The role of small dense LDL-C/large buoyant LDL-C ratio as an independent risk factor in patients with type 2 diabetes mellitus and metabolic syndrome

Dyslipidemia plays a key role in metabolic syndrome (MS), intricately linked to type 2 diabetes mellitus (T2DM). This study aimed to investigate the differences in low-density lipoprotein cholesterol (LDL-C) subfraction levels between T2DM and T2DM with MS, and identify the risk factors associated with the disease. A total of 246 individuals diagnosed with T2DM, including 144 T2DM patients with MS, and 147 healthy subjects were recruited. All participants underwent a comprehensive clinical evaluation. Lipoprotein subfraction analysis was performed using the Lipoprint LDL system. Multivariate logistic regression analysis revealed that several lipid markers, including triglyceride (TG), LDL-C, large buoyant LDL-C (lbLDL-C), small dense LDL-C (sdLDL-C), LDLC2-5, and sdLDL-C/lbLDL-C ratio, were identified as independent risk factors for T2DM. Additionally, TG, sdLDL-C, LDLC-4, LDLC-5, and sdLDL-C/lbLDL-C ratio were found to be independent risk factors for T2DM with MS. Furthermore, the results of the receiver operating characteristic (ROC) curves demonstrated that sdLDL-C, LDLC-4, LDLC-3, and sdLDL-C/lbLDL-C ratio exhibited excellent predictive performance for the risk of T2DM (AUC > 0.9). The sdLDL-C/lbLDL-C ratio emerges as a shared independent risk factor for T2DM and MS complications. Furthermore, sdLDL-C/lbLDL-C ratio, along with LDL-4 and LDL-3, exhibits noteworthy predictive capabilities for T2DM.

Heparan sulfate acts as an activator of the NLRP3 inflammasome promoting inflammatory response in the development of acute pancreatitis.

BACKGROUND: Accumulating evidence has shown that the NOD-like receptor protein 3 (NLRP3) inflammasome plays a crucial role in the inflammatory cascades involved in the development of acute pancreatitis (AP). However, the specific agonist responsible for activating the NLRP3 inflammasome in this process has not yet been identified. The purpose of this study is to clarify whether heparan sulfate (HS) works as an NLRP3 inflammasome activator to evoke inflammatory cascades in the progression of AP. METHODS: Two experimental mouse models of AP were utilized to investigate the pro-inflammatory activity of HS in the development of AP by measuring the secretion of inflammatory cytokines and the neutrophil infiltration in pancreatic tissue. The ability of HS to activate the NLRP3 inflammasome was evaluated both in vitro and in vivo. The nuclear factor kappa B (NF-κB)-mediated expression of NLRP3 inflammasome components in response to HS treatment was determined to decipher the role of HS in transcriptional priming of NLRP3 inflammasome. Furthermore, HS-triggered deubiquitination of NLRP3 was analyzed to reveal the promoting effect of HS on the NLRP3 inflammasome priming via a non-transcriptional pathway. RESULTS: High plasma level of HS was observed with a positive correlation to that of inflammatory cytokines in AP mice. Administration of HS to mice resulted in an exacerbated inflammatory profile, while reducing HS production by an inhibitor of heparanase significantly attenuated inflammatory response. Pharmacological inhibition or genetic deletion of NLRP3 substantially suppressed the HS-stimulated elevation of IL-1ß levels in AP mice. The in vitro data demonstrated that HS primarily serves as a priming signal for the activation of the NLRP3 inflammasome. HS possesses the ability to increase the transcriptional activity of NF-κB and TLR4/NF-κB-driven transcriptional pathway is employed for NLRP3 inflammasome priming. Moreover, HS-induced deubiquitination of NLRP3 is another pathway responsible for non-transcriptional priming of NLRP3 inflammasome. CONCLUSIONS: Our current work has unveiled HS as a new activator of the NLRP3 inflammasome responsible for the secondary inflammatory cascades during the development of AP, highlighting the HS-NLRP3 pathway as a potential target for future preventive and therapeutic approaches of AP.

A generalized interval-valued p,q Rung orthopair fuzzy Maclaurin symmetric mean and modified regret theory based sustainable supplier selection method.

A novel interval valued p,q Rung orthopair fuzzy (IVPQ-ROF) multiple attribute group decision making (MAGDM) method for sustainable supplier selection (SSS) is proposed in this paper. This study mainly contains two research points: (1) tackling the interrelation between attributes; and (2) describing the psychological state and risk attitude of decision makers (DMs). For the first research point, we introduce the Archimedean operation rules for interval valued p,q Rung orthopair fuzzy sets (IVPQ-ROFSs), then the generalized interval valued p, q Rung orthopair fuzzy Maclaurin symmetric mean (GIVPQ-ROFMSM) operator and the generalized interval valued p, q Rung orthopair fuzzy weighted Maclaurin symmetric mean (GIVPQ-ROFWMSM) operator are defined to reflect the correlation between attributes. For the second research point, we introduce the positive ideal degree (PID) and negative ideal degree (NID) based on projection of IVPQ-ROFSs, and modified regret theory. Both of them consider the best alternative and worst alternative, so as to reflect the psychological state and risk attitude of DMs. Finally, a SSS problem is presented to manifest the effectiveness of the designed method. We also provide sensitivity analysis and comparative analysis to further demonstrate the rationality and validity of the proposed method.

The natural course, treatment outcomes, and long-term prognosis of cervical spinal cord arteriovenous shunts.

OBJECTIVE: The highly intricate nature of the cervical spinal cord can cause arteriovenous shunts in these segments that may be associated with heightened clinical risks and treatment complexities. In this article, the authors aimed to provide a comprehensive analysis of the detailed natural course, treatment, and clinical outcomes of cervical spinal cord arteriovenous shunts (SCAVSs) based on the largest cohort to date. METHODS: Two hundred forty consecutive patients were included. Data on clinical presentation, angioarchitecture, treatment, and follow-up were retrospectively reviewed. RESULTS: The cohort demonstrated a greater prevalence of acute onset (63.3% vs 36.7%). Spontaneous recovery was observed in 63.7% of patients after onset, with a significantly elevated recovery rate observed among patients experiencing acute onset (72.4% vs 48.9%, p < 0.001). The risks of acute and gradual clinical deterioration after onset was 11.9%/year and 13.4%/year, respectively. Microsurgery was performed in 39.6% of patients, while the remaining 60.4% exclusively underwent embolization. The complete obliteration rate was 65.3% after microsurgery and 21.4% after embolization. The rate of treatment-related deterioration was 14.7% after microsurgery and 6.2% after embolization. After partial treatment, the acute and gradual deterioration rates were 4.1%/year and 6.6%/year, respectively. Lack of spontaneous recovery after onset was an independent predictor of embolization-related deterioration (OR 17.905, p = 0.007) and long-term gradual deterioration after partial treatment (HR 2.325, p = 0.021). After a median follow-up period of 32.55 months, prognosis was unfavorable in 16.7% of patients, with the sole independent risk factor being the absence of spontaneous recovery after onset (OR 2.476, p = 0.018). CONCLUSIONS: The outcomes of patients with cervical SCAVS were generally favorable, even in patients with only partial obliteration of the lesions. However, patients who did not show a trend toward spontaneous recovery after onset had a significantly elevated risk of unfavorable prognosis, highlighting the need for prompt clinical intervention.

GNA14 and GNAQ somatic mutations cause spinal and intracranial extra-axial cavernous hemangiomas.

Extra-axial cavernous hemangiomas (ECHs) are complex vascular lesions mainly found in the spine and cavernous sinus. Their removal poses significant risk due to their vascularity and diffuse nature, and their genetic underpinnings remain incompletely understood. Our approach involved genetic analyses on 31 tissue samples of ECHs employing whole-exome sequencing and targeted deep sequencing. We explored downstream signaling pathways, gene expression changes, and resultant phenotypic shifts induced by these mutations, both in vitro and in vivo. In our cohort, 77.4% of samples had somatic missense variants in GNA14, GNAQ, or GJA4. Transcriptomic analysis highlighted significant pathway upregulation, with the GNAQ c.626A>G (p.Gln209Arg) mutation elevating PI3K-AKT-mTOR and angiogenesis-related pathways, while GNA14 c.614A>T (p.Gln205Leu) mutation led to MAPK and angiogenesis-related pathway upregulation. Using a mouse xenograft model, we observed enlarged vessels from these mutations. Additionally, we initiated rapamycin treatment in a 14-year-old individual harboring the GNAQ c.626A>G (p.Gln209Arg) variant, resulting in gradual regression of cutaneous cavernous hemangiomas and improved motor strength, with minimal side effects. Understanding these mutations and their pathways provides a foundation for developing therapies for ECHs resistant to current therapies. Indeed, the administration of rapamycin in an individual within this study highlights the promise of targeted treatments in treating these complex lesions.

[Mechanism of total saponins of Panax japonicus against liver injury induced by acetaminophen in mice based on ERK/NF-κB/COX-2 signaling pathway].

This study investigated the effects and mechanisms of total saponins of Panax japonicus(TSPJ) against liver injury induced by acetaminophen(APAP). Male Kunming mice were randomly divided into a blank control group, TSPJ group(200 mg·kg~(-1), ig), model group, APAP+ TSPJ low-dose group(50 mg·kg~(-1), ig), APAP+ TSPJ medium-dose group(100 mg·kg~(-1), ig), APAP+ TSPJ high-dose group(200 mg·kg~(-1), ig), and APAP+ N-acetyl-L-cysteine group(200 mg·kg~(-1), ip). The administration group received the corresponding medications via ig or ip once a day for 14 consecutive days. After the last administration for one hour, except for the blank control group and TSPJ group, all groups of mice were given 500 mg·kg~(-1) APAP by gavage. After 24 hours, mouse serum and liver tissue were collected for serum alanine aminotransferase(ALT), aspartate aminotransferase(AST), reactive oxygen species(ROS), tumor necrosis factor alpha(TNF-α), interleukin-1 beta(IL-1ß), cyclooxygenase-2(COX-2), IL-6, IL-4, IL-10, as well as lactate dehydrogenase(LDH), glutathione(GSH), superoxide dismutase(SOD), catalase(CAT), total antioxidant capacity(T-AOC), malondialdehyde(MDA), and myeloperoxidase(MPO) liver tissue. Hematoxylin-eosin staining was used to observe the morphological changes of liver tissue. The mRNA expression levels of lymphocyte antigen 6G(Ly6G), galectin 3(Mac-2), TNF-α, IL-1ß, COX-2, IL-6, IL-4, and IL-10 in liver tissue were determined by quantitative real-time polymerase chain reaction(PCR). Western blot was utilized to detect the protein expression levels of Ly6G, Mac-2, extracellular regulated protein kinases(ERK), phosphorylated extracellular regulated protein kinases(p-ERK), COX-2, inhibitor of nuclear factor κB protein α(IκBα), phosphorylated inhibitor of nuclear factor κB protein α(p-IκBα), and nuclear factor-κB subunit p65(NF-κB p65) in cytosol and nucleus in liver tissue. The results manifested that TSPJ dramatically reduced liver coefficient, serum ALT, AST, ROS, TNF-α, IL-1ß, IL-6, and COX-2 levels, LDH, MPO, and MDA contents in liver tissue, and mRNA expressions of TNF-α, IL-1ß, and IL-6 in APAP-induced liver injury mice. It prominently elevated serum IL-4 and IL-10 levels, GSH, CAT, SOD, and T-AOC contents, and mRNA expressions of IL-4 and IL-10 in liver tissue, improved the degree of liver pathological damage, and suppressed neutrophil infiltration and macrophage recruitment in liver tissue. In addition, TSPJ lessened the mRNA and protein expressions of neutrophil marker Ly6G, macrophage marker Mac-2, and COX-2 in liver tissue, protein expressions of p-ERK, p-IκBα, and NF-κB p65 in nuclear, and p-ERK/ERK and p-IκBα/p-IκBα ratios and hoisted protein expression of NF-κB p65 in cytosol. These results suggest that TSPJ has a significant protective effect on APAP-induced liver injury in mice, and it can alleviate APAP-induced oxidative damage and inflammatory response. Its mechanism may be related to suppressing ERK/NF-κB/COX-2 signaling pathway activation, thus inhibiting inflammatory cell infiltration, cytokine production, and liver cell damage.

A novel method for extraction of high purity and high production Phytophthora sojae oospores.

BACKGROUND: Phytophthora sojae, a soil-borne oomycete pathogen, has been a yield limiting factor for more than 60 years on soybean. The resurgence of P. sojae (Phytophthora sojae) is primarily ascribed to the durable oospores found in soil and remnants of the disease. P. sojae is capable of infesting at any growth periods of the soybean, and the succeed infestation of P. sojae is predominantly attributed to long-lived oospores present in soil. Comprehending the molecular mechanisms that drive oospores formation and their significance in infestation is the key for effective management of the disease. However, the existing challenges in isolating and extracting significant quantities of oospores pose limitations in investigating the sexual reproductive stages of P. sojae. RESULTS: The study focused on optimizing and refining the culture conditions and extraction process of P. sojae, resulting in establishment of an efficient and the dependable method for extraction. Novel optimized approach was yielded greater quantities of high-purity P. sojae oospores than traditional methods. The novel approach exceeds the traditional approaches with respect to viability, survival ability, germination rates of new oospores and the pathogenicity of oospores in potting experiments. CONCLUSION: The proposed method for extracting P. sojae oospores efficiently yielded a substantial quantity of highly pure, viable, and pathogenic oospores. The enhancements in oospores extraction techniques will promote the research on the sexual reproductive mechanisms of P. sojae and lead to the creation of innovative and effective approaches for managing oomycete diseases.

Somatic BrafV600E mutation in the cerebral endothelium induces brain arteriovenous malformations.

Current treatments of brain arteriovenous malformation (BAVM) are associated with considerable risks and at times incomplete efficacy. Therefore, a clinically consistent animal model of BAVM is urgently needed to investigate its underlying biological mechanisms and develop innovative treatment strategies. Notably, existing mouse models have limited utility due to heterogenous and untypical phenotypes of AVM lesions. Here we developed a novel mouse model of sporadic BAVM that is consistent with clinical manifestations in humans. Mice with BrafV600E mutations in brain ECs developed BAVM closely resembled that of human lesions. This strategy successfully induced BAVMs in mice across different age groups and within various brain regions. Pathological features of BAVM were primarily dilated blood vessels with reduced vascular wall stability, accompanied by spontaneous hemorrhage and neuroinflammation. Single-cell sequencing revealed differentially expressed genes that were related to the cytoskeleton, cell motility, and intercellular junctions. Early administration of Dabrafenib was found to be effective in slowing the progression of BAVMs; however, its efficacy in treating established BAVM lesions remained uncertain. Taken together, our proposed approach successfully induced BAVM that closely resembled human BAVM lesions in mice, rendering the model suitable for investigating the pathogenesis of BAVM and assessing potential therapeutic strategies.

From Bi-Level to One-Level: A Framework for Structural Attacks to Graph Anomaly Detection.

The success of graph neural networks stimulates the prosperity of graph mining and the corresponding downstream tasks including graph anomaly detection (GAD). However, it has been explored that those graph mining methods are vulnerable to structural manipulations on relational data. That is, the attacker can maliciously perturb the graph structures to assist the target nodes in evading anomaly detection. In this article, we explore the structural vulnerability of two typical GAD systems: unsupervised FeXtra-based GAD and supervised graph convolutional network (GCN)-based GAD. Specifically, structural poisoning attacks against GAD are formulated as complex bi-level optimization problems. Our first major contribution is then to transform the bi-level problem into one-level leveraging different regression methods. Furthermore, we propose a new way of utilizing gradient information to optimize the one-level optimization problem in the discrete domain. Comprehensive experiments demonstrate the effectiveness of our proposed attack algorithm BinarizedAttack .

Summary of evidence on comprehensive healthcare for chemotherapy-induced peripheral neuropathy in cancer patients.

OBJECTIVE: This paper aims to provide an evidence-based summary of the most effective strategies for comprehensive healthcare of chemotherapy-induced peripheral neuropathy (CIPN) in cancer patients. METHOD: Following the "6S" model, relevant evidence on CIPN management was collected from reputable evidence-based resource websites and databases nationally and internationally. The included articles were evaluated for methodological quality, and evidence was extracted using the Australian JBI Evidence-based Health Care Center's literature evaluation standard (2016 edition). RESULTS: A total of 60 articles were included in this study, comprising 2 guidelines, 5 expert consensus statements, and 53 systematic reviews. The findings of these articles were summarized across 7 dimensions, including risk factor screening, assessment, diagnosis, prevention, treatment, management, and health education, resulting in the identification of 42 relevant pieces of evidence. CONCLUSIONS: This study provides a comprehensive synthesis of evidence-based recommendations for managing CIPN in cancer patients, offering guidance for healthcare professionals engaged in clinical practice. However, when implementing these recommendations, it is crucial to consider the individual patient's clinical circumstances, preferences, and expert judgment, ensuring feasibility and applicability in real-world clinical settings.

Successful treatment of Purpureocillium lilacinum pulmonary infection with isavuconazole: A case report.

BACKGROUND: Purpureocillium lilacinum (P. lilacinum) is a saprophytic fungus widespread in soil and vegetation. As a causative agent, it is very rarely detected in humans, most commonly in the skin. CASE SUMMARY: In this article, we reported the case of a 72-year-old patient with chronic lymphocytic leukemia who was admitted with cough and fever. Computed tomography revealed an infection in the right lower lobe. Bronchoalveolar lavage fluid culture and metagenomic next-generation sequencing were ultimately confirmed to have a pulmonary infection with P. lilacinum. She was eventually discharged with good outcomes after treatment with isavuconazole. CONCLUSION: Pulmonary infection with P. lilacinum was exceedingly rare. While currently there are no definitive therapeutic agents, there are reports of high resistance to amphotericin B and fluconazole and good sensitivity to second-generation triazoles. The present report is the first known use of isavuconazole for pulmonary P. lilacinum infection. It provides new evidence for the characterization and treatment of clinical P. lilacinum lung infections.

[Two kinds of percutaneous endoscopic lumbar decompression in the treatment of single level lumbar lateral recess stenosis].

OBJECTIVE: To prospectively compare the clinical efficacy and radiographic outcomes between interlaminar percutaneous endoscopic lumbar decompression(IL-PELD) and transforaminar percutaneous endoscopic lumbar decompression(TF-PELD) in the treatment of single-segment lumbar lateral recess stenosis. METHODS: From April 2018 to July 2021, 85 patients with single-segment lumbar lateral recess stenosis underment percutaneous endoscopic lumbar decompression.There were 44 males and 41 females, aged from 49 to 81 years old with an average of (65.5±8.3) years old, duration of lumbar lateral recess stenosis ranging from 3 to 83 months with an average of (26.7±16.5) months. They were divided into IL-PELD group and TF-PELD group according to the different operation methods. There were 47 patients in the IL-PELD group, including 28 males and 19 females aged from 50 to 80 yeaes old with an average age was (66.7±9.3) years old. The disease duration ranged from 3 to 65 months with an average of (25.7±15.0) months. There were 38 patients in the TF-PELD group, including 16 males and 22 females, aged from 51 to 78 years old with an average of(64.1±7.6) years old. The disease duration ranged from 4 to 73 months with an average of (27.9±18.3) months The operation time, intraoperative blood loss, intraoperative fluoroscopy, hospitalization day and complications of the two groups were recorded. Visual analogue scale (VAS) to evaluate low back pain and lower limb pain, Oswestry disability index(ODI) to evaluate lumbar function in preoperative and postoperative period(1month, 6 months and last follow-up)were recorded. the sagittal diameter of the lateral recess of the responsible intervertebral space in preoperative and 1 week after the operation were recorded. RESULTS: The operation was successfully completed in both groups without serious complications such as vascular injury, dural sac tear and nerve injury. The operation time in IL-PED group(69.3±19.3)min was significantly longer than that in TF-PELD group(57.5±14.5)min (P<0.05). There was no significant difference in the intraoperative blood loss between the two groups (P>0.05). The number of intraoperative fluoroscopy in TF-PELD group (8.8±2.6)times was significantly higher than that in IL-PED group(4.8±1.2)times (P<0.05). The hospitalization days of the two groups were not statistically significant (P>0.05). VAS for low back and lower extremity pain and ODI were (5.1±2.2), (6.9±1.3) scores and (71.4±12.6) % in IL-PELD group, and (4.7±1.8), (6.9±1.3) scores and (68.4±13.9)% in TF-PELD group. In the IL-PELD group, the VAS of low back pain was (2.4±1.5), (1.6±0.8), (1.4±0.9) scores, and the VAS of lower extremity pain was (3.0±1.2), (1.6±0.7), (1.5±1.0) scores, ODI was (32.6±11.9) %, (17.4±6.5) %, (19.3±9.3)%;In TF-PELD group, the VAS of low back pain was (2.6±1.4), (1.5±0.6), (1.4±1.0) scores, and the VAS of lower extremity pain was (2.8±1.2), (1.6±0.6), (1.5±1.2) scores, The ODI was (32.0±11.2) %, (15.0±6.1) %, and (20.0±11.3) %. The VAS and ODI of the two groups at each time point after operation were significantly improved compared with those before operation (P<0.05), but there was no statistically significant difference between the groups (P>0.05), and there was no statistically significant difference in the interaction between different time points and groups (P>0.05). At 1 week after operation, the sagittal diameter of lateral recess in both groups was significantly increased compared with that before operation (P<0.05), but there was no significant difference between the two groups at each time point (P>0.05). According to the modified Macnab criteria, IL-PELD group was rated as excellent in 24 cases, good in 19 cases and fair in 4 cases. In TF-PELD group the results were excellent in 19 cases, good in 15 cases, fair in 3 cases and poor in 1 case. There was no significant difference between the two groups (P>0.05). CONCLUSION: IL-PELD and TF-PELD can expand the lateral recess in the treatment of single level lumbar lateral recess stenosis, and have achieved good clinical effects.

AStruct: detection of allele-specific RNA secondary structure in structuromic probing data.

BACKGROUND: Uncovering functional genetic variants from an allele-specific perspective is of paramount importance in advancing our understanding of gene regulation and genetic diseases. Recently, various allele-specific events, such as allele-specific gene expression, allele-specific methylation, and allele-specific binding, have been explored on a genome-wide scale due to the development of high-throughput sequencing methods. RNA secondary structure, which plays a crucial role in multiple RNA-associated processes like RNA modification, translation and splicing, has emerged as an essential focus of relevant research. However, tools to identify genetic variants associated with allele-specific RNA secondary structures are still lacking. RESULTS: Here, we develop a computational tool called 'AStruct' that enables us to detect allele-specific RNA secondary structure (ASRS) from RT-stop based structuromic probing data. AStruct shows robust performance in both simulated datasets and public icSHAPE datasets. We reveal that single nucleotide polymorphisms (SNPs) with higher AStruct scores are enriched in coding regions and tend to be functional. These SNPs are highly conservative, have the potential to disrupt sites involved in m6A modification or protein binding, and are frequently associated with disease. CONCLUSIONS: AStruct is a tool dedicated to invoke allele-specific RNA secondary structure events at heterozygous SNPs in RT-stop based structuromic probing data. It utilizes allelic variants, base pairing and RT-stop information under different cell conditions to detect dynamic and functional ASRS. Compared to sequence-based tools, AStruct considers dynamic cell conditions and outperforms in detecting functional variants. AStruct is implemented in JAVA and is freely accessible at: https://github.com/canceromics/AStruct .

Comparative Bioequivalence and Food Effect of Two Formulations of 30-mg Nifedipine Controlled-Release Tablets in Healthy Chinese Adults.

Nifedipine is a potent antihypertensive medication classified as a dihydropyridine calcium channel blocker. The objective of this trial was to assess the bioequivalence of a 30-mg nifedipine controlled-release tablet and a reference drug in a cohort of healthy Chinese individuals. Two independent open-label, randomized, single-dose, crossover studies were conducted, 1 under fasting conditions (N = 44, with 1 participant dropping out midway) and the other under fed conditions (N = 44, with 4 participants dropping out midway). Plasma concentrations of nifedipine were determined using liquid chromatography-mass spectrometry, and pharmacokinetic (PK) parameters were calculated using noncompartmental analysis with Phoenix WinNonlin 8.0 software. In both fasting and fed studies, reasonable bioequivalence was observed for the PK parameters of both the test product and the reference drug. A good safety profile was demonstrated for both the test product and reference drug, with no serious adverse events reported, and both were similarly well tolerated. An important observation with food coadministration was that systemic exposure to nifedipine (based on area under the curve, AUC0-∞) was reduced by approximately 12%. The bioequivalence of the test product and reference drug under fasting/fed conditions in healthy subjects in China was demonstrated by the study results.

[Effect and complication among different kinds of spinal endoscopic surgery for lumbar disc herniation].

OBJECTIVE: To compare clinical efficacy and complication rate of percutaneous endoscopic transforaminal discectomy(PETD),percutaneous endoscopic interlaminar discectomy (PEID) and unilateral biportal endoscopic (UBE) in treating single-segment lumbar disc herniation(LDH). METHODS: From October 2019 to August 2021,121 LDH patients with single-segment treated by spinal endoscopy were retrospectively analyzed and divided into three groups. In PETD group,there were 48 patients,including 19 males and 29 females,aged from 18 to 72 years old with an average of (44.0±13.9) years old;3 patients with L3,4 segments,27 patients with L4,5 segments,and 18 patients with L5S1 segments. In PEID group,there were 43 patients,including 23 males and 20 females,aged from 20 to 69 years old with an average of (40.1±12.1) years old;1 patient with L3,4 segments,15 patients with L4,5 segments,and 27 patients with L5S1 segments. In UBE group,there were 30 patients,including 12 males and 18 females,aged from 29 to 72 years old with an average of (41.2±15.0) years old;1 patient with L3,4 segments,18 patients with L4,5 segments,and 11 patients with L5S1 segments. Operation time,blood loss,fluoroscopy times and complications among three groups were observed and compared. Before opertaion,3 months after operation and at the latest follow-up,visual analogue scale (VAS) was used to evaluate low back pain and lower extremity pain,Oswestry disfunction index (ODI) was used to evaluate lumbar function,and modified MacNab was used to evaluate clinical efficacy at the latest follow-up. RESULTS: All patients were performed endoscopic spinal surgery completly and were followed up for at least 12 months. One patient occurred dural sac rupture both in PETD and PEID group,and dural sac rupture was small,and there was no obvious discomfort after operation. Two patients were occurred intraoperative rupture of dural sac in UBE group. One patient was occurred cerebrospinal fluid leakage after operation,and was improved after rest in supine position and fluid rehydration. One patient without no significant postoperative discomfort. (1)There were no significant difference in operating time,blood loss and hospital stay between PETD and PEID group (P>0.05),while UBE group was higher than those of PETD and PEID group (P<0.05). There was no statistical significance in fluoroscopy times between PEID and UBE group (P>0.05),but PETD group was higher than that of PEID and UBE group (P<0.05). (2)VAS of low back pain at 3 months after operation in UBE group was higher than that in PETD and PEID group (P<0.05),but there was no significant difference between PETD and PEID group (P>0.05). At the latest follow-up,there was no significant difference in VAS of low back pain among three groups (P>0.05). (3)Lower extremity pain of VAS and ODI among 3 groups after operation were significantly improved at all time points compared with those before opertaion(P<0.05),and there were no statistical significance between groups (P>0.05),and there were no statistical significance in interaction between different time points and operation groups (P>0.05). (4) At the latest follow-up,according to the modified MacNab standard,the results of PETD group were excellent in 27 patients,good in 16 patients,moderate in 4 patients,poor in 1 patient;in PEID group,27 patients got excellent result,12 good,3 moderate,and 1 poor;in UBE group,16 patients got excellent,10 good,2 moderate,and 2 poor. There was no significant difference among three groups (χ2=0.308,P>0.05). Recurrence of lumbar disc herniation occurred in 1 patient among each three groups,symptoms were improved in 2 patients after symptomatic treatment,and 1 patient was treated in other hospitals. CONCLUSION: PETD,PEID and UBE techniques could achieve good early clinical effects in treating lumbar disc herniation with similar complication rates. Both of PETD and PEID are single-channel minimally invasive surgery,with mild intraoperative tissue damage and quick postoperative recovery; while intraoperative fluoroscopy of PETD was relatively more frequent, and PEID was more suitable for L5S1 segment;UBE is a two-channel surgery,in which the intraoperative soft tissue damage is more severe,but exposure is broad,which is more suitable for complex cases.

Unified Strategy Enables the Collective Syntheses of Structurally Diverse Indole Alkaloids.

Natural products and their analogues are significant sources of therapeutic lead compounds. However, synthetic strategies for generating large collections of these molecules remain a significant challenge. The most difficult step in their synthesis is the design of a common intermediate that can be easily transformed into natural products belonging to different families. This study demonstrates the evolution of synthetic tactics designed to assemble the functionalized piperidines present in indole alkaloids from a common intermediate. More importantly, we also report a previously unknown Ir- and Er-catalyzed dehydrogenative spirocyclization reaction that enables direct access to spirocyclic oxindole alkaloids. As a practical application, the asymmetric total syntheses of 29 natural alkaloids belonging to different families were accomplished by following a uniform synthetic route. The proposed methodology extends the capability of the iridium-catalyzed dehydrogenative coupling reaction to the realm of indole-alkaloid synthesis and provides new opportunities for the efficient preparation of natural product-like molecules.

In vitro and vivo anti-tumor activity and mechanisms of the new cryptotanshinone derivative 11 against hepatocellular carcinoma.

Global burden of hepatocellular carcinoma (HCC) is increasing. Chemotherapy and immunotherapy are the prevailing options for therapy. Developing new therapeutic strategies for HCC patients is still highly desirable. Recent studies demonstrate that cryptotanshinone is capable of inhibiting tumor growth in HCC and induces antitumor immunity in vitro. In our previous research, we discovered a new cryptotanshinone derivative 11 as an effective immunoregulatory enzyme indoleamine 2, 3-dioxygenase 1 (IDO1) inhibitor. This study aims to evaluate its in vitro and in vivo antitumor activity against hepatocellular carcinoma. 11 displayed robust anti-proliferative activity against HCC cell lines and promoted apoptosis of HCC cell line through the mitochondrial-mediated apoptotic pathway. In H22 tumor-bearing mice models, 11 exhibited significant in vivo anti-tumor activity with different administration routes. And no obvious toxicity was observed. RNA-seq analysis demonstrated the differential expressed genes and alteration of key pathways associated with immune responses after administration of 11. Up-regulation of anti-tumor cytokines and down-regulation of cytokines that promote tumor growth were indicated and further validated. Our study demonstrates that 11 exhibits promising anti-tumor activity both in vitro and in vivo against hepatocellular carcinoma cancer. It is a lead compound for HCC immunotherapy and is worthy for further development.

Oral cancer cell to endothelial cell communication via exosomal miR-21/RMND5A pathway.

Required for meiotic nuclear division 5 homolog A (RMND5A), a novel ubiquitin E3 Ligase, has been reported to correlate with poor prognosis of several cancers. However, its role in endothelial cells has not been reported. In this study, overexpression of RMND5A in human umbilical vein endothelial cells (HUVECs) was performed via lentiviral infection, followed by MTT, would healing and tube formation assay as well as signaling analysis. Moreover, crosstalk between HUVECs and oral squamous cell carcinoma (OSCC) cells was investigated by indirect co-culture with condition medium or tumor cell derived exosomes. Our results showed that overexpression of RMND5A reduced the proliferation, migration and tube formation ability of HUVECs by inhibiting the activation of ERK and NF-κB pathway. Interestingly, OSCC cells can inhibit RMND5A expression of endothelial cells via exosomal miR-21. In summary, our present study unveils that OSCC cells can activate endothelial cells via exosomal miR-21/RMND5A pathway to promote angiogenesis, which may provide novel therapeutic targets for the treatment of OSCC.