tbuckley/cabot-search huggingface dataset:
Polyethylenimine-complexed Plasmid Particles Targeting Focal Adhesion Kinase Function as Melanoma Tumor Therapeutics
Authors: Shufeng Li, Wei Dong, Yiwei Zong, Wu Yin, Guanghui Jin, Qingang Hu, Xiaofeng Huang, Wenhui Jiang, Zi-Chun Hua
Journal: Molecular Therapy (2007)

Focal adhesion kinase (FAK) is a non-receptor protein tyrosine kinase implicated in cell cycle progression and cell migration. Overexpression of FAK in a variety of tumors has suggested that FAK is a promising target for therapeutic intervention. In this study, we took advantage of a modified polyethylenimine (M-PEI) with high transfection efficiency for tumor cells and tissues, and targeted FAK function through both in vitro and in vivo approaches. The results demonstrated that both plasmid-encoded FAK small interfering RNA (siRNA) and overexpression of FAK-related non-kinase (FRNK, FAK dominant negative) dramatically inhibited in vitro B16F10 cell proliferation and invasion. We used two transplantable mouse tumor models of primary and metastatic melanoma to evaluate the therapeutic potential of PEI-complexed plasmids targeting FAK function. The results revealed that intratumoral delivery of PEI-complexed plasmids targeting FAK significantly suppressed primary tumor growth as well as metastasis of B16F10 cells into lung and lymph nodes. Both approaches prolonged the survival of the tumor-bearing mice. Taken together, these results indicate that intratumoral delivery of plasmid DNA targeting FAK function, using M-PEI as a gene carrier, represents a promising avenue for melanoma therapy. Focal adhesion kinase (FAK) is a non-receptor protein tyrosine kinase implicated in cell cycle progression and cell migration. Overexpression of FAK in a variety of tumors has suggested that FAK is a promising target for therapeutic intervention. In this study, we took advantage of a modified polyethylenimine (M-PEI) with high transfection efficiency for tumor cells and tissues, and targeted FAK function through both in vitro and in vivo approaches. The results demonstrated that both plasmid-encoded FAK small interfering RNA (siRNA) and overexpression of FAK-related non-kinase (FRNK, FAK dominant negative) dramatically inhibited in vitro B16F10 cell proliferation and invasion. We used two transplantable mouse tumor models of primary and metastatic melanoma to evaluate the therapeutic potential of PEI-complexed plasmids targeting FAK function. The results revealed that intratumoral delivery of PEI-complexed plasmids targeting FAK significantly suppressed primary tumor growth as well as metastasis of B16F10 cells into lung and lymph nodes. Both approaches prolonged the survival of the tumor-bearing mice. Taken together, these results indicate that intratumoral delivery of plasmid DNA targeting FAK function, using M-PEI as a gene carrier, represents a promising avenue for melanoma therapy.
Inflammation, Immunity, and Hypersensitivity
Authors: Frank W. Fitch
Journal: JAMA (1971)

An impressive array of authors have contributed the 11 chapters of this monograph which deals with the acute inflammatory process and with much of what is currently called immunopathology. Originally intended as part of a large treatise on general pathology, the present volume was prepared when plans for the larger text had to be abandoned. The topics covered in this volume have traditionally been considered together, and this relationship is most appropriate since a number of recent observations make it clear that complement components play major pathogenetic roles in a variety of inflammatory processes and that biologically important interrelationships exist between complement, coagulation, and fibrinolytic systems. The long first chapter deals with general aspects of the acute inflammatory reaction; vascular phenomena in inflammation and mechanisms by which inflammatory exudates and infiltrates occur are considered in detail, with emphasis on the chemical mediators of the reactions. Rather basic aspects of immunology
Primary Care-Reply
Authors: Diana Dryer Wright
Journal: JAMA (1977)

In Reply.—  Dr Burdette raises a number of interesting points. Perhaps the' most important issue has to do with how patients are classified. We depend a great deal on the concept of the diagnosis as a means for comparing groups of patients. In primary care we must be constantly aware that the diagnoses made are based on few, if any, reliable criteria. To expect a clear definition of a problem entity in a heterogeneous case mix such as that found in family practice may be overly optimistic. We deliberately chose to include all patients with evidence of an acute illness to avoid this trap of false accuracy. We 1 have used the diagnoses made by the various levels of provider to examine such differences within subgroups. When one controls for diagnosis, there is no substantial difference in outcome according to provider level. Moreover, there is no specific pattern of distribution
S -Adenosylmethionine Regulates Dual-Specificity Mitogen-Activated Protein Kinase Phosphatase Expression in Mouse and Human Hepatocytes
Authors: Maria Lauda Tomasi, Komal Ramani, Fernando Lopitz-Otsoa, Manuel S. Rodríguez, Tony W. H. Li, Kwangsuk Ko, Heping Yang, Fawzia Bardag-Gorce, Ainhoa Iglesias-Ara, Francesco Feo, Maria Rosa Pascale, José M. Mato, Shelly C. Lu
Journal: Hepatology (2010)

Increased mitogen-activated protein kinase (MAPK) activity correlates with a more malignant hepatocellular carcinoma (HCC) phenotype. There is a reciprocal regulation between p44/42 MAPK (extracellular signal-regulated kinase [ERK]1/2) and the dual-specificity MAPK phosphatase MKP-1/DUSP1. ERK phosphorylates DUSP1, facilitating its proteasomal degradation, whereas DUSP1 inhibits ERK activity. Methionine adenosyltransferase 1a ( Mat1a ) knockout (KO) mice express hepatic S -adenosylmethionine (SAM) deficiency and increased ERK activity and develop HCC. The aim of this study was to examine whether DUSP1 expression is regulated by SAM and if so, elucidate the molecular mechanisms. Studies were conducted using Mat1a KO mice livers, cultured mouse and human hepatocytes, and 20S and 26S proteasomes. DUSP1 messenger RNA (mRNA) and protein levels were reduced markedly in livers of Mat1a KO mice and in cultured mouse and human hepatocytes with protein falling to lower levels than mRNA. SAM treatment protected against the fall in DUSP1 mRNA and protein levels in mouse and human hepatocytes. SAM increased DUSP1 transcription, p53 binding to DUSP1 promoter, and stability of its mRNA and protein. Proteasomal chymotrypsin-like and caspase-like activities were increased in Mat1a KO livers and cultured hepatocytes, which was blocked by SAM treatment. SAM inhibited chymotrypsin-like and caspase-like activities by 40% and 70%, respectively, in 20S proteasomes and caused rapid degradation of some of the 26S proteasomal subunits, which was blocked by the proteasome inhibitor MG132. SAM treatment in Mat1a KO mice for 7 days raised SAM, DUSP1, mRNA and protein levels and lowered proteosomal and ERK activities. Conclusion: DUSP1 mRNA and protein levels are lower in Mat1a KO livers and fall rapidly in cultured hepatocytes. SAM treatment increases DUSP1 expression through multiple mechanisms, and this may suppress ERK activity and malignant degeneration. Hepatology 2010
The Activated Partial Thromboplastin Time
Authors: ROBERT B. FRANCIS
Journal: Annals of Internal Medicine (1986)

Letters and Corrections1 October 1986The Activated Partial Thromboplastin TimeROBERT B. FRANCIS JR., M.D.ROBERT B. FRANCIS JR., M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-105-4-626_2 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the editor: The statement by Drs. Suchman and Griner (1) that "normal APTT [activated partial thromboplastin time] and PT [prothrombin time] results essentially rule out a significant coagulation defect" (page 814) is not correct. Both factor XIII deficiency and alpha-2-antiplasmin deficiency produce severe bleeding without causing abnormalities in the PT and APTT. Failure to detect these rare but serious bleeding diatheses may result in ineffective or inappropriate therapy. The use of the platelet count and bleeding time is mentioned only in passing. The importance of these two tests in the evaluation of the patient with bleeding is inestimable and...Reference1. SUCHMANGRINER AP. Diagnostic uses of the activated partial thromboplastin time and prothrombin time. Ann Intern Med. 1986;104:810-6. LinkGoogle Scholar1. GRINERMAYEWSKIMUSHLINGREENLAND PRAP. Selection and interpretation of diagnostic tests and procedures: principles and applications. Ann Intern Med. 1981; 94:553-600. Google Scholar2. SUCHMANGRINER AP. Diagnostic uses of the activated partial thromboplastin time and prothrombin time. Ann Intern Med. 1986; 104:810-6. LinkGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: University of Southern California Los Angeles, CA 90033 PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 October 1986Volume 105, Issue 4Page: 626-627KeywordsHemorrhagePartial thromboplastin timePlateletsProthrombin time Issue Published: 1 October 1986 PDF DownloadLoading ...
Immunogenicity and Safety of a Meningococcal A Conjugate Vaccine in Africans
Authors: Samba O. Sow, Brown J. Okoko, Aldiouma Diallo, Simonetta Viviani, Ray Borrow, George Carlone, Milagritos Tapia, Adebayo K. Akinsola, Pascal Arduin, Helen Findlow, Cheryl Elie, Fadima Cheick Haidara, Richard A. Adegbola, Doudou Diop, Varsha Parulekar, Julie Chaumont, Lionel Martellet, Fatoumata Diallo, Olubukola T. Idoko, Yuxiao Tang, Brian D. Plikaytis, Prasad S. Kulkarni, Elisa Marchetti, F. Marc LaForce, Marie-Pierre Preziosi
Journal: New England Journal of Medicine (2011)

Group A meningococci are the source of major epidemics of meningitis in Africa. An affordable, highly immunogenic meningococcal A conjugate vaccine is needed.We conducted two studies in Africa to evaluate a new MenA conjugate vaccine (PsA-TT). In study A, 601 children, 12 to 23 months of age, were randomly assigned to receive PsA-TT, a quadrivalent polysaccharide reference vaccine (PsACWY), or a control vaccine (Haemophilus influenzae type b conjugate vaccine [Hib-TT]). Ten months later, these children underwent another round of randomization within each group to receive a full dose of PsA-TT, a one-fifth dose of PsACWY, or a full dose of Hib-TT, with 589 of the original participants receiving a booster dose. In study B, 900 subjects between 2 and 29 years of age were randomly assigned to receive PsA-TT or PsACWY. Safety and reactogenicity were evaluated, and immunogenicity was assessed by measuring the activity of group A serum bactericidal antibody (SBA) with rabbit complement and performing an IgG group A-specific enzyme-linked immunosorbent assay.In study A, 96.0% of the subjects in the PsA-TT group and 63.7% of those in the PsACWY group had SBA titers that were at least four times as high as those at baseline; in study B, 78.2% of the subjects in the PsA-TT group and 46.2% of those in the PsACWY group had SBA titers that were at least four times as high as those at baseline. The geometric mean SBA titers in the PsA-TT groups in studies A and B were greater by factors of 16 and 3, respectively, than they were in the PsACWY groups (P<0.001). In study A, the PsA-TT group had higher antibody titers at week 40 than the PsACWY group and had obvious immunologic memory after receiving a polysaccharide booster vaccine. Safety profiles were similar across vaccine groups, although PsA-TT recipients were more likely than PsACWY recipients to have tenderness and induration at the vaccination site. Adverse events were consistent with age-specific morbidity in the study areas; no serious vaccine-related adverse events were reported.The PsA-TT vaccine elicited a stronger response to group A antibody than the PsACWY vaccine. (Funded by the Meningitis Vaccine Project through a grant from the Bill and Melinda Gates Foundation; Controlled-Trials.com numbers, ISRCTN78147026 and ISRCTN87739946.).
US scientists back bill for free access to publicly funded science research
Authors: J. Hopkins
Journal: BMJ (2003)

A star studded group of US doctors and scientists is supporting legislation for publicly funded research to be made available free by “open access” on the internet, an initiative spearheaded by the Public Library of Science, a non-profit organisation (http://www.plos.org/).

Martin Sabo, a Democrat from the US state of Minnesota, has introduced legislation to the House of Representatives to prevent publicly funded researchers gaining copyright protection for their papers. Instead, under the proposed Public Access to Science Act, reports of research largely funded by taxpayers would be in the public domain.

Mr Sabo told the New York …
Atherosclerosis and Mitochondria
Authors: SIGMUND R. GREENBERG
Journal: Annals of Internal Medicine (1970)

Letters and Comments1 November 1970Atherosclerosis and MitochondriaSIGMUND R. GREENBERG, M.D.SIGMUND R. GREENBERG, M.D.Author, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-73-5-861_1 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the editor: Dr. Whereat's article (ANNALS, July 1970 issue) relating atherogenesis to carbon monoxide and "other mitochondrial election transport change inhibitors that contaminate our hazardous environment . . . as pollutants of our air," should serve as fuel for our ecologist friends. Having failed to communicate with his teachers and parents, the activist may now accuse us of attempted murder by strangulation, that is, by preventing normal respiration of their mitochondria.Since I see very few rabbits in my practice, I need more information concerning human arterial lipogenesis in an in vivo milieu—not deprived of growth hormone, epinephrine, thyroid...References1. WHEREATHULLORISHIMO AFM: The role of succinate in the regulation of fatty acid synthesis by heart mitochondria. J Biol Chem 242:4013-4022, 1967 CrossrefMedlineGoogle Scholar2. MARTIUSHESS CB: The mode of action of thyroxine (letter). Arch Biochem 33:486-487, 1951 CrossrefMedlineGoogle Scholar3. PIATNEK-LEUNISSENLEUNISSEN DR: Liver mitochondrial function in acute vs. chronic hyperthyroidism. Endocrinology 84:456-461, 1969 CrossrefMedlineGoogle Scholar4. LIEBER C: Metabolic effects produced by alcohol in the liver and other tissues. Advances Intern Med 18:151-199, 1968 Google Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Abington Hospital Abington, Pa. 19001 PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 November 1970Volume 73, Issue 5Page: 861-862KeywordsAtherosclerosisCarbon monoxideEpinephrineGrowth hormoneHomicideLipogenesisMitochondriaRabbitsRespirationThyroid hormones Issue Published: 1 November 1970 PDF DownloadLoading ...
Prophylactic Mastectomy — The Price of Fear
Authors: Andrea Eisen, Barbara L. Weber
Journal: New England Journal of Medicine (1999)

Recent progress in understanding the genetic basis of susceptibility to breast cancer has simultaneously allowed the identification of women at increased risk and spawned controversy over their care. Like such contentious issues as the utility of genetic testing, the question of prophylactic mastectomy elicits a wide range of opinions. However, the evaluation of divergent views of the efficacy of prophylactic mastectomy has been severely hampered by the almost complete absence of facts.The literature on prophylactic mastectomy is fraught with problems. Most important, there are no prospective, controlled trials of the reduction in the risk of breast cancer associated with . . .
Obesity and Its Management
Authors: Wayne Callaway
Journal: JAMA (1974)

If my library were limited to a single volume on obesity, I would choose this short monograph. Written by a British general practitioner, it reflects the practical problems of understanding and treating one of modern civilization's most pervasive disorders. It espouses no dogma; it entertains no speculations. It is by no means an exhaustive nor definitive text. Rather, it summarizes the author's extensive experience in the day-to-day management of obese patients, and it provides a commendably objective (although occasionally uncritical) review of the relevant clinical literature on this subject. The author appreciates several phenomena that sometimes escape his more academic colleagues: (1) Obesity does not have a single etiology. (2) Familial tendencies exist. (3) Psychological factors often exacerbate, but (in the general practice setting) rarely cause obesity. (4) Obesity is not simply a matter of gluttony—some fat people do, indeed, eat less than their slender but more active neighbors. (5)
Sjögren's Syndrome with Benign Purpura Hyperglobulinemia
Authors: David H. Fogel
Journal: New England Journal of Medicine (1959)

SJöGREN'S syndrome,1 otherwise known as kerato-conjunctivitis sicca, is a relatively rare condition of unknown cause. It comprises dryness of the eyes, nose, mouth and pharynx, enlargement of the lacrimal and parotid glands in some cases and joint changes characteristic of rheumatoid arthritis in approximately 80 per cent of the cases.Benign purpura hyperglobulinemia is a recurrent purpura, chiefly of the lower extremities, which occurs after overexertion, prolonged standing or infection. There are no other signs of a hemorrhagic disorder.Waldenström2 reported the first case of Sjögren's syndrome with benign purpura hyperglobulinemia. The following case is apparently the second reported in . . .
Kashmir crisis is worse than the Asian tsunami, says WHO
Authors: Peter Moszynski
Journal: BMJ (2005)

Acute health risks are adding to the suffering of the survivors of the earthquake in South Asia.

Problems in access have meant that many injured people are untreated and have developed gangrene and other life threatening conditions. The World Health Organization says that 26 hospitals in Pakistan have been destroyed or are too dangerous to keep open and that most clinics in the affected areas are thought to be destroyed or severely damaged.

“The number made homeless, the destruction of roads and infrastructure, and the terrain over which the catastrophe has struck make this a bigger disaster than the tsunami,” reports WHO's regional …
The Blame Game: Injuries, Insurance and Injustice
Authors: Miles J. Gullickson
Journal: JAMA (1987)

The senior author, a distinguished legal educator, has been for decades a preeminent voice among the increasing calls for reform in our fault-based tort and liability insurance system, which compensates accident victims so unpredictably, often unfairly, and sometimes irrationally excessively or not at all. Chapters are appropriately entitled "Unsettling Settlements," "(Mis)trial by Jury," "The Litigation Lottery," "The Injured Citizenry," and "Medical Malpractice's Malpractice," among others. The authors effectively dramatize the urgent need for a change in a system that is inefficient, expensive, and now is perniciously depriving consumers of some essential goods and services. Providers are driven out of operation because of constant threats of litigation that mock efforts at equitable compensation and destroy any expectation of reasonable reward. As examples, we note obstetricians and other specialists at high risk "retiring" to more congenial practices and are appalled that only one unwilling company remains as a source of diphtheria-pertussis-tetanus vaccine.
The adverse effect profile of oral azathioprine in pediatric atopic dermatitis, and recommendations for monitoring
Authors: Nicholas R. Fuggle, Walter Bragoli, Anjali Mahto, Mary Glover, Anna E. Martinez, Veronica A. Kinsler
Journal: Journal of the American Academy of Dermatology (2014)

Azathioprine is efficacious in the treatment of severe childhood atopic dermatitis; however, robust data on adverse effects in this population are lacking.We sought to assess adverse effects of azathioprine treatment in a pediatric atopic dermatitis cohort, and make recommendations for monitoring based on these data.Blood test results for all 82 children prescribed oral azathioprine for atopic dermatitis in our department between 2010 and 2012 were collated prospectively, and clinical notes were reviewed retrospectively.Mean age at commencing azathioprine was 8.3 years (SEM 0.4). Mean maximum doses were 2.4 mg/kg (SEM 0.1) and 1.5 mg/kg (SEM 0.1) for normal and reduced serum thiopurine-S-methyltransferase levels, respectively. Adverse effects on blood indices occurred in 34 of 82 patients (41%), with pronounced effects in 18 of 82 (22%) after a median time of 0.4 years. Two patients stopped therapy as a result of abnormal blood indices. Clinical adverse effects occurred in 16 of 82 (20%), two resulting in cessation of therapy. Incidence of adverse effects was unaffected by age, sex, thiopurine-S-methyltransferase level, and drug dose on multivariate regression.Comparison with other studies is limited by varying definitions of adverse effects.Oral azathioprine was associated with few pronounced adverse effects for the duration of use and dosage in this cohort. Recommendations for monitoring are made.
A case of heterozygous familial hypercholesterolemia associated with hyperthyroidism: Effects of triiodothyronine on low-density lipoprotein receptor and cholesterol synthesis
Authors: Toshihiro Haba, Yasuyuki Sakai, Junji Koizumi, Susumu Miyamoto, Hiroshi Mabuchi, Ryoyu Takeda
Journal: Metabolism (1983)
Serum cytokine profiles in experimental human malaria. Relationship to protection and disease course after challenge.
Authors: R Harpaz, R Edelman, S S Wasserman, M M Levine, J R Davis, M B Sztein
Journal: Journal of Clinical Investigation (1992)

Serum cytokine profiles were evaluated in immunized and nonimmunized human volunteers after challenge with infectious Plasmodium falciparum sporozoites. Three volunteers had been immunized with x-irradiated sporozoites and were fully protected from infection. Four nonimmune volunteers all developed symptomatic infection at which time they were treated. Sera from all volunteers were collected at approximately 20 time points during the 28-d challenge period; levels of IL-1 alpha, IL-1 beta, IL-2, IFN-gamma, tumor necrosis factor-alpha, IL-4, IL-6, granulocyte macrophage-colony-stimulating factor, and soluble CD4, CD8, and IL-2 receptor (sCD4, sCD8, and sIL-2R, respectively) were determined by ELISA. C-reactive protein (CRP) was assayed by radial immunodiffusion. Parasitemic subjects developed increases in CRP and IFN-gamma, with less marked increases in sIL-2R and sCD8; the other cytokines tested did not change. CRP increases were abrupt and occurred at the onset of fever (day 14 after challenge). IFN-gamma increases were also abrupt, preceding those of fever and CRP by one day. Increases in sIL-2R and sCD8 were more gradual. Increases in fever, CRP, IFN-gamma, and sCD8 were concordant in each volunteer. Early IL-6 increases were noted in the protected vaccinees. Thus, after challenge with virulent P. falciparum, unique systemic cytokine profiles were detectable both in immunized, nonparasitemic volunteers and in unvaccinated, parasitemic subjects. The contrasting cytokine profiles in the two groups may relate to mechanisms of protection and immunopathology in experimental human malaria.
The impact of beta‐adrenoreceptor gene polymorphisms on survival in patients with congestive heart failure*
Authors: Pascal de Groote, Nicolas Lamblin, Nicole Helbecque, Frédéric Mouquet, Eugène Mc Fadden, Xavier Hermant, Philippe Amouyel, Jean Dallongeville, Christophe Bauters
Journal: European Journal of Heart Failure (2005)