Small extracellular vesicles derived from human mesenchymal stem cells prevent Th17-dominant neutrophilic airway inflammation via immunoregulation on Th17 cells.

Type 17 helper T cells (Th17)-dominant neutrophilic airway inflammation is critical in the pathogenesis of steroid-resistant airway inflammation such as severe asthma. Small extracellular vesicles (sEV) derived from human mesenchymal stem cells (MSCs) display extensive therapeutic effects and advantages in many diseases. However, the role of MSC-sEV in Th17-dominant neutrophilic airway inflammation and the related mechanisms are still poorly studied. Here we found that MSC-sEV significantly alleviated the infiltration of inflammatory cells in peribronchial interstitial tissues and reduced levels of inflammatory cells, especially neutrophils, in bronchoalveolar lavage fluids (BALF) of mice with neutrophilic airway inflammation. Consistently, MSC-sEV significantly decreased levels of IL-17A in BALF and Th17 in lung tissues. Furthermore, we found that labelled MSC-sEV were taken up by human CD4+ T cells most obviously at 12 h after incubation, and distributed mostly in mouse lungs. More importantly, potential signaling pathways involved in the MSC-sEV mediated inhibition of Th17 polarization were found using RNA sequencing. Using Western blot, JAK2-STAT3 pathway was identified as an important role in the inhibition of Th17 polarization by MSC-sEV. We found that proteins in MSC-sEV were mostly involved in the therapeutic effects of MSC-sEV. In total, our study suggested that MSC-sEV could be a potential therapeutic strategy for the treatment of neutrophilic airway inflammation.

Dynamic flyer in barrel imaging via high intensity short-pulse laser.

The thin flyer is a small-scale flying object, which is well known as the core functional element of the initiator. Understanding how flyers perform has been a long-standing issue in detonator science. However, it remains a significant challenge to explore how the flyer is formed and functions in the barrel of the initiator via tabletop devices. In this study, we present dynamic and unprecedented images of flyer in barrel via high intensity short-pulse laser. Advanced radiography, coupled with a high-intensity picosecond laser X-ray source, has enabled the provision of state-of-the-art radiographs in a single-shot experiment for observing micron-scale flyer formation in a hollow cylinder in nanoseconds. The flyer was clearly visible in the barrel and was accelerated and restricted differently from that without the barrel. This first implementation of a tabletop X-ray source provided a new approach for capturing dynamic photographs of small-scale flying objects, which were previously reported to be accessible only via an X-ray phase-contrast imaging system at the advanced photon source. These efforts have led to a significant improvement of radiographic capability and a greater understanding of the mechanisms of "burst" of exploding foil initiators for this application.

Accumulation of antitumor polyketides by fermentation of Rubus delavayi Franch. with Clonostachys rogersoniana.

The aim of this work is to explore the effects of herbal medicine on secondary metabolites of microorganisms during fermentation. Clonostachys rogersoniana was found to metabolize only small amounts of polyketide glycosides rogerson B and C on fresh potatoes, but after replacing the medium to the medicinal plant Rubus delavayi Franch., the type and content of the metabolized polyketones showed significant changes. The sugars and glycosides in R. delavayi are probably responsible for the changes in secondary metabolites. Six polyketide glycosides including a new metabolite, rogerson F, and two potential antitumor compounds, TMC-151C and TMC-151D, were isolated from the extract of R. delavayi fermented by C. rogersoniana. In addition, 13C labeling experiments were used to trace the biosynthesis process of these compounds. TMC-151C and TMC-151D showed significant cytotoxic activity against PANC-1, K562 and HCT116 cancer cells but had no obvious cytotoxic activity against BEAS-2B human normal lung epithelial cells. The yields of TMC-151C and TMC-151D reached 14.37 ± 1.52 g/kg and 1.98 ± 0.43 g/kg, respectively, after fermentation at 28 °C for 30 days. This is the first study to confirm that herbal medicine can induce microbes to metabolize active compounds. And the technology of fermenting medicinal materials can bring more economic value to medicinal plants.

A Good Prognosis of Patients with Acute Pancreatitis Combined with Pulmonary Embolism: Early Identification and Intervention.

BACKGROUND: Pulmonary embolism (PE) is a relatively rare vascular complication of acute pancreatitis (AP), and its mortality rate is high. To our knowledge, relevant literature reports still need to be summarized. In this study, we analyzed the clinical characteristics, treatment, and prognosis of five patients with AP complicated by PE and summarized and reviewed the relevant literature. METHODS: Clinical data of patients with AP complicated by PE treated in Taizhou Hospital of Zhejiang Province between January 2017 and September 2022 were retrospectively collected. Combined with the relevant literature, the clinical characteristics, treatment, and prognoses of patients with AP combined with PE were analyzed and summarized. RESULTS: Five patients were eventually enrolled in this study. Among the five patients with AP complicated by PE, all (100%) had symptoms of malaise, primarily chest tightness, shortness of breath, and dyspnea. All patients (100%) had varied degrees of elevated D-dimer levels and a significant decrease in the pressure of partial oxygen (PO2) and pressure of arterial oxygen to fractional inspired oxygen concentration ratio (PaO2/FiO2). Computed tomographic angiography (CTA) or pulmonary ventilation/perfusion imaging revealed a pulmonary artery filling defect in these patients. One patient (20%) had left calf muscular venous thrombosis before the occurrence of PE. Four patients (80%) were treated with lowmolecular- weight heparin (LMWH), and one patient (20%) was treated with rivaroxaban during hospitalization; all continued oral anticoagulant therapy after discharge. All patients (100%) were cured and discharged. No patients showed recurrence of AP or PE. CONCLUSION: PE is a rare but life-threatening complication of AP. However, once diagnosed, early treatment with anticoagulation or radiological interventional procedures is effective, and the prognosis is good. Core Tips: Pulmonary embolism (PE) is a rare but life-threatening complication of acute pancreatitis (AP). Its early diagnosis and timely anticoagulation or radiological intervention can reduce mortality. However, only nine cases have been reported in the English literature thus far, and they are all case reports. Our study is the first systematic analysis of patients with AP combined with PE with a review of the relevant literature. Our patients and those reported in the literature were discharged with good prognoses under treatment such as anticoagulation and vascular intervention. These cases remind clinicians that, in patients with AP, especially those with risk factors for venous thrombosis, it is necessary to monitor the D-dimer level dynamically. Clinicians should pay attention to AP patients' symptoms and related examinations to reduce the chance of a missed diagnosis or misdiagnosis of PE.

Mesenchymal stem cells overexpressing interleukin-10 prevent allergic airway inflammation.

BACKGROUNDS: Allergic airway inflammation is prevalent worldwide and imposes a considerable burden on both society and affected individuals. This study aimed to investigate the therapeutic advantages of mesenchymal stem cells (MSCs) overexpressed interleukin-10 (IL-10) for the treatment of allergic airway inflammation, as both IL-10 and MSCs possess immunosuppressive properties. METHODS: Induced pluripotent stem cell (iPSC)-derived MSCs were engineered to overexpress IL-10 via lentiviral transfection (designated as IL-10-MSCs). MSCs and IL-10-MSCs were administered intravenously to mice with allergic inflammation induced by ovalbumin (OVA), and the features of allergic inflammation including inflammatory cell infiltration, Th cells in the lungs, and T helper 2 cell (Th2) cytokine levels in bronchoalveolar lavage fluid (BALF) were examined. MSCs and IL-10-MSCs were co-cultured with CD4+ T cells from patients with allergic rhinitis (AR), and the levels of Th2 cells and corresponding type 2 cytokines were studied. RNA-sequence was performed to further investigate the potential effects of MSCs and IL-10-MSCs on CD4+ T cells. RESULTS: Stable IL-10-MSCs were established and characterised by high IL-10 expression. IL-10-MSCs significantly reduced inflammatory cell infiltration and epithelial goblet cell numbers in the lung tissues of mice with allergic airway inflammation. Inflammatory cell and cytokine levels in BALF also decreased after the administration of IL-10-MSCs. Moreover, IL-10-MSCs showed a stronger capacity to inhibit the levels of Th2 after co-cultured with CD4+ T cells from patients with AR. Furthermore, we elucidated lower levels of IL-5 and IL-13 in IL-10-MSCs treated CD4+ T cells, and blockade of IL-10 significantly reversed the inhibitory effects of IL-10-MSCs. We also reported the mRNA profiles of CD4+ T cells treated with IL-10-MSCs and MSCs, in which IL-10 played an important role. CONCLUSION: IL-10-MSCs showed positive effects in the treatment of allergic airway inflammation, providing solid support for the use of genetically engineered MSCs as a potential novel therapy for allergic airway inflammation.

Guided isolation of secondary metabolites from Nectria sp. MHHJ-3 by molecular network strategy.

The fungus Nectria sp. MHHJ-3 was isolated from Illigera rhodantha. A molecular networking-guided the secondary metabolites investigation of Nectria sp. MHHJ-3 led to the isolation of ten metabolites (1-10), including two new naphthalenone derivatives, nectrianaphthalenones A (1) and B (2), and two new steroids, nectriasteroids A (3) and B (4). Their structures were elucidated by extensive spectroscopic analysis including the HRESIMS, 1D/2D NMR and electronic circular dichroism (ECD) spectra. A plausible biosynthetic pathway for 1-2 was proposed. Compounds 1 and 2 exhibited moderate acetylcholinesterase (AChE) inhibitory activities. Compounds 3 and 4 showed significant cytotoxic activity against selected tumor cells. Particularly, compound 3 exhibited the strongest activity against A549 cells with an IC50 value of 13.73 ± 0.03 µM, which was at the same grade with that of positive control cisplatin.

Association of biopsy core number and location with pain in patients undergoing a transperineal prostate biopsy under local anaesthesia: a secondary analysis of the APROPOS trial.

BACKGROUND: APROPOS was a multicentre, randomized, blinded trial focus on investigating the perineal nerve block versus the periprostatic block in pain control for men undergoing a transperineal prostate biopsy. In the analysis reported here, the authors aimed to evaluate the association of biopsy core count and location with pain outcomes in patients undergoing a transperineal prostate biopsy under local anesthesia. METHODS: APROPOS was performed at six medical centers in China. Patients with suspected prostate cancer were randomized to receive either a perineal nerve block or a periprostatic block (1:1), followed by a transperineal prostate biopsy. The secondary analysis outcomes were the worst pain experienced during the prostate biopsy and postbiopsy pain at 1,6, and 24 h. RESULTS: Between 12 August 2020 and 20 July 2022, a total of 192 patients were randomized in the original trial, and 188 were involved in this analysis, with 94 patients per group. Participants had a median (IQR) age of 68 (63-72) and a median (IQR) prostate volume of 42.51 (30.04-62.84). The patient population had a median (IQR) number of biopsy cores of 15 (12-17.50), and 26.06% of patients had a biopsy cores count of more than 15. After adjusting the baseline characteristics, the number of biopsy cores was associated with the worst pain during the biopsy procedure in both the perineal nerve block group ( ß 0.19, 95% CI: 0.12-0.26, P <0.001) and the periprostatic block group ( ß 0.16, 95% CI: 0.07-0.24, P <0.001). A similar association was also evident for the postbiopsy pain at 1, 6, and 24 h. A lesser degree of pain in both groups at any time (r range -0.57 to -0.01 for both groups) was associated with biopsy cores from the peripheral zone of the middle gland, while other locations were associated with a higher degree of pain. In addition, the location of the biopsy core had less of an effect on pain during the biopsy (r range -0.01-0.25 for both groups) than it did on postbiopsy pain (r range -0.57-0.60 for both groups). CONCLUSIONS: In this secondary analysis of a randomized trial, biopsy core count and location were associated with pain in patients undergoing a transperineal prostate biopsy under local anesthesia. These results may be helpful for making clinical decisions about the anesthetic approach for scheduled transperineal prostate biopsies.

Dendritic cells mediated by small extracellular vesicles derived from MSCs attenuated the ILC2 activity via PGE2 in patients with allergic rhinitis.

BACKGROUND: Mesenchymal stromal cells-derived small extracellular vesicles (MSC-sEVs) have recently attracted considerable attention because of their therapeutic potential in various immune diseases. We previously reported that MSC-sEVs could exert immunomodulatory roles in allergic airway inflammation by regulating group 2 innate lymphoid cell (ILC2) and dendritic cell (DC) functions. Therefore, this study aimed to investigate the indirect effects of MSC-sEVs on ILC2s from patients with allergic rhinitis (AR) via DCs. METHODS: Here, we isolated sEVs from induced pluripotent stem cells-MSCs using anion-exchange chromatography and mature DCs (mDCs) were treated with MSC-sEVs. sEV-mDCs were co-cultured with peripheral blood mononuclear cells from patients with AR or purified ILC2s. The levels of IL-13 and GATA3 in ILC2s were examined by flow cytometry. Bulk RNA sequence for mDCs and sEV-mDCs was employed to further probe the potential mechanisms, which were then validated in the co-culture systems. RESULTS: sEV-mDCs showed impaired capacity in priming the levels of IL-13 and GATA3 in ILC2s when compared with mDCs. Furthermore, there was higher PGE2 and IL-10 production from sEV-mDCs, and the blockade of them especially the former one reversed the inhibitory effects of sEV-mDCs. CONCLUSIONS: We demonstrated that MSC-sEVs were able to dampen the activating effects of mDCs on ILC2s in patients with AR. Mechanismly, the PGE2-EP2/4 axis played an essential role in the immunomodulatory effects of sEV-mDCs on ILC2s. Herein, we provided new insights into the mechanism underlying the therapeutic effects of MSC-sEVs in allergic airway inflammation.

Perineal nerve block versus periprostatic block for patients undergoing transperineal prostate biopsy (APROPOS): a prospective, multicentre, randomised controlled study.

Background: We aimed to investigate perineal nerve block versus periprostatic block in pain control for men undergoing a transperineal prostate biopsy. Methods: In this prospective, randomised, blinded and parallel-group trial, men in six Chinese hospitals with suspected prostate cancer were randomly assigned (1:1) at the point of local anaesthesia to receive a perineal nerve block or periprostatic block and followed by a transperineal prostate biopsy. Centres used their usual biopsy procedure. Operators who performed anaesthesia were trained in both techniques before the trial and were masked to the randomised allocation until the time of anaesthesia and were not involved in the subsequent biopsy procedure and any assessment or analysis. Other investigators and the patients were masked until trial completion. The primary outcome was the level of the worst pain experienced during the prostate biopsy procedure. Secondary outcomes included pain (post-biopsy at 1, 6 and 24 h), changes in blood pressure, heart rate and breathing rate during the biopsy procedure, external manifestations of pain during biopsy, anaesthesia satisfaction, the detection rate of PCa and clinically significant PCa. This trial is registered on ClinicalTrials.gov, NCT04501055. Findings: Between August 13, 2020, and July 20, 2022, 192 men were randomly assigned to perineal nerve block or periprostatic block, 96 per study group. Perineal nerve block was superior for the relief of pain during the biopsy procedure (mean 2.80 for perineal nerve block and 3.98 for periprostatic block; adjusted difference in means -1.17, P < 0.001). Although the perineal nerve block had a lower mean pain score at 1 h post-biopsy compared with the periprostatic block (0.23 vs 0.43, P = 0.042), they were equivalent at 6 h (0.16 vs 0.25, P = 0.389) and 24 h (0.10 vs 0.26, P = 0.184) respectively. For the change in vital signs during biopsy procedure, perineal nerve block was significantly superior to periprostatic block in terms of maximum value of systolic blood pressure, maximum value of mean arterial pressure and maximum value of heart rate. There are no statistical differences in average value of systolic blood pressure, average value of mean, average value of heart rate, diastolic blood pressure and breathing rate. Perineal nerve block was also superior to periprostatic block in external manifestations of pain (1.88 vs 3.00, P < 0.001) and anaesthesia satisfaction (8.93 vs 11.90, P < 0.001). Equivalence was shown for the detection rate of PCa (31.25% for perineal nerve block and 29.17% for periprostatic block, P = 0.753) or csPCa (23.96% for perineal nerve block and 20.83% for periprostatic block, P = 0.604). 33 (34.8%) of 96 patients in the perineal nerve block group and 40 (41.67%) of 96 patients in the periprostatic block group had at least one complication. Interpretation: Perineal nerve block was superior to periprostatic block in pain control for men undergoing a transperineal prostate biopsy. Funding: Grant 2019YFC0119100 from the National Key Research and Development Program of China.

Combined use of extracorporeal membrane oxygenation with interventional surgery for acute pancreatitis with pulmonary embolism: A case report.

BACKGROUND: Acute pancreatitis (AP) is an acute inflammatory process of the pancreas characterized by self-digestion of pancreatic tissue, which can trigger a systemic inflammatory response. Venous thrombosis, resulting from a hypercoagulable state, is a vascular complication of AP. AP complicated by pulmonary embolism (PE) is very rare, and the combined use of extracorporeal membrane oxygenation (ECMO) with a vascular interventional procedure for AP complicated by PE is even rarer. CASE SUMMARY: A 32-year-old man with a history of obesity developed rapidly worsening AP secondary to hypertriglyceridemia. During treatment, the patient developed chest tightness, shortness of breath, and cardiac arrest. Computed tomography (CT) scans of his upper abdomen were consistent with pancreatitis. PE was identified by chest CT angiography involving the right main pulmonary artery and multiple lobar pulmonary arteries. The patient's D-dimer level was significantly elevated (> 20 mg/L). The patient received high-frequency oxygen inhalation, continuous renal replacement therapies, anti-infective therapy, inhibition of pancreatic secretion, emergent endotracheal intubation, and advanced cardiac life support with cardiopulmonary resuscitation. Following both ECMO and a vascular interventional procedure, the patient recovered and was discharged. CONCLUSION: PE is a rare but potentially lethal complication of AP. The early diagnosis of PE is important because an accurate diagnosis and timely interventional procedures can reduce mortality. The combined use of ECMO with a vascular interventional procedure for AP complicated by PE can be considered a feasible treatment method. A collaborative effort between multiple teams is also vital.

Mesenchymal stromal cells-derived small extracellular vesicles modulate DC function to suppress Th2 responses via IL-10 in patients with allergic rhinitis.

Mesenchymal stromal cells (MSCs) are well known for their immunoregulatory roles on allergic inflammation particularly by acting on T cells, B cells, and dendritic cells (DCs). MSC-derived small extracellular vesicles (MSC-sEV) are increasingly considered as one of the main factors for the effects of MSCs on immune responses. However, the effects of MSC-sEV on DCs in allergic diseases remain unclear. MSC-sEV were prepared from the induced pluripotent stem cells (iPSC)-MSCs by anion-exchange chromatography, and were characterized with the size, morphology, and specific markers. Human monocyte-derived DCs were generated and cultured in the presence of MSC-sEV to differentiate the so-called sEV-immature DCs (sEV-iDCs) and sEV-mature DCs (sEV-mDCs), respectively. The phenotypes and the phagocytic ability of sEV-iDCs were analyzed by flow cytometry. sEV-mDCs were co-cultured with isolated CD4+ T cells or peripheral blood mononuclear cells (PBMCs) from patients with allergic rhinitis. The levels of Th1 and Th2 cytokines produced by T cells were examined by ELISA and intracellular flow staining. And the following mechanisms were further investigated. We demonstrated that MSC-sEV inhibited the differentiation of human monocytes to iDCs with downregulation of the expression of CD40, CD80, CD86, and HLA-DR, but had no effects on mDCs with these markers. However, MSC-sEV treatment enhanced the phagocytic ability of mDCs. More importantly, using anti-IL-10 monoclonal antibody or IL-10Rα blocking antibody, we identified that sEV-mDCs suppressed the Th2 immune response by reducing the production of IL-4, IL-9, and IL-13 via IL-10. Furthermore, sEV-mDCs increased the level of Treg cells. Our study identified that mDCs treated with MSC-sEV inhibited the Th2 responses, providing novel evidence of the potential cell-free therapy acting on DCs in allergic airway diseases.

A Prospective Study Comparing Cancer Detection Rates of Transperineal Prostate Biopsies Performed by Junior Urologists versus a Senior Consultant in a Real-World Setting.

INTRODUCTION: Prostate biopsy (PB) is a typical daily practice method for the diagnosis of prostate cancer (PCa). This study aimed to compare the PCa detection rates and peri- and postoperative complications of PB among 3 residents and a consultant. PATIENTS AND METHODS: A total of 343 patients who underwent PB between August 2018 and July 2019 were involved in this study. Residents were systematically trained for 2 weeks by a consultant for performing systematic biopsy (SB) and targeted biopsy (TB). And then, 3 residents and the consultant performed PB independently every quarter due to routine rotation in daily practice. The peri- and postoperative data were collected from a prospectively maintained database (www.pc-follow.cn). The primary outcome and secondary outcome were to compare the PCa detection rates and complications between the residents and consultant, respectively. RESULTS: There was no significant difference between the residents and consultant in terms of overall PCa detection rates of SB and TB or further stratified by prostate-specific antigen value and prostate imaging reporting and data system (PI-RADS) scores. We found the consultant had more TB cores (175 cores vs. 86-114 cores, p = 0.043) and shorter procedural time (mean 16 min vs. 19.7-20.1 min, p < 0.001) versus the residents. The complication rate for the consultant was 6.7% and 5%-8.2% for the residents, respectively (p = 0.875). CONCLUSIONS: The residents could get similar PCa detection and complication rates compared with that of the consultant after a 2-week training. However, the residents still need more cases to shorten the time of the biopsy procedure.

A Multicenter Single-Arm Objective Performance Criteria Trial to Determine the Efficacy and Safety of High-Frequency Irreversible Electroporation as Primary Treatment for Localized Prostate Cancer: A Study Protocol.

INTRODUCTION: The classical pathway for the therapy of low- to intermediate-risk localized prostate cancer is radical prostatectomy or radiation therapy, which has shown a high incidence of complications, including erectile dysfunction, urinary incontinence, and bowel injury. An alternative pathway is to perform an ablation by some energy to the localized lesion, known as focal therapy. High-frequency irreversible electroporation (H-FIRE) is nonthermal energy that can be used in cancer ablation to deliver pulsed high-voltage but low-energy electric current to the cell membrane and to invoke cell death. An H-FIRE pathway has been reported to be tissue-selective, which leads to fewer side effects. METHODS AND ANALYSIS: This is a multicenter and single-arm objective performance criteria (OPC) study, in which all men with localized prostate cancer are allocated to H-FIRE ablation. This trial will assess the efficacy and safety of the H-FIRE ablation for prostate cancer. Efficacy will be assessed by prostate biopsy 6 months after treatment while safety will be assessed by adverse event reports and questionnaires. The main inclusion criteria are moderate to low-risk prostate cancer in NCCN risk classification and had no previous therapy for prostate cancer. A sample size of 110 participants is required. The primary objective is to determine whether the detection rate of clinically significant cancer by prostate biopsy is less than 20% after the H-FIRE ablation. ETHICS AND DISSEMINATION: This study has obtained ethical approval by the ethics committee of all participating centers. The results of the study will be submitted for dissemination and publication in peer-reviewed journals. CONCLUSIONS: This multicenter single-arm objective performance criteria trial will evaluate the efficacy and safety of the use of high-frequency irreversible electroporation in treating prostate cancer. STRENGTHS AND LIMITATIONS OF THIS STUDY: A comprehensive evaluation of imaging and histopathology is used to determine the effect of treatment. Questionnaires were used to assess the treatment side effects. Multicenter and pragmatic designs capacitate higher generalizability. A limitation of this trial is that the prostate biopsy as an endpoint may not be as accurate as of the specimen from prostate prostatectomy. Another limitation is the 6-month follow-up time, making this trial challenging to come to firm conclusions regarding the efficacy and safety of IRE in the long term. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT03838432.

Plasma EVs Display Antigen-Presenting Characteristics in Patients With Allergic Rhinitis and Promote Differentiation of Th2 Cells.

Background: Allergic rhinitis (AR) is characterized by IgE-mediated mucosa response after exposure to allergens. Extracellular vesicles (EVs) are nano-size vesicles containing biological cargos for intercellular communications. However, the role of plasma EVs in pathogenesis of AR remains largely unknown. Methods: Plasma EVs from patients with AR were isolated, quantified, and characterized. The expression of Der p 1 and antigen-presenting molecules on EVs was determined by Western blot, flow cytometry, or ELISA. PKH26- and CFSE (carboxyfluorescein succinimidyl ester)-stained AR-EVs were used to determine the uptake of EVs by CD4+T cells and their effects on CD4+T cell proliferation, respectively. Results: Plasma EVs in healthy control (HC) and AR patients were similar in the concentration of particles, expression for specific EV markers, and both had structural lipid bilayer. However, the levels of Der p 1 on plasma EVs from both mild and moderate-severe AR patients were significantly higher than that on HC. The levels of antigen-presenting molecules on plasma EVs were similar from three subjects. Moreover, levels of Der p 1 on EVs in plasma, but not nasal secretion, were significantly associated with the symptom score of AR patients and level of plasma IL-13. Additionally, plasma EVs from patients with AR promoted the development of Th2 cells, while no effect was found on CD4+ T-cell proliferation. Conclusions: Plasma EVs derived from patients with AR exhibited antigen-presenting characteristics and promoted differentiation of Th2 cells, thus providing novel understanding of the pathogenesis of AR.

Anaesthesia in PROstate Biopsy Pain Obstruction Study: A Study Protocol for a Multicentre Randomised Controlled Study Evaluating the Efficacy of Perineal Nerve Block in Controlling Pain in Patients Undergoing Transperineal Prostate Biopsy.

Introduction: Transperineal prostate biopsy is as effective as the transrectal biopsy in detecting prostate cancer and has a lower risk of infection. However, concerning the procedural pain of the transperineal route, a higher level of anaesthesia is needed, which prevents this approach from being widely used. Although several methods of local anaesthesia to relieve pain during transperineal biopsy have been described, few well-designed trials have been conducted to assess the efficacy of local anaesthesia. Methods: This is a prospective, multicentre, randomised controlled study in men suspected of having prostate cancer and planning to undergo transperineal prostate biopsy. The aim of this trial is to determine whether the perineal nerve block and periprostatic block relieve pain to different extents in men undergoing transperineal biopsy. The main inclusion criteria are men aged between 18 and 80 years old, a prostate-specific antigen (PSA) level of 4-20 ng/ml, or/and suspicious rectal examination findings. A sample size of 190 participants, accounting for a 10% loss, is required. All participants will be randomly allocated at a ratio of 1:1 to the perineal nerve block (n = 95) and periprostatic block groups (n = 95). The primary outcome will be the level of the worst pain experienced during the transperineal prostate biopsy procedure, which will be measured by a numerical rating scale (NRS). The key secondary outcomes will include the pain severity score at 1, 6, and 24 h after prostate biopsy. Results: The primary outcome is the level of the worst pain experienced during the prostate biopsy procedure. The main secondary outcomes are as follows: (1) Post-biopsy pain severity score at 1, 6, and 24 h after the prostate biopsy; (2) Changes in blood pressure, heart rate and breathing rate during the biopsy procedure; (3) External manifestations of pain during biopsy; (4) Anaesthesia satisfaction; (5) The detection rate for clinically significant prostate cancer and any prostate cancer. Conclusion: Anaesthesia in PROstate biopsy Pain Obstruction Study (APROPOS) is randomised controlled trial aiming to determine the efficacy of the perineal nerve block in controlling pain in patients undergoing prostate biopsy via the transperineal approach. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT04501055.

IL-33 receptor expression on myeloid and plasmacytoid dendritic cells after allergen challenge in patients with allergic rhinitis.

The diversity of immune responses in allergic diseases is critically mediated by dendritic cells (DCs), including myeloid and plasmacytoid DCs. Allergen inhalation increased the release of IL-33 from patients with allergic rhinitis (AR), which affecting the downstream cells by binding to its receptor (ST2). However, the effects of inhaled allergens on the expression of ST2 by DCs and IL-33 on the function of mDCs are unknown. The levels of ST2+mDCs and ST2+pDCs in the blood from patients with AR and healthy subjects were examined using flow cytometry. Moreover, the patients were challenged using the allergens and the levels of ST2+mDCs and ST2+pDCs were investigated at different time points. We found that there were higher levels of ST2+ mDCs and ST2+ pDCs in patients with AR, and these levels were further increased 0.5 h after allergen inhalation. Additionally, the type 2 immune response was upregulated after challenge. IL-33 treatment increased the expression of ST2 on mDCs. Our study demonstrated that ST2 was upregulated on DCs after allergen inhalation and that mDCs responded directly to IL-33 through ST2, suggesting that the IL-33/ST2 axis might play an important role in the pathogenesis of allergic rhinitis by DCs.

[Remitting Seronegative Symmetrical Synovitis with Pitting Edema associated with Lung Malignancy:Case Report and Literature Review].

Remitting seronegative symmetrical synovitis with pitting edema(RS3PE),the inflammatory arthritis attacking mainly elderly males,is characterized by symmetrical synovitis with pitting edema of the dorsum of hands and feet and the absence of rheumatoid factor.RS3PE commonly accompanies malignant tumor,infections and other diseases.Here we report a case of RS3PE associated with lung malignancy and review other six cases to summarize the clinical features,treatment and prognosis.

Mesenchymal stem cells regulate type 2 innate lymphoid cells via regulatory T cells through ICOS-ICOSL interaction.

Group 2 innate lymphoid cells (ILC2s) are recognized as key controllers and effectors of type 2 inflammation. Mesenchymal stem cells (MSCs) have been shown to alleviate type 2 inflammation by modulating T lymphocyte subsets and decreasing TH 2 cytokine levels. However, the effects of MSCs on ILC2s have not been investigated. In this study, we investigated the potential immunomodulatory effects of MSCs on ILC2s in peripheral blood mononuclear cells (PBMCs) from allergic rhinitis patients and healthy subjects. We further investigated the mechanisms involved in the MSC modulation using isolated lineage negative (Lin- ) cells. PBMCs and Lin- cells were cocultured with induced pluripotent stem cell-derived MSCs (iPSC-MSCs) under the stimulation of epithelial cytokines IL-25 and IL-33. And the ILC2 levels and functions were examined and the possible mechanisms were investigated based on regulatory T (Treg) cells and ICOS-ICOSL pathway. iPSC-MSCs successfully decreased the high levels of IL-13, IL-9, and IL-5 in PBMCs in response to IL-25, IL-33, and the high percentages of IL-13+ ILC2s and IL-9+ ILC2s in response to epithelial cytokines were significantly reversed after the treatment of iPSC-MSCs. However, iPSC-MSCs were found directly to enhance ILC2 levels and functions via ICOS-ICOSL interaction in Lin- cells and pure ILC2s. iPSC-MSCs exerted their inhibitory effects on ILC2s via activating Treg cells through ICOS-ICOSL interaction. The MSC-induced Treg cells then suppressed ILC2s by secreting IL-10 in the coculture system. This study revealed that human MSCs suppressed ILC2s via Treg cells through ICOS-ICOSL interaction, which provides further insight to regulate ILC2s in inflammatory disorders.

Grade Evaluation of Salviae Miltiorrhizae Radix et Rhizoma Decoction Pieces Based on Relative Quality Constant / 中国实验方剂学杂志

Objective:To establish the grade evaluation standard of Salviae Miltiorrhizae Radix et Rhizoma decoction pieces combining traditional character evaluation and modern intrinsic quality analysis. Method:The appearance character parameters （thickness and weight） and contents of internal index components （tanshinones and salvianolic acid B） of 18 batches of Salviae Miltiorrhizae Radix et Rhizoma decoction pieces were determined， and the relative quality constant was calculated. The maximum value of the percentage quality constants of the tested samples was assumed to be 100%， the value ≥80% was classified as the first-class， ≥50% and <80% as the second-class， <50% as the third-class. Result:The relative quality constants of 18 batches of Salviae Miltiorrhizae Radix et Rhizoma decoction pieces ranged from 349 to 884. According to the percentage quality constant， 18 batches of samples were successfully divided into three grades. The relative quality constant of the first-class product was ≥707， including samples ds5， ds8 and ds14， accounting for about 17% of the total number of samples. The relative quality constant of the second-class product was ≥442 and <707， accounting for about 61% of the total number of samples. the other samples were of the third-class， and their relative quality constants were all <442. Conclusion:The method of relative quality constant overcomes the one-sidedness of the single method in the grade evaluation of Salviae Miltiorrhizae Radix et Rhizoma decoction pieces， and the evaluation results can objectively， reasonably and scientifically classify the grade of the decoction pieces， which can provide reference for the establishment of the grade standard of other decoction pieces.