tbuckley/cabot-search huggingface dataset:
European reference equations for CO and NO lung transfer
Authors: B. Aguilaniu, J. Maitre, S. Glénet, A. Gegout-Petit, H. Guénard
Journal: European Respiratory Journal (2008)

The aim of the present study was to calculate reference equations for carbon monoxide and nitric oxide transfer, measured in two distinct populations. The transfer factor of the lung for nitric oxide ( T L,NO ) and carbon monoxide ( T L,CO ) were measured in 303 people aged 18–94 yrs. Measurements were similarly made in two distant cities, using the single-breath technique. Capillary lung volume ( V c ) and membrane conductance, the diffusing capacity of the membrane ( D m ), for carbon monoxide ( D m,CO ) were derived. The transfer of both gases appeared to depend upon age, height, sex and localisation. The rate of decrease in both transfers increased after the age of 59 yrs. T L,NO /alveolar volume ( V A ) and T L,CO / V A were only age-dependent. The mean T L,NO / T L,CO was 4.75 and the mean D m / V c was 6.17 min −1 ·kPa −1 ; these parameters were independent of any covariate. V c and D m,CO calculations depend upon the choice of coefficients included in the Roughton–Forster equation. Values of 1.97 for D m,NO / D m,CO ratio and 12.86 min·kPa −1 for 1/red cell CO conductance are recommended. The scatter of transfer reference values in the literature, including the current study, is wide. The present results suggest that differences might be due to the populations themselves and not the methods alone.
RNF8 Regulates Assembly of RAD51 at DNA Double-Strand Breaks in the Absence of BRCA1 and 53BP1
Authors: Shinichiro Nakada, Rikako Miyamoto Yonamine, Koichi Matsuo
Journal: Cancer Research (2012)

The tumor suppressor protein BRCA1 localizes to sites of DNA double-strand breaks (DSB), promoting repair by homologous recombination through the recruitment of DNA damage repair proteins. In normal cells, homologous recombination largely depends on BRCA1. However, assembly of the pivotal homologous recombination regulator RAD51 can occur independently of BRCA1 in the absence of 53BP1, another DNA damage response protein. How this assembly process proceeds is unclear, but important to understand in tumor cell settings where BRCA1 is disabled. Here we report that RNF8 regulates BRCA1-independent homologous recombination in 53BP1-depleted cells. RNF8 depletion suppressed the recruitment of RAD51 to DSB sites without affecting assembly or phosphorylation of the replication protein RPA in neocarzinostatin-treated or X-ray-irradiated BRCA1/53BP1-depleted cells. Furthermore, RNF8/BRCA1/53BP1-depleted cells exhibited less efficient homologous recombination than BRCA1/53BP1-depleted cells. Intriguingly, neither RNF8 nor its relative RNF168 were required for RAD51 assembly at DSB sites in 53BP1-expressing cells. Moreover, RNF8-independent RAD51 assembly was found to be regulated by BRCA1. Together, our findings indicate a tripartite regulation of homologous recombination by RNF8, BRCA1, and 53BP1. In addition, our results predict that RNF8 inhibition may be a useful treatment of BRCA1-mutated/53BP1(low) cancers, which are considered resistant to treatment by PARP1 inhibitors and of marked current clinical interest.
DNA Polymorphism in a Worldwide Sample of Human X Chromosomes
Authors: Ning Yu, Yun-Xin Fu, Wen-Hsiung Li
Journal: Molecular Biology and Evolution (2002)

DNA sequence data from humans can provide insight into the history of modern humans and the genetic variability in human populations. We report here a study of human DNA sequence variation at an X-linked noncoding region of 10,346 bp. The sample consists of 62 X chromosomes from Africa, Europe, and Asia. Forty-four polymorphic sites were found among the 62 sequences, resulting in 23 different haplotypes. Statistical analyses of the data led to the following inferences. (1) There is strong evidence of human population expansion in the relatively recent past, and this population expansion has had a significant effect on the pattern of polymorphism at this locus. (2) Non-African populations were unlikely to have been derived from a very small number of African lineages. (3) There was considerable geographic subdivision in the ancient human population, which could be an important reason why many studies failed to detect population expansion. (4) The long-term effective population size of humans is between 12,000 and 15,000. And (5) a non-African specific variant was found at a frequency of 35% in non-Africans, an estimate supported by the genotyping of additional 80 non-African and 106 African X chromosomes. This variant could have arisen in Eurasia more than 140,000 years ago, predating the emergence of modern humans. Moreover, this haplotype and all other haplotypes coalesced to the most recent common ancestor of the sample, which was estimated to be older than 490,000 years. Therefore, this region may have a long history in Eurasia.
Investigation of the Association Between the Fecal Microbiota and Breast Cancer in Postmenopausal Women: a Population-Based Case-Control Pilot Study
Authors: James J. Goedert, Gieira Jones, Xing Hua, Xia Xu, Guoqin Yu, Roberto Flores, Roni T. Falk, Mitchell H. Gail, Jianxin Shi, Jacques Ravel, Heather Spencer Feigelson
Journal: JNCI Journal of the National Cancer Institute (2015)

We investigated whether the gut microbiota differed in 48 postmenopausal breast cancer case patients, pretreatment, vs 48 control patients. Microbiota profiles in fecal DNA were determined by Illumina sequencing and taxonomy of 16S rRNA genes. Estrogens were quantified in urine. Case-control comparisons employed linear and unconditional logistic regression of microbiota α-diversity (PD_whole tree) and UniFrac analysis of β-diversity, with two-sided statistical tests. Total estrogens correlated with α-diversity in control patients (Spearman Rho = 0.37, P = .009) but not case patients (Spearman Rho = 0.04, P = .77). Compared with control patients, case patients had statistically significantly altered microbiota composition (β-diversity, P = .006) and lower α-diversity (P = .004). Adjusted for estrogens and other covariates, odds ratio of cancer was 0.50 (95% confidence interval = 0.30 to 0.85) per α-diversity tertile. Differences in specific taxa were not statistically significant when adjusted for multiple comparisons. This pilot study shows that postmenopausal women with breast cancer have altered composition and estrogen-independent low diversity of their gut microbiota. Whether these affect breast cancer risk and prognosis is unknown.
Stressed out and asthmatic
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2005)

The ability to cope with stress may decrease susceptibility to asthma, according to Rangasamy and colleagues on page 47. The absence of the transcription factor Nrf2, which helps cells respond to oxidative stress, exacerbated allergic responses in mice, leading senior author Shyam Biswal to speculate that inducers of the Nrf2 pathway may have therapeutic potential for the treatment of human asthma.

Asthma is a complex disorder that involves the recruitment of inflammatory cells, including eosinophils, to the lungs. Once there, these cells release reactive oxygen species (ROS), which are thought to contribute to lung tissue damage. Levels of ROS are normally counterbalanced by antioxidants, which are present at lower levels in the airways of asthma patients.






Figure 

Influx of eosinophils (brown) into the lungs is increased in the absence of the transcription factor Nrf2 (bottom).




Here, Rangasamy and colleagues investigated the effect of oxidative stress on asthma in mice lacking Nrf2, which induces the expression of many antioxidant genes. They found that the lack of Nrf2 increased influx of cells into the airways, mucus production, airway hypersensitivity, and T helper 2 cytokine production—all characteristic symptoms of asthma—in response to challenge with an inhaled allergen.

Although the mechanisms involved remain largely unknown, the elevated cytokine levels likely resulted from increased activation of NF-κB, which is known to be activated by ROS. They now plan to look for alterations in the Nrf2 gene in asthma-prone humans, as they think defects in this gene might contribute to susceptibility to disease.
Night autonomic nerve activity and the effects of CPAP titration on it in obstructive sleep apnea syndrome
Authors: Keisaku Fujimoto, Midori Ura, Haruna Yamazaki
Journal: European Respiratory Journal (2014)

Purpose:  Sympathetic nerve activity (SymNA) has been suggested to be increased and contributed to the development of hypertension in obstructive sleep apnea syndrome (OSAS). The purpose is to examine the autonomic nerve activity (ANA) at night and the effects of CPAP titration in OSAS.   Subjects and methods:  Thirty-two patients with OSAS and 14 healthy volunteers without sleep disturbance and disordered breathing were recruited. All subjects were examined full polysomnography (PSG) and simultaneously measured ANA at night evaluated by complex demodulation analysis of the heart rate variability using a photoelectric pulse-wave sensor attached to a wrist. Fourteen patients of all were also examined CPAP titration and re-evaluated ANA. SymNA was estimated by LF/HF ratio and parasympathetic nerve activity (ParasymNA) was evaluated by occupancy and durability of high-powered HF.   Results:  OSAS showed a significant increased in LF/HF ratio and decreased both the occupancy and durability over 5 min of high-powered HF at night when compared with those in normal subjects. There were significant correlations between LF/HF ratio and AHI (r=0.57) or arousal index (r=0.51). CPAP titration was significantly decreased SymNA and improved parasymNA in OSAS.   Conclusion:  These findings suggest that the increased SymNA may contribute to the development of hypertension at night, and CPAP treatment may improved the increased SymNA and decreased blood pressure.
Prenatal Exposure to Alcohol Reduces Nephron Number and Raises Blood Pressure in Progeny
Authors: Stephen P. Gray, Kate M. Denton, Luise Cullen-McEwen, John F. Bertram, Karen M. Moritz
Journal: Journal of the American Society of Nephrology (2010)

Prenatal ethanol exposure is teratogenic, but the effects of ethanol on kidney development and the health of offspring are incompletely understood. Our objective was to investigate the effects of acute ethanol exposure during pregnancy on nephron endowment, mean arterial pressure, and renal function in offspring. We administered ethanol or saline by gavage to pregnant Sprague-Dawley rats on embryonic days 13.5 and 14.5. At 1 month of age, the nephron number was 15% lower and 10% lower in ethanol-exposed males and females, respectively, compared with controls. Mean arterial pressure, measured in conscious animals via indwelling tail-artery catheter, was 10% higher in both ethanol-exposed males and females compared with controls. GFR was 20% higher in ethanol-exposed males but 15% lower in ethanol-exposed females; moreover, males had increased proteinuria compared with controls. Furthermore, embryonic kidneys cultured in the presence of ethanol for 48 hours had 15% fewer ureteric branch points and tips than kidneys cultured in control media. Taken together, these data demonstrate that acute prenatal ethanol exposure reduces the number of nephrons, possibly as a result of inhibited ureteric branching morphogenesis, and that these changes affect adult cardiovascular and renal function.
Cost-Effectiveness of Filgrastim and Pegfilgrastim as Primary Prophylaxis Against Febrile Neutropenia in Lymphoma Patients
Authors: Nina Lathia, Pierre K. Isogai, Carlo De Angelis, Thomas J. Smith, Matthew Cheung, Nicole Mittmann, Jeffrey S. Hoch, Scott Walker
Journal: JNCI Journal of the National Cancer Institute (2013)

BackgroundFebrile neutropenia is a serious toxicity of cancer chemotherapy that is usually treated in hospital. We assessed the cost-effectiveness of filgrastim and pegfilgrastim as primary prophylaxis against febrile neutropenia in diffuse large B-cell lymphoma (DLBCL) patients undergoing chemotherapy.
Development of Retinoblastoma in the Absence of Telomerase Activity
Authors: J. Gupta, L.-P. Han, P. Wang, B. L. Gallie, S. Bacchetti
Journal: JNCI Journal of the National Cancer Institute (1996)

Background:The length and stability of telomeres (essential functional structures at the end of eukaryotic chromosomes) have been implicated in the control of cell lifespan. Most somatic cells lack telomerase, the enzyme that synthesizes telomeric DNA, and their telomeres shorten with cell division. Cells immortalized in vitro, on the other hand, express telomerase and maintain their telomeres. Telomerase activity has also been detected in the large majority of tumors from a variety of cancers. These observations have suggested that telomere maintenance is required for unlimited cell proliferation and that telomerase is a marker for cell immortality in vitro and in vivo.
MicroRNAs can regulate human APP levels
Authors: Neha Patel, David Hoang, Nathan Miller, Sara Ansaloni, Qihong Huang, Jack T Rogers, Jeremy C Lee, Aleister J Saunders
Journal: Molecular Neurodegeneration (2008)

A number of studies have shown that increased APP levels, resulting from either a genomic locus duplication or alteration in APP regulatory sequences, can lead to development of early-onset dementias, including Alzheimer's disease (AD). Therefore, understanding how APP levels are regulated could provide valuable insight into the genetic basis of AD and illuminate novel therapeutic avenues for AD. Here we test the hypothesis that APP protein levels can be regulated by miRNAs, evolutionarily conserved small noncoding RNA molecules that play an important role in regulating gene expression. Utilizing human cell lines, we demonstrate that miRNAs hsa-mir-106a and hsa-mir-520c bind to their predicted target sequences in the APP 3'UTR and negatively regulate reporter gene expression. Over-expression of these miRNAs, but not control miRNAs, results in translational repression of APP mRNA and significantly reduces APP protein levels. These results are the first to demonstrate that levels of human APP can be regulated by miRNAs.
Long-Term Clinical Outcomes After Drug-Eluting and Bare-Metal Stenting in Massachusetts
Authors: Laura Mauri, Treacy S. Silbaugh, Robert E. Wolf, Katya Zelevinsky, Ann Lovett, Zheng Zhou, Frederic S. Resnic, Sharon-Lise T. Normand
Journal: Circulation (2008)

Background— Drug-eluting stents (DES) reduce the need for repeat revascularization, but their long-term safety relative to that of bare-metal stents (BMS) in general use remains uncertain. We sought to compare the clinical outcome of patients treated with DES with that of BMS. Methods and Results— All adults undergoing percutaneous coronary intervention with stenting between April 1, 2003, and September 30, 2004, at non–US government hospitals in Massachusetts were identified from a mandatory state database. Patients were classified from the index admission according to stent types used. Clinical and procedural risk factors were collected prospectively. Risk-adjusted mortality, myocardial infarction, and revascularization rate differences (DES−BMS) were estimated through propensity score matching without replacement. A total of 11 556 patients were treated with DES, and 6237 were treated with BMS, with unadjusted 2-year mortality rates of 7.0% and 12.6%, respectively ( P &lt;0.0001). In 5549 DES patients matched to 5549 BMS patients, 2-year risk-adjusted mortality rates were 9.8% and 12.0%, respectively ( P =0.0002), whereas the respective rates for myocardial infarction and target-vessel revascularization were 8.3% versus 10.3% ( P =0.0005) and 11.0% versus 16.8% ( P &lt;0.0001). Conclusions— DES treatment was associated with lower rates of mortality, myocardial infarction, and target-vessel revascularization than BMS treatment in similar patients in a matched population-based study. Comprehensive follow-up in this inclusive population is warranted to identify whether similar safety and efficacy remain beyond 2 years.
Linezolid for XDR-TB
Authors: Richard D Turner
Journal: Thorax (2013)

Linezolid for XDR-TBThis randomised phase 2a trial in South Korea recruited 41 patients with sputum culturepositive pulmonary extensively drug-resistant tuberculosis (XDR-TB), who had failed to respond to 6 months of available treatment.Daily dosage of 600 mg linezolid was added either immediately or after a delay of two months.After four months of linezolid, or two consecutive negative sputum smears, patients continued either 300 mg or 600 mg daily for another 18 months.After 4 months, the primary outcome of sputum culture conversion was achieved in 15 of the 19 immediately treated patients, and in 7 of 20 in the delayed treatment group.Eighty-seven per cent of all linezolid-treated patients had negative sputum cultures after 6 months.Significant adverse events including myelosupression, peripheral neuropathy, ocular toxicity and rhabdomyolysis occurred in 82%.The majority resolved, but linezolid was consequently withdrawn in three patients.The lower dose of the drug was associated with fewer adverse events, but trough linezolid blood levels in the 300 mg group were lower than the mean minimum inhibitory concentration in nine patients including two who developed drug resistance.Resistance was also seen in two patients in the 600 mg group.Only 13 patients had completed 18 months of linezolid on protocol which was ongoing at the time of reporting.Linezolid is effective in chronic XDR-TB at the cost of frequent adverse events.The optimum dose and duration of therapy, as well as its exact place in an XDR-TB treatment regimen, remain unclear.Linezolid should be used only under experienced supervision.
Micro-Computed Tomography—Current Status and Developments
Authors: Erik L. Ritman
Journal: Annual Review of Biomedical Engineering (2004)

The recent rapid increase in interest in tomographic imaging of small animals and of human (and large animal) organ biopsies is driven largely by drug discovery, cancer detection/monitoring, phenotype identification and/or characterization, and development of disease detection methods and monitoring efficacies of drugs in disease treatment. In biomedical applications, micro-computed tomography (CT) scanners can function as scaled-down (i.e., mini) clinical CT scanners that provide a three-dimensional (3-D) image of most, if not the entire, torso of a mouse at image resolution (50-100 microm) scaled proportional to that of a human CT image. Micro-CT scanners, on the other hand, image specimens the size of intact rodent organs at spatial resolutions from cellular (20 microm) down to subcellular dimensions (e.g., 1 microm) and fill the resolution-hiatus between microscope imaging, which resolves individual cells in thin sections of tissue, and mini-CT imaging of intact volumes.
Mesenchymal stem cells are conditionally therapeutic in preclinical models of rheumatoid arthritis
Authors: Anastasia Papadopoulou, Minas Yiangou, Evangelia Athanasiou, Nikolaos Zogas, Panayotis Kaloyannidis, Ioannis Batsis, Athanasios Fassas, Achilles Anagnostopoulos, Evangelia Yannaki
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objective</h3> The role of mesenchymal stem cells (MSC) in experimental arthritis is undoubtedly conflicting. This study explored the effect of bone marrow-derived MSC in previously untested and pathogenetically different models of rheumatoid arthritis (RA). <h3>Methods</h3> MSC were tested both in an induced (adjuvant-induced) and a spontaneous (K/BxN) arthritis model. Arthritis was assessed clinically and histologically. The proliferation of splenocytes and fibroblast-like synoviocytes (FLS) in the presence of MSC was measured by radioactivity incorporation. Toll-like receptor (TLR) expression was measured by real-time PCR. T-regulatory cell (Treg) frequency, T-cell apoptosis and cytokine secretion were monitored by flow cytometry. <h3>Results</h3> MSC, in vitro, strongly inhibited critical cell populations; splenocytes and FLS. In contrast, MSC proved ineffective in vivo, unless they were administered before disease onset, an effect implying that the inflammatory arthritic milieu potentially abrogates MSC immunomodulatory properties. In order to alleviate inflammation before MSC infusion, the authors administered, at arthritis onset, a short course with a proteasome inhibitor, bortezomib, whereas MSC were infused when established disease was expected. The bortezomib plus MSC group demonstrated a significantly decreased arthritis score over arthritic, MSC-only, bortezomib-only groups, also confirmed by histology and immunohistochemistry. The bortezomib plus MSC combination restored TLR expression and Treg frequency in blood and normalised FLS and splenocyte proliferation, apoptosis and cytokine secretion. <h3>Conclusion</h3> MSC lose their immunomodulatory properties when infused in the inflammatory micromilieu of autoimmune arthritis. Conditioning of the recipient with bortezomib alters the disease microenvironment enabling MSC to modulate arthritis. Should milieu limitations also operate in human disease, this approach could serve as a strategy to treat RA by MSC.
Fibroblast Growth Factor 21 Levels in Young Healthy Females Display Day and Night Variations and Are Increased in Response to Short-Term Energy Deprivation Through a Leptin-Independent Pathway
Authors: Joo-Pin Foo, Konstantinos N. Aronis, John P. Chamberland, Jason Paruthi, Hyun-Seuk Moon, Christos S. Mantzoros
Journal: Diabetes Care (2012)

Fibroblast growth factor (FGF)-21 is an endocrine factor with potent metabolic effects. Its day-night patterns of secretion and/or its physiological response to energy deprivation and relationship to free fatty acids (FFAs) and/or leptin remain to be fully elucidated. We aim to elucidate day-night pattern of FGF-21 levels and its relationship to FFA, to assess whether energy deprivation alters its circulating patterns, and to examine whether leptin may mediate these changes.Six healthy lean females were studied for 72 h in a cross-over interventional study under three different conditions: on isocaloric diet and in a fasting state with administration of either placebo or metreleptin in physiological replacement doses. Blood samples were obtained hourly from 8:00 a.m. on day 4 until 8:00 a.m. on day 5.FGF-21 exhibited day-night variation pattern during the isocaloric fed state. Fasting significantly increased FGF-21 levels (P < 0.01) via a leptin-independent pathway. Day-night variation pattern in the fed state was lost on fasting. Leptin replacement in the hypoleptinemic state restored approximate entropy of FGF-21 time series but did not alter circulating levels. FGF-21 levels were closely cross-correlated with FFA levels in all three states.A day-night variation in the levels of FGF-21 exists in young lean females in the fed state. Energy deprivation increases FGF-21 levels via a leptin-independent pathway. The interaction between FGF-21 and starvation-induced lipolysis, as indicated by its close cross-correlations with FFA in both fed state and energy deprivation, needs to be studied further.