Single-Cell Spatial Transcriptomics Unveils Platelet-Fueled Cycling Macrophages for Kidney Fibrosis.

With the increasing incidence of kidney diseases, there is an urgent need to develop therapeutic strategies to combat post-injury fibrosis. Immune cells, including platelets, play a pivotal role in this repair process, primarily through their released cytokines. However, the specific role of platelets in kidney injury and subsequent repair remains underexplored. Here, the detrimental role of platelets in renal recovery following ischemia/reperfusion injury and its contribution to acute kidney injury  to chronic kidney disease transition is aimed to investigated. In this study, it is shown that depleting platelets accelerates injury resolution and significantly reduces fibrosis. Employing advanced single-cell and spatial transcriptomic techniques, macrophages as the primary mediators modulated by platelet signals is identified. A novel subset of macrophages, termed "cycling M2", which exhibit an M2 phenotype combined with enhanced proliferative activity is uncovered. This subset emerges in the injured kidney during the resolution phase and is modulated by platelet-derived thrombospondin 1 (THBS1) signaling, acquiring profibrotic characteristics. Conversely, targeted inhibition of THBS1 markedly downregulates the cycling M2 macrophage, thereby mitigating fibrotic progression. Overall, this findings highlight the adverse role of platelet THBS1-boosted cycling M2 macrophages in renal injury repair and suggest platelet THBS1 as a promising therapeutic target for alleviating inflammation and kidney fibrosis.

Detection of LAMA2 c.715C>G:p.R239G mutation in a newborn with raised creatine kinase: A case report.

BACKGROUND: We report a rare case of primary clinical presentation featuring elevated creatine kinase (CK) levels in a neonate, which is associated with the LAMA2 gene. In this case, a heterozygous mutation in exon5 of the LAMA2 gene, c.715C>G (resulting in a change of nucleotide number 715 in the coding region from cytosine to guanine), induced an amino acid alteration p.R239G (No. 239) in the patient, representing a missense mutation. This observation may be elucidated by the neonatal creatine monitoring mechanism, a phenomenon not previously reported. CASE SUMMARY: We analysed the case of a neonate presenting solely with elevated CK levels who was eventually discharged after supportive treatment. The chief complaint was identification of increased CK levels for 15 d and higher CK values for 1 d. Admission occurred at 18 d of age, and despite prolonged treatment with creatine and vitamin C, the elevated CK levels showed limited improvement. Whole exome sequencing revealed the presence of a c.715C>G mutation in LAMA2 in the newborn, correlating with a clinical phenotype. However, the available information offers insufficient evidence for clinical pathogenicity. CONCLUSION: Mutations in LAMA2 are associated with the clinical phenotype of increased neonatal CK levels, for which no specific treatment exists. Whole genome sequencing facilitates early diagnosis.

The requirement of the mitochondrial protein NDUFS8 for angiogenesis.

Mitochondria are important for the activation of endothelial cells and the process of angiogenesis. NDUFS8 (NADH:ubiquinone oxidoreductase core subunit S8) is a protein that plays a critical role in the function of mitochondrial Complex I. We aimed to investigate the potential involvement of NDUFS8 in angiogenesis. In human umbilical vein endothelial cells (HUVECs) and other endothelial cell types, we employed viral shRNA to silence NDUFS8 or employed the CRISPR/Cas9 method to knockout (KO) it, resulting in impaired mitochondrial functions in the endothelial cells, causing reduction in mitochondrial oxygen consumption and Complex I activity, decreased ATP production, mitochondrial depolarization, increased oxidative stress and reactive oxygen species (ROS) production, and enhanced lipid oxidation. Significantly, NDUFS8 silencing or KO hindered cell proliferation, migration, and capillary tube formation in cultured endothelial cells. In addition, there was a moderate increase in apoptosis within NDUFS8-depleted endothelial cells. Conversely, ectopic overexpression of NDUFS8 demonstrated a pro-angiogenic impact, enhancing cell proliferation, migration, and capillary tube formation in HUVECs and other endothelial cells. NDUFS8 is pivotal for Akt-mTOR cascade activation in endothelial cells. Depleting NDUFS8 inhibited Akt-mTOR activation, reversible with exogenous ATP in HUVECs. Conversely, NDUFS8 overexpression boosted Akt-mTOR activation. Furthermore, the inhibitory effects of NDUFS8 knockdown on cell proliferation, migration, and capillary tube formation were rescued by Akt re-activation via a constitutively-active Akt1. In vivo experiments using an endothelial-specific NDUFS8 shRNA adeno-associated virus (AAV), administered via intravitreous injection, revealed that endothelial knockdown of NDUFS8 inhibited retinal angiogenesis. ATP reduction, oxidative stress, and enhanced lipid oxidation were detected in mouse retinal tissues with endothelial knockdown of NDUFS8. Lastly, we observed an increase in NDUFS8 expression in retinal proliferative membrane tissues obtained from human patients with proliferative diabetic retinopathy. Our findings underscore the essential role of the mitochondrial protein NDUFS8 in regulating endothelial cell activation and angiogenesis.

Prognostic factors of primary intrascrotal rhabdomyosarcoma in children: a population-based study.

PURPOSE: Primary intrascrotal rhabdomyosarcoma (RMS) is a rare and aggressive tumor. The purpose of this study was to investigate the prognostic factors of intrascrotal RMS in children. METHODS: All pediatric patients with intrascrotal RMS diagnosed between 2000 and 2018 were identified using the Surveillance, Epidemiology, and End Results (SEER) database. To compare survival curves, the log-rank test was employed. A multivariate Cox proportional hazards model was developed to investigate the effect of each factor on overall survival (OS). A nomogram was created using the outcomes of the Cox regression model. RESULTS: A total of 102 pediatric patients with intrascrotal RMS were identified. Overall survival rates for all patients were 90.6% at 3-year and 87.2% at 5-year, respectively. Survival rates differed significantly by SEER stage and surgery; however, chemotherapy and removal of lymph nodes showed no significant difference. The outcome of Cox proportional hazard regression revealed that SEER stage and surgery were important independent predictors in this model. Furthermore, we developed a nomogram for predicting OS in pediatric intrascrotal RMS based on the Cox regression model. The risk of death increased with stage in patients. Additionally, patients who underwent surgery had a lower mortality risk than those who did not. CONCLUSIONS: Our findings show that SEER stage and surgery are the most important indicators of OS in children with intrascrotal RMS, providing critical epidemiological information for clinical therapy.

CNN-based diagnosis model of children's bladder compliance using a single intravesical pressure signal.

Bladder compliance assessment is crucial for diagnosing bladder functional disorders, with urodynamic study (UDS) being the principal evaluation method. However, the application of UDS is intricate and time-consuming in children. So it'S necessary to develop an efficient bladder compliance screen approach before UDS. In this study, We constructed a dataset based on UDS and designed a 1D-CNN model to optimize and train the network. Then applied the trained model to a dataset obtained solely through a proposed perfusion experiment. Our model outperformed other algorithms. The results demonstrate the potential of our model to alert abnormal bladder compliance accurately and efficiently.

Combined Analysis of the Transcriptome, Proteome and Metabolome in Human Cryopreserved Sperm.

PURPOSE: This study aimed to identify the altered pathways and genes associated with freezing damage in human sperm during cryopreservation by multiomics analysis. MATERIALS AND METHODS: Fifteen fresh human semen samples were collected for transcriptomic analysis, and another 5 fresh human semen samples were obtained for metabolomic analysis. For each semen sample, 1 mL was cryopreserved, and another 1 mL was left untreated for paired design. The results were then combined with previously published proteomic results to identify key genes/pathways. RESULTS: Cryopreservation significantly reduced sperm motility and mitochondrial structure. Transcriptomic analysis revealed altered mitochondrial function, including changes in tRNA-methyltransferase activity and adenosine tri-phosphate/adenosine di-phosphate transmembrane transporter activity. Metabolomic analysis showed that the citrate cycle in mitochondria was significantly altered. Combining transcriptomic, proteomic, and metabolomic analyses revealed 346 genes that were altered in at least two omics analyses. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that metabolic pathways were significantly altered and strongly associated with mitochondria. Five genes were altered in all three omics analyses: COL11A1, COL18A1, LPCAT3, NME1, and NNT. CONCLUSIONS: Five genes were identified by multiomics analysis in human cryopreserved sperm. These genes might have specific functions in cryopreservation. Explorations of the functions of these genes will be helpful for sperm cryopreservation and sperm motility improvement or even for reproduction in the future.

Autophagy of OTUD5 destabilizes GPX4 to confer ferroptosis-dependent kidney injury.

Ferroptosis is an iron-dependent programmed cell death associated with severe kidney diseases, linked to decreased glutathione peroxidase 4 (GPX4). However, the spatial distribution of renal GPX4-mediated ferroptosis and the molecular events causing GPX4 reduction during ischemia-reperfusion (I/R) remain largely unknown. Using spatial transcriptomics, we identify that GPX4 is situated at the interface of the inner cortex and outer medulla, a hyperactive ferroptosis site post-I/R injury. We further discover OTU deubiquitinase 5 (OTUD5) as a GPX4-binding protein that confers ferroptosis resistance by stabilizing GPX4. During I/R, ferroptosis is induced by mTORC1-mediated autophagy, causing OTUD5 degradation and subsequent GPX4 decay. Functionally, OTUD5 deletion intensifies renal tubular cell ferroptosis and exacerbates acute kidney injury, while AAV-mediated OTUD5 delivery mitigates ferroptosis and promotes renal function recovery from I/R injury. Overall, this study highlights a new autophagy-dependent ferroptosis module: hypoxia/ischemia-induced OTUD5 autophagy triggers GPX4 degradation, offering a potential therapeutic avenue for I/R-related kidney diseases.

Efficient Underground Tunnel Place Recognition Algorithm Based on Farthest Point Subsampling and Dual-Attention Transformer.

An autonomous place recognition system is essential for scenarios where GPS is useless, such as underground tunnels. However, it is difficult to use existing algorithms to fully utilize the small number of effective features in underground tunnel data, and recognition accuracy is difficult to guarantee. In order to solve this challenge, an efficient point cloud position recognition algorithm, named Dual-Attention Transformer Network (DAT-Net), is proposed in this paper. The algorithm firstly adopts the farthest point downsampling module to eliminate the invalid redundant points in the point cloud data and retain the basic shape of the point cloud, which reduces the size of the point cloud and, at the same time, reduces the influence of the invalid point cloud on the data analysis. After that, this paper proposes the dual-attention Transformer module to facilitate local information exchange by utilizing the multi-head self-attention mechanism. It extracts local descriptors and integrates highly discriminative global descriptors based on global context with the help of a feature fusion layer to obtain a more accurate and robust global feature representation. Experimental results show that the method proposed in this paper achieves an average F1 score of 0.841 on the SubT-Tunnel dataset and outperforms many existing state-of-the-art algorithms in recognition accuracy and robustness tests.

USP18 enhances the resistance of BRAF-mutated melanoma cells to vemurafenib by stabilizing cGAS expression to induce cell autophagy.

This study aims to discern the possible molecular mechanism of the effect of ubiquitin-specific peptidase 18 (USP18) on the resistance to BRAF inhibitor vemurafenib in BRAF V600E mutant melanoma by regulating cyclic GMP-AMP synthase (cGAS). The cancer tissues of BRAF V600E mutant melanoma patients before and after vemurafenib treatment were collected, in which the protein expression of USP18 and cGAS was determined. A BRAF V600E mutant human melanoma cell line (A2058R) resistant to vemurafenib was constructed with its viability, apoptosis, and autophagy detected following overexpression and depletion assays of USP18 and cGAS. Xenografted tumors were transplanted into nude mice for in vivo validation. Bioinformatics analysis showed that the expression of cGAS was positively correlated with USP18 in melanoma, and USP18 was highly expressed in melanoma. The expression of cGAS and USP18 was up-regulated in cancer tissues of vemurafenib-resistant patients with BRAF V600E mutant melanoma. Knockdown of cGAS inhibited the resistance to vemurafenib in A2058R cells and the protective autophagy induced by vemurafenib in vitro. USP18 could deubiquitinate cGAS to promote its protein stability. In vivo experimentations confirmed that USP18 promoted vemurafenib-induced protective autophagy by stabilizing cGAS protein, which promoted resistance to vemurafenib in BRAF V600E mutant melanoma cells. Collectively, USP18 stabilizes cGAS protein expression through deubiquitination and induces autophagy of melanoma cells, thereby promoting the resistance to vemurafenib in BRAF V600E mutant melanoma.

Cross-sectional study of characteristics of body composition of 24,845 children and adolescents aged 3-17 years in Suzhou.

BACKGROUND: We aimed to analyze the characteristics of the body composition of children and adolescents aged 3-17 in Suzhou, China. METHODS: A cross-sectional study between January 2020 and June 2022 using bioelectrical impedance was conducted to determine the fat mass (FM), fat-free mass (FFM), skeletal muscle mass, and protein and mineral contents of 24,845 children aged 3-17 who attended the Department of Child and Adolescent Healthcare, Children's Hospital of Soochow University, China. Measurement data was presented in tables as mean ± SD, and groups were compared using the independent samples t-test. RESULTS: FM and fat-free mass increased with age in both boys and girls. The fat-free mass of girls aged 14-15 decreased after reaching a peak, and that of boys in the same age group was higher than that of the girls (p < 0.05). There were no significant differences in FM between boys and girls younger than 9- and 10-years old. The percentage body fat (PBF) and FM index of girls increased rapidly between 11 and 15 years of age (p < 0.05), and those of boys aged 11-14 were significantly lower (p < 0.05), suggesting that the increase in body mass index (BMI) was mainly contributed by muscle mass (MM) in boys. CONCLUSIONS: The body composition of children and adolescents varies according to their age and sex. A misdiagnosis of obesity made on the basis of BMI alone can be avoided if BMI is used in combination with FM index, percentage body fat, and other indexes.

Spongioplasty with Buck's fascia covering dorsal inlay graft urethroplasty for primary hypospadias repair.

INTRODUCTION: Neourethral covering is an essential technique for preventing complications such as fistula and glans dehiscence in hypospadias repairs. The spongioplasty has been reported for neourethral coverage about 20 years ago. However, reports of the outcome are limited. OBJECTIVE: This study aimed to retrospectively evaluate the short-term outcome of spongioplasty with Buck's fascia covering dorsal inlay graft urethroplasty (DIGU). METHODS: From December 2019 to December 2020, 50 patients with primary hypospadias (median age at surgery, 37 months; range, 10 months-12 years) were treated by a single pediatric urologist. The patients underwent spongioplasty with Buck's fascia covering dorsal inlay graft urethroplasty in single stage. The penile length, glans width, urethral plate width and length, and the location of the meatus of the patients were recorded preoperatively. The patients were followed up,complications noted, and postoperative uroflowmetries at the one-year follow-up time were evaluated. RESULTS: The average width of glans was 12.92 ± 1.86 mm. A minor penile curvature was observed in all patients (≤30°). The patients were followed up for 12-24 months, and 47 patients (94%) were free from complications. A neourethra formed with a slit-like meatus at the tip of the glans, and the urinary stream was straight. Three patients had coronal fistulae (3/50) and no glans dehiscence, and the mean ± SD Qmax of postoperative uroflowmetry was 8.13 ± 3.8 ml/s. DISCUSSION: This study estimated the short-term outcome of the DIGU covered using spongioplasty with Buck's fascia as the second layer in patients diagnosed with primary hypospadias with a relatively small glans (average width <14 mm). However, only a few reports emphasize spongioplasty with Buck's fascia as the second layer and the DIGU procedure performed on a relatively small glans. The major limitations of this study were its short follow-up time and the retrospective data collection. CONCLUSIONS: Dorsal inlay graft urethroplasty combined with spongioplasty with Buck's fascia as coverage is an effective procedure. In our study, this combination had good short-term outcomes for primary hypospadias repair.

Glutathione metabolism rewiring protects renal tubule cells against cisplatin-induced apoptosis and ferroptosis.

Renal proximal tubular cells are highly vulnerable to different types of assaults during filtration and reabsorption, leading to acute renal dysfunction and eventual chronic kidney diseases (CKD). The chemotherapeutic drug cisplatin elicits cytotoxicity causing renal tubular cell death, but its executing mechanisms of action are versatile and elusive. Here, we show that cisplatin induces renal tubular cell apoptosis and ferroptosis by disrupting glutathione (GSH) metabolism. Upon cisplatin treatment, GSH metabolism is impaired leading to GSH depletion as well as the execution of mitochondria-mediated apoptosis and lipid oxidation-related ferroptosis through activating IL6/JAK/STAT3 signaling. Inhibition of JAK/STAT3 signaling reversed cell apoptosis and ferroptosis in response to cisplatin induction. Using a cisplatin-induced acute kidney injury (CAKI) mouse model, we found that inhibition of JAK/STAT3 significantly mitigates cisplatin nephrotoxicity with a reduced level of serum BUN and creatinine as well as proximal tubular distortion. In addition, the GSH booster baicalein also reclaims cisplatin-induced renal tubular cell apoptosis and ferroptosis as well as the in vivo nephrotoxicity. In conclusion, cisplatin disrupts glutathione metabolism, leading to renal tubular cell apoptosis and ferroptosis. Rewiring glutathione metabolism represents a promising strategy for combating cisplatin nephrotoxicity.

Jujuboside A attenuates sepsis-induced cardiomyopathy by inhibiting inflammation and regulating autophagy.

BACKGROUND: Jujuboside A (JuA), as a main effective component of Jujubogenin, has long been known as a sedative-hypnotic drug. The aim of the current study was to investigate the potential effect of JuA on sepsis-induced cardiomyopathy (SIC) induced by lipopolysaccharide (LPS). METHOD: Wide type C57BL/6 mice and neonatal rat cardiomyocytes (NRCMs) were exposed to LPS to establish myocardial toxicity models. Cardiac function of septic mice was detected by echocardiography. Moreover, the survival rate was calculated for 7 days. ELISA assays were used to analyze inflammatory factors in serum. Furthermore, western blotting, flow cytometry and TUNEL staining were performed to assess cell apoptosis and transmission electron microscopy detect the number of autophagosomes in myocardium. Finally, the expression of proteins related to pyroptosis, autophagy and oxidative stress was analyzed by western blotting and immunohistochemistry staining. RESULTS: Results showed that JuA pretreatment significantly improved the survival rate and cardiac function, and suppressed systemic inflammatory response in septic mice. Further study revealed that JuA could decrease cell apoptosis and pyroptosis; instead, it strengthened autophagy in SIC. Moreover, JuA also significantly decreased oxidative stress and nitrodative stress, as evidenced by suppressing the superoxide production and downregulating iNOS and gp91 expression in vivo. In addition, the autophagy inhibitor 3-MA significantly abolished the effect of JuA on autophagic activity in SIC. CONCLUSION: In conclusion, the findings indicated that JuA attenuates cardiac function via blocking inflammasome-mediated apoptosis and pyroptosis, at the same time by enhancing autophagy in SIC, heralding JuA as a potential therapy for sepsis.

Expression and clinical implications of PARs in the stenotic tissue of ureteropelvic junction obstruction.

Objective: To explore the expression and clinical implications of protease activated receptors (PARs) in the pathogenesis of children with ureteropelvic junction obstruction (UPJO). Material and methods: Immunohistochemistry was employed to investigate the distribution of PARs in both normal human ureteropelvic junction (UPJ) and cases of UPJO. Furthermore, PAR gene expression levels were assessed using real-time PCR (RT-PCR), and the patients in the UPJO group were stratified according to the Onen grading system. Subsequently, the clinical implications of PARs in UPJO were explored through RT-PCR analysis. Results: Immunofluorescence showed robust PAR2 expression in the control group compared with the UPJO group. The results of RT-PCR analysis revealed a significant decrease in the relative mRNA expression of PAR2 in the UPJO group compared to the control group. Notably, the relative RNA expression of PAR1 was significantly lower in the Onen-4 group compared to the control group. Furthermore, the relative mRNA expression of PAR2 exhibited a statistically significant difference among the Onen-3 group, Onen-4 group, and control group. Conclusions: PARs are widely distributed throughout the SIP syncytium of the UPJ and play a role in maintaining smooth muscle cells (SMCs) membrane potential by interacting with interstitial cells of Cajal (ICCs), as well as platelet-derived growth factor receptor alpha-positive cells (PDGFR α+ cells). The decreased expression of PAR1 suggests a higher preoperative Onen grade in UPJO patients. Furthermore, the downregulation of PAR2 effects at the UPJ may be involved in the loss of inhibitory neuromuscular transmission, disrupting the rhythmic peristalsis of the UPJ.

Long Non-Coding RNA CRNDE Functions as a Tumor Promoter by Modulating the ERK/MAPK Signaling Pathway in Neuroblastoma Cells.

OBJECTIVE: The long non-coding RNA (lncRNA) colorectal neoplasia differentially expressed (CRNDE) is considered a carcinogenic promoter in various human malignancies. However, the role and underlying mechanism of action of CRNDE during carcinogenesis in neuroblastoma remain unknown. METHODS: CRNDE transcript levels were detected in neuroblastoma tissues and adjacent normal tissues. The effects of CRNDE overexpression and knockdown on the viability of SH-SY5Y and SK-N-AS cells were determined using the Cell Counting Kit-8 (CCK-8) assay. Flow cytometry was performed to measure the role of CRNDE in apoptosis and the cell cycle in neuroblastoma cells. Moreover, the transwell assay was used to evaluate the role of CRNDE in the migration and invasion of tumor cells. The levels of ERK/MAPK pathway-related proteins were evaluated using western blotting. The in vivo role of CRNDE in tumor growth and apoptosis was evaluated in a xenograft mouse model of human neuroblastoma. RESULTS: The relative expression of CRNDE was significantly higher in neuroblastoma tissues than in the adjacent normal tissues. Moreover, knockdown of CRNDE inhibited tumor cell proliferation and induced apoptosis and cell cycle arrest, whereas elevation of CRNDE promoted cell growth and inhibited apoptosis in neuroblastoma cells. In addition, depletion of CRNDE suppressed migration and invasion, whereas overexpression of CRNDE enhanced the migratory and invasive potential of SH-SY5Y and SK-N-AS cells. At the mechanistic level, western blotting showed that CRNDE exerted its oncogenic role by affecting the ERK/MAPK signaling pathway. Furthermore, animal experiments confirmed that CRNDE promotes tumor growth and inhibits apoptosis in neuroblastoma in vivo. CONCLUSION: The present study revealed that CRNDE plays a critical role in the proliferation, apoptosis, migration, and invasion of neuroblastoma by altering the ERK/MAPK signaling pathway, representing a novel molecular target for the treatment of neuroblastoma.

Differences in meat quality between Angus cattle and Xinjiang brown cattle in association with gut microbiota and its lipid metabolism.

Gut microbiota plays important roles in mediating fat metabolic events in humans and animals. However, the differences of meat quality traits related to the lipid metabolism (MQT-LM) in association with gut microbiota involving in lipid metabolism have not been well explored between Angus cattle (AG) and Xinjiang brown cattle (BC). Ten heads of 18-month-old uncastrated male AG and BC (5 in each group) raised under the identical conditions were selected to test MQT-LM, i.e., the backfat thickness (BFT), the intramuscular fat (IMF) content, the intramuscular adipocyte areas (IAA), the eye muscle area (EMA), the muscle fiber sectional area (MFSA) and the muscle shear force after sacrifice. The gut microbiota composition and structure with its metabolic function were analyzed by means of metagenomics and metabolomics with rectal feces. The correlation of MQT-LM with the gut microbiota and its metabolites was analyzed. In comparison with AG, BC had significant lower EMA, IMF content and IAA but higher BFT and MFSA. Chao1 and ACE indexes of α-diversity were lower. ß-diversity between AG and BC were significantly different. The relative abundance of Bacteroidetes, Prevotella and Blautia and Prevotella copri, Blautia wexlerae, and Ruminococcus gnavus was lower. The lipid metabolism related metabolites, i.e., succinate, oxoglutaric acid, L-aspartic acid and L-glutamic acid were lower, while GABA, L-asparagine and fumaric acid were higher. IMF was positively correlated with Prevotella copri, Blautia wexlerae and Ruminococcus gnavus, and the metabolites succinate, oxoglutaric acid, L-aspartic acid and L-glutamic acid, while negatively with GABA, L-asparagine and fumaric acid. BFT was negatively correlated with Blautia wexlerae and the metabolites succinate, L-aspartic acid and L-glutamic acid, while positively with GABA, L-asparagine and fumaric acid. Prevotella Copri, Blautia wexlerae, and Ruminococcus gnavus was all positively correlated with succinate, oxoglutaric acid, while negatively with L-asparagine and fumaric acid. In conclusion, Prevotella copri, Prevotella intermedia, Blautia wexlerae, and Ruminococcus gnavus may serve as the potential differentiated bacterial species in association with MQT-LM via their metabolites of oxoglutaric acid, succinate, fumaric acid, L-aspartic acid, L-asparagine, L-glutamic acid and GABA between BC and AG.

WNT signaling modulates chemoresistance to temozolomide in p53-mutant glioblastoma multiforme.

Glioblastoma multiforme (GBM) has been characterized by the high incidence, therapy tolerance and relapse. The molecular events controlling GBM resistant to chemotherapy temozolomide (TMZ) remain to be elusive. Here, we identified WNT signaling was amplified by TMZ and mediated drug response in GBM. We found O6-methylguanine DNA methyltransferase (MGMT) was redundant to WNT-mediated chemoresistance, which was highly associated with p53 mutation status. In GBM with p53 mutation, loss of function of p53 downregulated miR-34a expression, which represses transcription of WNT ligand 6 (WNT6) by directly binding to 3' UTR of WNT6 mRNA, leading to activation of WNT signaling, and the eventual WNT-mediated chemoresistance to TMZ. Combined treatment of TMZ with WNT inhibitor or miR34a mimic induced drug sensitivity of p53-mutant GBM cells and extended survival in xenograft mice in vivo. Our findings provide insight into understanding the molecular mechanism of GBM chemoresistance to TMZ and facilitating to develop novel treatment strategy to combat p53-mutant GBM by targeting miR-34a/WNT6 axis.

Carboplatin activates the cGAS-STING pathway by upregulating the TREX-1 (three prime repair exonuclease 1) expression in human melanoma.

Human melanoma is a highly aggressive type of cancer, causing significant mortalities despite the advances in treatment. Carboplatin is a cisplatin analog necessary for the treatment of various cancers and can also be used to treat human melanoma. We assessed the effects and mechanisms leading to inhibited proliferation and induced apoptosis of human melanoma after carboplatin therapy in vitro and in vivo. TREX1, cGAS/STING, and apoptotic protein expressions were determined through RT-qPCR and western blot assays. Cell proliferation was validated through MTT assays. The study used SK-MEL-1 and SK-HEP-1 tumor cell line inoculations along with carboplatin in nude mice to validate the results. The TREX1 levels were down-regulated in human melanoma cell lines. TREX1 overexpression-induced apoptosis and decreased proliferation in the human melanoma cell lines. TREX1 overexpression also activated the cGAS/STING pathway to induce apoptosis and decrease cell growth. Carboplatin activated TREX1, induced apoptosis, and decreased proliferation in the human melanoma cancerous cell lines. Finally, carboplatin reduced the in-vivo tumor size and weight. In conclusion, the study revealed that carboplatin activated TREX1 and cGAS/STING pathways to upregulate apoptosis. The work also provides in vitro and in vivo evidence to understand the effects of TREX overexpression on tumor suppression. Targeting of TREX1/cGAS/STING pathway could be an effective therapeutic alternative to human melanoma.

Changes in prevalence of nosocomial infection pre- and post-COVID-19 pandemic from a tertiary Hospital in China.

BACKGROUND: Nosocomial infections (NIs) are an important cause of mortality, and increasing evidence reveals that the prevalence of NIs can be reduced through effective prevention and control measures. The aim of this study was to investigate the impact of the prevention and control measures for the COVID-19 pandemic on NIs. METHODS: A retrospective study was conducted to analyze the prevalence of NIs before and after COVID-19 pandemic for 6 months in the Children's Hospital of Soochow University. RESULTS: A total of 39,914 patients in 2019 and 34,645 patients in 2020 were admitted to the hospital during the study. There were 1.39% (481/34645) of patients with NIs in 2020, which was significantly lower than the 2.56% (1021/39914) of patients in 2019. The rate of critical and fatal cases was also decreased. In addition, the rate of appropriate handwashing, the number of protective gloves and aprons used per person and the number of healthcare staff per patients were significantly increased. Except for the ICU, the prevalence of nosocomial infection in most departments decreased from 2019 to 2020. Regarding the source of infections, a significant reduction was mainly observed in respiratory (0.99% vs 0.42%, p = 0.000) and digestive tract (0.63% vs 0.14%, p = 0.000). The microorganism analysis of respiratory infections indicated an obvious decline in acinetobacters and fungi. The most significant decline of pathogens in gastrointestinal infections was observed for rotavirus. The comparison of catheter-related nosocomial infections between 2019 and 2020 did not show significant differences. CONCLUSIONS: The prevention and control measures for the COVID-19 pandemic have reduced the nosocomial infection in almost all departments, except the ICU, mainly regarding respiratory, gastrointestinal, and oral infections, while catheter-related infections did not show any differences.