Superior outcomes and high-risk features with carfilzomib, lenalidomide, and dexamethasone combination therapy for patients with relapsed and refractory multiple myeloma: Results of the multicenter KMMWP2201 study.

Carfilzomib, lenalidomide, and dexamethasone (KRd) combination therapy improves the survival of patients with relapsed and/or refractory multiple myeloma (RRMM). Nonetheless, evidence on the use of KRd in Asian populations remains scarce. Accordingly, this study aimed at investigating this regimen's efficacy in a large group of patients. This retrospective study included patients with RRMM who were treated with KRd at 21 centers between February 2018 and October 2020. Overall, 364 patients were included (median age: 63 years). The overall response rate was 90% in responseevaluable patients, including 69% who achieved a very good partial response or deeper responses. With a median follow-up duration of 34.8 months, the median progression-free survival (PFS) was 23.4 months and overall survival (OS) was 59.5 months. Among adverse factors affecting PFS, highrisk cytogenetics, extramedullary disease, and doubling of monoclonal protein within 2 to 3 months prior to start of KRd treatment significantly decreased PFS and overall survival (OS) in multivariate analyses. Patients who underwent post-KRd stem cell transplantation (i.e.delayed transplant) showed prolonged PFS and OS. Grade 3 or higher adverse events (AEs) were observed in 56% of the patients, and non-fatal or fatal AE's that resulted in discontinuation of KRd were reported in 7% and 2% of patients, respectively. Cardiovascular toxicity was comparable to that reported in the ASPIRE study. In summary, KRd was effective in a large real-world cohort of patients with RRMM with long-term follow-up. These findings may further inform treatment choices in the treatment of patients with RRMM.

Interferon-Gamma Release Assay Combined with Renal Indicators to Reduce the False-Negativity of Latent Tuberculosis Infection in End-Stage Renal Disease with Hemodialysis Patients.

BACKGROUND: Tuberculosis (TB) is still the main cause of mortality due to a single transfectant, Mycobacterium tuberculosis (MTB). Latent tuberculosis infection (LTBI) is a condition characterized by the presence of tuberculosis (TB) that is not clinically apparent but nonetheless shows a sustained response to MTB. Presently, tuberculin skin test (TST) and interferon gamma (IFN-γ) release assays (IGRAs) are mainly used to detect LTBI via cell-mediated immunity of T-cells. For people with end-stage renal disease (ESRD), the diagnosis of patients infected with MTB is difficult because of T-cell dysfunction. To get more accurate diagnosis results of LTBI, it must compensate for the deficiency of IGRA tests. METHODS: Sixty-seven hemodialysis (HD) patients and 96 non-HD patients were enrolled in this study and the study population is continuously included. IFN-γ levels were measured by the QuantiFERON-TB Gold In-Tube (QFT-GIT) test. Kidney function indicators, blood urea nitrogen (BUN), serum creatinine (Cr), and estimated glomerular filtration rate (eGFR) were used to compensate for the declined IFN-γ levels in the IGRA test. RESULTS: In individuals who were previously undetected, the results of compensation with serum Cr increased by 10.81%, allowing for about 28% more detection, and compensation with eGFR increased by 5.41%, allowing for approximately 14% more detectable potential among them and employing both of them could enhance the prior shortcomings of IGRA tests. when both are used, the maximum compensation results show a sensitivity increase rate of 8.81%, and approximately 23% of patients who were previously undetectable may be found. CONCLUSION: Therefore, the renal function markers which are routine tests for HD patients to compensate for the deficiency of IGRA tests could increase the accuracy of LTBI diagnosis.

Subcutaneous Infliximab (CT-P13 SC) as Maintenance Therapy for Inflammatory Bowel Disease: Two Randomized Phase 3 Trials.

BACKGROUND AND AIMS: CT-P13 subcutaneous (SC), an SC formulation of the intravenous (IV) infliximab biosimilar CT-P13 IV, creates a unique exposure profile. We aimed to demonstrate superiority of CT-P13 SC versus placebo as maintenance therapy in patients with Crohn's disease (CD) and ulcerative colitis (UC). METHODS: Two randomized, placebo-controlled, double-blind studies were conducted in patients with moderately-to-severely active CD or UC and inadequate response/intolerance to corticosteroids and immunomodulators. All patients received open-label CT-P13 IV 5 mg/kg at weeks (W) 0, 2, and 6. At W10, clinical responders were randomized (2:1) to CT-P13 SC 120 mg or placebo every 2 weeks until W54 (maintenance phase) using pre-filled syringes. (Co-)primary endpoints were clinical remission and endoscopic response (CD) and clinical remission (UC) at W54 (all-randomized population). RESULTS: Overall, 396 patients with CD and 548 patients with UC received induction treatment. At W54 in the CD study, statistically significant higher proportions of CT-P13 SC- versus placebo-treated patients achieved clinical remission (62.3% versus 32.1%; P < 0.0001) and endoscopic response (51.1% versus 17.9%; P < 0.0001). In the UC study, clinical remission rates at W54 were statistically significantly higher with CT-P13 SC versus placebo (43.2% versus 20.8%; P < 0.0001). Achievement of key secondary endpoints was significantly higher with CT-P13 SC versus placebo across both studies. CT-P13 SC was well tolerated, with no new safety signals identified. CONCLUSION: CT-P13 SC was more effective than placebo as maintenance therapy and well tolerated in patients with moderately-to-severely active CD or UC who responded to CT-P13 IV induction. CLINICALTRIALS: gov, NCT03945019 (CD) and NCT04205643 (UC).

Long-term expandable mouse and human-induced nephron progenitor cells enable kidney organoid maturation and modeling of plasticity and disease.

Nephron progenitor cells (NPCs) self-renew and differentiate into nephrons, the functional units of the kidney. Here, manipulation of p38 and YAP activity allowed for long-term clonal expansion of primary mouse and human NPCs and induced NPCs (iNPCs) from human pluripotent stem cells (hPSCs). Molecular analyses demonstrated that cultured iNPCs closely resemble primary human NPCs. iNPCs generated nephron organoids with minimal off-target cell types and enhanced maturation of podocytes relative to published human kidney organoid protocols. Surprisingly, the NPC culture medium uncovered plasticity in human podocyte programs, enabling podocyte reprogramming to an NPC-like state. Scalability and ease of genome editing facilitated genome-wide CRISPR screening in NPC culture, uncovering genes associated with kidney development and disease. Further, NPC-directed modeling of autosomal-dominant polycystic kidney disease (ADPKD) identified a small-molecule inhibitor of cystogenesis. These findings highlight a broad application for the reported iNPC platform in the study of kidney development, disease, plasticity, and regeneration.

An AIE-based fluorescent probe to detect peroxynitrite levels in human serum and its cellular imaging.

An AIE-based fluorescent probe was designed to evaluate peroxynitrite levels in complex biological samples. The newly synthesized hydrazone-conjugated probe fluoresces strongly in the presence of peroxynitrite. Clinically, the peroxynitrite levels can be measured in human serum and cellular mitochondria with an LOD of 6.5 nM by fluorescence imaging in vitro.

TNF receptor 2 knockout mouse had reduced lung cancer growth and schizophrenia-like behavior through a decrease in TrkB-dependent BDNF level.

The relationship between schizophrenia (SCZ) and cancer development remains controversial. Based on the disease-gene association platform, it has been revealed that tumor necrosis factor receptor (TNFR) could be an important mediatory factor in both cancer and SCZ development. TNF-α also increases the expression of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) in the development of SCZ and tumor, but the role of TNFR in mediating the association between the two diseases remains unclear. We studied the vital roles of TNFR2 in the progression of tumor and SCZ-like behavior using A549 lung cancer cell xenografted TNFR2 knockout mice. TNFR2 knockout mice showed significantly decreased tumor size and weight as well as schizophrenia-like behaviors compared to wild-type mice. Consistent with the reduced tumor growth and SCZ-like behaviors, the levels of TrkB and BDNF expression were significantly decreased in the lung tumor tissues and pre-frontal cortex of TNFR2 knockout mice. However, intravenous injection of BDNF (160 µg/kg) to TNFR2 knockout mice for 4 weeks increased tumor growth and SCZ-like behaviors as well as TrkB expression. In in vitro study, significantly decreased cell growth and expression of TrkB and BDNF by siTNFR2 transfection were found in A549 lung cancer cells. However, the addition of BDNF (100 ng/ml) into TNFR2 siRNA transfected A549 lung cancer cells recovered cell growth and the expression of TrkB. These results suggest that TNFR2 could be an important factor in mediating the comorbidity between lung tumor growth and SCZ development through increased TrkB-dependent BDNF levels.

Validation of the 2022 European LeukemiaNet risk stratification for acute myeloid leukemia.

This study aimed to validate the 2022 European LeukemiaNet (ELN) risk stratification for acute myeloid leukemia (AML). A total of 624 newly diagnosed AML patients from 1998 to 2014 were included in the analysis. Genetic profiling was conducted using targeted deep sequencing of 45 genes based on recurrent driver mutations. In total, 134 (21.5%) patients had their risk classification reassessed according to the 2022 ELN risk stratification. Among those initially classified as having a favorable risk in 2017 (n = 218), 31 and 3 patients were reclassified as having intermediate risk or adverse risk, respectively. Among the three subgroups, the 2022 ELN favorable-risk group showed significantly longer survival outcomes than the other groups. Within the 2017 ELN intermediate-risk group (n = 298), 21 and 46 patients were reclassified as having favorable risk or adverse risk, respectively, and each group showed significant stratifications in survival outcomes. Some patients initially classified as having adverse risk in 2017 were reclassified into the intermediate-risk group (33 of 108 patients), but no prognostic improvements were observed in this group. A multivariable analysis identified the 2022 ELN risk stratification, age, and receiving allogeneic hematopoietic cell transplantation as significant prognostic factors for survival. The 2022 ELN risk stratification enables more precise decisions for proceeding with allogeneic hematopoietic cell transplantation for AML patients.

Thirty-day mortality after palliative radiotherapy in advanced cancer patients: Optimizing end-of-life care in Asia.

INTRODUCTION: Evidence-based guidelines recommend hypofractionated palliative radiotherapy (PRT); nonetheless, many patients receive prolonged course of PRT. To identify patients with limited benefits from PRT in end-of-life care, we evaluated the pattern of PRT at an Asian institution and factors associated with 30-day mortality after PRT (30dM). METHODS: We retrospectively reviewed 228 patients who died after PRT in Yonsei Wonju Severance Christian hospital between October 2014 and March 2022. The associations between clinical factors and survival were assessed using the Cox proportional hazards method. Survival was analysed using the existing models to evaluate their performance in our cohort. RESULTS: The median PRT duration was 13 (IQR, 7-15) days. Only 11.4% of the patients were treated with hypofractionated radiotherapy. One-third of the patients (32.9%) could not complete PRT and 39 (17.1%) died during PRT. The 30dM was 31.6%. The median time from PRT to death was 17 (IQR, 11-23) days for the patients who died within 30 days. The number of involved organs (≤2 vs. >2; P < 0.001), albumin level (<3.3 vs. ≥3.3; P = 0.016), admission during PRT (P < 0.001), admission 3 months before PRT (P = 0.036) and ICU care during PRT (P < 0.001) were prognostic factors. A comparison of survival based on the existing models yielded unsatisfactory results in our cohort. CONCLUSION: Almost one-third of the patients received PRT in the last 30 days of life. The use of hypofractionation for PRT was low in this Asian population. Further research is necessary to develop a predictive model of early mortality, allowing tailored end-of-life care for Asian patients.

Dimorphostylispilocorpus sp. nov. (Crustacea, Cumacea, Diastylidae), a new cumacean from Korean waters.

A new species of Cumacea belonging to the genus Dimorphostylis Zimmer was collected from the Dokdo and Ulleung Islands in the East Sea of Korea. The new species, Dimorphostylispilocorpussp. nov., can be distinguished from all other Dimorphostylis species by the combination of the body surface covered with numerous slender simple setae; carapace with one transverse, a pair of frontal, and three pairs of oblique ridges; three pairs of oblique ridges connected on a submedian carina; telson of the female with 1 pair of short simple and 1 short, stout simple seta centrally; 1 pair of stout simple and 3 pairs of short simple setae on the post-anal section; pleonite 5 of male with 1 spiniform seta on the ventral margin; post-anal section with 2 pairs of stout simple setae bearing a single subterminal setule on both sides; terminal margin with 3 stout simple setae; and a central seta slightly longer than the outer pair of setae. Full illustrations of the new species, including the mouthparts, are given in this paper. A key to the Korean species of Dimorphostylis is also provided.

Feature-based attentional control for distractor suppression.

To investigate whether attentional suppression is merely a byproduct of target facilitation or a result of independent mechanisms for distractor suppression, the present study examined whether attentional suppression takes place when target facilitation hardly occurs using a spatial cueing paradigm. Participants searched for target letters that were not red, i.e., a negative color. On each trial, a target color was randomly chosen among 12 colors to prevent establishing attentional control for target colors and to reduce intertrial priming for target colors. Immediately before a target display, a noninformative spatial cue was presented at one of the possible target locations. The cue was rendered in a negative color, which was to be ignored, to detect targets or the reference color, which was never presented for target and non-target letters. Experiment 1 showed that negative color cues captured attention less than reference color cues, suggesting feature-based attentional suppression. The suppression effect was replicated when the temporal interval between the onsets of the cue and target displays was reduced in Experiments 2 and 3, suggesting proactive suppression. Experiment 3 directly confirmed no attentional control settings for target colors and intertrial priming. These findings suggest that distractor features can guide attention at the pre-attentive stage when target features are not used to attend to targets.

A randomized, double-blind, single-dose, phase 1 study comparing the pharmacokinetics, pharmacodynamics, safety, and immunogenicity of denosumab biosimilar CT­P41 and reference denosumab in healthy males.

BACKGROUND: This study's objective was to demonstrate pharmacokinetic (PK) similarity and safety of denosumab biosimilar, CT­P41, and United States-licensed reference denosumab (US-denosumab) in healthy male Asian adults, considering also pharmacodynamic (PD) outcomes. RESEARCH DESIGN AND METHODS: This double-blind, two-arm, parallel-group, Phase 1 study randomized (1:1) healthy males to a single (60-mg) subcutaneous dose of CT­P41 or US-denosumab. Primary endpoints were area under the concentration - time curve (AUC) from time zero to infinity (AUC0-inf), AUC from time zero to the last quantifiable concentration (AUC0-last), and maximum serum concentration (Cmax). PK equivalence was determined if 90% confidence intervals (CIs) for ratios of geometric least-squares means (gLSMs) were within the predefined 80-125% equivalence margin. Secondary PK, PD, safety, and immunogenicity outcomes were also evaluated. RESULTS: Of 154 participants randomized (76 CT­P41; 78 US-denosumab), 151 received study drug (74 CT­P41; 77 US-denosumab). Primary and secondary PK results, PD results, safety, and immunogenicity were comparable between groups. Ninety percent CIs for ratios of gLSMs were within the predefined equivalence margin for AUC0-inf (100.4-114.7), AUC0-last (99.9-114.3), and Cmax (95.2-107.3). CONCLUSIONS: Following a single dose in healthy males, CT­P41 demonstrated PK equivalence with US-denosumab. TRIAL REGISTRATION: ClinicalTrials.gov: NCT06037395.

Clinical Validation of the Unparalleled Sensitivity of the Novel Allele-Discriminating Priming System Technology-Based EGFR Mutation Assay in Patients with Operable Non-Small Cell Lung Cancer.

PURPOSE: Recently, we developed allele-discriminating priming system (ADPS) technology. This method increases the sensitivity of conventional quantitative polymerase chain reaction up to 100 folds, with limit of detection, 0.01%, with reinforced specificity. This prospective study aimed to develop and validate the accuracy of ADPS epidermal growth factor receptor (EGFR) Mutation Test Kit using clinical specimens. MATERIALS AND METHODS: In total 189 formalin-fixed paraffin-embedded tumor tissues resected from patients with non-small cell lung cancer were used to perform a comparative evaluation of the ADPS EGFR Mutation Test Kit versus the cobas EGFR Mutation Test v2, which is the current gold standard. When the two methods had inconsistent results, next-generation sequencing-based CancerSCAN was utilized as a referee. RESULTS: The overall agreement of the two methods was 97.4% (93.9%-99.1%); the positive percent agreement, 95.0% (88.7%-98.4%); and the negative percent agreement, 100.0% (95.9%-100.0%). EGFR mutations were detected at a frequency of 50.3% using the ADPS EGFR Mutation Test Kit and 52.9% using the cobas EGFR Mutation Test v2. There were 10 discrepant mutation calls between the two methods. CancerSCAN reproduced eight ADPS results. In two cases, mutant allele fraction was ultra-low at 0.02% and 0.06%, which are significantly below the limit of detection of the cobas assay and CancerSCAN. Based on the EGFR genotyping by ADPS, the treatment options could be switched in five patients. CONCLUSION: The highly sensitive and specific ADPS EGFR Mutation Test Kit would be useful in detecting the patients who have lung cancer with EGFR mutation, and can benefit from the EGFR targeted therapy.

Efficacy and Safety of Candidate Biosimilar CT-P43 Versus Originator Ustekinumab in Moderate to Severe Plaque Psoriasis: 28-Week Results of a Randomised, Active-Controlled, Double-Blind, Phase III Study.

BACKGROUND: CT-P43 is a candidate ustekinumab biosimilar in clinical development. OBJECTIVES: This paper aims to demonstrate equivalent efficacy of CT-P43 to originator ustekinumab in adults with moderate to severe plaque psoriasis. METHODS: This double-blind, phase III trial randomised patients (1:1) to receive subcutaneous CT-P43 or originator ustekinumab (45/90 mg for patients with baseline body weight ≤ 100 kg/> 100 kg) at week 0 and week 4 in Treatment Period I. Prior to week 16 dosing in Treatment Period II, patients receiving originator ustekinumab were re-randomised (1:1) to continue originator ustekinumab or switch to CT-P43; patients initially randomised to CT-P43 continued receiving CT-P43 (at weeks 16, 28 and 40). The primary endpoint of the trial was mean per cent improvement from baseline in Psoriasis Area Severity Index (PASI) score at week 12. Equivalence was concluded if confidence intervals (CIs) for the estimate of treatment difference were within pre-defined equivalence margins: ± 10% [90% CI; modified intent-to-treat set; Food and Drug Administration (FDA) approach] or ± 15% [95% CI; full analysis set for patients only receiving 45 mg doses in Treatment Period I; European Medicines Agency (EMA) approach]. Additional efficacy, pharmacokinetic, safety and immunogenicity endpoints were evaluated through week 52. Results to week 28 are reported here. RESULTS: In Treatment Period I, 509 patients were randomised (CT-P43: N = 256; originator ustekinumab: N = 253). The mean per cent improvement in PASI score at week12 was 77.93% and 75.89% for CT-P43 and originator ustekinumab, respectively (FDA approach); per the EMA approach, corresponding values were 78.26% and 77.33%. Estimated treatment differences were 2.05 (90% CI -0.23, 4.32) and 0.94 (95% CI -2.29, 4.16); equivalence was achieved for both sets of assumptions. Further efficacy parameters and pharmacokinetic, safety and immunogenicity outcomes were comparable between treatment groups, including after switching from originator ustekinumab to CT-P43. CONCLUSIONS: CT-P43 demonstrated equivalent efficacy to originator ustekinumab in patients with moderate to severe plaque psoriasis, with comparable pharmacokinetic, safety and immunogenicity profiles. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04673786; date of registration: 17 December, 2020.

Super-Antioxidant Vitamin A Derivatives with Improved Stability and Efficacy Using Skin-Permeable Chitosan Nanocapsules.

Retinyl palmitate (RP) is a retinol ester with strong antioxidant and anti-inflammatory properties as an antiwrinkle agent. However, it has poor aqueous solubility and easily degrades into inactive forms for topical applications. Therefore, we developed chitosan-coated nanocapsules (ChiNCs) to encapsulate RP using a simple nanoprecipitation method for protection against physiological conditions and to enable deep skin penetration. The as-prepared RP-loaded nanocapsules (RP@ChiNCs) loaded with approximately 5 wt.% RP exhibited a hydrodynamic diameter of 86 nm and surface charge of 24 mV. They had adequate stability to maintain their physicochemical properties after lyophilization in a biological buffer. Notably, ChiNCs provided RP with remarkable protection against degradation for 4 weeks at 37 °C. Thus, RP@ChiNCs exhibited good antioxidant activity in situ for sufficiently long periods without considerable changes in their efficacy. Furthermore, ChiNCs enhanced the skin penetration of lipophilic RP based on the inherent nature of chitosan. RP@ChiNCs exhibited good in vitro antioxidant and anti-inflammatory effects without causing any cytotoxicity in dermal fibroblasts. Accordingly, they promoted cell proliferation in a wound-scratch test and enhanced collagen synthesis. These results suggest that RP@ChiNCs are promising candidates for cosmetic and biomedical applications.

Long-Term Efficacy and Safety of Eculizumab in Patients With Paroxysmal Nocturnal Hemoglobinuria and High Disease Burden: Real-World Data From Korea.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disorder characterized by uncontrolled terminal complement activation. Eculizumab, a monoclonal antibody C5 inhibitor was introduced in Korea in 2009 and has been the standard treatment option for PNH. METHODS: This study assessed the long-term efficacy/safety of eculizumab in PNH using real-world data from the Korean Health Insurance Review and Assessment Service. Eighty patients who initiated eculizumab from 2009-2020 were enrolled. RESULTS: At eculizumab initiation, the median age was 51.5 years, lactate dehydrogenase (LDH) 6.8 × upper limit of normal, and granulocyte clone size 93.0%. All patients had at least one PNH-related complication before eculizumab initiation, including renal failure (n = 36), smooth muscle spasm (n = 24), thromboembolism (n = 20), and pulmonary hypertension (n = 15). The median (range) duration of eculizumab treatment was 52.7 (1.0, 127.3) months (338.6 total treated patient-years). Despite high disease activity in the study population before treatment initiation, overall survival was 96.2% and LDH levels were stabilized in most patients during treatment. PNH-related complications at treatment initiation were resolved in 44.4% of patients with renal failure, 95.8% with smooth muscle spasm, 70.0% with thromboembolism, and 26.7% with pulmonary hypertension. Extravascular hemolysis occurred in 28.8% of patients (n = 23; 0.09 per patient-year) and breakthrough hemolysis in 18.8% (n = 15; 0.06 per patient-year). No treatment discontinuation cases related to eculizumab were observed. CONCLUSION: These data provided evidence for the long-term efficacy and safety of eculizumab in Korean PNH patients with high disease burdens.

Kikuchi-Fujimoto Disease: A Case of Febrile Cervical Lymphadenopathy With Hematological Abnormalities.

Kikuchi-Fujimoto disease (KFD), or histiocytic necrotizing lymphadenitis, is a benign but rare disorder associated with febrile cervical lymphadenopathy in young adults. Here, we discuss a case of a young female patient presenting with left tender cervical lymphadenopathy that progressed bilaterally with a fever of unknown origin. Laboratory parameters showed persistent leukopenia, especially neutropenia, which fluctuated with the degree of symptom severity. Two months were taken to confirm the diagnosis of KFD based on the histological interpretation of the lymph node biopsy. Supportive management with analgesics and paracetamol formed the main treatment. This case highlights the challenges and importance of diagnosing KFD to exclude other serious conditions such as lymphoma, tuberculosis, or lupus lymphadenitis that share similar clinical manifestations as KFD.

Feasibility of artificial intelligence-driven interfractional monitoring of organ changes by mega-voltage computed tomography in intensity-modulated radiotherapy of prostate cancer.

PURPOSE: High-dose radiotherapy (RT) for localized prostate cancer requires careful consideration of target position changes and adjacent organs-at-risk (OARs), such as the rectum and bladder. Therefore, daily monitoring of target position and OAR changes is crucial in minimizing interfractional dosimetric uncertainties. For efficient monitoring of the internal condition of patients, we assessed the feasibility of an auto-segmentation of OARs on the daily acquired images, such as megavoltage computed tomography (MVCT), via a commercial artificial intelligence (AI)-based solution in this study. MATERIALS AND METHODS: We collected MVCT images weekly during the entire course of RT for 100 prostate cancer patients treated with the helical TomoTherapy system. Based on the manually contoured body outline, the bladder including prostate area, and rectal balloon regions for the 100 MVCT images, we trained the commercially available fully convolutional (FC)-DenseNet model and tested its auto-contouring performance. RESULTS: Based on the optimally determined hyperparameters, the FC-DenseNet model successfully auto-contoured all regions of interest showing high dice similarity coefficient (DSC) over 0.8 and a small mean surface distance (MSD) within 1.43 mm in reference to the manually contoured data. With this well-trained AI model, we have efficiently monitored the patient's internal condition through six MVCT scans, analyzing DSC, MSD, centroid, and volume differences. CONCLUSION: We have verified the feasibility of utilizing a commercial AI-based model for auto-segmentation with low-quality daily MVCT images. In the future, we will establish a fast and accurate auto-segmentation and internal organ monitoring system for efficiently determining the time for adaptive replanning.

Safety and Effectiveness of Regdanvimab for COVID-19 Treatment: A Phase 4 Post-marketing Surveillance Study Conducted in South Korea.

INTRODUCTION: Regdanvimab, a neutralising monoclonal antibody (mAb) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), received approval for the treatment of coronavirus disease 2019 (COVID-19) in South Korea in 2021. The Ministry of Food and Drug Safety in South Korea mandate that new medications be re-examined for safety and effectiveness post-approval in at least 3000 individuals. This post-marketing surveillance (PMS) study was used to evaluate the safety and effectiveness of regdanvimab in real-world clinical care. METHODS: This prospective, multicentre, phase 4 PMS study was conducted between February 2021 and March 2022 in South Korea. Eligible patients were aged ≥ 18 years with confirmed mild COVID-19 at high risk of disease progression or moderate COVID-19. Patients were hospitalised and treated with regdanvimab (40 mg/kg, day 1) and then monitored until discharge, with a follow-up call on day 28. Adverse events (AEs) were documented, and the COVID-19 disease progression rate was used to measure effectiveness. RESULTS: Of the 3123 patients with COVID-19 infection identified, 3036 were eligible for inclusion. Approximately 80% and 5% of the eligible patients were diagnosed with COVID-19 during the delta- and omicron-dominant periods, respectively. Median (range) age was 57 (18-95) years, and 50.6% of patients were male. COVID-19 severity was assessed before treatment, and high-risk mild and moderate COVID-19 was diagnosed in 1030 (33.9%) and 2006 (66.1%) patients, respectively. AEs and adverse drug reactions (ADRs) were experienced by 684 (22.5%) and 363 (12.0%) patients, respectively. The most common ADR was increased liver function test (n = 62, 2.0%). Nine (0.3%) patients discontinued regdanvimab due to ADRs. Overall, 378 (12.5%) patients experienced disease progression after regdanvimab infusion, with extended hospitalisation/re-admission (n = 300, 9.9%) as the most common reason. Supplemental oxygen was required by 282 (9.3%) patients. Ten (0.3%) patients required intensive care monitoring and 3 (0.1%) died due to COVID-19. CONCLUSION: This large-scale PMS study demonstrated that regdanvimab was effective against COVID-19 progression and had an acceptable safety profile when used in real-world clinical practice.

Canonical Wnt transcriptional complexes are essential for induction of nephrogenesis but not maintenance or proliferation of nephron progenitors.

Wnt regulated transcriptional programs are associated with both the maintenance of mammalian nephron progenitor cells (NPC) and their induction, initiating the process of nephrogenesis. How opposing transcriptional roles are regulated remain unclear. Using an in vitro model replicating in vivo events, we examined the requirement for canonical Wnt transcriptional complexes in NPC regulation. In canonical transcription, Lef/Tcf DNA binding proteins associate the transcriptional co-activator ß-catenin. Wnt signaling is readily substituted by CHIR99021, a small molecule antagonist of glycogen synthase kinase-3ß (GSK3ß). GSK3ß inhibition blocks Gskß-dependent turnover of ß-catenin, enabling formation of Lef/Tcf/ß-catenin transcriptional complexes, and enhancer-mediated transcriptional activation. Removal of ß-catenin activity from NPCs under cell expansion conditions (low CHIR) demonstrated a non-transcriptional role for ß-catenin in the CHIR-dependent proliferation of NPCs. In contrast, CHIR-mediated induction of nephrogenesis, on switching from low to high CHIR, was dependent on Lef/Tcf and ß-catenin transcriptional activity. These studies point to a non-transcriptional mechanism for ß-catenin in regulation of NPCs, and potentially other stem progenitor cell types. Further, analysis of the ß-catenin-directed transcriptional response provides new insight into induction of nephrogenesis. Summary Statement: The study provides a mechanistic understanding of Wnt/ ß-catenin activity in self-renewal and differentiation of mammalian nephron progenitors.