Kyoto Pharmaceutical University

Cytokine receptor-like factor 2 (CRLF2) and interleukin-7 receptor α (IL-7Rα) form a receptor for thymic stromal lymphopoietin (TSLP). A somatic mutation consisting of the substitution of five amino acids (SLLLL) in the transmembrane domain of CRLF2 with three amino acids, including glutamic acid, isoleucine, and methionine (insEIM), which has been identified in acute lymphocytic leukemia, causes the TSLP-independent dimerization with IL-7Rα and activation. However, the dimerization mechanism remains unclear. In this study, we examined the involvement of the amino acids in the transmembrane domains of EIM CRLF2 and IL-7Rα in TSLP-independent activation. HEK293 cells were transfected with vectors encoding CRLF2 and IL-7Rα, or their mutants, in which the amino acid of the transmembrane domain was replaced with alanine. STAT5 phosphorylation was detected using western blotting, and receptor dimerization was analyzed using the NanoBiT assay. The substitution of glutamic acid within the insEIM mutation for alanine failed to cause the STAT5 phosphorylation in the absence of TSLP. Moreover, the alanine substation of the specific leucine residues in the transmembrane domains of both CRLF2 and IL-7Rα abrogated the TSLP-independent signal transduction and dimerization. The mutation of IL-7Rα W264 partially reduced the phosphorylation of STAT5 without affecting receptor dimerization. These results suggest that the amino acids in the transmembrane domains of EIM CRLF2 and IL-7Rα play at least three possible functions: interaction through hydrogen bonds, hydrophobic interaction, and signal transduction. Our findings contribute to a better understanding of the function of the transmembrane domains of cytokine receptors in their dimerization and signal transduction.

Multimodal analgesia (MMA) is recommended for postoperative pain management; however, studies evaluating the effect of tramadol-including MMA on numerical rating scale (NRS)-based postoperative pain levels and the length of stay (LOS) in the hospital are limited. Therefore, this study aimed to compare the before and after effects of tramadol-including MMA application, and assess its effect on postoperative NRS scores and LOS.

Patients who underwent spinal surgery under general anesthesia at the Rakuwakai Marutamachi Hospital in fiscal years 2020 and 2022 were included in this study. The outcomes between the pre- and post-intervention groups were compared through propensity score matching.

Following propensity score matching, 249 patients were included in each group. MMA application significantly decreased the median LOS from 10 to 9 days (p < 0.001). Additionally, the median NRS scores exhibited a significant decrease from 4 to 3 on postoperative day (POD) 3 (p = 0.0109) and from 3 to 2 on POD 5 (p = 0.0087). Following MMA application, the number of patients receiving additional analgesics decreased significantly, from 38 to 6 (p < 0.001).

The introduction of tramadol-including MMA can effectively reduce postoperative pain and decrease the LOS for patients undergoing spinal surgery.

Aim: Certain cancer cells depend on oxidative phosphorylation for survival; thus, inhibiting this process may be a promising treatment strategy. This study explored the structure-activity relationships of the mitochondrial inhibitor N-ethylene glycol-comprising alkyl thiophene-3-carboxamide 3.Methods & results: We synthesized and evaluated 13 analogs (5a-m) with different ethylene glycol units, heterocycles and connecting groups for their growth-inhibitory effects on A549 non-small cell lung cancer cells. We found that increasing the number of ethylene glycol units significantly enhanced inhibitory activity. Some analogs activated adenosine monophosphate-activated protein kinase, similar to 3. Notably, analog 5e, which contains tetraethylene glycol units, significantly inhibited tumor growth in vivo.Conclusion: Analog 5 may be a potential therapeutic agent for non-small cell lung cancer treatment.