tbuckley/cabot-search huggingface dataset:
Abstract 374: <i>KDR</i> amplification in NSCLC is associated with sensitivity to VEGFR tyrosine kinase inhibitors.
Authors: Monique B. Nilsson, Tina Cascone, Jayanthi Gudikote, Emily Roarty, Lixia Diao, Andrew Koo, Sumankalai Ramachandran, Erick Riquelme, Hai Tran, Ignacio Wistuba, David P. Carbone, John Heymach
Journal: Cancer Research (2013)

Abstract Targeted therapies designed to inhibit the vascular endothelial growth factor (VEGF) pathway have been extensively evaluated in the treatment of malignancies including Non-Small Cell Lung Cancer (NSCLC). VEGF pathway inhibitors such as bevacizumab, or the multitargeted receptor tyrosine kinase inhibitors (TKIs) vandetanib and sorafenib, have been shown to prolong progression-free survival (PFS) and/or overall survival (OS). These benefits, however, have been modest, seen only in subsets of patients. Thus, predictive markers for identifying which patients are likely to benefit are critically needed. Although expression of VEGF receptor-2 (VEGFR-2, also known as KDR) was initially thought to primarily occur in endothelial cells, VEGFR-2 has been detected on malignant cells, including lung cancer cells, and in NSCLC, overexpression of VEGFR-2 on tumor cells is associated with a poor clinical outcome. Amplification of KDR has been detected in lung cancer specimens at a relatively high frequency (9% and 32%). The consequences of KDR copy number gains (CNGs) are not yet understood. Recently, we have shown that NSCLC cell lines with KDR copy number gains (CNGs) were associated with in vitro resistance to platinum chemotherapy, and KDR CNG predicted worse overall survival in patients who received platinum adjuvant therapy but not in untreated patients. We investigated the hypothesis that NSCLC tumor cells with KDR CNG display increased sensitivity to VEGFR TKIs compared to tumor cells without KDR CNG. In tumor cell lines with KDR CNG, treatment with exogenous VEGF ligand enhanced cell motility and this was inhibited by VEGFR blockade with TKIs. Multiple receptor tyrosine kinases have been shown to drive HIF-1α levels, and NSCLC cells with KDR CNG express elevated levels of HIF-1α in normoxic conditions compared to NSCLC cell lines without KDR CNG. Here, we show that in NSCLC cell lines with KDR CNG, VEGFR TKIs decreased protein levels of HIF-1α and HIF-1α- regulated proteins. Furthermore, we report a clinical case in which a NSCLC patient with KDR CNG as determined by SNP array had a partial response to VEGFR inhibition with sorafenib. Citation Format: Monique B. Nilsson, Tina Cascone, Jayanthi Gudikote, Emily Roarty, Lixia Diao, Andrew Koo, Sumankalai Ramachandran, Erick Riquelme, Hai Tran, Ignacio Wistuba, David P. Carbone, John Heymach. KDR amplification in NSCLC is associated with sensitivity to VEGFR tyrosine kinase inhibitors. [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 374. doi:10.1158/1538-7445.AM2013-374
Endogenous oncornaviral gene expression in adult and fetal mice: quantitative, histologic, and physiologic studies of the major viral glycorprotein, gp70.
Authors: R A Lerner, C B Wilson, B C Villano, P J McConahey, F J Dixon
Journal: The Journal of Experimental Medicine (1976)

Endogenous expression of the murine leukemia virus (MuLV) genome has been studied in a number of strains of mice. Expression of the major envelope glycoprotein, gp70, is restricted to certain anatomical sites and cell types, prominent among which are lymphoid and epithelial cells. On a quantitative basis, the major site of gp70 expression is the male genital tract. During development, gp70 first appears in the hematopoietic liver of 14-day-old embryos and by day 18, it is already expressed at anatomical sites similar to those of the adult. In toto, these results show that control of expression of the MuLV genome in adult and developing mice is linked to differentiation.
Exercise, Fitness, and Mortality-Reply
Authors: Steven N. Blair
Journal: JAMA (1990)

In Reply.—  Dr Goldstein is correct in his suggestion that the inverse relation in our study between physical fitness and cancer mortality might be confounded by undiagnosed cancer present at baseline examination. Preclinical cancer could result in poor treadmill test performance and increase the likelihood of death due to cancer during follow-up. To address this issue, we excluded all cancer deaths that occurred in the cohort during the first 3 years of follow-up and reanalyzed the relation between fitness and cancer mortality. This exclusion left 55 cancer deaths in men and 13 in women. Age-adjusted cancer death rates per 10 000 person-years of observation in low-, moderate-, and high-fitness groups were 16.4, 6.1, and 4.5 in men and 13.5, 5.9, and 1.0 in women, respectively. These findings reduce the likelihood that preclinical cancer is the sole cause of the relation between fitness and cancer. However, residual confounding from prior cigarette
Reemergence of PML in Natalizumab-Treated Patients — New Cases, Same Concerns
Authors: Eugene O. Major
Journal: New England Journal of Medicine (2009)

When progressive multifocal leukoencephalopathy (PML), a rare demyelinating disease induced by JC virus, appeared in 2004 as a complication of natalizumab treatment for multiple sclerosis, a more common demyelinating disease, it seemed an odd twist of nature. PML had never been reported in patients with multiple sclerosis, and to find patients who simultaneously had two demyelinating diseases with very different origins and pathologic characteristics was a dramatic surprise.Natalizumab, a humanized monoclonal antibody that binds to the α4 integrin molecule at the β1 and β7 epitopes, is an adhesion-molecule inhibitor that prevents extravasation of T and B cells into . . .
Within- and Between-Home Variability in Indoor-Air Insecticide Levels during Pregnancy among an Inner-City Cohort from New York City
Authors: Robin M. Whyatt, Robin Garfinkel, Lori A. Hoepner, Darrell Holmes, Mejico Borjas, Megan K. Williams, Andria Reyes, Virginia Rauh, Frederica P. Perera, David E. Camann
Journal: Environmental Health Perspectives (2006)

BackgroundResidential insecticide use is widespread in the United States, but few data are available on the persistence and variability in levels in the indoor environment.ObjectiveThe study aim was to assess within- and between-home variability in indoor-air insecticides over the final 2 months of pregnancy among a cohort of African-American and Dominican women from New York City.MethodsWomen not employed outside the home were enrolled between February 2001 and May 2004 (n = 102); 9 insecticides and an adjuvant were measured in 48-hr personal air samples and 2-week integrated indoor air samples collected sequentially for 7.0 ± 2.3 weeks (n = 337 air samples).ResultsSixty-one percent of the women reported using pest control during the air samplings. Chlorpyrifos, diazinon, and propoxur were detected in 99–100% of personal and indoor samples (range, 0.4–641 ng/m3). Piperonyl butoxide (a pyrethroid adjuvant) was detected in 45.5–68.5% (0.2–608 ng/m3). There was little within-home variability and no significant difference in air concentrations within homes over time (p ≥ 0.2); between-home variability accounted for 88% of the variance in the indoor air levels of propoxur, 92% in chlorpyrifos, 94% in diazinon, and 62% in piperonyl butoxide (p < 0.001). Indoor and maternal personal air insecticide levels were highly correlated (r = 0.7–0.9, p < 0.001). Diazinon and chlorpyrifos levels declined 5-fold between 2001 and 2004 but were detected in all homes 1.5 and 2.5 years, respectively, after the U.S. Environmental Protection Agency ban on their residential use.ConclusionResults showed that the insecticides were persistent in the home with little variability in air concentrations over the 2 months and contributed to chronic maternal inhalation exposures during pregnancy.
Scavenger receptor a restrains T-cell activation and protects against concanavalin A-induced hepatic injury
Authors: Daming Zuo, Xiaofei Yu, Chunqing Guo, Hongxia Wang, Jie Qian, Huanfa Yi, Xiao Lu, Zhi-Ping Lv, John R. Subjeck, Huiping Zhou, Arun J. Sanyal, Zhengliang Chen, Xiang-Yang Wang
Journal: Hepatology (2012)

Abstract Negative feedback immune mechanisms are essential for maintenance of hepatic homeostasis and prevention of immune-mediated liver injury. We show here that scavenger receptor A (SRA/CD204), a pattern recognition molecule, is highly up-regulated in the livers of patients with autoimmune or viral hepatitis, and of mice during concanavalin A (Con A)-induced hepatitis (CIH). Strikingly, genetic SRA ablation strongly sensitizes mice to Con A-induced liver injury. SRA loss, increased mortality and liver pathology correlate with excessive production of IFN-γ and heightened activation of T cells. Increased liver expression of SRA primarily occurs in mobilized hepatic myeloid cells during CIH, including CD11b + Gr-1 + cells. Mechanistic studies establish that SRA on these cells functions as a negative regulator limiting T-cell activity and cytokine production. SRA-mediated protection from CIH is further validated by adoptive transfer of SRA + hepatic mononuclear cells or administration of a lentivirus-expressing SRA, which effectively ameliorates Con A-induced hepatic injury. Also, CIH and clinical hepatitis are associated with increased levels of soluble SRA. This soluble SRA displays a direct T-cell inhibitory effect and is capable of mitigating Con A-induced liver pathology. Conclusion : Our findings demonstrate an unexpected role of SRA in attenuation of Con A-induced, T-cell-mediated hepatic injury. We propose that SRA serves as an important negative feedback mechanism in liver immune homeostasis, and may be exploited for therapeutic treatment of inflammatory liver diseases. (Hepatology 2013)
Doctors challenge fairness of composition of NHS disciplinary panels
Authors: C. Dyer
Journal: BMJ (2010)

Three hospital doctors who were accused of misconduct by their employing trusts are challenging the composition of NHS disciplinary panels, which they say have too few independent members to guarantee them an impartial hearing.

The decisions in the three cases, which are set to be heard in two separate hearings at the High Court and Court of Appeal, could have important implications for the way NHS employers deal with disciplinary cases against doctors.

The three allege that the panels that hear conduct cases under the Department of Health’s maintaining high professional standards (MHPS) procedure, which are required to …
Point mutations in the N-<i>ras</i> oncogene in malignant melanoma and congenital naevi
Authors: J. CARR, R.M. MACKIE
Journal: British Journal of Dermatology (1994)

Summary DNA from formalin-fixed and paraffin-processed samples from 100 melanocytic lesions (39 malignant melanomas, 18 cases of dysplastic naevi, and 43 congenital naevi) was extracted, and the sequences around codons 12/13 and 61 of the N-ras oncogene were amplified using the polymerase chain reaction. The amplified product was then analysed both by dot-blotting and by direct sequencing for point mutations. By the dot-blotting technique, mutations were seen in 18 of 100 lesions. These were in one of five distant metastases (20%), in one of three nodal metastases (33%), in four of 31 (13%) primary melanomas, in none of 18 dysplastic naevi, and in 12 of 43 (28%) congenital naevi, all at codon 61. On direct sequencing, nine of 18 mutations were confirmed, in two of 31 (6%) primary tumours, one distant metastasis, and six of 43 (14%) congenital naevi. Of the 23 superficial spreading melanomas examined, eight were on sun-exposed skin. A superficial spreading melanoma, in which the N-ras mutation at codon 61 was confirmed, was on non-exposed skin, and an unconfirmed mutation was from an exposed site. One of three nodular melanomas with a confirmed mutation was on a light-exposed site, and the other two nodular melanomas were from non-exposed areas. All four lentigo maligna melanomas were from exposed sites, and one of these had an unconfirmed mutation. The only acral lentiginous melanoma, which had no mutation, was from a sun-exposed area. Ten of the 43 congenital or early onset naevi were on sun-exposed sites; six unconfirmed and five confirmed mutations were from lesions on non-sun-exposed sites (5/33; 15%), and one confirmed mutation was from a lesion on a sun-exposed area (1/10; 10%). Our results do not, therefore, support the hypothesis that N-ras mutations are specifically associated with primary melanomas arising on continually sun-exposed skin. The overall pattern suggests that N-ras mutations in isolation in melanocytic lesions are not frequent. This is the first report of N-ras mutations in congenital/early onset melanocytic naevi, and shows a relatively high incidence in comparison with that observed in melanomas in this study.
Defective Cardiac Ryanodine Receptor Regulation During Atrial Fibrillation
Authors: John A. Vest, Xander H.T. Wehrens, Steven R. Reiken, Stephan E. Lehnart, Dobromir Dobrev, Parag Chandra, Peter Danilo, Ursula Ravens, Michael R. Rosen, Andrew R. Marks
Journal: Circulation (2005)

Background— Ca 2+ leak from the sarcoplasmic reticulum (SR) may play an important role in triggering and/or maintaining atrial arrhythmias, including atrial fibrillation (AF). Protein kinase A (PKA) hyperphosphorylation of the cardiac ryanodine receptor (RyR2) resulting in dissociation of the channel-stabilizing subunit calstabin2 (FK506-binding protein or FKBP12.6) causes SR Ca 2+ leak in failing hearts and can trigger fatal ventricular arrhythmias. Little is known about the role of RyR2 dysfunction in AF, however. Methods and Results— Left and right atrial tissue was obtained from dogs with AF induced by rapid right atrial pacing (n=6 for left atrial, n=4 for right atrial) and sham instrumented controls (n=6 for left atrial, n=4 for right atrial). Right atrial tissue was also collected from humans with AF (n=10) and sinus rhythm (n=10) and normal cardiac function. PKA phosphorylation of immunoprecipitated RyR2 was determined by back-phosphorylation and by immunoblotting with a phosphospecific antibody. The amount of calstabin2 bound to RyR2 was determined by coimmunoprecipitation. RyR2 channel currents were measured in planar lipid bilayers. Atrial tissue from both the AF dogs and humans with chronic AF showed a significant increase in PKA phosphorylation of RyR2, with a corresponding decrease in calstabin2 binding to the channel. Channels isolated from dogs with AF exhibited increased open probability under conditions simulating diastole compared with channels from control hearts, suggesting that these AF channels could predispose to a diastolic SR Ca 2+ leak. Conclusions— SR Ca 2+ leak due to RyR2 PKA hyperphosphorylation may play a role in initiation and/or maintenance of AF.
Poor countries must promote healthy choices to reduce heart disease mortality
Authors: B. Roehr
Journal: BMJ (2010)

Cardiovascular disease is the leading cause of death in the world, and 80% of this mortality occurs in low and middle income countries. But a huge discrepancy exists between the burden of disease and efforts to reduce the number of deaths.

A new report from the US Institute of Medicine aims to address those challenges in feasible and practical ways, said Valentine Fuster, a cardiovascular specialist at Mount Sinai Medical Center, New York, who chaired the committee that wrote the report, released on 22 March.

“It is important to recognise that there is no single strategy that will work everywhere, so it is …
Effect of pinitol treatment on insulin action in subjects with insulin resistance.
Authors: A Davis, M Christiansen, J F Horowitz, S Klein, M K Hellerstein, R E Ostlund
Journal: Diabetes Care (2000)

OBJECTIVE: Endogenous low-molecular-weight glycans containing pinitol (3-O-methyl-D-chiro-inositol) and D-chiro-inositol are thought to mediate certain actions of insulin. We tested the hypothesis that oral administration of soybean-derived pinitol would improve insulin sensitivity in obese subjects (BMI = 36.6 kg/m2) with diet-treated type 2 diabetes or glucose intolerance (HbA1c = 6.8%). RESEARCH DESIGN AND METHODS: There were 22 subjects randomized to receive either pinitol 20 mg x kg(-1) x day(-1) (n = 12) or placebo (n = 10) in a 28-day double-blinded trial. RESULTS: No toxicity due to the pinitol was observed during the study The sensitivity of glucose and lipid metabolism to insulin were assessed by measurement of whole-body glucose, palmitate, and glycerol kinetics during basal conditions and a hyperinsulinemic-euglycemic clamp. Metabolic measurements were made at baseline and again at the end of the study Final plasma levels of pinitol were 48-fold (1.06 +/- 0.15 vs. 0.02 +/- 0.01 micromol/l, P &amp;lt; 0.0001) and D-chiro-inositol levels 14-fold (0.56 +/- 0.08 vs. 0.04 +/- 0.02 micromol/l, P &amp;lt; 0.0001) greater in the pinitol group compared with placebo. CONCLUSIONS: Four weeks of pinitol treatment did not alter baseline glucose production, insulin-mediated glucose disposal, or rates of appearance of free fatty acids and glycerol in plasma. We conclude that plasma levels of both pinitol and D-chiro-inositol are very responsive to pinitol ingestion, but insulin sensitivity does not increase after pinitol treatment in individuals with obesity and mild type 2 diabetes.
THE INFILTRATION METHOD OF ANESTHESIA IN OPHTHALMIC PRACTICE.
Authors: H. V. WÜRDEMANN
Journal: JAMA (1895)

Just six months ago we brought to the notice of the medical profession our<sup>1</sup>conclusions obtained by following out the line of experiments instituted but a few months before by Schleich,<sup>2</sup>of Berlin, relative to the anesthetic properties of water, and its application in surgical practice. The experimental stage has been passed and we are now able to substantiate some of his statements made in our first article which at that time were not yet proved. A brief resumé of Schleich's experiments may be advisable: this investigator was employed in research for the production of a better and less harmful method of local anesthesia than that which has hitherto obtained. He first experimented with hypodermatic injections of cocain and other drugs, finding that a 2 per cent. solution of cocain was the weakest which would produce anesthesia when introduced beneath the skin. A couple of syringefuls of this
Blood tests may predict early primary myelofibrosis in patients presenting with essential thrombocythemia
Authors: Alessandra Carobbio, Guido Finazzi, Juergen Thiele, Hans‐Michael Kvasnicka, Francesco Passamonti, Elisa Rumi, Marco Ruggeri, Francesco Rodeghiero, Maria Luigia Randi, Irene Bertozzi, Alessandro M. Vannucchi, Elisabetta Antonioli, Heinz Gisslinger, Veronika Buxhofer‐Ausch, Naseema Gangat, Alessandro Rambaldi, Ayalew Tefferi, Tiziano Barbui
Journal: American Journal of Hematology (2011)

According to World Health Organization (WHO)-defined criteria, patients presenting clinically as essential thrombocythemia (ET) may show early primary myelofibrosis (PMF) with accompanying thrombocythemia [1]. Previous clinicopathological studies revealed that laboratory parameters like gender-matched hemoglobin (Hb), white blood cell (WBC) count, and particularly lactate dehydrogenase (LDH) values are significantly different in PMF [2]. By strictly applying the WHO criteria, our investigation was aimed to study sensitivity and specificity of these features in an exploratory cohort of 536 patients and to validate the results on an independently recruited series of 321 strictly corresponding patients. The discriminatory power of these parameters (Hb, WBC, and LDH) was tested by plotting their receiver operating characteristic curves. The best performance was found for LDH (areas under the curve, AUC 5 0.7059). WBC and Hb had superimposable curves, with AUC of 0.6279 and 0.6257, respectively. A diagnostic algorithm was generated by applying these parameters in a stepwise fashion. Nearly half of the patients could be correctly allocated to WHO-defined ET or early PMF in both cohorts investigated. It is important to note that this result does not substitute bone marrow morphology with hematological parameters, however, in clinical practice may alert physicians to get more suspicious of early PMF in a patient presumably presenting with ET.
The Impact of T Helper and T Regulatory Cells on the Regulation of Anti-Double-Stranded DNA B Cells
Authors: Su-jean Seo, Michele L Fields, Jodi L Buckler, Amy J Reed, Laura Mandik-Nayak, Simone A Nish, Randolph J Noelle, Laurence A Turka, Fred D Finkelman, Andrew J Caton, Jan Erikson
Journal: Immunity (2002)
Atlas of Pediatric Surgery
Authors: John Raffensperger
Journal: JAMA (1966)

This work will be valuable to all who are learning, teaching, or doing pediatric surgery. Dr. White has described in one volume almost all the operations encountered in this specialty. The format of the book is pleasing. Illustrations are preceded by a brief discussion of the general plan and indications for operation. This atlas will have its most valuable place as a supplement to other currently available texts.  The operations are those which give the best results in the author's hands. These are well standardized and vary only in detail from one pediatric surgeon to another. One valuable feature is the presentation, seriatim, of alternative procedures when they are indicated. The chapter on intestinal atresia describes both the Mikulicz exteriorization, and resection and anastomosis. Another example is the two alternatives for Hirschprungs disease— Swenson's pull-through operation and Duhamel's procedure.  I take serious exception to two aspects of the therapy suggested
The Importance of Defining the Paraneoplastic Neurologic Disorders
Authors: Robert B. Darnell
Journal: New England Journal of Medicine (1999)

The paraneoplastic neurologic disorders are models of the way in which rare diseases can shed light on common clinical problems. Paraneoplastic neurologic disorders, which are neurologic degenerative disorders that occur in patients with neoplasms outside the nervous system, provide compelling examples of antitumor immunity and autoimmune neurologic disorders, and they have been defined through collaboration between clinicians and researchers. The most recent demonstration of such a collaboration is the study by Voltz and colleagues in this issue of the Journal.1 They report that some of the clinically diverse syndromes of limbic and brain-stem encephalitis can now be definitively classified . . .
A CASE OF DOUBLE SPONTANEOUS PNEUMOTHORAX
Authors: M. I. MARSHANK
Journal: JAMA (1918)

Spontaneous or natural pneumothorax is not an infrequent complication in pulmonary tuberculosis. Double spontaneous pneumothorax, however, is exceedingly rare. In a review of the indexed literature I was unable to find a single case report on record. <h3>REPORT OF CASE</h3> I. S., a man, aged 50 (Case 2714), a merchant, admitted, Jan. 2, 1917, presented a negative family history, aside from the fact that the father died of probable pulmonary tuberculosis. The patient had measles during childhood, but had made a good recovery with no complications. No other illness was noted until the onset of pulmonary tuberculosis about 1905. The type of onset was insidious, with anorexia, loss of weight, cough, expectoration, and night sweats. The patient later developed pain in the right axilla, and occasional streaked sputum. The sputum was found positive at that time. Since the onset in 1905, the patient had been subject to frequent colds and
ECHOCARDIOGRAPHIC PREDICTORS OF EARLY VERSUS LATE RIGHT VENTRICULAR FAILURE AMONG PATIENTS SUPPORTED WITH CONTINUOUS-FLOW LEFT VENTRICULAR ASSIST DEVICES
Authors: Rey Percival Vivo, Molham Aldeiri, Andrea Cordero-Reyes, Paulino Alvarez, Matthias Loebe, Brian Bruckner, Guillermo Torre-Amione, Arvind Bhimaraj, Barry Trachtenberg, Jerry Estep
Journal: Journal of the American College of Cardiology (2013)