tbuckley/cabot-search huggingface dataset:
Differential inhibition of human leukemic natural killer cell function by statins
Authors: Timothy Steele, Jon Crosbie, Marc Magnussen, Diana Bayer, Joan Ritho, Deb Potym-Torbert
Journal: Cancer Research (2008)

2412   The human leukemic natural killer cell line YT-INDY mimics many of the characteristics of normal natural killer cells. In addition, YT-INDY is a model for studying new therapies against these leukemias that have a poor prognosis. Using proliferation, cytotoxicity, and Western blot assays, our laboratory discovered that the cholesterol-lowering statin drugs inhibit YT-INDY proliferation, cytotoxicity, and ERK 1 and ERK 2 MAP kinase activation. The statin mechanism of action relies on interrupting the formation of cholesterol by inhibiting HMG-CoA reductase, which is responsible for controlling the rate of cholesterol production. Aside from their effects on LDL-cholesterol, statins have been shown to inhibit the growth of and induced apoptosis in various leukemia cell lines. When used in in vitro cytotoxicity assays, lovastatin, simvastatin, atorvastatin, fluvastatin, and mevastatin had profound inhibitory effects with IC509s ranging from 0.8-3.1 uM. Simvastatin and fluvastatin were found to be most potent in the cytotoxicity assay. Inhibition of cytotoxicity was reversed in the presence of 1.0 mM mevalonate and partially reversed with 0.5 mM mevalonate. In addition, the statins were effective in inhibiting proliferation of YT-INDY, when 25 uM of statin was added to cell culture. Significant inhibition was noted for up to 72 hrs. after addition of each statin. Finally, Western blot analysis revealed that phosphorylation of ERK 1 and ERK 2 was nearly completely lost at the following statin concentrations, lovastatin (6.2 uM), simvastatin (1.6 uM), mevastatin (6.2 uM), fluvastatin (1.6 uM), and atorvastatin (6.2 uM). All statin-induced p-ERK inhibition was reversed w/ 1.0 mM mevalonate and partially reversed w/ 0.5 mM mevalonate. Interestingly, pravastatin had no effect on YT-INDY cytotoxicity or ERK 1 and ERK 2 activation. From this study, we conclude that 1) ERK 1 and 2 are constitutively activated in resting YT-INDY cells, 2) all statins, except pravastatin, had profound inhibitory effects on YT-INDY cytotoxicity, proliferation, and ERK 1 and 2 activation at physiologic drug concentrations, 3) simvastatin and fluvastatin were found to be the most potent in abrogating cytotoxicity and ERK 1 and 2 activation, and 4) statin-induced inhibition of cytotoxicity and p-ERK activation could be fully reversed by 1 mM mevalonate and partially reversed by 0.5 mM mevalonate, signifying that the inhibition was likely due to inhibition of HMG CoA reductase. The novel effect of statins on leukemia cells is a new, and potentially exciting, field of research. Future studies will investigate whether statins have the potential to inhibit the proliferative capacity of this natural killer cell leukemia in vivo as a possible basis of therapy.
Abstract A19: Phosphorylation results in nuclear translocation of Dicer protein that increases metabolism, accelerates aging, and alters tumorigenesis
Authors: Neeraj K. Aryal, Swathi Arur, Guillermina Lozano
Journal: Cancer Research (2018)

Abstract Dicer is a well-conserved and essential gene that is required for the production of micro RNAs that play key roles during development and cancer. Several studies have associated aberrant Dicer expression in humans with developmental defects (Dicer1 syndrome) and poor prognosis in various cancers. One important mechanism of controlling protein stability and function is through post-translational modification. Recently, Extracellular signal-Regulated Kinase (ERK) dependent phosphorylation of Dicer during oogenesis has been shown to be essential in C. elegans. The phosphorylation sites in Dicer (Ser1718 and Ser1842 in mice) are well conserved and the phosphorylation is necessary and sufficient for Dicer's translocalization from cytoplasm to nucleus. We are interested in understanding the phosphorylation-mediated control of Dicer function during development and cancer. To understand the role of phospho-Dicer in mammals, we have generated five new Dicer1 alleles including phospho-mimetic mouse models with both serines replaced with aspartic acids (DicerS2D), only Ser1842 replaced with aspartic acid (DicerS1842D), and only Ser1718 replaced with aspartic acid (DicerS1718D). Phenotypic study shows that &amp;gt;75% of DicerS2D/S2D mutants and &amp;gt;60% of DicerS1842D/S1842D mutants die within five days after birth, while all heterozygous mutants and DicerS1718D/S1718D mice are phenotypically normal. The DicerS2D/S2D and DicerS1842D/S1842D survivors show signs of accelerated aging including smaller size, hunching of backbone, compromised weight gain, infertility, systemic tissue atrophy, and early lethality. We have also observed that DicerS2D/S2D animals and MEFs have increased metabolism as compared with wild type. Since aging and cancer are closely linked and altered metabolism is a hallmark of cancer, we hypothesize that phosphorylated Dicer produces an altered miRNA profile that affects metabolism, leading to developmental defects and tumorigenesis. Transcriptional profiling of MEFs and testes have shown that miRNA profiles are very different in mutants than in wild type, and the most affected pathways are metabolism and cancer. To test the role of phospho-Dicer in tumorigenesis, we crossed the DicerS2D allele into KRasLA1/+ driven nonmetastatic tumor model. The results show that phospho-Dicer reduces tumor-free survival, changes tumor spectrum, and drives metastasis in this tumor model. Citation Format: Neeraj K. Aryal, Swathi Arur, Guillermina Lozano. Phosphorylation results in nuclear translocation of Dicer protein that increases metabolism, accelerates aging, and alters tumorigenesis [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A19.
Long-term proton pump inhibitor use after <i>Helicobacter pylori</i> eradication may create a gastric environment for <i>N</i>-nitrosamine formation and gastric cancer development
Authors: Jun Kobayashi, Hiroyuki Uchida, Junta Ito
Journal: Gut (2018)

I read with great interest the recent article by Cheung et al reporting a duration-dependent association between the long-term use proton pump inhibitors (PPI) and an increased risk of gastric cancer in patients, even after Helicobacter pylori (HP) eradication therapy.1 Chronic gastritis due to HP infection induces mutagenesis through deamination and nitration of DNA, via a reaction with inducible nitric oxide synthase (iNOS)-derived NO and superoxide from inflammatory cells.2 However, Cheung et al further demonstrated that continued PPI treatment, even after HP eradication, could also increase the risk for gastric cancer. I support the findings of this paper from the perspective of the importance of physiological acidity in the formation of carcinogenic N -nitroso compounds (NOC) in the stomach.

Gastric …
Infrapatellar fat pad resection during total knee arthroplasty: yet another reason for?
Authors: Thomas J Ryan
Journal: Annals of the Rheumatic Diseases (2018)

Infrapatellar fat pad resection during total knee arthroplasty: yet another reason for?There has been an interesting series of commentaries based on the initial paper by Pan et al. [1][2][3][4] I note with interest the suggestion by Binks et al 4 that to preserve the infrapatellar fat pad (IPFP) and perform later arthroscopic resection on a case by case basis may be a viable option for management of anterior knee pain (AKP) after total knee arthroplasty (TKA).This is contrary to the solution offered by Han et al 3 to use a prospective MRI to screen patients prior to TKA with subsequent resection based on signal changes within the IPFP.This approach would however, prove difficult in the resource-constrained environment of most primary care facilities.Current arguments in support of preserving the IPFP are largely based around the incidence of postoperative AKP. 5 6 One area of conflicting evidence is the incidence of patella tendon shortening, also known as patella baja, after resection.Recent studies have shown no significant effect on postresection patella tendon length. 7 8 This suggests that postresection patella tendon length is unlikely to be a major factor when considering to resect the IPFP or not.The most common argument for IPFP resection is the increased surgical access to the knee.It is widely accepted that the most important aspect of knee arthroplasty is the correct fitting of components. 9Only with correctly fitting components can normal function be attained.In order to achieve this 'correct fit' the IPFP is often resected.Although this is a logical argument, there is no objective evidence in support of this.The study by Sekiya et al 10 showed that in patients with AKP following resection there was a significant proportion with scar tissue deep to the tendon.So perhaps it is insufficient resection and not the decision to remove the IPFP that results in AKP.And with recent studies showing a lack of patella tendon shortening post IPFP resection, limiting one argument for its preservation, this may be more accepted in the future.
Growth Plate Suppression in an Adolescent Patient With Acute Lymphoblastic Leukemia After Treatment
Authors: Ekaterina Tiktinsky, Daniel Levin, Sophia Lantsberg, Joseph Kapelushnik
Journal: Clinical Nuclear Medicine (2018)

Osteotoxic effect is a common adverse effect of chemotherapy for childhood acute lymphoblastic leukemia. The pathophysiology of impaired bone growth is multifactorial and can affect both osteoblast and osteoclast function. Significant contribution in affecting skeletal metabolism belongs to high-dose corticosteroid treatment. We present the case of a 12-year-old adolescent girl who was treated for high-risk pro-B acute lymphoblastic leukemia. The Tc-MDP bone scan, as a sensitive indicator of osteoblastic activity, shows that growth plate inhibition after intensive treatment may be temporary and reversible.
Russell Frederick Graham
Authors: Belinda Graham
Journal: BMJ (2018)

Russell Frederick Graham (“Freddie”) was born in Liverpool. The third of four siblings, he attended Booker Avenue Primary School as a child, followed by the renowned Liverpool Institute for Boys. A bright and studious teenager, Russell won a scholarship to study French and Spanish at Oxford University but, during the summer after his A levels, decided to instead pursue a career in medicine. He went personally to see the dean of Liverpool University Medical School, who agreed to allow him entry on the understanding that he would spend his first year catching up on the science he had missed while studying languages.

After qualifying Russell did his house jobs at Stanley Hospital in Liverpool. After …
Applying the phenotype approach for rosacea to practice and research
Authors: J. Tan, M. Berg, R.L. Gallo, J.Q. Del Rosso
Journal: British Journal of Dermatology (2018)

Rosacea diagnosis and classification have evolved since the 2002 National Rosacea Society expert panel subtype approach. Several working groups are now aligned to a more patient-centric phenotype approach, based on an individual's presenting signs and symptoms. However, subtyping is still commonplace across the field and an integrated strategy is required to ensure widespread progression to the phenotype approach.To provide practical recommendations that facilitate adoption of a phenotype approach across the rosacea field.A review of the literature and consolidation of rosacea expert experience.We identify challenges to implementing a phenotype approach in rosacea and offer practical recommendations to overcome them across clinical practice, interventional research, epidemiological research and basic science.These practical recommendations are intended to indicate the next steps in the progression from subtyping to a phenotype approach in rosacea, with the goals of improving our understanding of the disease, facilitating treatment developments and ultimately improving care for patients with rosacea.
Healthcare Resource Use and Cost Implications in the MOMENTUM 3 Long-Term Outcome Study
Authors: Mandeep R. Mehra, Christopher Salerno, Joseph C. Cleveland, Sean Pinney, Melana Yuzefpolskaya, Carmelo A. Milano, Akinobu Itoh, Daniel J. Goldstein, Nir Uriel, Sanjeev Gulati, Francis D. Pagani, Ranjit John, Robert Adamson, Roberta Bogaev, Vinay Thohan, Joyce Chuang, Poornima Sood, Scott Goates, Scott C. Silvestry
Journal: Circulation (2018)

Background: The MOMENTUM 3 trial compares the centrifugal HeartMate 3 (HM3) with the axial HeartMate II (HMII) continuous-flow left ventricular assist system in patients with advanced heart failure, irrespective of the intended goal of therapy. The trial’s 2-year clinical outcome (n=366) demonstrated superiority of the HM3 for the primary end point (survival free of a disabling stroke or reoperation to replace or remove a malfunctioning pump). This analysis evaluates health resource use and cost implications of the observed differences between the 2 devices while patients were enrolled in the trial. Methods: We analyzed all hospitalizations and their associated costs occurring after discharge from the implant hospitalization until censoring (study withdrawal, heart transplantation, and pump exchange with a nonstudy device or death). Each adjudicated episode of hospital-based care was used to calculate costs (device-attributable and non–device-attributable event costs), estimated by using trial data and payer administrative claims databases. Cost savings stratified by subgroups (study outcome [transplant, death, or ongoing on device], intended goal of therapy, type of insurance, or sex) were also assessed. Results: In 366 randomly assigned patients, 361 comprised the as-treated group (189 in the HM3 group and 172 in the HMII group), of whom 337 (177 in the HM3 group and 160 in the HMII group) were successfully discharged following implantation. The HM3 arm experienced fewer total hospitalizations per patient-year (HM3: 2.1±0.2 versus HMII: 2.7±0.2; P =0.015) and 8.3 fewer hospital days per patient-year on average (HM3: 17.1 days versus HMII: 25.5 days; P =0.003). These differences were driven by patients hospitalized for suspected pump thrombosis (HM3: 0.6% versus HMII: 12.5%; P &lt;0.001) and stroke (HM3: 2.8% versus HMII: 11.3%; P =0.002). Controlled for time spent in the study (average cumulative cost per patient-year), postdischarge HM3 arm costs were 51% lower than with the HMII (HM3: $37 685±4251 versus HMII: $76 599±11 889, P &lt;0.001) and similar in either bridge to transplant or destination therapy intent. Conclusions: In this 2-year outcome economic analysis of the MOMENTUM 3 trial, the HM3 demonstrated a reduction in rehospitalizations, hospital days spent during rehospitalizations, and a significant cost savings following discharge in comparison with the HMII left ventricular assist system, irrespective of the intended goal of therapy. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02224755.
Abstract B10: The polyploid state plays a tumor-suppressive role in the liver
Authors: Shuyuan Zhang, Kejin Zhou, Xin Luo, Lin Li, Liem Nguyen, Yu Zhang, Branden Tarlow, Daniel Siegwart, Hao Zhu
Journal: Cancer Research (2018)

Abstract Most cells in the liver are polyploid, but the functional role of polyploidy is unknown. Polyploidization normally occurs through cytokinesis failure and endoreduplication around the time of weaning. To interrogate the function of polyploidy while avoiding irreversible manipulations of essential cell cycle genes, we developed multiple orthogonal mouse models to transiently and potently alter liver ploidy. Premature weaning, as well as in vivo knockdown of E2f8 or Anln, allowed us to toggle between diploid and polyploid states. While there was no impact of ploidy alterations on liver function, metabolism, or regeneration, hyperpolyploid mice suppressed and hyperdiploid mice accelerated tumorigenesis in mutagen and high fat induced models. Mechanistically, the diploid state was more susceptible to Cas9-mediated tumor suppressor loss but was similarly susceptible to MYC oncogene activation, indicating that ploidy differentially protected the liver from distinct genomic aberrations. Our work suggests that polyploidy evolved in part to prevent malignant outcomes of liver injury. Citation Format: Shuyuan Zhang, Kejin Zhou, Xin Luo, Lin Li, Liem Nguyen, Yu Zhang, Branden Tarlow, Daniel Siegwart, Hao Zhu. The polyploid state plays a tumor-suppressive role in the liver [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B10.
Qudratulla Omar Khan
Authors: Faheem Shakur, Akbar Khan, Khalid Khan
Journal: BMJ (2018)

Qudratulla Omar Khan’s legacy is his unparalleled service to this patients and fellow humans. Colleagues and family describe his cheery smile and commitment to improving the wellbeing of the people around him. Hundreds of worshippers attended his funeral prayer—a testament to the man. He was a devout Muslim, whose work brought respect …
Abstract 21187: A Novel Mutations in <i>DPP10</i> Linked to Inherited J Wave Associated With Sudden Infant Death Syndrome by Augmentation of K <sub>v</sub> 4.3 Channel Current
Authors: Hector Barajas, Ryan Pfeiffer, Andy Powers, Tabhita Carrier, Yuesheng Wu, Timothy Knilans, Dan Hu
Journal: Circulation (2017)

Introduction: Mutations in genes encoding the α ( KCND3) and β ( KCNE3 ) subunits of genes encoding the cardiac transient outward potassium (Ito) have been associated with inherited cardiac arrhythmia syndromes such as Brugada Syndrome (BrS) and Sudden Infant Death Syndromes (SIDS). Hypothesis: Novel genetic variant in DPP10 associated with severe pediatric J Wave Syndrome (JWS), IVF and SIDS. Methods: The proband, a 16 year-old female, presented with atrial fibrillation and atrial septal defect. Subsequently she developed accentuated J waves in all ECG leads leading to repeated episodes of VT/VF (Type 3 ERS). Cilostazol proved effective in quieting VT/VF. She died of an electrical storm at 21 years of old. Genetic screening using Next Gen and Sanger methods uncovered a genetic variant in DPP10 but no variants in any other JWS susceptibility genes. Results: Transversion of thymine for guanine at nucleotide 15 predicted substitution of aspartic acid (D) for glutamine acid (E) at position 5 in exon 1b in the N-terminal of DPP10 (E5D) . The variation E5D was present in 5 unrelated patients with ERS (2), IVF (1) and BrS (3). E5D is highly conserved among species. Wild type (WT) and mutant genes were expressed in TSA201 cells and studied using whole-cell patch-clamp techniques at 37°C. Co-expression of KCND3 + KChIP2 + DPP10 /E5D generated Kv4.3 current density (I to ) 169.9% and 70.6% greater compared with KCND3 + KChIP2 + DPP10 /WT when homozygously and heterozygously expressed, respectively (n=9-12, p&lt;0.01). Inactivation of Ito and recovery from inactivation was slower in E5D channels. Quinidine (5 μM) and cilostazol (5 μM) inhibited I to by approximately 50% at +20 mV in E5D channels but less so (20 %) in WT channels. Conclusions: Our results provide, for the first time, evidence in support for the hypothesis that DDP10 is a novel susceptibility gene for life threatening arrhythmias associated with JWS. Our data suggest that DPP10- E5D contributes to the generation of a pathogenic substrate by boosting Ito and that Quinidine and Cilostazol serve as therapeutic options in this setting by reducing I to .
Risk factors for lung disease progression in children with cystic fibrosis
Authors: Marieke van Horck, Kim van de Kant, Bjorn Winkens, Geertjan Wesseling, Vincent Gulmans, Han Hendriks, Chris van der Grinten, Quirijn Jöbsis, Edward Dompeling
Journal: European Respiratory Journal (2018)

To identify potential risk factors for lung disease progression in children with cystic fibrosis (CF), we studied the longitudinal data of all children with CF (aged ≥5 years) registered in the Dutch CF Registry (2009-2014).Lung disease progression was expressed as a decline in lung function (forced expiratory volume in 1 s (FEV1) % pred) and pulmonary exacerbation rate. Potential risk factors at baseline included sex, age, best FEV1 % pred, best forced vital capacity % pred, genotype, body mass index z-score, pancreatic insufficiency, medication use (proton pump inhibitors (PPIs), prophylactic antibiotics and inhaled corticosteroids), CF-related diabetes, allergic bronchopulmonary aspergillosis and colonisation with Pseudomonas aeruginosaThe data of 545 children were analysed. PPI use was associated with both annual decline of FEV1 % pred (p=0.017) and future pulmonary exacerbation rate (p=0.006). Moreover, lower FEV1 % pred at baseline (p=0.007), prophylactic inhaled antibiotic use (p=0.006) and pulmonary exacerbations in the baseline year (p=0.002) were related to pulmonary exacerbations in subsequent years.In a cohort of Dutch children with CF followed for 5 years, we were able to identify several risk factors for future exacerbations. In particular, the association between PPI use and lung disease progression definitely requires further investigation.