Unveiling Hierarchical Self-Assembly of Triazolylferrocenyl Dendrimers: Producing Non-Traditional Intrinsically Green Fluorescent Vesosomes for Nanotheranostics.

Dendrimers and supramolecular chemistry continue to fascinate researchers due to the endless unrevealed potential of their combination. This study investigates the self-assembly process of a series of hydrophobic triazolylferrocenyl dendrimers in aqueous medium. Deep investigation through NMR spectroscopy, absorption UV-vis spectroscopy along with theoretical simulations demonstrates that the ferrocenyl moieties interact intramolecularly and intermolecularly driving the self-assembly process. Data obtained by DLS, NTA, SEM, TEM, and EF-TEM demonstrate that these dendrimers, in water, spontaneously self-assemble through a hierarchical process. The dendrimers first self-assemble into uniform nanovesicles, which in turn self-assemble into larger vesosomes. The resulting vesosomes emit green non-traditional intrinsic fluorescence, which is a property that emerged from the self-assembled architectures. The vesosomes are efficiently uptaken by cancer cells and induce significant cytotoxic activity against the cancer cell line MCF-7, up to the submicromolar concentration. Positive dendritic effects are identified in the fluorescence intensity and in the cytotoxic activity of the vesosomes, which follow the trend G0-9Fc < G1-27Fc < G2-81Fc. This work showcases the remarkable potential of combining the two dynamic fields of dendrimers and supramolecular chemistry, which resulted in green fluorescent vesosomes capable of performing the dual role of cell imaging and killing, with potential applications in nanotheranostics.

Tumor microenvironment as a complex milieu driving cancer progression: a mini review.

It has been spotlighted that the Tumor Microenvironment (TME) is crucial for comprehending cancer progression and therapeutic resistance. Therefore, this comprehensive review elucidates the intricate architecture of the TME, which encompasses tumor cells, immune components, support cells, and a myriad of bioactive molecules. These constituents collectively foster dynamic interactions that underpin tumor growth, metastasis, and nuanced responses to anticancer therapies. Notably, the TME's role extends beyond mere physical support, serving as a critical mediator in cancer-cell evolution, immune modulation, and treatment outcomes. Innovations targeting the TME, including strategies focused on the vasculature, immune checkpoints, and T-cell therapies, have forged new pathways for clinical intervention. However, the heterogeneity and complexity of the TME present significant challenges, necessitating deeper exploration of its components and their interplay to enhance therapeutic efficacy. This review underscores the imperative for integrated research strategies that amalgamate insights from tumor biology, immunology, and systems biology. Such an approach aims to refine cancer treatments and improve patient prognoses by exploiting the TME's complexity.

Bevacizumab improved prognosis for advanced EGFR-mutant lung adenocarcinoma with brain metastasis receiving cerebral radiotherapy.

OBJECTIVE: This study aimed to determine whether the combined use of bevacizumab could improve overall survival (OS) in patients with brain metastasis (BM), epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) undergoing cerebral radiotherapy. MATERIALS AND METHODS: A total of 237 patients with EGFR-mutant lung adenocarcinoma and BM met the inclusion criteria for this retrospective study, including 102 patients in the bevacizumab treatment group and 135 in the non-bevacizumab group. The Kaplan-Meier method was used for survival analysis. Univariate and multivariate analyses were performed to identify EGFR-mutated BM prognostic factors for these patients. RESULTS: At the end of the last follow-up period, 176 patients (74.3%) had died, and the median overall survival (OS) was 34.2 months. We observed a significant difference in the median OS between the bevacizumab and non-bevacizumab groups (45.8 months vs 30.0 months, P < 0.0001). Among the 178 (75.1%) patients who received cerebral radiotherapy, the median OS of patients in the bevacizumab + cerebral radiotherapy group was 45.8 months versus 32.0 months in the non-bevacizumab + cerebral radiotherapy group, respectively (P = 0.0007). Patients treated with bevacizumab after cerebral radiotherapy had a longer median OS than patients treated with bevacizumab before cerebral radiotherapy (59.4 months vs 33.7 months, P = 0.0198). In the univariate analysis, smoking status, Lung-molGPA scores, and bevacizumab therapy showed correlations (HR = 1.450, P = 0.045; HR = 0.700, P = 0.023; HR = 0.499, P < 0.001). Multivariate analysis showed that bevacizumab therapy alone (hazard ratio [HR] = 0.514; P < 0.001) was independently associated with improved OS. CONCLUSION: In patients with BM from EGFR-mutated NSCLC, cerebral radiotherapy with bevacizumab markedly improved OS. This improvement was more evident after cerebral radiotherapy.

Effect of 3D laparoscopy versus traditional laparotomy on serum tumor markers and coagulation function in patients with early-stage endometrial cancer.

OBJECTIVES: To investigate the impact of Three-Dimensional (3D) laparoscopy compared to traditional laparotomy on serum tumor markers and coagulation function in patients diagnosed with early-stage Endometrial Cancer (EC). METHOD: The authors retrospectively analyzed the clinical data of 75 patients diagnosed with early-stage EC and categorized them into two groups based on the surgical techniques employed. The 3D group consisted of 36 patients who underwent 3D laparoscopic surgery, while the Laparotomy group comprised 39 patients who underwent traditional laparotomy. The authors then compared the alterations in serum tumor markers and coagulation function between the two groups. RESULTS: Postoperatively, serum levels of CA125, CA199, and HE4 were notably reduced in both groups on the third day, with the levels being more diminished in the 3D group than in the Laparotomy Group (p < 0.05). Conversely, FIB levels escalated significantly in both groups on the third-day post-surgery, with a more pronounced increase in the 3D group. Additionally, PT and APTT durations were reduced and were more so in the 3D group than in the laparotomy group (p < 0.05). CONCLUSIONS: When juxtaposed with traditional laparotomy, 3D laparoscopic surgery for early-stage EC appears to be more efficacious, characterized by reduced complications, and expedited recovery. It can effectively mitigate serum tumor marker levels, attenuate the inflammatory response and damage to immune function, foster urinary function recovery, and enhance the quality of life. However, it exerts a more significant influence on the patient's coagulation parameters, necessitating meticulous prevention and treatment strategies for thromboembolic events in clinical settings.

Analysis of the prognostic value of uric acid on the efficacy of immunotherapy in patients with primary liver cancer.

PURPOSE: Uric acid (UA) plays a dual role as an antioxidant and a prooxidant in patients with malignant tumors; however, the relationship between serum UA and malignancy is currently unclear. This study aims to investigate the prognostic value of serum uric acid level before immunotherapy on the efficacy of primary liver cancer (PLC) immunotherapy, which might provide a basis for optimizing the comprehensive treatment scheme. METHODS: Patients with PLC who were admitted to the First Affiliated Hospital of Gannan Medical College from January 2019 to June 2022 and underwent immunotherapy were collected retrospectively. The difference between serum UA levels in patients with PLC, the correlation between serum UA levels, and the clinical characteristics of patients with PLC were analyzed using the chi-square test, and the survival was estimated using the Kaplan-Meier analysis. To further assess the prognostic significance of UA concentrations, univariate and multivariate Cox regression analyses were performed. RESULTS: Ninety-nine patients were included in this study cohort. The median follow-up was 7 months (range: 1-29 months), and 76 (76.8%) of the 99 patients with PLC died as of December 31, 2022. Serum UA concentrations ranged from 105 to 670 µmol/l, with a median of 269 µmol/l. The results showed that the serum UA level of patients with PLC was higher than that of healthy subjects (P < 0.001). After subgroup analyses, only male patients with liver cancer had higher serum UA levels than healthy men (P = 0.001). The results of the Kaplan-Meier analysis showed that higher UA levels were associated with poor overall survival (OS) (P = 0.005). In univariate analysis, the OS rate of patients with elevated serum UA levels was significantly lower than the cut-off value (hazard ratio [HR]: 3.191, 95% confidence interval [CI]: 1.456-6.993, P = 0.004), with a median survival time of 151 and 312 days in the high and low serum UA groups, respectively. The results of multivariate analysis showed that the UA level was an independent prognostic factor for immunotherapy in patients with PLC (HR: 3.131, 95% CI: 1.766-5.553, P < 0.001). CONCLUSIONS: The serum UA level is a reliable biomarker for predicting the prognosis of patients undergoing immunotherapy for PLC, and might provide a basis for the individualized treatment of these patients. Dynamic monitoring of the serum UA level may compensate for the deficiency of the current liver cancer staging system.

Nomogram for predicting overall survival after curative gastrectomy using inflammatory, nutritional and pathological factors.

PURPOSE: To establish a nomogram for predicting the overall survival (OS) in patients with gastric cancer (GC) based on inflammatory, nutritional and pathological factors. METHODS: GC patients underwent curative gastrectomy from January 2012 to June 2017 in our hospital were included, and were classified into training set and validation set with a ratio of 7:3. Then variables associated with OS were analyzed using univariate and multivariate Cox regression analysis. Nomograms predicting OS were built using variables from multivariable Cox models. Finally, Kaplan-Meier curve and Log-rank test were also conducted to analyze the 1-yr, 3-yr and 5-yr OS to validate the efficiency of risk stratification of the nomogram. RESULTS: A total of 366 GC patients were included. After univariate and multivariate Cox regression analysis, age (HR = 1.52, 95% CI = 1.01-2.30, P = 0.044), CA50 (HR = 1.90, 95% CI = 1.12-3.21, P = 0.017), PNI (HR = 1.65, 95% CI = 1.13-2.39, P = 0.009), SII (HR = 1.46, 95% CI = 1.03-2.08, P = 0.036), T stage (HR = 2.26, 95% CI = 1.01-5.05, P = 0.048; HR = 7.24, 95% CI = 3.64-14.40, P < 0.001) were independent influencing factors on the survival time of GC patients. Five factors including CEA, prognostic nutritional index (PNI), systemic immune-inflammation index (SII), ln (tumor size), T stage, and N stage were identified and entered the nomogram, which showed good discrimination and calibration in both sets. On internal validation, 1-yr, 3-yr and 5-yr nomogram demonstrated a good discrimination with an area under the ROC curve (AUC) of 0.77, 0.84 and 0.86, respectively. The AUC for 1-yr, 3-yr and 5-yr nomogram in validation set was 0.77, 0.79 and 0.81, respectively. The OS in low risk group of training cohort and validation cohort was significantly higher than that of intermediate risk group and high risk group, respectively. CONCLUSIONS: We established a nomogram based on PNI, SII and pathological factors for predicting OS in GC patients. In addition, its efficiency was validated by validation set and stratified analysis.

Effect of 3D laparoscopy versus traditional laparotomy on serum tumor markers and coagulation function in patients with early-stage endometrial cancer

Abstract Objectives To investigate the impact of Three-Dimensional (3D) laparoscopy compared to traditional laparotomy on serum tumor markers and coagulation function in patients diagnosed with early-stage Endometrial Cancer (EC). Method The authors retrospectively analyzed the clinical data of 75 patients diagnosed with early-stage EC and categorized them into two groups based on the surgical techniques employed. The 3D group consisted of 36 patients who underwent 3D laparoscopic surgery, while the Laparotomy group comprised 39 patients who underwent traditional laparotomy. The authors then compared the alterations in serum tumor markers and coagulation function between the two groups. Results Postoperatively, serum levels of CA125, CA199, and HE4 were notably reduced in both groups on the third day, with the levels being more diminished in the 3D group than in the Laparotomy Group (p < 0.05). Conversely, FIB levels escalated significantly in both groups on the third-day post-surgery, with a more pronounced increase in the 3D group. Additionally, PT and APTT durations were reduced and were more so in the 3D group than in the laparotomy group (p < 0.05). Conclusions When juxtaposed with traditional laparotomy, 3D laparoscopic surgery for early-stage EC appears to be more efficacious, characterized by reduced complications, and expedited recovery. It can effectively mitigate serum tumor marker levels, attenuate the inflammatory response and damage to immune function, foster urinary function recovery, and enhance the quality of life. However, it exerts a more significant influence on the patient's coagulation parameters, necessitating meticulous prevention and treatment strategies for thromboembolic events in clinical settings.

Pre-radiotherapy systemic immune inflammation index associated with overall survival in patients with advanced EGFR mutant non-small cell lung cancer receiving thoracic radiotherapy.

PURPOSE: This study aimed to investigate the prognostic potential of the pre-radiotherapy systemic immune-inflammation index (SII) for the survival of advanced lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) mutations, which might provide a basis for optimizing the comprehensive treatment scheme. METHODS: A total of 111 lung adenocarcinoma patients with EGFR mutations, who received thoracic radiotherapy, were included in this retrospective study. The primary endpoint of the study was based on the overall survival (OS) of patients. The receiver operating characteristic (ROC) curve analysis was performed to determine the optimal cut-off value of each immune inflammation index. Kaplan-Meier analysis was performed for the comparison of OS. The Cox proportional-hazard model was used for the multivariate and univariate regression analyses to determine the correlations of prognostic factors with the disease. RESULTS: SII was divided into the high SII group (≥ 620.2; 45.95%) and the low SII group (SII < 620.2; 54.05%) based on the optimal cutoff values. The median OS rates were 53.3 and 33.3 months in the low and high SII groups, respectively, showing statistically significant differences ( hazard ratio (HR) = 0.459; 95% CI 0.286-0.736; P < 0.001). The multivariate analysis showed that, after adjusting for the significant covariates, the SII values were independently associated with the improved OS of the patients (adjusted HR = 0.444; 95% CI 0.279-0.709; P = 0.001). The low NLR values were associated with the better OS of patients (HR = 0.509; 95% CI 0.326-0.792; P = 0.005) and vice versa (HR = 0.422; 95% CI 0.213-0.836; P < 0.001). The patients in the low LMR group before radiotherapy exhibited longer OS as compared to those in the high LMR group (HR = 0.497; 95% CI 0.308-0.802; P = 0.001). CONCLUSIONS: This study showed that these inflammatory indices might have an important prognostic potential for advanced lung adenocarcinoma patients with EGFR mutations, receiving thoracic radiotherapy and might provide a basis for the individualized treatment of these patients.

Long non-coding RNA SNHG1 promotes bladder cancer progression by upregulating EZH2 and repressing KLF2 transcription.

OBJECTIVE: Long Non-Coding RNAs (LncRNAs) act as an indispensable role in cancer development. The study aimed to investigate the role and mechanism of lncRNA Small Nucleolar RNA Host Gene 1 (SNHG1) in Bladder Cancer (BC) progression. METHOD: The expression, prognostic value, diagnostic value, and correlation of SNHG1, Enhancer of Zeste 2 polycomb repressive complex 2 subunit (EZH2), and Kruppel Like Factor 2 (KLF2) were analyzed through bioinformatics analysis. The expression was also validated in BC tissues and cell lines. Besides, their regulation and binding were tested via qPCR, Western blot, Dual-Luciferase Reporter Assay (DLRA), Argonaute RISC catalytic component 2-RNA Immunoprecipitation (AGO2-RIP), and Chromatin Immunoprecipitation (ChIP). A xenograft model in nude mice was also established. RESULTS: SNHG1 was significantly overexpressed in BC tissues and cells. Importantly, SNHG1 was associated with poor survival, and ROC curves revealed high diagnostic values. Moreover, by CCK8, wound healing, transwell, and Western blot analysis, SNHG1 knockdown significantly inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition of BC cells. Additionally, in vivo experiments showed that silencing SNHG1 hindered tumorigenesis and tumor growth. Regarding mechanism, the results of AGO2-RIP, ChIP or DLRA showed that SNHG1 played different roles at diverse subcellular sites. In the cytoplasm, SNHG1 acted as a competing endogenous RNA for miR-137-3p to promote EZH2 expression. In the nucleus, SNHG1 could interact with EZH2 to inhibit KLF2 transcription. CONCLUSION: Our study elucidated that SNHG1 formed a regulatory network and played an oncogenic role in BC, which provided a novel therapeutic target for BC treatment.

Immunomodulatory effects of Blaps rynchopetera extract.

PURPOSE: To explore the potential immunomodulatory effects of total extract and different polar parts from Blaps rynchopetera Fairmaire. METHODS: Phagocytic activity was evaluated by neutral red assay, and the effect of the immune function was investigated by normal and immunocompromised mice models. RESULTS: In vitro, total extract, as well as chloroform, ethyl acetate, n-butanol and water fractions could individually enhance the phagocytic ability of mouse peritoneal macrophages; in addition, chloroform and ethyl acetate fractions had an increasing tendency when combined stimulation with lipopolysaccharide (LPS). In vivo, ethyl acetate fraction (EAF) could enhance the immune organ index, increase the serum hemolysin level and peripheral blood immune cells of immunocompromised mice, while for normal mice, the effect was inconspicuous. CONCLUSIONS: Blaps rynchopetera extracts had noteworthy immunomodulatory effect, especially for individuals with immune disorders.

Identification of bZIP transcription factors and their responses to brown spot in pear.

Basic leucine zipper (bZIP) is a conserved transcription factor (TF) widely present in eukaryotes, and it plays an important role in regulating plant growth and stress responses. To better understand the white pear bZIP gene family, comprehensive bioinformatics analysis of the pear genome was performed. A total of 84 PbbZIP genes were identified, which were divided into 13 subfamilies by phylogenetic analysis. The 84 PbbZIP genes were all located in the nucleus, and 77 of those genes were unevenly distributed across the 17 chromosomes of white pear. The other 7 PbbZIP genes were located on the scaffold. Subsequent expression profile analysis showed that PbbZIP genes in exocarp were significantly upregulated or downregulated in 'Huangguan' pear with brown spot (BS) compared with healthy pear and in response to hormonal treatment with gibberellin A3 (GA3). These results provide helpful insights into the characteristics of PbbZIP genes and their responses to BS in 'Huangguan' pear.

Predicting benign, preinvasive, and invasive lung nodules on computed tomography scans using machine learning.

OBJECTIVE: The study objective was to investigate if machine learning algorithms can predict whether a lung nodule is benign, adenocarcinoma, or its preinvasive subtype from computed tomography images alone. METHODS: A dataset of chest computed tomography scans containing lung nodules was collected with their pathologic diagnosis from several sources. The dataset was split randomly into training (70%), internal validation (15%), and independent test sets (15%) at the patient level. Two machine learning algorithms were developed, trained, and validated. The first algorithm used the support vector machine model, and the second used deep learning technology: a convolutional neural network. Receiver operating characteristic analysis was used to evaluate the performance of the classification on the test dataset. RESULTS: The support vector machine/convolutional neural network-based models classified nodules into 6 categories resulting in an area under the curve of 0.59/0.65 when differentiating atypical adenomatous hyperplasia versus adenocarcinoma in situ, 0.87/0.86 with minimally invasive adenocarcinoma versus invasive adenocarcinoma, 0.76/0.72 atypical adenomatous hyperplasia + adenocarcinoma in situ versus minimally invasive adenocarcinoma, 0.89/0.87 atypical adenomatous hyperplasia + adenocarcinoma in situ versus minimally invasive adenocarcinoma + invasive adenocarcinoma, and 0.93/0.92 atypical adenomatous hyperplasia + adenocarcinoma in situ + minimally invasive adenocarcinoma versus invasive adenocarcinoma. Classifying benign versus atypical adenomatous hyperplasia + adenocarcinoma in situ + minimally invasive adenocarcinoma versus invasive adenocarcinoma resulted in a micro-average area under the curve of 0.93/0.94 for the support vector machine/convolutional neural network models, respectively. The convolutional neural network-based methods had higher sensitivities than the support vector machine-based methods but lower specificities and accuracies. CONCLUSIONS: The machine learning algorithms demonstrated reasonable performance in differentiating benign versus preinvasive versus invasive adenocarcinoma from computed tomography images alone. However, the prediction accuracy varies across its subtypes. This holds the potential for improved diagnostic capabilities with less-invasive means.

Immunomodulatory effects of Blaps rynchopetera extract

Purpose: To explore the potential immunomodulatory effects of total extract and different polar parts from Blaps rynchopetera Fairmaire. Methods: Phagocytic activity was evaluated by neutral red assay, and the effect of the immune function was investigated by normal and immunocompromised mice models. Results: In vitro, total extract, as well as chloroform, ethyl acetate, n-butanol and water fractions could individually enhance the phagocytic ability of mouse peritoneal macrophages; in addition, chloroform and ethyl acetate fractions had an increasing tendency when combined stimulation with lipopolysaccharide (LPS). In vivo, ethyl acetate fraction (EAF) could enhance the immune organ index, increase the serum hemolysin level and peripheral blood immune cells of immunocompromised mice, while for normal mice, the effect was inconspicuous. Conclusions: Blaps rynchopetera extracts had noteworthy immunomodulatory effect, especially for individuals with immune disorders.

Long non-coding RNA SNHG1 promotes bladder cancer progression by upregulating EZH2 and repressing KLF2 transcription

Abstract Objective: Long Non-Coding RNAs (LncRNAs) act as an indispensable role in cancer development. The study aimed to investigate the role and mechanism of lncRNA Small Nucleolar RNA Host Gene 1 (SNHG1) in Bladder Cancer (BC) progression. Method: The expression, prognostic value, diagnostic value, and correlation of SNHG1, Enhancer of Zeste 2 polycomb repressive complex 2 subunit (EZH2), and Kruppel Like Factor 2 (KLF2) were analyzed through bioinformatics analysis. The expression was also validated in BC tissues and cell lines. Besides, their regulation and binding were tested via qPCR, Western blot, Dual-Luciferase Reporter Assay (DLRA), Argonaute RISC catalytic component 2-RNA Immunoprecipitation (AGO2-RIP), and Chromatin Immunoprecipitation (ChIP). A xenograft model in nude mice was also established. Results: SNHG1 was significantly overexpressed in BC tissues and cells. Importantly, SNHG1 was associated with poor survival, and ROC curves revealed high diagnostic values. Moreover, by CCK8, wound healing, transwell, and Western blot analysis, SNHG1 knockdown significantly inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition of BC cells. Additionally, in vivo experiments showed that silencing SNHG1 hindered tumorigenesis and tumor growth. Regarding mechanism, the results of AGO2-RIP, ChIP or DLRA showed that SNHG1 played different roles at diverse subcellular sites. In the cytoplasm, SNHG1 acted as a competing endogenous RNA for miR-137-3p to promote EZH2 expression. In the nucleus, SNHG1 could interact with EZH2 to inhibit KLF2 transcription. Conclusion: Our study elucidated that SNHG1 formed a regulatory network and played an oncogenic role in BC, which provided a novel therapeutic target for BC treatment.

Diagnostic and prognostic value of serum miR-9-5p and miR-128-3p levels in early-stage acute ischemic stroke.

OBJECTIVES: To investigate the clinical utility of serum microRNA levels (miR-9-5p and miR-128-3p) in the diagnosis and prognosis of early-stage acute ischemic stroke (AIS). METHODS: We compared the differences in serum miR-9-5p and miR-128-3p levels between patients with AIS and healthy individuals (controls). The serum levels of miR-9-5p and miR-128-3p were quantified using quantitative real-time PCR, and the association of each miRNA with AIS was determined using receiver operator characteristic curve analysis. The predictive value of these indices in the diagnosis of early-stage AIS was evaluated in conjunction with that of computed tomography findings and neuron-specific enolase levels. The prognosis of patients with AIS was evaluated three months after their discharge from hospital using the modified Rankin scale, which classifies the prognosis as either favorable or poor. Logistic regression analysis was used to analyze the correlation between miR-9-5p and miR-128-3p levels and patient prognosis. RESULTS: The serum levels of miR-9-5p and miR-128-3p were upregulated in patients with AIS relative to those in healthy individuals. A pronounced correlation was identified between serum miR-9-5p and miR-128-3p levels and patient prognosis, with high levels of both miRNAs being associated with poor patient outcomes. CONCLUSION: Assessment of serum miR-9-5p and miR-128-3p levels is important for the early diagnosis and prognosis of AIS.

Antiviral Properties of Baicalin: a Concise Review.

Baicalin is one of the bioactive flavonoid glycosides isolated from the dried root of Scutellaria baicalensis Georgi, Lamiaceae, with antiviral properties. In recent years, the antiviral activity of baicalin has been widely investigated to explore its molecular mechanism of action. In this mini-review, the molecular mechanisms of action of baicalin as an antiviral agent are evaluated, which included three categories: the inhibition or stimulation of JAK/STAT, TLRs, and NF-κB pathways; up or down modulation of the expression levels of IFN, IL, SOCS1/3, PKR protein, Mx1 protein, and AP-1 protein; and inhibition of cell apoptosis caused by virus infection. In addition, clinical studies of baicalin are also discussed. This literature search suggested that baicalin can serve as a potential candidate for the development of a novel broad-spectrum antiviral drug. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s43450-021-00182-1.

Self-Assembly of a Triazolylferrocenyl Dendrimer in Water Yields Nontraditional Intrinsic Green Fluorescent Vesosomes for Nanotheranostic Applications.

The promising field of nanomedicine stimulates a continuous search for multifunctional nanotheranostic systems for imaging and drug delivery. Herein, we demonstrate that application of supramolecular chemistry's concepts in dendritic assemblies can enable the formation of advanced dendrimer-based nanotheranostic devices. A dendrimer bearing 81 triazolylferrocenyl terminal groups adopts a more compact shell-like structure in polar solvents with the ferrocenyl peripheral groups backfolding toward the hydrophobic dendrimer interior, while exposing the more polar triazole moieties as the dendritic shell. Akin to lipids, the compact dendritic structure self-assembles into uniform nanovesicles that in turn self-assemble into larger vesosomes in water. The vesosomes emit green nontraditional intrinsic fluorescence (NTIL), which is an emerging property as there are no classical fluorophores in the dendritic macromolecular structure. This work confirms the hypothesis that the NTIL emission is greatly enhanced by rigidification of the supramolecular assemblies containing heteroatomic subluminophores (HASLs) and by the presence of electron rich functional groups on the periphery of dendrimers. This work is the first one detecting NTIL in ferrocenyl-terminated dendrimers. Moreover, the vesosomes are stable in biological medium, are uptaken by cells, and show cytotoxic activity against cancer cells. Accordingly, the self-organization of these dendrimers into tertiary structures promotes the emergence of new properties enabling the same component, in this case, ferrocenyl group, to function as both antitumoral drug and fluorophore.

Electrocardiographic effect of artemisinin-piperaquine, dihydroartemisinin-piperaquine, and artemether-lumefantrine treatment in falciparum malaria patients.

INTRODUCTION: Artemisinin-based combination therapy (ACT), such as artemisinin-piperaquine (AP), dihydroartemisinin-piperaquine (DP), and artemether-lumefantrine (AL), is the first-line treatment for malaria in many malaria-endemic areas. However, we lack a detailed evaluation of the cardiotoxicity of these ACTs. This study aimed to analyze the electrocardiographic effects of these three ACTs in malaria patients. METHODS: We analyzed the clinical data of 89 hospitalized patients with falciparum malaria who had received oral doses of three different ACTs. According to the ACTs administered, these patients were divided into three treatment groups: 27 treated with AP (Artequick), 31 with DP (Artekin), and 31 with AL (Coartem). Electrocardiograms and other indicators were recorded before and after the treatment. The QT interval was calculated using Fridericia's formula (QTcF) and Bazett's formula (QTcB). RESULTS: Both QTcF and QTcB interval prolongation occurred in all three groups. The incidence of such prolongation between the three groups was not significantly different. The incidence of both moderate and severe prolongation was not significantly different between the three groups. The ΔQTcF and ΔQTcB of the three groups were not significantly different. The intra-group comparison showed significant prolongation of QTcF after AL treatment. CONCLUSIONS: Clinically recommended doses of DP, AL, and AP may cause QT prolongation in some malaria patients but do not cause torsades de pointes ventricular tachycardia or other arrhythmias.

Glucuronoxylomannan in the Cryptococcus species capsule as a target for Chimeric Antigen Receptor T-cell therapy.

BACKGROUND AIMS: The genus Cryptococcus comprises two major fungal species that cause clinical infections in humans: Cryptococcus gattii and Cryptococcus neoformans. To establish invasive human disease, inhaled cryptococci must penetrate the lung tissue and reproduce. Each year, about 1 million cases of Cryptococcus infection are reported worldwide, and the infection's mortality rate ranges from 20% to 70%. Many HIV+/AIDS patients are affected by Cryptococcus infections, with 220,000 cases of cryptococcal meningitis reported worldwide in this population every year (C. neoformans infection statistics, via the Centers for Disease Control and Prevention, https://www.cdc.gov/fungal/diseases/cryptococcosis-neoformans/statistics.html). To escape from host immune cell attack, Cryptococcus covers itself in a sugar-based capsule composed primarily of glucuronoxylomannan (GXM). To evade phagocytosis, yeast cells increase to a >45-µm perimeter and become titan, or giant, cells. Cryptococci virulence is directly proportional to the percentage of titan/giant cells present during Cryptococcus infection. To combat cryptococcosis, the authors propose the redirection of CD8+ T cells to target the GXM in the capsule via expression of a GXM-specific chimeric antigen receptor (GXMR-CAR). RESULTS: GXMR-CAR has an anti-GXM single-chain variable fragment followed by an IgG4 stalk in the extracellular domain, a CD28 transmembrane domain and CD28 and CD3-ς signaling domains. After lentiviral transduction of human T cells with the GXMR-CAR construct, flow cytometry demonstrated that 82.4% of the cells expressed GXMR-CAR on their surface. To determine whether the GXMR-CAR+ T cells exhibited GXM-specific recognition, these cells were incubated with GXM for 24 h and examined with the use of brightfield microscopy. Large clusters of proliferating GXMR-CAR+ T cells were observed in GXM-treated cells, whereas no clusters were observed in control cells. Moreover, the interaction of GXM with GXMR-CAR+ T cells was detected via flow cytometry by using a GXM-specific antibody, and the recognition of GXM by GXMR-CAR T cells triggered the secretion of granzyme and interferon gamma (IFN-γ). The ability of GXMR-CAR T cells to bind to the yeast form of C. neoformans was detected by fluorescent microscopy, but no binding was detected in mock-transduced control T cells (NoDNA T cells). Moreover, lung tissue sections were stained with Gomori Methenamine Silver and evaluated by NanoZoomer (Hamamatsu), revealing a significantly lower number of titan cells, with perimeters ranging from 50 to 130 µm and giant cells >130 µm in the CAR T-cell treated group when compared with other groups. Therefore, the authors validated the study's hypothesis by the redirection of GXMR-CAR+ T cells to target GXM, which induces the secretion of cytotoxic granules and IFN-γ that will aid in the control of cryptococcosis CONCLUSIONS: Thus, these findings reveal that GXMR-CAR+ T cells can target C. neoformans. Future studies will be focused on determining the therapeutic efficacy of GXMR-CAR+ T cells in an animal model of cryptococcosis.

Diagnostic and prognostic value of serum miR-9-5p and miR-128-3p levels in early-stage acute ischemic stroke

OBJECTIVES: To investigate the clinical utility of serum microRNA levels (miR-9-5p and miR-128-3p) in the diagnosis and prognosis of early-stage acute ischemic stroke (AIS). METHODS: We compared the differences in serum miR-9-5p and miR-128-3p levels between patients with AIS and healthy individuals (controls). The serum levels of miR-9-5p and miR-128-3p were quantified using quantitative real-time PCR, and the association of each miRNA with AIS was determined using receiver operator characteristic curve analysis. The predictive value of these indices in the diagnosis of early-stage AIS was evaluated in conjunction with that of computed tomography findings and neuron-specific enolase levels. The prognosis of patients with AIS was evaluated three months after their discharge from hospital using the modified Rankin scale, which classifies the prognosis as either favorable or poor. Logistic regression analysis was used to analyze the correlation between miR-9-5p and miR-128-3p levels and patient prognosis. RESULTS: The serum levels of miR-9-5p and miR-128-3p were upregulated in patients with AIS relative to those in healthy individuals. A pronounced correlation was identified between serum miR-9-5p and miR-128-3p levels and patient prognosis, with high levels of both miRNAs being associated with poor patient outcomes. CONCLUSION: Assessment of serum miR-9-5p and miR-128-3p levels is important for the early diagnosis and prognosis of AIS.