tbuckley/cabot-search huggingface dataset:
Genetic and T2 biomarkers linked to the efficacy of HDM sublingual immunotherapy in asthma
Authors: Ilka Hoof, Klaus Bønnelykke, Thomas Stranzl, Stephanie Brand, Xingnan Li, Mohamed H Shamji, Deborah A Meyers, Eric D Bateman, Eugene Bleecker, Peter Sejer Andersen
Journal: Thorax (2023)

Background Hypersensitivity to house dust mite (HDM) allergens is a common cause of allergic asthma symptoms and can be effectively treated with allergy immunotherapy (AIT). Objective To investigate whether genetic and type 2 (T2) inflammatory biomarkers correlate with disease severity in subjects with allergic asthma, and whether this can be modified by AIT. Methods MITRA ( NCT01433523 ) was a phase III, randomised, double-blind, placebo-controlled trial of HDM sublingual immunotherapy (SLIT)-tablets in adults with HDM allergic asthma. Post hoc analyses of the study population (N=742) evaluated associations between T2 inflammatory (blood eosinophils, eosinophil cationic protein (ECP), total IgE and tryptase) and genetic (single-nucleotide polymorphisms, SNP) biomarkers (n=582) for the primary study endpoint (time to first moderate/severe asthma exacerbation). SNP associations were verified in HDM-positive subgroup from an independent 3-year Severe Asthma Research Programme (SARP3) subject cohort. Results An increased asthma exacerbation risk in subjects homozygous for SNP rs7216389 (chromosomal locus 17q12-21) was reduced (p = 0.037) by treatment with HDM SLIT (HR=0.37 (95% CI 0.22 to 0.64), p&lt;0.001). The associations between exacerbation risk and 17q12-21 SNPs were replicated in the SARP3 HDM-positive subgroup. High levels of T2 biomarkers were associated with increased risk of asthma exacerbations in the placebo group. HDM SLIT-tablet treatment reduced this risk (blood eosinophils: HR=0.50 (95% CI 0.30 to 0.85); ECP: HR=0.45 (95% CI 0.29 to 0.87); tryptase: HR=0.45 (95% CI 0.25 to 0.80)). The treatment effect was higher (p = 0.006) for subjects with a higher number of elevated T2 biomarkers. Conclusions HDM SLIT-tablet AIT is efficacious in HDM-sensitised asthma subjects with a genetic asthma predisposition and/or an underlying T2 endotype. Trial registration number NCT01433523 .
Human peri‐gastruloids: a significant advancement in embryology research
Authors: Qin Yang, Ezra Burstein, Da Jia
Journal: MedComm (2023)

The peri-gastruloids comprise both embryonic (epiblast) and extraembryonic (hypoblast) tissues, faithfully mirroring crucial developmental events spanning from the immediate post-implantation phase to early organogenesis, encompassing the emergence of amniotic and yolk sac cavities, as well as the progression from bilaminar to trilaminar embryonic discs.
Integrated proteomics spotlight the proteasome as a therapeutic vulnerability in embryonal tumors with multilayered rosettes
Authors: Matthias Dottermusch, Ali Biabani, Tasja Lempertz, Yannis Schumann, Jelena Navolic, Shweta Godbole, Denise Obrecht, Stephan Frank, Mario M Dorostkar, Hannah Voß, Hartmut Schlüter, Stefan Rutkowski, Ulrich Schüller, Julia E Neumann
Journal: Neuro-Oncology (2023)

Abstract Background Embryonal tumors with multilayered rosettes (ETMR) are rare malignant embryonal brain tumors. The prognosis of ETMR is poor and novel therapeutic approaches are desperately needed. Comprehension of ETMR tumor biology is currently based on only few previous molecular studies, which mainly focused on the analyses of nucleic acids. In this study, we explored integrated ETMR proteomics. Methods Using mass spectrometry, proteome data were acquired from 16 ETMR and the ETMR cell line BT183. Proteome data were integrated with case-matched global DNA methylation data, publicly available transcriptome data, and proteome data of further embryonal and pediatric brain tumors. Results Proteome-based cluster analyses grouped ETMR samples according to histomorphology, separating neuropil-rich tumors with neuronal signatures from primitive tumors with signatures relating to stemness and chromosome organization. Integrated proteomics showcased that ETMR and BT183 cells harbor proteasome regulatory proteins in abundance, implicating their strong dependency on the proteasome machinery to safeguard proteostasis. Indeed, in vitro assays using BT183 highlighted that ETMR tumor cells are highly vulnerable toward treatment with the CNS penetrant proteasome inhibitor Marizomib. Conclusions In summary, histomorphology stipulates the proteome signatures of ETMR, and proteasome regulatory proteins are pervasively abundant in these tumors. As validated in vitro, proteasome inhibition poses a promising therapeutic option in ETMR.
Transmission Bottleneck Size Estimation from De Novo Viral Genetic Variation
Authors: Yike Teresa Shi, Jeremy D Harris, Michael A Martin, Katia Koelle
Journal: Molecular Biology and Evolution (2023)

Abstract Sequencing of viral infections has become increasingly common over the last decade. Deep sequencing data in particular have proven useful in characterizing the roles that genetic drift and natural selection play in shaping within-host viral populations. They have also been used to estimate transmission bottleneck sizes from identified donor–recipient pairs. These bottleneck sizes quantify the number of viral particles that establish genetic lineages in the recipient host and are important to estimate due to their impact on viral evolution. Current approaches for estimating bottleneck sizes exclusively consider the subset of viral sites that are observed as polymorphic in the donor individual. However, these approaches have the potential to substantially underestimate true transmission bottleneck sizes. Here, we present a new statistical approach for instead estimating bottleneck sizes using patterns of viral genetic variation that arise de novo within a recipient individual. Specifically, our approach makes use of the number of clonal viral variants observed in a transmission pair, defined as the number of viral sites that are monomorphic in both the donor and the recipient but carry different alleles. We first test our approach on a simulated dataset and then apply it to both influenza A virus sequence data and SARS-CoV-2 sequence data from identified transmission pairs. Our results confirm the existence of extremely tight transmission bottlenecks for these 2 respiratory viruses.
Pangenomics: A new era in the field of neurodegenerative diseases
Authors: Paolo Abondio, Francesco Bruno, Giuseppe Passarino, Alberto Montesanto, Donata Luiselli
Journal: Ageing Research Reviews (2023)

A pangenome is composed of all the genetic variability of a group of individuals, and its application to the study of neurodegenerative diseases may provide valuable insights into the underlying aspects of genetic heterogenetiy for these complex ailments, including gene expression, epigenetics, and translation mechanisms. Furthermore, a reference pangenome allows for the identification of previously undetected structural commonalities and differences among individuals, which may help in the diagnosis of a disease, support the prediction of what will happen over time (prognosis) and aid in developing novel treatments in the perspective of personalized medicine. Therefore, in the present review, the application of the pangenome concept to the study of neurodegenerative diseases will be discussed and analyzed for its potential to enable an improvement in diagnosis and prognosis for these illnesses, leading to the development of tailored treatments for individual patients from the knowledge of the genomic composition of a whole population.
PF497 INFLAMMATION‐DRIVEN HEME/IRON CYTOTOXICITY IN PARKINSON'S DISEASE
Authors: I. Lima, A.C. Pêgo, A.C. Martins, I. Sá Pereira, G. Martins, A. Kapitão, R. Gozzelino
Journal: HemaSphere (2019)

Background: Heme is a metallo‐compound, essential for the survival of most organisms. However, the ability of the central iron (Fe) atom, contained within its protoporphyrin ring, to participate in the Fenton reaction and generate highly reactive hydroxyl radicals renders heme potentially toxic. Under inflammatory conditions, the release of heme from hemoproteins leads to an exacerbated oxidative stress, a deleterious effect associated with tissue damage and disease severity. Aims: As immune‐mediated inflammatory diseases often cause a certain degree of hemolysis and vascular leakage, it is reasonable to assume that the cytotoxicity of heme/Fe may also affect less accessible organs, such as the brain, thus increasing the risk and severity of neurodegenerative diseases. Methods: This hypothesis has been investigated in mice, in which the exogenous administration of heme or the release of this molecule upon inflammation/infectionwas shown to enhance the severity of Parkinson's disease (PD). An increased susceptibility to pharmacologic PD was observed when mice are exposed to heme and subsequently treated with 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP), a neurotoxin precursor that, once converted into the active metabolite, irreversibly damages the dopaminergic neurons (DNs). Results: Our results demonstrate that from circulation, heme is capable to enter the brain and trigger neuroinflammation. While this is associated with the recruitment of immune cells, which breach the BBB and enter the brain, an increased level of circulating heme was shown to contribute to the occurrence of brain Fe overload, causing an exacerbated locomotor dysfunction in response to PD induction. Summary/Conclusion: Therefore, our findings suggest that the release of heme in circulation upon immune‐mediated inflammatory diseases is capable to prime the brain and contribute to the development of neurodegenerative diseases, such as PD.
PF484 MARKERS ASSOCIATED WITH SHORT SURVIVAL IN PATIENTS WITH WALDENSTRÖM MACROGLOBULINEMIA
Authors: G. Ruan, J. Abeykoon, S. Zanwar, M. Gertz, S. Ansell, C. Reeder, S. Ailawadhi, A. Dispenzieri, D. Dingli, M. Lacy, R. Go, N. Leung, F. Buadi, W. Gonsalves, R. Kyle, V. Rajkumar, S. Kumar, P. Kapoor
Journal: HemaSphere (2019)

Background: Waldenström Macroglobulinemia (WM) is a rare, indolent B‐cell lymphoplasmacytic malignancy. Patient outcomes are highly heterogeneous, with a proportion of patients surviving less than 5 years (short survivors) and another proportion that survive longer than 10 years. The laboratory parameters in the currently used International Prognostic Scoring System for WM (IPSSWM) include hemoglobin, serum IgM, platelet count, and serum β2‐microglobulin. Aims: We aim to identify unique patient characteristics and prognostic features associated with short survival in WM. Methods: The medical records of patients with active WM that were diagnosed at Mayo Clinic Rochester, Arizona, and Florida between January 1 st , 1996 and December 31 st , 2013 were reviewed. The patients with smoldering WM were excluded. Cohorts of patients who either survived ≤ 5 years (Short Survival Group) or those with an overall survival (OS) ≥ 10 years (Long Survival Group) from the diagnosis of active disease were compared. Survivors with a follow‐up of ≤ 5 years were not included in the analyses. Two‐sided Wilcoxon rank sum test and Chi square/Fisher's exact test were used to compare the continuous and categorical variables, respectively. The variables that were statistically significant on univariate analysis ( P &lt; 0.05) were included in a multivariate logisitic regression analysis. Results: Of 893 consecutively seen WM patients (median follow‐up of 9 years [95% CI 8.4–9.7]), we identified 387 patients who could be categorized into either the Short Survival Group (n = 171 patients, 44%) or the Long Survival Group (n = 216, 56%). The Short Survival Group had a median OS of 2.4 years (2.1–2.8) and median age at diagnosis of 73 years (42–93), while the Long Survival Group (n = 216, 56%) had a median OS of 18.9 years (16‐NR) and median age at diagnosis of 62 years (31–85). The baseline characteristics and significant findings between the two groups are listed in the Table. Parameters significant on univariate analysis included age &gt;65 years, albumin &lt; 3.5 g/dL, β2‐microglobulin &gt;3 μg/ml, and LDH &gt; upper limit of normal (ULN). On multivariate analysis, albumin &lt;3.5 g/dL and LDH &gt; ULN were independently associated with short survival. Among the Long Survivors, 60 (28%) patients survived 15 years or more. Summary/Conclusion: Lactate dehydrogenase above the ULN and serum albumin &lt;3.5 g/dL are independent biomarkers of short survival in WM. The MYD88 L265P status and the size of serum IgM are not prognostic in WM. Our data suggest the need for simplification of the current staging system with the use of widely available markers: serum albumin and lactate dehydrogenase. image
PF452 RUNX1 EXPRESSION IN NG2+ PERIVASCULAR CELLS IS REQUIRED FOR PROPER AORTIC EMBRYONIC HAEMATOPOIETIC ACTIVITY IN VIVO
Authors: Z.N. Gonzalez Galofre, T. Ventura, M. Crisan
Journal: HemaSphere (2019)

Background: Insight into the role of the niche in which the first haematopoietic stem cells (HSCs) emerge in vivo is still lacking. These adult‐type HSCs are generated in the ventral wall of the dorsal aorta within the aorta‐gonad‐mesonephros (AGM) region. In the bone marrow, HSCs are mainly located in close association with blood vessel walls. Cells expressing NG2, a cell surface proteoglycan found in both vasculogenic and angiogenic vasculature, have been shown to support adult HSC maintenance. Whether NG2 + cells also control HSC generation in the mouse embryo is still unknown. NG2 expression in the aortic mural cells starts shortly before HSC generation, and some NG2 + cells also express Runx1, a key haematopoietic transcription factor required for HSC generation. Aims: To investigate whether NG2 + Runx1 + cells control embryonic haematopoiesis in vivo. Methods: Runx1 was deleted in NG2 expressing cells by crossing Runx1 fl/fl mice with mice containing a Cre transgene under the NG2 promoter. I n vitro and in vivo functional assays were performed in E10 and E11 mouse embryos to assess haematopoietic activity. Three‐dimensional (3D) confocal imaging of the intact aorta was further used to confirm our results. To investigate whether NG2 + and NG2 + Runx1 + cells are haematopoietic and/or haematopoietic precursors, cell sorting and colony‐forming assays were carried out on WT, Runx1 GFP and NG2Cre‐TdTomato transgenic mice. Results: By 3D confocal imaging, we found that intra‐aortic haematopoietic clusters are dramatically reduced in number in homozygous KO mouse embryos (NG2Cre:Runx1 fl/fl ) compared to WT (NG2 + :Runx1 fl/+ ) controls. This was further confirmed by functional in vitro and in vivo assays. Both haematopoietic progenitors and haematopoietic stem cell activities are affected in the KO AGM. Depletion of Runx1 in NG2 + cells drastically impairs all haematopoietic progenitor numbers in the dorsal aorta of both E10.5 and E11 mouse embryos and, in vivo , KO AGM had a reduced capacity of reconstituting adult irradiated recipient mice. NG2 + cells (or NG2 + Runx1 + ) are not haematopoietic nor haematopoietic precursors suggesting that NG2 + Runx1 + cells act as a supportive niche for haematopoietic progenitor and stem cell generation at this stage. Summary/Conclusion: In conclusion, Runx1 expression in the hematopoietic niche is required prior to HPSC generation in the mouse embryo in vivo. Ongoing experiments aim to test whether this is time‐ and organ‐dependent.
PF475 PROGNOSTIC VALUE OF METABOLIC TUMOR VOLUME AND TOTAL LESION GLYCOLYSIS CALCULATION ON BASELINE 18F‐FDG‐PET‐CT IN PATIENTS WITH HODGKIŃS LYMPHOMA AND ITS CORRELATION WITH CLINICAL CHARACTERISTICS
Authors: K.E. Bermúdez Ferro, E. Paredes, F.O. Garcia, M.L. Moreno Martinez, M.D. C. Lome Maldonado, A.F. Ramírez Ibarguen
Journal: HemaSphere (2019)

Background: Hodgkin Lymphoma is a neoplasm with remission high rates with conventional therapy, however 20% does not respond or has relapsing disease. Multiple strategies have been investigated to predict the outcomes to treatment, one of them is interim PET CT to predict progression free survival (PFS). Other parameters that can be measured are total lesion glycolysis (TLG) and metabolic tumor volume (TMV), which might provide useful prognostic information at diagnosis that in the future could be the base for new risk assesment models. Aims: To assess the prognostic value of TMV and TLG measured by 18F FDG PET‐CT at the time of diagnosis of HL and its relation to PFS. Methods: It was selected patients with recent diagnosis of HL between 2009–2015 in the National Institute of Oncology, with a PET CT at diagnosis. It was calculation of TMV and TLG at time of diagnosis using the syringo.via V8108 software. To define the optimal cutoff the ROC curve was established using SPSS software and Kapla‐Meier curves were generated for survival analysis followed by the long rank test. Results: We identified 144 patients, 11 were excluded do to loss of follow up. With male predominance (53%). Median age was 36 years (16–83). The most of patients had advanced disease (70%). All patients received AVBD and 74% radiotherapy as consolidation. Complete remission was 80%. According ROC curves the cutoff for TLG was 2650 cm 3 . The clinical differences between patients with high TGL has been showed in Fig 1. The median follow‐up was 54 months (4–115), 5 years OS and PFS were 82.5% and 70% respectively. High TLG was a significant prognostic factor with 5y PFS 62% vs 76% (p = &lt;0.05). There was no difference in OS. In the univariate analysis other prognostic factor for PFS were extraganglionar disease (p = 0.045) and IPS prognostic scale above 3 points (p = 0.01). The cutoff for MTV was 350 cm 3 , however high MTV was not related to worse prognosis. Summary/Conclusion: In our population the cutoff for TLG were 2650 cm 3 associated to lower PFS and more tumor burden. MTV was not associated with lower PFS as previous reports. Furthermore, there is a strong correlation between this results and clinical characteristics, thus, it can be used as a strategy to decide the first treatment line. image
PF490 PRESENCE OF BRAFV600E MUTATION IN CHILDHOOD LCH CORRELATES WITH MULTISYSTEM DISEASE AND A POOR SURVIVAL
Authors: P. Bhatia, M. Singh, R. Srinivasan, N. Kakkar, A. Trehan, D. Bansal
Journal: HemaSphere (2019)

Background: Reports in LCH have observed BRAFV600E mutation in 35–40% cases of LCH and have demonstrated its relation with poor outcome. Aims: The aim of the study was to detect the presence of BRAFV600E mutation in children with LCH and to correlate with survival. Methods: Retrospective, Single centre, Case‐control study. Biopsy or FNAC diagnosed and immunochemistry confirmed (CD1a and S‐100 +ve) cases of LCH over 5‐years were retrieved. RQ‐PCR as well as Sanger sequencing for BRAFV600E mutation was performed. Ten cases of non‐LCH histiocytic proliferations were run as controls. Results: Thirty‐five LCH cases enrolled. 4 cases were excluded due to poor quality of DNA and 2 due to lack of follow up. The mean age was 2.5 years (0.4–11 yrs). Unisystem involvement was noted in 13/28 (46.5%) cases and multisystem in 15/28 (53.5%), including 13 with risk organ involvement. Of the 28 samples run on RQ‐PCR, BRAFV600E mutation was identified in 6/28 (21%) cases. The copy number threshold (Ct) values of positive cases ranged from 25.8–34.1 with a mean of 30.2. Sanger sequencing in all 28 samples confirmed positivity in 5/6 cases. One case did not yield reportable reads. There were no false negatives noted. Ten events (36%) were recorded, including 4 (14%) disease relapse, 3 (11%) deaths and 3 (11%) with progressive disease. All patients positive for mutation had multisystem involvement (100%) (p 0.0348), an EFS at 3‐years of 17% vs. 72% in negative group (p 0.0110) and an OS of 32.5% vs. 82% (p 0.0330). The lower BRAFV600E positivity than west could be likely due to archival samples and degraded DNA. Summary/Conclusion: The frequency for BRAFV600E positivity was low (21%), however, all positive cases had multisystem involvement and a poor 3‐year survival, confirming BRAFV600E to be a poor prognostic marker. image
PF465 UPREGULATION OF CD276 IN ENDOTHELIAL CELLS OF MURINE AND PDX ACUTE MYELOID LEUKAEMIA MODELS
Authors: A. Batsivari, D. Passaro, P. Chakravarty, M.G. Albornoz, G. Diana, L. Ariza McNaughton, A. Abarrategi, D. Bonnet
Journal: HemaSphere (2019)

Background: Haematopoietic stem cells (HSCs) reside atop of the blood hierarchy and localise in the bone marrow (BM). Acute myeloid leukaemia (AML) is caused by accumulation of mutations in the stem cell compartment, which blocks the differentiation of the myeloid lineage. AML also modulates the BM microenvironment but the mechanisms of action are largely unknown. We and others, demonstrated recently that BM marrow vasculature is damaged in AML engrafted mice (Passaro et al. 2017; Duarte et al. 2018). The arterioles are increased, while the sinusoidal endothelial cells are vastly decreased. In order to understand the mechanism underlining this change, we previously performed RNA‐sequencing of CD31 + endothelial cells (ECs) extracted from healthy and leukemic mice. Aims: This project aims to identify key processes that play a role in the crosstalk between AML cells and BM microenvironment and test whether modulating these niche factors can improve the current therapeutic regimen. Thus, herein we focused on the potential role of CD276 on ECs of AML engrafted mice. Methods: RNAseq of BM ECs from non‐transplanted or AML Patients’ Derived Xenograft (PDX) mice was performed. Flow cytometry and immunostaining of BM ECs were performed. ShRNA against CD276 is being used to define the effect of its knockdown in ECs on leukaemia engraftment in our 3D humanised scaffold model. Blocking antibodies against CD276 will also be tested in vivo . Results: Analysis of the RNAseq data showed that CD276 (B7‐H3) gene is among the top 100 differentially expressed genes and is particularly upregulated in ECs of AML engrafted mice. It has been demonstrated that CD276 is overexpressed specifically in ECs of solid tumours and its blockade leads to tumour shrinkage (Seaman et al. 2017). The protein network map of CD276 indicated that it can participate in immune responses as well as adhesion signalling pathways. Indeed, there are several such genes deregulated in the leukemic ECs suggesting that CD276 might have a functional role in transforming the BM niche. CD276 overexpression was validated in ECs PDX and murine AML models. Moreover, we also observed this upregulation in human ECs by using our humanised scaffolds seeded with AML cell lines. Summary/Conclusion: So far, our RNAseq analysis of healthy and leukemic PDX mice shows that CD276 is being upregulated in ECs. We confirmed this upregulation at the protein level both using mouse and human ECs. Our next step is to determine the consequence of CD276 downregulation on leukaemia engraftment.