that is known to play a role in fibrosis was significantly elevated in human pancreatic tumors.Dual inhibition of STAT3-NF-κB by Nexrutine may overcome problems associated with inhibition of either pathway.
Fungal extracellular polysaccharides in house dust as a marker for exposure to fungi: Relations with culturable fungi, reported home dampness, and respiratory symptoms
Authors: Jeroen Douwes, Betty van der Sluis, Gert Doekes, Frans van Leusden, Luc Wijnands, Rob van Strien, Arnoud Verhoeff, Bert Brunekreef
Journal: Journal of Allergy and Clinical Immunology (1999)
PROPERDIN FACTOR D
Authors: Douglas T. Fearon, K. Frank Austen, Shaun Ruddy
Journal: The Journal of Experimental Medicine (1974)

The protein in the properdin pathway responsible for conversion of precursor factor D to D has been isolated and found to be identical with properdin. Sequential ion exchange and gel filtration chromatography demonstrated identity between properdin protein, measured by radial immunodiffusion, and the capacity to activate D to D, assessed by formation of the intermediate, EAC43B(D). Properdin, purified in this manner, was homogeneous on acid polyacrylamide disc gel electrophoretic analysis, with the band of protein corresponding to the position of eluates in the replicate gel capable of activating highly purified D. Demonstration of the homogeneity of purified D by alkaline disc gel electrophoresis, coupled with the linear stoichiometric hemolytic titrations of each factor, indicates that direct interaction between properdin and D generates D. Thus, activation of D by properdin represents a mechanism in the properdin pathway by which D becomes available for formation of the C3b-dependent C3 convertase.
John Alan Mathews
Authors: M. S. R. Thompson
Journal: BMJ (2013)

John Alan Mathews was physician to the department of rheumatology, St Thomas’ Hospital from 1969 until his retirement in 2000. He had two well known medical uncles—Graham Apley, an orthopaedic surgeon, and Professor John Apley CBE, FRCP, a paediatrician, who likely stimulated his interest in medicine. He went to Haberdasher’s Aske’s School in Hampstead before reading medicine at Jesus College, Cambridge. There he was active in the college’s social life, even joining the esoteric fraternity “roosters,” and went down to Guy’s Hospital Medical School, qualifying in 1957. His six month preregistration medical post was at the Canadian Red Cross Memorial Hospital, Taplow, where his interest in rheumatology may have been kindled. After two years in general practice he returned to hospital medicine at St Peter’s Hospital, Chertsey, and then spent three years at the London Hospital, training in physical medicine.

John first came to St Thomas’ …
Human small intestinal contractions and aboral traction forces during fasting and after feeding.
Authors: N K Ahluwalia, D G Thompson, J Barlow, L Heggie
Journal: Gut (1994)

Small intestinal intraluminal pressure activity and aboral traction forces were explored in 19 healthy volunteers using a combined manometry and traction force detecting assembly sited in the upper small intestine. Each aboral traction event was classified as being associated with either a propagating or a stationary contraction and its force measured. During phase I no contractions or traction events were seen. During phase II, traction events related to propagating contractions mean (SEM) (2.2 (0.2)/min) and to stationary contractions (0.3 (0.1)/min) generated similar force/event (7.5(0.9 g v 8.7 (1.4) g, p &gt; 0.05). During phase III, all traction events were related to propagating contractions and generated 9.3 (2.4) g force/event (p &gt; 0.05 v phase II). After feeding, traction events related to propagating contractions generated similar force/event to those related to stationary contractions (5.9 (1.0) g v 9.3 (2.7) g, p &gt; 0.05 v each other and v fasting). No consistent pattern was seen in the temporal distribution of the traction events or in the pattern of the amplitude of the force of successive traction events.
Implementation and Evaluation of a Low-Literacy Diabetes Education Computer Multimedia Application
Authors: Ben S. Gerber, Irwin G. Brodsky, Kimberly A. Lawless, Louanne I. Smolin, Ahsan M. Arozullah, Everett V. Smith, Michael L. Berbaum, Paul S. Heckerling, Arnold R. Eiser
Journal: Diabetes Care (2005)

OBJECTIVE—To evaluate a clinic-based multimedia intervention for diabetes education targeting individuals with low health literacy levels in a diverse population. RESEARCH DESIGN AND METHODS—Five public clinics in Chicago, Illinois, participated in the study with computer kiosks installed in waiting room areas. Two hundred forty-four subjects with diabetes were randomized to receive either supplemental computer multimedia use (intervention) or standard of care only (control). The intervention includes audio/video sequences to communicate information, provide psychological support, and promote diabetes self-management skills without extensive text or complex navigation. HbA1c (A1C), BMI, blood pressure, diabetes knowledge, self-efficacy, self-reported medical care, and perceived susceptibility of complications were evaluated at baseline and 1 year. Computer usage patterns and implementation barriers were also examined. RESULTS—Complete 1-year data were available for 183 subjects (75%). Overall, there were no significant differences in change in A1C, weight, blood pressure, knowledge, self-efficacy, or self-reported medical care between intervention and control groups. However, there was an increase in perceived susceptibility to diabetes complications in the intervention group. This effect was greatest among subjects with lower health literacy. Within the intervention group, time spent on the computer was greater for subjects with higher health literacy. CONCLUSIONS—Access to multimedia lessons resulted in an increase in perceived susceptibility to diabetes complications, particularly in subjects with lower health literacy. Despite measures to improve informational access for individuals with lower health literacy, there was relatively less use of the computer among these participants.
An Official American Thoracic Society Policy Statement: Pay-for-Performance in Pulmonary, Critical Care, and Sleep Medicine
Authors: Jeremy M. Kahn, Damon C. Scales, David H. Au, Shannon S. Carson, J. Randall Curtis, R. Adams Dudley, Theodore J. Iwashyna, Jerry A. Krishnan, Janet R. Maurer, Richard Mularski, John Popovich, Gordon D. Rubenfeld, Tasnim Sinuff, John E. Heffner
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

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