We designed a transdermal system to serve as a delivery platform for benfotiamine utilizing the attributes of passive penetration enhancing molecules to penetrate through the outer layers of skin combined with the advance of incorporating various peripherally-acting vasodilators to enhance drug uptake. Benfotiamine, incorporated into this transdermal formulation, was applied to skin in an animal model in order to determine the ability to deliver this thiamine pro-drug effectively to the sub-epithelial layers. In this proof of concept study in guinea pigs, we found that a single topical application of either a solubilized form of benfotiamine (15 mg) or a microcrystalline suspension form (25 mg) resulted in considerable increases of the dephosphorylated benfotiamine (S-benzoylthiamine) in the skin tissue as well as in significant increases in the thiamine and thiamine phosphate pools compared to control animals. The presence of a ~8000x increase in thiamine and increases in its phosphorylated derivatives in the epidermis and dermis tissue of the test animals gives a strong indication that the topical treatment with benfotiamine works very well for the desired outcome of producing an intracellular increase of the activating cofactor pool for transketolase enzyme, which is implicated in the pathophysiology of diabetic neuropathy.
Abstract Lung adenocarcinoma (LUAD) is a prevalent form of non-small cell lung cancer with a rising incidence in recent years. Understanding the mutation characteristics of LUAD is crucial for effective treatment and prediction of this disease. Among the various mutations observed in LUAD, KRAS mutations are particularly common. Different subtypes of KRAS mutations can activate the Ras signaling pathway to varying degrees, potentially influencing the pathogenesis and prognosis of LUAD. This study aims to investigate the relationship between different KRAS mutation subtypes and the pathogenesis and prognosis of LUAD. A total of 63 clinical samples of LUAD were collected for this study. The samples were analyzed using targeted gene sequencing panels to obtain sequencing data. To complement the dataset, additional clinical and sequencing data were obtained from TCGA and MSK. The analysis revealed significantly higher Ki67 immunohistochemical scores in patients with missense mutations compared to controls. Moreover, the expression level of KRAS was found to be significantly correlated with Ki67 expression. Enrichment analysis indicated that KRAS missense mutations activated the SWEET_LUNG_CANCER_KRAS_DN and CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_2 pathways. Additionally, patients with KRAS missense mutations and high Ki67 IHC scores exhibited significantly higher tumor mutational burden levels compared to other groups, which suggests they are more likely to be responsive to ICIs. Based on the data from MSK and TCGA, it was observed that patients with KRAS missense mutations had shorter survival compared to controls, and Ki67 expression level could more accurately predict patient prognosis. In conclusion, when utilizing KRAS mutations as biomarkers for the treatment and prediction of LUAD, it is important to consider the specific KRAS mutant subtypes and Ki67 expression levels. These findings contribute to a better understanding of LUAD and have implications for personalized therapeutic approaches in the management of this disease.
Microfluidics-based devices play an important role in creating realistic microenvironments in which cell cultures can thrive. They can, for example, be used to monitor drug toxicity and perform medical diagnostics, and be in a static-, perfusion- or droplet-based device. They can also be used to study cell-cell, cell-matrix or cell-surface interactions. Cells can be either single cells, 3D cell cultures or co-cultures. Other organisms could include bacteria, zebra fish embryo, C. elegans, to name a few.
Abstract Programmed cell death 1 (PD‐1), a key immune checkpoint receptor, has been extensively studied for its role in regulating immune responses in cancer. However, recent research has unveiled a complex and dual role for PD‐1 in tumorigenesis. While PD‐1 is traditionally associated with immune cells, this article explores its expression in various cancer cells and its impact on cancer progression. PD‐1's functions extend beyond immune regulation, as it has been found to both promote and suppress tumor growth, depending on the cancer type. These findings have significant implications for the future of cancer treatment and our understanding of the immune response in the context of cancer. This article calls for further research into the multifaceted roles of PD‐1 to optimize its therapeutic potential and improve patient outcomes in the fight against cancer.
Abstract Cervical cancer (CC) is the most common gynecological malignant tumor. Immunotherapy has become a new model for the treatment of CC, especially advanced and recurrent cancer. At present, many studies are exploring the safety and efficacy of immunotherapy for advanced or recurrent CC. In this study, CIBERSORT was used to analyze the immune cell infiltration in CC patients, to evaluate the proportion of immune cell types in CC samples, to quantify the cell composition of the immune response, and to analyze its prognostic value. The expression profile datasets of CC were downloaded from the GEO. The differentially expressed genes (DEGs) between CC and normal cervical tissues were identified via R software (version 4.1.1), and their functions and pathways were enriched and analyzed. A protein–protein interaction network was constructed to screen the hub gene. Immune cell infiltration in CC was analyzed via scientific reverse convolution algorithm (CIBERSORT), and the hub gene was analyzed via survival analysis to screen the diagnostic biomarkers of CC. A total of 144 DEGs and 12 hub genes were identified. DEGs are mainly involved in molecular functions such as serine-peptidase activity, serine-hydrolase activity, and chemokine activity. The enrichment pathway is closely related to the interaction between viral proteins and cytokines and cytokine receptors, the interleukin 17 signaling pathway, and chemokine signaling pathway. The immune cell infiltration analysis showed that T cells were the main infiltrating immune cells in CC, especially T cells CD8+ and CD4+ . The survival analysis of the hub gene showed that CEP55, MCM2, RFC4, and RRM2 had high diagnostic value. CEP55, MCM2, RFC4, and RRM2 can be used as diagnostic markers for CC. CD8+ and CD4+ T cells are closely related to the occurrence and development of CC.
'/%3e%3cuse xlink:href='%23a' transform='rotate(144 450 300)'/%3e%3cuse xlink:href='%23a' transform='rotate(216 450 300)'/%3e%3cuse xlink:href='%23a' transform='rotate(288 450 300)'/%3e%3c/svg%3e)
'/%3e%3cuse xlink:href='%23a' transform='translate(288.889 -214.211)'/%3e%3cuse xlink:href='%23a' transform='translate(108 342.749)'/%3e%3cuse xlink:href='%23a' transform='translate(469.189 342.749)'/%3e%3c/svg%3e)
'/%3e%3cuse xlink:href='%23a' transform='rotate(23.036 .093 25.536)'/%3e%3cuse xlink:href='%23a' transform='rotate(45.87 1.273 16.18)'/%3e%3cuse xlink:href='%23a' transform='rotate(69.945 .996 12.078)'/%3e%3cuse xlink:href='%23a' transform='rotate(20.66 -19.689 31.932)'/%3e%3c/svg%3e)
'/%3e%3cuse xlink:href='%23a' transform='scale(-1 1)'/%3e%3c/g%3e%3cuse xlink:href='%23b' transform='rotate(72)'/%3e%3c/g%3e%3cuse xlink:href='%23b' transform='rotate(-72)'/%3e%3cuse xlink:href='%23c' transform='rotate(144)'/%3e%3c/svg%3e)