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Future directions for therapeutic strategies in post-ischaemic vascularization: a position paper from European Society of Cardiology Working group on Atherosclerosis and Vascular Biology.

Ke, 18/07/2018 - 21:27

Future directions for therapeutic strategies in post-ischaemic vascularization: a position paper from European Society of Cardiology Working group on Atherosclerosis and Vascular Biology.

Cardiovasc Res. 2018 Jul 17;:

Authors: Caporali A, Bäck M, Daemen MJ, Hoefer IE, Jones EA, Lutgens E, Matter CM, Bochaton-Piallat ML, Siekmann AF, Sluimer JC, Steffens S, Tuñón J, Vindis C, Wentzel JJ, Ylä-Herttuala S, Evans PC

Abstract
Modulation of vessel growth holds great promise for treatment of cardiovascular disease. Strategies to promote vascularization can potentially restore function in ischaemic tissues. On the other hand, plaque neovascularization has been shown to associate with vulnerable plaque phenotypes and adverse events. The current lack of clinical success in regulating vascularization illustrates the complexity of the vascularization process, which involves a delicate balance between pro- and anti-angiogenic regulators and effectors. This is compounded by limitations in the models used to study vascularization that do not reflect the eventual clinical target population.

PMID: 30016405 [PubMed - as supplied by publisher]

Biallelic tumor suppressor loss and DNA repair defects in de novo small cell prostate cancer.

Ke, 18/07/2018 - 21:27

Biallelic tumor suppressor loss and DNA repair defects in de novo small cell prostate cancer.

J Pathol. 2018 Jul 17;:

Authors: Chedgy EC, Vandekerkhove G, Herberts C, Annala M, Donoghue AJ, Sigouros M, Ritch E, Struss W, Konomura S, Liew J, Parimi S, Vergidis J, Hurtado-Coll A, Sboner A, Fazli L, Beltran H, Chi KN, Wyatt AW

Abstract
Small cell prostatic carcinoma (SCPC) is an aggressive pathology that is managed similarly to small cell lung cancer. SCPC can evolve from prostatic adenocarcinoma in response to androgen deprivation therapy, but in rare cases is present at initial cancer diagnosis. The molecular etiology of de novo SCPC is incompletely understood, due to the scarcity of tumor tissue and the short life expectancy of patients. Through a retrospective search of our regional oncology pharmacy database, we identified 18 patients diagnosed with de novo SCPC between 2004 and 2017. Ten patients had pure SCPC pathology and the remainder had some admixed adenocarcinoma foci, but all were treated with first-line platinum-based chemotherapy. Median overall survival was 28 months. We performed targeted DNA sequencing, whole exome sequencing and mRNA profiling on formalin-fixed paraffin-embedded archival tumor tissue. We observed frequent biallelic deletion and/or mutation of tumor suppressors TP53, RB1 and PTEN, similar to treatment-related SCPC. Indeed, at the RNA level pure de novo SCPC closely resembled treatment-related SCPC. However, five patients had biallelic loss of DNA repair genes including BRCA1, BRCA2, ATM or MSH2/6, potentially underlying the high genomic instability of this rare disease variant. Two patients with pure de novo SCPC harbored ETS gene rearrangements to androgen-driven promoters, consistent with evolution of de novo SCPC from an androgen-driven ancestor. Overall, our results reveal a highly aggressive molecular landscape that underlies this unusual pathologic variant, and propose opportunities for targeted therapy strategies in a disease with few treatment options. This article is protected by copyright. All rights reserved.

PMID: 30015382 [PubMed - as supplied by publisher]

Reproductive profiles and risk of breast cancer subtypes: a multi-center case-only study.

Ke, 18/07/2018 - 21:27
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Reproductive profiles and risk of breast cancer subtypes: a multi-center case-only study.

Breast Cancer Res. 2017 Nov 07;19(1):119

Authors: Brouckaert O, Rudolph A, Laenen A, Keeman R, Bolla MK, Wang Q, Soubry A, Wildiers H, Andrulis IL, Arndt V, Beckmann MW, Benitez J, Blomqvist C, Bojesen SE, Brauch H, Brennan P, Brenner H, Chenevix-Trench G, Choi JY, Cornelissen S, Couch FJ, Cox A, Cross SS, Czene K, Eriksson M, Fasching PA, Figueroa J, Flyger H, Giles GG, González-Neira A, Guénel P, Hall P, Hollestelle A, Hopper JL, Ito H, Jones M, Kang D, kConFab, Knight JA, Kosma VM, Li J, Lindblom A, Lilyquist J, Lophatananon A, Mannermaa A, Manoukian S, Margolin S, Matsuo K, Muir K, Nevanlinna H, Peterlongo P, Pylkäs K, Saajrang S, Seynaeve C, Shen CY, Shu XO, Southey MC, Swerdlow A, Teo SH, Tollenaar RAEM, Truong T, Tseng CC, van den Broek AJ, van Deurzen CHM, Winqvist R, Wu AH, Yip CH, Yu JC, Zheng W, Milne RL, Pharoah PDP, Easton DF, Schmidt MK, Garcia-Closas M, Chang-Claude J, Lambrechts D, Neven P

Abstract
BACKGROUND: Previous studies have shown that reproductive factors are differentially associated with breast cancer (BC) risk by subtypes. The aim of this study was to investigate associations between reproductive factors and BC subtypes, and whether these vary by age at diagnosis.
METHODS: We used pooled data on tumor markers (estrogen and progesterone receptor, human epidermal growth factor receptor-2 (HER2)) and reproductive risk factors (parity, age at first full-time pregnancy (FFTP) and age at menarche) from 28,095 patients with invasive BC from 34 studies participating in the Breast Cancer Association Consortium (BCAC). In a case-only analysis, we used logistic regression to assess associations between reproductive factors and BC subtype compared to luminal A tumors as a reference. The interaction between age and parity in BC subtype risk was also tested, across all ages and, because age was modeled non-linearly, specifically at ages 35, 55 and 75 years.
RESULTS: Parous women were more likely to be diagnosed with triple negative BC (TNBC) than with luminal A BC, irrespective of age (OR for parity = 1.38, 95% CI 1.16-1.65, p = 0.0004; p for interaction with age = 0.076). Parous women were also more likely to be diagnosed with luminal and non-luminal HER2-like BCs and this effect was slightly more pronounced at an early age (p for interaction with age = 0.037 and 0.030, respectively). For instance, women diagnosed at age 35 were 1.48 (CI 1.01-2.16) more likely to have luminal HER2-like BC than luminal A BC, while this association was not significant at age 75 (OR = 0.72, CI 0.45-1.14). While age at menarche was not significantly associated with BC subtype, increasing age at FFTP was non-linearly associated with TNBC relative to luminal A BC. An age at FFTP of 25 versus 20 years lowered the risk for TNBC (OR = 0.78, CI 0.70-0.88, p < 0.0001), but this effect was not apparent at a later FFTP.
CONCLUSIONS: Our main findings suggest that parity is associated with TNBC across all ages at BC diagnosis, whereas the association with luminal HER2-like BC was present only for early onset BC.

PMID: 29116004 [PubMed - indexed for MEDLINE]

More chronic GvHD and non-relapse mortality after peripheral blood stem cell compared with bone marrow in hematopoietic transplantation for paediatric acute lymphoblastic leukemia: a retrospective study on behalf of the EBMT Paediatric Diseases Working...

Ke, 18/07/2018 - 21:27
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More chronic GvHD and non-relapse mortality after peripheral blood stem cell compared with bone marrow in hematopoietic transplantation for paediatric acute lymphoblastic leukemia: a retrospective study on behalf of the EBMT Paediatric Diseases Working Party.

Bone Marrow Transplant. 2017 07;52(7):1071-1073

Authors: Simonin M, Dalissier A, Labopin M, Willasch A, Zecca M, Mouhab A, Chybicka A, Balduzzi A, Volin L, Peters C, Bader P, Dalle JH

PMID: 28394370 [PubMed - indexed for MEDLINE]

Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL.

Ti, 17/07/2018 - 21:27
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Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL.

Nat Commun. 2018 02 15;9(1):697

Authors: Schrader A, Crispatzu G, Oberbeck S, Mayer P, Pützer S, von Jan J, Vasyutina E, Warner K, Weit N, Pflug N, Braun T, Andersson EI, Yadav B, Riabinska A, Maurer B, Ventura Ferreira MS, Beier F, Altmüller J, Lanasa M, Herling CD, Haferlach T, Stilgenbauer S, Hopfinger G, Peifer M, Brümmendorf TH, Nürnberg P, Elenitoba-Johnson KSJ, Zha S, Hallek M, Moriggl R, Reinhardt HC, Stern MH, Mustjoki S, Newrzela S, Frommolt P, Herling M

Abstract
T-cell prolymphocytic leukemia (T-PLL) is a rare and poor-prognostic mature T-cell malignancy. Here we integrated large-scale profiling data of alterations in gene expression, allelic copy number (CN), and nucleotide sequences in 111 well-characterized patients. Besides prominent signatures of T-cell activation and prevalent clonal variants, we also identify novel hot-spots for CN variability, fusion molecules, alternative transcripts, and progression-associated dynamics. The overall lesional spectrum of T-PLL is mainly annotated to axes of DNA damage responses, T-cell receptor/cytokine signaling, and histone modulation. We formulate a multi-dimensional model of T-PLL pathogenesis centered around a unique combination of TCL1 overexpression with damaging ATM aberrations as initiating core lesions. The effects imposed by TCL1 cooperate with compromised ATM toward a leukemogenic phenotype of impaired DNA damage processing. Dysfunctional ATM appears inefficient in alleviating elevated redox burdens and telomere attrition and in evoking a p53-dependent apoptotic response to genotoxic insults. As non-genotoxic strategies, synergistic combinations of p53 reactivators and deacetylase inhibitors reinstate such cell death execution.

PMID: 29449575 [PubMed - indexed for MEDLINE]

Good responses but high TRM in adult patients after MSC therapy for GvHD.

Ti, 17/07/2018 - 21:27
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Good responses but high TRM in adult patients after MSC therapy for GvHD.

Bone Marrow Transplant. 2017 04;52(4):606-608

Authors: Salmenniemi U, Itälä-Remes M, Nystedt J, Putkonen M, Niittyvuopio R, Vettenranta K, Korhonen M

PMID: 27941780 [PubMed - indexed for MEDLINE]

Microdeletion of 7p12.1p13, including IKZF1, causes intellectual impairment, overgrowth, and susceptibility to leukaemia.

La, 14/07/2018 - 21:25
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Microdeletion of 7p12.1p13, including IKZF1, causes intellectual impairment, overgrowth, and susceptibility to leukaemia.

Br J Haematol. 2018 Jul 13;:

Authors: Järviaho T, Zachariadis V, Tesi B, Chiang S, Bryceson YT, Möttönen M, Niinimäki R, Bang B, Rahikkala E, Taylan F, Uusimaa J, Harila-Saari A, Nordgren A

PMID: 30004112 [PubMed - as supplied by publisher]

Networks of enzymatically oxidized membrane lipids support calcium-dependent coagulation factor binding to maintain hemostasis.

La, 14/07/2018 - 21:25
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Networks of enzymatically oxidized membrane lipids support calcium-dependent coagulation factor binding to maintain hemostasis.

Sci Signal. 2017 Nov 28;10(507):

Authors: Lauder SN, Allen-Redpath K, Slatter DA, Aldrovandi M, O'Connor A, Farewell D, Percy CL, Molhoek JE, Rannikko S, Tyrrell VJ, Ferla S, Milne GL, Poole AW, Thomas CP, Obaji S, Taylor PR, Jones SA, de Groot PG, Urbanus RT, Hörkkö S, Uderhardt S, Ackermann J, Vince Jenkins P, Brancale A, Krönke G, Collins PW, O'Donnell VB

Abstract
Blood coagulation functions as part of the innate immune system by preventing bacterial invasion, and it is critical to stopping blood loss (hemostasis). Coagulation involves the external membrane surface of activated platelets and leukocytes. Using lipidomic, genetic, biochemical, and mathematical modeling approaches, we found that enzymatically oxidized phospholipids (eoxPLs) generated by the activity of leukocyte or platelet lipoxygenases (LOXs) were required for normal hemostasis and promoted coagulation factor activities in a Ca2+- and phosphatidylserine (PS)-dependent manner. In wild-type mice, hydroxyeicosatetraenoic acid-phospholipids (HETE-PLs) enhanced coagulation and restored normal hemostasis in clotting-deficient animals genetically lacking p12-LOX or 12/15-LOX activity. Murine platelets generated 22 eoxPL species, all of which were missing in the absence of p12-LOX. Humans with the thrombotic disorder antiphospholipid syndrome (APS) had statistically significantly increased HETE-PLs in platelets and leukocytes, as well as greater HETE-PL immunoreactivity, than healthy controls. HETE-PLs enhanced membrane binding of the serum protein β2GP1 (β2-glycoprotein 1), an event considered central to the autoimmune reactivity responsible for APS symptoms. Correlation network analysis of 47 platelet eoxPL species in platelets from APS and control subjects identified their enzymatic origin and revealed a complex network of regulation, with the abundance of 31 p12-LOX-derived eoxPL molecules substantially increased in APS. In summary, circulating blood cells generate networks of eoxPL molecules, including HETE-PLs, which change membrane properties to enhance blood coagulation and contribute to the excessive clotting and immunoreactivity of patients with APS.

PMID: 29184033 [PubMed - indexed for MEDLINE]

When Nursing Care and Clinical Trials Coincide: A Qualitative Study of the Views of Nordic Oncology and Hematology Nurses on Ethical Work Challenges.

Pe, 13/07/2018 - 21:24
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When Nursing Care and Clinical Trials Coincide: A Qualitative Study of the Views of Nordic Oncology and Hematology Nurses on Ethical Work Challenges.

J Empir Res Hum Res Ethics. 2018 Jul 01;:1556264618783555

Authors: Godskesen TE, Petri S, Eriksson S, Halkoaho A, Mangset M, Pirinen M, Nielsen ZE

Abstract
This study investigated the kinds of ethical challenges experienced by nurses in oncology and hematology when nursing care and research overlap in clinical trials, and how the nurses handle such challenges. Individual interviews with 39 nurses from Sweden, Denmark, and Finland indicated that all nurses were positive about research, considering it essential for developing the best care. Ethical challenges exist, however; the most difficult were associated with the end-of-life patients, no longer responsive to standard therapy, who eagerly volunteer for cutting-edge drug trials in the hope of gaining therapeutic benefit. Many nurses lacked systematic strategies for addressing such challenges but found support from their nursing colleagues and relied on the research protocols to guide them.

PMID: 29998780 [PubMed - as supplied by publisher]

MYH9-Related Thrombocytopenia: Four Novel Variants Affecting the Tail Domain of the Non-Muscle Myosin Heavy Chain IIA Associated with a Mild Clinical Evolution of the Disorder.

To, 12/07/2018 - 21:23
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MYH9-Related Thrombocytopenia: Four Novel Variants Affecting the Tail Domain of the Non-Muscle Myosin Heavy Chain IIA Associated with a Mild Clinical Evolution of the Disorder.

Hamostaseologie. 2018 Jul 11;:

Authors: Zaninetti C, De Rocco D, Giangregorio T, Bozzi V, Demeter J, Leoni P, Noris P, Ryhänen S, Barozzi S, Pecci A, Savoia A

Abstract
MYH9-related disease (MYH9-RD) is an autosomal-dominant thrombocytopenia caused by mutations in the gene for non-muscle myosin heavy chain IIA (NMMHC-IIA). Patients present congenital macrothrombocytopenia and inclusions of NMMHC-IIA in leukocytes, and have a variable risk of developing kidney damage, sensorineural deafness, presenile cataracts and/or liver enzymes abnormalities. The spectrum of mutations found in MYH9-RD patients is limited and the incidence and severity of the non-congenital features are predicted by the causative MYH9 variant. In particular, different alterations of the C-terminal tail domain of NMMHC-IIA associate with remarkably different disease evolution. We report four novel MYH9 mutations affecting the tail domain of NMMHC-IIA and responsible for MYH9-RD in four families. Two variants cause amino acid substitutions in the coiled-coil region of NMMHC-IIA, while the other two are a splicing variant and a single nucleotide deletion both resulting in frameshift alterations of the short non-helical tailpiece. Characterization of phenotypes of affected individuals shows that all of these novel variants are associated with a mild clinical evolution of the disease.

PMID: 29996171 [PubMed - as supplied by publisher]

Antimicrobial Resistance in Gram-Negative Rods Causing Bacteremia in Hematopoietic Stem Cell Transplant Recipients: Intercontinental Prospective Study of the Infectious Diseases Working Party of the European Bone Marrow Transplantation Group.

To, 12/07/2018 - 21:23
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Antimicrobial Resistance in Gram-Negative Rods Causing Bacteremia in Hematopoietic Stem Cell Transplant Recipients: Intercontinental Prospective Study of the Infectious Diseases Working Party of the European Bone Marrow Transplantation Group.

Clin Infect Dis. 2017 Nov 13;65(11):1819-1828

Authors: Averbuch D, Tridello G, Hoek J, Mikulska M, Akan H, Yanez San Segundo L, Pabst T, Özçelik T, Klyasova G, Donnini I, Wu D, Gülbas Z, Zuckerman T, Botelho de Sousa A, Beguin Y, Xhaard A, Bachy E, Ljungman P, de la Camara R, Rascon J, Ruiz Camps I, Vitek A, Patriarca F, Cudillo L, Vrhovac R, Shaw PJ, Wolfs T, O'Brien T, Avni B, Silling G, Al Sabty F, Graphakos S, Sankelo M, Sengeloev H, Pillai S, Matthes S, Melanthiou F, Iacobelli S, Styczynski J, Engelhard D, Cesaro S

Abstract
Background: This intercontinental study aimed to study gram-negative rod (GNR) resistance in hematopoietic stem cell transplantation (HSCT).
Methods: GNR bacteremias occurring during 6 months post-HSCT (February 2014-May 2015) were prospectively collected, and analyzed for rates and risk factors for resistance to fluoroquinolones, noncarbapenem anti-Pseudomonas β-lactams (noncarbapenems), carbapenems, and multidrug resistance.
Results: Sixty-five HSCT centers from 25 countries in Europe, Australia, and Asia reported data on 655 GNR episodes and 704 pathogens in 591 patients (Enterobacteriaceae, 73%; nonfermentative rods, 24%; and 3% others). Half of GNRs were fluoroquinolone and noncarbapenem resistant; 18.5% carbapenem resistant; 35.2% multidrug resistant. The total resistance rates were higher in allogeneic HSCT (allo-HSCT) vs autologous HSCT (auto-HSCT) patients (P < .001) but similar in community-acquired infections. Noncarbapenem resistance and multidrug resistance were higher in auto-HSCT patients in centers providing vs not providing fluoroquinolone prophylaxis (P < .01). Resistance rates were higher in southeast vs northwest Europe and similar in children and adults, excluding higher fluoroquinolone- and β-lactam/β-lactamase inhibitor resistance rates in allo-HSCT adults. Non-Klebsiella Enterobacteriaceae were rarely carbapenem resistant. Multivariable analysis revealed resistance risk factors in allo-HSCT patients: fluoroquinolone resistance: adult, prolonged neutropenia, breakthrough on fluoroquinolones; noncarbapenem resistance: hospital-acquired infection, breakthrough on noncarbapenems or other antibiotics (excluding fluoroquinolones, noncarbapenems, carbapenems), donor type; carbapenem resistance: breakthrough on carbapenem, longer hospitalization, intensive care unit, previous other antibiotic therapy; multidrug resistance: longer hospitalization, breakthrough on β-lactam/β-lactamase inhibitors, and carbapenems. Inappropriate empiric therapy and mortality were significantly more common in infections caused by resistant bacteria.
Conclusions: Our data question the recommendation for fluoroquinolone prophylaxis and call for reassessment of local empiric antibiotic protocols. Knowledge of pathogen-specific resistance enables early appropriate empiric therapy. Monitoring of resistance is crucial.
Clinical Trials Registration: NCT02257931.

PMID: 29020364 [PubMed - indexed for MEDLINE]

Personalized laboratory medicine: a patient-centered future approach.

Ke, 11/07/2018 - 21:23
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Personalized laboratory medicine: a patient-centered future approach.

Clin Chem Lab Med. 2018 Jul 10;:

Authors: Prodan Žitnik I, Černe D, Mancini I, Simi L, Pazzagli M, Di Resta C, Podgornik H, Repič Lampret B, Trebušak Podkrajšek K, Sipeky C, van Schaik R, Brandslund I, Vermeersch P, Schwab M, Marc J, behalf of EFLM/ESPT working group of Personalised Laboratory Medicine on

Abstract
In contrast to population-based medical decision making, which emphasizes the use of evidence-based treatment strategies for groups of patients, personalized medicine is based on optimizing treatment at the level of the individual patient. The creation of molecular profiles of individual patients was made possible by the advent of "omics" technologies, based on high throughput instrumental techniques in combination with biostatistics tools and artificial intelligence. The goal of personalized laboratory medicine is to use advanced technologies in the process of preventive, curative or palliative patient management. Personalized medicine does not rely on changes in concentration of a single molecular marker to make a therapeutic decision, but rather on changes of a profile of markers characterizing an individual patient's status, taking into account not only the expected response to treatment of the disease but also the expected response of the patient. Such medical approach promises a more effective diagnostics with more effective and safer treatment, as well as faster recovery and restoration of health and improved cost effectiveness. The laboratory medicine profession is aware of its key role in personalized medicine, but to empower the laboratories, at least an enhancement in cooperation between disciplines within laboratory medicine will be necessary.

PMID: 29990304 [PubMed - as supplied by publisher]

Genome-wide meta-analysis of macronutrient intake of 91,114 European ancestry participants from the cohorts for heart and aging research in genomic epidemiology consortium.

Ke, 11/07/2018 - 21:23
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Genome-wide meta-analysis of macronutrient intake of 91,114 European ancestry participants from the cohorts for heart and aging research in genomic epidemiology consortium.

Mol Psychiatry. 2018 Jul 09;:

Authors: Merino J, Dashti HS, Li SX, Sarnowski C, Justice AE, Graff M, Papoutsakis C, Smith CE, Dedoussis GV, Lemaitre RN, Wojczynski MK, Männistö S, Ngwa JS, Kho M, Ahluwalia TS, Pervjakova N, Houston DK, Bouchard C, Huang T, Orho-Melander M, Frazier-Wood AC, Mook-Kanamori DO, Pérusse L, Pennell CE, de Vries PS, Voortman T, Li O, Kanoni S, Rose LM, Lehtimäki T, Zhao JH, Feitosa MF, Luan J, McKeown NM, Smith JA, Hansen T, Eklund N, Nalls MA, Rankinen T, Huang J, Hernandez DG, Schulz CA, Manichaikul A, Li-Gao R, Vohl MC, Wang CA, van Rooij FJA, Shin J, Kalafati IP, Day F, Ridker PM, Kähönen M, Siscovick DS, Langenberg C, Zhao W, Astrup A, Knekt P, Garcia M, Rao DC, Qi Q, Ferrucci L, Ericson U, Blangero J, Hofman A, Pausova Z, Mikkilä V, Wareham NJ, Kardia SLR, Pedersen O, Jula A, Curran JE, Zillikens MC, Viikari JS, Forouhi NG, Ordovás JM, Lieske JC, Rissanen H, Uitterlinden AG, Raitakari OT, Kiefte-de Jong JC, Dupuis J, Rotter JI, North KE, Scott RA, Province MA, Perola M, Cupples LA, Turner ST, Sørensen TIA, Salomaa V, Liu Y, Sung YJ, Qi L, Bandinelli S, Rich SS, de Mutsert R, Tremblay A, Oddy WH, Franco OH, Paus T, Florez JC, Deloukas P, Lyytikäinen LP, Chasman DI, Chu AY, Tanaka T

Abstract
Macronutrient intake, the proportion of calories consumed from carbohydrate, fat, and protein, is an important risk factor for metabolic diseases with significant familial aggregation. Previous studies have identified two genetic loci for macronutrient intake, but incomplete coverage of genetic variation and modest sample sizes have hindered the discovery of additional loci. Here, we expanded the genetic landscape of macronutrient intake, identifying 12 suggestively significant loci (P < 1 × 10-6) associated with intake of any macronutrient in 91,114 European ancestry participants. Four loci replicated and reached genome-wide significance in a combined meta-analysis including 123,659 European descent participants, unraveling two novel loci; a common variant in RARB locus for carbohydrate intake and a rare variant in DRAM1 locus for protein intake, and corroborating earlier FGF21 and FTO findings. In additional analysis of 144,770 participants from the UK Biobank, all identified associations from the two-stage analysis were confirmed except for DRAM1. Identified loci might have implications in brain and adipose tissue biology and have clinical impact in obesity-related phenotypes. Our findings provide new insight into biological functions related to macronutrient intake.

PMID: 29988085 [PubMed - as supplied by publisher]

Measurable residual disease, conditioning regimen intensity and age predict outcome of allogeneic hematopoietic cell transplantation for acute myeloid leukemia in first remission: a registry analysis of 2292 patients by the Acute Leukemia Working Party...

Su, 08/07/2018 - 21:22
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Measurable residual disease, conditioning regimen intensity and age predict outcome of allogeneic hematopoietic cell transplantation for acute myeloid leukemia in first remission: a registry analysis of 2292 patients by the Acute Leukemia Working Party European Society of Blood and Marrow Transplantation.

Am J Hematol. 2018 Jul 07;:

Authors: Gilleece MH, Labopin M, Yakoub-Agha I, Volin L, Socié G, Ljungman P, Huynh A, Deconinck E, Wu D, Bourhis JH, Cahn JY, Polge E, Mohty M, Savani BN, Nagler A

Abstract
Patients with acute myeloid leukemia (AML) in morphological first complete remission (CR1) pre-allogeneic hematopoietic cell transplantation (HCT) may have measurable residual disease (MRD) by molecular and immunophenotyping criteria. We assessed interactions of MRD status with HCT conditioning regimen intensity in patients aged <50 years (y) or ≥50y. This was a retrospective study by the European Society for Blood and Marrow Transplantation registry. Patients were >18y with AML CR1 MRD NEG/POS and recipients of HCT in 2000-2015. Conditioning regimens were myeloablative (MAC), reduced intensity (RIC) or non-myeloablative (NMA). Outcomes included leukemia free survival (LFS), overall survival (OS), relapse incidence (RI), non-relapse mortality (NRM), chronic graft-versus-host (cGVHD) and GVHD-free and relapse-free survival (GRFS). The 2292 eligible patients were categorized into 4 paired groups: <50y MRD POS MAC (N=240) vs RIC/NMA (N=58); <50y MRD NEG MAC (N=665) vs RIC/NMA (N=195); ≥50y MRD POS MAC (N=126) vs RIC/NMA (N=230) & ≥50y MRD NEG MAC (N=223) vs RIC/NMA (N=555). In multivariate analysis RIC/NMA was only inferior to MAC for patients in the <50y MRD POS group, with worse RI (HR 1.71) & LFS (HR 1.554). Patients <50Y MRD NEG had less cGVHD after RIC/NMA HCT (HR 0.714). GRFS was not significantly affected by conditioning intensity in any group. Patients aged <50y with AML CR1 MRD POS status should preferentially be offered MAC allo-HCT. Prospective studies are needed to address whether patients with AML CR1 MRD NEG may be spared the toxicity of MAC regimens. New approaches are needed for ≥50y AML CR1 MRD POS. This article is protected by copyright. All rights reserved.

PMID: 29981272 [PubMed - as supplied by publisher]

Telomere shortening correlates with leukemic stem cell burden at diagnosis of chronic myeloid leukemia.

Su, 08/07/2018 - 21:22
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Telomere shortening correlates with leukemic stem cell burden at diagnosis of chronic myeloid leukemia.

Blood Adv. 2018 Jul 10;2(13):1572-1579

Authors: Bouillon AS, Ventura Ferreira MS, Awad SA, Richter J, Hochhaus A, Kunzmann V, Dengler J, Janssen J, Ossenkoppele G, Westerweel PE, Te Boekhorst PAW, Mahon FX, Hjorth-Hansen H, Isfort S, Fioretos T, Hummel S, Schemionek M, Wilop S, Koschmieder S, Saußele S, Mustjoki S, Beier F, Brümmendorf TH

Abstract
Telomere length (TL) in peripheral blood (PB) cells of patients with chronic myeloid leukemia (CML) has been shown to correlate with disease stage, prognostic scores, response to therapy, and disease progression. However, due to considerable genetic interindividual variability, TL varies substantially between individuals, limiting its use as a robust prognostic marker in individual patients. Here, we compared TL of BCR-ABL-, nonleukemic CD34+CD38- hematopoietic stem cells (HSC) in the bone marrow of CML patients at diagnosis to their individual BCR-ABL+ leukemic stem cell (LSC) counterparts. We observed significantly accelerated telomere shortening in LSC compared with nonleukemic HSC. Interestingly, the degree of LSC telomere shortening was found to correlate significantly with the leukemic clone size. To validate the diagnostic value of nonleukemic cells as internal controls and to rule out effects of tyrosine kinase inhibitor (TKI) treatment on these nontarget cells, we prospectively assessed TL in 134 PB samples collected in deep molecular remission after TKI treatment within the EURO-SKI study (NCT01596114). Here, no significant telomere shortening was observed in granulocytes compared with an age-adjusted control cohort. In conclusion, this study provides proof of principle for accelerated telomere shortening in LSC as opposed to HSC in CML patients at diagnosis. The fact that the degree of telomere shortening correlates with leukemic clone's size supports the use of TL in leukemic cells as a prognostic parameter pending prospective validation. TL in nonleukemic myeloid cells seems unaffected even by long-term TKI treatment arguing against a reduction of telomere-mediated replicative reserve in normal hematopoiesis under TKI treatment.

PMID: 29980572 [PubMed - in process]

Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility.

La, 07/07/2018 - 21:21
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Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility.

PLoS One. 2018;13(7):e0197561

Authors: Earp M, Tyrer JP, Winham SJ, Lin HY, Chornokur G, Dennis J, Aben KKH, Anton-Culver H, Antonenkova N, Bandera EV, Bean YT, Beckmann MW, Bjorge L, Bogdanova N, Brinton LA, Brooks-Wilson A, Bruinsma F, Bunker CH, Butzow R, Campbell IG, Carty K, Chang-Claude J, Cook LS, Cramer DW, Cunningham JM, Cybulski C, Dansonka-Mieszkowska A, Despierre E, Doherty JA, Dörk T, du Bois A, Dürst M, Easton DF, Eccles DM, Edwards RP, Ekici AB, Fasching PA, Fridley BL, Gentry-Maharaj A, Giles GG, Glasspool R, Goodman MT, Gronwald J, Harter P, Hein A, Heitz F, Hildebrandt MAT, Hillemanns P, Hogdall CK, Høgdall E, Hosono S, Iversen ES, Jakubowska A, Jensen A, Ji BT, Jung AY, Karlan BY, Kellar M, Kiemeney LA, Kiong Lim B, Kjaer SK, Krakstad C, Kupryjanczyk J, Lambrechts D, Lambrechts S, Le ND, Lele S, Lester J, Levine DA, Li Z, Liang D, Lissowska J, Lu K, Lubinski J, Lundvall L, Massuger LFAG, Matsuo K, McGuire V, McLaughlin JR, McNeish I, Menon U, Milne RL, Modugno F, Moysich KB, Ness RB, Nevanlinna H, Odunsi K, Olson SH, Orlow I, Orsulic S, Paul J, Pejovic T, Pelttari LM, Permuth JB, Pike MC, Poole EM, Rosen B, Rossing MA, Rothstein JH, Runnebaum IB, Rzepecka IK, Schernhammer E, Schwaab I, Shu XO, Shvetsov YB, Siddiqui N, Sieh W, Song H, Southey MC, Spiewankiewicz B, Sucheston-Campbell L, Tangen IL, Teo SH, Terry KL, Thompson PJ, Thomsen L, Tworoger SS, van Altena AM, Vergote I, Vestrheim Thomsen LC, Vierkant RA, Walsh CS, Wang-Gohrke S, Wentzensen N, Whittemore AS, Wicklund KG, Wilkens LR, Woo YL, Wu AH, Wu X, Xiang YB, Yang H, Zheng W, Ziogas A, Lee AW, Pearce CL, Berchuck A, Schildkraut JM, Ramus SJ, Monteiro ANA, Narod SA, Sellers TA, Gayther SA, Kelemen LE, Chenevix-Trench G, Risch HA, Pharoah PDP, Goode EL, Phelan CM

Abstract
Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality in American women. Normal ovarian physiology is intricately connected to small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) which govern processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. We hypothesized that common germline variation in genes encoding small GTPases is associated with EOC risk. We investigated 322 variants in 88 small GTPase genes in germline DNA of 18,736 EOC patients and 26,138 controls of European ancestry using a custom genotype array and logistic regression fitting log-additive models. Functional annotation was used to identify biofeatures and expression quantitative trait loci that intersect with risk variants. One variant, ARHGEF10L (Rho guanine nucleotide exchange factor 10 like) rs2256787, was associated with increased endometrioid EOC risk (OR = 1.33, p = 4.46 x 10-6). Other variants of interest included another in ARHGEF10L, rs10788679, which was associated with invasive serous EOC risk (OR = 1.07, p = 0.00026) and two variants in AKAP6 (A-kinase anchoring protein 6) which were associated with risk of invasive EOC (rs1955513, OR = 0.90, p = 0.00033; rs927062, OR = 0.94, p = 0.00059). Functional annotation revealed that the two ARHGEF10L variants were located in super-enhancer regions and that AKAP6 rs927062 was associated with expression of GTPase gene ARHGAP5 (Rho GTPase activating protein 5). Inherited variants in ARHGEF10L and AKAP6, with potential transcriptional regulatory function and association with EOC risk, warrant investigation in independent EOC study populations.

PMID: 29979793 [PubMed - in process]

Up-front rituximab maintenance improves outcome in patients with follicular lymphoma: a collaborative Nordic study.

La, 07/07/2018 - 21:21
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Up-front rituximab maintenance improves outcome in patients with follicular lymphoma: a collaborative Nordic study.

Blood Adv. 2018 Jul 10;2(13):1562-1571

Authors: Madsen C, Clausen MR, Plesner TL, Pasanen A, Kuismanen T, Bentzen HH, Jørgensen JM, Sillesen IB, Himmelstrup BM, Rønnov-Jessen D, Jensen KR, Pettinger AM, Ludvigsen M, Leppä S, d'Amore FA

Abstract
The introduction of the anti-CD20 antibody rituximab in combination with chemotherapy (R-chemo) has improved the prognosis of patients with follicular lymphoma (FL). During the last decade, the addition of a maintenance treatment with rituximab (MR) after R-chemo has been tested with the hope of further improving the outcome of these patients. Using 2 independent population-based cohorts, we investigated the effect of up-front MR on time related end points as well as the risk of histological transformation (HT). FL patients were included if they: (1) completed first-line induction treatment with R-chemo, (2) were alive after induction treatment and eligible for MR, and (3) had no evidence of HT at this time point. The training cohort consisted of 733 Danish patients of whom 364 were consolidated with MR; 369 were not. Patients receiving MR more often had advanced clinical stage (90% vs 78%), high Follicular Lymphoma International Prognostic Index (FLIPI) score (64% vs 55%), and bone marrow infiltration (49% vs 40%). Those consolidated with MR had an improved 5-year overall survival (OS; 89% vs 81%; P = .001) and progression-free survival (PFS; 72% vs 60%; P < .001). In the training cohort, MR was associated with a reduction of HT risk (P = .049). Analyses of an independent validation cohort of 190 Finnish patients confirmed the favorable impact of MR on 5-year OS (89% vs 81%; P = .046) and PFS (70% vs 57%; P = .005) but did not find a reduced risk of HT. The present population-based data suggest that the outcome of patients with FL has improved after consolidation of R-chemo with MR.

PMID: 29976619 [PubMed - in process]

RIP1 has a role in CD40-mediated apoptosis in human follicular lymphoma cells.

Pe, 06/07/2018 - 21:20
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RIP1 has a role in CD40-mediated apoptosis in human follicular lymphoma cells.

Immunobiology. 2017 Nov;222(11):998-1003

Authors: Adem J, Eray M, Eeva J, Nuutinen U, Pelkonen J

Abstract
CD40 is a cell surface receptor which belongs to tumor necrosis factor receptor (TNFR) family members. It transmits signals that regulate diverse cellular responses such as proliferation, differentiation, adhesion molecule expression and apoptosis. Unlike other TNFR family members (TRAIL-R, Fas-R and TNFR1), the CD40 cytoplasmic tail lacks death domain. However, CD40 is capable of inducing apoptosis in different types of cancer cells including lymphoma. The apoptotic effect of CD40 is linked to the involvement of Fas, TRAIL or receptor interacting protein 1 (RIP1) kinase. We have previously shown that CD40 activation has anti-apoptotic or apoptotic effect in follicular lymphoma (FL) cell lines. In this study, we investigated the mechanism by which CD40 mediates apoptosis in a follicular lymphoma cell line, HF4.9. We show here that CD40-induced apoptosis was dependent on caspase-8 activation because caspase-8 specific inhibitor, Z-IETD-FMK completely prevented apoptosis. Therefore, the involvement of TRAIL, Fas and RIP1 in caspase-8 activation was examined. The exogenous TRAIL-induced apoptosis was fully prevented by anti-TRAIL neutralizing antibody. However, the antibody had no effect on CD40-induced apoptosis indicating that CD40 did not induce the expression of endogenous TRAIL in HF4.9 cells. Moreover, the cells were not sensitive to Fas-mediated apoptosis. Interestingly, RIP1 specific inhibitor, necrostatin-1 decreased CD40-induced apoptosis, which showed that RIP1 has a role in caspase-8 activation. In conclusion, the survival or apoptotic effects of CD40-mediated signaling might be related to the differentiation stages of FL cells.

PMID: 28610909 [PubMed - indexed for MEDLINE]

Haematopoietic Stem Cell Transplantation in Children Shifts the Coagulation System towards a Pro-Coagulant State.

Su, 01/07/2018 - 21:18

Haematopoietic Stem Cell Transplantation in Children Shifts the Coagulation System towards a Pro-Coagulant State.

Thromb Haemost. 2018 Jun 30;:

Authors: Långström S, Koskenvuo M, Huttunen P, Lassila R, Taskinen M, Ranta S, Heikinheimo M, Mäkipernaa A

Abstract
Coagulation system is disturbed by several mechanisms after allogeneic haematopoietic stem cell transplantation (HSCT). We evaluated the effect of HSCT on coagulation system by various conventional and investigational methods in 30 children and adolescents who received HSCT due to haematological malignancies. Pro-thrombin fragment 1 + 2, a specific measure of thrombin generation, and von Willebrand factor, a measure of endothelial activation, increased after conditioning treatment, and remained elevated until 3 months after HSCT (p < 0.05 for all comparisons to pre-conditioning treatment). D-dimer, a measure of fibrin turnover, was elevated from the second week onwards until 4 weeks after HSCT (p < 0.05). Endogenous thrombin potential was increased after conditioning, and at 2 weeks after HSCT (p < 0.05). Furthermore, the activities of acute phase reactants fibrinogen and coagulation factor VIII were increased (p < 0.05 for all comparisons to pre-conditioning treatment) from the first week onwards up to 3 weeks and 3 months after HSCT, respectively. Taken together, paediatric patients receiving HSCT demonstrate distinct and prolonged variations in the coagulation system towards a pro-coagulant state. This shift is of importance when estimating the risk of haemostatic and thrombotic complications in these children.

PMID: 29960273 [PubMed - as supplied by publisher]

Analysis of Circulating Cell-Free DNA Identifies Multiclonal Heterogeneity of BRCA2 Reversion Mutations Associated with Resistance to PARP Inhibitors.

La, 30/06/2018 - 21:15
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Analysis of Circulating Cell-Free DNA Identifies Multiclonal Heterogeneity of BRCA2 Reversion Mutations Associated with Resistance to PARP Inhibitors.

Cancer Discov. 2017 09;7(9):999-1005

Authors: Quigley D, Alumkal JJ, Wyatt AW, Kothari V, Foye A, Lloyd P, Aggarwal R, Kim W, Lu E, Schwartzman J, Beja K, Annala M, Das R, Diolaiti M, Pritchard C, Thomas G, Tomlins S, Knudsen K, Lord CJ, Ryan C, Youngren J, Beer TM, Ashworth A, Small EJ, Feng FY

Abstract
Approximately 20% of metastatic prostate cancers harbor mutations in genes required for DNA repair by homologous recombination repair (HRR) such as BRCA2 HRR defects confer synthetic lethality to PARP inhibitors (PARPi) such as olaparib and talazoparib. In ovarian or breast cancers, olaparib resistance has been associated with HRR restoration, including by BRCA2 mutation reversion. Whether similar mechanisms operate in prostate cancer, and could be detected in liquid biopsies, is unclear. Here, we identify BRCA2 reversion mutations associated with olaparib and talazoparib resistance in patients with prostate cancer. Analysis of circulating cell-free DNA (cfDNA) reveals reversion mutation heterogeneity not discernable from a single solid-tumor biopsy and potentially allows monitoring for the emergence of PARPi resistance.Significance: The mechanisms of clinical resistance to PARPi in DNA repair-deficient prostate cancer have not been described. Here, we show BRCA2 reversion mutations in patients with prostate cancer with metastatic disease who developed resistance to talazoparib and olaparib. Furthermore, we show that PARPi resistance is highly multiclonal and that cfDNA allows monitoring for PARPi resistance. Cancer Discov; 7(9); 999-1005. ©2017 AACR.See related commentary by Domchek, p. 937See related article by Kondrashova et al., p. 984See related article by Goodall et al., p. 1006This article is highlighted in the In This Issue feature, p. 920.

PMID: 28450426 [PubMed - indexed for MEDLINE]