tbuckley/cabot-search huggingface dataset:
Prevalence and Heterogeneity of <i>KRAS, BRAF</i>, and <i>PIK3CA</i> Mutations in Primary Colorectal Adenocarcinomas and Their Corresponding Metastases
Authors: Stephan E. Baldus, Karl-L. Schaefer, Rainer Engers, Dinah Hartleb, Nikolas H. Stoecklein, Helmut E. Gabbert
Journal: Clinical Cancer Research (2010)

Epidermal growth factor receptor (EGFR) antibody therapy is established in patients with wild-type KRAS colorectal carcinoma; however, up to 50% of these patients do not respond to this therapy. To identify the possible causes of this therapy failure, we searched for mutations in different EGFR-dependent signaling proteins and analyzed their distribution patterns in primary tumors and corresponding metastases.Tumor tissues, macrodissected from tumor centers, invasion fronts (n = 100), lymph nodes (n = 55), and distant metastases (n = 20), respectively, were subjected to DNA extraction and mutation analysis of KRAS, BRAF, and PIK3CA.Activating mutations were detected in 41% (KRAS), 7% (BRAF), and 21% (PIK3CA) of the primary tumors. By comparing tumor centers and invasion fronts, the intratumoral heterogeneity of KRAS, BRAF, and PIK3CA mutations was observed in 8%, 1%, and 5% of primary tumors, respectively. Heterogeneity between primary tumors and lymph node metastases was found in 31% (KRAS), 4% (BRAF), and 13% (PIK3CA) of the cases. Heterogeneity between primary tumors and distant metastases was present in two patients (10%) for KRAS and one patient for PIK3CA (5%), but not for BRAF. Discordant results between primary tumors and metastases could markedly be reduced by testing the additional tumor samples.Failure of EGFR antibody therapy in patients with wild-type KRAS colorectal cancer may result from activating BRAF or PIK3CA mutations and false-negative sequencing results caused by intratumoral heterogeneity. Due to the particularly high rates of heterogeneity between primary tumors and lymph node metastases, the latter are least suitable for diagnostic mutation analysis.
Curcumin Potentiates the Antitumor Effects of Bacillus Calmette-Guerin against Bladder Cancer through the Downregulation of NF-κB and Upregulation of TRAIL Receptors
Authors: Ashish M. Kamat, Sheeja T. Tharakan, Bokyung Sung, Bharat B. Aggarwal
Journal: Cancer Research (2009)

Although Bacillus Calmette-Guerin (BCG) intravesical therapy is a standard treatment for bladder cancer, eventual failure of response is a major problem. Treatments that can augment BCG therapy are urgently needed. We investigated whether curcumin, a component of Curcuma longa (also called turmeric), has potential to improve the current therapy using in vitro and in vivo MBT-2 murine tumor models. We found that curcumin potentiated BCG-induced apoptosis of human bladder cancer cells. BCG stimulated the release of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) from peripheral mononuclear neutrophils in a dose- and time-dependent manner, whereas curcumin enhanced the upregulation of TRAIL receptors. Electrophoretic mobility shift assay revealed that curcumin also suppressed the BCG-induced activation of the cell survival transcription factor NF-kappaB. In a syngeneic bladder cancer model, curcumin alone reduced the bladder tumor volume, but a significantly greater reduction was observed when BCG and curcumin were used in combination (P < 0.0001 versus control; P < 0.003 versus BCG alone). This was accompanied by a significant decrease in the proliferation marker Ki-67 (P < 0.01 versus control; P < 0.01 versus BCG alone) and microvessel density (CD31; P < 0.01 versus control; P < 0.01 versus BCG alone), decreased NF-kappaB in tumor tissue compared with the control, induced apoptosis, and decreased cyclin D1, vascular endothelial growth factor, cyclooxygenase-2, c-myc, and Bcl-2 expression in the tumor tissue. Upregulation of TRAIL receptor by the combination was also observed in tumor tissues. Overall, our results suggest that curcumin potentiates the antitumor effect of BCG through the inhibition of NF-kappaB and induction of TRAIL receptors in bladder cancer cells.
Tendon degeneration and chronic shoulder pain: changes in the collagen composition of the human rotator cuff tendons in rotator cuff tendinitis.
Authors: G P Riley, R L Harrall, C R Constant, M D Chard, T E Cawston, B L Hazleman
Journal: Annals of the Rheumatic Diseases (1994)

OBJECTIVES--To analyse the collagen composition of normal adult human supraspinatus tendon and to compare with: (1) a flexor tendon (the common biceps tendon) which is rarely involved in any degenerative pathology; (2) degenerate tendons from patients with chronic rotator cuff tendinitis. METHODS--Total collagen content, collagen solubility and collagen type were investigated by hydroxyproline analysis, acetic acid and pepsin digestion, cyanogen bromide peptide analysis, SDS-PAGE and Western blotting. RESULTS--The collagen content of the normal cadaver supraspinatus tendons (n = 60) was 96.3 micrograms HYPRO/mg dry weight (range 79.3-113.3) and there was no significant change across the age range 11 to 95 years. There was no significant difference from the common biceps tendon [93.3 (13.5) micrograms HYPRO/mg dry weight, n = 24]. Although extremely insoluble in both acetic acid and pepsin, much of the collagen was soluble after cyanogen bromide digestion [mean 47.9% (29.8)]. Seventeen per cent (10/60) of the 9normal9 cadaver supraspinatus tendon sample contained more than 5% type III collagen, although none of the common biceps tendons had significant amounts. Degenerate supraspinatus and subscapularis tendons had a reduced collagen content [83.8 (13.9) micrograms/mg dry weight and 76.9 (16.8) micrograms/mg dry wt respectively) and were more soluble in acetic acid, pepsin and cyanogen bromide (p &lt; 0.001). Eighty two per cent (14/17) of supraspinatus tendons and 100% (8/8) of subscapularis tendons from patients with tendinitis contained more than 5% type III collagen. CONCLUSIONS--The changes in collagen composition in rotator cuff tendinitis are consistent with new matrix synthesis, tissue remodelling and wound healing, in an attempt to repair the tendon defect, even in old and degenerate tendons. An increase in type III collagen in some 9normal9 cadaver supraspinatus tendons is evidence that changes in collagen synthesis and turnover may precede tendon rupture. These changes may be the result of repeated minor injury and microscopic fibre damage or a consequence of local factors such as reduced vascular perfusion, tissue hypoxia, altered mechanical forces and the influence of cytokines. These collagenous changes may accumulate with age and substantially weaken the tendon structure, predisposing the tendon to rotator cuff tendinitis and eventual tendon rupture.
Sizing Up the Enemy
Authors: C. Thomas Caskey
Journal: JAMA (1994)

Future students of medical history will encounter an impressive list of dread diseases diminished or eliminated during the 20th century. Polio and smallpox, for example, may seem as distant to them as the plagues of ancient Egypt. Perhaps another 20th-century scourge, cancer, will be among those counted as conquered enemies, and in that hope, we announce plans for a theme issue of<i>JAMA</i>devoted to discoveries in cancer research and related basic medical sciences and the application of these advances to medical practice. This publication initiative, highlighting progress in cancer research and treatment, will serve to demonstrate<i>JAMA</i>'s desire to lend emphasis to the significance of these efforts.
Induction of tolerance to 1-fluoro-2,4-dinitrobenzene contact sensitivity with hapten-modified lymphoid cells. II. Selective tolerance in F1 mice of T cell subsets recognizing 1-fluoro-2,4-dinitrobenzene associated with parental major histocompatibility complex antigens.
Authors: P J Conlon, J W Moorhead, S D Miller, H N Claman
Journal: The Journal of Experimental Medicine (1980)

F1 animals were tolerized to 1-fluoro-2,4-dinitrobenzene (DNFB) contact sensitivity with parentally derived, in vitro hapten-modified spleen cells. This tolerant state was found, upon adoptive transfer to naive parental strain recipients, to affect only that T cell subpopulation that recognized the parental haplotype of the cell used as the tolerogen, and did not inhibit the ability of the remaining T cell subset to confer immunity. This demonstrates that this tolerant state involves the inactivation of a cell required for the expression of contact sensitivity by recognizing DNFB in association with self major histocompatibility complex gene products.
Venous Relaxation Caused by Acetylcholine Acting on the Sympathetic Nerves
Authors: PAUL M. VANHOUTTE, JOHN T. SHEPHERD
Journal: Circulation Research (1973)

Experiments were performed to determine whether acetylcholine affects the sympathetic activation of the cutaneous veins of the dog. Changes in isometric tension of saphenous vein strips were recorded at 37°C in an organ bath. Addition of acetylcholine at 10 -11 to 10 -8 g/ml did not affect basal tension, but larger doses (5 x 10 -8 to 5 x 10 -7 g/ml) caused a contraction of the strips which varied from slight to marked. Acetylcholine at 10 -8 to 10 -7 g/ml caused a further increase in tension when it was added to strips already contracted by norepinephrine, tyramine, KCl, or BaCl 2 ; in contrast, similar doses of acetylcholine caused relaxation of strips contracted by liberation of norepinephrine from the nerve terminals by electrical stimulation (1-10 cps). This relaxation was not influenced by propranolol or hexamethonium but was abolished by atropine (10 -8 g/ml). In intact dogs, the lateral saphenous vein was perfused with autologous blood at constant flow. A sustained venoconstriction was induced either by electrical stimulation of the lumbar sympathetic chain or by a continuous infusion of norepinephrine. An infusion of acetylcholine (10 -7 to 10 -6 g/ml min -1 ) relaxed veins constricted by sympathetic stimulation but not those constricted by norepinephrine. Thus, acetylcholine, in doses smaller than those known to have a direct constrictor effect, causes relaxation of cutaneous veins, probably by inhibiting the release of norepinephrine from nerve terminals.
The management of anaphylaxis in childhood: position paper of the European academy of allergology and clinical immunology
Authors: A. Muraro, G. Roberts, A. Clark, P. A. Eigenmann, S. Halken, G. Lack, A. Moneret‐Vautrin, B. Niggemann, F. Rancé
Journal: Allergy (2007)

Anaphylaxis is a growing paediatric clinical emergency that is difficult to diagnose because a consensus definition was lacking until recently. Many European countries have no specific guidelines for anaphylaxis. This position paper prepared by the EAACI Taskforce on Anaphylaxis in Children aims to provide practical guidelines for managing anaphylaxis in childhood based on the limited evidence available. Intramuscular adrenaline is the acknowledged first‐line therapy for anaphylaxis, in hospital and in the community, and should be given as soon as the condition is recognized. Additional therapies such as volume support, nebulized bronchodilators, antihistamines or corticosteroids are supplementary to adrenaline. There are no absolute contraindications to administering adrenaline in children. Allergy assessment is mandatory in all children with a history of anaphylaxis because it is essential to identify and avoid the allergen to prevent its recurrence. A tailored anaphylaxis management plan is needed, based on an individual risk assessment, which is influenced by the child’s previous allergic reactions, other medical conditions and social circumstances. Collaborative partnerships should be established, involving school staff, healthcare professionals and patients’ organizations. Absolute indications for prescribing self‐injectable adrenaline are prior cardiorespiratory reactions, exercise‐induced anaphylaxis, idiopathic anaphylaxis and persistent asthma with food allergy. Relative indications include peanut or tree nut allergy, reactions to small quantities of a given food, food allergy in teenagers and living far away from a medical facility. The creation of national and European databases is expected to generate better‐quality data and help develop a stepwise approach for a better management of paediatric anaphylaxis.
Phase II Study of the Efficacy and Tolerability of Two Dosing Regimens of the Farnesyl Transferase Inhibitor, R115777, in Advanced Breast Cancer
Authors: Stephen R.D. Johnston, Tamas Hickish, Paul Ellis, Stephen Houston, Lloyd Kelland, Mitch Dowsett, Janine Salter, Bart Michiels, Juan Jose Perez-Ruixo, Peter Palmer, Angela Howes
Journal: Journal of Clinical Oncology (2003)

Purpose: R115777 is an orally active farnesyl transferase inhibitor that specifically blocks farnesylation of proteins involved in growth-factor–dependent cell-signal–transduction pathways. We conducted a phase II study in 76 patients with advanced breast cancer. Patients and Methods: Two cohorts of patients were recruited sequentially. The first cohort (n = 41) received a continuous dosing [CD] regimen of R115777 400 or 300 mg bid. The second cohort (n = 35) received 300 mg bid in a cyclical regimen of 21 days of treatment followed by 7 days of rest (intermittent dosing [ID]). Results: In the CD cohort, four patients (10%) had a partial response (PR) and six patients (15%) had stable disease at ≥ 24 weeks (SD). In the ID cohort, five patients (14%) had a PR and three patients (9%) had prolonged SD. The first six patients in the CD cohort treated at 400 mg bid all developed grade 3 to 4 neutropenia, so the subsequent 35 patients were treated at 300 mg bid. The incidence of hematologic toxicity was significantly lower in the ID than in the CD (300-mg bid) cohort: grade 3 to 4 neutropenia (14% v 43%; P = .016) and grade 3 to 4 thrombocytopenia (3% v 26%; P = .013). One patient in the ID cohort developed grade 2 to 3 neurotoxicity compared with 15 patients in the CD cohort (3% v 37%; P = .0004). Conclusion: The farnesyl transferase inhibitor R115777 has demonstrated clinical activity in patients with metastatic breast cancer, and the ID regimen has a significantly improved therapeutic index compared with the CD regimen.
Sequential DNA methylation changes are associated with DNMT3B overexpression in colorectal neoplastic progression
Authors: A. E. K. Ibrahim, M. J. Arends, A.-L. Silva, A. H. Wyllie, L. Greger, Y. Ito, S. L. Vowler, T. H.-M. Huang, S. Tavare, A. Murrell, J. D. Brenton
Journal: Gut (2010)

<h3>Background and aims</h3> Although aberrant methylation of key genes in the progression of colorectal neoplasia has been reported, no model-based analysis of the incremental changes through the intermediate adenoma stage has been described. In addition, the biological drivers for these methylation changes have yet to be defined. Linear mixed-effects modelling was used in this study to understand the onset and patterns of the methylation changes of <i>SFRP2</i>, <i>IGF2</i> DMR0, <i>H19</i>, <i>LINE-1</i> and a CpG island methylator phenotype (CIMP) marker panel, and they were correlated with DNA methyltransferase 3B (DNMT3B) levels of expression in a sample set representative of colorectal neoplastic progression. <h3>Methods</h3> Methylation of the above CpG islands was measured using quantitative pyrosequencing assays in 261 tissue samples. This included a prospective collection of 44 colectomy specimens with concurrent normal mucosa, adenoma and invasive cancer tissues. Tissue microarrays from a subset of 64 cases were used for immunohistochemical analysis of DNMT3B expression. <h3>Results</h3> It is shown that the onset and pattern of methylation changes during colorectal neoplastic progression are locus dependent. The CIMP marker <i>RUNX3</i> was the earliest CpG island showing significant change, followed by the CIMP markers <i>NEUROG1</i> and <i>CACNA1G</i> at the hyperplastic polyp stage. <i>SFRP2</i> and <i>IGF2</i> DMR0 showed significant methylation changes at the adenomatous polyp stage, followed by the CIMP markers <i>CDKN2A</i> and <i>hMLH1</i> at the adenocarcinoma stage. DNMT3B levels of immunohistochemical expression increased significantly (p&lt;0.001) from normal to hyperplastic and from adenomatous polyps to carcinoma samples. DNMT3B expression correlated positively with <i>SFRP2</i> methylation (r=0.42, p&lt;0.001, 95% CI 0.25 to 0.56), but correlated negatively with <i>IGF2</i> DMR0 methylation (r=0.26, p=0.01, 95% CI −0.45 to −0.05). A subset of the CIMP panel (<i>NEUROG1</i>, <i>CACNA1G</i> and <i>CDKN2A</i>) positively correlated with DNMT3B levels of expression (p&lt;0.05). <h3>Conclusion</h3> Hierarchical epigenetic alterations occur at transition points during colorectal neoplastic progression. These cumulative changes are closely correlated with a gain of DNMT3B expression, suggesting a causal relationship.
Pathophysiology, treatment, and animal and cellular models of human ischemic stroke
Authors: Trent M Woodruff, John Thundyil, Sung-Chun Tang, Christopher G Sobey, Stephen M Taylor, Thiruma V Arumugam
Journal: Molecular Neurodegeneration (2011)

Stroke is the world's second leading cause of mortality, with a high incidence of severe morbidity in surviving victims. There are currently relatively few treatment options available to minimize tissue death following a stroke. As such, there is a pressing need to explore, at a molecular, cellular, tissue, and whole body level, the mechanisms leading to damage and death of CNS tissue following an ischemic brain event. This review explores the etiology and pathogenesis of ischemic stroke, and provides a general model of such. The pathophysiology of cerebral ischemic injury is explained, and experimental animal models of global and focal ischemic stroke, and in vitro cellular stroke models, are described in detail along with experimental strategies to analyze the injuries. In particular, the technical aspects of these stroke models are assessed and critically evaluated, along with detailed descriptions of the current best-practice murine models of ischemic stroke. Finally, we review preclinical studies using different strategies in experimental models, followed by an evaluation of results of recent, and failed attempts of neuroprotection in human clinical trials. We also explore new and emerging approaches for the prevention and treatment of stroke. In this regard, we note that single-target drug therapies for stroke therapy, have thus far universally failed in clinical trials. The need to investigate new targets for stroke treatments, which have pleiotropic therapeutic effects in the brain, is explored as an alternate strategy, and some such possible targets are elaborated. Developing therapeutic treatments for ischemic stroke is an intrinsically difficult endeavour. The heterogeneity of the causes, the anatomical complexity of the brain, and the practicalities of the victim receiving both timely and effective treatment, conspire against developing effective drug therapies. This should in no way be a disincentive to research, but instead, a clarion call to intensify efforts to ameliorate suffering and death from this common health catastrophe. This review aims to summarize both the present experimental and clinical state-of-the art, and to guide future research directions.
c-met mRNA overexpression in human hepatocellular carcinoma
Authors: Loreto Boix, Jose Luis Rosa, Francesc Ventura, Antoni Castells, Jordi Bruix, Joan Rodés, Ramon Bartrons
Journal: Hepatology (1994)

This study was aimed at assessing the presence of c-met overexpression in human hepatocellular carcinoma and at determining whether this feature is associated with a definite clinical or pathological characteristic. Expression of c-met was determined by Northern-blot hybridization of a specific probe (human met proto-oncogene) in 18 tumoral and nontumoral liver samples obtained in 18 cirrhotic patients with hepatocellular carcinoma submitted to surgical treatment. Eight of the 18 hepatocellular carcinomas exhibited c-met overexpression, with an increase ranging between 2-fold and 10-fold when compared by densitometry with the surrounding liver. By contrast, in the remaining 10 cases c-met expression was almost identical to that of the surrounding nontumoral liver tissue. Overexpression of c-met was not related to either the age, sex, etiology or functional status of the underlying liver disease, or to the size of the tumor, to its differentiation degree or to the presence of pseudocapsule invasion and existence of additional neoplastic nodules. These data indicate that almost half of the human hepatocellular carcinomas exhibit c-met overexpression. Nevertheless, the biological relevance of this characteristic is not known.
Prognostic Significance of Tissue Transglutaminase in Drug Resistant and Metastatic Breast Cancer
Authors: Kapil Mehta, Jansina Fok, Fred R. Miller, Dimpy Koul, Aysegul A. Sahin
Journal: Clinical Cancer Research (2004)

Drug resistance and metastasis pose major impediments in the successful treatment of cancer. We previously reported that multidrug-resistant breast cancer cells exhibit high levels of tissue transglutaminase (TG2; EC 2.3.2.13). Because the drug-resistant and metastatic phenotypes are thought to share some common pathways, we sought to determine whether metastatic breast cancer cells express high levels of TG2.The metastatic breast cancer cell line MDA-MB-231 and the sublines derived from it were tested for TG2 expression. Similarly, several sublines derived from an immortal but normal breast epithelial cell line, MCF10A, representing various stages in breast cancer progression were studied for TG2 expression. The primary and nodal tumor samples from 30 patients with breast cancer were also studied for TG2 expression.The MDA-MB-231 cells expressed high basal levels of TG2. Two clones derived from this cell line, MDA231/cl.9 and MDA231/cl.16, showed a 10- to 15-fold difference in TG2 level. TG2-deficient MDA231/cl.9 cells exhibited higher sensitivity to doxorubicin and were less invasive than were the TG2-sufficient MDA231/cl.16 cells. The MCF10A-derived sublines had increased TG2 expression as they advanced from noninvasive to an invasive phenotype. Importantly, the metastatic lymph node tumors from patients with breast cancer showed significant higher levels of TG2 expression compared with the primary tumors from the same patients.TG2 expression is up-regulated in drug-resistant and metastatic breast cancer cells, and it can serve as a valuable prognostic marker for these phenotypes.