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Recent Discoveries


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Development and Validation of a Mucosal Impedance Contour Analysis System to Distinguish Esophageal Disorders.

Development and Validation of a Mucosal Impedance Contour Analysis System to Distinguish Esophageal Disorders.

Gastroenterology. 2019 Jan 31;:

Authors: Patel DA, Higginbotham T, Slaughter JC, Aslam M, Yuksel E, Katzka D, Gyawali CP, Mashi M, Pandolfino J, Vaezi MF

Abstract
BACKGROUND: Diagnostic testing for chronic esophageal disorders rely on histopathology analysis of biopsies or uncomfortable transnasal catheters or wireless pH monitoring, which capture abnormal intraluminal refluxate. We therefore developed a balloon mucosal impedance (MI) catheter system that instantly detects changes in esophageal mucosal integrity during endoscopy over a long segment of the esophagus. We performed a prospective study to evaluate the ability of a balloon-incorporated MI catheter to detect and evaluate esophageal disorders, including gastroesophageal reflux disease (GERD) and eosinophilic esophagitis (EoE).
METHODS: We performed a prospective study of 69 patients undergoing esophagogastroduodenoscopy with or without wireless pH monitoring. Patients were classified as having GERD (erosive esophagitis or abnormal pH; n = 24), EoE (confirmed with pathology analysis of tissues from both distal and proximal esophagus; n = 21), or non-GERD (normal results from esophagogastroduodenoscopy and pH tests; n = 24). Receiver operating characteristic curves (ROC) and area under the ROC curve (AUC) were used to compare the accuracy of balloon MI in diagnosis. Probabilities of assignment to each group (GERD, non-GERD, or EoE) were estimated using multinomial logistic regression. Association between MI patterns and diagnoses were validated using data from patients seen at 3 separate institutions.
RESULTS: MI pattern along the esophageal axis differed significantly (p <0.01) among patients with GERD, EoE and non-GERD. Patients with non-GERD had higher MI values along all measured segments. The MI pattern for GERD was easily distinguished from that of EoE: in patients with GERD, MI values were low in the distal esophagus and normalized along the proximal esophagus, whereas in patients with EoE, measurements were low in all segments of the esophagus. Intercept and rate of rise of MI value (slope) as distance increased from the squamo-columnar junction identified patients with GERD with an AUC = 0.67, patients with EoE with an AUC of 0.84, and patients with non-GERD with an AUC = 0.83 in the development cohort. One patient had an adverse event (reported mild chest pain after the procedure) and was discharged from the hospital without further events.
CONCLUSIONS: We developed a balloon MI catheter system that instantly detects changes in esophageal mucosal integrity during endoscopy and found it to be safe and able to identify patients with GERD, EoE, or non-GERD. We validated our findings in a separate cohort for patients.

PMID: 30711626 [PubMed - as supplied by publisher]

Endosomolytic polymersomes increase the activity of cyclic dinucleotide STING agonists to enhance cancer immunotherapy.

Endosomolytic polymersomes increase the activity of cyclic dinucleotide STING agonists to enhance cancer immunotherapy.

Nat Nanotechnol. 2019 Jan 21;:

Authors: Shae D, Becker KW, Christov P, Yun DS, Lytton-Jean AKR, Sevimli S, Ascano M, Kelley M, Johnson DB, Balko JM, Wilson JT

Abstract
Cyclic dinucleotide (CDN) agonists of stimulator of interferon genes (STING) are a promising class of immunotherapeutics that activate innate immunity to increase tumour immunogenicity. However, the efficacy of CDNs is limited by drug delivery barriers, including poor cellular targeting, rapid clearance and inefficient transport to the cytosol where STING is localized. Here, we describe STING-activating nanoparticles (STING-NPs)-rationally designed polymersomes for enhanced cytosolic delivery of the endogenous CDN ligand for STING, 2'3' cyclic guanosine monophosphate-adenosine monophosphate (cGAMP). STING-NPs increase the biological potency of cGAMP, enhance STING signalling in the tumour microenvironment and sentinel lymph node, and convert immunosuppressive tumours to immunogenic, tumoricidal microenvironments. This leads to enhanced therapeutic efficacy of cGAMP, inhibition of tumour growth, increased rates of long-term survival, improved response to immune checkpoint blockade and induction of immunological memory that protects against tumour rechallenge. We validate STING-NPs in freshly isolated human melanoma tissue, highlighting their potential to improve clinical outcomes of immunotherapy.

PMID: 30664751 [PubMed - as supplied by publisher]

Author Correction: Assembly of a pan-genome from deep sequencing of 910 humans of African descent.

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Author Correction: Assembly of a pan-genome from deep sequencing of 910 humans of African descent.

Nat Genet. 2019 Jan 15;:

Authors: Sherman RM, Forman J, Antonescu V, Puiu D, Daya M, Rafaels N, Boorgula MP, Chavan S, Vergara C, Ortega VE, Levin AM, Eng C, Yazdanbakhsh M, Wilson JG, Marrugo J, Lange LA, Williams LK, Watson H, Ware LB, Olopade CO, Olopade O, Oliveira RR, Ober C, Nicolae DL, Meyers DA, Mayorga A, Knight-Madden J, Hartert T, Hansel NN, Foreman MG, Ford JG, Faruque MU, Dunston GM, Caraballo L, Burchard EG, Bleecker ER, Araujo MI, Herrera-Paz EF, Campbell M, Foster C, Taub MA, Beaty TH, Ruczinski I, Mathias RA, Barnes KC, Salzberg SL

Abstract
In the version of this article initially published, the statement "there are no pan-genomes for any other animal or plant species" was incorrect. The statement has been corrected to "there are no reported pan-genomes for any other animal species, to our knowledge." We thank David Edwards for bringing this error to our attention. The error has been corrected in the HTML and PDF versions of the article.

PMID: 30647471 [PubMed - as supplied by publisher]

Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use.

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Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use.

Nat Genet. 2019 Jan 14;:

Authors: Liu M, Jiang Y, Wedow R, Li Y, Brazel DM, Chen F, Datta G, Davila-Velderrain J, McGuire D, Tian C, Zhan X, 23andMe Research Team, HUNT All-In Psychiatry, Choquet H, Docherty AR, Faul JD, Foerster JR, Fritsche LG, Gabrielsen ME, Gordon SD, Haessler J, Hottenga JJ, Huang H, Jang SK, Jansen PR, Ling Y, Mägi R, Matoba N, McMahon G, Mulas A, Orrù V, Palviainen T, Pandit A, Reginsson GW, Skogholt AH, Smith JA, Taylor AE, Turman C, Willemsen G, Young H, Young KA, Zajac GJM, Zhao W, Zhou W, Bjornsdottir G, Boardman JD, Boehnke M, Boomsma DI, Chen C, Cucca F, Davies GE, Eaton CB, Ehringer MA, Esko T, Fiorillo E, Gillespie NA, Gudbjartsson DF, Haller T, Harris KM, Heath AC, Hewitt JK, Hickie IB, Hokanson JE, Hopfer CJ, Hunter DJ, Iacono WG, Johnson EO, Kamatani Y, Kardia SLR, Keller MC, Kellis M, Kooperberg C, Kraft P, Krauter KS, Laakso M, Lind PA, Loukola A, Lutz SM, Madden PAF, Martin NG, McGue M, McQueen MB, Medland SE, Metspalu A, Mohlke KL, Nielsen JB, Okada Y, Peters U, Polderman TJC, Posthuma D, Reiner AP, Rice JP, Rimm E, Rose RJ, Runarsdottir V, Stallings MC, Stančáková A, Stefansson H, Thai KK, Tindle HA, Tyrfingsson T, Wall TL, Weir DR, Weisner C, Whitfield JB, Winsvold BS, Yin J, Zuccolo L, Bierut LJ, Hveem K, Lee JJ, Munafò MR, Saccone NL, Willer CJ, Cornelis MC, David SP, Hinds DA, Jorgenson E, Kaprio J, Stitzel JA, Stefansson K, Thorgeirsson TE, Abecasis G, Liu DJ, Vrieze S

Abstract
Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders1. They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6-11. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures.

PMID: 30643251 [PubMed - as supplied by publisher]

Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk.

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Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk.

Nat Genet. 2019 Jan 07;:

Authors: Jansen IE, Savage JE, Watanabe K, Bryois J, Williams DM, Steinberg S, Sealock J, Karlsson IK, Hägg S, Athanasiu L, Voyle N, Proitsi P, Witoelar A, Stringer S, Aarsland D, Almdahl IS, Andersen F, Bergh S, Bettella F, Bjornsson S, Brækhus A, Bråthen G, de Leeuw C, Desikan RS, Djurovic S, Dumitrescu L, Fladby T, Hohman TJ, Jonsson PV, Kiddle SJ, Rongve A, Saltvedt I, Sando SB, Selbæk G, Shoai M, Skene NG, Snaedal J, Stordal E, Ulstein ID, Wang Y, White LR, Hardy J, Hjerling-Leffler J, Sullivan PF, van der Flier WM, Dobson R, Davis LK, Stefansson H, Stefansson K, Pedersen NL, Ripke S, Andreassen OA, Posthuma D

Abstract
Alzheimer's disease (AD) is highly heritable and recent studies have identified over 20 disease-associated genomic loci. Yet these only explain a small proportion of the genetic variance, indicating that undiscovered loci remain. Here, we performed a large genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 cases, 383,378 controls). AD-by-proxy, based on parental diagnoses, showed strong genetic correlation with AD (rg = 0.81). Meta-analysis identified 29 risk loci, implicating 215 potential causative genes. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver, and microglia). Gene-set analyses indicate biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomization results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD.

PMID: 30617256 [PubMed - as supplied by publisher]

Serologic Response to Helicobacter pylori Proteins Associated With Risk of Colorectal Cancer Among Diverse Populations in the United States.

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Serologic Response to Helicobacter pylori Proteins Associated With Risk of Colorectal Cancer Among Diverse Populations in the United States.

Gastroenterology. 2019 01;156(1):175-186.e2

Authors: Butt J, Varga MG, Blot WJ, Teras L, Visvanathan K, Le Marchand L, Haiman C, Chen Y, Bao Y, Sesso HD, Wassertheil-Smoller S, Ho GYF, Tinker LE, Peek RM, Potter JD, Cover TL, Hendrix LH, Huang LC, Hyslop T, Um C, Grodstein F, Song M, Zeleniuch-Jacquotte A, Berndt S, Hildesheim A, Waterboer T, Pawlita M, Epplein M

Abstract
BACKGROUND & AIMS: Previous studies reported an association of the bacteria Helicobacter pylori, the primary cause of gastric cancer, and risk of colorectal cancer (CRC). However, these findings have been inconsistent, appear to vary with population characteristics, and may be specific for virulence factor VacA. To more thoroughly evaluate the potential association of H pylori antibodies with CRC risk, we assembled a large consortium of cohorts representing diverse populations in the United States.
METHODS: We used H pylori multiplex serologic assays to analyze serum samples from 4063 incident cases of CRC, collected before diagnosis, and 4063 matched individuals without CRC (controls) from 10 prospective cohorts for antibody responses to 13 H pylori proteins, including virulence factors VacA and CagA. The association of seropositivity to H pylori proteins, as well as protein-specific antibody level, with odds of CRC was determined by conditional logistic regression.
RESULTS: Overall, 40% of controls and 41% of cases were H pylori-seropositive (odds ratio [OR], 1.09; 95% CI, 0.99-1.20). H pylori VacA-specific seropositivity was associated with an 11% increased odds of CRC (OR, 1.11; 95% CI, 1.01-1.22), and this association was particularly strong among African Americans (OR, 1.45; 95% CI, 1.08-1.95). Additionally, odds of CRC increased with level of VacA antibody in the overall cohort (P = .008) and specifically among African Americans (P = .007).
CONCLUSIONS: In an analysis of a large consortium of cohorts representing diverse populations, we found serologic responses to H pylori VacA to associate with increased risk of CRC risk, particularly for African Americans. Future studies should seek to understand whether this marker is related to virulent H pylori strains carried in these populations.

PMID: 30296434 [PubMed - indexed for MEDLINE]

Model to Select On-Therapy vs Off-Therapy Tests for Patients With Refractory Esophageal or Extraesophageal Symptoms.

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Model to Select On-Therapy vs Off-Therapy Tests for Patients With Refractory Esophageal or Extraesophageal Symptoms.

Gastroenterology. 2018 12;155(6):1729-1740.e1

Authors: Patel DA, Sharda R, Choksi YA, Slaughter JC, Higginbotham T, Garrett CG, Francis DO, Ravi K, Hasak S, Katzka D, Gyawali CP, Vaezi MF

Abstract
BACKGROUND & AIMS: It is not clear whether we should test for reflux in patients with refractory heartburn or extraesophageal reflux (EER) symptoms, such as cough, hoarseness, or asthma. Guidelines recommend testing patients by pH monitoring when they are on or off acid-suppressive therapies based on pretest probability of reflux, determined by expert consensus. However, it is not clear what constitutes a low or high pretest probability of reflux in these patients. We aimed to develop a model that clinicians can use at bedside to estimate pretest probability of abnormal reflux.
METHODS: We performed a prospective study of 471 adult patients with refractory heartburn (n = 214) or suspected EER symptoms (n = 257) who underwent endoscopy with wireless pH monitoring while they were off acid-suppressive treatment and assigned them to groups based on symptoms at presentation (discovery cohort). Using data from the discovery cohort, we performed proportional odds ordinal logistic regression to select factors (easy to obtain demographic criteria and clinical symptoms such as heartburn, regurgitation, asthma, cough, and hoarseness) associated with esophageal exposure to acid. We validated our findings in a cohort of 118 patients with the same features from 2 separate tertiary care centers (62% women; median age 59 years; 62% with cough as presenting symptom).
RESULTS: Abnormal pH (>5.5% of time spent at pH <4) was found in 56% of patients with heartburn and 63% of patients with EER (P = .15). Within EER groups, abnormal pH was detected in a significantly larger proportion (80%) of patients with asthma compared with patients with cough (60%) or hoarseness (51%; P < .01). Factors significantly associated with abnormal pH in patients with heartburn were presence of hiatal hernia and body mass index >25 kg/m2. In patients with EER, the risk of reflux was independently associated with the presence of concomitant heartburn (odds ratio [OR] 2.0; 95% confidence interval [CI] 1.3-3.1), body mass index >25 kg/m2 (OR 2.1; 95% CI 1.5-3.1), asthma (OR 2.0; 95% CI 1.2-3.5), and presence of hiatal hernia (OR 1.9; 95% CI 1.2-3.1). When we used these factors to create a scoring system, we found that a score of ≤2 excluded patients with moderate to severe reflux, with a negative predictive value of 80% in the discovery cohort and a negative predictive value of 85% in the validation cohort.
CONCLUSION: We developed a clinical model to estimate pretest probability of abnormal pH in patients who were failed by proton pump inhibitor therapy. This system can help guide clinicians at bedside in determining the most appropriate diagnostic test in this challenging group of patients.

PMID: 30170117 [PubMed - indexed for MEDLINE]