tbuckley/cabot-search huggingface dataset:
Synthetic Lethal Therapy for KRAS Mutant Non-small-cell Lung Carcinoma with Nanoparticle-mediated CDK4 siRNA Delivery
Authors: Cheng-Qiong Mao, Meng-Hua Xiong, Yang Liu, Song Shen, Xiao-Jiao Du, Xian-Zhu Yang, Shuang Dou, Pei-Zhuo Zhang, Jun Wang
Journal: Molecular Therapy (2014)

The KRAS mutation is present in ∼20% of lung cancers and has not yet been effectively targeted for therapy. This mutation is associated with a poor prognosis in non-small-cell lung carcinomas (NSCLCs) and confers resistance to standard anticancer treatment drugs, including epidermal growth factor receptor tyrosine kinase inhibitors. In this study, we exploited a new therapeutic strategy based on the synthetic lethal interaction between cyclin-dependent kinase 4 (CDK4) downregulation and the KRAS mutation to deliver micellar nanoparticles (MNPs) containing small interfering RNA targeting CDK4 (MNPsiCDK4) for treatment in NSCLCs harboring the oncogenic KRAS mutation. Following MNPsiCDK4 administration, CDK4 expression was decreased, accompanied by inhibited cell proliferation, specifically in KRAS mutant NSCLCs. However, this intervention was harmless to normal KRAS wild-type cells, confirming the proposed mechanism of synthetic lethality. Moreover, systemic delivery of MNPsiCDK4 significantly inhibited tumor growth in an A549 NSCLC xenograft murine model, with depressed expression of CDK4 and mutational KRAS status, suggesting the therapeutic promise of MNPsiCDK4 delivery in KRAS mutant NSCLCs via a synthetic lethal interaction between KRAS and CDK4. The KRAS mutation is present in ∼20% of lung cancers and has not yet been effectively targeted for therapy. This mutation is associated with a poor prognosis in non-small-cell lung carcinomas (NSCLCs) and confers resistance to standard anticancer treatment drugs, including epidermal growth factor receptor tyrosine kinase inhibitors. In this study, we exploited a new therapeutic strategy based on the synthetic lethal interaction between cyclin-dependent kinase 4 (CDK4) downregulation and the KRAS mutation to deliver micellar nanoparticles (MNPs) containing small interfering RNA targeting CDK4 (MNPsiCDK4) for treatment in NSCLCs harboring the oncogenic KRAS mutation. Following MNPsiCDK4 administration, CDK4 expression was decreased, accompanied by inhibited cell proliferation, specifically in KRAS mutant NSCLCs. However, this intervention was harmless to normal KRAS wild-type cells, confirming the proposed mechanism of synthetic lethality. Moreover, systemic delivery of MNPsiCDK4 significantly inhibited tumor growth in an A549 NSCLC xenograft murine model, with depressed expression of CDK4 and mutational KRAS status, suggesting the therapeutic promise of MNPsiCDK4 delivery in KRAS mutant NSCLCs via a synthetic lethal interaction between KRAS and CDK4.
Biochemical aspects of α-l-fucosidase in hepatocellular carcinoma
Authors: Geneviève Leray, Yves Deugnier, Anne-Marie Jouanolle, Dominique Lehry, Jean-François Bretagne, Jean-Plerre Campion, Pierre Brissot, André Le Treut
Journal: Hepatology (1989)

Biochemical characteristics of alpha-L-fucosidase (alpha-L-fucoside hydrolase, EC 3.2.1.51) were studied in tumorous and nontumorous human hepatocellular carcinoma (n = 14). Five parameters were studied: (i) specific activity, (ii) thermostability, (iii) enzyme affinity for an artificial substrate (Km), (iv) isoenzyme patterns of the glycosidase before and after neuraminidase treatment and (v) pH influence on enzyme activity. The specific activity of alpha-L-fucosidase was significantly decreased in tumoral liver when compared to nontumoral liver. The curve of pH activity constantly showed a broad optimum centered near pH 5, whereas two optima were always observed in nontumoral areas. In contrast, there was no modification of the thermostability, the substrate affinity and the isoenzyme patterns of alpha-L-fucosidase in hepatocellular carcinoma.
Distinct roles for hepcidin and interleukin-6 in the recovery from anemia in mice injected with heat-killed Brucella abortus
Authors: Sara Gardenghi, Tom M. Renaud, Alessandra Meloni, Carla Casu, Bart J. Crielaard, Laura M. Bystrom, Noa Greenberg-Kushnir, Barbra J. Sasu, Keegan S. Cooke, Stefano Rivella
Journal: Blood (2013)
Advances in Surgical Treatment of Facial Nerve Paralysis in ChildrenFacial Nerve Paralysis in Children
Authors: Daniel Alam
Journal: JAMA (2011)

Background: Free muscle transfer for facial reanimation has become the standard of care in recent decades and is now the cornerstone intervention for dynamic smile reanimation. We sought to quantify smile excursion and quality-of-life (QOL) changes in our pediatric free gracilis recipients following reanimation.Methods: We quantified gracilis muscle excursion in 17 pediatric patients undergoing 19 consecutive pediatric free gracilis transplantation operations, using our validated SMILE program, as an objective measure of functional outcome. These were compared against excursion measured the same way in a cohort of 17 adults with 19 free gracilis operations. In addition, we prospectively evaluated QOL outcomes in these children using the Facial Clinimetric Evaluation (FaCE) instrument.Results: The mean gracilis excursion in our pediatric free gracilis recipients was 8.8 mm ± 5 mm, which matched adult results, but with fewer complete failures of less than 2-mm excursion, with 2 (11%) and 4 (21%), respectively. Quality-of-life measures indicated statistically significant improvements following dynamic smile reanimation (P = .01).Conclusions: Dynamic facial reanimation using free gracilis transfer in children has an acceptable success rate, yields improved commissure excursion, and improves QOL in the pediatric population. It should be considered first-line therapy for children with lack of a meaningful smile secondary to facial paralysis.
Helping parents identify severe illnesses in their children
Authors: D. Jewell
Journal: BMJ (1999)

General practice p 1740 

The management of sick children is both a microcosm of primary care and a test of its success—if we cannot get this right we cannot justify any claims to excellence. General practitioners see lots of children, and most of them have minor, self-limiting illness. The fourth national morbidity survey reports a consulting rate of 4.97 for children aged 4 and under, a rate exceeded only by those aged 75 and over. When the illnesses are classified as minor, intermediate, or serious the consulting rate for minor illness is the highest of any age group.1 General practitioners have the task of dealing with this high volume of work quickly and efficiently, without overtreating the children or making parents feel they have been the victims of perfunctory or, worse, incompetent care. At the same time, and most important of all, they must be able to identify the small numbers of children with serious illness.

For many general practitioners the amount of time that work with minor illnesses takes up, among adults as well as children, is a …
Adenomas of the Colon: Overexpression of p53 Protein and Risk Factors
Authors: A. H. Speroni, S. I. Vanzulli, R. P. Meiss
Journal: Endoscopy (1998)

Background and Study Aims: p53 gene mutation and the ensuing overexpression of its protein is one of the steps related to colorectal carcinogenesis. This study analyzed the relationships between immunohistochemically detected p53 protein accumulation in colonic adenomas and morphological and clinical indicators of risk of malignant transformation and relapse.
Long-term Prospective Population PK Study in GIST Patients—Response
Authors: Ron H.J. Mathijssen, Peter de Bruijn, Karel Eechoute, Alex Sparreboom
Journal: Clinical Cancer Research (2013)

We thank Chatelut and colleagues for their interest in our prospective population pharmacokinetic analysis of imatinib exposure in patients treated for gastrointestinal stromal tumor (1). In their letter to the editor, these authors suggested an alternative explanation for the approximately 30% decrease in imatinib exposure after a treatment duration of 3 months or longer. They hypothesized that this decrease in imatinib plasma concentrations resulted from a decrease in α1-acid-glycoprotein (AGP) levels with time. Because this theory could be plausible, at least as a factor contributing to the clearance of imatinib, we studied their hypothesis in the patients included in our study.For a subset of patients (n = 22), we prospectively determined plasma AGP concentrations during the first year of imatinib treatment. On the first day of imatinib treatment, and also at months 1, 6, and 12, AGP concentrations were correlated to a WinNonlin-derived area under the curve (AUC) of imatinib, and the sum of imatinib and active metabolite CGP74588, respectively. This metabolite results from a CYP3A-mediated conversion of imatinib (2). Next, we plotted AGP levels against the AUC ratio of active metabolite and parent drug.Interestingly, good correlations were found between AGP and imatinib, and the sum of imatinib and CGP74588, respectively. No correlation was seen for AGP and the AUC ratio. As we show in Fig. 1, a change in AGP resulted in a proportional change in drug AUC in many individual cases, although the magnitude of this change may differ substantially. Moreover, not only decreases in AGP over time were found but also substantial increases. This finding contrasts with the expectations mentioned in the letter. Although the correlation these authors found (Fig. 1) is quite good at first glance (r2 = 0.76; P < 0.001), we may wonder whether this correlation is useful (yet) in daily clinical practice, as a single AGP measurement may not be implemented directly into a dosing algorithm for imatinib. In our opinion, Judson's proposal (3), a scheme to integrate therapeutic drug monitoring in clinical practice, is probably more clinically applicable.Still, the correlation between AGP and imatinib exposure is very interesting, as the mechanisms behind the changes in drug exposure with time are not elucidated yet. As AGP levels did not correlate with the AUC ratio of CGP74588/imatinib, a relationship between AGP and CYP3A metabolism is less likely. Therefore, more research is warranted to discover the mechanisms behind the time dependency of imatinib.See the original Letter to the Editor, p. 949No potential conflicts of interest were disclosed.
MIBG Scintigraphy of a Patient with Pheochromocytoma on Labetalol Therapy
Authors: JACQUES MORAIS, HERV?? Le MAREC, PATRICK PELTIER, ALAIN CHETANNEAU, MIREILLE KREMER, MANUEL BARDIES, JEAN-FRAN??OIS CHATAL
Journal: Clinical Nuclear Medicine (1992)

A patient with pheochromocytoma was studied by MIBG scintigraphy while on labetalol therapy, which has been reported to interfere with imaging. Serial imaging was performed at 2, 18, 25, and 90 hours to obtain time/activity curves. Blood samples were taken at each imaging study to determine activity counts. Tumor activity per gram of tissue (surgery 116 hours after injection) was compared with blood activity. Tumor and blood activity decreased concurrently, whereas the decrease in peritumoral activity was faster, thus providing transiently improved contrast on 18− and 25-hour images. The diagnostic implications of these results are discussed.
Polio—Out of Sight, Out of Mind
Authors: James H. Sammons
Journal: JAMA (1977)

An entire generation of Americans has grown up with only a faint concept of the meaning of the word poliomyelitis. Most physicians who began their medical practice after the mid-1950s have never seen a person with paralytic polio. In the major epidemic years of the 1940s and 1950s, as many as 50,000 or more cases of clinical polio, with many deaths, were reported. An even more grim aftermath was the thousands of children and young adults left (more or less) crippled. At one time, some 2,000 persons were permanent residents of the "iron-lung" respirators as a result of crippling polio. But widespread use of polio vaccines since 1955 has resulted in the virtual elimination of paralytic poliomyelitis in the United States. The number of reported cases of paralytic poliomyelitis declined from more than 18,000 in 1954 to 32 cases in 1970 to only eight cases in 1976. The mass polio
Risk assessment for incident heart failure in individuals with atrial fibrillation
Authors: Renate B. Schnabel, Michiel Rienstra, Lisa M. Sullivan, Jenny X. Sun, Carlee B. Moser, Daniel Levy, Michael J. Pencina, João D. Fontes, Jared W. Magnani, David D. McManus, Steven A. Lubitz, Thomas M. Tadros, Thomas J. Wang, Patrick T. Ellinor, Ramachandran S. Vasan, Emelia J. Benjamin
Journal: European Journal of Heart Failure (2013)
EVALUATION OF FOUR RISK MODELS IN OPERATIVE AND 1 YEAR MORTALITY IN PATIENTS UNDERGOING AORTIC VALVE REPLACEMENT
Authors: Shrinivas Hebsur, Mark E. Willcox, Sari D. Holmes, Alan M. Speir, Anthony J. Rongione, Linda Henry, Sharon L. Hunt, Niv Ad
Journal: Journal of the American College of Cardiology (2011)
Obesity, dexfenfluramine, and pulmonary hypertension. A lesson not learned?
Authors: N F Voelkel, W R Clarke, T Higenbottam
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

"Obesity, dexfenfluramine, and pulmonary hypertension. A lesson not learned?." American journal of respiratory and critical care medicine, 155(3), pp. 786–788
Transfer of granulocyte-macrophage colony-stimulating factor gene to rat lung induces eosinophilia, monocytosis, and fibrotic reactions.
Authors: Z Xing, Y Ohkawara, M Jordana, F Graham, J Gauldie
Journal: Journal of Clinical Investigation (1996)

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic cytokine whose expression is increased in numerous respiratory diseases, particularly in asthma. However, the role of GM-CSF in the pathogenesis of these conditions in vivo remains unclear. Here, we report the functional activities of GM-CSF highly expressed in rat lung after intrapulmonary transfer of the gene coding for murine GM-CSF by using an adenoviral vector. This high, transient expression of GM-CSF led to the sustained but self-limiting accumulation of eosinophils and macrophages associated with tissue injury in the lung followed by varying degrees of irreversible fibrotic reactions observed in later stages. These results suggest that GM-CSF plays a previously unrealized role in the development of respiratory conditions characterized by eosinophilia, granuloma and/or fibrosis and provide the rationale for targeting this molecule in these diseases.
STUDIES IN RODENT POLIOMYELITIS
Authors: Claus W. Jungeblut, Rose R. Feiner, Murray Sanders
Journal: The Journal of Experimental Medicine (1942)

1. Murine SK poliomyelitis virus has been transferred from mouse to guinea pig with the establishment of a fixed strain of cavian passage virus. 2. The disease thus produced in guinea pigs is characterized by the occurrence of flaccid paralysis. Typical poliomyelitic lesions are found in the anterior horn of the spinal cord. 3. Guinea pigs are susceptible to infection with murine virus by the intracerebral, intravenous, intraperitoneal, and subcutaneous route; cavian passage virus produces paralysis only upon intracerebral or intravenous injection. Neither virus paralyzes guinea pigs by feeding or nasal instillation. 4. The potency of the virus (murine or cavian) in guinea pigs is considerably lower than in mice and compares with the titer of the original SK strain in monkeys. In paralyzed guinea pigs the virus is found only in the central nervous system and not in extraneural sites, such as blood or abdominal viscera. 5. Attempts to cultivate cavian passage virus in tissue culture have yielded evidence of some in vitro propagation but no passage virus has as yet been obtained by this method. 6. Cross neutralization tests with cavian passage virus in guinea pigs and with murine virus in mice have established the serological identity of the two viruses. Inactivation of cavian passage virus in guinea pigs by poliomyelitis-convalescent monkey sera is irregular. Complete neutralization has been obtained with a concentrated poliomyelitis horse serum. 7. Resistance to reinfection with potent virus can be demonstrated in convalescent guinea pigs as well as in guinea pigs which have survived a symptomless infection with either murine or cavian virus. This immunity is demonstrable by the power of the serum of such animals to neutralize the virus in vitro and by the ability of nerve tissue to dispose in vivo of the infectious agent. 8. Cavian passage virus has a limited pathogenicity for rhesus monkeys. Of a total of 35 monkeys injected intracerebrally with guinea pig passage virus 26 failed to respond with any manifest symptoms of disease; 8 monkeys showed various signs of definite involvement of the central nervous system consisting of tremor, convulsions, facial palsy, and localized pareses; 1 monkey developed typical flaccid paralysis. 9. Following injection with cavian virus the virus may be recovered from the tissues of normal monkeys but not from the tissues of convalescent monkeys shortly after a paralyzing attack of poliomyelitis due to SK or Aycock virus. 10. Immunization of monkeys with early cavian passage virus by the subcutaneous route has given no clear-cut evidence of protection against intracerebral reinfection with SK poliomyelitis virus. Neither has there been any evidence of effective interference in monkeys injected intravenously with early cavian passage virus and intracerebrally with RMV poliomyelitis virus. 11. The bearing of the experimental data upon the epidemiology of the human disease is discussed.
Early and Midterm Outcomes of Percutaneous Treatment of Symtomatic Stenosis of Lower Extremity and Chronic Limb Ischemia
Authors: Sakir Arslan, Isa Oner Yuksel, Erkan Koklu, Goksel Cagırcı, Selcuk Kucukseymen, Nermin Bayar, Akar Yilmaz, Zehra Erkal, Cem Yunus Bas, Gorkem Kus, Murat Esin
Journal: Journal of the American College of Cardiology (2013)
Transmission of the Severe Acute Respiratory Syndrome on Aircraft
Authors: Sonja J Olsen, Hsiao-Ling Chang, Terence Yung-Yan Cheung, Antony Fai-Yu Tang, Tamara L Fisk, Steven Peng-Lim Ooi, Hung-Wei Kuo, Donald Dah-Shyong Jiang, Kow-Tong Chen, Jim Lando, Kwo-Hsiung Hsu, Tzay-Jinn Chen, Scott F Dowell
Journal: New England Journal of Medicine (2003)

The severe acute respiratory syndrome (SARS) spread rapidly around the world, largely because persons infected with the SARS-associated coronavirus (SARS-CoV) traveled on aircraft to distant cities. Although many infected persons traveled on commercial aircraft, the risk, if any, of in-flight transmission is unknown.We attempted to interview passengers and crew members at least 10 days after they had taken one of three flights that transported a patient or patients with SARS. All index patients met the criteria of the World Health Organization for a probable case of SARS, and index or secondary cases were confirmed to be positive for SARS-CoV on reverse-transcriptase polymerase chain reaction or serologic testing.After one flight carrying a symptomatic person and 119 other persons, laboratory-confirmed SARS developed in 16 persons, 2 others were given diagnoses of probable SARS, and 4 were reported to have SARS but could not be interviewed. Among the 22 persons with illness, the mean time from the flight to the onset of symptoms was four days (range, two to eight), and there were no recognized exposures to patients with SARS before or after the flight. Illness in passengers was related to the physical proximity to the index patient, with illness reported in 8 of the 23 persons who were seated in the three rows in front of the index patient, as compared with 10 of the 88 persons who were seated elsewhere (relative risk, 3.1; 95 percent confidence interval, 1.4 to 6.9). In contrast, another flight carrying four symptomatic persons resulted in transmission to at most one other person, and no illness was documented in passengers on the flight that carried a person who had presymptomatic SARS.Transmission of SARS may occur on an aircraft when infected persons fly during the symptomatic phase of illness. Measures to reduce the risk of transmission are warranted.
The Coracoclavicular Joint and Related Pathological Conditions
Authors: W. H. D. De Haas, M. J. Kingma, F. Drucker
Journal: Annals of the Rheumatic Diseases (1965)

understanding of the congenital and acquired abnormalities described in the present paper.(A) Congenital Abnormalities(1) Coracoid Tubercle.-Innormal circumstances, the coracoclavicular ligaments arise from the elbow and part of the upper surface of the coracoid process and are inserted into the conoid tubercle and trapezoid line on the clavicle.The conoid tubercle, as a rule no more than a small rough surface eleva- tion, occasionally grows out in the direction of the coracoid process, in which case the term "coracoid tubercle", as proposed by Jaluvka (1956), would appear to be more appropriate.This author has shown how the process then "articulates" with the trapezoid ligament (a situation comparable to the articulation of the odontoid process of the axis with the transverse ligament of the atlas).The clavicular portion of the ligaments has atavistically maintained its bony structure, whereas the coracoid part has remained fibrous (Fig. 1).Fig. I.-Coracoid tubercle on clavicle; no reaction on coracoid process.
THE IMPORTANCE OF SYSTEMATIC EXAMINATIONS OF UTERINE SCRAPINGS AND EXCISED PORTIONS OF THE CERVIX.
Authors: PALMER FINDLEY
Journal: JAMA (1897)

This paper has for its object: 1, the emphasis of the importance of systematic examinations of uterine scrapings and excised portions as an aid to diagnosis in gynecology; 2, the presentation of a well known method of making such examinations; 3, the setting forth of its limitations; 4, the relation of the microscopic to the macroscopic appearances; 5, the relation of the microscopic findings to the clinical manifestations. It will be the purpose of the writer to demonstrate that such systematic examinations can be made by all who have a practical knowledge of microscopy; that without such systematic examinations a malignant growth will often escape detection until clinical manifestations point to a growth too far advanced to permit of a radical removal, and that many times such an examination is the only means of making a positive early diagnosis. It is the custom of the writer to preserve for examination
Freeze the Number of Medicare-Subsidized Graduate Medical Education Positions
Authors: Kenneth I. Shine
Journal: JAMA (1995)

The national debate over the nation's physician workforce continues. 1 There is increasing consensus that we are educating too many physicians, and a general agreement exists that this excess is reflected in too many subspecialists. 1,2 Some believe that market forces of supply and demand will ultimately resolve the generalist-subspecialist dilemma. Indeed, salaries for generalists are rising, income for subspecialists is falling, and managed care organizations are increasingly requiring subspecialists to serve as primary care providers or laying them off. Medical students seem to be responding to the marketplace by indicating an increasing interest in generalist careers. Within the relatively short period of time between 1992 and 1994, graduating seniors have increased their interest in generalism from 14% to 23% (unpublished data, Association of American Medical Colleges, 1995). Those who favor regulation argue that the market moves too slowly and that the patient care needs of academic health centers continue
A phase 1 trial of the anti-inhibitory KIR mAb IPH2101 for AML in complete remission
Authors: Norbert Vey, Jean-Henri Bourhis, Nicolas Boissel, Dominique Bordessoule, Thomas Prebet, Aude Charbonnier, Anne Etienne, Pascale Andre, François Romagne, Don Benson, Herve Dombret, Daniel Olive
Journal: Blood (2012)