Search

Background: There have been emerging clinical trials investigating the efficacy of synthetic-graft-augmented autografts in anterior cruciate ligament reconstruction (ACLR) in recent years. Hamstring tendon and Ligament Augmentation and Reconstruction System (LARS) are both widely discussed graft choices for ACLR., Purpose: To compare the clinical efficacy of hamstring tendon grafts with LARS-augmented hamstring tendon grafts in ACLR., Study Design: Systematic review and meta-analysis., Method: A systematic literature search was performed in PubMed, Embase and the Cochrane Library to identify primary evidence related to the comparison of ACLR with a hamstring tendon (HT) versus a hamstring tendon with LARS (HT + LARS). Quality assessment of the included studies was conducted using Newcastle-Ottawa Scale for non-RCTs. Quantitative analysis was conducted with Reviewer Manager 5.4. The primary outcomes compared were the Lysholm scale, Tegnar activity scale, International Knee Documentation Committee (IKDC) evaluation, KT-1000-based laxity, complication/retear rate and rate of return-to-sports. The secondary outcomes were the Knee Injury and Osteoarthritis Outcomes Score (KOOS), Global Rating of Change (GRC) scale, hop tests, isokinetic knee strength tests and radiographic and arthroscopic evaluations., Results: Six cohort studies with 710 participants were included in this study. Compared with the HT group, the HT + LARS group had better Lysholm scores at the 1-year follow-up (P = 0.0007) and at the final follow-up (P = 0.04). HT + LARS group had better IKDC scores at the 1-year follow-up (P = 0.003). The HT + LARS group had a better return-to-sports rate in short term. No significant difference in complications or re-surgery was observed. The secondary results revealed superior or non-inferior outcomes in the HT + LARS group., Conclusions: As grafts for ACLR, the use of hamstring tendons with LARS augmentation, compared with the use of hamstring tendons alone, in the short term, has significantly superior overall functional results and better early sports participation and non-inferior results in other comparisons. In the long term, the use of hamstring tendon with LARS augmentation demonstrated non-inferior results in terms of functional scores, knee stability, knee strength, complications and re-tear rate, etc., Competing Interests: Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests., (© 2024. The Author(s).)

Background: Evidence suggests that PTSD symptoms following public health emergencies are influenced by many factors. The aim of this study was to investigate the relationship between perceived social support and Post-traumatic stress disorder symptoms and to explore the chain-mediated role of resilience and positive coping style, among medical staff in Hubei Province, China, during a public health emergency., Methods: Convenience sampling was used to select medical staff from two general hospitals in Hubei Province in July 2022 for this study. A total of 2,751 medical staff were included in the study. Multidimensional Scale of Perceived Social Support, 10- itemConnor- Davidson resilience scale, Simplified Coping Style Questionnaire and The Post-traumatic stress disorder Checklist for DSM-5 were used to assess the levels of perceived social support, resilience, coping style and Post-traumatic stress disorder symptoms of medical staff two years after the public health emergency. Statistical descriptions were conducted using SPSS, and a structural equation model was established using AMOS to analyze the chain-mediated roles of resilience and positive coping style between perceived social support and Post-traumatic stress disorder symptoms., Results: Structural equation modeling results showed a standardized total effect of perceived social support on Post-traumatic stress disorder symptoms of -0.416 (95%CI [-0.456, -0.374], P < 0.001). Resilience mediated the effect of perceived social support and Post-traumatic stress disorder, with an indirect effect of -0.016 ( 95%CI [0.031, 0.001], P = 0.038). Positive coping mediated the effect of perceived social support and Post-traumatic stress disorder, with an indirect effect of -0.024 (95%CI [-0.035, -0.014], P < 0.001). Resilience and positive coping style chain-mediated between perceived social support and Post-traumatic stress disorder symptoms, mediating 17.1% of the total effect., Conclusion: Perceived social support has significant direct and indirect effects on Post-traumatic stress disorder symptoms and resilience. In addition, positive coping style act as chain mediators between perceived social support and Post-traumatic stress disorder symptoms. We suggest that strengthening perceived social support for medical staff can enhance their resilience, encouraging them to adopt positive coping, which in turn reduces the level of post-traumatic stress symptoms among medical staff following public health emergencies., (© 2024. The Author(s).)

Background: When discolored teeth are repaired with porcelain veneers, the thickness of the restorations should be increased appropriately using opaque porcelain and bonded by applying opaque luting resin cement to cover discolored substrates. However, its impact on the opalescent performance has not been reported yet., Purpose: To analyze the effects of opacity, body porcelain layer thickness, and luting resin cement on the opalescence properties of porcelain veneer restorations for discolored teeth., Methods: Ninety IPS d. SIGN A3 porcelain veneer specimens were prepared via powder-paste coating and sintering. Specimens were divided into three groups according to ceramic type and cement used or not: body porcelain group as control, body/opaque porcelain group and body/opaque porcelain-resin cement composite group. Each group was subdivided into three subgroups based on the thickness, 0.50, 0.75, and 1.00 mm (n = 10). Variolink N Bleach XL luting resin cement with thickness of 0.1 mm was applied to the bottoms of body/opaque porcelain specimens to produce body/opaque porcelain-resin cement composites. The opalescence (OP) values were calculated and the micromorphological characteristics were analyzed by scanning electron microscope (SEM). Statistical analysis was performed by using ANOVA test (P < 0.05)., Results: The opalescence values determined for the body porcelain groups with thicknesses of 0.50, 0.75, and 1.00 mm and body/opaque porcelain specimens with thicknesses of 0.45/0.05, 0.70/0.05, and 0.95/0.05 mm were 3.35 ± 0.15, 3.83 ± 0.10, 6.73 ± 0.25, 7.95 ± 0.34, 15.16 ± 0.60, and 16.49 ± 0.89, respectively. The specimens in the body and body/opaque porcelain groups exhibited significant increases in their opalescence values with increasing thickness (P = 0.00). The opalescence values of the specimens increased significantly with the addition of a 0.05 mm opaque porcelain layer (P = 0.00). The opalescence values of the composites containing body/opaque porcelain layers with thicknesses of 0.45/0.05, 0.70/0.05, and 0.95/0.05 mm and luting resin cement were 9.46 ± 0.17, 16.47 ± 0.15, and 18.38 ± 0.47, respectively. The opalescence values of the composite specimens increased significantly with an increase in the thickness of the porcelain layer(P = 0.00)., Conclusions: The opaque porcelain layer and opaque resin cement can significantly improve the opalescence properties of porcelain laminate veneers for discolored teeth, but the opalescence performance is still poor than natural teeth. The body porcelain only contributes to opalescence within a certain thickness range., (© 2024. The Author(s).)

Background: The incidence of comorbid depression and post-traumatic stress disorder (PTSD) symptoms is higher in snakebite victims. However, the present state and contributing factors of depression and PTSD among Chinese snakebite victims remain unclear., Methods: A representative sample of 6837 snakebite victims were assessed with the Post-traumatic Stress Disorder Checklist (Civilian Version) and The Center for Epidemiologic Studies Depression Scale. Multivariate analyses, including network analysis, evaluated the contributing factors of PTSD and depression symptoms caused by snake bites, as well as the bridge symptoms of comorbidity networks., Results: Among 6,837 snakebite victims, 79.5% reported PTSD symptoms and 81.4% reported depression symptoms. Comorbidity of PTSD and depression symptoms was found in 75.1%. Key factors included the presence sequelae after snakebite (OR PTSD  = 2.31, OR Depression  = 1.89), time to medical facilities (6-8 h: OR PTSD  = 3.17, OR Depression  = 2.46), and marital status (divorced/widowed: OR PTSD  = 1.78, OR Depression  = 1.76). Symptoms I1 ("Repeated disturbing memories") and D1 ("Bothered by things that don't usually bother me") bridged PTSD and depression networks., Conclusion: The primary psychological challenges for snakebite victims in China are PTSD and depression symptoms, which is concerning. Standardized diagnosis and treatments, timely medical care, and stable marital relationships can reduce risks. Additional psychological support and management of negative memories, especially for those with severe bridge symptoms, can be beneficial. Further research should concentrate on understanding victims' psychological states and developing effective interventions., (© 2024. The Author(s).)

Background: The 15q11.2 BP1-BP2 microdeletion syndrome is associated with developmental delays, language impairments, neurobehavioral disorders, and psychiatric complications. The aim of the present study was to provide prenatal and postnatal clinical data for 16 additional fetuses diagnosed with the 15q11.2 BP1-BP2 microdeletion syndrome in the Chinese population., Methods: A total of 5,789 pregnancy women that underwent amniocentesis were enrolled in the present study. Both karyotype analysis and chromosomal microarray analysis (CMA) were conducted on these subjects to detect chromosomal abnormalities and copy number variants (CNVs). Whole exome sequencing (WES) was performed to investigate sequence variants in subjects with clinical abnormalities after birth., Results: Sixteen fetuses with 15q11.2 BP1-BP2 microdeletion were identified in the present study, with a detection rate of 0.28% (16/5,789). The 15q11.2 BP1-BP2 microdeletion fragments ranged from 311.8 kb to 849.7 kb, encompassing the NIPA1, NIPA2, CYFIP1, and TUBGCP5 genes. The follow-up results regarding pregnancy outcomes showed that five cases opted for pregnancy termination, while the remaining cases continued with their pregnancies. Subsequent postnatal follow-up indicated that only one case with the 15q11.2 BP1-BP2 microdeletion displayed neurodevelopmental disorders, demonstrating an incomplete penetrance rate of 9.09% (1/11)., Conclusion: The majority of fetuses with the 15q11.2 microdeletion exhibit typical features during early childhood, indicating a low penetrance and mild impact. Nonetheless, pregnancies involving fetuses with the 15q11.2 microdeletion require thorough prenatal counseling. Additionally, enhanced supervision and extended postnatal monitoring are warranted for those who choose to proceed with their pregnancies., (© 2024. The Author(s).)

Background: TSPAN7 is an important factor in tumor progression. However, the precise function of TSPAN7 and its role in pan-cancer are not clear., Methods: Based on Xinhua cohort incorporating 370 patients with kidney neoplasm, we conducted differential expression analysis by immunohistochemistry between tumor and normal tissues, and explored correlations of TSPAN7 with patients' survival. Subsequently, we conducted a pan-cancer study, and successively employed differential expression analysis, competing endogenous RNA (ceRNA) analysis, protein-protein interaction (PPI) analysis, correlation analysis of TSPAN7 with clinical characteristics, tumor purity, tumor genomics, tumor immunity, and drug sensitivity. Last but not least, gene set enrichment analysis was applied to identify enriched pathways of TSPAN7., Results: In Xinhua cohort, TSPAN7 expression was significantly up-regulated (P-value = 0.0019) in tumor tissues of kidney neoplasm patients. High TSPAN7 expression was associated with decreases in overall survival (OS) (P-value = 0.009) and progression-free survival (P-value = 0.009), and it was further revealed as an independent risk factor for OS (P-value = 0.0326, HR = 5.66, 95%CI = 1.155-27.8). In pan-cancer analysis, TSPAN7 expression was down-regulated in most tumors, and it was associated with patients' survival, tumor purity, tumor genomics, tumor immunity, and drug sensitivity. The ceRNA network and PPI network of TSPAN7 were also constructed. Last but not least, the top five enriched pathways of TSPAN7 in various tumors were identified., Conclusion: TSPAN7 served as a promising biomarker of various tumors, especially kidney neoplasms, and it was closely associated with tumor purity, tumor genomics, tumor immunology, and drug sensitivity in pan-cancer level., (© 2024. The Author(s).)

Background: The current clinical management of carotid atherosclerosis is based on the control of risk factors and medicine. However, the risk of adverse events associated with the medicine resulting in concerns and low medication compliance makes it necessary to seek a safer alternative therapy. This study assessed the effectiveness and safety of acupuncture as a treatment for carotid atherosclerosis., Methods: In this randomized controlled trial, patients with carotid atherosclerotic plaques were included and randomly assigned (1:1) to receive real acupuncture or sham acupuncture for 12 weeks. The follow-up period was 12 weeks. The primary outcome included carotid intima-media thickness (cIMT), plaque score (PS), plaque volume (PV) and grey-scale median (GSM). Secondary outcome was pulse wave velocity (PWV). Adverse events results were recorded as safety outcomes., Results: From January 2021 to February 2022, 60 eligible patients were included. 55 patients (91.7%) completed the intervention and the 12-week follow-up and there was no statistical difference in demographics between the groups. At the end of treatment, the real acupuncture group had significantly reduced PS (P = 0.002), PV (P = 0.000), and improved GSM (P = 0.044). There was no significant difference in the reduction in cIMT (Left cIMT: P = 0.338, Right cIMT: P = 0.204) and PWV between the groups (the left BS: P = 0.429; the left ES: P = 0.701; the right BS: P = 0.211; the right ES: P = 0.083). Three mild adverse reactions occurred during the study., Conclusion: This study found that acupuncture had a certain effect on reducing the thickness and volume of carotid plaque and improving the stability of plaque with minor side effects. These findings suggest that acupuncture may be a potential alternative therapy for carotid atherosclerosis., Trial Registration: This trial has been registered at ClinicalTrials.gov (ChiCTR2100041762). Submitted 30 December 2020, Registered 4 January 2021 Prospectively registered., (© 2024. The Author(s).)

Poly (ADP-ribose) polymerase 1 (PARP1) is a multifunctional nuclear enzyme that catalyzes poly-ADP ribosylation in eukaryotic cells. In addition to maintaining genomic integrity, this nuclear enzyme is also involved in transcriptional regulation. PARP1 can trigger and maintain changes in the chromatin structure and directly recruit transcription factors. PARP1 also prevents DNA methylation. However, most previous reviews on PARP1 have focused on its involvement in maintaining genome integrity, with less focus on its transcriptional regulatory function. This article comprehensively reviews the transcriptional regulatory function of PARP1 and its application in disease treatment, providing new ideas for targeting PARP1 for the treatment of diseases other than cancer., (© 2024. The Author(s).)

Background: Previous studies have shown that the inflammatory potential of the diet is associated with a variety of chronic noncommunicable diseases characterized by a chronic low-grade inflammatory response. However, the relationships between dietary inflammatory potential and organismal inflammatory status and osteoporosis have been less studied. This study aimed to investigate the relationships among inflammatory diet, inflammatory state and osteoporosis in the Xinjiang multiethnic population., Methods: The participants consisted of 4452 adults aged 35 to 74 years from Xinjiang, China. The dietary inflammatory index (DII) was calculated using dietary data collected with a semiquantitative food frequency questionnaire, and information about osteoporosis was derived from quantitative ultrasound measurements. The relationships of the DII score and inflammatory factors with the risk of osteoporosis were analysed using multivariate logistic regression, and the nonlinear associations between DII and osteoporosis were further analysed using restricted cubic splines., Results: The results showed that proinflammatory diets were associated with a greater risk of osteoporosis (T3 vs. T1: OR = 1.87; 95% CI = 1.44, 2.45) and that there was no nonlinear relationship between the DII and the risk of osteoporosis. Increased concentrations of the inflammatory factors IL-6, IL-10, IL-12p70, IL-17, and IL-23 were associated with a greater risk of osteoporosis., Conclusions: The risk of osteoporosis can be reduced by increasing the consumption of an appropriate anti-inflammatory diet., (© 2024. The Author(s).)

Background: The potential involvement of circular RNAs (circRNAs) and N 6 -methyladenosine (m 6 A) modification in the progression of Wilms tumor (WT) has not been fully elucidated. This study investigates the regulatory mechanisms and clinical significance of m 6 A-modified circMARK2 and its role in WT progression., Methods: We identified dysregulated circRNAs through deep sequencing and validated their expression by qRT-PCR in WT tissues. The biological functions of circMARK2 were assessed using clone formation, transwell migration, and orthotopic animal models. To dissect the underlying mechanisms, we employed RNA immunoprecipitation, RNA pull-down, dual-luciferase reporter assays, Western blotting, and immunofluorescence and immunohistochemical staining., Results: CircMARK2, upregulated in WT tissues, was found to be m 6 A-modified and promoted cytoplasmic export. It facilitated WT progression by stabilizing LIN28B mRNA through the circMARK2/IGF2BP2 interaction. In vitro and in vivo studies demonstrated that circMARK2 enhances the malignant behavior of WT cells. Clinically, higher circMARK2 levels in tumor tissues of WT patients were linked to increased tumor aggressiveness and reduced survival rates., Conclusions: Our study provides the first comprehensive evidence that m 6 A-modified circMARK2 contributes to WT progression by enhancing LIN28B mRNA stability, promoting cellular aggressiveness. CircMARK2 emerges as a potential biomarker for prognosis and a promising target for therapeutic intervention in WT, underscoring the clinical relevance of m 6 A modification in pediatric renal cancer., (© 2024. The Author(s).)

Background: Pancreatic cancer (PC) is one of the most malignant cancers with highly aggressiveness and poor prognosis. N6-methyladenosine (m6A) have been indicated to be involved in PC development. Glucan Branching Enzyme 1 (GBE1) is mainly involved in cell glycogen metabolism. However, the function of GBE1 and Whether GBE1 occurs m6A modification in PC progression remains to be illustrated., Methods: The clinical prognosis of GBE1 was analyzed through online platform. The expression of GBE1 was obtained from online platform and then verified in normal and PC cell lines. Lentivirus was used to generated GBE1 stable-overexpression or knockdown PC cells. Cell Counting Kit (CCK-8), colony formation assay, sphere formation assay and flow cytometry assay were conducted to analyze cell proliferation and stemness ability in vitro. Subcutaneous and orthotopic mouse models were used to verify the function of GBE1 in vivo. RNA immunoprecipitation (RIP) assay, RNA stability experiment and western blots were conducted to explore the molecular regulation of GBE1 in PC., Results: GBE1 was significantly upregulated in PC and associated with poor prognosis of PC patients. Functionally, GBE1 overexpression facilitated PC cell proliferation and stemness-like properties, while knockdown of GBE1 attenuated the malignancy of PC cells. Importantly, we found the m6A modification of GBE1 RNA, and WTAP and IGF2BP3 was revealed as the m6A regulators to increase GBE1 mRNA stability and expression. Furthermore, c-Myc was discovered as a downstream gene of GBE1 and functional rescue experiments showed that overexpression of c-Myc could rescue GBE1 knockdown-induced PC cell growth inhibition., Conclusions: Our study uncovered the oncogenic role of GBE1/c-Myc axis in PC progression and revealed WTAP/IGF2BP3-mediated m6A modification of GBE1, which highlight the potential application of GBE1 in the targeted therapy of PC., (© 2024. The Author(s).)

Background: Wilms tumor is the most prevalent embryonal kidney malignancy in children worldwide. Previous genome-wide association study (GWAS) identified that LIM domain only 1 (LMO1) gene polymorphisms affected the susceptibility to develop certain tumor types. Apart from LMO1, the LMO gene family members also include LMO2-4, each of which has oncogenic potential., Methods: We conducted this five-center case‒control study to assess the correlations between single nucleotide polymorphisms in LMO family genes and Wilms tumor susceptibility. Odds ratios and 95% confidence intervals were calculated to evaluate the strength of the association., Results: We found LMO1 rs2168101 G > T and rs11603024 C > T as well as LMO2 rs7933499 G > A were significantly associated with Wilms tumor risk. Stratified analysis demonstrated a protective role of rs2168101 GT/TT genotypes against Wilms tumor in the subgroups of age ≤ 18 months, males and clinical stages I/II compared to the rs2168101 GG genotype. Nevertheless, carriers with the rs11603024 TT genotype were more likely to have an increased risk of Wilms tumor than those with rs11603024 CC/CT genotypes in age > 18 months. And the rs11603024 was identified as a protective polymorphism for reducing the risk of Wilms tumor in the sex- and gender- subgroup. Likewise, carriers with the rs7933499 GA/AA genotypes were at significantly elevated risk of Wilms tumor in age ≤ 18 months and clinical stages I/II., Conclusion: Overall, our study identified the importance of LMO family gene polymorphisms on Wilms tumor susceptibility in Chinese children. Further investigations are needed to validate our conclusions., (© 2024. The Author(s).)

Background: Long noncoding RNAs (lncRNAs) are implicated in the initiation and progression of diffuse large B-cell lymphoma (DLBCL). Small nucleolar RNA host gene 20 (SNHG20) has been recognized as a critical lncRNA in multiple human cancers. However, the role of SNHG20 and its underlying mechanism in DLBCL are still unclear., Methods: The expression levels of SNHG20, c-MYC, β-catenin, and ubiquitin-specific peptidase 14 (USP14) were measured by reverse transcription-quantitative polymerase chain reaction (RT‒qPCR) and immunoblotting. Cell Counting Kit-8 (CCK-8), 5-Ethynyl-2'-deoxyuridine (EdU) incorporation, and flow cytometry assays were used to assess the proliferation and apoptosis of DLBCL cells. The transcriptional regulation of SNHG20 by c-MYC was confirmed by a luciferase reporter assay and RNA immunoprecipitation. The interaction between USP14 and β-catenin was demonstrated using coimmunoprecipitation. A subcutaneous xenograft model was constructed to determine the role of SNHG20 in vivo., Results: In the present study, we found that SNHG20 expression was upregulated in DLBCL cell lines and tissues compared to their normal counterparts. SNHG20 knockdown prominently reduced the proliferation and induced the apoptosis of U2932 and OCI-LY3 cells. However, SNHG20 overexpression increased the proliferation and apoptosis resistance of DLBCL cells. Mechanistically, the expression of SNHG20 was positively regulated by c-MYC in DLBCL cells. C-MYC directly bound to the promoter of SNHG20 to activate its transcription. SNHG20 was expressed mainly in the cytosol in DLBCL cells. SNHG20 silencing did not impact USP14 expression but markedly decreased the level of β-catenin, the substrate of USP14, in DLBCL cells. USP14 overexpression increased the β-catenin level, and this increase was attenuated by SNHG20 knockdown. Treatment with the proteasome inhibitor MG132 abolished SNHG20 knockdown-induced β-catenin downregulation. Moreover, SNHG20 silencing reduced the half-life but increased the ubiquitination of β-catenin in DLBCL cells. SNHG20 knockdown weakened the interaction between both endogenous and exogenous USP14 and β-catenin. In turn, SNHG20 overexpression increased the c-MYC level, and this increase was attenuated by β-catenin knockdown. Importantly, β-catenin knockdown attenuated the SNHG20-mediated increase in DLBCL cell proliferation in vitro and tumour growth in vivo., Conclusions: Taken together, our results suggested that c-MYC-activated SNHG20 accelerated the proliferation and increased the apoptosis resistance of DLBCL cells via USP14-mediated deubiquitination of β-catenin. The c-MYC/SNHG20 positive feedback loop may be a new target for anti-DLBCL treatment., (© 2024. The Author(s).)

Background: Risks of recurrence and major bleeding with extended anticoagulation in Asian patients with venous thromboembolism (VTE) are similar to those in non-Asian patients but risks according to baseline risk factor profiles is not well documented., Methods: Subgroup analysis of two randomized trials, which compared once-daily rivaroxaban (20 mg or 10 mg) with placebo or aspirin (100 mg) for extended treatment in Asian patients with VTE who had completed 6-12 months of anticoagulation. Index events were classified as unprovoked, provoked by major persistent risk factors, minor persistent risk factors, minor transient risk factors, or major transient risk factors. One-year cumulative risks of recurrent VTE were calculated for these risk factor profiles., Results: 367 patients received rivaroxaban, 159 aspirin, and 48 placebo. For patients with unprovoked VTE, one-year cumulative incidences of recurrence in the 202 patients given rivaroxaban, the 89 given aspirin and the 28 given placebo were 1.6%, 5.8%, and 14.8%, respectively. For patients with VTE provoked by minor persistent risk factors, these incidences were 0% in the 74 patients given rivaroxaban, 9.3% in the 36 given aspirin, and 0% in the 12 given placebo. No recurrent VTE occurred in patients with VTE provoked by major persistent or transient risk factors or minor transient risk factors. Rivaroxaban was not associated with a significant increase in major bleeding., Conclusions: Rivaroxaban seems to be an effective and safe option for extended treatment in Asian patients, especially those presenting with unprovoked VTE. Subgroups of patients with provoked risk factors were too small to draw meaningful conclusions., Trial Registration: NCT00439725 and NCT02064439., (© 2024. The Author(s).)

Background: Hepatitis B virus (HBV) infection can cause liver failure, while individuals with Acquired Immunodeficiency Virus Disease (AIDS) are highly susceptible to various opportunistic infections, which can occur concurrently. The treatment process is further complicated by the potential occurrence of immune reconstitution inflammatory syndrome (IRIS), which presents significant challenges and contributes to elevated mortality rates., Case Presentation: The 50-year-old male with a history of chronic hepatitis B and untreated human immunodeficiency virus (HIV) infection presented to the hospital with a mild cough and expectoration, revealing multi-drug resistant pulmonary tuberculosis (MDR-PTB), which was confirmed by XpertMTB/RIF PCR testing and tuberculosis culture of bronchoalveolar lavage fluid (BALF). The patient was treated with a regimen consisting of linezolid, moxifloxacin, cycloserine, pyrazinamide, and ethambutol for tuberculosis, as well as a combination of bictegravir/tenofovir alafenamide/emtricitabine (BIC/TAF/FTC) for HBV and HIV viral suppression. After three months of treatment, the patient discontinued all medications, leading to hepatitis B virus reactivation and subsequent liver failure. During the subsequent treatment for AIDS, HBV, and drug-resistant tuberculosis, the patient developed disseminated cryptococcal disease. The patient's condition worsened during treatment with liposomal amphotericin B and fluconazole, which was ultimately attributed to IRIS. Fortunately, the patient achieved successful recovery after appropriate management., Conclusion: Enhancing medical compliance is crucial for AIDS patients, particularly those co-infected with HBV, to prevent HBV reactivation and subsequent liver failure. Furthermore, conducting a comprehensive assessment of potential infections in patients before resuming antiviral therapy is essential to prevent the occurrence of IRIS. Early intervention plays a pivotal role in improving survival rates., (© 2024. The Author(s).)

Background: Ischemic stroke (IS) and malignant tumor (MT) have high morbidity and mortality rates worldwide, and several associations exist between them. This study aimed to determine the effect of MT on hospital mortality in patients with IS., Methods: Based on their MT status, participants with IS in the Medical Information Mart for Intensive Care IV (MIMIC-IV) were divided into two groups. The primary outcome was in-hospital all causes mortality. Kaplan-Meier survival analysis was performed to evaluate the intergroup in-hospital mortality, and three Cox regression models were used to determine the association between MT and in-hospital mortality., Results: A total of 1605 participants (749 males and 856 females) were included in the study. The mean age was 72.030 ± 15.463 years. Of these, 257 (16%) patients died in the hospital. Kaplan-Meier analysis showed that the MT group had a significantly lower possibility of in-hospital survival than the non-MT group. In the unadjusted model, in-hospital mortality among MT patients had a higher odds ratio (OR) of 1.905 (95% CI, 1.320-2.748; P < 0.001) than the non-MT group. After adjusting for basic information, vital signs, and laboratory data, MT was also associated with increased in-hospital mortality (OR = 1.844, 95% CI: 1.255-2.708; P = 0.002)., Conclusions: Among the patients with IS, the risk of all causes in-hospital mortality was higher for MT than for patients non-MT. This finding can assist clinicians in more accurately assessing prognosis and making informed treatment decisions., (© 2024. The Author(s).)

Background: Ubiquitin-specific proteases (UBPs) are a large family of deubiquitinating enzymes (DUBs). They are widespread in plants and are critical for plant growth, development, and response to external stresses. However, there are few studies on the functional characteristics of the UBP gene family in the important staple crop, maize (Zea mays L.)., Results: In this study, we performed a bioinformatic analysis of the entire maize genome and identified 45 UBP genes. Phylogenetic analysis indicated that 45 ZmUBP genes can be divided into 15 subfamilies. Analysis of evolutionary patterns and divergence levels indicated that ZmUBP genes were present before the isolation of dicotyledons, were highly conserved and subjected to purifying selection during evolution. Most ZmUBP genes exhibited different expression levels in different tissues and developmental stages. Based on transcriptome data and promoter element analysis, we selected eight ZmUBP genes whose promoters contained a large number of plant hormones and stress response elements and were up-regulated under different abiotic stresses for RT-qPCR analysis, results showed that these genes responded to abiotic stresses and phytohormones to varying degrees, indicating that they play important roles in plant growth and stress response., Conclusions: In this study, the structure, location and evolutionary relationship of maize UBP gene family members were analyzed for the first time, and the ZmUBP genes that may be involved in stress response and plant growth were identified by combining promoter element analysis, transcriptome data and RT-qPCR analysis. This study informs research on the involvement of maize deubiquitination in stress response., (© 2024. The Author(s).)

Background: Postoperative delirium (POD) is a common complication after major surgery and can cause a variety of adverse effects. However, no large-scale national database was used to assess the occurrence and factors associated with postoperative delirium (POD) following hepatic resection., Methods: Patients who underwent hepatic resection from 2015 to 2019 were screened using the International Classification of Diseases (ICD) 10th edition clinical modification code from the National Inpatient Sample (NIS) Database. Peri-operative factors associated with delirium were screened and underwent statistical analysis to identify independent predictors for delirium following hepatic resection., Results: A total of 80,070 patients underwent hepatic resection over a five-year period from 2015 to 2019. The overall occurrence of POD after hepatic resection was 1.46% (1039 cases), with a slight upward trend every year. The incidence of elective admission was 6.66% lower (88.60% vs. 81.94%) than that of patients without POD after hepatic resection and 2.34% (45.53% vs. 43.19%) higher than that of patients without POD in teaching hospitals (P < 0.001). In addition, POD patients were 6 years older (67 vs. 61 years) and comprised 9.27% (56.69% vs. 47.42%) more male patients (P < 0.001) compared to the unaffected population. In addition, the occurrence of POD was associated with longer hospitalization duration (13 vs. 5 days; P < 0.001), higher total cost ($1,481,89 vs. $683,90; P < 0.001), and higher in-hospital mortality (12.61% vs. 4.11%; P < 0.001). Multivariate logistic regression identified hepatic resection-independent risk factors for POD, including non-elective hospital admission, teaching hospital, older age, male sex, depression, fluid and electrolyte disorders, coagulopathy, other neurological disorders, psychoses, and weight loss. In addition, the POD after hepatic resection has been associated with sepsis, dementia, urinary retention, gastrointestinal complications, acute renal failure, pneumonia, continuous invasive mechanical ventilation, blood transfusion, respiratory failure, and wound dehiscence / non-healing., Conclusion: Although the occurrence of POD after hepatic resection is relatively low, it is beneficial to investigate factors predisposing to POD to allow optimal care management and improve the outcomes of this patient population., (© 2024. The Author(s).)

Background: LncRNAs regulate tumorigenesis and development in a variety of cancers. We substantiate for the first time that LINC00606 is considerably expressed in glioblastoma (GBM) patient specimens and is linked with adverse prognosis. This suggests that LINC00606 may have the potential to regulate glioma genesis and progression, and that the biological functions and molecular mechanisms of LINC00606 in GBM remain largely unknown., Methods: The expression of LINC00606 and ATP11B in glioma and normal brain tissues was evaluated by qPCR, and the biological functions of the LINC00606/miR-486-3p/TCF12/ATP11B axis in GBM were verified through a series of in vitro and in vivo experiments. The molecular mechanism of LINC00606 was elucidated by immunoblotting, FISH, RNA pulldown, CHIP-qPCR, and a dual-luciferase reporter assay., Results: We demonstrated that LINC00606 promotes glioma cell proliferation, clonal expansion and migration, while reducing apoptosis levels. Mechanistically, on the one hand, LINC00606 can sponge miR-486-3p; the target gene TCF12 of miR-486-3p affects the transcriptional initiation of LINC00606, PTEN and KLLN. On the other hand, it can also regulate the PI3K/AKT signaling pathway to mediate glioma cell proliferation, migration and apoptosis by binding to ATP11B protein., Conclusions: Overall, the LINC00606/miR-486-3p/TCF12/ATP11B axis is involved in the regulation of GBM progression and plays a role in tumor regulation at transcriptional and post-transcriptional levels primarily through LINC00606 sponging miR-486-3p and targeted binding to ATP11B. Therefore, our research on the regulatory network LINC00606 could be a novel therapeutic strategy for the treatment of GBM., (© 2024. The Author(s).)

Background: The genetic diversity of yak, a key domestic animal on the Qinghai-Tibetan Plateau (QTP), is a vital resource for domestication and breeding efforts. This study presents the first yak pangenome obtained through the de novo assembly of 16 yak genomes., Results: We discovered 290 Mb of nonreference sequences and 504 new genes. Our pangenome-wide presence and absence variation (PAV) analysis revealed 5,120 PAV-related genes, highlighting a wide range of variety-specific genes and genes with varying frequencies across yak populations. Principal component analysis (PCA) based on binary gene PAV data classified yaks into three new groups: wild, domestic, and Jinchuan. Moreover, we proposed a 'two-haplotype genomic hybridization model' for understanding the hybridization patterns among breeds by integrating gene frequency, heterozygosity, and gene PAV data. A gene PAV-GWAS identified a novel gene (BosGru3G009179) that may be associated with the multirib trait in Jinchuan yaks. Furthermore, an integrated transcriptome and pangenome analysis highlighted the significant differences in the expression of core genes and the mutational burden of differentially expressed genes between yaks from high and low altitudes. Transcriptome analysis across multiple species revealed that yaks have the most unique differentially expressed mRNAs and lncRNAs (between high- and low-altitude regions), especially in the heart and lungs, when comparing high- and low-altitude adaptations., Conclusions: The yak pangenome offers a comprehensive resource and new insights for functional genomic studies, supporting future biological research and breeding strategies., (© 2024. The Author(s).)

Background: The incidence of hemiparetic limb dysfunction reaches 85% in stroke patients, emerging as a critical factor influencing their daily lives. However, the effectiveness of current rehabilitation treatments is considerably limited, particularly in patients with upper extremity impairment. This study aims to conduct a prospective clinical trial to validate the safety and effectiveness of gamma oscillations induced by 40-Hz visual-auditory stimulation in treating post-stroke upper limb dysfunction and to explore the relevant mechanisms., Methods: This trial is a prospective, randomized controlled, double-blind study. All enrolled patients were randomly assigned to two groups. The experimental group received intervention through 40-Hz visual-auditory stimulation, while the control group underwent intervention with randomly matched visual-auditory stimulation frequencies. The primary efficacy endpoint is the change in motor function. Secondary efficacy endpoints include motor-evoked potentials, cerebral hemodynamic changes, neural network connectivity, and alterations in synaptic-related genes. Safety evaluation included major adverse events, all-cause mortality, and photosensitive epilepsy. Assessments will be conducted at baseline, after a 14-day treatment period, and during subsequent follow-up visits (at 3 and 6 months) post-treatment. The differences between the two groups will be compared., Discussion: This study will evaluate the safety and efficacy of gamma oscillations induced by 40-Hz visual-auditory stimulation in treating patients with upper extremity dysfunction after an acute cerebral stroke. Concurrently, we will explore potential mechanisms, including changes in synaptic-related genes and neural network connectivity. This trial is expected to provide evidence for the effectiveness of this new technique in treating upper extremity dysfunction after a stroke and improving patients' quality of life., Trial Registration: The study protocol has been registered with the Chinese Clinical Trial Registry (ChiCTR) under registration number ChiCTR2300076579 on October 12, 2023., (© 2024. The Author(s).)

Background: Osteoarthritis (OA), the most common joint disease, is linked with chondrocyte apoptosis and extracellular matrix (ECM) degradation. Charged multivesicular body protein 5 (CHMP5), a member of the multivesicular body, has been reported to serve as an anti-apoptotic protein to participate in leukemia development. However, the effects of CHMP5 on apoptosis and ECM degradation in OA remain unclear., Methods: In this study, quantitative proteomics was performed to analyze differential proteins between normal and OA patient articular cartilages. The OA mouse model was constructed by the destabilization of the medial meniscus (DMM). In vitro, interleukin-1 beta (IL-1β) was used to induce OA in human chondrocytes. CHMP5 overexpression and silencing vectors were created using an adenovirus system. The effects of CHMP5 on IL-1β-induced chondrocyte apoptosis were investigated by CCK-8, flow cytometry, and western blot. The effects on ECM degradation were examined by western blot and immunofluorescence. The potential mechanism was explored by western blot and Co-IP assays., Results: Downregulated CHMP5 was identified by proteomics in OA patient cartilages, which was verified in human and mouse articular cartilages. CHMP5 overexpression repressed cell apoptosis and ECM degradation in OA chondrocytes. However, silencing CHMP5 exacerbated OA chondrocyte apoptosis and ECM degradation. Furthermore, we found that the protective effect of CHMP5 against OA was involved in nuclear factor kappa B (NF-κB) signaling pathway., Conclusions: This study demonstrated that CHMP5 repressed IL-1β-induced chondrocyte apoptosis and ECM degradation and blocked NF-κB activation. It was shown that CHMP5 might be a novel potential therapeutic target for OA in the future., (© 2024. The Author(s).)

Recent studies have found a link between deep vein thrombosis and inflammatory reactions. N6-methyladenosine (m6A), a crucial element in immunological regulation, is believed to contribute to the pathophysiology of venous thromboembolism (VTE). However, how the m6A-modified immune microenvironment is involved in VTE remains unclear. In the present study, we identified a relationship between VTE and the expression of several m6A regulatory elements by analyzing peripheral blood samples from 177 patients with VTE and 88 healthy controls from public GEO databases GSE19151 and GSE48000. We used machine learning to identify essential genes and constructed a diagnostic model for VTE using multivariate logistic regression. Unsupervised cluster analysis revealed a marked difference between m6A modification patterns in terms of immune cell infiltration, inflammatory reactivity, and autophagy. We identified two m6A-related autophagy genes (i.e., CHMP2B and SIRT1) and the crucial m6A regulator YTHDF3 using bioinformatics. We also examined two potential mechanisms through which YTHDF3 may affect VTE. m6A modification, immunity, and autophagy are closely linked in VTE, offering novel mechanistic and therapeutic insights., (© 2024. The Author(s).)

Background: Prostate cancer (PCa) is becoming the most common malignancy in men worldwide. We investigated the effect of astragaloside IV combined with PESV on the gut microbiota and metabolite of PCa mice and the process of treating PCa., Methods: Nude mice were genetically modified to develop tumors characteristic of PCa. The treatment of PCa mice involved the administration of a combination of astragaloside IV and peptides derived from scorpion venom (PESV). Feces were collected for both 16 S rDNA and metabolic analysis. Fecal supernatant was extracted and used for fecal transplantation in PCa mice. Tumor development was observed in both PCa mice and nude mice. Tumor histopathology was examined, and the expression of inflammatory factors and the AGE-RAGE axis in PCa tissues were analyzed., Results: PCa mice treated with Astragaloside IV in combination with PESV showed a significant reduction in tumor volume and weight, and stabilization of gut microbiota and metabolites. At the Genus level, significant differences were observed in Porphyromonas, Corynebacterium, Arthromitus and Blautia, and the differential metabolites were PA16&#95;016&#95;0, Astragaloside+, Vitamin A acid, Nardosinone, a-Nortestoster, D-Pantethine, Hypoxanthine, Pregnenolone, cinnamic acid, Pyridoxa, Cirtruline and Xanthurenate. There was a correlation between gut microbiota and metabolites. After the fecal transplantation, tumor growth was effectively suppressed in the PCa mice. Notably, both the mRNA and protein levels of the receptor for advanced glycation end products (RAGE) were significantly decreased. Furthermore, the expression of inflammatory factors, namely NF-κB, TNF-α, and IL-6, in the tumor tissues was significantly attenuated. Conversely, upregulation of RAGE led to increased inflammation and reversed tumor growth in the mice., Conclusion: Astragaloside IV combined with PESV could treat PCa by intervening in gut microbiota composition and metabolite by targeting RAGE., (© 2024. The Author(s).)

Background: Knee osteoarthritis (KOA) is a prevalent and debilitating condition that markedly affects the sit-to-stand (STS) activity of patients, a prerequisite for daily activities. Biomechanical recognition of movements in patients with mild KOA is currently attracting attention. However, limited studies have been conducted solely on the observed differences in sagittal plane movement and muscle activation., Aim: This study aimed to identify three-dimensional biomechanical and muscle activation characteristics of the STS activity in patients with mild KOA., Methods: A cross-sectional study was conducted to observe the differences between patients with mild KOA and a control group (CG). It was conducted to observe the differences in muscle activation, including root mean square (RMS%) and integrated electromyography (items), kinematic parameters like range of motion (ROM) and maximum angular velocity, as well as dynamic parameters such as joint moment and vertical ground reaction force (vGRF)., Results: Patients with mild KOA had a higher body mass index and longer task duration. In the sagittal plane, patients with KOA showed an increased ROM of the pelvic region, reduced ROM of the hip-knee-ankle joint, and diminished maximum angular velocity of the knee-ankle joint. Furthermore, patients with KOA displayed increased knee-ankle joint ROM in the coronal plane and decreased ankle joint ROM in the horizontal plane. Integrated vGRF was higher in both lower limbs, whereas the vGRF of the affected side was lower. Furthermore, patients showed a decreased peak adduction moment (PADM) and increased peak external rotation moment in the knee joint and smaller PADM and peak internal rotation moment in the ankle joint. The affected side exhibited decreased RMS% and iEMG values of the gluteus medius, vastus medialis, and vastus lateralis muscles, as well as a decreased RMS% of the rectus femoris muscle. Conversely, RMS% and iEMG values of the biceps femoris, lateral gastrocnemius, and medial gastrocnemius muscles were higher., Conclusion: The unbalanced activation characteristics of the anterior and posterior muscle groups, combined with changes in joint moment in the three-dimensional plane of the affected joint, may pose a potential risk of injury to the irritated articular cartilage., (© 2024. The Author(s).)

Background: Tissue engineering has attracted recent attention as a promising bone repair and reconstruction approach. Dental pulp stem cells (DPSCs) are pluripotent and can differentiate into bone cells with the correct environment and substrate. Therefore, suitable scaffold materials are essential for fabricating functional three-dimensional (3D) tissue and tissue regeneration. Composite scaffolds consisting of biodegradable polymers are very promising constructs. This study aims to verify the biological function of human DPSCs seeded onto composite scaffolds based on graphene oxide (GO) and poly-L-lactic acid (PLLA)., Methods: The surface morphology was observed under scanning electron microscopy (SEM). Chemical composition was evaluated with Fourier transform infrared (FTIR) spectroscopy. The biocompatibility of GO/PLLA scaffolds was assessed using phalloidin staining of cytoskeletal actin filaments, live/dead staining, and a CCK-8 assay. The effect of GO/PLLA scaffolds on cell osteogenic differentiation was detected through ALP staining, ALP activity assays, and alizarin red S staining, complemented by quantitative real-time PCR (qRT-PCR) analysis., Results: Our data showed that GO and PLLA are successfully integrated and the GO/PLLA scaffolds exhibit favorable bioactivity and biocompatibility towards DPSCs. Additionally, it was observed that the 0.15% GO/PLLA scaffold group promoted DPSC proliferation and osteogenic differentiation by forming more calcium nodules, showing a higher intensity of ALP staining and ALP activity, and enhancing the expression levels of differentiation marker genes RUNX2 and COL1., Conclusions: These results demonstrate that the GO/PLLA scaffold is a feasible composite material suitable for cell culture and holds promising applications for oral bone tissue engineering., (© 2024. The Author(s).)

Objective: Capillary leak syndrome (CLS) is characterized by severe systemic edema without specific treatment, resulting in a high mortality rate. This study investigated whether there is organ edema in neonatal CLS patients and specific treatment strategies to improve patient prognosis., Methods: Thirty-seven newborns diagnosed with CLS were included in this study. (1) Routine point-of-care ultrasound (POCUS) was used to identify whether the patients had visceral edema or fluid collection. (2) All patients were treated with 3% NaCl intravenously, and the clinical manifestations, laboratory indices and outcomes were compared before and after treatment., Results: (1) Diffuse severe edema was found in 92.0% of the patients. (2) The POCUS examination revealed that CLS patients exhibited significant visceral edema in addition to diffuse severe edema, which included pulmonary edema in 67.6%, cerebral edema in 37.8%, severe intestinal edema in 24.3%, severe myocardial edema in 8.1%, pericardial effusion in 5.4%, pleural effusion in 29.7% and peritoneal effusion in 18.9%. Two patients (5.45%) had only myocardial edema without other manifestations. (3) Before and after the intravenous injection of 3% NaCl, there were no significant differences in the serum sodium or potassium levels of CLS patients, while the hemoglobin and hematocrit levels were significantly lower after treatment (p < 0.01). Her plasma ALB concentration and arterial pressure returned to normal levels after the treatment was completed. (4) All the patients survived, and no side effects or complications were observed during or after treatment with 3% NaCl., Conclusions: (1) In addition to diffuse severe edema, visceral edema and effusion are common and important clinical manifestations of neonatal CLS and need to be detected by routine POCUS. (2) The intravenous injection of 3% NaCl is a safe, effective and specific treatment strategy for neonatal CLS, with a survival rate of 100% and no adverse effects., (© 2024. The Author(s).)

Background: Although lung and breast cancers are common malignancies, the occurrence of primary synchronous neoplasms involving these organs has been rarely reported in literature., Case Presentation: A 75-year-old female patient presented at a local hospital with a ten-day history of dizziness and slurred speech. A CT contrast-enhanced scan revealed a 4.2 cm mass in the lower lobe of the right lung and a 3.8 cm space-occupying lesion in the right breast. Subsequent breast ultrasound identified a hypoechoic lesion measuring5.41 × 4.75 × 3.06 cm in the right breast, and an ultrasound-guided biopsy confirmed the presence of infiltrating ductal carcinoma of the right breast. The immunohistochemistry analysis of the breast mass revealed positive staining for ER, PR, HER-2, AR and Ki67 in the tumor cells, while negative staining was observed for P63, Calponin, CK5/6 and CK14. MR imaging of the head detected abnormal signals in the right frontal lobe (3.6 cm×2.9 cm in size), left cerebellar hemisphere, and punctate enhancement in the left temporal lobe, indicating potential metastasis. Pathological examination of a lung biopsy specimen confirmed the presence of small cell lung cancer (SCLC). Furthermore, immunohistochemistry analysis of the lung lesions demonstrated positive staining for TTF-1, CK-Pan, Syn, CgA, CD56, P53 (90%) and Ki67 (70%), and negative staining for NapsinA and P40 in the tumor cells. The patient's diagnosis of SCLC with stage cT2bN0M1c IVB and brain metastases (BM), as well as invasive ductal breast carcinoma (IDC), was confirmed based on the aforementioned results. Whereupon we proposed a treatment plan consisting of whole-brain radiation (40 Gy/20fractions), focal radiotherapy (60 Gy/20fractions), and adjuvant concurrent chemotherapy with oral etoposide (50 mg on days 1 to 20)., Conclusions: To the best of our knowledge, the present case is the first of its kind to describe the synchronous double cancer, consisting of primary SCLC and IDC., (© 2024. The Author(s).)

Reduced graphene oxide (rGO) is an graphene oxide (GO) derivative of graphene, which has a large specific surface area and exhibited satisfactory physicochemical characteristics. In this experiment, GO was reduced by PDA to generate PDA-GO complex, and then PDA-GO was combined with Chitosan (CS) to synthesize PDA-GO/CS composite scaffold. PDA-GO was added to CS to improve the degradation rate of CS, and it was hoped that PDA-GO/CS composite scaffolds could be used in bone tissue engineering. Physicochemical and antimicrobial properties of the different composite scaffolds were examined to find the optimal mass fraction. Besides, we examined the scaffold's biocompatibility by Phalloidin staining and Live and Dead fluorescent staining.Finally, we applied ALP staining, RT-qPCR, and Alizarin red S staining to detect the effect of PDA-GO/CS on the osteogenic differentiation of human dental pulp stem cells (hDPSCs). The results showed that PDA-GO composite was successfully prepared and PDA-GO/CS composite scaffold was synthesized by combining PDA-GO with CS. Among them, 0.3%PDA-GO/CS scaffolds improves the antibacterial activity and hydrophilicity of CS, while reducing the degradation rate. In vitro, PDA-GO/CS has superior biocompatibility and enhances the early proliferation, migration and osteogenic differentiation of hDPSCs. In conclusion, PDA-GO/CS is a new scaffold materialsuitable for cell culture and has promising application prospect as scaffold for bone tissue engineering., (© 2024. The Author(s).)

Background: Transcranial alternating current stimulation (tACS) has proven to be an effective treatment for improving cognition, a crucial factor in motor learning. However, current studies are predominantly focused on the motor cortex, and the potential brain mechanisms responsible for the therapeutic effects are still unclear. Given the interconnected nature of motor learning within the brain network, we have proposed a novel approach known as multi-target tACS. This study aims to ascertain whether multi-target tACS is more effective than single-target stimulation in stroke patients and to further explore the potential underlying brain mechanisms by using techniques such as transcranial magnetic stimulation (TMS) and magnetic resonance imaging (MRI)., Methods: This study employs a double-blind, sham-controlled, randomized controlled trial design with a 2-week intervention period. Both participants and outcome assessors will remain unaware of treatment allocation throughout the study. Thirty-nine stroke patients will be recruited and randomized into three distinct groups, including the sham tACS group (SS group), the single-target tACS group (ST group), and the multi-target tACS group (MT group), at a 1:1:1 ratio. The primary outcomes are series reaction time tests (SRTTs) combined with electroencephalograms (EEGs). The secondary outcomes include motor evoked potential (MEP), central motor conduction time (CMCT), short interval intracortical inhibition (SICI), intracortical facilitation (ICF), magnetic resonance imaging (MRI), Box and Block Test (BBT), and blood sample RNA sequencing. The tACS interventions for all three groups will be administered over a 2-week period, with outcome assessments conducted at baseline (T0) and 1 day (T1), 7 days (T2), and 14 days (T3) of the intervention phase., Discussion: The study's findings will determine the potential of 40-Hz tACS to improve motor learning in stroke patients. Additionally, it will compare the effectiveness of multi-target and single-target approaches, shedding light on their respective improvement effects. Through the utilization of techniques such as TMS and MRI, the study aims to uncover the underlying brain mechanisms responsible for the therapeutic impact. Furthermore, the intervention has the potential to facilitate motor learning efficiency, thereby contributing to the advancement of future stroke rehabilitation treatment., Trial Registration: Chinese Clinical Trial Registry ChiCTR2300073465. Registered on 11 July 2023., (© 2024. The Author(s).)

Background: Etomidate has been advocated for anesthesia in older and critically ill patients because of its hemodynamic stability. Clinical studies have shown that dexmedetomidine has neuroprotective and anti-inflammatory properties and improves postoperative cognitive dysfunction in older patients. The present study was to evaluate the effects of the combination of etomidate and dexmedetomidine with different anaesthesia time on postoperative cognitive function in older patients., Methods: A total of 132 older patients undergoing ureteroscopic holmium laser lithotripsy were randomly divided into EN group and ED group equally. Patients whose surgery time was less than or equal to 1 h in each group were allocated to short-time surgery group (EN 1 group and ED 1 group), and whose surgery time was more than 1h were allocated to long-term surgery group (EN 2 group and ED 2 group). The primary outcome was the score of the Mini-Mental State Examination. The secondary outcomes were State-Trait Anxiety Inventory scores, Riker sedation agitation scores, Zung Self-Rating Depression Scale scores, the memory span for Arabic numerals, the plasma concentrations of S-100 calcium-binding protein B and neuron specific enolase, the time to spontaneous respiration, recovery, and extubation., Results: The MMSE scores at t 2-3 were higher in ED 1 and ED 2 groups than in EN 1 and EN 2 groups (p<0.05). Compared with ED 1 and ED 2 groups, the ZSDS scores, the S-AI scores and the T-AI scores at t 1-2 were higher in EN 1 and EN 2 groups (p<0.05), respectively. The recalled Arabic numbers at t 1-3 were higher in ED 2 group than in EN 2 group (p<0.05). The plasma concentration of S-100β at t 1-2 in EN 1 group and t 1-3 in EN 2 group were higher than that in ED 1 and ED 2 groups (p<0.05), respectively. Compared with ED 1 and ED 2 groups, the plasma concentrations of NSE were higher at t 1-3 in EN 1 group and t 1-4 in EN 2 group (p<0.05), respectively., Conclusion: The administration of dexmedetomidine could improve postoperative cognitive dysfunction, emergence agitation, depression and anxiety, attenuate the plasma concentrations of S-100β and NSE in older patients undergoing total intravenous anaesthesia with etomidate., Trial Registration: Registration number: ChiCTR1800015421, Date: 29/03/2018., (© 2024. The Author(s).)

Objective: The aim of this work was to investigate the immunological effect of MENK by analyzing the protein spectrum and bioinformatics of macrophage RAW264.7, and to explore the relationship between macrophage and ferroptosis., Result: We employed proteomic analysis to identify differentially expressed proteins (DEPs) between macrophages and macrophages intervened by MENK. A total of 208 DEPs were identified. Among these, 96 proteins had upregulated expression and 112 proteins had downregulated expression. Proteomic analysis revealed a significant enrichment of DEPs associated with iron metabolism. The identification of hub genes was conducted using KEGG pathway diagrams and protein-protein interaction (PPI) analysis. The hub genes identified in this study include HMOX1 and Ferritin (FTH and FTL). A correlation was established between HMOX1, FTH, and FTL in the GO and KEGG databases. The results of PCR, WB and immunofluorescence showed that MENK downregulated the level of HMOX1 and FTH., Conclusion: MENK had the potential to become an adjuvant chemotherapy drug by regulating iron metabolism in macrophages, reducing levels of HMOX1 and ferritin. We proposed an innovative research direction on the therapeutic potential of MENK, focusing on the relationship between ferroptosis and macrophage activity., (© 2024. The Author(s).)

Background: Paracetamol induces hepatotoxicity and subsequent liver injury, which may increase the risk of liver cancer, but epidemiological evidence remains unclear. We conducted this study to evaluate the association between paracetamol use and the risk of liver cancer., Methods: This prospective study included 464,244 participants free of cancer diagnosis from the UK Biobank. Incident liver cancer was identified through linkage to cancer and death registries and the National Health Service Central Register using the International Classification of Diseases (ICD)-10 codes (C22). An overlap-weighted Cox proportional hazards model was utilized to calculate the hazard ratio (HR) and 95% confidence interval (CI) for the risk of liver cancer associated with paracetamol use. The number needed to harm (NNH) was calculated at 10 years of follow-up., Results: During a median of 12.6 years of follow-up, 627 cases of liver cancer were identified. Paracetamol users had a 28% higher risk of liver cancer than nonusers (HR 1.28, 95% CI 1.06-1.54). This association was robust in several sensitivity analyses and subgroup analyses, and the quantitative bias analysis indicated that the result remains sturdy to unmeasured confounding factors (E-value 1.88, lower 95% CI 1.31). The NNH was 1106.4 at the 10 years of follow-up., Conclusion: The regular use of paracetamol was associated with a higher risk of liver cancer. Physicians should be cautious when prescribing paracetamol, and it is recommended to assess the potential risk of liver cancer to personalize the use of paracetamol., (© 2024. The Author(s).)

Background: Currently, the value of oral selective estrogen receptor degraders (SERDs) for hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (aBC) after progression on ≥ 1 line of endocrine therapy (ET) remains controversial. We conducted a meta-analysis to evaluate progression-free survival (PFS) and safety benefits in several clinical trials., Materials and Methods: Cochrane Library, Embase, PubMed, and conference proceedings (SABCS, ASCO, ESMO, and ESMO Breast) were searched systematically and comprehensively. Random effects models or fixed effects models were used to assess pooled hazard ratios (HRs) and 95% confidence intervals (CIs) for treatment with oral SERDs versus standard of care., Results: A total of four studies involving 1,290 patients were included in our analysis. The hazard ratio (HR) of PFS showed that the oral SERD regimen was better than standard of care in patients with HR+/HER2- aBC after progression on ≥ 1 line of ET (HR: 0.75, 95% CI: 0.62-0.91, p = 0.004). In patients with ESR1 mutations, the oral SERD regimen provided better PFS than standard of care (HR: 0.58, 95% CI: 0.47-0.71, p < 0.00001). Regarding patients with disease progression following previous use of CDK4/6 inhibitors, PFS benefit was observed in oral SERD-treatment arms compared to standard of care (HR: 0.75, 95% CI: 0.64-0.87, p = 0.0002)., Conclusions: The oral SERD regimen provides a significant PFS benefit compared to standard-of-care ET in patients with HR+/HER2- aBC after progression on ≥ 1 line of ET. In particular, we recommend oral SERDs as a preferred choice for those patients with ESR1m, and it could be a potential replacement for fulvestrant. The oral SERD regimen is also beneficial after progression on CDK4/6 inhibitors combined with endocrine therapy., (© 2023. The Author(s).)

Background: This retrospective study aimed to assess the suitability of POSSUM and its modified versions, E-PASS and its modified score, SRS, and SORT scores for predicting postoperative complications and mortality in patients undergoing laparoscopic radical gastrectomy for gastric cancer., Materials and Methods: Data analysis was performed on 349 patients who underwent laparoscopic radical gastrectomy at Tianjin Medical University General Hospital between January 2016 and December 2021. The discriminative ability of the scoring systems was evaluated using the area under the receiver operating characteristic curve (AUC). The primary endpoint focused on the prediction of postoperative complications, while the secondary endpoint assessed the prediction of postoperative mortality., Results: Among the scoring systems evaluated, the modified E-PASS (mE-PASS) score exhibited the highest AUC (0.846) and demonstrated the highest sensitivity (81%) and specificity (79%) for predicting postoperative complications. All other scores, except for POSSUM, showed moderate discriminative ability in predicting complications. In terms of predicting postoperative mortality, the E-PASS score had the highest AUC (0.978), while the mE-PASS score displayed the highest sensitivity (76%) and specificity (90%). Notably, both E-PASS and mE-PASS scores exhibited excellent discriminative ability., Conclusions: The P-POSSUM, O-POSSUM, E-PASS, mE-PASS, SRS, and SORT scoring systems are useful tools for predicting postoperative outcomes in laparoscopic radical gastrectomy. Among them, the mE-PASS score demonstrated the best predictive power. However, the POSSUM system could only be applicable to predict postoperative mortality., (© 2023. The Author(s).)

Background: Recurrent lateral patellar dislocation (RLPD) poses a significant threat to patients' quality of life due to knee pain, patellofemoral cartilage damage, and potential traumatic arthritis. Predictive scoring systems have been developed to assess the risk of RLPD; however, their relative accuracy remains uncertain., Purpose: To investigate the accuracy of the multiple regression models to predict the individual risk of recurrent LPD., Methods: The Patellar Instability probability calculator (PIP), Recurrent Instability of the Patella Score (RIP), and Patellar Instability Severity Score (PIS) scoring rules were measured in 171 patients with a history of patellar dislocation and 171 healthy individuals. Three prediction models were calculated based on the data to predict the risk of recurrent lateral patellar dislocation. The inter-observer and intra-observer reliability of each measurement parameter was evaluated. The predictive capacity of the three-prediction model was investigated using the receiver operating characteristic curve., Results: In the case group of 171 patients, PIS accurately predicted recurrent lateral Patella dislocation in 143 patients. RIP was 96, and PIP was 83. The positive predictive values were 92.9%, 64%, and 68% respectively. In the control group of 171 patients, the PIS was validated in 160 patients who would not experience dislocations. RIP was 117, and PIP was 50. The negative predictive values were 85.1%, 60.9%, and 36.2%, respectively. The area under the curve score for the PIS was 0.866, and the RIP was 0.673. the PIP was 0.678., Conclusion: RIP and PIP did not work to predict LPD. PIS can accurately predict recurrent lateral patellar dislocation. It can aid doctors in making treatment decisions., Level of Evidence: Level III, retrospective comparative study., (© 2023. The Author(s).)

Background: Copper-induced cell death, or "cuproptosis," as an apoptotic process, has recently received much attention in human diseases. Recent studies on cuproptosis have provided novel insights into the pathogenesis of various diseases, especially cancers. However, the association between neuroblastoma (NB) and cuproptosis in terms of their clinical outcomes, tumorigenesis, and treatment response remains unclear., Methods: To determine the role of cuproptosis in NB tumorigenesis and progression, this study employed a systematic technique to explore the characteristic patterns of 10 key cuproptosis-related genes (CUGs) in NB. Consensus clustering analysis of the TARGET and GEO databases divided the NB patients into two subgroups that showed different clinicopathological attributes, molecular patterns, survival outcomes, disease-associated pathways, tumor immune microenvironment (TIME) features, and treatment responses. Moreover, a cuproptosis scoring scheme was established, which divided the patients with NB into two groups with high scores and low scores as per the median score. Furthermore, this research developed a nomogram and risk signature on the basis of this cuproptosis score to better elucidate its function in predicting NB prognosis. In vitro experiments were carried out using Transwell Assay, HLECs tube formation assay, Colony formation assay, Western Blotting Assay, Immunohistochemical (IHC) Staining, Immunofluorescence (IF) Staining and Flow Cytometry Analysis., Results: The results demonstrated that the established cuproptosis score and prediction model could effectively distinguish between the individuals in low and high-risk groups and had a high predictive value. Lastly, bioinformatics analysis and in vitro experiments enabled the identification of PDHA1, a key CUG, which was involved in both DNA replication-related pathways and the cell cycle. It was also associated with tumorigenesis and progression of NB., Conclusion: Cuproptosis, especially PDHA1, play a crucial role in the TIME characteristics, tumor progression, and long-term prognosis of NB. The patterns of cuproptosis assessed in this research may improve the understanding of the overall concept of NB tumorigenesis, thus facilitating the development of more effective therapeutic interventions., (© 2023. The Author(s).)

Background: Polyploid giant cancer cells (PGCCs), a specific type of cancer stem cells (CSCs), can be induced by hypoxic microenvironments, chemical reagents, radiotherapy, and Chinese herbal medicine. Moreover, PGCCs can produce daughter cells that undergo epithelial-mesenchymal transition, which leads to cancer recurrence and disseminated metastasis. Vimentin, a mesenchymal cell marker, is highly expressed in PGCCs and their daughter cells (PDCs) and drives migratory persistence. This study explored the molecular mechanisms by which vimentin synergistically regulates PGCCs to generate daughter cells with enhanced invasive and metastatic properties., Methods: Arsenic trioxide (ATO) was used to induce the formation of PGCCs in Hct116 and LoVo cells. Immunocytochemical and immunohistochemical assays were performed to determine the subcellular localization of vimentin. Cell function assays were performed to compare the invasive metastatic abilities of the PDCs and control cells. The molecular mechanisms underlying vimentin expression and nuclear translocation were investigated by real-time polymerase chain reaction, western blotting, cell function assays, cell transfection, co-immunoprecipitation, and chromatin immunoprecipitation, followed by sequencing. Finally, animal xenograft experiments and clinical colorectal cancer samples were used to study vimentin expression in tumor tissues., Results: Daughter cells derived from PGCCs showed strong proliferative, migratory, and invasive abilities, in which vimentin was highly expressed and located in both the cytoplasm and nucleus. Vimentin undergoes small ubiquitin-like modification (SUMOylation) by interacting with SUMO1 and SUMO2/3, which are associated with nuclear translocation. P62 regulates nuclear translocation of vimentin by controlling SUMO1 and SUMO2/3 expression. In the nucleus, vimentin acts as a transcription factor that regulates CDC42, cathepsin B, and cathepsin D to promote PDC invasion and migration. Furthermore, animal experiments and human colorectal cancer specimens have confirmed the nuclear translocation of vimentin., Conclusion: P62-dependent SUMOylation of vimentin plays an important role in PDC migration and invasion. Vimentin nuclear translocation and overexpressed P62 of cancer cells may be used to predict patient prognosis, and targeting vimentin nuclear translocation may be a promising therapeutic strategy for metastatic cancers., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Novel prophylactic drugs and vaccination strategies for protection against influenza virus should induce specific effector T-cell immune responses in pulmonary airways and peripheral lymphoid organs. Designing approaches that promote T-cell-mediated responses and memory T-cell differentiation would strengthen host resistance to respiratory infectious diseases. The results of this study showed that pulmonary delivery of MENK via intranasal administration reduced viral titres, upregulated opioid receptor MOR and DOR, increased the proportions of T-cell subsets including CD8 + T cells, CD8 + T EM cells, NP/PA-effector CD8 + T EM cells in bronchoalveolar lavage fluid and lungs, and CD4 + /CD8 + T CM cells in lymph nodes to protect mice against influenza viral challenge. Furthermore, we demonstrated that, on the 10th day of infection, the proportions of CD4 + T M and CD8 + T M cells were significantly increased, which meant that a stable T CM and T EM lineage was established in the early stage of influenza infection. Collectively, our data suggested that MENK administered intranasally, similar to the route of natural infection by influenza A virus, could exert antiviral activity through upregulating T-cell-mediated adaptive immune responses against influenza virus., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Caspase 6 is an essential regulator in innate immunity, inflammasome activation and host defense. We aimed to characterize the causal mechanism of Caspase 6 in liver sterile inflammatory injury., Methods: Human liver tissues were harvested from patients undergoing ischemia-related hepatectomy to evaluate Caspase 6 expression. Subsequently, we created Caspase 6-knockout (Caspase 6 KO ) mice to analyze roles and molecular mechanisms of macrophage Caspase 6 in murine models of liver ischemia/reperfusion (IR) injury., Results: In human liver biopsies, Caspase 6 expression was positively correlated with more severe histopathological injury and higher serum ALT/AST level at one day postoperatively. Moreover, Caspase 6 was mainly elevated in macrophages but not hepatocytes in ischemic livers. Unlike in controls, the Caspase 6-deficient livers were protected against IR injury, as evidenced by inhibition of inflammation, oxidative stress and iron overload. Disruption of macrophage NF-κB essential modulator (NEMO) in Caspase 6-deficient livers deteriorated liver inflammation and ferroptosis. Mechanistically, Caspase 6 deficiency spurred NEMO-mediated IκBα phosphorylation in macrophage. Then phosphorylated-inhibitor of NF-κBα (p-IκBα) co-localized with receptor-interacting serine/ threonine-protein kinase 1 (RIPK1) in the cytoplasm to degradate RIPK1 under inflammatory conditions. The disruption of RIPK1-IκBα interaction preserved RIPK1 degradation, triggering downstream apoptosis signal-regulating kinase 1 (ASK1) phosphorylation and inciting NIMA-related kinase 7/NOD-like receptor family pyrin domain containing 3 (NEK7/NLRP3) activation in macrophages. Moreover, ablation of macrophage RIPK1 or ASK1 diminished NEK7/NLRP3-driven inflammatory response and dampened hepatocyte ferroptosis by reducing HMGB1 release from macrophages., Conclusions: Our findings underscore a novel mechanism of Caspase 6 mediated RIPK1-IκBα interaction in regulating macrophage NEK7/NLRP3 function and hepatocytes ferroptosis, which provides therapeutic targets for clinical liver IR injury. Video Abstract., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Purpose: This study aimed to evaluate the efficacy of arthroscopic sciatic neurolysis for treating deep gluteal syndrome (DGS) and to analyse the application value of high-frequency ultrasound during perioperative period., Methods: Between June 2020 and February 2022, 30 patients with DGS who underwent failed conservative treatment were retrospectively analysed. Lateral arthroscopic exploration of the deep gluteal space and sciatic neurolysis were performed. In addition to pelvic X-ray, lumbar disc and hip magnetic resonance imaging (MRI), ultrasonography of the sciatic nerve was also performed in all patients. The visual analogue scale pain score (VAS), modified Harris hip score (mHHS) and Benson symptom-rating scale were used to evaluate the clinical efficacy. The correlation between preoperative sciatic nerve ultrasound and arthroscopic findings was analysed., Results: The median follow-up for these patients was 13 months (range,12-21 months). Preoperative ultrasonography showed precise morphological changes in 26 sciatic nerves of patients. The VAS score decreased from 5.0 (4.0, 6.0) preoperatively to 0.5 (0, 1.0) postoperatively (p < 0.001), and the mHHS increased from 64.0 (57.0, 67.0) preoperatively to 95.0 (93.0, 97.0) postoperatively (p < 0.001). The Benson symptom score was excellent in 15 cases, good in 12 cases, fair in 2 cases, poor in 1 case; thus, the score was excellent or good in 90% of the cases. Preoperative ultrasound diagnosis and intra-operative findings matched up in all cases. There were four cases of transient numbness in the posterior thigh., Conclusions: Arthroscopic sciatic neurolysis is a safe and effective treatment option for DGS patients who fail conservative treatment. Ultrasound diagnosis matched the arthroscopic findings perfectly. Preoperative Doppler ultrasound can assist surgical decision-making, guide intraoperative release., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: The role of prophylactic antibiotics in preventing ventilator-associated pneumonia (VAP) in patients undergoing invasive mechanical ventilation (IMV) remains unclear. This network meta-analysis compared the efficacy and safety of antibiotic prophylaxis in preventing VAP in an IMV population in intensive-care units (ICUs)., Methods: We searched the PubMed, Web of Science, Embase, and Cochrane Library databases from inception to December 2021, to identify relevant studies assessing the impact of prophylactic antibiotics on the incidence of VAP, the mortality, and the duration of ICU stays and hospitalization to perform a meta-analysis., Results: Thirteen studies (2144 patients) were included, 12 of which were selected for the primary analysis, which revealed that treatment with prophylactic antibiotics resulted in a lower VAP rate compared with control groups [risk ratio (RR) = 0.62]. Bayesian network meta-analysis indicated that aerosolized tobramycin and intravenous ampicillin-sulbactam presented the greatest likelihood being the most efficient regimen for reducing VAP., Conclusions: Antibiotic prophylaxis may reduce the incidence of VAP, but not the mortality, for adult patients undergoing IMV in ICUs. Tobramycin via nebulization and ampicillin-sulbactam via intravenous administration presented the greatest likelihood of being the most efficient regimen for preventing VAP. However, well-designed randomized studies are warranted before definite recommendations can be made., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Mulberry (Morus alba L.) leaf, as a medicinal and food homologous traditional Chinese medicine, has a clear therapeutic effect on type 2 diabetes mellitus (T2DM), yet its underlying mechanisms have not been totally clarified. The study aimed to explore the mechanism of mulberry leaf in the treatment of T2DM through tandem mass tag (TMT)-based quantitative proteomics analysis of skeletal muscle., Methods: The anti-diabetic activity of mulberry leaf extract (MLE) was evaluated by using streptozotocin-induced diabetic rats at a dose of 4.0 g crude drug /kg p.o. daily for 8 weeks. Fasting blood glucose, body weight, food and water intake were monitored at specific intervals, and oral glucose tolerance test and insulin tolerance test were conducted at the 7th and 8th week respectively. At the end of the experiment, levels of glycated hemoglobin A1c, insulin, free fat acid, leptin, adiponectin, total cholesterol, triglyceride, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol were assessed and the pathological changes of rat skeletal muscle were observed by HE staining. TMT-based quantitative proteomic analysis of skeletal muscle and bioinformatics analysis were performed and differentially expressed proteins (DEPs) were validated by western blot. The interactions between the components of MLE and DEPs were further assessed using molecular docking., Results: After 8 weeks of MLE intervention, the clinical indications of T2DM such as body weight, food and water intake of rats were improved to a certain extent, while insulin sensitivity was increased and glycemic control was improved. Serum lipid profiles were significantly reduced, and the skeletal muscle fiber gap and atrophy were alleviated. Proteomic analysis of skeletal muscle showed that MLE treatment reversed 19 DEPs in T2DM rats, regulated cholesterol metabolism, fat digestion and absorption, vitamin digestion and absorption and ferroptosis signaling pathways. Key differential proteins Apolipoprotein A-1 (ApoA1) and ApoA4 were successfully validated by western blot and exhibited strong binding activity to the MLE's ingredients., Conclusions: This study first provided skeletal muscle proteomic changes in T2DM rats before and after MLE treatment, which may help us understand the molecular mechanisms, and provide a foundation for developing potential therapeutic targets of anti-T2DM of MLE., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Tau protein serves a pro-inflammatory function in neuroinflammation. However, the role of tau in other inflammatory disorders such as rheumatoid arthritis (RA) is less explored. This study is to investigate the role of endogenous tau and the potential mechanisms in the pathogenesis of inflammatory arthritis., Methods: We established collagen-induced arthritis (CIA) model in wild-type and Tau-/- mice to compare the clinical score and arthritis incidence. Micro-CT analysis was used to evaluate bone erosion of ankle joints. Histological analysis was performed to assess inflammatory cell infiltration, cartilage damage, and osteoclast activity in the ankle joints. Serum levels of pro-inflammatory cytokines were measured by ELISA. The expression levels of macrophage markers were determined by immunohistochemistry staining and quantitative real-time PCR., Results: Tau expression was upregulated in joints under inflammatory condition. Tau deletion in mice exhibited milder inflammation and protected against the progression of CIA, evidenced by reduced serum levels of pro-inflammatory cytokines and attenuated bone loss, inflammatory cell infiltration, cartilage damage, and osteoclast activity in the ankle joints. Furthermore, tau deficiency led to the inhibition of classically activated type 1 (M1) macrophage polarization in the synovium., Conclusion: Tau is a previously unrecognized critical regulator in the pathogenesis of RA and may provide a potential therapeutic target for autoimmune and inflammatory joint diseases., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Cholangiocarcinoma (CCA) is a highly aggressive malignant tumor, and its diagnosis is still a challenge. This study aimed to identify a novel bile marker for CCA diagnosis based on proteomics and establish a diagnostic model with deep learning., Methods: A total of 644 subjects (236 CCA and 408 non-CCA) from two independent centers were divided into discovery, cross-validation, and external validation sets for the study. Candidate bile markers were identified by three proteomics data and validated on 635 clinical humoral specimens and 121 tissue specimens. A diagnostic multi-analyte model containing bile and serum biomarkers was established in cross-validation set by deep learning and validated in an independent external cohort., Results: The results of proteomics analysis and clinical specimen verification showed that bile clusterin (CLU) was significantly higher in CCA body fluids. Based on 376 subjects in the cross-validation set, ROC analysis indicated that bile CLU had a satisfactory diagnostic power (AUC: 0.852, sensitivity: 73.6%, specificity: 90.1%). Building on bile CLU and 63 serum markers, deep learning established a diagnostic model incorporating seven factors (CLU, CA19-9, IBIL, GGT, LDL-C, TG, and TBA), which showed a high diagnostic utility (AUC: 0.947, sensitivity: 90.3%, specificity: 84.9%). External validation in an independent cohort (n = 259) resulted in a similar accuracy for the detection of CCA. Finally, for the convenience of operation, a user-friendly prediction platform was built online for CCA., Conclusions: This is the largest and most comprehensive study combining bile and serum biomarkers to differentiate CCA. This diagnostic model may potentially be used to detect CCA., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Lymph node micrometastasis is an important prognostic factor in breast cancer, but patients with different numbers of involved lymph nodes are all divided into the same N1mi stage without distinction. We designed this study to compare the prognosis and local treatment recommendations of N1mi breast cancer patients with different numbers of micrometastatic lymph nodes., Patients and Methods: A total of 27,032 breast cancer patients with T1-2N1miM0 stage from the Surveillance, Epidemiology, and End Results (SEER) database (2004-2019) who underwent breast surgery were included in this retrospective study. Patients were divided into three groups for prognosis comparison according to the number of micrometastatic lymph nodes: N1mi with 1 (Nmi = 1), 2 (Nmi = 2), or more (Nmi ≥ 3) involved lymph nodes. We explored the characteristics and survival outcomes of the population receiving different local treatments, including different axillary surgery types and whether receiving radiotherapy or not. Univariate and multivariate Cox proportional hazards regression analysis were used to compare the overall survival (OS) and breast cancer-specific survival (BCSS) in different groups. Stratified analyses and interaction analyses were also applied to explore the predictive significance of different involved lymph nodes numbers. Propensity score matching (PSM) method was utilized to balance the differences between groups., Results: Univariate and multivariate Cox regression analysis indicated that nodal status was an independent prognostic factor. After adjustment for other prognostic factors, there was a significant difference in prognosis between Nmi = 1 group and Nmi = 2 group [adjusted hazard ratio (HR) 1.145, 95% confidence interval (CI): 1.047-1.251, P = 0.003], and patients with Nmi ≥ 3 group had a significantly poorer prognosis (adjusted HR 1.679, 95% CI 1.589-2.407; P < 0.001). The proportion of N1mi patients only underwent sentinel lymph nodes biopsy (SLNB) gradually increased from 2010 (P trend  < 0.001). After adjusting for other factors, N1mi patients who underwent axillary lymph nodes dissection (ALND) was associated with significant survival benefit than SLNB (adjusted HR 0.932, 95%CI 0.874-0.994; P = 0.033), the same goes for receiving radiotherapy (adjusted HR 1.107, 95%CI 1.030-1.190; P = 0.006). Further stratified analysis showed that in the SLNB subgroup, radiotherapy was associated with a significant survival benefit (HR 1.695, 95%CI 1.534-1.874; P < 0.001), whereas in the ALND subgroup, there was no significant prognostic difference with or without radiotherapy (HR 1.029, 95%CI 0.933-1.136; P = 0.564)., Conclusion: Our study indicates that the increasing number of lymph node micrometastases was associated a worse prognosis of N1mi breast cancer patients. In addition, ALND does provide a significant survival benefit for these patients, while the benefit from local radiotherapy may be of even greater importance., (© 2023. The Author(s).)