Combined effects of cadmium and sulfamethoxazole on Eisenia fetida: Insights into accumulation, subcellular partitioning, biomarkers and toxicological responses.

Cadmium (Cd) and sulfamethoxazole (SMX) frequently coexist in farmlands, yet their synergistic toxicological impacts on terrestrial invertebrates remain unexplored. In this study, earthworms were exposed to artificial soils percolated with Cd (5 mg/kg), SMX (5 mg/kg) or combination of them for 7 days, followed by a 12-day elimination phase in uncontaminated soil. The uptake of Cd and SMX by the earthworms, along with their subcellular distribution, was meticulously analyzed. Additionally, a suite of biomarkers-including superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), and weight loss-were evaluated to assess the health status of the earthworms and the toxicological effects of the Cd and SMX mixture. Notably, the cotreatment with Cd and SMX resulted in a significantly higher weight loss in Eisenia fetida (41.25 %) compared to exposure to Cd alone (26.84 %). Moreover, the cotreatment group exhibited substantially higher concentrations of Cd in the total internal body, fraction C (cytosol), and fraction E (tissue fragments and cell membranes) in Eisenia fetida compared to Cd alone counterparts. The combined exposure also significantly elevated the SMX levels in the total body and fraction C compared with the SMX-only treated earthworms. Additionally, Eisenia fetida subjected to the combined treatment showed markedly increased activities of SOD, CAT, and MDA compared to those treated with Cd alone. The effect addition indices (EAIs), ranging from 1.00 to 2.23, unequivocally demonstrated a synergistic effect of the combined treatments. Interestingly, relocating the earthworms to clean soil did not mitigate the observed adverse effects. These findings underscore the increased risk posed by the Cd-SMX complex to terrestrial invertebrates in agricultural areas.

Lymph node metastasis prediction and biological pathway associations underlying DCE-MRI deep learning radiomics in invasive breast cancer.

BACKGROUND: The relationship between the biological pathways related to deep learning radiomics (DLR) and lymph node metastasis (LNM) of breast cancer is still poorly understood. This study explored the value of DLR based on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in LNM of invasive breast cancer. It also analyzed the biological significance of DLR phenotype based on genomics. METHODS: Two cohorts from the Cancer Imaging Archive project were used, one as the training cohort (TCGA-Breast, n = 88) and one as the validation cohort (Breast-MRI-NACT Pilot, n = 57). Radiomics and deep learning features were extracted from preoperative DCE-MRI. After dual selection by principal components analysis (PCA) and relief methods, radiomics and deep learning models for predicting LNM were constructed by the random forest (RF) method. A post-fusion strategy was used to construct the DLR nomograms (DLRNs) for predicting LNM. The performance of the models was evaluated using the receiver operating characteristic (ROC) curve and Delong test. In the training cohort, transcriptome data were downloaded from the UCSC Xena online database, and biological pathways related to the DLR phenotypes were identified. Finally, hub genes were identified to obtain DLR gene expression (RadDeepGene) scores. RESULTS: DLRNs were based on area under curve (AUC) evaluation (training cohort, AUC = 0.98; validation cohort, AUC = 0.87), which were higher than single radiomics models or GoogLeNet models. The Delong test (radiomics model, P = 0.04; GoogLeNet model, P = 0.01) also validated the above results in the training cohorts, but they were not statistically significant in the validation cohort. The GoogLeNet phenotypes were related to multiple classical tumor signaling pathways, characterizing the biological significance of immune response, signal transduction, and cell death. In all, 20 genes related to GoogLeNet phenotypes were identified, and the RadDeepGene score represented a high risk of LNM (odd ratio = 164.00, P < 0.001). CONCLUSIONS: DLRNs combining radiomics and deep learning features of DCE-MRI images improved the preoperative prediction of LNM in breast cancer, and the potential biological characteristics of DLRN were identified through genomics.

Engineered Exosomes with ATF5-Modified mRNA Loaded in Injectable Thermogels Alleviate Osteoarthritis by Targeting the Mitochondrial Unfolded Protein Response.

Osteoarthritis (OA) progression is highly associated with chondrocyte mitochondrial dysfunction and disorders of catabolism and anabolism of the extracellular matrix (ECM) in the articular cartilage. The mitochondrial unfolded protein response (UPRmt), which is an integral component of the mitochondrial quality control (MQC) system, is essential for maintaining chondrocyte homeostasis. We successfully validated the pivotal role of activating transcription factor 5 (ATF5) in upregulating the UPRmt, mitigating IL-1ß-induced inflammation and mitochondrial dysfunction, and promoting balanced metabolism in articular cartilage ECM, proving its potential as a promising therapeutic target for OA. Modified mRNAs (modRNAs) have emerged as novel and efficient gene delivery vectors for nucleic acid therapeutic approaches. In this study, we combined Atf5-modRNA (modAtf5) with engineered exosomes derived from bone mesenchymal stem cells (ExmodAtf5) to exert cytoprotective effects on chondrocytes in articular cartilage via Atf5. However, the rapid localized metabolization of ExmodAtf5 limits its application. PLGA-PEG-PLGA (Gel), an injectable thermosensitive hydrogel, was used as a carrier of ExmodAtf5 (Gel@ExmodAtf5) to achieve a sustained release of ExmodAtf5. In vitro and in vivo, the use of Gel@ExmodAtf5 was shown to be a highly effective strategy for OA treatment. The in vivo therapeutic effect of Gel@ExmodAtf5 was evidenced by the preservation of the intact cartilage surface, low OARSI scores, fewer osteophytes, and mild subchondral bone sclerosis and cystic degeneration. Consequently, the combination of ExmodAtf5 and PLGA-PEG-PLGA could significantly enhance the therapeutic efficacy and prolong the exosome release. In addition, the mitochondrial protease ClpP enhanced chondrocyte autophagy by modulating the mTOR/Ulk1 pathway. As a result of our research, Gel@ExmodAtf5 can be considered to be effective at alleviating the progression of OA.

Relationship between chemokine/chemokine receptor and glioma prognosis and outcomes: Systematic review and meta-analysis.

BACKGROUND: Glioma is a primary tumor originating from the central nervous system, and despite ongoing efforts to improve treatment, its overall survival rate remains low. There are a limited number of reports regarding the clinical grading, prognostic impact, and utility of chemokines. Therefore, conducting a meta-analysis is necessary to obtain convincing and conclusive results. METHODS: A comprehensive literature search was conducted using various databases, including PubMed, Web of Science, The Cochrane Library, Embase, Ovid Medline, CNKI, Wanfang Database, VIP, and CBM. The search encompassed articles published from the inception of the databases until March 2024. The estimated odds ratio (ORs), standard mean difference (SMDs), and hazard ratio (HR) with their corresponding 95% confidence intervals (95% CI) were calculated to assess the predictive value of chemokine and receptor levels in glioma risk. Additionally, heterogeneity tests and bias tests were performed to evaluate the reliability of the findings. RESULTS: This meta-analysis included a total of 36 studies, involving 2,480 patients diagnosed with glioma. The results revealed a significant association between the expression levels of CXCR4 (n = 8; OR = 22.28; 95 % CI = 11.47-43.30; p = 0.000), CXCL12 (n = 4; OR = 10.69; 95 % CI = 7.03-16.24; p = 0.000), CCL2 (n = 6; SMD = -0.83; 95 % CI = -0.98--0.67; p = 0.000), CXCL8 (n = 3; SMD = 0.75; 95 % CI = 0.47-1.04; p = 0.000), CXCR7 (n = 3; OR = 20.66; 95 % CI = 10.20-41.82; p = 0.000), CXCL10 (n = 2; SMD = 3.27; 95 % CI = 2.91-3.62; p = 0.000) and the risk of glioma. Additionally, a significant correlation was observed between CXCR4 (n = 8; OR = 4.39; 95 % CI = 3.04-6.32; p = 0.000), (n = 6; SMD = 1.37; 95 % CI = 1.09-1.65; p = 0.000), CXCL12 (n = 6; OR = 6.30; 95 % CI = 3.87-10.25; p = 0.000), (n = 5; ES = 2.25; 95 % CI = 1.15-3.34; p = 0.041), CCL2 (n = 3; OR = 9.65; 95 % CI = 4.55-20.45; p = 0.000), (n = 4; SMD = -1.47; 95 % CI = -1.68--1.26; p = 0.000), and CCL18 (n = 3; SMD = 1.62; 95 % CI = 1.30-1.93; p = 0.000) expression levels and high-grade glioma (grades 3-4). Furthermore, CXCR4 (HR = 2.38, 95 % CI = 1.66-3.40; p = 0.000) exhibited a strong correlation with poor overall survival (OS) rates in glioma patients. CONCLUSION: The findings of this study showed a robust association between elevated levels of CXCR4, CXCL12, CCL2, CXCL8, CXCL10 and CXCR7 with a higher risk of glioma. Furthermore, the WHO grading system was validated by the strong correlation shown between higher expression of CXCR4, CXCL12, CCL2, and CCL18 and WHO high-grade gliomas (grades 3-4). Furthermore, the results of the meta-analysis suggested that CXCR4 might be a helpful biomarker for predicting the worse prognosis of glioma patients.

CD39+ tumor infiltrating T cells from colorectal cancers exhibit dysfunctional phenotype.

Recent studies revealed that CD39 was highly expressed in tumor-specific CD4+ tumor infiltrating lymphocytes (TILs). However, the divergent function of CD39+ T cells remains to be elucidated in colorectal cancer (CRC). In this study, T cells from CRC patients and tumor-bearing mice were isolated to evaluate the function of CD39 in T cells. We found that CD39 was elevated in intratumoral T cells from CRC patients, and negatively correlated with cytokine secretion capacity. T cell activation induced CD39 expression, and CD39+ T cells produced more IFN-γ in response to CRC tumor antigens. In addition, CD39+ T cells in the spleens of tumor-bearing mice exhibited a stronger anti-tumor activity in vitro than CD39- T cells, but there was no significant difference in the anti-tumor activities between CD39- TILs and CD39+ TILs. Moreover, we found that CD39+ T cells expressed higher checkpoint molecules and contained a higher proportion of Treg cells than CD39- T cells, suggesting that CD39+ T cells may be correlated with an immunosuppressive phenotype. And CD39 expression on T cells could convert pro-inflammatory eATP to immunosuppressive eADO. However, both T cells from the vaccinated-wild-type mice and CD39-/- mice could recognize and eliminate tumor cells in vitro, and adoptive transfer of these T cells resulted in tumor growth inhibition in tumor-bearing mice. In conclusion, our study revealed the divergent functions of CD39+ T cells, which were reactive to tumor antigen but exhibited a dysfunctional phenotype.

Combined microfocused ultrasound and delicate pulsed light for facial rejuvenation: A prospective, randomized, and split-face study.

OBJECTIVES: Public's interest in noninvasive skin rejuvenation treatments continues to grow. The advantage of combination therapy lies in that it can target different aspects of skin rejuvenation. This study aimed to assess the efficacy and safety of microfocused ultrasound (MFU) combined with delicate pulsed light (DPL) for facial rejuvenation. METHODS: Twenty-one patients with facial relaxation were enrolled. All patients received whole-face MFU treatment, and one side of the face was randomly assigned to receive DPL. MFU treatment was performed at Months 0 and 3, while DPL treatment was performed at Months 1, 2, 4, and 5. The length and angle of the nasolabial fold and perioral wrinkles, melanin index (MI), erythema index (EI), transepidermal water loss (TEWL), and follow-up time were recorded at Months 0, 3, and 6. Side effects were recorded during treatment and each follow-up visit. RESULTS: Twenty patients successfully completed the study. At the sixth month, the average length of perioral wrinkles and nasolabial folds on the combined side decreased by 11.5% (pwithin < 0.001) and 6.5% (pwithin = 0.011), while 8.3% (pwithin = 0.012) and 3.8% (pwithin = 0.02) on the MFU side. Compared with MFU treatment alone, the combined treatment also showed significant improvements in nasolabial fold angle (from 28.8 ± 3.4° to 32.7 ± 5.0°) and perioral wrinkle angle (from 39.3 ± 5.0° to 43.7 ± 5.1°). In addition, the combined side had greater benefits than the MFU side in improving MI, EI, TEWL, and skin elasticity (pbetween < 0.05). Except for one patient who withdrew due to increased skin sensitivity after MFU treatment, other subjects did not experience permanent or serious side effects. CONCLUSIONS: The combination of MFU and DPL for facial rejuvenation treatment is safe and effective. The combined treatment has better efficacy in skin firmness, and improving skin tone.

Hematoporphyrin monomethyl ether-mediated photodynamic therapy for acquired port-wine stain at lower extremity: Two case reports.

Two cases of acquired port-wine stain (APWS) at lower extremity were treated with hematoporphyrin monomethyl ether (HMME) and 532 nm LED green light-mediated photodynamic therapy (HMME-PDT). No serious adverse reactions were observed during or post-treatment period. Five-month follow-up showed significant reduction of red patches after a single HMME-PDT treatment in both cases.

Treatment of old femoral neck fractures in young adults with a medial buttress plate combined with three cannulated screws and iliac autograft: Surgical technique and preliminary results.

OBJECTIVES: Whether the application of MBP plus cannulated screws works for old femoral neck fractures (OFNF) is unknown. The purpose of this study is to present a case series of OFNF in young adults using calcar buttress plate and three cannulated screws with autologous iliac bone grafts. METHODS: We conducted a retrospective study of eleven young patients (6 males and 5 females) with femoral neck fractures who were treated with open reduction and internal fixation at a single center between 2013 and 2021. The subjects had trauma-to-surgery intervals longer than 3weeks and all were fixed with a calcar buttress plate combined with three cannulated screws, which were supplemented by autologous iliac bone grafts. RESULTS: All eleven cases achieved radiological union under the surgery technique, which occurred on average at 4.46±1.29months after surgery. Complications included femoral neck shortening in all cases, heterotopic ossification in three cases, and osteonecrosis of the femoral head in two cases. One patient with osteonecrosis of the femoral head received total hip arthroplasty. In follow-ups of 24-52months, the median Harris hip score was 81.64±15.39. CONCLUSIONS: The medial buttress plate in combination with three cannulated screws and iliac autograft may be a good choice for treating old femoral neck fractures in young adults. LEVEL OF EVIDENCE: IV, case series.

Regulation of NCOA4-mediated iron recycling ameliorates paraquat-induced lung injury by inhibiting ferroptosis.

Paraquat (PQ) is an irreplaceable insecticide in many countries for the advantage of fast-acting and broad-spectrum. However, PQ was classified as the most prevailing poisoning substance for suicide with no specific antidote. Therefore, it is imperative to develop more effective therapeutic agents for the treatment of PQ poisoning. In the present study, both the RNA-Seq and the application of various cell death inhibitors reflected that ferroptosis exerts a crucial regulatory role in PQ poisoning. Moreover, we found PQ strengthens lipid peroxidation as evidenced by different experimental approaches. Of note, pretreatment of iron chelation agent DFO could ameliorate the ferroptotic cell death and alleviate the ferroptosis-related events. Mechanistically, PQ treatment intensively impaired mitochondrial homeostasis, enhanced phosphorylation of AMPK, accelerated the autophagy flux and triggered the activation of Nuclear receptor coactivator 4-ferritin heavy chain (NCOA4-FTH) axis. Importantly, the activation of autophagy was observed prior to the degradation of ferritin, and inhibition of autophagy could inhibit the accumulation of iron caused by the ferritinophagy process. Genetic and pharmacological inhibition of ferritinophagy could alleviate the lethal oxidative events, and rescue the ferroptotic cell death. Excitingly, in the mouse models of PQ poisoning, both the administration of DFO and adeno-associated virus-mediated FTH overexpression significantly reduced PQ-induced ferroptosis and improved the pathological characteristics of pulmonary fibrosis. In summary, the current work provides an in-depth study on the mechanism of PQ intoxication, describes a framework for the further understanding of ferroptosis in PQ-associated biological processes, and demonstrates modulation of iron metabolism may act as a promising therapeutic agent for the management of PQ toxicity.

Biomimetic bright optotheranostics for metastasis monitoring and multimodal image-guided breast cancer therapeutics.

Nanoparticle formulations blending optical imaging contrast agents and therapeutics have been a cornerstone of preclinical theranostic applications. However, nanoparticle-based theranostics clinical translation faces challenges on reproducibility, brightness, photostability, biocompatibility, and selective tumor targeting and penetration. In this study, we integrate multimodal imaging and therapeutics within cancer cell-derived nanovesicles, leading to biomimetic bright optotheranostics for monitoring cancer metastasis. Upon NIR light irradiation, the engineered optotheranostics enables deep visualization and precise localization of metastatic lung, liver, and solid breast tumors along with solid tumor ablation. Metastatic cell-derived nanovesicles (∼80 ± 5 nm) are engineered to encapsulate imaging (emissive organic dye and gold nanoparticles) and therapeutic agents (anticancer drug doxorubicin and photothermally active organic indocyanine green dye). Systemic administration of biomimetic bright optotheranostic nanoparticles shows escape from mononuclear phagocytic clearance with (i) rapid tumor accumulation (3 h) and retention (up to 168 h), (ii) real-time monitoring of metastatic lung, liver, and solid breast tumors and (iii) 3-fold image-guided solid tumor reduction. These findings are supported by an improvement of X-ray, fluorescence, and photoacoustic signals while demonstrating a tumor reduction (201 mm3) in comparison with single therapies that includes chemotherapy (134 mm3), photodynamic therapy (72 mm3), and photothermal therapy (88mm3). The proposed innovative platform opens new avenues to improve cancer diagnosis and treatment outcomes by allowing the monitorization of cancer metastasis, allowing the precise cancer imaging, and delivering synergistic therapeutic agents at the solid tumor site.

Feasibility study on the clinical application of CT-based synthetic brain T1-weighted MRI: comparison with conventional T1-weighted MRI.

OBJECTIVES: This study aimed to examine the equivalence of computed tomography (CT)-based synthetic T1-weighted imaging (T1WI) to conventional T1WI for the quantitative assessment of brain morphology. MATERIALS AND METHODS: This prospective study examined 35 adult patients undergoing brain magnetic resonance imaging (MRI) and CT scans. An image synthesis method based on a deep learning model was used to generate synthetic T1WI (sT1WI) from CT data. Two senior radiologists used sT1WI and conventional T1WI on separate occasions to independently measure clinically relevant brain morphological parameters. The reliability and consistency between conventional and synthetic T1WI were assessed using statistical consistency checks, comprising intra-reader, inter-reader, and inter-method agreement. RESULTS: The intra-reader, inter-reader, and inter-method reliability and variability mostly exhibited the desired performance, except for several poor agreements due to measurement differences between the radiologists. All the measurements of sT1WI were equivalent to that of T1WI at 5% equivalent intervals. CONCLUSION: This study demonstrated the equivalence of CT-based sT1WI to conventional T1WI for quantitatively assessing brain morphology, thereby providing more information on imaging diagnosis with a single CT scan. CLINICAL RELEVANCE STATEMENT: Real-time synthesis of MR images from CT scans reduces the time required to acquire MR signals, improving the efficiency of the treatment planning system and providing benefits in the clinical diagnosis of patients with contraindications such as presence of metal implants or claustrophobia. KEY POINTS: • Deep learning-based image synthesis methods generate synthetic T1-weighted imaging from CT scans. • The equivalence of synthetic T1-weighted imaging and conventional MRI for quantitative brain assessment was investigated. • Synthetic T1-weighted imaging can provide more information per scan and be used in preoperative diagnosis and radiotherapy.

Mass spectrometry analysis of intact protein N-glycosylation signatures of cells and sera in pancreatic adenocarcinomas. / èƒ°è ºç™Œç»†èƒžå’Œè¡€æ¸ å®Œæ•´è›‹ç™½è´¨N-糖基化特征的质谱分析.

Pancreatic cancer is among the most malignant cancers, and thus early intervention is the key to better survival outcomes. However, no methods have been derived that can reliably identify early precursors of development into malignancy. Therefore, it is urgent to discover early molecular changes during pancreatic tumorigenesis. As aberrant glycosylation is closely associated with cancer progression, numerous efforts have been made to mine glycosylation changes as biomarkers for diagnosis; however, detailed glycoproteomic information, especially site-specific N-glycosylation changes in pancreatic cancer with and without drug treatment, needs to be further explored. Herein, we used comprehensive solid-phase chemoenzymatic glycoproteomics to analyze glycans, glycosites, and intact glycopeptides in pancreatic cancer cells and patient sera. The profiling of N-glycans in cancer cells revealed an increase in the secreted glycoproteins from the primary tumor of MIA PaCa-2 cells, whereas human sera, which contain many secreted glycoproteins, had significant changes of glycans at their specific glycosites. These results indicated the potential role for tumor-specific glycosylation as disease biomarkers. We also found that AMG-510, a small molecule inhibitor against Kirsten rat sarcoma viral oncogene homolog (KRAS) G12C mutation, profoundly reduced the glycosylation level in MIA PaCa-2 cells, suggesting that KRAS plays a role in the cellular glycosylation process, and thus glycosylation inhibition contributes to the anti-tumor effect of AMG-510.

FBXO31 is upregulated by METTL3 to promote pancreatic cancer progression via regulating SIRT2 ubiquitination and degradation.

FBXO31, a member of F-box family to comprise of SCF complex, contributes to a pivotal role in cancer progression. However, the possible involvements of FBXO31 in PC are unelucidated. Here, we reported that FBXO31 was overexpressed in PC patients, which was negatively associated with survival in PC patients. Furthermore, FBXO31 significantly enhanced growth, migration and invasion of PC cells in vitro. Consistently, FBXO31 overexpression promoted tumor growth in nude mice. Mechanistically, SIRT2 was a target of FBXO31 and interacted with FBXO31. Protein half-life and ubiquitination analysis demonstrated that FBXO31 promoted proteasome-dependent degradation of SIRT2. In addition, FBXO31 binds to sirtuin-type domain of SIRT2. Moreover, SIRT2 is required for the oncogenic role of FBXO31 in PC progression. Impressively, METTL3 induced m6A modification of FBXO31 and up-regulated FBXO31 expression, subsequently leading to SIRT2 down-regulation in PC cells. The results showed that METTL3 enhanced FBXO31 mRNA translation in YTHDF1-dependent manner. Taken together, we suggest that METTL3-FBXO31-SIRT2 axis was involved in PC tumorigenesis, which could identify new targets for PC treatment.

Hydrophilic Peptide and Glycopeptide as Immobilized Sorbents for Glycosylation Analysis.

Hydrophilic interaction liquid chromatography (HILIC) is widely used for glycopeptide enrichment in shot-gun glycoproteomics to enhance the glycopeptide signal and minimize the ionization competition of peptides. In this work, we have developed a novel hydrophilic material (glycoHILIC) based on glycopeptides and peptides to provide hydrophilic properties. GlycoHILIC was synthesized by oxidizing cotton and then reacting the resulting aldehyde with the N-terminus of the glycopeptide or peptide by reductive amination. Due to the large amount of hydrophilic carbohydrates and hydrophilic amino acids contained in glycopeptides, glycoHILIC showed significantly better enrichment of glycopeptides than cotton itself. Our results demonstrate that glycoHILIC has high selectivity, a low detection limit, and good stability. Over 257 unique N-linked glycosylation sites in 1477 intact N-glycopeptides from 146 glycoproteins were identified from 1 µL of human serum using glycoHILIC. Serum analysis of pancreatic cancer patients found that 38 N-glycopeptides among 21 glycoproteins changed significantly, of which 7 N-glycopeptides increased and 31 N-glycopeptides decreased. These results demonstrate that glycoHILIC can be used for glycopeptide enrichment and analysis.

Changes of B cell subsets in different types of diabetes and its effect on the progression of latent autoimmune diabetes in adults.

PURPOSE: Developmental abnormalities in B cells is one of the key players in autoimmune diabetes, but little is known about its role in latent autoimmune diabetes in adults (LADA). This study aimed to investigate the distribution of B cell subsets in different types of diabetes and to analyze their correlations with other biochemical parameters. METHODS: A total of 140 participants were prospectively enrolled from January 2021 to December 2022. Diabetes-related autoantibodies and laboratory indicators were tested. Flow cytometry was used to analyze the percentage of circulating B cell subsets and T follicular cells. The correlation of B cell subsets with different indicators was assessed by Spearman's correlation method. RESULTS: We observed that the Naïve phenotype cells tended to be less frequent in patients with diabetes than in healthy controls. The frequency of plasmablasts (PB) and Breg cell-related phenotype (B10) were significantly higher in LADA. Notably, the percentage of PB was positively associated with levels of islet cell antibody (ICA) and insulin autoantibody (IAA), but inversely associated with fasting C-peptide (FCP), further indicating that PB may promote the destruction of ß-cell in patients with diabetes. CONCLUSIONS: This study showed that patients with LADA had significantly altered frequencies of B cell subsets, particularly in the naïve to memory B cell ratio. Our study provided valuable information on the distribution characteristics of B cell subsets in LADA and suggested the feasibility of B-cell targeted therapy in LADA patients.

Circ_0002395 promotes aerobic glycolysis and proliferation in pancreatic adenocarcinoma cells via miR-548c-3p/PDK1 axis.

Circular RNAs (circRNAs) showing unusual expressions have been discovered in pancreatic adenocarcinoma (PAAD). However, the functions and underlying mechanisms of these circRNAs still remain largely unclear. Our current study discovered a notable increase in the expression of circRNA hsa_circ_0002395 (circ_0002395) in both PAAD tissues and cell lines. This up-regulation of circ_0002395 was found to be associated with larger tumor sizes and lymph node metastasis. Furthermore, our findings showed that circ_0002395 facilitated aerobic glycolysis and cell proliferation in PAAD cells by regulating the miR-548c-3p/PDK1 axis. Mechanistically, we identified circ_0002395 as a competing endogenous RNA (ceRNA) that sponged miR-548c-3p, thereby promoting PDK1 expression and aerobic glycolysis, and ultimately resulting in the enhancement of cell proliferation. Our findings found that circ_0002395 promoted proliferation of PAAD cells by enhancing PDK1 expression and aerobic glycolysis by sponging miR-548c-3p.

Diagnostic Potential of Serum Glycome Analysis in Lung Cancer: A Glycopattern Study.

Lung cancer is the leading cause of cancer-related death, with high morbidity and mortality rates due to the lack of reliable methods for diagnosing lung cancer at an early stage. Low-dose computed tomography can help detect abnormal areas in the lungs, but only 16% of cases are diagnosed early. Tests for lung cancer markers are often employed to determine genetic expression or mutations in lung carcinogenesis. Serum glycome analysis is a promising new method for early lung cancer diagnosis as glycopatterns exhibit significant differences in lung cancer patients. In this study, we employed a solid-phase chemoenzymatic method to systematically compare glycopatterns in benign cases, adenocarcinoma before and after surgery, and advanced stages of adenocarcinoma. Our findings indicate that serum high-mannose levels are elevated in both benign cases and adenocarcinoma, while complex N-glycans, including fucose and 2,6-linked sialic acid, are downregulated in the serum. Subsequently, we developed an algorithm that utilizes 16 altered N-glycans, 7 upregulated and 9 downregulated, to generate a score based on their intensity. This score can predict the stages of cancer progression in patients through glycan characterization. This methodology offers a potential means of diagnosing lung cancer through serum glycome analysis.

A Modified Approach to Measuring Femoro-Epiphyseal Acetabular Roof (FEAR) Index Has Better Intraobserver and Interobserver Reliability Compared With the Original FEAR Index.

PURPOSE: To propose a modified approach to measuring the femoro-epiphyseal acetabular roof (FEAR) index while still abiding by its definition and biomechanical basis, and to compare the intra- and interobserver reliabilities of the original and the modified FEAR index. To propose a classification for medial sourcil edges. METHODS: We retrospectively reviewed a consecutive series of patients treated with periacetabular osteotomy and/or hip arthroscopy at a single institute. Patients with unilateral or bilateral symptomatic borderline hip(s) were included. Hips with remarkable osteoarthritis, deformities, history of previous surgery, or without symptoms were excluded. A modified FEAR index was defined using a best-fit circle to determine the sourcil line and 2 ancillary lines connecting femoral head and sourcil edges to determine epiphyseal line. Lateral center-edge angle, Sharp angle, Tönnis angle on all hips, as well as FEAR index with original and modified approaches, were measured. Intra- and interobserver reliability were calculated as intraclass correlation coefficients (ICCs) for the FEAR index with both approaches and other alignments. A classification was proposed to categorize medial sourcil edges. ICCs for the 2 approaches across different sourcil groups also were calculated. RESULTS: After we reviewed 411 patients, 49 were finally included. Thirty-two patients (40 hips) were identified as having borderline dysplasia defined by a lateral center-edge angle of 18 to 25°. Intraobserver ICCs for the modified method were good to excellent for borderline hips; poor to excellent for developmental dysplasia of the hip; and moderate to excellent for normal hips. As for interobserver reliability, the modified approach outperformed original approach with moderate-to-good interobserver reliability (developmental dysplasia of the hip group, ICC = 0.650; borderline dysplasia group, ICC = 0.813; normal hip group, ICC = 0.709). The medial sourcil edge was classified to 3 groups upon its morphology. Type II (39.0%) and III (43.9%) sourcil were the dominant patterns. The sourcil classification had substantial intraobserver agreement (observer 4, kappa = 0.68; observer 1, kappa = 0.799) and moderate interobserver agreement (kappa = 0.465). The modified approach to FEAR index possessed greater interobserver reliability in all medial sourcil edge patterns. CONCLUSIONS: The modified FEAR index has better intra- and interobserver reliability compared with the original approach in all hip groups and sourcil groups. Type II and III sourcil types account for the majority, to which the modified approach is better. LEVEL OF EVIDENCE: Level II, development of diagnostic criteria (consecutive patients with consistently applied reference standard and blinding).

Diversity when interpreting evidence in network meta-analyses (NMAs) on similar topics: an example case of NMAs on diabetic macular oedema.

BACKGROUND: Different network meta-analyses (NMAs) on the same topic result in differences in findings. In this review, we investigated NMAs comparing aflibercept with ranibizumab for diabetic macular oedema (DME) in the hope of illuminating why the differences in findings occurred. METHODS: Studies were searched for in English and Chinese electronic databases (PubMed, Embase, Cochrane Library, Web of Science, CNKI, Wanfang, VIP; see detailed search strategy in the main body). Two independent reviewers systematically screened to identify target NMAs that included a comparison of aflibercept and ranibizumab in patients with DME. The key outcome of interest in this review is the change in best-corrected visual acuity (BCVA), including various ways of reporting (such as the proportion of participants who gain ≥ 10 ETDRS letters at 12 months; average change in BCVA at 12 months). RESULTS: For the binary outcome of BCVA, different NMAs all agreed that there is no clear difference between the two treatments, while continuous outcomes all favour aflibercept over ranibizumab. We discussed four points of particular concern that are illustrated by five similar NMAs, including network differences, PICO (participants, interventions, comparators, outcomes) differences, different data from the same measures of effect, and differences in what is truly significant. CONCLUSIONS: A closer inspection of each of these trials shows how the methods, including the searches and analyses, all differ, but the findings, although presented differently and sometimes interpreted differently, were similar.

Context-aware single-cell multiome approach identified cell-type specific lung cancer susceptibility genes.

Genome-wide association studies (GWAS) identified over fifty loci associated with lung cancer risk. However, the genetic mechanisms and target genes underlying these loci are largely unknown, as most risk-associated-variants might regulate gene expression in a context-specific manner. Here, we generated a barcode-shared transcriptome and chromatin accessibility map of 117,911 human lung cells from age/sex-matched ever- and never-smokers to profile context-specific gene regulation. Accessible chromatin peak detection identified cell-type-specific candidate cis-regulatory elements (cCREs) from each lung cell type. Colocalization of lung cancer candidate causal variants (CCVs) with these cCREs prioritized the variants for 68% of the GWAS loci, a subset of which was also supported by transcription factor abundance and footprinting. cCRE colocalization and single-cell based trait relevance score nominated epithelial and immune cells as the main cell groups contributing to lung cancer susceptibility. Notably, cCREs of rare proliferating epithelial cell types, such as AT2-proliferating (0.13%) and basal cells (1.8%), overlapped with CCVs, including those in TERT. A multi-level cCRE-gene linking system identified candidate susceptibility genes from 57% of lung cancer loci, including those not detected in tissue- or cell-line-based approaches. cCRE-gene linkage uncovered that adjacent genes expressed in different cell types are correlated with distinct subsets of coinherited CCVs, including JAML and MPZL3 at the 11q23.3 locus. Our data revealed the cell types and contexts where the lung cancer susceptibility genes are functional.