bluuebunny/crossref_metadata_2025_split huggingface dataset:
NGS-Based Diagnostics in Hematopathology: Strategies for Implementation in a Clinical Environment
Authors: Elenitoba-Johnson Kojo S.J. 
Published: April 2021

The advent of next generation sequencing (NGS) has dramatically impacted the practice of hematopathology and the role of the clinical laboratory in information management and reporting. While the ability to simultaneously interrogate multiple gene loci for copy number, single nucleotide and large structural variations from one platform affords detailed examination of the genomes of hematologic malignancies, the integration of pre-analytical and technical workflows in genomic diagnostics and bioinformatics to ensure a seamless transmission of clinically relevant information offers opportunities for enhancement. In this session, a review of the parameters to be considered encompassing target selection, assay design, validation and performance specification test implementation will be covered. Considerations for options for reporting of clinical laboratory results to clinicians and oncologists to facilitate delivery of precision medicine will be examined.

Disclosures
Elenitoba-Johnson: Genomenon: Equity Ownership.
Clonal Evolution and Relapse in Adult De Novo Acute Myeloid Leukemia
Authors: Ley Timothy J. 
Published: April 2021

Patients with intermediate risk AML have unpredictable outcomes. Some do extremely well with conventional induction and consolidation chemotherapy, while others do poorly. The discovery of nearly all mutations associated with AML pathogenesis created an important database that has allowed investigators from around the world to use panel tests to assess the mutational landscapes of thousands of patients with known outcomes. Although these studies have been extremely informative, they have not dramatically altered the ability to accurately predict whether an individual intermediate-risk AML patient will relapse. The reasons are multifold. First, there is enormous combinatorial complexity of the mutations associated with AML. At least three mutations are required for the development of most AML cases, but since there are more than 250 recurrently mutated genes, the combinatorial possibilities are enormous. Secondly, because virtually all patients with AML present with clonal heterogeneity, and since individual subclones have different susceptibilities to chemotherapy, it has been difficult to predict outcomes based solely on the mutational composition of a patient at presentation. Further, since most subclones are 'invisible' to flow cytometric methods, and do not contain well-established mutations in genes that are recurrently mutated in AML, we cannot yet predict whether a subclone may be refractory to chemotherapy, or have extraordinary relapse potential . To overcome these issues, we asked whether information based on the clearance of the subclones from each patient could "integrate" this critical information in a practical way, and ultimately improve risk assessment. This study (Klco et al, JAMA 2015) suggested that a practical evaluation of mutation clearance after induction therapy could represent an improvement in our ability to predict whether intermediate risk patients who fail to clear their mutations after induction would benefit from allogeneic transplantation as their primary consolidation. A prospective clinical trial designed to answer this question is underway. Efforts to identify the properties of subclones that have high relapse potential, using single cell RNA-seq, and the sequencing of the relapse genomes of additional AML cases, will also be discussed.

Disclosures
No relevant conflicts of interest to declare.
Congenital Sideroblastic Anemias: Iron and Heme Lost in Mitochondrial Translation
Authors: Fleming Mark D. 
Published: April 2021

The congenital sideroblastic anemias (CSAs) are an uncommon, diverse class of inherited hematopoietic disorders characterized by pathological deposition of iron in the mitochondria of erythroid precursors. In recent years, the genetic causes of several clinically distinctive forms of CSA have been elucidated, which has revealed common themes in their pathogenesis. In particular, most, if not all, can be attributed to disordered mitochondrial heme synthesis, iron-sulfur cluster biogenesis or pathways related to mitochondrial protein synthesis. This presentation will summarize the clinical features, molecular genetics, and pathophysiology of the CSAs in the context of these pathways with particular emphasis on new disease entities and how characterization these phenotypes can contribute to CSA diagnostics and therapeutics.

Disclosures
No relevant conflicts of interest to declare.
RNA Methylation and Its Role in the Hematopoietic System
Authors: Lyko Frank 
Published: April 2021

Abstract
RNA methylation represents a novel expansion of traditional epigenetic concepts. RNAs can be methylated at adenine and at cytosine residues, and both modifications have distinct regulatory potential. Our work focuses on the DNMT2 enzyme, which is a member of the animal (cytosine-5) DNA methyltransferase family and has long been considered to function as a DNA methyltransferase. However, a DNA methyltransferase activity could not be confirmed conclusively and more recent work clearly demonstrates that DNMT2 is a tRNA methyltransferase. This unexpected substrate is interpreted to reflect an evolutionary ancient substrate switch from DNA to tRNA that expanded the epigenetic regulatory capacity of the DNMT family to also include RNA. To analyze the function of DNMT2, we performed a detailed analysis of knockout mice. These mice are viable and fertile, but also show a reduction of hematopoietic stem and progenitor cell populations and a cell-autonomous defect in their differentiation.1 RNA bisulfite sequencing revealed that Dnmt2 methylates C38 of tRNA Asp(GTC), Gly(GCC), and Val(AAC). Proteomic analyses from primary bone marrow cells uncovered systematic differences in protein expression that are due to specific codon mistranslation by tRNAs lacking DNMT2-dependent methylation. Together, these results illustrate the regulatory capacity of DNMT2-mediated tRNA methylation in genome recoding.2 Our current work addresses additional mechanistic aspects that link tRNA methylation to translational fidelity and investigates the relevance of DNMT2-mediated tRNA methylation for leukemogenesis.
1. Tuorto F, Herbst F, Alerasool N, et al. The tRNA methyltransferase Dnmt2 is required for accurate polypeptide synthesis during haematopoiesis. EMBO J. 2015;34(18):2350-2362.
2. Tuorto F, Lyko F. Genome recoding by tRNA modifications. Open Biol. 2016;6(12):160287.

Disclosures
No relevant conflicts of interest to declare.
Whole Exome Sequencing in Patients With Hematologic Malignancies: Ready for Real-Time Precision Medicine?
Authors: Haferlach Torsten 
Published: April 2021

In the last decade the landscape in hematological diseases has been newly defined. New platforms and assays in research have been used, new pathways, variations in genes and targets for precision medicine have been detected. Next generation sequencing (NGS) contributed a lot to these important achievements. In parallel, NGS has emerged from a research tool to a diagnostic tool and is increasingly applied in routine diagnostic laboratories. Today, NGS techniques are capable of facilitating diagnostics to detect mutations, many variants of uncertain significance, translocations but also gains and losses of chromosomal material. We now have to define, which scenario will be useful for daily routine, which application should still be considered research and how we can improve in the next few years. For sure, NGS is able to reproduce findings from Sanger sequencing to detect variants in single genes as well as to apply gene panels. The latter approach is increasingly used. It will substitute Sanger sequencing in many cases. Also the investigation of gene fusions and translocations will soon be available by NGS based assays in a routine setting. So far, whole exome sequencing (WES) studies have been published from several groups on AML, MDS, CML, ALL, lymphoma entities, CLL or myeloma, in a total ~ 1,500 cases. However, the investigation by WES or even whole genome sequencing so far is not a method of choice in routine diagnostics in hematology. The drawbacks are not only the technical applicability or costs but much more important: data handling and interpretation, and data storage. This is especially true as curated data is still limited and easy-to-use software applications are needed for routine application. If big data sets shall contribute in a routine diagnostic approach, significant bioinformatic processing is mandatory. Further, in many circumstances today WES is hampered as germline material is often missing and data have to be calculated from the "tumor only" sample. Therefore, the routine use of WES to define targets for precision medicine in hematology in a timely manner has only been established in very few places worldwide. The technique itself, instruments, assays and bioinformatic tools will however have the chance to be included in routine workflows at a reasonable turn-around-time within the next 5 years. This will shift or abolish several of today´s standard techniques.

Disclosures
Haferlach: MLL Munich Leukemia Laboratory: Employment, Equity Ownership.
Reversible cerebral vasoconstriction syndrome (RCVS): an interesting case report
Authors: Togha Mansoureh , Babaei Mahsa , Ghelichi Parvin Ganji 
Published: April 2021

AbstractBackgroundReversible Cerebral Vasoconstriction Syndrome is a condition of transient cerebral vascular spasms, which usually presents with recurrent thunderclap headaches and recovers within 3 months. Several probable triggers and underlying factors, such as sex hormones, vasoactive drugs, head trauma or surgery, and tumors, have been implicated.Case presentationIn this paper, we presenta53-year-old woman with thunderclap headaches and normal lab tests who was radio-clinically diagnosed with reversible cerebral vasoconstriction syndrome and treated accordingly. Then, she experienced the recurrence of RCVS after about 2 years and headaches after 1 year in association with high blood pressure, high blood sugar, hypothyroidism, hyperlipidemia, and a urine metanephrine level of 5 times higher than the normal limit, suggesting a diagnosis of pheochromocytoma. After confirmation of the diagnosis with further imaging studies, surgical removal of the tumor resolved all the signs and symptoms.ConclusionOften underdiagnosed, pheochromocytoma could be an important condition associated with RCVS. It is important for clinicians to bear this diagnosis in mind while dealing with similar cases of recurrent thunderclap headaches.
Behavioral sensitization induced by methamphetamine causes differential alterations in gene expression and histone acetylation of the prefrontal cortex in rats
Authors: Li Hui , Chen Jing-An , Ding Qian-Zhi , Lu Guan-Yi , Wu Ning , Su Rui-Bin , Li Fei , Li Jin 
Published: April 2021

Abstract
Background
Methamphetamine (METH) is one of the most widely abused illicit substances worldwide; unfortunately, its addiction mechanism remains unclear. Based on accumulating evidence, changes in gene expression and chromatin modifications might be related to the persistent effects of METH on the brain. In the present study, we took advantage of METH-induced behavioral sensitization as an animal model that reflects some aspects of drug addiction and examined the changes in gene expression and histone acetylation in the prefrontal cortex (PFC) of adult rats.

Methods
We conducted mRNA microarray and chromatin immunoprecipitation (ChIP) coupled to DNA microarray (ChIP-chip) analyses to screen and identify changes in transcript levels and histone acetylation patterns. Functional enrichment analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, were performed to analyze the differentially expressed genes. We then further identified alterations in ANP32A (acidic leucine-rich nuclear phosphoprotein-32A) and POU3F2 (POU domain, class 3, transcription factor 2) using qPCR and ChIP-PCR assays.

Results
In the rat model of METH-induced behavioral sensitization, METH challenge caused 275 differentially expressed genes and a number of hyperacetylated genes (821 genes with H3 acetylation and 10 genes with H4 acetylation). Based on mRNA microarray and GO and KEGG enrichment analyses, 24 genes may be involved in METH-induced behavioral sensitization, and 7 genes were confirmed using qPCR. We further examined the alterations in the levels of the ANP32A and POU3F2 transcripts and histone acetylation at different periods of METH-induced behavioral sensitization. H4 hyperacetylation contributed to the increased levels of ANP32A mRNA and H3/H4 hyperacetylation contributed to the increased levels of POU3F2 mRNA induced by METH challenge-induced behavioral sensitization, but not by acute METH exposure.

Conclusions
The present results revealed alterations in transcription and histone acetylation in the rat PFC by METH exposure and provided evidence that modifications of histone acetylation contributed to the alterations in gene expression caused by METH-induced behavioral sensitization.
Crystalline deposits in the cornea and various areas of the kidney as symptoms of an underlying monoclonal gammopathy: a case report
Authors: Lindemann C. , Enders P. , Brinkkoetter P. T. , Völker L. A. 
Published: April 2021

AbstractBackgroundPlasma cell dyscrasias (PCD) are characterized by an abnormal production of intact monoclonal immunoglobulins or parts such as heavy or light chains. In most cases, the monoclonal protein (also termed paraprotein) is produced by a clonal plasma cell population. The production of monoclonal proteins can result in deposits of various types and localization depending on the type, amount, and electrochemical properties of the paraprotein. One histopathologic presentation, albeit rare, are crystalline deposits. They can form in various organs and hence cause a wide spectrum of symptoms.Case presentationA 49-year-old man presented to the emergency department with eyestrain and foreign body sensation after overhead drilling. Examination of the eyes revealed crystalline deposits in the cornea of both eyes. After additional diagnostic testing, deposits were attributed to free light chains. Monoclonal gammopathy of undetermined significance (MGUS) was diagnosed according to serum electrophoresis and immunofixation. Four years later, new onset of proteinuria was detected. A percutaneous biopsy of the kidney showed severe light chain podocytopathy with secondary focal segmental glomerulosclerosis (FSGS) and light chain proximal tubulopathy (LCPT). In these lesions, crystalline deposits identical to the corneal deposits were found in ultrastructural and immunofluorescent analysis. The patient was diagnosed with monoclonal gammopathy of renal significance (MGRS), and a plasma cell directed therapy was initiated.ConclusionsPCD can present with a wide array of symptoms and are notoriously difficult to diagnose. Extrarenal manifestations such as crystalline deposits in the cornea are one possible manifestation. The case presented herein emphasizes the notion that extrarenal paraprotein deposits warrant a thorough search for the underlying clonal disease.
TIM3 expression on TILs is associated with poor response to neoadjuvant chemotherapy in patients with locally advanced triple-negative breast cancer
Authors: Cabioglu Neslihan , Onder Semen , Oner Gizem , Karatay Hüseyin , Tukenmez Mustafa , Muslumanoglu Mahmut , İgci Abdullah , Eralp Yeşim , Aydiner Adnan , Saip Pınar , Yavuz Ekrem , Ozmen Vahit 
Published: April 2021

Abstract
Background
The expression of immune checkpoint receptors (ICRs) on tumor-infiltrating lymphocytes (TILs) is associated with better response to immunotherapies via immune checkpoint inhibitors. Therefore, we investigated various ICR expressions on TILs in patients with locally advanced triple-negative breast cancer (TNBC) after neoadjuvant chemotherapy (NAC).

Methods
Expressions of ICRs were examined immunohistochemically in surgical specimens (n = 61) using monoclonal antibodies for PDL-1, PD-1, TIM-3, LAG-3, and CTLA-4. Positivity was defined as staining > 1% on TILs.

Results
The median age was 49 (24–76) years. The majority of patients were clinically T3–4 (n = 31, 50.8%) and clinically N1–3 (n = 58, 95.1%) before NAC. Of those, 82% were found to have CTLA-4 positivity, whereas PD1, PDL-1, LAG3, and TIM-3 expressions on TILs were 62.3, 50.9, 26.2, and 68.9%. A high expression of CTLA-4 was found to be associated with a better chemotherapy response (OR = 7.94, 95% CI: 0.9–70.12, p = 0.06), whereas TIM-3 positivity was contrarily associated with a worse chemotherapy response (OR = 0.253, 95% CI: 0.066–0.974, p = 0.047) as measured by the MDACC Residual Cancer Burden Index. At a 47-month follow-up, ypN0 (DFS; HR = 0.31, 95% CI: 0.12–0.83, p = 0.02 and DSS; HR = 0.21, 95% CI: 0.07–0.62, p = 0.005) and CTLA-4 high expression on TILs (DFS; HR = 0.38, 95% CI: 0.17–0.85, p = 0.019 and DSS; HR = 0.34, 95% CI: 0.15–0.78, p = 0.01) were found to be associated with improved survival.

Conclusions
These findings demonstrate that CTLA-4, PD-1, PDL-1, and TIM-3 were highly expressed in TNBC. Based on these high expression patterns, further studies directed towards combined therapies are warranted in advanced TNBC in future.
Factors for the optimal selection of granulocyte colony-stimulating factor preparations and predictors for R-CHOP dose reductions/delays among patients with non-Hodgkin B-cell lymphoma (STOP FN in NHL 2 subanalysis)
Authors: Yokoyama Masahiro , Kusano Yoshiharu , Inoue Norihito , Nishimura Noriko , Mishima Yuko , Nukada Tomoyuki , Hatake Kiyohiko , Terui Yasuhito 
Published: April 2021

Abstract
Background
A classification tree was used to analyze background factors for granulocyte colony-stimulating factor (G-CSF) preparation selection for febrile neutropenia (FN) prophylaxis in Japanese patients with non-Hodgkin B-cell lymphoma receiving the first R-CHOP cycle.

Methods
This was a subanalysis of the retrospective observational study STOP FN in NHL 2 (UMIN000029534). Patient characteristics, changes in neutrophil count, incidence and severity of neutropenia, and risk factors for dose reduction/delay of R-CHOP were assessed by G-CSF formulation.

Results
Among 234 patients in cycle 1, 25.6% received no G-CSF preparation, 52.1% received daily G-CSF, and 22.2% received pegfilgrastim. Pegfilgrastim use was most frequent among patients aged ≥ 80 years, while that of daily G-CSF was most frequent in patients with lymphocyte count (LC) < 1000 cells/μL. Changes in neutrophil count were more marked with pegfilgrastim compared with daily G-CSF and no G-CSF. Relevant factors for G-CSF preparation selection in the first R-CHOP cycle were age ≥ 80 years and LC < 1000 cells/μL; for chemotherapy dose reduction were FN onset in cycle 1 and female sex; and for dose delay was hemoglobin (< 12 g/dL). After cycle 2 and onward, pegfilgrastim use increased markedly (72.6%) compared with cycle 1 (22.2%), with significantly greater proportions continuing pegfilgrastim use and switching from daily G-CSF.

Conclusion
Relevant factors for G-CSF preparation selection were age ≥ 80 years and LC < 1000 cells/μL. The use of pegfilgrastim increased markedly after cycle 2. These results may be useful for selecting appropriate G-CSF preparations in the first R-CHOP cycle.

Trial registration
UMIN000029534; registered on 13 October 2017, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000033733.
Sleep problems are related to commuting accidents rather than to workplace accidents
Authors: Vargas-Garrido Héctor , Moyano-Díaz Emilio , Andrades Katherinne 
Published: April 2021

Abstract
Background
This study aimed to verify the relationships between sleep problems and both commuting and workplace accidents in workers of both sexes.

Methods
The study was carried out with a sample of workers (n = 2993; 50.2% female) from the Chilean Quality of Life Survey (ENCAVI) 2015–2016, while the rates of both workplace and commuting accidents were extracted from the statistics of the Superintendence of Social Security (SUSESO 2015; 180,036 and 52,629 lost-time accidents, respectively).

Results
Chilean workers sleep less than the rest of the people in the country (MW = 7.14 vs. MO = 7.33; t (6789) = − 5.19; p < .001), while the Chilean people as a whole sleep less compared to those of other countries (7.24 h per day). Likewise, it was found that sleep problems are more strongly related to commuting than to workplace accidents. In this vein, sleep quantity can explain 24% of the variance in commuting accidents’ rates (Stepwise Method; R2 = .30, F (1.14) = 5.49, p < .05; β = −.55, p < .05), by using aggregated data with all types of commuting roles (driver of a vehicle, a passenger of public or private transport, or as a pedestrian).

Conclusions
Our findings show that sleep quantity has a more robust relationship with commuting than workplace accidents, a neglected issue so far. Future prevention programs should emphasize sleep hygiene and focus on commuting to and from work.
Application of 3D modeling and fusion technology of medical image data in image teaching
Authors: Yuan Quan , Chen Xiaomei , Zhai Jian , Chen Yadi , Liu Qingxiang , Tan Zhongxiao , Chen Gao , Zhuang Kangle , Zhang Jianying , Xu Xi , Qiang Di , Shao Xuefei 
Published: April 2021

Abstract
Background
We combined anatomy with imaging, transformed the 2D information of various imaging techniques into 3D information, and form the assessment system of real medical imaging cases in order to make up for the deficiencies in the current teaching of the medical imaging technology students.

Methods
A total of 460 medical imaging students were selected and randomly divided into two groups. The research group received the teaching of the fusion of the original CT and MR data 3D model and the original image combined with 3D anatomical image. CT and MRI data are imported through load DICOM of 3D slicer. Different tissues and organs are segmented by threshold and watershed algorithm of segment editor module. Models are exported through export / import models and label maps in segmentation. Save the NHDR file of the original data and Obj file of the corresponding model through save the NHDR and corresponding Obj files are loaded into probe 1.0 software. The software can give different colors to the three-dimensional models of different organs or tissues to display the stereo models and related data, and display the hook edges of organ models on coronal, sagittal and axial images. At the same time, annotation can be established in the corresponding anatomical position. Finally, it can be saved as a single file of Hwl, and the teaching can be opened at any time through the program of probe 1.0. Statistical analysis Academic self-efficacy scale and Self-directed learning ability scale was adopted by self-directed learning evaluation scale between two groups.

Results
Compare the theoretical scores and case analysis scores of the two groups. The scores of the study and control groups were significantly higher than those of the control group. Before the experiment, no significant difference was detected in the self-efficacy of learning ability and learning behavior between the two groups, while after the experiment, these differences between the two groups were statistically significan. Moreover, the learning ability self-efficacy and learning behavior of the two groups of students after the experiment was significantly higher than that before the experiment. The self-efficacy of the learning behavior of the control group was higher after the experiment than that before the experiment, albeit the difference was not statistically significant.

Conclusions
The modern, information-based and humanized experimental teaching mode will be constantly improved under the support of PACS system in order to optimize the medical imaging teaching activities for the development of modern medical education.