BACKGROUND: Asthma is a common chronic inflammatory airway disease and intermittent hypoxia is increasingly recognized as a factor that may impact disease progression. The present study investigated whether intermittent hypoxia (IH) could aggravate asthma by promoting hypoxia-inducible factor-1α (HIF-1α)/nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain-containing protein 3 (NLRP3)/interleukin (IL)-1β-dependent pyroptosis and the inflammatory response and further elucidated the underlying molecular mechanisms involved. METHODS: A total of 49 patients diagnosed with severe bronchial asthma and diagnosed by polysomnography were enrolled at Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, between January 2022 and December 2022, and their general data and induced sputum were collected. BEAS-2B cells were treated with IL-13 and subjected to IH. An ovalbumin (OVA)-treated mouse model was also used to assess the effects of chronic intermittent hypoxia (CIH) on asthma. Pyroptosis, the inflammatory response, and related signalling pathways were assessed in vivo and in vitro . RESULTS: In this study, as the apnoea and hypopnea index (AHI) increased, the proportion of patients with uncontrolled asthma increased. The proportions of neutrophils and the levels of IL-6, IL-8, HIF-1α and NLRP3 in induced sputum were related to the AHI. NLRP3-mediated pyroptosis, which could be mediated by the HIF-1α signalling pathway, was activated in IL-13 plus IH-treated BEAS-2B cells and in the lungs of OVA/CIH mice. HIF-1α downregulation significantly reduced lung pyroptosis and ameliorated neutrophil inflammation by modulating the NLRP3/IL-1β pathway both in vitro and in vivo . Similarly, pretreatment with LW6, an inhibitor of HIF-1α, effectively blocked the generation of inflammatory cytokines in neutrophils. In addition, administration of the NLRP3 activator nigericin obviously increased lung neutrophil inflammation. CONCLUSIONS Obstructive sleep apnoea-hypopnea syndrome (OSAHS) is a risk factor for asthma exacerbation. IH aggravates neutrophil inflammation in asthma via NLRP3/IL-1β-dependent pyroptosis mediated by the HIF-1α signalling pathway, which should be considered a potential therapeutic target for the treatment of asthma with OSAHS.
NLR Family, Pyrin Domain-Containing 3 Protein/metabolism* ; Humans ; Asthma/metabolism* ; Animals ; Pyroptosis/physiology* ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism* ; Mice ; Signal Transduction/physiology* ; Male ; Hypoxia/metabolism* ; Female ; Interleukin-1beta/metabolism* ; Adult ; Inflammation/metabolism* ; Middle Aged ; Mice, Inbred C57BL

Pancreatic cancer is a highly lethal malignancy that is usually diagnosed at an advanced stage because of its absence of early symptoms and lack of effective screening tools. Although existing treatments (e.g., surgery, chemotherapy, and radiotherapy) can provide temporary relief, the therapeutic effect of pancreatic cancer remains limited, with major issues related to drug resistance and recurrence. In recent years, immunotherapy and targeted therapy have provided renewed hope to the treatment of pancreatic cancer. The immune microenvironment of pancreatic cancer is complex and strongly immunosuppressive. Immune cells such as tumor-associated macrophages and regulatory T cells can weaken the antitumor function of the immune system by secreting inhibitory factors, thereby enabling the tumor to evade immune surveillance. Meanwhile, immune escape is exacerbated by the infiltration of hypo-immune cells and the role of tumor-associated fibroblasts in the tumor microenvironment of pancreatic cancer. In response to these immune escape mechanisms, combining immunotherapy with targeted therapy has emerged as a focal point of current research. This review compiles the characteristics of the immune microenvironment in pancreatic cancer based on current literature, aiming to provide a basis and insights for related drug development.

Organoids are in vitro-cultured three-dimensional (3D) miniature structures derived from human pluripotent stem cells or adult stem cells from healthy individuals or patients. Compared to traditional two-dimensional (2D) cell lines or animal models, organoids are regarded as more promising high-fidelity models, possessing unique advantages in terms of disease modeling, drug development, the establishment of living biobanks, and the exploration of personalized treatment. Over recent years, the rapid development of organoid technology has brought new hopes for innovating preclinical experimental tumor models and promoting clinical personalized diagnosis and treatment. This review is intended to introduce the development status and latest progress of organoids in the field of radiotherapy for tumors, explore the advantages and limitations of organoid models for cancer, and prospect for its application in the field of radiotherapy.

Pancreatic cancer,as a common malignant tumor of the digestive system,has a very low survival rate.In recent years,pancreatic cancer has made great progress in diagnostic methods,radiation therapy techniques,and systemic chemotherapy,but its therapeutic effect has not been considerably improved.As a new type of tumor research platform,organoids have made research progress in many fields.Constructing pancreatic cancer organoids is of great research value to guide the individualized treatment of pancreatic cancer.This article reviews the research and clinical application prospect of organoid model in radiotherapy of pancreatic cancer.

To evaluate the safety and efficacy of neoadjuvant radiohormonal therapy for oligometastatic prostate cancer (OMPC), we conducted a 3 + 3 dose escalation, prospective, phase I/II, single-arm clinical trial (CHiCTR1900025743), in which long-term neoadjuvant androgen deprivation was adopted 1 month before radiotherapy, comprising intensity modulated radiotherapy to the pelvis, and stereotactic body radiation therapy to all extra-pelvic bone metastases for 4-7 weeks, at 39.6, 45, 50.4, and 54 Gy. Robotic-assisted radical prostatectomy was performed after 5-14 weeks. The primary outcome was treatment-related toxicities and adverse events; secondary outcomes were radiological treatment response, positive surgical margin (pSM), postoperative prostate-specific antigen (PSA), pathological down-grading and tumor regression grade, and survival parameters. Twelve patients were recruited from March 2019 to February 2020, aging 66.2 years in average (range, 52-80). Median baseline PSA was 62.0 ng/mL. All underwent RARP successfully without open conversions. Ten patients recorded pathological tumor down-staging (83.3%), and 5 (41.7%) with cN1 recorded negative regional lymph nodes on final pathology. 66.7% (8/12) recorded tumor regression grading (TRG) -I and 25% (3/12) recorded TRG-II. Median follow-up was 16.5 months. Mean radiological progression-free survival (RPFS) was 21.3 months, with 2-year RPFS of 83.3%. In all, neoadjuvant radiohormonal therapy is well tolerated for oligometastatic prostate cancer.
Male ; Humans ; Prostatic Neoplasms/radiotherapy* ; Prostate-Specific Antigen/therapeutic use* ; Neoadjuvant Therapy ; Androgen Antagonists/therapeutic use* ; Prospective Studies

Objective:To compare dose distributions of hypofractionated radiotherapy for pancreatic cancer between IMPT and VMAT.Methods:Ten pancreatic cancer cases were included in this retrospective study. Photon (Edge) and proton (Proteus?PLUS) plans were designed by Eclipse and RayStation TPS, respectively. All plans were transferred to MIM system for extraction of parameters, which included Dmin, Dmean and Dmax of PTV, conformity index (CI), new conformity index (nCI), homogeneity index (HI), gradient index (GI), coverage, Dmax and dose-volume of the organs at risk (OARs). Results:There was no significant difference in CI between the two groups. The higher PTV Dmin, Dmean, Dmax, D98%, D2%, HI, coverage and the better GI, D2 cmwere found in VMAT ( t/ Z=-4.63-5.32, P<0.05). The lower 10%_PD was found in IMPT ( t=-7.47, P<0.05). Regarding the OARs, Dmax of the intestine, stomach, and duodenum and Dmean of the left kidney were similar between two groups without significant difference ( P>0.05). The D5 cm 3 of the intestine, D10 cm 3 of the stomach, D5 cm 3 and D10 cm 3 of the duodenum, D2/3 of the left kidney, Dmean and D2/3 of the right kidney were lower in IMPT than those in VMAT ( t/ Z=-8.12--2.60, P<0.05). However, the Dmax and D0.35 cm 3 of the spinal cord were higher in IMPT than those in VMAT ( t=7.30, 6.77, P<0.05). Conclusions:Both of hypofractionated radiotherapy plans of pancreatic cancer designed by VMAT and IMPT could meet clinical needs. No significant difference was found in Dmax of the adjacent gastrointestinal tracts between the two groups. While IMPT had the advantage over VMAT in the case of lower dose-volumes of the gastrointestinal tracts. Nevertheless, less protections of the OARs in front of the tumor volume could be provided by IMPT compared with VMAT.

Objective:To compare the dose distribution among CyberKnife, Tomotherapy, Edge, Triology and γ-knife in stereotactic body radiation therapy (SBRT) for pancreatic cancer.Methods:Clinical data of 10 panreatic cancer patients receiving CyberKinife treatment were retrospectively analyzed. The treatment plans were designed by five apparatuses from five centers according to the uniform requirement. All plans were transferred to MIM system for the extraction of parameters, which mainly included D min, D mean and D max of PTV, conformity index (CI), new conformity index (nCI), homogeneity index (HI), gradient index (GI), coverage, D max and dose-volume of the stomach and bowel. Results:The best CI and nCI were obtained in Triology ( P<0.001), and the worst HI was found in γ-knife ( P<0.001). The best GI was found in CyberKnife, followed by γ-knife and Tomotherapy, and Edge showed the worst GI ( P<0.001). The highest D min of PTV was found in both Edge and Triology, while lower D min of PTV was found in CyberKnife and Tomotherapy ( P<0.001). Additionally, γ-knife provided the highest D mean and D max of PTV ( P<0.001). Regarding the organs at risk, the lowest D max and D 5cm 3 of the bowel ( P<0.001), D max of the stomach ( P=0.003), D max( P=0.001), D 5cm 3 ( P<0.001) and D 10cm 3 ( P=0.005) of the duodenum, D max( P<0.001) and D 0.35cm 3 ( P<0.001) of the spinal cord were found in CyberKnife. The highest D max of the bowel was found in γ-knife. Furthermore, the highest D 5cm 3 of the duodenum was demonstrated in Edge ( P<0.001) and Tomotherapy provided the highest D max( P<0.001) and D 0.35cm 3 of the spinal cord ( P<0.001). Conclusions:All five radiotherapy apparatuses can meet the requirement of SBRT for pancreatic cancer. More rapid dose fall-off could be obtained via CyberKnife and γ-knife. Triology and Edge provide better target conformity. CyberKnife can better protect the gastrointestinal tract.

Objective To evaluate the efficacy of stereotactic body radiation therapy (SBRT) on the survival of patients with early stage pancreatic cancer.Methods The clinical data of 103 T1-2N0M0 pancreatic cancer patients treated by CyberKnife SBRT at the Department of Radiation Oncology of Changhai Hospital from January 2012 to December 2016 was retrospectively analyzed.Kaplan-Meier method was used for survival analysis and Cox proportional hazards model was utilized to identify survival related factors.Results The median overall survival(OS) of T1-2N0M0 pancreatic cancer patients who had unresectable pancreatic cancer or refused surgery was 17.7 (16.1-19.3) months.1-year and 2-year OS rate were 86.3％ and 24.6％,respectively.The median progression free survival(PFS) was 13.0(10.7-15.3) months.1-year and 2-year PFS rate were 54.5％ and 6.3％,respectively.Patients with chemoradiation,BED10 ≥60 Gy and CA19-9 decrease ＞ 50％ after treatment had longer OS and PFS.Conclusions SBRT is a safe and effective treatment for patients with T1-2N0M0 pancreatic cancer.

Objective To identify the effect of stereotactic body radiation therapy (SBRT) on the survival of patients with recurrent pancreatic cancer after surgery.Methods The data of 104 patients with recurrent pancreatic cancer after surgery who underwent SBRT in the Department of Radiation Oncology of Changhai Hospital,Navy Medical University from February 2012 to December 2016 were retrospectively analyzed.The prescription doses ranged from 35-40 Gy/4-8 f.Survival analysis was performed using the Kaplan-Meier method,and relevant factors affecting patients' survival were screened by the Cox proportional hazards model.Results The median overall survival (OS) and progression free survival (PFS) was 12.5 (11.0-14.0) months and 7.3 (6.0-8.7) months,respectively,while the 1-year rate of OS and PFS was 55.8％ and 22.1％,respectively.Multivariate analysis indicated that tumor stage,biological effect dose (α/β =10,BED10),the decrease of CA19-9 level after treatment,and follow-up chemotherapy were all related factors affecting overall survival;tumor stage,BED10,the degree of pain relief and the decrease of CA19-9 level after treatment were related factors affecting PFS.Conclusions Patients suffering recurrent pancreatic cancer with early tumor stage,normal CA19-9 level and mild pain before treatment could be better treated by SBRT,BED10 ≥60 Gy and follow-up chemotherapy after radiotherapy can prolong the survival of patients.

Objective To comprehensively analyse the immunophenotype of primary pancreatic cancer,providing biological clues for treating pancreatic cancer.Methods The genome nap of 177 primary pancreatic cancer patients from the Cancer Genome Atlas (TCGA) database were enrolled.The overall immune infiltration score (IIS),T cell infiltration score (TIS) and antigen presenting machinery (APM) score were quantified for each specimen.By using unsupervised clustering,the patients were divided into immune-high group and immune-low group according to IIS,TIS,and APM scores.The differences on the inffiltration of immune cell subtype,expression of immune checkpoint and immunological function evaluation were compared between two groups.Results In the radiotherapy population,the survival rate of immune-high group was slightly higher than that of immune-low group with no statistical significance.The immune-high group had more infiltrated neutrophils (63.4％ vs 36.6％),eosinophils (75.5％ vs 24.5％),activated CD4 + memory T lymphocytes (80.7％ vs 19.3％),naive CD4 + T lymphocytes (81.2％ vs 18.8％) and naive B lymphocytes (59.5％ vs 40.5％) compared with immune low group;while the immune-low group had more activated NK cells (67.3％ vs 32.7％),regulatory T lymphocytes (68.9％ vs 31.1％),T follicular helper (67.7％ vs 32.3％),and activated mast cells (62.9％ vs 37.1％).Co-stimulatory molecules such as CD28,ICOS,CD40,CD40L,CD27,CD27L,4-1BB,OX40,GITR and co-inhibitory molecules including CTLA-4,PD-L2,PD-1,VISTA,LAG-3,TIGIT,Galectin-9,TIM-3,and IDO-1 were significantly higher expressed in the immune-low group (all P ＜ 0.05).The PC1 value of principal component analysis of chemokine expression levels and the cytolytic activity (CYT) in the immune-high group were significantly higher (all P ＜0.001).Conclusions Clustering on the three inmune quantification scores could be preliminarily used for immunophenotyping pancreatic cancer.The immune-high group may have synergistic effect with radiation therapy.Treatment with immune checkpoint inhibitor may be effective in immune-low group.