Aberrant R-loop-mediated immune evasion, cellular communication, and metabolic reprogramming affect cancer progression: a single-cell analysis.

Dysregulation of R-loop homeostasis is closely related to various human diseases, including cancer. However, the causality of aberrant R-loops in tumor progression remains unclear. In this study, using single-cell RNA-sequencing datasets from lung adenocarcinoma (LUAD), we constructed an R-loop scoring model to characterize the R-loop state according to the identified R-loop regulators related to EGFR mutations, tissue origins, and TNM stage. We then evaluated the relationships of the R-loop score with the tumor microenvironment (TME) and treatment response. Furthermore, the potential roles of FANCI-mediated R-loops in LUAD were explored using a series of in vitro experiments. Results showed that malignant cells with low R-loop scores displayed glycolysis and epithelial-mesenchymal transition pathway activation and immune escape promotion, thereby hampering the antitumor therapeutic effects. Cell communication analysis suggested that low R-loop scores contributed to T cell exhaustion. We subsequently validated the prognostic value of R-loop scores by using bulk transcriptome datasets across 33 tumor types. The R-loop scoring model well predicted patients' therapeutic response to targeted therapy, chemotherapy, or immunotherapy in 32 independent cohorts. Remarkably, changes in R-loop distribution mediated by FANCI deficiency blocked the activity of Ras signaling pathway, suppressing tumor-cell proliferation and dissemination. In conclusion, this study reveals the underlying molecular mechanism of metabolic reprogramming and T cell exhaustion under R-loop score patterns, and the changes in R-loops mediated by R-loop regulators resulting in tumor progression. Therefore, incorporating anticancer methods based on R-loop or R-loop regulators into the treatment schemes of precision medicine may be beneficial.

Larotrectinib versus infigratinib for adult patients with both glioma and tyrosine kinase alterations after failure of initial therapies: Efficacy and safety analysis.

OBJECTIVES: To compare the efficacy and safety of larotrectinib with those of infigratinib in adult glioma patients with tyrosine kinase alterations. METHODS: Patients received oral infigratinib 125 mg (IN cohort, n = 125) or oral larotrectinib (LB cohort, n = 105) until unacceptable toxicity or disease progression. RESULTS: Duration of treatment was longer in the LB cohort than in the IN cohort (8 [9.5-6.25] months vs. 5.5 [6-5.25] months, p < 0.0001). Patients with partial responses (p = 0.0424) and overall survival (p = 0.03) were higher in the IN cohort than those in the LB cohort. The number of patients with disease progression was higher in the LB cohort (p = 0.0015). All the patients reported diarrhea, fatigue, vomiting, constipation, and decreased appetite. Patients in the IN cohort reported hyperphosphatemia, hyperlipasemia, stomatitis, dry skin, alopecia, dyspepsia, onycholysis, palmar-plantar erythrodysesthesia, nail disorders, and dry eyes. Patients in the LB cohort reported upper respiratory tract infections, pyrexia, cough, anemia, bacterial/viral infections, conjunctivitis, urinary tract infections, headaches, ataxia, dizziness, and muscle tremors. A total of 30 (24 %) and 40 (38 %) patients from the IN and the LB cohorts died at the follow-up of 18 months (p = 0.03). Patients who received bevacizumab initial therapy had higher overall survival (p = 0.048). CONCLUSIONS: Infigratinib has higher efficacy and overall survival than larotrectinib but has higher adverse effects in the management of both glioma and tyrosine kinase alterations after failure of initial therapies. Initial bevacizumab therapy is associated with a higher overall survival.

Construction of a serum diagnostic signature based on m5C-related miRNAs for cancer detection.

Currently, no clinically relevant non-invasive biomarkers are available for screening of multiple cancer types. In this study, we developed a serum diagnostic signature based on 5-methylcytosine (m5C)-related miRNAs (m5C-miRNAs) for multiple-cancer detection. Serum miRNA expression data and the corresponding clinical information of patients were collected from the Gene Expression Omnibus database. Serum samples were then randomly assigned to the training or validation cohort at a 1:1 ratio. Using the identified m5C-miRNAs, an m5C-miRNA signature for cancer detection was established using a support vector machine algorithm. The constructed m5C-miRNA signature displayed excellent accuracy, and its areas under the curve were 0.977, 0.934, and 0.965 in the training cohort, validation cohort, and combined training and validation cohort, respectively. Moreover, the diagnostic capability of the m5C-miRNA signature was unaffected by patient age or sex or the presence of noncancerous disease. The m5C-miRNA signature also displayed satisfactory performance for distinguishing tumor types. Importantly, in the detection of early-stage cancers, the diagnostic performance of the m5C-miRNA signature was obviously superior to that of conventional tumor biomarkers. In summary, this work revealed the value of serum m5C-miRNAs in cancer detection and provided a new strategy for developing non-invasive and cost effective tools for large-scale cancer screening.

Comparison of in vivo behaviors of intramuscularly long-acting celecoxib nanosuspensions with different particle sizes for the postoperative pain treatment.

Celecoxib (CXB) has a good analgesic effect on postoperative acute pain, but clinically its compliance is compromised because of frequent administration. Therefore, the development of injectable celecoxib nanosuspensions (CXB-NS) for long-acting analgesic effects is highly desirable. However, how the particle size affects the in vivo behaviors of CXB-NS remains unclear. Herein, CXB-NS with different sizes were prepared by the wet-milling method. Following intramuscular (i.m.) injection in rats (50 mg/kg), all CXB-NS achieved sustained systemic exposure and long-acting analgesic effects. More importantly, CXB-NS showed size-dependent pharmacokinetic profiles and analgesic effects, and the smallest CXB-NS (about 0.5 µm) had the highest Cmax, T1/2, and AUC0-240h and the strongest analgesic effects on incision pain. Therefore, small sizes are preferred for long action by i.m. injection, and the CXB-NS developed in this study were alternative formulations for the treatment of postoperative acute pain.

Cylindrical granules in the development of mesalazine solid formulations (â ): Physical properties, compression behaviors, and tableting performances.

Cylindrical granules have been employed in the pharmaceutical industry. However, to our knowledge, the study on the compressibility and tabletability of cylindrical granules has not been reported. This study aimed to explore the effects of the physical properties of cylindrical granules on the compression behaviors and the tableting performances, with mesalazine (MSZ) as a model drug. First, the six formulations of MSZ cylindrical granules were extruded by changing the ethanol proportion in the binder. Then, the physical characteristics of MSZ cylindrical granules were systematically studied. Subsequently, the compressibility and tabletability were evaluated using different mathematic models. It was worth noting that highly porous cylindrical granules possessed favorable compressibility and good tabletability due to the increased pore volume, reduced density, and decreased fracture forces. Finally, dissolution tests were conducted and highly porous granules showed higher dissolution rates than the less porous ones, but an opposite trend was observed for the corresponding tablets. This study proved the importance of physical properties in the tableting process of cylindrical granules and provided strategies to improve their compressibility and tabletability.

Thiol-modified hyaluronic acid improves the physical stability of curcumin-zein nanoparticles by forming disulfide bonds with zein.

Zein-based nanoparticles have been developed in the food industry. However, their poor pH stability and unfavorable ionic strength stability remain a challenge even with the use of polysaccharides (such as hyaluronic acid) as stabilizers. To address this shortcoming, an improved strategy based on the disulfide bonds between thiol-modified hyaluronic acid (HASH) and zein was proposed. In this study, curcumin-zein nanoparticles (ZNs-HASH) were prepared with HASH as a stabilizer. The ZNs-HASH displayed similar particle sizes and spherical structures with ZNs and ZNs-HA (HA as a stabilizer). The Fourier transform infrared spectroscopy demonstrated the formation of disulfide bonds between zein and HASH. Among the three formulations tested, ZNs-HASH exhibited the highest pH and salt ion stability and the strongest antioxidant capacity. This study provided new insights for the improvement of physical stability of zein nanoparticles and the development of oral bioactive substances by chemical modification of natural polysaccharides.

Liquid-liquid phase separation drug aggregate: Merit for oral delivery of amorphous solid dispersions.

As a promising strategy, amorphous solid dispersion has been extensively employed in improving the oral bioavailability of insoluble drugs. Despite the numerous advantages, the problems associated with supersaturation stability limit its further application. Recently, the formation and stability of the liquid-liquid phase separation drug aggregate (LLPS-DA) have been found to be vital for supersaturation maintenance. An in-depth review of LLPS-DA was required to further explore the supersaturation maintenance mechanism in vivo. Hence, this study aimed to present a short review to introduce the LLPS-DA, highlight the in vivo advantages for oral administration, and discuss the prospects to help understand the in vivo behavior of LLPS-DA.

Larotrectinib versus infigratinib for adult patients with both glioma and tyrosine kinase alterations after failure of initial therapies: Efficacy and safety analysis

Abstract Objectives To compare the efficacy and safety of larotrectinib with those of infigratinib in adult glioma patients with tyrosine kinase alterations. Methods Patients received oral infigratinib 125 mg (IN cohort, n = 125) or oral larotrectinib (LB cohort, n = 105) until unacceptable toxicity or disease progression. Results Duration of treatment was longer in the LB cohort than in the IN cohort (8 [9.5-6.25] months vs. 5.5 [6-5.25] months, p < 0.0001). Patients with partial responses (p = 0.0424) and overall survival (p = 0.03) were higher in the IN cohort than those in the LB cohort. The number of patients with disease progression was higher in the LB cohort (p = 0.0015). All the patients reported diarrhea, fatigue, vomiting, constipation, and decreased appetite. Patients in the IN cohort reported hyperphosphatemia, hyperlipasemia, stomatitis, dry skin, alopecia, dyspepsia, onycholysis, palmar-plantar erythrodysesthesia, nail disorders, and dry eyes. Patients in the LB cohort reported upper respiratory tract infections, pyrexia, cough, anemia, bacterial/viral infections, conjunctivitis, urinary tract infections, headaches, ataxia, dizziness, and muscle tremors. A total of 30 (24 %) and 40 (38 %) patients from the IN and the LB cohorts died at the follow-up of 18 months (p = 0.03). Patients who received bevacizumab initial therapy had higher overall survival (p = 0.048). Conclusions Infigratinib has higher efficacy and overall survival than larotrectinib but has higher adverse effects in the management of both glioma and tyrosine kinase alterations after failure of initial therapies. Initial bevacizumab therapy is associated with a higher overall survival.