Background: Chronic pain significantly affects daily activities, mental health, and the interpersonal relationships of patients. Consequently, physicians use various treatments to manage pain. This study investigated the perceptions of treatment, accompanying symptoms, and other problems in patients with chronic pain. Methods: The authors enrolled patients with chronic pain from 19 university hospitals in South Korea. Data was collected on age, gender, diagnosis, disease duration, severity of pain, perception of pain treatment, and accompanying symptoms or problems using an anonymous survey comprising 19 questions. Results: In total, 833 patients with chronic pain completed the survey, and 257 (31.0%) and 537 (64.5%) patientsexpressed concerns about the potential adverse effects of medication and opioid addiction, respectively. Personalitychanges such as irritability or anger were the most frequent accompanying symptoms in 507 (63.8%) patients, followed by depression and sleep disturbance in 462 (58.1%) and 450 (54.5%) patients, respectively. Depression (P = 0.001) and anxiety (P = 0.029) were more common among women, whereas divorce (P = 0.016), family conflict (P < 0.001), unemployment (P < 0.001), suicide attempts (P < 0.001), and restrictions on economic activity (P < 0.001) were more common among men. The frequency of accompanying symptoms, except for suicidal ideation,was higher in the younger patients aged ≤ 40 years than in the older patients aged > 40 years. Conclusions Many patients with chronic pain had concerns about adverse effects or medication tolerance and experienced anxiety, depression, or sleep disturbances. The prevalence of accompanying problems varies according to age and gender.

Auricular vagus nerve stimulation (aVNS) is one of the promising neuromodulation techniques due to its non-invasiveness, convenience, and effectiveness. aVNS has been suggested as a potential treatment for neurodegenerative diseases showing impaired cerebrospinal fluid (CSF) dynamics. Improving CSF flow has been proposed as a key mechanism of the therapeutic effect on neurodegenerative diseases. However, aVNS parameters have been set empirically and the effective parameter that maximize the effect remains elusive. Here we show that 30 minutes of low-frequency aVNS increased arterial vasomotion events and enhanced cortical CSF influx along the branches of middle cerebral arteries. By using in vivo two photon imaging or widefield fluorescence microscopy with plasma and CSF tracers for visualizing blood vessels and perivascular spaces, arterial vasomotion and cortical CSF influx dynamics were acquired. The low-frequency (2 Hz) aVNS, but not middleand high-frequency (40 and 100 Hz) aVNS, significantly increased the number of vasomotion events compared to the sham group. Accordingly, in the CSF imaging, 2 Hz of aVNS markedly enhanced the CSF influx. Our findings demonstrate that lowfrequency aVNS is the effective parameter in respect to modulating vasomotion and CSF influx, resulting in brain clearance effect.

Peyronie’s disease is an acquired condition characterized by penile deformities caused by fibrosis of the penile tunica albuginea, leading to symptoms such as penile pain, erectile dysfunction, and other associated issues. Despite extensive research, the pathophysiology of this condition remains poorly understood, and standardized diagnostic and treatment protocols are lacking. While clinical guidelines from several professional societies exist, they do not consistently account for factors such as patient ethnicity, geography, and socioeconomic status. Thus, the Korean Society for Sexual Medicine and Andrology (KSSMA) aimed to develop recommendations tailored to clinical practice in Korea. These recommendations summarize the latest evidence, including clinical practice guidelines from various international professional societies, and represent the consensus opinion of an expert group within the KSSMA. They encompass all aspects of Peyronie’s disease, including the definition, diagnosis, non-surgical interventions, and surgical treatment options.

BACKGROUND: Exogenous Cushing’s syndrome, which results from prolonged glucocorticoid treatment, is associated with metabolic abnormalities. Previously, we reported the inhibitory effect of tonsil-derived mesenchymal stem cell conditioned medium (T-MSC CM) on glucocorticoid signal transduction. In this study, we investigated the therapeutic efficacy of T-MSCs in a mouse model of exogenous Cushing’s syndrome. METHODS: Exogenous Cushing’s syndrome model mice was generated by corticosterone administration in the drinking water for 5 weeks, and T-MSCs were injected intraperitoneally twice during the third week. Serum lipid profiles were measured using a chemistry analyzer. HepG2 cells were treated with dexamethasone and co-cultured with T-MSCs.Expression levels of genes involved in cholesterol metabolism were examined using real-time PCR. Low-density lipoprotein receptor (LDLR) protein levels were determined using western blotting and immunohistochemistry. Liver RNA extracted from the CORT and CORT ? MSC mouse groups was used for transcriptome sequencing analysis and protein– protein interaction analysis. RESULTS: Weight reduction and improvements in dyslipidemia by T-MSC administration were observed only in female mice. T-MSCs reduce circulating LDL cholesterol levels by downregulating liver X receptor a (LXRa) and inducible degrader of LDLR (IDOL) expression, thereby stabilizing LDLRs in the liver. Transcriptome analysis of liver tissue revealed pathways that are regulated by T-MSCs administration. CONCLUSION Administration of MSCs to female mice receiving chronic corticosterone treatment reduced the circulating LDL cholesterol level by downregulating the LXRa–IDOL axis in hepatocytes. These results suggest that T-MSCs may offer a novel therapeutic strategy for managing exogenous Cushing’s syndrome by regulating cholesterol metabolism.

Background: Kelch-like ECH-associated protein 1 (KEAP1)–nuclear factor erythroid- 2-related factor 2 (NRF2) pathway is a major regulator protecting cells from oxidative and metabolic stress. Studies have revealed that this pathway is involved in mediating resistance to cytotoxic chemotherapy and immunotherapy; however, its implications in oncogene-addicted tumors are largely unknown. This study aimed to elucidate whether this pathway could be a potential therapeutic target for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer. Methods: We measured the baseline expression of NRF2 using EGFR-mutant parental cells and acquired gefitinib resistant cells. We investigated whether NRF2 inhibition affected cell death in vitro and tumor growth in vivo using a xenograft mouse model, and compared the transcriptional changes before and after NRF2 inhibition. Results: Baseline NRF2 expression was enhanced in PC9 and PC9 with gefitinib resistance (PC9/GR) cells than in other cell lines, with a more prominent expression in PC9/ GR. The NRF2 inhibitor induced NRF2 downregulation and cell death in a dose-dependent manner. Cotreatment with an NRF2 inhibitor enhanced osimertinib-induced cell death in vitro, and potentiated tumor growth inhibition in a PC9/GR xenograft model. Finally, RNA sequencing revealed that NRF2 inhibition resulted in the altered expression of multiple genes involved in various signaling pathways. Conclusion We identified that NRF2 inhibition enhanced cell death and inhibited tumor growth in tyrosine kinase inhibitor (TKI)-resistant lung cancer with EGFR-mutation. Thus, NRF2 modulation may be a novel therapeutic strategy to overcome the resistance to EGFR-TKIs.

Purpose: This retrospective cohort study aimed to investigate the association between the use of pain medications with varying cyclooxygenase-2 (COX-2) selectivity and the incidence of endometriosis (EMS) in women. Materials and Methods: Medical records from January 1, 1994, to December 31, 2022, were retrospectively analyzed. The cohort included 33406 patients diagnosed with any pain-related condition who were prescribed either selective COX-2 inhibitors or nonsteroidal anti-inflammatory drugs (NSAIDs). Patients were followed for up to 5 years from the cohort entry date. The incidence of EMS was compared between the two medication groups using Cox proportional hazards models, adjusting for confounding factors such as age, past drug use, and prior diagnosis. Results: The incidence rates of EMS were 3.00 per 1000 person-years in the COX-2 inhibitor group and 3.97 per 1000 person-years in the NSAIDs group. After adjustment for confounders, the hazard ratio for EMS incidence in the COX-2 inhibitor group compared to the NSAIDs group was 0.77 [95% confidence interval (CI), 0.63 to 0.93; p<0.01], indicating a significantly lower risk in the COX-2 inhibitor group. Subgroup analysis revealed that this association was particularly significant in younger women aged 20– 44 years, with a hazard ratio of 0.71 (95% CI, 0.54 to 0.95; p<0.05) in this age group. Conclusion The findings suggest that COX-2 inhibitors may reduce the incidence of EMS compared to traditional NSAIDs, highlighting their potential as a strategic option for managing EMS, particularly among younger women. Further prospective studies are needed to confirm these findings.

Neurodegenerative diseases (NDDs), characterized by the progressive deterioration of the structure and function of the nervous system, represent a significant global health challenge. Emerging research suggests that the gut microbiota plays a critical role in regulating neurodegeneration via modulation of the gut-brain axis. Probiotics, defined as live microorganisms that confer health benefits to the host, have garnered significant attention owing to their therapeutic potential in NDDs. This review examines the current research trends related to the microbiome-gut-brain axis across various NDDs, highlighting key findings and their implications. Additionally, the effects of specific probiotic strains, including Lactobacillus plantarum, Bifidobacterium breve, and Lactobacillus rhamnosus, on neurodegenerative processes were assessed, focusing on their potential therapeutic benefits. Overall, this review emphasizes the potential of probiotics as promising therapeutic agents for NDDs, underscoring the importance of further investigation into this emerging field.

Pancreatic ductal adenocarcinoma (PDAC) exhibits an altered metabolic profile compared to normal pancreatic tissue. However, studies on actual pancreatic tissues are limited. Untargeted metabolomics analysis was conducted on 54 pairs of tumor and matched normal tissues. Taurine levels were validated via immunohistochemistry (IHC) on separate PDAC and normal tissues.Bioinformatics analysis of transcriptomics and proteomics data evaluated genes associated with taurine metabolism. Identified taurine-associated gene was validated through gene modulation. Clinical implications were evaluated using patient data. Metabolomics analysis showed a 2.51-fold increase in taurine in PDAC compared to normal tissues (n=54). IHC confirmed this in independent samples (n=99 PDAC, 19 normal). Bioinformatics identified 2-aminoethanethiol dioxygenase (ADO) as a key gene modulating taurine metabolism. IHC on a tissue microarray (39 PDAC, 10 normal) confirmed elevated ADO in PDAC. The ADOTaurine axis correlated with PDAC recurrence and disease-free survival. ADO knockdown reduced cancer cell proliferation and tumor growth in a mouse xenograft model. The MEK-related signaling pathway is suggested to be modulated by ADO-Taurine metabolism. Our multi-omics investigation revealed elevated taurine synthesis mediated by ADO upregulation in PDAC. The ADOTaurine axis may serve as a biomarker for PDAC prognosis and a therapeutic target.

Purpose: Inotuzumab ozogamicin (INO) has demonstrated a safe bridging role to allogeneic hematopoietic stem cell transplantation (HSCT) in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL). How‑ ever, hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is frequently observed. This study aimed to identify significant features of INO-associated VOD/SOS. Methods: We reviewed seven cases of hepatic VOD/SOS that developed either during INO salvage or after alloge‑ neic HSCT following INO-induced complete remission (CR). Diagnosis and severity grading of VOD/SOS were based on the revised criteria from the European Society for Blood and Marrow Transplantation. Defibrotide was used to treat severe to very severe cases. Results: Four patients developed VOD/SOS during INO salvage therapy (at 21 and 36 days post-INO1, 77 days postINO3, and 21 days post-INO5), while three were diagnosed at 2, 5, and 10 days post-HSCT following INO-induced CR.Doppler ultrasonography revealed preserved portal vein flow (range 10.2–26.0 cm/sec) and normal hepatic artery resistive index (RI, range 0.56–0.74) in all but one patient (RI 0.83). Despite this, all patients presented with massive ascites and progressively elevated total bilirubin levels. All cases were classified as severe to very severe; six were treated with defibrotide and one underwent liver transplantation. Most patients ultimately died owing to VOD/SOS progression. Conclusion Post-INO VOD/SOS manifested as two different clinical settings and was characterized by preserved portal vein flow, which complicated diagnosis. Despite timely defibrotide administration, clinical outcomes were poor.These findings emphasize the need for vigilance and potential consideration of prophylactic strategies for prevention of INO-associated VOD/SOS.

Purpose: This study evaluates the prognostic significance of tumor size at disease progression (PD) and depth of response (DOR) in cancer patients. Materials and Methods: We performed post hoc analysis using data from six prospective clinical trials conducted by the Korean Cancer Study Group. Patients with tumor size at PD was categorized into ‘Mild PD’ and ‘Significant PD’ based on the cutoff values of relative change from baseline using maximally selected rank statistics. The overall survival (OS) and progression-free survival (PFS) were compared between PD and DOR categories. Results: Among the 194 evaluable patients, 130 experienced PD. A 35.48% decrease from baseline in tumor size at PD was chosen for the cutoff between mild and significant PD for OS (mild PD: tumor size from the baseline ≤ −35.48%; significant PD > −35.48%). The mild PD had superior OS compared to the significant PD (25.8 vs. 12.8 months; Hazard ratio [HR] 0.47, 95% CI 0.266-0.843, p=0.009). When using an exploratory cutoff based on whether the tumor size was below vs. exceeded from the baseline (mild PD: tumor size from the baseline ≤ 0%; significant PD > 0%), OS remained significantly longer in the mild PD (17.1 vs. 11.8 months; HR 0.60, 95% CI 0.392-0.932, p=0.021). The greatest DOR was associated with the longest OS and PFS (p<0.001 for both). Conclusion Tumor size at PD and DOR were significant prognostic factors for progressive disease. Maintaining a sufficiently reduced tumor size even during PD was associated with better survival outcomes.