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Early CD8+-recovery independently predicts low probability of disease relapse but also associates with severe GVHD after allogeneic HSCT.

Pe, 21/09/2018 - 22:02

Early CD8+-recovery independently predicts low probability of disease relapse but also associates with severe GVHD after allogeneic HSCT.

PLoS One. 2018;13(9):e0204136

Authors: Ranti J, Kurki S, Salmenniemi U, Putkonen M, Salomäki S, Itälä-Remes M

Abstract
In this single-center study we retrospectively evaluated the impact of early reconstitution of different lymphocyte subsets on patient outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We found that CD8+ T-cell counts exceeding 50x106/l as early as on day 28 post-transplantation correlated significantly with decreased relapse risk, with three-year relapse rates of 17.0% and 55.6% (P = 0.002), but were also associated with severe acute and chronic GVHD. Incidence of grade III-IV acute GVHD was 30.5% for those with early CD8+ T-cell recovery compared to 2.1% for those with lower CD8+ T-cell counts on day 28 post-transplant (HR = 20.24, P = 0.004). Early CD8+ T-cell reconstitution did not, however, affect the overall survival. Multivariate analysis showed that slow CD8+ T-cell reconstitution was strongly associated with increased risk of relapse (HR = 3.44, P = 0.026). A weaker correlation was found between CD4+ reconstitution and relapse-risk, but there was no such association with CD19+ B-cells or NK-cells. In conclusion, the early CD8+ T-cell recovery on day 28 post-transplant is associated with the lower risk of relapse but also predicts the impending severe GVHD, and thus could be useful in guiding timely treatment decisions.

PMID: 30235281 [PubMed - in process]

Fifth Åland Island conference on von Willebrand disease.

Ke, 19/09/2018 - 22:01
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Fifth Åland Island conference on von Willebrand disease.

Haemophilia. 2018 May;24 Suppl 4:5-19

Authors: Berntorp E, Ågren A, Aledort L, Blombäck M, Cnossen MH, Croteau SE, von Depka M, Federici AB, Goodeve A, Goudemand J, Mannucci PM, Mourik M, Önundarson PT, Rodeghiero F, Szántó T, Windyga J

Abstract
The fifth Åland Island meeting on von Willebrand disease (VWD) was held on the Åland Islands, Finland, from 22 to 24 September 2016-90 years after the first case of VWD was diagnosed in a patient from the Åland Islands in 1926. This meeting brought together experts in the field of VWD to share knowledge and expertise on current trends and challenges in VWD. Topics included the storage and release of von Willebrand factor (VWF), epidemiology and diagnostics in VWD, treatment of VWD, angiogenesis and VWF inhibitors.

PMID: 29687935 [PubMed - indexed for MEDLINE]

Thromboembolism prophylaxis in patients with Philadelphia-negative myeloproliferative neoplasms-Clinical practice among Nordic specialists.

Ke, 19/09/2018 - 22:01
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Thromboembolism prophylaxis in patients with Philadelphia-negative myeloproliferative neoplasms-Clinical practice among Nordic specialists.

Eur J Haematol. 2018 May;100(5):475-478

Authors: Bjerrum OW, Samuelsson J, Ghanima W, Kauppila M, Andersen CL, Nordic Myeloproliferative Neoplasm Study Group

Abstract
BACKGROUND: Patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) have higher risks of developing thromboembolisms compared to the general population. International guidelines on the management of MPNs therefore include recommendations concerning thromboembolism prophylaxis. In clinical practice, strict adherence to guidelines may be challenging and dependent on factors such as physician experience, outpatient clinic setting, and access to therapy; however, no data exist on physician adherence or patient compliance to thromboembolism prophylaxis in MPNs.
OBJECTIVES: The Nordic Myeloproliferative Neoplasm Study Group (NMPN) performed a survey among Nordic hematology specialists with the aim of documenting the implementation of international recommendations in a region of Northern Europe with similar healthcare systems.
RESULTS: The study showed that Nordic specialists managed their patients in accordance with international guidelines concerning medical intervention, but to a lesser degree regarding the management of additional cardiovascular risk factors. The survey also drew attention to the common clinical dilemma of combining antiaggregatory agents with vitamin K antagonists (VKA), or novel oral anticoagulants (NOAC), as well as phlebotomy limits in female polycythemia vera patients.
CONCLUSIONS: The results of this study highlight the importance of considering all risk factors for thrombosis and an optimal collaboration with the primary healthcare sector.

PMID: 29427461 [PubMed - indexed for MEDLINE]

Weekly recombinant FIX prophylaxis for severe haemophilia B in normal clinical practice: data from UKHCDO and Finland.

Ti, 11/09/2018 - 21:56
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Weekly recombinant FIX prophylaxis for severe haemophilia B in normal clinical practice: data from UKHCDO and Finland.

Haemophilia. 2017 05;23(3):e240-e243

Authors: Scott M, Nummi V, Lassila R, Xiang H, Hay CRM

PMID: 28520204 [PubMed - indexed for MEDLINE]

Salvage use of allogeneic hematopoietic stem cell transplantation after reduced intensity conditioning from unrelated donors in multiple myeloma. A study by the Plasma Cell Disorders subcommittee of the European Group for Blood and Marrow Transplant...

La, 08/09/2018 - 21:54
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Salvage use of allogeneic hematopoietic stem cell transplantation after reduced intensity conditioning from unrelated donors in multiple myeloma. A study by the Plasma Cell Disorders subcommittee of the European Group for Blood and Marrow Transplant Chronic Malignancies Working Party.

Haematologica. 2017 07;102(7):e271-e274

Authors: Sobh M, Michallet M, Dubois V, Iacobelli S, Koster L, Van Biezen A, Fegueux N, Tabrizi R, Finke J, El-Cheikh J, Schipperus M, Meijer E, von dem Borne P, Petersen E, Russell N, Tholouli E, Passweg J, Garban F, Maertens J, Chevalier P, Maillard N, Volin L, Francois S, Lioure B, Beguin Y, Gluckman E, Ruggeri A, Garderet L, Kröger N

PMID: 28428268 [PubMed - indexed for MEDLINE]

Characterization of an X-chromosome-linked telomere biology disorder in females with DKC1 mutation.

Pe, 07/09/2018 - 21:54
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Characterization of an X-chromosome-linked telomere biology disorder in females with DKC1 mutation.

Leukemia. 2018 Sep 05;:

Authors: Hirvonen EAM, Peuhkuri S, Norberg A, Degerman S, Hannula-Jouppi K, Välimaa H, Kilpivaara O, Wartiovaara-Kautto U

PMID: 30185935 [PubMed - as supplied by publisher]

Severe neutropenia after rituximab-treatment of multiple sclerosis.

Pe, 07/09/2018 - 21:54
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Severe neutropenia after rituximab-treatment of multiple sclerosis.

Mult Scler Relat Disord. 2018 Feb;20:3-5

Authors: Rissanen E, Remes K, Airas L

Abstract
We present here the first MS-case where rituximab-treatment led to grade IV neutropenia, with hospitalization and treatment of a serious infection with broad-spectrum antibiotics. The neutropenia resolved promptly with granulocyte-colony stimulating factor-treatment and the patient recovered well. Due to risk of recurring neutropenia rituximab-treatment was not re-administered. We discuss the mechanisms and occurrence of neutropenia as a side effect to rituximab-treatment of MS, and remind of the importance of monitoring rituximab-treated MS-patients for this rare but potentially dangerous side effect.

PMID: 29253744 [PubMed - indexed for MEDLINE]

Case-control analysis of truncating mutations in DNA damage response genes connects TEX15 and FANCD2 with hereditary breast cancer susceptibility.

To, 06/09/2018 - 21:53
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Case-control analysis of truncating mutations in DNA damage response genes connects TEX15 and FANCD2 with hereditary breast cancer susceptibility.

Sci Rep. 2017 04 06;7(1):681

Authors: Mantere T, Tervasmäki A, Nurmi A, Rapakko K, Kauppila S, Tang J, Schleutker J, Kallioniemi A, Hartikainen JM, Mannermaa A, Nieminen P, Hanhisalo R, Lehto S, Suvanto M, Grip M, Jukkola-Vuorinen A, Tengström M, Auvinen P, Kvist A, Borg Å, Blomqvist C, Aittomäki K, Greenberg RA, Winqvist R, Nevanlinna H, Pylkäs K

Abstract
Several known breast cancer susceptibility genes encode proteins involved in DNA damage response (DDR) and are characterized by rare loss-of-function mutations. However, these explain less than half of the familial cases. To identify novel susceptibility factors, 39 rare truncating mutations, identified in 189 Northern Finnish hereditary breast cancer patients in parallel sequencing of 796 DDR genes, were studied for disease association. Mutation screening was performed for Northern Finnish breast cancer cases (n = 578-1565) and controls (n = 337-1228). Mutations showing potential cancer association were analyzed in additional Finnish cohorts. c.7253dupT in TEX15, encoding a DDR factor important in meiosis, associated with hereditary breast cancer (p = 0.018) and likely represents a Northern Finnish founder mutation. A deleterious c.2715 + 1G > A mutation in the Fanconi anemia gene, FANCD2, was over two times more common in the combined Finnish hereditary cohort compared to controls. A deletion (c.640_644del5) in RNF168, causative for recessive RIDDLE syndrome, had high prevalence in majority of the analyzed cohorts, but did not associate with breast cancer. In conclusion, truncating variants in TEX15 and FANCD2 are potential breast cancer risk factors, warranting further investigations in other populations. Furthermore, high frequency of RNF168 c.640_644del5 indicates the need for its testing in Finnish patients with RIDDLE syndrome symptoms.

PMID: 28386063 [PubMed - indexed for MEDLINE]

ORP4L is essential for T-cell acute lymphoblastic leukemia cell survival.

Ti, 04/09/2018 - 21:51
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ORP4L is essential for T-cell acute lymphoblastic leukemia cell survival.

Nat Commun. 2016 09 01;7:12702

Authors: Zhong W, Yi Q, Xu B, Li S, Wang T, Liu F, Zhu B, Hoffmann PR, Ji G, Lei P, Li G, Li J, Li J, Olkkonen VM, Yan D

Abstract
Metabolic pathways are reprogrammed in cancer to support cell survival. Here, we report that T-cell acute lymphoblastic leukemia (T-ALL) cells are characterized by increased oxidative phosphorylation and robust ATP production. We demonstrate that ORP4L is expressed in T-ALL but not normal T-cells and its abundance is proportional to cellular ATP. ORP4L acts as an adaptor/scaffold assembling CD3ɛ, Gαq/11 and PLCβ3 into a complex that activates PLCβ3. PLCβ3 catalyzes IP3 production in T-ALL as opposed to PLCγ1 in normal T-cells. Up-regulation of ORP4L thus results in a switch in the enzyme responsible for IP3-induced endoplasmic reticulum Ca(2+) release and oxidative phosphorylation. ORP4L knockdown results in suboptimal bioenergetics, cell death and abrogation of T-ALL engraftment in vivo. In summary, we uncovered a signalling pathway operating specifically in T-ALL cells in which ORP4L mediates G protein-coupled ligand-induced PLCβ3 activation, resulting in an increase of mitochondrial respiration for cell survival. Targeting ORP4L might represent a promising approach for T-ALL treatment.

PMID: 27581363 [PubMed - indexed for MEDLINE]

Global Mortality From Firearms, 1990-2016.

La, 01/09/2018 - 21:49
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Global Mortality From Firearms, 1990-2016.

JAMA. 2018 Aug 28;320(8):792-814

Authors: Global Burden of Disease 2016 Injury Collaborators, Naghavi M, Marczak LB, Kutz M, Shackelford KA, Arora M, Miller-Petrie M, Aichour MTE, Akseer N, Al-Raddadi RM, Alam K, Alghnam SA, Antonio CAT, Aremu O, Arora A, Asadi-Lari M, Assadi R, Atey TM, Avila-Burgos L, Awasthi A, Ayala Quintanilla BP, Barker-Collo SL, Bärnighausen TW, Bazargan-Hejazi S, Behzadifar M, Behzadifar M, Bennett JR, Bhalla A, Bhutta ZA, Bilal AI, Borges G, Borschmann R, Brazinova A, Campuzano Rincon JC, Carvalho F, Castañeda-Orjuela CA, Dandona L, Dandona R, Dargan PI, De Leo D, Dharmaratne SD, Ding EL, Phuc Do H, Doku DT, Doyle KE, Driscoll TR, Edessa D, El-Khatib Z, Endries AY, Esteghamati A, Faro A, Farzadfar F, Feigin VL, Fischer F, Foreman KJ, Franklin RC, Fullman N, Futran ND, Gebrehiwot TT, Gutiérrez RA, Hafezi-Nejad N, Haghparast Bidgoli H, Hailu GB, Haro JM, Hassen HY, Hawley C, Hendrie D, Híjar M, Hu G, Ilesanmi OS, Jakovljevic M, James SL, Jayaraman S, Jonas JB, Kahsay A, Kasaeian A, Keiyoro PN, Khader Y, Khalil IA, Khang YH, Khubchandani J, Ahmad Kiadaliri A, Kieling C, Kim YJ, Kosen S, Krohn KJ, Kumar GA, Lami FH, Lansingh VC, Larson HJ, Linn S, Lunevicius R, Magdy Abd El Razek H, Magdy Abd El Razek M, Malekzadeh R, Carvalho Malta D, Mason-Jones AJ, Matzopoulos R, Memiah PTN, Mendoza W, Meretoja TJ, Mezgebe HB, Miller TR, Mohammed S, Moradi-Lakeh M, Mori R, Nand D, Tat Nguyen C, Le Nguyen Q, Ningrum DNA, Akpojene Ogbo F, Olagunju AT, Patton GC, Phillips MR, Polinder S, Pourmalek F, Qorbani M, Rahimi-Movaghar A, Rahimi-Movaghar V, Rahman M, Rai RK, Ranabhat CL, Rawaf DL, Rawaf S, Rowhani-Rahbar A, Safdarian M, Safiri S, Sagar R, Salama JS, Sanabria J, Santric Milicevic MM, Sarmiento-Suárez R, Sartorius B, Satpathy M, Schwebel DC, Seedat S, Sepanlou SG, Shaikh MA, Sharew NT, Shiue I, Singh JA, Sisay M, Skirbekk V, Soares Filho AM, Stein DJ, Stokes MA, Sufiyan MB, Swaroop M, Sykes BL, Tabarés-Seisdedos R, Tadese F, Tran BX, Thanh Tran T, Ukwaja KN, Vasankari TJ, Vlassov V, Werdecker A, Ye P, Yip P, Yonemoto N, Younis MZ, Zaidi Z, El Sayed Zaki M, Hay SI, Lim SS, Lopez AD, Mokdad AH, Vos T, Murray CJL

Abstract
Importance: Understanding global variation in firearm mortality rates could guide prevention policies and interventions.
Objective: To estimate mortality due to firearm injury deaths from 1990 to 2016 in 195 countries and territories.
Design, Setting, and Participants: This study used deidentified aggregated data including 13 812 location-years of vital registration data to generate estimates of levels and rates of death by age-sex-year-location. The proportion of suicides in which a firearm was the lethal means was combined with an estimate of per capita gun ownership in a revised proxy measure used to evaluate the relationship between availability or access to firearms and firearm injury deaths.
Exposures: Firearm ownership and access.
Main Outcomes and Measures: Cause-specific deaths by age, sex, location, and year.
Results: Worldwide, it was estimated that 251 000 (95% uncertainty interval [UI], 195 000-276 000) people died from firearm injuries in 2016, with 6 countries (Brazil, United States, Mexico, Colombia, Venezuela, and Guatemala) accounting for 50.5% (95% UI, 42.2%-54.8%) of those deaths. In 1990, there were an estimated 209 000 (95% UI, 172 000 to 235 000) deaths from firearm injuries. Globally, the majority of firearm injury deaths in 2016 were homicides (64.0% [95% UI, 54.2%-68.0%]; absolute value, 161 000 deaths [95% UI, 107 000-182 000]); additionally, 27% were firearm suicide deaths (67 500 [95% UI, 55 400-84 100]) and 9% were unintentional firearm deaths (23 000 [95% UI, 18 200-24 800]). From 1990 to 2016, there was no significant decrease in the estimated global age-standardized firearm homicide rate (-0.2% [95% UI, -0.8% to 0.2%]). Firearm suicide rates decreased globally at an annualized rate of 1.6% (95% UI, 1.1-2.0), but in 124 of 195 countries and territories included in this study, these levels were either constant or significant increases were estimated. There was an annualized decrease of 0.9% (95% UI, 0.5%-1.3%) in the global rate of age-standardized firearm deaths from 1990 to 2016. Aggregate firearm injury deaths in 2016 were highest among persons aged 20 to 24 years (for men, an estimated 34 700 deaths [95% UI, 24 900-39 700] and for women, an estimated 3580 deaths [95% UI, 2810-4210]). Estimates of the number of firearms by country were associated with higher rates of firearm suicide (P < .001; R2 = 0.21) and homicide (P < .001; R2 = 0.35).
Conclusions and Relevance: This study estimated between 195 000 and 276 000 firearm injury deaths globally in 2016, the majority of which were firearm homicides. Despite an overall decrease in rates of firearm injury death since 1990, there was variation among countries and across demographic subgroups.

PMID: 30167700 [PubMed - in process]

TEDDI: radiotherapy delivery in deep inspiration for pediatric patients - a NOPHO feasibility study.

La, 01/09/2018 - 21:49
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TEDDI: radiotherapy delivery in deep inspiration for pediatric patients - a NOPHO feasibility study.

Radiat Oncol. 2018 Mar 27;13(1):56

Authors: Lundgaard AY, Hjalgrim LL, Rechner LA, Josipovic M, Joergensen M, Aznar MC, Berthelsen AK, Borgwardt L, Johansen C, Loft A, Safwat A, Vaalavirta L, Specht L, Maraldo MV

Abstract
BACKGROUND: Radiotherapy (RT) delivered in deep inspiration breath-hold (DIBH) is a simple technique, in which changes in patient anatomy can significantly reduce the irradiation of the organs at risk (OARs) surrounding the treatment target. DIBH is routinely used in the treatment of some adult patients to diminish the risk of late effects; however, no formalized studies have addressed the potential benefit of DIBH in children.
METHODS/DESIGN: TEDDI is a multicenter, non-randomized, feasibility study. The study investigates the dosimetric benefit of RT delivered in DIBH compared to free breathing (FB) in pediatric patients. Also, the study aims to establish the compliance to DIBH and to determine the accuracy and reproducibility in a pediatric setting. Pediatric patients (aged 5-17 years) with a tumor in the mediastinum or upper abdomen with the possible need of RT will be included in the study. Written informed consent is obligatory. Prior to any treatment, patients will undergo a DIBH training session followed by a diagnostic PET/CT- or CT-staging scan in both DIBH and FB. If the patient proceeds to RT, a RT planning CT scan will be performed in both DIBH and FB and two separate treatment plans will be calculated. The superior treatment plan, i.e. equal target coverage and lowest overall dose to the OARs, will be chosen for treatment. Patient comfort will be assessed daily by questionnaires and by adherence to the respiratory management procedure.
DISCUSSION: RT in DIBH is expected to diminish irradiation of the OARs surrounding the treatment target and thereby reduce the risk of late effects in childhood cancer survivors.
TRIAL REGISTRATION: The Danish Ethical Committee (H-16035870, approved November 24th 2016, prospectively registered). The Danish Data Protection Agency (2012-58-0004, approved January 1st 2017, prospectively registered). Registered at clinicaltrials.gov ( NCT03315546 , October 20th  2017, retrospectively registered).

PMID: 29587881 [PubMed - indexed for MEDLINE]

Blood graft composition and post-transplant recovery in myeloma patients mobilized with plerixafor: a prospective multicenter study.

Pe, 31/08/2018 - 21:49
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Blood graft composition and post-transplant recovery in myeloma patients mobilized with plerixafor: a prospective multicenter study.

Leuk Lymphoma. 2018 Aug 30;:1-9

Authors: Valtola J, Silvennoinen R, Ropponen A, Siitonen T, Säily M, Sankelo M, Putkonen M, Partanen A, Pyörälä M, Savolainen ER, Mäntymaa P, Pelkonen J, Jantunen E, Varmavuo V

Abstract
The composition of autologous blood grafts after cryopreservation, post-transplant hematological recovery up to 1 year and immune recovery up to 6 months as well as outcome was analyzed in 87 patients with multiple myeloma (MM). The patients receiving added plerixafor due to poor mobilization (11%) were compared to those mobilized with G-CSF or cyclophosphamide (CY) plus G-CSF. The use of plerixafor was found to significantly affect the graft composition as there was a significantly higher proportion of the more primitive CD34+ cells, higher number of T and B lymphocytes as well as NK cells in the grafts of patients who received also plerixafor. The hematological recovery after auto-SCT was comparable between the groups. The recovery of CD3+CD4+ T cells was faster in plerixafor mobilized patients at 1 and 3 months post-transplant. There were no significant differences in progression-free (PFS) or overall survival (OS) according to the plerixafor use.

PMID: 30160591 [PubMed - as supplied by publisher]

Biomarkers to diagnose ventricular dysfunction in childhood cancer survivors: a systematic review.

Pe, 31/08/2018 - 21:49
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Biomarkers to diagnose ventricular dysfunction in childhood cancer survivors: a systematic review.

Heart. 2018 Aug 29;:

Authors: Leerink JM, Verkleij SJ, Feijen EAM, Mavinkurve-Groothuis AMC, Pourier MS, Ylänen K, Tissing WJE, Louwerens M, van den Heuvel MM, van Dulmen-den Broeder E, de Vries ACH, Ronckers CM, van der Pal HJH, Kapusta L, Loonen J, Bellersen L, Pinto YM, Kremer LCM, Kok WEM

Abstract
OBJECTIVE: To systematically review the literature and assess the diagnostic value of biomarkers in detection of late-onset left ventricular (LV) dysfunction in childhood cancer survivors (CCS) treated with anthracyclines.
METHODS: We systematically searched the literature for studies that evaluated the use of biomarkers for detection of LV dysfunction in CCS treated with anthracyclines more than 1 year since childhood cancer diagnosis. LV dysfunction definitions were accepted as an ejection fraction <50% or <55% and/or a fractional shortening <28%, <29% or <30%. Contingency tables were created to assess diagnostic accuracies of biomarkers for diagnosing LV dysfunction.
RESULTS: Of 1362 original studies screened, eight heterogeneous studies evaluating four different biomarkers in mostly asymptomatic CCS were included. In four studies, an abnormal N-terminal pro-B-type natriuretic peptide (NT-proBNP, cut-off range 63-125 ng/L) had low sensitivity (maximally 22%) and a specificity of up to 97% for detection of LV dysfunction. For troponin levels, in five studies one patient had an abnormal troponin value as well as LV dysfunction, while in total 127 patients had LV dysfunction without troponin elevations above cut-off values (lowest 0.01 ng/mL). Two studies that evaluated brain natriuretic peptide and nitric oxide were underpowered to draw conclusions.
CONCLUSIONS: In individual studies, the diagnostic value of NT-proBNP for detection of LV dysfunction in CCS is limited. Troponins have no role in detecting late-onset LV dysfunction with cut-off values as low as 0.01 ng/mL. Further study on optimal NT-proBNP cut-off values for rule out or rule in of LV dysfunction is warranted.

PMID: 30158136 [PubMed - as supplied by publisher]

In silico and preclinical drug screening identifies dasatinib as a targeted therapy for T-ALL.

To, 30/08/2018 - 21:49
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In silico and preclinical drug screening identifies dasatinib as a targeted therapy for T-ALL.

Blood Cancer J. 2017 09 08;7(9):e604

Authors: Laukkanen S, Grönroos T, Pölönen P, Kuusanmäki H, Mehtonen J, Cloos J, Ossenkoppele G, Gjertsen B, Øystein B, Heckman C, Heinäniemi M, Kontro M, Lohi O

PMID: 28885610 [PubMed - indexed for MEDLINE]

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus.

To, 30/08/2018 - 21:49
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Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus.

Nat Commun. 2016 09 07;7:12675

Authors: Lawrenson K, Kar S, McCue K, Kuchenbaeker K, Michailidou K, Tyrer J, Beesley J, Ramus SJ, Li Q, Delgado MK, Lee JM, Aittomäki K, Andrulis IL, Anton-Culver H, Arndt V, Arun BK, Arver B, Bandera EV, Barile M, Barkardottir RB, Barrowdale D, Beckmann MW, Benitez J, Berchuck A, Bisogna M, Bjorge L, Blomqvist C, Blot W, Bogdanova N, Bojesen A, Bojesen SE, Bolla MK, Bonanni B, Børresen-Dale AL, Brauch H, Brennan P, Brenner H, Bruinsma F, Brunet J, Buhari SA, Burwinkel B, Butzow R, Buys SS, Cai Q, Caldes T, Campbell I, Canniotto R, Chang-Claude J, Chiquette J, Choi JY, Claes KB, GEMO Study Collaborators, Cook LS, Cox A, Cramer DW, Cross SS, Cybulski C, Czene K, Daly MB, Damiola F, Dansonka-Mieszkowska A, Darabi H, Dennis J, Devilee P, Diez O, Doherty JA, Domchek SM, Dorfling CM, Dörk T, Dumont M, Ehrencrona H, Ejlertsen B, Ellis S, EMBRACE, Engel C, Lee E, Evans DG, Fasching PA, Feliubadalo L, Figueroa J, Flesch-Janys D, Fletcher O, Flyger H, Foretova L, Fostira F, Foulkes WD, Fridley BL, Friedman E, Frost D, Gambino G, Ganz PA, Garber J, García-Closas M, Gentry-Maharaj A, Ghoussaini M, Giles GG, Glasspool R, Godwin AK, Goldberg MS, Goldgar DE, González-Neira A, Goode EL, Goodman MT, Greene MH, Gronwald J, Guénel P, Haiman CA, Hall P, Hallberg E, Hamann U, Hansen TV, Harrington PA, Hartman M, Hassan N, Healey S, Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON), Heitz F, Herzog J, Høgdall E, Høgdall CK, Hogervorst FB, Hollestelle A, Hopper JL, Hulick PJ, Huzarski T, Imyanitov EN, KConFab Investigators, Australian Ovarian Cancer Study Group, Isaacs C, Ito H, Jakubowska A, Janavicius R, Jensen A, John EM, Johnson N, Kabisch M, Kang D, Kapuscinski M, Karlan BY, Khan S, Kiemeney LA, Kjaer SK, Knight JA, Konstantopoulou I, Kosma VM, Kristensen V, Kupryjanczyk J, Kwong A, de la Hoya M, Laitman Y, Lambrechts D, Le N, De Leeneer K, Lester J, Levine DA, Li J, Lindblom A, Long J, Lophatananon A, Loud JT, Lu K, Lubinski J, Mannermaa A, Manoukian S, Le Marchand L, Margolin S, Marme F, Massuger LF, Matsuo K, Mazoyer S, McGuffog L, McLean C, McNeish I, Meindl A, Menon U, Mensenkamp AR, Milne RL, Montagna M, Moysich KB, Muir K, Mulligan AM, Nathanson KL, Ness RB, Neuhausen SL, Nevanlinna H, Nord S, Nussbaum RL, Odunsi K, Offit K, Olah E, Olopade OI, Olson JE, Olswold C, O'Malley D, Orlow I, Orr N, Osorio A, Park SK, Pearce CL, Pejovic T, Peterlongo P, Pfeiler G, Phelan CM, Poole EM, Pylkäs K, Radice P, Rantala J, Rashid MU, Rennert G, Rhenius V, Rhiem K, Risch HA, Rodriguez G, Rossing MA, Rudolph A, Salvesen HB, Sangrajrang S, Sawyer EJ, Schildkraut JM, Schmidt MK, Schmutzler RK, Sellers TA, Seynaeve C, Shah M, Shen CY, Shu XO, Sieh W, Singer CF, Sinilnikova OM, Slager S, Song H, Soucy P, Southey MC, Stenmark-Askmalm M, Stoppa-Lyonnet D, Sutter C, Swerdlow A, Tchatchou S, Teixeira MR, Teo SH, Terry KL, Terry MB, Thomassen M, Tibiletti MG, Tihomirova L, Tognazzo S, Toland AE, Tomlinson I, Torres D, Truong T, Tseng CC, Tung N, Tworoger SS, Vachon C, van den Ouweland AM, van Doorn HC, van Rensburg EJ, Van't Veer LJ, Vanderstichele A, Vergote I, Vijai J, Wang Q, Wang-Gohrke S, Weitzel JN, Wentzensen N, Whittemore AS, Wildiers H, Winqvist R, Wu AH, Yannoukakos D, Yoon SY, Yu JC, Zheng W, Zheng Y, Khanna KK, Simard J, Monteiro AN, French JD, Couch FJ, Freedman ML, Easton DF, Dunning AM, Pharoah PD, Edwards SL, Chenevix-Trench G, Antoniou AC, Gayther SA

Abstract
A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10(-20)), ER-negative BC (P=1.1 × 10(-13)), BRCA1-associated BC (P=7.7 × 10(-16)) and triple negative BC (P-diff=2 × 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10(-3)) and ABHD8 (P<2 × 10(-3)). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3'-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.

PMID: 27601076 [PubMed - indexed for MEDLINE]

MicroRNAs regulate key cell survival pathways and mediate chemosensitivity during progression of diffuse large B-cell lymphoma.

Ke, 29/08/2018 - 21:49
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MicroRNAs regulate key cell survival pathways and mediate chemosensitivity during progression of diffuse large B-cell lymphoma.

Blood Cancer J. 2017 Dec 15;7(12):654

Authors: Leivonen SK, Icay K, Jäntti K, Siren I, Liu C, Alkodsi A, Cervera A, Ludvigsen M, Hamilton-Dutoit SJ, d'Amore F, Karjalainen-Lindsberg ML, Delabie J, Holte H, Lehtonen R, Hautaniemi S, Leppä S

Abstract
Despite better therapeutic options and improved survival of diffuse large B-cell lymphoma (DLBCL), 30-40% of the patients experience relapse or have primary refractory disease with a dismal prognosis. To identify biological correlates for treatment resistance, we profiled microRNAs (miRNAs) of matched primary and relapsed DLBCL by next-generation sequencing. Altogether 492 miRNAs were expressed in the DLBCL samples. Thirteen miRNAs showed significant differential expression between primary and relapse specimen pairs. Integration of the differentially expressed miRNAs with matched mRNA expression profiles identified highly anti-correlated, putative targets, which were significantly enriched in cancer-associated pathways, including phosphatidylinositol (PI)), mitogen-activated protein kinase (MAPK), and B-cell receptor (BCR) signaling. Expression data suggested activation of these pathways during disease progression, and functional analyses validated that miR-370-3p, miR-381-3p, and miR-409-3p downregulate genes on the PI, MAPK, and BCR signaling pathways, and enhance chemosensitivity of DLBCL cells in vitro. High expression of selected target genes, that is, PIP5K1 and IMPA1, was found to be associated with poor survival in two independent cohorts of chemoimmunotherapy-treated patients (n = 92 and n = 233). Taken together, our results demonstrate that differentially expressed miRNAs contribute to disease progression by regulating key cell survival pathways and by mediating chemosensitivity, thus representing potential novel therapeutic targets.

PMID: 29242506 [PubMed - indexed for MEDLINE]

Neurokinin-1 receptor (NK1R) inhibition sensitizes APL cells to anti-tumor effect of arsenic trioxide via restriction of NF-κB axis: Shedding new light on resistance to Aprepitant.

Ma, 27/08/2018 - 21:47
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Neurokinin-1 receptor (NK1R) inhibition sensitizes APL cells to anti-tumor effect of arsenic trioxide via restriction of NF-κB axis: Shedding new light on resistance to Aprepitant.

Int J Biochem Cell Biol. 2018 Aug 23;:

Authors: Bashash D, Safaroghli-Azar A, Bayati S, Razani E, Pourbagheri-Sigaroodi A, Gharehbaghian A, Momeny M, Sanjadi M, Rezaie-Tavirani M, Ghaffari SH

Abstract
While a batch of efforts are fastened on synthesizing the novel targeted anti-cancer agents, recent investigations have achieved a breakthrough in identifying a favorable anti-tumor activity for some supportive drugs, which their safety have been confirmed thus far. The results of the present study highlighted the efficacy of Aprepitant, an oral antagonist of the neurokinin-1 receptor (NK1R), against both APL (NB4) and pre-B ALL (Nalm-6) cell lines; however, a differential sensitivity pattern was found in these cells. To the best of our knowledge, this is the first time that the molecular mechanisms of resistance to Aprepitant have been investigated and, herein, we proposed that the effectiveness of Aprepitant could be overshadowed, at least partially, through over-activated nuclear factor-κB in Nalm-6 pre-B ALL cells. In contrast to Nalm-6, the cytotoxic property of Aprepitant in NB4 was divulged at the lower concentrations. Of particular interest, we found that the cytotoxicity of the inhibitor became even more evident in the synergistic experiments, where an enhanced reduction in viability was noted after treatment of NB4 cells with ATO-plus-Aprepitant. The stimulatory effect of NK1R inhibition on ATO cytotoxicity is probably mediated through up-regulation of p73, which can subsequently engage p21 and NF-κB pathway via transcriptional suppression of c-Myc. Taken together, the present study suggests that inhibition of NK1R using Aprepitant, either alone or in combination with chemotherapeutic drugs, could be a novel therapeutic strategy for the treatment of acute leukemia, especially APL, that may be clinically accessible in the near future.

PMID: 30145367 [PubMed - as supplied by publisher]