tbuckley/cabot-search huggingface dataset:
Imaging Pharmacodynamics of the α-Folate Receptor–Targeted Thymidylate Synthase Inhibitor BGC 945
Authors: Radhakrishna G. Pillai, Martin Forster, Meg Perumal, Fraser Mitchell, Julius Leyton, Franklin I. Aibgirhio, Oksana Golovko, Ann L. Jackman, Eric O. Aboagye
Journal: Cancer Research (2008)

Abstract The assessment of tissue-specific pharmacodynamics is desirable in the development of tumor-targeted therapies. Plasma deoxyuridine (dUrd) levels, a measure of systemic thymidylate synthase (TS) inhibition, has limited application for studying the pharmacodynamics of novel TS inhibitors targeted to the high affinity α-folate receptor (FR). Here, we have evaluated the utility of [18F]fluorothymidine positron emission tomography ([18F]FLT-PET) for imaging the tissue pharmacodynamics of BGC 945, an FR-targeted antifolate TS inhibitor; the nontargeted antifolate BGC 9331 was used for comparison. TS inhibition by both drugs induced a concentration-dependent increase in [3H]thymidine uptake in FR-positive human epidermoid KB cells. Membrane-associated equilibrative nucleoside transporter type 1 levels increased from 55,720 ± 6,101 to 118,700 ± 5,193 and 130,800 ± 10,800 per cell at 100 μg/mL of BGC 9331 and BGC 945, respectively, suggesting this as a potential mechanism of increased nucleoside uptake. In keeping with these in vitro findings, tumor [18F]FLT accumulation in KB xenografts increased by ≥2-fold after drug treatment with maximal levels at 1 to 4 hours and 4 to 24 hours after BGC 9331 and BGC 945 treatment, respectively. Of interest to FR targeting, BGC 9331, but not BGC 945, induced accumulation of [18F]FLT uptake in intestine, a proliferative and TS-responsive tissue. For both drugs, quantitative changes in tumor [18F]FLT uptake were associated with increased tumor dUrd levels. In conclusion, we have validated the utility of [18F]FLT-PET to image TS inhibition induced by antifolates and shown the tumor-specific activity of BGC 945. This imaging biomarker readout will be useful in the early clinical development of BGC 945. [Cancer Res 2008;68(10):3827–34]
Effects of c-erbB2 Overexpression on the Drug Sensitivities of Normal Human Mammary Epithelial Cells
Authors: M. S. Orr
Journal: JNCI Journal of the National Cancer Institute (2000)

Overexpression of the gene c-erbB2, which encodes a receptor tyrosine kinase, in breast tumors has been linked with either increased or decreased response of breast cancer patients to various therapies. In breast cancer cell lines, overexpression of exogenous c-erbB2 sometimes alters drug sensitivities but sometimes has no effect. To avoid the genetic complexities associated with established cancer cell lines, normal human mammary epithelial cells (HMECs) were studied to determine whether c-erbB2 overexpression by itself would alter chemosensitivity.HMECs were designed to overexpress c-erbB2, and these cells were then evaluated for alterations in chemosensitivity.HMECs overexpressing c-erbB2 failed to show any alterations in chemosensitivity to a panel of chemotherapeutic agents, as indicated by 95% confidence intervals on growth curves of cells treated with or without the agent of interest. With the use of fluorescence-activated cell sorting to enrich for HMECs overexpressing c-erbB2 on their surface, an 85% pure population of cells was isolated and their chemosensitivity was evaluated. Again, the cells failed to display any alterations in chemosensitivity.These results suggest that overexpression of c-erbB2 is not sufficient by itself to induce changes in chemosensitivity. Cellular studies using normal human cells in which the complexity of the system can be carefully controlled by the addition of one, two, or even more genes associated with cancer development may provide valuable information about how the products of the genes interact with each other and which combinations are critical in regulating chemosensitivity.
Phase II Study of Safety and Efficacy of Motesanib in Patients With Progressive or Symptomatic, Advanced or Metastatic Medullary Thyroid Cancer
Authors: Martin J. Schlumberger, Rossella Elisei, Lars Bastholt, Lori J. Wirth, Renato G. Martins, Laura D. Locati, Barbara Jarzab, Furio Pacini, Chantal Daumerie, Jean-Pierre Droz, Michael J. Eschenberg, Yu-Nien Sun, Todd Juan, Daniel E. Stepan, Steven I. Sherman
Journal: Journal of Clinical Oncology (2009)

Purpose This phase II study investigated the efficacy and tolerability of motesanib, an investigational, highly selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3; platelet-derived growth factor receptor; and Kit in advanced medullary thyroid cancer (MTC). Patients and Methods Patients with locally advanced or metastatic, progressive or symptomatic MTC received motesanib 125 mg/d orally for up to 48 weeks or until unacceptable toxicity or disease progression. The primary end point was objective response by independent review. Other end points included duration of response, progression-free survival, safety, pharmacokinetics, and changes in tumor markers. Results Of 91 enrolled patients who received motesanib, two (2%) achieved objective response (95% CI, 0.3% to 7.7%); their duration of response was 32 weeks (censored) and 21 weeks (disease progressed). Eighty-one percent of patients had stable disease (48% had durable stable disease ≥ 24 weeks), 8% had disease progression as best response, and 9% were not evaluated; 76% experienced a decrease from baseline in target lesion measurement. Median progression-free survival was 48 weeks (95% CI, 43 to 56 weeks). Among patients with tumor marker analysis, 69 (83%) of 83 and 63 (75%) of 84 had decreased serum calcitonin and carcinoembryonic antigen during treatment, respectively, compared with baseline. The most common treatment-related adverse events were diarrhea (41%), fatigue (41%), hypothyroidism (29%), hypertension (27%), and anorexia (27%). In pharmacokinetic analyses, motesanib trough concentrations were lower compared with differentiated thyroid cancer patients from the same study. Conclusion Although the objective response rate was low, a significant proportion of MTC patients (81%) achieved stable disease while receiving motesanib.
Stromal Expression of Connective Tissue Growth Factor Promotes Angiogenesis and Prostate Cancer Tumorigenesis
Authors: Feng Yang, Jennifer A. Tuxhorn, Steven J. Ressler, Stephanie J. McAlhany, Truong D. Dang, David R. Rowley
Journal: Cancer Research (2005)

Abstract Our previous studies have defined reactive stroma in human prostate cancer and have developed the differential reactive stroma (DRS) xenograft model to evaluate mechanisms of how reactive stroma promotes carcinoma tumorigenesis. Analysis of several normal human prostate stromal cell lines in the DRS model showed that some rapidly promoted LNCaP prostate carcinoma cell tumorigenesis and others had no effect. These differential effects were due, in part, to elevated angiogenesis and were transforming growth factor (TGF)-β1 mediated. The present study was conducted to identify and evaluate candidate genes expressed in prostate stromal cells responsible for this differential tumor-promoting activity. Differential cDNA microarray analyses showed that connective tissue growth factor (CTGF) was expressed at low levels in nontumor-promoting prostate stromal cells and was constitutively expressed in tumor-promoting prostate stromal cells. TGF-β1 stimulated CTGF message expression in nontumor-promoting prostate stromal cells. To evaluate the role of stromal-expressed CTGF in tumor progression, either engineered mouse prostate stromal fibroblasts expressing retroviral-introduced CTGF or 3T3 fibroblasts engineered with mifepristone-regulated CTGF were combined with LNCaP human prostate cancer cells in the DRS xenograft tumor model under different extracellular matrix conditions. Expression of CTGF in tumor-reactive stroma induced significant increases in microvessel density and xenograft tumor growth under several conditions tested. These data suggest that CTGF is a downstream mediator of TGF-β1 action in cancer-associated reactive stroma and is likely to be one of the key regulators of angiogenesis in the tumor-reactive stromal microenvironment.
Stimulation of Aldosterone Biosynthesis in Adrenal Mitochondria by Sodium Depletion*
Authors: Elisa T. Marusic, Patrick J. Mulrow
Journal: Journal of Clinical Investigation (1967)

The effect of various factors on the conversion of corticosterone to aldosterone was studied in an isolated mitochondrial system from rat adrenal glands. The adrenal mitochondrial fraction from rats on a low sodium diet has a greater capacity for converting corticosterone to aldosterone than mitochondria from rats fed a normal diet. After 1 day on a low sodium diet the amount converted was 162% and after the 2nd and 4th day the amounts converted were 239 and 242%, respectively, compared to a value of 100% for the control rats. Sodium and(or) potassium added in vitro did not affect the conversion of corticosterone to aldosterone. The specificity of the sodium depletion stimulus on the conversion of corticosterone to aldosterone was established by comparing two other mitochondrial enzymes from glomerulosa cell mitochondria. Succinic dehydrogenase and 11 beta-hydroxylase were measured in normal and sodium-depleted rats and no difference in activity of either enzyme was found. The data are consistent with the view that sodium depletion stimulates the last step in aldosterone biosynthesis by causing a specific enzymatic change in adrenal mitochondria.
THE CARBOHYDRATES OF GONOCOCCUS AND MENINGOCOCCUS
Authors: C. Phillip Miller, Alden K. Boor
Journal: The Journal of Experimental Medicine (1934)

The alcohol-insoluble polysaccharides of gonococcus and meningococcus were found to contain 4.2 and 3.7 per cent nitrogen respectively, to be protein-free by chemical test, to reduce FehIing-Benedict solution only after hydrolysis. They were non-toxic for rabbits and mice, and failed to engender antibodies (precipitins) in rabbits. They produced no cutaneous reactions in normal, snuffle-free rabbits, but caused typical allergic reactions of the delayed type in rabbits rendered hypersensitive to these organisms. Both carbohydrates reacted in high dilution with Antipneumococcus Serum Type III. For comparison, carbohydrates were prepared also from Micrococcus catarrhalis, Streptococcus hemolyticus, Staphylococcus aureus, and a rough strain of pneumococcus.
On the Origin and Domestication History of Barley (Hordeum vulgare)
Authors: A. Badr, K. M, R. Sch, H. El Rabey, S. Effgen, H. H. Ibrahim, C. Pozzi, W. Rohde, F. Salamini
Journal: Molecular Biology and Evolution (2000)

Remains of barley (Hordeum vulgare) grains found at archaeological sites in the Fertile Crescent indicate that about 10,000 years ago the crop was domesticated there from its wild relative Hordeum spontaneum. The domestication history of barley is revisited based on the assumptions that DNA markers effectively measure genetic distances and that wild populations are genetically different and they have not undergone significant change since domestication. The monophyletic nature of barley domestication is demonstrated based on allelic frequencies at 400 AFLP polymorphic loci studied in 317 wild and 57 cultivated lines. The wild populations from Israel-Jordan are molecularly more similar than are any others to the cultivated gene pool. The results provided support for the hypothesis that the Israel-Jordan area is the region in which barley was brought into culture. Moreover, the diagnostic allele I of the homeobox gene BKn-3, rarely but almost exclusively found in Israel H. spontaneum, is pervasive in western landraces and modern cultivated varieties. In landraces from the Himalayas and India, the BKn-3 allele IIIa prevails, indicating that an allelic substitution has taken place during the migration of barley from the Near East to South Asia. Thus, the Himalayas can be considered a region of domesticated barley diversification.
The prevalence and characteristics of intravenous (IV) antibiotics allergy in adult patient with cystic fibrosis (CF)
Authors: Ravi Beri, Reema Jassal, Deep Shah, Waeil Bashari, Sarah Whewall, Angela Norcup, Albert Yick-Hou Lim
Journal: European Respiratory Journal (2012)

Background:   CF patients have increased risk of antibiotics allergy. There is little information on the prevalence and characteristics of IV antibiotics in adult CF patients.   Objectives:   To determine the prevalence and the role of CFTR genotype in IV antibiotics allergy in adult CF patients, and to describe the characteristics of allergy.   Methods:   A retrospective study on all CF patients attending the regional adult CF centre at University Hospital of North Staffordshire between January 2009 and December 2010. Age, sex, CFTR genotype, BMI, spirometry, sputum microbiology/ mycology,  Aspergillus  serology, allergic reactions, the type and the number of courses of IV antibiotics administered were recorded.   Results:   39 of 54 patients received at least 1 course of IV antibiotic were studied. 16 patients with allergy (mean (±SE) age 28.1± 2.0, 10 female) and 23 without (mean (±SE) age 28.5± 2.6, 10 female). The 2 groups had similar spirometry (FEV 1  % predicted 42.9± 4.7 and 51.5± 4.6) and BMI. No differences in sex,  ABPA  and  Aspergillus  sensitisation occurrence. 50% of the allergic patients were DF508/DF508.  The risk of allergy was 22% on  Ceftazidime , 18% on  Tazobactam,  17% on  Meropenem , 15% on  Colistin , 12% on  Aztreonam  and 5% on  Tobramycin.  The common clinical manifestations were nausea/vomiting (27%), arthralgia (19%) and diarrhoea (16%). The overall prevalence of IV antibiotics allergy was 41% (16/39). 10 antibiotics desensitisations were performed with a success rate of 70%.   Conclusions:   IV antibiotics allergy is common,  Ceftazidime  has the highest risk and no correlation with CFTR genotype. Further study is required to determine the risk factors for IV antibiotics allergy.
Patient-Reported and Actionable Safety Events in CKD
Authors: Jennifer S. Ginsberg, Min Zhan, Clarissa J. Diamantidis, Corinne Woods, Jingjing Chen, Jeffrey C. Fink
Journal: Journal of the American Society of Nephrology (2014)

Patients with CKD are at high risk for adverse safety events because of the complexity of their care and impaired renal function. Using data from our observational study of predialysis patients with CKD enrolled in the Safe Kidney Care study, we estimated the baseline frequency of adverse safety events and determined to what extent these events co-occur. We examined patient-reported adverse safety incidents (class I) and actionable safety findings (class II), conditioned on participant use of drugs that might cause such an event, and we used association analysis as a data-mining technique to identify co-occurrences of these events. Of 267 participants, 185 (69.3%) had at least one class I or II event, 102 (38.2%) had more than one event, and 48 (18.0%) had at least one event from both classes. The adjusted conditional rates of class I and class II events ranged from 2.9 to 57.6 per 100 patients and from 2.2 to 8.3 per 100 patients, respectively. The most common conditional class I and II events were patient-reported hypoglycemia and hyperkalemia (serum potassium>5.5 mEq/L), respectively. Reporting of hypoglycemia (in patients with diabetes) and falling or severe dizziness (in patients without diabetes) were most frequently paired with other adverse safety events. We conclude that adverse safety events are common and varied in CKD, with frequent association between disparate events. Further work is needed to define the CKD "safety phenotype" and identify patients at highest risk for adverse safety events.
Revising and Assessing Axis II, Part II: Toward an Empirically Based and Clinically Useful Classification of Personality Disorders
Authors: Drew Westen, Jonathan Shedler
Journal: American Journal of Psychiatry (1999)

The DSM-IV classification of personality disorders has not proven satisfying to either researchers or clinicians. Incremental changes to categories and criteria using structured interviews may no longer be useful in attempting to refine axis II. An alternative approach that quantifies clinical observation may prove useful in developing a clinically rich, useful, empirically grounded classification of personality pathology.A total of 496 experienced psychiatrists and psychologists used the Shedler-Westen Assessment Procedure-200 (SWAP-200) to describe current patients diagnosed with axis II personality disorders. The SWAP-200 is an assessment tool that allows clinicians to provide detailed, clinically rich descriptions of patients in a systematic and quantifiable form. A statistical technique, Q-analysis, was used to identify naturally occurring groupings of patients with personality disorders, based on shared psychological features. The resulting groupings represent an empirically derived personality disorder taxonomy.The analysis found 11 naturally occurring diagnostic categories, some of which resembled current axis II categories and some of which did not. The findings suggest that axis II falls short in its attempt to "carve nature at the joints": In some cases it puts patients who are psychologically dissimilar in the same diagnostic category, and in others it makes diagnostic distinctions where none likely exist. It also fails to recognize a large category of patients best characterized as having a dysphoric personality constellation. The empirically derived classification system appears to be more faithful to the clinical data and to avoid many problems inherent in the current axis II taxonomy.The approach presented here may be helpful in refining the existing taxonomy of personality disorders and moving toward a system of classification that lies on a firmer clinical and empirical foundation. In addition, it can help to bridge the gap that often exists between research and clinical approaches to personality pathology.
Overexpression of transforming growth factor- 1 in fetal monkey lung results in prenatal pulmonary fibrosis
Authors: A.F. Tarantal, H. Chen, T.T. Shi, C-H. Lu, A.B. Fang, S. Buckley, M. Kolb, J. Gauldie, D. Warburton, W. Shi
Journal: European Respiratory Journal (2010)

Altered transforming growth factor (TGF)-β expression levels have been linked to a variety of human respiratory diseases, including bronchopulmonary dysplasia and pulmonary fibrosis. However, a causative role for aberrant TGF-β in neonatal lung diseases has not been defined in primates. Exogenous and transient TGF-β1 overexpression in fetal monkey lung was achieved by transabdominal ultrasound-guided fetal intrapulmonary injection of adenoviral vector expressing TGF-β1 at the second or third trimester of pregnancy. The lungs were then harvested near term, and fixed for histology and immunohistochemistry. Lung hypoplasia was observed where TGF-β1 was overexpressed during the second trimester. The most clearly marked phenotype consisted of severe pulmonary and pleural fibrosis, which was independent of the gestational time point when TGF-β1 was overexpressed. Increased cell proliferation, particularly in α-smooth muscle actin-positive myofibroblasts, was detected within the fibrotic foci. But epithelium to mesenchyme transdifferentiation was not detected. Massive collagen fibres were deposited on the inner and outer sides of the pleural membrane, with an intact elastin layer in the middle. This induced fibrotic pathology persisted even after adenoviral-mediated TGF-β1 overexpression was no longer evident. Therefore, overexpression of TGF-β1 within developing fetal monkey lung results in severe and progressive fibrosis in lung parenchyma and pleural membrane, in addition to pulmonary hypoplasia.
Effectiveness Over Time of Varicella Vaccine
Authors: Marietta Vázquez
Journal: JAMA (2004)

Reports of outbreaks of varicella in highly immunized groups have increased concern about the effectiveness of varicella vaccine.To assess whether the effectiveness of varicella vaccine is affected either by time since vaccination or by age at the time of vaccination.Case-control study conducted from March 1997 through June 2003.Twenty different group practices in southern Connecticut.Case subjects, identified by active surveillance of all practices, consisted of 339 eligible children 13 months or older who were clinically diagnosed as having chickenpox and who also had a polymerase chain reaction (PCR) test result that was positive for varicella-zoster virus DNA. For each case subject, 2 controls were selected, matched by both age and pediatric practice.The effectiveness of the vaccine, especially the effects of time since vaccination and age at the time of vaccination, adjusted for possible confounders.Although the adjusted overall effectiveness of the vaccine was 87% (95% confidence interval, 81%-91%; P<.001), there was a substantial difference in the vaccine's effectiveness in the first year after vaccination (97%) and in years 2 to 8 after vaccination (84%, P =.003). The vaccine's effectiveness in year 1 was substantially lower if the vaccine was administered at younger than 15 months (73%) than if it was administered at 15 months or older (99%, P =.01), although the difference in effectiveness overall for children immunized at younger than 15 months was not statistically significantly different than for those immunized at 15 months or older (81% vs 88%, P =.17). Most cases of chickenpox in vaccinees were mild.Although varicella vaccine is effective, its effectiveness decreases significantly after 1 year, although most cases of breakthrough disease are mild. If administered at younger than 15 months, the vaccine's effectiveness was lower in the first year after vaccination, but the difference in effectiveness was not statistically significant for subsequent years.