tbuckley/cabot-search huggingface dataset:
Genetic Validation of the Protein Arginine Methyltransferase PRMT5 as a Candidate Therapeutic Target in Glioblastoma
Authors: Fengting Yan, Lapo Alinari, Mark E. Lustberg, Ludmila Katherine Martin, Hector M. Cordero-Nieves, Yeshavanth Banasavadi-Siddegowda, Selene Virk, Jill Barnholtz-Sloan, Erica Hlavin Bell, Jeffrey Wojton, Naduparambil K. Jacob, Arnab Chakravarti, Michal O. Nowicki, Xin Wu, Rosa Lapalombella, Jharna Datta, Bo Yu, Kate Gordon, Amy Haseley, John T. Patton, Porsha L. Smith, John Ryu, Xiaoli Zhang, Xiaokui Mo, Guido Marcucci, Gerard Nuovo, Chang-Hyuk Kwon, John C. Byrd, E. Antonio Chiocca, Chenglong Li, Said Sif, Samson Jacob, Sean Lawler, Balveen Kaur, Robert A. Baiocchi
Journal: Cancer Research (2014)

Abstract Glioblastoma is the most common and aggressive histologic subtype of brain cancer with poor outcomes and limited treatment options. Here, we report the selective overexpression of the protein arginine methyltransferase PRMT5 as a novel candidate theranostic target in this disease. PRMT5 silences the transcription of regulatory genes by catalyzing symmetric dimethylation of arginine residues on histone tails. PRMT5 overexpression in patient-derived primary tumors and cell lines correlated with cell line growth rate and inversely with overall patient survival. Genetic attenuation of PRMT5 led to cell-cycle arrest, apoptosis, and loss of cell migratory activity. Cell death was p53-independent but caspase-dependent and enhanced with temozolomide, a chemotherapeutic agent used as a present standard of care. Global gene profiling and chromatin immunoprecipitation identified the tumor suppressor ST7 as a key gene silenced by PRMT5. Diminished ST7 expression was associated with reduced patient survival. PRMT5 attenuation limited PRMT5 recruitment to the ST7 promoter, led to restored expression of ST7 and cell growth inhibition. Finally, PRMT5 attenuation enhanced glioblastoma cell survival in a mouse xenograft model of aggressive glioblastoma. Together, our findings defined PRMT5 as a candidate prognostic factor and therapeutic target in glioblastoma, offering a preclinical justification for targeting PRMT5-driven oncogenic pathways in this deadly disease. Cancer Res; 74(6); 1752–65. ©2014 AACR.
Coagulation and fibrosis in chronic liver disease
Authors: V Calvaruso, S Maimone, A Gatt, E Tuddenham, M Thursz, M Pinzani, A K Burroughs
Journal: Gut (2008)

In the hepatic tissue repair mechanism, hepatic stellate cells (HSCs) are recruited at the site of injury and their changes reflect paracrine stimulation by all neighbouring cell types, including sinusoidal endothelial cells, Kupffer cells, hepatocytes, platelets and leucocytes. Thrombin converts circulating fibrinogen to fibrin, promotes platelet aggregation, is a potent activator of endothelial cells, acts as a chemoattractant for inflammatory cells and is a mitogen and chemoattractant for fibroblasts and vascular smooth muscle cells. Most of the cellular effects elicited by thrombin are mediated via a family of widely expressed G-protein-coupled receptors termed protease activated receptors (PARs). All known members of the PAR family stimulate cell proliferation/activation in a rat HSC line. Thrombin receptors are constitutively expressed in the liver, and their expression increases in parallel with the severity and/or the duration of liver disease. In human studies, thrombotic risk factors were found to be independently associated with the extent of fibrosis; severity of hepatitis C virus (HCV)-associated liver disease appears to be less in patients with haemophilia when compared with those with HCV alone. Several studies, based mostly on rat models, demonstrate that anticoagulants or antiplatelet agents prevent hepatic necrosis and fibrosis by acting on HSCs. These drugs could be therapeutic agents in patients with chronic liver disease and specific studies should be initiated.
Explicit Prognostic Information and Reassurance About Nonabandonment When Entering Palliative Breast Cancer Care: Findings From a Scripted Video-Vignette Study
Authors: Liesbeth M. van Vliet, Elsken van der Wall, Nicole M. Plum, Jozien M. Bensing
Journal: Journal of Clinical Oncology (2013)

When discussing the transition to palliative care for patients with breast cancer, oncologists have to find a balance between giving explicit information while not overwhelming patients and being realistic while remaining hopeful. It is unclear whether patients prefer more or less explicit prognostic information, and reassuring patients that they will not be abandoned may provide realistic hope. We assessed the effect of explicit prognostic information and reassurance about nonabandonment at the transition to palliative care.An experimental 2 × 2 study was used. Four scripted videos of a bad news conversation were created that differed only in the level of "explicitness of prognosis" and "reassurance about nonabandonment" (high v low). Patients with and survivors of breast cancer (n = 51) and healthy women (n = 53) watched the video-vignettes. The effects of the different communications on participants' anxiety, uncertainty, self-efficacy, and satisfaction were assessed by using multilevel analyses that explored the moderating influences of monitoring/blunting scores.The highly explicit/highly reassuring video yielded the most positive outcomes, and the less explicit/less reassuring video, the most negative (P ≤ .05 for all outcome measures except anxiety). The main effects found were that explicitness and reassurance decreased participants' uncertainty (P < .001 and P = .002, respectively) and anxiety (only after reassurance; P = .001) while increasing self-efficacy (P = .004 and P < .001, respectively) and satisfaction (P < .001 and P < .001, respectively). High monitors seemed least positive, mainly following explicitness.Explicit prognostic information may lead to better outcomes than general information. In addition, reassurance about nonabandonment might provide realistic hope but should be lived up to. More research is needed to translate these findings into clinical care.
Disseminated tuberculosis in interferon gamma gene-disrupted mice.
Authors: A M Cooper, D K Dalton, T A Stewart, J P Griffin, D G Russell, I M Orme
Journal: The Journal of Experimental Medicine (1993)

The expression of protective immunity to Mycobacterium tuberculosis in mice is mediated by T lymphocytes that secrete cytokines. These molecules then mediate a variety of roles, including the activation of parasitized host macrophages, and the recruitment of other mononuclear phagocytes to the site of the infection in order to initiate granuloma formation. Among these cytokines, interferon gamma (IFN-gamma) is believed to play a key role is these events. In confirmation of this hypothesis, we show in this study that mice in which the IFN-gamma gene has been disrupted were unable to contain or control a normally sublethal dose of M. tuberculosis, delivered either intravenously or aerogenically. In such mice, a progressive and widespread tissue destruction and necrosis, associated with very high numbers of acid-fast bacilli, was observed. In contrast, despite the lack of protective immunity, some DTH-like reactivity could still be elicited. These data, therefore, indicate that although IFN-gamma may not be needed for DTH expression, it plays a pivotal and essential role in protective cellular immunity to tuberculosis infection.
Unusual Evolution of Interspersed Repeat Sequences in the Drosophila ananassae Subgroup
Authors: Masafumi Nozawa, Masahiko Kumagai, Tadashi Aotsuka, Koichiro Tamura
Journal: Molecular Biology and Evolution (2006)

New repeat sequences were found in the Drosophila ananassae genome sequence. They accounted for approximately 1.2% of the D. ananassae genome and were estimated to be more abundant in genomes of its closely related species belonging to the Drosophila bipectinata complex, whereas it was entirely absent in the Drosophila melanogaster genome. They were interspersed throughout euchromatic regions of the genome, usually as short tandem arrays of unit sequences, which were mostly 175–200 bp long with two distinct peaks at 180 and 189 bp in the length distribution. The nucleotide differences among unit sequences within the same array (locus) were much smaller than those between separate loci, suggesting within-locus concerted evolution. The phylogenetic tree of the repeat sequences from different loci showed that divergences between sequences from different chromosome arms occurred only at earlier stages of evolution, while those within the same chromosome arm occurred thereafter, resulting in the increase in copy number. We found RNA polymerase III promoter sequences (A box and B box), which play a critical role in retroposition of short interspersed elements. We also found conserved stem-loop structures, which are possibly associated with certain DNA rearrangements responsible for the increase in copy number within a chromosome arm. Such an atypical combination of characteristics (i.e., wide dispersal and tandem repetition) may have been generated by these different transposition mechanisms during the course of evolution.
Effect of inhaled fluticasone on bronchial responsiveness to neurokinin A in asthma
Authors: J. Van Schoor, G.F. Joos, R.A. Pauwels
Journal: European Respiratory Journal (2002)

Neurokinin (NK) A causes airway narrowing in patients with asthma through direct and indirect mechanisms. The effects of the inhaled glucocorticosteroid fluticasone propionate (FP) on the bronchial responsiveness to NKA and methacholine were studied. Patients (n=11) with mild asthma participated in a randomized, double-blind, placebo-controlled crossover trial. FP (500 µg b.i.d ) or matched placebo was administered via Diskhaler TM for 14 days. Bronchial challenges were performed on days 1 and 13 (methacholine) and 0 and 14 (NKA) for each treatment period. At the active treatment period, the mean log 2 provocative concentration causing a 20% fall in the forced expiratory volume in one second (PC 20 )±sem for NKA was −12.72±0.63 at the beginning and −9.77±0.49 at the end of the period (p&lt;0.0001), while under placebo, it was −12.16±0.82 and −12.19±0.51 respectively (ns). At the active treatment period, the mean log 2 PC 20 for methacholine was −5.25±0.40 at the beginning and −4.22±0.31 at the end of the period (p=0.012), while under placebo, it was −5.47±0.47 and −5.24±0.42 respectively (ns). The reduction in response to NKA was significantly larger than that for methacholine. A 2-week course of an inhaled steroid reduces bronchial responsiveness to neurokinin A, an effect more pronounced than the reduction in bronchial responsiveness to methacholine.
Abnormal hematopoietic phenotypes in Pim kinase triple knockout mice
Authors: Ningfei An, Andrew S Kraft, Yubin Kang
Journal: Journal of Hematology & Oncology (2013)

Abstract Background Pim ( p roviral i nsertion in m urine lymphoma) kinases are a small family of constitutively active, highly conservative serine/threonine oncogenic kinases and have 3 members: Pim1, Pim2, and Pim3. Pim kinases are also implicated in the regulation of B- and T- cell responses to cytokines and hematopoietic growth factors. The roles of Pim kinases in the regulation of primitive hematopoietic stem cells (HSCs) are largely unknown. Methods In the current study, Pim1 −/− 2 −/− 3 −/− triple knockout (TKO) mice were used to determine the role of Pim kinases in hematopoiesis. Peripheral blood hematological parameters were measured in Pim TKO mice and age-matched wild-type (WT) controls. Primary, secondary, and competitive transplantations were performed to assay the long-term repopulating HSCs in Pim TKO mice. In vivo BrdU incorporation assay and ex vivo Ki67 staining and caspase 3 labeling were performed to evaluate the proliferation and apoptosis of HSCs in Pim TKO mice. Results Compared to age-matched WT controls, Pim TKO mice had lower peripheral blood platelet count and exhibited erythrocyte hypochromic microcytosis. The bone marrow cells from Pim TKO mice demonstrated decreased hematopoietic progenitor colony-forming ability. Importantly, Pim TKO bone marrow cells had significantly impaired capacity in rescuing lethally irradiated mice and reconstituting hematopoiesis in primary, secondary and competitive transplant models. In vivo BrdU incorporation in long-term HSCs was reduced in Pim TKO mice. Finally, cultured HSCs from Pim TKO mice showed reduced proliferation evaluated by Ki67 staining and higher rate of apoptosis via caspase 3 activation. Conclusions Pim kinases are not only essential in the hematopoietic lineage cell development, but also important in HSC expansion, self-renewal, and long-term repopulation.
Modulation of Cardiac Gap Junction Expression and Arrhythmic Susceptibility
Authors: Stephan B. Danik, Fangyu Liu, Jie Zhang, H. Jacqueline Suk, Gregory E. Morley, Glenn I. Fishman, David E. Gutstein
Journal: Circulation Research (2004)

Connexin43 (Cx43), the predominant ventricular gap junction protein, is critical for maintaining normal cardiac electrical conduction, and its absence in the mouse heart results in sudden arrhythmic death. The mechanisms linking reduced Cx43 abundance in the heart and inducibility of malignant ventricular arrhythmias have yet to be established. In this report, we investigate arrhythmic susceptibility in a murine model genetically engineered to express progressively decreasing levels of Cx43. Progressively older cardiac-restricted Cx43 conditional knockout (CKO) mice were selectively bred to produce a heart-specific Cx43-deficient subline ("O-CKO" mice) in which the loss of Cx43 in the heart occurs more gradually. O-CKO mice lived significantly longer than the initial series of CKO mice but still died suddenly and prematurely. At 25 days of age, cardiac Cx43 protein levels decreased to 59% of control values (P<0.01), but conduction velocity was not significantly decreased and no O-CKO mice were inducible into sustained ventricular tachyarrhythmias. By 45 days of age, cardiac Cx43 abundance had decreased in a heterogeneous fashion to 18% of control levels, conduction velocity had slowed to half of that observed in control hearts, and 80% of O-CKO mice were inducible into lethal tachyarrhythmias. Enhanced susceptibility to induced arrhythmias was not associated with altered invasive hemodynamic measurements or changes in ventricular effective refractory period. Thus, moderately severe reductions in Cx43 abundance are associated with slowing of impulse propagation and a dramatic increase in the susceptibility to inducible ventricular arrhythmias.
Association of PD-1, PD-1 Ligands, and Other Features of the Tumor Immune Microenvironment with Response to Anti–PD-1 Therapy
Authors: Janis M. Taube, Alison Klein, Julie R. Brahmer, Haiying Xu, Xiaoyu Pan, Jung H. Kim, Lieping Chen, Drew M. Pardoll, Suzanne L. Topalian, Robert A. Anders
Journal: Clinical Cancer Research (2014)

Immunomodulatory drugs differ in mechanism-of-action from directly cytotoxic cancer therapies. Identifying factors predicting clinical response could guide patient selection and therapeutic optimization.Patients (N = 41) with melanoma, non-small cell lung carcinoma (NSCLC), renal cell carcinoma (RCC), colorectal carcinoma, or castration-resistant prostate cancer were treated on an early-phase trial of anti-PD-1 (nivolumab) at one institution and had evaluable pretreatment tumor specimens. Immunoarchitectural features, including PD-1, PD-L1, and PD-L2 expression, patterns of immune cell infiltration, and lymphocyte subpopulations, were assessed for interrelationships and potential correlations with clinical outcomes.Membranous (cell surface) PD-L1 expression by tumor cells and immune infiltrates varied significantly by tumor type and was most abundant in melanoma, NSCLC, and RCC. In the overall cohort, PD-L1 expression was geographically associated with infiltrating immune cells (P < 0.001), although lymphocyte-rich regions were not always associated with PD-L1 expression. Expression of PD-L1 by tumor cells and immune infiltrates was significantly associated with expression of PD-1 on lymphocytes. PD-L2, the second ligand for PD-1, was associated with PD-L1 expression. Tumor cell PD-L1 expression correlated with objective response to anti-PD-1 therapy, when analyzing either the specimen obtained closest to therapy or the highest scoring sample among multiple biopsies from individual patients. These correlations were stronger than borderline associations of PD-1 expression or the presence of intratumoral immune cell infiltrates with response.Tumor PD-L1 expression reflects an immune-active microenvironment and, while associated other immunosuppressive molecules, including PD-1 and PD-L2, is the single factor most closely correlated with response to anti-PD-1 blockade. Clin Cancer Res; 20(19); 5064-74. ©2014 AACR.
Divergent Mitochondrial Respiratory Chains in Phototrophic Relatives of Apicomplexan Parasites
Authors: Pavel Flegontov, Jan Michálek, Jan Janouškovec, De-Hua Lai, Milan Jirků, Eva Hajdušková, Aleš Tomčala, Thomas D. Otto, Patrick J. Keeling, Arnab Pain, Miroslav Oborník, Julius Lukeš
Journal: Molecular Biology and Evolution (2015)

Four respiratory complexes and ATP-synthase represent central functional units in mitochondria. In some mitochondria and derived anaerobic organelles, a few or all of these respiratory complexes have been lost during evolution. We show that the respiratory chain of Chromera velia, a phototrophic relative of parasitic apicomplexans, lacks complexes I and III, making it a uniquely reduced aerobic mitochondrion. In Chromera, putative lactate:cytochrome c oxidoreductases are predicted to transfer electrons from lactate to cytochrome c, rendering complex III unnecessary. The mitochondrial genome of Chromera has the smallest known protein-coding capacity of all mitochondria, encoding just cox1 and cox3 on heterogeneous linear molecules. In contrast, another photosynthetic relative of apicomplexans, Vitrella brassicaformis, retains the same set of genes as apicomplexans and dinoflagellates (cox1, cox3, and cob).
CD98hc (<i>SLC3A2</i>) regulation of skin homeostasis wanes with age
Authors: Etienne Boulter, Soline Estrach, Aurélia Errante, Catherine Pons, Laurence Cailleteau, Floriane Tissot, Guerrino Meneguzzi, Chloé C. Féral
Journal: The Journal of Experimental Medicine (2013)

Skin aging is linked to reduced epidermal proliferation and general extracellular matrix atrophy. This involves factors such as the cell adhesion receptors integrins and amino acid transporters. CD98hc (SLC3A2), a heterodimeric amino acid transporter, modulates integrin signaling in vitro. We unravel CD98hc functions in vivo in skin. We report that CD98hc invalidation has no appreciable effect on cell adhesion, clearly showing that CD98hc disruption phenocopies neither CD98hc knockdown in cultured keratinocytes nor epidermal β1 integrin loss in vivo. Instead, we show that CD98hc deletion in murine epidermis results in improper skin homeostasis and epidermal wound healing. These defects resemble aged skin alterations and correlate with reduction of CD98hc expression observed in elderly mice. We also demonstrate that CD98hc absence in vivo induces defects as early as integrin-dependent Src activation. We decipher the molecular mechanisms involved in vivo by revealing a crucial role of the CD98hc/integrins/Rho guanine nucleotide exchange factor (GEF) leukemia-associated RhoGEF (LARG)/RhoA pathway in skin homeostasis. Finally, we demonstrate that the deregulation of RhoA activation in the absence of CD98hc is also a result of impaired CD98hc-dependent amino acid transports.
The Big Idea: Paediatric oncological pathology – a new phenomenon
Authors: EKF Lacey, NMP Clarke
Journal: Journal of the Royal Society of Medicine (2008)

Chemotherapy and radiotherapy are provoking orthopaedic complications with serious therapeutic dilemmas. We want to highlight the importance of early recognition of these complications and the difficulties in their management. Survival rates in children with oncological diseases have significantly increased and patients now frequently survive into adulthood due to the successful advances in chemotherapy and radiotherapy treatment over the last decade. We are therefore seeing an increase in the longer term complications of these treatments. For example, from our experience we have two specific cases, one of bilateral slipped capital femoral epiphyses (SCFE) and another of bilateral avascular necrosis of the femoral heads, which occurred in association with combination chemotherapy and irradiation treatment for leukaemia. Anecdotal evidence states an increase in the prevalence of SCFE and avascular necrosis, despite research previously stating the causative associated risks. These previously unrecognized radiation-related growth disturbances may be more likely to be seen in the future. 1
Comparative Effectiveness of Minimally Invasive vs Open Radical Prostatectomy
Authors: Jim C. Hu
Journal: JAMA (2009)

Minimally invasive radical prostatectomy (MIRP) has diffused rapidly despite limited data on outcomes and greater costs compared with open retropubic radical prostatectomy (RRP).To determine the comparative effectiveness of MIRP vs RRP.Population-based observational cohort study using US Surveillance, Epidemiology, and End Results Medicare linked data from 2003 through 2007. We identified men with prostate cancer who underwent MIRP (n = 1938) vs RRP (n = 6899).We compared postoperative 30-day complications, anastomotic stricture 31 to 365 days postoperatively, long-term incontinence and erectile dysfunction more than 18 months postoperatively, and postoperative use of additional cancer therapies, a surrogate for cancer control.Among men undergoing prostatectomy, use of MIRP increased from 9.2% (95% confidence interval [CI], 8.1%-10.5%) in 2003 to 43.2% (95% CI, 39.6%-46.9%) in 2006-2007. Men undergoing MIRP vs RRP were more likely to be recorded as Asian (6.1% vs 3.2%), less likely to be recorded as black (6.2% vs 7.8%) or Hispanic (5.6% vs 7.9%), and more likely to live in areas with at least 90% high school graduation rates (50.2% vs 41.0%) and with median incomes of at least $60,000 (35.8% vs 21.5%) (all P < .001). In propensity score-adjusted analyses, MIRP vs RRP was associated with shorter length of stay (median, 2.0 vs 3.0 days; P<.001) and lower rates of blood transfusions (2.7% vs 20.8%; P < .001), postoperative respiratory complications (4.3% vs 6.6%; P = .004), miscellaneous surgical complications (4.3% vs 5.6%; P = .03), and anastomotic stricture (5.8% vs 14.0%; P < .001). However, MIRP vs RRP was associated with an increased risk of genitourinary complications (4.7% vs 2.1%; P = .001) and diagnoses of incontinence (15.9 vs 12.2 per 100 person-years; P = .02) and erectile dysfunction (26.8 vs 19.2 per 100 person-years; P = .009). Rates of use of additional cancer therapies did not differ by surgical procedure (8.2 vs 6.9 per 100 person-years; P = .35).Men undergoing MIRP vs RRP experienced shorter length of stay, fewer respiratory and miscellaneous surgical complications and strictures, and similar postoperative use of additional cancer therapies but experienced more genitourinary complications, incontinence, and erectile dysfunction.
Minimal residual disease–based role of imatinib as a first-line interim therapy prior to allogeneic stem cell transplantation in Philadelphia chromosome–positive acute lymphoblastic leukemia
Authors: Seok Lee, Dong-Wook Kim, Yoo-Jin Kim, Nak-Gyun Chung, Yoo-Li Kim, Ji-Yeon Hwang, Chun-Choo Kim
Journal: Blood (2003)