tbuckley/cabot-search huggingface dataset:
Comparative Genomic Analysis of Primary Versus Metastatic Colorectal Carcinomas
Authors: Efsevia Vakiani, Manickam Janakiraman, Ronglai Shen, Rileen Sinha, Zhaoshi Zeng, Jinru Shia, Andrea Cercek, Nancy Kemeny, Michael D'Angelica, Agnes Viale, Adriana Heguy, Philip Paty, Timothy A. Chan, Leonard B. Saltz, Martin Weiser, David B. Solit
Journal: Journal of Clinical Oncology (2012)

To compare the mutational and copy number profiles of primary and metastatic colorectal carcinomas (CRCs) using both unpaired and paired samples derived from primary and metastatic disease sites.We performed a multiplatform genomic analysis of 736 fresh frozen CRC tumors from 613 patients. The cohort included 84 patients in whom tumor tissue from both primary and metastatic sites was available and 31 patients with pairs of metastases. Tumors were analyzed for mutations in the KRAS, NRAS, BRAF, PIK3CA, and TP53 genes, with discordant results between paired samples further investigated by analyzing formalin-fixed, paraffin-embedded tissue and/or by 454 sequencing. Copy number aberrations in primary tumors and matched metastases were analyzed by comparative genomic hybridization (CGH).TP53 mutations were more frequent in metastatic versus primary tumors (53.1% v 30.3%, respectively; P < .001), whereas BRAF mutations were significantly less frequent (1.9% v 7.7%, respectively; P = .01). The mutational status of the matched pairs was highly concordant (> 90% concordance for all five genes). Clonality analysis of array CGH data suggested that multiple CRC primary tumors or treatment-associated effects were likely etiologies for mutational and/or copy number profile differences between primary tumors and metastases.For determining RAS, BRAF, and PIK3CA mutational status, genotyping of the primary CRC is sufficient for most patients. Biopsy of a metastatic site should be considered in patients with a history of multiple primary carcinomas and in the case of TP53 for patients who have undergone interval treatment with radiation or cytotoxic chemotherapies.
<i>CHEK2</i>*1100delC Screening of Asian Women With a Family History of Breast Cancer Is Unwarranted
Authors: Ann S.G. Lee, Peter Ang
Journal: Journal of Clinical Oncology (2008)

TO THE EDITOR: We read with interest the article by Weisher et al in which the authors recommend genotyping for CHEK2*1100delC, in addition to BRCA1 and BRCA2 mutation screening, for women with a family history of breast cancer. In their report, only Northern or Eastern European ethnic groups and not other ethnic groups, were subjected to meta-analyses to determine breast cancer risks associated with this CHEK2 mutation. CHEK2*1100delC genotyping studies of Asian populations of Korean, Chinese, Japanese, South Indian, and Singaporean origin have so far not identified this mutation. Table 1 presents a summary of the Asian subjects that have been screened for the CHEK2*1100delC mutation. None of our 94 Singaporean subjects of Asian descent who underwent genetic testing for BRCA1 and BRCA2 mutations utilizing a comprehensive strategy had the CHEK2*1100delC mutation. Screening was done using the multiplex ligation-dependent probe amplification method (P045 BRCA2/CHEK2 kit; MRC-Holland, Amsterdam, the Netherlands). All of these women had either a family history of breast or ovarian cancer or early-onset breast cancer, and were predominantly of Chinese, Malay, and Indian ethnicities. Therefore, based on the reasons outlined above and the points mentioned by Offit and Garber pertaining to population heterogeneity, cancer spectrum, variable penetrance, and the occurrence of phenocopies, we believe that genetic testing for CHEK2*1100delC in Asian women with a family history of breast cancer is not warranted.
Increasing dose of methylprednisolone pulse therapy treats desquamative interstitial pneumonia in a child
Authors: K Paul, U Klettke, J Moldenhauer, KM Muller, I Kleinau, K Magdorf, U Wahn
Journal: European Respiratory Journal (1999)

A 10 yr old male with hypoxaemia, progressive infiltration on the chest radiograph and biopsy-proven desquamative interstitial pneumonia was treated with daily oral prednisolone for 6 months. Intravenous methylprednisolone pulses were concomitantly administered in doses averaging 10 mg x kg body weight(-1) on three consecutive days every 4-6 weeks. After 6 months improvement could be noted and oral steroids were stopped, while pulse therapy continued. Three months later, when seven pulses had been administered, a relapse occurred and the clinical status deteriorated. Instead of reinstating daily systemic steroids, the dose of methylprednisolone pulses was increased to 20 mg x kg body weight(-1) i.v. given on three consecutive days and repeat pulses every 4 weeks. This was followed by continuous improvement. After 24 months corticosteroid pulses were terminated. Normal lung function, serum lactate dehydrogenase, blood gases upon exertion and regular development was achieved. During the course of treatment, the child has grown 10 cm. It is concluded that the effect of corticosteroid pulse therapy on interstitial lung disease in childhood is dose-dependent and that the dose can be adjusted to the effect observed.
Tuberin Inhibits Production of the Matrix Protein Fibronectin in Diabetes
Authors: Samy L. Habib, Mukesh Yadav, Shaza Tizani, Basant Bhandari, Anthony J. Valente
Journal: Journal of the American Society of Nephrology (2012)

Exposure of proximal tubular epithelial cells to high glucose contributes to the accumulation of tubulointerstitial and matrix proteins in diabetic nephropathy, but how this occurs is not well understood. We investigated the effect of the signaling molecule tuberin, which modulates the mammalian target of rapamycin pathway, on renal hypertrophy and fibronectin expression. We found that the kidney mass was significantly greater in partially tuberin-deficient (TSC2(+/-) ) diabetic rats than wild-type diabetic rats. Furthermore, TSC2(+/-) rats exhibited significant increases in the basal levels of phospho-tuberin and fibronectin expression in the kidney cortex. Increased levels of phosphorylated tuberin associated with an increase in fibronectin expression in both wild-type and TSC2(+/-) diabetic rats. Treatment with insulin abrogated the diabetes-induced increase in fibronectin expression. In vitro, high glucose enhanced fibronectin expression in TSC2(+/-) primary proximal tubular epithelial cells; both inhibition of Akt and inhibition of the mammalian target of rapamycin could prevent this effect of glucose. In addition, forced expression of tuberin in tuberin-null cells abolished the expression of fibronectin protein. Taken together, these data suggest that tuberin plays a central role in the development of renal hypertrophy and in modulating the production of the matrix protein fibronectin in diabetes.
A TaqMan Low-Density Array to Predict Outcome in Advanced Hodgkin's Lymphoma Using Paraffin-Embedded Samples
Authors: Beatriz Sánchez-Espiridión, Abel Sánchez-Aguilera, Carlos Montalbán, Carmen Martin, Rafael Martinez, Joaquín González-Carrero, Concepción Poderos, Carmen Bellas, Manuel F. Fresno, Cesar Morante, Maria J. Mestre, Miguel Mendez, Francisco Mazorra, Eulogio Conde, Angel Castaño, Pedro Sánchez-Godoy, José F. Tomas, Manolo M. Morente, Miguel A. Piris, Juan F. García
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Despite major advances in the treatment of classic Hodgkin's lymphoma (cHL), ∼30% of patients in advanced stages may eventually die as result of the disease, and current methods to predict prognosis are rather unreliable. Thus, the application of robust techniques for the identification of biomarkers associated with treatment response is essential if new predictive tools are to be developed. Experimental Design: We used gene expression data from advanced cHL patients to identify transcriptional patterns from the tumoral cells and their nonneoplastic microenvironment, associated with lack of maintained treatment response. Gene-Set Enrichment Analysis was used to identify functional pathways associated with unfavorable outcome that were significantly enriched in either the Hodgkin's and Reed-Sternberg cells (regulation of the G2-M checkpoint, chaperones, histone modification, and signaling pathways) or the reactive cell microenvironment (mainly represented by specific T-cell populations and macrophage activation markers). Results: To explore the pathways identified previously, we used a series of 52 formalin-fixed paraffin-embedded advanced cHL samples and designed a real-time PCR-based low-density array that included the most relevant genes. A large majority of the samples (82.7%) and all selected genes were analyzed successfully with this approach. Conclusions: The results of this assay can be combined in a single risk score integrating these biological pathways associated with treatment response and eventually used in a larger series to develop a new molecular outcome predictor for advanced cHL.
The Clinical Effect of the Dual-Targeting Strategy Involving PI3K/AKT/mTOR and RAS/MEK/ERK Pathways in Patients with Advanced Cancer
Authors: Toshio Shimizu, Anthony W. Tolcher, Kyriakos P. Papadopoulos, Muralidhar Beeram, Drew W. Rasco, Lon S. Smith, Shelly Gunn, Leslie Smetzer, Theresa A. Mays, Brianne Kaiser, Michael J. Wick, Cathy Alvarez, Aracely Cavazos, Gina L. Mangold, Amita Patnaik
Journal: Clinical Cancer Research (2012)

This study evaluated the clinical relevance of the dual-targeting strategy involving PI3K/AKT/mTOR and RAF/MEK/ERK pathways.We investigated safety, efficacy, and correlations between tumor genetic alterations and clinical benefit in 236 patients with advanced cancers treated with phase I study drugs targeting phosphoinositide 3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) pathways in our Phase I Clinical Trials Program.Seventy-six (32.2%) patients received a PI3K pathway inhibitor in combination with a MAPK pathway inhibitor (D), whereas 124 (52.5%) and 36 (15.3%), respectively, received an inhibitor of either the PI3K or MAPK pathways (S). The rates of drug-related grade >III adverse events were 18.1% for (S) and 53.9% for (D; P < 0.001); the rates of dose-limiting toxicities were 9.4% for (S) and 18.4% for (D; P = 0.06). The most frequent grade >III adverse events were transaminase elevations, skin rash, and mucositis. In our comprehensive tumor genomic analysis, of 9 patients who harbored coactivation of both pathways (colorectal cancer, n = 7; melanoma, n = 2), all 5 patients treated with (D) had tumor regression ranging from 2% to 64%.These results suggest that dual inhibition of both pathways may potentially exhibit favorable efficacy compared with inhibition of either pathway, at the expense of greater toxicity. Furthermore, this parallel pathway targeting strategy may be especially important in patients with coexisting PI3K pathway genetic alterations and KRAS or BRAF mutations and suggests that molecular profiling and matching patients with combinations of these targeted drugs will need to be investigated in depth.
A Clinical Trial of Continuous Subcutaneous Insulin Infusion Versus Multiple Daily Injections in Older Adults With Type 2 Diabetes
Authors: William H. Herman, Liza L. Ilag, Susan L. Johnson, Catherine L. Martin, Joyce Sinding, Abdulaziz Al Harthi, Cynthia D. Plunkett, Frankie B. LaPorte, Ray Burke, Morton B. Brown, Jeffery B. Halter, Philip Raskin
Journal: Diabetes Care (2005)

OBJECTIVE—To compare the efficacy and safety of continuous subcutaneous insulin infusion (CSII) and multiple daily injection (MDI) in older adults with insulin-treated type 2 diabetes and to assess treatment satisfaction and quality of life. RESEARCH DESIGN AND METHODS—Adults (n = 107) ≥60 years of age (mean age 66 years) with insulin-treated type 2 diabetes (mean duration 16 years, BMI 32 kg/m2, and HbA1C [A1C] 8.2%) were randomized to CSII (using insulin lispro) or MDI (using insulin lispro and insulin glargine) in a two-center, 12-month, prospective, randomized, controlled clinical trial. Efficacy was assessed with A1C, safety by frequency of hypoglycemia, and treatment satisfaction and quality of life with the Diabetes Quality of Life Clinical Trial Questionnaire and the 36-item short-form health survey, version 2. RESULTS—Forty-eight CSII subjects (91%) and 50 MDI subjects (93%) completed the study. Mean A1C fell by 1.7 ± 1.0% in the CSII group to 6.6% and by 1.6 ± 1.2% in the MDI group to 6.4%. The difference in A1C between treatment groups was not statistically significant (P = 0.20). Eighty-one percent of CSII subjects and 90% of MDI subjects experienced at least one episode of minor (self-treated) hypoglycemia (P = 0.17), and three CSII and six MDI subjects experienced severe hypoglycemia (P = 0.49). Rates of severe hypoglycemia were similarly low in the two groups (CSII 0.08 and MDI 0.23 events per person-year, P = 0.61). Weight gain did not differ between groups (P = 0.70). Treatment satisfaction improved significantly with both CSII and MDI (P &amp;lt; 0.0001), and the difference between groups was not statistically significant (P = 0.58). CONCLUSIONS—In older subjects with insulin-treated type 2 diabetes, both CSII and MDI achieved excellent glycemic control with good safety and patient satisfaction.
The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion
Authors: Allan Tsung, Rohit Sahai, Hiroyuki Tanaka, Atsunori Nakao, Mitchell P. Fink, Michael T. Lotze, Huan Yang, Jianhua Li, Kevin J. Tracey, David A. Geller, Timothy R. Billiar
Journal: The Journal of Experimental Medicine (2005)

High-mobility group box 1 (HMGB1) is a nuclear factor that is released extracellularly as a late mediator of lethality in sepsis as well as after necrotic, but not apoptotic, death. Here we demonstrate that in contrast to the delayed role of HMGB1 in the systemic inflammation of sepsis, HMGB1 acts as an early mediator of inflammation and organ damage in hepatic ischemia reperfusion (I/R) injury. HMGB1 levels were increased during liver I/R as early as 1 h after reperfusion and then increased in a time-dependent manner up to 24 h. Inhibition of HMGB1 activity with neutralizing antibody significantly decreased liver damage after I/R, whereas administration of recombinant HMGB1 worsened I/R injury. Treatment with neutralizing antibody was associated with less phosphorylation of c-Jun NH2-terminal kinase and higher nuclear factor–κB DNA binding in the liver after I/R. Toll-like receptor 4 (TLR4)-defective (C3H/Hej) mice exhibited less damage in the hepatic I/R model than did wild-type (C3H/HeOuj) mice. Anti-HMGB1 antibody failed to provide protection in C3H/Hej mice, but successfully reduced damage in C3H/Ouj mice. Together, these results demonstrate that HMGB1 is an early mediator of injury and inflammation in liver I/R and implicates TLR4 as one of the receptors that is involved in the process.
Ultrasound measurement of the acromioclavicular joint
Authors: A P Rozin
Journal: Annals of the Rheumatic Diseases (2009)

The acromioclavicular joint (ACJ) is a widely used, versatile and complex gliding synovial joint that provides stability and increases function; the ability to raise the arm above the head with a greater degree of arm rotation. The ACJ is vulnerable to trauma, instability, dislocation, osteoarthritis and synovitis.1 The ACJ is assessed for dislocation, fluid collection, cysts and bone erosions,2 3 but measurement of normal ACJ parameters is still unclear. That makes it difficult to interpret ACJ pathology.4 Ultrasound (US) enables direct imaging of the ACJ and has been proven to be as accurate as x ray assessment.4

The aim of the present study was to obtain US dimensions of the ACJ in healthy volunteers. US assessment (SonoSite Titan with 5–10 MHz L38 linear …
Bronchodilatation and the site of airway resistance in severe chronic bronchitis.
Authors: N J Douglas, I Davidson, M F Sudlow, D C Flenley
Journal: Thorax (1979)

Twenty-one patients with severe chronic bronchitis and emphysema (FEV1 less than 1 1) inhaled 80 microgram of the atropine-like agent ipratropium or placebo in a double-blind study and three hours later inhaled 200 microgram salbutamol. After 80 microgram ipratropium, mean FEV1 was significantly greater than after 200 microgram salbutamol (P less than 0.025), but the difference was only 40 ml and the clinical significance of this difference is unproved. There was no correlation between the patient9s response to ipratropium and the response to salbutamol. When salbutamol was administered three hours after ipratropium, the FEV1 rose to higher levels than after either agent alone (P less than 0.01). Studies breathing 80% helium/20% oxygen suggest that ipratropium dilates both large and small airways. There was no correlation between the response to helium/oxygen and the response to either bronchodilator. The results suggest that in severe chronic bronchitis and emphysema ipratropium is at least as effective as salbutamol, and that such patients should have reversibility studies with salbutamol alone, ipratropium alone, and after both agents together. The combination of ipratropium and salbutamol may be clinically useful.
Therapy of steroid-induced bone loss in adult asthmatics with calcium, vitamin D, and a diphosphonate.
Authors: H Worth, D Stammen, E Keck
Journal: American Journal of Respiratory and Critical Care Medicine (1994)

In a prospective, controlled, and randomized clinical trial, we examined the effects of treatment with vitamin D (1,000 IU/d), calcium (1 g/d), and ethane-1-hydroxy-1,1-diphosphonate (EHDP; 7.5 mg/kg body weight) on vertebral bone mass in fourteen asthmatics undergoing long-term treatment with systemically applied corticosteroids. The extent of steroid-induced bone loss was judged by vertebral bone density of the lumbar spine measured by dual-photon absorptiometry as well as by vertebral crush fracture incidence examined by conventional X-ray. Results of the measurements before treatment and after six mo were compared with those of an untreated control group of nineteen asthmatics. Bone density increased during the observation period by 5% in the treated group, compared with a decrease of 4.3% in the untreated control group (p < 0.01). Moreover, in the treated group no radiologically visible new fractures occurred; in the control group new fractures were observed in four patients. There were no serious side effects of the applied drugs during the 6-mo period. Therefore, the combination of EHDP, calcium, and vitamin D appears to be a useful regimen for the management of steroid-induced bone loss in adult asthmatics.
Renal Tubular Epithelial Expression of the Costimulatory Molecule B7RP-1 (Inducible Costimulator Ligand)
Authors: P. Wahl
Journal: Journal of the American Society of Nephrology (2002)

MHC class II-expressing renal tubular epithelial cells (TEC) are able to present foreign peptide antigens to T cells. The costimulatory signals that are required for effective T cell activation upon antigen presentation by TEC have not been characterized. Various cultured TEC lines were examined for expression of the recently described costimulatory molecule B7RP-1 (B7h), a ligand of the T cell molecule inducible costimulator (ICOS), and expression was compared with that of B7.1, B7.2, and CD40. B7RP-1 and CD40 were abundantly expressed by cultured murine and human TEC, whereas B7.1 and B7.2 could not be detected. Stimulation with lipopolysaccharide or tumor necrosis factor-alpha did not induce B7.1 or B7.2 expression and did not alter B7RP-1 expression. Interestingly, interleukin-2 production by T cell hybridomas after antigen presentation by TEC was enhanced by blocking antibodies to B7RP-1 and ICOS. In contrast, blocking antibodies to B7RP-1 or ICOS exerted inhibitory effects on anti-CD3-activated murine splenocyte proliferation. Immunohistochemical staining of normal human kidneys demonstrated strong constitutive B7RP-1 expression in distal tubules, collecting ducts, and urothelium. In human kidneys with allograft rejection or interstitial nephritis, distinct B7RP-1 staining was also detected in proximal tubules, in areas of mononuclear infiltration. In conclusion, the B7RP-1/ICOS pathway negatively regulates T cell activation upon MHC class II-restricted antigen presentation by TEC. Because B7RP-1 is also expressed by tubules in vivo, it can be speculated that the B7RP-1/ICOS pathway could play an inhibitory role in TEC-mediated immune activation in the kidney.
Skin Cancer Prevention: Sunnyside Up or Scrambled?
Authors: J. E. Fielding, S. M. Teutsch
Journal: JNCI Journal of the National Cancer Institute (2010)

JNCI | Editorials 445 Reduce preventable cancers. Sounds straightforward enough. Find the underlying causes, reduce or eliminate those risks, and voila — Prevention! Skin cancers are undeniably common, with a real mortality risk. Melanoma alone is the eighth leading cause of cancer in the United States ( 1 ) and also has a high mortality rate. In addition, although squamous cell cancers are relatively less fatal, they still account for 20% of skin cancer deaths. The single most preventable risk factor for skin cancer is UV exposure. So what could be simpler than reducing that exposure through sunscreens and by decreasing the time spent in the sun during peak hours? Framed this way, the public health challenge is to change behavior. This Skin Cancer Prevention: Sunnyside Up or Scrambled?
Human Cytomegalovirus Glycoprotein UL141 Targets the TRAIL Death Receptors to Thwart Host Innate Antiviral Defenses
Authors: Wendell Smith, Peter Tomasec, Rebecca Aicheler, Andrea Loewendorf, Ivana Nemčovičová, Eddie C.Y. Wang, Richard J. Stanton, Matt Macauley, Paula Norris, Laure Willen, Eva Ruckova, Akio Nomoto, Pascal Schneider, Gabriele Hahn, Dirk M. Zajonc, Carl F. Ware, Gavin W.G. Wilkinson, Chris A. Benedict
Journal: Cell Host & Microbe (2013)

Death receptors (DRs) of the TNFR superfamily contribute to antiviral immunity by promoting apoptosis and regulating immune homeostasis during infection, and viral inhibition of DR signaling can alter immune defenses. Here we identify the human cytomegalovirus (HCMV) UL141 glycoprotein as necessary and sufficient to restrict TRAIL DR function. Despite showing no primary sequence homology to TNF family cytokines, UL141 binds the ectodomains of both human TRAIL DRs with affinities comparable to the natural ligand TRAIL. UL141 binding promotes intracellular retention of the DRs, thus protecting virus infected cells from TRAIL and TRAIL-dependent NK cell-mediated killing. The identification of UL141 as a herpesvirus modulator of the TRAIL DRs strongly implicates this pathway as a regulator of host defense to HCMV and highlights UL141 as a pleiotropic inhibitor of NK cell effector function.