tbuckley/cabot-search huggingface dataset:
Monoketone analogs of curcumin, a new class of Fanconi anemia pathway inhibitors
Authors: Igor Landais, Sanne Hiddingh, Matthew McCarroll, Chao Yang, Aiming Sun, Mitchell S Turker, James P Snyder, Maureen E Hoatlin
Journal: Molecular Cancer (2009)

Abstract Background The Fanconi anemia (FA) pathway is a multigene DNA damage response network implicated in the repair of DNA lesions that arise during replication or after exogenous DNA damage. The FA pathway displays synthetic lethal relationship with certain DNA repair genes such as ATM (Ataxia Telangectasia Mutated) that are frequently mutated in tumors. Thus, inhibition of FANCD2 monoubiquitylation (FANCD2-Ub), a key step in the FA pathway, might target tumor cells defective in ATM through synthetic lethal interaction. Curcumin was previously identified as a weak inhibitor of FANCD2-Ub. The aim of this study is to identify derivatives of curcumin with better activity and specificity. Results Using a replication-free assay in Xenopus extracts, we screened monoketone analogs of curcumin for inhibition of FANCD2-Ub and identified analog EF24 as a strong inhibitor. Mechanistic studies suggest that EF24 targets the FA pathway through inhibition of the NF-kB pathway kinase IKK. In HeLa cells, nanomolar concentrations of EF24 inhibited hydroxyurea (HU)-induced FANCD2-Ub and foci in a cell-cycle independent manner. Survival assays revealed that EF24 specifically sensitizes FA-competent cells to the DNA crosslinking agent mitomycin C (MMC). In addition, in contrast with curcumin, ATM-deficient cells are twofold more sensitive to EF24 than matched wild-type cells, consistent with a synthetic lethal effect between FA pathway inhibition and ATM deficiency. An independent screen identified 4H-TTD, a compound structurally related to EF24 that displays similar activity in egg extracts and in cells. Conclusions These results suggest that monoketone analogs of curcumin are potent inhibitors of the FA pathway and constitute a promising new class of targeted anticancer compounds.
Regulation of Chorionic Gonadotropin Gene Expression*
Authors: J. LARRY JAMESON, ANTHONY N. HOLLENBERG
Journal: Endocrine Reviews (1993)

CHORIONIC gonadotropin (CG) is a placental hormone that maintains the corpus luteum of pregnancy. Because CG is expressed at high levels soon after fertilization and implantation, it is used to detect pregnancy at early stages and to monitor the progress of pregnancy during the first trimester (1). CG is also produced in trophoblastic disease and in a variety of different malignancies, and it is useful as a tumor marker in these conditions (2). The mechanisms that control CG production have been investigated extensively, and there are several recent comprehensive reviews (3, 4). CG is a heterodimer composed of α- and β-subunits (Fig. 1). The α-subunit is identical to that in other members of the glycoprotein hormone family (TSH, FSH, LH), whereas the β-subunits in each of the hormones are distinct and confer receptor and biological specificity (5). Little hormone is stored intracellularly and, for the most part, hormone secretion reflects de novo biosynthesis. Therefore, many recent studies have focused on the transcriptional control of CG biosynthesis. The complementary DNAs encoding the α- and β- subunits of CG were among the first hormone sequences to be cloned (2, 6, 7), reflecting, in part, their abundance in the placenta. The α and β genes (8–10) were isolated soon after the cDNAs. The availability of several different CG producing cell lines (3, 4) has allowed relatively rapid progress in the identification of regulatory DNA elements and transcription factors that control CG α- and β-gene transcription. The purpose of this review is to summarize and evaluate recent studies on the structures and transcriptional control of the CG α- and β-genes. Because cAMP is believed to play a central role in the regulation of CG gene transcription, much of the available data concern mechanisms for transcriptional control by the protein kinase A pathway. Information derived from studies of the CG model system may also enhance our understanding of other cAMP-regulated genes.
Effects of different maize (Zea mays L.) - soybean (Glycine max (L.) Merrill) intercropping patterns on yields and land equivalent ratio
Authors: J M M Matusso, J N Mugwe, M Mucheru-Muna
Journal: Journal of Clinical Oncology (2013)

In central highlands of Kenya, the low soil fertility and inability to replenish it are amongst the major constraints affecting the productivity of maize and cash crops, leading to hunger and poverty. The adoption of ISFM technologies such as maize-soybean intercropping system is being promoted as one of the options to address low crop productivity among the farmers. This study intended to determine the effects of maize-soybean intercropping patterns on yields and to quantify the land equivalent ratio (LER) of different maize–soybean intercropping patterns in the two contrasting sites. The experiment was arranged in a randomized complete block design (RCBD) with four replications. The treatments were four maize (M) – soybean (S) intercropping patterns (conventional=1M:1S; MBILI-MBILI=2M:2S; 2M:4S; 2M:6S) and two sole crops of maize and soybean, respectively. The results showed that in both sites during the both seasons maize stover and grain yields were significantly affected by the intercropping pattern. During 2012 LR at Embu site the MBILI treatment produced significantly higher stover and grain yields (13.12 t ha-1, p=0.0001 and 6.11 t ha-1, p<0.0001, respectively) than all other treatments. During 2012 SR, still the MBILI treatment had recorded significantly the highest stover and grain yield (7.62 t ha-1, p<0.0001 and 5.62 t ha-1 p=0.0467, respectively) than all other treatments. During 2012 LR at Kamujine site the conventional treatment produced significantly the highest stover yield (3.87 t ha-1, p=0.0461) than only the 2M:6S treatment. During 2012 SR at Kamujine site, the MBILI treatment had recorded significantly the highest stover and grain yield (6.55 t ha-1, p=0.0005 and 3.55 t ha-1 p=0.0006, respectively) than all other treatments. During both seasons in both sites, the soybean yield was significantly affected by the intercropping pattern. During the 2012 LR, the yields were reduced by 60 and 81% due to the intercropping with maize, at Embu and Kamujine, respectively; whereas, during the 2012 SR, the yields were reduced by 52 and 78% as effect of intercropping with maize, at Embu and Kamujine, respectively. During both seasons at both locations, the partial land equivalent ratio (LER) values were significantly affected by the intercropping patterns (p<0.0001).

	Key words: Maize-soybean yields, land equivalent ratio, intercropping patterns, central highlands, Kenya.
Biodegradable and Biocompatible Poly(Ethylene Glycol)‐based Hydrogel Films for the Regeneration of Corneal Endothelium
Authors: Berkay Ozcelik, Karl D. Brown, Anton Blencowe, Katharina Ladewig, Geoffrey W. Stevens, Jean‐Pierre Y. Scheerlinck, Keren Abberton, Mark Daniell, Greg G. Qiao
Journal: Advanced Healthcare Materials (2014)

Corneal endothelial cells (CECs) are responsible for maintaining the transparency of the human cornea. Loss of CECs results in blindness, requiring corneal transplantation. In this study, fabrication of biocompatible and biodegradable poly(ethylene glycol) (PEG)‐based hydrogel films (PHFs) for the regeneration and transplantation of CECs is described. The 50‐μm thin hydrogel films have similar or greater tensile strengths to human corneal tissue. Light transmission studies reveal that the films are &gt;98% optically transparent, while in vitro degradation studies demonstrate their biodegradation characteristics. Cell culture studies demonstrate the regeneration of sheep corneal endothelium on the PHFs. Although sheep CECs do not regenerate in vivo, these cells proliferate on the films with natural morphology and become 100% confluent within 7 d. Implantation of the PHFs into live sheep corneas demonstrates the robustness of the films for surgical purposes. Regular slit lamp examinations and histology of the cornea after 28 d following surgery reveal minimal inflammatory responses and no toxicity, indicating that the films are benign. The results of this study suggest that PHFs are excellent candidates as platforms for the regeneration and transplantation of CECs as a result of their favorable biocompatibility, degradability, mechanical, and optical properties.
Surgical treatment of ruptures of the Achilles tendon: a review of long-term results.
Authors: M Krueger-Franke, C H Siebert, S Scherzer
Journal: British Journal of Sports Medicine (1995)

The rupture of the Achilles tendon is frequently sports-related. In the time from 1 January, 1978 until 31 December, 1988, we treated 358 men and 54 women with such an injury at the Staatliche Orthopaedische Klinik in Munich. The average age of these patients was 43 years. The site of the rupture was generally located between 3-5 cm proximal of the distal insertion of the tendon. In the follow-up examination of 122 patients with surgical treatment of tendo calcaneus ruptures 85% showed 'good' to 'very good' subjective results. Of the operated patients 97% would choose the same treatment under similar circumstances. The isokinetic studies demonstrated a loss of static and dynamic strength in plantar flexion of the ankle joint of 9.1%, and 16.7% respectively, when compared to the healthy contralateral side. The ultrasound examination revealed a thickening of the tendon and of the dorsal paratenon with changes in the internal structure of the injured Achilles tendon. In spite of these favourable results, the high complication rate of 15.1% shows the need for new and extensive studies regarding the various alternative treatment forms, such as functional, non-operative options, to finally resolve the debate about the optimal treatment of Achilles tendon ruptures.
A water-filled body plethysmograph for the measurement of pulmonary capillary blood flow during changes of intrathoracic pressure
Authors: Yoshikazu Kawakami, Harold A. Menkes, Arthur B. DuBois
Journal: Journal of Clinical Investigation (1970)

A water-filled body plethysmograph was constructed to measure gas exchange in man. As compared to an air-filled plethysmograph, its advantages were greater sensitivity, less thermal drift, and no change from adiabatic to isothermal conditions after a stepwise change of pressure. When five subjects were completely immersed within it and were breathing to the ambient atmosphere, they had a normal heart rate, oxygen consumption, CO(2) output, and functional residual capacity. Pulmonary capillary blood flow ([unk]Qc) during and after Valsalva and Mueller maneuvers was calculated from measurements of N(2)O uptake. Control measurements of [unk]Qc were 2.58 liters/min per m(2) at rest and 3.63 liters/min per m(2) after moderate exercise. During the Valsalva maneuver at rest (intrapulmonary pressure: 24, SD 3.0, mm Hg), [unk]Qc decreased from a control of 2.58, SD 0.43, liters/min per m(2) to 1.62, SD 0.26, liters/min per m(2) with a decrease in pulmonary capillary stroke volume from a control of 42.4, SD 8.8, ml/stroke per m(2) to 25.2, SD 5.5, ml/stroke per m(2). After release of the Valsalva, there was an overshoot in [unk]Qc averaging +0.78, SD 0.41, liter/min per m(2) accompanied by a significant increase in heart rate. Similar changes occurred during and after the Valsalva following moderate exercise. During the Mueller maneuver at rest and after exercise, [unk]Qc, heart rate, and central stroke volume did not change significantly.
Relationship of the diaphragm to the inferior vena cava in human embryos and fetuses
Authors: A. A. Pearson, R. W. Sauter, R. C. Oler
Journal: Thorax (1971)

The attachment of the inferior vena cava to the diaphragm is compared with that of the oesophagus and the aorta. The development of this attachment is described in human embryos and fetuses. In older fetuses the attached border of the diaphragm splits into several layers at its junction with the inferior vena cava. The insertion of the right crus of the diaphragm into the posterior wall of the inferior vena cava is thought to have physiological significance. The left phrenic nerve supplies the left half of the diaphragm and the left component of the right crus. The right phrenic nerve supplies the right half of the diaphragm including the right component of the right crus.
Risk of Stroke Associated With Abciximab Among Patients Undergoing Percutaneous Coronary Intervention
Authors: K. Martijn Akkerhuis
Journal: JAMA (2001)

Abciximab, a potent inhibitor of the platelet glycoprotein IIb/IIIa receptor, reduces thrombotic complications in patients undergoing percutaneous coronary intervention (PCI). Because of its potent inhibition of platelet aggregation, the effect of abciximab on risk of stroke is a concern.To determine whether abciximab use among patients undergoing PCI is associated with an increased risk of stroke.Combined analysis of data from 4 double-blind, placebo-controlled, randomized trials (EPIC, CAPTURE, EPILOG, and EPISTENT) conducted between November 1991 and October 1997 at a total of 257 academic and community hospitals in the United States and Europe.A total of 8555 patients undergoing PCI with or without stent deployment for a variety of indications were randomly assigned to receive a bolus and infusion of abciximab (n = 5476) or matching placebo (n = 3079). One treatment group in EPIC received a bolus of abciximab only.Risk of hemorrhagic and nonhemorrhagic stroke within 30 days of treatment among abciximab and placebo groups.No significant difference in stroke rate was observed between patients assigned abciximab (n = 22 [0.40%]) and those assigned placebo (n = 9 [0.29%]; P =.46). Excluding the EPIC abciximab bolus-only group, there were 9 strokes (0.30%) among 3023 patients who received placebo and 15 (0.32%) in 4680 patients treated with abciximab bolus plus infusion, a difference of 0.02% (95% confidence interval [CI], -0.23% to 0.28%). The rate of nonhemorrhagic stroke was 0.17% in patients treated with abciximab and 0.20% in patients treated with placebo (difference, -0.03%; 95% CI, -0.23% to 0.17%), and the rates of hemorrhagic stroke were 0.15% and 0.10%, respectively (difference, 0.05%; 95% CI, -0.11% to 0.21%). Among patients treated with abciximab, the rate of hemorrhagic stroke in patients receiving standard-dose heparin in EPIC, CAPTURE, and EPILOG was higher than in those receiving low-dose heparin in the EPILOG and EPISTENT trials (0.27% vs 0.04%; P =.057).Abciximab in addition to aspirin and heparin does not increase the risk of stroke in patients undergoing PCI. Patients undergoing PCI and treated with abciximab should receive low-dose, weight-adjusted heparin.
Chimeric Antigen Receptor–Modified T Cells in Chronic Lymphoid Leukemia
Authors: David L. Porter, Bruce L. Levine, Michael Kalos, Adam Bagg, Carl H. June
Journal: New England Journal of Medicine (2011)

We designed a lentiviral vector expressing a chimeric antigen receptor with specificity for the B-cell antigen CD19, coupled with CD137 (a costimulatory receptor in T cells [4-1BB]) and CD3-zeta (a signal-transduction component of the T-cell antigen receptor) signaling domains. A low dose (approximately 1.5×10(5) cells per kilogram of body weight) of autologous chimeric antigen receptor-modified T cells reinfused into a patient with refractory chronic lymphocytic leukemia (CLL) expanded to a level that was more than 1000 times as high as the initial engraftment level in vivo, with delayed development of the tumor lysis syndrome and with complete remission. Apart from the tumor lysis syndrome, the only other grade 3/4 toxic effect related to chimeric antigen receptor T cells was lymphopenia. Engineered cells persisted at high levels for 6 months in the blood and bone marrow and continued to express the chimeric antigen receptor. A specific immune response was detected in the bone marrow, accompanied by loss of normal B cells and leukemia cells that express CD19. Remission was ongoing 10 months after treatment. Hypogammaglobulinemia was an expected chronic toxic effect.
Induction of Tolerance in Autoimmune Diseases Rather Than Cure of Cancer by Interleukin-2 Therapy
Authors: Christian Dejaco, Christina Duftner, Michael Schirmer
Journal: Journal of Clinical Oncology (2006)

TO THEEDITOR: Onceinterleukin-2(IL-2)wasdiscovered,itwas quickly used for the in vitro stimulation of lymphocytes and it was administeredtocancerpatientsinordertoexpandantitumoreffector cells. 1 Unfortunately, IL-2-based immunotherapy lacked response in approximately 80% of patients. 2 Cesana et al 2 demonstrated that treatment with IL-2 resulted in an increased prevalence of peripheral blood CD4CD25 hi regulatory T cells (TREGs) in a subset of patients with renal cell carcinoma and metastatic melanoma, which lack clinical response. TREGs may suppress antitumor immuneresponsesandexogenousIL-2maythereforeleadtoprogression, rather than cure of cancer. 3 The selective manipulation of TREGs is of growing interest for rheumatologists as reduced prevalences and functional defects of TREGs have been implemented in the pathogenesis of various autoimmune diseases. Indeed, TREGs were successfully activated by CD28-superagonist antibodies in vivo, and polyclonally expanded TREGs significantly reduced inflammation in animal models of arthritisexvivo. 4,5 ToleranceinductionbyexogenousIL-2wouldalsobe an interesting therapeutic strategy for autoimmune diseases, as IL-2 deficient mice display a profound reduction of TREGs and develop fatal lymphoproliferative disease with multiorgan autoimmunity. 1 Similarly, the neutralization of circulating IL-2 for a limited period of time can elicit autoimmune disease in wildtype mice by reducing natural TREGs. 6
Standardization of Estrogen Receptor Measurement in Breast Cancer Suggests False-Negative Results Are a Function of Threshold Intensity Rather Than Percentage of Positive Cells
Authors: Allison W. Welsh, Christopher B. Moeder, Sudha Kumar, Peter Gershkovich, Elaine T. Alarid, Malini Harigopal, Bruce G. Haffty, David L. Rimm
Journal: Journal of Clinical Oncology (2011)

Recent misclassification (false negative) incidents have raised awareness concerning limitations of immunohistochemistry (IHC) in assessment of estrogen receptor (ER) in breast cancer. Here we define a new method for standardization of ER measurement and then examine both change in percentage and threshold of intensity (immunoreactivity) to assess sources for test discordance.An assay was developed to quantify ER by using a control tissue microarray (TMA) and a series of cell lines in which ER immunoreactivity was analyzed by quantitative immunoblotting in parallel with the automated quantitative analysis (AQUA) method of quantitative immunofluorescence (QIF). The assay was used to assess the ER protein expression threshold in two independent retrospective cohorts from Yale and was compared with traditional methods.Two methods of analysis showed that change in percentage of positive cells from 10% to 1% did not significantly affect the overall number of ER-positive patients. The standardized assay for ER on two Yale TMA cohorts showed that 67.9% and 82.5% of the patients were above the 2-pg/μg immunoreactivity threshold. We found 9.1% and 19.7% of the patients to be QIF-positive/IHC-negative, and 4.0% and 0.4% to be QIF-negative/IHC-positive for a total of 13.1% and 20.1% discrepant cases when compared with pathologists' judgment of threshold. Assessment of survival for both cohorts showed that patients who were QIF-positive/pathologist-negative had outcomes similar to those of patients who had positive results for both assays.Assessment of intensity threshold by using a quantitative, standardized assay on two independent cohorts suggests discordance in the 10% to 20% range with current IHC methods, in which patients with discrepant results have prognostic outcomes similar to ER-positive patients with concordant results.
From BPD to COPD? The hypothesis is intriguing but we lack lung pathology data in humans
Authors: M. Filippone, S. Carraro, E. Baraldi
Journal: European Respiratory Journal (2010)

<h3>Objective:</h3> To identify genetic loci associated with plasma tau concentrations in healthy elders and individuals with Alzheimer disease. <h3>Methods:</h3> Four hundred sixty-three non-Hispanic white individuals exceeding quality control criteria were included from the Alzheimer9s Disease Neuroimaging Initiative (ADNI-1) cohort. Association of plasma tau with genetic polymorphisms was performed with a linear regression model. Significant associations were validated in an independent replication cohort consisting of 431 healthy elders or individuals with mild cognitive impairment recruited from the University of California, San Francisco Memory and Aging Center. <h3>Results:</h3> The minor allele (A) of rs242557 in the microtubule-associated protein tau gene (<i>MAPT</i>) was associated with higher plasma tau levels at genome-wide significance (<i>p</i> = 4.85 × 10<sup>−9</sup>, empiric family-wise error corrected <i>p</i> = 0.0024) in a dose-dependent fashion. This association was also observed in the replication cohort (<i>p</i> = 1.0 × 10<sup>−5</sup>; joint analysis <i>p</i> = 1.2 × 10<sup>−12</sup>). Single nucleotide polymorphisms near <i>PARK2</i> (rs2187213) (<i>p</i> = 6.15 × 10<sup>−6</sup>), <i>IL2RA</i> (rs7072793, rs7073236) (<i>p</i> = 7.89 × 10<sup>−6</sup>), and an intergenic locus on 9p21.3 (rs7047280) (<i>p</i> = 8.13 × 10<sup>−6</sup>) were identified as suggestive loci associated with plasma tau levels. <h3>Conclusions:</h3> <i>MAPT</i> H1c haplotype (rs242557) has previously been identified as a genetic risk factor for progressive supranuclear palsy and corticobasal degeneration. The current findings suggest that plasma tau concentration could be an endophenotype for identifying risk for 4-repeat tauopathies in older individuals.
Expression of Vascular Endothelial Growth Factor in Uveal Melanoma Is Independent of 6p21-Region Copy Number
Authors: Mohamed H. Abdel-Rahman, Elson L. Craig, Frederick H. Davidorf, Charis Eng
Journal: Clinical Cancer Research (2005)

Overexpression of vascular endothelial growth factor (VEGF) and overrepresentation of the 6p region have been reported with a wide variation in uveal melanoma. The aim of the current study is to identify the frequency of copy number alteration in the 6p21 region and its correlation with the expression of VEGF in uveal melanoma.We studied 88 uveal melanomas for copy number change in the 6p region by comparative genomic hybridization and/or chromogenic in situ hybridization. Expression of VEGF protein was estimated by immunohistochemistry. In 15 tumors, VEGF mRNA expression was also studied by quantitative reverse transcription-PCR (RT-PCR) and VEGF splice variants were detected by RT-PCR.Copy number of the 6p21 region was successfully estimated in 37 tumors. In 10 (27%) of those, overrepresentation of the 6p21 region was detected. There was no statistically significant difference in VEGF expression between tumors with and without gain of 6p21 (P = 0.82). VEGF expression was not confined to the tumors and was also detected in the surrounding normal tissue. Expression of VEGF, detected by quantitative RT-PCR, was concordant with expression of VEGF protein. Different VEGF isoforms were expressed in different tumors with no obvious correlation with disease status.VEGF is overexpressed in a significant number of uveal melanomas. It should be noted that VEGF is not a candidate oncogene in uveal melanoma with 6p gain/amplification. VEGF overexpression other than structural amplification is probably significant in the pathogenesis of uveal melanomas, and its mechanism must be sought.