bluuebunny/crossref_metadata_2025_split huggingface dataset:
In Vivo Effects of LSD1 Inhibition By Small Chemical Inhibitors in Sickle Cell Mice
Authors: Le Cuong , Myers Greggory , Habara Alawi , Jearawiriyapaisarn Natee , Lee Mary , Chui David H.K. , Steinberg Martin H. , Engel James , Cui Shuaiying 
Published: April 2021

Abstract
For the past decades the principal strategy for treating the β-globinopathies [sickle cell disease (SCD) and β-thalassemia] has been to devise methods for increasing the levels of fetal hemoglobin (HbF) in adult erythroid cells, as a strong clinical literature has demonstrated that high HbF levels ameliorate disease pathophysiology.
We originally reported the lysine-specific histone demethylase 1 (LSD1) as a new protein involved in the regulation of the fetal γ-globin genes. Inhibition of LSD1 using either RNAi or by the momoamine oxidase inhibitor tranylcypromine in primary human erythroid progenitor cells induces HbF to therapeutic levels. Thus, inhibition of LSD1 activity presents a novel exploratory avenue as a therapeutic strategy to treat SCD. Subsequent studies using another inhibitor RN-1 showed that RN-1 treatment of SCD mice results in increased HbF synthesis and leads to effective improvement of many aspects of the disease pathology normally associated with sickle cell disease.
Here we report studies designed to examine the in vivo effects of some additional, publically available small molecule chemical inhibitors of LSD1 on HbF synthesis and erythroid physiology in SCD mice. In control SCD mice treated with DMSO only, the number of HbF positive cells was about 2.5% of total in RBC, while in SCD mice exposed to GSK-LSD1, or OG-L002, there was a statistically significant increase in the percentage of HbF positive cells after 4 weeks of treatment (up to 8%, or 6% respectively). Furthermore, sickled RBCs and reticulocytes are significantly reduced while the number of mature erythrocytes increased markedly in the peripheral blood of GSK-LSD1, or OG-L002 treated SCD mice. These findings suggest that GSK-LSD1 and/or OG-L002 could be potentially new HbF inducers based on LSD1 inhibition. We believe that these experiments will be of wide general interest and will be the foundation for development of small molecule therapeutics with which to treat hemoglobinopathies.

Disclosures
No relevant conflicts of interest to declare.
Emerging T Cell Engineering Approaches: New Targets and New Cell Sources
Authors: Dotti Gianpietro 
Published: April 2021

Abstract
The field of chimeric antigen receptors (CARs) in hematologic malignancies has been largely dominated by the adoptive transfer of T cells expressing the CD19-specific CAR for therapy of acute lymphoid leukemia and non-Hodgkin's lymphomas. More recently other target antigens have been tested in phase I studies with the aim to either mitigate the B cell aplasia, caused by CD19-specific CAR-Ts in B-lymphoid malignancies, or to target other malignancies non-expressing CD19. Two new targets such as k-light chain of human immunoglobulins to target B-cell lymphomas and CD30 to target Hodgkin's lymphoma have completed phase I studies showing antitumor activity. Efforts are also dedicated to contain the toxicities associated with the infusion of CD19.CAR-T cells by including safety switches. The inducible-Caspase9 (iC9) may represent a precise strategy to modulate these toxicities by eliminating CAR-Ts in a dose-dependent manner, allowing either a selective containment of CAR-T cell expansion or complete deletion. Finally, while polyclonal activated T cells are generally used in clinical trials as a platform to engraft CARs, other sources like NK cells and NKT cells can potentially be explored in specific clinical situations such as after allogeneic T-cells, since both NK and NKT cells do not carry the risk of graft-versus-host disease (GVHD).

Disclosures
Dotti: Cell Medica and BluebirdBio: Research Funding.
Understanding the Genome: Professional Guidelines in Clinical Genomic Testing and Interpretation
Authors: Lyon Elaine 
Published: April 2021

Abstract
The rapid evolution of genomic testing gives new meaning to the term "high-complexity testing." Variant classification is clearly challenging, but with the aid of American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) professional guidelines for combining evidence used in conjunction with national efforts, laboratories may be better able to standardize and establish quality metrics. Additionally, guidelines for evaluating types of evidence and interpreting sequence variations have been developed. This session will review these guidelines to address expectations of data quality, as well as elements of reporting identified variants and their interpretations. Efforts by the molecular community to address consistency in using these guidelines will also be shown. The objectives of this presentation are to list technical guidelines for genomic sequencing to ensure quality data, to describe evidence used to classify variants, and to identify variability in how evidences are used.

Disclosures
Lyon: Complete Genomics: Consultancy; Korean Society for Medical and Molecular Genetics: Honoraria; Association for Molecular Pathology: Honoraria; American College of Medical Genetics and Genomics: Membership on an entity's Board of Directors or advisory committees.
Beyond Cytosine Methylation: Ten-Eleven Translocation Proteins, Oxidized Methylcytosines, and Cancer
Authors: Rao Anjana 
Published: April 2021

We discovered some years ago that enzymes of the TET (Ten-Eleven Translocation) family were a new class of epigenetic regulators that altered the modification status of cytosine bases in DNA. The three mammalian TET enzymes - TET1, TET2 and TET3 - successively oxidize the methyl group of 5-methylcytosine (5mC) to yield 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). These modified cytosine bases (together termed oxidized methylcytosines, oxi-mC) facilitate DNA demethylation and are also novel epigenetic marks. DNA methylation has long been linked to developmental processes and to oncogenesis; similarly TET proteins, which alter DNA modification status, are implicated in numerous biological processes, including cell lineage specification, embryonic development, neuronal function, somatic cell reprogramming and cancer. Loss-of-function mutations in the TET2 gene are frequently associated with lymphoid and myeloid cancers in humans. Using mouse models and biochemical and genome-wude approaches, we have analysed the role of TET proteins and oxi-mC in immune and haematopoietic cells. I will describe the data and discuss possible mechanisms.

Disclosures
Rao: Cambridge Epigenetix: Consultancy, Membership on an entity's Board of Directors or advisory committees.
Zinc-dependent multimerization of mutant calreticulin is required for MPL binding and MPN pathogenesis
Authors: Rivera Jeanne F. , Baral April J. , Nadat Fatima , Boyd Grace , Smyth Rachael , Patel Hershna , Burman Emma L. , Alameer Ghadah , Boxall Sally A. , Jackson Brian R. , Baxter E. Joanna , Laslo Peter , Green Anthony R. , Kent David G. , Mullally Ann , Chen Edwin 
Published: April 2021

Abstract
Calreticulin (CALR) is mutated in the majority of JAK2/MPL-unmutated myeloproliferative neoplasms (MPNs). Mutant CALR (CALRdel52) exerts its effect by binding to the thrombopoietin receptor MPL to cause constitutive activation of JAK-STAT signaling. In this study, we performed an extensive mutagenesis screen of the CALR globular N-domain and revealed 2 motifs critical for CALRdel52 oncogenic activity: (1) the glycan-binding lectin motif and (2) the zinc-binding domain. Further analysis demonstrated that the zinc-binding domain was essential for formation of CALRdel52 multimers, which was a co-requisite for MPL binding. CALRdel52 variants incapable of binding zinc were unable to homomultimerize, form CALRdel52-MPL heteromeric complexes, or stimulate JAK-STAT signaling. Finally, treatment with zinc chelation disrupted CALRdel52-MPL complexes in hematopoietic cells in conjunction with preferential eradication of cells expressing CALRdel52 relative to cells expressing other MPN oncogenes. In addition, zinc chelators exhibited a therapeutic effect in preferentially impairing growth of CALRdel52-mutant erythroblasts relative to unmutated erythroblasts in primary cultures of MPN patients. Together, our data implicate zinc as an essential cofactor for CALRdel52 oncogenic activity by enabling CALRdel52 multimerization and interaction with MPL, and suggests that perturbation of intracellular zinc levels may represent a new approach to abrogate the oncogenic activity of CALRdel52 in the treatment of MPNs.
Short-term earnings mobility in the Canadian and German context: the role of cognitive skills
Authors: Pullman Ashley , Gauly Britta , Lechner Clemens M. 
Published: April 2021

AbstractIt is well-established that human capital contributes to unequal levels of earnings mobility. Individuals with higher levels of human capital, typically measured through education, earn more on average and are privy to greater levels of upward change over time. Nevertheless, other factors may have an incremental effect over education, namely cognitive ability and the skill demands of employment. To deepen insight into whether these aspects contribute to earnings mobility over a four-year period, the present study examines positional change in Canada and Germany—two contexts typified as examples of liberal and coordinated market economies. A series of descriptive indices and relative change models assess how different measures of human capital are associated with earnings mobility. The results indicate that, while individuals with higher cognitive skills experience greater earnings stability and upward mobility in both countries, there is only an incremental effect of skills on mobility in Germany once we account for educational credentials. The results also provide evidence on the role of skill demands for earnings mobility; in both countries, advanced skills at work are associated with greater short-term mobility, even while controlling for cognitive ability and other factors. Together the results showcase how longitudinal data containing detailed measures of human capital allow for deeper insight into what facilitates earnings mobility.
Functional genomics of a Spiroplasma associated with the carmine cochineals Dactylopius coccus and Dactylopius opuntiae
Authors: Vera-Ponce León Arturo , Dominguez-Mirazo Marian , Bustamante-Brito Rafael , Higareda-Alvear Víctor , Rosenblueth Mónica , Martínez-Romero Esperanza 
Published: April 2021

Abstract
Background
Spiroplasma is a widely distributed endosymbiont of insects, arthropods, and plants. In insects, Spiroplasma colonizes the gut, hemolymph, and reproductive organs of the host. Previous metagenomic surveys of the domesticated carmine cochineal Dactylopius coccus and the wild cochineal D. opuntiae reported sequences of Spiroplasma associated with these insects. However, there is no analysis of the genomic capabilities and the interaction of this Spiroplasma with Dactylopius.

Results
Here we present three Spiroplasma genomes independently recovered from metagenomes of adult males and females of D. coccus, from two different populations, as well as from adult females of D. opuntiae. Single-copy gene analysis showed that these genomes were > 92% complete. Phylogenomic analyses classified these genomes as new members of Spiroplasma ixodetis.
Comparative genome analysis indicated that they exhibit fewer genes involved in amino acid and carbon catabolism compared to other spiroplasmas. Moreover, virulence factor-encoding genes (i.e., glpO, spaid and rip2) were found incomplete in these S. ixodetis genomes. We also detected an enrichment of genes encoding the type IV secretion system (T4SS) in S. ixodetis genomes of Dactylopius. A metratranscriptomic analysis of D. coccus showed that some of these T4SS genes (i.e., traG, virB4 and virD4) in addition to the superoxide dismutase sodA of S. ixodetis were overexpressed in the ovaries.

Conclusion
The symbiont S. ixodetis is a new member of the bacterial community of D. coccus and D. opuntiae. The recovery of incomplete virulence factor-encoding genes in S. ixodetis of Dactylopius suggests that this bacterium is a non-pathogenic symbiont. A high number of genes encoding the T4SS, in the S. ixodetis genomes and the overexpression of these genes in the ovary and hemolymph of the host suggest that S. ixodetis use the T4SS to interact with the Dactylopius cells. Moreover, the transcriptional differences of S. ixodetis among the gut, hemolymph and ovary tissues of D. coccus indicate that this bacterium can respond and adapt to the different conditions (e.g., oxidative stress) present within the host. All this evidence proposes that there is a strong interaction and molecular signaling in the symbiosis between S. ixodetis and the carmine cochineal Dactylopius.
Analgesic efficacy of postoperative bilateral, ultrasound-guided, posterior transversus abdominis plane block for laparoscopic colorectal cancer surgery: a randomized, prospective, controlled study
Authors: Zhao Yang , Zhang Han-Ying , Yuan Zong-Yi , Han Yi , Chen Yi-Rong , Liu Qi-lin , Zhu Tao 
Published: April 2021

Abstract
Background
We assessed whether a postoperative bilateral, ultrasound-guided, posterior transversus abdominis plane (TAP) block could reduce 24 h rescue tramadol requirement compared with placebo in patients undergoing elective laparoscopic colorectal cancer surgery.

Methods
Patients scheduled to undergo elective laparoscopic surgery following the diagnosis of colorectal cancer were included in this study and randomized into Group and Group Control. The patients received a postoperative bilateral, ultrasound-guided, posterior TAP block in either 20 mL of 0.5% ropivacaine (Group TAP) per side or an equivalent volume of normal saline (Group Control). The primary outcome was the cumulative consumption of rescue tramadol within 24 h after the surgery. Secondary endpoints included (1) resting and movement numerical rating scale (NRS) pain scores at 2, 4, 6, 12, 24, 48, and 72 h; (2) incidences of related side effects; (3) time to the first request for rescue tramadol; (4) patient satisfaction regarding postoperative analgesia; (5) time to restoration of intestinal function; (6) time to mobilization; and (7) the length of hospital stay.

Results
In total, 92 patients were randomized, and 82 patients completed the analysis. The total rescue tramadol requirement (median [interquartile range]) within the first 24 h was lower in Group TAP (0 [0, 87.5] mg) than in Group Control (100 [100, 200] mg), P < 0.001. The posterior TAP block reduced resting and movement NRS pain scores at 2, 4, 6, 12, and 24 h after surgery (all P < 0.001) but showed similar scores at 48 h or 72 h. A higher level of satisfaction with postoperative analgesia was observed in Group TAP on day 1 (P = 0.002), which was similar on days 2 (P = 0.702) and 3 (P = 0.551), compared with the Group Control. A few incidences of opioid-related side effects (P < 0.001) and a lower percentage of patients requiring rescue tramadol analgesia within 24 h (P < 0.001) were observed in Group TAP. The time to the first request for rescue analgesia was prolonged, and the time to mobilization and flatus was reduced with a shorter hospital stay in Group TAP as compared with Group Control.

Conclusions
A postoperative bilateral, ultrasound-guided, posterior TAP block resulted in better pain management and a faster recovery in patients undergoing laparoscopic colorectal cancer surgery, without adverse effects.

Trial registration
The study was registered at http://www.chictr.org.cn (ChiCTR-IPR-17012650; Sep 12, 2017).
Differential trends of admissions in accident and emergency departments during the COVID-19 pandemic in Germany
Authors: Jaehn Philipp , Holmberg Christine , Uhlenbrock Greta , Pohl Andreas , Finkenzeller Thomas , Pawlik Michael T. , Quack Ivo , Ernstberger Antonio , Rockmann Felix , Schreyer Andreas G. 
Published: April 2021

Abstract
Background
Recent studies have shown a decrease of admissions to accident and emergency (A&E) departments after the local outbreaks of COVID-19. However, differential trends of admission counts, for example according to diagnosis, are less well understood. This information is crucial to inform targeted intervention. Therefore, we aimed to compare admission counts in German A&E departments before and after 12th march in 2020 with 2019 according to demographic factors and diagnosis groups.

Methods
Routine data of all admissions between 02.12.2019–30.06.2020 and 01.12.2018–30.06.2019 was available from six hospitals in five cities from north-western, eastern, south-eastern, and south-western Germany. We defined 10 diagnosis groups using ICD-10 codes: mental disorders due to use of alcohol (MDA), acute myocardial infarction (AMI), stroke or transient ischemic attack (TIA), heart failure, pneumonia, chronic obstructive pulmonary disease (COPD), cholelithiasis or cholecystitis, back pain, fractures of the forearm, and fractures of the femur. We calculated rate ratios comparing different periods in 12.03.2020–30.06.2020 with 12.03.2019–30.06.2019.

Results
Forty-one thousand three hundred fifty-three cases were admitted between 12.03.2020–30.06.2020 and 51,030 cases between 12.03.2019–30.06.2019. Admission counts prior to 12.03. were equal in 2020 and 2019. In the period after 12.03., the decrease of admissions in 2020 compared to 2019 was largest between 26.03. and 08.04. (− 30%, 95% CI − 33% to − 27%). When analysing the entire period 12.03.-30.06., the decrease of admissions was heterogeneous among hospitals, and larger among people aged 0–17 years compared to older age groups. In the first 8 weeks after 12.03., admission counts of all diagnoses except femur fractures and pneumonia declined. Admissions with pneumonia increased in this early period. Between 07.05. and 30.6.2020, we noted that admissions with AMI (+ 13%, 95% CI − 3% to + 32%) and cholelithiasis or cholecystitis (+ 20%, 95% CI + 1% to + 44%) were higher than in 2019.

Conclusions
Our results suggest differential trends of admission counts according to age, location, and diagnosis. An initial decrease of admissions with MDA, AMI, stroke or TIA, heart failure, COPD, cholelithiasis or cholecystitis, and back pain imply delays of emergency care in Germany. Finally, our study suggests a delayed increase of admissions with AMI and cholelithiasis or cholecystitis.
Relationship between mortality and use of sodium bicarbonate at the time of dialysis initiation: a prospective observational study
Authors: Morooka Hikaru , Yamamoto Junichiro , Tanaka Akihito , Inaguma Daijo , Maruyama Shoichi 
Published: April 2021

Abstract
Background
Patients with chronic kidney disease often experience metabolic acidosis. Whether oral sodium bicarbonate can reduce mortality in patients with metabolic acidosis has been debated for years. Hence, this study was conducted to evaluate the utility of sodium bicarbonate in patients who will undergo dialysis therapy. In this study, we investigated the effect of oral sodium bicarbonate therapy on mortality in patients with end-stage kidney disease (ESKD) initiated on dialysis therapy.

Methods
We conducted an observational study of patients when they started dialysis therapy. There were 17 centres participating in the Aichi Cohort Study of Prognosis in Patients Newly Initiated into Dialysis. Data were available on patients’ sex, age, use of sodium bicarbonate, drug history, medical history, vital data, and laboratory data. We investigated whether patients on oral sodium bicarbonate for more than three months before dialysis initiation had a better prognosis than those without sodium bicarbonate therapy. The primary outcome was defined as all-cause mortality.

Results
The study included 1524 patients with chronic kidney disease who initiated dialysis between October 2011 and September 2013. Among them, 1030 were men and 492 women, with a mean age of 67.5 ± 13.1 years. Of these, 677 used sodium bicarbonate and 845 did not; 13.6% of the patients in the former group and 21.2% of those in the latter group died by March 2015 (p <  0.001). Even after adjusting for various factors, the use of sodium bicarbonate independently reduced mortality (p <  0.001).

Conclusions
The use of oral sodium bicarbonate at the time of dialysis initiation significantly reduced all-cause mortality in patients undergoing dialysis therapy.
An autopsy-proven case of Corticobasal degeneration heralded by Pontine infarction
Authors: Yoo Dallah , Park Sung-Hye , Yu Sungwook , Ahn Tae-Beom 
Published: April 2021

Abstract
Background
Neurodegenerative disorders are characterized by insidious progression with poorly-delineated long latent period. Antecedent clinical insult could rarely unmask latent neurodegenerative disorders. Here, we report an autopsy-proven case of corticobasal degeneration which was preceded by a lacunar infarction.

Case presentation
A 58-year-old man presented with acute ataxia associated with a lacunar infarction in the right paramedian pons. His ataxia persisted with additional progressive gait difficulty and left arm clumsiness. Six months later, a follow-up neurological examination showed asymmetrical bradykinesia, apraxia, dystonic posturing, postural instability, and mild ataxia of the left limbs. Cognitive examination revealed frontal executive dysfunction and visuospatial difficulties. Dopamine transporter imaging scan demonstrated bilateral reduced uptakes in mid-to-posterior putamen, more prominent on the right side. Levodopa-unresponsive parkinsonism, asymmetric limb dystonia, and ideomotor apraxia became more conspicuous, while limb ataxia gradually vanished. The patient became unable to walk without assistance after 1 year, and died 4 years after the symptom onset. Autopsy findings showed frontoparietal cortical atrophy, ballooned neurons, and phosphorylated tau-positive astrocytic plaques and neuropil threads with gliosis and neuronal loss, confirming the corticobasal degeneration.

Conclusions
The case illustrates that precedent clinical events such as stroke might tip a patient with subclinical CBS into overt clinical manifestations.