tbuckley/cabot-search huggingface dataset:
Association of Computed Tomography Morphologic Criteria With Pathologic Response and Survival in Patients Treated With Bevacizumab for Colorectal Liver Metastases
Authors: Yun Shin Chun
Journal: JAMA (2009)

<h3>Context</h3>The standard criteria used to evaluate tumor response, the Response Evaluation Criteria in Solid Tumors (RECIST), were developed to assess tumor shrinkage after cytotoxic chemotherapy and may be limited in assessing response to biologic agents, which have a cytostatic mechanism of action.<h3>Objective</h3>To validate novel tumor response criteria based on morphologic changes observed on computed tomography (CT) in patients with colorectal liver metastases treated with bevacizumab-containing chemotherapy regimens.<h3>Design, Setting, and Patients</h3>A total of 234 colorectal liver metastases were analyzed from 50 patients who underwent hepatic resection after preoperative chemotherapy that included bevacizumab at a comprehensive US cancer center from 2004 to 2007; date of last follow-up was March 2008. All patients underwent routine contrast-enhanced CT at the start and end of preoperative therapy. Three blinded, independent radiologists evaluated images for morphologic response, based on metastases changing from heterogeneous masses with ill-defined margins into homogeneous hypoattenuating lesions with sharp borders. These criteria were validated with a separate cohort of 82 patients with unresectable colorectal liver metastases treated with bevacizumab-containing chemotherapy.<h3>Main Outcome Measures</h3>Response determined using morphologic criteria and RECIST was correlated with pathologic response in resected liver specimens and with patient survival.<h3>Results</h3>Interobserver agreement for scoring morphologic changes was good among 3 radiologists (κ, 0.68-0.78; 95% confidence interval [CI], 0.51-0.93). In resected tumor specimens, the median (interquartile range [IQR]) percentages of residual tumor cells for optimal morphologic response was 20% (10%-30%); for incomplete response, 50% (30%-60%); and no response, 70% (60%-70%; P &lt; .001). With RECIST, the median (IQR) percentages of residual tumor cells were for partial response 30% (10%-60%); for stable disease, 50% (20%-70%); and for progressive disease, 70% (65%-70%; P = .04). Among patients who underwent hepatic resection, median overall survival was not yet reached with optimal morphologic response and 25 months (95% CI, 20.2-29.8 months) with incomplete or no morphologic response (P = .03). In the validation cohort, patients with optimal morphologic response had median overall survival of 31 months (95% CI, 26.8-35.2 months) compared with 19 months (95% CI, 14.6-23.4 months) with incomplete or no morphologic response (P = .009). RECIST did not correlate with survival in either the surgical or validation cohort.<h3>Conclusion</h3>Among patients with colorectal liver metastases treated with bevacizumab-containing chemotherapy, CT-based morphologic criteria had a statistically significant association with pathologic response and overall survival.
Effect of Rapamycin Alone and in Combination with Sorafenib in an Orthotopic Model of Human Hepatocellular Carcinoma
Authors: Zheng Wang, Jian Zhou, Jia Fan, Shuang-Jian Qiu, Yao Yu, Xiao-Wu Huang, Zhao-You Tang
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Novel therapeutic strategies are needed to prevent the tumor recurrence or metastasis after liver transplantation for hepatocellular carcinoma (HCC). This study was to investigate the effect of rapamycin, alone and in combination with sorafenib, on HCC in vivo. Experimental Design: Xenograft of a highly metastatic human HCC tumor (LCI-D20) was used to evaluate primary tumor growth and lung metastasis after treatment with rapamycin alone or in combination with sorafenib. Tumor cell proliferation was determined by Ki-67 immunostaining. To detect tumor cell apoptosis, the terminal deoxynucleotidyl-transferase–mediated dUTP nick-end labeling assay was used. Tumor angiogenesis was investigated by using a monoclonal anti-CD31 antibody. A vascular endothelial growth factor ELISA kit was used to measure vascular endothelial growth factor protein levels in the mice serum. Results: Rapamycin, alone and in combination with sorafenib, strongly inhibited primary tumor growth and lung metastases in LCI-D20 model. Furthermore, the combination therapy significantly enhanced the effect of antitumor on primary tumor growth compared with single treatment with either rapamycin (P &amp;lt; 0.001) or sorafenib (P &amp;lt; 0.001). Rapamycin alone inhibited HCC cell proliferation, induced apoptosis, and decreased tumor angiogenesis. Nevertheless, the combination therapy showed a significant inhibition of tumor cell proliferation (P &amp;lt; 0.05). Additionally, the combination therapy also further enhanced suppression of tumor cell angiogenesis compared with rapamycin treatment (P &amp;lt; 0.01). However, the induction of apoptosis in combination therapy group was not significantly higher than in the rapamycin-treated group (P &amp;gt; 0.05). Conclusions: The combination therapy of rapamycin and sorafenib could be a new and promising therapeutic approach to the treatment of HCC and prevention of HCC recurrence after liver transplantation.
Virological response after 6 week triple-drug regimens for hepatitis C: a proof-of-concept phase 2A cohort study
Authors: Anita Kohli, Anuoluwapo Osinusi, Zayani Sims, Amy Nelson, Eric G Meissner, Lisa L Barrett, Dimitra Bon, Miriam M Marti, Rachel Silk, Colleen Kotb, Chloe Gross, Tim A Jolley, Sreetha Sidharthan, Tess Petersen, Kerry Townsend, D'Andrea Egerson, Rama Kapoor, Emily Spurlin, Michael Sneller, Michael Proschan, Eva Herrmann, Richard Kwan, Gebeyehu Teferi, Rohit Talwani, Gabbie Diaz, David E Kleiner, Brad J Wood, Jose Chavez, Stephen Abbott, William T Symonds, G Mani Subramanian, Phillip S Pang, John McHutchison, Michael A Polis, Anthony S Fauci, Henry Masur, Shyam Kottilil
Journal: The Lancet (2015)
Randomized, Open-Label Phase III Trial of Docetaxel Plus High-Dose Calcitriol Versus Docetaxel Plus Prednisone for Patients With Castration-Resistant Prostate Cancer
Authors: Howard I. Scher, Xiaoyu Jia, Kim Chi, Ronald de Wit, William R. Berry, Peter Albers, Brian Henick, David Waterhouse, Dean J. Ruether, Peter J. Rosen, Anthony A. Meluch, Luke T. Nordquist, Peter M. Venner, Axel Heidenreich, Luis Chu, Glenn Heller
Journal: Journal of Clinical Oncology (2011)

To compare the efficacy and safety of docetaxel plus high-dose calcitriol (DN-101) to docetaxel plus prednisone in an open-label phase III trial.Nine hundred fifty-three men with metastatic castration-resistant prostate cancer (CRPC) were randomly assigned to Androgen-Independent Prostate Cancer Study of Calcitriol Enhancing Taxotere (ASCENT; 45 μg DN-101, 36 mg/m(2) docetaxel, and 24 mg dexamethasone weekly for 3 of every 4 weeks) or control (5 mg prednisone twice daily with 75 mg/m(2) docetaxel and 24 mg dexamethasone every 3 weeks) arms. The primary end point was overall survival (OS), assessed by the Kaplan-Meier method.At an interim analysis, more deaths were noted in the ASCENT arm, and the trial was halted. The median-follow-up for patients alive at last assessment was 11.7 months. Median OS was 17.8 months (95% CI, 16.0 to 19.5) in the ASCENT arm and 20.2 months (95% CI, 18.8 to 23.0) in the control arm (log-rank P = .002). Survival remained inferior after adjusting for baseline variables (hazard ratio, 1.33; P = .019). The two arms were similar in rates of total and serious adverse events. The most frequent adverse events were GI (reported in 75% of patients), and blood and lymphatic disorders (48%). Docetaxel toxicity leading to dose modification was more frequent in the ASCENT (31%) than in the control arm (15%).ASCENT treatment was associated with shorter survival than the control. This difference might be due to either weekly docetaxel dosing, which, in a prior study, showed a trend toward inferior survival compared with an every-3-weeks regimen, or DN-101 therapy.
Molecular Mechanisms of Impaired Urinary Concentrating Ability in Glucocorticoid-Deficient Rats
Authors: Yung-Chang Chen, Melissa A. Cadnapaphornchai, Sandra N. Summer, Sandor Falk, Chunling Li, Weidong Wang, Robert W. Schrier
Journal: Journal of the American Society of Nephrology (2005)

The purpose of this study was to examine urinary concentrating ability and protein expression of renal aquaporins and ion transporters in glucocorticoid-deficient (GD) rats in response to water deprivation as compared with control rats. Rats underwent bilateral adrenalectomies, followed only by aldosterone replacement (GD) or both aldosterone and dexamethasone replacement (control). As compared with control rats, the GD rats demonstrated a decrease in cardiac output and mean arterial pressure. In response to 36-h water deprivation, GD rats demonstrated significantly greater urine flow rate and decreased urine osmolality as compared with control rats at comparable serum osmolality and plasma vasopressin concentrations. The initiator of the countercurrent concentrating mechanism, the sodium-potassium-2 chloride co-transporter, was significantly decreased, as was the medullary osmolality in the GD rats versus control rats. There was also a decrease in inner medulla aquaporin-2 (AQP2) and urea transporter A1 (UT-A1) in GD rats as compared with control rats. There was a decrease in outer medulla Gsalpha protein, an important factor in vasopressin-mediated regulation of AQP2. Immunohistochemistry studies confirmed the decreased expression of AQP2 and UT-A1 in kidneys of GD rats as compared with control. In summary, impairment in the urinary concentrating mechanism was documented in GD rats in association with impaired countercurrent multiplication, diminished osmotic equilibration via AQP2, and diminished urea equilibration via UT-A1. These events occurred primarily in the relatively oxygen-deficient medulla and may have been initiated, at least in part, by the decrease in mean arterial pressure and thus renal perfusion pressure in this area of the kidney.
Gout treatment: should we aim for rapid crystal dissolution?
Authors: Eliseo Pascual, Mariano Andrés, Paloma Vela
Journal: Annals of the Rheumatic Diseases (2013)

Monosodium urate crystal deposition in gout precedes the first attack and, while hyperuricaemia persists, it grows and expands to other sites. Fortunately, it is reversible and slowly dissolves when serum uric acid (SUA) is lowered below its saturation point of about 6.8 mg/dl and with certainty below 6 mg/dl. Crystals finally disappear from joints, taking longer in those patients with longer disease duration, probably because of a larger accumulated load of crystals. The SUA level achieved affects the velocity of crystal dissolution and tophi reduction. Accordingly, by deciding the SUA level cut-off point to be achieved by treatment we are determining the time of crystal disappearance and cure of gout. 6 mg/dl is the usual target level, but lower levels appear appropriate to us, particularly in certain situations.
Therapeutic Potential of Lung Epithelial Progenitor Cells Derived from Embryonic and Induced Pluripotent Stem Cells
Authors: Rick A. Wetsel, Dachun Wang, Daniel G. Calame
Journal: Annual Review of Medicine (2010)

Embryonic stem (ES) cells derived from preimplantation blastocysts and induced pluripotent stem (iPS) cells generated from somatic cell sources are pluripotent and capable of indefinite expansion in vitro. They provide a possible unlimited source of cells that could be differentiated into lung progenitor cells for potential clinical use in pulmonary regenerative medicine. Because of inherent difficulties in deriving endodermal cells from undifferentiated cell cultures, applications using lung epithelial cells derived from ES and iPS cells have lagged behind similar efforts devoted to other tissues, such as the heart and spinal cord. However, during the past several years, significant advances in culture, differentiation, and purification protocols, as well as in bioengineering methodologies, have fueled enthusiasm for the development of stem cell–based lung therapeutics. This article provides an overview of recent research achievements and discusses future technical challenges that must be met before the promise of stem cell applications for lung disease can be realized.
Patched1 Functions as a Gatekeeper by Promoting Cell Cycle Progression
Authors: Christelle Adolphe, Rehan Hetherington, Tammy Ellis, Brandon Wainwright
Journal: Cancer Research (2006)

Abstract Mutations in the Hedgehog receptor, Patched 1 (Ptch1), have been linked to both familial and sporadic forms of basal cell carcinoma (BCC), leading to the hypothesis that loss of Ptch1 function is sufficient for tumor progression. By combining conditional knockout technology with the inducible activity of the Keratin6 promoter, we provide in vivo evidence that loss of Ptch1 function from the basal cell population of mouse skin is sufficient to induce rapid skin tumor formation, reminiscent of human BCC. Elimination of Ptch1 does not promote the nuclear translocation of β-catenin and does not induce ectopic activation or expression of Notch pathway constituents. In the absence of Ptch1, however, a large proportion of basal cells exhibit nuclear accumulation of the cell cycle regulators cyclin D1 and B1. Collectively, our data suggest that Ptch1 likely functions as a tumor suppressor by inhibiting G1-S phase and G2-M phase cell cycle progression, and the rapid onset of tumor progression clearly indicates Ptch1 functions as a “gatekeeper.” In addition, we note the high frequency and rapid onset of tumors in this mouse model makes it an ideal system for testing therapeutic strategies, such as Patched pathway inhibitors. (Cancer Res 2006; 66(4): 2081-8)
Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice
Authors: Patrick Seale, Heather M. Conroe, Jennifer Estall, Shingo Kajimura, Andrea Frontini, Jeff Ishibashi, Paul Cohen, Saverio Cinti, Bruce M. Spiegelman
Journal: Journal of Clinical Investigation (2010)

The white adipose organ is composed of both subcutaneous and several intra-abdominal depots. Excess abdominal adiposity is a major risk factor for metabolic disease in rodents and humans, while expansion of subcutaneous fat does not carry the same risks. Brown adipose produces heat as a defense against hypothermia and obesity, and the appearance of brown-like adipocytes within white adipose tissue depots is associated with improved metabolic phenotypes. Thus, understanding the differences in cell biology and function of these different adipose cell types and depots may be critical to the development of new therapies for metabolic disease. Here, we found that Prdm16, a brown adipose determination factor, is selectively expressed in subcutaneous white adipocytes relative to other white fat depots in mice. Transgenic expression of Prdm16 in fat tissue robustly induced the development of brown-like adipocytes in subcutaneous, but not epididymal, adipose depots. Prdm16 transgenic mice displayed increased energy expenditure, limited weight gain, and improved glucose tolerance in response to a high-fat diet. shRNA-mediated depletion of Prdm16 in isolated subcutaneous adipocytes caused a sharp decrease in the expression of thermogenic genes and a reduction in uncoupled cellular respiration. Finally, Prdm16 haploinsufficiency reduced the brown fat phenotype in white adipose tissue stimulated by β-adrenergic agonists. These results demonstrate that Prdm16 is a cell-autonomous determinant of a brown fat-like gene program and thermogenesis in subcutaneous adipose tissues.
Case–Control Estimation of the Impact of Oncolytic Adenovirus on the Survival of Patients With Refractory Solid Tumors
Authors: Anna Kanerva, Anniina Koski, Ilkka Liikanen, Minna Oksanen, Timo Joensuu, Otto Hemminki, Juni Palmgren, Kari Hemminki, Akseli Hemminki
Journal: Molecular Therapy (2014)

Oncolytic immunotherapy with cytokine armed replication competent viruses is an emerging approach in cancer treatment. In a recent randomized trial, an increase in response rate was seen but the effect on overall survival is not known with any virus. To facilitate randomized trials, we performed a case-control study assessing the survival of 270 patients treated in an Advanced Therapy Access Program (ATAP), in comparison to matched concurrent controls from the same hospital. The overall survival of all virus treated patients was not increased over controls. However, when analysis was restricted to GMCSF-sensitive tumor types treated with GMSCF-coding viruses, a significant improvement in median survival was present (from 170 to 208 days, P = 0.0012, N = 148). An even larger difference was seen when analysis was restricted to good performance score patients (193 versus 292 days, P = 0.034, N = 90). The survival of ovarian cancer patients was especially promising as median survival nearly quadrupled (P = 0.0003, N = 37). These preliminary data lend support to initiation of randomized clinical trials with GMCSF-coding oncolytic adenoviruses.
Reduction of experimental canine myocardial reperfusion injury by a monoclonal antibody (anti-Mo1, anti-CD11b) that inhibits leukocyte adhesion.
Authors: P J Simpson, R F Todd, J C Fantone, J K Mickelson, J D Griffin, B R Lucchesi
Journal: Journal of Clinical Investigation (1988)

A monoclonal antibody (904) that binds to a leukocyte cell adhesion-promoting glycoprotein, (Mo1; CD11b/CD18) was administered (1 mg/kg, iv.) to open chest anesthetized dogs 45 min after the induction of regional myocardial ischemia. Ischemia was produced by occluding the left circumflex coronary artery (LCX) for 90 min and then reperfusing for 6 h. There was no difference between control and antibody treated groups with respect to arterial blood pressure, heart rate, or LCX blood flow. Administration of antibody produced no observable effect on circulating neutrophil counts, suggesting that antibody-bound neutrophils were not cleared from the circulation. The mean size of myocardial infarct expressed as percentage of the area at risk of infarction that resulted was reduced by 46% with anti-Mo1 treatment (25.8 +/- 4.7%, n = 8) compared to control (47.6 +/- 5.7%, n = 8; P less than 0.01). The area at risk of infarction was similar between groups. Circulating (serum) antibody excess was confirmed in all 8 anti-Mo1 treated dogs by immunofluorescence analysis. Analysis of ST segment elevation on the electrocardiogram as an indicator of the severity of ischemia suggests that the anti-Mo1 reduces infarct size independent of the severity of ischemia. An additional group of dogs (n = 5) was tested with a control monoclonal antibody of the same subtype (murine IgG1) and was found to produce no significant reduction in myocardial infarct size. Accumulation of neutrophils within the myocardium was significantly attenuated with 904 treatment when analyzed by histological methods. These data demonstrate that administration of anti-Mo1 monoclonal antibody after the induction of regional myocardial ischemia results in reduced myocardial reperfusion injury as measured by ultimate infarct size.
C-reactive protein (CRP) levels in obstructive sleep apnea (OSA) patients and relation to severity of OSA
Authors: Juan-Jose Garrido, Daniel Fernandez-Berges, Francisco-Javier Felix, Maria-Jose Zaro
Journal: European Respiratory Journal (2011)

Introduction: CRP has been proposed as a cardiovascular risk marker. OSA is associated to metabolic syndrome and major cardiovascular events.

Objetives: To study CRP levels in OSA patients in comparison to healthy people, and the relationship between severity of OSA and CRP levels.

Method: Case-control study including 100 consecutive diagnosed OSA patients and 113 healthy people ramdomly selected from general population. Age, sex, hypertension, diabetes, dislipemia, body mass index (BMI), smoking, Epworth scale, spirometry, respiratory disturbance index (RDI) and high sensitivity CRP (hsCRP) were recorded.

Results: Cases and controls characteristics are shown in Table 1.

View this table:

Table 1. Case and control characteristics





Multiple regression model analysis coefficients of CRP levels in OSA patients are shown in Table 2.

View this table:

Table 2. Multiple linear regression model coefficients for hsCRP levels in OSA patients





Conclusion: Althoug OSA patients shows slightly higher levels of hsCRP than healthy people in our sample, other factors rather than severity of OSA measured by the RDI influence that issue.
Genetic Evidence for Long-Term Population Decline in a Savannah-Dwelling Primate: Inferences from a Hierarchical Bayesian Model
Authors: Jay F Storz, Mark A Beaumont, Susan C Alberts
Journal: Molecular Biology and Evolution (2002)

The purpose of this study was to test for evidence that savannah baboons (Papio cynocephalus) underwent a population expansion in concert with a hypothesized expansion of African human and chimpanzee populations during the late Pleistocene. The rationale is that any type of environmental event sufficient to cause simultaneous population expansions in African humans and chimpanzees would also be expected to affect other codistributed mammals. To test for genetic evidence of population expansion or contraction, we performed a coalescent analysis of multilocus microsatellite data using a hierarchical Bayesian model. Markov chain Monte Carlo (MCMC) simulations were used to estimate the posterior probability density of demographic and genealogical parameters. The model was designed to allow interlocus variation in mutational and demographic parameters, which made it possible to detect aberrant patterns of variation at individual loci that could result from heterogeneity in mutational dynamics or from the effects of selection at linked sites. Results of the MCMC simulations were consistent with zero variance in demographic parameters among loci, but there was evidence for a 10- to 20-fold difference in mutation rate between the most slowly and most rapidly evolving loci. Results of the model provided strong evidence that savannah baboons have undergone a long-term historical decline in population size. The mode of the highest posterior density for the joint distribution of current and ancestral population size indicated a roughly eightfold contraction over the past 1,000 to 250,000 years. These results indicate that savannah baboons apparently did not share a common demographic history with other codistributed primate species.
Prothrombotic and reduced fibrinolytic state in association with homocysteinemia: the framingham offspring study
Authors: G.H. Toller, H. Silbershatz, R.B. D'Agostino, P.W.F. Wilson, P. Sutherland, I. Lipinska, M.A. Mittleman, P.F. Jacques, A. Bostom, J. Selhub
Journal: Journal of the American College of Cardiology (1998)
Dual mycobacterial infection in the setting of leflunomide treatment for rheumatoid arthritis
Authors: S Agrawal, A Sharma
Journal: Annals of the Rheumatic Diseases (2006)

Halothane has been found to undergo a reductive defluorination. This reaction requires an active cytochrome P-450 system and NADPH, and is inducible by phenobarbital and polychlorinated biphenyls but not by methylcholanthrene. The fluoride release occurs only under low O2 tension, while high O2 tension results in the oxidation of halothane to trifluoroacetic acid, inorganic bromide, and chloride. The release of the inorganic fluoride is linear up to 60 min. Because the conditions required for fluoride release and the binding of a halothane metabolite to microsomal phospholipids are similar, the defluorinated halothane molecule is assumed to be involved with this binding. However, based on the amount of fluoride released, the defluorinated halothane metabolite represents only approximately 60% of the total amount of halothane metabolite bound, which suggests that more than one metabolite may be involved in the binding.