tbuckley/cabot-search huggingface dataset:
The preclinical pharmacology of WP1066, a potent small molecule inhibitor of the JAK2/STAT3 pathway
Authors: Timothy Madden, Reza Kazerooni, Jeffrey Myer, Kirk Culotta, Nicholas Donato, Mary J. Johansen, Yasuko Kondo, David Mack, Waldemar Priebe
Journal: Cancer Research (2006)

4853  The Stat3 pathway, constitutively activated in many cancers, is associated with the regulation of many survival proteins including survivin, Mcl-1, and the Bcl family. Inhibition of Stat3 signaling leads to an inhibition of cancer cell growth and to the induction of apoptosis. A number of attempts have been made to abrogate Stat3 activity, including the use of ligands to inhibit upstream signaling events or silencing Stat3 with oligonucleotides, none of which have been successful in vivo. We report here on the first potent small molecule inhibitor of Stat3 with demonstrated in vivo activity. Studies of WP1066 in our laboratories demonstrated proapoptotic and antiproliferative activity at concentrations of 3-5 μM, in vitro, in a variety of tumor cell types. In order to determine the utility of this compound in vivo we examined the tissue stability, pharmacokinetics, drug distribution, and bioavailability in CD1 mice. Briefly, animals (10 per timepoint) were administered WP1066 (10 and 40 mg/kg) as an IV bolus and sacrificed at various out to 24 hours post-dose. Tissues were harvested and following extraction analyzed for WP1066 content using tandem LC/MS. In vitro studies were also conducted to determine the overall stability of this molecule in rodent plasma. For oral bioavailability studies animals were dosed by gavage with 40 mg/kg and samples obtained over the same 24 hour period. The mean achieved peak plasma concentrations following 10 and 40 mg/kg IV doses were 1.05 and 4.31 μM respectively. Mean drug half life was 4.5 hours and terminal concentrations measured at 12 and 18 hours were 0.03 and 0.13 μM, at the low and high doses, respectively. Tissue stability studies demonstrated an in vitro plasma half-life of 2.6 hrs. Preliminary oral bioavailability studies yielded mean peak plasma concentrations of > 1 μM and an estimated bioavailability of 0.2. Studies of U87 tumor bearing mice given drug by IV bolus demonstrated an accumulation of WP1066 in tumor tissue many fold greater than the simultaneously measured plasma concentration. These studies coupled with our in vivo efficacy studies indicate that WP1066 is the first small molecule inhibitor of Stat3 capable of achieving and maintaining tissue concentrations associated with drug activity in vivo.
National Library of Medicine to Help Consumers Use Online Health Data
Authors: J Stephenson
Journal: JAMA (2000)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
760. Dual Therapeutic Utility of Proteasome Modulating Agents for Pharmico-Gene Therapy of the Cystic Fibrosis Airway
Authors: Young-Kook Choi, Barry J. Byrne, Sihong Song
Journal: Molecular Therapy (2004)

Top of pageAbstract
It has been observed that DNA-dependent protein kinase (DNA-PK) inhibits adeno-associated virus (AAV) DNA integration in vitro and in vivo (Song et al PNAS 2004). In order to test the effect of DNA-PK on AAV replication, we have infect MO59J (DNA-PK negative) and MO59K (DNA-PK positive) cells with a recombinant virus (UF5) in the presence or absence of a helper virus (carrying AAV rep and cap genes). Hirt DNA were isolated 2 days after infection, and subjected to southern blot analysis. Data showed that the abundance of replicated monomer of the vector DNA was lower in MO59K cells than in MO59J suggesting DNA-PK may inhibit AAV replication. To avoid the effect from the difference other than DNA-PK between the two cell lines, we have employed the small interfering RNA (siRNA) technology to decrease DNA-PK expression in MO59K cells. Synthetic siRNAs for human DNA-PKcs were transfected into MO59K cells. Total RNA were extracted at 2 or 4 days after transfection. RT-PCR analysis showed that DNA-PKcs mRNA was nearly undetectable after 25, and 35 cycles. These results indicate that siRNAs can efficiently target DNA-PKcs, thus provide a powerful tool for creating cell or animal models to study the cellular effects on AAV replication and integration.
Proton pump inhibitors may mask early gastric cancer
Authors: S M Griffin, S A Raimes
Journal: BMJ (1998)

Gastric cancer is still widely regarded as an incurable condition in the West. However, this nihilistic approach is no longer tenable as this cancer is eminently curable if it is diagnosed and treated at an early stage.1 The five year survival of patients undergoing appropriate surgery for early gastric cancer is greater than 90%. Screening of the asymptomatic population, such as occurs in Japan, would not be feasible or cost effective in Western countries, so early diagnosis has to rely on symptomatic patients presenting to their general practitioners, who then recognise the importance of the symptoms and refer them for endoscopy. Since the early symptoms are often indistinguishable from those of benign ulcer disease, the inappropriate use of powerful antiulcer drugs has had the effect of masking the true diagnosis in some cases.

A significant proportion of patients with early gastric cancer do experience symptoms and in most these are typical dyspeptic symptoms.2 For this reason …
Telephone Psychotherapy and Care Management for Depression
Authors: Tawee Tanvetyanon
Journal: JAMA (2004)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Stimulation of DNA Synthesis by Human Placental Lactogen or Insulin in Organ Cultures of Benign Human Breast Tumors
Authors: Welsch Cw, McManus Mj
Journal: Cancer Research (1977)

Twenty biopsy specimens of benign human breast tumors obtained from 20 patients were processed into small slices and individually cultured for 2 days in Medium 199. The medium was supplemented with bovine insulin (5.0 microgram/ml), human placental lactogen (HPL) (10.0 microgram/ml), or ovine prolactin (10.0 microgram/ml). Four hr prior to termination, [3H]thymidine was added to the culture medium to determine DNA synthesis. The addition of insulin to the culture medium consistently increased: (a) the mean incorporation of [3H]thymidine into chemically extracted DNA (p less than 0.05); (b) the mean number of [3H]thymidine-radiolabeled epithelial cells (p less than 0.05), and (c) the mean number of epithelial cells bearing mitotic figures. The addition of HPL increased the mean number of [3H]thymidine-radiolabeled epithelial cells (p less than 0.05) and the mean number of epithelial cells bearing mitotic figures (p less than 0.05). [3H]Thymidine incorporation into chemically extracted DNA was also increased when HPL was added to the medium, although this increase did not quite achieve the 5% level of significance. The addition of ovine prolactin to the culture medium did not have any significant effect on DNA synthesis. This study provides evidence that insulin and HPL are direct stimulants of DNA synthesis of the epithelium contained in benign human breast tumors.
Switching to adalimumab in patients with moderate to severe psoriasis who have failed on etanercept: a retrospective case cohort study
Authors: R.T. Woolf, C.H. Smith, K. Robertson, J.N.W.N. Barker
Journal: British Journal of Dermatology (2010)

Conflicts of interest: C.H.S., invited speaker and grant/research support Abbott, Janssen‐Cilag, Schering‐Plough, Serono, Wyeth; J.N.W.N.B., advisory boards for Abbott, Janssen‐Cilag, Novartis, Schering‐Plough, Wyeth; grant/research support Abbott, Janssen‐Cilag, Schering‐Plough, Serono, Wyeth. Madam, Tumour necrosis factor (TNF) antagonists are effective in chronic plaque psoriasis; however, some patients do not respond and a significant number lose their initial response with time.1, 2 Etanercept (a soluble TNF receptor) was the first TNF antagonist recommended by the National Institute for Health and Clinical Excellence (NICE) for use in the U.K. for severe chronic plaque psoriasis resistant to standard systemic therapy.3 However, few outcome data exist for TNF antagonists (specifically the anti‐TNF monoclonal antibody adalimumab) in patients with recalcitrant psoriasis who have failed on etanercept therapy. We report the results of a single‐centre, retrospective, open‐label study that aimed to assess the efficacy of adalimumab in patients with chronic plaque psoriasis who had previously failed on etanercept therapy.
Towards a European registry of severe allergic reactions: current status of national registries and future needs
Authors: M. Worm, F. Timmermans, A. Moneret‐Vautrin, A. Muraro, I. I. Malmheden Yman, M. Lövik, S. Hattersley, R. Crevel
Journal: Allergy (2010)

The incidence of severe allergic reactions is largely unknown and information about triggering allergens, aggravating factors, demography of patients and medical care is lacking. A European wide registry could provide a powerful tool to improve the management of severe allergic reactions from both a medical and a public health perspective. Analysis of existing registries regarding the type and quality of data being collected was used to develop a plan for a pan-European registry, including the type of system to be used and the range of data to be entered. Surveillance will provide evidence for the efficacy of risk management measures and may identify the emergence of new allergenic foods, and aid monitoring of novel foods, ingredients and technologies. Patients need a clear indication of factors that may increase their risk of having an adverse reaction, which such a registry can help compile. Based on the collected data, food businesses will be able to develop educational programmes for allergen risk assessment and allergen risk communication. Finally, and most importantly preventive measures can be developed and government agencies receive population based data which may be relevant for legislative purposes.
FDA Speeds Smoking Cessation Drug Review
Authors: Bridget M Kuehn
Journal: JAMA (2006)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Analysis of candidate genes of phenotypic expression in idiopathic pulmonary fibrosis
Authors: Patrícia Caetano Mota, António Carlos Ferreira, Carlos Daniel Vasconcelos, Miguel Luz Soares, Natália Melo, José Miguel Pereira, Conceição Souto Moura, António Morais, José Agostinho Marques
Journal: European Respiratory Journal (2014)

Introduction:  The pathogenesis of idiopathic pulmonary fibrosis (IPF) is probably based on the interaction between environmental and genetic factors. The identification of the latter is crucial for early diagnosis, accurate prognosis and the development of new therapeutic approaches.   Aim:  To identify genetic variants of phenotypic expression in IPF in the portuguese population.   Methods:  30 IPF patients (diagnosis based on ATS/ERS/JRS/ALAT statement) and 36 controls were included. Allele and genotype distributions of 8 single nucleotide polymorphisms (SNPs) of 5 candidate genes were analyzed: PLAU (Urokinase-type plasminogen activator), BMPR1A (Bone morphogenetic protein receptor type-1A), SERPINB1 (Leukocyte elastase inhibitor), SFTPA1 (Surfactant protein A1) and MUC5B (Mucin 5B).   Results:  There were no associations between the analyzed variants of PLAU, BMPR1A, SERPINB1 and SFTPA1 genes and IPF. Analysis of the rs35705950 polymorphism in the promoter region of the MUC5B gene revealed a strong association of the variant allele (T) with IPF. Allele frequencies were 46% among IPF patients and 17% in controls (allelic association with IPF, P=1.5x10 -5 ). The odds ratio for disease among individuals who are heterozygous and those homozygous for the variant allele of this SNP is 5.7 (95%confidence interval [CI], 1.8 to 18.1) and 17.9 (95%CI, 1.8 to 179.1), respectively.   Conclusions:  The rs35705950 polymorphism is associated with IPF in this sample of the portuguese population. This pilot study confirms the association described in U.S. patients with IPF and indicates that the variant allele represents a susceptibility factor that acts in conjunction with environmental and/or physiological factors.
Abstract 1962: Macrophages mediate gemcitabine resistance of pancreatic adenocarcinoma by up-regulating cytidine deaminase
Authors: Moran Amit, Noam Weizman1, Yoav Binenbaum, Ayelet Shabtay-Orbach, Richard J. Wong, Ziv Gil
Journal: Cancer Research (2014)

Abstract Resistance to pharmacologic agents used in chemotherapy is common in most human carcinomas, including pancreatic ductal adenocarcinoma (PDA), which is resistant to almost all drugs, including gemcitabine, a nucleoside analog used as first-line treatment. Poor survival rates of PDA patients have, therefore, not changed much over 4 decades. Recent data indicated that tumor-associated macrophages (TAMs), which are abundant in the microenvironment of several tumors, including PDA, secrete pro-tumorigenic factors which contribute to cancer progression and dissemination. In this study, we show for the first time that TAMs can also induce chemoresistance of PDA by reducing gemcitabine-induced apoptosis. Macrophages co-cultured with cancer cells or TAMs conditioned medium significantly reduced apoptosis and activation of the caspase-3 pathway during gemcitabine treatment. In vivo PDA models of mice, which have reduced macrophage recruitment and activation, demonstrated improved response to gemcitabine compared to controls. Similarly, inhibition of monocytes/macrophages trafficking by a CSF1-receptor antagonist GW2580 augmented the effect of gemcitabine in a transgenic mouse PDA model that was resistant to gemcitabine alone. Analysis of multiple proteins involved in gemcitabine delivery and metabolism revealed that TAMs induced upregulation of cytidine deaminase (CDA), the enzyme that metabolizes the drug following its transport into the cell. Decreasing CDA expression by PDA cells blocked the protective effect of TAMs against gemcitabine. These results provide the first evidence of a paracrine effect of TAMs, which mediates acquired resistance of cancer cells to chemotherapy. Modulation of macrophage trafficking or inhibition of CDA may offer a new strategy for augmenting the response of PDA to chemotherapy. Citation Format: Moran Amit, Noam Weizman1, Yoav Binenbaum, Ayelet Shabtay-Orbach, Richard J. Wong, Ziv Gil. Macrophages mediate gemcitabine resistance of pancreatic adenocarcinoma by up-regulating cytidine deaminase. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1962. doi:10.1158/1538-7445.AM2014-1962
Brain Sabotages Sobriety, Right on Cue
Authors: Brian Vastag
Journal: JAMA (2004)

NEW HAVEN, CONN—Ivan Petrovich Pavlov never had it so good. He may have won the 1904 Nobel Prize in Physiology or Medicine—but only after collecting buckets of bodily fluids from his famously hungry dogs. A century later, his scientific progeny measure anticipation with brain scans, not drool pans. The feisty physiologist would likely be pleased. Researchers peeking into the brain with sophisticated imaging are beginning to map the neurobiology of craving. While discovering why alcohol and other drug habits can be so hard to kick, they are also documenting the brain damage caused by alcoholism. “Clearly, chronic alcohol use changes the brain,” said Raymond Anton, MD, Medical University of South Carolina, Charleston, speaking at a recent meeting on neuroimaging of alcohol disorders held at Yale University School of Medicine in New Haven, Conn. Many of these changes sensitize individuals with addiction to specific cues—the sights, sounds, smells of their drink of choice. Even if they don’t drool, the brain betrays them. It appears that deeply entrenched neural patterns light up the brain’s memory, pleasure, and reward circuits moments before a sober alcoholic recognizes the familiar urge. One key question is how, exactly, these preconscious moments undermine sobriety. “In recovery, can this response predict who will relapse?” asked Daniel Mathalon, MD, PhD, an imaging researcher at Yale. “That’s a question we’re now equipped to try to answer,” he said.
Microcirculation patterns other than loops and networks in choroidal and ciliary body melanomas11None of the investigators has any proprietary interest that could cause or be perceived to be a conflict of interest.
Authors: Robert Folberg, Xue Chen, H.Culver Boldt, Jacob Pe’er, C.Kice Brown, Robert F Woolson, Andrew J Maniotis
Journal: Ophthalmology (2001)
The functions and regulation of the arousal of anger
Authors: Raymond W. Novaco
Journal: American Journal of Psychiatry (1976)

Anger is paradoxically one of the most talked about but least studied of human emotions. The author presents a model of anger arousal that emphasizes the adaptive as well as the maladaptive roles of anger in terms of the diverse functions anger serves in affecting behavior. In light of the fact that competence in anger management involves dealing with stress situations that require patience, composure, and constructive thought for their resolution, he discusses cognitive self-control processes affecting the regulation of anger.
FRIEDREICH'S ATAXIA
Authors: A. C. Woofter, B. S. Parks
Journal: Annals of Internal Medicine (1942)

Case Reports1 October 1942FRIEDREICH'S ATAXIAA. C. WOOFTER, M.D., F.A.C.P., B. S. PARKS, M.D.A. C. WOOFTER, M.D., F.A.C.P.Search for more papers by this author, B. S. PARKS, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-17-4-744 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptIn 1861 Nicolaus Friedreich first described a primary hereditary spinal cord disease which caused progressive ataxia of first the legs and then the arms, but without paralysis of the sphincters or disturbance of the senses. He correctly assigned the major pathologic lesions to the region of the posterior and lateral columns, designating it a chronic degenerative atrophy, but thought it closely related to tabes dorsalis, a belief which was later disproved. Following this several similar cases were reported and later many variations from the usual type were described, such as those in which cerebellar involvement predominated, a form now classed...Refererences1. BOYD W: Pathology of internal diseases, 1931, Lea and Febiger, Philadelphia. CrossrefGoogle Scholar2. CECIL RL: A textbook of medicine, 1939, W. B. Saunders Co., Philadelphia. Google Scholar3. STENGEL A: A textbook of pathology, 1912, W. B. Saunders Co., Philadelphia. Google Scholar4. WECHSLER IS: Textbook of clinical neurology, 1939, W. B. Saunders Co., Philadelphia. Google Scholar5. OSLER W: Principles and practice of medicine, 1938, D. Appleton-Century Co., New York. Google Scholar6. MORSE JL: Clinical pediatrics, 1926, W. B. Saunders Co., Philadelphia. Google Scholar7. BLUMER G: Bedside diagnosis, 1928, W. B. Saunders Co., Philadelphia. Google Scholar8. STRÜMPELSEYFARTHMARSHALLOTTLEY : A practice of medicine, 1931, F. A. Davis Co., Philadelphia. Google Scholar9. STARR MA: Organic and functional nervous diseases, 1913, Lea and Febiger, Philadelphia. Google Scholar10. ABT IA: Pediatrics, 1925, W. B. Saunders Co., Philadelphia. Google Scholar11. ALBUTT TC: System of medicine, vol. vii, 1931, Macmillan Co., New York. Google Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Parkersburg, West Virginia*Received for publication October 23, 1937.†Deceased. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 October 1942Volume 17, Issue 4Page: 744-750KeywordsAtaxiaAtrophyGenetic diseasesLesionsParalysisProgressive diseasesSpinal cord Issue Published: 1 October 1942 PDF DownloadLoading ...
Polymorphisms affecting vitamin D–binding protein modify the relationship between serum vitamin D (25[OH]D3) and food allergy
Authors: Jennifer J Koplin, Noor H A Suaini, Peter Vuillermin, Justine A Ellis, Mary Panjari, Anne-Louise Ponsonby, Rachel L Peters, Melanie C Matheson, David Martino, Thanh Dang, Nicholas J Osborne, Pamela Martin, Adrian Lowe, Lyle C Gurrin, Mimi L K Tang, Melissa Wake, Terry Dwyer, John Hopper, Shyamali C Dharmage, Katrina J Allen
Journal: Journal of Allergy and Clinical Immunology (2015)