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Correction: Supportive care during pediatric hematopoietic stem cell transplantation: beyond infectious diseases. A report from workshops on supportive care of the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow...

8 tuntia 25 min sitten
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Correction: Supportive care during pediatric hematopoietic stem cell transplantation: beyond infectious diseases. A report from workshops on supportive care of the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT).

Bone Marrow Transplant. 2020 Feb 20;:

Authors: Nava T, Ansari M, Dalle JH, de Heredia CD, Güngör T, Trigoso E, Falkenberg U, Bertaina A, Gibson B, Jarisch A, Balduzzi A, Boenig H, Krivan G, Vettenranta K, Matic T, Buechner J, Kalwak K, Lawitschka A, Yesilipek A, Lucchini G, Peters C, Turkiewicz D, Niinimäki R, Diesch T, Lehrnbecher T, Sedlacek P, Hutt D, Dalissier A, Wachowiak J, Yaniv I, Stein J, Yalçin K, Sisinni L, Deiana M, Ifversen M, Kuhlen M, Meisel R, Bakhtiar S, Cesaro S, Willasch A, Corbacioglu S, Bader P

Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.

PMID: 32080355 [PubMed - as supplied by publisher]

The burden of unintentional drowning: global, regional and national estimates of mortality from the Global Burden of Disease 2017 Study.

8 tuntia 25 min sitten
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The burden of unintentional drowning: global, regional and national estimates of mortality from the Global Burden of Disease 2017 Study.

Inj Prev. 2020 Feb 20;:

Authors: Franklin RC, Peden AE, Hamilton EB, Bisignano C, Castle CD, Dingels ZV, Hay SI, Liu Z, Mokdad AH, Roberts NLS, Sylte DO, Vos T, Abady GG, Abosetugn AE, Ahmed R, Alahdab F, Andrei CL, Antonio CAT, Arabloo J, Arba AAK, Badiye AD, Bakkannavar SM, Banach M, Banik PC, Banstola A, Barker-Collo SL, Barzegar A, Bayati M, Bhardwaj P, Bhaumik S, Bhutta ZA, Bijani A, Boloor A, Carvalho F, Chowdhury MAK, Chu DT, Colquhoun SM, Dagne H, Dagnew B, Dandona L, Dandona R, Daryani A, Dharmaratne SD, Dibaji Forooshani ZS, Do HT, Driscoll TR, Eagan AW, El-Khatib Z, Fernandes E, Filip I, Fischer F, Gebremichael B, Gupta G, Haagsma JA, Hassan S, Hendrie D, Hoang CL, Hole MK, Holla R, Hostiuc S, Househ M, Ilesanmi OS, Inbaraj LR, Irvani SSN, Islam MM, Ivers RQ, Jayatilleke AU, Joukar F, Kalhor R, Kanchan T, Kapoor N, Kasaeian A, Khan M, Khan EA, Khubchandani J, Krishan K, Kumar GA, Lauriola P, Lopez AD, Madadin M, Majdan M, Maled V, Manafi N, Manafi A, McKee M, Meles HG, Menezes RG, Meretoja TJ, Miller TR, Mithra P, Mohammadian-Hafshejani A, Mohammadpourhodki R, Mohebi F, Molokhia M, Mustafa G, Negoi I, Nguyen CT, Nguyen HLT, Olagunju AT, Olagunju TO, Padubidri JR, Pakshir K, Pathak A, Polinder S, Pribadi DRA, Rabiee N, Radfar A, Rana SM, Rickard J, Safari S, Salamati P, Samy AM, Sarker AR, Schwebel DC, Senthilkumaran S, Shaahmadi F, Shaikh MA, Shin JI, Singh PK, Soheili A, Stokes MA, Suleria HAR, Tarigan IU, Temsah MH, Tesfay BE, Valdez PR, Veisani Y, Ye P, Yonemoto N, Yu C, Yusefzadeh H, Zaman SB, Zhang ZJ, James SL

Abstract
BACKGROUND: Drowning is a leading cause of injury-related mortality globally. Unintentional drowning (International Classification of Diseases (ICD) 10 codes W65-74 and ICD9 E910) is one of the 30 mutually exclusive and collectively exhaustive causes of injury-related mortality in the Global Burden of Disease (GBD) study. This study's objective is to describe unintentional drowning using GBD estimates from 1990 to 2017.
METHODS: Unintentional drowning from GBD 2017 was estimated for cause-specific mortality and years of life lost (YLLs), age, sex, country, region, Socio-demographic Index (SDI) quintile, and trends from 1990 to 2017. GBD 2017 used standard GBD methods for estimating mortality from drowning.
RESULTS: Globally, unintentional drowning mortality decreased by 44.5% between 1990 and 2017, from 531 956 (uncertainty interval (UI): 484 107 to 572 854) to 295 210 (284 493 to 306 187) deaths. Global age-standardised mortality rates decreased 57.4%, from 9.3 (8.5 to 10.0) in 1990 to 4.0 (3.8 to 4.1) per 100 000 per annum in 2017. Unintentional drowning-associated mortality was generally higher in children, males and in low-SDI to middle-SDI countries. China, India, Pakistan and Bangladesh accounted for 51.2% of all drowning deaths in 2017. Oceania was the region with the highest rate of age-standardised YLLs in 2017, with 45 434 (40 850 to 50 539) YLLs per 100 000 across both sexes.
CONCLUSIONS: There has been a decline in global drowning rates. This study shows that the decline was not consistent across countries. The results reinforce the need for continued and improved policy, prevention and research efforts, with a focus on low- and middle-income countries.

PMID: 32079663 [PubMed - as supplied by publisher]

Novel Hemizygous IL2RG p.(Pro58Ser) Mutation Impairs IL-2 Receptor Complex Expression on Lymphocytes Causing X-Linked Combined Immunodeficiency.

To, 20/02/2020 - 16:08
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Novel Hemizygous IL2RG p.(Pro58Ser) Mutation Impairs IL-2 Receptor Complex Expression on Lymphocytes Causing X-Linked Combined Immunodeficiency.

J Clin Immunol. 2020 Feb 19;:

Authors: Tuovinen EA, Grönholm J, Öhman T, Pöysti S, Toivonen R, Kreutzman A, Heiskanen K, Trotta L, Toiviainen-Salo S, Routes JM, Verbsky J, Mustjoki S, Saarela J, Kere J, Varjosalo M, Hänninen A, Seppänen MRJ

Abstract
Hypomorphic IL2RG mutations may lead to milder phenotypes than X-SCID, named variably as atypical X-SCID or X-CID. We report an 11-year-old boy with a novel c. 172C>T;p.(Pro58Ser) mutation in IL2RG, presenting with atypical X-SCID phenotype. We also review the growing number of hypomorphic IL2RG mutations causing atypical X-SCID. We studied the patient's clinical phenotype, B, T, NK, and dendritic cell phenotypes, IL2RG and CD25 cell surface expression, and IL-2 target gene expression, STAT tyrosine phosphorylation, PBMC proliferation, and blast formation in response to IL-2 stimulation, as well as protein-protein interactions of the mutated IL2RG by BioID proximity labeling. The patient suffered from recurrent upper and lower respiratory tract infections, bronchiectasis, and reactive arthritis. His total lymphocyte counts have remained normal despite skewed T and B cells subpopulations, with very low numbers of plasmacytoid dendritic cells. Surface expression of IL2RG was reduced on his lymphocytes. This led to impaired STAT tyrosine phosphorylation in response to IL-2 and IL-21, reduced expression of IL-2 target genes in patient CD4+ T cells, and reduced cell proliferation in response to IL-2 stimulation. BioID proximity labeling showed aberrant interactions between mutated IL2RG and ER/Golgi proteins causing mislocalization of the mutated IL2RG to the ER/Golgi interface. In conclusion, IL2RG p.(Pro58Ser) causes X-CID. Failure of IL2RG plasma membrane targeting may lead to atypical X-SCID. We further identified another carrier of this mutation from newborn SCID screening, lost to closer scrutiny.

PMID: 32072341 [PubMed - as supplied by publisher]

Plasma proteomics of biomarkers for inflammation or cancer cannot predict relapse in chronic myeloid leukaemia patients stopping tyrosine kinase inhibitor therapy.

La, 15/02/2020 - 16:04
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Plasma proteomics of biomarkers for inflammation or cancer cannot predict relapse in chronic myeloid leukaemia patients stopping tyrosine kinase inhibitor therapy.

Leuk Res. 2020 Jan 23;90:106310

Authors: Söderlund S, Persson I, Ilander M, Guilhot J, Hjorth-Hansen H, Koskenvesa P, Richter J, Saussele S, Mustjoki S, Olsson-Strömberg U

Abstract
Several studies have now shown that chronic myeloid leukaemia (CML) patients in deep molecular remission may discontinue tyrosine kinase inhibitor (TKI) treatment with a treatment free remission (TFR) rate of approximately 40-60 %. Some factors influencing the possibility of TFR have been described but better tools are needed for individual prediction of long-term TFR. Herein, two multiplex panels were utilised to analyse a total of 162 different plasma proteins from 56 patients included in the TKI stopping trial EURO-SKI (Saussele et al., 2018). The purpose was to identify possible plasma protein markers for prediction of successful TKI discontinuation and to evaluate effects of TKI discontinuation on plasma protein profiles. No protein biomarkers sampled before TKI discontinuation could separate relapse cases from non-relapse cases but some plasma proteins differed between patients who relapsed and those who remained in TFR when followed over time after TKI cessation. In conclusion, the plasma protein markers in this study could not predict relapse after TKI discontinuation but may be of use to understand the mechanisms involved in maintenance of TFR.

PMID: 32058176 [PubMed - as supplied by publisher]

Diagnostics and treatment of diffuse intrinsic pontine glioma: where do we stand?

La, 15/02/2020 - 16:04
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Diagnostics and treatment of diffuse intrinsic pontine glioma: where do we stand?

J Neurooncol. 2019 Oct;145(1):177-184

Authors: El-Khouly FE, Veldhuijzen van Zanten SEM, Santa-Maria Lopez V, Hendrikse NH, Kaspers GJL, Loizos G, Sumerauer D, Nysom K, Pruunsild K, Pentikainen V, Thorarinsdottir HK, Rutkauskiene G, Calvagna V, Drogosiewicz M, Dragomir M, Deak L, Kitanovski L, von Bueren AO, Kebudi R, Slavc I, Jacobs S, Jadrijevic-Cvrlje F, Entz-Werle N, Grill J, Kattamis A, Hauser P, Pears J, Biassoni V, Massimino M, Lopez Aguilar E, Torsvik IK, Joao Gil-da-Costa M, Kumirova E, Cruz-Martinez O, Holm S, Bailey S, Hayden T, Thomale UW, Janssens GOR, Kramm CM, van Vuurden DG

Abstract
INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) is a rare clinically, neuro-radiologically, and molecularly defined malignancy of the brainstem with a median overall survival of approximately 11 months. Our aim is to evaluate the current tendency for its treatment in Europe in order to develop (inter)national consensus guidelines.
METHODS: Healthcare professionals specialized in DIPG were asked to fill in an online survey with questions regarding usual treatment strategies at diagnosis and at disease progression in their countries and/or their centers, respectively.
RESULTS: Seventy-four healthcare professionals responded to the survey, of which 87.8% were pediatric oncologists. Only 13.5% of the respondents biopsy all of their patients, 41.9% biopsy their patients infrequently. More than half of the respondents (54.1%) treated their patients with radiotherapy only at diagnosis, whereas 44.6% preferred radiotherapy combined with chemotherapy. When the disease progresses, treatment strategies became even more diverse, and the tendency for no treatment increased from 1.4% at diagnosis to 77.0% after second progression. 36.5% of the healthcare professionals treat children younger than 3 years differently than older children at diagnosis. This percentage decreased, when the disease progresses. Most of the participants (51.4%) included less than 25% of their patients in clinical trials.
CONCLUSION: This survey demonstrates a large heterogeneity of treatment regimens, especially at disease progression. We emphasize the need for international consensus guidelines for the treatment of DIPG, possible by more collaborative clinical trials.

PMID: 31522324 [PubMed - indexed for MEDLINE]

Effect of Linseed (Linum usitatissimum) Groats-Based Mixed Feed Supplements on Diet Nutrient Digestibility and Blood Parameters of Horses.

Pe, 14/02/2020 - 16:04
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Effect of Linseed (Linum usitatissimum) Groats-Based Mixed Feed Supplements on Diet Nutrient Digestibility and Blood Parameters of Horses.

Animals (Basel). 2020 Feb 10;10(2):

Authors: Saastamoinen M, Särkijärvi S

Abstract
Linseed (Linum usitatissimum) and its by-products are common supplements used in equine diets and are claimed to have beneficial health effects. In this study, the effect of linseed groat-based fibrous feed supplements on diet digestibility was studied. Also, possible detrimental health effects due to continuous feeding of supplemental feeds containing linseed were examined by evaluating blood parameters. The experimental design was arranged as two balanced 3 × 3 Latin Squares. The horses were individually fed at the maintenance energy level, the forage-to-concentrate ratio being 70:30, with three diets: (A) Control diet consisting of dried hay and whole oats; (B) Control diet + Feed 1; and (C) Control diet + Feed 2. Feed 1 contained 70% of linseed groats, 15% dried carrot, 10% dried garlic and 5% molasses. Feed 2 contained 65% linseed groats, 15% molassed sugar-beet pulp, 10% dried garlic, 5% dried carrot and 5% molasses. Digestibility data were obtained by using chromium mordanted straw as an indigestible external marker for the estimation of apparent digestibility. Blood samples were collected from the jugular vein at the end of each feeding period to evaluate the possible effects of the supplemented diets B and C on the health of the horses. Diets B and C had a higher digestibility of crude protein compared to the control diet A (p < 0.05). In addition, the digestibility of ether extract was higher in the supplemented diets than in the basal feeding (p < 0.01). There were no statistically significant differences or trends (p > 0.05) in the blood parameters between the treatments. It is concluded that linseed groat-based supplements (offering approximately 6.3%-6.7% linseed groats in the diet's dry matter (DM), or 0.8 g/kg BW/d), and feed containing soluble fibre sources (sugar-beet pulp, dehydrated carrot), improved the crude protein and fat digestibility of hay-oats diets of horses, and can be used, for example, in feeding strategies replacing grains in the horse rations in order to reduce the intake of starch without any adverse effects on the blood parameters and health of the horses.

PMID: 32050686 [PubMed]

The Effect of Auricular Acupressure on Sleep Disturbance Among Patients With Leukemia: A Feasibility Study.

To, 13/02/2020 - 16:04
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The Effect of Auricular Acupressure on Sleep Disturbance Among Patients With Leukemia: A Feasibility Study.

Holist Nurs Pract. 2020 Mar/Apr;34(2):103-112

Authors: Liu XR, Rana N, Wong NS, James C, Lu J, Xu X

Abstract
Auricular acupressure (AA) is widely used in East Asia and Europe to manage patients with sleep disturbance. This feasibility study was performed to demonstrate the potential of AA for sleep disturbance in patients with leukemia. Thirty-two patients with leukemia with poor sleep quality received AA 3 times a day for a total of 4 weeks. The Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep quality at baseline, at a 2-week intervention, and after a 4-week intervention. Compared with baseline scores, PSQI scores and the use of sleep medicine were significantly improved at week 2 and week 4 (P < .05). As a potential safety therapy, AA could be an alternative or complementary intervention to improve sleep quality for patients with leukemia with sleep disturbance.

PMID: 32049696 [PubMed - in process]

Mutation accumulation in cancer genes relates to nonoptimal outcome in chronic myeloid leukemia.

Ke, 12/02/2020 - 16:04
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Mutation accumulation in cancer genes relates to nonoptimal outcome in chronic myeloid leukemia.

Blood Adv. 2020 Feb 11;4(3):546-559

Authors: Adnan Awad S, Kankainen M, Ojala T, Koskenvesa P, Eldfors S, Ghimire B, Kumar A, Kytölä S, Kamel MM, Heckman CA, Porkka K, Mustjoki S

Abstract
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm accounting for ∼15% of all leukemia. Progress of the disease from an indolent chronic phase to the more aggressive accelerated phase or blast phase (BP) occurs in a minority of cases and is associated with an accumulation of somatic mutations. We performed genetic profiling of 85 samples and transcriptome profiling of 12 samples from 59 CML patients. We identified recurrent somatic mutations in ABL1 (37%), ASXL1 (26%), RUNX1 (16%), and BCOR (16%) in the BP and observed that mutation signatures in the BP resembled those of acute myeloid leukemia (AML). We found that mutation load differed between the indolent and aggressive phases and that nonoptimal responders had more nonsilent mutations than did optimal responders at the time of diagnosis, as well as in follow-up. Using RNA sequencing, we identified other than BCR-ABL1 cancer-associated hybrid genes in 6 of the 7 BP samples. Uncovered expression alterations were in turn associated with mechanisms and pathways that could be targeted in CML management and by which somatic alterations may emerge in CML. Last, we showed the value of genetic data in CML management in a personalized medicine setting.

PMID: 32045476 [PubMed - in process]

Common oral diseases, hyposalivation and survival post-HSCT, a longitudinal study.

Ke, 12/02/2020 - 16:04
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Common oral diseases, hyposalivation and survival post-HSCT, a longitudinal study.

Eur J Haematol. 2019 Oct;103(4):300-306

Authors: Uutela P, Passweg J, Halter J, Gerull S, Weiger R, Mauramo E, Waltimo T, Mauramo M

Abstract
OBJECTIVES: Haematopoietic stem cell transplantation (HSCT) recipients are at risk of side effects within the oral cavity. The purpose of this study was to examine progression of common oral diseases and hyposalivation and their associations with survival in allogeneic HSCT recipients.
METHODS: Two hundred and sixty nine adult HSCT recipients treated with HSCT between 2008 and 2016 were included in this study. The associations of caries, decayed, missing, filled teeth (DMFT) index, radiological attachment loss and stimulated salivary flow rate with 6-month survival and the progression of the oral disorders within 2 years were examined.
RESULTS: Forty HSCT recipients (14.8%) deceased within 6 months post-HSCT. Among the deceased recipients, hyposalivation and caries were more common pre-HSCT than in recipients who survived over 6 months (P < 0.05). HSCT recipients with hyposalivation pre-HSCT had higher risk of death (HR: 1.90, 95% CI:1.00-3.60; P = 0.044) within 6 months post-HSCT compared with recipients without hyposalivation. Hyposalivation pre-HSCT was associated with a higher DMFT index score (P < 0.05) and a smaller number of teeth (P < 0.005) 24 months post-HSCT in comparison with those without hyposalivation.
CONCLUSIONS: Hyposalivation and caries were associated with a lower rate of survival in HSCT recipients. Additionally, hyposalivation predisposed to deterioration of oral health post-HSCT.

PMID: 31240771 [PubMed - indexed for MEDLINE]

Hospital admission for neurologic disorders among 5-year survivors of noncentral nervous system tumors in childhood: A cohort study within the Adult Life after Childhood Cancer in Scandinavia study.

Ke, 12/02/2020 - 16:04
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Hospital admission for neurologic disorders among 5-year survivors of noncentral nervous system tumors in childhood: A cohort study within the Adult Life after Childhood Cancer in Scandinavia study.

Int J Cancer. 2020 02 01;146(3):819-828

Authors: Kenborg L, Linnet KM, de Fine Licht S, Bautz A, Holmqvist AS, Tryggvadottir L, Madanat-Harjuoja LM, Stovall M, Heilmann C, Albieri V, Hasle H, Winther JF, ALiCCS study group

Abstract
Large, comprehensive studies of the risk for neurologic disorders among long-term survivors of noncentral nervous system (CNS) childhood cancers are lacking. Thus, the aim of our study was to assess the lifetime risk of Nordic non-CNS childhood cancer survivors for neurologic disorders. We identified 15,967 5-year survivors of non-CNS childhood cancer diagnosed in Denmark, Iceland, Finland and Sweden in 1943-2008, and 151,118 matched population comparison subjects. In-patient discharge diagnoses of neurologic disorders were used to calculate relative risks (RRs) and absolute excess risks (AERs). A neurologic disorder was diagnosed in 755 of the survivors while 370 were expected, yielding a RR of 2.0 (95% confidence interval (CI) 1.9-2.2). The highest risks were found among survivors of neuroblastoma (4.1; 95% CI 3.2-5.3) and leukemia (2.8; 95% CI 2.4-3.2). The AER decreased from 331 (278-383) excess neurologic disorders per 100,000 person-years 5-9 years after diagnosis to 82 (46-118) ≥ 20 years after diagnosis. Epilepsy was the most common diagnosis (n = 229, 1.4% of all survivors), and significantly increased risks were seen among survivors of eight out of 12 types of childhood cancer. Survivors of neuroblastoma had remarkably high risks (RR ≥ 10) for hospitalization for paralytic syndromes and hydrocephalus, while survivors of leukemia had additional high risks for dementia and encephalopathy. In conclusion, survivors of non-CNS childhood cancer are at high risk for neurologic disorders, especially within the first decade after diagnosis. Therefore, intensive follow-up to identify those who require close management is needed.

PMID: 30980681 [PubMed - indexed for MEDLINE]

Temporal and geographical variations in colorectal cancer incidence in Northern Iran 2004-2013.

Ke, 12/02/2020 - 16:04
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Temporal and geographical variations in colorectal cancer incidence in Northern Iran 2004-2013.

Cancer Epidemiol. 2019 04;59:143-147

Authors: Hasanpour-Heidari S, Fazel A, Semnani S, Khandoozi SR, Amiriani T, Sedaghat S, Hosseinpoor R, Azarhoush R, Poorabbasi M, Naeimi-Tabiei M, Roshandel G, Bray F, Weiderpass E

Abstract
INTRODUCTION: Colorectal cancer (CRC) is one of the most common cancers in the Golestan province, Northern Iran. The purpose of this study is to describe colorectal cancer incidence patterns and trends in the province 2004-2013.
METHODS: Data on CRC cases were obtained from the Golestan Population-based Cancer Registry (GPCR). The GPCR is a high-quality cancer registry that collects data on primary cancers according to internationally accepted standard protocols. Age-standardized Incidence rates (ASR) were calculated and the 10-year trend quantified using the average annual percentage change (AAPC) from Joinpoint regressions.
RESULTS: The overall ASR of CRC were higher in men (14.8 per 100,000 person-years) and the urban populations (35.4), relative to women (11.5) and the rural populations (17.1), respectively. The overall incidence rate was observed to significantly increase 2004-2013 in men (AAPC = 7.3; 95%CI: 2.9-11.8) and women (AAPC = 6.6; 95%CI: 2.7-10.6). The analysis also showed that urban areas (AAPC = 8.1; 95%CI: 2.4-14.1) had a relatively more rapid increase in rates compared to rural areas (AAPC = 6.9; 95%CI: 2.2-11.7).
CONCLUSIONS: CRC incidence rates in Golestan have been rising during the most recent decade, with a higher incidence and more rapid increases among men and the urban populations. The underlying risk factors should be assessed in the context of developing CRC prevention interventions in Golestan.

PMID: 30771699 [PubMed - indexed for MEDLINE]

Age-associated changes in the immune system may influence the response to anti-PD1 therapy in metastatic melanoma patients.

Ma, 10/02/2020 - 16:03
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Age-associated changes in the immune system may influence the response to anti-PD1 therapy in metastatic melanoma patients.

Cancer Immunol Immunother. 2020 Feb 08;:

Authors: Kasanen H, Hernberg M, Mäkelä S, Brück O, Juteau S, Kohtamäki L, Ilander M, Mustjoki S, Kreutzman A

Abstract
Anti-PD1 treatment has improved the survival of metastatic melanoma patients, yet it is unknown which patients benefit from the treatment. In this exploratory study, we aimed to understand the effects of anti-PD1 therapy on the patients' immune system and discover the characteristics that would result in successful treatment. We collected peripheral blood (PB) samples from 17 immuno-oncology-naïve metastatic melanoma patients before and after 1 and 3 months of anti-PD1 therapy. In addition, matching tumor biopsies at the time of diagnosis were collected for tissue microarray. The complete blood counts, PB immunophenotype, serum cytokine profiles, and tumor-infiltrating lymphocytes were analyzed and correlated with the clinical data. Patients were categorized based on their disease control into responders (complete response, partial response, stable disease > 6 months, N = 11) and non-responders (progressive disease, stable disease ≤ 6 months, N = 6). During therapy, the PB natural killer T (NKT) cell frequency, expression of CD25 and CD45RO on cytotoxic natural killer (NK) cells, and serum CXC chemokine levels were significantly increased in responders. Furthermore, higher age together with age-associated characteristics from PB, lower frequency of PB-naïve CD8+ T cells, and elevated levels of serum MCP-4 and OPG were discovered as baseline predictors of treatment response. We therefore propose that in addition to T cells, anti-PD1 treatment is associated with NK- and NKT-cell population dynamics, and that the age-associated characteristics from PB together with older age may contribute to prolonged PFS in anti-PD1-treated melanoma patients.

PMID: 32036449 [PubMed - as supplied by publisher]

Supportive care during pediatric hematopoietic stem cell transplantation: beyond infectious diseases. A report from workshops on supportive care of the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation...

La, 08/02/2020 - 16:02
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Supportive care during pediatric hematopoietic stem cell transplantation: beyond infectious diseases. A report from workshops on supportive care of the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT).

Bone Marrow Transplant. 2020 Feb 06;:

Authors: Nava T, Ansari M, Dalle JH, de Heredia CD, Güngör T, Trigoso E, Falkenberg U, Bertaina A, Gibson B, Jarisch A, Balduzzi A, Boenig H, Krivan G, Vettenranta K, Matic T, Büchner J, Kalwak K, Lawitschka A, Yesilipek A, Lucchini G, Peters C, Turkiewicz D, Niinimäki R, Diesch T, Lehrnbecher T, Sedlacek P, Hutt D, Dalissier A, Wachowiak J, Yaniv I, Stein J, Yalçin K, Sisinni L, Deiana M, Ifversen M, Kuhlen M, Miesel R, Bakhtiar S, Cesaro S, Willasch A, Corbacioglu S, Bader P

Abstract
Hematopoietic stem cell transplantation (HSCT) is currently the standard of care for many malignant and nonmalignant blood diseases. As several treatment-emerging acute toxicities are expected, optimal supportive measurements critically affect HSCT outcomes. The paucity of good clinical studies in supportive practices gives rise to the establishment of heterogeneous guidelines across the different centers, which hampers direct clinical comparison in multicentric studies. Aiming to harmonize the supportive care provided during the pediatric HSCT in Europe, the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) promoted dedicated workshops during the years 2017 and 2018. The present paper describes the resulting consensus on the management of sinusoidal obstructive syndrome, mucositis, enteral and parenteral nutrition, iron overload, and emesis during HSCT.

PMID: 32029909 [PubMed - as supplied by publisher]

Clinicopathological features and prognostic value of SOX11 in childhood acute lymphoblastic leukemia.

La, 08/02/2020 - 16:02
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Clinicopathological features and prognostic value of SOX11 in childhood acute lymphoblastic leukemia.

Sci Rep. 2020 Feb 06;10(1):2043

Authors: Grönroos T, Mäkinen A, Laukkanen S, Mehtonen J, Nikkilä A, Oksa L, Rounioja S, Marincevic-Zuniga Y, Nordlund J, Pohjolainen V, Paavonen T, Heinäniemi M, Lohi O

Abstract
Acute lymphoblastic leukemia is marked by aberrant transcriptional features that alter cell differentiation, self-renewal, and proliferative features. We sought to identify the transcription factors exhibiting altered and subtype-specific expression patterns in B-ALL and report here that SOX11, a developmental and neuronal transcription factor, is aberrantly expressed in the ETV6-RUNX1 and TCF3-PBX1 subtypes of acute B-cell leukemias. We show that a high expression of SOX11 leads to alterations of gene expression that are typically associated with cell adhesion, migration, and differentiation. A high expression is associated with DNA hypomethylation at the SOX11 locus and a favorable outcome. The results indicate that SOX11 expression marks a group of patients with good outcomes and thereby prompts further study of its use as a biomarker.

PMID: 32029838 [PubMed - in process]

Heparan sulfates are critical regulators of the inhibitory megakaryocyte-platelet receptor G6b-B.

La, 08/02/2020 - 16:02
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Heparan sulfates are critical regulators of the inhibitory megakaryocyte-platelet receptor G6b-B.

Elife. 2019 08 22;8:

Authors: Vögtle T, Sharma S, Mori J, Nagy Z, Semeniak D, Scandola C, Geer MJ, Smith CW, Lane J, Pollack S, Lassila R, Jouppila A, Barr AJ, Ogg DJ, Howard TD, McMiken HJ, Warwicker J, Geh C, Rowlinson R, Abbott WM, Eckly A, Schulze H, Wright GJ, Mazharian A, Fütterer K, Rajesh S, Douglas MR, Senis YA

Abstract
The immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptor G6b-B is critical for platelet production and activation. Loss of G6b-B results in severe macrothrombocytopenia, myelofibrosis and aberrant platelet function in mice and humans. Using a combination of immunohistochemistry, affinity chromatography and proteomics, we identified the extracellular matrix heparan sulfate (HS) proteoglycan perlecan as a G6b-B binding partner. Subsequent in vitro biochemical studies and a cell-based genetic screen demonstrated that the interaction is specifically mediated by the HS chains of perlecan. Biophysical analysis revealed that heparin forms a high-affinity complex with G6b-B and mediates dimerization. Using platelets from humans and genetically modified mice, we demonstrate that binding of G6b-B to HS and multivalent heparin inhibits platelet and megakaryocyte function by inducing downstream signaling via the tyrosine phosphatases Shp1 and Shp2. Our findings provide novel insights into how G6b-B is regulated and contribute to our understanding of the interaction of megakaryocytes and platelets with glycans.

PMID: 31436532 [PubMed - indexed for MEDLINE]

Hemap: An Interactive Online Resource for Characterizing Molecular Phenotypes across Hematologic Malignancies.

La, 08/02/2020 - 16:02
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Hemap: An Interactive Online Resource for Characterizing Molecular Phenotypes across Hematologic Malignancies.

Cancer Res. 2019 05 15;79(10):2466-2479

Authors: Pölönen P, Mehtonen J, Lin J, Liuksiala T, Häyrynen S, Teppo S, Mäkinen A, Kumar A, Malani D, Pohjolainen V, Porkka K, Heckman CA, May P, Hautamäki V, Granberg KJ, Lohi O, Nykter M, Heinäniemi M

Abstract
Large collections of genome-wide data can facilitate the characterization of disease states and subtypes, permitting pan-cancer analysis of molecular phenotypes and evaluation of disease context for new therapeutic approaches. We analyzed 9,544 transcriptomes from more than 30 hematologic malignancies, normal blood cell types, and cell lines, and showed that disease types could be stratified in a data-driven manner. We then identified cluster-specific pathway activity, new biomarkers, and in silico drug target prioritization through interrogation of drug target databases. Using known vulnerabilities and available drug screens, we highlighted the importance of integrating molecular phenotype with drug target expression for in silico prediction of drug responsiveness. Our analysis implicated BCL2 expression level as an important indicator of venetoclax responsiveness and provided a rationale for its targeting in specific leukemia subtypes and multiple myeloma, linked several polycomb group proteins that could be targeted by small molecules (SFMBT1, CBX7, and EZH1) with chronic lymphocytic leukemia, and supported CDK6 as a disease-specific target in acute myeloid leukemia. Through integration with proteomics data, we characterized target protein expression for pre-B leukemia immunotherapy candidates, including DPEP1. These molecular data can be explored using our publicly available interactive resource, Hemap, for expediting therapeutic innovations in hematologic malignancies. SIGNIFICANCE: This study describes a data resource for researching derailed cellular pathways and candidate drug targets across hematologic malignancies.

PMID: 30940663 [PubMed - indexed for MEDLINE]

Unfavorable Reduction in the Ratio of Endothelin B to A Receptors in Experimental 5/6 Nephrectomy and Adenine Models of Chronic Renal Insufficiency.

Pe, 07/02/2020 - 16:02
Related Articles

Unfavorable Reduction in the Ratio of Endothelin B to A Receptors in Experimental 5/6 Nephrectomy and Adenine Models of Chronic Renal Insufficiency.

Int J Mol Sci. 2020 Jan 31;21(3):

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

Abstract
Chronic renal insufficiency (CRI) is characterized by increased endothelin 1 (ET-1) synthesis. We studied rat kidney endothelin receptor A (ETA) and receptor B (ETB) expressions after 12 and 27 weeks of 5/6 nephrectomy, and after 12 weeks of 0.3% adenine diet, representing proteinuric and interstitial inflammation models of CRI, respectively. Uric acid and calcium-phosphate metabolism were modulated after 5/6 nephrectomy, while ETA blocker and calcimimetic were given with adenine. Endothelin receptor mRNA levels were measured using RT-qPCR and protein levels using autoradiography (5/6 nephrectomy) or ELISA (adenine model). Both 12 and 27 weeks after 5/6 nephrectomy, kidney cortex ETA protein was increased by ~60% without changes in ETB protein, and the ETB:ETA ratio was reduced. However, the ETB:ETA mRNA ratio did not change. In the adenine model, kidney ETA protein was reduced by ~70%, while ETB protein was suppressed by ~95%, and the ETB:ETA ratio was reduced by ~85%, both at the protein and mRNA levels. The additional interventions did not influence the observed reductions in the ETB:ETA ratio. To conclude, unfavorable reduction in the ETB:ETA protein ratio was observed in two different models of CRI. Therefore, ETA blockade may be beneficial in a range of diseases that cause impaired kidney function.

PMID: 32023824 [PubMed - in process]

Allogeneic stem cell transplantation in AML with t(6;9)(p23;q34);DEK-NUP214 shows a favourable outcome when performed in first complete remission.

To, 06/02/2020 - 16:01
Related Articles

Allogeneic stem cell transplantation in AML with t(6;9)(p23;q34);DEK-NUP214 shows a favourable outcome when performed in first complete remission.

Br J Haematol. 2020 Feb 05;:

Authors: Díaz-Beyá M, Labopin M, Maertens J, Alijurf M, Passweg J, Dietrich B, Schouten H, Socié G, Schaap N, Schwerdtfeger R, Volin L, Michallet M, Polge E, Sierra J, Mohty M, Esteve J, Nagler A, Acute Leukaemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT)

Abstract
Acute myeloid leukaemia (AML) with t(6;9)(p23;q34) is a poor-risk entity, commonly associated with FLT3-ITD (internal tandem duplication). Allogeneic stem-cell tranplantation (allo-SCT) is recommended, although studies analysing the outcome of allo-SCT in this setting are lacking. We selected 195 patients with t(6;9) AML, who received a first allo-SCT between 2000 and 2016 from the EBMT (European Society for Blood and Marrow Transplantation) registry. Disease status at time of allo-SCT was the strongest independent prognostic factor, with a two-year leukaemia-free survival and relapse incidence of 57% and 19% in patients in CR1 (first complete remission), 34% and 33% in CR2 (second complete remission), and 24% and 49% in patients not in remission, respectively (P < 0·001). This study, which represents the largest one available in t(6;9) AML, supports the recommendation to submit these patients to allo-SCT in CR1.

PMID: 32020596 [PubMed - as supplied by publisher]

Prognostic implications of the microenvironment for follicular lymphoma under immunomodulation therapy.

To, 06/02/2020 - 04:01
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Prognostic implications of the microenvironment for follicular lymphoma under immunomodulation therapy.

Br J Haematol. 2020 Feb 03;:

Authors: Menter T, Tzankov A, Zucca E, Kimby E, Hultdin M, Sundström C, Beiske K, Cogliatti S, Banz Y, Cathomas G, Karjalainen-Lindsberg ML, Grobholz R, Mazzucchelli L, Sander B, Hawle H, Hayoz S, Dirnhofer S

Abstract
Follicular lymphoma (FL) constitutes a significant proportion of lymphomas and shows frequent relapses. Beyond conventional chemotherapy, new therapeutic approaches have emerged, focussing on the interplay between lymphoma cells and the microenvironment. Here we report the immunophenotypic investigation of the microenvironment of a clinically well-characterized prospective cohort (study SAKK35/10, NCT00544219) of 154 treatment-naïve FL patients in need of therapy, who have been treated with rituximab only or a combination of rituximab and the immunomodulatory drug lenalidomide/Revlimid® A high ratio of CD4- to CD8-positive T cells (P = 0·009) and increased amounts of PD1+ tumour-infiltrating T cells (P = 0·007) were associated with inferior progression-free survival in the whole cohort. Interestingly, the prognostic impact of PD1+ T cells and the CD4/CD8 ratio lost its significance in the subgroup treated with R2 . In the latter group, high amounts of GATA3+ T helper (Th2) equivalents were associated with better progression-free survival (P < 0·001). We identified tumour microenvironmental features that allow prognostic stratification with respect to immuno- and combined immuno- and immunomodulatory therapy. Our analysis indicates that lenalidomide may compensate the adverse prognostic implication of higher amounts of CD4+ and, particularly, PD1+ T cells and that it has favourable effects mainly in cases with higher amounts of Th2 equivalents.

PMID: 32012230 [PubMed - as supplied by publisher]

The CAFA challenge reports improved protein function prediction and new functional annotations for hundreds of genes through experimental screens.

To, 06/02/2020 - 04:01
Related Articles

The CAFA challenge reports improved protein function prediction and new functional annotations for hundreds of genes through experimental screens.

Genome Biol. 2019 11 19;20(1):244

Authors: Zhou N, Jiang Y, Bergquist TR, Lee AJ, Kacsoh BZ, Crocker AW, Lewis KA, Georghiou G, Nguyen HN, Hamid MN, Davis L, Dogan T, Atalay V, Rifaioglu AS, Dalkıran A, Cetin Atalay R, Zhang C, Hurto RL, Freddolino PL, Zhang Y, Bhat P, Supek F, Fernández JM, Gemovic B, Perovic VR, Davidović RS, Sumonja N, Veljkovic N, Asgari E, Mofrad MRK, Profiti G, Savojardo C, Martelli PL, Casadio R, Boecker F, Schoof H, Kahanda I, Thurlby N, McHardy AC, Renaux A, Saidi R, Gough J, Freitas AA, Antczak M, Fabris F, Wass MN, Hou J, Cheng J, Wang Z, Romero AE, Paccanaro A, Yang H, Goldberg T, Zhao C, Holm L, Törönen P, Medlar AJ, Zosa E, Borukhov I, Novikov I, Wilkins A, Lichtarge O, Chi PH, Tseng WC, Linial M, Rose PW, Dessimoz C, Vidulin V, Dzeroski S, Sillitoe I, Das S, Lees JG, Jones DT, Wan C, Cozzetto D, Fa R, Torres M, Warwick Vesztrocy A, Rodriguez JM, Tress ML, Frasca M, Notaro M, Grossi G, Petrini A, Re M, Valentini G, Mesiti M, Roche DB, Reeb J, Ritchie DW, Aridhi S, Alborzi SZ, Devignes MD, Koo DCE, Bonneau R, Gligorijević V, Barot M, Fang H, Toppo S, Lavezzo E, Falda M, Berselli M, Tosatto SCE, Carraro M, Piovesan D, Ur Rehman H, Mao Q, Zhang S, Vucetic S, Black GS, Jo D, Suh E, Dayton JB, Larsen DJ, Omdahl AR, McGuffin LJ, Brackenridge DA, Babbitt PC, Yunes JM, Fontana P, Zhang F, Zhu S, You R, Zhang Z, Dai S, Yao S, Tian W, Cao R, Chandler C, Amezola M, Johnson D, Chang JM, Liao WH, Liu YW, Pascarelli S, Frank Y, Hoehndorf R, Kulmanov M, Boudellioua I, Politano G, Di Carlo S, Benso A, Hakala K, Ginter F, Mehryary F, Kaewphan S, Björne J, Moen H, Tolvanen MEE, Salakoski T, Kihara D, Jain A, Šmuc T, Altenhoff A, Ben-Hur A, Rost B, Brenner SE, Orengo CA, Jeffery CJ, Bosco G, Hogan DA, Martin MJ, O'Donovan C, Mooney SD, Greene CS, Radivojac P, Friedberg I

Abstract
BACKGROUND: The Critical Assessment of Functional Annotation (CAFA) is an ongoing, global, community-driven effort to evaluate and improve the computational annotation of protein function.
RESULTS: Here, we report on the results of the third CAFA challenge, CAFA3, that featured an expanded analysis over the previous CAFA rounds, both in terms of volume of data analyzed and the types of analysis performed. In a novel and major new development, computational predictions and assessment goals drove some of the experimental assays, resulting in new functional annotations for more than 1000 genes. Specifically, we performed experimental whole-genome mutation screening in Candida albicans and Pseudomonas aureginosa genomes, which provided us with genome-wide experimental data for genes associated with biofilm formation and motility. We further performed targeted assays on selected genes in Drosophila melanogaster, which we suspected of being involved in long-term memory.
CONCLUSION: We conclude that while predictions of the molecular function and biological process annotations have slightly improved over time, those of the cellular component have not. Term-centric prediction of experimental annotations remains equally challenging; although the performance of the top methods is significantly better than the expectations set by baseline methods in C. albicans and D. melanogaster, it leaves considerable room and need for improvement. Finally, we report that the CAFA community now involves a broad range of participants with expertise in bioinformatics, biological experimentation, biocuration, and bio-ontologies, working together to improve functional annotation, computational function prediction, and our ability to manage big data in the era of large experimental screens.

PMID: 31744546 [PubMed - indexed for MEDLINE]