Volume 12, Issue 5

Histological transformation from lung adenocarcinoma (ADC) to small cell lung carcinoma (SCLC), large cell neuroendocrine carcinoma (LCNEC), squamous cell carcinoma (SCC), and sarcomatoid carcinoma (PSC) after targeted therapies is recognized as a mechanism of resistance in ADC treatments. Patients with transformed lung cancer typically experience a poor prognosis and short survival time. However, effective treatment options for these patients are currently lacking. Therefore, understanding the mechanisms underlying histological transformation is crucial for the development of effective therapies. Hypotheses including intra-tumoral heterogeneity, cancer stem cells, and alteration of suppressor genes have been proposed to explain the mechanism of histological transformation. In this review, we provide a comprehensive overview of the known molecular features and signaling pathways of transformed tumors, and summarized potential therapies based on previous findings.

Objective We aimed to investigate the pharmacokinetics, safety, efficacy, and immunogenicity of different dosing regimens (weekly and every three weeks) of inetetamab in combination with vinorelbine in human epidermal growth factor receptor 2 (HER2)+ patients with metastatic breast cancer who had received one or more chemotherapy regimens. Methods HER2+ patients with metastatic breast cancer who had received one or more chemotherapy regimens were included. Eligible patients received inetetamab administered weekly or every three weeks in combination with vinorelbine injection chemotherapy. Pharmacokinetics, safety, efficacy, and immunogenicity were compared between the groups. Results Sixty HER2+ patients were randomized into a single-week administration group ( n = 29) and a three-week administration group ( n = 31). After the final dose in the single-week administration group and the three-week administration group, the mean C max values were 79.773 μg/mL and 146.083 μg/mL; the mean C min values were 30.227 μg/mL and 11.926 μg/mL; the mean AUC tau values were 7328.443 μg·h/mL and 22647.101 μg·h/mL; and the mean C av values were 43.622 μg/ mL and 44.935 μg/mL, respectively. The best overall response (BOR) rates at 24 weeks and unconfirmed BOR rates at 24 weeks were both 40.7% in the single-week dosing group and 40.7% in the three-week dosing group, and the 24-week confirmed disease control rates (DCRs) were 88.9% and 81.5%, respectively. The incidence of adverse events (AEs) was generally consistent across all levels. Conclusion There were slight differences in the mean C max , C min , AUC tau and C av between the three-week dosing group and the single-week dosing group, and the mean steady-state concentrations of C av were comparable; however, there were no differences in efficacy, safety or immunogenicity between the two groups.

Background and Objectives Androgenetic alopecia is one of the common types of hair loss and has become a medical and social problem due to its increasingly young onset. Existing therapies, although effective, have serious side effects and therefore better treatments need to be sought. The aim of this study was to evaluate the efficacy of umbilical cord mesenchymal stem cell-derived exosomes in the treatment of androgenetic alopecia and to investigate the mechanism of exosome regulation of hair growth. Methods First, we randomly divided 20 C57BL/6J mice into blank group, model group, positive control group and exosomal hydrogel group, and mice were treated with hair removal on the back. The mice were injected intraperitoneally with dihydrotestosterone solution except for the blank group. At the end of the experiment, new hairs were collected and the differences in length, diameter and number of hair follicles were compared among the groups; the histopathological changes of hair follicles were observed by HE staining; the expression of androgen receptor mRNA and protein in skin tissues were compared; and the skin tissues were analyzed by real-time PCR, western blotting, immunofluorescence staining and transcriptome sequencing. Finally, the results of transcriptome sequencing experiments were verified by real-time PCR, western blotting and other techniques for the corresponding genes and proteins. Results Compared with the blank group, mice in the model group had shorter hair length and reduced hair diameter, and pathological observation showed that the total number of hair follicles was significantly reduced and the hair follicles were miniaturized; compared with the model group, mice in the positive control and exosome groups had longer hair length, larger hair diameter and more hair follicles; the androgen receptor mRNA content and protein expression in the skin tissue of mice in the model group were significantly higher than those in the blank group, and the protein expression in the exosome gel group was lower than that in the model group. Similarly, compared with the model group, the expression of stemness-related proteins K15 and CD200 in the skin tissues of mice in the exosome group increased, and the expression of PCNA, a protein related to cell proliferation, increased. The KEGG data showed that the differential genes were mainly enriched in the RAS/ERK pathway. Conclusions In this study, we demonstrated the therapeutic effect of umbilical cord MSC-derived exosomes on androgenetic alopecia and verified that exosomes regulate hair follicle stem cell stemness through the RAS/ERK pathway to promote hair proliferation and thus hair growth in mice with androgenetic alopecia, providing a potential therapeutic strategy for androgenetic alopecia.

Background and Objective Atrial fibrillation (AF) and coronary heart disease (CHD) are closely related to metabolic dysregulation. However, the metabolic characteristics of AF patients with concomitant CHD remain unclear. The aims of this study were to elucidate the metabolic profiles of patients with AF and CHD to seek new therapeutic targets and related factors of AF combined with CHD. Methods Untargeted metabolomics and targeted oxylipins profiling were performed to characterize the serum metabolome landscape of patients with AF, CHD, and AF comorbid CHD. Results The serum metabolic fingerprints of patients with AF comorbid CHD were significantly differentiated from normal controls (NC) and individuals with AF or CHD alone, and the differentiated metabolites dominated by a variety of lipid alterations in the phospholipid and fatty acid metabolism. Furthermore, the targeted profiles of oxylipins demonstrated that the levels of arachidonic acid derivatives including prostaglandins, leukotrienes, hydroxy-docosahexaenoic acids, hydroxy-eicostetraenoic acids and hydroxy-eicosatrienoic acids in patients with AF and CHD were significantly different from those in the NC, AF, and CHD groups. Several prostaglandins were positively associated with echocardiographic indicators of myocardial remodeling. Conclusions This study updates metabolic insights of AF and CHD and provides potential therapeutic targets for preventing or treating AF comorbid CHD.

Background Gastroesophageal reflux disease (GERD) is a prevalent gastrointestinal disorder associated with a range of cardiovascular and metabolic complications. However, the relationship between GERD and blood pressure components, lipid profile, and cardiovascular diseases remains unclear. Methods Leveraging genetic variants associated with GERD as instrumental variables, we performed this Mendelian randomization (MR) analyses. Blood pressure components, lipid profile parameters, as well as cardiovascular diseases were considered as outcomes. Furthermore, we conducted reverse MR analysis to explore the association of these factors with the risk of GERD. Results Our MR analysis discovered a potential causal influence of GERD on blood pressure components, with genetically predicted GERD positively associated with systolic blood pressure (β = 0.053, P = 0.036), diastolic blood pressure (β = 0.100, P < 0.001), and mean arterial pressure (β = 0.106, P < 0.001). Additionally, genetically predicted GERD showed a significant impact on lipid profile, leading to increased genetically predicted levels of low-density lipoprotein (LDL) cholesterol (β = 0.093, P < 0.001), and triglycerides (β = 0.153, P < 0.001), while having a negative effect on high-density lipoprotein (HDL) cholesterol (β = -0.115, P = 0.002). Furthermore, our study indicated a noteworthy causal association between genetically predicted GERD and increased risk of myocardial infarction [odds ratio (OR) = 1.272, P = 0.019)] and hypertension (OR = 1.357, P < 0.001). No significant association was found between GERD and pulse pressure, total cholesterol, heart failure, and atrial fibrillation ( P > 0.05). Reverse MR analysis indicates that blood pressure components, lipid profile, and cardiovascular diseases do not lead to an increased risk of GERD (all P > 0.05). Furthermore, mediation MR analysis reveals that LDL cholesterol (proportion mediated: 19.99%, 95% CI: 4.49% to 35.50%), HDL cholesterol (proportion mediated: 11.71%, 95% CI: 5.23% to 18.19%), and hypertension (proportion mediated: 35.09%, 95% CI: 24.66% to 45.53%) mediated the effect of GERD on myocardial infarction, while other factors did not participate in this pathway. Conclusions This MR study provides evidence supporting a causal relationship between GERD and alterations in blood pressure components, lipid profile, and increased risk of cardiovascular diseases.