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OBJECTIVE: In light of the increasing importance of immunotherapy in bladder cancer treatment, this study is aim to investigate the expression and clinical significance of programmed cell surface death-1 (PD-1) in bladder cancer patients without lymph node metastasis, and to compare and analyze the difference of PD-1 in draining lymph nodes and tumor tissues. METHODS: The expression of PD-1 on T cells and the proportion of positive PD-1 + T cells of IFN-γ and CD105a were detected by flow cytometry, and the correlation between PD-1 expression and clinical parameters was analyzed. RESULTS: The percentage of PD-1 positive cells in drainage lymph nodes was higher than that in tumor tissues (P < 0.001). PD-1 positive cells accounted for the highest proportion in CD3 + T cells. The proportion of IFN-γ-positive PD-1 + T cells in draining lymph nodes was significantly higher than that in tumor tissues (P < 0.001), while there was no significant difference in CD105a positive PD-1 + T cells between tumor tissues and draining lymph nodes. Pathological grade, tumor size and stage were positively correlated with PD-1 expression level in the lymph nodes. CONCLUSION: The high expression of PD-1 in patients with bladder cancer without lymph node metastasis, especially in draining lymph nodes, suggests that PD-1 may play a key role in the regulation of tumor immune microenvironment. The correlation between PD-1 and clinical parameters indicates its potential prognostic value. These findings provide important clinical implications for PD-1 targeted therapy, but further prospective studies are needed to determine the application value of PD-1 in therapeutic strategies.
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PURPOSE: To evaluate the chemotherapeutic activity of temozolomide counter to mammary carcinoma. METHODS: In-vitro anticancer activity has been conducted on MCF7 cells, and mammary carcinoma has been induced in Wistar rats by introduction of 7, 12-Dimethylbenz(a)anthracene (DMBA), which was sustained for 24 weeks. Histopathology, immunohistochemistry, cell proliferation study and apoptosis assay via TUNEL method was conducted to evaluate an antineoplastic activity of temozolomide in rat breast tissue. RESULTS: IC50 value of temozolomide in MCF7 cell has been obtained as 103 µM, which demonstrated an initiation of apoptosis. The temozolomide treatment facilitated cell cycle arrest in G2/M and S phase dose dependently. The treatment with temozolomide suggested decrease of the hyperplastic abrasions and renovation of the typical histological features of mammary tissue. Moreover, temozolomide therapy caused the downregulation of epidermal growth factor receptor, extracellular signal-regulated kinase, and metalloproteinase-1 expression and upstream of p53 and caspase-3 proliferation to indicate an initiation of apoptotic events. CONCLUSIONS: The occurrence of mammary carcinoma has been significantly decreased by activation of apoptotic pathway and abrogation of cellular propagation that allowable for developing a suitable mechanistic pathway of temozolomide in order to facilitate chemotherapeutic approach.
Subject(s)
Antineoplastic Agents, Alkylating , Apoptosis , ErbB Receptors , Rats, Wistar , Temozolomide , Temozolomide/pharmacology , Temozolomide/therapeutic use , Animals , Apoptosis/drug effects , Female , ErbB Receptors/drug effects , ErbB Receptors/antagonists & inhibitors , Antineoplastic Agents, Alkylating/pharmacology , Antineoplastic Agents, Alkylating/therapeutic use , Matrix Metalloproteinase 1/drug effects , Matrix Metalloproteinase 1/metabolism , Cell Proliferation/drug effects , Dacarbazine/analogs & derivatives , Dacarbazine/pharmacology , Dacarbazine/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Humans , MCF-7 Cells , Extracellular Signal-Regulated MAP Kinases/metabolism , Extracellular Signal-Regulated MAP Kinases/drug effects , Immunohistochemistry , Reproducibility of Results , Rats , Mammary Neoplasms, Experimental/drug therapy , Mammary Neoplasms, Experimental/pathologyABSTRACT
Globally, prostate cancer is the most commonly diagnosed tumor and a cause of death in older men. Abiraterone, an orally administered irreversible CYP17 inhibitor, is employed to treat prostate cancer. However, abiraterone has several clinical limitations, such as poor water solubility, low dissolution rate, low bioavailability, and toxic side effects in the liver and kidney. Therefore, there is a need to identify high-efficiency and low-toxicity water-soluble abiraterone derivatives. In this work, we aimed to design and synthesize a series of abiraterone derivatives by methoxypoly(ethylene glycol) (mPEG) modification. Their antitumor activities and toxicology were analyzed in vitro and in vivo. The most potent compound, 2e, retained the principle of action on the CYP17 enzyme target and significantly improved the abiraterone water solubility, cell permeability, and blood safety. No significant abnormalities were observed in toxicology. mPEG-modification significantly improved abiraterone's antitumor activity and efficiency while reducing the associated toxic effects. The finding will provide a theoretical basis for future clinical application of mPEG-modified abiraterone.
Subject(s)
Androstenes , Antineoplastic Agents , Polyethylene Glycols , Prostatic Neoplasms , Solubility , Male , Humans , Androstenes/pharmacology , Androstenes/chemistry , Animals , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Polyethylene Glycols/chemistry , Mice , Cell Line, Tumor , Xenograft Model Antitumor Assays , Steroid 17-alpha-Hydroxylase/antagonists & inhibitors , Steroid 17-alpha-Hydroxylase/metabolismABSTRACT
Covalently linking an adjuvant to an antigenic protein enhances its immunogenicity by ensuring a synergistic delivery to the immune system, fostering a more robust and targeted immune response. Most adjuvant-protein conjugate vaccines incorporate only one adjuvant due to the difficulties in its synthesis. However, there is a growing interest in developing vaccines with multiple adjuvants designed to elicit a more robust and targeted immune response by engaging different aspects of the immune system for complex diseases where traditional vaccines fall short. Here, we pioneer the synthesis of a dual-adjuvants protein conjugate Vaccine 1 by assembling a toll-like receptor 7/8 (TLR7/8) agonist, an invariant natural killer T cell (iNKT) agonist with a clickable bicyclononyne (BCN). The BCN group can bio-orthogonally react with azide-modified severe acute respiratory syndrome coronavirus-2 receptor-binding domain (SARS-CoV-2 RBD) trimer antigen to give the three-component Vaccine 1. Notably, with a mere 3 µg antigen, it elicited a balanced subclass of IgG titers and 20-fold more IgG2a than control vaccines, highlighting its potential for enhancing antibody-dependent cellular cytotoxicity. This strategy provides a practicable way to synthesize covalently linked dual immunostimulants. It expands the fully synthetic self-adjuvant protein vaccine that uses a single adjuvant to include two different types of adjuvants.
Subject(s)
Adjuvants, Immunologic , COVID-19 Vaccines , COVID-19 , Natural Killer T-Cells , SARS-CoV-2 , Toll-Like Receptor 7 , Toll-Like Receptor 8 , Toll-Like Receptor 7/agonists , Toll-Like Receptor 7/immunology , SARS-CoV-2/immunology , Animals , Natural Killer T-Cells/immunology , COVID-19 Vaccines/immunology , COVID-19 Vaccines/pharmacology , Toll-Like Receptor 8/agonists , Toll-Like Receptor 8/immunology , Humans , Adjuvants, Immunologic/pharmacology , Adjuvants, Immunologic/chemistry , Mice , COVID-19/prevention & control , COVID-19/immunology , Spike Glycoprotein, Coronavirus/immunology , Antibodies, Viral/immunology , Female , Adjuvants, Vaccine/chemistry , Adjuvants, Vaccine/pharmacology , Immunoglobulin G/immunologyABSTRACT
Vaccines typically work by eliciting an immune response against larger antigens like polysaccharides or proteins. Small molecules like nicotine, on their own, usually cannot elicit a strong immune response. To overcome this, anti-nicotine vaccines often conjugate nicotine molecules to a carrier protein by carbodiimide crosslinking chemistry to make them polymeric and more immunogenic. The reaction is sensitive to conditions such as pH, temperature, and the concentration of reactants. Scaling up the reaction from laboratory to industrial scales while maintaining consistency and yield can be challenging. Despite various approaches, no licensed anti-nicotine vaccine has been approved so far due to the susboptimal antibody titers. Here, we report a novel approach to conjugate maleimide-modified nicotine hapten with a disulfide bond-reduced carrier protein in an organic solvent. It has two advantages compared with other approaches: (1) The protein was unfolded to make the peptide conformation more flexible and expose more conjugation sites; (2) thiol-maleimide "click" chemistry was utilized to conjugate the disulfide bond-reduced protein and maleimide-modified nicotine due to its availability, fast kinetics, and bio-orthogonality. Various nicotine conjugate vaccines were prepared via this strategy, and their immunology effects were investigated by using MPL and QS-21 as adjuvants. The in vivo study in mice showed that the nicotine-BSA conjugate vaccines induced high anti-nicotine IgG antibody titers, compared with vaccines prepared by using traditional condensation methods, indicating the success of the current strategy for further anti-nicotine or other small-molecule vaccine studies. The enhancement was more significant by using MPL and QS-21 than that of traditional aluminum adjuvants.
ABSTRACT
A novel method for the glycosylation of selenoglycosides activated by iodosylbenzene was developed. The glycosylation reaction conditions were mild, fast, and efficient, with a high tolerance to diverse protecting groups and a wide substrate scope, which is advantageous for synthesizing complex glycosides. In addition, selenoglycosides were shown to be orthogonal to thioglycosides under the promotion of iodosylbenzene. Notably, a high yield of the poorly reactive glucuronidation reaction product was obtained by acetyl-protected selenoglycoside. Finally, the orthogonal one-pot synthesis of ß-(1â6) oligoglucans demonstrated the usefulness of this method in oligosaccharide synthesis.
Subject(s)
Iodobenzenes , Thioglycosides , Glycosylation , Glycosides , OligosaccharidesABSTRACT
Adjuvants enhance the body's immune response to a vaccine, often leading to better protection against diseases. Monophosphoryl lipid A analogues (MPLA, TLR4 agonists), α-galactosylceramide analogues (NKT cell agonists), and imidazoquinoline compounds (TLR7/8 agonists) are emerging novel adjuvants on market or under clinical trials. Despite significant interest in these adjuvants, a direct comparison of their adjuvant activities remains unexplored. We initially assessed the activities of various adjuvants from three distinct categories using the SARS-CoV-2 RBD trimer antigen. TLR4 and TLR7/8 agonists are discovered to elicit robust IgG2a/2b antibodies, which is crucial for eliciting antibody dependent cytotoxicity. While α-galactosylceramide analogs induced mainly IgG1 antibody. Then, because of the flexibility of the TLR7/8 agonist, we designed and synthesized a tri-component self-adjuvanting SARS-CoV-2 RBD vaccine, featuring a covalent TLR7 agonist and targeting mannoside. Animal studies indicated that this vaccine generated antigen-specific humoral immunity. Yet, its immunogenicity seems compromised, indicating the complexity of the vaccine.
Subject(s)
Adjuvants, Immunologic , COVID-19 Vaccines , COVID-19 , SARS-CoV-2 , Toll-Like Receptor 7 , Toll-Like Receptor 7/agonists , Animals , COVID-19 Vaccines/immunology , SARS-CoV-2/immunology , Adjuvants, Immunologic/pharmacology , Humans , COVID-19/prevention & control , COVID-19/immunology , COVID-19/virology , Female , Mice , Antibodies, Viral/blood , Antibodies, Viral/immunology , Immunogenicity, Vaccine , Adjuvants, Vaccine , Spike Glycoprotein, Coronavirus/immunology , Mice, Inbred BALB C , Immunity, Humoral/drug effects , Immunoglobulin G/blood , Immunoglobulin G/immunologyABSTRACT
BACKGROUND: Numerous studies have explored the therapeutic potential of microRNA (miR) in myocardial infarction (MI) treatment. This study focuses on the role of miR-322-5p in MI, particularly in its regulatory interaction with B-cell translocation gene 2 (BTG2). MATERIALS AND METHODS: Expression levels of miR-322-5p and BTG2 were assessed in a rat MI model. Adenovirus altering miR-322-5p or BTG2 expression were administered to MI rats. Evaluation included cardiac function, inflammation, myocardial injury, pathological changes, apoptosis, and NF-κB pathway-related genes in MI rats post-targeted treatment. The miR-322-5p and BTG2 targeting relationship was investigated. RESULTS: MI rats exhibited low miR-322-5p and high BTG2 expression in the myocardial tissues. Restoration of miR-322-5p enhanced cardiac function, alleviated inflammation and myocardial injury, mitigated pathological changes and apoptosis, and deactivated the NF-κB pathway in MI rats. BTG2 expression was negatively-regulated by miR-322-5p. Overexpressed BTG2 counteracted miR-322-5p-induced cardioprotection on MI rats. CONCLUSION: This study provides evidence that miR-322-5p protects against MI by suppressing BTG2 expression.
Subject(s)
Immediate-Early Proteins , MicroRNAs , Myocardial Infarction , Animals , Male , Rats , Apoptosis , Disease Models, Animal , Immediate-Early Proteins/genetics , Immediate-Early Proteins/metabolism , MicroRNAs/metabolism , MicroRNAs/genetics , Myocardial Infarction/genetics , Myocardial Infarction/metabolism , Myocardial Infarction/pathology , NF-kappa B/metabolism , Rats, Sprague-Dawley , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolismABSTRACT
Mitophagy is a selective autophagy for the degradation of damaged or excessive mitochondria to maintain intracellular homeostasis. In Magnaporthe oryzae, a filamentous ascomycetous fungus that causes rice blast, the most devastating disease of rice, mitophagy occurs in the invasive hyphae to promote infection. To date, only a few proteins are known to participate in mitophagy and the mechanisms of mitophagy are largely unknown in pathogenic fungi. Here, by a yeast two-hybrid screen with the core autophagy-related protein MoAtg8 as a bait, we obtained a MoAtg8 interactor MoAti1 (MoAtg8-interacting protein 1). Fluorescent observations and protease digestion analyses revealed that MoAti1 is primarily localized to the peripheral mitochondrial outer membrane and is responsible for recruiting MoAtg8 to mitochondria under mitophagy induction conditions. MoAti1 is specifically required for mitophagy, but not for macroautophagy and pexophagy. Infection assays suggested that MoAti1 is required for mitophagy in invasive hyphae during pathogenesis. Notably, no homologues of MoAti1 were found in rice and human protein databases, indicating that MoAti1 may be used as a potential target to control rice blast. By the host-induced gene silencing (HIGS) strategy, transgenic rice plants targeted to silencing MoATI1 showed enhanced resistance against M. oryzae with unchanged agronomic traits. Our results suggest that MoATI1 is required for mitophagy and pathogenicity in M. oryzae and can be used as a target for reducing rice blast.
Subject(s)
Ascomycota , Magnaporthe , Oryza , Humans , Mitophagy , Autophagy/genetics , Fungal Proteins/genetics , Fungal Proteins/metabolism , Plants, Genetically Modified/metabolism , Oryza/microbiology , Plant Diseases/microbiologyABSTRACT
Heparin, an anticoagulant with a century-long history of use, has been investigated over the past decade as a potential drug delivery vehicle. Despite its safety and efficacy, its interactions with many proteins through specific sulfate patterns can complicate drug delivery by mediating diverse biological functions. Here, we present the synthesis of a three-component drug delivery system comprising de-sulfated heparin as the carrier, galactose as the targeting moiety, and paclitaxel as the therapeutic drug. Removal of sulfates eliminated most of its anticoagulant effects in all intermediates. Through coupling with galactose and paclitaxel, the system improved the solubility of the drug and achieved selective targeting and efficient drug delivery to HepG2 cells, a liver carcinoma cell line with high galactose receptor expression. While the three-component system exhibited a slightly higher IC50 value than native paclitaxel, demonstrating its efficacy as a drug carrier, the IC50 value for the normal human liver cell line QSG7701 was significantly higher, indicating its selectivity and safety. Our study introduces a novel approach utilizing desulfated heparin as a carrier, warranting further investigation to unlock its potential in targeted drug delivery strategies.
Subject(s)
Heparin , Paclitaxel , Humans , Paclitaxel/pharmacology , Galactose , Sulfates/metabolism , Anticoagulants , Drug Delivery SystemsABSTRACT
Surgical site infections (SSIs) may pose a significant risk to patients undergoing surgery. This study aims to explore the risk factors for SSIs in patients undergoing laparoscopic radical nephrectomy for renal cell carcinoma and the impact of infection on tumour-specific survival (CSS) after nephrectomy for renal cell carcinoma. To explore the risk factors for SSIs in patients undergoing laparoscopic radical nephrectomy for renal cell carcinoma and the impact of infection on tumour-specific survival (CSS) after nephrectomy for renal cell carcinoma. A retrospective analysis was conducted on 400 patients in our hospital from June 2021 to June 2023. This study divided patients into two groups: those with SSI and those without SSI. Collect general data and information related to the operating room. Clearly defined inclusion and exclusion criteria. Select surgical time, laminar mobile operating room use, and intraoperative hypothermia as observation indicators. Perform statistical analysis using SPSS 25.0 software, including univariate, multivariate, and survival analyses of wound-infected and uninfected patients. Out of 400 patients, 328 had no SSIs, 166 died during follow-up, 72 had SSIs, and 30 died during follow-up. There was no statistically significant difference (p > 0.05) in comparing primary data between individuals without SSIs and those with SSIs. There were statistically significant differences (p < 0.05) in surgical time, nonlaminar flow operating room use, and intraoperative hypothermia. The postoperative survival time of SSI patients with a tumour diameter of 7.0-9.9 cm was significantly longer than that of SSI patients, and the difference was statistically significant (p < 0.05). The occurrence of severe infection in patients with other tumour diameters did not affect postoperative survival, and the difference was not statistically significant (p > 0.05). After multiple factor analysis, it was found that severe infection can prolong the postoperative survival of patients with tumour diameter exceeding 7 cm (HR = 0.749, p < 0.05). This study identified nonlaminar flow operating rooms, prolonged surgical time, and intraoperative hypothermia as significant risk factors for SSIs. After nephrectomy for renal cell carcinoma patients with a tumour diameter of 7-9.9 µ m, perioperative infection can prolong their survival. However, it has no significant effect on patients with other tumour diameters.
Subject(s)
Carcinoma, Renal Cell , Hypothermia , Kidney Neoplasms , Laparoscopy , Humans , Carcinoma, Renal Cell/surgery , Surgical Wound Infection/epidemiology , Survival Rate , Retrospective Studies , Hypothermia/complications , Hypothermia/surgery , Nephrectomy/adverse effects , Laparoscopy/adverse effects , Kidney Neoplasms/surgeryABSTRACT
Multicolor afterglow patterns with transparent and traceless features are important for the exploration of new functionalities and applications. Herein, we report a direct in situ patterning technique for fabricating afterglow carbon dots (CDs) based on laser direct writing (LDW) for the first time. We explore a facile step-scanning method that reduces the heat-affected zone and avoids uneven heating, thus producing a fine-resolution afterglow CD pattern with a minimum line width of 80 µm. Unlike previous LDW-induced luminescence patterns, the patterned CD films are traceless and transparent, which is mainly attributed to a uniform heat distribution and gentle temperature rise process. Interestingly, by regulating the laser parameters and CD precursors, an increased carbonization and oxidation degree of CDs could be obtained, thus enabling time-dependent, tunable afterglow colors from blue to red. In addition, we demonstrate their potential applications in the in situ fabrication of flexible and stretchable optoelectronics.
ABSTRACT
Regulation of the fluorescence through crystalizing from the matrix in the Carbon dots (CDs)-based solid-state materials has been verified to be one of the effective methods, yet there are not only challenges in preparing such materials efficiently, but also insufficient insight into their regulation mechanisms. Here, a one-pot solvothermal route to synthesize a series of CDs-based composites with crystalline matrix is reported. These crystals exhibited multicolor fluorescence with the feature of multi-peaks emissions with increasing temperatures from 140 â to 220 â, in which the orange emitting O-CDs@PA and the yellow emitting Y-CDs@PA crystals obtained the FLQYs of 22% and 68% respectively due to relatively stable crystalline structures. After comparative analysis to both crystals in detail, the core and the groups associated with them on the interface between CDs and matrix were adjusted in size and species during structural transformation of the crystal matrix, which changes radically the energy band structures to influence fluorescent emitting of both crystals ultimately. In addition, the reasons resulting in higher FLQY for Y-CDs@PA were provided leveraging the schematic illustration presumed based on the PL properties of both crystals. Because of the optimal optical performances, these fluorescent materials promised to fabricate WLED devices and obtained a number of photometric parameters endowed these WLED devices with the feature of warm-white light.
ABSTRACT
3-Deoxy-d-manno-oct-2-ulosonic acid (Kdo) is an eight-carbon monosaccharide found widely in bacterial lipopolysaccharides (LPSs) and capsule polysaccharides (CPSs). We developed an indirect method for the stereoselective synthesis of α-Kdo glycosides with a C3-p-tolylthio-substituted Kdo phosphite donor. The presence of the p-tolylthio group enhanced the reactivity, suppressed the formation of elimination by-products (2,3-enes), and provided complete α-stereocontrol. A variety of Kdo α-glycosides were synthesized by our method in excellent yields (up to 98 %). After glycosylation, the p-tolylthio group can be efficiently removed by free-radical reduction. Subsequently, the orthogonality of the phosphite donor and thioglycoside donor was demonstrated by the one-pot synthesis of a trisaccharide in Helicobacter pylori and Neisseria meningitidis LPS. Moreover, an efficient total synthesis route to the challenging 4,5-branched Kdo trisaccharide in LPSs from several A. baumannii strains was highlighted. To demonstrate the high reactivity of our approach further, the highly crowded 4,5,7,8-branched Kdo pentasaccharide was synthesized as a model molecule for the first time. Additionally, the reaction mechanism was investigated by DFT calculations.
Subject(s)
Glycosides , Phosphites , Oligosaccharides , Sugar Acids , Lipopolysaccharides , TrisaccharidesABSTRACT
Purpose: To evaluate the chemotherapeutic activity of temozolomide counter to mammary carcinoma. Methods: In-vitro anticancer activity has been conducted on MCF7 cells, and mammary carcinoma has been induced in Wistar rats by introduction of 7, 12-Dimethylbenz(a)anthracene (DMBA), which was sustained for 24 weeks. Histopathology, immunohistochemistry, cell proliferation study and apoptosis assay via TUNEL method was conducted to evaluate an antineoplastic activity of temozolomide in rat breast tissue. Results: IC50 value of temozolomide in MCF7 cell has been obtained as 103 µM, which demonstrated an initiation of apoptosis. The temozolomide treatment facilitated cell cycle arrest in G2/M and S phase dose dependently. The treatment with temozolomide suggested decrease of the hyperplastic abrasions and renovation of the typical histological features of mammary tissue. Moreover, temozolomide therapy caused the downregulation of epidermal growth factor receptor, extracellular signal-regulated kinase, and metalloproteinase-1 expression and upstream of p53 and caspase-3 proliferation to indicate an initiation of apoptotic events. Conclusions: The occurrence of mammary carcinoma has been significantly decreased by activation of apoptotic pathway and abrogation of cellular propagation that allowable for developing a suitable mechanistic pathway of temozolomide in order to facilitate chemotherapeutic approach.
Subject(s)
Animals , Rats , Breast Neoplasms/drug therapy , Apoptosis , Temozolomide , Animals, LaboratoryABSTRACT
BACKGROUND: Upstream stimulatory factors (USFs) are members of the basic helix-loop-helix leucine zipper transcription factor family, including USF1, USF2, and USF3. The first two members have been well studied compared to the third member, USF3, which has received scarce attention in cancer research to date. Despite a recently reported association of its alteration with thyroid carcinoma, its expression has not been previously analyzed. METHODS: We comprehensively analyzed differential levels of USFs expression, genomic alteration, DNA methylation, and their prognostic value across different cancer types and the possible correlation with tumor-infiltrating immune cells and drug response by using different bioinformatics tools. RESULTS: Our findings established that USFs play an important role in cancers related to the urinary system and justify the necessity for further investigation. We implemented and offer a useful ShinyApp to facilitate researchers' efforts to inquire about any other gene of interest and to perform the analysis of drug response in a user-friendly fashion at http://zzdlab.com:3838/Drugdiscovery/.
Subject(s)
DNA-Binding Proteins , Neoplasms , Humans , Upstream Stimulatory Factors/genetics , Upstream Stimulatory Factors/metabolism , DNA-Binding Proteins/metabolism , Neoplasms/geneticsABSTRACT
Introduction: The optimal percutaneous coronary intervention (PCI) strategy for coronary left main (LM) bifurcation lesions remains controversial. This meta-analysis compared the medium and long-term follow-up clinical outcomes of single vs. systematic dual stenting strategies of LM bifurcation lesions. Methods: We systematically identified studies published within 5 years comparing single vs. systematic double stenting strategies for LM bifurcation lesions. The primary endpoint was medium-term (1 year) and long-term (at least 3 years) all-cause death. Secondary outcomes included major adverse cardiovascular events (MACEs), target lesion revascularization (TLR), overall occurrence of stent thrombosis (ST), cardiovascular (CV) mortality, and myocardial infarction (MI). Results: Two randomized controlled trials and nine observational studies with 7,318 patients were included in this meta-analysis. In terms of the medium-term follow-up clinical outcomes, our pooled analysis showed that use of the systematic dual stenting strategy was associated with a lower ST risk (odds ratio [OR] = 0.43, 95% confidence interval [CI]: 0.20-0.89, P = 0.02) and cardiac death risk (OR = 0.43, 95% CI: 0.21-0.89, P = 0.02) compared to the single stenting strategy; there was no significant difference between the two strategies regarding rates of all-cause death, MACE, TLR, and MI. Patients with long-term follow-up showed comparable observed clinical outcomes between the two strategies. Most importantly, for patients with true LM bifurcation, the risk of all-cause death, ST, and CV mortality following the systematic dual stenting strategy was significantly lower than the single stenting strategy. Conclusions: For patients with LM bifurcation lesions, both the systematic dual stenting strategy and single stenting strategy demonstrated comparable results in terms of all-cause mortality during medium-term and long-term follow-up. However, the systematic dual stenting strategy showed a tendency towards lower incidence of ST and CV mortality compared to the single stenting strategy during medium-term follow-up. Consequently, the systematic dual stenting strategy yielded superior clinical outcomes for patients with LM bifurcation lesions.
ABSTRACT
Rice false smut caused by Ustilaginoidea virens is becoming one of the most devastating diseases in rice production areas in the world. Revealing U. virens potential pathogenic mechanisms provides ideas for formulating more effective prevention and control strategies. Sucrose non-fermenting 1 (Snf1) protein kinase plays a critical role in activating transcription and suppressing gene expression, as well as in cellular response to various stresses, such as nutrient limitation. In our study, we identified the Snf1 homolog UvSnf1 and analyzed its biological functions in U. virens. The expression level of UvSnf1 was dramatically up-regulated during invasion, indicating that UvSnf1 may participate in infection. Phenotypic analyses of UvSnf1 deletion mutants revealed that UvSnf1 is necessary for hyphae growth, spore production, and virulence in U. virens. Moreover, UvSnf1 promotes U. virens to use unfavorable carbon sources when the sucrose is insufficient. In addition, deletion of UvSnf1 down-regulates the expression of the cell wall-degrading enzymes (CWDEs) genes under sucrose limitation conditions in U. virens. Further analyses showed that CWDEs (UvCut1 and UvXyp1) are not only involved in growth, spore production, and virulence but are also required for the utilization of carbon sources. In conclusion, this study demonstrates that UvSnf1 plays vital roles in virulence and carbon source utilization in U. virens, and one of the possible mechanisms is playing a role in regulating the expression of CWDE genes.
Subject(s)
Hypocreales , Protein Kinases , Virulence/genetics , Sucrose , Hypocreales/genetics , Plant DiseasesABSTRACT
Background: The clinical value of the Syntax score in patients with non-ST segment elevation myocardial infarction (NSTEMI) has been well established. The neutrophil-lymphocyte ratio (NLR), the platelet-lymphocyte ratio (PLR), the high sensitivity C-reactive protein (hsCRP)-albumin ratio (hsCAR), and systemic immune-inflammatory (SII) index are promising systemic inflammation (SI) biomarkers in coronary artery diseases. However, studies which compare the predicting value of these SI indicators with the Syntax score in NSTEMI patients are limited. Material and Methods: NSTEMI patients who underwent coronary angiography (CAG) in our department were retrospectively enrolled. Both univariable and multivariable logistic regression analyses were performed to evaluate the clinical value between SI biomarkers and Syntax score in these patients. The area under the receiver operating characteristic curve (ROC) was used to compare the clinical values of these parameters in predicting 6-month major cardiovascular events (MACE) and over-all mortality. Results: A total of 429 NSTEMI patients were finally enrolled in this study. The level of NLR, PLR, as well as hsCAR, and SII in patients with high Syntax scores, are significantly higher than patients with the low Syntax score. Multivariable logistic regression analysis demonstrated that all of the SI indicators but not the Syntax score were the independent risk factors of 6-month MACE in NSTEMI patients. ROC showed that all of the SI indicators had better predictive value than the Syntax score in these patients (0.637, 0.592, 0.631, 0.590, 0.559, respectively) in predicting MACE and similar predictive value in over-all mortality (0.530, 0.524, 0.761, 0.553, 0.620, respectively). Conclusion: Novel SI biomarkers including NLR, PLR, hsCAR, and SII have better predictive value in MACE and similar predictive value in over-all mortality compared with Syntax score in NSTEMI patients.
ABSTRACT
For the treatment of bacterial infections, photodynamic antimicrobial chemotherapy (PACT) has the advantage of circumventing multi-drug resistance. In this work, new cationic photosensitizers against multi-drug resistant Proteus mirabilis (MRPM) were designed and synthesized by the conjugation of amino phenyl porphyrin with basic amino acid L-ornithine. Their photoinactivation efficacies against MRPM in vitro were reported and include the influence of laser energy, uptake, MIC and MBC, dose-dependent photoinactivation effects, membrane integrity, and fluorescence imaging. The PACT in vivo was evaluated using a wound mouse model infected by MRPM. Photosensitizer 4d displayed high photo inactivation efficacy against MRPM at 7.81 µM under illumination, and it could accelerate wound healing via bactericidal effect. These ornithine-porphyrin conjugates are potential photosensitizers for PACT in the treatment of MRPM infection.