bluuebunny/crossref_metadata_2025_split huggingface dataset:
Complete Hematologic and Cytogenetic Remission of Acute Myeloid Leukemia in an Elderly Patient Treated with Decitabine and Venetoclax: A Case Report
Authors: Paredes Hanrry Jerry , Gonzalez M. Francisco 
Published: November 2019

We present the case of a 77 year old woman, Caucasian, with medical history of diabetes mellitus, hyperthyroidism, hypertension and hyperlipidemia, that suddenly develops progressive articular pain, dyspnea at rest, easy bruising /ecchymosis in soft tissues, weakness and nose bleeding. At admission no visceromegaly was noted, gums and lymph nodes were normal. Initial lab workup showed severe anemia (Hb 7.7 g/dL), leukocytosis (19.1 x 10^3/uL) with monocytosis (51%) and left shift, severe thrombocytopenia (Plt 33 x 10^3/uL), hyperfibrinogenemia, hyperglycemia and hyperuricemia. Bone marrow morphology was conclusive of Acute Myeloid Leukemia with 45 % of blasts, hypercellular with progressive trilineage hematopoiesis and no ringed sideroblasts. Flow cytometry of peripheral blood detected only 0.8 % of blasts (CD34+) with positive myeloid markers. Flow cytometry of bone marrow detected 17 % of myeloid blasts expressing CD34+, HLA-DR, CD117, cytoplasmic (cy) MPO, CD13, partial CD11b, negative for cyTdT and cy CD79a. Genetically, 5q31/EGR1 deletion (86%) and gain of 20q12 (64%), with no other anomalies or mutations were found.
Patient was treated with Decitabine 20mg/m2 IV daily x 10 d, followed by Venetoclax starting gradually from 100 mg escalating up to 300 mg oral as induction therapy. Complications during this phase were pleural effusion, C. difficile-associated diarrhea, urinary infection due to Enterococcus faecium, anemia, thrombocytopenia that required blood and platelet transfusions. After the first cycle of therapy a new bone marrow done showed morphologically < 2 % of blasts with moderate pancytopenia, but presence still of 10 % of CD34+ myeloblasts detected by flow cytometry. After a second course of therapy Decitabine/Venetoclax, peripheral blood leukocytes and platelets normalized, persisting only moderate anemia with no transfusion requirements. Bone marrow FISH report was normal, Del 5q disappeared, no detection of aberrations associated to myelodysplastic syndrome, and no detection of other abnormalities (results below the cut-off) were described, however a new pathogenic alteration in the DNMT3A gene not described before in other cases was detected with the New Generation System analysis.
At the moment of presenting this case report there is a leukemia-free survival of 6 months, with impressing improvement in the general status.
Conclusion: Therapy with the combination Decitabine/Venetoclax is a good alternative for treating elderly patients with AML, sparing the aggressiveness of regular induction chemotherapies and a tremendous impact in inducing cytogenetic remission.

Disclosures
No relevant conflicts of interest to declare.
Management of Delayed Elimination of High-Dose Methotrexate in Community Oncology Practices Can Mitigate Its Effect on Length of Hospital Stay, Treatment Dose-Density, Acute Kidney Injury, Dialysis, and Death
Authors: Howard Scott , Harry McKeon Tad , John Sfondouris , Marada Suresh , Napier Nicholas 
Published: November 2019

Background
High-dose methotrexate (HDMTX, doses higher than 500 mg/m2) is an essential component of therapy for several hematologic cancers but requires meticulous supportive care and therapeutic drug monitoring to deliver safely. Community oncologists manage 85% of adults with cancer in the USA but may lack infrastructure to support HDMTX administration and patient outcomes can be compromised by avoidance of HDMTX when it would have been appropriate, toxicities, and early discontinuation after toxicity occurs.
Methods
We evaluated HDMTX use and outcomes in the Guardian Research Network, (www.GuardianResearch.org), a non-profit USA clinical trials consortium of 110 community oncology centers with a database containing patients' entire medical, including all demographics, diagnoses, labs, medications, procedures, encounters, and notes of all kinds (clinical, radiology reports). Anonymized, de-identified data about HDMTX doses, administration, supportive care, and outcomes was analyzed to determine its safety and efficacy in the community setting.
Results
Of 529784 cancer patients diagnosed from 2011 through 2019, 230 received at 1 to 18 courses of HDMTX (median 3) for acute lymphoblastic leukemia (n=41), NHL (n=142), or other cancers (n=47). Patient characteristics are shown in the Table. In 106 cases (46%), patients received only 1 or 2 doses of HDMTX, usually due to delayed methotrexate clearance and acute kidney injury (AKI). Only 2 patients (1%) received dialysis, but 23 (10%) died within 28 days of a HDMTX course. Survival at 3 years for patients who received only 1 or 2 doses of HDMTX was 50% (Standard error, SE 6%), compared to 71% for those who received 3 or 4 doses (SE 6%) and 64% for patients who received 5 or more doses (SE 7%), p=0.002. Age older than 80 years predicted survival (p=0.02), but no other patient features, including: race (p=0.40), sex (p=0.72), cancer type (p=0.82). In multivariable Cox proportional hazards analysis, receiving 2 or less HDMTX courses was associated with a hazard ratio (HR) of 2.0 (95% CI 1.3 to 3.3, p=0.004) and age increased the risk of death for each decade older than 50 years (HR 4.8 for patients older than 80 years, 95% CI 1.6 to 14, p=0.004.
Conclusions
HDMTX can be safely delivered in community oncology practices, but requires meticulous supportive care to allow completion of all doses and maximize survival
Figure

Disclosures
Howard: BTG: Consultancy, Research Funding; Servier: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; EUSA: Consultancy; Resonance: Equity Ownership.
Outcome of Morbidly Obese Patients with Acute Venous Thromboembolism Managed with Direct Oral Anticoagulants
Authors: Anusim Nwabundo , Ionescu Filip , Jindal Vishal , Gupta Ruby , Jaiyesimi Ishmael , Gaikazian Susanna 
Published: November 2019

Background.
Obesity is a major epidemic affecting all age groups in the USA. It has been associated with venous thromboembolism (VTE), which requires prolonged anticoagulation. Classic options (vitamin K antagonists, heparins) are increasingly replaced by direct oral anticoagulants (DOACs), which have not been well studied in patients with body mass index (BMI) > 40kg/m2 or weight above 120 kg. Despite limited safety and efficacy data, patients and their caregivers often opted for this medication owing to its ease of administration, lack of requirement for frequent laboratory testing and for dietary restrictions.
Methods.
This is a retrospective study of all morbidly obese patients (BMI > 40kg/m2) diagnosed with acute VTE managed with DOACs at Beaumont hospital between January of 2018 and December of 2018. Data regarding demographics, specific DOAC, major bleeding (hemoglobin decrease by 2 g/dL) and new or progressive thrombosis were recorded during a sixty-day follow up. Data was analyzed using JMP statistical software.
Results
A total of 42 patients diagnosed with acute VTE received DOACs during the study period. Most were female (76%); the median BMI was 44 (IQR 42-60) and mean age was 57. Most patients had a BMI of 40-50 kg/m2 (n=34, 81%) compared to BMI 50-60 kg/m2 (n=6, 14%) and BMI >60kg/m2 (n=6, 14%). Apixaban was the most frequently used DOAC (n=27, 65%). No clinically significant bleeding occurred during the study period. There were 2 thrombotic episodes (5% of patients) within 60 days of starting a DOAC; both occurred in patients receiving rivaroxaban. One event was present in the BMI 40-50kg/m2 group and one in the >60kg/m2 group.
Conclusions
DOACs appear to be safe and efficacious for the management of VTE in the morbidly obese population. Future studies may focus on the comparative efficacy of apixaban and rivaroxaban in the morbidly obese population.

Disclosures
No relevant conflicts of interest to declare.
EZH2 Gain-of-Function Mutations Generate a Lymphoma-Permissive Immune Niche
Authors: Béguelin Wendy , Teater Matthew R , Meydan Cem , Phillip Jude M , Melnick Ari 
Published: November 2019

The polycomb histone methyltransferase protein EZH2 is highly expressed and mutated in approximately 25% of the two most common subtypes of non-Hodgkin's lymphoma: follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL). Both of these tumor types originate from germinal center (GC) B-cells, which are highly proliferative cells that form transiently during the T-cell dependent humoral immune response. Wild type EZH2 plays a critical role in the formation of GC B-cells and mutant EZH2 drives malignant transformation of these cells in vivo. These lymphoma-associated mutations of EZH2 are gain-of-function and enhance EZH2 methyltransferase activity, which cause abnormally efficient H3K27me3, enhancing repression of transcription. Of note, EZH2 mutant lymphomas manifest aberrant suppression of antigen presentation pathways, such as loss or reduced expression of MHC-I and MHC-II, and reduced T-cell infiltrates. We show that mice engineered to conditionally express mutant Ezh2Y641F specifically in GC B-cells exhibited massive GC hyperplasia with expansion of the "light zone" -the GC niche where B-cells are selected based on the affinity of their antibodies- and extended follicular dendritic cells network. With chimeric bone marrow transplantation experiments we found that Ezh2Y641F provides a competitive advantage to activated B-cells in seeding and expanding the T-cell dependent GC reaction. Liquid chromatography separation and mass spectrometry of histone tryptic peptides revealed a massive increase in H3K27me3 in Ezh2Y641F GC B-cells, at the expense of a reduction in H3K27me2. Remarkably, we observed increased unmodified and decreased H3K27me1, indicating a loss-of-function mono-methylase activity of Ezh2Y641F. We confirmed an extensive global gain of H3K27me3 by ChIP-seq, with massive spreading of the mark both upstream and downstream TSS. RNA-seq analysis showed differential expression of genes involved in antigen processing and presentation and immune response, suggesting that B-cell selection process is altered in Ezh2Y641F GC light zone. Therefore, we hypothesized that, through an epigenetic mechanism, Ezh2 mutation makes B-cells less dependent of T-cells by aberrantly suppressing genes involved in the immune synapse. Indeed, inhibition of the interaction between TFH and GC B-cell in vivo using anti CD40L antibody, abrogated GC reaction in WT but not in Ezh2Y641F mice. Of note, EZH2 mutant GCs manifest a massive expansion of the follicular dendritic cell network in spite of lack of T-cell dependence, a finding that reflects low grade FL histology. Hence, EZH2 mutant lymphomas might progress due to acquired immune escape, which is a critical consideration when designing precision, tailored immune-therapy regimens.

Disclosures
Melnick: Constellation: Consultancy; Janssen: Research Funding; Epizyme: Consultancy.
Results from a multidisciplinary clinic guided by geriatric assessment before stem cell transplantation in older adults
Authors: Derman Benjamin A. , Kordas Keriann , Ridgeway Jean , Chow Selina , Dale William , Lee Sang Mee , Aguada Elingel , Jakubowiak Andrzej J. , Jasielec Jagoda , Kline Justin , Kosuri Satyajit , Larson Richard A. , Liu Hongtao , Mortel Mylove , Odenike Olatoyosi , Pisano Jennifer , Riedell Peter , Stock Wendy , Bishop Michael R. , Artz Andrew S. 
Published: November 2019

Key Points
GA to guide an MDC evaluation to optimize older adult candidates for hematopoietic cellular therapy is feasible and practical. An MDC evaluation for older adults before transplantation holds promise to mitigate transplant-related morbidity and mortality.
Inhibition of phosphatidylinositol 3-kinase by PX-866 suppresses temozolomide-induced autophagy and promotes apoptosis in glioblastoma cells
Authors: Harder Bryan G. , Peng Sen , Sereduk Christopher P. , Sodoma Andrej M. , Kitange Gaspar J. , Loftus Joseph C. , Sarkaria Jann N. , Tran Nhan L. 
Published: November 2019

Abstract
Background
Temozolomide (TMZ) is the most commonly used chemotherapeutic agent used to treat glioblastoma (GBM), which causes significant DNA damage to highly proliferative cells. Our observations have added to accumulating evidence that TMZ induces stress-responsive cellular programs known to promote cell survival, including autophagy. As such, targeting these survival pathways may represent new vulnerabilities of GBM after treatment with TMZ.

Methods
Using the T98G human glioma cell line, we assessed the molecular signaling associated with TMZ treatment, the cellular consequences of using the pan-PI3K inhibitor PX-866, and performed clonogenic assays to determine the effect sequential treatment of TMZ and PX-866 had on colony formation. Additionally, we also use subcutaneous GBM patient derived xenograft (PDX) tumors to show relative LC3 protein expression and correlations between survival pathways and molecular markers which dictate clinical responsiveness to TMZ.

Results
Here, we report that TMZ can induce autophagic flux in T98G glioma cells. GBM patient-derived xenograft (PDX) tumors treated with TMZ also display an increase in the autophagosome marker LC3 II. Additionally, O6-methylguanine-DNA-methyltransferase (MGMT) expression correlates with PI3K/AKT activity, suggesting that patients with inherent resistance to TMZ (MGMT-high) would benefit from PI3K/AKT inhibitors in addition to TMZ. Accordingly, we have identified that the blood-brain barrier (BBB) penetrant pan-PI3K inhibitor, PX-866, is an early-stage inhibitor of autophagic flux, while maintaining its ability to inhibit PI3K/AKT signaling in glioma cells. Lastly, due to the induction of autophagic flux by TMZ, we provide evidence for sequential treatment of TMZ followed by PX-866, rather than combined co-treatment, as a means to shut down autophagy-induced survival in GBM cells and to enhance apoptosis.

Conclusions
The understanding of how TMZ induces survival pathways, such as autophagy, may offer new therapeutic vulnerabilities and opportunities to use sequential inhibition of alternate pro-survival pathways that regulate autophagy. As such, identification of additional ways to inhibit TMZ-induced autophagy could enhance the efficacy of TMZ.
The assessment of efficient representation of drug features using deep learning for drug repositioning
Authors: Moridi Mahroo , Ghadirinia Marzieh , Sharifi-Zarchi Ali , Zare-Mirakabad Fatemeh 
Published: November 2019

Abstract
Background
De novo drug discovery is a time-consuming and expensive process. Nowadays, drug repositioning is utilized as a common strategy to discover a new drug indication for existing drugs. This strategy is mostly used in cases with a limited number of candidate pairs of drugs and diseases. In other words, they are not scalable to a large number of drugs and diseases. Most of the in-silico methods mainly focus on linear approaches while non-linear models are still scarce for new indication predictions. Therefore, applying non-linear computational approaches can offer an opportunity to predict possible drug repositioning candidates.

Results
In this study, we present a non-linear method for drug repositioning. We extract four drug features and two disease features to find the semantic relations between drugs and diseases. We utilize deep learning to extract an efficient representation for each feature. These representations reduce the dimension and heterogeneity of biological data. Then, we assess the performance of different combinations of drug features to introduce a pipeline for drug repositioning. In the available database, there are different numbers of known drug-disease associations corresponding to each combination of drug features. Our assessment shows that as the numbers of drug features increase, the numbers of available drugs decrease. Thus, the proposed method with large numbers of drug features is as accurate as small numbers.

Conclusion
Our pipeline predicts new indications for existing drugs systematically, in a more cost-effective way and shorter timeline. We assess the pipeline to discover the potential drug-disease associations based on cross-validation experiments and some clinical trial studies.
MLW-gcForest: a multi-weighted gcForest model towards the staging of lung adenocarcinoma based on multi-modal genetic data
Authors: Dong Yunyun , Yang Wenkai , Wang Jiawen , Zhao Juanjuan , Qiang Yan , Zhao Zijuan , Kazihise Ntikurako Guy Fernand , Cui Yanfen , Yang Xiaotong , Liu Siyuan 
Published: November 2019

Abstract
Background
Lung cancer is one of the most common types of cancer, among which lung adenocarcinoma accounts for the largest proportion. Currently, accurate staging is a prerequisite for effective diagnosis and treatment of lung adenocarcinoma. Previous research has used mainly single-modal data, such as gene expression data, for classification and prediction. Integrating multi-modal genetic data (gene expression RNA-seq, methylation data and copy number variation) from the same patient provides the possibility of using multi-modal genetic data for cancer prediction. A new machine learning method called gcForest has recently been proposed. This method has been proven to be suitable for classification in some fields. However, the model may face challenges when applied to small samples and high-dimensional genetic data.

Results
In this paper, we propose a multi-weighted gcForest algorithm (MLW-gcForest) to construct a lung adenocarcinoma staging model using multi-modal genetic data. The new algorithm is based on the standard gcForest algorithm. First, different weights are assigned to different random forests according to the classification performance of these forests in the standard gcForest model. Second, because the feature vectors generated under different scanning granularities have a diverse influence on the final classification result, the feature vectors are given weights according to the proposed sorting optimization algorithm. Then, we train three MLW-gcForest models based on three single-modal datasets (gene expression RNA-seq, methylation data, and copy number variation) and then perform decision fusion to stage lung adenocarcinoma. Experimental results suggest that the MLW-gcForest model is superior to the standard gcForest model in constructing a staging model of lung adenocarcinoma and is better than the traditional classification methods. The accuracy, precision, recall, and AUC reached 0.908, 0.896, 0.882, and 0.96, respectively.

Conclusions
The MLW-gcForest model has great potential in lung adenocarcinoma staging, which is helpful for the diagnosis and personalized treatment of lung adenocarcinoma. The results suggest that the MLW-gcForest algorithm is effective on multi-modal genetic data, which consist of small samples and are high dimensional.
Design and structural characterisation of olfactomedin-1 variants as tools for functional studies
Authors: Pronker Matti F. , van den Hoek Hugo , Janssen Bert J. C. 
Published: November 2019

AbstractBackgroundOlfactomedin-1 (Olfm1; also known as Noelin or Pancortin) is a highly-expressed secreted brain and retina protein and its four isoforms have different roles in nervous system development and function. Structural studies showed that the long Olfm1 isoform BMZ forms a disulfide-linked tetramer with a V-shaped architecture. The tips of the Olfm1 “V” each consist of two C-terminal β-propeller domains that enclose a calcium binding site. Functional characterisation of Olfm1 may be aided by new biochemical tools derived from these core structural elements.ResultsHere we present the production, purification and structural analysis of three novel monomeric, dimeric and tetrameric forms of mammalian Olfm1 for functional studies. We characterise these constructs structurally by high-resolution X-ray crystallography and small-angle X-ray scattering. The crystal structure of the Olfm1 β-propeller domain (to 1.25 Å) represents the highest-resolution structure of an olfactomedin family member to date, revealing features such as a hydrophilic tunnel containing water molecules running into the core of the domain where the calcium binding site resides. The shorter Olfactomedin-1 isoform BMY is a disulfide-linked tetramer with a shape similar to the corresponding region in the longer BMZ isoform.ConclusionsThese recombinantly-expressed protein tools should assist future studies, for example of biophysical, electrophysiological or morphological nature, to help elucidate the functions of Olfm1 in the mature mammalian brain. The control over the oligomeric state of Olfm1 provides a firm basis to better understand the role of Olfm1 in the (trans-synaptic) tethering or avidity-mediated clustering of synaptic receptors such as post-synaptic AMPA receptors and pre-synaptic amyloid precursor protein. In addition, the variation in domain composition of these protein tools provides a means to dissect the Olfm1 regions important for receptor binding.
Transcriptional profiling predicts running promotes cerebrovascular remodeling in young but not midlife mice
Authors: Foley Kate E. , Yang Hongtian Stanley , Graham Leah C. , Howell Gareth R. 
Published: November 2019

Abstract
Background
The incidence of dementia and cognitive decline is increasing with no therapy or cure. One of the reasons treatment remains elusive is because there are various pathologies that contribute to age-related cognitive decline. Specifically, with Alzheimer’s disease, targeting to reduce amyloid beta plaques and phosphorylated tau aggregates in clinical trials has not yielded results to slow symptomology, suggesting a new approach is needed. Interestingly, exercise has been proposed as a potential therapeutic intervention to improve brain health and reduce the risk for dementia, however the benefits throughout aging are not well understood.

Results
To better understand the effects of exercise, we preformed transcriptional profiling on young (1–2 months) and midlife (12 months) C57BL/6 J (B6) male mice after 12 weeks of voluntary running. Data was compared to age-matched sedentary controls. Interestingly, the midlife running group naturally broke into two cohorts based on distance ran - either running a lot and more intensely (high runners) or running less and less intensely (low runners). Midlife high runners had lower LDL cholesterol as well as lower adiposity (%fat) compared to sedentary, than midlife low runners compared to sedentary suggesting more intense running lowered systemic markers of risk for age-related diseases including dementias. Differential gene analysis of transcriptional profiles generated from the cortex and hippocampus showed thousands of differentially expressed (DE) genes when comparing young runners to sedentary controls. However, only a few hundred genes were DE comparing either midlife high runners or midlife low runners to midlife sedentary controls. This indicates that, in our study, the effects of running are reduced through aging. Gene set enrichment analyses identified enrichment of genes involved in extracellular matrix (ECM), vascular remodeling and angiogenesis in young runners but not midlife runners. These genes are known to be expressed in multiple vascular-related cell types including astrocytes, endothelial cells, pericytes and smooth muscle cells.

Conclusions
Taken together these results suggest running may best serve as a preventative measure to reduce risk for cerebrovascular decline. Ultimately, this work shows that exercise may be more effective to prevent dementia if introduced at younger ages.