tbuckley/cabot-search huggingface dataset:
Renal Tubulointerstitial Changes after Internal Irradiation with α-Particle–Emitting Actinium Daughters
Authors: Jaspreet Singh Jaggi, Surya V. Seshan, Michael R. McDevitt, Krista LaPerle, George Sgouros, David A. Scheinberg
Journal: Journal of the American Society of Nephrology (2005)

The effect of external gamma irradiation on the kidneys is well described. However, the mechanisms of radiation nephropathy as a consequence of targeted radionuclide therapies are poorly understood. The functional and morphologic changes were studied chronologically (from 10 to 40 wk) in mouse kidneys after injection with an actinium-225 (225Ac) nanogenerator, a molecular-sized, antibody-targeted, in vivo generator of alpha-particle-emitting elements. Renal irradiation from free, radioactive daughters of 225Ac led to time-dependent reduction in renal function manifesting as increase in blood urea nitrogen. The histopathologic changes corresponded with the decline in renal function. Glomerular, tubular, and endothelial cell nuclear pleomorphism and focal tubular cell injury, lysis, and karyorrhexis were observed as early as 10 wk. Progressive thinning of the cortex as a result of widespread tubulolysis, collapsed tubules, glomerular crowding, decrease in glomerular cellularity, interstitial inflammation, and an elevated juxtaglomerular cell count were noted at 20 to 30 wk after treatment. By 35 to 40 wk, regeneration of simplified tubules with tubular atrophy and loss with focal, mild interstitial fibrosis had occurred. A lower juxtaglomerular cell count with focal cytoplasmic vacuolization, suggesting increased degranulation, was also observed in this period. A focal increase in tubular and interstitial cell TGF-beta1 expression starting at 20 wk, peaking at 25 wk, and later declining in intensity with mild increase in the extracellular matrix deposition was noticed. These findings suggest that internally delivered alpha-particle irradiation-induced loss of tubular epithelial cells triggers a chain of adaptive changes that result in progressive renal parenchymal damage accompanied by a loss of renal function. These findings are dissimilar to those seen after gamma or beta irradiation of kidneys.
Characterization of the HDAC1 Complex That Regulates the Sensitivity of Cancer Cells to Oxidative Stress
Authors: Takuya Kato, Yohei Shimono, Masaki Hasegawa, Mayumi Jijiwa, Atsushi Enomoto, Naoya Asai, Yoshiki Murakumo, Masahide Takahashi
Journal: Cancer Research (2009)

Histone deacetylases (HDAC) are involved in carcinogenesis through their regulation of cell proliferation, differentiation, and survival. The inhibitors of HDAC exhibit profound synergistic effects in cancer treatment when combined with other anticancer drugs. However, the molecular mechanisms underlying this synergy are not fully understood. Here, we show that HDAC1 increases the resistance of cancer cells to oxidative stress by negatively regulating the expression of thioredoxin binding protein 2 (TBP-2). We found that the recruitment of HDAC1 to the TBP-2 promoter is mediated by a protein complex consisting of RET finger protein (RFP; also called TRIM27) and the trimeric transcription factor NF-Y. Accordingly, RNA interference-mediated depletion of RFP led to the disruption of the protein complex and a marked increase in the sensitivity of cancer cells to cisplatin, a potent inducer of oxidative stress. Furthermore, high levels of RFP expression correlated with down-regulation of TBP-2 in human colon cancers and were associated with poor clinical outcome. These findings reveal the diverse cancer-promoting activities of HDAC1 and identify RFP as a key regulator that provides cancer cells with resistance to anticancer drugs.
Cardiac remodelling hinders activation of cyclooxygenase-2, diminishing protection by delayed pharmacological preconditioning: role of HIF1α and CREB
Authors: Jianhua Feng, Eliana Lucchinetti, Gregor Fischer, Min Zhu, Kathrin Zaugg, Marcus C. Schaub, Michael Zaugg
Journal: Cardiovascular Research (2008)

We tested whether delayed pharmacologic preconditioning elicited by isoflurane is protective in infarct-remodelled hearts. Male Wistar rats were treated with the preconditioning drug isoflurane 6 weeks after permanent ligation of the left anterior descending coronary artery. Twenty-four and 48 h later, hearts were perfused on the Langendorff system and treated with cyclooxygenase-2 or 12-lipoxygenase inhibitors before exposure to 40 min of ischaemia followed by 90 min of reperfusion. Infarct size was determined by triphenyltetrazolium chloride staining and lactate dehydrogenase release. Cyclooxygenase-2 expression and activity were measured by Western blotting and colorimetric assay. Nuclear translocation of cyclooxygenase-2-inducing transcription factors HIF1α, CREB, STAT3, and NFκB was determined. Post-infarct, remodelled hearts exhibit alterations in cellular signalling, time course and extent of isoflurane-induced late protection. While remodelled, preconditioned hearts exhibited protection exclusively at 24 h, healthy hearts showed sustained protection for up to 48 h, which correlated with cyclooxygenase-2 protein expression and enzymatic activity. The cyclooxygenase-2 inhibitors celecoxib and NS-398, but not the 12-lipoxygenase inhibitor cinnamyl-3,4-dihydroxycyanocinnamate, abolished delayed protection in both healthy and remodelled hearts, identifying cyclooxygenase-2 as a key mediator of late protection in both models. Isoflurane induced nuclear translocation of HIF1α in all hearts, but CREB was exclusively activated in healthy but not remodelled myocardium, which expressed higher levels of the CREB antagonist ICER. Delayed protection by isoflurane in remodelled hearts was more vulnerable to inhibition by celecoxib. Isoflurane failed to mobilize cyclooxygenase-2-inducing CREB in ICER-overexpressing, remodelled hearts, which was associated with a shortening of the second window of protection.
Demographic and medical consequences of the postponement of parenthood
Authors: L. Schmidt, T. Sobotka, J. G. Bentzen, A. Nyboe Andersen
Journal: Human Reproduction Update (2011)

BACKGROUNDAcross the developed world couples are postponing parenthood. This review assesses the consequences of delayed family formation from a demographic and medical perspective. One main focus is on the quantitative importance of pregnancy postponement.
Identification of the CD4+ T cell as a major pathogenic factor in ischemic acute renal failure
Authors: Melissa J. Burne, Frank Daniels, Asmaa El Ghandour, Shamila Mauiyyedi, Robert B. Colvin, Michael P. O’Donnell, Hamid Rabb
Journal: Journal of Clinical Investigation (2001)

Leukocytes have been implicated in the pathogenesis of ischemic acute renal failure (ARF), but the roles of the individual cell types involved are largely unknown. Recent indirect evidence suggests that T cells may play an important role in a murine model of ARF. In the current study, we found that mice deficient in T cells (nu/nu mice) are both functionally and structurally protected from postischemic renal injury. Reconstitution of nu/nu mice with wild-type T cells restored postischemic injury. We then analyzed the contribution of the individual T cell subsets to postischemic injury and found that mice deficient in CD4+ T cells, but not mice deficient in CD8+ T cells, were significantly protected from ARF. Direct evidence for a pathophysiologic role of the CD4+ T cell was obtained when reconstitution of CD4-deficient mice with wild-type CD4+ T cells restored postischemic injury. In addition, adoptive transfers of CD4+ T cells lacking either the costimulatory molecule CD28 or the ability to produce IFN-γ were inadequate to restore injury phenotype. These results demonstrate that the CD4+ T cell is an important mediator of ischemic ARF, and targeting this cell may yield novel therapies.
Ancestral Resurrection of the Drosophila S2E Enhancer Reveals Accessible Evolutionary Paths through Compensatory Change
Authors: Carlos Martinez, Joshua S. Rest, Ah-Ram Kim, Michael Ludwig, Martin Kreitman, Kevin White, John Reinitz
Journal: Molecular Biology and Evolution (2014)

Upstream regulatory sequences that control gene expression evolve rapidly, yet the expression patterns and functions of most genes are typically conserved. To address this paradox, we have reconstructed computationally and resurrected in vivo the cis-regulatory regions of the ancestral Drosophila eve stripe 2 element and evaluated its evolution using a mathematical model of promoter function. Our feed-forward transcriptional model predicts gene expression patterns directly from enhancer sequence. We used this functional model along with phylogenetics to generate a set of possible ancestral eve stripe 2 sequences for the common ancestors of 1) D. simulans and D. sechellia; 2) D. melanogaster, D. simulans, and D. sechellia; and 3) D. erecta and D. yakuba. These ancestral sequences were synthesized and resurrected in vivo. Using a combination of quantitative and computational analysis, we find clear support for functional compensation between the binding sites for Bicoid, Giant, and Krüppel over the course of 40-60 My of Drosophila evolution. We show that this compensation is driven by a coupling interaction between Bicoid activation and repression at the anterior and posterior border necessary for proper placement of the anterior stripe 2 border. A multiplicity of mechanisms for binding site turnover exemplified by Bicoid, Giant, and Krüppel sites, explains how rapid sequence change may occur while maintaining the function of the cis-regulatory element.
Efficacy of Meta-Cognitive Therapy for Adult ADHD
Authors: Mary V. Solanto, David J. Marks, Jeanette Wasserstein, Katherine Mitchell, Howard Abikoff, Jose Ma. J. Alvir, Michele D. Kofman
Journal: American Journal of Psychiatry (2010)

The authors investigated the efficacy of a 12-week manualized meta-cognitive therapy group intervention designed to enhance time management, organization, and planning in adults with attention deficit hyperactivity disorder (ADHD).Eighty-eight clinically referred adults who met DSM-IV criteria for ADHD according to clinical and structured diagnostic interviews and standardized questionnaires were stratified by ADHD medication use and otherwise randomly assigned to receive meta-cognitive therapy or supportive psychotherapy in a group modality. Meta-cognitive therapy uses cognitive-behavioral principles and methods to impart skills and strategies in time management, organization, and planning and to target depressogenic and anxiogenic cognitions that undermine effective self-management. The supportive therapy condition controlled for nonspecific aspects of treatment by providing support while avoiding discussion of cognitive-behavioral strategies. Therapeutic response was assessed by an independent (blind) evaluator via structured interview before and after treatment as well as by self-report and collateral informant behavioral ratings.General linear models comparing change from baseline between treatments revealed statistically significant effects for self-report, collateral report, and independent evaluator ratings of DSM-IV inattention symptoms. In dichotomous indices of therapeutic response, a significantly greater proportion of members of the meta-cognitive therapy group demonstrated improvement compared with members of the supportive therapy group. Logistic regression examining group differences in operationally defined response (controlling for baseline ADHD severity) revealed a robust effect of treatment group (odds ratio=5.41; 95% CI=1.77-16.55).Meta-cognitive therapy yielded significantly greater improvements in dimensional and categorical estimates of severity of ADHD symptoms compared with supportive therapy. These findings support the efficacy of meta-cognitive therapy as a viable psychosocial intervention.
Rubber band abrasive biopsy of esophagus
Authors: J. M. Gospe
Journal: JAMA (1968)

<h3>To the Editor:—</h3> In a recent editorial (<b>203</b>:356, 1968), it was indicated that the incidence of complete heart block in acute myocardial infarction ranges from 3 to 6% of all cases. It was also noted that several investigators report salvage rates as high as 10% of these patients, with the conclusion that similar salvage among all cases of postinfarction complete heart block could result in "the saving of 10,000 to 15,000 lives annually." The per annum total mortality from acute myocardial infarction in this country is generally accepted as about 500,000 individuals. Since it is known that 60% to 75% of all myocardial infarction deaths occur before the patient is admitted to the hospital<sup>1</sup>and also that the inhospital death rate from transmural myocardial infarction is about 25%,<sup>2</sup>then the mortality from significant, ie, transmural, myocardial infarction is about 50%.<sup>3</sup>This would indicate that the total
Yin Yang 1 promotes hepatic steatosis through repression of farnesoid X receptor in obese mice
Authors: Yan Lu, Zhimin Ma, Zhijian Zhang, Xuelian Xiong, Xiaolin Wang, Huijie Zhang, Guojun Shi, Xuefeng Xia, Guang Ning, Xiaoying Li
Journal: Gut (2013)

<h3>Background</h3> Non-alcoholic fatty liver disease (NAFLD) is characterised by accumulation of excessive triglycerides in the liver. Obesity is usually associated with NAFLD through an unknown mechanism. <h3>Objective</h3> To investigate the roles of Yin Yang 1 (YY1) in the progression of obesity-associated hepatosteatosis. <h3>Methods</h3> Expression levels of hepatic YY1 were identified by microarray analysis in high-fat-diet (HFD)-induced obese mice. Liver triglyceride metabolism was analysed in mice with YY1 overexpression and suppression. <h3>Results</h3> YY1 expression was markedly upregulated in HFD-induced obese mice and NAFLD patients. Overexpression of YY1 in healthy mice promoted hepatosteatosis under high-fat dietary conditions, whereas liver-specific ablation of YY1 using adenoviral shRNA ameliorated triglyceride accumulation in obese mice. At the molecular level, YY1 suppressed farnesoid X receptor (FXR) expression through binding to the YY1 responsive element at intron 1 of the FXR gene. <h3>Conclusions</h3> These findings indicate that YY1 plays a crucial role in obesity-associated hepatosteatosis, through repression of FXR expression.
Largest healthcare privatisation plan in Spain is to go ahead, despite massive opposition
Authors: A. Garcia Rada
Journal: BMJ (2013)

More than 300 staff from half the 270 primary care centres in the Madrid region have tendered letters of resignation to their local health authorities in a protest against a plan to privatise six hospitals, 10% of primary care centres, and all auxiliary services in the region. The plan is expected to be implemented this summer.

The resignations will take effect once the regional government invites tenders for private companies to run the primary care centres, expected in the next two months.

Javier Fernandez-Lasquetty, head of the regional health department, has dismissed the resignations. …
Deep short-read sequencing of chromosome 17 from the mouse strains A/J and CAST/Ei identifies significant germline variation and candidate genes that regulate liver triglyceride levels
Authors: Ian Sudbery, Jim Stalker, Jared T Simpson, Thomas Keane, Alistair G Rust, Matthew E Hurles, Klaudia Walter, Dee Lynch, Lydia Teboul, Steve D Brown, Heng Li, Zemin Ning, Joseph H Nadeau, Colleen M Croniger, Richard Durbin, David J Adams
Journal: Genome biology (2009)

Genome sequences are essential tools for comparative and mutational analyses. Here we present the short read sequence of mouse chromosome 17 from the Mus musculus domesticus derived strain A/J, and the Mus musculus castaneus derived strain CAST/Ei. We describe approaches for the accurate identification of nucleotide and structural variation in the genomes of vertebrate experimental organisms, and show how these techniques can be applied to help prioritize candidate genes within quantitative trait loci.
Use of statins is associated with an increased risk of rheumatoid arthritis
Authors: H J I de Jong, O H Klungel, L van Dijk, R J Vandebriel, H G M Leufkens, JW van der Laan, J W Cohen Tervaert, H van Loveren
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Objectives</h3> Statins offer significant cardiovascular benefits. Their use, however, influences immune regulation, which may potentially facilitate autoimmunity, eventually resulting in autoimmune diseases such as rheumatoid arthritis (RA).The authors studied whether statin use was associated with an increased risk of developing RA by conducting a case–control study using the Netherlands Information Network of General Practice database. <h3>Methods</h3> The authors identified 508 patients aged 40 years or older with a first-time diagnosis of RA in the period 2001–2006. Each RA case was matched to five controls for age, sex and index date, which was selected 1 year before the first diagnosis of RA. Odds ratios for the first-time diagnosis of RA were verified by a referral to a rheumatologist and/or at least one prescription of disease-modifying anti-rheumatic drugs and/or two prescriptions of corticosteroids after the date of first diagnosis. <h3>Results</h3> Cases were more often users of statins (15.9%) compared to controls (8.6%). After adjustment for cardiovascular risk factors and use of comedication, statin use was associated with an increased risk of incident RA (adjusted OR, 1.71 (95% CI 1.16 to 2.53); p=0.007). A consistent trend of increasing risk with increased cumulative duration, cumulative defined daily doses and number of prescriptions was not observed. However, a small trend between the potency of statin treatment and the risk of RA was found. <h3>Conclusions</h3> Statin use seems to be associated with an increased risk of developing RA. Our findings should be replicated by additional studies.
Internal biliary drainage, unlike external drainage, does not suppress the regeneration of cholestatic rat liver after partial hepatectomy
Authors: Hideaki Suzuki, Shinsuke Iyomasa, Yuji Nimura, Shonen Yoshida
Journal: Hepatology (1994)

We previously showed that hepatic cells proliferate in obstructive jaundice alone without partial hepatectomy and found that external biliary drainage for obstructive jaundice markedly suppresses liver regeneration after partial hepatectomy. In this study, we produced a model system for internal biliary drainage in which bile was drained into the stomach of rat fed a liquid diet. The regeneration capacity of the liver was assessed on the basis of the induction of DNA polymerase-alpha activity, as well as the mitotic index of hepatic cells. A remarkable difference was observed in the regeneration capacities of cholestatic livers between two groups--one in which jaundice was released by the internal and one by external biliary drainage before hepatectomy. After 5 days of internal biliary drainage, the regeneration capacity remained at a level comparable to that of sham-operated control rats, in sharp contrast to the impaired regeneration after external biliary drainage. These results clearly indicate that internal biliary drainage is preferable for release of biliary obstruction before partial resection of cholestatic liver.
Guanosine triphosphate cyclohydrolase I regulates nitric oxide synthesis in renal proximal tubules.
Authors: B Amoah-Apraku, S S Tang, J R Ingelfinger, N J Guzman
Journal: Journal of the American Society of Nephrology (1995)

The synthesis of nitric oxide by proximal tubule-inducible nitric oxide synthase requires tetrahydrobiopterin as a cofactor. To determine whether tetrahydrobiopterin synthesis is required for nitric oxide production, nitrite release by mouse proximal tubule cells treated with 2,4-diamino-6-hydroxypyrimidine, an inhibitor of the rate-limiting enzyme in the de novo synthesis of tetrahydrobiopterin from guanosine triphosphate, guanosine triphosphate cyclohydrolase I, was measured. Treatment with lipopolysaccharide (0.1 micrograms/mL) and interferon-gamma (100 U/mL) for 12 h increased nitrite production from 2.7 +/- 0.2 to 25.4 +/- 1.3 nmol/mg of protein (P < 0.001; N = 9). 2,4-Diamino-6-hydroxypyrimidine (6 mM) reduced lipopolysaccharide/interferon-gamma-induced nitrite production by 53.1 +/- 3.4%. Sepiapterin, a substrate for tetrahydrobiopterin synthesis via the dihydrofolate reductase-dependent pterin salvage pathway, prevented the inhibition by 2,4-diamino-6-hydroxypyrimidine, an effect that was blocked by methotrexate. In conclusion, guanosine triphosphate cyclohydrolase I activity is required for cytokine-induced nitric oxide production by proximal tubular epithelium. The inhibition of guanosine triphosphate cyclohydrolase I could prove useful in the treatment of nitric oxide-mediated renal disorders.
Barrier function regulates epidermal lipid and DNA synthesis
Authors: E. PROKSCH, W.M. HOLLERAN, G.K. MENON, P.M. ELIAS, K.R. FEINGOLD
Journal: British Journal of Dermatology (1993)

The stratum corneum, the permeability barrier between the internal milieu and the environment, is composed of fibrous protein-enriched corneocytes and a lipid-enriched intercellular matrix. The lipids are a mixture of sphingolipids, cholesterol and free fatty acids, which form intercellular membrane bilayers. Lipid synthesis occurs in the keratinocytes in all nucleated layers of the epidermis, and the newly synthesized lipids are delivered by lamellar bodies to the interstices of the stratum corneum during epidermal differentiation. Disruption of barrier function by topical acetone treatment results in an increase in the synthesis of free fatty acids, sphingolipids and cholesterol in the living layers of the epidermis, leading to barrier repair. Cholesterol and sphingolipid synthesis are regulated by the rate-limiting enzymes HMG CoA reductase and serine palmitoyi transferase (SPT). respectively. Acute barrier disruption leads to an increase in both enzymes, but with a different time curve: increase in HMG CoA reductase activity begins at 1.5 h, whereas the increase in SPT activity occurs 6 h after barrier impairment. Topical application of HMG CoA reductase or SPT inhibitors after acetone treatment delays barrier repair, providing further evidence for a role of cholesterol and sphingolipids in epidermal barrier function. Repeated application of lovastatin to untreated skin results in disturbed barrier function accompanied by increased DNA synthesis and epidermal hyperplasia. Therefore, we have examined the specific relationship between barrier function and epidermal DNA synthesis. After acute and chronic disturbances not only lipid, but also DNA synthesis, is stimulated. Thus, stimulation of DNA synthesis leading to epidermal hyperplasia may be a second mechanism by which the epidermis repairs defects in barrier function. The link between barrier function and both lipid and DNA synthesis is supported further by occlusion studies. Artificial barrier repair by latex occlusion prevents an increase in both lipid and DNA synthesis. In addition, increased epidermal lipid and DNA synthesis in essential fatty-acid deficiency can be reversed by topical applications of the n-6 unsaturated fatty acids, linoleic or columbinic acid. These studies may be of relevance in understanding the pathogenesis of hyperproliferative skin diseases, such as ichthyosis, psoriasis, atopic dermatitis, and irritant contact dermatitis.
Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial
Authors: Naiyer A Rizvi, Julien Mazières, David Planchard, Thomas E Stinchcombe, Grace K Dy, Scott J Antonia, Leora Horn, Hervé Lena, Elisa Minenza, Bertrand Mennecier, Gregory A Otterson, Luis T Campos, David R Gandara, Benjamin P Levy, Suresh G Nair, Gérard Zalcman, Jürgen Wolf, Pierre-Jean Souquet, Editta Baldini, Federico Cappuzzo, Christos Chouaid, Afshin Dowlati, Rachel Sanborn, Ariel Lopez-Chavez, Christian Grohe, Rudolf M Huber, Christopher T Harbison, Christine Baudelet, Brian J Lestini, Suresh S Ramalingam
Journal: The Lancet Oncology (2015)