Boosting the Electroreduction of CO2 to CO by Ligand Engineering of Gold Nanoclusters.

The electrochemical CO2 reduction reaction (CO2RR) has been widely studied as a promising means to convert anthropogenic CO2 into valuable chemicals and fuels. In this process, the alkali metal ions present in the electrolyte are known to significantly influence the CO2RR activity and selectivity. In this study, we report a strategy for preparing efficient electrocatalysts by introducing a cation-relaying ligand, namely 6-mercaptohexanoic acid (MHA), into atom-precise Au25 nanoclusters (NCs). The CO2RR activity of the synthesized Au25(MHA)18 NCs was compared with that of Au25(HT)18 NCs (HT = 1-hexanethiolate). While both NCs selectively produced CO over H2, the CO2-to-CO conversion activity of the Au25(MHA)18 NCs was significantly higher than that of the Au25(HT)18 NCs when the catholyte pH was higher than the pKa of MHA, demonstrating the cation-relaying effect of the anionic terminal group. Mechanistic investigations into the CO2RR occurring on the Au25 NCs in the presence of different catholyte cations and concentrations revealed that the CO2-to-CO conversion activities of these Au25 NCs increased in the order Li+ < Na+ < K+ < Cs+, and are gated by the cation-coupled electron transfer step. These results were confirmed by the Nernstian shifts of the polarization curves at different cation concentrations.

Radiopharmaceuticals for Skeletal Muscle PET Imaging.

The skeletal muscles account for approximately 40% of the body weight and are crucial in movement, nutrient absorption, and energy metabolism. Muscle loss and decline in function cause a decrease in the quality of life of patients and the elderly, leading to complications that require early diagnosis. Positron emission tomography/computed tomography (PET/CT) offers non-invasive, high-resolution visualization of tissues. It has emerged as a promising alternative to invasive diagnostic methods and is attracting attention as a tool for assessing muscle function and imaging muscle diseases. Effective imaging of muscle function and pathology relies on appropriate radiopharmaceuticals that target key aspects of muscle metabolism, such as glucose uptake, adenosine triphosphate (ATP) production, and the oxidation of fat and carbohydrates. In this review, we describe how [18F]fluoro-2-deoxy-D-glucose ([18F]FDG), [18F]fluorocholine ([18F]FCH), [11C]acetate, and [15O]water ([15O]H2O) are suitable radiopharmaceuticals for diagnostic imaging of skeletal muscles.

Evaluating the validity and reliability of the Korean version of Scales for Outcomes in Parkinson's Disease-Cognition.

Objective: The Scales for Outcomes in Parkinson's Disease-Cognition (SCOPA-Cog) was developed to screen for cognition in PD. In this study, we aimed to evaluate the validity and reliability of the Korean version of the SCOPA-cog. Methods: We recruited 129 PD patients from 31 clinics with movement disorders in South Korea. The original version of the SCOPA-cognition was translated into Korean using the translation-retranslation method. The test-rest method with an intraclass correlation coefficient (ICC) and Cronbach's alpha coefficient were used to assess reliability. The Spearman's Rank correlation analysis with Montreal Cognitive Assessment-Korean version (MOCA-K) and Korean Mini-Mental State Examination (K-MMSE) were used to assess concurrent validity. Results: The Cronbach's alpha coefficient was 0.797, and the ICC was 0.887. Spearman's rank correlation analysis showed a significant correlation with the K-MMSE and MOCA-K scores (r = 0.546 and r = 0.683, respectively). Conclusions: Our results demonstrate that K-SCOPA-Cog exhibits good reliability and validity.

Donor body mass index over 30 is no barrier for pure laparoscopic donor right hepatectomy.

Backgrounds/Aims: Challenges arise when translating pure laparoscopic donor right hepatectomy (PLDRH) results from Asian to Western donors, due to differences in body mass index (BMI). This study compares the outcomes of PLDRH and conventional open donor right hepatectomy (CDRH) in donors with BMI over 30. Methods: Medical records of live liver donors (BMI > 30) undergoing right hepatectomy (2010-2021) were compared: 25 PLDRH cases vs. 19 CDRH cases. Donor and recipient demographics, operative details, and outcomes were analyzed. Results: PLDRH and CDRH had similar donor and recipient characteristics. PLDRH had longer liver removal and warm ischemic times, but a shorter post-liver removal duration than CDRH. Donor complication rates were comparable, with the highest complication being grade IIIa in PLDRH, necessitating needle aspiration for biloma on postoperative day 11. Fortunately, this donor fully recovered without additional treatment. No complications exceeding Clavien-Dindo grade IIIa occurred in either group. Recipient outcomes between the groups were similar. Conclusions: This study supports PLDRH as a viable option for donors with BMI over 30, challenging the notion that high BMI should deter considering PLDRH. The findings provide valuable insights into the safety and feasibility of PLDRH, encouraging further exploration of this technique in diverse donor populations.

Kinetic modeling of the plasma pharmacokinetic profiles of ADAMTS13 fragment and its Fc-fusion counterpart in mice.

Introduction: Fusion of the fragment crystallizable (Fc) to protein therapeutics is commonly used to extend the circulation time by enhancing neonatal Fc-receptor (FcRn)-mediated endosomal recycling and slowing renal clearance. This study applied kinetic modeling to gain insights into the cellular processing contributing to the observed pharmacokinetic (PK) differences between the novel recombinant ADAMTS13 fragment (MDTCS) and its Fc-fusion protein (MDTCS-Fc). Methods: For MDTCS and MDTCS-Fc, their plasma PK profiles were obtained at two dose levels following intravenous administration of the respective proteins to mice. The plasma PK profiles of MDTCS were fitted to a kinetic model with three unknown protein-dependent parameters representing the fraction recycled (FR) and the rate constants for endocytosis (kup, for the uptake into the endosomes) and for the transfer from the plasma to the interstitial fluid (kpi). For MDTCS-Fc, the model was modified to include an additional parameter for binding to FcRn. Parameter optimization was done using the Cluster Gauss-Newton Method (CGNM), an algorithm that identifies multiple sets of approximate solutions ("accepted" parameter sets) to nonlinear least-squares problems. Results: As expected, the kinetic modeling results yielded the FR of MDTCS-Fc to be 2.8-fold greater than that of MDTCS (0.8497 and 0.3061, respectively). In addition, MDTCS-Fc was predicted to undergo endocytosis (the uptake into the endosomes) at a slower rate than MDTCS. Sensitivity analyses identified the association rate constant (kon) between MDTCS-Fc and FcRn as a potentially important factor influencing the plasma half-life in vivo. Discussion: Our analyses suggested that Fc fusion to MDTCS leads to changes in not only the FR but also the uptake into the endosomes, impacting the systemic plasma PK profiles. These findings may be used to develop recombinant protein therapeutics with extended circulation time.

Diagnosis, Treatment, and Follow-Up of Giant-Cell Arteritis: A Retrospective Multicenter Study.

BACKGROUND AND PURPOSE: Giant-cell arteritis (GCA) is the most common type of vasculitis in the elderly and is associated with high risks of visual loss and recurrence. Owing to its rarity in Asian populations, the current clinical interventions for these patients are not well known. Here we aimed to characterize the current management status of patients with GCA using Korean multicenter data. METHODS: This retrospective study analyzed medical records of patients with GCA at six Korean university hospitals from February 2009 to November 2022. GCA had originally been diagnosed based on the 1990 American College of Rheumatology (ACR) criteria, and cases were selected for inclusion in this study based on the 2022 ACR/European Alliance of Associations for Rheumatology criteria. We evaluated treatments, follow-up periods, and outcomes (relapse, remission, and adverse drug reactions) in patients with GCA with or without arteritic anterior ischemic optic neuropathy (AAION). RESULTS: This study analyzed 18 patients with a median age of 75.5 years that included 12 females (66.7%). Seven patients (38.8%) had AAION. All patients initially received prednisolone treatment, while four (22.2%) underwent adjuvant treatment with methotrexate and azathioprine during prednisolone tapering. During the median follow-up of 3.5 months (interquartile range: 2.0-23.2 months), 4 patients (22.2%) had prednisolone-related adverse reactions, 2 (11.1%) relapsed, and 13 (72.3%) dropped out. Nine patients (50.0%) experienced remission, with this being sustained in four (36.4%). CONCLUSIONS: This study observed high dropout rates and short follow-ups. Adverse effects of prednisolone were common, and relapses occurred in approximately one-tenth of Korean patients with GCA. Thus, optimizing GCA treatment necessitates regular monitoring and long-term follow-up.

Pulmonary-vein-to-pulmonary-artery ratio can be utilized to evaluate myxomatous mitral valve disease progression in dogs.

OBJECTIVE: To evaluate the diagnostic value of pulmonary-vein-to-pulmonary-artery ratio (PV:PA) in dogs with myxomatous mitral valve degeneration (MMVD), classified according to the American College of Veterinary Internal Medicine (ACVIM) consensus guidelines. ANIMALS: 80 client-owned dogs with either MMVD (n = 65) or no cardiovascular disease (control group; n = 15) between August 5, 2020, and July 19, 2023. METHODS: This is a retrospective study. Dogs with MMVD were classified according to ACVIM consensus guidelines. Echocardiograms, thoracic radiographs, and other measurements needed in this study were reviewed in all dogs. Spearman correlation was used to determine the correlation between the PV:PA and the following variables: vertebral heart size, vertebral left atrial size, left-atrium-to-aorta ratio, normalized left ventricular internal diameter, and peak transmitral early diastolic velocity. Receiver operating characteristic (ROC) curve analysis was used to evaluate the value of PV:PA in distinguishing between stages B1 and B2 and stages B2 and C. RESULTS: All conventional indices showed correlations with PV:PA. The area under the ROC curve (AUC) for stages B1 and B2 was 0.83, and the cutoff value for differentiating stage B2 was 1.52. The AUC for stages B2 and C was 0.81, and the cutoff value for differentiating stage C was 2.09. CLINICAL RELEVANCE: PV:PA was significantly different between control and the stage B1 group, stage B1 and B2 group, and stage B2 and C group. PV:PA can be an index that can be used in evaluating MMVD dogs.

Mechanical Activation of Graphite for Na-Ion Battery Anodes: Unexpected Reversible Reaction on Solid Electrolyte Interphase via X-Ray Analysis.

Although sodium-ion batteries (SIBs) offer promising low-cost alternatives to lithium-ion batteries (LIBs), several challenges need to be overcome for their widespread adoption. A primary concern is the optimization of carbon anodes. Graphite, vital to the commercial viability of LIBs, has a limited capacity for sodium ions. Numerous alternatives to graphite are explored, particularly focusing on disordered carbons, including hard carbon. However, compared with graphite, most of these materials underperform in LIBs. Furthermore, the reaction mechanism between carbon and sodium ions remains ambiguous owing to the structural diversity of disordered carbon. A straightforward mechanical approach is introduced to enhance the sodium ion storage capacity of graphite, supported by comprehensive analytical techniques. Mechanically activated graphite delivers a notable reversible capacity of 290.5 mAh·g-1 at a current density of 10 mA·g-1. Moreover, it maintains a capacity of 157.7 mAh·g-1 even at a current density of 1 A·g-1, benefiting from the defect-rich structure achieved by mechanical activation. Soft X-ray analysis revealed that this defect-rich carbon employs a sodium-ion storage mechanism distinct from that of hard carbon. This leads to an unexpected reversible reaction on the solid electrolyte surface. These insights pave the way for innovative design approaches for carbon electrodes in SIB anodes.

Developmental self-reactivity determines pathogenic Tc17 differentiation potential of naive CD8+ T cells in murine models of inflammation.

The differentiation of naive CD8+ T cells into effector cells is important for establishing immunity. However, the effect of heterogeneous naive CD8+ T cell populations is not fully understood. Here, we demonstrate that steady-state naive CD8+ T cells are composed of functionally heterogeneous subpopulations that differ in their ability to differentiate into type 17 cytotoxic effector cells (Tc17) in a context of murine inflammatory disease models, such as inflammatory bowel disease and graft-versus-host disease. The differential ability of Tc17 differentiation is not related to T-cell receptor (TCR) diversity and antigen specificity but is inversely correlated with self-reactivity acquired during development. Mechanistically, this phenomenon is linked to differential levels of intrinsic TCR sensitivity and basal Suppressor of Mothers Against Decapentaplegic 3 (SMAD3) expression, generating a wide spectrum of Tc17 differentiation potential within naive CD8+ T cell populations. These findings suggest that developmental self-reactivity can determine the fate of naive CD8+ T cells to generate functionally distinct effector populations and achieve immense diversity and complexity in antigen-specific T-cell immune responses.

Soft tissue myxoma manifesting as a slowly growing subcutaneous mass in the anterior chest wall: A case report.

Soft tissue myxomas are benign mesenchymal neoplasms typically found in the intramuscular components of the proximal extremities. However, soft tissue myxomas in the chest wall are rare. We report the case of a 41-year-old woman with soft tissue myxoma who presented with a slowly growing, palpable lump on her left anterior chest wall that has been present for several years. Mammography revealed an oval, circumscribed, and hyperdense mass in the retromammary fat layer of the upper inner quadrant of the left breast. Ultrasonography revealed an oval, circumscribed, and hypoechoic mass with internal echoes and multiple microcystic spaces. A triangular hyperechoic area adjacent to the pole of the mass and peripheral hyperechoic rim were also detected. The patient underwent surgical excision and was diagnosed with soft tissue myxoma with subcutaneous manifestation.

Squamous Cell Carcinoma Arising From Epidermal Cyst: A Case Series of 9 Patients With a Literature Review.

ABSTRACT: Epidermal cysts are among the most common benign subcutaneous tumors. However, malignant transformation of benign epidermal cysts into squamous carcinomas has been reported. Owing to its low incidence rate, the clinical and pathological features of this condition are not well understood. This study aimed to analyze the clinical and pathological characteristics of the malignant transformation of epidermal cysts, which could suggest an appropriate treatment strategy. We conducted a retrospective study of 9 patients diagnosed with squamous cell carcinoma arising from epidermal cysts. All patients underwent surgical excision, and clinical information regarding patient demographics, tumor characteristics, treatment, and outcomes was analyzed. The average age at diagnosis was 57.3 years, with an average latency period of 15.4 years. Five patients had undergone prior cyst excision or drainage, with an average of 2.3 episodes of recurrence. Surgical excision was the primary treatment in all cases, and 2 patients with margin involvement at the final pathology underwent re-excision with additional resection margins. No recurrence was observed during the follow-up period. Four patients had immune dysregulation due to an underlying chronic kidney disease or cancer. Our study emphasizes the need for increased awareness of squamous cell carcinoma arising from epidermal cysts in patients with a history of cyst existence or recurrence, especially those with immune deficiencies. We expect these findings to contribute to early suspicion of malignant transformation and guide adequate clinical decision-making.

Impact of Preformed Donor-specific Antibodies in Comparison to ABO Incompatibility in Living Donor Liver Transplantation: A Propensity Score-Matched Analysis.

BACKGROUND: Immunological factors play a pivotal role in the outcomes of solid organ transplantation. We aimed to elucidate the effects of donor-specific antibodies (DSAs) and ABO compatibility on living donor liver transplantation (LDLT) outcomes. METHODS: A retrospective analysis was conducted on 584 LDLT recipients from 2015 to 2020. The recipients were stratified into 3 groups: ABO-compatible recipients without DSAs (group 1), ABO-compatible recipients with DSAs (group 2), and ABO-incompatible recipients without DSAs (group 3). Propensity score matching was used for balanced comparisons. RESULTS: In the matched comparisons, group 2 exhibited a higher incidence of T cell-mediated rejection compared with group 1 (22.7% versus 4.5%, P = 0.030). Despite this, the 5-y survival rates were similar between groups 1 and 2 (81.6% versus 95.5%, P = 0.085). Group 3, in comparison with group 1, showed elevated rates of cytomegalovirus infection (23.2% versus 7.3%, P = 0.008), T cell-mediated rejection (28.0% versus 7.3%, P = 0.001), and antibody-mediated rejection (13.4% versus 0%, P = 0.001). However, the survival rates were comparable between group 3 and group 1 (82.0% versus 86.5%, P = 0.220, respectively). Comparisons between group 2 and group 3 did not reveal significant differences in postoperative outcomes or survival rates (P > 0.05). CONCLUSIONS: DSA positivity and ABO incompatibility contribute to distinct posttransplant complications in LDLT. The integrated consideration of both factors in pretransplant assessment may enhance risk stratification and inform tailored interventions. Further research is required to corroborate these findings and provide mechanistic insights.

Effect of Remimazolam- versus Propofol-Based Total Intravenous General Anesthesia on Intraoperative Hemodynamic Stability for Major Spine Surgery in the Prone Position: A Randomized Controlled Trial.

Background and Objectives: Remimazolam offers advantages over propofol in terms of hemodynamic stability. However, it remains unclear whether remimazolam-based total intravenous anesthesia (TIVA) can reduce intraoperative hypotension compared to propofol-based TIVA, especially after prone positioning. In this study, we compared the effects of remimazolam- and propofol-based TIVA on intraoperative hemodynamic stability in patients undergoing surgery in the prone position. Materials and Methods: This study randomly assigned patients undergoing major spinal surgery in the prone position to the propofol or remimazolam group. Target-controlled infusion (2-3.5 µg/mL for induction and 2-3 µg/mL for maintenance) was used in the propofol group and continuous infusion (6 mg/kg/h for induction and 1-2 mg/kg/h for maintenance) was used in the remimazolam group; target-controlled infusion (3-5 ng/mL) of remifentanil was performed in both groups. The primary outcomes were the incidence of hypotensive episodes during the first hour after prone positioning. The secondary outcomes included the incidence of severe hypotension and the total amount of inotropic or vasopressor medication. Systolic and mean arterial pressure, heart rate, cardiac index and output, stroke volume, stroke volume variation, and pleth variability index were also evaluated. These variables were recorded per minute for the first 10 min after prone positioning, and every 10 min thereafter. Results: The study enrolled 94 patients (47 patients in each group). The incidence of hypotension or severe hypotension did not differ significantly between the two groups during the first hour after prone positioning. The total amount of ephedrine administered during the first hour after prone positioning was lesser (p = 0.020) and the mean arterial pressure during the initial 10 min after prone positioning was higher in the remimazolam group (p = 0.003). Conclusions: Our study uncovered no significant differences in the incidence of hypotension between remimazolam- and propofol-based TIVA in patients undergoing major spine surgery in prone position.

A Nationwide Study on HER2-low Breast Cancer in South Korea: Its Incidence of 2022 Real World Data and the Importance of Immunohistochemical Staining Protocols.

Purpose: Notable effectiveness of trastuzumab deruxtecan (T-DXd) in patients with HER2-low advanced breast cancer (BC) has focused pathologists' attention. We studied the incidence and clinicopathologic characteristics of HER2-low BC, and the effects of immunohistochemistry (IHC) associated factors on HER2 IHC results. Materials and Methods: The Breast Pathology Study Group of the Korean Society of Pathologists conducted a nationwide study using real-world data on HER2 status generated between January 2022 and December 2022. Information on HER2 IHC protocols at each participating institution was also collected. Results: Total 11,416 patients from twenty-five institutions included in this study. Of these patients, 40.7% (range: 6.0%-76.3%) were classified as HER2-zero, 41.7% (range: 10.5%-69.1%) as HER2-low, and 17.5% (range: 6.7%-34.0%) as HER2-positive. HER2-low tumors were associated with positive ER and PR statuses (p<0.001 and p<0.001, respectively). Antigen retrieval times (≥ 36 min vs. < 36 min) and antibody incubation times (≥ 12 min vs. < 12 min) affected on the frequency of HER2 IHC 1+ BC at institutions using the PATHWAY HER2 (4B5) IHC assay and BenchMark XT or Ultra staining instruments. Furthermore, discordant results between core needle biopsy (CNB) and subsequent resection specimen HER2 statuses were observed in 24.1% (787/3259) of the patients. Conclusion: The overall incidence of HER2-low BC in South Korea concurs with those reported in previously published studies. Significant inter-institutional differences in HER2 IHC protocols were observed, and it may have impact on HER2-low status. Thus, we recommend standardizing HER2 IHC conditions to ensure precise patient selection for targeted therapy.

Direct-write 3D printing of plasmonic nanohelicoids by circularly polarized light.

Chiral plasmonic surfaces with 3D "forests" from nanohelicoids should provide strong optical rotation due to alignment of helical axis with propagation vector of photons. However, such three-dimensional nanostructures also demand multi-step nanofabrication, which is incompatible with many substrates. Large-scale photonic patterns on polymeric and flexible substrates remain unattainable. Here, we demonstrate the substrate-tolerant direct-write printing and patterning of silver nanohelicoids with out-of-plane 3D orientation using circularly polarized light. Centimeter-scale chiral plasmonic surfaces can be produced within minutes using inexpensive medium-power lasers. The growth of nanohelicoids is driven by the symmetry-broken site-selective deposition and self-assembly of the silver nanoparticles (NPs). The ellipticity and wavelength of the incident photons control the local handedness and size of the printed nanohelicoids, which enables on-the-fly modulation of nanohelicoid chirality during direct writing and simple pathways to complex multifunctional metasurfaces. Processing simplicity, high polarization rotation, and fine spatial resolution of the light-driven printing of stand-up helicoids provide a rapid pathway to chiral plasmonic surfaces, accelerating the development of chiral photonics for health and information technologies.

Thickness of melanocytes in giant congenital melanocytic nevus for complete surgical excision: clinicopathological evaluation of 117 lesions according to the area and size.

BACKGROUND: Giant congenital melanocytic nevi (GCMN) are usually defined as nevi that exceed 20 cm in maximal diameter or 15% of the total body surface area. There have been reports of life-long malignant change risks arising from GCMN, leading to surgical excision of GCMN. This study aims to evaluate the thickness of melanocytes based on clinical factors in order to provide objective information for the complete resection of the lesion. METHODS: Overall, 75 patients diagnosed with GCMN between 2000 and 2021 were included, and their clinical records were collected retrospectively. 117 pathologic slides obtained during excision were reviewed to measure nevus thickness. Clinical factors were assessed with a generalized estimated equation model for association with nevus thickness. RESULTS: The thickness of nevus was significantly associated with the location and size. Nevus thickness was more superficial in the distal extremity than in the head and trunk (P = 0.003 [head]; P < 0.001 [trunk]; P = 0.091 [Proximal extremity]). Nevi sized 60 cm or more were significantly deeper than those measuring 20-29.9 cm (P = 0.035). An interaction between size and location existed (P < 0.001). Trunk and distal extremity lesions consistently exhibited uniform thickness regardless of lesion size, whereas head and proximal extremity lesions showed variations in thickness based on lesion size. CONCLUSION: GCMNs have differences in thickness according to location and size. Therefore, it is necessary to devise an approach optimized for each patient to treat GCMN. In the study, it was emphasized that the thickness of GCMN is correlated with clinical factors, specifically the location and size of the nevus. Consequently, these findings underscore the need for individualized treatment plans for effective surgical intervention.

Hybrid Lymphovenous Anastomosis Surgery Guided by Intraoperative Mesenteric Intranodal Lymphangiography for Refractory Nontraumatic Chylous Ascites: A Case Report.

Refractory chylous ascites can cause significant nutritional and immunologic morbidity, but no clear treatment has been established. This article introduces a case of a 22-year-old female patient with an underlying lymphatic anomaly who presented with refractory chylous ascites after laparoscopic adnexectomy for ovarian teratoma which aggravated after thoracic duct embolization. Ascites (>3,000 mL/d) had to be drained via a percutaneous catheter to relieve abdominal distention and consequent dyspnea, leading to significant cachexia and weight loss. Two sessions of hybrid lymphovenous anastomosis (LVA) surgery with intraoperative mesenteric lymphangiography guidance were performed to decompress the lymphatics. The first LVA was done between inferior mesenteric vein and left para-aortic enlarged lymphatics in a side-to-side manner. The daily drainage of chylous ascites significantly decreased to 130 mL/day immediately following surgery but increased 6 days later. An additional LVA was performed between right ovarian vein and enlarged lymphatics in aortocaval area in side-to-side and end-to-side manner. The chylous ascites resolved subsequently without any complications, and the patient was discharged after 2 weeks. The patient regained weight without ascites recurrence after 22 months of follow-up. This case shares a successful experience of treating refractory chylous ascites with lymphatic anomaly through LVA, reversing the patient's life-threatening weight loss. LVA was applied with a multidisciplinary approach using intraoperative mesenteric lipiodol, and results showed the possibility of expanding its use to challenging problems in the intraperitoneal cavity.

Clinical Workflow of Cone Beam Computer Tomography-Based Daily Online Adaptive Radiotherapy with Offline Magnetic Resonance Guidance: The Modular Adaptive Radiotherapy System (MARS).

PURPOSE: The Ethos (Varian Medical Systems) radiotherapy device combines semi-automated anatomy detection and plan generation for cone beam computer tomography (CBCT)-based daily online adaptive radiotherapy (oART). However, CBCT offers less soft tissue contrast than magnetic resonance imaging (MRI). This work aims to present the clinical workflow of CBCT-based oART with shuttle-based offline MR guidance. METHODS: From February to November 2023, 31 patients underwent radiotherapy on the Ethos (Varian, Palo Alto, CA, USA) system with machine learning (ML)-supported daily oART. Moreover, patients received weekly MRI in treatment position, which was utilized for daily plan adaptation, via a shuttle-based system. Initial and adapted treatment plans were generated using the Ethos treatment planning system. Patient clinical data, fractional session times (MRI + shuttle transport + positioning, adaptation, QA, RT delivery) and plan selection were assessed for all fractions in all patients. RESULTS: In total, 737 oART fractions were applied and 118 MRIs for offline MR guidance were acquired. Primary sites of tumors were prostate (n = 16), lung (n = 7), cervix (n = 5), bladder (n = 1) and endometrium (n = 2). The treatment was completed in all patients. The median MRI acquisition time including shuttle transport and positioning to initiation of the Ethos adaptive session was 53.6 min (IQR 46.5-63.4). The median total treatment time without MRI was 30.7 min (IQR 24.7-39.2). Separately, median adaptation, plan QA and RT times were 24.3 min (IQR 18.6-32.2), 0.4 min (IQR 0.3-1,0) and 5.3 min (IQR 4.5-6.7), respectively. The adapted plan was chosen over the scheduled plan in 97.7% of cases. CONCLUSION: This study describes the first workflow to date of a CBCT-based oART combined with a shuttle-based offline approach for MR guidance. The oART duration times reported resemble the range shown by previous publications for first clinical experiences with the Ethos system.

Targeted deletion of CD244 on monocytes promotes differentiation into anti-tumorigenic macrophages and potentiates PD-L1 blockade in melanoma.

BACKGROUND: In the myeloid compartment of the tumor microenvironment, CD244 signaling has been implicated in immunosuppressive phenotype of monocytes. However, the precise molecular mechanism and contribution of CD244 to tumor immunity in monocytes/macrophages remains elusive due to the co-existing lymphoid cells expressing CD244. METHODS: To directly assess the role of CD244 in tumor-associated macrophages, monocyte-lineage-specific CD244-deficient mice were generated using cre-lox recombination and challenged with B16F10 melanoma. The phenotype and function of tumor-infiltrating macrophages along with antigen-specific CD8 T cells were analyzed by flow cytometry and single cell RNA sequencing data analysis, and the molecular mechanism underlying anti-tumorigenic macrophage differentiation, antigen presentation, phagocytosis was investigated ex vivo. Finally, the clinical feasibility of CD244-negative monocytes as a therapeutic modality in melanoma was confirmed by adoptive transfer experiments. RESULTS: CD244fl/flLysMcre mice demonstrated a significant reduction in tumor volume (61% relative to that of the CD244fl/fl control group) 14 days after tumor implantation. Within tumor mass, CD244fl/flLysMcre mice also showed higher percentages of Ly6Clow macrophages, along with elevated gp100+IFN-γ+ CD8 T cells. Flow cytometry and RNA sequencing data demonstrated that ER stress resulted in increased CD244 expression on monocytes. This, in turn, impeded the generation of anti-tumorigenic Ly6Clow macrophages, phagocytosis and MHC-I antigen presentation by suppressing autophagy pathways. Combining anti-PD-L1 antibody with CD244-/- bone marrow-derived macrophages markedly improved tumor rejection compared to the anti-PD-L1 antibody alone or in combination with wild-type macrophages. Consistent with the murine data, transcriptome analysis of human melanoma tissue single-cell RNA-sequencing dataset revealed close association between CD244 and the inhibition of macrophage maturation and function. Furthermore, the presence of CD244-negative monocytes/macrophages significantly increased patient survival in primary and metastatic tumors. CONCLUSION: Our study highlights the novel role of CD244 on monocytes/macrophages in restraining anti-tumorigenic macrophage generation and tumor antigen-specific T cell response in melanoma. Importantly, our findings suggest that CD244-deficient macrophages could potentially be used as a therapeutic agent in combination with immune checkpoint inhibitors. Furthermore, CD244 expression in monocyte-lineage cells serve as a prognostic marker in cancer patients.