Radiofrequency ablation with sine and square electrical waveforms to enhance ablation range.

Radiofrequency ablation (RFA) is a local treatment modality for primary liver cancers. Although various input parameters of the RF generator have been adjusted to improve the ablation ranges, the limited ablation ranges remain an obstacle to RFA. This study aimed to compare the ablation ranges and efficacy of sine and square electrical waveforms in a mouse tumor model. An RF generator with an adjustable electrical waveform was developed, and its ablation range in the porcine liver was compared. For all RF parameters, the square electrical waveform ablation range was greater than that of the sine electrical waveform (all p < 0.001) in the porcine liver. The 45 BALB/c nude mice were used to evaluate the efficacy of the two electrical waveforms after the RFA. The mean tumor volume in the square group was significantly lower than that in the sine group (p < 0.001), indicating a higher survival rate (60%). The cellular coagulative necrosis, inflammatory cell infiltration, heat shock proteins, cellular necrosis, and tumor necrosis were significantly greater in square electrical waveform than in sine electrical waveform (all; p < 0.05). RFA with square electrical waveforms has therapeutic potential for tumor management with an enhanced ablation range.

Development and validation of next-generation sequencing panel for personalized Helicobacter pylori eradication treatment targeting multiple species.

Introduction: The decreasing Helicobacter pylori eradication rate is primarily attributed to antibiotic resistance, and further exacerbated by uniform drug administration disregarding a host's metabolic capability. Consequently, applying personalized treatment based on antibiotic resistance-associated variants and the host's metabolic phenotype can potentially increase the eradication rate. Method: A custom next-generation sequencing panel for personalized H. pylori eradication treatment (NGS-PHET) was designed which targeted the regions for amoxicillin, clarithromycin, metronidazole, tetracycline, and levofloxacin-resistance in H. pylori and human proton-pump inhibitor (PPI) metabolism. The libraries were constructed following customized methods and sequenced simultaneously. The customized framework criteria, grounded in previously reported antibiotic resistance associated variants and the host's PPI metabolism, was applied to the NGS-PHET results and suggested a personalized treatment for each subject, which was validated through each subject's actual eradication outcome. Results: Both previously reported and novel variants were identified from H. pylori sequencing results. Concurrently, five CYP2C19 homozygous extensive metabolizers and three CYP3A4 intermediate metabolizers were identified. Among the total of 12 subjects, clarithromycin triple therapy was suggested for five subjects, bismuth quadruple therapy was suggested for six subjects, and rifabutin triple therapy was suggested for one subject by following the customized framework criteria. The treatment suggestion for nine of the 12 subjects was consistent with the treatment that each subject achieved eradication with. Discussion: Applying the methodology using the NGS-PHET and customized framework helps to perform eradication treatment quickly and effectively in most patients with antibiotic-resistant H. pylori strains, and is also useful in research to find novel antibiotic-resistance candidates.

Association between TGF-ß/BMP signaling pathway polymorphisms and the risk of primary ovarian insufficiency in Korean women.

BACKGROUND: Primary ovarian insufficiency (POI) is one of the leading female infertility diseases in which ovarian function stops before the age of 40. Reports that POI is associated with transforming growth factor (TGF)-ß/bone morphogenetic protein (BMP) signaling pathway-associated genes (e.g., TGF-ß, and BMP15) have been continuous since publication that the TGF-ß superfamily acts as important regulators for ovary and placenta function in humans. Mechanistically, the secretion of follicle-stimulating hormone, progesterone, and estrogen is affected by the TGF-ß superfamily in granulosa cells, which are involved in the development of theca cells, oocytes, and granulosa cells. OBJECTIVE: This study aimed to identify the association between genes related to the TGF-ß/BMP signaling pathway and the risk of POI pathogenesis. METHODS: Possible associations between six gene polymorphisms and POI susceptibility were examined in 139 patients with POI and 345 control subjects. RESULTS: Allele combination of TGFBR1 rs334348 G > A and TGFBR3 rs1805110G > A exhibited association with decreased POI risk (adjusted odds ratio [AOR] = 0.165; 95% confidence interval [CI] 0.032-0.847; P = 0.031). Also, TGFBR1 rs1590 G > T and rs334348 G > A and TGFBR3 rs1805110 G > A allele combination exhibited association with decreased POI risk (OR = 0.553; 95% CI 0.374-0.816; P = 0.003). CONCLUSION: This study suggests that polymorphisms in the TGF-ß signaling pathway genes can be useful biomarkers for POI diagnosis and treatment.

The Role of Direct Oral Anticoagulants in Managing Myeloproliferative Neoplasms Patients.

Purpose: Thrombosis and bleeding significantly affect morbidity and mortality in myeloproliferative neoplasms (MPNs). The efficacy and safety of direct oral anticoagulants (DOACs) in MPN patients remain uncertain. Materials and Methods: We conducted a large, retrospective, nationwide cohort study using the Korean Health Insurance Review and Assessment Service database from 2010 to 2021. Results: Out of the 368 MPN patients included in the final analysis, 62.8% were treated with DOACs for atrial fibrillation (AF), and 37.2% for venous thromboembolism (VTE). The AF group was statistically older with higher CHA2DS2-VASc scores compared to the VTE group. Antiplatelet agents were used in 51.1% of cases, and cytoreductive drugs in 79.3%, with hydroxyurea being the most common (64.9%). The median follow-up was 22.3 months, with one-year cumulative incidence rates of thrombosis and bleeding at 11.1% and 3.7%, respectively. Multivariate analysis identified CHA2DS2-VASc scores ≥ 3 (HR=3.48), concomitant antiplatelet use (HR = 2.57), and cytoreduction (HR=2.20) as significant thrombosis risk factors but found no significant predictors for major bleeding. Conclusion: Despite the limitations of retrospective data, DOAC treatment in MPN patients seems effective and has an acceptable bleeding risk.

Clinicians' Prediction of Survival Is Most Useful for Palliative Care Referral.

Background: Timely palliative transition in patients with advanced cancer is essential for their improved quality of life and overall survival (OS). Most prognostic models have been developed focusing on weeks' survival. The current study aimed to compare the accuracies of several indicators, such as the Karnofsky Performance Scale (KPS), Clinicians' Prediction of Survival (CPS), and Edmonton Symptom Assessment System (ESAS), for predicting the survival of patients. Methods: Two hundred patients were enrolled at a single tertiary cancer center in South Korea between 2016 and 2019. We compared the discrimination of CPS versus KPS and ESAS total scores using the area under the receiver operating characteristic curve (AUROC) in 3-month and 6-month survival predictions. Results: The median age of patients was 66.0 years, and 128 (64%) were male. Two-thirds (66%) of the patients had an Eastern Cooperative Oncology Group performance status of 0 or 1, and 55.5% had a KPS of 80% or higher. The values of AUROC of CPS, KPS, and ESAS total score in 3-month survival prediction were 0.80 (95% confidence interval [CI]: 0.73-0.88), 0.71 (95% CI: 0.62-0.79), and 0.71 (95% CI: 0.62-0.81), respectively, whereas those in 6-month survival were 0.82 (95% CI: 0.76-0.88), 0.70 (95% CI: 0.63-0.78), and 0.63 (95% CI: 0.55-0.71), respectively. Conclusion: CPS showed the highest accuracy in predicting 3- and 6-month survival, whereas KPS had an acceptable accuracy. Experienced clinicians can rely on CPS to predict survival in months. We recommend the use of KPS with CPS to assist inexperienced clinicians.

Protective effect of Korean red ginseng water extract on levothyroxine-induced hyperthyroidism and propylthiouracil-induced hypothyroidism in rats.

Background: Korean red ginseng extract (KRGE) (Family: Araliaceae) is one of the most widely used traditional herbs in Asia. Multiple studies have shown that KRGE has anti-inflammation, anti-fatigue, anti-obesity, anti-oxidant, and anti-cancer effects. Methods: Sprague-Dawley rats were divided into five groups for PTU-induced hypothyroidism and six groups for LT4-induced hyperthyroidism. At the experiment's conclusion, rats were sacrificed, and blood, thyroid gland, and liver samples were collected. Body weight was recorded weekly, and serum hormone levels were assessed using enzyme-linked immunoassay. Thyroid gland and liver tissues were stained with hematoxylin and eosin. KRGE was prepared in 0.5% CMC and stored at 4 °C before administration. Results: In the LT4-induced hyperthyroidism model, KRGE prevented decreases in body weight, thyroid gland weight, liver weight, serum glucose, and thyroid hormone levels compared to the PTU group. It also reduced increases in T3, T4, and serum aspartate aminotransferase levels after LT4 treatment. Additionally, KRGE improved thyroid gland and liver histopathology, effects not observed in the PTU-induced hypothyroidism model. Conclusion: All things considered, our research points to KRGE's potential protective role in rat hyperthyroidism caused by LT4 by lowering thyroid hormone production.

Biophysically stressed vascular smooth muscle cells express MCP-1 via a PDGFR-ß-HMGB1 signaling pathway.

Vascular smooth muscle cells (VSMCs) under biophysical stress play an active role in the progression of vascular inflammation, but the precise mechanisms are unclear. This study examined the cellular expression of monocyte chemoattractant protein 1 (MCP-1) and its related mechanisms using cultured rat aortic VSMCs stimulated with mechanical stretch (MS, equibiaxial cyclic stretch, 60 cycles/ min). When the cells were stimulated with 10% MS, MCP-1 expression was markedly increased compared to those in the cells stimulated with low MS intensity (3% or 5%). An enzyme-linked immunosorbent assay revealed an increase in HMGB1 released into culture media from the cells stimulated with 10% MS compared to those stimulated with 3% MS. A pretreatment with glycyrrhizin, a HMGB1 inhibitor, resulted in the marked attenuation of MCP-1 expression in the cells stimulated with 10% MS, suggesting a key role of HMGB1 on MCP-1 expression. Western blot analysis revealed higher PDGFR-α and PDGFR-ß expression in the cells stimulated with 10% MS than 3% MS-stimulated cells. In the cells deficient of PDGFR-ß using siRNA, but not PDGFR-α, HMGB1 released into culture media was significantly attenuated in the 10% MS-stimulated cells. Similarly, MCP-1 expression induced in 10% MS-stimulated cells was also attenuated in cells deficient of PDGFR-ß. Overall, the PDGFR-ß signaling plays a pivotal role in the increased expression of MCP-1 in VSMCs stressed with 10% MS. Therefore, targeting PDGFR-ß signaling in VSMCs might be a promising therapeutic strategy for vascular complications in the vasculatures under excessive biophysical stress.

Association of TP53 Mutation Status and Sex with Clinical Outcome in NSCLC Treated with Immune Checkpoint Inhibitors: A Retrospective Cohort Study.

Purpose: Some studies suggest that TP53 mutations are associated with the response to immune checkpoint inhibitors (ICI) in patients with non-small cell lung cancer (NSCLC) and also contribute to sex disparities in several cancers. Thus, we hypothesized that TP53 mutations might serve as sex-dependent genomic biomarkers of ICI treatment response in patients with NSCLC. Materials and Methods: Clinical data of 100 patients with metastatic NSCLC treated with ICI monotherapy at Seoul National University Bundang Hospital (SNUBH) were retrospectively reviewed. Genomic and clinical datasets of TCGA and an ICI-treated lung cancer cohort (cBioPortal) were also analyzed. Results: In SNUBH cohort, no statistically significant difference was observed in disease control rate per the TP53 mutation status (p=0.503); however, female patients with TP53 mutated (MT) had a significantly prolonged median progression-free survival (PFS) compared to wild-type (WT) (6.1 months in TP53 MT vs. 2.6 months in TP53 WT; p=0.021). PD-L1 high (≥50%) expression was significantly enriched in female patients with TP53 MT (p=0.001). The analysis from publicly available dataset also revealed that females with NSCLC with TP53 MT showed significantly longer PFS than those with TP53 WT (p<0.001). In TCGA analysis, expression of immune-related genes, and TMB score in TP53 MT females were higher than in males without TP53 MT. Conclusion: Female patients with NSCLC with TP53 mutations had high PD-L1 expression and showed favorable clinical outcomes following ICI therapy, suggesting a need for further research to explore the role of TP53 mutations for sex disparities in response to ICI therapy.

Proximally positioned femoral grafts decrease passive anterior tibial subluxation in anterior cruciate ligament reconstruction using a posterior trans-septal portal.

PURPOSE: To compare the anterior and posterior trans-septal (TS) portal approaches in anterior cruciate ligament reconstruction (ACLR) by evaluating femoral tunnel positioning and passive anterior tibial subluxation (PATS). METHODS: A total of 205 patients who underwent primary ACLR using the outside-in technique between March 2018 and December 2021 were retrospectively enrolled. Patients were classified into two groups based on the viewing techniques: the anterior group was treated using anteromedial or anterolateral portals (n = 155), and the TS group was treated using posterior TS portal (n = 55). The relative locations of the femoral tunnel were evaluated using the deep-shallow planes (X-axis) and superior-inferior planes (Y-axis) with the quadrant method in the lateral femoral condyle on a 3-dimensional computed tomography image. Anterior tibial subluxation for the lateral and medial compartments relative to the femoral condyles was evaluated as measured on magnetic resonance imaging. Knee laxity was assessed using the pivot-shift test and stress radiography. RESULTS: In the posterior TS group, the femoral tunnel was usually located deeper on the X-axis and more superior on the Y-axis, which corresponds to a more proximal position, than in the anterior group (deeper on the X-axis and superior on the Y-axis). Moreover, the femoral tunnel locations in this group were more compactly distributed than those in the anterior group. The TS group showed significantly better reduction of postoperative PATS in the lateral compartments than the anterior group (anterior group vs. TS group: lateral compartment, 3.2 ± 3.1 vs. 4.5 ± 3.2 mm; p = .016). Significantly better results were found in the TS group for knee stability as assessed by the pivot-shift grade (p = .044); however, there were no significant differences between the two groups with respect to patient-reported outcome measures (p > .05) and other complications (p = .090). CONCLUSION: Our results suggest that positioning the femoral tunnel using the posterior TS portal approach may lead to better outcomes in terms of PATS and rotational stability compared to the anterior portal approach in ACLR.

Role of induction chemotherapy in advanced-stage olfactory neuroblastoma.

OBJECTIVES: To evaluate the treatment outcomes in patients with advanced-stage olfactory neuroblastoma (ONB) who received induction chemotherapy (IC). MATERIALS AND METHODS: The clinical data of 38 patients with advanced-stage ONB who received initial IC were retrospectively analyzed. The response was defined using the Response Evaluation Criteria in Solid Tumors version 1.1. Patients with complete remission or partial remission were defined as responders. RESULTS: Seventeen (44.7%) patients responded to IC. The response rate was higher in patients with high Hyams grade tumor (III/IV) compared to those with low-grade tumors (I/II) (60% vs. 22.2%, p = 0.038). Overall, the 5-year cancer-specific survival (CSS) rate was 76.0%. Among nonresponders to IC, a significant difference in 5-year CSS rates was observed between surgery with adjuvant radiotherapy (RT) (100%) versus definitive RT or chemoradiotherapy (CRT) (68.6%) (log-rank p = 0.006). However, for responders, there was no significant difference in 5-year CSS rates between surgery with adjuvant therapy (75%) and definitive RT or CRT (51.1%) (log-rank p = 0.536). When only high-grade tumors were considered among responders, the 5-year CSS rate was significantly higher in patients who received RT or CRT (51.4%) compared to those who underwent surgery with adjuvant therapy (0%) (log-rank p = 0.008). CONCLUSION: In advanced-stage ONB, RT or CRT may be preferable for high-grade tumor responding to IC. Higher response rate and a potential role for induction IC in determining the optimal definitive treatment modality suggest a positive role for advanced-stage high-grade ONB.

Anti-Inflammatory Effect of Atorvastatin and Rosuvastatin on Monosodium Urate-Induced Inflammation through IL-37/Smad3-Complex Activation in an In Vitro Study Using THP-1 Macrophages.

Objective: The pleiotropic effect of hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) is responsible for potent defense against inflammatory response. This study evaluated the inhibitory effects of HMG-CoA reductase inhibitors on the monosodium urate (MSU)-induced inflammatory response through the regulation of interleukin-37 (IL-37) expression. Methods: Serum was collected from patients with gout (n = 40) and from healthy controls (n = 30). The mRNA and protein expression of the target molecules IL-1ß, IL-37, caspase-1, and Smad3 were measured in THP-1 macrophages stimulated with MSU, atorvastatin, or rosuvastatin using a real-time quantitative polymerase chain reaction and Western blot assay. Transfection with IL-1ß or Smad3 siRNA in THP-1 macrophages was used to verify the pharmaceutical effect of statins in uric-acid-induced inflammation. Results: Serum IL-37 levels in gout patients were significantly higher than in controls (p < 0.001) and was associated with the serum uric acid level (r = 0.382, p = 0.008). THP-1 cells stimulated with MSU markedly induced IL-37 mRNA expression and the transition of IL-37 from the cytoplasm to the nucleus. Recombinant IL-37 treatment dose-dependently inhibited activation of caspase-1 and IL-1ß in MSU-induced inflammation. Atorvastatin and rosuvastatin attenuated caspase-1 activation and mature IL-1ß expression but augmented translocation of IL-37 from the cytoplasm to the nucleus. Atorvastatin and rosuvastatin induced phosphorylation of Smad3 in THP-1 cells treated with MSU crystals. Statins potently attenuated translocation of IL-37 from the cytoplasm to the nucleus in THP-1 macrophages transfected with Smad3 siRNA compared to cells with negative control siRNA. Conclusions: This study revealed that statins inhibit the MSU-induced inflammatory response through phosphorylated Smad3-mediated IL-37 expression in THP-1 macrophages.

Randomized, Double-Blind, Active-Controlled Phase 3 Study to Evaluate Efficacy and Safety of Zastaprazan Compared With Esomeprazole in Erosive Esophagitis.

INTRODUCTION: Zastaprazan is a potent potassium-competitive acid blocker developed to treat gastroesophageal reflux disease. The aim of this study was to evaluate the efficacy and safety of zastaprazan compared with esomeprazole in patient with erosive esophagitis (EE). METHODS: A phase III, multicenter, randomized, double-blind, noninferiority clinical study was conducted with 300 subjects with confirmed EE. Subjects were randomized to receive zastaprazan 20 mg or esomeprazole 40 mg once daily up to 8 weeks. The primary end point was the cumulative proportion of subject with healed EE confirmed by endoscopy at week 8. The secondary end points included the healing rate at week 4, symptom response, and quality of life assessment. Safety profiles and serum gastrin levels were also assessed. RESULTS: In the full analysis set, the cumulative healing rate at week 8 were 97.92% (141/144) for zastaprazan and 94.93% (131/138) ( P = 0.178) for esomeprazole. The healing rate at week 4 in the zastaprazan group was higher than the esomeprazole group (95.14% [137/144] vs 87.68% [121/138]; P = 0.026). There was no significant difference between groups in healing rates (the per-protocol set) at week 8 and week 4, symptom responses, quality of life assessments, and safety profiles. In addition, serum gastrin levels increased during treatment in both groups, with a significant difference between the 2 groups ( P = 0.047), but both decreased after treatment. DISCUSSION: An 8-week therapy of zastaprazan 20 mg is noninferior to esomeprazole 40 mg in subjects with predominantly low-grade EE. The healing rate at week 4 appears to be higher for zastaprazan than esomeprazole.

Inhibition of Toll-like Receptors Alters Macrophage Cholesterol Efflux and Foam Cell Formation.

Arterial macrophage cholesterol accumulation and impaired cholesterol efflux lead to foam cell formation and the development of atherosclerosis. Modified lipoproteins interact with toll-like receptors (TLR), causing an increased inflammatory response and altered cholesterol homeostasis. We aimed to determine the effects of TLR antagonists on cholesterol efflux and foam cell formation in human macrophages. Stimulated monocytes were treated with TLR antagonists (MIP2), and the cholesterol efflux transporter expression and foam cell formation were analyzed. The administration of MIP2 attenuated the foam cell formation induced by lipopolysaccharides (LPS) and oxidized low-density lipoproteins (ox-LDL) in stimulated THP-1 cells (p < 0.001). The expression of ATP-binding cassette transporters A (ABCA)-1, ABCG-1, scavenger receptor (SR)-B1, liver X receptor (LXR)-α, and peroxisome proliferator-activated receptor (PPAR)-γ mRNA and proteins were increased (p < 0.001) following MIP2 administration. A concentration-dependent decrease in the phosphorylation of p65, p38, and JNK was also observed following MIP2 administration. Moreover, an inhibition of p65 phosphorylation enhanced the expression of ABCA1, ABCG1, SR-B1, and LXR-α. TLR inhibition promoted the cholesterol efflux pathway by increasing the expression of ABCA-1, ABCG-1, and SR-B1, thereby reducing foam cell formation. Our results suggest a potential role of the p65/NF-kB/LXR-α/ABCA1 axis in TLR-mediated cholesterol homeostasis.

Longitudinal assessment of urinary ALCAM, HPX, and PRDX6 in Korean patients with systemic lupus erythematosus: implications for disease activity monitoring and treatment response.

Introduction: This study aimed to demonstrate the potential of activated leukocyte cell adhesion molecule (ALCAM), hemopexin (HPX), and peroxiredoxin 6 (PRDX6) as urine biomarkers for systemic lupus erythematosus (SLE). Methods: Urine samples were collected from 138 Korean patients with SLE from the Ajou Lupus Cohort and 39 healthy controls (HC). The concentrations of urine biomarkers were analyzed using enzyme-linked immunosorbent assay kits specific for ALCAM, HPX, and PRDX6, respectively. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic utility, and Pearson's correlation analysis was conducted to assess the relationships between the disease activity and urine biomarkers. Results: Patients with SLE and patients with lupus nephritis (LN) showed significantly elevated ALCAM, HPX, and PRDX6 levels compared with HCs. ALCAM, HPX, and PRDX6 showed significant diagnostic values, especially for lupus nephritis (LN), with areas under the receiver operating characteristic curve for LN was 0.850 for ALCAM (95% CI, 0.778-0.921), 0.781 for HPX (95% CI, 0.695-0.867), and 0.714 for PRDX6 (95% CI, 0.617-0.812). Correlation analysis revealed that all proteins were significantly associated with anti-double stranded DNA antibody (ALCAM, r = 0.350, p < 0.001; HPX, r = 0.346, p < 0.001; PRDX6, r = 0.191, p = 0.026) and SLEDAI (ALCAM, r = 0.526, p < 0.001; HPX, r = 0.479, p < 0.001; PRDX6, r = 0.262, p = 0.002). Results from the follow-up of the three biomarker levels in these patients revealed a significant decrease, showing a positive correlation with changes in SLEDAI-2k scores (ALCAM, r = 0.502, p < 0.001; HPX, r = 0.475, p < 0.001; PRDX6, r = 0.245, p = 0.026), indicating their potential as indicators for tracking disease activity. Discussions: Urinary ALCAM, HPX, and PRDX6 levels have diagnostic value and reflect disease activity in Korean patients with SLE, emphasizing their potential for non-invasive monitoring and treatment response evaluation.

Bone-targeted lipoplex-loaded three-dimensional bioprinting bilayer scaffold enhanced bone regeneration.

Clinical bone-morphogenetic protein 2 (BMP2) treatment for bone regeneration, often resulting in complications like soft tissue inflammation and ectopic ossification due to high dosages and non-specific delivery systems, necessitates research into improved biomaterials for better BMP2 stability and retention. To tackle this challenge, we introduced a groundbreaking bone-targeted, lipoplex-loaded, three-dimensional bioprinted bilayer scaffold, termed the polycaprolactone-bioink-nanoparticle (PBN) scaffold, aimed at boosting bone regeneration. We encapsulated BMP2 within the fibroin nanoparticle based lipoplex (Fibroplex) and functionalized it with DSS6 for bone tissue-specific targeting. 3D printing technology enables customized, porous PCL scaffolds for bone healing and soft tissue growth, with a two-step bioprinting process creating a cellular lattice structure and a bioink grid using gelatin-alginate hydrogel and DSS6-Fibroplex, shown to support effective nutrient exchange and cell growth at specific pore sizes. The PBN scaffold is predicted through in silico analysis to exhibit biased BMP2 release between bone and soft tissue, a finding validated by in vitro osteogenic differentiation assays. The PBN scaffold was evaluated for critical calvarial defects, focusing on sustained BMP2 delivery, prevention of soft tissue cell infiltration and controlled fiber membrane pore size in vivo. The PBN scaffold demonstrated a more than eight times longer BMP2 release time than that of the collagen sponge, promoting osteogenic differentiation and bone regeneration in a calvarial defect animal. Our findings suggest that the PBN scaffold enhanced the local concentration of BMP2 in bone defects through sustained release and improved the spatial arrangement of bone formation, thereby reducing the risk of heterotopic ossification.

Updates on the mechanisms of toxicities associated with monoclonal antibodies targeting growth factor signaling and immune cells in cancer.

Monoclonal antibody (mAb)-based immunotherapy currently is considered to be an optimal therapeutic approach to cancer treatment, either in combination with surgery, radiation, and/or chemotherapy or alone. Various solid tumors and hematological malignancies have been characterized by distinct molecular targets, which could be utilized as innovative anticancer agents. Notably, receptor tyrosine kinases, including HER2, EGFR, VEGFR, and PDGFR, which act as receptors for growth factors, serve as crucial target proteins, expanding their role in the cancer therapeutic market. In contrast to conventional anticancer agents that directly target cancer cells, the advent of immunotherapy introduces novel approaches, such as immune checkpoint blockers (ICBs) and mAbs targeting surface antigens on immune cells in hematological malignancies and lymphomas. While these immunotherapies have mitigated the acquired resistance observed in traditional targeted therapies, they also exhibit diverse toxicities. Herein, this review focuses on describing the well-established toxicities and newly proposed mechanisms of monoclonal antibody toxicity in recent studies. Understanding these molecular mechanisms is indispensable to overcoming the limitations of mAbs-based therapies, facilitating the development of innovative anticancer agents, and uncovering novel indications for cancer treatment in the future.

Skeletal-Related Events in Patients With Multiple Myeloma: A Comprehensive Retrospective Cohort Study.

BACKGROUND: Multiple myeloma (MM) patients are at risk of skeletal-related events (SREs) like spinal cord compression, pathologic fractures, bone surgery, and radiation to bone. Real-world data regarding SREs in MM are limited. METHODS: We conducted a large, retrospective, nationwide cohort study using the Korean Health Insurance Review and Assessment Service (HIRA) database from 2007 to 2018. RESULTS: Over a 12-year study period, we identified 6,717 patients who developed symptomatic MM. After a median follow-up of 35.1 months (interquartile range [IQR], 20.8-58.2 months), 43.6% of these patients experienced SREs, and 39.6% had four or more SREs. One in five patients (20.0%) experienced pathologic fractures within the first year of follow-up. The median time to first SRE was 9.6 months (IQR, 1.2-25.8 months), with 3.0 months in the group with prior SREs and 19.8 months in the group without prior SREs. During follow-up, 78.5% of patients received bisphosphonates. Multiple logistic regression analysis revealed several factors associated with an increased risk of SREs, including being female (odds ratio [OR], 1.44), aged 50 or older (OR, 1.87), having cerebrovascular disease (OR, 1.34), undergoing first-line chemotherapy regimens not containing bortezomib or lenalidomide (OR, 1.49), and being in the group with prior SREs and bisphosphonate use (OR, 5.63), compared to the group without prior SREs and without bisphosphonate use. CONCLUSION: This population-based study is the first to report the incidence and risk factors of SREs in Korean MM patients, which can be used to assess their bone health.

Role of chemokines CXCL9, CXCL10, CXCL11, and CXCR3 in the serum and minor salivary gland tissues of patients with Sjögren's syndrome.

This study aimed to investigate the serum and expression levels of C-X-C motif chemokine ligand 9 (CXCL9), CXCL10, CXCL11, and CXC receptor 3 (CXCR3) in minor salivary glands (MSGs) of patients with primary Sjögren's syndrome (pSS), and to explore their correlations with clinical parameters. Serum samples from 49 patients diagnosed with pSS, 33 patients with rheumatoid arthritis (RA), and 30 healthy controls (HCs) were collected for measurements of CXCL9, CXCL10, CXCL11, and CXCR3. Additionally, CXCL levels in the MSG tissues were measured in 41 patients who underwent MSG biopsy. Correlations between CXCL and CXCL/CXCR levels in serum/MSG tissues and clinical factors/salivary scintigraphy parameters were analyzed. Serum CXCL11 and CXCR3 showed statistically significant differences among patients with pSS and RA and HCs (serum CXCL11, pSS:RA:HC = 235.6 ± 500.1 pg/mL:90.0 ± 200.3 pg/mL:45.9 ± 53.6 pg/mL; p = 0.041, serum CXCR3, pSS:RA:HC = 3.27 ± 1.32 ng/mL:3.29 ± 1.17 ng/mL:2.00 ± 1.12 ng/mL; p < 0.001). Serum CXCL10 showed a statistically significant difference between pSS (64.5 ± 54.2 pg/mL) and HCs (18.6 ± 18.1 pg/mL, p < 0.001), while serum CXCL9 did not exhibit a significant difference among the groups. Correlation analysis of clinical factors revealed that serum CXCL10 and CXCL11 levels positively correlated with erythrocyte sedimentation rate (r = 0.524, p < 0.001 and r = 0.707, p < 0.001, respectively), total protein (r = 0.375, p = 0.008 and r = 0.535, p < 0.001, respectively), globulin (r = 0.539, p < 0.001 and r = 0.639, p < 0.001, respectively), and European Alliance of Associations for Rheumatology SS Disease Activity Index (r = 0.305, p = 0.033 and r = 0.321, p = 0.025). Additionally, serum CXCL10 negatively correlated with the Schirmer test score (r = - 0.354, p = 0.05), while serum CXCL11 positively correlated with the biopsy focus score (r = 0.612, p = 0.02). In the MSG tissue, the percentage of infiltrating CXCL9-positive cells was highest (75.5%), followed by CXCL10 (29.1%) and CXCL11 (27.9%). In the correlation analysis, CXCL11-expressing cells were inversely related to the mean washout percentage on salivary gland scintigraphy (r = - 0.448, p = 0.007). Our study highlights distinct serum and tissue chemokine patterns in pSS, emphasizing CXCL9's potential for early diagnosis. This suggests that CXCL10 and CXCL11 are indicators of disease progression, warranting further investigation into their roles in autoimmune disorders beyond pSS.

Exploration of neuroanatomical characteristics to differentiate prodromal Alzheimer's disease from cognitively unimpaired amyloid-positive individuals.

Differentiating clinical stages based solely on positive findings from amyloid PET is challenging. We aimed to investigate the neuroanatomical characteristics at the whole-brain level that differentiate prodromal Alzheimer's disease (AD) from cognitively unimpaired amyloid-positive individuals (CU A+) in relation to amyloid deposition and regional atrophy. We included 45 CU A+ participants and 135 participants with amyloid-positive prodromal AD matched 1:3 by age, sex, and education. All participants underwent 18F-florbetaben positron emission tomography and 3D structural T1-weighted magnetic resonance imaging. We compared the standardized uptake value ratios (SUVRs) and volumes in 80 regions of interest (ROIs) between CU A+ and prodromal AD groups using independent t-tests, and employed the least absolute selection and shrinkage operator (LASSO) logistic regression model to identify ROIs associated with prodromal AD in relation to amyloid deposition, regional atrophy, and their interaction. After applying False Discovery Rate correction at < 0.1, there were no differences in global and regional SUVR between CU A+ and prodromal AD groups. Regional volume differences between the two groups were observed in the amygdala, hippocampus, entorhinal cortex, insula, parahippocampal gyrus, and inferior temporal and parietal cortices. LASSO logistic regression model showed significant associations between prodromal AD and atrophy in the entorhinal cortex, inferior parietal cortex, both amygdalae, and left hippocampus. The mean SUVR in the right superior parietal cortex (beta coefficient = 0.0172) and its interaction with the regional volume (0.0672) were also selected in the LASSO model. The mean SUVR in the right superior parietal cortex was associated with an increased likelihood of prodromal AD (Odds ratio [OR] 1.602, p = 0.014), particularly in participants with lower regional volume (OR 3.389, p < 0.001). Only regional volume differences, not amyloid deposition, were observed between CU A+ and prodromal AD. The reduced volume in the superior parietal cortex may play a significant role in the progression to prodromal AD through its interaction with amyloid deposition in that region.

Longitudinal Comparative Analysis of Circulating Tumor DNA and Matched Tumor Tissue DNA in Patients with Metastatic Colorectal Cancer Receiving Palliative First-Line Systemic Anti-Cancer Therapy.

Purpose: This study aimed to compare tumor tissue DNA (ttDNA) and circulating tumor DNA (ctDNA) to explore the clinical applicability of ctDNA and to better understand clonal evolution in patients with metastatic colorectal cancer undergoing palliative first-line systemic therapy. Materials and Methods: We performed targeted sequencing analysis of 88 cancer-associated genes using germline DNA, ctDNA at baseline (baseline-ctDNA), and ctDNA at progressive disease (PD-ctDNA). The results were compared with ttDNA data. Results: Among 208 consecutively enrolled patients, we selected 84 (41 males; median age 59, range 35 to 90) with all four sample types available. A total of 202 driver mutations were found in 34 genes. ttDNA exhibited the highest mutation frequency (n=232), followed by baseline-ctDNA (n=155) and PD-ctDNA (n=117). Sequencing ctDNA alongside ttDNA revealed additional mutations in 40 patients (47.6%). PD-ctDNA detected 13 novel mutations in 10 patients (11.9%) compared to ttDNA and baseline-ctDNA. Notably, 7 mutations in 5 patients (6.0%) were missense or nonsense mutations in APC, TP53, SMAD4, and CDH1 genes. In baseline-ctDNA, higher maximal variant allele frequency (VAF) values (p=0.010) and higher VAF values of APC (p=0.012), TP53 (p=0.012), and KRAS (p=0.005) mutations were significantly associated with worse overall survival. Conclusion: While ttDNA remains more sensitive than ctDNA, our ctDNA platform demonstrated validity and potential value when ttDNA was unavailable. Post-treatment analysis of PD-ctDNA unveiled new pathogenic mutations, signifying cancer's clonal evolution. Additionally, baseline-ctDNA's VAF values were prognostic after treatment.