bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human genetic associations of the airway microbiome in chronic obstructive pulmonary disease
Authors: Gao Jingyuan , Yang Yuqiong , Xiang Xiaopeng , Zheng Huimin , Yi Xinzhu , Wang Fengyan , Liang Zhenyu , Chen Dandan , Shi Weijuan , Wang Lingwei , Wu Di , Feng Shengchuan , Huang Qiaoyun , Li Xueping , Shu Wensheng , Chen Rongchang , Zhong Nanshan , Wang Zhang 
Published: April 2024

AbstractLittle is known about the relationships between human genetics and the airway microbiome. Deeply sequenced airway metagenomics, by simultaneously characterizing the microbiome and host genetics, provide a unique opportunity to assess the microbiome-host genetic associations. Here we performed a co-profiling of microbiome and host genetics with the identification of over 5 million single nucleotide polymorphisms (SNPs) through deep metagenomic sequencing in sputum of 99 chronic obstructive pulmonary disease (COPD) and 36 healthy individuals. Host genetic variation was the most significant factor associated with the microbiome except for geography and disease status, with its top 5 principal components accounting for 12.11% of the microbiome variability. Within COPD individuals, 113 SNPs mapped to candidate genes reported as genetically associated with COPD exhibited associations with 29 microbial species and 48 functional modules (P < 1 × 10−5), where Streptococcus salivarius exhibits the strongest association to SNP rs6917641 in TBC1D32 (P = 9.54 × 10−8). Integration of concurrent host transcriptomic data identified correlations between the expression of host genes and their genetically-linked microbiome features, including NUDT1, MAD1L1 and Veillonella parvula, TTLL9 and Stenotrophomonas maltophilia, and LTA4H and Haemophilus influenzae. Mendelian randomization analyses revealed a potential causal link between PARK7 expression and microbial type III secretion system, and a genetically-mediated association between COPD and increased relative abundance of airway Streptococcus intermedius. These results suggest a previously underappreciated role of host genetics in shaping the airway microbiome and provide fresh hypotheses for genetic-based host-microbiome interactions in COPD.
Comprehensive analysis of m6A modification in immune infiltration, metabolism and drug resistance in hepatocellular carcinoma
Authors: Shi Yunxing , Li Kai , Yuan Yichuan , Wang Chenwei , Yang Zhiwen , Zuo Dinglan , Niu Yi , Qiu Jiliang , Li Binkui , Yuan Yunfei , He Wei 
Published: April 2024

AbstractN6-methyladenosine (m6A) is important in regulating mRNA stability, splicing, and translation, and it also contributes to tumor development. However, there is still limited understanding of the comprehensive effects of m6A modification patterns on the tumor immune microenvironment, metabolism, and drug resistance in hepatocellular carcinoma (HCC). In this study, we utilized unsupervised clustering based on the expression of 23 m6A regulators to identify m6A clusters. We identified differential m6A modification patterns and characterized m6A-gene-cluster A, which exhibited poorer survival rates, a higher abundance of Treg cells, and increased expression of TGFβ in the tumor microenvironment (TME). Additionally, m6A-gene-cluster A demonstrated higher levels of glycolysis activity, cholesterol metabolism, and fatty acid biosynthesis. We also found that the m6A score was associated with prognosis and drug resistance. Patients with a low m6A score experienced worse prognoses, which were linked to an abundance of Treg cells, upregulation of TGFβ, and increased metabolic activity. HCC patients with a higher m6A score showed improved prognosis following sorafenib treatment and immunotherapy. In conclusion, we reveals the association between m6A modification patterns and the tumor immune microenvironment, metabolism, and drug resistance in HCC. Furthermore, the m6A score holds potential as a predictive factor for the efficacy of targeted therapy and immunotherapy in HCC.
Significance of PSCA as a novel prognostic marker and therapeutic target for cancer
Authors: Nayerpour Dizaj Tina , Doustmihan Abolfazl , Sadeghzadeh Oskouei Behnaz , Akbari Morteza , Jaymand Mehdi , Mazloomi MirAhmad , Jahanban-Esfahlan Rana 
Published: April 2024

AbstractOne of the contributing factors in the diagnosis and treatment of most cancers is the identification of their surface antigens. Cancer tissues or cells have their specific antigens. Some antigens that are present in many cancers elicit different functions. One of these antigens is the prostate stem cell antigen (PSCA) antigen, which was first identified in the prostate. PSCA is a cell surface protein that has different functions in different tissues. It can play an inhibitory role in cell proliferation as well as a tumor-inducing role. PSCA has several genetic variants involved in cancer susceptibility in some tissues, so identifying the characteristics of this antigen and its relationship with clinical features can provide more information on diagnosis and treatment of patients with cancers. Most studies on the PSCA have focused on prostate cancer. While it is also expressed in other cancers, little attention has been paid to its role as a valuable diagnostic, prognostic, and therapeutic tool in other cancers. PSCA has several genetic variants that seem to play a significant role in cancer susceptibility in some tissues, so identifying the characteristics of this antigen and its relationship and variants with clinical features can be beneficial in concomitant cancer therapy and diagnosis, as theranostic tools. In this study, we will review the alteration of the PSCA expression and its polymorphisms and evaluate its clinical and theranostics significance in various cancers.
Efficacy and safety of bispecific antibodies vs. immune checkpoint blockade combination therapy in cancer: a real-world comparison
Authors: Cheng Linyan , Chen Lujun , Shi Yuan , Gu Weiying , Ding Weidong , Zheng Xiao , Liu Yan , Jiang Jingting , Zheng Zhuojun 
Published: April 2024

AbstractEmerging tumor immunotherapy methods encompass bispecific antibodies (BSABs), immune checkpoint inhibitors (ICIs), and adoptive cell immunotherapy. BSABs belong to the antibody family that can specifically recognize two different antigens or epitopes on the same antigen. These antibodies demonstrate superior clinical efficacy than monoclonal antibodies, indicating their role as a promising tumor immunotherapy option. Immune checkpoints are also important in tumor immunotherapy. Programmed cell death protein-1 (PD-1) is a widely acknowledged immune checkpoint target with effective anti-tumor activity. PD-1 inhibitors have demonstrated notable therapeutic efficacy in treating hematological and solid tumors; however, more than 50% of patients undergoing this treatment exhibit a poor response. However, ICI-based combination therapies (ICI combination therapies) have been demonstrated to synergistically increase anti-tumor effects and immune response rates. In this review, we compare the clinical efficacy and side effects of BSABs and ICI combination therapies in real-world tumor immunotherapy, aiming to provide evidence-based approaches for clinical research and personalized tumor diagnosis and treatment.
Approaches to locum physician recruitment and retention: a systematic review
Authors: Ferreira Nathan , McKenna Odessa , Lamb Iain R. , Campbell Alanna , DeMiglio Lily , Orrantia Eliseo 
Published: April 2024

AbstractA robust workforce of locum tenens (LT) physicians is imperative for health service stability. A systematic review was conducted to synthesize current evidence on the strategies used to facilitate the recruitment and retention of LT physicians. English articles up to October 2023 across five databases were sourced. Original studies focusing on recruitment and retention of LT’s were included. An inductive content analysis was performed to identify strategies used to facilitate LT recruitment and retention. A separate grey literature review was conducted from June–July 2023. 12 studies were retained. Over half (58%) of studies were conducted in North America. Main strategies for facilitating LT recruitment and retention included financial incentives (83%), education and career factors (67%), personal facilitators (67%), clinical support and mentorship (33%), and familial considerations (25%). Identified subthemes were desire for flexible contracts (58%), increased income (33%), practice scouting (33%), and transitional employment needs (33%). Most (67%) studies reported deterrents to locum work, with professional isolation (42%) as the primary deterrent-related subtheme. Grey literature suggested national physician licensure could enhance license portability, thereby increasing the mobility of physicians across regions. Organizations employ five main LT recruitment facilitators and operationalize these in a variety of ways. Though these may be incumbent on local resources, the effectiveness of these approaches has not been evaluated. Consequently, future research should assess LT the efficacy of recruitment and retention facilitators. Notably, the majority of identified LT deterrents may be mitigated by modifying contextual factors such as improved onboarding practices.
KLF5 promotes the ossification process of ligamentum flavum by transcriptionally activating CX43
Authors: Guo Hubing , Yang Lingxia , Liu Jin , Chen Liqi , Huang Yufeng , Li Jinsong 
Published: April 2024

Abstract
Background
Ossification of ligamentum flavum (OLF) is a prevalent degenerative spinal disease, typically causing severe neurological dysfunction. Kruppel-like factor 5 (KLF5) plays an essential role in the regulation of skeletal development. However, the mechanism KLF5 plays in OLF remains unclear, necessitating further investigative studies.

Methods
qRT-PCR, immunofluorescent staining and western blot were used to measure the expression of KLF5. Alkaline Phosphatase (ALP) staining, Alizarin red staining (ARS), and the expression of Runt-related transcription factor 2 (RUNX2), osteopontin (OPN), and osteocalcin (OCN) were used to evaluate the osteogenic differentiation. Luciferase activity assay and ChIP-PCR were performed to investigate the molecular mechanisms.

Results
KLF5 was significantly upregulated in OLF fibroblasts in contrast to normal ligamentum flavum (LF) fibroblasts. Silencing KLF5 diminished osteogenic markers and mineralized nodules, while its overexpression had the opposite effect, confirming KLF5’s role in promoting ossification. Moreover, KLF5 promotes the ossification of LF by activating the transcription of Connexin 43 (CX43), and overexpressing CX43 could reverse the suppressive impact of KLF5 knockdown on OLF fibroblasts’ osteogenesis.

Conclusion
KLF5 promotes the OLF by transcriptionally activating CX43. This finding contributes significantly to our understanding of OLF and may provide new therapeutic targets.
Exosomes derived from M2 macrophages prevent steroid-induced osteonecrosis of the femoral head by modulating inflammation, promoting bone formation and inhibiting bone resorption
Authors: Yuan Na , Zhang Weiying , Yang Weizhou , Ji Wenchen , Li Jia 
Published: April 2024

AbstractInflammatory reactions are involved in the development of steroid-induced osteonecrosis of the femoral head(ONFH). Studies have explored the therapeutic efficacy of inhibiting inflammatory reactions in steroid-induced ONFH and revealed that inhibiting inflammation may be a new strategy for preventing the development of steroid-induced ONFH. Exosomes derived from M2 macrophages(M2-Exos) display anti-inflammatory properties. This study aimed to examine the preventive effect of M2-Exos on early-stage steroid-induced ONFH and explore the underlying mechanisms involved. In vitro, we explored the effect of M2-Exos on the proliferation and osteogenic differentiation of bone marrow-derived mesenchymal stem cells(BMMSCs). In vivo, we investigated the role of M2-Exos on inflammation, osteoclastogenesis, osteogenesis and angiogenesis in an early-stage rat model of steroid-induced ONFH. We found that M2-Exos promoted the proliferation and osteogenic differentiation of BMMSCs. Additionally, M2-Exos effectively attenuated the osteonecrotic changes, inhibited the expression of proinflammatory mediators, promoted osteogenesis and angiogenesis, reduced osteoclastogenesis, and regulated the polarization of M1/M2 macrophages in steroid-induced ONFH. Taken together, our data suggest that M2-Exos are effective at preventing steroid-induced ONFH. These findings may be helpful for providing a potential strategy to prevent the development of steroid-induced ONFH.
A middle lobe sparing sleeve resection versus bilobectomy for right lower central non-small cell lung cancer: a retrospective propensity score matched cohort study
Authors: Wang Jiongjie , Guo Jichao , Shi Haizhan , Chen Xiangru , He Wenxin , Li Zhixin 
Published: April 2024

Abstract
Objectives
The right lower sleeve lobectomy is a rarely performed major lung resection.This study aims to evaluate the safety and effectiveness of this procedure by comparing to right lower bilobectomy in non-small cell lung cancer patients.

Methods
We retrospectively reviewed a prospective database of non-small cell lung cancer patients who underwent right lower sleeve lobectomy (group S) or right lower bilobectomy (group B) from January 2014 to January 2020 in Shanghai Pulmonary Hospital. Propensity score matching method was applied to balance confounders between the two groups, resulting in 41 matched pairs.The analysis was performed to compare perioperative outcomes, long-term survival, and postoperative pulmonary volume between the two groups.

Results
No significant differences in the characteristics were observed between the two matched groups.Major postoperative complications developed in 31.7% of the patients in group B and 12.1% of the patients in group S (P = 0.032).Intervention rate for surgical residual cavity in group B is significantly higher than those patients in group S(21.9%vs7.3%,p = 0.037).The postoperative right lateral and overall lung volume in group S were both significantly larger than that in group B (P = 0.026,P = 0.001,respectively).

Conclusions
Compared to bi-lobectomy, a middle lobe sparing sleeve resection obtains a less prevalence of major complications, smaller postoperative residual air space and similar long-term survival for selected central right lower NSCLC patients.
Comprehensive DNA methylation profiling by MeDIP-NGS identifies potential genes and pathways for epithelial ovarian cancer
Authors: Gautam Priyanka , Gupta Sameer , Sachan Manisha 
Published: April 2024

AbstractOvarian cancer, among all gynecologic malignancies, exhibits the highest incidence and mortality rate, primarily because it is often presents with non-specific or no symptoms during its early stages. For the advancement of Ovarian Cancer Diagnosis, it is crucial to identify the potential molecular signatures that could significantly differentiate between healthy and ovarian cancerous tissues and can be used further as a diagnostic biomarker for detecting ovarian cancer. In this study, we investigated the genome-wide methylation patterns in ovarian cancer patients using Methylated DNA Immunoprecipitation (MeDIP-Seq) followed by NGS. Identified differentially methylated regions (DMRs) were further validated by targeted bisulfite sequencing for CpG site-specific methylation profiles. Furthermore, expression validation of six genes by Quantitative Reverse Transcriptase-PCR was also performed. Out of total 120 differentially methylated genes (DMGs), 68 genes were hypermethylated, and 52 were hypomethylated in their promoter region. After analysis, we identified the top 6 hub genes, namely POLR3B, PLXND1, GIGYF2, STK4, BMP2 and CRKL. Interestingly we observed Non-CpG site methylation in the case of POLR3B and CRKL which was statistically significant in discriminating ovarian cancer samples from normal controls. The most significant pathways identified were focal adhesion, the MAPK signaling pathway, and the Ras signaling pathway. Expression analysis of hypermethylated genes was correlated with the downregulation of the genes. POLR3B and GIGYF2 turned out to be the novel genes associated with the carcinogenesis of EOC. Our study demonstrated that methylation profiling through MeDIP-sequencing has effectively identified six potential hub genes and pathways that might exacerbate our understanding of underlying molecular mechanisms of ovarian carcinogenesis.
Mortality rates in Norwegian HEMS—a retrospective analysis from Central Norway
Authors: Wekre Stian Lande , Uleberg Oddvar , Næss Lars Eide , Haugland Helge 
Published: April 2024

Abstract
Background
Helicopter Emergency Medical Services (HEMS) provide rapid and specialized care to critically ill or injured patients. Norwegian HEMS in Central Norway serves an important role in pre-hospital emergency medical care. To grade the severity of patients, HEMS uses the National Advisory Committee for Aeronautics’ (NACA) severity score. The objective of this study was to describe the short- and long term mortality overall and in each NACA-group for patients transported by HEMS Trondheim using linkage of HEMS and hospital data.

Methods
The study used a retrospective cohort design, aligning with the STROBE recommendations. Patient data from Trondheim HEMS between 01.01.2017 and 31.12.2019 was linked to mortality data from a hospital database and analyzed. Kaplan Meier plots and cumulative mortality rates were calculated for each NACA group at day one, day 30, and one year and three years after the incident.

Results
Trondheim HEMS responded to 2224 alarms in the included time period, with 1431 patients meeting inclusion criteria for the study. Overall mortality rates at respective time points were 10.1% at day one, 13.4% at 30 days, 18.5% at one year, and 22.3% at three years. The one-year cumulative mortality rates for each NACA group were as follows: 0% for NACA 1 and 2, 2.9% for NACA 3, 10.1% for NACA 4, 24.7% for NACA 5 and 49.5% for NACA 6. Statistical analysis with a global log-rank test indicated a significant difference in survival outcomes among the groups (p < 2⋅10− 16).

Conclusion
Among patients transported by Trondheim HEMS, we observed an incremental rise in mortality rates with increasing NACA scores. The study further suggests that a one-year follow-up may be sufficient for future investigations into HEMS outcomes.
Characterizing glucokinase variant mechanisms using a multiplexed abundance assay
Authors: Gersing Sarah , Schulze Thea K. , Cagiada Matteo , Stein Amelie , Roth Frederick P. , Lindorff-Larsen Kresten , Hartmann-Petersen Rasmus 
Published: April 2024

Abstract
Background
Amino acid substitutions can perturb protein activity in multiple ways. Understanding their mechanistic basis may pinpoint how residues contribute to protein function. Here, we characterize the mechanisms underlying variant effects in human glucokinase (GCK) variants, building on our previous comprehensive study on GCK variant activity.

Results
Using a yeast growth-based assay, we score the abundance of 95% of GCK missense and nonsense variants. When combining the abundance scores with our previously determined activity scores, we find that 43% of hypoactive variants also decrease cellular protein abundance. The low-abundance variants are enriched in the large domain, while residues in the small domain are tolerant to mutations with respect to abundance. Instead, many variants in the small domain perturb GCK conformational dynamics which are essential for appropriate activity.

Conclusions
In this study, we identify residues important for GCK metabolic stability and conformational dynamics. These residues could be targeted to modulate GCK activity, and thereby affect glucose homeostasis.
National genomic epidemiology investigation revealed the spread of carbapenem-resistant Escherichia coli in healthy populations and the impact on public health
Authors: Li Yan , Zhang Yanyan , Sun Xinran , Wu Yuchen , Yan Zelin , Ju Xiaoyang , Huang Yonglu , Zhou Hongwei , Wang Zhiqiang , Wang Shaolin , Zhang Rong , Li Ruichao 
Published: April 2024

Abstract
Background
Carbapenem-resistant Escherichia coli (CREC) has been considered as WHO priority pathogens, causing a great public health concern globally. While CREC from patients has been thoroughly investigated, the prevalence and underlying risks of CREC in healthy populations have been overlooked. Systematic research on the prevalence of CREC in healthy individuals was conducted here. We aimed to characterize CREC collected from healthy populations in China between 2020 and 2022 and to compare the genomes of CREC isolates isolated from healthy individuals and clinical patients.

Methods
We present a nationwide investigation of CREC isolates among healthy populations in China, employing robust molecular and genomic analyses. Antimicrobial susceptibility testing, whole-genome sequencing, and bioinformatics were utilized to analyze a cohort of CREC isolates (n = 113) obtained from fecal samples of 5 064 healthy individuals. Representative plasmids were extracted for third-generation nanopore sequencing. We previously collected 113 non-duplicate CREC isolates (59 in 2018, 54 in 2020) collected from ICU patients in 15 provinces and municipalities in China, and these clinical isolates were used to compare with the isolates in this study. Furthermore, we employ comparative genomics approaches to elucidate molecular variations and potential correlations between clinical and non-clinical CREC isolates.

Results
A total of 147 CREC isolates were identified from 5 064 samples collected across 11 provinces in China. These isolates were classified into 64 known sequence types (STs), but no dominant STs were observed. In total, seven carbapenemase genes were detected with blaNDM-5 (n = 116) being the most prevalent one. Genetic environments and plasmid backbones of blaNDM were conserved in CREC isolated from healthy individuals. Furthermore, we compared clinical and healthy human-originated CRECs, revealing noteworthy distinctions in 23 resistance genes, including blaNDM-1, blaNDM-5, and blaKPC (χ2 test, p < 0.05). Clinical isolates contained more virulence factors associated with iron uptake, adhesion, and invasion than those obtained from healthy individuals. Notably, CREC isolates generally found healthy people are detected in hospitalized patients.

Conclusions
Our findings underscore the significance of healthy populations-derived CRECs as a crucial reservoir of antibiotic resistance genes (ARGs). This highlights the need for ongoing monitoring of CREC isolates in healthy populations to accurately assess the potential risks posed by clinical CREC isolates.