bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structural, functional, and mechanistic insights uncover the fundamental role of orphan connexin-62 in platelets
Authors: Sahli Khaled A. , Flora Gagan D. , Sasikumar Parvathy , Maghrabi Ali H. , Holbrook Lisa-Marie , AlOuda Sarah K. , Elgheznawy Amro , Sage Tanya , Stainer Alexander R. , Adiyaman Recep , AboHassan Mohammad , Crescente Marilena , Kriek Neline , Vaiyapuri Sakthivel , Bye Alexander P. , Unsworth Amanda J. , Jones Chris I. , McGuffin Liam J. , Gibbins Jonathan M. 
Published: August 2020

Abstract
Connexins oligomerise to form hexameric hemichannels in the plasma membrane that can further dock together on adjacent cells to form gap junctions and facilitate intercellular trafficking of molecules. In this study, we report the expression and function of an orphan connexin, connexin-62 (Cx62), in human and mouse (Cx57, mouse homolog) platelets. A novel mimetic peptide (62Gap27) was developed to target the second extracellular loop of Cx62, and 3-dimensional structural models predicted its interference with gap junction and hemichannel function. The ability of 62Gap27 to regulate both gap junction and hemichannel-mediated intercellular communication was observed using fluorescence recovery after photobleaching analysis and flow cytometry. Cx62 inhibition by 62Gap27 suppressed a range of agonist-stimulated platelet functions and impaired thrombosis and hemostasis. This was associated with elevated protein kinase A–dependent signaling in a cyclic adenosine monophosphate–independent manner and was not observed in Cx57-deficient mouse platelets (in which the selectivity of 62Gap27 for this connexin was also confirmed). Notably, Cx62 hemichannels were observed to function independently of Cx37 and Cx40 hemichannels. Together, our data reveal a fundamental role for a hitherto uncharacterized connexin in regulating the function of circulating cells.
β-Catenin–TCF/LEF signaling promotes steady-state and emergency granulopoiesis via G-CSF receptor upregulation
Authors: Danek Petr , Kardosova Miroslava , Janeckova Lucie , Karkoulia Elena , Vanickova Karolina , Fabisik Matej , Lozano-Asencio Carlos , Benoukraf Touati , Tirado-Magallanes Roberto , Zhou Qiling , Burocziova Monika , Rahmatova Sarka , Pytlik Robert , Brdicka Tomas , Tenen Daniel G. , Korinek Vladimir , Alberich-Jorda Meritxell 
Published: August 2020

AbstractThe canonical Wnt signaling pathway is mediated by interaction of β-catenin with the T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) transcription factors and subsequent transcription activation of Wnt-target genes. In the hematopoietic system, the function of the pathway has been mainly investigated by rather unspecific genetic manipulations of β-catenin that yielded contradictory results. Here, we used a mouse expressing a truncated dominant negative form of the human TCF4 transcription factor (dnTCF4) that specifically abrogates β-catenin-TCF/LEF interaction. Disruption of the β-catenin-TCF/LEF interaction resulted in the accumulation of immature cells and reduced granulocytic differentiation. Mechanistically, dnTCF4 progenitors exhibited downregulation of the Csf3r gene, reduced granulocyte colony-stimulating factor (G-CSF) receptor levels, attenuation of downstream Stat3 phosphorylation after G-CSF treatment, and impaired G-CSF-mediated differentiation. Chromatin immunoprecipitation assays confirmed direct binding of TCF/LEF factors to the promoter and putative enhancer regions of CSF3R. Inhibition of β-catenin signaling compromised activation of the emergency granulopoiesis program, which requires maintenance and expansion of myeloid progenitors. Consequently, dnTCF4 mice were more susceptible to Candida albicans infection and more sensitive to 5-fluorouracil-induced granulocytic regeneration. Importantly, genetic and chemical inhibition of β-catenin-TCF/LEF signaling in human CD34+ cells reduced granulocytic differentiation, whereas its activation enhanced myelopoiesis. Altogether, our data indicate that the β-catenin-TCF/LEF complex directly regulates G-CSF receptor levels, and consequently controls proper differentiation of myeloid progenitors into granulocytes in steady-state and emergency granulopoiesis. Our results uncover a role for the β-catenin signaling pathway in fine tuning the granulocytic production, opening venues for clinical intervention that require enhanced or reduced production of neutrophils.
Role of c-Myc haploinsufficiency in the maintenance of HSCs in mice
Authors: Sheng Yue , Ma Rui , Yu Chunjie , Wu Qiong , Zhang Steven , Paulsen Kimberly , Zhang Jiwang , Ni Hongyu , Huang Yong , Zheng Yi , Qian Zhijian 
Published: August 2020

Abstract
This study was conducted to determine the dosage effect of c-Myc on hematopoiesis and its distinct role in mediating the Wnt/β-catenin pathway in hematopoietic stem cell (HSC) and bone marrow niche cells. c-Myc haploinsufficiency led to ineffective hematopoiesis by inhibiting HSC self-renewal and quiescence and by promoting apoptosis. We have identified Nr4a1, Nr4a2, and Jmjd3, which are critical for the maintenance of HSC functions, as previously unrecognized downstream targets of c-Myc in HSCs. c-Myc directly binds to the promoter regions of Nr4a1, Nr4a2, and Jmjd3 and regulates their expression. Our results revealed that Nr4a1 and Nr4a2 mediates the function of c-Myc in regulating HSC quiescence, whereas all 3 genes contribute to the function of c-Myc in the maintenance of HSC survival. Adenomatous polyposis coli (Apc) is a negative regulator of the Wnt/β-catenin pathway. We have provided the first evidence that Apc haploinsufficiency induces a blockage of erythroid lineage differentiation through promoting secretion of IL6 in bone marrow endothelial cells. We found that c-Myc haploinsufficiency failed to rescue defective function of Apc-deficient HSCs in vivo but it was sufficient to prevent the development of severe anemia in Apc–heterozygous mice and to significantly prolong the survival of those mice. Furthermore, we showed that c-Myc–mediated Apc loss induced IL6 secretion in endothelial cells, and c-Myc haploinsufficiency reversed the negative effect of Apc-deficient endothelial cells on erythroid cell differentiation. Our studies indicate that c-Myc has a context-dependent role in mediating the function of Apc in hematopoiesis.
Ixazomib, dexamethasone, and rituximab in treatment-naive patients with Waldenström macroglobulinemia: long-term follow-up
Authors: Castillo Jorge J. , Meid Kirsten , Flynn Catherine A. , Chen Jiaji , Demos Maria G. , Guerrera Maria L. , Kofides Amanda , Liu Xia , Munshi Manit , Tsakmaklis Nicholas , Patterson Christopher J. , Yang Guang , Hunter Zachary , Treon Steven P. 
Published: August 2020

Abstract
Proteasome inhibition is a standard of care for the primary treatment of patients with Waldenström macroglobulinemia (WM). We present the long-term follow-up of a prospective, phase II clinical trial that evaluated the combination of ixazomib, dexamethasone, and rituximab (IDR) in 26 treatment-naive patients with WM. IDR was administered as 6 monthly induction cycles followed by 6 every-2-month maintenance cycles. The MYD88 L265P mutation was detected in all patients, and CXCR4 mutations were detected in 15 patients (58%). The median time to response (TTR) and time to major response (TTMR) were 2 and 6 months, respectively. Patients with and without CXCR4 mutations had median TTR of 3 months and 1 month, respectively (P = .003), and median TTMR of 10 months and 3 months, respectively (P = .31). The overall, major, and very good partial response (VGPR) rates were 96%, 77%, and 19%, respectively. The rate of VGPR in patients with and without CXCR4 mutations were 7% and 36%, respectively (P = .06). The median progression-free survival (PFS) was 40 months, the median duration of response (DOR) was 38 months, and the median time to next treatment (TTNT) was 40 months. PFS, DOR, and TTNT were not affected by CXCR4 mutational status. The safety profile was excellent with no grade 4 adverse events or deaths to date. IDR provides a safe and effective frontline treatment option for symptomatic patients with WM. This study was registered at www.clinicaltrials.gov as #NCT02400437.
Clinical and radiologic correlates of neurotoxicity after axicabtagene ciloleucel in large B-cell lymphoma
Authors: Strati Paolo , Nastoupil Loretta J. , Westin Jason , Fayad Luis E. , Ahmed Sairah , Fowler Nathan H. , Hagemeister Fredrick B. , Lee Hun J. , Iyer Swaminathan P. , Nair Ranjit , Parmar Simrit , Rodriguez Maria A. , Samaniego Felipe , Steiner Raphael E. , Wang Michael , Pinnix Chelsea C. , Adkins Sherry , Claussen Catherine M. , Martinez Charles S. , Hawkins Misha C. , Johnson Nicole A. , Singh Prachee , Mistry Haleigh E. , Horowitz Sandra , George Shirley , Feng Lei , Kebriaei Partow , Shpall Elizabeth J. , Neelapu Sattva S. , Tummala Sudhakar , Chi T. Linda 
Published: August 2020

AbstractNeurotoxicity or immune effector cell-associated neurotoxicity syndrome (ICANS) is the second most common acute toxicity after chimeric antigen receptor (CAR) T-cell therapy. However, there are limited data on the clinical and radiologic correlates of ICANS. We conducted a cohort analysis of 100 consecutive patients with relapsed or refractory large B-cell lymphoma (LBCL) treated with standard of care axicabtagene ciloleucel (axi-cel). ICANS was graded according to an objective grading system. Neuroimaging studies and electroencephalograms (EEGs) were reviewed by an expert neuroradiologist and neurologist. Of 100 patients included in the study, 68 (68%) developed ICANS of any grade and 41 (41%) had grade ≥3. Median time to ICANS onset was 5 days, and median duration was 6 days. ICANS grade ≥3 was associated with high peak ferritin (P = .03) and C-reactive protein (P = .001) levels and a low peak monocyte count (P = .001) within the 30 days after axi-cel infusion. Magnetic resonance imaging was performed in 38 patients with ICANS and revealed 4 imaging patterns with features of encephalitis (n = 7), stroke (n = 3), leptomeningeal disease (n = 2), and posterior reversible encephalopathy syndrome (n = 2). Abnormalities noted on EEG included diffuse slowing (n = 49), epileptiform discharges (n = 6), and nonconvulsive status epilepticus (n = 8). Although reversible, grade ≥3 ICANS was associated with significantly shorter progression-free (P = .02) and overall survival (progression being the most common cause of death; P = .001). Our results suggest that imaging and EEG abnormalities are common in patients with ICANS, and high-grade ICANS is associated with worse outcome after CAR T-cell therapy in LBCL patients.
Exploring perceptions, attitudes and beliefs of Thai patients with type 2 diabetes mellitus as they relate to medication adherence at an out-patient primary care clinic in Chiang Mai, Thailand
Authors: Jiraporncharoen Wichuda , Pinyopornpanish Kanokporn , Junjom Korsin , Dejkriengkraikul Nisachol , Wisetborisut Anawat , Papachristou Iliatha , Hashmi Ahmar , Angkurawaranon Chaisiri 
Published: August 2020

Abstract
Background
Within the sphere of diabetes self-management, much emphasis has been placed on medication adherence. There has been a shift in thinking about medication adherence, moving from “compliance” and historically paternalistic models of care, to seeking better ways of characterizing dynamic and complex relationships that determine medication adherence and diabetes control. This study sought to understand the relationship between patient’s attitudes and medication adherence for oral anti-diabetics in Thailand.

Methods
In-depth interviews of patients with type 2 diabetes mellitus, taking oral anti-diabetic drugs, at the out-patient clinic run by the Department of Family Medicine, Chiang Mai University between May and December 2016. Thematic analysis followed the WHO framework for medication adherence in chronic disease to explore patient’s attitudes and their influence on medication compliance.

Results
Of 24 patients, 9 were men. The mean age was 62 years (SD 8.9 years). 67% had high compliance. Four themes were identified as important factors related to medication adherence: attitudes toward disease, attitudes toward treatment, attitudes toward family support and attitudes toward health care team. Specifically, symptoms at diagnosis, understanding and acceptance in taking medication, the presence of family support and the perception of concern by the doctor relate to improved medication compliance.

Conclusions
Medication adherence in Thai patients with diabetes requires support from both the health care providers and the family. The patient’s perception of the doctor’s concern creates greater patient trust in the health care team. This trust, along with family support, helps deepen patients’ understanding of the disease, accept the chronic nature of their disease, and engenders a positive attitude towards taking medication that can improve medication adherence.
Effect of endometrial thickness and embryo quality on live-birth rate of fresh IVF/ICSI cycles: a retrospective cohort study
Authors: Lv Hong , Li Xiuzhu , Du Jiangbo , Ling Xiufeng , Diao Feiyang , Lu Qun , Tao Shiyao , Huang Lei , Chen Shiyao , Han Xiumei , Zhou Kun , Xu Bo , Liu Xiaoyu , Ma Hongxia , Xia Yankai , Shen Hongbing , Hu Zhibin , Jin Guangfu , Guan Yichun , Wang Xinru 
Published: August 2020

AbstractBackgroundSuccessful implantation and delivery require both the functional embryo and receptive endometrium in assisted reproductive technology (ART) cycles. However, little is known about embryo-endometrial interaction on live-birth. We aimed to investigate the independent effect and interaction of endometrial thickness (EMT) and embryo quality on live-birth in fresh embryo transfer (ET) cycles.MethodsWe conducted a retrospective cohort study including 15,012 ART cycles between 2013 and 2016 in three centers in China. Poisson regression with generalized estimating equations was employed to calculate relative risks (RRs) and 95% confidence intervals (CIs). We estimated the interaction of embryo quality and EMT on live-birth rate (LBR).ResultsThe LBR per cycle was 42.8% overall. LBR increased with increasing EMT and reached a plateau (50.6 to 54.2%) when EMT was 11 mm or thicker. Embryo quality represented by cumulative score was associated with LBR independently of number of embryos transferred and EMT. LBR was not increased with thicker EMT when only Q1 cleavage-stage embryo transferred (aRR 0.95, 95%CI 0.61–1.46). LBR was not increased significantly with thicker EMT with transfer of two good-quality cleavage-stage embryos and any blastocyst combination except Q1 group. There was significant interaction between EMT and embryo quality on LBR for cleavage-stage ETs (P=0.023).ConclusionsThis study demonstrated the nonlinear EMT-LBR association and the EMT cut-off value of 11 mm which may be of more clinical significance for predicting live-birth. Embryo quality is an independent prognostic tool for LBR. Our finding of significant embryo-endometrial interaction indicates combination of EMT and embryos quality might improve the prognostic value in clinical practice for live-birth in patients undergoing transfer of 1–2 fresh cleavage-stage embryos.
The prevalence of rheumatoid arthritis in middle-aged and elderly people living in Naqu City, Tibet, Autonomous Region of China
Authors: Zhang Qingxi , Liu Qiang , Lin Chutong , Baima Yangjin , Li Hu , Gong Hongqiang , Lin Jianhao 
Published: August 2020

Abstract
Objective
To estimate the prevalence of rheumatoid arthritis (RA) in the Tibet Autonomous Region (China).

Methods
A population-based cross-sectional survey was conducted on 1458 residents of Luoma Town, Tibet Autonomous Region, who were aged ≥ 40 years old. We interviewed participants using questionnaires, and rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPA), and C-reactive protein (CRP) were determined. The identification of RA in this study was on the basis of criteria issued by the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) guideline.

Results
Herein, 782 participants completed all items of RA. The overall prevalence of RA was 4.86%, and the prevalence was higher in women than that in men (7.14% vs. 2.56%, p = 0.005). The age-standardized prevalence of RA was 6.30% (95% confidence interval (CI) 4.20–8.64%), which was 2.46% (95% CI 1.04%, 4.10%) and 9.59% (95% CI 5.93%, 13.77%) in men and women, respectively.

Conclusion
The prevalence of RA is relatively higher in the Tibet than that in other areas of China.
Genetic deletion of microRNA-22 blunts the inflammatory transcriptional response to status epilepticus and exacerbates epilepsy in mice
Authors: Almeida Silva Luiz F. , Reschke Cristina R. , Nguyen Ngoc T. , Langa Elena , Sanz-Rodriguez Amaya , Gerbatin Rogerio R. , Temp Fernanda R. , de Freitas Mayara L. , Conroy Ronan M. , Brennan Gary P. , Engel Tobias , Henshall David C. 
Published: August 2020

AbstractMicroRNAs perform important roles in the post-transcriptional regulation of gene expression. Sequencing as well as functional studies using antisense oligonucleotides indicate important roles for microRNAs during the development of epilepsy through targeting transcripts involved in neuronal structure, gliosis and inflammation. MicroRNA-22 (miR-22) has been reported to protect against the development of epileptogenic brain networks through suppression of neuroinflammatory signalling. Here, we used mice with a genetic deletion of miR-22 to extend these insights. Mice lacking miR-22 displayed normal behaviour and brain structure and developed similar status epilepticus after intraamygdala kainic acid compared to wildtype animals. Continuous EEG monitoring after status epilepticus revealed, however, an accelerated and exacerbated epilepsy phenotype whereby spontaneous seizures began sooner, occurred more frequently and were of longer duration in miR-22-deficient mice. RNA sequencing analysis of the hippocampus during the period of epileptogenesis revealed a specific suppression of inflammatory signalling in the hippocampus of miR-22-deficient mice. Taken together, these findings indicate a role for miR-22 in establishing early inflammatory responses to status epilepticus. Inflammatory signalling may serve anti-epileptogenic functions and cautions the timing of anti-inflammatory interventions for the treatment of status epilepticus.
TOB-STOP-COP (TOBacco STOP in COPd trial): study protocol—a randomized open-label, superiority, multicenter, two-arm intervention study of the effect of “high-intensity” vs. “low-intensity” smoking cessation intervention in active smokers with chronic obstructive pulmonary disease
Authors: Saeed Mohamad Isam , Sivapalan Pradeesh , Eklöf Josefin , Ulrik Charlotte Suppli , Pisinger Charlotta , Lapperre Therese , Tønnesen Philip , Hoyer Nils , Janner Julie , Karlsson Marie Lavesen , Bech Charlotte Sandau , Marså Kristoffer , Godtfredsen Nina , Brøndum Eva , Munk Birgit , Raaschou Merete , Browatzski Andrea , Lütken Pernille , Jensen Jens-Ulrik Stæhr 
Published: August 2020

Abstract
Background
Cigarette smoking is the leading cause of chronic obstructive pulmonary disease (COPD), and it contributes to the development of many other serious diseases. Smoking cessation in COPD patients is known to improve survival and reduce the number of hospitalization-requiring acute exacerbations of COPD. However, smoking cessation interventions in these patients have only been successful for approximately 15–20% for consistent smoking abstinence in 12 months. Thus, more effective interventions are needed for this patient group. The aim of this study is to determine whether a high-intensity intervention compared to a low-intensity intervention can increase the proportion of persistent (> 12 months) anamnestic and biochemical smoking cessation in active smokers with COPD.

Methods
This study is a randomized controlled trial. A total of 600 active smokers with COPD will be randomly assigned 1:1 to either a standard treatment (guideline-based municipal smoking cessation program, “low intensity” group) or an intervention (“high-intensity” group) group, which consists of group sessions, telephone consultations, behavior design, hotline, and “buddy-matching” (smoker matched with COPD patient who has ceased smoking). Both groups will receive pharmacological smoking cessation. The primary endpoint is anamnestic and biochemical (cotinine analysis in urine) validated smoking cessation after 12 months.

Discussion
The potential benefit of this project is to improve smoking cessation rates and thereby reduce smoking-related exacerbations of COPD. In addition, the project can potentially benefit from increasing the quality of life and longevity of COPD patients and reducing the risk of other smoking-related diseases.

Trial registration
ClinicalTrials.gov NCT04088942. Registered on 13 September 2019
A population-based gene expression signature of molecular clock phase from a single epidermal sample
Authors: Wu Gang , Ruben Marc D. , Francey Lauren J. , Smith David F. , Sherrill Joseph D. , Oblong John E. , Mills Kevin J. , Hogenesch John B. 
Published: August 2020

Abstract
Background
For circadian medicine to influence health, such as when to take a drug or undergo a procedure, a biomarker of molecular clock phase is required––one that is easily measured and generalizable across a broad population. It is not clear that any circadian biomarker yet satisfies these criteria.

Methods
We analyzed 24-h molecular rhythms in human dermis and epidermis at three distinct body sites, leveraging both longitudinal (n = 20) and population (n = 154) data. We applied cyclic ordering by periodic structure (CYCLOPS) to order the population samples where biopsy time was not recorded. With CYCLOPS-predicted phases, we used ZeitZeiger to discover potential biomarkers of clock phase.

Results
Circadian clock function was strongest in the epidermis, regardless of body site. We identified a 12-gene expression signature that reported molecular clock phase to within 3 h (mean error = 2.5 h) from a single sample of epidermis––the skin’s most superficial layer. This set performed well across body sites, ages, sexes, and detection platforms.

Conclusions
This research shows that the clock in epidermis is more robust than dermis regardless of body site. To encourage ongoing validation of this putative biomarker in diverse populations, diseases, and experimental designs, we developed SkinPhaser––a user-friendly app to test biomarker performance in datasets (https://github.com/gangwug/SkinPhaser).