Light-Triggered PROTAC Nanoassemblies for Photodynamic IDO Proteolysis in Cancer Immunotherapy.

While proteolysis-targeting chimeras (PROTACs) hold great potential for persistently reprogramming the immunosuppressive tumor microenvironment (ITM) via targeted protein degradation, precisely activating them in tumor tissues and preventing uncontrolled proteolysis at off-target sites remain challenging. Herein, we report a light-triggered PROTAC nanoassembly (LPN) for photodynamic indoleamine 2,3-dioxygenase (IDO) proteolysis. The LPN is derived from the self-assembly of prodrug conjugates, which comprise a PROTAC, cathepsin B-specific cleavable peptide linker and photosensitizer, without any additional carrier materials. In colon tumor models, intravenously injected LPNs initially silence the activity of PROTACs and accumulate significantly in targeted tumor tissues due to an enhanced permeability and retention (EPR) effect. Subsequently, the cancer biomarker cathepsin B begins to trigger the release of active PROTACs from the LPNs through enzymatic cleavage of the linkers. Upon light irradiation, tumor cells undergo immunogenic cell death (ICD) induced by photodynamic therapy (PDT) to promote the activation of effector T cells, while the continuous IDO degradation of PROTAC simultaneously blocks tryptophan metabolite-regulated regulatory T cell-mediated immunosuppression. Such LPN-mediated combinatorial photodynamic IDO proteolysis effectively inhibits tumor growth, metastasis and recurrence. Collectively, this study presents a promising nanomedicine, designed to synergize PROTACs with other immunotherapeutic modalities, for more effective and safer cancer immunotherapy. This article is protected by copyright. All rights reserved.

Mucoadhesive Mesalamine Prodrug Nanoassemblies to Target Intestinal Macrophages for the Treatment of Inflammatory Bowel Disease.

While mesalamine, a 5-aminosalicylic acid (5-ASA), is pivotal in the management of inflammatory bowel disease (IBD) through both step-up and top-down approaches in clinical settings, its widespread utilization is limited by low bioavailability at the desired site of action due to rapid and extensive absorption in the upper gastrointestinal (GI) tract. Addressing mesalamine's pharmacokinetic challenges, here, we introduce nanoassemblies composed exclusively of a mesalamine prodrug that pairs 5-ASA with a mucoadhesive and cathepsin B-cleavable peptide. In an IBD model, orally administered nanoassemblies demonstrate enhanced accumulation and sustained retention in the GI tract due to their mucoadhesive properties and the epithelial enhanced permeability and retention (eEPR) effect. This retention enables the efficient uptake by intestinal pro-inflammatory macrophages expressing high cathepsin B, triggering a burst release of the 5-ASA. This cascade fosters the polarization toward an M2 macrophage phenotype, diminishes inflammatory responses, and simultaneously facilitates the delivery of active agents to adjacent epithelial cells. Therefore, the nanoassemblies show outstanding therapeutic efficacy in inhibiting local inflammation and contribute to suppressing systemic inflammation by restoring damaged intestinal barriers. Collectively, this study highlights the promising role of the prodrug nanoassemblies in enhancing targeted drug delivery, potentially broadening the use of mesalamine in managing IBD.

Learning Curve for Endoscopic Transsphenoidal Surgery: A Systematic Review and Meta-Analysis.

BACKGROUND: Endoscopic transsphenoidal surgery (ETSS) is emerging as an effective, minimally invasive surgery technique for brain tumors of the pituitary fossa. Using a surgical endoscope, surgeons can obtain a broader, nearer, and more apparent visual field with minimal keyhole entrance. However, ETSS may require a steep learning curve to achieve technical competence and relevant outcomes. Moreover, there is no consensus on the learning process of ETSS. We aimed to review and determine the technical proficiency points of ETSS and discuss how to accelerate the learning curve. METHODS: Core databases, including PubMed, Embase, and the Cochrane Library, were systematically searched for learning curve studies that demonstrated the clinical outcomes and learning status of ETSS for pituitary adenomas using numerical data. Quality assessments of the included articles were performed using the Newcastle-Ottawa scale. The cutoff points were evaluated based on various outcome measures. RESULTS: Eleven full-text articles, representing 2780 cases, were selected from 317 screened studies. The outcome measures were operative time, tumor removal, endocrinological results, visual field, and surgical complications. The plateaus or cutoff points in the learning curve varied with a mean of 103 ± 139.43 (range, 9-500) cases. CONCLUSIONS: ETSS is an efficient and minimally invasive alternative surgical option for pituitary tumors. Plateau points may differ according to outcome measures, patient selection, training status, and surgical conditions. Therefore, great care should be taken when interpreting the learning curve. A systematic training program is essential to improve the learning process of endoscopic neurosurgical procedures.

Treatment Outcome of the Brain Metastases in Peri-Rolandic Area: Comparison Between Surgery and Stereotactic Radiosurgery.

BACKGROUND: Brain metastases of peri-Rolandic area is crucial as it directly impacts the quality of life for cancer patients. Surgery or stereotactic radiosurgery (SRS) is considered for peri-Rolandic brain metastases as for other brain metastases. However, the benefit of each treatment modality on functional outcome has not been clearly defined for this tumor. The purpose of this study is to compare the functional course of each treatment and to suggest an effective treatment for patients' quality of life. METHODS: Fifty-two patients who had undergone SRS or surgery for brain metastasis confirmed by enhanced MRI were enrolled retrospectively. Overall survival (OS), progression free survival (PFS), and functional outcomes were estimated using the Kaplan-Meier method, univariate, multivariate analysis, and Cox proportional hazards regression. RESULTS: Median OS and PFS were 13.3 months and 8.9 months in our study population. Treatment modalities were not significant factors for OS and PFS. Extracranial systemic cancer progression was significant factor for both parameters (p=0.030 for OS and p=0.040 for PFS). Median symptom improvement (improvement of at least 1 grade after surgery compared to preoperative state) time was significantly shorter in surgery group than in the SRS group (10.5 days vs. 37.5 days, p=0.034). CONCLUSION: Surgery for brain metastases can contribute to a positive quality of life for the remaining duration of the patient's life.

Synthesis of Sulfonated Polyphenylene Block Copolymers via In Situ Generation of Ni(0).

Proton exchange membranes (PEMs) fabricated from sulfonated polyphenylenes (sPP) exhibit superior proton conductivity and electrochemical performance. However, the Ni(0) catalyst required for Colon's cross-coupling reaction for the synthesis of sPP block copolymers is expensive. Therefore, in this study, we generated Ni(0) in situ from an inexpensive Ni(II) salt in the presence of the reducing metal Zn and NaI. The sPP block copolymers were synthesized from neopentyl-protected 3,5- and 2,5-dichlorobenzenesulfonates and oligo(arylene ether ketone) using the catalyst NiBr2(PPh3)2. The block copolymers synthesized using our strategy and the Ni(0) catalyst exhibited comparable polydispersity index values and high molecular weights. Thin, transparent, and bendable PEMs fabricated using selected high-molecular-weight sPP block copolymers synthesized via our strategy exhibited similar proton conductivities to those of the block copolymers synthesized using the Ni(0) catalyst. We believe that our strategy will promote the synthesis of similar multifunctional block copolymers.

Combined petrosal approach for a huge retroclival meningioma preserving the cranial nerves.

Surgery for petroclival meningioma is challenging because cranial nerve preservation during tumor removal can be very complex. For small- to medium-sized tumors, the anatomical relationship between tumor and neurovascular structures can be assessed before surgery. However, in large tumors, cranial nerves usually cannot be seen in preoperative images. The authors present a case of a 65-year-old woman who presented with gait disturbance and hearing loss and was diagnosed with huge retroclival meningioma involving the cavernous sinus, Meckel's cave, and internal acoustic meatus. In this video, they explain the radiographical, anatomical, and surgical considerations and demonstrate the surgical technique. The video can be found here: https://stream.cadmore.media/r10.3171/2022.1.FOCVID21221.

Thirty-year clinical experience in gamma knife radiosurgery for trigeminal schwannomas.

We aimed to evaluate the radiographic and clinical outcomes after gamma knife radiosurgery (GKRS) for trigeminal schwannomas (TSs). A total of 87 patients who underwent GKRS for TSs between 1990 and 2020 were enrolled. The mean tumor volume was 4.3 cm3. The median prescribed dose for the margins of the tumor was 13 Gy. The median follow-up duration was 64.3 months (range 12.0-311.5 months). The overall local tumor control rate was 90%, and the symptom response rate was 93%. The response rate for each symptom was 88% for facial pain, 97% for facial sensory change, and 86% for cranial nerve deficits. Nineteen (22%) patients showed transient swelling, which had regressed at the time of the last follow-up. Cystic tumors were associated with transient swelling (p = 0.04). A tumor volume of < 2.7 cm3 was associated with local tumor control in univariable analysis. Transient swelling was associated with symptom control failure in both univariable and multivariable analyses (p = 0.04, odds ratio 14.538). GKRS is an effective treatment for TSs, both for local control and symptom control.

Posterior Fossa Teratomas in Adults : A Systematic Review.

OBJECTIVE: The occurrence of posterior fossa teratomas in adulthood is extremely rare. In this study, we aimed to report our experience with two cases of posterior fossa mature teratoma in adults who underwent surgical resection. We also performed a systematic review of published papers available to date. METHODS: We retrospectively reviewed the electronic medical records of patients who had onset of posterior fossa teratomas in adulthood at our institute between 1995 and 2020. We evaluated the clinical, radiographic, and pathological features of mature teratomas at the posterior fossa in adulthood. Furthermore, we searched the PubMed, EMBASE, and Web of Science database and reviewed published articles. RESULTS: We found 507 articles on database review; of them, 102 were duplicates and 389 were excluded based on the inclusion criteria. Finally, 16 cases of posterior fossa from the web search and related articles. Subsequently, we added two cases that underwent surgery at our institute. We analyzed a total of 18 cases of mature teratomas. Headache was the most common (55.6%) symptom. The teratomas showed heterogeneous signals on magnetic resonance imaging. Thirteen patients (72.2%) had lesion at midline, five patients (27.8%) had calcification. Surgical resection was performed in all patients. No studies reported recurrence after resection. CONCLUSION: The occurrence of posterior fossa teratomas in adulthood is difficult to diagnose at the initial stage. Radiographic diagnosis alone can lead to misdiagnosis. Pathological confirmation is essential. Surgical resection is a curative option for posterior fossa teratomas in adulthood.

Intracranial solitary fibrous tumor/hemangiopericytoma: tumor reclassification and assessment of treatment outcome via the 2016 WHO classification.

PURPOSE: As per the 2016 World Health Organization (WHO) guidelines on the classification of central nervous system tumors, solitary fibrous tumors (SFTs) and hemangiopericytomas (HPCs) constitute a single disease entity, known as SFT/HPC. This study provides a clinical analysis of these tumors and describes the treatment outcomes of SFT/HPCs. METHODS: This retrospective study included 76 patients with histopathologically proven SFT/HPC. Reclassification according to the 2016 WHO guideline was done for patients who were diagnosed with SFT or HPC based on the 2007 WHO classification. Recurrence-free survival (RFS) and overall survival (OS) were evaluated for all patients and subgroups. RESULTS: The median follow-up period was 77.9 months. The median RFS and OS were 126.5 and 136.8 months, respectively. The 1-, 5-, 10-, and 15-year RFS rates were 93%, 72%, 40%, and 40%, respectively. The 1-, 5-, 10- and 15-year OS rates were 97%, 89%, 54%, and 35%, respectively. In multivariable analyses, stereotactic radiosurgery (SRS; p = 0.009, hazard ratio [HR] 6.986), female sex (p = 0.023, HR 1.76), and age over 45 (p = 0.037, HR 2.74) were associated with shorter RFS. Patients who underwent SRS as initial treatment had a shorter OS than that of patients who underwent primary resection (p < 0.001, HR 12.86). CONCLUSIONS: High-grade tumors tended to have worse OS and occur extracranial metastases earlier than low-grade tumors. The median RFS was not different between grade II and III tumors. Male sex, younger age, and GTR were associated with a better RFS. A history of SRS before tumor resection was associated with a shorter RFS and OS.

Survival outcome and prognostic factors in anaplastic oligodendroglioma: a single-institution study of 95 cases.

The aim of this study was to evaluate prognostic factors including surgical, radiographic, and histopathologic analyses in anaplastic oligodendroglioma (AO) patients. We reviewed the electronic records of 95 patients who underwent surgery and were diagnosed with AO for 20 years. The primary endpoints were progression-free survival (PFS) and overall survival (OS). Univariate and multivariable analyses included clinical, histopathological, and radiographic prognostic factors. Subgroup analysis was performed in isocitrate dehydrogenase (IDH1/2)-mutant and 1p/19q-codeleted patients. The median PFS and OS were 24.7 months and 50.8 months, respectively. The 1-, 3-, 5-, and 10-year PFS were 75.8%, 42.9%, 32.4%, and 16.4%, respectively. Furthermore, the 1-, 3-, 5-, and 10-year OS were 98.9%, 76.9%, 42.9%, and 29.7%, respectively. The median PFS and OS of the IDH1/2-mutant and 1p/19q-codeleted patients were 54.2 and 57.8 months, respectively. In univariate analyses, young age, frontal lobe, weak enhancement, gross total resection (GTR), low Ki-67 index, 1p/19q codeletion, and IDH1/2 mutations were associated with a favorable outcome. In multivariable analyses, IDH1/2 mutation was related to better PFS and OS. In subgroup analysis, GTR was associated with favorable outcomes.

Synthetic Approaches for Poly(Phenylene) Block Copolymers via Nickel Coupling Reaction for Fuel Cell Applications.

Several methods to synthesize poly(phenylene) block copolymers through the nickel coupling reaction were attempted to reduce the use of expensive nickel catalysts in polymerization. The model reaction for poly(phenylene) having different types of dichlorobenzene derivative monomers illustrated the potential use of cost-effective catalysts, such as NiBr2 and NiCl2, as alternatives to more expensive catalysts (e.g., bis(1,5-cyclooctadiene)nickel(0) (Ni(COD)2)). By catalyzing the polymerization of multi-block poly(phenylene) with NiBr2 and NiCl2, random copolymers with similar molecular weights could be prepared. However, these catalysts did not result in a high-molecular-weight polymer, limiting their wide scale application. Further, the amount of Ni(COD)2 could be reduced in this study by approximately 50% to synthesize poly(phenylene) multi-block copolymers, representing significant cost savings. Gel permeation chromatography and nuclear magnetic resonance results showed that the degree of polymerization and ion exchange capacity of the copolymers were almost the same as those achieved through conventional polymerization using 2.5 times as much Ni(COD)2. The flexible quaternized membrane showed higher chloride ion conductivity than commercial Fumatech membranes with comparable water uptake and promising chemical stability.

Primary central nervous system lymphoma involving the hypothalamic-pituitary axis: a case series and pooled analysis.

PURPOSE: Primary central nervous system lymphoma (PCNSL) involving the hypothalamic-pituitary axis (H-P axis) is a rare intracranial neoplasm. We aimed to determine the unique characteristics and treatment outcomes of patients with PCNSL at the H-P axis and review the literature. METHODS: We retrospectively reviewed the electronic medical records of patients with PCNSL in our institute from 2000 to 2017. We analyzed patient characteristics, clinicopathologic features, imaging results, and treatment outcomes. Furthermore, we searched the PubMed database and gathered more cases from published studies to analyze patient treatment outcomes. RESULTS: A total of 488 patients were diagnosed with central nervous system lymphoma at our institute. Seven (1.4%) patients had H-P axis involvement, five had diffuse large B-cell lymphoma, and two had mucosa-associated lymphoid tissue lymphoma. All patients had anterior pituitary lobe dysfunction, and two had posterior lobe dysfunction. The median progression-free survival (PFS) for seven patients was 29.0 (range: 0.9-48.1) months, and the 3-year survival rate was 42.9%. Pooled analysis included 45 patients. The median PFS for these patients was 7.0 months (0.9-52.0), and the 2-year survival rate was 20%. Univariate and multivariate analyses revealed that the patients with visual field defects had better prognosis (p = 0.0153 and 0.043, respectively). CONCLUSION: PCNSL at the H-P axis is associated with a higher rate of pituitary dysfunction than other parasellar pathologies. PCNSL at the H-P axis has a worse treatment outcome than PCNSL at other sites. However, visual field defect is related to a favorable prognosis in these patients.

One-Pot Synthesis of Proton Exchange Membranes from Anion Exchange Membrane Precursors.

Proton exchange membranes (PEMs) play a critical role in many electrochemical devices that could solve the shortcomings of current energy storage and conversion systems. Hydrocarbon-based PEMs are an attractive alternative for replacing the state-of-the-art perfluorosulfonic acid PEMs; however, synthetic routes are generally limited to sulfonation of aromatic units (pre- or postpolymerization functionalization). Here we disclose a facile and scalable one-pot synthetic method of converting an alkyl halide functionality to a sulfonate in polymer systems. With this method, sulfonated hydrocarbon PEMs can be conveniently prepared from a precursor polymer of anion exchange membranes which have recently experienced significant advances. Polyphenylene type PEMs (BPSA and mTPSA in this report) were generated in one-pot SN2 reaction of bromoalkyl side chains of polymers followed by oxidation. These PEMs showed excellent proton conductivity with BPSA showing 250 mS/cm in water at 80 °C, nearly 1.5 times higher than that of Nafion 212. Furthermore, the separation of the sulfonic acid group from the rigid backbone with a flexible alkyl chain mitigates excessive water uptake and in-plane swelling ratio of the polymer, despite having a high ion exchange capacity of 2.6 mequiv/g. Oxidative stability was also shown to be superior for hydrocarbon-based PEMs with negligible changes in mass, NMR, and proton conductivity.

Efficacy of automated percutaneous lumbar discectomy for lumbar disc herniation in young male soldiers.

Lumbar disc herniation (LDH) often results in back pain and radicular pain and is frequently treated with minimally invasive non-surgical methods in Korean Armed Forces Hospitals. Automated percutaneous lumbar discectomy (APLD) has been reported to have good clinical outcomes with low complication rates; however, the clinical efficacy of APLD performed in young male soldiers is uncertain. In order to clarify the efficacy of APLD for the treatment of LDH in young male soldiers, we designed a retrospective case-control study to compare patients who received APLD with patients treated with epidural steroid injection (ESI) alone.A total of 181 patients were enrolled and divided into the APLD (n = 92) and ESI (n = 89) groups according to the treatment modality. A simple logistic regression analysis was conducted to clarify the difference between the two. To optimize patient selection, APLD group was additionally divided for subgroup analysis into favorable (n = 59) and unfavorable (n = 33) groups based on satisfaction scales. A simple logistic analysis was also performed.The differences between pre- and postoperative numerical rating scale of pain (P = .0027) and hospital-own satisfaction scale (P = .0045) of the APLD group were significantly better compared to those of the ESI group. In terms of subgroup analysis, single-level pathology (P = 0.244) and protruded disc (P = .0443) were associated with favorable outcomes, whereas dual pathology and extruded disc were related with unfavorable outcomes.APLD using Dekompressor, performed in young male soldiers with back and radicular pain owing to LDH, showed better clinical outcomes compared to the ESI only therapy. Additionally, a single-level pathology with protruded disc was associated with favorable outcomes and may be indicated for treatment.

MAPKs and NF­κB pathway inhibitory effect of bisdemethoxycurcumin on phorbol­12­myristate­13­acetate and A23187­induced inflammation in human mast cells.

Inflammation­associated damage may occur in any tissue following infection, exposure to toxins, following ischemia, and in allergic and auto­immune reactions. Inflammation may also result from mast cell degranulation induced by the intracellular calcium concentration. The inflammatory process may be inhibited by compounds that affect mast cells. Bisdemethoxycurcumin [1,7­bis(4­hydroxyphenyl) hepta­1,6­diene­3,5­dione, BDCM] is the active component of turmeric. It has anticancer, antioxidant and antibacterial properties. To investigate the molecular mechanism associated with the anti­inflammatory activity of BDCM, human mast cell line 1 (HMC­1) cells were treated with phorbol­12­myristate­13­acetate (PMA) and calcium ionophore A23187 (A23187) to induce the inflammatory process. Various HMC­1 cells were pretreated with BDCM prior to stimulation of inflammation. BDCM inhibited the inflammation­triggered production of cytokines including interleukin (IL)­6, IL­8, and tumor necrosis factor (TNF)­α. BDCM inhibition extended to the gene level. In activated HMC­1 cells, phosphorylation levels of extracellular signal­regulated kinase, c­jun N­terminal kinase and p38 mitogen­activated protein kinase were decreased by treatment with BDCM. BDCM also inhibited nuclear factor­(NF)­κB activation and IκB degradation. In conclusion, BDCM suppresses the expression of TNF­α, IL­8, and IL­6 by inhibiting the NF­κB and mitogen activated protein kinase signaling pathways.

Microwave-Assisted Protein Digestion in a Plate Well for Facile Sampling and Rapid Digestion.

Protein digestion is one of the most important processes in proteomic analysis. Here, we report microwave-assisted protein digestion in a plate well, which allows for facile sampling as well as rapid protein digestion based on the combination of highly stable enzyme immobilization and 3D printing technologies. Trypsin (TR) was immobilized on polystyrene-based nanofibers via an enzyme coating (EC) approach. The EC with stabilized TR activity was assembled with the 3D-printed structure in the plate well (EC/3D), which provides two separated compartments for the solution sampling and the TR-catalyzed protein digestion, respectively. EC/3D can effectively prevent the interference of sampling by accommodating EC in the separated compartment from the sampling hole in the middle. EC/3D in the plate well maintained its protein digestion performance under shaking over 160 days. Microwave irradiation enabled the digestion of bovine serum albumin within 10 min, generating the MALDI-TOF MS results of 75.0% sequence coverage and 61 identified peptides. EC/3D maintained its protein digestion performance under microwave irradiation after 30 times of recycled uses. EC/3D in the plate well has demonstrated its potential as a robust and facile tool for the development of an automated protein digestion platform. The combination of stable immobilized enzymes and 3D-printed structures can be potentially utilized not only for the protein digestion, but also for many other enzyme applications, including bioconversion and biosensors.

Stringent Nucleotide Recognition by the Ribosome at the Middle Codon Position.

Accurate translation of the genetic code depends on mRNA:tRNA codon:anticodon base pairing. Here we exploit an emissive, isosteric adenosine surrogate that allows direct measurement of the kinetics of codon:anticodon University of California base formation during protein synthesis. Our results suggest that codon:anticodon base pairing is subject to tighter constraints at the middle position than at the 5'- and 3'-positions, and further suggest a sequential mechanism of formation of the three base pairs in the codon:anticodon helix.

Induction of Integrin Signaling by Steroid Sulfatase in Human Cervical Cancer Cells.

Steroid sulfatase (STS) is an enzyme responsible for the hydrolysis of aryl and alkyl sulfates. STS plays a pivotal role in the regulation of estrogens and androgens that promote the growth of hormone-dependent tumors, such as those of breast or prostate cancer. However, the molecular function of STS in tumor growth is still not clear. To elucidate the role of STS in cancer cell proliferation, we investigated whether STS is able to regulate the integrin signaling pathway. We found that overexpression of STS in HeLa cells increases the protein and mRNA levels of integrin ß1 and fibronectin, a ligand of integrin α5ß1. Dehydroepiandrosterone (DHEA), one of the main metabolites of STS, also increases mRNA and protein expression of integrin ß1 and fibronectin. Further, STS expression and DHEA treatment enhanced phosphorylation of focal adhesion kinase (FAK) at the Tyr 925 residue. Moreover, increased phosphorylation of ERK at Thr 202 and Tyr 204 residues by STS indicates that STS activates the MAPK/ ERK pathway. In conclusion, these results suggest that STS expression and DHEA treatment may enhance MAPK/ERK signaling through up-regulation of integrin ß1 and activation of FAK.

Auranofin Suppresses Plasminogen Activator Inhibitor-2 Expression through Annexin A5 Induction in Human Prostate Cancer Cells.

Auranofin has been developed as antirheumatic drugs, which is currently under clinical development for the treatment of chronic lymphocytic leukemia. Previous report showed that auranofin induced apoptosis by enhancement of annexin A5 expression in PC-3 cells. To understand the role of annexin A5 in auranofin-mediated apoptosis, we performed microarray data analysis to study annexin A5-controlled gene expression in annexin A5 knockdown PC-3 cells. Of differentially expressed genes, plasminogen activator inhibitor (PAI)-2 was increased by annexin A5 siRNA confirmed by qRT-PCR and western blot. Treatment with auranofin decreased PAI-2 and increased annexin A5 expression as well as promoting apoptosis. Furthermore, auranofin-induced apoptosis was recovered by annexin A5 siRNA but it was promoted by PAI-2 siRNA. Interestingly, knockdown of annexin A5 rescued PAI-2 expression suppressed by auranofin. Taken together, our study suggests that induction of annexin A5 by auranofin may enhance apoptosis through suppression of PAI-2 expression in PC-3 cells.