tbuckley/cabot-search huggingface dataset:
Abstract LB-301: MicroRNA target screen identifies NEK9 pathway as a crucial component regulating proliferation of cancer cells lacking functional p53
Authors: Naoto Tsuchiya
Journal: Cancer Research (2015)

Abstract An abnormality of TP53 is one of the hallmarks of human cancer, and a major cause of human cancer development. Therefore, selective elimination of p53-inactivated cancer cells represents an ideal therapeutic strategy. We previously identified miR-22 as a tumor-suppressive miRNA, which induces apoptosis in p53 wild type (WT) cancer cells, but it causes cell cycle arrest in p53-deficient cancer cells (Cancer Res. 2011). This finding led us to hypothesize that miR-22 has a unique set of target genes that determined the fate of cancer cells according to p53 mutation status. In this study, using miR-22 as a screening tool, we tried to identify factors that play important roles in proliferation and cell cycle progression of p53-inactivated cancer cells. The screen identified NIMA-related kinase 9 (NEK9) as such a crucial regulator. Both in vitro and in vivo, depletion of NEK9 selectively inhibited cell proliferation of p53-inactivated cancer cells, and expression of the NEK9 open reading frame restored proliferation. The resultant cell cycle arrest occurred pre-dominantly in G1 phase and exhibited features of pre-mature senescence. Furthermore, repression of NEK9 affected expression of a wide range of genes encoding factors involved in mRNA processing, receptor signaling and cell cycle regulation, suggesting that NEK9 plays a role in controlling these processes in p53-deficient cells. Importantly, high level expression of both NEK9 and p53 mutant proteins in lung adenocarcinoma specimens were associated with poor prognosis, suggesting that NEK9 confers some advantages for malignant progression of p53 mutant cancer. Collectively, our findings indicated that a novel NEK9 network, which is specifically activated in p53-deficient context, is a crucial cellular component responsible for the growth capacity of cancer cells lacking functional p53. Citation Format: Naoto Tsuchiya. MicroRNA target screen identifies NEK9 pathway as a crucial component regulating proliferation of cancer cells lacking functional p53. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-301. doi:10.1158/1538-7445.AM2015-LB-301
AAV gene transfer delays disease onset in a TPP1-deficient canine model of the late infantile form of Batten disease
Authors: Martin L. Katz, Luis Tecedor, Yonghong Chen, Baye G. Williamson, Elena Lysenko, Fred A. Wininger, Whitney M. Young, Gayle C. Johnson, Rebecca E. H. Whiting, Joan R. Coates, Beverly L. Davidson
Journal: Science Translational Medicine (2015)

AAV-mediated gene transfer to ependymal cells in a dog model of Batten disease provides sustained enzyme replacement and delays disease onset.
An abnormal secretion of soluble mediators contributes to the hematopoietic-niche dysfunction in low-risk myelodysplastic syndrome
Authors: M Martini, S Capodimonti, M G Iachininoto, A Cocomazzi, E R Nuzzolo, M T Voso, L Teofili, L M Larocca
Journal: Blood Cancer Journal (2015)

An abnormal secretion of soluble mediators contributes to the hematopoietic-niche dysfunction in low-risk myelodysplastic syndrome
Structure, Organization, and Regulation of the Complement Genes
Authors: R D Campbell, S K Law, K B Reid, R B Sim
Journal: Annual Review of Immunology (1988)

Exhausted CD8 T (Tex) cells are a distinct cell lineage that arise during chronic infections and cancers in animal models and humans. Tex cells are characterized by progressive loss of effector functions, high and sustained inhibitory receptor expression, ...Read More
The Pharmacology of the Gastric Acid Pump: The H+,K+ ATPase
Authors: G Sachs, J M Shin, C Briving, B Wallmark, S Hersey
Journal: The Annual Review of Pharmacology and Toxicology (1995)

The gastric H+,K+ ATPase--the gastric acid pump--is the molecular target for the class of antisecretory drugs called the proton-pump inhibitors (PPIs). These compounds--omeprazole, lansoprazole, and pantoprazole--contain, as their core structure, 2-pyridyl methylsulfinyl benzimidazole. The H+,K+ ATPase is a heterodimer composed of a 1034-amino acid catalytic alpha peptide and a glycosylated 291-amino acid beta subunit. The alpha subunit probably contains 10 membrane-spanning sequences; the beta, a single transmembrane segment. The PPIs have a pKa of about 4.0; hence they accumulate only in the acidic secretory canaliculus of the stimulated parietal cell. Here they undergo conversion to a cationic sulfenamide, which then reacts with available cysteines on the extracytoplasmic face of the alpha subunit. Omeprazole reacts and forms disulfide bonds with cys813(822) and cys892; lansoprazole, with cys813(822), cys892, and cys321; and pantoprazole, with cys813 and -822. The antisecretory effect of the drugs reflects their short plasma half-life (approximately 60 min), the number of active pumps during that time, and the recovery of pumps following biosynthesis and reversal of inhibition. These drugs also show synergism with either amoxicillin or clari- thromycin in eradicating Helicobacter pylori, an organism shown to be important in duodenal and gastric ulcer disease. Their action is probably due to elevation of pH in the environment of the organism, rather than to any direct action.
Medians and Milestones in Describing the Path to Cancer Cures
Authors: Matthew D. Hellmann, Mark G. Kris, Charles M. Rudin
Journal: JAMA Oncology (2015)

This Viewpoint argues for adding the "milestone" metric of cancer treatment outcomes to the conventional "median" improvement metric because the median misses important milestones of treatment success (eg, 1-, 2-, and 5-year survival) in the tail end of the survival curve.
Regulation of Pigeon Cropmilk Secretion and Parental Behaviors by Prolactin
Authors: N D Horseman, J D Buntin
Journal: Annual Review of Nutrition (1995)

Prolactin stimulates the growth and development of specialized epithelial cells lining the cropsac of pigeons and doves (family Columbidae), leading to formation of “cropmilk,” which is fed to the newly hatched squab. This system of milk feeding is unique among birds. To support the feeding of cropmilk, a complex array of behavioral adaptations are also supported by high levels of prolactin secretion in columbids during parenting. These specializations include elevated food intake (hyperphagia), nest attendance, and regurgitation feeding of the squab. Although prolactin is clearly important for these behavioral adaptations, the precise physiological and mechanistic bases for these behavioral effects remain controversial. The molecular mechanisms of prolactin action in the cropsac epithelium have been studied by cloning prolactin-induced genes, by cloning and expressing the pigeon prolactin receptor, and by analyzing the transcription factors that are activated after prolactin treatment. The avian (pigeon) prolactin receptor is a member of the cytokine receptor superfamily and uniquely contains a complete duplication of the extracellular ligand-binding domain. One of the early signal­transducing actions of prolactin in cropsac epithelium is the activation of signal transducer and activator of transcription (STAT) proteins via tyrosine phosphorylation. This fundamental signaling pathway is shared with mammalian prolactin target tissues. The convergent evolution of milk feeding and the behaviors that support parenting in columbids and mammals has depended on adaptation of both conserved mechanisms and divergent physiological processes.
Pharmacists and computerised prescribing can help
Authors: S. M Cotter
Journal: BMJ (1995)

Avoiding drug errorsRead the label EDITOR,-The diversity of drug packaging that R E Ferner criticises has existed for many years.'What Ferner now identifies is a move towards standardisation through pharmaceutical manufacturers' adoption of the NHS ampoule labelling specification.The work leading to this has been described by Nunn.2The NHS specification seeks to establish a standard for labels, with the information presented in a consistent format and printed in the most legible way.The problem with diversity is that practitioners use features such as colour, shape, etc as a substitute for correct reading and inspection of the label.Use of such substitutes is both fallible and dangerous.The company whose products are illustrated in Femer's letter manufactures nearly 100 different ampoules.To differentiate between that number of products by use of colour, shape, etc is obviously impossible.Femer's hypothetical practitioner with modest presbyopia would obviously find it easier to read the labels illustrated than the text of the letter criticising the labels.The only way to be sure of the contents of an ampoule (or any other product) is to read the label.
Urinary Sodium and Potassium Excretion and CKD Progression
Authors: Jiang He, Katherine T. Mills, Lawrence J. Appel, Wei Yang, Jing Chen, Belinda T. Lee, Sylvia E. Rosas, Anna Porter, Gail Makos, Matthew R. Weir, L. Lee Hamm, John W. Kusek
Journal: Journal of the American Society of Nephrology (2015)

CKD is a major risk factor for ESRD, cardiovascular disease, and premature death. Whether dietary sodium and potassium intake affect CKD progression remains unclear. We prospectively studied the association of urinary sodium and potassium excretion with CKD progression and all-cause mortality among 3939 patients with CKD in the Chronic Renal Insufficiency Cohort Study. Urinary sodium and potassium excretion were measured using three 24-hour urine specimens, and CKD progression was defined as incident ESRD or halving of eGFR. During follow-up, 939 CKD progression events and 540 deaths occurred. Compared with the lowest quartile of urinary sodium excretion (<116.8 mmol/24 h), hazard ratios (95% confidence intervals) for the highest quartile of urinary sodium excretion (≥194.6 mmol/24 h) were 1.54 (1.23 to 1.92) for CKD progression, 1.45 (1.08 to 1.95) for all-cause mortality, and 1.43 (1.18 to 1.73) for the composite outcome of CKD progression and all-cause mortality after adjusting for multiple covariates, including baseline eGFR. Additionally, compared with the lowest quartile of urinary potassium excretion (<39.4 mmol/24 h), hazard ratios for the highest quartile of urinary potassium excretion (≥67.1 mmol/24 h) were 1.59 (1.25 to 2.03) for CKD progression, 0.98 (0.71 to 1.35) for all-cause mortality, and 1.42 (1.15 to 1.74) for the composite outcome. These data indicate that high urinary sodium and potassium excretion are associated with increased risk of CKD progression. Clinical trials are warranted to test the effect of sodium and potassium reduction on CKD progression.
The Influence of the Diet of the Progression of Renal Insufficiency
Authors: W E Mitch
Journal: Annual Review of Medicine (1984)

Although dietary protein restriction will protect the residual renal function of rats with chronic renal failure (CRF), the mechanism for this beneficial effect is unknown. Since methods for measuring the progression of renal insufficiency in individual patients have become available, a similar protective effect of dietary manipulation has been sought in patients with CRF. Available evidence indicates that dietary manipulation can substantially slow the loss of renal function at early and late stages of CRF.
American Society of Clinical Oncology: a society in transition.
Authors: J H Glick
Journal: Journal of Clinical Oncology (1996)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1996.14.8.2388 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 8708732 American Society of Clinical Oncology: a society in transition. J H GlickxJ H GlickSearch for articles by this author Show More University of Pennsylvania Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, USA. https://doi.org/10.1200/JCO.1996.14.8.2388 First Page PDF © 1996 by American Society of Clinical Oncology
Ifosfamide: should the honeymoon be over?
Authors: B A Kamen, E Frenkel, O M Colvin
Journal: Journal of Clinical Oncology (1995)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1995.13.2.307 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 7844590 Ifosfamide: should the honeymoon be over? B A KamenxB A KamenSearch for articles by this author , E FrenkelxE FrenkelSearch for articles by this author , O M ColvinxO M ColvinSearch for articles by this author https://doi.org/10.1200/JCO.1995.13.2.307 First Page PDF © 1995 by American Society of Clinical Oncology
The Biology of Cachectin/TNF -- A Primary Mediator of the Host Response
Authors: B Beutler, A Cerami
Journal: Annual Review of Immunology (1989)

Exhausted CD8 T (Tex) cells are a distinct cell lineage that arise during chronic infections and cancers in animal models and humans. Tex cells are characterized by progressive loss of effector functions, high and sustained inhibitory receptor expression, ...Read More
The role of hazard vulnerability assessments in disaster preparedness and prevention in China
Authors: Yan Du, Yibo Ding, Zixiong Li, Guangwen Cao
Journal: Military Medical Research (2015)

China is prone to disasters and escalating disaster losses. Effective disaster mitigation is the foundation for efficient disaster response and rescue and for reducing the degree of hazardous impacts on the population. Vulnerability refers to the population's capacity to anticipate, cope with, and recover from the impact of a hazardous event. A hazard vulnerability assessment (HVA) systematically evaluates the damage that could be caused by a potential disaster, the severity of the impact, and the available medical resources during a disaster to reduce population vulnerability and increase the capacity to cope with disasters. In this article, we summarized HVA team membership, content (disaster identification, probability and consequences), and methods and procedures for an HVA that can be tailored to China's needs. We further discussed the role of epidemiology in an HVA. Disaster epidemiology studies the underlying causes of disasters to achieve effective disaster prevention and reduction. In addition, we made several recommendations that are already in practice in developed countries, such as the U.S., for future implementation in China and other developing countries. An effective HVA plan is crucial for successful disaster preparedness, response, and recovery.
Strong Constraint on Human Genes Escaping X-Inactivation Is Modulated by their Expression Level and Breadth in Both Sexes
Authors: Andrea Slavney, Leonardo Arbiza, Andrew G. Clark, Alon Keinan
Journal: Molecular Biology and Evolution (2015)

In eutherian mammals, X-linked gene expression is normalized between XX females and XY males through the process of X chromosome inactivation (XCI). XCI results in silencing of transcription from one ChrX homolog per female cell. However, approximately 25% of human ChrX genes escape XCI to some extent and exhibit biallelic expression in females. The evolutionary basis of this phenomenon is not entirely clear, but high sequence conservation of XCI escapers suggests that purifying selection may directly or indirectly drive XCI escape at these loci. One hypothesis is that this signal results from contributions to developmental and physiological sex differences, but presently there is limited evidence supporting this model in humans. Another potential driver of this signal is selection for high and/or broad gene expression in both sexes, which are strong predictors of reduced nucleotide substitution rates in mammalian genes. Here, we compared purifying selection and gene expression patterns of human XCI escapers with those of X-inactivated genes in both sexes. When we accounted for the functional status of each ChrX gene's Y-linked homolog (or "gametolog"), we observed that XCI escapers exhibit greater degrees of purifying selection in the human lineage than X-inactivated genes, as well as higher and broader gene expression than X-inactivated genes across tissues in both sexes. These results highlight a significant role for gene expression in both sexes in driving purifying selection on XCI escapers, and emphasize these genes' potential importance in human disease.
Clinical Strategies for Solitary Pulmonary Nodule
Authors: D E Midthun, S J Swensen, J R Jett
Journal: Annual Review of Medicine (1992)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), emerged in China in December 2019 and quickly spread around the globe, killing more than 4 million people and causing a severe economic crisis. ...Read More
Efficacy of psychotropic drugs in functional dyspepsia: systematic review and meta-analysis
Authors: Alexander C Ford, Pavit Luthra, Jan Tack, Guy E Boeckxstaens, Paul Moayyedi, Nicholas J Talley
Journal: Gut (2015)

Objective Functional dyspepsia (FD) is a chronic gastroduodenal disorder. Individuals with FD demonstrate visceral hypersensitivity, abnormal central pain processing, and low mood, but it is unclear whether psychotropic drugs are an effective treatment for the condition. We performed a systematic review and meta-analysis of randomised controlled trials (RCTs). Design MEDLINE, EMBASE, EMBASE Classic, PsychINFO and the Cochrane Controlled Trials Register were searched (up to June 2015) for RCTs recruiting adults with FD comparing psychotropic drugs with placebo. We contacted authors directly to maximise trial eligibility and minimise risk of bias for studies. Dichotomous symptom data were pooled to obtain relative risk (RR) of remaining symptomatic after therapy, with 95% CIs. Results The search identified 2795 citations; 13 RCTs (1241 patients) were eligible. Ten trials were at low risk of bias. The RR of FD symptoms not improving with psychotropic drugs versus placebo was 0.78 (95% CI 0.68 to 0.91) (number needed to treat=6; 95% CI 4 to 16). However, benefit was limited to antipsychotics and tricyclic antidepressants. When only studies that excluded individuals with coexistent mood disorder were considered, there was no benefit. Total numbers of adverse events and adverse events leading to withdrawal were significantly more common, with a number needed to harm of 21 for both. Conclusions Psychotropic drugs may be an effective treatment for FD, but the effect appears to be limited to antipsychotics and tricyclic antidepressants with fewer trials for other agents, meaning that firm conclusions for efficacy cannot be made. More data from high quality RCTs are required to support their use in the treatment of FD.
The Oncolytic Adenovirus VCN-01 as Therapeutic Approach Against Pediatric Osteosarcoma
Authors: Naiara Martínez-Vélez, Enric Xipell, Beatriz Vera, Arlet Acanda de la Rocha, Marta Zalacain, Lucía Marrodán, Marisol Gonzalez-Huarriz, Gemma Toledo, Manel Cascallo, Ramón Alemany, Ana Patiño, Marta M. Alonso
Journal: Clinical Cancer Research (2015)

Osteosarcoma is the most common malignant bone tumor in children and adolescents. Despite aggressive chemotherapy, more than 30% of patients do not respond and develop bone or lung metastasis. Oncolytic adenoviruses engineered to specifically destroy cancer cells are a feasible option for osteosarcoma treatment. VCN-01 is a replication-competent adenovirus specifically engineered to replicate in tumors with a defective RB pathway, presents an enhanced infectivity through a modified fiber and an improved distribution through the expression of a soluble hyaluronidase. The aim of this study is to elucidate whether the use of VCN-01 would be an effective therapeutic strategy for pediatric osteosarcoma.We used osteosarcoma cell lines established from patients with metastatic disease (531MII, 678R, 588M, and 595M) and a commercial cell line (143B). MTT assays were carried out to evaluate the cytotoxicity of VCN-01. Hexon assays were used to evaluate the replication of the virus. Western blot analysis was performed to assess the expression levels of viral proteins and autophagic markers. The antitumor effect of VCN-01 was evaluated in orthotopic and metastatic osteosarcoma murine animal models.This study found that VCN-01, a new generation genetically modified oncolytic adenovirus, administered locally or systemically, had a potent antisarcoma effect in vitro and in vivo in mouse models of intratibial and lung metastatic osteosarcoma. Moreover, VCN-01 administration showed a safe toxicity profile.These results uncover VCN-01 as a promising strategy for osteosarcoma, setting the bases to propel a phase I/II trial for kids with this disease. Clin Cancer Res; 22(9); 2217-25. ©2015 AACR.
Total body irradiation after high-dose cytarabine in mantle cell lymphoma: a comparison of Nordic MCL2, HOVON-45, and European MCL Younger trials
Authors: E Hoster, C H Geisler, J Doorduijn, B van der Holt, J Walewski, J Bloehdorn, V Ribrag, G Salles, M Hallek, C Pott, M Szymczyk, A Kolstad, A Laurell, R Räty, M Jerkeman, M Van't Veer, J C Kluin-Nelemans, W Klapper, M Unterhalt, M Dreyling, O Hermine
Journal: Leukemia (2015)
Dietary counselling with the Dietary Approaches to Stop Hypertension (DASH) diet for Chinese patients with grade 1 hypertension: a parallel-group, randomised controlled trial
Authors: Martin C S Wong, Mandy W M Kwan, Harry H X Wang, Brian C Y Fong, Wai Man Chan, De X Zhang, Shannon T S Li, Queenie K Y Lee, Bryan P Yan, Andrew J S Coats, Sian M Griffiths
Journal: The Lancet (2015)
Uncovering the diagnosis
Authors: Justin B Seashore, Jeffrey J Silbiger, Oleg Epelbaum
Journal: Thorax (2015)

JBS (Medicine Resident): A 63-year-old African-American woman presented to the emergency department with progressive dyspnoea of 2-weeks’ duration. She denied chest pain, palpitations or syncope. Her medical history was significant for hypertension and diabetes mellitus. She never smoked and denied occupational exposures. She was born and raised in New York State, taking annual trips to North Carolina.

On examination, she was obese and appeared dyspnoeic. She was afebrile with a blood pressure of 152/74 mm Hg, a heart rate of 98 bpm, a respiratory rate of 20/min and an oxygen saturation of 97% while breathing ambient air. The jugular venous pulse was elevated. Heart sounds were normal, and there was no murmur, gallop, rub or click. Lungs were clear to auscultation and percussion. There was trace pedal oedema. The remainder of the examination was unremarkable.

Initial laboratory evaluation was notable for a serum glucose level of 260 mg/dL (normal range 74–126 mg/dL). Complete blood count and serial troponin measurements were normal. The ECG revealed sinus tachycardia at 100 bpm with borderline low QRS voltage and rare ectopy (figure 1A). The chest radiograph showed an increase in the cardiac silhouette compared with a film obtained 10 months earlier (figure 1B–D). There was no pulmonary vascular congestion, but tiny pleural effusions were seen on the lateral projection. Echocardiography demonstrated a large pericardial effusion (figure 1E) with diastolic inversion of the right atrial and right ventricular free walls consistent with tamponade physiology. Left ventricular size and function were normal. The patient underwent pericardiocentesis, which yielded 860 mL of clear yellow, lymphocyte-predominant fluid. Biochemical analysis revealed lactate dehydrogenase—130 U/L (serum 276 U/L), total protein—5.8 g/dL (serum 7.9 g/dL) and glucose—162 mg/dL.



Figure 1 
(A) ECG showing sinus tachycardia at 100 bpm with atrial premature complexes and borderline low QRS voltage. (B) Posteroanterior chest radiograph with an enlarged cardiac silhouette and clear lung fields. (C) Lateral …