bluuebunny/crossref_metadata_2025 huggingface dataset:
Pan-cancer analysis of the prognosis and immunological role of AKAP12: A potential biomarker for resistance to anti-VEGF inhibitors
Authors: Liang Qiuju , Peng Jinwu , Xu Zhijie , Li Zhilan , Jiang Feng , Ouyang Lingzi , Wu Shangjun , Fu Chencheng , Liu Ying , Liu Yuanhong , Yan Yuanliang
Published: August 2022

The primary or acquired resistance to anti-VEGF inhibitors remains a common problem in cancer treatment. Therefore, identifying potential biomarkers enables a better understanding of the precise mechanism. Through the GEO database, three profiles associated with bevacizumab (BV) resistance to ovarian cancer, glioma, and non-small-cell lung carcinoma, respectively, were collected for the screening process, and two genes were found. A-kinase anchor protein 12 (AKAP12), one of these two genes, correlates with tumorigenesis of some cancers. However, the role of AKAP12 in pan-cancer remains poorly defined. The present study first systematically analyzed the association of AKAP12 with anti-VEGF inhibitors’ sensitivity, clinical prognosis, DNA methylation, protein phosphorylation, and immune cell infiltration across various cancers via bioinformatic tools. We found that AKAP12 was upregulated in anti-VEGF therapy-resistant cancers, including ovarian cancer (OV), glioblastoma (GBM), lung cancer, and colorectal cancer (CRC). A high AKAP12 expression revealed dismal prognoses in OV, GBM, and CRC patients receiving anti-VEGF inhibitors. Moreover, AKAP12 expression was negatively correlated with cancer sensitivity towards anti-VEGF therapy. Clinical prognosis analysis showed that AKAP12 expression predicted worse prognoses of various cancer types encompassing colon adenocarcinoma (COAD), OV, GBM, and lung squamous cell carcinoma (LUSC). Gene mutation status may be a critical cause for the involvement of AKAP12 in resistance. Furthermore, lower expression of AKAP12 was detected in nearly all cancer types, and hypermethylation may explain its decreased expression. A decreased phosphorylation of T1760 was observed in breast cancer, clear-cell renal cell carcinoma, and lung adenocarcinoma. For the immunologic significance, AKAP12 was positively related to the abundance of pro-tumor cancer-associated fibroblasts (CAFs) in various types of cancer. The results of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis suggested that “cell junction organization” and “MAPK pathway” participated in the effect of AKAP12. Importantly, we discovered that AKAP12 expression was greatly associated with metastasis of lung adenocarcinoma as well as differential and angiogenesis of retinoblastoma through investigating the single-cell sequencing data. Our study showed that the dual role of AKAP12 in various cancers and AKAP12 could serve as a biomarker of anti-VEGF resistance in OV, GBM, LUSC, and COAD.
Stemness analysis in hepatocellular carcinoma identifies an extracellular matrix gene–related signature associated with prognosis and therapy response
Authors: Chen Lei , Zhang Dafang , Zheng Shengmin , Li Xinyu , Gao Pengji
Published: August 2022

Background: Tumor stemness is the stem-like phenotype of cancer cells, as a hallmark for multiple processes in the development of hepatocellular carcinoma (HCC). However, comprehensive functions of the regulators of tumor cell’s stemness in HCC remain unclear.

Methods: Gene expression data and clinical information of HCC samples were downloaded from The Cancer Genome Atlas (TCGA) dataset as the training set, and three validation datasets were derived from Gene Expression Omnibus (GEO) and International Cancer Genome Consortium (ICGC). Patients were dichotomized according to median mRNA expression–based stemness index (mRNAsi) scores, and differentially expressed genes were further screened out. Functional enrichment analysis of these DEGs was performed to identify candidate extracellular matrix (ECM)–related genes in key pathways. A prognostic signature was constructed by applying least absolute shrinkage and selection operator (LASSO) to the candidate ECM genes. The Kaplan–Meier curve and receiver operating characteristic (ROC) curve were used to evaluate the prognostic value of the signature. Correlations between signatures and genomic profiles, tumor immune microenvironment, and treatment response were also explored using multiple bioinformatic methods.

Results: A prognostic prediction signature was established based on 10 ECM genes, including TRAPPC4, RSU1, ILK, LAMA1, LAMB1, FLNC, ITGAV, AGRN, ARHGEF6, and LIMS2, which could effectively distinguish patients with different outcomes in the training and validation sets, showing a good prognostic prediction ability. Across different clinicopathological parameter stratifications, the ECMs signature still retains its robust efficacy in discriminating patient with different outcomes. Based on the risk score, vascular invasion, α-fetoprotein (AFP), T stage, and N stage, we further constructed a nomogram (C-index = 0.70; AUCs at 1-, 3-, and 5-year survival = 0.71, 0.75, and 0.78), which is more practical for clinical prognostic risk stratification. The infiltration abundance of macrophages M0, mast cells, and Treg cells was significantly higher in the high-risk group, which also had upregulated levels of immune checkpoints PD-1 and CTLA-4. More importantly, the ECMs signature was able to distinguish patients with superior responses to immunotherapy, transarterial chemoembolization, and sorafenib.

Conclusion: In this study, we constructed an ECM signature, which is an independent prognostic biomarker for HCC patients and has a potential guiding role in treatment selection.
miRNA transcriptome and myofiber characteristics of lamb skeletal muscle during hypertrophic growth1
Authors: Greene M. A. , Powell R. , Bruce T. , Bridges W. C. , Duckett S. K.
Published: August 2022

Postnatal muscle growth is achieved through hypertrophy of the muscle fibers and is impacted by the activity of satellite cells, the quiescent muscle stem cell. Several miRNAs are preferentially expressed in skeletal muscle and could provide a mechanism for increasing muscle hypertrophy through satellite cell proliferation and/or differentiation. The objectives of this study were to: 1) Characterize the miRNA transcriptome of the longissimus thoracis et lumborum muscle at several developmental timepoints [gestational d 85 (PN1), 110 (PN2), 133 (PN3), postnatal d 42 (PW1), 65 (PW2), 243 (MAT)] during muscle hypertrophy in lambs, and 2) examine miR-29a, identified in sequencing to be differentially regulated across development, loss of function on satellite cell proliferation and differentiation. Muscle fiber characteristics showed drastic increases (p < 0.0001) in fiber size and alterations in muscle fiber type occur during pre and postnatal development. miRNA sequencing comparisons were performed in developmental order (PN1 vs. PN2, PN2 vs. PN3, PN3 vs. PW1, PW1 vs. PW2, PW2 vs. MAT). There were 184 differentially expressed (Padj < 0.05) miRNA, 142 unique miRNA, from all 5 comparisons made. The transitional stage (PN3 vs. PW1) had the largest number (115) of differentially expressed miRNA. Inhibition of miR-29a in satellite cell culture increased (p < 0.05) cell proliferation and differentiation capacity. Characterization of the miRNA transcriptome provides valuable insights into the miRNA involved in muscle fiber hypertrophy and the potential importance of the transitional period.
Willingness to utilize cervical cancer screening among Ethiopian women aged 30–65 years
Authors: Desta Adugna Alemu , Alemu Fikadu Tolesa , Gudeta Moges Beya , Dirirsa Dejene Edosa , Kebede Andualem Gezahegn
Published: August 2022

Background

Cervical cancer screening is a means of detecting cervical cancer early, before it develops, in order to reduce disease mortality and morbidity. When women are screened for cervical cancer between the ages of 30 and 40 years at least one time in their life, their risk of cancer could be decreased by 25–36%. Despite this advantage, cervical cancer screening coverage in Ethiopia is still <2%. As a result, we wanted to see how ready women in the Girar Jarso district, Ethiopia, were to get a cervical cancer test.

Methodology

Community-based cross-sectional study was done using a stratified cluster sampling technique among 855 women aged 30–65 years in the Girar Jarso district, Ethiopia, from 1 June 2021 to 1 September 2021. A pretested and semi-structured interviewer-administered questionnaire was used to collect the data. EpiData management version 4.6 was used to enter data, which was then exported to SPSS version 23 for analysis. Logistic regression analysis was performed, and variables with ap-value of <0.05 were taken as statistically significant predictors of the willingness to utilize cervical cancer screening.

Results

Of the 855 women, only 315 (46.7%, CI = 43–50.3) women were willing to be checked for cervical cancer, with 181 (21.2%) women having been screened at least one time in their life. Age of 30–39 years [AOR = 2.80 (95% CI: 1.05, 7.48)], urban resident [AOR = 2.12 (95% CI: 1.06, 4.48)], positive attitude [AOR = 1.68 (95% CI: 1.11, 2.53)], wealth status, awareness of cervical cancer, and low perceived barriers were independent predictors of the willingness to utilize cervical cancer screening.

Conclusion and recommendation

The willingness to utilize cervical cancer screening services is low in the Girar Jarso district. To improve community awareness and attitude, continued and sustainable advocacy on the value of cervical cancer screening should be offered through mass media and health extension workers.
Astrocytes regulate vascular endothelial responses to simulated deep space radiation in a human organ-on-a-chip model
Authors: Verma Sonali D. , Passerat de la Chapelle Estrella , Malkani Sherina , Juran Cassandra M. , Boyko Valery , Costes Sylvain V. , Cekanaviciute Egle
Published: August 2022

Central nervous system (CNS) damage by galactic cosmic ray radiation is a major health risk for human deep space exploration. Simulated galactic cosmic rays or their components, especially high Z-high energy particles such as 56Fe ions, cause neurodegeneration and neuroinflammation in rodent models. CNS damage can be partially mediated by the blood-brain barrier, which regulates systemic interactions between CNS and the rest of the body. Astrocytes are major cellular regulators of blood-brain barrier permeability that also modulate neuroinflammation and neuronal health. However, astrocyte roles in regulating CNS and blood-brain barrier responses to space radiation remain little understood, especially in human tissue analogs. In this work, we used a novel high-throughput human organ-on-a-chip system to evaluate blood-brain barrier impairments and astrocyte functions 1-7 days after exposure to 600 MeV/n 56Fe particles and simplified simulated galactic cosmic rays. We show that simulated deep space radiation causes vascular permeability, oxidative stress, inflammation and delayed astrocyte activation in a pattern resembling CNS responses to brain injury. Furthermore, our results indicate that astrocytes have a dual role in regulating radiation responses: they exacerbate blood-brain barrier permeability acutely after irradiation, followed by switching to a more protective phenotype by reducing oxidative stress and pro-inflammatory cytokine and chemokine secretion during the subacute stage.
Impact of antiretroviral therapy in primary HIV infection on natural killer cell function and the association with viral rebound and HIV DNA following treatment interruption
Authors: Pace Matthew , Ogbe Ane , Hurst Jacob , Robinson Nicola , Meyerowitz Jodi , Olejniczak Natalia , Thornhill John P. , Jones Mathew , Waters Anele , Lwanga Julianne , Kuldanek Kristen , Hall Rebecca , Zacharopoulou Panagiota , Martin Genevieve E. , Brown Helen , Nwokolo Nneka , Peppa Dimitra , Fox Julie , Fidler Sarah , Frater John
Published: August 2022

Natural Killer (NK) cells play a key role in controlling HIV replication, with potential downstream impact on the size of the HIV reservoir and likelihood of viral rebound after antiretroviral therapy (ART) cessation. It is therefore important to understand how primary HIV infection (PHI) disrupts NK cell function, and how these functions are restored by early ART. We examined the impact of commencing ART during PHI on phenotypic and functional NK cell markers at treatment initiation (baseline), 3 months, 1 year, and 2 years in seven well-characterised participants in comparison to HIV seronegative volunteers. We then examined how those NK cell properties differentially impacted by ART related to time to viral rebound and HIV DNA levels in 44 individuals from the SPARTAC trial who stopped ART after 48 weeks treatment, started during PHI. NK cell markers that were significantly different between the seven people with HIV (PWH) treated for 2 years and HIV uninfected individuals included NKG2C levels in CD56dim NK cells, Tim-3 expression in CD56bright NK cells, IFN-γ expressed by CD56dim NK cells after IL-12/IL-18 stimulation and the fraction of Eomes-/T-bet+ in CD56dim and CD56bright NK cells. When exploring time to viral rebound after stopping ART among the 44 SPARTAC participants, no single NK phenotypic marker correlated with control. Higher levels of IL-12/IL-18 mediated NK cell degranulation at baseline were associated with longer times to viral rebound after treatment interruption (P=0.028). Additionally, we found higher fractions of CD56dim NK cells in individuals with lower levels of HIV DNA (P=0.048). NKG2A and NKp30 levels in CD56neg NK cells were higher in patients with lower HIV DNA levels (p=0.00174, r=-0.49 and p=0.03, r= -0.327, respectively) while CD27 levels were higher in those with higher levels of HIV DNA (p=0.026). These data show NK cell functions are heterogeneously impacted by HIV infection with a mixed picture of resolution on ART, and that while NK cells may affect HIV DNA levels and time to viral rebound, no single NK cell marker defined delayed viral rebound.
CRX-527 induced differentiation of HSCs protecting the intestinal epithelium from radiation damage
Authors: Liu Dongshu , Dong Suhe , Liu Cong , Du Jicong , Wang Sinian , Yu Huijie , Li Wei , Chen Zhongmin , Peng Renjun , Jiang Qisheng , Zou Mengying , Li Fengsheng , Zhang Rong
Published: August 2022

Recently, Toll-like receptors (TLRs) have been extensively studied in radiation damage, but the inherent defects of high toxicity and low efficacy of most TLR ligands limit their further clinical transformation. CRX-527, as a TLR4 ligand, has rarely been reported to protect against radiation. We demonstrated that CRX-527 was safer than LPS at the same dose in vivo and had almost no toxic effect in vitro. Administration of CRX-527 improved the survival rate of total body irradiation (TBI) to 100% in wild-type mice but not in TLR4-/- mice. After TBI, hematopoietic system damage was significantly alleviated, and the recovery period was accelerated in CRX-527-treated mice. Moreover, CRX-527 induced differentiation of HSCs and the stimulation of CRX-527 significantly increased the proportion and number of LSK cells and promoted their differentiation into macrophages, activating immune defense. Furthermore, we proposed an immune defense role for hematopoietic differentiation in the protection against intestinal radiation damage, and confirmed that macrophages invaded the intestines through peripheral blood to protect them from radiation damage. Meanwhile, CRX-527 maintained intestinal function and homeostasis, promoted the regeneration of intestinal stem cells, and protected intestinal injury from lethal dose irradiation. Furthermore, After the use of mice, we found that CRX-527 had no significant protective effect on the hematopoietic and intestinal systems of irradiated TLR4-/- mice. in conclusion, CRX-527 induced differentiation of HSCs protecting the intestinal epithelium from radiation damage.
Immunoinformatic analysis of the whole proteome for vaccine design: An application to Clostridium perfringens
Authors: Soto Luis F. , Romaní Ana C. , Jiménez-Avalos Gabriel , Silva Yshoner , Ordinola-Ramirez Carla M. , Lopez Lapa Rainer M. , Requena David
Published: August 2022

Clostridium perfringens is a dangerous bacterium and known biological warfare weapon associated with several diseases, whose lethal toxins can produce necrosis in humans. However, there is no safe and fully effective vaccine against C. perfringens for humans yet. To address this problem, we computationally screened its whole proteome, identifying highly immunogenic proteins, domains, and epitopes. First, we identified that the proteins with the highest epitope density are Collagenase A, Exo-alpha-sialidase, alpha n-acetylglucosaminidase and hyaluronoglucosaminidase, representing potential recombinant vaccine candidates. Second, we further explored the toxins, finding that the non-toxic domain of Perfringolysin O is enriched in CTL and HTL epitopes. This domain could be used as a potential sub-unit vaccine to combat gas gangrene. And third, we designed a multi-epitope protein containing 24 HTL-epitopes and 34 CTL-epitopes from extracellular regions of transmembrane proteins. Also, we analyzed the structural properties of this novel protein using molecular dynamics. Altogether, we are presenting a thorough immunoinformatic exploration of the whole proteome of C. perfringens, as well as promising whole-protein, domain-based and multi-epitope vaccine candidates. These can be evaluated in preclinical trials to assess their immunogenicity and protection against C. perfringens infection.
An overview of JAK/STAT pathways and JAK inhibition in alopecia areata
Authors: Lensing Maddison , Jabbari Ali
Published: August 2022

Alopecia Areata (AA) is a common autoimmune disease characterized by non-scarring hair loss ranging from patches on the scalp to complete hair loss involving the entire body. Disease onset is hypothesized to follow the collapse of immune privilege of the hair follicle, which results in an increase in self-peptide/MHC expression along the follicular epithelium. Hair loss is associated with infiltration of the hair follicle with putatively self-reactive T cells. This process is thought to skew the hair follicle microenvironment away from a typically homeostatic immune state towards one of active inflammation. This imbalance is mediated in part by the dominating presence of specific cytokines. While interferon-γ (IFNγ) has been identified as the key player in AA pathogenesis, many other cytokines have also been shown to play pivotal roles. Mechanistic studies in animal models have highlighted the contribution of common gamma chain (γc) cytokines such as IL-2, IL-7, and IL-15 in augmenting disease. IFNγ and γccytokines signal through pathways involving receptor activation of Janus kinases (JAKs) and signal transducers and activators of transcription (STATs). Based on these findings, JAK/STAT pathways have been targeted for the purposes of therapeutic intervention in the clinical setting. Case reports and series have described use of small molecule JAK inhibitors leading to hair regrowth among AA patients. Furthermore, emerging clinical trial results show great promise and position JAK inhibitors as a treatment strategy for patients with severe or recalcitrant disease. Demonstrated efficacy from large-scale clinical trials of the JAK inhibitor baricitinib led to the first-in-disease FDA-approved treatment for AA in June of 2022. This review aims to highlight the JAK/STAT signaling pathways of various cytokines involved in AA and how targeting those pathways may impact disease outcomes in both laboratory and clinical settings.
Role of the CCL2-CCR2 axis in cardiovascular disease: Pathogenesis and clinical implications
Authors: Zhang Haixia , Yang Ke , Chen Feng , Liu Qianqian , Ni Jingyu , Cao Weilong , Hua Yunqing , He Feng , Liu Zhihao , Li Lan , Fan Guanwei
Published: August 2022

The CCL2-CCR2 axis is one of the major chemokine signaling pathways that has received special attention because of its function in the development and progression of cardiovascular disease. Numerous investigations have been performed over the past decades to explore the function of the CCL2-CCR2 signaling axis in cardiovascular disease. Laboratory data on the CCL2-CCR2 axis for cardiovascular disease have shown satisfactory outcomes, yet its clinical translation remains challenging. In this article, we describe the mechanisms of action of the CCL2-CCR2 axis in the development and evolution of cardiovascular diseases including heart failure, atherosclerosis and coronary atherosclerotic heart disease, hypertension and myocardial disease. Laboratory and clinical data on the use of the CCL2-CCR2 pathway as a targeted therapy for cardiovascular diseases are summarized. The potential of the CCL2-CCR2 axis in the treatment of cardiovascular diseases is explored.
The cuproptosis-related signature associated with the tumor environment and prognosis of patients with glioma
Authors: Wang Weichen , Lu Zhichao , Wang Maoyu , Liu Zongheng , Wu Bing , Yang Chengkai , Huan He , Gong Peipei
Published: August 2022

Background

Copper ions are essential for cellular physiology. Cuproptosis is a novel method of copper-dependent cell death, and the cuproptosis-based signature for glioma remains less studied.

Methods

Several glioma datasets with clinicopathological information were collected from TCGA, GEO and CGGA. Robust Multichip Average (RMA) algorithm was used for background correction and normalization, cuproptosis-related genes (CRGs) were then collected. The TCGA-glioma cohort was clustered using ConsensusClusterPlus. Univariate Cox regression analysis and the Random Survival Forest model were performed on the differentially expressed genes to identify prognostic genes. The cuproptosis-signature was constructed by calculating CuproptosisScore using Multivariate Cox regression analysis. Differences in terms of genomic mutation, tumor microenvironment, and enrichment pathways were evaluated between high- or low-CuproptosisScore. Furthermore, drug response prediction was carried out utilizing pRRophetic.

Results

Two subclusters based on CRGs were identified. Patients in cluster2 had better clinical outcomes. The cuproptosis-signature was constructed based on CuproptosisScore. Patients with higher CuproptosisScore had higher WHO grades and worse prognosis, while patients with lower grades were more likely to develop IDH mutations or MGMT methylation. Univariate and Multivariate Cox regression analysis demonstrated CuproptosisScore was an independent prognostic factor. The accuracy of the signature in prognostic prediction was further confirmed in 11 external validation datasets. In groups with high-CuproptosisScore, PIK3CA, MUC16, NF1, TTN, TP53, PTEN, and EGFR showed high mutation frequency. IDH1, TP53, ATRX, CIC, and FUBP1 demonstrated high mutation frequency in low-CuproptosisScore group. The level of immune infiltration increased as CuproptosisScore increased. SubMap analysis revealed patients with high-CuproptosisScore may respond to anti-PD-1 therapy. The IC50 values of Bexarotene, Bicalutamide, Bortezomib, and Cytarabine were lower in the high-CuproptosisScore group than those in the low-CuproptosisScore group. Finally, the importance of IGFBP2 in TCGA-glioma cohort was confirmed.

Conclusion

The current study revealed the novel cuproptosis-based signature might help predict the prognosis, biological features, and appropriate treatment for patients with glioma.
CRISPR/Cas9 based blockade of IL-10 signaling impairs lipid and tissue homeostasis to accelerate atherosclerosis
Authors: Shi Haozhe , Guo Jiabao , Yu Qiongyang , Hou Xinlin , Liu Lili , Gao Mingming , Wei Lili , Zhang Ling , Huang Wei , Wang Yuhui , Liu George , Tontonoz Peter , Xian Xunde
Published: August 2022

Interleukin-10 (IL-10) is a widely recognized immunosuppressive factor. Although the concept that IL-10 executes an anti-inflammatory role is accepted, the relationship between IL-10 and atherosclerosis is still unclear, thus limiting the application of IL-10-based therapies for this disease. Emerging evidence suggests that IL-10 also plays a key role in energy metabolism and regulation of gut microbiota; however, whether IL-10 can affect atherosclerotic lesion development by integrating lipid and tissue homeostasis has not been investigated. In the present study, we developed a human-like hamster model deficient in IL-10 using CRISPR/Cas9 technology. Our results showed that loss of IL-10 changed the gut microbiota in hamsters on chow diet, leading to an increase in lipopolysaccharide (LPS) production and elevated concentration of LPS in plasma. These changes were associated with systemic inflammation, lipodystrophy, and dyslipidemia. Upon high cholesterol/high fat diet feeding, IL-10-deficient hamsters exhibited abnormal distribution of triglyceride and cholesterol in lipoprotein particles, impaired lipid transport in macrophages and aggravated atherosclerosis. These findings show that silencing IL-10 signaling in hamsters promotes atherosclerosis by affecting lipid and tissue homeostasis through a gut microbiota/adipose tissue/liver axis.
Accelerated dispersion curve calculations for periodic vibro-acoustic structures
Authors: Cool Vanessa , Naets Frank , Van Belle Lucas , Desmet Wim , Deckers Elke
Published: August 2022

Over the years, metamaterials have shown their potential in a wide range of different disciplines, e.g. optics, electromagnetics, dynamics etc. Metamaterials are, often periodic, engineered structures made of conventional materials but which exhibit properties not encountered in nature. In the field of noise and vibration, metamaterials have received increasing interest since they can obtain frequency ranges of high noise and vibration attenuation, called stop bands. Their performance is often investigated by means of dispersion curves, which are calculated based on a single unit cell and assuming a structure of infinite periodic extent. Nowadays, the attenuation of acoustic and structural waves is commonly tackled as two separate problems, whereby either acoustic or structural dispersion curves are used. Recently, vibro-acoustic unit cell designs have come to the fore which can exhibit appealing characteristics, such as simultaneous structural and acoustic stop bands. To consider the vibro-acoustic coupling in these unit cell designs during the performance predictions, vibro-acoustic dispersion curve calculations are thus required. However, these computations are typically cumbersome to perform due to the associated high computational cost and therefore, often, uncoupled dispersion curves are used during the performance assessment. Although several unit cell model order reduction approaches have recently been proposed to accelerate the dispersion curve computations, such as the Bloch mode synthesis (BMS) and Generalized Bloch mode synthesis (GBMS), they are not readily applicable to vibro-acoustic unit cells. To accelerate vibro-acoustic dispersion curve calculations, this work extends the BMS and GBMS techniques towards 2D and 3D periodic vibro-acoustic systems. To balance accuracy versus speed, the extended BMS reduction basis is constructed using a split set of vibro-acoustic coupled modes, while the extended GBMS reduction basis uses the uncoupled modes. Several verification cases demonstrate that strongly accelerated vibro-acoustic dispersion curve computations are achieved whereby the vibro-acoustic coupling inside the unit cell is accurately accounted for.
Low protein diet supplemented with ketoacids on muscle wasting in chronic kidney disease: A clinical trial
Authors: Zhang Yueyue , Gu Lijie , Wang Ling , Rong Shu , Yuan Weijie
Published: August 2022

Aim

Nutrition is an important part of the care of patients with chronic kidney disease (CKD). However, there is limited clinical research on the skeletal muscle nutrition of patients with CKD. We carried out this study to find out whether a low-protein diet supplemented with ketoacids (LPD + KA) could improve muscle wasting in patients with CKD.

Methods

Patients were enrolled in this non-blind, parallel-group, randomized trial assessing the nutritional status of CKD, randomly assigned to either the LPD + KA group or conventional LPD group. Blood samples such as Hemoglobin, Cystatin C, Creatinine, BUN, Albumin, Pre- Albumin, Glycerin Trilaurate, and Cholesterol were measured at baseline and every 3 months. The parameters of skeletal muscle and other body composition were assessed before and after dietary intervention for 12 months.

Results

A total of 58 patients with CKD completed the study and were available for further analysis. The hemoglobin and albumin were observed to be markedly improved in the LPD + KA group during the follow-up as compared to baseline. Body mass index and total body water index of both groups were increased upon follow-up but the increase in the LPD + KA group was comparatively higher. Moreover, an increase in body fat%, skeletal muscle mass index, and appendicular skeletal muscle mass index was observed in both groups between baseline and follow-up, but it was statistically insignificant.

Conclusion

This study did not find a significant improvement of KAs on muscle wasting, and a long time or more indices study may need to find the effects of the LPD + KA diets.

Clinical trial registration

[www.ClinicalTrials.gov], identifier [NCT02568020].
A novel necroptosis-related gene signature for predict prognosis of glioma based on single-cell and bulk RNA sequencing
Authors: Guo Kai , Duan Xinxin , Zhao Jiahui , Sun Boyu , Liu Xiaoming , Zhao Zongmao
Published: August 2022

Background:Glioma is the most fatal neoplasm among the primary intracranial cancers. Necroptosis, a form of programmed cell death, is correlated with tumor progression and immune response. But, the role of necroptosis-related genes (NRGs) in glioma has not been well-uncovered.

Methods:Single-cell and bulk RNA sequencing data, obtained from publicly accessed databases, were used to establish a necroptosis-related gene signature for predicting the prognosis of glioma patients. Multiple bioinformatics algorithms were conducted to evaluate the efficacy of the signature. The relative mRNA level of each signature gene was validated by quantitative real-time reverse transcription PCR (qRT-PCR) in glioma cell lines compared to human astrocytes.

Results:In this predicted prognosis model, patients with a high risk score showed a shorter overall survival, which was verified in the testing cohorts. The signature risk score was positively related with immune cell infiltration and some immune check points, such as CD276 (B7-H3), CD152 (CTLA-4), CD223 (LAG-3), and CD274 (PD-L1). Single-cell RNA sequencing analysis confirmed that the glioma microenvironment consists of various immune cells with different markers. The eight NRGs of the signature were detected to be expressed in several immune cells. QRT-PCR results verified that all the eight signature genes were differentially expressed between human astrocytes and glioma cells.

Conclusion:The eight NRGs correlate with the immune microenvironment of glioma according to our bioinformatics analysis. This necroptosis-related gene signature may evaluate the precise methodology of predicting prognosis of glioma and provide a novel thought in glioma investigation.
Complement C3a receptor inactivation attenuates retinal degeneration induced by oxidative damage
Authors: Wang Shaojun , Du Lu , Yuan Shunzong , Peng Guang-Hua
Published: August 2022

Retinal degeneration causes vision loss and threatens the health of elderly individuals worldwide. Evidence indicates that the activation of the complement system is associated with retinal degeneration. However, the mechanism of complement signaling in retinal degeneration needs to be further studied. In this study, we show that the expression of C3 and C3a receptor (C3ar1) is positively associated with the inflammatory response and retinal degeneration. Genetic deletion of C3 and pharmacological inhibition of C3ar1 resulted in the alleviation of neuroinflammation, prevention of photoreceptor cell apoptosis and restoration of visual function. RNA sequencing (RNA-seq) identified a C3ar1-dependent network shown to regulate microglial activation and astrocyte gliosis formation. Mechanistically, we found that STAT3 functioned downstream of the C3-C3ar1 pathway and that the C3ar1-STAT3 pathway functionally mediated the immune response and photoreceptor cell degeneration in response to oxidative stress. These findings reveal an important role of C3ar1 in oxidative-induced retinal degeneration and suggest that intervention of the C3ar1 pathway may alleviate retinal degeneration.
Impact of local anesthetics on epigenetics in cancer
Authors: Bezu Lucillia , Kepp Oliver , Kroemer Guido
Published: August 2022

Defective silencing of tumor suppressor genes through epigenetic alterations contributes to oncogenesis by perturbing cell cycle regulation, DNA repair or cell death mechanisms. Reversal of such epigenetic changes including DNA hypermethylation provides a promising anticancer strategy. Until now, the nucleoside derivatives 5-azacytidine and decitabine are the sole DNA methyltransferase (DNMT) inhibitors approved by the FDA for the treatment of specific hematological cancers. Nevertheless, due to their nucleoside structure, these inhibitors directly incorporate into DNA, which leads to severe side effects and compromises genomic stability. Much emphasis has been placed on the development of less toxic epigenetic modifiers. Recently, several preclinical studies demonstrated the potent epigenetic effects of local anesthetics, which are routinely used during primary tumor resection to relief surgical pain. These non-nucleoside molecules inhibit DNMT activity, affect the expression of micro-RNAs and repress histone acetylation, thus exerting cytotoxic effects on malignant cells. The in-depth mechanistic comprehension of these epigenetic effects might promote the use of local anesthetics as anticancer drugs.
Development and validation of a prognosis prediction model based on 18 endoplasmic reticulum stress-related genes for patients with lung adenocarcinoma
Authors: Shu Long , Liu Shuang , Tao Yongguang
Published: August 2022

Background

Endoplasmic reticulum (ER) stress had a crucial impact on cell survival, proliferation, and metastasis in various cancers. However, the role of ER stress in lung adenocarcinoma remains unclear.

Method

Gene expression and clinical data of lung adenocarcinoma (LUAD) samples were extracted from The Cancer Genome Atlas (TCGA) and three Gene Expression Omnibus (GEO) datasets. ER stress score (ERSS) was constructed based on hub genes selected from 799 ER stress-related genes by least absolute shrinkage and selection operator (LASSO) regression. A Cox regression model, integrating ERSS and the TNM stage, was developed to predict overall survival (OS) in TCGA cohort and was validated in GEO cohorts. Gene set enrichment analysis (GSEA), single-sample GSEA (ssGSEA), and gene mutation analyses were performed to further understand the molecular features of ERSS. The tumor immune infiltration was evaluated by ESTIMATE, CIBERSORT, and xCell algorithms. The receiver operating characteristic (ROC) curves were used to evaluate the predictive value of the risk model. p< 0.05 was considered statistically significant.

Results

One hundred fifty-seven differentially expressed genes (DEGs) were identified between tumor and para-carcinoma tissues, and 45 of them significantly correlated with OS. Next, we identified 18 hub genes and constructed ERSS by LASSO regression. Multivariate analysis demonstrated that higher ERSS (p< 0.0001, hazard ratio (HR) = 3.8, 95%CI: 2.8–5.2) and TNM stage (p< 0.0001, HR = 1.55, 95%CI: 1.34–1.8) were independent predictors for worse OS. The prediction model integrating ERSS and TNM stage performed well in TCGA cohort (area under the curve (AUC) at five years = 0.748) and three GEO cohorts (AUC at 5 years = 0.658, 0.717, and 0.739). Pathway enrichment analysis showed that ERSS significantly correlated with unfolded protein response. Meanwhile, pathways associated with the cell cycle, growth, and metabolism were significantly enriched in the high ERSS group. Patients with SMARCA4, TP53, and EGFR mutations showed significantly higher ERSS (p = 4e−04, 0.0027, and 0.035, respectively). Tissues with high ERSS exhibited significantly higher infiltration of M1 macrophages, activated dendritic cells, and lower infiltration of CD8+ T cells and B cells, which indicate an activated tumor antigen-presenting but suppressive immune response status.

Conclusion

We developed and validated an ER stress-related risk model that exhibited great predictive value for OS in patients with LUAD. Our work also expanded the understanding of the role of ER stress in LUAD.
SHMT2 regulates serine metabolism to promote the progression and immunosuppression of papillary renal cell carcinoma
Authors: Kong Weiyu , Wang Zhongyuan , Chen Nuoran , Mei Yiwen , Li Yang , Yue Yulin
Published: August 2022

Recent research has demonstrated the diverse relationship between tumour metabolism and the tumour microenvironment (TME), for example, abnormal serine metabolism. This study investigated the role of serine metabolism in papillary renal cell carcinoma (pRCC) focusing on the prognostic value and regulatory mechanisms. Gene expression profiles and clinical data of patients with pRCC were obtained from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database. Kaplan–Meier curves were used for survival analysis and consensus clustering for tumour serine metabolic signatures extraction. Functional analysis, including the Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene set enrichment analysis (GSEA), was applied to explore the biological characteristics. The gene set variation analysis (GSVA), single-sample GSEA (ssGSEA), and Estimation of Stromal and Immune cells in Malignant Tumour tissues using Expression data (ESTIMATE) methods were utilised to estimate the immune infiltration in the various subtypes. Five serine metabolic genes (SMGs) were used to classify patients with pRCC, with four clusters identified with diverse prognoses and immune features based on these survival-related SMGs. Further analysis of the best and worst clusters (B and D clusters) revealed variations in survival, clinical progression, oncogenic pathways, and TME, which included immune infiltration scores, immunosuppressive cell infiltration, and expression of immune checkpoints. In addition, SMGs, especially SHMT2, exacerbated the carcinogenesis and immunosuppressive cells in pRCC, thus promoting tumour proliferation. In conclusion, higher SHMT2 gene expression and higher serine metabolism in tumour cells are associated with poorer clinical outcomes in pRCC. SHMT2 is a potential novel target gene for targeted therapy and immunotherapy in pRCC.
Lurbinectedin in small cell lung cancer
Authors: Manzo Anna , Sforza Vincenzo , Carillio Guido , Palumbo Giuliano , Montanino Agnese , Sandomenico Claudia , Costanzo Raffaele , Esposito Giovanna , Laudato Francesca , Mercadante Edoardo , La Manna Carmine , Muto Paolo , Totaro Giuseppe , De Cecio Rossella , Picone Carmine , Piccirillo Maria Carmela , Pascarella Giacomo , Normanno Nicola , Morabito Alessandro
Published: August 2022

Few treatment options are available for patients with small cell lung cancer (SCLC) in progression after a first-line therapy. A novel therapeutic approach is represented by lurbinectedin, a synthetic derivative of trabectedin that works by inhibiting oncogenic transcription and promoting apoptosis in tumor cells. A phase II basket trial demonstrated the activity of lurbinectedin at the dose of 3.2 mg/m2 in patients with SCLC who had failed a previous chemotherapy, with a response rate of 35.2%, a median progression-free survival (mPFS) of 3.5 months, and a median overall survival (mOS) of 9.3 months. Common severe adverse events (grades 3–4) were hematological disorders, including anemia (9%), leukopenia (29%), neutropenia (46%), and thrombocytopenia (7%). On the basis of the positive results of this phase II study, on June 2020, lurbinectedin was approved by the Food and Drug Administration as second line for SCLC patients in progression on or after platinum-based therapy. The subsequent phase III trial comparing the combination of lurbinectedin plus doxorubicin vs. CAV (cyclophosphamide, Adriamycin, and vincristine) or topotecan did not demonstrate an improvement in overall survival, although the experimental arm showed a superior safety profile. Combinations of lurbinectedin with other drugs, cytotoxic agents and immune checkpoint inhibitors, are currently under investigation. The results of these studies should better define the optimal clinical application of lurbinectedin.
Predictive value of NLR and PLR in response to preoperative chemotherapy and prognosis in locally advanced gastric cancer
Authors: Wang Wentao , Tong Yilin , Sun Shulan , Tan Yuen , Shan Zexing , Sun Fan , Jiang Chengyao , Zhu Yanmei , Zhang Jianjun
Published: August 2022

Purpose

Pretreatment neutrophil-to-lymphocyte (NLR) and platelet-to-lymphocyte (PLR) ratios are markers of systemic inflammation. In patients with locally advanced gastric cancer (GC), the utility of these ratios in predicting tumor regression grade (TRG) after neoadjuvant chemotherapy (NCT) remains unclear.

Methods

This retrospective study examined 283 locally advanced GC patients who underwent NCT and radical surgery. The receiver operating characteristic (ROC) curve analysis and the Youden index were applied to identify optimal NLR/PLR cutpoints. The Kaplan–Meier method was used to estimate overall survival (OS) and disease-free survival (DFS). Univariate/multivariate analyses were conducted by the logistic regression method.

Results

TRG grade proved significantly worse in patients with high values of both NLR and PLR whether in univariate (OR = 3.457; p = 0.044) or multivariate (OR = 6.876; p = 0.028) analysis. The degree of tumor differentiation was an independent predictive factor for TRG (OR = 2.874; p = 0.037) in multivariate analysis. In the subgroup analyses, NLR predicted OS (p = 0.04) and DFS (p = 0.03) in female patients, whereas PLR was predictive of both OS (p = 0.026) and DFS (p = 0.018) in patients with clinical TNM stage 3 disease and dissected lymph node counts <28. PLR similarly predicted OS in patients <65 years old (p = 0.049), those with positive lymph nodes (p = 0.021), or those with moderate or poorly differentiated tumors (p = 0.049).

Conclusion

Pretreatment NLR and PLR together serve to independently predict TRG after NCT and surgery in patients with locally advanced GC. Screening for patients with high NLR and PLR values may allow them to benefit upfront from alternatives to NCT.
Publication trends and hotspots of drug resistance in colorectal cancer during 2002-2021: A bibliometric and visualized analysis
Authors: Zhao Peng-yue , Jiao Ya-nan , Ma Zhao-fu , Yan Yang , Li Yu-xuan , Hu Shi-dong , Li Song-yan , Du Xiao-hui
Published: August 2022

Background

Chemotherapy, radiotherapy, targeted therapy and immunotherapy have demonstrated expected clinical efficacy, while drug resistance remains the predominant limiting factor to therapeutic failure in patients with colorectal cancer (CRC). Although there have been numerous basic and clinical studies on CRC resistance in recent years, few publications utilized the bibliometric method to evaluate this field. The objective of current study was to provide a comprehensive analysis of the current state and changing trends of drug resistance in CRC over the past 20 years.

Methods

The Web of Science Core Collection (WOSCC) was utilized to extracted all studies regarding drug resistance in CRC during 2002-2021. CiteSpace and online platform of bibliometrics were used to evaluate the contributions of various countries/regions, institutions, authors and journals in this field. Moreover, the recent research hotspots and promising future trends were identified through keywords analysis by CiteSpace and VOSviewer.

Results

1451 related publications from 2002 to 2021 in total were identified and collected. The number of global publications in this field has increased annually. China and the USA occupied the top two places with respect to the number of publications, contributing more than 60% of global publications. Sun Yat-sen University and Oncotarget were the institution and journal which published the most papers, respectively. Bardelli A from Italy was the most prolific writer and had the highest H-index. Keywords burst analysis identified that “Growth factor receptor”, “induced apoptosis” and “panitumumab” were the ones with higher burst strength in the early stage of this field. Analysis of keyword emergence time showed that “oxaliplatin resistance”, “MicroRNA” and “epithelial mesenchymal transition (EMT)” were the keywords with later average appearing year (AAY).

Conclusions

The number of publications and research interest on drug resistance in CRC have been increasing annually. The USA and China were the main driver and professor Bardelli A was the most outstanding researcher in this field. Previous studies have mainly concentrated on growth factor receptor and induced apoptosis. Oxaliplatin resistance, microRNA and EMT as recently appeared frontiers of research that should be closely tracked in the future.
Endocytosis of the thrombopoietin receptor Mpl regulates megakaryocyte and erythroid maturation in mice
Authors: Eaton Nathan , Boyd Emily K. , Biswas Ratnashree , Lee-Sundlov Melissa M. , Dlugi Theresa A. , Ramsey Haley E. , Zheng Shikan , Burns Robert T. , Sola-Visner Martha C. , Hoffmeister Karin M. , Falet Hervé
Published: August 2022

Dnm2fl/fl Pf4-Cre (Dnm2Plt–/–) mice lacking the endocytic GTPase dynamin 2 (DNM2) in platelets and megakaryocytes (MKs) develop hallmarks of myelofibrosis. At the cellular level, the tyrosine kinase JAK2 is constitutively active but decreased in expression in Dnm2Plt–/– platelets. Additionally, Dnm2Plt–/– platelets cannot endocytose the thrombopoietin (TPO) receptor Mpl, leading to elevated circulating TPO levels. Here, we assessed whether the hyperproliferative phenotype of Dnm2Plt–/– mice was due to JAK2 constitutive activation or to elevated circulating TPO levels. In unstimulated Dnm2Plt–/– platelets, STAT3 and, to a lower extent, STAT5 were phosphorylated, but their phosphorylation was slowed and diminished upon TPO stimulation. We further crossed Dnm2Plt–/– mice in the Mpl–/– background to generate Mpl–/–Dnm2Plt–/– mice lacking Mpl ubiquitously and DNM2 in platelets and MKs. Mpl–/– Dnm2Plt–/– platelets had severely reduced JAK2 and STAT3 but normal STAT5 expression. Mpl–/– Dnm2Plt–/– mice had severely reduced bone marrow MK and hematopoietic stem and progenitor cell numbers. Additionally, Mpl–/– Dnm2Plt–/– mice had severe erythroblast (EB) maturation defects, decreased expression of hemoglobin and heme homeostasis genes and increased expression of ribosome biogenesis and protein translation genes in spleen EBs, and developed anemia with grossly elevated plasma erythropoietin (EPO) levels, leading to early fatality by postnatal day 25. Mpl–/– Dnm2Plt+/+ mice had impaired EB development at three weeks of age, which normalized with adulthood. Together, the data shows that DNM2-dependent Mpl-mediated endocytosis in platelets and MKs is required for steady-state hematopoiesis and provides novel insights into a developmentally controlled role for Mpl in normal erythropoiesis, regulating hemoglobin and heme production.