bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of causal associations between uric acid and 25-hydroxyvitamin D levels
Authors: Han Yingdong , Zhang Yun , Zeng Xuejun
Published: December 2022

Background

Previous observational studies have revealed the association between serum uric acid and 25-hydroxyvitamin D. However, the causality and the direction of the associations remain unknown. Thus, we performed a two-sample bidirectional Mendelian Randomization (MR) analysis to investigate the causal association between uric acid and 25-hydroxyvitamin D and to determine the direction of the association.

Method

Based on the summary-level GWAS data from large genome-wide association studies, several steps were taken in our analysis to select eligible single-nucleotide polymorphisms (SNPs), which were strongly related to exposure as the instrumental variables. We used different analytical methods, such as inverse-variance weighting (IVW) method, weighted median, MR-Egger regression, and weighted mode method, to make our result more robust and reliable. The IVW method was used as the primary analysis. The Cochran’s Q test, MR-Egger intercept test, MR-PRESSO method, and “leave-one-out” sensitivity analysis was performed to evaluate the heterogeneities, horizontal pleiotropy, and robustness of the results. MR analyses were also conducted using genetic risk scores (GRS) as instrumental variables in both directions by using the same summary-level GWAS data.

Results

Our two-sample MR analysis suggested a causal association of genetically predicted uric acid on 25-hydroxyvitamin D [IVW method: β(SE), −0.0352(0.0149); p = 0.0178], which suggested that a per mg/dl increase in uric acid was associated with a decrease of 0.74 nmol/L of 25-hydroxyvitamin D, and the above results remained stable in the sensitivity analysis. By contrast, four MR methods suggested no causal relationship of 25-hydroxyvitamin D on serum uric acid [IVW β(SE), 0.0139 (0.0635); p = 0.826; MR-Egger β(SE), 0.0671 (0.108); p = 0.537; weighted median β(SE), 0.0933 (0.0495); p = 0.0598; weighted mode β(SE), 0.0562 (0.0463); p = 0.228, respectively]. After excluding the SNPs, which were associated with confounding factors and outlier SNPs, the IVW method suggested that there was still no causal association of 25-hydroxyvitamin D on serum uric acid. The GRS approach showed similar results.

Conclusions

Serum uric acid may causally affect the 25-hydroxyvitamin D levels, whereas the causal role of 25-hydroxyvitamin D on uric acid was not supported in our MR analysis. Our findings suggest that increased levels of uric acid should prompt investigation for vitamin D deficiency.
Vitamin D pathway gene variation rs3740165 is associated with serological uric acid levels in healthy Chinese women
Authors: Gu Jiemei , Yue Hua , Wang Chun , Zhang Hao , Hu Weiwei , Zhang Zhenlin
Published: December 2022

Aim

To investigate the relationship between gene polymorphisms involved in the vitamin D metabolic pathway and serum uric acid (UA) levels in Chinese women.

Methods

Fifteen key genes within the vitamin D metabolic pathway were screened using 96 single nucleotide polymorphisms in a group of 1,206 (37.96 ± 13.08 years) unrelated healthy Chinese women (aged 20–85 years). Blood and urine tests were performed at the same time. The Wilcoxon Mann–Whitney test was used to compare groups aged ≤50 years and >50 years. The mean serum UA values were computed within each group of homozygous referent, heterozygous, and homozygous variant genotypes for each single nucleotide polymorphism.

Results

The exclusion process left 1,169 participants (38.16 ± 13.13 years) for analysis. One single nucleotide polymorphism in the CUBN gene (rs3740165) was identified as being significantly associated with serum UA levels in the group aged over 50 years. The wild type (C/C) population had higher serum UA levels in this group (P<0.001). In women aged over 50 years, allele C was associated with a higher risk of hyperuricemia than allele T (odds ratio 2.752, 95% confidence interval 1.458–5.192; P = 0.002). There was also a higher risk of hyperuricemia in genotype TC + CC compared with genotype TT (odds ratio 3.326, 95% confidence interval 1.513–7.313; P = 0.003) in women over 50 years of age.

Conclusion

The results suggest that the CUBN gene contributes to variability in serum UA levels in healthy Chinese Han women over 50 years of age.
Applying the RE-AIM implementation framework to evaluate diabetes health coaching in individuals with type 2 diabetes: A systematic review and secondary analysis
Authors: Racey Megan , Jovkovic Milos , Alliston Paige , Sherifali Diana
Published: December 2022

Background

Diabetes health coaching continues to emerge as an effective intervention to support diabetes self-management. While previous systematic reviews have focused on the effectiveness of diabetes health coaching programs in adults with type 2 diabetes (T2DM), limited literature is available on its implementation. This review examines what aspects of diabetes health coaching interventions for adults living with type 2 diabetes have been reported using the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework to optimize implementation.

Methods

We examined the included studies from our recently completed systematic review, which searched 6 databases for randomized controlled trials (RCTs) of health coaching interventions delivered by a health professional for adults with T2DM. Reviewers screened citations and extracted data for study characteristics and the 5 dimensions (62 criteria) of the RE-AIM framework.

Results

9 diabetes health coaching RCTs were included in this review. 12 criteria were reported by all the included studies and 21 criteria were not reported by any of the studies. The included studies all reported on more than 20 RE-AIM criteria, ranging from 21 to 27. While Reach was the best reported construct by the included studies, followed by Effectiveness and Implementation, the criteria within the Adoption and Maintenance constructs were rarely mentioned by these studies. In general, there was also wide variation in how each of the criteria were reported on by study authors

Conclusions

Due to the paucity of reporting of the RE-AIM components for diabetes health coaching, limited implementation and clinical practice implications can be drawn. The lack of detail regarding implementation approaches to diabetes health coaching greatly limits the interpretation and comparisons across studies to best inform the application of this intervention to support diabetes self-management.

Systematic review registration

PROSPERO identifier, CRD42022347478
Spatial accessibility analysis of green space from a health-benefit perspective: Implications for healthy urban development
Authors: Wei Xiangrui , Zhao Chunrong , Yan Li , Fu Juanlin , Bao Ying , Liu Xiao
Published: December 2022

The spatial accessibility of urban park green space (UPGS) plays a crucial role in promoting the healthy development of cities and their residents. However, previous studies have overestimated the accessibility of UPGS and failed to adequately consider the impact of variegated parks on residents’ needs. To fill this gap in the research, we first propose an improved two-step floating catchment area (Huff-2SFCA) method that takes into consideration the trade-offs between supply, demand, and walking time to calculate the UPGS accessibility index for the built-up area of Mianyang, China. Next, we assess the spatial characteristics of UPGS accessibility from both partial and overall points of view and further explore the relationship between accessibility and population size. Our results show that (1) every street area has a different form of UPGS construction, and most of these spaces are of poor quality; (2) municipal-level parks are significantly more accessible than district-level parks, community-level parks, or neighborhood-level parks; (3) the overall distribution of accessibility is generally characterized by a decreasing trend along both sides of the river, with poor overall accessibility; and (4) 243 residential districts are located in high-demand–low-supply areas that need improving. This study can be employed to identify areas that are underserved by UPGS and can provide a basis for improving the accessibility of UPGS and promoting its health benefits.
Addressing diversity and inclusion challenges in global neuro-psychiatric and behavioral genomics research
Authors: Matshabane Olivia P. , Whitted Calandra G. , Koehly Laura M.
Published: December 2022

Advancements in neuro-psychiatric and behavioral genomics offer significant opportunities for better understanding the human brain, behavior and associated disorders. Such advancements may help us prevent, manage and/or cure complex conditions. The serious challenge confronted by these disciplines however is diversity. Both fields lack diversity in terms of genomic reference datasets needed for discovery research, engagement of diverse communities in translational research and in terms of diverse and multidisciplinary scientific teams. This is a challenge because diversity is needed on all levels in order to increase representation and inclusion of all populations across the globe as we move research activities forward. The lack of diversity can translate to an inability to use scientific innovations from these fields for the benefit of all people everywhere and signifies a missed opportunity to address pervasive global health inequities. In this commentary we identify three persistent barriers to reaching diversity targets while focusing on discovery and translational science. Additionally, we propose four suggestions on how to advance efforts and rapidly move towards achieving diversity and inclusion in neuro-psychiatric and behavioral genomics. Without systematically addressing the diversity gap within these fields, the benefits of the science may not be relevant and accessible to all people.
Etoricoxib as a treatment of choice for patients with SLCO2A1 mutation exhibiting autosomal recessive primary hypertrophic osteoarthropathy: A case report
Authors: Albawa'neh Areej , Al Mansoori Mariam Ghareeb , Diab Sehriban , Al Jasmi Fatma , Akawi Nadia
Published: December 2022

We reported a 22-year-old Emirati male with autosomal recessive primary hypertrophic osteoarthropathy caused by a possibly pathogenic homozygous non-synonymous variant in the SLCO2A1 gene (NM_005630.3: c.289C>T, p. Arg97Cys) presenting with joint swelling, forehead furrowing, and significant clubbing in all fingers and toes. Currently, no standard treatments are approved for this disease; medical care is palliative and includes non-steroidal anti-inflammatory drugs, corticosteroids, tamoxifen, retinoids, and risedronate. Colchicine may be helpful for the pain due to subperiosteal new bone formation. Our patient was treated with etoricoxib 60 mg once daily and showed a significant clinical improvement at the 6-month mark that was reversed upon the withdrawal of this medication. This case report highlights the importance of placing etoricoxib among first-line therapy recommendations for cases with confirmed primary hypertrophic osteoarthropathy diagnosis. To the best of our knowledge, this is the only case of primary hypertrophic osteoarthropathy from the Middle Eastern population of Arab ethnicity that has responded to non-steroidal anti-inflammatory drug therapy.
Construction of an immunogenic cell death-based risk score prognosis model in breast cancer
Authors: Li Yanling , Feng Jianyuan , Wang Ting , Li Mingcui , Zhang Hanyu , Rong Zhiyuan , Cheng Weilun , Duan Yunqiang , Chen Ziang , Hu Anbang , Yu Tianshui , Zhang Jiarui , Shang Yuhang , Zou Yiyun , Ma Fei , Guo Baoliang
Published: December 2022

Immunogenic cell death (ICD) is a form of regulated cell death that elicits immune response. Common inducers of ICD include cancer chemotherapy and radiation therapy. A better understanding of ICD might contribute to modify the current regimens of anti-cancer therapy, especially immunotherapy. This study aimed to identify ICD-related prognostic gene signatures in breast cancer (BC). An ICD-based gene prognostic signature was developed using Lasso-cox regression and Kaplan-Meier survival analysis based on datasets acquired from the Cancer Genome Atlas and Gene Expression Omnibus. A nomogram model was developed to predict the prognosis of BC patients. Gene Set Enrichment Analysis (GESA) and Gene Set Variation Analysis (GSVA) were used to explore the differentially expressed signaling pathways in high and low-risk groups. CIBERSORT and ESTIMATE algorithms were performed to investigate the difference of immune status in tumor microenvironment of different risk groups. Six genes (CALR, CLEC9A, BAX, TLR4, CXCR3, and PIK3CA) were selected for construction and validation of the prognosis model of BC based on public data. GSEA and GSVA analysis found that immune-related gene sets were enriched in low-risk group. Moreover, immune cell infiltration analysis showed that the immune features of the high-risk group were characterized by higher infiltration of tumor-associated macrophages and a lower proportion of CD8+ T cells, suggesting an immune evasive tumor microenvironment. We constructed and validated an ICD-based gene signature for predicting prognosis of breast cancer patients. Our model provides a tool with good discrimination and calibration abilities to predict the prognosis of BC, especially triple-negative breast cancer (TNBC).
Substance abuse and the risk of severe COVID-19: Mendelian randomization confirms the causal role of opioids but hints a negative causal effect for cannabinoids
Authors: Jabalameli M. Reza , Zhang Zhengdong D.
Published: December 2022

Since the start of the COVID-19 global pandemic, our understanding of the underlying disease mechanism and factors associated with the disease severity has dramatically increased. A recent study investigated the relationship between substance use disorders (SUD) and the risk of severe COVID-19 in the United States and concluded that the risk of hospitalization and death due to COVID-19 is directly correlated with substance abuse, including opioid use disorder (OUD) and cannabis use disorder (CUD). While we found this analysis fascinating, we believe this observation may be biased due to comorbidities (such as hypertension, diabetes, and cardiovascular disease) confounding the direct effect of SUD on severe COVID-19 illness. To answer this question, we sought to investigate the causal relationship between substance abuse and medication-taking history (as a proxy trait for comorbidities) with the risk of COVID-19 adverse outcomes. Our Mendelian randomization analysis confirms the causal relationship between OUD and severe COVID-19 illness but suggests an inverse causal effect for cannabinoids. Considering that COVID-19 mortality is largely attributed to disturbed immune regulation, the possible modulatory impact of cannabinoids in alleviating cytokine storms merits further investigation.
Dynamics of circulating follicular helper T cell subsets and follicular regulatory T cells in rheumatoid arthritis patients according to HLA-DRB1 locus
Authors: Ferrero Paola V. , Onofrio Luisina I. , Acosta Cristina del Valle , Zacca Estefania R. , Ponce Nicolas E. , Mussano Eduardo , Onetti Laura B. , Cadile Ignacio I. , Costantino Alicia B. , Werner Marina L. , Mas Luciana A. , Alvarellos Teresita , Montes Carolina L. , Acosta Rodríguez Eva V. , Gruppi Adriana
Published: December 2022

B cells, follicular helper T (Tfh) cells and follicular regulatory T (Tfr) cells are part of a circuit that may play a role in the development or progression of rheumatoid arthritis (RA). With the aim of providing further insight into this topic, here we evaluated the frequency of different subsets of Tfh and Tfr in untreated and long-term treated RA patients from a cohort of Argentina, and their potential association with particular human leukocyte antigen (HLA) class-II variants and disease activity. We observed that the frequency of total Tfh cells as well as of particular Tfh subsets and Tfr cells were increased in seropositive untreated RA patients. Interestingly, when analyzing paired samples, the frequency of Tfh cells was reduced in synovial fluid compared to peripheral blood, while Tfr cells levels were similar in both biological fluids. After treatment, a decrease in the CCR7loPD1hi Tfh subset and an increase in the frequency of Tfr cells was observed in blood. In comparison to healthy donors, seropositive patients with moderate and high disease activity exhibited higher frequency of Tfh cells while seropositive patients with low disease activity presented higher Tfr cell frequency. Finally, we observed that HLA-DRB1*09 presence correlated with higher frequency of Tfh and Tfr cells, while HLA-DRB1*04 was associated with increased Tfr cell frequency. Together, our results increase our knowledge about the dynamics of Tfh and Tfr cell subsets in RA, showing that this is altered after treatment.
Immune responses to SARS-CoV-2 in vaccinated patients receiving checkpoint blockade immunotherapy for cancer
Authors: Piening Alexander , Ebert Emily , Khojandi Niloufar , Alspach Elise , Teague Ryan M.
Published: December 2022

Vaccination against SARS-CoV-2 has been successful in protecting patients with cancer from severe infections, but how immune responses against COVID-19 vaccination interact with those elicited during cancer immunotherapy has not been fully described. Immune checkpoint blockade (ICB) disrupts inhibitory pathways in immune cells to improve function and induce tumor immunity but can often cause serious immune related adverse events (IRAEs). Because COVID-19 vaccination and ICB both boost immune responses, it is imperative to understand if combining these regimens causes synergistic enhancement of the immune system. Specifically, whether ICB impacts anti-vaccine immunity in previously vaccinated patients is important since a large percentage of newly diagnosed cancer patients eligible for immunotherapy will have already been vaccinated against COVID-19. To address this, we investigated the influence of ICB on SARS-CoV-2-spike protein (SP) antibody titers and T cell responses in cancer patients previously vaccinated against COVID-19. Human blood samples were collected from 29 vaccinated patients and 12 unvaccinated control patients at baseline (prior to ICB) and following two rounds of ICB infusion. Anti-SARS-CoV-2-SP IgG titers and T cell responses were quantified. Compared to responses at baseline, there was no significant difference in these immune responses after immunotherapy in vaccinated individuals (P=0.4583, P=0.4571, respectively). We interpret these results as evidence that ICB immunotherapy does not significantly enhance SARS-CoV-2-specific antibody titers or T cell responses. Although our study lacks corresponding IRAE rates, the results provide humoral and cellular immunological data that support recent reports documenting the clinical safety and efficacy of COVID-19 vaccination in patients receiving ICB. Additional longitudinal prospective studies, such as the VOICE study (ClinicalTrials.gov identifier NCT04715438) and CAPTURE study (ClinicalTrials.gov identifier NCT03226886), are warranted and will provide broader safety and immunological data defining the effect of systemic cancer therapies on COVID-19 immunity.
High-risk genotypes for type 1 diabetes are associated with the imbalance of gut microbiome and serum metabolites
Authors: Yue Tong , Tan Huiling , Wang Chaofan , Liu Ziyu , Yang Daizhi , Ding Yu , Xu Wen , Yan Jinhua , Zheng Xueying , Weng Jianping , Luo Sihui
Published: December 2022

Background

The profile of gut microbiota, serum metabolites, and lipids of type 1 diabetes (T1D) patients with different human leukocyte antigen (HLA) genotypes remains unknown. We aimed to explore gut microbiota, serum metabolites, and lipids signatures in individuals with T1D typed by HLA genotypes.

Methods

We did a cross-sectional study that included 73 T1D adult patients. Patients were categorized into two groups according to the HLA haplotypes they carried: those with any two of three susceptibility haplotypes (DR3, DR4, DR9) and without any of the protective haplotypes (DR8, DR11, DR12, DR15, DR16) were defined as high-risk HLA genotypes group (HR, n=30); those with just one or without susceptibility haplotypes as the non-high-risk HLA genotypes group (NHR, n=43). We characterized the gut microbiome profile with 16S rRNA gene amplicon sequencing and analyzed serum metabolites with liquid chromatography-mass spectrometry.

Results

Study individuals were 32.5 (8.18) years old, and 60.3% were female. Compared to NHR, the gut microbiota of HR patients were characterized by elevated abundances of Prevotella copri and lowered abundances of Parabacteroides distasonis. Differential serum metabolites (hypoxanthine, inosine, and guanine) which increased in HR were involved in purine metabolism. Different lipids, phosphatidylcholines and phosphatidylethanolamines, decreased in HR group. Notably, Parabacteroides distasonis was negatively associated (p ≤ 0.01) with hypoxanthine involved in purine metabolic pathways.

Conclusions

The present findings enabled a better understanding of the changes in gut microbiome and serum metabolome in T1D patients with HLA risk genotypes. Alterations of the gut microbiota and serum metabolites may provide some information for distinguishing T1D patients with different HLA risk genotypes.
MYCBP2 expression correlated with inflammatory cell infiltration and prognosis immunotherapy in thyroid cancer patients
Authors: Wang Guilin , Miao Chen , Mo Lijun , Kahlert Ulf D. , Wu Jinfeng , Ou Minglin , Huang Renxiang , Feng Ruifa , Pang Weiyi , Shi Wenjie
Published: December 2022

Introduction

Immune checkpoint inhibitors (ICIs) have shown promising results for the treatment of multiple cancers. ICIs and related therapies may also be useful for the treatment of thyroid cancer (TC). In TC, Myc binding protein 2 (MYCBP2) is correlated with inflammatory cell infiltration and cancer prognosis. However, the relationship between MYCBP2 expression and ICI efficacy in TC patients is unclear.

Methods

We downloaded data from two TC cohorts, including transcriptomic data and clinical prognosis data. The Tumor Immune Dysfunction and Exclusion (TIDE) algorithm was used to predict the efficacy of ICIs in TC patients. MCPcounter, xCell, and quanTIseq were used to calculate immune cell infiltration scores. Gene set enrichment analysis (GSEA) and single sample GSEA (ssGSEA) were used to evaluate signaling pathway scores. Immunohistochemical (IHC) analysis and clinical follow up was used to identify the MYCBP2 protein expression status in patients and associated with clinical outcome.

Results

A higher proportion of MYCBP2-high TC patients were predicted ICI responders than MYCBP2-low patients. MYCBP2-high patients also had significantly increased infiltration of CD8+ T cells, cytotoxic lymphocytes (CTLs), B cells, natural killer (NK) cells and dendritic cells (DC)s. Compared with MYCBP2-low patients, MYCBP2-high patients had higher expression of genes associated with B cells, CD8+ T cells, macrophages, plasmacytoid dendritic cells (pDCs), antigen processing and presentation, inflammatory stimulation, and interferon (IFN) responses. GSEA and ssGSEA also showed that MYCBP2-high patients had significantly increased activity of inflammatory factors and signaling pathways associated with immune responses.In addiation, Patients in our local cohort with high MYCBP2 expression always had a better prognosis and greater sensitivity to therapy while compared to patients with low MYCBP2 expression after six months clinic follow up.

Conclusions

In this study, we found that MYCBP2 may be a predictive biomarker for ICI efficacy in TC patients. High MYCBP2 expression was associated with significantly enriched immune cell infiltration. MYCBP2 may also be involved in the regulation of signaling pathways associated with anti-tumor immune responses or the production of inflammatory factors.
Novel potential biomarkers for severe alcoholic liver disease
Authors: Huang Jia , Yu Jiachi , Wang Jianan , Liu Jiayu , Xie Wei , Li Ruibing , Wang Chengbin
Published: December 2022

Background

Alcoholic liver disease (ALD) is a leading cause of advanced liver disease; however, minor clinical symptoms in the early stage frequently result in delayed diagnosis and therapy. Invasive liver biopsy, the gold standard for diagnosing ALD, is unsuitable for repetitive analysis. This study aims to identify potential serum biomarkers that could contribute to non-invasive disease screening and monitoring.

Methods

Label-free LC-MS/MS quantitative proteomics analysis was performed to identify differentially expressed proteins in the discovery cohort, followed by bioinformatics analysis based on the KEGG, GO, and String databases. Prioritized proteins were validated subsequently by quantitative assays. The area under the receiver operating characteristic curve (AUROC) was used to assess the diagnosis performance of potential biomarkers.

Results

A total of 161 differentially expressed proteins were identified in the discovery cohort, of which 123 were up-regulated and 38 were down-regulated. B2M, IGFALS, and IGFBP3 were evaluated, and all demonstrated excellent diagnosis performance with AUROCs of over 0.9 when distinguishing patients with severe ALD from healthy controls. The AUROC values of B2M, IGFBP3, and IGFALS were 0.7131, 0.8877, and 0.9896 for differentiating severe ALD from non-severe ALD to indicate disease severity. B2M could distinguish patients with non-severe ALD and HC participants with an AUROC value of 0.8985. The efficiency of multiple combinations of these biomarkers was superior to that of the existing liver fibrosis evaluation indices used to monitor disease progression, with AUROC values of over 0.9. IGFALS showed a positive correlation with ALT/AST (r=0.4648, P=0.0009) and may be developed as a therapeutic target.

Conclusion

This proteomic study identified three novel candidate proteins as promising circulating biomarkers for clinical diagnosis and disease progression and also provided the proteomic atlas for ALD pathophysiological mechanisms.
Engineered M2a macrophages for the treatment of osteoarthritis
Authors: Liang Chi , Wu Song , Xia Guang , Huang Junjie , Wen Zi , Zhang Wenxiu , Cao Xu
Published: December 2022

Background

Macrophage is a central regulator of innate immunity. Its M2 subsets, such as interstitial synovial macrophages, have been found to play critical roles in suppressing chronic inflammation and maintaining homeostasis within the joint. These macrophages have great potential as a disease-modifying cell therapy for osteoarthritis (OA). However, this has not yet been studied.

Methods

Macrophages were isolated from the bone marrow of rats. We constructed a stable macrophage that “locked” in anti-inflammatory and pro-regenerative M2a polarity (L-M2a) by simultaneously knocking out tumor necrosis factor receptor 1 (TNFR1) and overexpressing IL-4 using Cas9-ribonuclear proteins (Cas9-RNP) and electroporation. In vitro, these L-M2a macrophages were treated with OA synovial fluid or co-cultured with OA chondrocytes or fibroblast-like synoviocytes (FLS). In vivo, L-M2a macrophages were injected intra-articularly to evaluate their homing and engrafting abilities and therapeutic effects on OA progression using a rat model.

Results

L-M2a macrophages displayed a typical anti-inflammatory phenotype similar to that of M2 macrophages in vitro. In OA microenvironment, L-M2a macrophages maintained a stable anti-inflammatory phenotype, whereas unmodified M2 macrophages lost their phenotype and switched to M1 polarity. L-M2a macrophages demonstrated a potent anti-inflammatory effect in crosstalk with OA-FLSs and an anti-degenerative effect in crosstalk with senescent OA chondrocytes. In vivo, compared with M2 macrophages and exosomes, L-M2a macrophages exhibited significantly superior therapeutic effects in OA by successfully resolving inflammation, restoring tissue homeostasis, and promoting cartilage regeneration.

Conclusion

The engineered L-M2a macrophages maintained a superior anti-inflammatory and pro-regenerative capacity in the inflammatory OA microenvironment and represents an ideal new strategy for the disease-modifying therapy of OA.
The role of immune cells in modulating chronic inflammation and osteonecrosis
Authors: Zheng Jianrui , Yao Zhi , Xue Lixiang , Wang Deli , Tan Zhen
Published: December 2022

Osteonecrosis occurs when, under continuous stimulation by adverse factors such as glucocorticoids or alcohol, the death of local bone and marrow cells leads to abnormal osteoimmune function. This creates a chronic inflammatory microenvironment, which interferes with bone regeneration and repair. In a variety of bone tissue diseases, innate immune cells and adaptive immune cells interact with bone cells, and their effects on bone metabolic homeostasis have attracted more and more attention, thus developing into a new discipline - osteoimmunology. Immune cells are the most important regulator of inflammation, and osteoimmune disorder may be an important cause of osteonecrosis. Elucidating the chronic inflammatory microenvironment regulated by abnormal osteoimmune may help develop potential treatments for osteonecrosis. This review summarizes the inflammatory regulation of bone immunity in osteonecrosis, explains the pathophysiological mechanism of osteonecrosis from the perspective of osteoimmunology, and provides new ideas for the treatment of osteonecrosis.
A first-in-human phase 1 study of cavrotolimod, a TLR9 agonist spherical nucleic acid, in healthy participants: Evidence of immune activation
Authors: Daniel Weston L. , Lorch Ulrike , Mix Scott , Bexon Alice S.
Published: December 2022

Introduction

Tumor immunotherapy is designed to control malignancies through the host immune response but requires circumventing tumor-dysregulated immunomodulation through immunostimulation, relieving immunorepression, or a combination of both approaches. Here we designed and characterized cavrotolimod (formerly AST-008), an immunostimulatory spherical nucleic acid (SNA) compound targeting Toll-like receptor 9 (TLR9). We assessed the safety and pharmacodynamic (PD) properties of cavrotolimod in healthy participants in a first-in-human Phase 1 study under protocol AST-008-101 (NCT03086278; https://clinicaltrials.gov/ct2/show/NCT03086278).

Methods

Healthy participants aged 18 to 40 years were enrolled to evaluate four dose levels of cavrotolimod across four cohorts. Each cohort included four participants, and all received a single subcutaneous dose of cavrotolimod. The dose levels were 5, 10, 12.5 and 18.8 µg/kg.

Results and discussion

Cavrotolimod was well tolerated and elicited no serious adverse events or dose limiting toxicities at the doses tested. The results demonstrated that cavrotolimod is a potent innate immune activator, specifically stimulating Th1-type immune responses, and exhibits PD properties that may result in anti-tumor effects in patients with cancer. This study suggests that cavrotolimod is a promising clinical immunotherapy agent.
Application of B cell immortalization for the isolation of antibodies and B cell clones from vaccine and infection settings
Authors: Boswell Kristin L. , Watkins Timothy A. , Cale Evan M. , Samsel Jakob , Andrews Sarah F. , Ambrozak David R. , Driscoll Jefferson I. , Messina Michael A. , Narpala Sandeep , Hopp Christine S. , Cagigi Alberto , Casazza Joseph P. , Yamamoto Takuya , Zhou Tongqing , Schief William R. , Crompton Peter D. , Ledgerwood Julie E. , Connors Mark , Gama Lucio , Kwong Peter D. , McDermott Adrian , Mascola John R. , Koup Richard A.
Published: December 2022

The isolation and characterization of neutralizing antibodies from infection and vaccine settings informs future vaccine design, and methodologies that streamline the isolation of antibodies and the generation of B cell clones are of great interest. Retroviral transduction to express Bcl-6 and Bcl-xL and transform primary B cells has been shown to promote long-term B cell survival and antibody secretion in vitro, and can be used to isolate antibodies from memory B cells. However, application of this methodology to B cell subsets from different tissues and B cells from chronically infected individuals has not been well characterized. Here, we characterize Bcl-6/Bcl-xL B cell immortalization across multiple tissue types and B cell subsets in healthy and HIV-1 infected individuals, as well as individuals recovering from malaria. In healthy individuals, naïve and memory B cell subsets from PBMCs and tonsil tissue transformed with similar efficiencies, and displayed similar characteristics with respect to their longevity and immunoglobulin secretion. In HIV-1-viremic individuals or in individuals with recent malaria infections, the exhausted CD27-CD21- memory B cells transformed with lower efficiency, but the transformed B cells expanded and secreted IgG with similar efficiency. Importantly, we show that this methodology can be used to isolate broadly neutralizing antibodies from HIV-infected individuals. Overall, we demonstrate that Bcl-6/Bcl-xL B cell immortalization can be used to isolate antibodies and generate B cell clones from different B cell populations, albeit with varying efficiencies.
Immune-related gene-based prognostic index for predicting survival and immunotherapy outcomes in colorectal carcinoma
Authors: Liang Zhongqing , Sun Ruolan , Tu Pengcheng , Liang Yan , Liang Li , Liu Fuyan , Bian Yong , Yin Gang , Zhao Fan , Jiang Mingchen , Gu Junfei , Tang Decai
Published: December 2022

Introduction

Colorectal cancer shows high incidence and mortality rates. Immune checkpoint blockade can be used to treat colorectal carcinoma (CRC); however, it shows limited effectiveness in most patients.

Methods

To identify patients who may benefit from immunotherapy using immune checkpoint inhibitors, we constructed an immune-related gene prognostic index (IRGPI) for predicting the efficacy of immunotherapy in patients with CRC. Transcriptome datasets and clinical information of patients with CRC were used to identify differential immune-related genes between tumor and para-carcinoma tissue. Using weighted correlation network analysis and Cox regression analysis, the IRGPI was constructed, and Kaplan–Meier analysis was used to evaluate its predictive ability. We also analyzed the molecular and immune characteristics between IRGPI high-and low-risk subgroups, performed sensitivity analysis of ICI treatment, and constructed overall survival-related receiver operating characteristic curves to validate the IRGPI. Finally, IRGPI genes and tumor immune cell infiltration in CRC model mice with orthotopic metastases were analyzed to verify the results.

Results

The IRGPI was constructed based on the following 11 hub genes: ADIPOQ, CD36, CCL24, INHBE, UCN, IL1RL2, TRIM58, RBCK1, MC1R, PPARGC1A, and LGALS2. Patients with CRC in the high-risk subgroup showed longer overall survival than those in the low-risk subgroup, which was confirmed by GEO database. Clinicopathological features associated with cancer progression significantly differed between the high- and low-risk subgroups. Furthermore, Kaplan–Meier analysis of immune infiltration showed that the increased infiltration of naïve B cells, macrophages M1, and regulatory T cells and reduced infiltration of resting dendritic cells and mast cells led to a worse overall survival in patients with CRC. The ORC curves revealed that IRGPI predicted patient survival more sensitive than the published tumor immune dysfunction and rejection and tumor inflammatory signature

Discussion

Thus, the low-risk subgroup is more likely to benefit from ICIs than the high-risk subgroup. CRC model mice showed higher proportions of Tregs, M1 macrophages, M2 macrophages and lower proportions of B cells, memory B cell immune cell infiltration, which is consistent with the IRGPI results. The IRGPI can predict the prognosis of patients with CRC, reflect the CRC immune microenvironment, and distinguish patients who are likely to benefit from ICI therapy.
Terpenoids and other secondary metabolites produced by the Eutypella fungi and their bioactivities
Authors: Zhou Yuwei , He Jingxin , Cui Hui
Published: December 2022

The fungi Eutypella could metabolize a myriad of natural products with unique structures and diverse bioactivities, which were deemed as key sources for lead compounds in drug discovery. Since the first research on the genus Eutypella in 2009, a myriad of secondary metabolites including terpenoids, alkaloids, and polyketides have been discovered in this genus, and most of them exhibited significant pharmacological activities. However, there are no systematic reviews that reported about the structures and bioactivities of Eutypella up to now. In this review, a total of 153 secondary metabolites and 42 references have been systematically summarized, and we found that the terpenoids (68.09%) and alkaloids (19.15%) were the new main components of this fungi, and the primary antiproliferative activity (64.89%) was mainly derived from the terpenoids and alkaloids. Thus, this review about the chemical diversity and biological activities of the metabolites from the fungus Eutypella provided a new perspective for the development of new drugs for pharmacologists.
Fortnightly variability of horizontal salinity gradient affects exchange flow in the Sumjin River estuary
Authors: Cho Eun-Byeol , Tak Yong-Jin , Cho Yang-Ki , Na Hanna
Published: December 2022

The horizontal salinity gradient has been reported to play a crucial role in fortnightly variability of estuarine exchange flow in short estuaries. However, spatiotemporal variations in the salinity gradient and exchange flow have not been examined over an entire short estuary, as only data observed only at specific points was available. We analyzed the variation in salinity gradient along the entire Sumjin River estuary and its effect on the exchange flow over fortnightly tidal cycles based on observations and numerical model experiments. The salinity gradient and exchange flow were in different phases between the lower and upper estuaries by 6–7 days. The maximum salinity gradient periodically reciprocated along the channel as a result of salt flux changes determined by vertical mixing. The stronger exchange flow (> 0.04 m s-1) changed location from mouth to head of estuary while the tidal range decreased, resulting from variability of the salinity gradient. The horizontal salinity gradient is large enough to overwhelm the vertical mixing effect on the exchange flow. The spatiotemporal changes of strong exchange flow correspond well with the horizontal Richardson number value (> 3). This study suggests that for the health of estuarine ecosystems, it is important to determine the spatiotemporal variation in exchange flow throughout the estuary.
Interfacial regulation of aqueous synthesized metal-semiconductor hetero-nanocrystals
Authors: Li Shouyuan , Sun Shaoyang , Li Xinyuan , Zhang Jiatao
Published: December 2022

Integrating metal and semiconductor components to form metal-semiconductor heterostructures is an attractive strategy to develop nanomaterials for optoelectronic applications, and the rational regulation of their heterointerfaces could effectively influence their charge transfer properties and further determine their performance. Considering the natural large lattice mismatch between metal and semiconductor components, defects and low crystalline heterointerfaces could be easily generated especially for heterostructures with large contacting areas such as core-shell and over quantum-sized nanostructures. The defective interfaces of heterostructures could lead to the undesirable recombination of photo-induced electrons and holes, which would decrease their performances. Based on these issues, the perspective focusing on the most recent progress in the aqueous synthesis of metal-semiconductor heterostructures with emphasis on heterointerface regulation is proposed, especially in the aspect of non-epitaxial growth strategies initiated by cation exchange reaction (CER). The enhanced optoelectronic performance enabled by precise interfacial regulations is also illustrated. We hope this perspective could provide meaningful insights for researchers on nano synthesis and optoelectronic applications.
Hysterectomy by transvaginal natural orifice transluminal endoscopic surgery: An Italian initial experience
Authors: Interdonato Maria Lieta , Scollo Paolo , Bignardi Tommaso , Massimello Francesca , Ferrara Martina , Donatiello Gianluca , Caretto Marta , Mannella Paolo , Pecorino Basilio , Meroni Mario Giuseppe , Simoncini Tommaso
Published: December 2022

Background

The aim of this study is to evaluate the initial feasibility, safety, and outcomes of hysterectomy performed by transvaginal natural orifice transluminal endoscopic surgery (vNOTES) at three institutions in Italy.

Materials and methods

All women who underwent vNOTES hysterectomy ± salpingo-oophorectomy for benign indications at three tertiary referral medical centers between July 2019 and April 2021 were included in a retrospective analysis. All vNOTESs were performed with the use of Alexis® and Vpath Gel paths® (Applied Medical). Perioperative data were extracted from patient records. Patient satisfaction and dyspareunia were prospectively inquired about at 60 days and 6 months.

Results

Forty-six patients underwent vNOTES in the study period. Indications for surgery included myomas ± metrorrhagia (52.2%), H-Sil/in situ cervical cancer (10.7%), adenomyosis ± metrorrhagia (8.7%), BRCA 1-2 mutations (6.5%), endometrial hyperplasia (6.5%), ovarian cyst + history of breast cancer (6.5%), metrorrhagia (6.5%), and hydatidiform mole (2.2%). The mean operation time was 91.1 (±32.6) minutes. The mean hemoglobin drop was 1.2 (±0.8). The mean visual analog scale at 24 h for post-operative pain was 3.3 (±1.8). Secondary to our limited experience with the surgical technique, we favor discharge only from day 1. The mean length of hospital stay was 2 (±1.4) days. Two conversions to conventional laparoscopy were reported (4.3%), due to an obliterated pouch of Douglas and a preoperative complication. Two post-operative complications were reported (4.3%). Overall, our data on peri- and post-operative outcomes are similar to those already published for vNOTES.

Conclusion

Our initial experience suggests that introducing vNOTES as an alternative to conventional surgery is feasible and may offer some advantages in selected women.
Pre-anesthetic use of butorphanol for the prevention of emergence agitation in thoracic surgery: A multicenter, randomized controlled trial
Authors: Meng Tao , Lin Xiaowen , Li Ximing , Yue Fangli , Zhang Yuzhu , Wang Yingbin , Gu Jianhua , Yang Zaiqi , Yu Hongli , Lv Kun , Liang Shengyong , Li Xingda , Zhu Weibo , Yu Gang , Li Tao , Ren Yujia , Li Yandong , Xu Jianjun , Xu Weimin , Wang Shu , Wu Jianbo
Published: December 2022

Background

Emergence agitation (EA) is common in patients after general anesthesia (GA) and is associated with poor outcomes. Patients with thoracic surgery have a higher incidence of EA compared with other surgery. This study aimed to investigate the impact of pre-anesthetic butorphanol infusion on the incidence of EA in patients undergoing thoracic surgery with GA.

Materials and methods

This prospective randomized controlled trial (RCT) was conducted in 20 tertiary hospitals in China. A total of 668 patients undergoing elective video-assisted thoracoscopic lobectomy/segmentectomy for lung cancer were assessed for eligibility, and 620 patients were enrolled. In total, 296 patients who received butorphanol and 306 control patients were included in the intention-to-treat analysis. Patients in the intervention group received butorphanol 0.02 mg/kg 15 min before induction of anesthesia. Patients in the control group received volume-matched normal saline in the same schedule. The primary outcome was the incidence of EA after 5 min of extubation, and EA was evaluated using the Riker Sedation-Agitation Scale (RSAS). The incidence of EA was determined by the chi-square test, with a significance of P < 0.05.

Results

In total, 296 patients who received butorphanol and 306 control patients were included in the intention-to-treat analysis. The incidence of EA 5 min after extubation was lower with butorphanol treatment: 9.8% (29 of 296) vs. 24.5% (75 of 306) in the control group (P = 0.0001). Patients who received butorphanol had a lower incidence of drug-related complications (including injecting propofol pain and coughing with sufentanil): 112 of 296 vs. 199 of 306 in the control group (P = 0.001) and 3 of 296 vs. 35 of 306 in the control group (P = 0.0001).

Conclusion

The pre-anesthetic administration of butorphanol reduced the incidence of EA after thoracic surgery under GA.

Clinical trial registration

[http://www.chictr.org.cn/showproj.aspx?proj=42684], identifier [ChiCTR1900025705].
Perforating scleral vessels adjacent to myopic choroidal neovascularization achieved a poor outcome after intravitreal anti-VEGF therapy
Authors: Yao Wangjing , Xu Jiawen , She Xiangjun , Yu Jiangxin , Liang Zhi , Ye Xin , Tao Jiwei , Wu Sulan , Mao Jianbo , Chen Yiqi , Zhang Yun , Shen Lijun
Published: December 2022

Background

This study aimed to summarize the features of perforating scleral vessels (PSVs) in patients with myopic choroidal neovascularization (CNV) (mCNV) using optical coherence tomography angiography (OCTA) and to identify the associations with the response after intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy.

Methods

A consecutive series of naïve patients who had mCNV and received intravitreal anti-VEGF therapy with a follow-up duration of 12 months or more were enrolled. The prevalence, location, and branches of PSVs were analyzed. Projection-resolved OCTA (PR-OCTA) was used to analyze the neovascular signals between CNV and PSVs. Best corrected visual acuity (BCVA) and central macular thickness (CMT) were measured. The proportion of CMT change relative to baseline was used to assess therapeutic response.

Results

A total of 44 eyes from 42 patients with mCNV were enrolled. PSVs were identified in 41 out of 44 eyes. Branches were identified in the PSVs of 24 eyes (57.14%), and 20 eyes did not have PSV branches (47.62%). In eight eyes (18.18%), PSVs were adjacent to mCNV, and in 36 eyes (81.82%), PSVs were not adjacent to mCNV. After anti-VEGF therapy for mCNV, BCVA increased (F = 6.119, p < 0.001) and CMT decreased (F = 7.664, p < 0.001). In the eyes where PSVs were adjacent to mCNV, BCVA improvements (F = 7.649, p = 0.009) were poor, and changes in CMT were small.

Conclusion

The eyes with PSVs adjacent to mCNV showed poor therapeutic responses after intravitreal anti-VEGF therapy.