Association between immune checkpoint inhibitor and cytomegalovirus infection: A pharmacovigilance study based on the adverse event reporting system.

Immune checkpoint inhibitor (ICI)-induced adverse events due to excessive immune stimulation are problematic in immunotherapy. The activation of viral infection triggered by ICI-induced dysregulated immunity has been proposed; however, this association remains inconsistent. This study investigated the association between ICI administration and cytomegalovirus (CMV) infections, a pathogen linked to immune abnormalities and reactivation, using the Food and Drug Administration Adverse Event Reporting System. We used the crude data set and immunocompromise-free data set from the fourth quarter of 2012 to 2023. The disproportionality between CMV infection and ICI was analyzed using reporting odds ratio (ROR) and information component (IC) methodologies. Disproportionality between ipilimumab and nivolumab combination case and CMV infection was observed in the crude (ROR: 2.83, 95% confidence interval [CI]: 2.32-3.47; IC: 1.48, 95% CI: 1.14-1.73) and immunocompromise-free data set (ROR: 1.76, 95% CI: 1.33-2.33; IC: 0.80, 95% CI: 0.33-1.14), whereas disproportionality between other ICI and CMV infection was not observed in the immunocompromise-free data set. Multiple sensitivity analyses and time-scan analysis also revealed the consistent disproportionality between ipilimumab and nivolumab combination cases and CMV infection, regardless of the host's immune status. While further research is warranted to validate our findings, these results highlight new insights into ICI-induced viral infections and suggest the importance of considering the possibility of CMV infections during ipilimumab and nivolumab combination therapy, regardless of the host's immune status.

Effect of a novel siRNA delivery system, siRNA ternary complex, on melanoma lung metastasis.

In this study, we determined effects of an anionic siRNA delivery vector, siRNA ternary complex, which is constructed with biodegradable dendrigraft poly-L-lysine (DGL) and γ-polyglutamic acid (γ-PGA) on the melanoma cells and melanoma lung metastasis. The siRNA ternary complex showed high cellular uptake and silencing effect in melanoma cell line B16-F10/Luc cells. After intravenous administration of the siRNA ternary complex, high silencing effect was also observed in the lung of B16-F10/Luc melanoma metastasis model mice. Therefore, we applied vascular endothelial growth factor (VEGF)-siRNA on the siRNA ternary complex and determined the effect on the melanoma lung metastasis. The siRNA ternary complex containing VEGF-siRNA reduced VEGF protein levels significantly in in vitro and in vivo, and the complex successfully inhibited melanoma lung metastasis. This biodegradable and effective siRNA delivery vector, siRNA ternary complex, could be available for clinical trials.

Effect of pre-treatment with EGFR-TKIs on immune checkpoint inhibitor-associated interstitial lung disease in lung cancer patients: Analysis using a Japanese claims database.

BACKGROUND: Immune checkpoint inhibitors (ICI) and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) are key drugs for the treatment of EGFR mutation-positive lung cancer. While previous studies reported that the concomitant use of these drugs increases the risk of interstitial lung disease (ILD), the impact of sequential treatment on ILD risk is unknown. This study aimed to analyze the impact of EGFR-TKI pre-treatment on the risk of developing ILD after subsequent ICI administration. MATERIALS AND METHODS: We conducted a retrospective study using a Japanese health insurance claims database. ILD-naive lung cancer patients who had first ICI administration during the screening period from July 2014 to February 2019 were selected. Patients who had ILD within 1 year of receiving the first ICI dose were included in the ILD group. Multivariate logistic regression analysis was conducted to evaluate the effect of pre-treatment with EGFR-TKI on the development of ICI-associated ILD. RESULTS: A total of 353 patients were included, of which 61 were included in the ILD group. The median time to onset of ILD after ICI administration was 3 months. Multivariate logistic regression analysis revealed that pre-treatment with EGFR-TKI was not associated with ICI-associated ILD (odds ratio: 0.26, 95% confidence interval: 0.033 - 2.01). CONCLUSION: Although further analyses are required to confirm our findings, this study indicated that pre-treatment with EGFR-TKI might not increase the ILD risk after ICI treatment.

A low prognostic nutritional index is associated with increased remote infections within 30 days of colorectal surgery: A retrospective cohort study.

OBJECTIVE: This study aimed to identify risk factors for remote infection (RI) within 30 days after colorectal surgery. METHODS: This retrospective study included 660 patients who underwent colorectal surgery at Yamaguchi University Hospital or Ube Kosan Central Hospital between April 2015 and March 2019. Using electronic medical records, we identified the incidence of surgical site infection and RI within 30 days after surgery and obtained information on associated factors. Univariate and multivariable analyses were performed to identify significant risk factors in 607 (median age, 71 years) patients. RESULTS: Seventy-eight (13%) and 38 (6.3%) patients had surgical site infection and RI, respectively. Of the 38 patients diagnosed with RI, 14 (36.8%) had a bloodstream infection, 13 (34.2%) had a urinary tract infection, 8 (21.1%) had a Clostridioides difficile infection, and 7 (18.4%) had respiratory tract infections. Multivariable analysis showed that a preoperative prognostic nutritional index of ≤40 (OR, 2.30; 95% CI, 1.07-4.92; P = .032), intraoperative blood transfusion (OR (odds ratio), 3.06; 95% CI, 1.25-7.47; P = .014), and concomitant stoma creation (OR, 4.13; 95% CI, 1.93-8.83; P = .0002) were significant RI predictors. CONCLUSIONS: Nutritional interventions prompted by low preoperative prognostic nutritional index in colorectal surgery may lead to decreases in postoperative RI.

Analysis of vaporized caffeine in smoke from e-cigarettes using liquid chromatography-tandem mass spectrometry and clarification of minor components.

PURPOSE: Electronic cigarettes (e-cigarettes) are used widely, and e-cigarettes containing caffeine (Caf) have recently become commercially available. However, no risk evaluation of these Caf-containing products has been performed to date. Such an evaluation requires a sensitive analytical method for quantifying Caf in smoke from e-cigarettes. The aim of this study was to establish a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantifying vaporized Caf from commercially available e-cigarettes, and to determine minor components related to Caf in cigarette smoke extract (CSE). METHODS: A sampling system for Caf using a suction pump was designed and sampling conditions were optimized. RESULTS: The optimized LC-MS/MS conditions allowed the sensitive determination of Caf in smoke with a limit of detection of 0.03 ng/mL at a signal-to-noise ratio of 3. The method was applied to CSEs from five e-cigarette products and the concentration of Caf ranged from 0.894 ± 0.090 to 3.32 ± 0.14 µg/mL smoke (n = 3). Additionally, minor components related to Caf, such as theobromine, theophylline, and paraxanthine, were detected in CSE and in e-liquid at very low concentrations, indicating that they were impurities in e-liquid and vaporized along with Caf. CONCLUSION: This is the first report to determine the concentration of vaporized Caf using an LC-MS/MS method and to clarify several minor components in smoke from e-cigarettes.

Pharmacoeconomic study of biologics for psoriasis treatment based on real-world drug survival.

The efficacy of biologics in psoriasis treatment is clinically proven; however, biologics are expensive. In this study, we assessed the real-world cost-effectiveness of biologics for psoriasis treatment by evaluating the relationship between biologic drug survival (DS) and total medical-treatment costs from a pharmacoeconomic viewpoint. Furthermore, the effects of patient factors on cost-effectiveness were investigated. We retrospectively reviewed the medical records of 135 cases who received either a tumor necrosis factor-alpha (TNF-α) monoclonal antibody (TNF-mab), interleukin (IL)-17 mab, or IL23p19-mab for psoriasis from January 2010 to June 2020 at Yamaguchi University Hospital. We compared the monthly medical-treatment costs according to biologic classification and found that costs of medical services, tests, and external preparations required for the treatment process were significantly higher in the TNF-mab group than in the other groups, and the total medical costs associated with TNF-mab treatment were significantly higher than those of IL17-mab treatment. The total monthly cost of medical care was lower in the long-term DS group than in the short-term group. The number of prescriptions for external preparations, comprising Vitamin D3 and corticosteroid, was significantly higher in the long-term DS group than in the short-term group; in the TNF-mab group, the proportion of patients without smoking habits was significantly higher in the long-term group as well. Our study indicated that when costly biologics are used for psoriasis treatment, the maintenance of long-term DS and appropriate patient guidance might improve the quality of medical care, thus allowing cost-effective medical care.

Evaluation of the Antiemetic Effect of Premedication Optimized by Pharmaceutical Support in Cisplatin Regimens.

Cisplatin is classified as a drug with high emetic risk; thus, the use of aprepitant or fosaprepitant in addition to a 5-hydroxytryptamine-3 (5-HT3) receptor antagonist and dexamethasone is recommended for antiemetic therapy. Further, hydration is required to prevent renal dysfunction, and the use of magnesium has been proposed as a part of the hydration procedure. When fosaprepitant is chosen for antiemetic therapy because the patient has dysphagia, and magnesium is added to the hydration procedure, there may be an incompatibility between the two drugs that reduces the antiemetic effect. In our hospital, in a former regimen, these two drugs were administered concurrently as premedication for regimens containing cisplatin. We varied the conditions so that in a revised regimen the two drugs did not come into contact due to pharmaceutical support, and we conducted a retrospective study to determine the difference in the antiemetic effect. The observation period was 2 years (from October 2015 to September 2017) for the former regimen group (n = 89) and 2 years (from October 2017 to September 2019) for the revised regimen group (n = 177). Comparison of the former and revised regimen groups revealed sex (p = 0.012); anticancer drug dosage (p = 0.006); and variation of premedication condition (p = 0.043) as factors affected by the revised regimen. Optimization of the premedication regimen was a form of necessary pharmaceutical support to maintain the patient's QOL.

Development of a DNA Vaccine for Melanoma Metastasis by Inhalation Based on an Analysis of Transgene Expression Characteristics of Naked pDNA and a Ternary Complex in Mouse Lung Tissues.

The present study investigated a pulmonary delivery system of plasmid DNA (pDNA) and its application to melanoma DNA vaccines. pCMV-Luc, pEGFP-C1, and pZsGreen were used as a model pDNA to evaluate transfection efficacy after inhalation in mice. Naked pDNA and a ternary complex, consisting of pDNA, dendrigraft poly-l-lysine (DGL), and γ-polyglutamic acid (γ-PGA), both showed strong gene expression in the lungs after inhalation. The transgene expression was detected in alveolar macrophage-rich sites by observation using multi-color deep imaging. On the basis of these results, we used pUb-M, which expresses melanoma-related antigens (ubiquitinated murine melanoma gp100 and tyrosinase-related protein 2 (TRP2) peptide epitopes), as DNA vaccine for melanoma. The inhalation of naked pUb-M and its ternary complex significantly inhibited the metastasis of B16-F10 cells, a melanoma cell line, in mice. The levels of the inflammatory cytokines, such as TNF-α, IFN-γ, and IL-6, which enhance Th1 responses, were higher with the pUb-M ternary complex than with naked pUb-M and pEGFP-C1 ternary complex as control. In conclusion, we clarified that the inhalation of naked pDNA as well as its ternary complex are a useful technique for cancer vaccination.

Methotrexate-Coated Complexes of Plasmid DNA and Polyethylenimine for Gene Delivery.

Folate receptors are overexpressed on the surface cancer cells. We successfully constructed a new gene delivery vector of methotrexate (MTX)-coated plasmid DNA-polyethylenimine (pDNA-PEI) complexes (PEI complexes) by electrostatic binding. The stable anionic nanoparticle was optimized at MTX charge ratios of 120 or more. pDNA-PEI-MTX complexes (MTX complexes) demonstrated gene expression efficiency as high as cationic pDNA-PEI complexes in the mouse melanoma cell line, B16-F10. The MTX complexes were taken up by the cell-specific uptake mechanisms via the folate receptor. MTX-coated complexes are useful as endocytosis ligands. The MTX120 complexes exhibited no blood aggregation. The transgene efficiency of MTX120 complexes in the liver and spleen after their intravenous administration was higher than that of PEI complexes. Therefore, MTX complexes are expected as a new gene vector in the future.

Splenic Delivery System of pDNA through Complexes Electrostatically Constructed with Protamine and Chondroitin Sulfate.

We developed and optimized a novel gene delivery vector constructed electrostatically with an anionic biological component and a cationic biological component. Cationic binary complexes of plasmid DNA (pDNA) with novo-protamine sulfate as a medical product (PRT complexes) demonstrated high gene expression with minimal cytotoxicity, likely related with its total cationic charge. Subsequently, anionic compounds were added to the PRT complexes to form ternary complexes with neutral or anionic charges. Among the anionic compounds examined, chondroitin sulfate sodium (CS) as a medical product encapsulated the PRT complexes to produce stable ternary complexes (CS complexes) at charge ratios of ≥4 with pDNA. CS complexes exhibited high gene expression without cytotoxicity in mouse melanoma cell line, B16-F10 cells, in vitro. An inhibition study with endocytosis inhibitors suggested that PRT complexes were mainly taken up by caveolae-mediated endocytosis, and CS complexes were mainly taken up by clathrin-mediated endocytosis in B16-F10 cells. We found that CS complexes including pDNA encoding Oplophorus gracilirostris luciferase induced selective gene expression in the spleen after intravenous administration into ddY male mice. Thus, we successfully constructed useful gene vectors with biological components as medical products.

Gene delivery system of pDNA using the blood glycoprotein fetuin.

Fetuin is a biocompatible plasma protein and strongly enhances phagocytosis of bacteria, DNA and apoptotic cells by peripheral blood cells such as monocytes, macrophages and dendritic cells. We developed a novel gene delivery system: ternary complexes constructed with pDNA, polyethylenimine (PEI) and fetuin. Without covalent binding, fetuin was able to coat pDNA-PEI complexes, and stable anionic nanoparticles formed at a weight ratio greater than 30. Optimised pDNA-PEI-fetuin complexes significantly decreased the cytotoxicity of pDNA-PEI complexes in the melanoma cell line B16F10. Furthermore, the pDNA-PEI-fetuin complexes had higher transgene efficiency compared to that of commercial lipofectin previously reported in B16F10 cells despite an anionic surface. The pDNA-PEI-fetuin complexes did not agglutinate with erythrocytes. The pDNA-PEI-fetuin complexes had high gene expression in the spleen after intravenous administration in mice. Thus, the pDNA-PEI-fetuin complexes were a useful in vivo gene delivery system with tropism for the spleen.

Biocompatible complex coated with glycosaminoglycan for gene delivery.

The purpose of this study was to develop a ternary complex of plasmid DNA (pDNA) electrostatically assembled with dendrigraft poly-l-lysine (DGL) and biodegradable glycosaminoglycan for effective and secure gene delivery. High gene expression of pDNA/DGL complex was confirmed with slight cytotoxicity and erythrocyte agglutination. Anionic ternary complexes of 55.4-223.8 nm were formed by the addition of a glycosaminoglycan such as chondroitin sulfate A (CS-A), chondroitin sulfate B (CS-B), chondroitin sulfate C (CS-C) or hyaluronic acid (HA). Using the cell line B16-F10, most of the ternary complexes showed only weak gene expression and little cytotoxicity, although the pDNA/DGL/CS-A complexes maintained a certain level of gene expression. In particular, the pDNA/DGL/CS-A8 complexes showed significantly higher gene expression than pDNA/DGL complexes in the presence of fetal bovine serum. Gene expression from the pDNA/DGL/CS-A8 complex was inhibited by a high concentration of CS-A and endocytosis inhibitors. After intravenous administration of the pDNA/DGL/CS-A8 complex and the pDNA/DGL complex into ddY mice, high gene expression was observed in the reticuloendothelial systems, the pDNA/DGL/CS-A complex is expected to be useful for gene therapy.

Application of biodegradable dendrigraft poly-l-lysine to a small interfering RNA delivery system.

Dendrigraft poly-l-lysine (DGL), including its central core, consists entirely of lysine, hence it is completely biodegradable. We applied DGL in a small interfering RNA (siRNA) delivery system. Binary complexes with siRNA and DGL had particle sizes of 23-73 nm and ζ-potentials of 34-42 mV. The siRNA-DGL complexes showed significant silencing effects in a mouse colon carcinoma cell line expressing luciferase (Colon26/Luc cells). The siRNA-DGL complexes induced slight cytotoxicity and hematological toxicity at a high charge ratio of DGL to siRNA, probably because of their cationic charges. Therefore, we recharged the siRNA-DGL complexes with γ-polyglutamic acid (γ-PGA), a biodegradable anionic compound, which was reported to reduce the cytotoxicity of cationic complexes. The ternary complexes showed particle sizes of 35-47 nm at a charge ratio of greater than 14 to siRNA with negative charges. Strong silencing effects of the ternary complexes were observed in Colon26/Luc cells without cytotoxicity or hematological toxicity. The cellular uptake and degradation of the binary and ternary complexes were confirmed by fluorescence microscopy. The ternary complexes suppressed luciferase activity in the tumor after direct injection into the tumors of mice bearing Colon26/Luc cells. Thus, a potentially important siRNA delivery system was constructed using biodegradable DGL.

Evaluation of Antiemetic Therapy for Hepatic Transcatheter Arterial Infusion Chemotherapy with Cisplatin.

Antiemetic prophylaxis with aprepitant, a 5-hydroxytryptamine3 (5-HT3) receptor antagonist and dexamethasone is recommended for patients receiving intravenous cisplatin chemotherapy. Whether the same antiemetic regime is superior for hepatic transcatheter arterial infusion chemotherapy with cisplatin (CDDP-TAI) is unknown. We conducted a retrospective study of antiemetic prophylaxis protection against chemotherapy-induced nausea and vomiting (CINV) in CDDP-TAI at Nagasaki University Hospital. The rate of complete response (CR) to antiemetics in the acute (<24 h) and delayed phases (24-120 h) was measured. Twenty-four patients were treated with a 5-HT3 receptor antagonist (granisetron or azasetron) and dexamethasone on the day of chemotherapy (day 1 only). There was a significant difference between the CR rates in the acute and delayed phases, 91.6, and 69.7%, respectively. Combination of a 5-HT3 antagonist and dexamethasone on day 1 is effective against acute CINV, but not delayed CINV during CDDP-TAI. These results may help guide the management of nausea and vomiting during CDDP-TAI to achieve better tolerance and compliance for fewer interventions and increased favorable therapeutic outcomes.

Splenic gene delivery system using self-assembling nano-complex with phosphatidylserine analog.

The recognition of phosphatidylserine on the erythrocyte membrane mediates erythrophagocytosis by resident spleen macrophages. The application of phosphatidylserine to a gene vector may be a novel approach for splenic drug delivery. Therefore, we chose 1,2-dioleoyl-sn-glycero-3-phospho-L-serin (DOPS) as an analogue of phosphatidylserine for splenic gene delivery of plasmid DNA (pDNA). In the present study, we successfully prepared a stable pDNA ternary complex using DOPS and polyethyleneimine (PEI) and evaluated its efficacy and safety. The pDNA/PEI complex had a positive charge and showed high transgene efficacy, although it caused cytotoxicity and agglutination. The addition of DOPS changed the ζ-potential of the pDNA/PEI complex to negative. It is known that anionic complexes are not taken up well by cells. Surprisingly, however, the pDNA/PEI/DOPS complex showed relatively high transgene efficacy in vitro. Fluorescence microscope observation revealed that the pDNA/PEI/DOPS complex internalized the cells while maintaining the complex formation. The injection of the pDNA/PEI complex killed most mice within 24 h at high doses, although all mice in the pDNA/PEI/DOPS complex group survived. The ternary complex with DOPS showed markedly better safety compared with the pDNA/PEI complex. The pDNA/PEI/DOPS complex showed high gene expression selectively in the spleen after intravenous injection into mice. Thus the ternary complex with DOPS can be used to deliver pDNA to the spleen, in which immune cells are abundant. It appears to have an excellent safety level, although further study to determine the mechanism of action is necessary.

Quaternary complexes modified from pDNA and poly-l-lysine complexes to enhance pH-buffering effect and suppress cytotoxicity.

We developed a modified complex of pDNA and poly-l-lysine (PLL) by the addition of poly-l-histidine (PLH) and γ-polyglutamic acid (γ-PGA) to enhance its pH-buffering effect and suppress cytotoxicity. The binary and ternary complexes of pDNA with PLL or/and PLH showed particle sizes of approximately 52-76 nm with cationic surface charge. The ternary complexes showed much higher gene expression than the binary complexes with PLL. The mixed solution of PLL and PLH showed higher buffering capacity than PLL solution. The high gene expression of ternary complexes was reduced by bafilomycin A1 . These results indicated the addition of PLH to PLL complexes promoted endosomal escape by enhancing the pH-buffering effect. The binary and ternary complexes showed cytotoxicity and blood agglutination because of their cationic surface charge. We therefore developed quaternary complexes by the addition of anionic γ-PGA, which was reported to decrease the toxicity of cationic complexes. In fact, quaternary complexes showed no cytotoxicity and blood agglutination. Also, quaternary complexes showed higher gene expression than ternary complexes regardless of their anionic surface charge. Quaternary complexes showed selectively high gene expression in the spleen after their intravenous administration. Thus, we successfully developed the quaternary complexes with high gene expression and no toxicity.

Secure and effective gene delivery system of plasmid DNA coated by polynucleotide.

Polynucleotides are anionic macromolecules which are expected to transfer into the targeted cells through specific uptake mechanisms. So, we developed polynucleotides coating complexes of plasmid DNA (pDNA) and polyethylenimine (PEI) for a secure and efficient gene delivery system and evaluated their usefulness. Polyadenylic acid (polyA), polyuridylic acid (polyU), polycytidylic acid (polyC), and polyguanylic acid (polyG) were examined as the coating materials. pDNA/PEI/polyA, pDNA/PEI/polyU, and pDNA/PEI/polyC complexes formed nanoparticles with a negative surface charge although pDNA/PEI/polyG was aggregated. The pDNA/PEI/polyC complex showed high transgene efficiency in B16-F10 cells although there was little efficiency in pDNA/PEI/polyA and pDNA/PEI/polyU complexes. An inhibition study strongly indicated the specific uptake mechanism of pDNA/PEI/polyC complex. Polynucleotide coating complexes had lower cytotoxicity than pDNA/PEI complex. The pDNA/PEI/polyC complex showed high gene expression selectively in the spleen after intravenous injection into mice. The pDNA/PEI/polyC complex showed no agglutination with erythrocytes and no acute toxicity although these were observed in pDNA/PEI complex. Thus, we developed polynucleotide coating complexes as novel vectors for clinical gene therapy, and the pDNA/PEI/polyC complex as a useful candidate for a gene delivery system.

Novel siRNA delivery system using a ternary polymer complex with strong silencing effect and no cytotoxicity.

We developed a novel small interfering RNA (siRNA) delivery system using a ternary complex with polyethyleneimine (PEI) and γ-polyglutamic acid (γ-PGA), which showed silencing effect and no cytotoxicity. The binary complexes of siRNA with PEI were approximately 73-102 nm in particle size and 45-52 mV in ζ-potential. The silencing effect of siRNA/PEI complexes increased with an increase of PEI, and siRNA/PEI complexes with a charge ratio greater than 16 showed significant luciferase knockdown in a mouse colon carcinoma cell line regularly expressing luciferase (Colon26/Luc cells). However, strong cytotoxicity and blood agglutination were observed in the siRNA/Lipofectamine complex and siRNA/PEI16 complex. Recharging cationic complexes with an anionic compound was reported to be a promising method for overcoming these toxicities. We therefore prepared ternary complexes of siRNA with PEI (charge ratio 16) by the addition of γ-PGA to reduce cytotoxicity and deliver siRNA. As expected, the cytotoxicity of the ternary complexes decreased with an increase of γ-PGA content, which decreased the ζ-potential of the complexes. A strong silencing effect comparable to siRNA/Lipofectamine complex was discovered in ternary complexes including γ-PGA with an anionic surface charge. The high incorporation of ternary complexes into Colon26/Luc cells was confirmed with fluorescence microcopy. Having achieved knockdown of an exogenously transfected gene, the ability of the complex to mediate knockdown of an endogenous housekeeping gene, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), was assessed in B16-F10 cells. The ternary complex (siRNA/PEI16/γ-PGA12 complex) exhibited a significant GAPDH knockdown effect. Thus, we developed a useful siRNA delivery system.

Expression of steroidogenic enzymes in human sebaceous glands.

Androgens are well known to influence sebum synthesis and secretion. Various factors related to androgen biosynthesis are expressed in human sebaceous glands. In this study, immunohistochemical analysis of human skin specimens from 43 subjects indicated that various androgen-producing and -metabolizing enzymes were functionally localized to sebocytes accumulating lipid droplets and that the exclusive expression of 17ß-hydroxysteroid dehydrogenase type 2 (17ß-HSD2 (HSD17B2)) in sebaceous glands was negatively correlated with that of peroxisome proliferator-activated receptor gamma (PPARγ (PPARG)), which also significantly changed in an age-dependent manner. We also demonstrated that the changes of 17ß-HSD2 expression in human immortalized sebocytes (SZ95) influenced the expressions of sebogenesis-related factors. In addition, the overexpression of 17ß-HSD2 in SZ95 significantly increased the androstenedione production and markedly decreased the amounts of testosterone and dihydrotestosterone when DHEA was added externally. On the other hand, the phosphorylation of mammalian target of rapamycin, which is well known to induce sebum secretion and the onset and/or aggravation of acne, was increased by the addition of testosterone in the presence of IGF1 in hamster sebocytes. These results all indicated that local androgen biosynthesis and metabolism in human sebaceous glands could play a pivotal role in sebum synthesis and secretion.