tbuckley/cabot-search huggingface dataset:
Abstract 1340: A mouse model of metastatic intestinal cancers associated with Fbw7- and p53-loss
Authors: Jonathan E. Grim, Sue Knoblaugh, Amanda Hagar, Jessica Hespelt, Jherek Swanger, Katherine Guthrie, Thomas Small, William M. Grady, Keiichi Nakayama, Bruce E. Clurman
Journal: Cancer Research (2012)

Abstract Colon cancer is a leading cause of cancer deaths in the USA, where it accounts for up to 50,000 deaths per year. Mouse models that recapitulate the genetic changes seen in human colon cancers are useful tools for biological and preclinical applications, but most available models develop adenomatous lesions that rarely metastasize. The Fbw7 tumor suppressor is a core component of a ubiquitin ligase complex that negatively regulates a number of proteins associated with genomic instability and cancer, including cyclin E, c-myc, Mcl-1, and Notch. Our previous work shows that Fbw7 cooperates with the p53 tumor suppressor to control genetic instability in vitro, and both Fbw7 and p53 are frequently deregulated in human colon cancers. We hypothesized that coordinate deletion of these two tumor suppressors would promote intestinal cancers in mice. To accomplish intestine specific deletion of these pathways, we interbred genetically engineered mice encoding conditional Fbw7 and p53 alleles with the VillinCre strain. Examination of normal intestines from the resulting Fbw7(fl/fl); p53(fl/fl); villinCre (FPV) animals showed abnormal proliferation and differentiation along the crypt-villus axis compared to control animals. Strikingly, the majority (55%) of FPV mice developed adenocarcinomas in the small intestine and cecum (median survival 70 weeks of age), and these tumors frequently metastasized to the lymph nodes and liver (in 36% and 14% of tumor bearing animals, respectively). Analysis of cancer tissues showed clear evidence of genetic instability in the majority of tumors. Finally, FPV tumors were readily grown as cell lines in vitro which could, in turn, grow as allografts in both immunodeficient and immunocompetent recipients. Notably, comparison of primary tumors and allografted cell lines showed similar pathological features and patterns of metastasis. This work confirms the critical role of the Fbw7 and p53 pathways in suppressing genetic instability and cancer development. Furthermore, the described FPV models recapitulate critical features of human colon cancer and should prove useful for studies of cancer biology, prevention, and therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1340. doi:1538-7445.AM2012-1340
Transmission of Hepatitis C Virus from Mothers to Infants
Authors: Hitoshi Ohto, Sousuke Terazawa, Nobuhiko Sasaki, Nobutaka Sasaki, Kunihiko Hino, Chieko Ishiwata, Makoto Kako, Niro Ujiie, Chikara Endo, Akira Matsui, Hiroaki Okamoto, Shunji Mishiro
Journal: New England Journal of Medicine (1994)

Although there are case reports of vertical transmission of hepatitis C virus (HCV), it remains uncertain to what extent infected mothers transmit this virus to their infants.We investigated the transmission of HCV from infected mothers to their babies by analyzing HCV RNA in the blood. Three independent studies were performed. First, 7698 parturient women were tested for anti-HCV antibodies; 53 were positive. Their 54 infants (including one set of twins) were followed prospectively for at least six months and tested for HCV disease were prospectively studied. Third, the families of three HCV-infected infants were examined retrospectively.Of the 53 antibody-positive mothers, 31 were also positive for serum HCV RNA: Three of the 54 babies born to these mothers (5.6 percent) became positive for HCV RNA during the follow-up period. None of the babies of the 22 women who were antibody-positive but HCV RNA-negative became positive for HCV RNA: In the second study, HCV RNA was detected in one of the six infants of infected mothers. In the third study, HCV RNA was detected in the mothers of the three HCV-infected infants. In each of the seven infected infants we studied, the genomic sequence of HCV was almost identical to that from the mother. These seven mothers had significantly higher titers of HCV RNA than did the mothers of infants with no evidence of infection (mean [+/- SD], 10(6.4 +/- 0.5) vs. 10(4.4 +/- 1.5) per milliliter; P < 0.001).HCV is vertically transmitted from mother to infant, and the risk of transmission is correlated with the titer of HCV RNA in the mother.
Abstract 4573: STINGVAX - A novel tumor vaccine with cyclic dinucleotides - can induce potent anti-tumor responses <i>in vivo</i>.
Authors: Thomas W. Dubensky, Meredith L. Leong, David B. Kanne, Edward E. Lemmens, Ken Metchette, Weiqun Liu, Marcella Fasso, Juan Fu, Joshua J. Woodward, Drew Pardoll, Daniel A. Portnoy, Young J. Kim
Journal: Cancer Research (2013)

Abstract Cyclic dinucleotides (CDN) are ubiquitous bacterial intracellular messengers, and they have recently been shown to also function as a pathogen associated molecular pattern (PAMP) molecules that are sensed by eukaryotic host Stimulator of Interferon Genes (STING) that can activate the TBK-1/IRF-3 signaling pathway to induce type I interferon and other co-regulated genes. CDN was found to induce STING dependent augmentation of T-cell priming in multiple vaccination models, potentially by activating dendritic cells. We formulated CDN with a GM-CSF secreting tumor cell vaccine (STINGVAX) to mobilize and as well as activate dendritic cells both in vitro and in vivo. STINGVAX was tested in a stringent B16 melanoma treatment model, and we demonstrated significant reduction of tumor growth rate in vivo. STINGVAX's anti-tumor response was correlated with increased tumor infiltrating CD8 T-cells as well as increased number of p15E tumor-specific cytotoxic T-cells. STINGVAX's in vivo anti-tumor response was T-cell dependent as well as STING dependent. When we combined STINGVAX with multiple TLR 4/7/8 agonists signaling through the MyD88/TRIF pathway that is distinct from CDN/STING/TBK-1 signaling treatment of palpable B16 tumor resulted in regression of 30-60% of these non-immunogenic tumors. When the STINGVAX treated tumor microenvironment was examined, both IFNγ+CD8+ and PD-L1 was upregulated, potentially demonstrating an adaptive immune resistance mechanism which would render STINGVAX an excellent candidate to be combined with anti-PD-1 blockade. Cumulatively, STINGVAX is a novel tumor vaccine with a high potential for translation in clinical oncology. Citation Format: Thomas W. Dubensky, Meredith L. Leong, David B. Kanne, Edward E. Lemmens, Ken Metchette, Weiqun Liu, Marcella Fasso, Juan Fu, Joshua J. Woodward, Drew Pardoll, Daniel A. Portnoy, Young J. Kim. STINGVAX - A novel tumor vaccine with cyclic dinucleotides - can induce potent anti-tumor responses in vivo. [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 4573. doi:10.1158/1538-7445.AM2013-4573
Cullen’s and Grey Turner’s Signs in Acute Pancreatitis
Authors: Xavier Valette, Damien du Cheyron
Journal: New England Journal of Medicine (2015)

A 63-year-old man with no history of alcohol abuse presented with sudden, severe epigastric pain. The serum lipase level was elevated, a finding consistent with acute pancreatitis. Despite supportive care with fluid hydration, pain medication, and bowel rest, the patient's condition deteriorated.
Triamcinolone in Dermatologic Conditions
Authors: Edmund F. Finnerty
Journal: New England Journal of Medicine (1960)

SYSTEMIC corticosteroid therapy has, since ACTH and cortisone were first used therapeutically, proved its value in the treatment of many dermatologic conditions. Although its application has been limited by development of the side effects often associated with steroid therapy, the use of steroids has been considered mandatory in such conditions as acute disseminated lupus erythematosus, exfoliative dermatitis and bullous eruptions of the skin, including pemphigus, in which they have often been life saving.1 2 3 4 It is in these conditions, however, largely as a result of the use of large doses over long periods, that the adverse side effects accompanying steroid therapy . . .
O134 IDENTIFYING APPROACHES TO INTERVENTION IN PRIMARY SCLEROSING CHOLANGITIS (PSC): EFFECTOR FUNCTIONS OF CD28 NEGATIVE T CELLS AND THEIR MODULATION BY VITAMIN D
Authors: E. Liaskou, L.E. Jeffery, S. Suresh, P. Trivedi, G. Reynolds, T. Bruns, D.H. Adams, D.M. Sansom, G.M. Hirschfield
Journal: Journal of Hepatology (2014)
Stat Bite Predictive Value of Prostate Cancer Tests
Authors: M. K. Brawer
Journal: JNCI Journal of the National Cancer Institute (1993)

Journal Article Stat Bite Predictive Value of Prostate Cancer Tests Get access Michael K. Brawer, M.D. Michael K. Brawer, M.D. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 85, Issue 9, 5 May 1993, Page 695, https://doi.org/10.1093/jnci/85.9.695 Published: 05 May 1993
A new effect of IL-4 on human γδ T cells: promoting regulatory Vδ1 T cells via IL-10 production and inhibiting function of Vδ2 T cells
Authors: Yujia Mao, Shanshan Yin, Jianmin Zhang, Yu Hu, Bo Huang, Lianxian Cui, Ning Kang, Wei He
Journal: Cellular and Molecular Immunology (2015)
Abstract 2089: MiR-205 role in triple negative breast cancer
Authors: Marilena V. Iorio, Claudia Piovan, Gianpiero Di Leva, Patrizia Casalini, Monica Tortoreto, Ilaria Plantamura, Cristian Taccioli, Carlo M. Croce, Elda Tagliabue
Journal: Cancer Research (2010)

Abstract An increasing number of experimental evidences show that microRNAs can have a causal role in breast cancer tumorigenesis as a novel class of oncogenes or tumor suppressor genes, depending on the targets they regulate. miR-205, down-modulated in breast cancer versus normal breast tissue, was originally associated to absence of vascular invasion and shown to be involved in the EMT. Moreover, we recently demonstrated that miR-205 directly targets HER3 receptor and impairs the Akt-mediated survival pathway, thus inhibiting clonogenic potential of SKBr3 cells and increasing the responsiveness to tyrosin-kinase inhibitors. Considering the striking evidences of a major role of miR-205 as oncosuppressor in breast cancer, we decided to investigate its possible involvement in another tumor subgroup, extremely aggressive and still lacking a specific therapy: triple negative breast tumors. Here we show that re-introduction of miR-205 in the triple negative breast cancer cell line MDA-MB-231 led to a dramatic reduction of both proliferation and clonogenic potential as well as migration capability. Notably, miR-205 also significantly inhibited the in vivo growth in xenograft models obtained injecting stable clones of MDA-MB-231 cells transfected with a miR-205-encoding plasmid or the empty vector. Investigating alternative pathways potentially regulated by miR-205 in this model, we noticed that many of the predicted targets are actually interconnected and related to adhesion and migration processes. Indeed, this microRNA seems to be involved in the control of cell-cell and cell-matrix adhesion regulating the expression of extracellular matrix-related molecules. Among them, we focused on LAMC1, reported to be involved in cell adhesion, differentiation, migration, signaling and metastasis. By Western Blot and Luciferase assay, we demonstrated that miR-205 directly targets LAMC1 in MDA-MB-231 cells. In conclusion, miR-205 exerts a role as oncosuppressor gene also in triple negative breast cancer: it exerts a dramatic inhibition of proliferation and migration in triple negative MDA-MB-231 cell line, at least partially through direct regulation of LAMC1. These evidences not only underline the consistent role of miR-205 in the biology of different breast cancer subgroups, but provide the rational bases for a therapeutic intervention miRs-based. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2089.
Fortnightly review: Adverse drug reactions
Authors: M. Pirmohamed, A. M Breckenridge, N. R Kitteringham, B K. Park
Journal: BMJ (1998)

An adverse drug reaction is any undesirable effect of a drug beyond its anticipated therapeutic effects occurring during clinical use. In contrast, an adverse drug event is an untoward occurrence after exposure to a drug that is not necessarily caused by the drug.1

When a drug is marketed little is known about its safety in clinical use because only about 1500 patients are likely to have been exposed to it.1,2 Thus drug safety assessment should be considered an integral part of everyday clinical practice since detection and diagnosis often depend on clinical acumen. 


In this article we review the current status of adverse drug reactions, briefly describing the complexity of the more bizarre reactions and outlining a strategy to eliminate serious adverse drug reactions. 


Summary points 


Adverse drug reactions are a common clinical problem 


They are diagnosed on clinical grounds from the temporal relation between the start and finish of drug treatment and the onset and offset of the reaction 


Pharmacological adverse reactions are generally dose-dependent, related to the pharmacokinetic properties of the drug, and resolve when the dose is reduced 


Idiosyncratic adverse reactions are not related to the known pharmacology of the drug, do not show any simple dose-response relation, and resolve only when treatment is discontinued 


Vigilance by clinicians in detecting, diagnosing, and reporting adverse reactions is important for continued drug safety monitoring
Case 27-2011
Authors: Harland S. Winter, Debra A. Gervais, John A. Branda
Journal: New England Journal of Medicine (2011)

A 17-year-old boy was admitted to the hospital because of a 6-week history of abdominal pain, constipation, and weight loss. Gastrointestinal radiographs showed narrowing of the cecum. CT scans showed peritoneal implants and a mediastinal mass.
THU0355 Efficacy and Safety of Adalimumab in Patients with Ankylosing Spondylitis and Total Spinal Ankylosis in Croatia: One Year Follow-Up
Authors: F. Grubišić, S. Grazio, Ð. Babić-Naglić, J. Morović-Vergles, B. Anić, T. Kehler, S. Novak, P. Perić, M. Hanih, A. Gudelj, N. Ljubičić-Marković
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Patients with ankylosing spondylitis (AS) who develop total spinal ankylosis (TSA) experience more functional impairment and are at higher risk for serious complications (e.g. spinal fractures). They also might have more signs and symptoms of active disease (1) <h3>Objectives</h3> To evaluate the efficacy and safety of adalimumab in patients with AS and TSA. Primary endpoint. The ASsessment in AS International Working Group criteria for 20% improvement (ASAS20) at week 12 and 52. Type of research. Multicenter, prospective. <h3>Methods</h3> Nineteen patients (17 men, 2 women; mean age 49.1 ± 11.2 years) diagnosed with AS according to the 1987 modified NY criteria and TSA were recruited from the databases of eight rheumatology departments in Croatia. All patients had active disease (BASDAI ≥ 4) and treated with adalimumab (40mg/bi-weekly) (2). A structured questionnaire containing demographic and clinical data was used. Following variables were evaluated at week 12 and 52: function using BASFI, disease activity using BASDAI, patient’s and physician’s global assessment of disease activity, total back pain and fatigue, all of them measured on visual analogue scale (VAS). Both efficacy and safety results are summarised descriptively. <h3>Results</h3> Mean disease duration was 20.2± 11.6 years. Compared to baseline measures, there was a significant improvement in BASFI and BASDAI at week 52: BASFI (6.9 ± 1.19 and 3.13 ± 1.54, respectively) and BASDAI (6.8 ± 1.03 and 2.28 ± 1.45, respectively). Significant improvement was also seen at baseline and week 52 in other observed variables: patient’s and physician’s global assessment, total back pain and fatigue. At month 3 ASAS20 was reached in 18/19 patients and at months 12 in 17/19 patients. Injection site erythema was reported in 2 patients only at first months of the treatment. No serious side effects were observed during 12-month treatment with adalimumab. <h3>Conclusions</h3> In our 12-month study adalimumab treatment of patients with AS and TSA resulted in clinically significant improvement regarding function and disease activity. No serious adverse side effects were reported in our cohort. <h3>References</h3> van der Heijde D, Pangan AL, Schiff MH, Braun J, Borofsky M, Torre J, Davis JC Jr, Wong RL, Kupper H, Collantes E. Adalimumab effectively reduces signs and symptoms of active ankylosing spondylitis in patients with total spinal ankylosis. Ann Rheum Dis. 2008; 67(9): 1218–1221. Babić-Naglić D, Laktasić N, Jajić Z, Anić B, Morović-Vergles J, Curković B; Croatian Society for Rheumatology. Proposal of Croatian Society for Rheumatology for anti-TNF-alpha therapy in adult patients with spondyloarthritides. Reumatizam. 2007;54(1):20-30 <h3>Disclosure of Interest</h3> None Declared
Thames regions take over London initiative Londoners call for independent inquiry into health crisis Government refuses to meet students on loans Medical education funding to be reviewed BMA offers to meet ministers over government fees BMA's 1995 annual meeting
Authors: L. Beecham
Journal: BMJ (1995)

# Thames regions take over London initiative {#article-title-2}

At the end of March the London Implementation Group will formally hand over responsibility for carrying forward the objectives in Making London Better to North and South Thames Regional Health Authorities.1 Making London Better was the government's response to Sir Bernard Tomlinson's 1992 inquiry into London's health service and the London Implementation Group was set up as a task force for a time limited purpose as part of the NHS Executive to provide the impetus for change.2

In a letter to regional directors and chairmen of district health authorities and trusts in the London Initiative Zone the minister for health, Mr Gerald Malone, says that the structure of London's health service is much simpler than when the group was first set up. Almost all the providers will be trusts by 1 April and health authorities have been brought together into seven commissioning agencies. By the same date a quarter of the population in London will be in fundholding practices.

The London Implementation Group has formed alliances with the voluntary and independent sectors to raise the profile of primary care, and the Primary Health Care Forum, which has advised the group on development plans for primary and community care developments in London, will continue under the chairman ship of Sir William Staveley, who is chairman of the North Thames RHA.

Mr Malone said that …
IMCT-07THERAPEUTIC OUTCOMES OF INTRATHECAL INTERLEUKIN-2 IN METASTATIC MELANOMA PATIENTS WITH LEPTOMENINGEAL DISEASE (LMD)
Authors: Isabella C. Glitza, Michelle Rohlfs, Roland Bassett, Ida John, Jessie Richard, Masood Iqbal, Theresa Bernzen, Donna Gerber, Carol Lacey, Adi Diab, Roda Amaria, Scott E Woodman, Sapna Patel, Cassian Yee, Wen-Jen Hwu, Ian E McCutcheon, Amy Heimberger, Patrick Hwu, Nicholas Papadopoulos, Michael A Davies
Journal: Neuro-Oncology (2015)

BACKGROUND: Melanoma patients with LMD have a median survival of 1.8 months; there is significant medical need for innovative therapeutic strategies. METHODS: Stage IV melanoma patients were diagnosed with LMD by positive CSF cytology and/or leptomeningeal enhancement on post-contrast MRI. Patients received treatment with 1-5 doses/week of intrathecal IL-2 (IT IL2) for 4 weeks, followed by weekly injections for 4 weeks, then every other week depending on tolerance and response. The patients were ultimately given maintenance dosing of a single injection every 1-3 months under FDA approved compassionate-use investigational new drug application. Log-rank tests and Cox proportional hazards regression were used to assess statistical significance. RESULTS: The median age among 42 pts (32 male, 10 female) was 46.7 years (range 18.8-71.0). Symptoms due to increased intracranial pressure developed initially in all pts, and were controlled with supportive medications and/or CSF removal. The median overall survival (OS) was 9.1 months (range 0.7 - 86.2); 16% of pts had OS > 24 mos. Pts with LMD only without extracranial disease (ECD) (n = 4) had a median OS of 38.4 months. Pts with LMD with controlled ECD (n = 19, median OS 11.0 months) survived longer than pts with progressive ECD (n = 11, 6.5 mos; p = 0.30). Previous or concurrent brain metastases had no impact on OS. Shorter OS was associated with the presence of neurological symptoms at baseline (HR 2.1, p = 0.03). OS was not significantly associated with age, gender, LDH, or BRAF mutation status. CONCLUSIONS: The results support that IT IL2 can potentially improve the OS in a subset of pts, particularly those with no or controlled ECD, negative cytology, and no neurological symptoms. Furthermore, these results provide a strong rationale to evaluate IT immunotherapy in prospective clinical trials.
Abstract 3444: Exon 4 of osteopontin: A unique target to reduce malignant behavior in non-small cell lung cancer
Authors: Jessica S. Donington, Chandra M. Goparaju, Mark Slomiany, Nathalie Hirsch, Harvey I. Pass
Journal: Cancer Research (2012)

Abstract INTRODUCTION: Osteopontin (OPN) is a ubiquitous protein associated with a wide range of normal and pathologic functions. It is a central regulator of malignant phenotype in non-small cell lung cancer (NSCLC). OPNa, the full length isoform, is disproportionately expressed in NSCLC tumors and cell lines, and increases malignant behavior when over expressed. OPNc, the shortest isoform, does not induce malignant properties when expressed in NSCLC. The only structural difference between OPNa and OPNc is the transcription of exon 4. The hypothesis of this project is that a small interfering peptide to OPN exon 4 will reduce in vitro malignant activity in NSCLC. METHODS: A 16-amino acid peptide which mimics the central sequence in OPN exon 4 and a scrambled sham were constructed and florescent labeled. Three NSCLC cell lines, H358 (low), A549 (moderate), and H460 (high endogenous OPN) were used in binding, proliferation, and invasion assays in presence of exon 4 mimic or sham. Cisplatin sensitivity was performed with peptides in A549. RESULTS: There was florescent evidence for cell surface binding of the exon 4 mimic in all of the NSCLC cell lines without binding of the sham. The exon 4 mimic significantly decreased in vitro invasion and proliferation in the A549 and H460 cell lines, with a lesser effect in H358 with low endogenous OPN. (Table) The exon 4 mimic increased cisplatin sensitivity, decreasing cell viability 2-fold compared to sham and control at cisplatin concentrations 0.1-0.8 uM/ml. CONCLUSIONS: Exon 4 of OPN has not previously been identified as a regulatory region essential for OPN's effect on malignant behavior. We have evidence for an un-described cell surface receptor to this region. A small mimicking peptide to OPN exon 4 significantly decreased in vitro malignant behavior, suggesting interference with important regulatory pathways. This novel binding site could serve as an ideal for target for antibody or small molecule therapies in NSCLC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3444. doi:1538-7445.AM2012-3444