CD44-Targeted Facile Enzymatic Activatable Chitosan Nanoparticles for Efficient Antitumor Therapy and Reversal of Multidrug Resistance.

Nanoparticles are attractive platforms for the delivery of various anticancer therapeutics. Nevertheless, their applications are still limited by the relatively low drug loading capacity and the occurrence of multidrug resistance (MDR) against chemotherapeutics. In this study, we report that the integration of d-α-tocopherol succinate (VES) residue with both chitosan and paclitaxel (PTX) led to significant improvement of drug loading capacity and drug loading efficiency through the enhancement of drug/carrier interaction. After the incorporation of hyaluronic acid containing PEG side chains (HA-PEG), higher serum stability and more efficient cellular uptake were obtained. Due to HA coating, VES residues and the enzymatic responsive drug release property, such facile nanoparticles actively targeted cancer cells that overexpress CD44 receptor and efficiently reversed the MDR of treated cells, but caused no significant toxicity to mouse fibroblast (NIH-3T3). More importantly, with HA-PEG coating, longer blood circulation and more effective tumor accumulation were achieved for prodrug nanoparticles. Finally, superior anticancer activity and excellent safety profile was demonstrated by HA-PEG coated enzymatically activatable prodrug nanoparticles compared to commercially available Taxol formulation.

Flavobacterium buctense sp. nov., isolated from freshwater.

A gram-negative, non-gliding motile, aerobic bacterium, designated as strain T7(T), was isolated from freshwater of Chishui River flowing through Maotai town, Guizhou Province, southwest of China. Based on the 16S rRNA gene sequence analysis, the isolate was identified as a member of the genus Flavobacterium and that shared less than 97 % sequence similarities with recognized Flavobacterium species. Its closest phylogenetic relative was Flavobacterium dankookense (96.9 %), followed by Flavobacterium cheonhonense (96.8 %) and Flavobacterium macrobrachii (96.7 %). The strain formed smooth yellow colonies on R2A plates, and cells were observed to be short rods. Strain T7(T) was found to be able to grow at 15-30 °C (optimum 25 °C), at NaCl concentration of 0-0.5 % (optimum 0 %) and at pH 6.5-9.5 (optimum pH 7.5). Catalase and oxidase tests were positive. Polar lipids of strain T7(T) included phosphatidylethanolamine, four unidentified polar lipids, one unidentified phospholipid and one unidentified aminolipid. Chemotaxonomic analysis revealed menaquinone-6 as the dominant respiratory quinone and C(15:0), iso-C(15:0) and iso-C(15:1) as the major fatty acids. The DNA G+C content of strain T7(T) was determined to be 38.2 mol%. On the basis of phylogenetic, phenotypic and genetic data obtained in this study, strain T7(T) represents a novel species of the genus Flavobacterium, for which the name Flavobacterium buctense sp. nov. is proposed. The type strain is T7(T) (=JCM 30750=CGMCC 1.15216).

Cardiovascular adverse events associated with antibody-drug conjugates (ADCs): a pharmacovigilance study based on the FAERS database.

Objective: As a novel drug formulation, antibody drug conjugates (ADCs) are widely used in various types of cancer. However, clinically, there is a lack of attention to the CVD produced by them, as well as a lack of research on the real-world situation. Using the Food and Drug Administration Adverse Event Reporting System (FAERS) database, to ensure its clinical safety application, we analyzed post-marketing data on antitumor ADCs to identify risk factors and drugs associated with the risk of cardiovascular events. Research design and methods: We used OpenVigil 2.1 to conduct a database query for adverse events (AEs) reported to the FAERS database between the time the drug was launched and the second quarter of 2023. Cardiovascular adverse events (AEs) were grouped into fourteen narrow categories using the Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries (SMQs), and the reporting odds ratio (ROR) and the proportional reporting ratio (PRR) for reporting the association between different drugs and cardiovascular disease (CVD) risk were calculated. Results: In the FAERS database, 1863 AEs associated with CVD we studied were identified in patients receiving ADC therapy. Most reports came from people aged ≥65, but a significant number of cases were found to be unknown. The number of patients with antibody-drug conjugates (ADCs)-related CVD cases aged <18 years, 18-64 years, and≥ 65 years was 52 (2.79%), 586 (31.45%), and 613 (32.90%), respectively. The proportion of female patients (834, 44.77%) was higher than that of male patients (752, 40.37%). Death (770 reports), disability (9 reports), Hospitalization initial or prolonged (407 reports), and life-threatening reactions (187 reports). Of the 770 deaths reported, 103 (31.7%) were associated with brentuximab vedotin, 10 (24.4%) with sacituzumab govitecan, 22 (19.3%) with enfortumab vedotin, and 35 (34.7%) with trastuzumab emtansine.49 (41.2%) cases were associated with polatuzumab vedotin, 62 (29%) with trastuzumab deruxtecan, 423 (54.3%) with gemtuzumab ozogamicin, and 66 (38.8%) with inotuzumab ozogamicin. In a disproportionate number of SMQS, cardiac failure (n = 277) and embolic and thrombotic events, venous (n = 446) were the most frequently reported CVD-related AEs in ADCs. Conclusion: By mining the FAERS database, we provided relevant information on the association between ADC use and cardiovascular-associated AEs. ADCs were associated with increased cardiovascular toxicity, deserving distinct monitoring and appropriate management. Further research is needed to confirm these findings and assess causality.

Risk Factors for Tracheostomy after Traumatic Cervical Spinal Cord Injury: A 10-Year Study of 456 Patients.

OBJECTIVES: To explore the difference between tracheostomy and non-tracheostomy and identify the risk factors associated with the need for tracheostomy after traumatic cervical spinal cord injury (TCSCI). METHODS: The demographic and injury characteristics of 456 TCSCI patients, treated in the Xinqiao Hospital from 2010 to 2019, were retrospective analyzed. Patients were divided into the tracheostomy group (n = 63) and the non-tracheostomy group (n = 393). Variables included were age, gender,smoking history, mechanism of injury, concomitant injury, American Spinal Injury Association (ASIA) Impairment Scale, the neurological level of injury, Cervical Spine Injury Severity Score (CSISS), surgery, and length of stay in ICU and hospital. SPSS 25.0 (SPSS, Chicago, IL) was used for statistical analysis and ROC curve drawing. Chi-square analysis was applied to find out the difference of variables between the tracheostomy and non-tracheostomy groups. Univariate logistic regression analysis (ULRA) and multiple logistic regression analysis (MLRA) were used to identify risk factors for tracheostomy. The area under the ROC curve (AUC) was used to evaluate the performance of these risk factors. RESULTS: Of 456 patients who met the inclusion criteria, 63 (13.8%) underwent tracheostomy. There were differences in age (χ2 = 6.615, P = 0.032), mechanism of injury (χ2 = 9.87, P = 0.036), concomitant injury (χ2 = 6.131, P = 0.013),ASIA Impairment Scale (χ2 = 123.08, P < 0.01), the neurological level of injury (χ2 = 34.74, P < 0.01), and CSISS (χ2 = 19.612, P < 0.01) between the tracheostomy and non-tracheostomy groups. Smoking history, CSISS ≥ 7, AIS A and, NLI ≥ C5 were identified as potential risk factors for tracheostomy by ULRA. Smoking history (OR = 2.960, 95% CI: 1.524-5.750, P = 0.001), CSISS ≥ 7 (OR = 4.599, 95% CI: 2.328-9.085, P = 0.000), AIS A (OR = 14.213, 95% CI: 6.720-30.060, P = 0.000) and NLI ≥ C5 (OR = 8.312, 95% CI: 1.935-35.711, P = 0.004) as risk factors for tracheostomy were determined by MLRA. The AUC for the risk factors of tracheostomy after TCSCI was 0.858 (95% CI: 0.810-0.907). CONCLUSIONS: Smoking history, CSISS ≥ 7, AIS A and, NLI ≥ C5 were identified as risk factors needing of tracheostomy in patients with TCSCI. These risk factors may be important to assist the clinical decision of tracheostomy.