bluuebunny/crossref_metadata_2025_split huggingface dataset:
miR-130b and miR-128a are essential lineage-specific codrivers of t(4;11) MLL-AF4 acute leukemia
Authors: Malouf Camille , Antunes Eric T. B. , O’Dwyer Michael , Jakobczyk Hélène , Sahm Franziska , Landua Sophie-Luise , Anderson Richard A. , Soufi Abdenour , Halsey Christina , Ottersbach Katrin 
Published: June 2021

Abstract
t(4;11) MLL-AF4 acute leukemia is one of the most aggressive malignancies in the infant and pediatric population, yet we have little information on the molecular mechanisms responsible for disease progression. This impairs the development of therapeutic regimens that can address the aggressive phenotype and lineage plasticity of MLL-AF4–driven leukemogenesis. This study highlights novel mechanisms of disease development by focusing on 2 microRNAs (miRNAs) upregulated in leukemic blasts from primary patient samples: miR-130b and miR-128a. We show that miR-130b and miR-128a are downstream targets of MLL-AF4 and can individually drive the transition from a pre-leukemic stage to an acute leukemia in an entirely murine Mll-AF4 in vivo model. They are also required to maintain the disease phenotype. Interestingly, miR-130b overexpression led to a mixed/B-cell precursor (BCP)/myeloid leukemia, propagated by the lymphoid-primed multipotent progenitor (LMPP) population, whereas miR-128a overexpression resulted in a pro-B acute lymphoblastic leukemia (ALL), maintained by a highly expanded Il7r+c-Kit+ blast population. Molecular and phenotypic changes induced by these two miRNAs fully recapitulate the human disease, including central nervous system infiltration and activation of an MLL-AF4 expression signature. Furthermore, we identified 2 downstream targets of these miRNAs, NR2F6 and SGMS1, which in extensive validation studies are confirmed as novel tumor suppressors of MLL-AF4+ leukemia. Our integrative approach thus provides a platform for the identification of essential co-drivers of MLL-rearranged leukemias, in which the preleukemia to leukemia transition and lineage plasticity can be dissected and new therapeutic approaches can be tested.
Degradation of Janus kinases in CRLF2-rearranged acute lymphoblastic leukemia
Authors: Chang Yunchao , Min Jaeki , Jarusiewicz Jamie A. , Actis Marisa , Yu-Chen Bradford Shanshan , Mayasundari Anand , Yang Lei , Chepyala Divyabharathi , Alcock Lisa J. , Roberts Kathryn G. , Nithianantham Stanley , Maxwell Dylan , Rowland Lauren , Larsen Randolph , Seth Aman , Goto Hiroaki , Imamura Toshihiko , Akahane Koshi , Hansen Baranda S. , Pruett-Miller Shondra M. , Paietta Elisabeth M. , Litzow Mark R. , Qu Chunxu , Yang Jun J. , Fischer Marcus , Rankovic Zoran , Mullighan Charles G. 
Published: June 2021

Abstract
CRLF2-rearranged (CRLF2r) acute lymphoblastic leukemia (ALL) accounts for more than half of Philadelphia chromosome-like (Ph-like) ALL and is associated with a poor outcome in children and adults. Overexpression of CRLF2 results in activation of Janus kinase (JAK)-STAT and parallel signaling pathways in experimental models, but existing small molecule inhibitors of JAKs show variable and limited efficacy. Here, we evaluated the efficacy of proteolysis-targeting chimeras (PROTACs) directed against JAKs. Solving the structure of type I JAK inhibitors ruxolitinib and baricitinib bound to the JAK2 tyrosine kinase domain enabled the rational design and optimization of a series of cereblon (CRBN)-directed JAK PROTACs utilizing derivatives of JAK inhibitors, linkers, and CRBN-specific molecular glues. The resulting JAK PROTACs were evaluated for target degradation, and activity was tested in a panel of leukemia/lymphoma cell lines and xenograft models of kinase-driven ALL. Multiple PROTACs were developed that degraded JAKs and potently killed CRLF2r cell lines, the most active of which also degraded the known CRBN neosubstrate GSPT1 and suppressed proliferation of CRLF2r ALL in vivo, e.g. compound 7 (SJ988497). Although dual JAK/GSPT1-degrading PROTACs were the most potent, the development and evaluation of multiple PROTACs in an extended panel of xenografts identified a potent JAK2-degrading, GSPT1-sparing PROTAC that demonstrated efficacy in the majority of kinase-driven xenografts that were otherwise unresponsive to type I JAK inhibitors, e.g. compound 8 (SJ1008030). Together, these data show the potential of JAK-directed protein degradation as a therapeutic approach in JAK-STAT–driven ALL and highlight the interplay of JAK and GSPT1 degradation activity in this context.
Depalmitoylation rewires FLT3-ITD signaling and exacerbates leukemia progression
Authors: Lv Kaosheng , Ren Jian-Gang , Han Xu , Gui Jun , Gong Chujie , Tong Wei 
Published: June 2021

Abstract
Internal tandem duplication within FLT3 (FLT3-ITD) is one of the most frequent mutations in acute myeloid leukemia (AML) and correlates with a poor prognosis. Whereas the FLT3 receptor tyrosine kinase is activated at the plasma membrane to transduce PI3K/AKT and RAS/MAPK signaling, FLT3-ITD resides in the endoplasmic reticulum and triggers constitutive STAT5 phosphorylation. Mechanisms underlying this aberrant FLT3-ITD subcellular localization or its impact on leukemogenesis remain poorly established. In this study, we discovered that FLT3-ITD is S-palmitoylated by the palmitoyl acyltransferase ZDHHC6. Disruption of palmitoylation redirected FLT3-ITD to the plasma membrane and rewired its downstream signaling by activating AKT and extracellular signal-regulated kinase pathways in addition to STAT5. Consequently, abrogation of palmitoylation increased FLT3-ITD–mediated progression of leukemia in xenotransplant-recipient mouse models. We further demonstrate that FLT3 proteins were palmitoylated in primary human AML cells. ZDHHC6-mediated palmitoylation restrained FLT3-ITD surface expression, signaling, and colonogenic growth of primary FLT3-ITD+ AML. More important, pharmacological inhibition of FLT3-ITD depalmitoylation synergized with the US Food and Drug Administration–approved FLT3 kinase inhibitor gilteritinib in abrogating the growth of primary FLT3-ITD+ AML cells. These findings provide novel insights into lipid-dependent compartmentalization of FLT3-ITD signaling in AML and suggest targeting depalmitoylation as a new therapeutic strategy to treat FLT3-ITD+ leukemias.
Migraine and neuroinflammation: the inflammasome perspective
Authors: Kursun Oguzhan , Yemisci Muge , van den Maagdenberg Arn M. J. M. , Karatas Hulya 
Published: June 2021

AbstractBackgroundNeuroinflammation has an important role in the pathophysiology of migraine, which is a complex neuro-glio-vascular disorder. The main aim of this review is to highlight findings of cortical spreading depolarization (CSD)-induced neuroinflammatory signaling in brain parenchyma from the inflammasome perspective. In addition, we discuss the limited data of the contribution of inflammasomes to other aspects of migraine pathophysiology, foremost the activation of the trigeminovascular system and thereby the generation of migraine pain.Main bodyInflammasomes are signaling multiprotein complexes and key components of the innate immune system. Their activation causes the production of inflammatory cytokines that can stimulate trigeminal neurons and are thus relevant to the generation of migraine pain. The contribution of inflammasome activation to pain signaling has attracted considerable attention in recent years. Nucleotide-binding domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) is the best characterized inflammasome and there is emerging evidence of its role in a variety of inflammatory pain conditions, including migraine. In this review, we discuss, from an inflammasome point of view, cortical spreading depolarization (CSD)-induced neuroinflammatory signaling in brain parenchyma, the connection with genetic factors that make the brain vulnerable to CSD, and the relation of the inflammasome with diseases that are co-morbid with migraine, including stroke, epilepsy, and the possible links with COVID-19 infection.ConclusionNeuroinflammatory pathways, specifically those involving inflammasome proteins, seem promising candidates as treatment targets, and perhaps even biomarkers, in migraine.
Female paraurethral leiomyoma: a case report
Authors: Mazhari Farhat , Singh Roopam , Kerketta Kirti Anima , Pathak Nilay , Singh Neha 
Published: June 2021

Abstract
Background
Leiomyoma is a benign fibromuscular neoplasm originating from smooth muscle cells. Paraurethral leiomyoma is an extremely rare, benign, hormone-dependent growth from the mesenchymal cells in paraurethral space of female urethra. They usually appear in the reproductive age group women, mean age of presentation being approximately 41 years.

Case presentation
A 48-year-old woman presented with palpable mass at vagina and weak urinary stream. She underwent clinical examination and CT scan and MRI imaging followed by transvaginal excision of the mass. Histopathological examination confirmed paraurethral leiomyoma.

Conclusions
Paraurethral leiomyoma owing to its rare incidence poses a diagnostic dilemma for the gynecologists. Radiological imaging techniques help in diagnosis. Surgical excision via vaginal route is the treatment of choice. Diagnosis is confirmed by histopathology.
Multiple paths to cold tolerance: the role of environmental cues, morphological traits and the circadian clock gene vrille
Authors: Poikela Noora , Tyukmaeva Venera , Hoikkala Anneli , Kankare Maaria 
Published: June 2021

Abstract
Background
Tracing the association between insect cold tolerance and latitudinally and locally varying environmental conditions, as well as key morphological traits and molecular mechanisms, is essential for understanding the processes involved in adaptation. We explored these issues in two closely-related species, Drosophila montana and Drosophila flavomontana, originating from diverse climatic locations across several latitudes on the coastal and mountainous regions of North America. We also investigated the association between sequence variation in one of the key circadian clock genes, vrille, and cold tolerance in both species. Finally, we studied the impact of vrille on fly cold tolerance and cold acclimation ability by silencing it with RNA interference in D. montana.

Results
We performed a principal component analysis (PCA) on variables representing bioclimatic conditions on the study sites and used latitude as a proxy of photoperiod. PC1 separated the mountainous continental sites from the coastal ones based on temperature variability and precipitation, while PC2 arranged the sites based on summer and annual mean temperatures. Cold tolerance tests showed D. montana to be more cold-tolerant than D. flavomontana and chill coma resistance (CTmin) of this species showed an association with PC2. Chill coma recovery time (CCRT) of both species improved towards northern latitudes, and in D. flavomontana this trait was also associated with PC1. D. flavomontana flies were darkest in the coast and in the northern mountainous populations, but coloration showed no linkage with cold tolerance. Body size decreased towards cold environments in both species, but only within D. montana populations largest flies showed fastest recovery from cold. Finally, both the sequence analysis and RNAi study on vrille suggested this gene to play an essential role in D. montana cold resistance and acclimation, but not in recovery time.

Conclusions
Our study demonstrates the complexity of insect cold tolerance and emphasizes the need to trace its association with multiple environmental variables and morphological traits to identify potential agents of natural selection. It also shows that a circadian clock gene vrille is essential both for short- and long-term cold acclimation, potentially elucidating the connection between circadian clock system and cold tolerance.
Transcriptomic analysis of shell repair and biomineralization in the blue mussel, Mytilus edulis
Authors: Yarra Tejaswi , Ramesh Kirti , Blaxter Mark , Hüning Anne , Melzner Frank , Clark Melody S. 
Published: June 2021

Abstract
Background
Biomineralization by molluscs involves regulated deposition of calcium carbonate crystals within a protein framework to produce complex biocomposite structures. Effective biomineralization is a key trait for aquaculture, and animal resilience under future climate change. While many enzymes and structural proteins have been identified from the shell and in mantle tissue, understanding biomieralization is impeded by a lack of fundamental knowledge of the genes and pathways involved. In adult bivalves, shells are secreted by the mantle tissue during growth, maintenance and repair, with the repair process, in particular, amenable to experimental dissection at the transcriptomic level in individual animals.

Results
Gene expression dynamics were explored in the adult blue mussel, Mytilus edulis, during experimentally induced shell repair, using the two valves of each animal as a matched treatment-control pair. Gene expression was assessed using high-resolution RNA-Seq against a de novo assembled database of functionally annotated transcripts. A large number of differentially expressed transcripts were identified in the repair process. Analysis focused on genes encoding proteins and domains identified in shell biology, using a new database of proteins and domains previously implicated in biomineralization in mussels and other molluscs. The genes implicated in repair included many otherwise novel transcripts that encoded proteins with domains found in other shell matrix proteins, as well as genes previously associated with primary shell formation in larvae. Genes with roles in intracellular signalling and maintenance of membrane resting potential were among the loci implicated in the repair process. While haemocytes have been proposed to be actively involved in repair, no evidence was found for this in the M. edulis data.

Conclusions
The shell repair experimental model and a newly developed shell protein domain database efficiently identified transcripts involved in M. edulis shell production. In particular, the matched pair analysis allowed factoring out of much of the inherent high level of variability between individual mussels. This snapshot of the damage repair process identified a large number of genes putatively involved in biomineralization from initial signalling, through calcium mobilization to shell construction, providing many novel transcripts for future in-depth functional analyses.
A mixed-methods study evaluating the impact of an excursion-based social group on quality of life of older adults
Authors: Siette Joyce , Jorgensen Mikaela , Nguyen Amy , Knaggs Gilbert , Miller Stuart , Westbrook Johanna I. 
Published: June 2021

Abstract
Background
Social isolation is an increasing concern for older adults who live in the community. Despite some availability of social support programs to address social isolation, their effectiveness is not routinely measured. This study aimed to evaluate an innovative excursion-based program offering unique social experiences to older adults receiving aged care services.

Methods
This six-month before and after mixed-methods study evaluated the outcomes of an Australian excursion-based program which offered social and physical outings to bring older adults receiving aged care services into the wider community. The study combined two parts: Part 1 was a pre-post survey assessing the quality of life of older adults who received the excursion-based program for 6 months (n = 56; two time-points, analysed using signed rank test) and Part 2 involved qualitative in-depth, semi-structured interviews (n = 24 aged care staff, older adults and carers; analysed using thematic analysis).

Results
Older adults experienced a significant increase in quality of life scores (p < 0.001) between baseline and 6 months. Interviews confirmed these observations and suggested that benefits of participation included increased opportunities for social participation, psychological wellbeing, physical function, and carer respite. Interviews also revealed being in a group setting, having tailored, convenient and accessible activities, alongside supportive staff were key drivers in improving the wellbeing of participants.

Conclusions
Participating in an excursion-based community program may improve wellbeing in older adults. Aging policy should focus on prioritizing initiatives that promote social connectivity with the wider community and assist in improving outcomes for older adults.
Tobacco use in the Myeloproliferative neoplasms: symptom burden, patient opinions, and care
Authors: Christensen Sarah F. , Scherber Robyn M. , Mazza Gina L. , Dueck Amylou C. , Brochmann Nana , Andersen Christen L. , Hasselbalch Hans C. , Mesa Ruben A. , Geyer Holly L. 
Published: June 2021

Abstract
Background
Patients with Philadelphia-negative Myeloproliferative Neoplasms (MPN) suffer from numerous symptoms and decreased quality of life. Smoking is associated with an increased symptom burden in several malignancies. The aim of this study was to analyze the association between smoking and MPN-related symptom burden and explore MPN patients’ opinions on smoking.

Methods
A total of 435 patients with MPN participated in a cross-sectional internet-based survey developed by the Mayo Clinic and the Myeloproliferative Neoplasm Quality of Life Group. Patients reported their demographics, disease characteristics, tobacco use, and opinions on tobacco use. In addition, MPN-related symptoms were reported via the validated 10-item version of the Myeloproliferative Neoplasms Symptom Assessment Form.

Results
Current/former smokers reported worse fatigue (mean severity 5.6 vs. 5.0, p = 0.02) and inactivity (mean severity 4.0 vs. 3.4, p = 0.03) than never smokers. Moreover, current/former smokers more frequently experienced early satiety (68.5% vs. 58.3%, p = 0.03), inactivity (79.9% vs. 71.1%, p = 0.04), and concentration difficulties (82.1% vs. 73.1%, p = 0.04). Although not significant, a higher total symptom burden was observed for current/former smokers (mean 30.4 vs. 27.0, p = 0.07). Accordingly, overall quality of life was significantly better among never smokers than current/former smokers (mean 3.5 vs. 3.9, p = 0.03). Only 43.2% of the current/former smokers reported having discussed tobacco use with their physician, and 17.5% did not believe smoking increased the risk of thrombosis.

Conclusion
The current study suggests that smoking may be associated with increased prevalence and severity of MPN symptoms and underscores the need to enhance patient education and address tobacco use in the care of MPN patients.
A positive-feedback loop between HBx and ALKBH5 promotes hepatocellular carcinogenesis
Authors: Qu Siming , Jin Li , Huang Hanfei , Lin Jie , Gao Weiwu , Zeng Zhong 
Published: June 2021

Abstract
Background
Hepatitis B Virus (HBV) contributes to liver carcinogenesis via various epigenetic mechanisms. The newly defined epigenetics, epitranscriptomics regulation, has been reported to involve in multiple cancers including Hepatocellular Carcinoma (HCC). Our previous study found that HBx, HBV encodes X protein, mediated H3K4me3 modification in WDR5-dependent manner to involve in HBV infection and contribute to oncogene expression. AlkB Homolog 5 (ALKBH5), one of epitranscriptomics enzymes, has been identified to be associated with various cancers. However, whether and how ALKBH5 is dysregulated in HBV-related HCC remains unclear yet. This study aims to investigate ALKBH5 function, clinical significance and mechanism in HBV related HCC (HBV-HCC) patients derived from Chinese people.

Methods
The expression pattern of ALKBH5 was evaluated by RT-qPCR, Western blot, data mining and immunohistochemistry in total of 373 HBV-HCC tissues and four HCC cell lines. Cell Counting Kit 8 (CCK8) assay, Transwell and nude mouse model were performed to assess ALKBH5 function by both small interference RNAs and lentiviral particles. The regulation mechanism of ALKBH5 was determined in HBx and WDR5 knockdown cells by CHIP-qPCR. The role of ALKBH5 in HBx mRNA N6-methyladenosine (m6A) modification was further evaluated by MeRIP-qPCR and Actinomycin D inhibitor experiment in HBV-driven cells and HBx overexpression cells.

Result
ALKBH5 increased in tumor tissues and predicts a poor prognosis of HBV-HCC. Mechanically, the highly expressed ALKBH5 is induced by HBx-mediated H3K4me3 modification of ALKBH5 gene promoter in a WDR5-dependent manner after HBV infection. The increased ALKBH5 protein catalyzes the m6A demethylation of HBx mRNA, thus stabilizing and favoring a higher HBx expression level. Furthermore, there are positive correlations between HBx and ALKBH5 in HBV-HCC tissues, and depletion of ALKBH5 significantly inhibits HBV-driven tumor cells’ growth and migration in vitro and in vivo.

Conclusions
HBx-ALKBH5 may form a positive-feedback loop to involve in the HBV-induced liver carcinogenesis, and targeting the loop at ALKBH5 may provide a potential way for HBV-HCC treatment.
Reaching early adolescents with a complex intervention for HIV prevention: findings from a cohort study to evaluate DREAMS in two informal settlements in Nairobi, Kenya
Authors: Mulwa Sarah , Osindo Jane , Wambiya Elvis O. , Gourlay Annabelle , Maina Beatrice W. , Orindi Benedict O. , Floyd Sian , Ziraba Abdhalah , Birdthistle Isolde 
Published: June 2021

AbstractBackgroundThe DREAMS Partnership promotes combination HIV prevention among adolescent girls and young women. We examined the extent to which DREAMS interventions reached early adolescent girls (EAG; aged 10–14 years) in two informal settlements in Nairobi, and the characteristics of those reached, after 3 years of implementation.MethodsWe utilized three data rounds from a randomly-sampled cohort of EAG established in 2017 in Korogocho and Viwandani informal settlements where DREAMS interventions were implemented. Interventions were classified as individual or contextual-level, with individual interventions further categorised as primary (prioritised for this age group), or secondary. We summarised self-reported invitation to participate in DREAMS, and uptake of eight interventions that were supported by DREAMS, during 2017–2019. Multivariable logistic regression analysis was used to identify individual and household characteristics associated with invitation to DREAMS and uptake of primary interventions.ResultsData were available for 606, 516 (retention rate of 85%) and 494 (82%) EAG in 2017, 2018 and 2019, respectively. Proportions invited to DREAMS increased from 49% in 2017, to 77% by 2018, and to 88% by 2019. School-based HIV and violence prevention, and HIV testing and counselling were the most accessed interventions (both at 82%). Cumulative uptake of interventions was higher among those invited to participate in DREAMS compared to those never invited, particularly for new interventions such as social asset building and financial capability training. Contextual-level interventions were accessed infrequently. Most of those invited both in 2017 and 2018 accessed ≥3 interventions (96%), and 55% received all three primary interventions by 2019.ConclusionsUptake of DREAMS interventions among a representative sample of EAG was high and quickly increased over the implementation period. The majority accessed multiple interventions, indicating that it is feasible to integrate and deliver a package of interventions to EAG in a challenging informal context.