tbuckley/cabot-search huggingface dataset:
Longitudinal RNA-Seq Analysis of the Repeatability of Gene Expression and Splicing in Human Platelets Identifies a Platelet <i>SELP</i> Splice QTL
Authors: Matthew T. Rondina, Deepak Voora, Lukas M. Simon, Hansjörg Schwertz, Julie F. Harper, Olivia Lee, Seema C. Bhatlekar, Qing Li, Alicia S. Eustes, Emilie Montenont, Robert A. Campbell, Neal D. Tolley, Yasuhiro Kosaka, Andrew S. Weyrich, Paul F. Bray, Jesse W. Rowley
Journal: Circulation Research (2019)

Longitudinal studies are required to distinguish within versus between-individual variation and repeatability of gene expression. They are uniquely positioned to decipher genetic signal from environmental noise, with potential application to gene variant and expression studies. However, longitudinal analyses of gene expression in healthy individuals-especially with regards to alternative splicing-are lacking for most primary cell types, including platelets.To assess repeatability of gene expression and splicing in platelets and use repeatability to identify novel platelet expression quantitative trait loci (QTLs) and splice QTLs.We sequenced the transcriptome of platelets isolated repeatedly up to 4 years from healthy individuals. We examined within and between individual variation and repeatability of platelet RNA expression and exon skipping, a readily measured alternative splicing event. We find that platelet gene expression is generally stable between and within-individuals over time-with the exception of a subset of genes enriched for the inflammation gene ontology. We show an enrichment among repeatable genes for associations with heritable traits, including known and novel platelet expression QTLs. Several exon skipping events were also highly repeatable, suggesting heritable patterns of splicing in platelets. One of the most repeatable was exon 14 skipping of SELP. Accordingly, we identify rs6128 as a platelet splice QTL and define an rs6128-dependent association between SELP exon 14 skipping and race. In vitro experiments demonstrate that this single nucleotide variant directly affects exon 14 skipping and changes the ratio of transmembrane versus soluble P-selectin protein production.We conclude that the platelet transcriptome is generally stable over 4 years. We demonstrate the use of repeatability of gene expression and splicing to identify novel platelet expression QTLs and splice QTLs. rs6128 is a platelet splice QTL that alters SELP exon 14 skipping and soluble versus transmembrane P-selectin protein production.
Reply to Won Ho Kim, Hyun-Kyu Yoon, Chang Wook Jeong’s Letter to Editor re: Carlo Bravi, Emily Vertosick, Nicole Benfante, et al. Impact of Acute Kidney Injury, Its Duration on Long-term Renal Function After Partial Nephrectomy. Eur Urol 2019;76:398–403
Authors: Carlo A. Bravi
Journal: European Urology (2019)
Back-to-Back Discovery, Co-Precision, and Prevention
Authors: Barbara Casadei, Josep Tabernero
Journal: JACC CardioOncology (2019)

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Together, our 2 societies, the European Society of Cardiology (ESC) and the European Society of Medical Oncology (ESMO), have clocked up more than a century advancing their respective fields. Although ESMO is half the age of the ESC, it draws a similar
Real-world survival with first-line (1L) chemotherapy in patients (PTS) with advanced non-small cell lung cancer (ANSCLC)
Authors: D. Waterhouse, K.A. Betts, J. Zhao, S. Rao, K. Gupte-Singh, M. Rutstein, M.K. Higashi, L. Schwartzberg
Journal: Annals of Oncology (2019)
Autism risk in offspring can be assessed through quantification of male sperm mosaicism
Authors: Martin W. Breuss, Danny Antaki, Renee D. George, Morgan Kleiber, Kiely N. James, Laurel L. Ball, Oanh Hong, Ileena Mitra, Xiaoxu Yang, Sara A. Wirth, Jing Gu, Camila A. B. Garcia, Madhusudan Gujral, William M. Brandler, Damir Musaev, An Nguyen, Jennifer McEvoy-Venneri, Renatta Knox, Evan Sticca, Martha Cristina Cancino Botello, Javiera Uribe Fenner, Maria Cárcel Pérez, Maria Arranz, Andrea B. Moffitt, Zihua Wang, Amaia Hervás, Orrin Devinsky, Melissa Gymrek, Jonathan Sebat, Joseph G. Gleeson
Journal: Nature Medicine (2019)
Preclinical Efficacy of a PSMA-Targeted Thorium-227 Conjugate (PSMA-TTC), a Targeted Alpha Therapy for Prostate Cancer
Authors: Stefanie Hammer, Urs B. Hagemann, Sabine Zitzmann-Kolbe, Aasmund Larsen, Christine Ellingsen, Solene Geraudie, Derek Grant, Baard Indrevoll, Roger Smeets, Oliver von Ahsen, Alexander Kristian, Pascale Lejeune, Hartwig Hennekes, Jenny Karlsson, Roger M. Bjerke, Olav B. Ryan, Alan S. Cuthbertson, Dominik Mumberg
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Prostate-specific membrane antigen (PSMA) is an attractive target for radionuclide therapy of metastatic castration-resistant prostate cancer (mCRPC). PSMA-targeted alpha therapy (TAT) has shown early signs of activity in patients with prostate cancer refractory to beta radiation. We describe a novel, antibody-based TAT, the PSMA-targeted thorium-227 conjugate PSMA-TTC (BAY 2315497) consisting of the alpha-particle emitter thorium-227 complexed by a 3,2-HOPO chelator covalently linked to a fully human PSMA-targeting antibody. Experimental Design: PSMA-TTC was characterized for affinity, mode of action, and cytotoxic activity in vitro. Biodistribution, pharmacokinetics, and antitumor efficacy were investigated in vivo using cell line and patient-derived xenograft (PDX) models of prostate cancer. Results: PSMA-TTC was selectively internalized into PSMA-positive cells and potently induced DNA damage, cell-cycle arrest, and apoptosis in vitro. Decrease in cell viability was observed dependent on the cellular PSMA expression levels. In vivo, PSMA-TTC showed strong antitumor efficacy with T/C values of 0.01 to 0.31 after a single injection at 300 to 500 kBq/kg in subcutaneous cell line and PDX models, including models resistant to standard-of-care drugs such as enzalutamide. Furthermore, inhibition of both cancer and cancer-induced abnormal bone growth was observed in a model mimicking prostate cancer metastasized to bone. Specific tumor uptake and efficacy were demonstrated using various PSMA-TTC doses and dosing schedules. Induction of DNA double-strand breaks was identified as a key mode of action for PSMA-TTC both in vitro and in vivo. Conclusions: The strong preclinical antitumor activity of PSMA-TTC supports its clinical evaluation, and a phase I trial is ongoing in mCRPC patients (NCT03724747).
Skin Associated Staphylococcus Aureus Contributes to Disease Progression in CTCL
Authors: Cosmin A Tegla, Alberto M Herrera, Angelina M Seffens, Melania H Fanok, George Dean, John Kawaoka, Mary E Laird, Yi Fulmer, Andreas Willerslev-Olsen, Kenneth B. Hymes, Jo-Ann Latkowski, Niels Odum, Stefan Feske, Bo Shopsin, Victor Torres, Marshall E. Kadin, Larisa J Geskin, Sergei B. Koralov
Journal: Blood (2019)
Changes in the Place of Death in the United States
Authors: Sarah H Cross, Haider J Warraich
Journal: New England Journal of Medicine (2019)

To the Editor: Where people die is an impor tant determinant of patient and caregiver expe rience.To assess changes in place of death, we analyzed data from the Centers for Disease Control and Prevention and the National Center for Health Statistics database for natural deaths in the United States from 2003 through 2017.Cause of death was defined as the medical con dition that had started the events that led direct ly to death, as recorded by the physician on the death certificate. 1 Deaths from external causes were excluded.Between 2003 and 2017, there were nearly 35.2 million natural deaths (Fig. 1).Most were attributed to cardiovascular disease (29.3%), followed by cancer (24.5%), respiratory disease (10.5%), dementia (7.9%), and stroke (5.9%).In 2003, a total of 905,874 deaths occurred in hospitals (39.7%), which decreased to 764,424 (29.8%) in 2017, whereas the number of deaths at nursing facilities decreased from 538,817 (23.6%) to 534,714 (20.8%).The number of deaths at home increased from 543,874 (23.8%) in 2003 to 788,757 (30.7%) in 2017, whereas the number of deaths at hospice facilities increased from 5395 (0.2%) to 212,652 (8.3%).These trends were seen across all disease groups.Younger patients, female patients, and racial and ethnic minorities had lower odds of death at home than did older patients, male patients, and white patients.Patients with cancer had the greatest odds of death at home and death at a hospice facility and the lowest odds of death at a nursing facility relative to other conditions.Patients with dementia had the greatest odds of death at a nursing facility, and patients with re spiratory disease had the greatest odds of death at a hospital.Patients with stroke had the lowest odds of death at home, and patients with cardio
Abstract C65: Identifying mechanisms of macrophage-mediated metastasis and therapy resistance in PDAC
Authors: Tony J. Wu, Oliver Cast, Danish Memon, Alejandro Jimenez-Sanchez, Anne Machel, Sebastian Kehrloesser, Michael B. Gill, Martin L. Miller
Journal: Cancer Research (2019)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by desmoplasia, with macrophages as one of the most abundant, multifunctional immune cell populations in the tumor microenvironment (TME) and a major component of the immune infiltrate. To best improve clinical outcomes, consideration must be placed on targeted therapeutics that blunt heterotypic interactions between tumor cells and supporting cells within the TME. Here, we provide new insight into the dichotomous relationship between epithelial and mesenchymal phenotypes of PDAC cells in 3D culture. We report the ability of PDAC mesenchymal cells to form vascular mimicry-like structures in a 3D in vitro assay of invasion. Additionally, we demonstrate that macrophages have the ability to impart a proinvasive phenotype to PDAC cells when co-cultured in 3D, irrespective of EMT (epithelial-to-mesenchymal transition) status. To elucidate a mechanism for this macrophage-mediated proinvasive phenotype, we employed an unbiased, multi-omics approach. First, PDAC cell lines and primary macrophages were CTAP (cell-type specific labeling using amino acid precursors) labeled and admixed together for a prolonged period of time. To identify cell of origin of novel RNA and proteins, these mixed co-cultures were FACS sorted for downstream RNA-sequencing analysis or harvested in bulk for downstream proteome and secretome analysis. Preliminary integration of cell culture transcriptomes with CTAP-TMT (tandem mass tag) proteomes and secretomes implicates several key epithelial- and macrophage-derived signaling molecules as principal instructing signals for mediating the observed proinvasive phenotype. Blockade of this signaling axis, by inhibition of the signaling molecules or their receptors, disrupted the crosstalk between the two cell types and impaired the ability of macrophages to impart a proinvasive phenotype to PDAC cells. These preliminary preclinical data, recapitulated in vivo, suggest that targeting the TME of patients by using a staging regimen of chemokine inhibitor to disrupt tumor-macrophage cell interactions, followed with therapeutic modalities such as gemcitabine (and/or immunotherapy), would improve upon standard of care and inform future treatment options for PDAC in the clinic. Citation Format: Tony J. Wu, Oliver Cast, Danish Memon, Alejandro Jimenez-Sanchez, Anne Machel, Sebastian Kehrloesser, Michael B. Gill, Martin L. Miller. Identifying mechanisms of macrophage-mediated metastasis and therapy resistance in PDAC [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C65.
Investigation of the mechanism of action of anti-PD-1 treatment by systematic depletion of different immune cell populations in syngeneic models
Authors: L. Bourre, Y. Jin, J. Muntel, H. Yu, K. Beeler, R. Bruderer, Y. Shan, A. Xiaoyu An, D. Xuesong Ouyang, H. Qixiang Li
Journal: Annals of Oncology (2019)
Needle-knife deroofing of a symptomatic type III choledochal cyst
Authors: Giuseppe Vanella, Michiel Bronswijk, Schalk van der Merwe
Journal: Endoscopy (2019)

An 11-year-old patient was referred to our endoscopy unit following two bouts of acute pancreatitis of unclear cause. Because autoimmune or toxic causes were ruled out and mutation analysis for cystic fibrosis transmembrane regulator and serine protease inhibitors, Kazal type 1, was unrevealing, cross-sectional imaging by magnetic resonance imaging (MRI) ([Fig. 1]) and a subsequent endoscopic ultrasound (EUS) were performed, both showing a cystic structure at the distal common bile duct (CBD) ([Fig. 2], arrow). It was stipulated that local compression of a choledochal cyst could be directly causing the recurrent episodes of acute pancreatitis. The patient therefore consented to undergo endoscopic retrograde cholangiopancreatograpy (ERCP) with sphincterotomy. ERCP revealed a cystic, pre-papillary contrast opacification, findings compatible with a Todani type III choledochocele ([Fig. 3]). Following sphincterotomy, insufficient drainage was achieved because the cystic juxtapapillary lesion remained unchanged ([Fig. 4]). Subsequently, a needle-knife-assisted technique was used (NeedleCut3V, Olympus Medical Systems, Tokyo, Japan), which achieved a successful cystotomy and complete drainage of the choledochal cyst ([Video 1]) [1]. One month later at endoscopic follow-up, resolution of the choledochocele was seen ([Fig. 5]).
Overcoming the delivery barrier of oligonucleotide drugs and enhancing nucleoside drug efficiency: The use of nucleolipids
Authors: Xinyang Zhou, Shuhe Wang, Yuejie Zhu, Yufei Pan, Lihe Zhang, Zhenjun Yang
Journal: Medicinal Research Reviews (2019)

Abstract With the rapid development of synthetic technology and biological technology, many nucleic acid‐based drugs have entered the clinical trials. However, their inherent disabilities in actively and efficiently penetrating cell membranes still severely restrict their further application. The main drawback of cationic lipids, which have been widely used as nonviral vectors of nucleic acids, is their high cytotoxicity. A series of nucleoside‐based or nucleotide‐based nucleolipids have been reported in recent years, due to their oligonucleotide delivery capacity and low toxicity in comparison with cationic lipids. Lipophilic prodrugs of nucleoside analogs have extremely similar structures with nucleolipid vectors and are thus helpful for improving the transmembrane ability. This review introduces the progress of nucleolipids and provides new strategies for improving the delivery efficiency of nucleic acid‐based drugs, as well as lipophilic prodrugs of nucleosides or nucleotides for antiviral or anticancer therapies.
Role of senescent fibroblasts in the development of idiopathic guttate hypomelanosis
Authors: J.Y. Kim, S.‐H. Lee, Y. Ahn, E.J. Lee, M.‐Y. Park, S. Hwang, A. Almurayshid, B.J. Lim, S.H. Oh
Journal: British Journal of Dermatology (2019)

Abstract

BACKGROUND:

Idiopathic guttate hypomelanosis (IGH) is a common hypopigmentary disorder occurring mainly on exposed areas in elderly individuals. Long-term sun exposure is thought to be a main cause of IGH but the pathogenesis is still unknown.

OBJECTIVE:

The aim of this study was to find out the pathogenesis of IGH through investigating the effect of senescent fibroblasts on melanogenesis and melanocyte survival.

METHODS:

Lesional and perilesional normal skins were obtained from patients with IGH (n=30). Skin tissues were stained with p16, a senescence marker as well as senescence-associated secretory phenotype (SASP) including MMP-1, MMP-2 and type IV collagen. In addition, the functional role of UVB-induced senescent fibroblasts in melanocytes was investigated in the aspect of melanogenesis and melanocyte survival.

RESULTS:

A significant higher number of p16-positive cells were observed in the dermis of IGH lesion than in perilesional normal skin. MMP-1 expression was significantly higher in the lesions of IGH and type IV collagen was significantly degraded in the basement membrane zone of IGH lesions. UVB-induced senescence of fibroblasts was established through in vitro experiment. When the culture media from UVB-induced senescent fibroblasts was incubated in melanocytes, the expression of p16 and p21 as well as SA-?-Gal-staining intensity were significantly increased in melanocytes. In addition, increased levels of cleaved caspase 3 and reduced number of Ki67-positive cells were observed in melanocytes treated with culture media from senescent fibroblast.

CONCLUSIONS:

Senescent fibroblasts might contribute to the development of IGH through induction of melanocyte senescence and apoptosis in melanocytes via SASP.
Phase I Clinical Trial of the Wee1 Inhibitor Adavosertib (AZD1775) with Irinotecan in Children with Relapsed Solid Tumors: A COG Phase I Consortium Report (ADVL1312)
Authors: Kristina A. Cole, Sharmistha Pal, Rachel A. Kudgus, Heba Ijaz, Xiaowei Liu, Charles G. Minard, Bruce R. Pawel, John M. Maris, Daphne A. Haas-Kogan, Stephan D. Voss, Stacey L. Berg, Joel M. Reid, Elizabeth Fox, Brenda J. Weigel
Journal: Clinical Cancer Research (2019)

Adavosertib (AZD1775), an inhibitor of WEE1 kinase, potentiates replicative stress induced by oncogenes or chemotherapy. Antitumor activity of adavosertib has been demonstrated in preclinical models of pediatric cancer. This phase I trial was performed to define dose-limiting toxicities (DLT), recommended phase II dose (RP2D), and pharmacokinetics of adavosertib in combination with irinotecan in children and adolescents with relapsed or refractory solid tumors or primary central nervous system tumors.Using a 3+3 escalation design, five dose cohorts of the combination of adavosertib and irinotecan (50/70; 65/70; 65/90; 85/90; 110/90 mg/m2/day) delivered on days 1-5 of a 21-day cycle were studied. Pharmacokinetics and analysis of peripheral blood γH2AX was performed.Thirty-seven patients were enrolled; 27 were evaluable. The median (range) age was 14 (2-20) years. Twenty-five (93%) received prior chemotherapy (median, three regimens) and 21 (78%) received prior radiotherapy. Eleven patients had a primary central nervous system (CNS) malignancy. Common toxicities were hematologic and gastrointestinal. Two patients receiving adavosertib (110 mg/m2) in combination with irinotecan (90 mg/m2) experienced dose-limiting grade 3 dehydration. A patient with Ewing sarcoma had a confirmed partial response and 2 patients (ependymoma and neuroblastoma) had prolonged stable disease (≥ 6 cycles). Pharmacokinetics of adavosertib were variable but generally dose proportional and clearance was lower in younger patients.Adavosertib (85 mg/m2) in combination with irinotecan (90 mg/m2) administered orally for 5 days was the MTD in children and adolescents with solid and CNS tumors.
Abstract 13406: The Novel Biased Apelin Receptor Agonist MM07 Attenuates Monocrotaline-Induced Pulmonary Arterial Hypertension
Authors: Peiran Yang, Alexi Crosby, Guido Buonincontri, Janet J Maguire, Rhoda E Kuc, Stephen J Sawiak, Nicholas W Morrell, Anthony P Davenport
Journal: Circulation (2015)

Introduction: Apelin, a ligand of the G protein-coupled apelin receptor, is a vasodilator and a positive cardiac inotrope. Apelin expression is reduced in pulmonary arterial hypertension (PAH) and administration is reported to be beneficial in animal models of PAH. A synthetic biased apelin receptor agonist (MM07) that preferentially activates G protein-dependent signalling could be used to reduce the detrimental cardiac hypertrophy that contributes to heart failure whilst retaining the beneficial actions of apelin. The effect of MM07 has not been tested in an animal model of PAH. Hypothesis: We hypothesised that MM07 would attenuate PAH pathogenesis in the rat model of monocrotaline (MCT)-induced PAH. Methods: Male Sprague Dawley rats (187±2g) were randomly assigned to receive MCT (60mg/kg body weight) or saline subcutaneously on day 0. From day 1, animals in both groups were given daily intraperitoneal injections of either MM07 (1mg/kg body weight) or saline for 20 days. On day 21, the animals were anaesthetized and right ventricular systolic pressure (RVSP) was measured as a surrogate of pulmonary arterial pressure. Subsequently, hearts were dissected and the weight ratio of right ventricle compared to left ventricle and septum (RV/(LV+S)) was determined as an indicator of right ventricular hypertrophy. Data between groups were compared using one-way ANOVA with Tukey’s post-test. Results: Compared to saline control, as expected, the MCT group showed elevated RVSP (19.8±2.0mmHg, n=4 vs 45.8±8.4mmHg, n=5, p≤0.01) and RV/(LV+S) (0.22±0.01 vs 0.41±0.02, p≤0.001). Compared to the MCT group both parameters were significantly reduced in MCT-injected rats treated with MM07 (RVSP 28.8±2.7mmHg p≤0.05; RV/(LV+S) 0.29±0.01, p≤0.001, n=6). MM07 alone (n=4) did not alter right ventricular parameters (RVSP 20.6±1.2mmHg, p≥0.05; RV/(LV+S) 0.23±0.01, p≥0.05) in control animals. Conclusions: In this proof principle study we have shown for the first time that a biased apelin receptor agonist, MM07, significantly attenuated the development of PAH in an animal model. The predicted additional benefit of a G protein-biased agonist used chronically for PAH is less receptor desensitisation and cardiac remodelling that are mediated via β-arrestin pathways.
Colorectal Cancer Care Among Young Adult Patients After the Dependent Coverage Expansion Under the Affordable Care Act
Authors: Leticia Nogueira, Neetu Chawla, Xuesong Han, Ahmedin Jemal, K Robin Yabroff
Journal: JNCI Journal of the National Cancer Institute (2019)

Abstract The effect of the Dependent Coverage Expansion (DCE) under the Affordable Care Act (ACA) on receipt of colorectal cancer treatment has yet to be determined. We identified newly diagnosed DCE–eligible (aged 19–25 years, n = 1924) and DCE–ineligible (aged 27–34 years, n = 8313) colorectal cancer patients from the National Cancer Database from 2007 to 2013. All statistical tests were two-sided. Post-ACA, there was a statistically significant increase in early-stage diagnosis among DCE–eligible (15 percentage point increase, confidence interval = 9.8, 20.2; P &amp;lt; .001), but not DCE–ineligible (P = .09), patients. DCE–eligible patients resected for IIB–IIIC colorectal cancer were more likely to receive timely adjuvant chemotherapy (hazard ratio = 1.34, 95% confidence interval = 1.05 to 1.71; 7.0 days’ decrease in restricted mean time from surgery to chemotherapy, P = .01), with no differences in DCE–ineligible patients (hazard ratio = 1.10, 95% confidence interval = 0.98 to 1.24; 2.1 days’ decrease, P = .41) post-ACA. Our findings highlight the role of the ACA in improving access to potentially lifesaving cancer care, including a shift to early-stage diagnosis and more timely receipt of adjuvant chemotherapy.
Rozanolixizumab, an Anti-FcRn Antibody: Final Results from a Phase II, Multiple-Dose Study in Patients with Primary Immune Thrombocytopenia
Authors: Tadeusz Robak, Maciej Kaźmierczak, Isidro Jarque, Vasile Musteata, Jacek Trelinski, Nichola Cooper, Peter Kiessling, Ute Massow, Franz Woltering, Rose Snipes, Juan Ke, Grant Langdon, Birgit Haier, James B. Bussel, Stephen Jolles
Journal: Blood (2019)