Glioblastoma (GBM) is the most malignant form of glioma. Glioma stem cells (GSCs) contribute to the initiation, progression, and recurrence of GBM via their self-renewal potential and tumorigenicity. This review presents a brief overview of the influences of two protein posttranslational modifications in GSCs on the properties of GSCs and malignancy of GBM: (I) the ubiquitination of transforming growth factor (TGF)-β receptor (TGFBR) by SMAD-specific E3 ubiquitin protein ligase 2 (SMURF2) and (II) the phosphorylation of extracellular signal-regulated kinase 5 (ERK5) by mitogen-activated protein kinase/ERK kinase 5 (MEK5). The phosphorylation state of SMURF2Thr249 regulates the stemness and tumorigenicity of GSCs via the ubiquitin-dependent modification of the TGFBR–SMAD–SOX axis, along with the downregulation of SMURF2Thr249 phosphorylation in patients with GBM. MEK5 controls the self-renewal and tumorigenic potential of GSCs by phosphorylating the ERK5–signal transducer and activator of transcription 3 (STAT3) axis concomitant with high expression and activity of ERK5 in GSCs. These findings contributed to our understanding of the molecular mechanisms underlying the maintenance of the stemness and tumorigenicity of GSCs through protein posttranslational modifications. We propose that these two protein posttranslational modifications in GSCs might be explored as an effective therapeutic approach against various cancers whose malignancies are associated with the stemness of cancer stem cells.

Erectile responses in reproduction have not been analyzed extensively because of the limitation of their visualization analyses of inner penile structure and its dynamic changes. In addition, the complex and rapid changes of erectile responses require new manipulation techniques suitable to regulate erected and flaccid status. The current review describes novel strategies for the above visualization of erection and regulation of the erectile responses.

This study established an orthotopic mouse model of colorectal cancer (CRC) liver metastasis to investigate the inhibitory effects of combined phytic acid (IP6) and inositol (INS) at different ratios on CRC liver metastasis, as well as their impact on the phosphatidylinositol 3-kinase/serine/threonine protein kinase (PI3K/AKT) signaling pathway and macrophage polarization. Combined treatment with varying ratios of IP6 and INS significantly enhanced survival rates and reduced both cecal tumor weight and the incidence of liver metastasis. Flow cytometry indicated an increased CD4⁺/CD8⁺ T cell ratio and a decrease in regulatory T cells, with the 1 : 3 group showing the most pronounced effects (p < 0.05). Cytokine levels were modulated after treatment with varying IP6-to-INS ratios, with a significant reduction in CCL20, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) (p < 0.05), and an increase in IL-10 and transforming growth factor-β (TGF-β) (p < 0.05). Western blot analysis confirmed a significant downregulation of PI3K/AKT pathway proteins, including PI3K, phosphorylated (p)-PI3K, AKT, p-AKT, and mammalian target of rapamycin (p < 0.05), with the 1 : 3 group exhibiting the greatest effect. Additionally, the expression of M2 macrophage polarization-related proteins CD163 and CD206 was downregulated (p < 0.05). Our findings suggest that the combination of IP6 and INS alleviates CRC metastasis by downregulating the PI3K/AKT pathway and influencing macrophage polarization, with the most significant inhibitory effect observed at an IP6-to-INS ratio of 1 : 3.

Retinoic acid receptor-related orphan receptor gamma (RORγ) is a key transcriptional factor that plays a crucial role in the differentiation and activation of Type 17 cells, such as interleukin-17 (IL-17)-producing CD4⁺ T (Th17) cells and CD8⁺ T (Tc17) cells, which are known to boost antitumor responses. Although a RORγ agonist (LYC-55716) has been under clinical evaluation, the precise effects of RORγ agonists on immune cells within tumor environments remain unclear. In our study, we investigated the role of tumor-infiltrating immune cells in the MC38 syngeneic mouse model of colorectal cancer using Compound-34, a novel orally available RORγ-selective agonist we discovered. Our findings revealed that Compound-34 exerts its antitumor efficacy by modulating immune cell activity rather than directly targeting tumor cells. Specifically, Compound-34 increased the infiltration of effector T cells, including Th17 and Tc1 (interferon [IFN]-γ⁺ CD8⁺ T) cells, as well as innate immune cells like natural killer (NK) and natural killer T (NKT) cells, within the MC38 tumor tissue. Following the administration of Compound-34, there was an increase in IFNγ and Granzyme B within the MC38 tumor tissue, accompanied by an increase in the infiltration of cytotoxic immune cells. Moreover, the addition of Th17-derived cytokines to MC38 cells stimulated the release of CXCL10, a chemokine crucial for immune cell recruitment. These results offer valuable insights into the immunomodulatory and therapeutic potential of RORγ agonists in cancer immunotherapy, highlighting their role in enhancing immune cell infiltration and activity within tumors.

Pharmacists provide pharmacological management prior to a physician visit, which is effective for the smooth introduction of biologics and the avoidance of serious side effects. However, pharmacists face challenges in implementing pharmacological management through dispensing alone. Furthermore, reports on the high risk of side effects associated with biologics remain limited. In this study, we investigated the cost-effectiveness and clinical impact of pharmaceutical management in outpatient pharmaceutical clinics for inflammatory immune diseases, from before the introduction of biologics until 52 weeks after introduction. The number of pharmacological management cases and their associated cost-effectiveness were compared between dispensing and outpatient pharmaceutical clinic groups. Patients aged ≥18 years with an autoimmune disease who were instructed to self-inject biologics between April 2018 and March 2023 were included. The primary outcome was the number of pharmacological management cases performed at the time of biologic introduction. A total of 264 eligible patients were identified, of whom 54 were excluded. After propensity score matching, patients were assigned to 2 groups (n = 67 each). Pharmacological management was significantly more common in the outpatient pharmaceutical clinic group (p < 0.05) than in the dispensing group. In the outpatient clinic group, 10 patients (14.9%) avoided severe adverse events, whereas avoidance was not observed in the dispensing group. The financial benefits of pharmacological management were 915000 and 26091000 yen in the dispensing and outpatient pharmaceutical clinic groups, respectively. Overall, this study demonstrated that pharmacist-led outpatient clinics targeting inflammatory autoimmune diseases can help prevent serious adverse drug reactions and are significantly cost-effective.

A luciferase reporter gene assay demonstrates that a methanol extract of the aerial parts of Euphorbia lathyris L. activates reporter gene expression mediated by CCAAT-enhancer-binding protein homologous protein (CHOP) transcriptional activity in the human pancreatic cancer cell line MIA PaCa-2. We isolated 2 lathyrane-type diterpenoids, euphorbia factor L1 (EFL1) and L3 (EFL3), from the extracts. This is the first report of their isolation from aerial parts of this plant. Treatment of the MIA PaCa-2 with EFL1 or EFL3 increased the levels of phosphorylated inositol-requiring enzyme 1 alpha (IRE1α), activating transcription factor 4 (ATF4) and CHOP, involved in the endoplasmic reticulum (ER) stress pathway and cleaved poly (ADP-ribose) polymerase protein (PARP), as apoptotic markers, and inhibited cell proliferation. Thus, EFL1 and EFL3 may be useful in the development of treatments for pancreatic cancer.

Oncolytic viruses, which kill tumor cells by tumor cell-specific replication, elicit superior antitumor immunity by efficiently activating the innate immune system. However, innate immunity-mediated inflammation is an undesirable consequence that often induces cellular production of immunosuppressive cellular factors. Among various immunosuppressive cellular factors, much attention has recently been focused on prostaglandin E2 (PGE2). In this study, we examined PGE2 production in human tumor cells following treatment with the mammalian orthoreovirus type 3 Dearing strain (hereafter reovirus), which has been used as an oncolytic virus in preclinical and clinical studies. Reovirus significantly induced PGE2 secretion from several types of human tumor cells in a virus titer-dependent manner. A nuclear factor-kappa B (NF-κB) inhibitor, BAY11-7082, and a cyclooxygenase 2 (COX2) inhibitor, celecoxib, significantly inhibited PGE2 secretion, indicating that NF-κB and COX2 played a crucial role in reovirus-induced PGE2 production. Moreover, UV-irradiated reovirus (UV-Reo), which lost virus replication ability, did not increase PGE2 secretion. In addition, inhibitors of cathepsins B and L, cysteine lysosomal proteases crucial for reovirus replication, significantly reduced PGE2 secretion. These results indicate that reovirus replication in tumor cells is important for reovirus-induced PGE2 production. Attention should be paid to possible PGE2 production in tumors following reovirus treatment.

Cancer-associated thrombosis is the second leading cause of death in patients with cancer. The highly metastatic triple-negative mouse breast cancer cell line 4T1 induces thrombus formation that is dependent on neutrophil extracellular traps (NETs) in transplanted mice when exposed to certain stimuli, such as lipopolysaccharide (LPS) injection. These findings suggest that 4T1 transplantation into mice increases the susceptibility to NET release, followed by thrombus formation in response to external stimuli. However, the blood levels of coagulation-associated factors in 4T1-bearing mice that are in a primed state without any stimulation remain unknown. In this study, we analyzed coagulation and fibrinolytic factors in the plasma of mice orthotopically transplanted with 4T1 cells. In 4T1-bearing mice, a NET marker, citrullinated histone H3, was detected in the tumor tissues and lungs, but not in the plasma. The presence of fibrin(ogen)-containing Ly6G-positive cell clusters in the lung vasculature suggested that NET release and NET-induced microthrombus formation occurred in the lungs. In plasma, increased levels of tissue factor and active and total plasminogen activator inhibitor-1 (PAI-1) suggested enhanced procoagulant activity and suppressed fibrinolysis. However, plasma thrombin–antithrombin complex levels, which reflect overt thrombin activation that forms fibrin clots, were similar in 4T1-bearing and non-transplanted mice. These findings indicate that 4T1 cell growth and metastasis in mice establish a pre-thrombotic state characterized by NET release and procoagulant potential, which requires a secondary trigger, such as LPS, to develop into pathological thrombosis. Therefore, 4T1-bearing mice may be useful as an in vivo model for exploring secondary triggers of pathological thrombosis.

Platycodon grandiflorum (P. grandiflorum), a traditional Chinese herbal medicine, possesses various biological activities. Among its constituents, polygalacin D (PGD) stands out as one of the principal compounds. This study determined the regulatory effect of PGD on breast cancer progression. Breast cancer cells MCF-7 and BT474 were treated with different concentrations of PGD. Colony formation assays, the detection of Ki67 expression, and cell cycle analysis were performed to verify the effect of PGD on the proliferation of breast cancer cells. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining, flow cytometry, and examination of caspase-3 activity were conducted to assess the changes in apoptosis following PGD treatment. In addition, the co-treatment of PGD and cisplatin (DDP) on cells was performed to explore the effect of PGD on the chemosensitivity of DDP. Furthermore, bioinformation analysis suggested that histone deacetylase 1 (HDAC1) and HDAC2 were the downstream factors of PGD, and the effect of PGD on their expression was assessed. PGD inhibited breast cancer cell proliferation, as evidenced by reduced colony formation, downregulation of Ki67 expression, and induction of cell cycle arrest. Additionally, PGD treatment significantly increased caspase-3 activity and elevated the rate of cell apoptosis and TUNEL-positive cells. Furthermore, PGD was found to enhance the chemosensitivity to DDP. Mechanistically, PGD reduced the expression of HDAC1 and HDAC2 by promoting their protein degradation. Cell proliferation induced by HDAC1 or HDAC2 was also overcome by PGD. In conclusion, PGD was confirmed as an effective tumor inhibitor that suppressed the development of breast cancer by regulating HDAC1 and HDAC2.

Area under the concentration–time curve (AUC)-guided vancomycin dosing is recommended to measure peak and trough concentrations. While recent studies have shown that AUC on Day 1 and Day 2 are associated with early clinical response and nephrotoxicity, data confirming the accuracy of AUC estimation using trough-only data on Day 1 and Day 2 are scarce. The aim of this study was to evaluate the agreement of AUC calculated using trough-only data compared with 2-point sampling on Day 1 and Day 2 using the Bayesian-based, free web application PAT (Practical AUC-guided TDM for vancomycin). We conducted a single-center, cohort study to evaluate the agreement of AUC calculated using trough-only data compared to peak–trough sampling on Day 1 and Day 2. The ratios of trough/peak–trough AUC for AUC_0–24 and AUC_24–48 were within the acceptable range of 0.8–1.2. Furthermore, AUCs estimated using trough-only data and those estimated using peak–trough concentrations showed high agreement. In addition, multivariate ordinal logistic regression analysis showed that estimated glomerular filtration rate and serum albumin were significant factors affecting the deviation of trough/peak–trough AUC_24–48 (p = 0.001 and p = 0.040, respectively). In conclusion, trough-only data may be sufficient for AUC estimation in AUC-guided dosing in patients identified as suitable candidates, even when obtained on Day 2. Further, renal function and serum albumin were found to be factors affecting the agreement rate of AUC on Day 2 when using trough-only data.