Spatially resolved whole-transcriptomic and proteomic profiling of lung cancer and its immune-microenvironment according to PD-L1 expression.

The expression of PD-L1 on tumor cells (TCs) is used as an immunotherapy biomarker in lung cancer, but heterogeneous intratumoral expression is often observed. Using a Digital Spatial Profiling, we performed proteomic and whole-transcriptomic analyses of TCs and immune cells (ICs) in spatially matched areas based on tumor PD-L1 expression and the status of the immune microenvironment. Our findings were validated using immunohistochemistry, The Cancer Genome Atlas, and immunotherapy cohorts. ICs in areas with high PD-L1 expression on TCs showed more features indicative of immunosuppression and exhaustion than ICs in areas with low PD-L1 expression on TCs. TCs highly expressing PD-L1 within immune-inflamed (IF) areas show up-regulation of pro-inflammatory processes, whereas TCs highly expressing PD-L1 within immune-deficient (ID) areas show up-regulation of various metabolic processes. Using differentially expressed genes of TCs between the IF and ID areas, we identified a novel prognostic gene signature for lung cancer. In addition, a high ratio of CD8+ cells to M2 macrophages was found to predict favorable outcomes in patients with PD-L1-expressing lung cancer after immune checkpoint inhibitor therapy. This study demonstrates that TCs and ICs have distinct spatial features within the tumor microenvironment that are related to tumor PD-L1 expression and IC infiltration.

Effectiveness of Alternative Nostril Breathing on Blood Pressure: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: Hypertension, a significant risk factor for cardiovascular disease, has a high prevalence rate globally. While drug use is the most common approach, lifestyle improvements are crucial. Recently, there has been a notable upsurge of interest in various breathing methods, including device-induced breathing techniques like Resperate. However, the reliance on a device for these techniques has prompted the popularity of alternative breathing methods that can be performed without any external devices. One such method that has gained significant attention is alternative nostril breathing, which serves as an alternative medical treatment known for its effectiveness in reducing blood pressure. Therefore, this study aimed to systematically investigate the therapeutic effects of alternate nostril breathing. METHODS: We selected 16 articles published in English, Korean, and Chinese databases, of which 14 met the eligibility criteria, and a systematic literature review was conducted. A meta-analysis was conducted on six qualified studies. Meta and sensitivity analyses were conducted using a random effects model of six randomized clinical trials (RCTs). RESULTS: Results of alternative nostril breathing (ANB) on 1,377 participants have been reported based on the effects of systolic and diastolic blood pressure (SBP and DBP). Both the lone ANB and combined yoga programs resulted in significant reductions in SBP and DBP. Meta-analysis of the 6 trials with 525 participants demonstrated that ANB was better in reducing SBP than that of the control group (nonintervention or placebo) (mean difference [MD]: -7.16, 95% confidence interval [CI]: -7.86 to -6.45, I2: 93%). Moreover, ANB was better in reducing DBP than that of the control group (nonintervention or placebo) (MD: -5.16, 95% CI: -5.89 to -4.44, I2: 87%). CONCLUSION: The results of the study are valid; however, attention is needed when interpreting the results because the heterogeneity exceeds 75%. A systematic review of 14 studies found that ANB can improve cardiovascular indicators, such as SBP and DBP, as well as non-cardiovascular factors, such as fatigue, intraocular pressure, and memory. However, the review noted that implementing double blinding in studies on yoga breathing intervention is difficult, and most studies were not double-blinded, suggesting the need for high-quality RCTs in the future.

A case report on hemopneumothorax caused by acupuncture at Huatuo-Jiaji points.

Acupuncture is generally safe; however, severe side effects, such as syncope and pneumothorax (PTX), have sometimes been reported. No cases of hemopneumothorax following acupuncture have been reported in Korea. This study reports a case of progression and prognosis of hemopneumothorax after acupuncture in a patient who visited a hospital for digestive disorders and underwent acupuncture treatment at the Huatuo-Jiaji points to control the autonomic nerves. The patient complained of shortness of breath and chest pain after acupuncture. However, neither the patient nor the doctor suspected PTX. Chest radiography, conducted after a day, confirmed hemopneumothorax of the right lung, and the patient was immediately hospitalized. During hospitalization, oxygen therapy and medication were administered, and the patient was discharged 6 days later. However, PTX recurred, and the patient was rehospitalized. The patient was discharged after 4 days, and it was confirmed that he was completely cured, as evident from both radiation findings and patient symptoms on day 20. This study demonstrates that physicians should pay more attention to and be aware of PTX and its symptoms when performing acupuncture on the thoracic chest.

Mixture of Rhodiola rosea and Nelumbo nucifera Extracts Ameliorates Sleep Quality of Adults with Sleep Disturbance.

Chronic sleep disturbance affects daily functioning, leading to decreased concentration, fatigue, and higher healthcare costs. Traditional insomnia medications are often associated with adverse side effects. This study investigated the efficacy of a novel compound derived from Rhodiola rosea and Nelumbo nucifera extracts (named RNE) in improving sleep quality with fewer side effects. The study included individuals between the ages of 20 and 65 with subthreshold insomnia and evaluated the effects of RNE on sleep, fatigue, and quality of life. Participants took 750 mg of RNE daily at bed-time for two weeks. The study used the Insomnia Severity Index (ISI), the Pittsburgh Sleep Quality Index (PSQI), a sleep diary, the Fatigue Severity Scale (FSS), and the Short Form 36 Health Survey (SF-36) for assessments. Of the 20 participants, 13 completed the study and showed significant improvements in sleep quality. The results showed improvements in ISI and PSQI scores, a 57% reduction in wake-time after sleep onset, and improved sleep efficiency. Although FSS scores remained unchanged, significant improvements were seen in SF-36 physical and mental health scores. The results suggest that RNE is an effective, low-risk option for sleep disturbance, significantly improving sleep quality and overall wellbeing without significant side effects.

Adverse events of herbal decoction: A systematic review and meta-analysis over past 10 years.

BACKGROUND: Herbal decoctions (HDs) are the oldest and most common herbal medicine formulations. Different HDs exist, and some consumers are concerned that they may become contaminated during manufacturing. Therefore, the need for a safety assessment of HDs has been raised. This study aimed to investigate the adverse events (AEs) associated with HDs by comprehensively analyzing randomized controlled trials (RCTs) using systematic reviews and meta-analyses. METHODS: A systematic search was conducted on PubMed, Embase, and the Cochrane Library for articles published up to November 2022. The included RCTs compared HDs with other treatments published between 2013 and 2022, and the risk of bias was assessed using RevMan 5.4. Meta-analyses of the number of AEs associated with HDs reported in the included RCTs were also performed. RESULTS: The systematic review included 26 RCTs, and the meta-analysis included 17 RCTs that reported AEs. The meta-analysis comparing HDs with active controls showed that both the number of AEs (14 studies; risk ratio (RR)= 0.50 cases, 95 % confidence interval (CI) [0.29, 0.88]; I2 = 42 %) and the number of patients who complained of AEs (seven studies; RR=0.51 patients, 95 % CI [0.28, 0.94]; I2 =9 %) were fewer in the HDs group than in the active control groups. CONCLUSION: This study showed that HDs are safer than other conventional medications based on the results of qualitative and quantitative syntheses of RCTs.

Epithelial-mesenchymal transition induced by tumor cell-intrinsic PD-L1 signaling predicts a poor response to immune checkpoint inhibitors in PD-L1-high lung cancer.

BACKGROUND: We investigated the role of tumor cell-intrinsic PD-L1 signaling in the epithelial-mesenchymal transition (EMT) in non-small-cell lung cancer (NSCLC) and the role of EMT as a predictive biomarker for immune checkpoint inhibitor (ICI) therapy. METHODS: PD-L1-overexpressing or PD-L1-knockdown NSCLC cells underwent RNA-seq and EMT phenotype assessment. Mouse lung cancer LLC cells were injected into nude mice. Two cohorts of patients with NSCLC undergoing ICI therapy were analyzed. RESULTS: RNA-seq showed that EMT pathways were enriched in PD-L1-high NSCLC cells. EMT was enhanced by PD-L1 in NSCLC cells, which was mediated by transforming growth factor-ß (TGFß). PD-L1 promoted the activation of p38-MAPK by binding to and inhibiting the protein phosphatase PPM1B, thereby increasing the TGFß production. Tumor growth and metastasis increased in nude mice injected with PD-L1-overexpressing LLC cells. In the ICI cohort, EMT signature was higher in patients with progressive disease than in those with responses, and EMT was significantly associated with poor survival in PD-L1-high NSCLC. In PD-L1-high NSCLC, EMT was associated with increased M2-macrophage and regulatory T-cell infiltrations and decreased cytotoxic T-cell infiltration. CONCLUSIONS: Tumor cell-intrinsic PD-L1 function contributes to NSCLC progression by promoting EMT. EMT may predict an unfavorable outcome after ICI therapy in PD-L1-high NSCLC.

Deep learning-assisted monitoring of trastuzumab efficacy in HER2-Overexpressing breast cancer via SERS immunoassays of tumor-derived urinary exosomal biomarkers.

Monitoring drug efficacy is significant in the current concept of companion diagnostics in metastatic breast cancer. Trastuzumab, a drug targeting human epidermal growth factor receptor 2 (HER2), is an effective treatment for metastatic breast cancer. However, some patients develop resistance to this therapy; therefore, monitoring its efficacy is essential. Here, we describe a deep learning-assisted monitoring of trastuzumab efficacy based on a surface-enhanced Raman spectroscopy (SERS) immunoassay against HER2-overexpressing mouse urinary exosomes. Individual Raman reporters bearing the desired SERS tag and exosome capture substrate were prepared for the SERS immunoassay; SERS tag signals were collected to prepare deep learning training data. Using this deep learning algorithm, various complicated mixtures of SERS tags were successfully quantified and classified. Exosomal antigen levels of five types of cell-derived exosomes were determined using SERS-deep learning analysis and compared with those obtained via quantitative reverse transcription polymerase chain reaction and western blot analysis. Finally, drug efficacy was monitored via SERS-deep learning analysis using urinary exosomes from trastuzumab-treated mice. Use of this monitoring system should allow proactive responses to any treatment-resistant issues.

Postpartum Maternal Anxiety Affects the Development of Food Allergy Through Dietary and Gut Microbial Diversity During Early Infancy.

PURPOSE: We aimed to investigate the mediating factors between maternal anxiety and the development of food allergy (FA) in children until 2 years from birth. METHODS: In this longitudinal cohort of 122 mother-child dyads from pregnancy to 24 months of age, we regularly surveyed maternal psychological states, infant feeding data, and allergic symptoms and collected stool samples at 6 months of age for microbiome analysis. Considering the temporal order of data collection, we investigated serial mediating effects and indirect effects among maternal anxiety, dietary diversity (DD), gut microbial diversity, and FA using structural equation modeling. RESULTS: Among the 122 infants, 15 (12.3%) were diagnosed with FA. Increased maternal anxiety between 3 and 6 months after delivery was associated with a lower DD score. Infants with low DD at 4 months showed low gut microbial richness, which was associated with FA development. When the infants were grouped into 4 subtypes, using consensus clustering of 13 gut bacteria significantly associated with maternal anxiety and DD, Prevotella, Eubacterium, Clostridiales and Lachnospiraceae were more abundant in the group with lower FA occurrence. CONCLUSIONS: Postpartum maternal anxiety, mediated by reduced DD and gut microbial diversity, may be a risk factor for the development of FA in infants during the first 2 years of life.

Safety of herbal decoctions: A scoping review of clinical studies in South Korea focusing on liver and kidney functions.

ETHNOPHARMACOLOGICAL RELEVANCE: Approximately 27% of individuals seeking Korean medicine (KM) services in South Korea are prescribed herbal decoctions. The South Korean government has considered the validity of providing National Health Insurance coverage for herbal decoctions. Therefore, it is important to investigate their safety. AIM OF THE STUDY: To investigate the safety of herbal decoctions commonly prescribed by KM doctors and to assess their effects on liver and kidney function by comprehensively analyzing Korean clinical studies in a scoping review. MATERIALS AND METHODS: The Arksey and O'Malley framework and modified methods were applied in this scoping review. A comprehensive search of seven electronic health databases was conducted, and relevant clinical studies published between 2000 and 2022 were identified. Subsequently, only clinical studies reporting the results of liver and/or renal function tests in patient prescribed herbal decoctions by KM doctors were included. The characteristics of the included clinical studies and the reported proportion of each liver and/or renal function indicator were analyzed. Meta-analyses of the effects of herbal decoction on liver and/or renal function reported in prospective cohort studies were also performed. RESULTS: Fifty-nine clinical studies were included in this review. The proportion of prospective cohort studies markedly decreased in the 2010s compared to the 2000s, while there was no noticeable change in the number of relevant clinical studies. Herbal decoctions were prescribed for less than one month in most included studies. Abnormal changes in liver or renal function indicators were identified in a small number of studies (3.70% and 7.69%, respectively). In a meta-analysis of 15 prospective cohort studies, no statistically significant changes in four liver function indices and two renal function indices were observed before and after the prescription of herbal decoctions. CONCLUSIONS: Qualitative and quantitative analyses demonstrated favorable safety profiles for herbal decoctions. This scoping review includes the gaps noted between clinical application and research regarding the safety profiles of herbal decoctions. These findings could be used as evidence to support the inclusion of herbal decoction prescriptions in the National Health Insurance coverage in South Korea.

Colorimetric Detection of HER2-Overexpressing-Cancer-Derived Exosomes in Mouse Urine Using Magnetic-Polydiacetylene Nanoparticles.

Breast cancer (BC) is a major global health problem, with ≈20-25% of patients overexpressing human epidermal growth factor receptor 2 (HER2), an aggressive marker, yet access to early detection and treatment varies across countries. A low-cost, equipment-free, and easy-to-use polydiacetylene (PDA)-based colorimetric sensor is developed for HER2-overexpressing cancer detection, designed for use in low- and middle-income countries (LMICs). PDA nanoparticles are first prepared through thin-film hydration. Subsequently, hydrophilic magnetic nanoparticles and HER2 antibodies are sequentially conjugated to them. The synthesized HER2-MPDA can be concentrated and separated by a magnetic field while inheriting the optical characteristics of PDA. The specific binding of HER2 antibody in HER2-MPDA to HER2 receptor in HER2-overexpressing exosomes causes a blue-to-red color change by altering the molecular structure of the PDA backbone. This colorimetric sensor can simultaneously separate and detect HER2-overexpressing exosomes. HER2-MPDA can detect HER2-overexpressing exosomes in the culture medium of HER2-overexpressing BC cells and in mouse urine samples from a HER2-overexpressing BC mouse model. It can selectively isolate and detect only HER2-overexpressing exosomes through magnetic separation, and its detection limit is found to be 8.5 × 108 particles mL-1. This colorimetric sensor can be used for point-of-care diagnosis of HER2-overexpressing BC in LMICs.

An immuno-magnetophoresis-based microfluidic chip to isolate and detect HER2-Positive cancer-derived exosomes via multiple separation.

Exosomes are useful for cancer diagnosis and monitoring. However, clinical samples contain impurities that complicate direct analyses of cancer-derived exosomes. Therefore, a microfluidic chip-based magnetically labeled exosome isolation system (MEIS-chip) was developed as a lab-on-a-chip platform for human epidermal growth factor receptor 2 (HER2)-positive cancer diagnosis and monitoring. Various magnetic nanoclusters (MNCs) were synthesized with different degrees of magnetization, and antibodies were introduced to capture HER2-overexpressing and common exosomes using immunoaffinity. MNC-bonded exosomes were separated into different exits according to their magnetization degrees. The MEIS-chip efficiently separated HER2-overexpressing exosomes from common exosomes that did not contain disease-related information. The simultaneous separation of HER2-and non-HER2-overexpressing exosomes provided a means of analyzing high-purity HER2-overexpressing exosomes while minimizing the contribution of non-target exosomes, reducing misdiagnosis risk. Notably, common exosomes served as a negative control for monitoring real-time changes in HER2 expression. These findings support the application of MEIS-chip for cancer diagnosis and treatment monitoring via effective exosome isolation.

Chromatographic Method for Monitoring of Pesticide Residues and Risk Assessment for Herbal Decoctions Used in Traditional Korean Medicine Clinics.

The presence of pesticide residues in herbs and the herbal products derived from them raises serious health concerns. This study was conducted to investigate the residual pesticide concentrations and assess potential human health risks from herbal medicines used in traditional Korean medicine clinics. A total of 40 samples of herbal decoctions were collected from 10 external herbal dispensaries. The pesticide residues were analyzed by the multiresidue method for 320 different pesticides using liquid chromatography tandem mass spectrometry (LC-MS/MS) and gas chromatography tandem mass spectrometry (GC-MS/MS). As a result of the monitoring, carbendazim was detected at 0.01 and 0.03 µg/g in eight samples and no pesticide was detected in the other herbal decoctions. Carbendazim was set for each individual item as less than 0.05 µg/g in Paeoniae radix, less than 0.05 µg/g in Cassiae semen, less than 2.0 µg/g in Lycii fructus, and less than 10 µg/g in Schisandrae fructus (dried). Therefore, the results of this study suggested that the detected pesticide residues in herbal decoctions could not be considered as posing a serious health risk.

CNN-Based Fault Detection of Scan Matching for Accurate SLAM in Dynamic Environments.

This paper proposes a method for CNN-based fault detection of the scan-matching algorithm for accurate SLAM in dynamic environments. When there are dynamic objects in an environment, the environment that is detected by a LiDAR sensor changes. Thus, the scan matching of laser scans is likely to fail. Therefore, a more robust scan-matching algorithm to overcome the faults of scan matching is needed for 2D SLAM. The proposed method first receives raw scan data in an unknown environment and executes ICP (Iterative Closest Points) scan matching of laser scans from a 2D LiDAR. Then, the matched scans are converted into images, which are fed into a CNN model for its training to detect the faults of scan matching. Finally, the trained model detects the faults when new scan data are provided. The training and evaluation are performed in various dynamic environments, taking real-world scenarios into account. Experimental results showed that the proposed method accurately detects the faults of scan matching in every experimental environment.

Potential of Mycobacterium tuberculosis chorismate mutase (Rv1885c) as a novel TLR4-mediated adjuvant for dendritic cell-based cancer immunotherapy.

For clinical application by dendritic cell (DC)-based cancer immunotherapy, a proper adjuvant system to elicit a strong anticancer immune response is needed. Here, we investigated the potential of chorismate mutase (TBCM, Rv1885c), a putative Mycobacterium tuberculosis (TB) virulence factor, as an immunoadjuvant in DC-based tumor immunotherapy. First, we found that TBCM functionally activated DCs by upregulating costimulatory molecules, increasing the secretion of proinflammatory cytokines, enhancing migration and inducing the Th1-type immune response in a dose-dependent manner via TLR4-mediated signaling. In addition, subcutaneous injection of TBCM-activated DCs loaded with cell lysates led to reduced tumor mass, enhanced mouse survival and lowered tumor incidence in lung carcinoma (LLC) cell-bearing mice. This is mainly mediated by functional cytotoxic T lymphocyte-mediated oncolytic activity and inhibition of cancer proliferation- and metastasis-related genes. Moreover, TBCM-induced DCs can also generate memory CD4 T cells and exert long-term tumor prevention effects. In conclusion, our findings suggest that TBCM (Rv1885c), a novel TLR4 agonist, could be used as an immunoadjuvant for DC-based cancer immunotherapy.

Distinct impacts of major El Niño events on Arctic temperatures due to differences in eastern tropical Pacific sea surface temperatures.

The El Niño Southern Oscillation (ENSO) is a climate mode in the tropical Pacific. The ENSO teleconnections are known to affect Arctic temperature; however, the robustness of this relationship remains debated. We find that Arctic surface temperatures during three major El Niño events are remarkably well simulated by a state-of-the-art model when nudged to the observed pantropical sea surface temperatures (SSTs). SST perturbation experiments show that the 1982-1983 warm pan-Arctic and the 1997-1998 cold pan-Arctic during winter can be explained by far eastern equatorial Pacific SSTs being higher during 1997-1998 than 1982-1983. Consistently, during the 2017-2018 La Niña, unusually low SSTs in the same region contributed to pan-Arctic warming. These pan-Arctic responses to the SSTs are realized through latent heating anomalies over the western and eastern tropical Pacific. These results highlight the importance of accurately representing SST amplitude and pattern for Arctic climate predictions.

Home-Based Up-Dosing in Build-Up Phase of Oral Immunotherapy of Egg Allergy Is Safe and Feasible in Real-World Practice.

Oral immunotherapy (OIT) has emerged to build sustained unresponsiveness or tolerance in patients with egg allergy. However, it is important to increase compliance and ensure safety because OIT requires an extended period of time and has a risk of side effects like anaphylaxis. We aimed to show the feasibility and safety of OIT during the build-up phase using a home-based, up-dosing method in children with egg allergy. Sixteen patients aged 4 to 12 years with egg allergy were enrolled. Patients increased the dose of boiled egg white (EW) by 5% per day at home and 25% per month at the hospital, with a target dose of 40 g of boiled EW (4.0 g of EW proteins). A historical control group (n = 16) was matched for age, sex, and clinical characteristics for comparisons with the OIT group. Oral food challenge (OFC) tests were performed after completing the build-up phase. In the OIT group, 93.8% (15/16) of patients achieved desensitization, with only 1 patient discontinuing OIT before the maintenance phase due to repeated allergic reactions. Mild allergic reactions and anaphylaxis occurred in 12 (75.0%) and 2 patients (12.5%), respectively. However, there were no significant adverse reactions such as serious anxiety or life-threatening events that required discontinuation of treatment. On the contrary, only 1 patient (6.3%) in the control group passed an OFC of 40 g of boiled EW during the same period (P < 0.001). Our results suggest that home-based up-dosing protocols using boiled eggs may be safe and feasible for the build-up phase of OIT in children with egg allergy.

Recombinant Mycobacterium paragordonae Expressing SARS-CoV-2 Receptor-Binding Domain as a Vaccine Candidate Against SARS-CoV-2 Infections.

At present, concerns that the recent global emergence of SARS-CoV-2 variants could compromise the current vaccines have been raised, highlighting the urgent demand for new vaccines capable of eliciting T cell-mediated immune responses, as well as B cell-mediated neutralizing antibody production. In this study, we developed a novel recombinant Mycobacterium paragordonae expressing the SARS-CoV-2 receptor-binding domain (RBD) (rMpg-RBD-7) that is capable of eliciting RBD-specific immune responses in vaccinated mice. The potential use of rMpg-RBD-7 as a vaccine for SARS-CoV-2 infections was evaluated in in vivo using mouse models of two different modules, one for single-dose vaccination and the other for two-dose vaccination. In a single-dose vaccination model, we found that rMpg-RBD-7 versus a heat-killed strain could exert an enhanced cell-mediated immune (CMI) response, as well as a humoral immune response capable of neutralizing the RBD and ACE2 interaction. In a two-dose vaccination model, rMpg-RBD-7 in a two-dose vaccination could also exert a stronger CMI and humoral immune response to neutralize SARS-CoV-2 infections in pseudoviral or live virus infection systems, compared to single dose vaccinations of rMpg-RBD or two-dose RBD protein immunization. In conclusion, our data showed that rMpg-RBD-7 can lead to an enhanced CMI response and humoral immune responses in mice vaccinated with both single- or two-dose vaccination, highlighting its feasibility as a novel vaccine candidate for SARS-CoV-2. To the best of our knowledge, this study is the first in which mycobacteria is used as a delivery system for a SARS-CoV-2 vaccine.

Natural Course and Prognostic Factors of Immediate-Type Peanut Allergy in Children.

BACKGROUND: Predicting food allergy resolution is essential to minimize the number of restricted foods in children. However, there have been no studies on the natural history of peanut allergy (PA) in Korea. OBJECTIVE: This study aimed to evaluate the natural course and prognostic factors of immediate-type PA in children till the age of 10 years. METHODS: We retrospectively collected data of 122 children who developed PA before 60 months of age from 3 tertiary hospitals in Korea. Diagnosis and resolution of PA was defined as an oral food challenge test or a convincing history of symptoms within 2 h after peanut ingestion. The prognostic factors for resolution of PA were identified using the Cox proportional hazard model. RESULTS: The median (interquartile range) age at diagnosis was 2.0 (1.3-3.0) years. Among the 122 children, PA resolved in 18 (14.8%) children. The level of peanut-specific IgE (sIgE) at diagnosis in the persistence group was significantly higher than that in the resolution group (p = 0.026). The probabilities of resolution of PA were 10.3% and 32.8% at the ages of 6 and 10 years, respectively. A peanut-sIgE level ≥1 kU/L at diagnosis was significantly associated with persistent PA (hazard ratio, 5.99; 95% confidence interval, 1.89-18.87). CONCLUSIONS: Only 10.3% of our patients had a probability of developing spontaneous resolution of PA by 6 years of age. Peanut-sIgE levels ≥1 kU/L at diagnosis were associated with the persistence of PA.

Recombinant Mycobacterium smegmatis delivering a fusion protein of human macrophage migration inhibitory factor (MIF) and IL-7 exerts an anticancer effect by inducing an immune response against MIF in a tumor-bearing mouse model.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a pleotropic inflammatory cytokine that is overexpressed in a number of cancer types including most types of human cancer. Inhibition of MIF signaling can restore anticancer immune responses in tumor microenvironments. In this study, we aimed to develop a therapeutic vaccine capable of inhibiting tumor development by inducing anti-MIF immune responses. METHODS: We introduced a recombinant Mycobacterium smegmatis (rSmeg-hMIF-hIL-7) vaccine that could deliver a fusion protein of human macrophage migration inhibitory factor (MIF) and interleukin 7, which could act as a target antigen and as an adjuvant of cancer vaccine, respectively. We checked the anticancer potential of the vaccine in a tumor-bearing mouse model. RESULTS: We found that rSmeg-hMIF-hIL-7 showed enhanced oncolytic activity compared with PBS, BCG or Smeg in MC38-bearing mice, and there was an increase in the humoral and cell-mediated immune responses against MIF. rSmeg-hMIF-hIL-7 can also induce a neutralizing effect regarding MIF tautomerase activity in the serum of vaccinated mice. We also found downregulation of MIF, CD74, and CD44, which are related to the MIF signaling pathway and PI3K/Akt and MMP2/9 signaling, which are regulated by MIF in the tumor tissue of rSmeg-hMIF-hIL-7-vaccinated mice, suggesting a significant role of the anti-MIF immune response to rSmeg-hMIF-hIL-7 in its anticancer effect. In addition, rSmeg-hMIF-hIL-7 treatment led to enhanced activation of CD4+ and CD8+ T cells in the tumor regions of vaccinated mice, also contributing to the anticancer effect. This trend was also found in LLC-bearing and PanO2-bearing mouse models. In addition, rSmeg-hMIF-hIL-7 treatment exerted an enhanced anticancer effect with one of the immune checkpoint inhibitors, the anti-PD-L1 antibody, in a tumor-bearing mouse model. CONCLUSIONS: In conclusion, our data showed that rSmeg-hMIF-hIL-7 exerts a strong antitumor immune response in mice, possibly by inhibiting the MIF-dependent promotion of tumorigenesis by the anti-MIF immune response and via enhanced cytotoxic T cell recruitment into tumor microenvironments. We also found that it also exerted an enhanced anticancer effect with immune checkpoint inhibitors. These results suggest that rSmeg-hMIF-hIL-7 is a potential adjuvant for cancer immunotherapy. This is the first report to prove anticancer potential of immunotherapeutic vaccine targeting immune response against MIF.