tbuckley/cabot-search huggingface dataset:
Intratumoral Heterogeneity in <i>EGFR</i>-Mutant NSCLC Results in Divergent Resistance Mechanisms in Response to EGFR Tyrosine Kinase Inhibition
Authors: Margaret Soucheray, Marzia Capelletti, Inés Pulido, Yanan Kuang, Cloud P. Paweletz, Jeffrey H. Becker, Eiki Kikuchi, Chunxiao Xu, Tarun B. Patel, Fatima Al-shahrour, Julián Carretero, Kwok-Kin Wong, Pasi A. Jänne, Geoffrey I. Shapiro, Takeshi Shimamura
Journal: Cancer Research (2015)

Abstract Non–small cell lung cancers (NSCLC) that have developed resistance to EGF receptor (EGFR) tyrosine kinase inhibitor (TKI), including gefitinib and erlotinib, are clinically linked to an epithelial-to-mesenchymal transition (EMT) phenotype. Here, we examined whether modulating EMT maintains the responsiveness of EGFR-mutated NSCLCs to EGFR TKI therapy. Using human NSCLC cell lines harboring mutated EGFR and a transgenic mouse model of lung cancer driven by mutant EGFR (EGFR-Del19-T790M), we demonstrate that EGFR inhibition induces TGFβ secretion followed by SMAD pathway activation, an event that promotes EMT. Chronic exposure of EGFR-mutated NSCLC cells to TGFβ was sufficient to induce EMT and resistance to EGFR TKI treatment. Furthermore, NSCLC HCC4006 cells with acquired resistance to gefitinib were characterized by a mesenchymal phenotype and displayed a higher prevalence of the EGFR T790M mutated allele. Notably, combined inhibition of EGFR and the TGFβ receptor in HCC4006 cells prevented EMT but was not sufficient to prevent acquired gefitinib resistance because of an increased emergence of the EGFR T790M allele compared with cells treated with gefitinib alone. Conversely, another independent NSCLC cell line, PC9, reproducibly developed EGFR T790M mutations as the primary mechanism underlying EGFR TKI resistance, even though the prevalence of the mutant allele was lower than that in HCC4006 cells. Thus, our findings underscore heterogeneity within NSCLC cells lines harboring EGFR kinase domain mutations that give rise to divergent resistance mechanisms in response to treatment and anticipate the complexity of EMT suppression as a therapeutic strategy. Cancer Res; 75(20); 4372–83. ©2015 AACR.
Disposable platform provides visual and color-based point-of-care anemia self-testing
Authors: Erika A. Tyburski, Scott E. Gillespie, William A. Stoy, Robert G. Mannino, Alexander J. Weiss, Alexa F. Siu, Rayford H. Bulloch, Karthik Thota, Anyela Cardenas, Wilena Session, Hanna J. Khoury, Siobhán O’Connor, Silvia T. Bunting, Jeanne Boudreaux, Craig R. Forest, Manila Gaddh, Traci Leong, L. Andrew Lyon, Wilbur A. Lam
Journal: Journal of Clinical Investigation (2014)

BACKGROUND. Anemia, or low blood hemoglobin (Hgb) levels, afflicts 2 billion people worldwide. Currently, Hgb levels are typically measured from blood samples using hematology analyzers, which are housed in hospitals, clinics, or commercial laboratories and require skilled technicians to operate. A reliable, inexpensive point-of-care (POC) Hgb test would enable cost-effective anemia screening and chronically anemic patients to self-monitor their disease. We present a rapid, stand-alone, and disposable POC anemia test that, via a single drop of blood, outputs color-based visual results that correlate with Hgb levels.
Motorcycle rider conspicuity and crash related injury: case-control study
Authors: Susan Wells, Bernadette Mullin, Robyn Norton, John Langley, Jennie Connor, Rod Jackson, Roy Lay-Yee
Journal: BMJ (2004)

<h3>Abstract</h3> <b>Objective</b> To investigate whether the risk of motorcycle crash related injuries is associated with the conspicuity of the driver or vehicle. <b>Design</b> Population based case-control study. <b>Setting</b> Auckland region of New Zealand from February 1993 to February 1996. <b>Participants</b> 463 motorcycle drivers (cases) involved in crashes leading to hospital treatment or death; 1233 motorcycle drivers (controls) recruited from randomly selected roadside survey sites. <b>Main outcome measures</b> Estimates of relative risk of motorcycle crash related injury and population attributable risk associated with conspicuity measures, including the use of reflective or fluorescent clothing, headlight operation, and colour of helmet, clothing, and motorcycle. <b>Results</b> Crash related injuries occurred mainly in urban zones with 50 km/h speed limit (66%), during the day (63%), and in fine weather (72%). After adjustment for potential confounders, drivers wearing any reflective or fluorescent clothing had a 37% lower risk (multivariate odds ratio 0.63, 95% confidence interval 0.42 to 0.94) than other drivers. Compared with wearing a black helmet, use of a white helmet was associated with a 24% lower risk (multivariate odds ratio 0.76, 0.57 to 0.99). Self reported light coloured helmet versus dark coloured helmet was associated with a 19% lower risk. Three quarters of motorcycle riders had their headlight turned on during the day, and this was associated with a 27% lower risk (multivariate odds ratio 0.73, 0.53 to 1.00). No association occurred between risk and the frontal colour of drivers9 clothing or motorcycle. If these odds ratios are unconfounded, the population attributable risks are 33% for wearing no reflective or fluorescent clothing, 18% for a non-white helmet, 11% for a dark coloured helmet, and 7% for no daytime headlight operation. <b>Conclusions</b> Low conspicuity may increase the risk of motorcycle crash related injury. Increasing the use of reflective or fluorescent clothing, white or light coloured helmets, and daytime headlights are simple, cheap interventions that could considerably reduce motorcycle crash related injury and death.
Human Brain Metabolic Response to Caffeine and the Effects of Tolerance
Authors: Stephen R. Dager, Matthew E. Layton, Wayne Strauss, Todd L. Richards, Aaron Heide, Seth D. Friedman, Alan A. Artru, Cecil E. Hayes, Stefan Posse
Journal: American Journal of Psychiatry (1999)

Since there is limited information concerning caffeine's metabolic effects on the human brain, the authors applied a rapid proton echo-planar spectroscopic imaging technique to dynamically measure regional brain metabolic responses to caffeine ingestion. They specifically measured changes in brain lactate due to the combined effects of caffeine's stimulation of glycolysis and reduction of cerebral blood flow.Nine heavy caffeine users and nine caffeine-intolerant individuals, who had previously discontinued or substantially curtailed use of caffeinated products because of associated anxiety and discomforting physiological arousal, were studied at baseline and then during 1 hour following ingestion of caffeine citrate (10 mg/kg). To assess state-trait contributions and the effects of caffeine tolerance, five of the caffeine users were restudied after a 1- to 2-month caffeine holiday.The caffeine-intolerant individuals, but not the regular caffeine users, experienced substantial psychological and physiological distress in response to caffeine ingestion. Significant increases in global and regionally specific brain lactate were observed only among the caffeine-intolerant subjects. Reexposure of the regular caffeine users to caffeine after a caffeine holiday resulted in little or no adverse clinical reaction but significant rises in brain lactate which were of a magnitude similar to that observed for the caffeine-intolerant group.These results provide direct evidence for the loss of caffeine tolerance in the human brain subsequent to caffeine discontinuation and suggest mechanisms for the phenomenon of caffeine intolerance other than its metabolic effects on elevating brain lactate.
Role of vascular endothelial growth factor-A in development of abdominal aortic aneurysm
Authors: Hidehiro Kaneko, Toshihisa Anzai, Toshiyuki Takahashi, Takashi Kohno, Masayuki Shimoda, Aya Sasaki, Hideyuki Shimizu, Toshiyuki Nagai, Yuichiro Maekawa, Koichi Yoshimura, Hiroki Aoki, Tsutomu Yoshikawa, Yasunori Okada, Ryohei Yozu, Satoshi Ogawa, Keiichi Fukuda
Journal: Cardiovascular Research (2011)

Increased angiogenesis, chronic inflammation, and extracellular matrix degradation are the major pathological features of abdominal aortic aneurysm (AAA). We sought to elucidate the role of vascular endothelial growth factor (VEGF)-A, a potent angiogenic and proinflammatory factor, in the development of AAA. Human AAA samples showed increased VEGF-A expression, neovascularization, and macrophage infiltration compared with normal aortic walls. AAA was induced in mice by periaortic application of CaCl2. AAA mice were treated with soluble VEGF-A receptor (sFlt)-1 or phosphate-buffered saline and sacrificed 6 weeks after the operation. Treatment with sFlt-1 resulted in reduced aneurysm size, restored wavy structure of the elastic lamellae, reduced Mac-2+ monocytes/macrophages, CD3+ T-lymphocytes, and CD31+ vessels, and attenuated matrix metalloproteinase (MMP)-2 and 9 activity in periaortic tissue of AAA. Increased aortic mRNA expression of monocyte chemotactic protein-1, tumour necrosis factor-α, and intercellular adhesion molecule-1 in AAA was attenuated by sFlt-1 treatment. VEGF-A was overexpressed in the aortic wall of human and experimental AAA. Treatment with sFlt-1 inhibited AAA development in mice, in association with reduced neoangiogenesis, infiltration of inflammatory cells, MMP activity, and extracellular matrix degradation. These findings suggest a crucial role of VEGF-A in the development of AAA.
No difference in cardiac event-free survival between positron emission tomography-guided and single-photon emission computed tomography-guided patient management
Authors: Hans-Marc J Siebelink, Paul K Blanksma, Harry J.G.M Crijns, Jeroen J Bax, Ad J van Boven, Tsjerk Kingma, D.Albertus Piers, Jan Pruim, Piet L Jager, Willem Vaalburg, Ernst E van der Wall
Journal: Journal of the American College of Cardiology (2001)
Effects of phthalate esters on the developing reproductive tract of male rats
Authors: P. M. D. Foster
Journal: Human Reproduction Update (2001)

Phthalate esters are a large group of chemical agents used predominantly as plasticizers and solvents. Certain members of this chemical class have been shown to cause reproductive and developmental toxicity. Recent attention has focused on the potential of these agents to interfere with male reproductive development through a postulated antiandrogenic mechanism. Observations have focused on di-n-butyl phthalate (DBP), di-(2-ethylhexyl) phthalate (DEHP) and butyl benzylphthalate, with most information relating to dose–response relationships obtained for DBP. Neither DBP, DEHP nor their major metabolites interacted with human or rodent androgen receptors (AR) in transcriptional activation assays. DBP was administered during the critical window of development of the male reproductive system, after which the resulting offspring were examined until adulthood. DBP elicited marked effects on the developing male reproductive tract, including malformations of the epididymis and vas deferens, and hypospadias. Retention of thoracic nipples/areolae and reductions in anogenital distance were also noted. Surprisingly, Leydig cell adenomas were induced in some male offspring at 100 days of age. All these events occurred in the absence of any toxicity in the pregnant dam. Examination of testes from fetal rats indicated markedly reduced testosterone levels and increased Leydig cell numbers after DBP administration to the dams. Leydig cells were positive for AR and 3-betahydroxysteroid dehydrogenase.
Long-Term Prognosis of Rheumatic Fever Patients Receiving Regular Intramuscular Benzathine Penicillin
Authors: DOROTHY G. TOMPKINS, BERNARD BOXERBAUM, JEROME LIEBMAN
Journal: Circulation (1972)

The prognosis for 115 rheumatic fever patients subsequently receiving regular intramuscular penicillin prophylaxis for at least 5 years was studied. Average follow-up was 9.3 years, and 57 patients were followed for 10 years or longer. Of the 79 patients with acute mitral regurgitation, 70% lost their murmur from 4 days to 8.5 years after it was first heard. This is in contrast to those with acute aortic regurgitation which persisted in 73%. No patient developed mitral or aortic stenosis: this suggests that regular prophylaxis may prevent the development of stenosis. Congestive failure, cardiomegaly, and arrhythmia correlated closely with persistence of murmurs, but increased P-R interval, acute QRS or T-voltage variation or both, and ST-T abnormalities did not.
Transcriptional regulation of epithelial-mesenchymal transition
Authors: Yingqi Teng, Michael Zeisberg, Raghu Kalluri
Journal: Journal of Clinical Investigation (2007)

It has become increasingly obvious that the notion of a terminally differentiated cell is likely a simplified concept. Epithelial-mesenchymal transition (EMT), during which epithelial cells assume a mesenchymal phenotype, is a key event occurring during normal development and pathological processes. Multiple extracellular stimuli and transcriptional regulators can trigger EMT, but how such distinct signaling pathways orchestrate the complex cellular events that facilitate EMT is not well understood. In this issue of the JCI, Venkov et al. report on their examination of fibroblasts resulting from EMT and describe a novel protein-DNA complex that is essential for transcription of fibroblast-specific protein 1 (FSP1) and sufficient to induce early EMT events (see the related article beginning on page 482). Collectively, their results suggest that this complex is an important regulator of the EMT transcriptome.
Phase II Trial of Carmustine Plus O<sup>6</sup>-Benzylguanine for Patients With Nitrosourea-Resistant Recurrent or Progressive Malignant Glioma
Authors: Jennifer A. Quinn, James Pluda, M. Eileen Dolan, Shannon Delaney, Richard Kaplan, Jeremy N. Rich, Allan H. Friedman, David A. Reardon, John H. Sampson, O. Michael Colvin, Michael M. Haglund, Anthony E. Pegg, Robert C. Moschel, Roger E. McLendon, James M. Provenzale, Sridharan Gururangan, Sandra Tourt-Uhlig, James E. Herndon, Darell D. Bigner, Henry S. Friedman
Journal: Journal of Clinical Oncology (2002)

PURPOSE: We conducted a phase II trial of carmustine (BCNU) plus the O 6 -alkylguanine-DNA alkyltransferase inhibitor O 6 -benzylguanine (O 6 -BG) to define the activity and toxicity of this regimen in the treatment of adults with progressive or recurrent malignant glioma resistant to nitrosoureas. PATIENTS AND METHODS: Patients were treated with O 6 -BG at an intravenous dose of 120 mg/m 2 followed 1 hour later by 40 mg/m 2 of BCNU, with cycles repeated at 6-week intervals. RESULTS: Eighteen patients were treated (15 with glioblastoma multiforme, two with anaplastic astrocytoma, and one with malignant glioma). None of the 18 patients demonstrated a partial or complete response. Two patients exhibited stable disease for 12 weeks before their tumors progressed. Three patients demonstrated stable disease for 6, 12, and 18 weeks before discontinuing therapy because of hematopoietic toxicity. Twelve patients experienced reversible ≥ grade 3 hematopoietic toxicity. There was no difference in half-lives (0.56 ± 0.21 hour v 0.54 ± 0.20 hour) or area under the curve values (4.8 ± 1.7 μg/mL/h v 5.0 ± 1.3 μg/mL/h) of O 6 -BG for patients receiving phenytoin and those not treated with this drug. CONCLUSION: These results indicate that O 6 -BG plus BCNU at the dose schedule used in this trial is unsuccessful in producing tumor regression in patients with nitrosourea-resistant malignant glioma, although stable disease was seen in five patients for 6, 12, 12, 12, and 18 weeks. Future use of this approach will require strategies to minimize dose-limiting toxicity of BCNU such as regional delivery or hematopoietic stem-cell protection.
Fetal Pain
Authors: Susan J. Lee, Henry J. Peter Ralston, Eleanor A. Drey, John Colin Partridge, Mark A. Rosen
Journal: JAMA (2005)

Proposed federal legislation would require physicians to inform women seeking abortions at 20 or more weeks after fertilization that the fetus feels pain and to offer anesthesia administered directly to the fetus. This article examines whether a fetus feels pain and if so, whether safe and effective techniques exist for providing direct fetal anesthesia or analgesia in the context of therapeutic procedures or abortion.Systematic search of PubMed for English-language articles focusing on human studies related to fetal pain, anesthesia, and analgesia. Included articles studied fetuses of less than 30 weeks' gestational age or specifically addressed fetal pain perception or nociception. Articles were reviewed for additional references. The search was performed without date limitations and was current as of June 6, 2005.Pain perception requires conscious recognition or awareness of a noxious stimulus. Neither withdrawal reflexes nor hormonal stress responses to invasive procedures prove the existence of fetal pain, because they can be elicited by nonpainful stimuli and occur without conscious cortical processing. Fetal awareness of noxious stimuli requires functional thalamocortical connections. Thalamocortical fibers begin appearing between 23 to 30 weeks' gestational age, while electroencephalography suggests the capacity for functional pain perception in preterm neonates probably does not exist before 29 or 30 weeks. For fetal surgery, women may receive general anesthesia and/or analgesics intended for placental transfer, and parenteral opioids may be administered to the fetus under direct or sonographic visualization. In these circumstances, administration of anesthesia and analgesia serves purposes unrelated to reduction of fetal pain, including inhibition of fetal movement, prevention of fetal hormonal stress responses, and induction of uterine atony.Evidence regarding the capacity for fetal pain is limited but indicates that fetal perception of pain is unlikely before the third trimester. Little or no evidence addresses the effectiveness of direct fetal anesthetic or analgesic techniques. Similarly, limited or no data exist on the safety of such techniques for pregnant women in the context of abortion. Anesthetic techniques currently used during fetal surgery are not directly applicable to abortion procedures.
Microvascular permeability is related to circulating levels of tumour necrosis factor-? in pre-eclampsia
Authors: N ANIMNYAME, J GAMBLE, S SOORANNA, M JOHNSON, P STEER
Journal: Cardiovascular Research (2003)

Introduction: The mechanism for the increased microvascular permeability which, underline many of the complications of pre-eclampsia, remain unexplained. It has been suggested that a factor present in the maternal circulation in pregnancies complicated by the disease may be responsible for increased microvascular permeability. In this study, we have investigated the relationship between filtration capacity (Kf), an index of microvascular permeability, and maternal levels of VEGF, leptin and TNF-α, all of which are known permeability factors whose plasma levels are increased in pre-eclampsia. Methods: We used a small cumulative pressure step venous congestion plethysmography protocol to compare Kf, an index of microvascular permeability, during the third trimester of 20 women with pre-eclampsia, 18 normal pregnant women and 18 non-pregnant female matched controls. Blood samples were obtained to measure plasma levels of VEGF, leptin, TNF-α plasma protein concentrations and full blood count. Results: Microvascular filtration capacity (Kf) was significantly increased in pre-eclampsia compared to the other groups (P≪0.0001, ANOVA). Kf was also increased in the normal pregnant group when compared to the non-pregnant controls (P = 0.02). Plasma levels of VEGF, leptin and TNF-α were significantly greater in pre-eclampsia compared to normal pregnancy and non-pregnant controls (P<0.0001, ANOVA, for all three analyses). Total plasma protein and albumin concentrations were significantly lower in the normal pregnant and pre-eclamptic groups, compared to the non-pregnant controls (P<0.0001, ANOVA). Kf was significantly related to TNF-α in pre-eclampsia (r = 0.53, P = 0.018), and with VEGF in the non-pregnant controls (r = 0.6, P = 0.02). No significant relationship was observed between Kf and VEGF, leptin and TNF-α during normal pregnancy. There was a significant inverse correlation between plasma albumin concentration and filtration capacity in the normal pregnant (r = −0.94, P<0.0001) and non-pregnant (r = −0.87, P<0.0001) groups but not in the women with pre-eclampsia (r = −0.18, P = 0.8). Conclusions: These data show that that microvascular filtration capacity is significantly increased in pre-eclampsia, and correlates with circulating levels of TNF-α but not leptin or VEGF.
Nitric Oxide Induces Early Viral Transcription Coincident with Increased DNA Damage and Mutation Rates in Human Papillomavirus–Infected Cells
Authors: Lanlan Wei, Patti E. Gravitt, Hebin Song, Anastacia M. Maldonado, Michelle A. Ozbun
Journal: Cancer Research (2009)

Abstract High-risk human papillomavirus (HPV) infections are necessary but insufficient causes of cervical cancers. Other risk factors for cervical cancer (e.g., pregnancy, smoking, infections causing inflammation) can lead to high and sustained nitric oxide (NO) concentrations in the cervix, and high NO levels are related to carcinogenesis through DNA damage and mutation. However, the effects of NO exposure in HPV-infected cells have not been investigated. In this study, we used the NO donor DETA-NO to model NO exposure to cervical epithelium. In cell culture media, 24-hour exposure to 0.25 to 0.5 mmol/L DETA-NO yielded a pathologically relevant NO concentration. Exposure of cells maintaining episomal high-risk HPV genomes to NO increased HPV early transcript levels 2- to 4-fold but did not increase viral DNA replication. Accompanying increased E6 and E7 mRNA levels were significant decreases in p53 and pRb protein levels, lower apoptotic indices, increased DNA double-strand breaks, and higher mutation frequencies when compared with HPV-negative cells. We propose that NO is a molecular cofactor with HPV infection in cervical carcinogenesis, and that modifying local NO cervical concentrations may constitute a strategy whereby HPV-related cancer can be reduced.[Cancer Res 2009;69(11):4878–84]
Pay for perfomance and the quality of diabetes management in individuals with and without co-morbid medical conditions
Authors: Christopher Millett, Alex Bottle, Anthea Ng, Vasa Curcin, Mariam Molokhia, Sonia Saxena, Azeem Majeed
Journal: Journal of the Royal Society of Medicine (2009)

Summary Objective To examine the impact of the Quality and Outcomes Framework, a major pay-for-performance incentive introduced in the UK during 2004, on diabetes management in patients with and without co-morbidity. Design Cohort study comparing actual achievement of treatment targets in 2004 and 2005 with that predicted by the underlying (pre-intervention) trend in diabetes patients with and without co-morbid conditions. Setting A total of 422 general practices participating in the General Practice Research Database. Main outcomes measures Achievement of diabetes treatment targets for blood pressure (&lt; 140/80 mm Hg), HbA1c (≤ 7.0%) and cholesterol (≤ 5 mmol/L). Results The percentage of diabetes patients with co-morbidity reaching blood pressure and cholesterol targets exceeded that predicted by the underlying trend during the first two years of pay for perfomance (by 3.1% [95% CI 1.1–5.1] for BP and 4.1% [95% CI 2.2–6.0] for cholesterol among patients with ≥ 5 co-morbidities in 2005). Similar improvements were evident in patients without co-morbidity, except for cholesterol control in 2004 (−0.2% [95% CI −1.7–1.4]). The percentage of patients meeting the HbA1c target in the first two years of this program was significantly lower than predicted by the underlying trend in all patients, with the greatest shortfall in patients without co-morbidity (3.8% [95% CI 2.6–5.0] lower in 2005). Patients with co-morbidity remained significantly more likely to meet treatment targets for cholesterol and HbA1c than those without after the introduction of pay for perfomance. Conclusions Diabetes patients with co-morbid conditions appear to have benefited more from this pay-for-performance program than those without co-morbidity.