tbuckley/cabot-search huggingface dataset:
Epigenetic modifications are associated with inter-species gene expression variation in primates
Authors: Xiang Zhou, Carolyn E Cain, Marsha Myrthil, Noah Lewellen, Katelyn Michelini, Emily R Davenport, Matthew Stephens, Jonathan K Pritchard, Yoav Gilad
Journal: Genome biology (2014)

Abstract Background Changes in gene regulation have long been thought to play an important role in evolution and speciation, especially in primates. Over the past decade, comparative genomic studies have revealed extensive inter-species differences in gene expression levels, yet we know much less about the extent to which regulatory mechanisms differ between species. Results To begin addressing this gap, we perform a comparative epigenetic study in primate lymphoblastoid cell lines, to query the contribution of RNA polymerase II and four histone modifications, H3K4me1, H3K4me3, H3K27ac, and H3K27me3, to inter-species variation in gene expression levels. We find that inter-species differences in mark enrichment near transcription start sites are significantly more often associated with inter-species differences in the corresponding gene expression level than expected by chance alone. Interestingly, we also find that first-order interactions among the five marks, as well as chromatin states, do not markedly contribute to the degree of association between the marks and inter-species variation in gene expression levels, suggesting that the marginal effects of the five marks dominate this contribution. Conclusions Our observations suggest that epigenetic modifications are substantially associated with changes in gene expression levels among primates and may represent important molecular mechanisms in primate evolution.
Quantitative structural study of pulmonary circulation in the newborn with aortic atresia, stenosis, or coarctation.
Authors: S G Haworth, L Reid
Journal: Thorax (1977)

Study of the structural features of the pulmonary circulation in various types of congenital heart disease makes it possible to correlate function and structure in the fetal and newborn lung. We applied quantitative morphometric techniques to the injected and inflated lungs of newborn infants who had died with obstruction to left ventricular outflow from aortic atresia, stenosis, or coarctation. The structure and development of the pulmonary circulation was judged by the number of arteries and veins and their size and wall structure, with particular attention to vessels within the respiratory unit. The study established for the first time that the structure of the pulmonary circulation is modified by the antenatal abnormalities in blood flow that occur through the heart and great vessels in the presence of congenital heart disease. Fetal multiplication of intra-acinar arteries in aortic atresia and stenosis is increased as also is the muscularity of both pre- and intra-acinar arteries and veins, muscle extending into smaller and more peripheral vessels than is normal at birth. When the pulmonary circulation is normal before birth but arterial pressure and flow are abnormally increased at birth, as in coarctation with patent ductus and ventricular septal defect, an increase in arterial diameter and muscularity is apparent within the first week of life.
Streamlining weaning: protocols and weaning units
Authors: A K Simonds
Journal: Thorax (2005)

Use of weaning protocols and specialised weaning units for patients who fail to wean from mechanical ventilation

Discontinuation of ventilation is estimated to take up to 40% of the total duration of ventilatory support, and around 3–6% of patients admitted to the intensive care unit (ICU) require a prolonged course of mechanical ventilation (MV).1 Patients being liberated from ventilatory support therefore occupy a significant number of ICU beds and have a major impact on healthcare resources. There have been several recent key developments in the field of weaning—the use of weaning protocols, ventilatory strategies to reduce the need for invasive ventilation and facilitate successful extubation, and the creation of regional long term ventilator units. All have the potential to affect weaning outcome, but how valuable are they in practice?

In 1996 Ely and colleagues2 showed that the implementation of a standardised protocol of daily trials of spontaneous breathing performed by nursing staff reduced the total duration of MV from 6 to 4.5 days, and complications such as need for reintubation, tracheostomy, and duration of MV >21 days were also decreased, resulting in a reduction in ICU costs. Similar protocols have reduced the duration of MV, although not necessarily ICU stay.3 Smyrnios et al 4 implemented a hospital-wide weaning protocol and found a decrease in the need for tracheostomy by a third and a reduction in mean hospital stay from 37.5 to 24.7 days, resulting in a 30% fall in cost per case.

Despite these findings, weaning protocols have not been taken up universally. For example, in a survey of ICUs in England commissioned by the Department of Health, protocol directed weaning was reported in less than one in five units.5 This may be due to a variety of reasons including differences in healthcare practice and cultures, …
Circumcision in HIV-infected men and its effect on HIV transmission to female partners in Rakai, Uganda: a randomised controlled trial
Authors: Maria J Wawer, Frederick Makumbi, Godfrey Kigozi, David Serwadda, Stephen Watya, Fred Nalugoda, Dennis Buwembo, Victor Ssempijja, Noah Kiwanuka, Lawrence H Moulton, Nelson K Sewankambo, Steven J Reynolds, Thomas C Quinn, Pius Opendi, Boaz Iga, Renee Ridzon, Oliver Laeyendecker, Ronald H Gray
Journal: The Lancet (2009)
Molecular Pathways: Vasculogenic Mimicry in Tumor Cells: Diagnostic and Therapeutic Implications
Authors: Dawn A. Kirschmann, Elisabeth A. Seftor, Katharine M. Hardy, Richard E.B. Seftor, Mary J.C. Hendrix
Journal: Clinical Cancer Research (2012)

Abstract Tumor cell vasculogenic mimicry (VM) describes the functional plasticity of aggressive cancer cells forming de novo vascular networks, thereby providing a perfusion pathway for rapidly growing tumors, transporting fluid from leaky vessels, and/or connecting with endothelial-lined vasculature. The underlying induction of VM seems to be related to hypoxia, which may also promote the plastic, transendothelial phenotype of tumor cells capable of VM. Since its introduction in 1999 as a novel paradigm for melanoma tumor perfusion, many studies have contributed new insights into the underlying molecular pathways supporting VM in a variety of tumors, including melanoma, glioblastoma, carcinomas, and sarcomas. In particular, critical VM-modulating genes are associated with vascular (VE-cadherin, EphA2, VEGF receptor 1), embryonic and/or stem cell (Nodal, Notch4), and hypoxia-related (hypoxia-inducible factor, Twist1) signaling pathways. Each of these pathways warrants serious scrutiny as potential therapeutic, vascular targets, and diagnostic indicators of plasticity, drug resistance, and the aggressive metastatic phenotype. Clin Cancer Res; 18(10); 2726–32. ©2012 AACR.
Lectin characterization of cystogenesis in the SBM transgenic model of polycystic kidney disease.
Authors: V D'Agati, M Trudel
Journal: Journal of the American Society of Nephrology (1992)

The generation of a novel transgenic mouse model of polycystic kidney disease with a construct (SBM) that links the coding region of the c-myc proto-oncogene to the simian virus 40 enhancer and beta-globin promoter was previously reported (see reference 1). In order to determine the site of origin and histogenesis of renal cysts in this model, lectin/immunohistochemical and electron microscopic studies on mice of varying ages (from birth to adulthood) are described here. Cysts are detectable at birth and increase in number and diameter with age. Cysts predominantly involve the collecting tubules of young transgenic mice but progressively affect the proximal tubules with advancing age. A minority of cysts are of distal tubular origin in all age groups studied. Tubular hyperplasias are primarily reactive with proximal tubular markers and appear to precede the development of proximal tubular cysts in adult mice. This particular phenotypic evolution of polycystic kidney disease with advancing age suggests that the cystogenic potential of the transgene is modulated by yet unidentified tubular segment-specific responses.
Inhibition of T Helper Cell Type 2 Cell Differentiation and Immunoglobulin E Response by Ligand-Activated Vα14 Natural Killer T Cells
Authors: Junqing Cui, Naohiro Watanabe, Tetsu Kawano, Masakatsu Yamashita, Tohru Kamata, Chiori Shimizu, Motoko Kimura, Eiko Shimizu, Jyunzo Koike, Haruhiko Koseki, Yujiro Tanaka, Masaru Taniguchi, Toshinori Nakayama
Journal: The Journal of Experimental Medicine (1999)

Murine Vα14 natural killer T (NKT) cells are thought to play a crucial role in various immune responses, including infectious, allergic, and autoimmune diseases. Because Vα14 NKT cells produce large amounts of both interleukin (IL)-4 and interferon (IFN)-γ upon in vivo stimulation with a specific ligand, α-galactosylceramide (α-GalCer), or after treatment with anti-CD3 antibody, a regulatory role on helper T (Th) cell differentiation has been proposed for these cells. However, the identity of the cytokine produced by Vα14 NKT cells that play a dominant role on the Th cell differentiation still remains controversial. Here, we demonstrate by using Vα14 NKT-deficient mice that Vα14 NKT cells are dispensable for the induction of antigen-specific immunoglobulin (Ig)E responses induced by ovalbumin immunization or Nippostrongylus brasiliensis infection. However, upon in vivo activation with α-GalCer, Vα14 NKT cells are found to suppress antigen-specific IgE production. The suppression appeared to be IgE specific, and was not detected in either Vα14 NKT– or IFN-γ–deficient mice. Consistent with these results, we also found that ligand-activated Vα14 NKT cells inhibited Th2 cell differentiation in an in vitro induction culture system. Thus, it is likely that activated Vα14 NKT cells exert a potent inhibitory effect on Th2 cell differentiation and subsequent IgE production by producing a large amount of IFN-γ. In marked contrast, our studies have revealed that IL-4 produced by Vα14 NKT cells has only a minor effect on Th2 cell differentiation.
Colloidal silver for lung disease in cystic fibrosis
Authors: Vr Baral, Al Dewar, Gj Connett
Journal: Journal of the Royal Society of Medicine (2008)

Cystic Fibrosis (CF) families commonly consider alternative or complimentary therapies of questionable value. We report the case of a 12-year-old boy with severe CF lung complications who was treated by his family with colloidal silver.
Fate of connexin43 in cardiac tissue harbouring a disease-linked connexin43 mutant
Authors: Janet L. Manias, Isabelle Plante, Xiang-Qun Gong, Qing Shao, Jared Churko, Donglin Bai, Dale W. Laird
Journal: Cardiovascular Research (2008)

More than 40 mutations in the GJA1 gene encoding connexin43 (Cx43) have been linked to oculodentodigital dysplasia (ODDD), a pleiotropic, autosomal dominant disorder. We hypothesized that even with a significant reduction in the levels of Cx43 in a mutant mouse model of ODDD (Gja1(Jrt/+)) harbouring a G60S mutation (Cx43(G60S)), cardiomyocyte function may only be moderately compromised given that a majority of mutant mice typically survive.Western blotting and quantitative reverse transcriptase-polymerase chain reaction in conjunction with immunofluorescence were used to assess the expression and localization of Cx43 in hearts and cultured cardiomyocytes from wild-type and Gja1(Jrt/+) mice. Dye-coupling and dual whole cell patch-clamp recordings were also used to assess the gap junction channel status in cultured cardiomyocytes from wild-type and mutant mice. Cardiac tissue from adult Gja1(Jrt/+) mice revealed a 60-80% reduction in Cx43 protein with a preferential loss of the highly phosphorylated forms of Cx43. Compensation via the up-regulation of Cx40 or Cx45 was not observed. Immunofluorescent analysis of cultured cardiomyocytes revealed a trafficking defect, with a decrease in Cx43 plaques and a large population of Cx43 being retained in the Golgi apparatus. However, cultured cardiomyocytes from mutant mice remained beating with a 50% decrease in coupling conductance.These results suggest that the Cx43(G60S) mutant impairs normal trafficking and function of co-expressed Cx43 with no dramatic effect on cardiomyocyte function, suggesting that Cx43 is biosynthesized in excess of an essential need.
Does a History of Childhood Sexual Abuse Affect Sexual Outcomes in Breast Cancer Survivors?
Authors: Gail E. Wyatt, Tamra Burns Loeb, Katherine A. Desmond, Patricia A. Ganz
Journal: Journal of Clinical Oncology (2005)

Purpose Little is known about a history of childhood sexual abuse (CSA) in breast cancer survivors and its relationship to sexual functioning after cancer. As part of a larger survey study examining sexuality and intimacy in breast cancer survivors, we conducted in-person interviews with a subsample of participants. Methods A total of 147 women in Los Angeles, CA, and Washington, DC, completed a structured interview that addressed sexual socialization and a history of sexual abuse. Trained female interviewers conducted the interviews. Descriptive statistics and regression analyses were used to examine the prevalence of CSA, and its potential impact on sexual health and functioning. Results One in three women reported at least one CSA incident. Among women who had experienced CSA, 71% reported a single incident, and 22% reported a penetrative form of sexual contact. In multivariate regression analyses examining physical and psychological aspects of sexuality and body image, CSA was not a significant predictor of physical discomfort. However, a history of penetrative CSA was a significant predictor of psychological discomfort (P = .02). Conclusion The prevalence of CSA in this sample was similar to the general population literature on this topic. In this small sample, a past history of CSA did not contribute significantly to the physical discomforts associated with sexual intimacy after breast cancer; however, our findings suggest that a past history of penetrative CSA is associated with increased psychological discomfort, and may warrant additional examination in future research.
Notch Pathway Inhibition Using PF-03084014, a γ-Secretase Inhibitor (GSI), Enhances the Antitumor Effect of Docetaxel in Prostate Cancer
Authors: Di Cui, Jinlu Dai, Jill M. Keller, Atsushi Mizokami, Shujie Xia, Evan T. Keller
Journal: Clinical Cancer Research (2015)

Abstract Purpose: To investigate the efficacy and mechanisms of Notch signaling inhibition as an adjuvant to docetaxel in castration-resistant prostate cancer (CRPC) using a γ-secretase inhibitor (GSI), PF-03084014. Experimental Design: The effect of PF-03084014 on response to docetaxel was evaluated in docetaxel-sensitive and docetaxel-resistant CRPC cell lines in vitro and in murine models. Both soft tissue and bone sites were evaluated in vivo. Impacts on cell proliferation, apoptosis, cancer stem cells, and angiogenesis were evaluated. Results: The combination of PF-03084014 plus docetaxel reduced both docetaxel-sensitive and docetaxel-resistant CRPC tumor growth in soft tissue and bone greater than either agent alone. Antitumor activity was associated with PF-03084014–induced inhibition of Notch pathway signaling; decreased survival signals (cyclin E; MEK/ERK, PI3K/AKT, EGFR and NF-κB pathway; BCL-2, BCL-XL); increased apoptotic signals (BAK, BAX; cleaved caspase-3); reduced microvessel density; reduced epithelial–mesenchymal transition; and reduced cancer stem–like cells in the tumor. Conclusions: These results reveal that PF-03084014 enhances docetaxel-mediated tumor response and provides a rationale to explore GSIs as adjunct therapy in conjunction with docetaxel for men with CRPC. Clin Cancer Res; 21(20); 4619–29. ©2015 AACR. See related commentary by Zhang and Armstrong, p. 4505
A Phase II, Randomized, Study of Weekly APG101+Reirradiation versus Reirradiation in Progressive Glioblastoma
Authors: Wolfgang Wick, Harald Fricke, Klaus Junge, Grigory Kobyakov, Tobias Martens, Oliver Heese, Benedikt Wiestler, Maximilian G. Schliesser, Andreas von Deimling, Josef Pichler, Elena Vetlova, Inga Harting, Jürgen Debus, Christian Hartmann, Claudia Kunz, Michael Platten, Martin Bendszus, Stephanie E. Combs
Journal: Clinical Cancer Research (2014)

Abstract Purpose: Preclinical data indicate anti-invasive activity of APG101, a CD95 ligand (CD95L)–binding fusion protein, in glioblastoma. Experimental Design: Patients (N = 91) with glioblastoma at first or second progression were randomized 1:2 between second radiotherapy (rRT; 36 Gy; five times 2 Gy per week) or rRT+APG101 (400 mg weekly i.v.). Patient characteristics [N = 84 (26 patients rRT, 58 patients rRT+APG101)] were balanced. Results: Progression-free survival at 6 months (PFS-6) rates were 3.8% [95% confidence interval (CI), 0.1–19.6] for rRT and 20.7% (95% CI, 11.2–33.4) for rRT+APG101 (P = 0.048). Median PFS was 2.5 (95% CI, 2.3–3.8) months and 4.5 (95% CI, 3.7–5.4) months with a hazard ratio (HR) of 0.49 (95% CI, 0.27–0.88; P = 0.0162) adjusted for tumor size. Cox regression analysis adjusted for tumor size revealed a HR of 0.60 (95% CI, 0.36–1.01; P = 0.0559) for rRT+APG101 for death of any cause. Lower methylation levels at CpG2 in the CD95L promoter in the tumor conferred a stronger risk reduction (HR, 0.19; 95% CI, 0.06–0.58) for treatment with APG101, suggesting a potential biomarker. Conclusions: CD95 pathway inhibition in combination with rRT is an innovative concept with clinical efficacy. It warrants further clinical development. CD95L promoter methylation in the tumor may be developed as a biomarker. Clin Cancer Res; 20(24); 6304–13. ©2014 AACR.
Airway disease in upper and lower lobes in lungs of patients with and without emphysema.
Authors: J L Wright, B J Wiggs, J C Hogg
Journal: Thorax (1984)

To determine whether pathological changes in the small airways are evenly distributed throughout the lung and whether there is an association of small airway disease with emphysema, pathological abnormalities of the small airways were graded in the upper and lower lobes of 13 surgical lung specimens. Except for slightly increased degrees of respiratory bronchiolar inflammation in the lower lobe, no differences were found between the two sites, nor was there any relationship between the presence of pathological abnormalities in the small airways and the presence of centrilobular emphysema. It is concluded that the predilection of centrilobular emphysema for the upper lung zone is not associated with a difference in intensity of airway disease between upper and lower lobes.
A 2-Stage Phase II Design with Direct Assignment Option in Stage II for Initial Marker Validation
Authors: Ming-Wen An, Sumithra J. Mandrekar, Daniel J. Sargent
Journal: Clinical Cancer Research (2012)

Biomarkers are critical to targeted therapies, as they may identify patients more likely to benefit from a treatment. Several prospective designs for biomarker-directed therapy have been previously proposed, differing primarily in the study population, randomization scheme, or both. Recognizing the need for randomization, yet acknowledging the possibility of promising but inconclusive results after a stage I cohort of randomized patients, we propose a 2-stage phase II design on marker-positive patients that allows for direct assignment in a stage II cohort. In stage I, marker-positive patients are equally randomized to receive experimental treatment or control. Stage II has the option to adopt "direct assignment" whereby all patients receive experimental treatment. Through simulation, we studied the power and type I error rate of our design compared with a balanced randomized two-stage design, and conducted sensitivity analyses to study the effect of timing of stage I analysis, population shift effects, and unbalanced randomization. Our proposed design has minimal loss in power (<1.8%) and increased type I error rate (<2.1%) compared with a balanced randomized design. The maximum increase in type I error rate in the presence of a population shift was between 3.1% and 5%, and the loss in power across possible timings of stage I analysis was less than 1.2%. Our proposed design has desirable statistical properties with potential appeal in practice. The direct assignment option, if adopted, provides for an "extended confirmation phase" as an alternative to stopping the trial early for evidence of efficacy in stage I.
More mature and more promiscuous
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2005)

Epithelial cells in the thymus teach T cells what to ignore by presenting them with a comprehensive array of tissue-restricted self-antigens (TRAs) during development. According to Derbinski and colleagues on page 33, this promiscuous expression of TRAs—one of the mechanisms behind central T cell tolerance—increases as the epithelial cells mature.

Teaching T cells how to distinguish self-tissues from foreign invaders is essential for the prevention of autoimmune disease. This education process occurs in the thymus and depends on the presentation of a diverse array of self-antigens to developing thymocytes—a function of medullary thymic epithelial cells (mTECs). T cells that recognize these self-antigens are either deleted or become regulatory T cells.






Figure 

Self-antigens normally expressed only in individual tissues (labelled) are made in mTECs as they mature.




Recent studies have shown that the transcriptional regulator Aire (autoimmune regulator), which is highly expressed in mTECs, drives the expression of many of these TRAs. But not all TRAs depend on Aire, and Aire expression is not limited to mTECs. Thus, the rules that govern the thymic expression of these tightly regulated genes remain largely mysterious.

Derbinski et al. now show that the expression of a majority of TRAs increases as the mTECs differentiate in the thymus, suggesting an intricate link between mTEC maturity and TRA expression. The level of Aire expression mirrored the increase in TRA expression, consistent with the established role of Aire in this process. The authors confirm, however, that Aire does not act alone, as many TRAs are up-regulated in mature mTECs from mice lacking the transcriptional regulator.

How do differentiating mTECs turn on these genes that are normally expressed only in peripheral tissue? The answer is not completely clear, but Derbinski and colleagues show that regulation occurs at many levels. Some TRAs were expressed by transcriptional read-through of genes that are clustered together in a contiguous chromosomal region. Others depended on de-repression of genes normally silenced by genetic imprinting. But exactly how mTEC differentiation triggers these changes in gene expression remains to be determined.