bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biomarkers associated with blinatumomab outcomes in acute lymphoblastic leukemia
Authors: Wei Andrew H. , Ribera Josep-Maria , Larson Richard A. , Ritchie David , Ghobadi Armin , Chen Yuqi , Anderson Abraham , Dos Santos Cedric E. , Franklin Janet , Kantarjian Hagop 
Published: February 2021

AbstractThis study aimed to identify biomarkers for clinical outcomes in a phase 3 clinical study of blinatumomab or chemotherapy in adults with Philadelphia chromosome-negative relapsed/refractory B-cell precursor acute lymphoblastic leukemia. Patients were randomized 2:1 to receive blinatumomab, a BiTE® therapy, for 4 weeks (9 μg/day cycle 1 week 1, 28 μg/day thereafter) every 6 weeks, or chemotherapy. Baseline blood samples were evaluated to identify biomarkers prognostic (both treatment groups) or predictive (either treatment groups) for overall survival, event-free survival, hematologic remission, minimal residual disease (MRD) response, duration of response, or adverse events. Baseline values were balanced between treatment groups. Prognostic biomarkers were platelets, tumor burden, and percentage of T cells: each 1-log increase in platelets at baseline was prognostic for improved 6-month survival; lower tumor burden was prognostic for hematologic remission; and a higher percentage of CD3+ T-cells was prognostic for MRD response. Consistent with the BiTE mechanism of action, higher percentage of CD45+ CD3+ CD8+ T cells was associated with hematologic remission following blinatumomab. No examined biomarkers were significant for the risk of grade ≥3 adverse events. Incorporating baseline biomarkers into future studies may help to identify subgroups most likely to benefit from blinatumomab.
Menin is necessary for long term maintenance of meningioma-1 driven leukemia
Authors: Libbrecht Clara , Xie Hongbo M. , Kingsley Molly C. , Haladyna Jessica N. , Riedel Simone S. , Alikarami Fatemeh , Lenard Alexandra , McGeehan Gerard M. , Ernst Patricia , Bernt Kathrin M. 
Published: February 2021

AbstractTranslocations of Meningioma-1 (MN1) occur in a subset of acute myeloid leukemias (AML) and result in high expression of MN1, either as a full-length protein, or as a fusion protein that includes most of the N-terminus of MN1. High levels of MN1 correlate with poor prognosis. When overexpressed in murine hematopoietic progenitors, MN1 causes an aggressive AML characterized by an aberrant myeloid precursor-like gene expression program that shares features of KMT2A-rearranged (KMT2A-r) leukemia, including high levels of Hoxa and Meis1 gene expression. Compounds that target a critical KMT2A–Menin interaction have proven effective in KMT2A-r leukemia. Here, we demonstrate that Menin (Men1) is also critical for the self-renewal of MN1-driven AML through the maintenance of a distinct gene expression program. Genetic inactivation of Men1 led to a decrease in the number of functional leukemia-initiating cells. Pharmacologic inhibition of the KMT2A–Menin interaction decreased colony-forming activity, induced differentiation programs in MN1-driven murine leukemia and decreased leukemic burden in a human AML xenograft carrying an MN1-ETV6 translocation. Collectively, these results nominate Menin inhibition as a promising therapeutic strategy in MN1-driven leukemia.
The placental lipidome of maternal antenatal depression predicts socio-emotional problems in the offspring
Authors: Wong Gerard , Weir Jacquelyn M. , Mishra Priti , Huynh Kevin , Nijagal Brunda , Gupta Varsha , Broekman Birit F. P. , Chong Mary Foong-Fong , Chan Shiao-Yng , Tan Kok Hian , Tull Dedreia , McConville Malcolm , Calder Philip C. , Godfrey Keith M. , Chong Yap Seng , Gluckman Peter D. , Meaney Michael J. , Meikle Peter J. , Karnani Neerja 
Published: February 2021

AbstractWhile maternal mental health strongly influences neurodevelopment and health in the offspring, little is known about the determinants of inter-individual variation in the mental health of mothers. Likewise, the in utero biological pathways by which variation in maternal mental health affects offspring development remain to be defined. Previous studies implicate lipids, consistent with a known influence on cognitive and emotional function, but the relevance for maternal mental health and offspring neurodevelopment is unclear. This study characterizes the placental and circulatory lipids in antenatal depression, as well as socio-emotional outcomes in the offspring. Targeted liquid chromatography-mass spectrometry covering 470 lipid species was performed on placenta from 186 women with low (n = 70) or high (n = 116) levels of antenatal depressive symptoms assessed using the Edinburgh Postnatal Depression Scale at 26 weeks’ gestation. Child socio-emotional outcomes were assessed from the Child Behavior Check List (CBCL) at 48 months. Seventeen placental lipid species showed an inverse association with antenatal EPDS scores. Specifically, lower levels of phospholipids containing LC-PUFAs: omega-3 docosapentaenoic acid (DPA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and omega-6 arachidonic acid (AA) were significantly associated with depressive symptoms. Additional measurement of LC-PUFA in antenatal plasma samples at mid-gestation confirmed the reduced circulation of these specific fatty acids in mothers. Reduced concentration of the placental phospholipids also predicted poorer socio-emotional outcomes in the offspring. This study provides new insights into the role of the materno-fetal lipid cross-talk as a mechanism linking maternal mental health to that of the offspring. These findings show the potential utility of nutritional approaches among pregnant women with depressive symptoms to reduce offspring risk for later socio-emotional problems.
Disrupted-in-schizophrenia 1 enhances the quality of circadian rhythm by stabilizing BMAL1
Authors: Lee Su Been , Park Jihyun , Kwak Yongdo , Park Young-Un , Nhung Truong Thi My , Suh Bo Kyoung , Woo Youngsik , Suh Yeongjun , Cho Eunbyul , Cho Sehyung , Park Sang Ki 
Published: February 2021

AbstractDisrupted-in-schizophrenia 1 (DISC1) is a scaffold protein that has been implicated in multiple mental disorders. DISC1 is known to regulate neuronal proliferation, signaling, and intracellular calcium homeostasis, as well as neurodevelopment. Although DISC1 was linked to sleep-associated behaviors, whether DISC1 functions in the circadian rhythm has not been determined yet. In this work, we revealed that Disc1 expression exhibits daily oscillating pattern and is regulated by binding of circadian locomotor output cycles kaput (CLOCK) and Brain and muscle Arnt-like protein-1 (BMAL1) heterodimer to E-box sequences in its promoter. Interestingly, Disc1 deficiency increases the ubiquitination of BMAL1 and de-stabilizes it, thereby reducing its protein levels. DISC1 inhibits the activity of GSK3β, which promotes BMAL1 ubiquitination, suggesting that DISC1 regulates BMAL1 stability by inhibiting its ubiquitination. Moreover, Disc1-deficient cells and mice show reduced expression of other circadian genes. Finally, Disc1-LI (Disc1 knockout) mice exhibit damped circadian physiology and behaviors. Collectively, these findings demonstrate that the oscillation of DISC1 expression is under the control of CLOCK and BMAL1, and that DISC1 contributes to the core circadian system by regulating BMAL1 stability.
Cntn4, a risk gene for neuropsychiatric disorders, modulates hippocampal synaptic plasticity and behavior
Authors: Oguro-Ando Asami , Bamford Rosemary A. , Sital Wiedjai , Sprengers Jan J. , Zuko Amila , Matser Jolien M. , Oppelaar Hugo , Sarabdjitsingh Angela , Joëls Marian , Burbach J. Peter. H. , Kas Martien J. 
Published: February 2021

AbstractNeurodevelopmental and neuropsychiatric disorders, such as autism spectrum disorders (ASD), anorexia nervosa (AN), Alzheimer’s disease (AD), and schizophrenia (SZ), are heterogeneous brain disorders with unknown etiology. Genome wide studies have revealed a wide variety of risk genes for these disorders, indicating a biological link between genetic signaling pathways and brain pathology. A unique risk gene is Contactin 4 (Cntn4), an Ig cell adhesion molecule (IgCAM) gene, which has been associated with several neuropsychiatric disorders including ASD, AN, AD, and SZ. Here, we investigated the Cntn4 gene knockout (KO) mouse model to determine whether memory dysfunction and altered brain plasticity, common neuropsychiatric symptoms, are affected by Cntn4 genetic disruption. For that purpose, we tested if Cntn4 genetic disruption affects CA1 synaptic transmission and the ability to induce LTP in hippocampal slices. Stimulation in CA1 striatum radiatum significantly decreased synaptic potentiation in slices of Cntn4 KO mice. Neuroanatomical analyses showed abnormal dendritic arborization and spines of hippocampal CA1 neurons. Short- and long-term recognition memory, spatial memory, and fear conditioning responses were also assessed. These behavioral studies showed increased contextual fear conditioning in heterozygous and homozygous KO mice, quantified by a gene-dose dependent increase in freezing response. In comparison to wild-type mice, Cntn4-deficient animals froze significantly longer and groomed more, indicative of increased stress responsiveness under these test conditions. Our electrophysiological, neuro-anatomical, and behavioral results in Cntn4 KO mice suggest that Cntn4 has important functions related to fear memory possibly in association with the neuronal morphological and synaptic plasticity changes in hippocampus CA1 neurons.
DNA methylation differences associated with social anxiety disorder and early life adversity
Authors: Wiegand Ariane , Kreifelts Benjamin , Munk Matthias H. J. , Geiselhart Nadja , Ramadori Katia E. , MacIsaac Julia L. , Fallgatter Andreas J. , Kobor Michael S. , Nieratschker Vanessa 
Published: February 2021

AbstractSocial anxiety disorder (SAD) is a psychiatric disorder characterized by extensive fear in social situations. Multiple genetic and environmental factors are known to contribute to its pathogenesis. One of the main environmental risk factors is early life adversity (ELA). Evidence is emerging that epigenetic mechanisms such as DNA methylation might play an important role in the biological mechanisms underlying SAD and ELA. To investigate the relationship between ELA, DNA methylation, and SAD, we performed an epigenome-wide association study for SAD and ELA examining DNA from whole blood of a cohort of 143 individuals using DNA methylation arrays. We identified two differentially methylated regions (DMRs) associated with SAD located within the genesSLC43A2andTNXB. As this was the first epigenome-wide association study for SAD, it is worth noting that both genes have previously been associated with panic disorder. Further, we identified two DMRs associated with ELA within theSLC17A3promoter region and theSIAH3gene and several DMRs that were associated with the interaction of SAD and ELA. Of these, the regions withinC2CD2LandMRPL28showed the largest difference in DNA methylation. Lastly, we found that two DMRs were associated with both the severity of social anxiety and ELA, however, neither of them was found to mediate the contribution of ELA to SAD later in life. Future studies are needed to replicate our findings in independent cohorts and to investigate the biological pathways underlying these effects.
The psychiatric phenotypes of 1q21 distal deletion and duplication
Authors: Linden Stefanie C. , Watson Cameron J. , Smith Jacqueline , Chawner Samuel J. R. A. , Lancaster Thomas M. , Evans Ffion , Williams Nigel , Skuse David , Raymond F. Lucy , Hall Jeremy , Owen Michael J. , Linden David E. J. , Green-Snyder LeeAnne , Chung Wendy K. , Maillard Anne M. , Jacquemont Sébastien , van den Bree Marianne B. M. 
Published: February 2021

AbstractCopy number variants are amongst the most highly penetrant risk factors for psychopathology and neurodevelopmental deficits, but little information about the detailed clinical phenotype associated with particular variants is available. We present the largest study of the microdeletion and -duplication at the distal 1q21 locus, which has been associated with schizophrenia and intellectual disability, in order to investigate the range of psychiatric phenotypes. Clinical and cognitive data from 68 deletion and 55 duplication carriers were analysed with logistic regression analysis to compare frequencies of mental disorders between carrier groups and controls, and linear mixed models to compare quantitative phenotypes. Both children and adults with copy number variants at 1q21 had high frequencies of psychopathology. In the children, neurodevelopmental disorders were most prominent (56% for deletion, 68% for duplication carriers). Adults had increased prevalence of mood (35% for deletion [OR = 6.6 (95% CI: 1.4–40.1)], 55% for duplication carriers [8.3 (1.4–55.5)]) and anxiety disorders (24% [1.8 (0.4–8.4)] and 55% [10.0 (1.9–71.2)]). The adult group, which included mainly genetically affected parents of probands, had an IQ in the normal range. These results confirm high prevalence of neurodevelopmental disorders associated with CNVs at 1q21 but also reveal high prevalence of mood and anxiety disorders in a high-functioning adult group with these CNVs. Because carriers of neurodevelopmental CNVs who show relevant psychopathology but no major cognitive impairment are not currently routinely receiving clinical genetic services widening of genetic testing in psychiatry may be considered.
The neuroprogressive nature of major depressive disorder: evidence from an intrinsic connectome analysis
Authors: Liu Jin , Fan Yiming , Ling-Li Zeng  , Liu Bangshan , Ju Yumeng , Wang Mi , Dong Qiangli , Lu Xiaowen , Sun Jinrong , Zhang Liang , Guo Hua , Futao Zhao  , Weihui Li  , Zhang Li , Li Zexuan , Liao Mei , Zhang Yan , Hu Dewen , Li Lingjiang 
Published: February 2021

AbstractMajor depressive disorder (MDD) is a prevailing chronic mental disorder with lifetime recurring episodes. Recurrent depression (RD) has been reported to be associated with greater severity of depression, higher relapse rate and prominent functioning impairments than first-episode depression (FED), suggesting the progressive nature of depression. However, there is still little evidence regarding brain functional connectome. In this study, 95 medication-free MDD patients (35 with FED and 60 with RD) and 111 matched healthy controls (HCs) underwent resting-state functional magnetic resonance imaging (fMRI) scanning. After six months of treatment with paroxetine, 56 patients achieved clinical remission and finished their second scan. Network-based statistics analysis was used to explore the changes in functional connectivity. The results revealed that, compared with HCs, patients with FED exhibited hypoconnectivity in the somatomotor, default mode and dorsal attention networks, and RD exhibited hyperconnectivity in the somatomotor, salience, executive control, default mode and dorsal attention networks, as well as within and between salience and executive control networks. Moreover, the disrupted components in patients with current MDD did not change significantly when the patients achieved remission after treatment, and sub-hyperconnectivity and sub-hypoconnectivity were still found in those with remitted RD. Additionally, the hypoconnectivity in FED and hyperconnectivity in RD were associated with the number of episodes and total illness duration. This study provides initial evidence supporting that impairment of intrinsic functional connectivity across the course of depression is a progressive process.
Low dose oral ketamine treatment in chronic suicidality: An open-label pilot study
Authors: Can Adem T. , Hermens Daniel F. , Dutton Megan , Gallay Cyrana C. , Jensen Emma , Jones Monique , Scherman Jennifer , Beaudequin Denise A. , Yang Cian , Schwenn Paul E. , Lagopoulos Jim 
Published: February 2021

AbstractRecently, low-dose ketamine has been proposed as a rapid-acting treatment option for suicidality. The majority of studies to date have utilised intravenous (IV) ketamine, however, this route of administration has limitations. On the other hand, oral ketamine can be administered in a range of settings, which is important in treating suicidality, although studies as to safety and feasibility are lacking. n = 32 adults (aged 22–72 years; 53% female) with chronic suicidal thoughts participated in the Oral Ketamine Trial on Suicidality (OKTOS), an open-label trial of sub-anaesthetic doses of oral ketamine over 6 weeks. Participants commenced with 0.5 mg/kg of ketamine, which was titrated to a maximum 3.0 mg/kg. Follow-up assessments occurred at 4 weeks after the final dose. The primary outcome measure was the Beck Scale for Suicide Ideation (BSS) and secondary measures included scales for suicidality and depressive symptoms, and measures of functioning and well-being. Mean BSS scores significantly reduced from a high level of suicidal ideation at the pre-ketamine (week 0) timepoint to below the clinical threshold at the post-ketamine (week 6) timepoint. The proportion of participants that achieved clinical improvement within the first 6 weeks was 69%, whereas 50% achieved a significant improvement by the follow-up (week 10) timepoint. Six weeks of oral ketamine treatment in participants with chronic suicidality led to significant reduction in suicidal ideation. The response observed in this study is consistent with IV ketamine trials, suggesting that oral administration is a feasible and tolerable alternative treatment for chronic suicidality.
Multi-omic and multi-species meta-analyses of nicotine consumption
Authors: Palmer Rohan H. C. , Benca-Bachman Chelsie E. , Huggett Spencer B. , Bubier Jason A. , McGeary John E. , Ramgiri Nikhil , Srijeyanthan Jenani , Yang Jingjing , Visscher Peter M. , Yang Jian , Knopik Valerie S. , Chesler Elissa J. 
Published: February 2021

AbstractCross-species translational approaches to human genomic analyses are lacking. The present study uses an integrative framework to investigate how genes associated with nicotine use in model organisms contribute to the genetic architecture of human tobacco consumption. First, we created a model organism geneset by collecting results from five animal models of nicotine exposure (RNA expression changes in brain) and then tested the relevance of these genes and flanking genetic variation using genetic data from human cigarettes per day (UK BioBankN = 123,844; all European Ancestry). We tested three hypotheses: (1) DNA variation in, or around, the ‘model organism geneset’ will contribute to the heritability to human tobacco consumption, (2) that the model organism genes will be enriched for genes associated with human tobacco consumption, and (3) that a polygenic score based off our model organism geneset will predict tobacco consumption in the AddHealth sample (N = 1667; all European Ancestry). Our results suggested that: (1) model organism genes accounted for ~5–36% of the observed SNP-heritability in human tobacco consumption (enrichment: 1.60–31.45), (2) model organism genes, but not negative control genes, were enriched for the gene-based associations (MAGMA, H-MAGMA, SMultiXcan) for human cigarettes per day, and (3) polygenic scores based on our model organism geneset predicted cigarettes per day in an independent sample. Altogether, these findings highlight the advantages of using multiple species evidence to isolate genetic factors to better understand the etiological complexity of tobacco and other nicotine consumption.
Synergistic inhibition of histone modifiers produces therapeutic effects in adult Shank3-deficient mice
Authors: Zhang Freddy , Rein Benjamin , Zhong Ping , Shwani Treefa , Conrow-Graham Megan , Wang Zi-Jun , Yan Zhen 
Published: February 2021

AbstractAutism spectrum disorder (ASD) is a lifelong developmental disorder characterized by social deficits and other behavioral abnormalities. Dysregulation of epigenetic processes, such as histone modifications and chromatin remodeling, have been implicated in ASD pathology, and provides a promising therapeutic target for ASD. Haploinsufficiency of theSHANK3gene is causally linked to ASD, so adult (3–5 months old)Shank3-deficient male mice were used in this drug discovery study. We found that combined administration of the class I histone deacetylase inhibitor Romidepsin and the histone demethylase LSD1 inhibitor GSK-LSD1 persistently ameliorated the autism-like social preference deficits, while each individual drug alone was largely ineffective. Another behavioral abnormality in adultShank3-deficient male mice, heightened aggression, was also alleviated by administration of the dual drugs. Furthermore, Romidepsin/GSK-LSD1 treatment significantly increased transcriptional levels of NMDA receptor subunits in prefrontal cortex (PFC) of adultShank3-deficient mice, resulting in elevated synaptic expression of NMDA receptors and the restoration of NMDAR synaptic function in PFC pyramidal neurons. These results have offered a novel pharmacological intervention strategy for ASD beyond early developmental periods.
The association of clinical correlates, metabolic parameters, and thyroid hormones with suicide attempts in first-episode and drug-naïve patients with major depressive disorder comorbid with anxiety: a large-scale cross-sectional study
Authors: Zhou Yongjie , Ren Wenchao , Sun Qianqian , Yu Katherine M. , Lang Xiaoe , Li Zezhi , Zhang Xiang Yang 
Published: February 2021

AbstractThe associated factors of suicide attempts in patients with major depressive disorder (MDD) comorbid with anxiety remains unclear. To the best of our knowledge, this is the first study with a large sample size that examines the risk factors of suicide attempts in first-episode drug-naïve (FEND) MDD patients comorbid with anxiety and includes clinical correlates, metabolic parameters, and thyroid hormone levels. A total of 1718 FEDN MDD patients were enrolled. The Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA), and Positive and Negative Syndrome Scale (PANSS) were used to assess the symptoms of patients. Metabolic parameters and thyroid hormone levels were measured. The prevalence of suicide attempts in MDD patients comorbid anxiety symptoms was 24.28%, which was 9.51 times higher than that in MDD patients without anxiety symptoms (3.25%). Compared to non-attempters, MDD patients with anxiety symptoms who attempted suicide scored higher on HAMD and HAMA, and had higher systolic blood pressure, higher levels of thyroid stimulating hormone (TSH), and thyroid peroxidases antibody (TPOAb), which were also correlated with suicide attempts in MDD patients comorbid anxiety symptoms. The combination of HAMA score, HAMD score, and TSH could differentiate suicide attempters from non-suicide attempters. Further, the age of onset, illness duration, BMI, TSH, and TPOAb were associated with the times of suicide attempts in MDD patients comorbid anxiety symptoms. Our results demonstrate high prevalence of suicide attempts in MDD patients comorbid anxiety symptoms. Several clinical correlates, metabolic parameters, and thyroid hormones function contribute to the suicide attempts in MDD patients comorbid anxiety symptoms.