tbuckley/cabot-search huggingface dataset:
Genomic positional conservation identifies topological anchor point RNAs linked to developmental loci
Authors: Paulo P. Amaral, Tommaso Leonardi, Namshik Han, Emmanuelle Viré, Dennis K. Gascoigne, Raúl Arias-Carrasco, Magdalena Büscher, Luca Pandolfini, Anda Zhang, Stefano Pluchino, Vinicius Maracaja-Coutinho, Helder I. Nakaya, Martin Hemberg, Ramin Shiekhattar, Anton J. Enright, Tony Kouzarides
Journal: Genome biology (2018)

The mammalian genome is transcribed into large numbers of long noncoding RNAs (lncRNAs), but the definition of functional lncRNA groups has proven difficult, partly due to their low sequence conservation and lack of identified shared properties. Here we consider promoter conservation and positional conservation as indicators of functional commonality. We identify 665 conserved lncRNA promoters in mouse and human that are preserved in genomic position relative to orthologous coding genes. These positionally conserved lncRNA genes are primarily associated with developmental transcription factor loci with which they are coexpressed in a tissue-specific manner. Over half of positionally conserved RNAs in this set are linked to chromatin organization structures, overlapping binding sites for the CTCF chromatin organiser and located at chromatin loop anchor points and borders of topologically associating domains (TADs). We define these RNAs as topological anchor point RNAs (tapRNAs). Characterization of these noncoding RNAs and their associated coding genes shows that they are functionally connected: they regulate each other’s expression and influence the metastatic phenotype of cancer cells in vitro in a similar fashion. Furthermore, we find that tapRNAs contain conserved sequence domains that are enriched in motifs for zinc finger domain-containing RNA-binding proteins and transcription factors, whose binding sites are found mutated in cancers. This work leverages positional conservation to identify lncRNAs with potential importance in genome organization, development and disease. The evidence that many developmental transcription factors are physically and functionally connected to lncRNAs represents an exciting stepping-stone to further our understanding of genome regulation.
Abstract 19325: Genetic Ablation of the P2y2 Nucleotide Receptor Reduces Atherosclerosis in Mice
Authors: Cheikh Seye, Shaomin Qian
Journal: Circulation (2012)

Objective: We have shown that nucleotide binding to P2Y2 receptor induces endothelial activation via enhanced VCAM-1 expression leading to intimal recruitment of monocyte/macrophage. Here, we sought to determine whether genetic ablation of P2Y2 receptor affects the development of atherosclerosis. Methods and Results: Western blot and immumofluorescence analysis revealed that P2Y2 receptor deficiency in ApoE mice is accompanied by a sharp reduction in basal VCAM-1 expression levels. To analyze the consequence of P2Y2 receptor deficiency in endothelial function, we examined transmigration of monocytes isolated from the peripheral blood of wt or P2Y2R −/− mice across wt or P2Y2R −/− endothelial monolayers in response to monocyte chemoattractant protein-1. Absence of P2Y 2 R in endothelial cells significantly impaired monocyte transmigration. Remarkably, loss of P2Y2 receptor in monocytes did not significantly impair transmigration in the presence (transendothelial) or absence (chemotaxis) of P2Y2R +/+ endothelial monolayers, suggesting that endothelial P2Y2R is relatively more important than monocytic P2Y 2 R in regulating monocyte motility. The absence of P2Y 2 R did not significantly change the plasma cholesterol or triglyceride levels; however, lipid deposition in the lesion, as demonstrated by Oil Red O–positive region, was decreased by 47% in the aortic preparation from ApoE−/−/P2Y2R+/+ mice. Notably, P2Y2R deficiency in ApoE−/− resulted in a 52% reduction in the area of aortic sinus lesion as compared to ApoE −/− mice. Consistent with reduced lesion size, decreased macrophage content was observed in the sinus aortic lesions of ApoE−/−/P2Y 2 R −/− mice. Staining for SMC showed that most of the SMCs were in the intimal area close to the lumen. The staining showed a 36% decrease in ApoE−/−/P2Y 2 R −/− when compared with ApoE −/− /P2Y2R +/+ mice. Staining with Sirius red showed that the interstitial collagen content of the lesions of ApoE −/− /P2Y2R +/+ mice was 2-fold higher than in ApoE−/−/P2Y2R −/−mice. Conclusion: These observations suggest that genetic ablation of P2Y 2 R significantly decreases both macrophage accumulation and interstitial fibrosis but also reduces smooth muscle cell content of sinus aortic lesions.
PB1811 A SINGLE ARM MULTICENTENNIAL CLINICAL STUDY IN THE TREATMENT OF PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA(PCNSL) WITH ALTERNATIVE CHEMOTHERAPY SEQUENT WITH AUTOLOGOUS TRANSPLANTATION
Authors: S. zhou, J. Li, Q. Wen, S. Wang, S. Lou, T. Yang, B. Li, X. Liu, X. Han, L. Gao, C. Zhang, P. Kong, L. Gao, Y. Liu, X. Zhang
Journal: HemaSphere (2019)

Background: Primary central nervous system lymphoma(PCNSL)is a highly aggressive form of lymphoma with poor clinical outcomes and lack of a standard treatment regimen. Aims: To explore the methods of treatment in PCNSL. Methods: Patients aged 18‐60 years with newly diagnosised PCNSL are treated with MTX+CDOD (Cyclophosphamide 750 mg/m2 d1, Doxorubicin HCl 40 mg/m2 d1, Vindesine 4 mg d1, dexamethasone 10 mg d1‐5, MTX 3 g/m2 d2) /MTX+HD‐Ara‐C (cytarabine 1.5 g/m2 q12 h d1‐2, methotrexate 3 g/m2 d3) Alternative chemotherapy for 6 total cycles, whose response evaluation is more than partial remission(PR) then sequentially with ASCT. Results: From June 2017 to June 2018, 17 patients in five hospitals in southwest China accepted CDOD+MTX/HD‐Ara‐C+MTX Alternative chemotherapy sequent with ASCT. The median age was 46(32‐57), 9 males and 8 females, among the pathological types, 1 patient was high‐grade B‐cell lymphoma, and the rest were DLBCL. Two patients dropped out of the study at course 4 and 5 of chemotherapy for disease progression, the remaining 15 patients received ASCT sequentially. Before transplantation, 12 patients reached complete remission(CR), 3 patients reached PR. The overall remission rate of chemotherapy is 88%. After transplantation, 13 patients CR, 2 patients still PR. By January 2019, the median follow‐up time was 9 months(7‐12), two patients relapsed and one patient died after recurrence, the median overall survival(OS) is 9months9(7‐12), and the median progression free survival(PFS) is also 9 months9(6‐12). No grade III/IV hematological or non‐hematological adverse events were observed. Summary/Conclusion: Our preliminary results show that RCDOD+MTX/HD‐Ara‐C+MTX alternative chemotherapy sequent with ASCT is a effective and safe trentment for PCNSL, and long‐term follow‐up is needed to further evaluate its efficacy.
AB0493 IMMUNOGLOBULINS AFTER ACUTE PHYSICAL EXERCISE IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS
Authors: Rosane Gouveia Vilela Machado, Jozelia Rêgo, Ana Carolina de Oliveira e Silva Montandon, Heloísa Gouveia Machado, Cláudio André Barbosa Lira, Ludimila Paula Vaz Cardoso, Michelle Rocha Parise, Ricardo Borges Viana, Vitalina Barbosa, Nílzio Da Silva
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Moderate exercise improves the functions of the immune system. The results of serum immunoglobulins in response to acute physical exercise are conflicting, but in general, there is an increase in serum immunoglobulins in athletes and non-athletes after maximal and submaximal exercise. The effects of acute physical exercise on serum immunoglobulin in patients with systemic lupus erythematosus are unknown. <h3>Objectives</h3> To determine the serum levels of IgG, IgM and IgA immunoglobulins in patients with systemic lupus erythematosus after a single session of acute aerobic exercise. <h3>Methods</h3> Thirty-one women with SLE (ACR1997 and/or SLICC 2012 criteria),11 with active lupus and 20 with inactive lupus, and 24 healthy women, who were matched by gender, age, and body mass index, participated in this study. All subjects underwent a maximal exercise test on motorized treadmill, with increases in velocity every minute until exhaustion, to evaluate the speed (km/h), heart rate, Borg scale (6-20), and the reason for stopping the test (fatigue and/or dyspnea). Samples of blood were collected in the morning, after an 8-hour fast and immediately after acute physical activity, and stored in a freezer at -80°C until the tests were performed. Immunoglobulin IgG, IgM and IgA assay was performed by turbitometry according to the manufacturer (Turbiquest, Labtest Diagnostic S.A). <h3>Results</h3> There was an increase in both IgG and IgA serum levels after physical activity in SLE patients (p = 0.004 for IgG and p = 0.002 for IgA) and healthy controls (p &lt;0.001 for IgG and p &lt;0.001 for IgA) (Figure1). Inactive SLE patients showed higher levels of IgG and IgA after exercise (p = 0.006 and p = 0.010, respectively) (Figure 2), in comparison with the active SLE patients. There was no difference in IgM serum levels before and after the exercise test in both groups. <h3>Conclusion</h3> Patients with SLE, mainly with inactive disease, responded to acute physical exercise with increased IgG and IgA serum levels, similarly to healthy controls. <h3>References</h3> [1] Nehlsen-Cannarella SL, et al. The effects of acute moderate exercise on lymphocyte function and serum immunoglobulin levels. Int J Sports Med. 1991; 12(4): 391-398.. [2] Nieman DC and Nehlsen-Cannarella SL.The effects of acute and chronic exercise of immunoglobulins. Sports Med. 1991; 11(3): 183-201. [3] Ochoa-Martínez PY, et al. Cinética de la inmunoglobulina-A salival (IgAs) en adultos jóvenes con capacidad aeróbica promedio o excelente antes y después de una prueba de esfuerzo máximo. Revista Chilena de Infectología, 2017; 34: 27-32. <h3>Disclosure of Interests</h3> None declared
PB1987 SELECTIVE ACTIVATION OF TOLEROGENIC CELL DEATH PATHWAYS IN MESENCHYMAL STROMAL CELLS
Authors: R. Savoldelli, T. cheung, A. Galleu, F. Dazzi
Journal: HemaSphere (2019)

Background: Mesenchymal stromal cells (MSCs) have been successfully employed for their tolerogenic and immunosuppressive capabilities in different conditions. We have demonstrated that, following infusion, MSCs undergo apoptosis and that this apoptosis results in an immunosuppressive activity. However, it is unclear how MSCs respond to different death inducing stimuli and whether MSCs from different sources respond similarly when following analogous patterns. Aims: To characterize the molecular response of MSCs, obtained from different sources, to distinct cell death stimuli. Methods: MSCs were isolated from human bone marrow (BM‐MSCs) or umbilical cord (UC‐MSCs) of healthy donors and exposed to recombinant human Tumor necrosis factor‐a(TNF‐a) and Interferon‐g(IFN‐g) in combination or individually, anti‐FAS (activator), TNF‐related apoptosis‐inducing ligand (TRAIL), phytohemagglutinin (PHA) activated Peripheral Blood Mononuclear Cells (PHA‐aPBMCs), hydrogen peroxide (H 2 O 2 ) with or without the presence of the pan‐caspase inhibitor Z‐VAD. After 24 h, the cells were harvested and stained for annexin V/7‐AAD and analyzed by flow‐cytometry. The cancer cell line MCF‐7 was used as a positive control. Results: BM‐MSCs showed high sensitivity to apoptosis induction when treated with FAS activator (11% of AnnV+/7‐AAD‐ and 72% AnnV+/7‐AAD+) and PHA‐aPBMCs (7% of AnnV+/7‐AAD‐ and 78% AnnV+/7‐AAD). Conversely, UC‐MSCs were more resistant to apoptosis mediated by FAS, since the percentages of AnnV+/7‐AAD‐ and AnnV+/7‐AAD+ were 63% and 9%. Both BM‐MSCs or UC‐MSCs were only marginally sensitive to TRAIL (35% of apoptosis). In all cases, apoptosis induction was caspase dependent, as demonstrated by the significant reduction (p &lt; 0.001) of the proportion of apoptotic cells in both BM‐MSCs and UC‐MSCs in the presence of the pan‐caspase inhibitor Z‐VAD. Conversely, neither BM‐MSCs or UC‐MSCs were induced to undergo apoptosis when treated with TNF‐aalso at very high concentrations or in combination with IFN‐g. The efficacy of the recombinant TNF‐ain inducing cell death was confirmed by using the cell line MCF‐7 as sensitive controls. Finally, all MSCs were sensitive to H 2 O 2 . Summary/Conclusion: MSCs exhibit varying susceptibility to different apoptotic stimuli. Interestingly, although this property seems to be maintained across different tissues of MSC origin, we could find variable degrees of sensitivity to specific stimuli, thus suggesting that different MSCs may play distinct roles according to the specific environment.
PB1705 CBC PARAMETERS BASED DERIVED PREDICTIVE FACTOR FOR ACUTE PROMYELOCYTE LEUKEMIA
Authors: R.Z.H. Haider, S. Buoro, R. Simon‐Lopez, E. De Paula, T.S. Shamsi
Journal: HemaSphere (2019)

Background: Acute promyelocytic leukemia (APML) due to coagulopathies drives hematological distress in clinical practices. A targeted and timely offered treatment can be a benefitting tool for patients. Aims: Present study was conducted to introduce pre‐microscopic screening of patients with acute promyelocytic leukemia (APML) through research potential parameters generated by routine hematology analyzers during CBC analysis. Methods: Blood samples of controls and patients (APML and other hematological neoplasms) were analyzed on Sysmex XN‐1000. Peripheral blood film was examined for morphological diagnosis. CBC parameters and values for intensities of white blood cell's side, forward, and side florescence light scatter were recorded from analyzer software. Statistical and machine learning (unsupervised) tools were used to evaluate the predictive power of routine and research CBC parameters. Novel APML factor was derived from white blood cell and platelet count along mean value of neutrophil side fluorescence light (NE‐SFL) through logistic regression. At proposed cutoff value (‐2.011), APML factor was challenged for prediction of APML among present study cases. Results: Values for white blood cell (WBC), platelet, and NE‐SFL were exceptionally discriminative for APML 5.65, 29.5, and 54.4 respectively in comparison to non‐APML 7.96, 219, and 47.00 respectively cases. In combination, WBC and platelet count increased the predictive power of NE‐SFL when utilized in derivation of our proposed “APML factor”: ‐4.5070 + (0.049213 x NE‐SFL) + (‐0.017431 x PLT) + (‐0.0058366 x WBC). This factor gave robust impact in differentiation of APML with high values 0.935 and 0.985 for sensitivity and negative predictive power (NPP) respectively at cutoff of ‐2.011. Summary/Conclusion: Our proposed APML factor has strong potential to be incorporate/calculate and examine as part of CBC report for early prediction of APML.
PB1824 MARITAL STATUS AS A PROGNOSTIC FACTOR IN DIFFUSE LARGE B‐CELL LYMPHOMA, SEER DATA BASED STUDY
Authors: M. Ahmed, A. Pandu, T. Darwish, N. Mostafa
Journal: HemaSphere (2019)

Background: Studies showed that marital status has an impact on the survival of patients with different types of cancers. There's no study, up to our knowldge, that discussed the prognostic impact of marital status on the outcome of Diffuse Large B‐cell Lymphoma (DLBCL) Patients. Aims: To assess the impact of marital status on the outcome of patients with DLBCL before and after the addition of Rituximab to the treatment. Methods: We reviewed the Surveillance, Epidemiology, and End Results (SEER) registry and compared survival trends among DLBCL patients from 1973 to 2015. Patients were classified according to their marital status into 3 gropus; Group I (married), group II (Single) and group III (Widowed/Divored/separated) Results: We identified 118293 patients above the age 19 years, (54% males, 85% white, 62% are 60+ years), staging information was available for 90% of cases, were distributed between early stage (I/II) and advanced stage (III/IV) (45% each). Fifty Eight percent of patients were in group I, 16% in gruop II and 26% in group 3. After excluding patients with missed data it was found that group III are significantly associated with older age (&gt;60 years) and female sex compared to group I and group II with p‐value 0.00 each. Median overall survival time (OS) in pre‐Rituximab era (Diagnosed 1997 or before) was 29 Months compared to 213 Months in post‐Rituximab era (after 1997). Before introduction of Rituximab There was statically significant difference in the OS of Married group (50 Months) compared to Single (15 months)and widowed/divorced/separated group (17 months), P Value 0.00. After 1997, Married &amp; single patients were associated with better outcome with Median OS of (227 Months) compared to (63 months) in the widowed/divorced/separated group, p‐value 0.00. Summary/Conclusion: Marital status has a prognostic significance on the outcome of DLBCL. Widowed/divorced/separated group had worse prognosis than married group, this group may need more social support to improve their outcome.
Relevance of Endoxifen Concentrations: Absence of Evidence Is Not Evidence of Absence
Authors: C. Louwrens Braal, Jos H. Beijnen, Stijn L.W. Koolen, Esther Oomen-de Hoop, Neeltje Steeghs, Agnes Jager, Alwin D.R. Huitema, Ron H.J. Mathijssen
Journal: Journal of Clinical Oncology (2019)

We read the article by Sanchez-Spitman et al 1 reporting on their CYPTAM study about the association between CYP2D6 genotype and clinical outcome in the adjuvant treatment of breast cancer with tamoxifen.We acknowledge that a lack of association was shown and that solely the determination of CYP2D6 genotype has limited relevance for clinical practice in this setting.However, we do not agree with Sanchez-Spitman et al 1 on their interpretation of the data on the association between endoxifen concentrations (which is the most relevant tamoxifen metabolite) and recurrence of breast cancer.In our opinion, the authors are jumping to conclusions, because the primary end point of this study was not to investigate the relationship between endoxifen concentrations and clinical outcome.Instead, the study was amended in 2017 to explore endoxifen concentrations in relation to recurrence-free survival and was underpowered to draw solid conclusions on this end point, with a hazard ratio of 2.0 as input into their sample size calculations.This hazard ratio cannot be considered realistic to study the effects of endoxifen concentrations on recurrence-free survival. 2
PB1968 TWO NEW MUTATIONS AND MOLECULAR CHARACTERIZATION OF G6PD GENE AMONG THAI CHILDREN WITH G6PD DEFICIENCY
Authors: C. Traivaree, B. Boonyawat, A. Photi‐a, C. Monsereenusorn, T. Phetthong
Journal: HemaSphere (2019)

Background: Glucose‐6‐phosphate dehydrogenase (G6PD) deficiency is the most common X‐linked inherited erythroenzymopathy in Thailand. The clinical and hematological manifestations of G6PD deficiency is variable. Aims: This study aimed to characterize the spectrum of G6PD gene mutations in Thai pediatric patients who were followed‐up in Phramongkutklao Hospital, a tertiary center in central Thailand. Methods: A total of 102 children including 73 males (71.6%) and 29 females (28.4%) were included in our study. Mutation analysis was performed by direct DNA sequencing of the G6PD gene. Neonatal hyperbilirubinemia was the most common (87.3%) clinical manifestation in this study. Results: Molecular analysis of G6PD gene in 102 G6PD‐deficient Thai children identified a total of 12 mutational types. G6PD Viangchan (871G&gt;A) was the most common (46.2%) identified mutation. G6PD Canton (1376G &gt; T) was the second most common and was identified in 15.4%, followed by G6PD Kaiping (1388G &gt; A) 14.4% and G6PD Mahidol (487G &gt; A) 8.6%, respectively. Eight uncommon G6PD mutations including G6PD Quing Yan (392G &gt; T) (3.8%), G6PD Aures (143C &gt; T) (1.9%), G6PD Coimbra (592C &gt; T) (1.9%), G6PD Songklanagarind (196T &gt; A) (1.9%), G6PD Union (1360C &gt; T) (1.9%), G6PD Valladolid (406C &gt; T) (1.9%), G6PD Chinese‐5 (1024C &gt; T) (1%) and G6PD Mediterranean (563C &gt; T) (1%) were identified in this study. G6PD Valladolid and G6PD Aures were firstly identified in Thai populations. Summary/Conclusion: This study characterizes the molecular heterogeneity of G6PD variants causing G6PD deficiency in Thai children. Our study demonstrated the efficiency of direct DNA sequencing which can identify mutations in all 102 patients.
<i>NFKBIA</i> deletion in triple-negative breast cancer.
Authors: Markus Bredel, Hyunsoo Kim, Nanda K. Thudi, Denise M. Scholtens, James A. Bonner, Branimir I. Sikic
Journal: Journal of Clinical Oncology (2013)

1012 Background: While effective, target-directed therapies are available for ER-positive and HER2-amplified breast cancer, adjuvant therapeutic options for triple-negative breast cancer (TNBC) are limited in the absence of well-defined molecular targets. Constitutive activation of oncogenic nuclear factor kB (NFkB) has been associated with ER-negative or basal-like (BL) breast cancers, but the underlying mechanism of this activation remains undefined. We previously showed that deletion of the endogenous NFkB repressor gene NFKBIA associates with EGFR non-amplified glioblastoma multiforme and portends unfavorable clinical outcome (Bredel et al. NEJM 2011). Methods: We analyzed &gt;5,000 human breast cancers for deletions, mutations and/or expression of NFKBIA. We studied tumor suppressor activity of NFKBIA and the effect of targeted NFkB inhibition in cell culture with various NFKBIA genotypes. We compared molecular results with outcomes of affected persons. Results: NFKBIA is often (10.8%) deleted but not mutated in breast cancer. NFKBIA deletions are significantly associated with TNBC (32.8%) and particularly frequent in the BL subtype (36.7%). Loss of NFKBIA exerts a haploinsufficient effect on NFKBIA expression and the transactivation of several NF-kB target genes with important roles in breast carcinogenesis. Restoration of NFKBIA expression or pharmacologic NFkB inhibition attenuates the malignant phenotype of cells cultured from TNBC with NFKBIA deletion. Deletion and low expression of NFKBIA are highly associated with unfavorable overall survival, independent of patient age, tumor stage, nodal status, and tumor subtype. Loss of NFKBIA expression portends significantly poorer disease-specific survival, recurrence-free survival, and distant metastasis-free survival. Moreover, NFKBIA expression is significantly associated with duration of metastasis-free survival in subgroups of patients with brain or lung metastases from breast cancer. Conclusions: NFKBIA is a new, prognostically relevant, molecular target in TNBC, which remains a clinically challenging subtype of breast cancer with limited treatment options.
Reduced Hvcn1 In Neutrophils Of Individuals With Cystic Fibrosis Alters Phagosomal Ph And Degranulation
Authors: N. Browne, M. M. White, M. Milner, C. Foley, F. Gargoum, P. Hawkins, S. Qayyum, E. Reeves, N. G. McElvaney
Journal: American Journal of Respiratory and Critical Care Medicine (2017)