bluuebunny/crossref_metadata_2025_split huggingface dataset:
The FoxP1 gene regulates lung function, production of matrix metalloproteinases and inflammatory mediators, and viability of lung epithelia
Authors: Andreas Alexis , Maloy Abby , Nyunoya Toru , Zhang Yingze , Chandra Divay 
Published: October 2022

Abstract
Background
Genes involved in lung development may become dysregulated in adult life and contribute to the pathogenesis of lung diseases. Multiple genes regulate lung development, including Forkhead box protein P1-4 (FoxP1-4).

Methods
We examined the association between variants in the FoxP1-4 genes and lung function using data from a GWAS that included close to 400,000 individuals and 20 million SNPs.

Results
More than 100 variants in the FoxP1 gene, but none in the FoxP2-4 genes, are associated with lung function. The sentinel variant in the FoxP1 gene associated with FEV1 was rs1499894 (C > T), while the sentinel variant in the FoxP1 gene associated with FVC was rs35480566 (A > G). Those with the T allele instead of the C allele for rs1499894, or the G allele instead of the A allele for rs35480566 had increased FoxP1 mRNA levels in transcriptomic data, higher FEV1 and FVC, and reduced odds of being diagnosed with idiopathic pulmonary fibrosis. Further, knockdown of FoxP1 in lung epithelial cells by RNA interference led to increased mRNA levels for matrix metalloproteinases 1, 2, 3 and pro-inflammatory cytokines IL-6 & IL-8, as well as reduced cell viability after exposure to cigarette smoke—all processes implicated in the pathogenesis of COPD and IPF.

Conclusions
Our results suggest that the protein encoded by the FoxP1 gene may protect against the development of COPD and IPF. A causal role for FoxP1 in the pathogenesis of COPD and IPF may warrant further investigation, and FoxP1 may be a novel therapeutic target for these lung disorders.
CpG island status as an epigenetic alteration for NIS promoter in thyroid neoplasms; a cross-sectional study with a systematic review
Authors: Zarkesh Maryam , Arab Noman , Abooshahab Raziyeh , Heydarzadeh Shabnam , Sheikholeslami Sara , Nozhat Zahra , Salehi Jahromi Marziyeh , Fanaei Seyed Ahmad , Hedayati Mehdi 
Published: October 2022

Abstract
Background
Gene silence via methylation of the CpG islands is cancer's most common epigenetic modification. Given the highly significant role of NIS in thyroid cancer (TC) differentiation, this cross-sectional study aimed to investigate the DNA methylation pattern in seven CpG islands (CpG1-7 including +846, +918, +929, +947, +953, +955, and +963, respectively) of the NIS promoter in patients diagnosed with papillary (PTC), follicular (FTC), and multinodular goiter (MNG). Additionally, a systematic review of the literature was conducted to compare our results with studies concerning methylation of the NIS gene promoter.

Methods
Thyroid specimens from 64 patients met the eligibility criteria, consisting of 28 PTC, 9 FTC, and 27 benign MNG cases. The mRNA of NIS was tested by qRT-PCR. The bisulfite sequencing PCR (BSP) technique was performed to evaluate the promoter methylation pattern of the NIS gene. Sequencing results were received in chromatograph, FASTA, SEQ, and pdf formats and were analyzed using Chromas. The methylation percentage at each position and for each sample was calculated by mC/(mC+C) formula for all examined CpGs; following that, the methylation percentage was also calculated at each CpG site. Besides, a literature search was conducted without restricting publication dates. Nine studies met the eligibility criteria after removing duplicates, unrelated articles, and reviews.

Results
NIS mRNA levels decreased in tumoral tissues of PTC (P = 0.04) and FTC (P = 0.03) patients compared to their matched non-tumoral ones. The methylation of NIS promoter was not common in PTC samples, but it was frequent in FTC (P < 0.05). Significant differences were observed in the methylation levels in the 4th(+ 947), 6th(+ 955), and 7th(+ 963) CpGs sites in the forward strand of NIS promoter between FTC and MNG tissues (76.34 ± 3.12 vs 40.43 ± 8.42, P = 0.004, 69.63 ± 3.03 vs 23.29 ± 6.84, P = 0.001 and 50.33 ± 5.65 vs 24 ± 6.89, P = 0.030, respectively). There was no significant correlation between the expression and methylation status of NIS in PTC and FTC tissues.

Conclusion
Perturbation in NIS promoter’s methylation individually may have a potential utility in differentiating MNG and FTC tissues. The absence of a distinct methylation pattern implies the importance of other epigenetic processes, which may alter the production of NIS mRNA. In addition, according to the reversibility of DNA methylation, it is anticipated that the design of particular targeted demethylation medicines will lead to a novel cancer therapeutic strategy.
Etomoxir, a carnitine palmitoyltransferase 1 inhibitor, combined with temozolomide reduces stemness and invasiveness in patient-derived glioblastoma tumorspheres
Authors: Shim Jin-Kyoung , Choi Seonah , Yoon Seon-Jin , Choi Ran Joo , Park Junseong , Lee Eun Hee , Cho Hye Joung , Lee Suji , Teo Wan-Yee , Moon Ju Hyung , Kim Hyun Sil , Kim Eui Hyun , Cheong Jae-Ho , Chang Jong Hee , Yook Jong In , Kang Seok-Gu 
Published: October 2022

Abstract
Introduction
The importance of fatty acid oxidation (FAO) in the bioenergetics of glioblastoma (GBM) is being realized. Etomoxir (ETO), a carnitine palmitoyltransferase 1 (CPT1) inhibitor exerts cytotoxic effects in GBM, which involve interrupting the FAO pathway. We hypothesized that FAO inhibition could affect the outcomes of current standard temozolomide (TMZ) chemotherapy against GBM.

Methods
The FAO-related gene expression was compared between GBM and the tumor-free cortex. Using four different GBM tumorspheres (TSs), the effects of ETO and/or TMZ was analyzed on cell viability, tricarboxylate (TCA) cycle intermediates and adenosine triphosphate (ATP) production to assess metabolic changes. Alterations in tumor stemness, invasiveness, and associated transcriptional changes were also measured. Mouse orthotopic xenograft model was used to elucidate the combinatory effect of TMZ and ETO.

Results
GBM tissues exhibited overexpression of FAO-related genes, especially CPT1A, compared to the tumor-free cortex. The combined use of ETO and TMZ further inhibited TCA cycle and ATP production than single uses. This combination treatment showed superior suppression effects compared to treatment with individual agents on the viability, stemness, and invasiveness of GBM TSs, as well as better downregulation of FAO-related gene expression. The results of in vivo study showed prolonged survival outcomes in the combination treatment group.

Conclusion
ETO, an FAO inhibitor, causes a lethal energy reduction in the GBM TSs. When used in combination with TMZ, ETO effectively reduces GBM cell stemness and invasiveness and further improves survival. These results suggest a potential novel treatment option for GBM.
Bargaining with patriarchy through the life course: obstacles faced (and overcome) by women leaders in Kerala’s health sector
Authors: Nambiar Devaki , Benny Gloria , Sankar D Hari 
Published: October 2022

Abstract
Background
The COVID-19 pandemic has helped shine the spotlight on the role of women’s leadership in tackling the world’s health and health system challenges. The proportion of women occupying senior leadership positions in the health sector is less compared to males, even as they constitute a vast majority of the work force. The South Indian state of Kerala is an exception to this trend, a phenomenon that we sought to understand and contextualise. We undertook a study to understand the personal and professional journeys of some women leaders in the Kerala health sector to determine the antecedents of their leadership positions, the challenges that came their way in leadership, and strategies adopted to overcome these challenges. We also investigated into how these experiences shaped their styles and approaches to leadership.

Methods
We conducted a qualitative study involving semi-structured in-depth interviews with women leaders. Sixteen women leaders were identified from public records and through peer nomination and interviewed in their language of preference following written informed consent procedures. Interviews focused on participants’ professional and personal trajectories, work-life balance, style of leadership, challenges, enablers, lessons learned in their path, and their vision for the health system. The interviews conducted in Malayalam were transliterated into English and thematically analysed using Atlas.Ti8 software by three researchers.

Results
Our study participants were aged 40 to around 80 years, from 8 out of 14 districts of the state. Women leaders in Kerala’s health sector faced challenges through the life-course: during their early school education, in professional service as well as in their roles as leaders. There were myriad experiences – including gender stereotyping and discrimination at the intersection of gender and other social identities. Women developed manifold ways of overcoming them and evolve unique – and again myriad—leadership styles.

Conclusions
Women leaders in Kerala have faced shared challenges through their life-course to climb up the ranks of leadership; each leader has adopted unique ways of overcoming them and developed similarly unique leadership styles. At each life stage there were bargains with patriarchy – involving family members (often as allies), against formal and informal institutional rules, managers, peers and subordinates., which in turn suggests a feminist consciousness on the part of Kerala women leaders as well as the society in which they are seeking to lead.
Improving cancer immunotherapy by rationally combining oncolytic virus with modulators targeting key signaling pathways
Authors: Zhu Zhi , McGray A. J. Robert , Jiang Weijian , Lu Binfeng , Kalinski Pawel , Guo Zong Sheng 
Published: October 2022

AbstractOncolytic viruses (OVs) represent a new class of multi-modal immunotherapies for cancer, with OV-elicited antitumor immunity being key to their overall therapeutic efficacy. Currently, the clinical effectiveness of OV as monotherapy remains limited, and thus investigators have been exploring various combinations with other anti-cancer agents and demonstrated improved therapeutic efficacy. As cancer cells have evolved to alter key signaling pathways for enhanced cell proliferation, cancer progression and metastasis, these cellular and molecular changes offer promising targets for rational cancer therapy design. In this regard, key molecules in relevant signaling pathways for cancer cells or/and immune cells, such as EGFR-KRAS (e.g., KRASG12C), PI3K-AKT-mTOR, ERK-MEK, JAK-STAT, p53, PD-1-PD-L1, and epigenetic, or immune pathways (e.g., histone deacetylases, cGAS-STING) are currently under investigation and have the potential to synergize with OV to modulate the immune milieu of the tumor microenvironment (TME), thereby improving and sustaining antitumor immunity. As many small molecule modulators of these signaling pathways have been developed and have shown strong therapeutic potential, here we review key findings related to both OV-mediated immunotherapy and the utility of small molecule modulators of signaling pathways in immuno-oncology. Then, we focus on discussion of the rationales and potential strategies for combining OV with selected modulators targeting key cellular signaling pathways in cancer or/and immune cells to modulate the TME and enhance antitumor immunity and therapeutic efficacy. Finally, we provide perspectives and viewpoints on the application of novel experimental systems and technologies that can propel this exciting branch of medicine into a bright future.
Eicosanoid lipidome activation in post-mortem brain tissues of individuals with APOE4 and Alzheimer’s dementia
Authors: Ebright Brandon , Assante Isaac , Poblete Roy A. , Wang Shaowei , Duro Marlon V. , Bennett David A. , Arvanitakis Zoe , Louie Stan G. , Yassine Hussein N. 
Published: October 2022

AbstractBackgroundChronic neuroinflammation is one of the hallmarks of late-onset Alzheimer’s disease (AD) dementia pathogenesis. Carrying the apolipoprotein ε4 (APOE4) allele has been associated with an accentuated response to brain inflammation and increases the risk of AD dementia progression. Among inflammation signaling pathways, aberrant eicosanoid activation plays a prominent role in neurodegeneration.MethodsUsing brains from the Religious Order Study (ROS), this study compared measures of brain eicosanoid lipidome in older persons with AD dementia to age-matched controls with no cognitive impairment (NCI), stratified byAPOEgenotype.ResultsLipidomic analysis of the dorsolateral prefrontal cortex demonstrated lower levels of omega-3 fatty acids eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and DHA-derived neuroprotectin D1 (NPD-1) in persons with AD dementia, all of which associated with lower measures of cognitive function. A significant interaction was observed between carrying theAPOE4allele and higher levels of both pro-inflammatory lipids and pro-resolving eicosanoid lipids on measures of cognitive performance and on neuritic plaque burden. Furthermore, analysis of lipid metabolism pathways implicated activation of calcium-dependent phospholipase A2 (cPLA2), 5-lipoxygenase (5-LOX), and soluble epoxide hydrolase (sEH) enzymes.ConclusionThese findings implicate activation of the eicosanoid lipidome in the chronic unresolved state of inflammation in AD dementia, which is increased in carriers of theAPOE4allele, and identify potential therapeutic targets for resolving this chronic inflammatory state.
Increasing brain glucose metabolism by ligustrazine piperazine ameliorates cognitive deficits through PPARγ-dependent enhancement of mitophagy in APP/PS1 mice
Authors: Li Zongyang , Meng Xiangbao , Ma Guoxu , Liu Wenlan , Li Weiping , Cai Qian , Wang Sicen , Huang Guodong , Zhang Yuan 
Published: October 2022

AbstractPPARγ agonists have been proven to be neuroprotective in vitro and in vivo models of Alzheimer’s disease (AD). In the present study, we identified ligustrazine piperazine derivative (LPD) as a novel PPARγ agonist, which was detected by a dual-luciferase reporter assay system. LPD treatment dose-dependently reduced Aβ40 and Aβ42 levels in PC12 cells stably transfected with APP695swe and PSEN1dE9. Intragastric administration of LPD for 3 months dose-dependently reversed cognitive deficits in APP/PS1 mice. LPD treatment substantially decreased hippocampal Aβ plaques in APP/PS1 mice and decreased the levels of Aβ40 and Aβ42 in vivo and in vitro. Moreover, LPD treatment induced mitophagy in vivo and in vitro and increased brain 18F-FDG uptake in APP/PS1 mice. LPD treatment significantly increased OCR, ATP production, maximal respiration, spare respiratory capacity, and basal respiration in APP/PS1 cells. Mechanistically, LPD treatment upregulated PPARγ, PINK1, and the phosphorylation of Parkin (Ser65) and increased the LC3-II/LC3-I ratio but decreased SQSTM1/p62 in vivo and in vitro. Importantly, all these protective effects mediated by LPD were abolished by cotreatment with the selective PPARγ antagonist GW9662. In summary, LPD could increase brain glucose metabolism and ameliorate cognitive deficits through PPARγ-dependent enhancement of mitophagy in APP/PS1 mice.
Postnatal developmental trajectory of sex-biased gene expression in the mouse pituitary gland
Authors: Hou Huayun , Chan Cadia , Yuki Kyoko E. , Sokolowski Dustin , Roy Anna , Qu Rihao , Uusküla-Reimand Liis , Faykoo-Martinez Mariela , Hudson Matt , Corre Christina , Goldenberg Anna , Zhang Zhaolei , Palmert Mark R. , Wilson Michael D. 
Published: October 2022

Abstract
Background
The pituitary gland regulates essential physiological processes such as growth, pubertal onset, stress response, metabolism, reproduction, and lactation. While sex biases in these functions and hormone production have been described, the underlying identity, temporal deployment, and cell-type specificity of sex-biased pituitary gene regulatory networks are not fully understood.

Methods
To capture sex differences in pituitary gene regulation dynamics during postnatal development, we performed 3’ untranslated region sequencing and small RNA sequencing to ascertain gene and microRNA expression, respectively, across five postnatal ages (postnatal days 12, 22, 27, 32, 37) that span the pubertal transition in female and male C57BL/6J mouse pituitaries (n = 5–6 biological replicates for each sex at each age).

Results
We observed over 900 instances of sex-biased gene expression and 17 sex-biased microRNAs, with the majority of sex differences occurring with puberty. Using miRNA–gene target interaction databases, we identified 18 sex-biased genes that were putative targets of 5 sex-biased microRNAs. In addition, by combining our bulk RNA-seq with publicly available male and female mouse pituitary single-nuclei RNA-seq data, we obtained evidence that cell-type proportion sex differences exist prior to puberty and persist post-puberty for three major hormone-producing cell types: somatotropes, lactotropes, and gonadotropes. Finally, we identified sex-biased genes in these three pituitary cell types after accounting for cell-type proportion differences between sexes.

Conclusion
Our study reveals the identity and postnatal developmental trajectory of sex-biased gene expression in the mouse pituitary. This work also highlights the importance of considering sex biases in cell-type composition when understanding sex differences in the processes regulated by the pituitary gland.
Impact of the national hepatitis B immunization program in China: a modeling study
Authors: Liu Zhixi , Li Mengying , Hutton David W. , Wagner Abram L. , Yao Ye , Zhu Wenlong , Cao Lingsheng , Tang Shenglan , Pan Jinhua , Wang Yesheng , Zhao Qi , Ren Hong , Wang Ying , Wang Weibing 
Published: October 2022

Abstract
Background
Elimination of hepatitis B virus (HBV) is a striking challenge for countries with high or moderate disease burden. Therefore, using China as a practical case to share experiences for similar countries may accelerate the achievement of the WHO 2030 target of 90% reduction in HBV-related incidence. We aim to evaluate the impact of national HBV immunization strategies in China; and the feasibility to achieve WHO 2030 targets under different scenarios.

Methods
We constructed an expanded Susceptible-Exposed-Infectious-Recovered (SEIR) model and decision tree-Markov model to estimate the epidemic of HBV in China, assess the feasibility of 2030 Elimination Goals through the projections and conduct the economic analysis. Least square method was used to calibrate the expanded SEIR model by yearly data of laboratory-confirmed HBV cases from 1990 to 2018. Two models were separately used to evaluate the impact and cost-effectiveness of HBV vaccine by comparing prevalence of chronic HBV infections, quality-adjusted life-years (QALYs), incremental cost effectiveness ratio and benefit–cost ratio (BCR) under various intervention options, providing a basis for exploring new containment strategies.

Results
Between 1990 and 2020, the number of chronic HBV infections decreased by 33.9%. The current status quo would lead to 55.73 million infections (3.95% prevalence) in 2030, compared to 90.63 million (6.42% prevalence) of the “Without the NIP” scenario (NIP: National Immunization Program), 114.78 million (8.13% prevalence) without any interventions. The prevention of mother to child transmission (PMTCT) strategy showed a net benefit as 12,283.50 dollars per person, with BCR as 12.66, which is higher than that of universal vaccination at 9.49. Compared with no screening and no vaccination, the PMTCT strategy could save 7726.03 dollars for each QALY increase.

Conclusions
Our findings proved the HBV vaccination has demonstrated a substantial positive impact on controlling the epidemic of HBV in terms of effectiveness and economy after about 30 years of implementation of the national hepatitis B immunization program which also provided containment experience for high or medium burden countries. As for China, the next step should focus on exploring strategies to improve diagnosis and treatment coverage to reduce the burden of HBV-related deaths and ultimately eliminate HBV.
The Saturne cementless dual-mobility cup grants satisfactory long-term survival
Authors: Gaillard Thierry , Ramos-Pascual Sonia , Saffarini Mo , Piton Jean-Pierre 
Published: October 2022

Abstract
Purpose
To report long-term survival and clinical outcomes of primary total hip arthroplasty (THA) using a Saturne cementless dual-mobility (DM) cup, and investigate whether patient demographics or surgical parameters affect clinical scores.

Methods
A consecutive series of primary THAs implanted with Saturne cementless DM cups between 01/09/2009–31/12/ 2011 was retrospectively assessed. Patients were postoperatively evaluated using modified Harris hip score (mHHS) and forgotten joint score (FJS). Complications, reoperations, and revisions were noted. Regression analyses were performed to determine associations of postoperative mHHS with preoperative and intraoperative variables. Ten-year Kaplan–Meier survival was calculated.

Results
Of 308 patients (308 hips), 111 (36%) had died with their original cups in place, 29 (9%) were lost-to-follow-up, and 5 (2%) required cup revision, leaving a final cohort of 163 (53%) with their original cup in place at a follow-up of ≥ 10 years. Ten-year survival was 98% considering cup revision for any reason as endpoint; 99% considering cup revision for aseptic loosening as endpoint; 96% considering stem revision for any reason as endpoint; and 96% considering any revision as endpoint. The final cohort of 163 patients was assessed at 11 ± 1 years (range, 10–13), mHHS was 85 ± 16 (range, 31–100) and FJS was 84 ± 24 (range, 0–100). Multivariable regression analysis revealed that postoperative mHHS significantly worsened with age (β = -0.48, p = 0.007) and BMI (β = -0.70, p = 0.008), as well as for 22 mm head sizes (β = -6.98, p = 0.046).

Conclusions
The Saturne DM cup granted satisfactory survival and clinical outcomes at a minimum follow-up of 10 years, and resulted in no cases of intra- or extra-prosthetic dislocations.