Clinical and Molecular Characteristics of Patients with Bloodstream Infections Caused by KPC and NDM Co-Producing Carbapenem-Resistant Klebsiella pneumoniae.

Purpose: Klebsiella pneumoniae carbapenemase (KPC) and New Delhi metallo-ß-lactamase (NDM) co-producing carbapenem-resistant Klebsiella pneumoniae (KPC-NDM-CRKP) isolates have been increasingly reported worldwide but have not yet been systematically studied. Thus, we have conducted a study to compare the risk factors, molecular characteristics, and mortality involved in clinical bloodstream infections (BSIs) caused by KPC-NDM-CRKP and KPC-CRKP strains. Methods: A retrospective study was conducted on 231 patients with BSIs caused by CRKP at Jinling Hospital in China from January 2020 to December 2022. Antimicrobial susceptibility testing, carbapenemase genes detection and whole-genome sequencing were performed subsequently. Results: Overall, 231 patients were included in this study: 25 patients with KPC-NDM-CRKP BSIs and 206 patients with KPC-CRKP BSIs. Multivariate analysis implicated ICU-acquired BSI, surgery within 30 days, and longer stay of hospitalization prior to CRKP isolation as independent risk factors for KPC-NDM-CRKP BSIs. The 30-day mortality rate of the KPC-NDM-CRKP BSIs group was 56% (14/25) compared with 32.5% (67/206) in the KPC-CRKP BSIs control group (P = 0.02). The ICU-acquired BSIs, APACHE II score at BSI onset, and BSIs caused by KPC-NDM-CRKP were independent predictors for 30-day mortality in patients with CRKP bacteremia. The most prevalent ST in KPC-NDM-CRKP isolates was ST11 (23/25, 92%), followed by ST15 (2/25, 8%). Conclusion: In patients with CRKP BSIs, KPC-NDM-CRKP was associated with an excess of mortality. The likelihood that KPC-NDM-CRKP will become the next "superbug" highlights the significance of epidemiologic surveillance and clinical awareness of this pathogen.

The epigenetic regulators EP300/CREBBP represent promising therapeutic targets in MLL-rearranged acute myeloid leukemia.

Acute myeloid leukemia (AML) with mixed-lineage leukemia (MLL) gene rearrangements (MLL-r) is an aggressive subtype of blood cancer with dismal prognosis, underscoring the urgent need for novel therapeutic strategies. E1A-binding protein (EP300) and CREB-binding protein (CREBBP) function as essential transcriptional coactivators and acetyltransferases, governing leukemogenesis through diverse mechanisms. Targeting EP300/CREBBP holds great promise for treating leukemia with some certain cytogenetic abnormalities. Here, we demonstrated that EP300 and CREBBP are core epigenetic regulators in the pathogenesis of MLL-r AML through assaying the transposase-accessible chromatin with high-throughput sequencing (ATAC-seq). Knocking-out EP300/CREBBP and inhibitor (A-485) treatment depressed the MLL-r cells proliferation, while the MLL wild-type cells remained uninfluenced. We found that the CDK4/RB/E2F axis was downregulated specifically in MLL-r AML cell after A-485 treatment by RNA-seq, western blot and cut-tag analyses. EP300/CREBBP inhibitor selectively exerted potent anti-leukemia activity through blocking the MLL-r-BET complex binding to H3K27Ac modification on critical genes loci, distinct from global histone acetylation. Collectively, our study identified EP300/CREBBP as a critical epigenetic driver of MLL-r leukemia and validated their therapeutic potential through targeting inhibition, offering a promising avenue for improving clinical outcomes in this aggressive leukemia.

The interplay of growth-regulating factor 5 and BZR1 in coregulating chlorophyll degradation in poplar.

Chlorophyll (Chl) is essential for plants to carry out photosynthesis, growth and development processes. Growth-regulating factors (GRFs) play a vital role in regulating Chl degradation in plants. However, the molecular mechanism by which GRF5 regulates Chl degradation in poplar remains unknown. Here we found that overexpression of PpnGRF5-1 increased Chl content in leaves and promoted chloroplast development in poplar. Overexpression of PpnGRF5-1 in poplar delayed Chl degradation induced by external factors, such as hormones, darkness and salt stress. PpnGRF5-1 responded to brassinosteroid (BR) signalling during BR-induced Chl degradation and reduced the expression levels of Chl degradation and senescence-related genes. PpnGRF5-1 inhibited the expression of Chl b reductases PagNYC1 and PagNOL. PpnGRF5-1 could interact with PagBZR1 in the nucleus. PagBZR1 also inhibited the expression of PagNYC1. In addition, we found that the protein-protein interaction between PagBZR1 and PpnGRF5-1 enhanced the inhibitory effect of PpnGRF5-1 on the Chl b reductases PagNYC1 and PagNOL. BZR1 and GRF5-1 were upregulated, and NOL and NYC1 were downregulated in triploid poplars compared to diploids. This study revealed a new mechanism by which PpnGRF5-1 regulates Chl degradation in poplars and lays the foundation for comprehensively analysing the molecular mechanism of Chl metabolism in triploid poplars.

Dapagliflozin Improves Angiogenesis after Hindlimb Ischemia through the PI3K-Akt-eNOS Pathway.

Recently, the vascular protective effect of anti-diabetic agents has been receiving much attention. Sodium glucose cotransporter 2 (SGLT2) inhibitors had demonstrated reductions in cardiovascular (CV) events. However, the therapeutic effect of dapagliflozin on angiogenesis in peripheral arterial disease was unclear. This study aimed to explore the effect and mechanism of dapagliflozin on angiogenesis after hindlimb ischemia. We first evaluated the effect of dapagliflozin on post-ischemic angiogenesis in the hindlimbs of rats. Laser doppler imaging was used to detect the hindlimb blood perfusion. In addition, we used immunohistochemistry to detect the density of new capillaries after ischemia. The relevant signaling pathways of dapagliflozin affecting post-ischemic angiogenesis were screened through phosphoproteomic detection, and then the mechanism of dapagliflozin affecting post-ischemic angiogenesis was verified at the level of human umbilical vein endothelial cells (HUVECs). After subjection to excision of the left femoral artery, all rats were randomly distributed into two groups: the dapagliflozin group (left femoral artery resection, receiving intragastric feeding with dapagliflozin (1 mg/kg/d), for 21 consecutive days) and the model group, that is, the positive control group (left femoral artery resection, receiving intragastric feeding with citric acid-sodium citrate buffer solution (1 mg/kg/d), for 21 consecutive days). In addition, the control group, that is the negative control group (without left femoral artery resection, receiving intragastric feeding with citric acid-sodium citrate buffer solution (1 mg/kg/d), for 21 consecutive days) was added. At day 21 post-surgery, the dapagliflozin-treatment group had the greatest blood perfusion, accompanied by elevated capillary density. The results showed that dapagliflozin could promote angiogenesis after hindlimb ischemia. Then, the ischemic hindlimb adductor-muscle tissue samples from three rats of model group and dapagliflozin group were taken for phosphoproteomic testing. The results showed that the PI3K-Akt-eNOS signaling pathway was closely related to the effect of dapagliflozin on post-ischemic angiogenesis. Our study intended to verify this mechanism from the perspective of endothelial cells. In vitro, dapagliflozin enhanced the tube formation, migration, and proliferation of HUVECs under ischemic and hypoxic conditions. Additionally, the dapagliflozin administration upregulated the expression of angiogenic factors phosphorylated Akt (p-Akt) and phosphorylated endothelial nitric oxide synthase (p-eNOS), as well as vascular endothelial growth factor A (VEGFA), both in vivo and in vitro. These benefits could be blocked by either phosphoinositide 3-kinase (PI3K) or eNOS inhibitor. dapagliflozin could promote angiogenesis after ischemia. This effect might be achieved by promoting the activation of the PI3K-Akt-eNOS signaling pathway. This study provided a new perspective, new ideas, and a theoretical basis for the treatment of peripheral arterial disease.

Nucleotides as new co-formers in co-amorphous systems: Enhanced dissolution rate, water solubility and physical stability.

Developing co-amorphous systems is an attractive strategy to improve the dissolution rate of poorly water-soluble drugs. Various co-formers have been investigated. However, previous studies revealed that it is a challenge to develop satisfied acidic co-formers, e.g., acidic amino acids showed much poorer co-former properties than neutral and basic amino acids. Only a few acidic co-formers have been reported, such as aspartic acid, glutamic acid, and some other organic acids. Thus, this study aims to explore the possibility of adenosine monophosphate and adenosine diphosphate used as acidic co-formers. Mebendazole, celecoxib and tadalafil were used as the model drugs. The drug-co-former co-amorphous systems were prepared via ball milling and confirmed using XRPD. The dissolution study suggested that the solubility and dissolution rate of the drug-co-formers systems were increased significantly compared to the corresponding crystalline and amorphous drugs. The stability study revealed that using the two nucleotides as co-formers enhanced the physical stability of pure amorphous drugs. Molecular interactions were observed in MEB-co-former and TAD-co-former systems and positively affected the pharmaceutical performance of the investigated co-amorphous systems. In conclusion, the two nucleotides could be promising potential acidic co-formers for co-amorphous systems.

Association analyses between the variants of SNAP25, SV2C and ST3GAL2 and the efficacy of botulinum toxin A in the treatment of the primary Meige syndrome.

Objective: Individual differences were observed in the clinical efficacy of Botulinum toxin A (BoNT-A) in the treatment of the primary Meige syndrome. Our study aimed to explore the potential associations between the clinical efficacy of BoNT-A in the treatment of the primary Meige syndrome and variants of SNAP25, SV2C and ST3GAL2, which are involving in the translocation of the BoNT-A in vivo. Methods: Patients with the primary Meige syndrome treated with BoNT-A were enrolled. Clinical efficacy was evaluated by the maximum improvement rate of motor symptoms and the duration of efficacy. Variants of SNAP25, SV2C and ST3GAL2 were obtained by Sanger sequencing. Another cohort diagnosed with primary cervical dystonia was also enrolled in the replication stage. Results: Among the 104 primary Meige syndrome patients, 80 patients (76.9%) had a good efficacy (the maximum improvement rate of motor symptoms ≥30%) and 24 (23. 1%) had a poor (the maximum improvement rate of motor symptoms <30%). As to the duration of efficacy, 52 patients (50.0%) had a long duration of efficacy (≥4 months), and 52 (50.0%) had a short (<4 months). In terms of primary Meige syndrome, SNAP25 rs6104571 was found associating with the maximum improvement rate of motor symptoms (Genotype: P = 0.02, OR = 0.26; Allele: P = 0.013, OR = 0.29), and SV2C rs31244 was found associating with the duration of efficacy (Genotype: P = 0.024, OR = 0.13; Allele: P = 0.012, OR = 0.13). Besides, we also conducted the association analyses between the variants and BoNT-A-related adverse reactions. Although, there was no statistical difference between the allele of SV2C rs31244 and BoNT-A-related adverse reactions, there was a trend (P = 0.077, OR = 2.56). In the replication stage, we included 39 patients with primary cervical dystonia to further expanding the samples' size. Among the 39 primary cervical dystonia patients, 25 patients (64.1%) had a good efficacy (the maximum improvement rate of motor symptoms ≥50%) and 14 (35.9%) had a poor (the maximum improvement rate of motor symptoms <50%). As to the duration of efficacy, 32 patients (82.1%) had a long duration of efficacy (≥6 months), and 7 (17.9%) had a short (<6 months). Integrating primary Meige syndrome and primary cervical dystonia, SV2C rs31244 was still found associating with the duration of efficacy (Genotype: P = 0.002, OR = 0. 23; Allele: P = 0.001, OR = 0. 25). Conclusion: In our study, SNAP25 rs6104571 was associated with the maximum improvement rate of motor symptoms in patients with primary Meige syndrome treated with BoNT-A, and patients carrying this variant had a lower improvement rate of motor symptoms. SV2C rs31244 was associated with duration of treatment in patients with primary Meige syndrome treated with BoNT-A and patients carrying this variant had a shorter duration of treatment. Patients with primary Meige syndrome carrying SV2C rs31244 G allele have an increase likelihood of BoNT-A-related adverse reactions. Involving 39 patients with primary cervical dystonia, the results further verify that SV2C rs31244 was associated with duration of treatment and patients carrying this variant had a shorter duration of treatment.

Prognosis and therapeutic significance of IGF-1R-related signaling pathway gene signature in glioma.

Background: Glioma is the most common cancer of the central nervous system with poor therapeutic response and clinical prognosis. Insulin-like growth factor 1 receptor (IGF-1R) signaling is implicated in tumor development and progression and induces apoptosis of cancer cells following functional inhibition. However, the relationship between the IGF-1R-related signaling pathway genes and glioma prognosis or immunotherapy/chemotherapy is poorly understood. Methods: LASSO-Cox regression was employed to develop a 16-gene risk signature in the TCGA-GBMLGG cohort, and all patients with glioma were divided into low-risk and high-risk subgroups. The relationships between the risk signature and the tumor immune microenvironment (TIME), immunotherapy response, and chemotherapy response were then analyzed. Immunohistochemistry was used to evaluate the HSP90B1 level in clinical glioma tissue. Results: The gene risk signature yielded superior predictive efficacy in prognosis (5-year area under the curve: 0.875) and can therefore serve as an independent prognostic indicator in patients with glioma. The high-risk subgroup exhibited abundant immune infltration and elevated immune checkpoint gene expression within the TIME. Subsequent analysis revealed that patients in the high-risk subgroup benefited more from chemotherapy. Immunohistochemical analysis confirmed that HSP90B1 was overexpressed in glioma, with significantly higher levels observed in glioblastoma than in astrocytoma or oligodendrocytoma. Conclusion: The newly identified 16-gene risk signature demonstrates a robust predictive capacity for glioma prognosis and plays a pivotal role in the TIME, thereby offering valuable insights for the exploration of novel biomarkers and targeted therapeutics.

Ferrous Selenide Stabilized Black Phosphorus Heterojunction Sonosensitizer for MR Imaging-Guided Sonodynamic Therapy of Bladder Cancer.

It is urgent to develop an alternative dynamic therapy-based method to overcome the limited efficacy of traditional therapy methods for bladder cancer and the damage caused to patients. Sonodynamic therapy (SDT) has the advantages of high tissue penetration, high spatiotemporal selectivity, and being non-invasive, representing an emerging method for eradicating deep solid tumors. However, the effectiveness of SDT is often hindered by the inefficient production of reactive oxygen species and the nondegradability of the sonosensitizer. To improve the anti-tumor effect of SDT on bladder cancer, herein, a BP-based heterojunction sonosensitizer (BFeSe2) was synthesized by anchoring FeSe2 onto BP via P-Se bonding to enhance the stability and the effect of SDT. As a result, BFeSe2 showed great cytotoxicity to bladder cancer cells under ultrasound (US) irradiation. BFeSe2 led to a notable inhibition effect on tumor growth in subcutaneous tumor models and orthotopic tumor models under US irradiation. In addition, BFeSe2 could also enhance T2-weighted magnetic resonance imaging (MRI) to achieve monitoring and guide treatment of bladder cancer. In general, BFeSe2 sonosensitizer integrates MRI functions for precise treatment, promising great clinical potential for the theranostics of bladder cancer.

The quantitative parameters based on marrow metabolism derived from synthetic MRI: A pilot study of prognostic value in participants with newly diagnosed multiple myeloma.

BACKGROUND: The value of SyMRI-derived parameters from lumbar marrow for predicting early treatment response and optimizing the risk stratification of the Revised International Staging System (R-ISS) in participants with multiple myeloma (MM) is unknown. METHODS: We prospectively enrolled participants with newly diagnosed MM before treatment. The SyMRI of lumbar marrow was used to calculate T1, T2, and PD values and the clinical features were collected. All participants were divided into good response (≥VGPR) and poor response (

Synapse-Related Serum and P300 Biomarkers Predict the Occurrence of Mild Cognitive Impairment in Depression.

Background: Cognitive impairment is one of the common concomitant symptoms of depression. The aims of the present study were to predict the occurrence of mild cognitive impairment (MCI) in patients with depression. Methods: In this study, 217 patients with depression were recruited. Demographic data, serum indices and ERP indices from all participants were collected in the baseline period. The participants were followed for one year, and data from 200 patients were included in final analysis. Patients with depression were divided into those with MCI group (DWM group; n=145) and those without MCI (DWOM group; n=55). Data from the DWM group and the DWOM group were used to construct a logistic regression model, and a receiver operating characteristic (ROC) curve was drawn. Another 72 patients were used to validate the accuracy of our model. Results: Compared with DWOM individuals, DWM individuals were more likely to live alone (P<0.05), had lower baseline serum levels of brain-derived neurotrophic factor (BDNF), fibroblast growth factor 2 (FGF2), and fibroblast growth factor 22 (FGF22) (P<0.05), and exhibited higher baseline latencies of P300, mismatch negativity (MMN), and N200 (P<0.05). Baseline serum BDNF and FGF22 levels, along with the P300 latency, were selected to construct the regression model using logistic regression. The regression equation was [Formula: see text], and the combination of the 3 indices yielded an area under the ROC curve (AUC) of 0.790 and a predictive accuracy of 0.806. Conclusion: The logistic regression model and ROC curves based on serum BDNF and FGF22 levels and the P300 latency could provide a more effective means to predict the occurrence of MCI in patients with depression.

Mechanism of Porphyra Yezoensis Polysaccharides in Inhibiting Hyperoxalate-Induced Renal Injury and Crystal Deposition.

Oxidative damage to the kidneys is a primary factor in the occurrence of kidney stones. This study explores the inhibitory effect of Porphyra yezoensis polysaccharides (PYP) on oxalate-induced renal injury by detecting levels of oxidative damage, expression of adhesion molecules, and damage to intracellular organelles and revealed the molecular mechanism by molecular biology methods. Additionally, we validated the role of PYP in vivo using a crystallization model of hyperoxalate-induced rats. PYP effectively scavenged the overproduction of reactive oxygen species (ROS) in HK-2 cells, inhibited the adhesion of calcium oxalate (CaOx) crystals on the cell surface, unblocked the cell cycle, restored the depolarization of the mitochondrial membrane potential, and inhibited cell death. PYP upregulated the expression of antioxidant proteins, including Nrf2, HO-1, SOD, and CAT, while decreasing the expression of Keap-1, thereby activating the Keap1/Nrf2 signaling pathway. PYP inhibited CaOx deposition in renal tubules in the rat crystallization model, significantly reduced high oxalate-induced renal injury, decreased the levels of the cell surface adhesion proteins, improved renal function in rats, and ultimately inhibited the formation of kidney stones. Therefore, PYP, which has crystallization inhibition and antioxidant properties, may be a therapeutic option for the treatment of kidney stones.

Development of a whole spinal MRI-based tumor burden scoring method in participants with multiple myeloma: a pilot study of prognostic significance.

The aim of the study was to develop a new whole spinal MRI-based tumor burden scoring method in participants with newly diagnosed multiple myeloma (MM) and to explore its prognostic significance. We prospectively recruited participants with newly diagnosed MM; performed whole spinal MRI (sagittal FSE T1WI, sagittal IDEAL T2WI, and axial FLAIR T2WI) on them; and collected their clinical data, early treatment response, progression-free survival (PFS), and overall survival (OS). We developed a new tumor burden scoring method according to the extent of bone marrow infiltration in five MRI patterns. All participants were divided into good response and poor response groups after four treatment cycles. Univariate, multivariate analyses, and ROC were used to determine the performance of independent predictors. Thresholds for PFS and OS were calculated using X-tile, and their prognostic significance were assessed by Kaplan-Meier. The Kruskal-Wallis H test was used to compare the differences of tumor burden score between the revised International Staging System (R-ISS) stages. The new tumor burden scoring method was used in 62 participants (median score, 12; range, 0-18). The tumor burden score (OR 1.266, p = 0.002) was an independent predictor of poor response and the AUC was 0.838. Higher tumor burden scores were associated with shorter PFS (p = 0.002) and OS (p = 0.011). The tumor burden score was higher in R-ISS-III than in R-ISS-I and R-ISS-II (p = 0.016 and p = 0.006, respectively). The tumor burden score was an excellent predictor of prognosis and may serve as a supplemental marker for R-ISS.

Ultra-conformal epidermal antenna for multifunctional motion artifact-free sensing and point-of-care monitoring.

Accurate acquisition of physiological and physical information from human tissue is essential for health monitoring, disease prevention and treatment. The existing antennas with traditional rigid or flexible substrates are susceptible to motion artifacts in wearable applications due to the miniaturization limitation and lack of proper adhesion and conformal interfaces with the skin. Recent advances in wearable radio frequency (RF) bioelectronics directly drawn on the skin are a promising solution for future skin-interfaced devices. Herein, we present a first-of-its kind epidermal antenna architecture with skin as the antenna substrate, which is ultra-low profile, ultra-conformal, ultra-compact, and simple fabrication without specialized equipment. The radiation unit and ground of antenna are drawn directly on the skin with the strong adhesion and ultra conformality. Therefore, this RF device is highly adaptable to motion. As a proof-of- feasibility, epidermal antenna can be freely drawn on demand at different locations on the skin for the development of temperature sensor, skin hydration sensor, strain sensor, glucose sensor and other devices. An epidermal antenna-based temperature sensor can offer accurate and real-time monitoring of human body temperature changes in the ultra-wideband (UWB) range. The results during the monitoring of hydration level with and without stretching show that the epidermal antenna drawn on the skin is motion artifact-free. We also designed an epidermal antenna array employing a horseshoe-shaped configuration for the precise identification of various gestures. In addition, the non-invasive blood glucose level (BGL) monitoring results during the in-vivo experiments report high correlation between the epidermal antenna responses and BGLs, without any time hysteresis. After the prediction of BGL by BP network, all the predicted BGL values are fallen 100% into the clinically acceptable zones. Together, these results show that epidermal antenna offers a promising new approach for biosensing platform.

Distribution and antimicrobial resistance patterns of urinary pathogens in preoperative midstream urine cultures from Chinese patients with urinary calculi: a meta-analysis.

BACKGROUND AND OBJECTIVE: This study comprehensively evaluates the distribution patterns and antimicrobial resistance profiles of urinary pathogens in Preoperative midstream urine cultures collected from patients with urinary calculi in China over the last two decades. METHODS: A cross-sectional analysis of 41 studies was conducted. A systematic search across various databases, including Wanfang Data, CNKI, SinoMed, Embase, PubMed, and Web of Science, was carried out, covering the time period from 2002 to 2022. Using R 4.2.1 software, a meta-analysis was performed to assess heterogeneity using Cochran's Q test and the I2 statistic. RESULTS: In the analysis of preoperative midstream urine cultures from Chinese patients with urinary calculi, gram-negative bacteria dominated at 69%, with Escherichia coli (43%), Klebsiella pneumoniae (8%), Proteus mirabilis (6%), Pseudomonas aeruginosa (5%), Acinetobacter baumannii (3%), and Enterobacter cloacae (4%) being prominent. Gram-positive organisms included Enterococcus faecalis (9%), Enterococcus faecium (5%), and Staphylococcus aureus (4%). Over time, proportions of Proteus mirabilis, Enterococcus faecalis, and Staphylococcus aureus decreased, while Klebsiella pneumoniae and Pseudomonas aeruginosa increased. Notably, Escherichia coli proportion reduced from 37 to 33% within the last two decades. Antimicrobial resistance analysis indicated declining resistance in E. coli (e.g., co-trimoxazole from 73 to 55%, gentamicin from 64 to 40%), but rising resistance in piperacillin and cefotaxime (34-60%). Enterococcus faecalis exhibited increasing resistance to ampicillin (5-69%), gentamicin (59-94%), and tetracycline (77-89%) over time, while resistance to levofloxacin and ciprofloxacin notably decreased (72-16% and 49-8%, respectively). CONCLUSION: Over the past two decades, the proportion of gram-negative bacteria was declined, while the proportion of gram-positive bacteria increased. Escherichia coli remained the most common pathogen in the urine culture of patients with urinary calculi in China and the resistance of Escherichia coli to commonly used antibiotics increased. Clinicians should select appropriate antibiotics according to the results of urine culture and drug sensitivity test to reduce the occurrence of antibiotic resistance.

Predicting the status of lymphovascular space invasion using quantitative parameters from synthetic MRI in cervical squamous cell carcinoma without lymphatic metastasis.

Purpose: To investigate the value of quantitative longitudinal relaxation time (T1), transverse relaxation time (T2), and proton density (PD) maps derived from synthetic magnetic resonance imaging (MRI) for evaluating the status of lymphovascular space invasion (LVSI) in cervical squamous cell carcinoma (CSCC) without lymph node metastasis (LNM). Material and methods: Patients with suspected cervical cancer who visited our hospital from May 2020 to March 2023 were collected. All patients underwent preoperative MRI, including routine sequences and synthetic MRI. Patients with pathologically confirmed CSCC without lymphatic metastasis were included in this study. The subjects were divided into negative- and positive-LVSI groups based on the status of LVSI. Quantitative parameters of T1, T2, and PD values derived from synthetic MRI were compared between the two groups using independent samples t-test. Receiver operating characteristic curves were used to determine the diagnostic efficacy of the parameters. Results: 59 patients were enrolled in this study and were classified as positive (n = 32) and negative LVSI groups (n = 27). T1 and T2 values showed significant differences in differentiating negative-LVSI from positive-LVSI CSCC (1307.39 ± 122.02 vs. 1193.03 ± 107.86, P<0.0001; 88.42 ± 7.24 vs. 80.99 ± 5.50, P<0.0001, respectively). The area under the curve (AUC) for T1, T2 values and a combination of T1 and T2 values were 0.756, 0.799, 0.834 respectively, and there is no statistically significant difference in the diagnostic efficacy between individual and combined diagnosis of each parameter. Conclusions: Quantitative parameters derived from synthetic MRI can be used to evaluate the LVSI status in patients with CSCC without LNM.

Identification of SV2C and DENR as Key Biomarkers for Parkinson's Disease Based on Bioinformatics, Machine Learning, and Experimental Verification.

The objective of this study is to investigate the potential biomarkers and therapeutic target genes for Parkinson's disease (PD). We analyzed four datasets (GSE8397, GSE20292, GSE20163, GSE20164) from the Gene Expression Omnibus database. We employed weighted gene co-expression network analysis and differential expression analysis to select genes and perform functional analysis. We applied three algorithms, namely, random forest, support vector machine recursive feature elimination, and least absolute shrinkage and selection operator, to identify hub genes, perform functional analysis, and assess their clinical diagnostic potential using receiver operating characteristic (ROC) curve analysis. We employed the xCell website to evaluate differences in the composition patterns of immune cells in the GEO datasets. We also collected serum samples from PD patients and established PD cell model to validate the expression of hub genes using enzyme-linked immunosorbent assay and quantitative real-time polymerase chain reaction. Our findings identified SV2C and DENR as two hub genes for PD and decreased in PD brain tissue compared with controls. ROC analysis showed effectively value of SV2C and DENR to diagnose PD, and they were downregulated in the serum of PD patients and cell model. Functional analysis revealed that dopamine vesicle transport and synaptic vesicle recycling are crucial pathways in PD. Besides, the differences in the composition of immune cells, especially basophils and T cells, were discovered between PD and controls. In summary, our study identifies SV2C and DENR as potential biomarkers for diagnosing PD and provides a new perspective for exploring the molecular mechanisms of PD.

Histone deacetylase 6 suppression of renal tubular epithelial cell promotes interstitial mineral deposition via alpha-tubulin acetylation.

Randall's plaque (RP) is derived from interstitial mineral deposition and is highly prevalent in renal calcium oxalate (CaOx) stone disease, which is predictive of recurrence. This study shows that histone deacetylase 6 (HDAC6) levels are suppressed in renal tubular epithelial cells in RP samples, in kidney tissues of hyperoxaluria rats, and in hyper-oxalate-treated or mineralized cultured renal tubular epithelial (MDCK) cells in vitro. Mineral deposition in MDCK cells was exacerbated by HDAC6 inhibition but alleviated by HDAC6 overexpression. Surprisingly, the expression of some osteogenic-associated proteins, were not increased along with the increasing of mineral deposition, and result of single-cell RNA sequencing of renal papillae samples revealed that epithelial cells possess lower calcific activity, suggesting that osteogenic-transdifferentiation may not have actually occurred in tubular epithelial cells despite mineral deposition. The initial mineral depositions facilitated by HDAC6 inhibitor were localized in extracellular dome rather than inside the cells, moreover, suppression of HDAC6 significantly increased the calcium content of co-cultured renal interstitial fibroblasts (NRK49F) and enhanced mineral deposition of indirectly co-cultured NRK49F cells, suggesting that HDAC6 may influence trans-MDCK monolayer secretion of mineral. Further experiments revealed that this regulatory role was partially alpha-tubulinLys40 acetylation dependent. Collectively, these results suggest that hyper-oxalate exposure led to HDAC6 suppression in renal tubular epithelial cells, which may contribute to interstitial mineral deposition by promoting alpha-tubulinLys40 acetylation. Therapeutic agents that influence HDAC6 activity may be beneficial in preventing RP and CaOx stone formation.