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Endoscopic management of pancreatobiliary neoplasms.

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Endoscopic management of pancreatobiliary neoplasms.

Gastroenterology. 2018 Feb 16;:

Authors: Wang AY, Yachimski PS

Abstract
Endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP) are the mainstays of interventional endoscopic practice. EUS occupies a central role in the diagnosis of pancreatobiliary neoplasms and offers a platform for a wide range of direct tumor therapies. Initial steps have demonstrated the feasibility of such applications in animal models and pilot studies. Larger clinical trials and incorporation of EUS-based therapies into cooperative cancer studies might demonstrate an impact in the clinical prognosis of patients with pancreatic cancer. ERCP plays an important role in elucidating indeterminate biliary strictures and in treating patients with malignant biliary obstruction who are symptomatic or have borderline resectable or unresectable disease. ERCP-directed ablative therapies enable neoadjuvant and palliative intervention in patients with malignant biliary obstruction, in particular perihilar cholangiocarcinoma. Additional comparative, multicenter studies are needed to better understand the safety and efficacy of endobiliary brachytherapy, photodynamic therapy, and radiofrequency ablation in patients with pancreatobiliary malignancies.

PMID: 29458151 [PubMed - as supplied by publisher]

Opioid Analgesic Use and Risk for Invasive Pneumococcal Diseases: A Nested Case-Control Study.

Opioid Analgesic Use and Risk for Invasive Pneumococcal Diseases: A Nested Case-Control Study.

Ann Intern Med. 2018 Feb 13;:

Authors: Wiese AD, Griffin MR, Schaffner W, Stein CM, Greevy RA, Mitchel EF, Grijalva CG

Abstract
Background: Although certain opioid analgesics have immunosuppressive properties and increase the risk for infections in animals, the clinical effects of prescription opioid use on infection risk among humans are unknown.
Objective: To test the hypothesis that prescription opioid use is an independent risk factor for invasive pneumococcal disease (IPD).
Design: Nested case-control study.
Setting: Tennessee Medicaid database linked to Medicare and Active Bacterial Core surveillance system databases (1995 to 2014).
Patients: 1233 case patients with IPD aged 5 years and older matched to 24 399 control participants by diagnosis date, age, and county of residence.
Measurements: Opioid use was measured on the basis of pharmacy prescription fills. Invasive pneumococcal disease was defined by the isolation of Streptococcus pneumoniae from a normally sterile site. The odds of current opioid use were compared between the case and control groups, accounting for known IPD risk factors. Secondary analyses categorized opioid use by opioid characteristics, applied an IPD risk score to assure comparability between exposure groups, and analyzed pneumonia and nonpneumonia IPD cases separately.
Results: Persons in the case group had greater odds than control participants of being current opioid users (adjusted odds ratio [aOR], 1.62 [95% CI, 1.36 to 1.92]). Associations were strongest for opioids that were long acting (aOR, 1.87 [CI, 1.24 to 2.82]), of high potency (aOR, 1.72 [CI, 1.32 to 2.25]), or were used at high dosages (50 to 90 morphine milligram equivalents [MME]/d: aOR, 1.71 [CI, 1.22 to 2.39]; ≥90 MME/d: aOR, 1.75 [CI, 1.33 to 2.29]). Results were consistent when the IPD risk score was taken into account and pneumonia and nonpneumonia IPD were analyzed separately.
Limitations: Unmeasured confounding and measurement error, although sensitivity analyses suggested that neither was likely to affect results. Actual opioid use and other nonprescription use (such as illicit opioid use) were not measured.
Conclusion: Opioid use is associated with an increased risk for IPD and represents a novel risk factor for these diseases.
Primary Funding Source: National Institutes of Health.

PMID: 29435555 [PubMed - as supplied by publisher]

Classification and Reporting of Potentially Proarrhythmic Common Genetic Variation in Long QT Syndrome Genetic Testing.

Classification and Reporting of Potentially Proarrhythmic Common Genetic Variation in Long QT Syndrome Genetic Testing.

Circulation. 2018 Feb 06;137(6):619-630

Authors: Giudicessi JR, Roden DM, Wilde AAM, Ackerman MJ

Abstract
The acquired and congenital forms of long QT syndrome represent 2 distinct but clinically and genetically intertwined disorders of cardiac repolarization characterized by the shared final common pathway of QT interval prolongation and risk of potentially life-threatening arrhythmias. Over the past 2 decades, our understanding of the spectrum of genetic variation that (1) perturbs the function of cardiac ion channel macromolecular complexes and intracellular calcium-handling proteins, (2) underlies acquired/congenital long QT syndrome susceptibility, and (3) serves as a determinant of QT interval duration in the general population has grown exponentially. In turn, these molecular insights led to the development and increased utilization of clinically impactful genetic testing for congenital long QT syndrome. However, the widespread adoption and potential misinterpretation of the 2015 American College of Medical Genetics and Genomics variant classification and reporting guidelines may have contributed unintentionally to the reduced reporting of common genetic variants, with compelling epidemiological and functional evidence to support a potentially proarrhythmic role in patients with congenital and acquired long QT syndrome. As a result, some genetic testing reports may fail to convey the full extent of a patient's genetic susceptibility for a potentially life-threatening arrhythmia to the ordering healthcare professional. In this white paper, we examine the current classification and reporting (or lack thereof) of potentially proarrhythmic common genetic variants and investigate potential mechanisms to facilitate the reporting of these genetic variants without increasing the risk of diagnostic miscues.

PMID: 29431662 [PubMed - in process]

Selective Inhibition of Nuclear Export With Oral Selinexor for Treatment of Relapsed or Refractory Multiple Myeloma.

Selective Inhibition of Nuclear Export With Oral Selinexor for Treatment of Relapsed or Refractory Multiple Myeloma.

J Clin Oncol. 2018 Jan 30;:JCO2017755207

Authors: Vogl DT, Dingli D, Cornell RF, Huff CA, Jagannath S, Bhutani D, Zonder J, Baz R, Nooka A, Richter J, Cole C, Vij R, Jakubowiak A, Abonour R, Schiller G, Parker TL, Costa LJ, Kaminetzky D, Hoffman JE, Yee AJ, Chari A, Siegel D, Fonseca R, Van Wier S, Ahmann G, Lopez I, Kauffman M, Shacham S, Saint-Martin JR, Picklesimer CD, Choe-Juliak C, Stewart AK

Abstract
Purpose Selinexor, a first-in-class, oral, selective exportin 1 (XPO1) inhibitor, induces apoptosis in cancer cells through nuclear retention of tumor suppressor proteins and the glucocorticoid receptor, along with inhibition of translation of oncoprotein mRNAs. We studied selinexor in combination with low-dose dexamethasone in patients with multiple myeloma refractory to the most active available agents. Patients and Methods This phase II trial evaluated selinexor 80 mg and dexamethasone 20 mg, both orally and twice weekly, in patients with myeloma refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide (quad-refractory disease), with a subset also refractory to an anti-CD38 antibody (penta-refractory disease). The primary end point was overall response rate (ORR). Results Of 79 patients, 48 had quad-refractory and 31 had penta-refractory myeloma. Patients had received a median of seven prior regimens. The ORR was 21% and was similar for patients with quad-refractory (21%) and penta-refractory (20%) disease. Among patients with high-risk cytogenetics, including t(4;14), t(14;16), and del(17p), the ORR was 35% (six of 17 patients). The median duration of response was 5 months, and 65% of responding patients were alive at 12 months. The most common grade ≥ 3 adverse events were thrombocytopenia (59%), anemia (28%), neutropenia (23%), hyponatremia (22%), leukopenia (15%), and fatigue (15%). Dose interruptions for adverse events occurred in 41 patients (52%), dose reductions occurred in 29 patients (37%), and treatment discontinuation occurred in 14 patients (18%). Conclusion The combination of selinexor and dexamethasone has an ORR of 21% in patients with heavily pretreated, refractory myeloma with limited therapeutic options.

PMID: 29381435 [PubMed - as supplied by publisher]

Reply.

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J Allergy Clin Immunol. 2018 Jan 19;:

Authors: Stone CA, Hemler JA, Commins SP, Schuyler AJ, Phillips EJ, Peebles RS, Fahrenholz JM

PMID: 29370925 [PubMed - as supplied by publisher]

Pevonedistat, a first-in-class NEDD8-activating enzyme (NAE) inhibitor, combined with azacitidine, in patients with AML.

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Pevonedistat, a first-in-class NEDD8-activating enzyme (NAE) inhibitor, combined with azacitidine, in patients with AML.

Blood. 2018 Jan 18;:

Authors: Swords RT, Coutre S, Maris MB, Zeidner JF, Foran JM, Cruz J, Erba HP, Berdeja JG, Tam W, Vardhanabhuti S, Pawlikowska-Dobler I, Faessel HM, Dash AB, Sedarati F, Dezube BJ, Faller DV, Savona MR

Abstract
Pevonedistat (TAK-924/MLN4924) is a novel inhibitor of NEDD8-activating enzyme (NAE) with single-agent activity in relapsed/refractory acute myeloid leukemia (AML). We performed a phase 1b study (NCT01814826) of pevonedistat (PEV) with azacitidine (AZA) based on synergistic activity seen preclinically. Primary objectives included safety and tolerability, and secondary objectives included pharmacokinetics (PK) and disease response. Patients ≥60 years with treatment-naïve AML, unfit for standard induction therapy, received PEV 20 or 30 mg/m2 IV on days 1, 3, and 5, combined with fixed-dose AZA (75 mg/m2 IV/SC) on days 1-5, 8, and 9, every 28 days. The most common treatment-emergent adverse events were constipation (48%), nausea (42%), fatigue (42%), and anemia (39%). In total, 11 deaths were observed and considered unrelated to study therapy by the investigators. Transient elevations in AST and ALT were dose limiting. The recommended phase 2 dose of PEV in this combination is 20 mg/m2 PEV PK was not altered by the addition of AZA. Overall response rate (ORR) based on an ITT analysis was 50% (20 CR, 5 CRi, 7 PR), with an 8.3-month median duration of remission. In patients receiving ≥6 cycles of therapy (n = 23, 44%), ORR was 83%. In patients with TP53 mutations, the composite CR/PR rate was 80% (4/5). Two of these patients stayed on study for >10 cycles. Baseline bone marrow blast percentage or cytogenetic/molecular risk did not influence ORR.

PMID: 29348128 [PubMed - as supplied by publisher]

Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome.

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Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome.

Circ Res. 2018 Jan 17;:

Authors: van den Berg MP, Almomani R, Biaggioni I, van Faassen M, van der Harst P, Silljé HH, Mateo Leach I, Hemmelder M, Navis G, Luijckx GJ, de Brouwer AP, Venselaar H, Verbeek MM, van der Zwaag PA, Jongbloed JD, van Tintelen JP, Wevers RA, Kema IP

Abstract
Rationale: Orthostatic hypotension is a common clinical problem, but the underlying mechanisms have not been fully delineated. Objective: We describe two families, with four patients in total, suffering from severe life-threatening orthostatic hypotension due to a novel cause. Methods and Results: As in dopamine β-hydroxylase deficiency (DβH), concentrations of norepinephrine and epinephrine in the patients were very low. Plasma DβH activity, however, was normal and the DBH gene had no mutations. Molecular genetic analysis was performed to determine the underlying genetic cause. Homozygosity mapping and exome and Sanger sequencing revealed pathogenic homozygous mutations in the gene encoding cytochrome b561 (CYB561); a missense variant c.262G>A, p.Gly88Arg in exon 3 in the Dutch family and a nonsense mutation (c.131G>A, p.Trp44*) in exon 2 in the American family. Expression of CYB561 was investigated using RNA from different human adult and fetal tissues, transcription of RNA into cDNA and real-time quantitative polymerase chain reaction. The CYB561 gene was found to be expressed in many human tissues, in particular the brain. The CYB561 protein defect leads to a shortage of ascorbate inside the catecholamine secretory vesicles leading to a functional DβH deficiency. The concentration of the catecholamines and downstream metabolites was measured in brain and adrenal tissue of six CYB561 knockout mice (reporter-tagged deletion allele (post-Cre), genetic background C57BL/6NTac). The concentration of norepinephrine and normetanephrine was decreased in whole brain homogenates of the CYB561(-/-) mice compared to wild type mice (p<0.01) and the concentration of normetanephrine and metanephrine was decreased in adrenal glands (p<0.01), recapitulating the clinical phenotype. The patients responded favorably to treatment with L-dihydroxyphenylserine, which can be converted directly to norepinephrine. Conclusions: This study is the first to implicate cytochrome b561 in disease by showing that pathogenic mutations in CYB561 cause an as yet unknown disease in neurotransmitter metabolism causing orthostatic hypotension. as yet unknown disease in neurotransmitter metabolism causing orthostatic hypotension.

PMID: 29343526 [PubMed - as supplied by publisher]

Pharmacological blockade of ASCT2-dependent glutamine transport leads to antitumor efficacy in preclinical models.

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Pharmacological blockade of ASCT2-dependent glutamine transport leads to antitumor efficacy in preclinical models.

Nat Med. 2018 Jan 15;:

Authors: Schulte ML, Fu A, Zhao P, Li J, Geng L, Smith ST, Kondo J, Coffey RJ, Johnson MO, Rathmell JC, Sharick JT, Skala MC, Smith JA, Berlin J, Washington MK, Nickels ML, Manning HC

Abstract
The unique metabolic demands of cancer cells underscore potentially fruitful opportunities for drug discovery in the era of precision medicine. However, therapeutic targeting of cancer metabolism has led to surprisingly few new drugs to date. The neutral amino acid glutamine serves as a key intermediate in numerous metabolic processes leveraged by cancer cells, including biosynthesis, cell signaling, and oxidative protection. Herein we report the preclinical development of V-9302, a competitive small molecule antagonist of transmembrane glutamine flux that selectively and potently targets the amino acid transporter ASCT2. Pharmacological blockade of ASCT2 with V-9302 resulted in attenuated cancer cell growth and proliferation, increased cell death, and increased oxidative stress, which collectively contributed to antitumor responses in vitro and in vivo. This is the first study, to our knowledge, to demonstrate the utility of a pharmacological inhibitor of glutamine transport in oncology, representing a new class of targeted therapy and laying a framework for paradigm-shifting therapies targeting cancer cell metabolism.

PMID: 29334372 [PubMed - as supplied by publisher]

Glucagon-like peptide 1 signaling inhibits allergen-induced lung IL-33 release and reduces group 2 innate lymphoid cell (ILC2) cytokine production in vivo.

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Glucagon-like peptide 1 signaling inhibits allergen-induced lung IL-33 release and reduces group 2 innate lymphoid cell (ILC2) cytokine production in vivo.

J Allergy Clin Immunol. 2018 Jan 10;:

Authors: Toki S, Goleniewska K, Reiss S, Zhang J, Bloodworth MH, Stier MT, Zhou W, Newcomb DC, Ware LB, Stanwood GD, Galli A, Boyd KL, Niswender KD, Peebles RS

Abstract
BACKGROUND: IL-33 is one of the most consistently associated gene candidates for asthma identified by GWAS. Studies in mice and in human cells have confirmed the importance of IL-33 in inducing type-2 cytokine production from both group 2 innate lymphoid cells (ILC2) and Th2 cells. However, there are no pharmacologic agents known to inhibit IL-33 release from airway cells.
OBJECTIVE: To determine the effect of glucagon like peptide receptor-1 GLP-1R signaling on aeroallergen-induced airway IL-33 production and release and on innate type-2 airway inflammation.
METHODS: BALB/c mice were challenged intranasally with Alternaria extract for 4 consecutive days. GLP-1R agonist or the vehicle was administered starting either 2 days before the first Alternaria extract-challenge or 1 day after the first Alternaria extract-challenge.
RESULTS: GLP-1R agonist treatment starting 2 days before the first Alternaria extract-challenge decreased IL-33 release in the BAL fluid and DUOX1 mRNA expression 1 h after the first Alternaria extract-challenge, and IL-33 expression in lung epithelial cells 24 h after the last Alternaria extract-challenge. Further, GLP-1R agonist significantly decreased the number of ILC2 expressing IL-5 and IL-13, the lung protein expression of type-2 cytokines and chemokines, the number of perivascular eosinophils, mucus production, and airway responsiveness compared with vehicle treatment. GLP-1R agonist treatment starting one day after the first Alternaria extract-challenge also significantly decreased eosinophilia and type-2 cytokine and chemokine expression in the airway after 4 days of Alternaria extract-challenge.
CONCLUSION: These results reveal that GLP-1R signaling may be a potential therapy to reduce IL-33 release and inhibit the ILC2 response to protease-containing aeroallergens, such as Alternaria.

PMID: 29331643 [PubMed - as supplied by publisher]

Nasopharyngeal Lactobacillus is Associated with Childhood Wheezing Illnesses Following Acute Respiratory Syncytial Virus Infection in Infancy.

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Nasopharyngeal Lactobacillus is Associated with Childhood Wheezing Illnesses Following Acute Respiratory Syncytial Virus Infection in Infancy.

J Allergy Clin Immunol. 2018 Jan 09;:

Authors: Rosas-Salazar C, Shilts MH, Tovchigrechko A, Schobel S, Chappell JD, Larkin EK, Gebretsadik T, Halpin RA, Nelson KE, Moore ML, Anderson LJ, Peebles RS, Das SR, Hartert TV

Abstract
BACKGROUND: Early-life acute respiratory infection (ARI) with respiratory syncytial virus (RSV) has been strongly associated with the development of childhood wheezing illnesses, but the pathways underlying this association are poorly understood.
OBJECTIVE: To examine the role of the nasopharyngeal microbiome in the development of childhood wheezing illnesses following RSV ARI in infancy.
METHODS: We conducted a nested cohort study of 118 previously healthy, term infants with confirmed RSV ARI by RT-PCR. We used next-generation sequencing of the V4 region of the 16S rRNA gene to characterize the nasopharyngeal microbiome during RSV ARI. Our main outcome of interest was 2-year subsequent wheeze.
RESULTS: One hundred thirteen (95.8%) of the 118 infants had 2-year outcome data. Of these, 46 (40.7%) had parental report of subsequent wheeze. There was no association between the overall taxonomic composition, diversity, and richness of the nasopharyngeal microbiome during RSV ARI with the development of subsequent wheeze. However, the nasopharyngeal detection and abundance of Lactobacillus was consistently higher in infants who did not develop this outcome. Lactobacillus also ranked first among the different genera in a model distinguishing infants with and without subsequent wheeze.
CONCLUSION: The nasopharyngeal detection and increased abundance of Lactobacillus during RSV ARI in infancy are associated with a reduced risk of childhood wheezing illnesses at age 2 years.

PMID: 29330010 [PubMed - as supplied by publisher]

Geographic Variation in Cardiac Rehabilitation Participation in Medicare and Veterans Affairs Populations: An Opportunity for Improvement?

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Geographic Variation in Cardiac Rehabilitation Participation in Medicare and Veterans Affairs Populations: An Opportunity for Improvement?

Circulation. 2018 Jan 05;:

Authors: Beatty AL, Truong M, Schopfer DW, Shen H, Bachmann JM, Whooley MA

Abstract
Background -Cardiac rehabilitation is strongly recommended after myocardial infarction (MI), percutaneous coronary intervention (PCI), or coronary artery bypass surgery (CABG), but is historically underused. We sought to evaluate variation in cardiac rehabilitation participation across the United States. Methods -From administrative data from the Veterans Affairs (VA) healthcare system and a 5% Medicare sample, we used ICD-9 codes to identify patients hospitalized for MI, PCI, or CABG from 2007-2011. After excluding patients who died within 30 days of hospitalization, we calculated the percent of patients who participated in one or more outpatient visits for cardiac rehabilitation during the 12 months after hospitalization. We estimated adjusted and standardized rates of participation in cardiac rehabilitation by state using hierarchical logistic regression models. Results -Overall, participation in cardiac rehabilitation was 16.3% (23,403/143,756) in Medicare and 10.3% (9,123/88,826) in VA. However, participation rates varied widely across states, ranging from 3.2% to 41.8% in Medicare and 1.2% to 47.6% in VA. Similar regional variation was observed in both populations. Patients in the West North Central region (Iowa, Kansas, Minnesota, Missouri, Nebraska, North Dakota, and South Dakota) had the highest participation, while those in the Pacific region (Alaska, California, Hawaii, Oregon, and Washington) had the lowest participation in both Medicare (33.7% vs. 10.6%) and VA (16.6% vs. 5.1%) populations. Significant hospital-level variation was also present, with participation ranging from 3-75% in Medicare and 1-43% in VA. Conclusions -Cardiac rehabilitation participation remains low overall in both Medicare and VA populations. However, there is remarkably similar regional variation, with some regions and hospitals achieving high rates of participation in both populations. This provides an opportunity to identify best practices from higher-performing hospitals and regions that could be used to improve cardiac rehabilitation participation in lower-performing hospitals and regions.

PMID: 29305529 [PubMed - as supplied by publisher]

Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma.

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Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma.

N Engl J Med. 2018 Jan 04;378(1):35-47

Authors: Sullivan KM, Goldmuntz EA, Keyes-Elstein L, McSweeney PA, Pinckney A, Welch B, Mayes MD, Nash RA, Crofford LJ, Eggleston B, Castina S, Griffith LM, Goldstein JS, Wallace D, Craciunescu O, Khanna D, Folz RJ, Goldin J, St Clair EW, Seibold JR, Phillips K, Mineishi S, Simms RW, Ballen K, Wener MH, Georges GE, Heimfeld S, Hosing C, Forman S, Kafaja S, Silver RM, Griffing L, Storek J, LeClercq S, Brasington R, Csuka ME, Bredeson C, Keever-Taylor C, Domsic RT, Kahaleh MB, Medsger T, Furst DE, SCOT Study Investigators

Abstract
Background Despite current therapies, diffuse cutaneous systemic sclerosis (scleroderma) often has a devastating outcome. We compared myeloablative CD34+ selected autologous hematopoietic stem-cell transplantation with immunosuppression by means of 12 monthly infusions of cyclophosphamide in patients with scleroderma. Methods We randomly assigned adults (18 to 69 years of age) with severe scleroderma to undergo myeloablative autologous stem-cell transplantation (36 participants) or to receive cyclophosphamide (39 participants). The primary end point was a global rank composite score comparing participants with each other on the basis of a hierarchy of disease features assessed at 54 months: death, event-free survival (survival without respiratory, renal, or cardiac failure), forced vital capacity, the score on the Disability Index of the Health Assessment Questionnaire, and the modified Rodnan skin score. Results In the intention-to-treat population, global rank composite scores at 54 months showed the superiority of transplantation (67% of 1404 pairwise comparisons favored transplantation and 33% favored cyclophosphamide, P=0.01). In the per-protocol population (participants who received a transplant or completed ≥9 doses of cyclophosphamide), the rate of event-free survival at 54 months was 79% in the transplantation group and 50% in the cyclophosphamide group (P=0.02). At 72 months, Kaplan-Meier estimates of event-free survival (74% vs. 47%) and overall survival (86% vs. 51%) also favored transplantation (P=0.03 and 0.02, respectively). A total of 9% of the participants in the transplantation group had initiated disease-modifying antirheumatic drugs (DMARDs) by 54 months, as compared with 44% of those in the cyclophosphamide group (P=0.001). Treatment-related mortality in the transplantation group was 3% at 54 months and 6% at 72 months, as compared with 0% in the cyclophosphamide group. Conclusions Myeloablative autologous hematopoietic stem-cell transplantation achieved long-term benefits in patients with scleroderma, including improved event-free and overall survival, at a cost of increased expected toxicity. Rates of treatment-related death and post-transplantation use of DMARDs were lower than those in previous reports of nonmyeloablative transplantation. (Funded by the National Institute of Allergy and Infectious Diseases and the National Institutes of Health; ClinicalTrials.gov number, NCT00114530 .).

PMID: 29298160 [PubMed - in process]

Kidney Transplantation in a Patient Lacking Cytosolic Phospholipase A2 Proves Renal Origins of Urinary PGI-M and TX-M.

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Kidney Transplantation in a Patient Lacking Cytosolic Phospholipase A2 Proves Renal Origins of Urinary PGI-M and TX-M.

Circ Res. 2018 Jan 03;:

Authors: Mitchell J, Knowles RB, Kirkby NS, Reed DM, Edin ML, White WE, Chan MV, Longhurst H, Yaqoob M, Milne GL, Zeldin DC, Warner TD

Abstract
Rationale: The balance between vascular prostacyclin which is anti-thrombotic and platelet thromboxane A2 which is pro-thrombotic is fundamental to cardiovascular health. Prostacyclin and thromboxane A2 are formed following the concerted actions of cytosolic phospholipase A2 (cPLA2α) and cyclooxygenase. Urinary 2,3-dinor-6-keto PGF1α (PGI-M) and 11-dehydro-TXB2 (TX-M) have been taken as biomarkers of prostacyclin and thromboxane A2 formation with the circulation and used to explain cyclooxygenase biology and patient phenotypes, despite concerns that urinary PGI-M and TX-M originate in the kidney. Objective: We report data from a remarkable patient carrying an extremely rare genetic mutation in cPLA2α, causing almost complete loss of prostacyclin and thromboxane A2, who was transplanted with a normal kidney resulting in an experimental scenario of 'whole body cPLA2α knockout, kidney specific knock-in'. By studying this patient, we can determine definitively the contribution of the kidney to the productions of PGI-M and TX-M and test their validity as markers of prostacyclin and thromboxane A2 in the circulation. Methods and Results: Metabolites were measured using LC-MS/MS. Endothelial cells were grown from blood progenitors. Before kidney transplantation the patient's endothelial cells and platelets released negligible levels of prostacyclin (measured as 6-ketoPGF1α) and thromboxane A2 (measured as TXB2), respectively. Likewise, the urinary levels of PGI-M and TX-M were very low. Following transplantation and the establishment of normal renal function the levels of PGI-M and TX-M in the patient's urine rose to within normal ranges while endothelial production of prostacyclin and platelet production of thromboxane A2 remained negligible. Conclusions: This data shows that PGI-M and TX-M can be derived exclusively from the kidney without contribution from prostacyclin made by endothelial cells or thromboxane A2 by platelets in the general circulation. Previous work relying upon urinary metabolites of prostacyclin and thromboxane A2 as markers of whole body endothelial and platelet function now requires re-evaluation.

PMID: 29298774 [PubMed - as supplied by publisher]

Endoplasmic reticulum stress in the pathogenesis of fibrotic disease.

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Endoplasmic reticulum stress in the pathogenesis of fibrotic disease.

J Clin Invest. 2018 Jan 02;128(1):64-73

Authors: Kropski JA, Blackwell TS

Abstract
Eukaryotic cells contain an elegant protein quality control system that is crucial in maintaining cellular homeostasis; however, dysfunction of this system results in endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR). Severe or prolonged ER stress is associated with the development of degenerative and fibrotic disorders in multiple organs, as evidenced by the identification of disease-causing mutations in epithelial-restricted genes that lead to protein misfolding or mistrafficking in familial fibrotic diseases. Emerging evidence implicates ER stress and UPR signaling in a variety of profibrotic mechanisms in individual cell types. In epithelial cells, ER stress can induce apoptosis, inflammatory signaling, and epithelial-mesenchymal transition. In other cell types, ER stress is linked to myofibroblast activation, macrophage polarization, and T cell differentiation. ER stress-targeted therapies have begun to emerge using approaches that range from global enhancement of chaperone function to selective targeting of activated ER stress sensors and other downstream mediators. As the complex regulatory mechanisms of this system are further clarified, there are opportunities to develop new disease-modifying therapeutic strategies in a wide range of chronic fibrotic diseases.

PMID: 29293089 [PubMed - in process]

Evaluating the contribution of rare variants to type 2 diabetes and related traits using pedigrees.

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Evaluating the contribution of rare variants to type 2 diabetes and related traits using pedigrees.

Proc Natl Acad Sci U S A. 2017 Dec 26;:

Authors: Jun G, Manning A, Almeida M, Zawistowski M, Wood AR, Teslovich TM, Fuchsberger C, Feng S, Cingolani P, Gaulton KJ, Dyer T, Blackwell TW, Chen H, Chines PS, Choi S, Churchhouse C, Fontanillas P, King R, Lee S, Lincoln SE, Trubetskoy V, DePristo M, Fingerlin T, Grossman R, Grundstad J, Heath A, Kim J, Kim YJ, Laramie J, Lee J, Li H, Liu X, Livne O, Locke AE, Maller J, Mazur A, Morris AP, Pollin TI, Ragona D, Reich D, Rivas MA, Scott LJ, Sim X, Tearle RG, Teo YY, Williams AL, Zöllner S, Curran JE, Peralta J, Akolkar B, Bell GI, Burtt NP, Cox NJ, Florez JC, Hanis CL, McKeon C, Mohlke KL, Seielstad M, Wilson JG, Atzmon G, Below JE, Dupuis J, Nicolae DL, Lehman D, Park T, Won S, Sladek R, Altshuler D, McCarthy MI, Duggirala R, Boehnke M, Frayling TM, Abecasis GR, Blangero J

Abstract
A major challenge in evaluating the contribution of rare variants to complex disease is identifying enough copies of the rare alleles to permit informative statistical analysis. To investigate the contribution of rare variants to the risk of type 2 diabetes (T2D) and related traits, we performed deep whole-genome analysis of 1,034 members of 20 large Mexican-American families with high prevalence of T2D. If rare variants of large effect accounted for much of the diabetes risk in these families, our experiment was powered to detect association. Using gene expression data on 21,677 transcripts for 643 pedigree members, we identified evidence for large-effect rare-variant cis-expression quantitative trait loci that could not be detected in population studies, validating our approach. However, we did not identify any rare variants of large effect associated with T2D, or the related traits of fasting glucose and insulin, suggesting that large-effect rare variants account for only a modest fraction of the genetic risk of these traits in this sample of families. Reliable identification of large-effect rare variants will require larger samples of extended pedigrees or different study designs that further enrich for such variants.

PMID: 29279374 [PubMed - as supplied by publisher]

Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

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Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

Nat Genet. 2018 Jan;50(1):26-41

Authors: Turcot V, Lu Y, Highland HM, Schurmann C, Justice AE, Fine RS, Bradfield JP, Esko T, Giri A, Graff M, Guo X, Hendricks AE, Karaderi T, Lempradl A, Locke AE, Mahajan A, Marouli E, Sivapalaratnam S, Young KL, Alfred T, Feitosa MF, Masca NGD, Manning AK, Medina-Gomez C, Mudgal P, Ng MCY, Reiner AP, Vedantam S, Willems SM, Winkler TW, Abecasis G, Aben KK, Alam DS, Alharthi SE, Allison M, Amouyel P, Asselbergs FW, Auer PL, Balkau B, Bang LE, Barroso I, Bastarache L, Benn M, Bergmann S, Bielak LF, Blüher M, Boehnke M, Boeing H, Boerwinkle E, Böger CA, Bork-Jensen J, Bots ML, Bottinger EP, Bowden DW, Brandslund I, Breen G, Brilliant MH, Broer L, Brumat M, Burt AA, Butterworth AS, Campbell PT, Cappellani S, Carey DJ, Catamo E, Caulfield MJ, Chambers JC, Chasman DI, Chen YI, Chowdhury R, Christensen C, Chu AY, Cocca M, Collins FS, Cook JP, Corley J, Corominas Galbany J, Cox AJ, Crosslin DS, Cuellar-Partida G, D'Eustacchio A, Danesh J, Davies G, Bakker PIW, Groot MCH, Mutsert R, Deary IJ, Dedoussis G, Demerath EW, Heijer M, Hollander AI, Ruijter HM, Dennis JG, Denny JC, Angelantonio E, Drenos F, Du M, Dubé MP, Dunning AM, Easton DF, Edwards TL, Ellinghaus D, Ellinor PT, Elliott P, Evangelou E, Farmaki AE, Farooqi IS, Faul JD, Fauser S, Feng S, Ferrannini E, Ferrieres J, Florez JC, Ford I, Fornage M, Franco OH, Franke A, Franks PW, Friedrich N, Frikke-Schmidt R, Galesloot TE, Gan W, Gandin I, Gasparini P, Gibson J, Giedraitis V, Gjesing AP, Gordon-Larsen P, Gorski M, Grabe HJ, Grant SFA, Grarup N, Griffiths HL, Grove ML, Gudnason V, Gustafsson S, Haessler J, Hakonarson H, Hammerschlag AR, Hansen T, Harris KM, Harris TB, Hattersley AT, Have CT, Hayward C, He L, Heard-Costa NL, Heath AC, Heid IM, Helgeland Ø, Hernesniemi J, Hewitt AW, Holmen OL, Hovingh GK, Howson JMM, Hu Y, Huang PL, Huffman JE, Ikram MA, Ingelsson E, Jackson AU, Jansson JH, Jarvik GP, Jensen GB, Jia Y, Johansson S, Jørgensen ME, Jørgensen T, Jukema JW, Kahali B, Kahn RS, Kähönen M, Kamstrup PR, Kanoni S, Kaprio J, Karaleftheri M, Kardia SLR, Karpe F, Kathiresan S, Kee F, Kiemeney LA, Kim E, Kitajima H, Komulainen P, Kooner JS, Kooperberg C, Korhonen T, Kovacs P, Kuivaniemi H, Kutalik Z, Kuulasmaa K, Kuusisto J, Laakso M, Lakka TA, Lamparter D, Lange EM, Lange LA, Langenberg C, Larson EB, Lee NR, Lehtimäki T, Lewis CE, Li H, Li J, Li-Gao R, Lin H, Lin KH, Lin LA, Lin X, Lind L, Lindström J, Linneberg A, Liu CT, Liu DJ, Liu Y, Lo KS, Lophatananon A, Lotery AJ, Loukola A, Luan J, Lubitz SA, Lyytikäinen LP, Männistö S, Marenne G, Mazul AL, McCarthy MI, McKean-Cowdin R, Medland SE, Meidtner K, Milani L, Mistry V, Mitchell P, Mohlke KL, Moilanen L, Moitry M, Montgomery GW, Mook-Kanamori DO, Moore C, Mori TA, Morris AD, Morris AP, Müller-Nurasyid M, Munroe PB, Nalls MA, Narisu N, Nelson CP, Neville M, Nielsen SF, Nikus K, Njølstad PR, Nordestgaard BG, Nyholt DR, O'Connel JR, O'Donoghue ML, Olde Loohuis LM, Ophoff RA, Owen KR, Packard CJ, Padmanabhan S, Palmer CNA, Palmer ND, Pasterkamp G, Patel AP, Pattie A, Pedersen O, Peissig PL, Peloso GM, Pennell CE, Perola M, Perry JA, Perry JRB, Pers TH, Person TN, Peters A, Petersen ERB, Peyser PA, Pirie A, Polasek O, Polderman TJ, Puolijoki H, Raitakari OT, Rasheed A, Rauramaa R, Reilly DF, Renström F, Rheinberger M, Ridker PM, Rioux JD, Rivas MA, Roberts DJ, Robertson NR, Robino A, Rolandsson O, Rudan I, Ruth KS, Saleheen D, Salomaa V, Samani NJ, Sapkota Y, Sattar N, Schoen RE, Schreiner PJ, Schulze MB, Scott RA, Segura-Lepe MP, Shah SH, Sheu WH, Sim X, Slater AJ, Small KS, Smith AV, Southam L, Spector TD, Speliotes EK, Starr JM, Stefansson K, Steinthorsdottir V, Stirrups KE, Strauch K, Stringham HM, Stumvoll M, Sun L, Surendran P, Swift AJ, Tada H, Tansey KE, Tardif JC, Taylor KD, Teumer A, Thompson DJ, Thorleifsson G, Thorsteinsdottir U, Thuesen BH, Tönjes A, Tromp G, Trompet S, Tsafantakis E, Tuomilehto J, Tybjaerg-Hansen A, Tyrer JP, Uher R, Uitterlinden AG, Uusitupa M, Laan SW, Duijn CM, Leeuwen N, van Setten J, Vanhala M, Varbo A, Varga TV, Varma R, Velez Edwards DR, Vermeulen SH, Veronesi G, Vestergaard H, Vitart V, Vogt TF, Völker U, Vuckovic D, Wagenknecht LE, Walker M, Wallentin L, Wang F, Wang CA, Wang S, Wang Y, Ware EB, Wareham NJ, Warren HR, Waterworth DM, Wessel J, White HD, Willer CJ, Wilson JG, Witte DR, Wood AR, Wu Y, Yaghootkar H, Yao J, Yao P, Yerges-Armstrong LM, Young R, Zeggini E, Zhan X, Zhang W, Zhao JH, Zhao W, Zhou W, Zondervan KT, CHD Exome+ Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, EPIC InterAct Consortium, INTERVAL Study, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Understanding Society Scientific Group, Rotter JI, Pospisilik JA, Rivadeneira F, Borecki IB, Deloukas P, Frayling TM, Lettre G, North KE, Lindgren CM, Hirschhorn JN, Loos RJF

Abstract
Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.

PMID: 29273807 [PubMed - in process]

Long-term Diet Quality and Risk of Type 2 Diabetes Among Urban Chinese Adults.

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Long-term Diet Quality and Risk of Type 2 Diabetes Among Urban Chinese Adults.

Diabetes Care. 2017 Dec 21;:

Authors: Yu D, Zheng W, Cai H, Xiang YB, Li H, Gao YT, Shu XO

Abstract
OBJECTIVE: Little evidence exists regarding long-term diet quality and the risk of type 2 diabetes among Asian populations, who have undergone a nutrition transition and a diabetes epidemic.
RESEARCH DESIGN AND METHODS: A total of 117,919 Chinese men and women, 40-74 years old, free of diabetes, cardiovascular disease, and cancer at baseline, were followed from 1996 to 2015. Diet quality was assessed by a healthy diet score (HDS) based on eight commonly consumed food groups previously suggested to be related to diabetes. Long-term diet quality and its changes were assessed by repeated surveys using food-frequency questionnaires.
RESULTS: We identified 6,111 incident diabetes cases during a mean follow-up of 11.5 years. Higher HDS was associated with lower diabetes risk (hazard ratio [HR] 0.85; 95% CI 0.78-0.92) in the highest vs. lowest quintile, Pcontinuous <0.0001) after adjustment for potential confounders including BMI. Maintaining a high HDS during follow-up was associated with 26% lower risk compared with a consistently low HDS (HR 0.74; 95% CI 0.63-0.85). The inverse association between HDS and diabetes was observed regardless of participants' age, sex, smoking and exercise habits, obesity status, and metabolic disease status but was more prominent among those who participated in leisure-time exercise (Pinteraction = 0.004). When considered jointly, a sustained high HDS plus exercise was associated with a 45% reduced risk of diabetes (HR 0.55; 95% CI 0.45-0.67).
CONCLUSIONS: A high-quality diet, especially maintained over the long term and in conjunction with leisure-time exercise, is associated with lower risk of type 2 diabetes among urban Chinese adults.

PMID: 29269510 [PubMed - as supplied by publisher]