The BTLA-HVEM axis restricts CAR T cell efficacy in cancer.

The efficacy of T cell-based immunotherapies is limited by immunosuppressive pressures in the tumor microenvironment. Here we show a predominant role for the interaction between BTLA on effector T cells and HVEM (TNFRSF14) on immunosuppressive tumor microenvironment cells, namely regulatory T cells. High BTLA expression in chimeric antigen receptor (CAR) T cells correlated with poor clinical response to treatment. Therefore, we deleted BTLA in CAR T cells and show improved tumor control and persistence in models of lymphoma and solid malignancies. Mechanistically, BTLA inhibits CAR T cells via recruitment of tyrosine phosphatases SHP-1 and SHP-2, upon trans engagement with HVEM. BTLA knockout thus promotes CAR signaling and subsequently enhances effector function. Overall, these data indicate that the BTLA-HVEM axis is a crucial immune checkpoint in CAR T cell immunotherapy and warrants the use of strategies to overcome this barrier.

Belantamab Mafodotin, Pomalidomide, and Dexamethasone in Multiple Myeloma.

BACKGROUND: Triplet or quadruplet therapies incorporating proteasome inhibitors, immunomodulators, and anti-CD38 antibodies have led to prolonged survival among patients with newly diagnosed multiple myeloma; however, most patients have a relapse. Frontline lenalidomide therapy has increased the number of patients with lenalidomide-refractory disease at the time of the first relapse. METHODS: In this phase 3, randomized, open-label trial, we evaluated belantamab mafodotin, pomalidomide, and dexamethasone (BPd), as compared with pomalidomide, bortezomib, and dexamethasone (PVd), in lenalidomide-exposed patients who had relapsed or refractory myeloma after at least one line of therapy. The primary end point was progression-free survival. Disease response and safety were also assessed. RESULTS: A total of 302 patients underwent randomization; 155 were assigned to the BPd group, and 147 to the PVd group. At a median follow-up of 21.8 months (range, <0.1 to 39.2), the 12-month estimated progression-free survival with BPd was 71% (95% confidence interval [CI], 63 to 78), as compared with 51% (95% CI, 42 to 60) with PVd (hazard ratio for disease progression or death, 0.52; 95% CI, 0.37 to 0.73; P<0.001). Data on overall survival were immature. The percentage of patients with a response to treatment (partial response or better) was 77% (95% CI, 70 to 84) in the BPd group and 72% (95% CI, 64 to 79) in the PVd group; 40% (95% CI, 32 to 48) and 16% (95% CI, 11 to 23), respectively, had a complete response or better. Grade 3 or higher adverse events occurred in 94% of the patients in the BPd group and 76% of those in the PVd group. Ocular events occurred in 89% of the patients who received BPd (grade 3 or 4 in 43%) and 30% of those who received PVd (grade 3 or 4 in 2%); ocular events in the BPd group were managed with belantamab mafodotin dose modification. Ocular events led to treatment discontinuation in 9% of the patients in the BPd group and in no patients in the PVd group. CONCLUSIONS: Among lenalidomide-exposed patients with relapsed or refractory myeloma, BPd conferred a significantly greater benefit than PVd with respect to progression-free survival, as well as deeper, more durable responses. Ocular events were common but were controllable by belantamab mafodotin dose modification. (Funded by GSK; DREAMM-8 ClinicalTrials.gov number, NCT04484623; EudraCT number, 2018-004354-21.).

Belantamab Mafodotin, Bortezomib, and Dexamethasone for Multiple Myeloma.

BACKGROUND: Belantamab mafodotin had single-agent activity in patients with relapsed or refractory multiple myeloma, a finding that supports further evaluation of the agent in combination with standard-care therapies. METHODS: In this phase 3, open-label, randomized trial, we evaluated belantamab mafodotin, bortezomib, and dexamethasone (BVd), as compared with daratumumab, bortezomib, and dexamethasone (DVd), in patients who had progression of multiple myeloma after at least one line of therapy. The primary end point was progression-free survival. Key secondary end points were overall survival, response duration, and minimal residual disease (MRD)-negative status. RESULTS: In total, 494 patients were randomly assigned to receive BVd (243 patients) or DVd (251 patients). At a median follow-up of 28.2 months (range, 0.1 to 40.0), median progression-free survival was 36.6 months (95% confidence interval [CI], 28.4 to not reached) in the BVd group and 13.4 months (95% CI, 11.1 to 17.5) in the DVd group (hazard ratio for disease progression or death, 0.41; 95% CI, 0.31 to 0.53; P<0.001). Overall survival at 18 months was 84% in the BVd group and 73% in the DVd group. An analysis of the restricted mean response duration favored BVd over DVd (P<0.001). A complete response or better plus MRD-negative status occurred in 25% of the patients in the BVd group and 10% of those in the DVd group. Grade 3 or higher adverse events occurred in 95% of the patients in the BVd group and 78% of those in the DVd group. Ocular events were more common in the BVd group than in the DVd group (79% vs. 29%); such events were managed with dose modifications, and events of worsening visual acuity mostly resolved. CONCLUSIONS: As compared with DVd therapy, BVd therapy conferred a significant benefit with respect to progression-free survival among patients who had relapsed or refractory multiple myeloma after at least one line of therapy. Most patients had grade 3 or higher adverse events. (Funded by GSK; DREAMM-7 ClinicalTrials.gov number, NCT04246047; EudraCT number, 2018-003993-29.).

Mezigdomide plus Dexamethasone in Relapsed and Refractory Multiple Myeloma.

BACKGROUND: Despite recent progress, multiple myeloma remains incurable. Mezigdomide is a novel cereblon E3 ubiquitin ligase modulator with potent antiproliferative and tumoricidal activity in preclinical models of multiple myeloma, including those resistant to lenalidomide and pomalidomide. METHODS: In this phase 1-2 study, we administered oral mezigdomide in combination with dexamethasone to patients with relapsed and refractory myeloma. The primary objectives of phase 1 (dose-escalation cohort) were to assess safety and pharmacokinetics and to identify the dose and schedule for phase 2. In phase 2 (dose-expansion cohort), objectives included the assessment of the overall response (partial response or better), safety, and efficacy of mezigdomide plus dexamethasone at the dose and schedule determined in phase 1. RESULTS: In phase 1, a total of 77 patients were enrolled in the study. The most common dose-limiting toxic effects were neutropenia and febrile neutropenia. On the basis of the phase 1 findings, investigators determined the recommended phase 2 dose of mezigdomide to be 1.0 mg, given once daily in combination with dexamethasone for 21 days, followed by 7 days off, in each 28-day cycle. In phase 2, a total of 101 patients received the dose identified in phase 1 in the same schedule. All patients in the dose-expansion cohort had triple-class-refractory multiple myeloma, 30 patients (30%) had received previous anti-B-cell maturation antigen (anti-BCMA) therapy, and 40 (40%) had plasmacytomas. The most common adverse events, almost all of which proved to be reversible, included neutropenia (in 77% of the patients) and infection (in 65%; grade 3, 29%; grade 4, 6%). No unexpected toxic effects were encountered. An overall response occurred in 41% of the patients (95% confidence interval [CI], 31 to 51), the median duration of response was 7.6 months (95% CI, 5.4 to 9.5; data not mature), and the median progression-free survival was 4.4 months (95% CI, 3.0 to 5.5), with a median follow-up of 7.5 months (range, 0.5 to 21.9). CONCLUSIONS: The all-oral combination of mezigdomide plus dexamethasone showed promising efficacy in patients with heavily pretreated multiple myeloma, with treatment-related adverse events consisting mainly of myelotoxic effects. (Funded by Celgene, a Bristol-Myers Squibb Company; CC-92480-MM-001 ClinicalTrials.gov number, NCT03374085; EudraCT number, 2017-001236-19.).

SERS-based microdevices for use as in vitro diagnostic biosensors.

Advances in surface-enhanced Raman scattering (SERS) detection have helped to overcome the limitations of traditional in vitro diagnostic methods, such as fluorescence and chemiluminescence, owing to its high sensitivity and multiplex detection capability. However, for the implementation of SERS detection technology in disease diagnosis, a SERS-based assay platform capable of analyzing clinical samples is essential. Moreover, infectious diseases like COVID-19 require the development of point-of-care (POC) diagnostic technologies that can rapidly and accurately determine infection status. As an effective assay platform, SERS-based bioassays utilize SERS nanotags labeled with protein or DNA receptors on Au or Ag nanoparticles, serving as highly sensitive optical probes. Additionally, a microdevice is necessary as an interface between the target biomolecules and SERS nanotags. This review aims to introduce various microdevices developed for SERS detection, available for POC diagnostics, including LFA strips, microfluidic chips, and microarray chips. Furthermore, the article presents research findings reported in the last 20 years for the SERS-based bioassay of various diseases, such as cancer, cardiovascular diseases, and infectious diseases. Finally, the prospects of SERS bioassays are discussed concerning the integration of SERS-based microdevices and portable Raman readers into POC systems, along with the utilization of artificial intelligence technology.

Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis.

BACKGROUND: Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+ plasma cells. Daratumumab, a human CD38-targeting antibody, may improve outcomes for this disease. METHODS: We randomly assigned patients with newly diagnosed AL amyloidosis to receive six cycles of bortezomib, cyclophosphamide, and dexamethasone either alone (control group) or with subcutaneous daratumumab followed by single-agent daratumumab every 4 weeks for up to 24 cycles (daratumumab group). The primary end point was a hematologic complete response. RESULTS: A total of 388 patients underwent randomization. The median follow-up was 11.4 months. The percentage of patients who had a hematologic complete response was significantly higher in the daratumumab group than in the control group (53.3% vs. 18.1%) (relative risk ratio, 2.9; 95% confidence interval [CI], 2.1 to 4.1; P<0.001). Survival free from major organ deterioration or hematologic progression favored the daratumumab group (hazard ratio for major organ deterioration, hematologic progression, or death, 0.58; 95% CI, 0.36 to 0.93; P = 0.02). At 6 months, more cardiac and renal responses occurred in the daratumumab group than in the control group (41.5% vs. 22.2% and 53.0% vs. 23.9%, respectively). The four most common grade 3 or 4 adverse events were lymphopenia (13.0% in the daratumumab group and 10.1% in the control group), pneumonia (7.8% and 4.3%, respectively), cardiac failure (6.2% and 4.8%), and diarrhea (5.7% and 3.7%). Systemic administration-related reactions to daratumumab occurred in 7.3% of the patients. A total of 56 patients died (27 in the daratumumab group and 29 in the control group), most due to amyloidosis-related cardiomyopathy. CONCLUSIONS: Among patients with newly diagnosed AL amyloidosis, the addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone was associated with higher frequencies of hematologic complete response and survival free from major organ deterioration or hematologic progression. (Funded by Janssen Research and Development; ANDROMEDA ClinicalTrials.gov number, NCT03201965.).

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.

Amphiregulin normalizes altered circuit connectivity for social dominance of the CRTC3 knockout mouse.

Social hierarchy has a profound impact on social behavior, reward processing, and mental health. Moreover, lower social rank can lead to chronic stress and often more serious problems such as bullying victims of abuse, suicide, or attack to society. However, its underlying mechanisms, particularly their association with glial factors, are largely unknown. In this study, we report that astrocyte-derived amphiregulin plays a critical role in the determination of hierarchical ranks. We found that astrocytes-secreted amphiregulin is directly regulated by cAMP response element-binding (CREB)-regulated transcription coactivator 3 (CRTC3) and CREB. Mice with systemic and astrocyte-specific CRTC3 deficiency exhibited a lower social rank with reduced functional connectivity between the prefrontal cortex, a major social hierarchy center, and the parietal cortex. However, this effect was reversed by astrocyte-specific induction of amphiregulin expression, and the epidermal growth factor domain was critical for this action of amphiregulin. These results provide evidence of the involvement of novel glial factors in the regulation of social dominance and may shed light on the clinical application of amphiregulin in the treatment of various psychiatric disorders.

Real-world outcome of patients with extensively pretreated multiple myeloma who were treated with selinexor and dexamethasone: a Korean multicenter retrospective analysis.

The outcomes of patients with myeloma after exposed to penta-classes are extremely poor. Selinexor is the first approved exportin inhibitor for those patients, but intractable toxicities may limit its use. This retrospective study evaluated the real-world efficacy and safety of selinexor plus dexamethasone (XD) and involved 48 patients with multiple myeloma, who were treated from November 2020 to October 2022. Their median age was 64 years, and the median number of prior lines of therapy was 6. The overall response rate was 25%, and the median progression-free survival (PFS) was 2.1 months (95% confidence interval (CI), 1.7-2.5). Patients on a reduced initial dose, delayed treatment, and dose reduction had better PFS. After XD treatment failure, 17 patients received subsequent therapy and had a median PFS of 2.4 months. The median overall survival was 4.6 months (95% CI, 2.3-6.9). Among the patients, 12 (25%) and 17 (35%) experienced dose reduction and delayed treatment, respectively. Our data show that the real-world efficacy of XD treatment in heavily pretreated patients was modest and that improving treatment adherence through reducing initial doses or delaying treatments may improve patient outcomes.

The establishment of a multiple myeloma clinical registry in the Asia-Pacific region: The Asia-Pacific Myeloma and Related Diseases Registry (APAC MRDR).

BACKGROUND: Multiple myeloma (MM) is the second most common haematological cancer worldwide. Along with related diseases including monoclonal gammopathy of undetermined significance (MGUS), plasma cell leukaemia (PCL) and plasmacytoma, MM incidence is rising, yet it remains incurable and represents a significant disease burden. Clinical registries can provide important information on management and outcomes, and are vital platforms for clinical trials and other research. The Asia-Pacific Myeloma and Related Diseases Registry (APAC MRDR) was developed to monitor and explore variation in epidemiology, treatment regimens and their impact on clinical outcomes across this region. Here we describe the registry's design and development, initial data, progress and future plans. METHODS: The APAC MRDR was established in 2018 as a multicentre collaboration across the Asia-Pacific, collecting prospective data on patients newly diagnosed with MM, MGUS, PCL and plasmacytoma in Korea, Singapore, Malaysia and Taiwan, with China recently joining. Development of the registry required a multidisciplinary team of clinicians, researchers, legal and information technology support, and financial resources, as well as local clinical context from key opinion leaders in the APAC region. Written informed consent is obtained and data are routinely collected throughout treatment by hospital staff. Data are stored securely, meeting all local privacy and ethics requirements. Data were collected from October 2018 to March 2024. RESULTS: Over 1700 patients from 24 hospitals have been enrolled onto the APAC MRDR to date, with the majority (86%) being newly diagnosed with MM. Bortezomib with an immunomodulatory drug was most frequently used in first-line MM therapy, and lenalidomide-based therapy was most common in second-line. Establishment and implementation challenges include regulatory and a range of operational issues. CONCLUSION: The APAC MRDR is providing 'real-world' data to participating sites, clinicians and policy-makers to explore factors influencing outcomes and survival, and to support high quality studies. It is already a valuable resource that will continue to grow and support research and clinical collaboration in MM and related diseases across the APAC region.

QuantiFERON monitor predicts early cytomegalovirus infection and viral burden in allogeneic hematopoietic stem cell transplantation.

INTRODUCTION: Cytomegalovirus (CMV) infection is a major cause of transplantation-related morbidity and mortality. This study assessed the utility of the QuantiFERON monitor (QFM; Qiagen) for the prediction of early CMV infection and viral burden. METHODS: QuantiFERON-CMV (QF-CMV; Qiagen) and QFM were measured at the post-allogeneic hematopoietic stem cell transplantation (HSCT) week 4. CMV DNA was measured at every visit until post-HSCT week 24. The QFM cutoff specific to CMV infection was established. RESULT: At the post-HSCT week 4, the QFM cutoff predicting CMV infection was 86.95 IU/mL. While QF-CMV results at the post-HSCT week 4 were associated with high-level CMV infection (CMV DNA ≥ 5,000 IU/mL) but not with CMV infection (CMV DNA ≥ 500 IU/mL), QFM was associated with both CMV infection and high-level CMV infection. Both indeterminate QF-CMV and nonreactive QFM were associated with increased peak CMV DNA. CONCLUSION: Low QFM is a risk factor for CMV infection and increased CMV viral loads. QFM at post-HSCT week 4 can be utilized as an assay to predict the risk and burden of early CMV infection in HSCT recipients, in conjunction with other risk factors.

The selection of a nitrogen precursor for the construction of N-doped titanium dioxide with enhanced photocatalytic activity for the removal of gaseous toluene.

The preparation of nitrogen-doped TiO2 (i.e., N-TiO2) catalysts is a highly effective option to improve the photocatalytic activity of TiO2. Nonetheless, relatively little is known about the effects of dopant precursors selected for their preparation with regard to the photocatalytic efficacy. In this study, three types of dopants are selected and used as N sources (urea (U), melamine (M), and aqueous ammonia (A)) for N-TiO2 samples with the name codes of NTU, NTM, and NTA, respectively. The photocatalytic efficacy of these N-TiO2 samples is examined against toluene in a packed bed flow reactor. Under optimal conditions (e.g., relative humidity (RH) = 20% and gas hourly space velocity (GHSV) = 1698 h-1), the superiority of NTA is evident over others with a quantum efficiency (QE) of 7.03 × 10-4 molecules photon-1, a space time yield (STY) of 1.38 × 10-4 molecules photon-1 mg-1, and a specific clean air delivery rate (SCADR) of 1148.8 L g-1 h-1. The analysis based on in-situ diffuse reflectance infrared Fourier transform spectroscopy and gas chromatography-mass spectrometry confirms the formation of several intermediates such as benzyl alcohol, benzaldehyde, benzoic acid, and alkane species through ring opening reactions. In addition, the prepared NTA photocatalyst exhibits the highest toluene photocatalytic degradation efficiency among all TiO2-based catalysts surveyed to date. Overall, this study offers as a valuable guideline for the development of advanced TiO2 catalytic systems (such as N-TiO2) for the treatment of aromatic hydrocarbons in indoor air.

Short-term storability of volatile organic compounds in bag sampling systems under ambient conditions.

Although bag sampling is a common quantification tool for volatile organic compounds (VOCs), it can serve as a major source of experimental bias, when storing even over a short duration (<24 h). To learn more about the reliability of the bag sampling method, the temporal stability of 27 VOCs (classified into five groups (i.e., aldehydes, nonpolar aromatic hydrocarbons, aliphatic carboxylic acids, phenol and methylphenols, and miscellaneous odorants) is assessed using poly-ester aluminum (PEA) bags at five intervals over a day (0.17, 1, 2, 6, and 24 h). In terms of reproducibility (e.g., relative standard error [RSEt, %]), nonpolar aromatic hydrocarbons (BTXS) exhibit the highest consistency (e.g., average RSE <1.55%). Considerable loss of VOCs is observed in the preparation of gaseous standards from a liquid phase standard when assessed by gas/liquid (G/L) ratio. Further, VOCs with lower molecular weights (e.g., propionaldehyde: 77%-94.4%) and branched molecular structures (e.g., isovaleraldehyde: 67.2%-78.9%) tend to have high G/L ratio (e.g., relative to valeraldehyde: 55.1%-66%). The overall relative recovery (RR; %) values of VOCs indicate an exponential decrease over 24 h. BTXS maintain fairly good RR values (above 94.3% at all intervals), possibly due to the nonpolar structure with uniform distribution of π electrons. In contrast, indole and skatole show the least preservation after 24 h (e.g., RR4 values of 10.9% and 24.6%, respectively) due to their highly reactive characteristics. The storability of VOCs appears to be affected by a number of variables (e.g., molecular weight, presence of ethyl branch, and time: e.g., R2 > 0.9). The results of this study offer valuable guidelines for the accurate quantification of VOC levels in air.

Low-temperature thermocatalytic removal of formaldehyde in air using copper manganite spinels.

The removal of formaldehyde (FA) is vital for indoor air quality management in light of its carcinogenic propensity and adverse environmental impact. A series of copper manganite spinel structures (e.g., CuMn2O4) are prepared using the sol-gel combustion method and treated with reduction or oxidation pretreatment at 300 °C condition. Accordingly, CuMn2O4-O ("O" suffix for oxidation pre-treatment in air) is identified as the best performer to achieve 100% conversion (XFA) of FA (50 ppm) at 90 °C; its performance, if assessed in terms of reaction kinetic rate (r) at XFA = 10%, is 5.02E-03 mmol g-1 h-1. The FA removal performance increases systematically with decreases in flow rate, FA concentration, and relative humidity (RH) or with increases in bed mass. The reaction pathways and intermediates of FA catalytic oxidation on CuMn2O4-A are studied with density functional theory simulations, temperature-programmed characterization experiments, and in-situ diffuse reflectance infrared Fourier transform spectroscopy. The synergistic combination of large quantities of adsorbed oxygen (OA) species and oxidized metal species (e.g., Cu2+) contribute to the enhanced catalytic performance of CuMn2O4-O to oxidize FA into CO2 with the reaction intermediates of H2CO2 (DOM), HCOO-, and CO. The present study is expected to provide valuable insights into the thermocatalytic oxidation of FA over spinel CuMn2O4 materials and their catalytic performances in relation to the key process variables.

Reduced and modified graphene oxide with Ag/V2O5 as a ternary composite visible light photocatalyst against dyes and pesticides.

Water pollution by dyes and pesticides poses significant threats to our ecosystem. In this research, a visible-light ternary composite photocatalytic system was fabricated using graphene oxide (GO) by reducing with N2H4, modifying with KOH, and decorating with Ag/V2O5. The fabricated photocatalysts were characterized through FTIR, SEM, XRD, BET, PL, EDX, ESR, UV-vis spectroscopy, TGA, ESI-MS, and Raman spectroscopy. The point zero charge of the reduced and modified GO (RMGO/Ag/V2O5) was measured to be 6.7 by the pH drift method. This ternary composite was able to achieve complete removal of methyl orange (MO) and chlorpyrifos (CP) in solutions in 80 min under the optimum operation conditions (e.g., in terms of pollutant/catalyst concentrations, pH effects, and contact time). The role of active species responsible for photocatalytic activity was confirmed by scavenger analysis and ESR investigations. The potential mechanism for photocatalytic activity was studied through a fragmentation process carried out by MS analysis. Through nonlinear fitting of the experimental data, MO and CP exhibited the best fit results with the pseudo 1st-order kinetics (quantum yields of 1.07 × 10-3 and 2.16 × 10-3 molecules photon-1 and space-time yields of 1.53 × 10-5 and 2.7 × 10-5 molecules photon-1 mg-1, respectively). The structure of the nanomaterials remained mostly intact to support increased stability and reusability of the prepared photocatalysts even after 10 successive regeneration cycles.

CX3CR1+ Macrophage Facilitates the Resolution of Allergic Lung Inflammation via Interacting CCL26.

Rationale: The resolution of inflammation is an active process coordinated by mediators and immune cells to restore tissue homeostasis. However, the mechanisms for resolving eosinophilic allergic lung inflammation triggered by inhaled allergens have not been fully elucidated. Objectives: Our objectives were to investigate the cellular mechanism of tissue-resident macrophages involved in the resolution process of eosinophilic lung inflammation. Methods: For the study, we used the institutional review board-approved protocol for human subsegmental bronchoprovocation with allergen, mouse models for allergic lung inflammation, and novel transgenic mice, including a conditional CCL26 knockout. The samples were analyzed using mass cytometry, single-cell RNA sequencing, and biophysical and immunological analyses. Measurements and Main Results: We compared alveolar macrophage (AM) subsets in the BAL before and after allergen provocation. In response to provocation with inhaled allergens, the subsets of AMs are dynamically changed in humans and mice. In the steady state, the AM subset expressing CX3CR1 is a relatively small fraction in bronchoalveolar space and lung tissue but drastically increases after allergen challenges. This subset presents unique patterns of gene expression compared with classical AMs, expressing high C1q family genes. CX3CR1+ macrophages are activated by airway epithelial cell-derived CCL26 via a receptor-ligand interaction. The binding of CCL26 to the CX3CR1+ receptor induces CX3CR1+ macrophages to secrete C1q, subsequently facilitating the clearance of eosinophils. Furthermore, the depletion of CX3CR1 macrophages or CCL26 in airway epithelial cells delays the resolution of allergic lung inflammation displaying prolonged tissue eosinophilia. Conclusions: These findings indicate that the CCL26-CX3CR1 pathway is pivotal in resolving eosinophilic allergic lung inflammation.

Cardiovascular disease risk and associated physical activity factors in gastrointestinal cancer survivors.

INTRODUCTION: Although the risk of CVD is increased in cancer survivors, few studies have investigated the CVD risk in survivors of gastrointestinal (GI) cancer. Therefore, we evaluated the CVD risk using the 10-year atherosclerotic cardiovascular disease (ASCVD) risk score for GI cancer survivors and associated physical activity factors. METHODS: Using the 2014-2019 Korean National Health and Nutrition Examination Surveys, data were collected for 262 GI cancer survivors and 1,310 cancer-free controls matched at a 1:5 ratio based on age and sex. The International Physical Activity Questionnaire Short-Form was used to assess physical activity, and the Euro QoL Questionnaire 5-Dimensional Classification (EQ-5D) was used to assess the health-related quality of life. RESULTS: A multiple logistic regression analysis demonstrated a lower risk of ASCVD in GI cancer survivors than in controls (adjusted odds ratio [aOR] = 0.73, 95% confidence interval [CI] = 0.55-0.97). Moreover, the risk of having a high ASCVD score was significantly lower in individuals who performed sufficient aerobic physical activity (aOR = 0.59, 95% CI = 0.47-0.75) and those with an EQ-5D score 1 or 2 (aOR = 0.36, 95% CI = 0.20-0.65 and aOR = 0.31, 95% CI = 0.16-0.58, respectively). CONCLUSIONS: This population-based study demonstrated that engaging in sufficient physical activity can reduce the ASCVD risk among GI cancer survivors.

A Multicenter Analysis of Clinical Features and Long-Term Outcomes of POEMS Syndrome in Korea.

BACKGROUND: POEMS syndrome is a rare form of plasma cell dyscrasia characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal proteins, and skin changes. Owing to its low incidence, there are few reports regarding this syndrome. This multicenter study included 84 patients diagnosed with POEMS syndrome in South Korea. METHODS: We retrospectively evaluated 84 patients diagnosed with POEMS syndrome at 8 hospitals in South Korea between January 2000 and October 2022. The clinical characteristics and treatment outcomes were analyzed. RESULTS: The median patient age was 53 years (range, 26-77 years), and 63.1% of the patients were male. All patients had peripheral neuropathy, and 81 (96.4%) had monoclonal plasma cell proliferation. Plasma vascular endothelial growth factor levels were available for 32 patients with a median of 821 pg/mL (range, 26-12,900 pg/mL). Other common features included skin changes (54.2%), volume overload (71.4%), and organomegaly (72.6%). Of the 84 patients, 75 received initial treatment (local radiotherapy, 6 [8.0%]; chemotherapy, 17 [22.7%]; both chemotherapy and local radiotherapy, 9 [12.0%]), upfront autologous stem cell transplantation (ASCT), 43 (57.3%; with induction chemotherapy, n = 12, 16.0%; without induction chemotherapy, n = 31, 41.3%). The median follow-up duration was 40.7 months. The 5-year overall survival (OS) was 78%, and the 5-year progression-free survival (PFS) was 55%. Patients who underwent upfront ASCT and were diagnosed after 2014 had a longer OS and PFS. CONCLUSION: The demographics of Korean patients with POEMS syndrome were similar to those reported previously. Because of the introduction of new treatment agents and the reduced rate of transplant-related mortality related to ASCT, the treatment outcomes of Korean patients with POEMS syndrome have improved in recent years.

Development of a FRET aptasensor based on MoS2-doped Zn-MOF as luminophore for selective detection of cadmium in aqueous solutions.

A robust "on-off" fluorescent aptasensor was developed using nanohybrids of molybdenum sulfide (MoS2) quantum dot (QD)-doped zinc metal-organic frameworks (Zn-MOF) for selective and sensitive detection of cadmium ions (Cd2+) in water. This nanohybrid (MoS2@Zn-MOF), synthesized via "bottle around the ship" methodology, exhibited a high-intensity fluorescence emission centered at 430 nm (λEm) (blue) on excitation at 320 nm (λEx). Further, the conjugation of this fluorophore to phosphate-modified cadmium aptamer (Cd-2-2) was achieved through carbodiimide reaction. The hybridization of prepared sensing probe (MoS2@Zn-MOF/Cd-2-2 aptamer) was done with dabcyl-conjugated complementary DNA (cDNA), acting as energy donor-acceptor pair in the fluorescence resonance energy transfer (FRET) system. This hybridization causes the fluorescence quenching of the nanohybrid. In the presence of Cd2+, the aptamer from the fabricated nano-biosensing probe binds to these ions, resulting in release of dabcyl-cDNA oligomer. This release of dabcyl-cDNA oligomer from the sensing probes restores the fluorescence of the nanohybrid. Under optimized conditions (sensing probe/dabcyl-cDNA ratio 1/7, pH 7.4, and temp 28 °C), the sensing probe showed a fast response time of 1 min. The fluorescence intensity of the nanohybrid can be utilized to determine the concentration of Cd2+. The proposed aptasensor achieved highly sensitive detection of Cd2+ with a limit of detection (LOD) of 0.24 ppb over the range of 1 × 10-9 to 1 × 10-4 M along with minimal effects of interferences (e.g., Hg2+, Pb2+, and Zn2+) and good reproducibility. The designed aptasensor based on MoS2@Zn-MOF nanofluorophore offers a highly sensitive and selective approach for rapid screening of metal ions in aqueous environments.

Complement C1q essential for aeroallergen sensitization via CSF1R+ conventional dendritic cells type 2.

BACKGROUND: Dendritic cells (DCs) are heterogeneous, comprising multiple subsets with unique functional specifications. Our previous work has demonstrated that the specific conventional type 2 DC subset, CSF1R+cDC2s, plays a critical role in sensing aeroallergens. OBJECTIVE: It remains to be understood how CSF1R+cDC2s recognize inhaled allergens. We sought to elucidate the transcriptomic programs and receptor-ligand interactions essential for function of this subset in allergen sensitization. METHODS: We applied single-cell RNA sequencing to mouse lung DCs. Conventional DC-selective knockout mouse models were employed, and mice were subjected to inhaled allergen sensitization with multiple readouts of asthma pathology. Under the clinical arm of this work, human lung transcriptomic data were integrated with mouse data, and bronchoalveolar lavage (BAL) specimens were collected from subjects undergoing allergen provocation, with samples assayed for C1q. RESULTS: We found that C1q is selectively enriched in lung CSF1R+cDC2s, but not in other lung cDC2 or cDC1 subsets. Depletion of C1q in conventional DCs significantly attenuates allergen sensing and features of asthma. Additionally, we found that C1q binds directly to human dust mite allergen, and the C1q receptor CD91 (LRP1) is required for lung CSF1R+cDC2s to recognize the C1q-allergen complex and induce allergic lung inflammation. Lastly, C1q is enriched in human BAL samples following subsegmental allergen challenge, and human RNA sequencing data demonstrate close homology between lung IGSF21+DCs and mouse CSF1R+cDC2s. CONCLUSIONS: C1q is secreted from the CSF1R+cDC2 subset among conventional DCs. Our data indicate that the C1q-LRP1 axis represents a candidate for translational therapeutics in the prevention and suppression of allergic lung inflammation.