Subscribe to syöte PubMed PubMed
NCBI: db=pubmed; Term=(finland) AND hematology
Syötteen kokonainen osoite. 10 tuntia 17 min sitten

Defective WNT signaling associates with bone marrow fibrosis-a cross-sectional cohort study in a family with WNT1 osteoporosis.

La, 18/11/2017 - 23:42
Related Articles

Defective WNT signaling associates with bone marrow fibrosis-a cross-sectional cohort study in a family with WNT1 osteoporosis.

Osteoporos Int. 2017 Nov 16;:

Authors: Mäkitie RE, Niinimäki R, Kakko S, Honkanen T, Kovanen PE, Mäkitie O

Abstract
This study explores bone marrow function in patients with defective WNT1 signaling. Bone marrow samples showed increased reticulin and altered granulopoiesis while overall hematopoiesis was normal. Findings did not associate with severity of osteoporosis. These observations provide new insight into the role of WNT signaling in bone marrow homeostasis.
INTRODUCTION: WNT signaling regulates bone homeostasis and survival and self-renewal of hematopoietic stem cells. Aberrant activation may lead to osteoporosis and bone marrow pathology. We aimed to explore bone marrow findings in a large family with early-onset osteoporosis due to a heterozygous WNT1 mutation.
METHODS: We analyzed peripheral blood samples, and bone marrow aspirates and biopsies from 10 subjects with WNT1 mutation p.C218G. One subject was previously diagnosed with idiopathic myelofibrosis and others had no previously diagnosed hematologic disorders. The findings were correlated with the skeletal phenotype, as evaluated by number of peripheral and spinal fractures and bone mineral density.
RESULTS: Peripheral blood samples showed no abnormalities in cell counts, morphology or distributions but mild increase in platelet count. Bone marrow aspirates (from 8/10 subjects) showed mild decrease in bone marrow iron storages in 6 and variation in cell distributions in 5 subjects. Bone marrow biopsies (from 6/10 subjects) showed increased bone marrow reticulin (grade MF-2 in the myelofibrosis subject and grade MF-1 in 4 others), and an increase in overall, and a shift towards early-phase, granulopoiesis. The bone marrow findings did not associate with the severity of skeletal phenotype.
CONCLUSIONS: Defective WNT signaling associates with a mild increase in bone marrow reticulin and may predispose to myelofibrosis, while overall hematopoiesis and peripheral blood values are unaltered in individuals with a WNT1 mutation. In this family with WNT1 osteoporosis, bone marrow findings were not related to the severity of osteoporosis.

PMID: 29147753 [PubMed - as supplied by publisher]

Genetic polymorphism related to monocyte-macrophage function is associated with graft-versus-host disease.

Pe, 17/11/2017 - 23:41
Related Articles

Genetic polymorphism related to monocyte-macrophage function is associated with graft-versus-host disease.

Sci Rep. 2017 Nov 15;7(1):15666

Authors: Hyvärinen K, Ritari J, Koskela S, Niittyvuopio R, Nihtinen A, Volin L, Gallardo D, Partanen J

Abstract
Despite detailed human leukocyte antigen (HLA) matching and modern immunosuppressive therapy, severe graft-versus-host disease (GvHD) remains a major hurdle for successful allogeneic hematopoietic stem cell transplantation (HSCT). As the genetic diversity in GvHD complicates the systematic discovery of associated variants across populations, we studied 122 GvHD-associated single nucleotide polymorphisms (SNPs) in 492 HLA-matched sibling HSCT donor-recipient pairs from Finland and Spain. The association between these candidate SNPs and grade III-IV acute GvHD and extensive chronic GvHD was assessed. The functional effects of the variants were determined using expression and cytokine quantitative trait loci (QTL) database analyses. Clear heterogeneity was observed in the associated markers between the two populations. Interestingly, the majority of markers, such as those annotated to IL1, IL23R, TLR9, TNF, and NOD2 genes, are related to the immunological response by monocytes-macrophages to microbes, a step that precedes GvHD as a result of intestinal lesions. Furthermore, cytokine QTL analysis showed that the GvHD-associated markers regulate IL1β, IFNγ, and IL6 responses. These results support a crucial role for the anti-microbial response in GvHD risk. Furthermore, despite apparent heterogeneity in the genetic markers associated with GvHD, it was possible to identify a biological pathway shared by most markers in both populations.

PMID: 29142307 [PubMed - in process]

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

To, 09/11/2017 - 23:34
Related Articles

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 - in process]

Quality of life with biweekly docetaxel and capecitabine in advanced gastro-oesophageal cancer.

To, 09/11/2017 - 23:34
Related Articles

Quality of life with biweekly docetaxel and capecitabine in advanced gastro-oesophageal cancer.

Support Care Cancer. 2017 Sep;25(9):2771-2777

Authors: Korkeila EA, Salminen T, Kallio R, Mikkola M, Auvinen P, Pyrhönen S, Ristamäki R

Abstract
PURPOSE: This study aimed to evaluate the feasibility and tolerability of biweekly docetaxel with capecitabine as first-line treatment in advanced gastro-oesophageal cancer.
METHODS: Fifty-three patients at median age of 61 years with advanced gastric cancer were included in this prospective, non-randomized, multicentre phase II trial to receive intravenous docetaxel 50 mg/m(2) on days 1 and 15, and oral capecitabine 1250 mg/m(2) every 12 h, on days 1-7 and 15-21 of each 28-day cycle. QOL was assessed using EORTC QLQ-C30, together with the gastric module (QLQ-STO 22).
RESULTS: Forty-six patients were evaluable for QOL analyses. No deterioration in global health status was found. Social functioning scores improved, and eating difficulties and pain were alleviated during treatment. The most common grade 3 or 4 toxicity was neutropenia (47%), whereas neutropenic fever was uncommon (6%). The clinical benefit rate was 60%, including complete and partial responses as well as stabilized disease. Median overall survival was 8.8 months (95% CI 5.8-11.9 months), and median time to progression was 6.2 months (95% CI 4.9-7.5 months).
CONCLUSIONS: Biweekly docetaxel with capecitabine is a feasible treatment in AGC, delivered on an outpatient basis, with no need for central venous access device. No deterioration of global health status was reported. In addition, pain and eating difficulties were alleviated during study treatment. This trial is registered at ClinicalTrials.gov , number NCT00669370.

PMID: 28424889 [PubMed - indexed for MEDLINE]

Primary immunodeficiency associated with chromosomal aberration - an ESID survey.

Ke, 08/11/2017 - 23:34
Related Articles

Primary immunodeficiency associated with chromosomal aberration - an ESID survey.

Orphanet J Rare Dis. 2016 08 02;11(1):110

Authors: Schatorjé E, van der Flier M, Seppänen M, Browning M, Morsheimer M, Henriet S, Neves JF, Vinh DC, Alsina L, Grumach A, Soler-Palacin P, Boyce T, Celmeli F, Goudouris E, Hayman G, Herriot R, Förster-Waldl E, Seidel M, Simons A, de Vries E

Abstract
BACKGROUND: Patients with syndromic features frequently suffer from recurrent respiratory infections, but little is known about the spectrum of immunological abnormalities associated with their underlying chromosomal aberrations outside the well-known examples of Down and DiGeorge syndromes. Therefore, we performed this retrospective, observational survey study.
METHODS: All members of the European Society for Immunodeficiencies (ESID) were invited to participate by reporting their patients with chromosomal aberration (excluding Down and DiGeorge syndromes) in combination with one or more identified immunological abnormalities potentially relating to primary immunodeficiency. An online questionnaire was used to collect the patient data.
RESULTS: Forty-six patients were included from 16 centers (24 males, 22 females; median age 10.4 years [range 1.0-69.2 years]; 36 pediatric, 10 adult patients). A variety of chromosomal aberrations associated with immunological abnormalities potentially relating to primary immune deficiency was reported. The most important clinical presentation prompting the immunological evaluation was 'recurrent ear-nose-throat (ENT) and airway infections'. Immunoglobulin isotype and/or IgG-subclass deficiencies were the most prevalent immunological abnormalities reported.
CONCLUSIONS: Our survey yielded a wide variety of chromosomal aberrations associated with immunological abnormalities potentially relating to primary immunodeficiency. Although respiratory tract infections can often also be ascribed to other causes (e.g. aspiration or structural abnormalities), we show that a significant proportion of patients also have an antibody deficiency requiring specific treatment (e.g. immunoglobulin replacement, antibiotic prophylaxis). Therefore, it is important to perform immunological investigations in patients with chromosomal aberrations and recurrent ENT or airway infections, to identify potential immunodeficiency that can be specifically treated.

PMID: 27484815 [PubMed - indexed for MEDLINE]

Activation of plasmacytoid dendritic cells by apoptotic particles - mechanism for the loss of immunologic tolerance in Sjögren's syndrome.

Ti, 07/11/2017 - 23:33
Related Articles

Activation of plasmacytoid dendritic cells by apoptotic particles - mechanism for the loss of immunologic tolerance in Sjögren's syndrome.

Clin Exp Immunol. 2017 Nov 04;:

Authors: Ainola M, Porola P, Takakubo Y, Przybyla B, Kouri VP, Tolvanen TA, Hänninen A, Nordström DC

Abstract
Sjögren's syndrome (SS) is a common autoimmune disease targeting salivary and lacrimal glands. It is strongly female-dominant characterized by low estrogen levels combined with a local intracrine dihydrotestosterone defect. We hypothesized that these hormonal deficits lead to increased apoptosis of the epithelial cells and plasmacytoid dendritic cell (pDC) mediated pro-inflammatory host responses. Expression of Toll-like receptors (TLRs) 7 and 9 and cytokine profile was studied in pDCs treated with apoptotic particles collected in consecutive centrifugation steps of media from apoptotic cells. Expression and localization of SS autoantigens in these particles was also analysed. Furthermore, the effects of sex steroids were studied in pDCs cultured with several concentrations of dihydrotestosterone and 17-β-estradiol, and in saliva of patient treated with dehydroepiandrosterone. Apoptosis of the epithelial cells led to cleavage and translocation of SS-autoantigens, α-fodrin and SS-A, into apoptotic particles. The apoptosis-induced apoptotic particles contained also other SS-autoantigen hy1-RNA. These particles were internalized by pDCs in size-dependent manner and affected TLRs 7 and 9 expression and the production of proinflammatory cytokines. The analysed androgens protected cells from apoptosis, influenced redistribution of autoantigens and diminished the apoptotic particle -stimulated increase of the TLRs in pDCs. Our findings suggest that the formation of apoptotic particles may play a role in loss of immune tolerance, manifested by production of autoantibodies and the onset of autoinflammation in SS. This article is protected by copyright. All rights reserved.

PMID: 29105068 [PubMed - as supplied by publisher]

TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy.

Ti, 07/11/2017 - 23:33
Related Articles

TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy.

Blood. 2017 Oct 26;130(17):1903-1910

Authors: Eskelund CW, Dahl C, Hansen JW, Westman M, Kolstad A, Pedersen LB, Montano-Almendras CP, Husby S, Freiburghaus C, Ek S, Pedersen A, Niemann C, Räty R, Brown P, Geisler CH, Andersen MK, Guldberg P, Jerkeman M, Grønbæk K

Abstract
Despite recent advances in lymphoma treatment, mantle cell lymphoma (MCL) remains incurable, and we are still unable to identify patients who will not benefit from the current standard of care. Here, we explore the prognostic value of recurrent genetic aberrations in diagnostic bone marrow (BM) specimens from 183 younger patients with MCL from the Nordic MCL2 and MCL3 trials, which represent current standard-of-care regimens. In the univariate model, mutations of TP53 (11%) and NOTCH1 (4%), and deletions of TP53 (16%) and CDKN2A (20%), were significantly associated with inferior outcomes (together with MIPI, MIPI-c, blastoid morphology, and Ki67 > 30%); however, in multivariate analyses, only TP53 mutations (HR, 6.2; P < .0001) retained prognostic impact for overall survival (OS), whereas TP53 mutations (HR, 6.9; P < .0001) and MIPI-c high-risk (HR, 2.6; P = .003) had independent prognostic impact on time to relapse. TP53-mutated cases had a dismal outcome, with a median OS of 1.8 years, and 50% relapsed at 1.0 years, compared to a median OS of 12.7 years for TP53-unmutated cases (P < .0001). TP53 mutations were significantly associated with Ki67 > 30%, blastoid morphology, MIPI high-risk, and inferior responses to both induction- and high-dose chemotherapy. In conclusion, we show that TP53 mutations identify a phenotypically distinct and highly aggressive form of MCL with poor or no response to regimens including cytarabine, rituximab, and autologous stem-cell transplant (ASCT). We suggest patients with MCL should be stratified according to TP53 status, and that patients with TP53 mutations should be considered for experimental frontline trials exploring novel agents.

PMID: 28819011 [PubMed - indexed for MEDLINE]

Angiopoietin receptor Tie2 is required for vein specification and maintenance via regulating COUP-TFII.

Ti, 07/11/2017 - 23:33
Related Articles

Angiopoietin receptor Tie2 is required for vein specification and maintenance via regulating COUP-TFII.

Elife. 2016 Dec 22;5:

Authors: Chu M, Li T, Shen B, Cao X, Zhong H, Zhang L, Zhou F, Ma W, Jiang H, Xie P, Liu Z, Dong N, Xu Y, Zhao Y, Xu G, Lu P, Luo J, Wu Q, Alitalo K, Koh GY, Adams RH, He Y

Abstract
Mechanisms underlying the vein development remain largely unknown. Tie2 signaling mediates endothelial cell (EC) survival and vascular maturation and its activating mutations are linked to venous malformations. Here we show that vein formation are disrupted in mouse skin and mesentery when Tie2 signals are diminished by targeted deletion of Tek either ubiquitously or specifically in embryonic ECs. Postnatal Tie2 attenuation resulted in the degeneration of newly formed veins followed by the formation of haemangioma-like vascular tufts in retina and venous tortuosity. Mechanistically, Tie2 insufficiency compromised venous EC identity, as indicated by a significant decrease of COUP-TFII protein level, a key regulator in venogenesis. Consistently, angiopoietin-1 stimulation increased COUP-TFII in cultured ECs, while Tie2 knockdown or blockade of Tie2 downstream PI3K/Akt pathway reduced COUP-TFII which could be reverted by the proteasome inhibition. Together, our results imply that Tie2 is essential for venous specification and maintenance via Akt mediated stabilization of COUP-TFII.

PMID: 28005008 [PubMed - indexed for MEDLINE]

Outcome after relapse of myelodysplastic syndrome and secondary acute myeloid leukemia after allogeneic stem cell transplantation: a retrospective registry analysis on 698 patients by the Chronic Malignancies Working Party of European Society of Blood...

Su, 05/11/2017 - 23:32
Related Articles

Outcome after relapse of myelodysplastic syndrome and secondary acute myeloid leukemia after allogeneic stem cell transplantation: a retrospective registry analysis on 698 patients by the Chronic Malignancies Working Party of European Society of Blood and Marrow Transplantation.

Haematologica. 2017 Nov 03;:

Authors: Schmid C, de Wreede LC, van Biezen A, Finke J, Ehninger G, Ganser A, Volin L, Niederwieser D, Beelen D, Alessandrino P, Kanz L, Schleuning M, Passweg J, Veelken H, Maertens J, Cornelissen JJ, Blaise D, Gramatzki M, Milpied N, Yakub-Agha I, Mufti G, Rovira M, Arnold R, De Witte T, Robin M, Kröger N

Abstract
No standard exists for the treatment of myelodysplastic syndrome relapsing after allogeneic stem cell transplantation. We performed a retrospective registry analysis of outcome and risk factors in 698 patients, treated with different strategies. Median overall survival from relapse was 4.7 months (4.1-5.3), 2-year survival was 17.7% (14.8-21.2%). Shorter remission after transplantation (p<0.001), advanced disease (p=0.001), older age (p=0.007), unrelated donor (p=0.008) and acute Graft-versus-Host disease before relapse (p<0.001) adversely influenced survival, At 6 months from relapse, patients either had received no cellular treatment, (i.e. palliative chemotherapy or best supportive care, n=375), donor lymphocyte infusion (n=213), or second transplant (n=110). Treatment groups were analyzed separately because of imbalanced characteristics and difficulties to retrospectively evaluate the reason for individual treatments. Among patients receiving no cellular therapy, 109 were alive at 6 months from relapse, achieving a median overall survival from this landmark of 8.9 (5.1-12.6) months. Two-year survival was 29.7%. Recipients of donor lymphocytes achieved a median survival from first infusion of 6.0 (3.7-8.3) months with 2-year survival of 27.6%. Longer remission after first transplantation (p<0.001) and younger age (p=0.009) predicted better outcome. Among recipients of a second transplantation, median survival from second transplant was 4.2 months (2.5-5.9), 2-year survival was 17.0%. Longer remission after first transplantation (p<0.001), complete remission at second transplant (p=0.008), no prior chronic Graft-versus-Host disease (p<0.001) and change to a new donor (p=0.04) predicted better outcome The data allow to identify patients benefitting from donor lymphocyte infusion and second transplantation, and may serve as baseline for prospective trials.

PMID: 29101205 [PubMed - as supplied by publisher]

Intensity-based dual model method for generation of synthetic CT images from standard T2-weighted MR images - Generalized technique for four different MR scanners.

La, 04/11/2017 - 23:32
Related Articles

Intensity-based dual model method for generation of synthetic CT images from standard T2-weighted MR images - Generalized technique for four different MR scanners.

Radiother Oncol. 2017 Oct 30;:

Authors: Koivula L, Kapanen M, Seppälä T, Collan J, Dowling JA, Greer PB, Gustafsson C, Gunnlaugsson A, Olsson LE, Wee L, Korhonen J

Abstract
BACKGROUND AND PURPOSE: Recent studies have shown that it is possible to conduct entire radiotherapy treatment planning (RTP) workflow using only MR images. This study aims to develop a generalized intensity-based method to generate synthetic CT (sCT) images from standard T2-weighted (T2w) MR images of the pelvis.
MATERIALS AND METHODS: This study developed a generalized dual model HU conversion method to convert standard T2w MR image intensity values to synthetic HU values, separately inside and outside of atlas-segmented bone volume contour. The method was developed and evaluated with 20 and 35 prostate cancer patients, respectively. MR images with scanning sequences in clinical use were acquired with four different MR scanners of three vendors.
RESULTS: For the generated synthetic CT (sCT) images of the 35 prostate patients, the mean (and maximal) HU differences in soft and bony tissue volumes were 16 ± 6 HUs (34 HUs) and -46 ± 56 HUs (181 HUs), respectively, against the true CT images. The average of the PTV mean dose difference in sCTs compared to those in true CTs was -0.6 ± 0.4% (-1.3%).
CONCLUSIONS: The study provides a generalized method for sCT creation from standard T2w images of the pelvis. The method produced clinically acceptable dose calculation results for all the included scanners and MR sequences.

PMID: 29097012 [PubMed - as supplied by publisher]

Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types.

La, 04/11/2017 - 23:32
Related Articles

Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types.

Cancer Discov. 2016 Sep;6(9):1052-67

Authors: Kar SP, Beesley J, Amin Al Olama A, Michailidou K, Tyrer J, Kote-Jarai Z, Lawrenson K, Lindstrom S, Ramus SJ, Thompson DJ, ABCTB Investigators, Kibel AS, Dansonka-Mieszkowska A, Michael A, Dieffenbach AK, Gentry-Maharaj A, Whittemore AS, Wolk A, Monteiro A, Peixoto A, Kierzek A, Cox A, Rudolph A, Gonzalez-Neira A, Wu AH, Lindblom A, Swerdlow A, AOCS Study Group & Australian Cancer Study (Ovarian Cancer), APCB BioResource, Ziogas A, Ekici AB, Burwinkel B, Karlan BY, Nordestgaard BG, Blomqvist C, Phelan C, McLean C, Pearce CL, Vachon C, Cybulski C, Slavov C, Stegmaier C, Maier C, Ambrosone CB, Høgdall CK, Teerlink CC, Kang D, Tessier DC, Schaid DJ, Stram DO, Cramer DW, Neal DE, Eccles D, Flesch-Janys D, Edwards DR, Wokozorczyk D, Levine DA, Yannoukakos D, Sawyer EJ, Bandera EV, Poole EM, Goode EL, Khusnutdinova E, Høgdall E, Song F, Bruinsma F, Heitz F, Modugno F, Hamdy FC, Wiklund F, Giles GG, Olsson H, Wildiers H, Ulmer HU, Pandha H, Risch HA, Darabi H, Salvesen HB, Nevanlinna H, Gronberg H, Brenner H, Brauch H, Anton-Culver H, Song H, Lim HY, McNeish I, Campbell I, Vergote I, Gronwald J, Lubiński J, Stanford JL, Benítez J, Doherty JA, Permuth JB, Chang-Claude J, Donovan JL, Dennis J, Schildkraut JM, Schleutker J, Hopper JL, Kupryjanczyk J, Park JY, Figueroa J, Clements JA, Knight JA, Peto J, Cunningham JM, Pow-Sang J, Batra J, Czene K, Lu KH, Herkommer K, Khaw KT, kConFab Investigators, Matsuo K, Muir K, Offitt K, Chen K, Moysich KB, Aittomäki K, Odunsi K, Kiemeney LA, Massuger LF, Fitzgerald LM, Cook LS, Cannon-Albright L, Hooning MJ, Pike MC, Bolla MK, Luedeke M, Teixeira MR, Goodman MT, Schmidt MK, Riggan M, Aly M, Rossing MA, Beckmann MW, Moisse M, Sanderson M, Southey MC, Jones M, Lush M, Hildebrandt MA, Hou MF, Schoemaker MJ, Garcia-Closas M, Bogdanova N, Rahman N, NBCS Investigators, Le ND, Orr N, Wentzensen N, Pashayan N, Peterlongo P, Guénel P, Brennan P, Paulo P, Webb PM, Broberg P, Fasching PA, Devilee P, Wang Q, Cai Q, Li Q, Kaneva R, Butzow R, Kopperud RK, Schmutzler RK, Stephenson RA, MacInnis RJ, Hoover RN, Winqvist R, Ness R, Milne RL, Travis RC, Benlloch S, Olson SH, McDonnell SK, Tworoger SS, Maia S, Berndt S, Lee SC, Teo SH, Thibodeau SN, Bojesen SE, Gapstur SM, Kjær SK, Pejovic T, Tammela TL, GENICA Network, PRACTICAL consortium, Dörk T, Brüning T, Wahlfors T, Key TJ, Edwards TL, Menon U, Hamann U, Mitev V, Kosma VM, Setiawan VW, Kristensen V, Arndt V, Vogel W, Zheng W, Sieh W, Blot WJ, Kluzniak W, Shu XO, Gao YT, Schumacher F, Freedman ML, Berchuck A, Dunning AM, Simard J, Haiman CA, Spurdle A, Sellers TA, Hunter DJ, Henderson BE, Kraft P, Chanock SJ, Couch FJ, Hall P, Gayther SA, Easton DF, Chenevix-Trench G, Eeles R, Pharoah PD, Lambrechts D

Abstract
UNLABELLED: Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10(-8) seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10(-5) in the three-cancer meta-analysis.
SIGNIFICANCE: We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052-67. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 932.

PMID: 27432226 [PubMed - indexed for MEDLINE]

Total joint replacement in inhibitor-positive haemophilia: Long-term outcome analysis in fifteen patients.

Pe, 03/11/2017 - 23:31
Related Articles

Total joint replacement in inhibitor-positive haemophilia: Long-term outcome analysis in fifteen patients.

World J Orthop. 2017 Oct 18;8(10):777-784

Authors: Danielson H, Lassila R, Ylinen P, Yrjönen T

Abstract
AIM: To collect data from joint replacement in inhibitor patients, evaluate haemostatic and patient outcomes, and analyse the costs.
METHODS: We report our 21-year, single-centre cumulative experience of 15 joint arthroplasties in six inhibitor patients.
RESULTS: Two low responder inhibitor patients were in the early days treated with FVIII, whereas bypassing agents were used in the rest of the high responder patients. The primary haemostatic outcome was good in 8/15, fair in 4/15 and poor in 3/15 operations. The overall patient outcome, including joint health and patient satisfaction, was good in 10/15, fair 4/15 and poor in 1/15. No deep infections were observed. Cost analysis was most beneficial in low responders and in two immune-tolerized, high responder patients. In all cases, factor replacement comprised the main treatment costs.
CONCLUSION: Our experience supports the initial use of bypassing agents as well as preoperative immune-tolerance induction when possible. Despite the challenges of haemostasis and severe joint disease, total joint arthroplasty can reach a good outcome, even in inhibitor patients. The risk for deep infection might be smaller than previously reported. Individual planning, intense multidisciplinary teamwork and execution of operations should be centralised in a professional unit.

PMID: 29094008 [PubMed]

Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels.

To, 02/11/2017 - 23:31
Related Articles

Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels.

J Med Genet. 2016 Jul;53(7):441-9

Authors: van Leeuwen EM, Sabo A, Bis JC, Huffman JE, Manichaikul A, Smith AV, Feitosa MF, Demissie S, Joshi PK, Duan Q, Marten J, van Klinken JB, Surakka I, Nolte IM, Zhang W, Mbarek H, Li-Gao R, Trompet S, Verweij N, Evangelou E, Lyytikäinen LP, Tayo BO, Deelen J, van der Most PJ, van der Laan SW, Arking DE, Morrison A, Dehghan A, Franco OH, Hofman A, Rivadeneira F, Sijbrands EJ, Uitterlinden AG, Mychaleckyj JC, Campbell A, Hocking LJ, Padmanabhan S, Brody JA, Rice KM, White CC, Harris T, Isaacs A, Campbell H, Lange LA, Rudan I, Kolcic I, Navarro P, Zemunik T, Salomaa V, LifeLines Cohort Study, Kooner AS, Kooner JS, Lehne B, Scott WR, Tan ST, de Geus EJ, Milaneschi Y, Penninx BW, Willemsen G, de Mutsert R, Ford I, Gansevoort RT, Segura-Lepe MP, Raitakari OT, Viikari JS, Nikus K, Forrester T, McKenzie CA, de Craen AJ, de Ruijter HM, CHARGE Lipids Working Group, Pasterkamp G, Snieder H, Oldehinkel AJ, Slagboom PE, Cooper RS, Kähönen M, Lehtimäki T, Elliott P, van der Harst P, Jukema JW, Mook-Kanamori DO, Boomsma DI, Chambers JC, Swertz M, Ripatti S, Willems van Dijk K, Vitart V, Polasek O, Hayward C, Wilson JG, Wilson JF, Gudnason V, Rich SS, Psaty BM, Borecki IB, Boerwinkle E, Rotter JI, Cupples LA, van Duijn CM

Abstract
BACKGROUND: So far, more than 170 loci have been associated with circulating lipid levels through genome-wide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels.
METHODS: We used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from ∼60 000 individuals in the discovery stage and ∼90 000 samples in the replication stage.
RESULTS: Our study resulted in the identification of five new associations with circulating lipid levels at four loci. All four loci are within genes that can be linked biologically to lipid metabolism. One of the variants, rs116843064, is a damaging missense variant within the ANGPTL4 gene.
CONCLUSIONS: This study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels.

PMID: 27036123 [PubMed - indexed for MEDLINE]

Exome-wide association study of plasma lipids in >300,000 individuals.

Ti, 31/10/2017 - 23:30

Exome-wide association study of plasma lipids in >300,000 individuals.

Nat Genet. 2017 Oct 30;:

Authors: Liu DJ, Peloso GM, Yu H, Butterworth AS, Wang X, Mahajan A, Saleheen D, Emdin C, Alam D, Alves AC, Amouyel P, Di Angelantonio E, Arveiler D, Assimes TL, Auer PL, Baber U, Ballantyne CM, Bang LE, Benn M, Bis JC, Boehnke M, Boerwinkle E, Bork-Jensen J, Bottinger EP, Brandslund I, Brown M, Busonero F, Caulfield MJ, Chambers JC, Chasman DI, Chen YE, Chen YI, Chowdhury R, Christensen C, Chu AY, Connell JM, Cucca F, Cupples LA, Damrauer SM, Davies G, Deary IJ, Dedoussis G, Denny JC, Dominiczak A, Dubé MP, Ebeling T, Eiriksdottir G, Esko T, Farmaki AE, Feitosa MF, Ferrario M, Ferrieres J, Ford I, Fornage M, Franks PW, Frayling TM, Frikke-Schmidt R, Fritsche LG, Frossard P, Fuster V, Ganesh SK, Gao W, Garcia ME, Gieger C, Giulianini F, Goodarzi MO, Grallert H, Grarup N, Groop L, Grove ML, Gudnason V, Hansen T, Harris TB, Hayward C, Hirschhorn JN, Holmen OL, Huffman J, Huo Y, Hveem K, Jabeen S, Jackson AU, Jakobsdottir J, Jarvelin MR, Jensen GB, Jørgensen ME, Jukema JW, Justesen JM, Kamstrup PR, Kanoni S, Karpe F, Kee F, Khera AV, Klarin D, Koistinen HA, Kooner JS, Kooperberg C, Kuulasmaa K, Kuusisto J, Laakso M, Lakka T, Langenberg C, Langsted A, Launer LJ, Lauritzen T, Liewald DCM, Lin LA, Linneberg A, Loos RJF, Lu Y, Lu X, Mägi R, Malarstig A, Manichaikul A, Manning AK, Mäntyselkä P, Marouli E, Masca NGD, Maschio A, Meigs JB, Melander O, Metspalu A, Morris AP, Morrison AC, Mulas A, Müller-Nurasyid M, Munroe PB, Neville MJ, Nielsen JB, Nielsen SF, Nordestgaard BG, Ordovas JM, Mehran R, O'Donnell CJ, Orho-Melander M, Molony CM, Muntendam P, Padmanabhan S, Palmer CNA, Pasko D, Patel AP, Pedersen O, Perola M, Peters A, Pisinger C, Pistis G, Polasek O, Poulter N, Psaty BM, Rader DJ, Rasheed A, Rauramaa R, Reilly DF, Reiner AP, Renström F, Rich SS, Ridker PM, Rioux JD, Robertson NR, Roden DM, Rotter JI, Rudan I, Salomaa V, Samani NJ, Sanna S, Sattar N, Schmidt EM, Scott RA, Sever P, Sevilla RS, Shaffer CM, Sim X, Sivapalaratnam S, Small KS, Smith AV, Smith BH, Somayajula S, Southam L, Spector TD, Speliotes EK, Starr JM, Stirrups KE, Stitziel N, Strauch K, Stringham HM, Surendran P, Tada H, Tall AR, Tang H, Tardif JC, Taylor KD, Trompet S, Tsao PS, Tuomilehto J, Tybjaerg-Hansen A, van Zuydam NR, Varbo A, Varga TV, Virtamo J, Waldenberger M, Wang N, Wareham NJ, Warren HR, Weeke PE, Weinstock J, Wessel J, Wilson JG, Wilson PWF, Xu M, Yaghootkar H, Young R, Zeggini E, Zhang H, Zheng NS, Zhang W, Zhang Y, Zhou W, Zhou Y, Zoledziewska M, Charge Diabetes Working Group, EPIC-InterAct Consortium, EPIC-CVD Consortium, GOLD Consortium, VA Million Veteran Program, Howson JMM, Danesh J, McCarthy MI, Cowan CA, Abecasis G, Deloukas P, Musunuru K, Willer CJ, Kathiresan S

Abstract
We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.

PMID: 29083408 [PubMed - as supplied by publisher]

Post-Transplantation Cyclophosphamide-Based Haploidentical Transplantation as Alternative to Matched Sibling or Unrelated Donor Transplantation for Hodgkin Lymphoma: A Registry Study of the Lymphoma Working Party of the European Society for Blood and...

Ti, 31/10/2017 - 23:30
Related Articles

Post-Transplantation Cyclophosphamide-Based Haploidentical Transplantation as Alternative to Matched Sibling or Unrelated Donor Transplantation for Hodgkin Lymphoma: A Registry Study of the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation.

J Clin Oncol. 2017 Oct 20;35(30):3425-3432

Authors: Martínez C, Gayoso J, Canals C, Finel H, Peggs K, Dominietto A, Castagna L, Afanasyev B, Robinson S, Blaise D, Corradini P, Itälä-Remes M, Bermúdez A, Forcade E, Russo D, Potter M, McQuaker G, Yakoub-Agha I, Scheid C, Bloor A, Montoto S, Dreger P, Sureda A, Lymphoma Working Party of the European Group for Blood and Marrow Transplantation

Abstract
Purpose To compare the outcome of patients with Hodgkin lymphoma who received post-transplantation cyclophosphamide-based haploidentical (HAPLO) allogeneic hematopoietic cell transplantation with the outcome of patients who received conventional HLA-matched sibling donor (SIB) and HLA-matched unrelated donor (MUD). Patients and Methods We retrospectively evaluated 709 adult patients with Hodgkin lymphoma who were registered in the European Society for Blood and Marrow Transplantation database who received HAPLO (n = 98), SIB (n = 338), or MUD (n = 273) transplantation. Results Median follow-up of survivors was 29 months. No differences were observed between groups in the incidence of acute graft-versus-host disease (GVHD). HAPLO was associated with a lower risk of chronic GVHD (26%) compared with MUD (41%; P = .04). Cumulative incidence of nonrelapse mortality at 1 year was 17%, 13%, and 21% in HAPLO, SIB, and MUD, respectively, and corresponding 2-year cumulative incidence of relapse or progression was 39%, 49%, and 32%, respectively. On multivariable analysis, relative to SIB, nonrelapse mortality was similar in HAPLO ( P = .26) and higher in MUD ( P = .003), and risk of relapse was lower in both HAPLO ( P = .047) and MUD ( P < .001). Two-year overall survival and progression-free survival were 67% and 43% for HAPLO, 71% and 38% for SIB, and 62% and 45% for MUD, respectively. There were no significant differences in overall survival or progression-free survival between HAPLO and SIB or MUD. The rate of the composite end point of extensive chronic GVHD and relapse-free survival was significantly better for HAPLO (40%) compared with SIB (28%; P = .049) and similar to MUD (38%; P = .59). Conclusion Post-transplantation cyclophosphamide-based HAPLO transplantation results in similar survival outcomes compared with SIB and MUD, which confirms its suitability when no conventional donor is available. Our results also suggest that HAPLO results in a lower risk of chronic GVHD than MUD transplantation.

PMID: 28846465 [PubMed - indexed for MEDLINE]

Endothelin A receptor blocker and calcimimetic in the adenine rat model of chronic renal insufficiency.

Su, 29/10/2017 - 23:28
Related Articles

Endothelin A receptor blocker and calcimimetic in the adenine rat model of chronic renal insufficiency.

BMC Nephrol. 2017 Oct 27;18(1):323

Authors: Törmänen S, Pörsti I, Lakkisto P, Tikkanen I, Niemelä O, Paavonen T, Mustonen J, Eräranta A

Abstract
BACKGROUND: We studied whether endothelin receptor antagonist and calcimimetic treatments influence renal damage and kidney renin-angiotensin (RA) components in adenine-induced chronic renal insufficiency (CRI).
METHODS: Male Wistar rats (n = 80) were divided into 5 groups for 12 weeks: control (n = 12), 0.3% adenine (Ade; n = 20), Ade + 50 mg/kg/day sitaxentan (n = 16), Ade + 20 mg/kg/day cinacalcet (n = 16), and Ade + sitaxentan + cinacalcet (n = 16). Blood pressure (BP) was measured using tail-cuff, kidney histology was examined, and RA components measured using RT-qPCR.
RESULTS: Adenine caused tubulointerstitial damage with severe CRI, anemia, hyperphosphatemia, 1.8-fold increase in urinary calcium excretion, and 3.5-fold and 18-fold increases in plasma creatinine and PTH, respectively. Sitaxentan alleviated tubular atrophy, while sitaxentan + cinacalcet combination reduced interstitial inflammation, tubular dilatation and atrophy in adenine-rats. Adenine diet did not influence kidney angiotensin converting enzyme (ACE) and AT4 receptor mRNA, but reduced mRNA of renin, AT1a, AT2, (pro)renin receptor and Mas to 40-60%, and suppressed ACE2 to 6% of that in controls. Sitaxentan reduced BP by 8 mmHg, creatinine, urea, and phosphate concentrations by 16-24%, and PTH by 42%. Cinacalcet did not influence BP or creatinine, but reduced PTH by 84%, and increased hemoglobin by 28% in adenine-rats. The treatments further reduced renin mRNA by 40%, while combined treatment normalized plasma PTH, urinary calcium, and increased ACE2 mRNA 2.5-fold versus the Ade group (p < 0.001).
CONCLUSIONS: In adenine-induced interstitial nephritis, sitaxentan improved renal function and tubular atrophy. Sitaxentan and cinacalcet reduced kidney renin mRNA by 40%, while their combination alleviated tubulointerstitial damage and urinary calcium loss, and increased kidney tissue ACE2 mRNA.

PMID: 29078759 [PubMed - in process]

Evaluation of effect of preoperative chemotherapy on Wilms' tumor histopathology.

Su, 29/10/2017 - 00:28
Related Articles

Evaluation of effect of preoperative chemotherapy on Wilms' tumor histopathology.

J Pediatr Surg. 2017 Oct 06;:

Authors: Taskinen S, Lohi J, Koskenvuo M, Taskinen M

Abstract
PURPOSE: To evaluate usefulness of cutting needle biopsy (CNB) to recognize pediatric renal tumors and to predict the evolution of histology during preoperative chemotherapy of Wilms tumors.
METHODS: Ninety pediatric patients were operated for renal tumors at our institution in 1988-2015. We included all 64 patients who had undergone CNB at diagnosis and whose CNB and nephrectomy samples were available for re-evaluation.
RESULTS: The CNB was diagnostic in all 59 Wilms tumors but only in two out of five non-Wilms tumors. Anaplasia was missed by CNB in one of three with diffuse anaplasia in nephrectomy specimens. In Wilms tumors the proportions of the blastemal, stromal and epithelial components were 55% (IQR 25-85), 28% (IQR 10-58) and 2% (IQR 0-10) in CNB samples and 5% (IQR 0-64), 15% (IQR 0-50) and 15% (IQR 0-44) in the nephrectomy specimens (p-values 0.002, 0.599 and 0.005 respectively). The degree of tumor necrosis was in median 80% (IQR 21-97), after preoperative chemotherapy. The degree of tumor necrosis after chemotherapy had a positive correlation with the proportion of blastemal component (p=0.008) and a negative correlation with proportion of epithelial component in pre-chemotherapy CNB samples (p<0.001).
CONCLUSIONS: Wilms tumors are usually recognizable unlike non-Wilms tumors in CNB at diagnosis. In Wilms tumors, high blastemal cell content is associated with significant tumor necrosis during pre-operative chemotherapy. Our results do not support routine use of CNB in diagnosis of renal tumors.
TYPE OF STUDY: Retrospective review.
LEVEL OF EVIDENCE: Level III.

PMID: 29074135 [PubMed - as supplied by publisher]

International Forum on GMP-grade human platelet lysate for cell propagation.

La, 28/10/2017 - 00:27
Related Articles

International Forum on GMP-grade human platelet lysate for cell propagation.

Vox Sang. 2017 Oct 25;:

Authors: Strunk D, Lozano M, Marks DC, Loh YS, Gstraunthaler G, Schennach H, Rohde E, Laner-Plamberger S, Öller M, Nystedt J, Lotfi R, Rojewski M, Schrezenmeier H, Bieback K, Schäfer R, Bakchoul T, Waidmann M, Jonsdottir-Buch SM, Montazeri H, Sigurjonsson OE, Iudicone P, Fioravanti D, Pierelli L, Introna M, Capelli C, Falanga A, Takanashi M, López-Villar O, Burnouf T, Reems JA, Pierce J, Preslar AM, Schallmoser K

PMID: 29071726 [PubMed - as supplied by publisher]

Prothrombotic state in young females with severe early-onset obesity.

La, 28/10/2017 - 00:27
Related Articles

Prothrombotic state in young females with severe early-onset obesity.

Pediatr Res. 2017 Oct 25;:

Authors: Loid P, Långström S, Viljakainen H, Mäkipernaa A, Heikinheimo M, Mäkitie O

PMID: 29068434 [PubMed - as supplied by publisher]