Immunogenic cell death (ICD) is a form of regulated cell death (RCD) induced by various stresses and produces antitumor immunity
damage-associated molecular patterns (DAMPs) release or exposure, ...mainly including high mobility group box 1 (HMGB1), calreticulin (CRT), adenosine triphosphate (ATP), and heat shock proteins (HSPs). Emerging evidence has suggested that ionizing radiation (IR) can induce ICD, and the dose, type, and fractionation of irradiation influence the induction of ICD. At present, IR-induced ICD is mainly verified
in mice and there is few clinical evidence about it. To boost the induction of ICD by IR, some strategies have shown synergy with IR to enhance antitumor immune response, such as hyperthermia, nanoparticles, and chemotherapy. In this review, we focus on the molecular mechanisms of ICD, ICD-promoting factors associated with irradiation, the clinical evidence of ICD, and immunogenic forms of cell death. Finally, we summarize various methods of improving ICD induced by IR.
Similar to other local therapeutic methods, local interstitial radiotherapy (IRT) also suffers from insufficient systematic immune activation, resulting in tumor metastasis.
Mn-based IRT ...radiosensitizers consisting of
I, MnO
and bovine serum albumin (BSA) (
I-MnO
-BSA) were engineered. Such Mn-based IRT radiosensitizers successfully unlocked radiogenetics to magnify systematic immune responses of local IRT via remodeling hypoxic and immunosuppressive microenvironments and resist tumor metastasis. The MnO
in
I-MnO
-BSA caused decomposition of H
O
enriched in tumors to generate O
for alleviating hypoxic microenvironment and removing tumor resistances to IRT. Concurrently, hypoxia mitigation by such radiosensitizers-unlocked radiogenetics can effectively remodel immunosuppressive microenvironment associated with regulatory T (Treg) cells and tumor-associated macrophages (TAMs) infiltration inhibition to induce immunogenic cell death (ICD), which, along with hypoxia mitigation, activates systematic immune responses. More intriguingly,
I-MnO
-BSA-enabled radiogenetics can upregulate PD-L1 expression, which allows anti-PD-L1-combined therapy to exert a robust antitumor effect on primary tumors and elicit memory effects to suppress metastatic tumors in both tumor models (4T1 and CT26).
IRT radiosensitizer-unlocked radiogenetics and the corresponding design principle provide a general pathway to address the insufficient systematic immune responses of local IRT.
The use of phase analysis techniques to assess left ventricular mechanical dyssynchrony (LVMD) has been well documented. However, artifacts have reduced the accuracy of the assessment due to soft ...tissue attenuation, so little information is available about the effects of obesity on LVMD. The aim of this study was to evaluate LVMD in patients with simple obesity by SPECT with a new cadmium-zinc telluride (CZT) detector and to explore the effects of obesity on left ventricular wall motion. We retrospectively analyzed 95 patients with myocardial perfusion imaging (MPI) images without perfusion defects, of which 55 were diagnosed with simple obesity (BMI > 30), and 40 non-obese patients (BMI < 25) matched for age and sex were used as controls. The five-point method was used to analyze the MPI images of the two groups, and the complete cardiac function parameters including phase bandwidth (PBW) and phase standard deviation (PSD) were obtained. Although the PBW values of the two groups were within the normal range (cut-off value > 90°), the PBW (35.4 ± 28 vs 24.9 ± 7.5,
P
< .001; 36.6 ± 18.4 vs 28.7 ± 9.1,
P
= 0.01) and PSD (8.7 ± 7.6 vs 5.9 ± 2,
P
= 0.02; 9.2 ± 4.9 vs 7.1 ± 2.7,
P
= 0.01) of the obese group were larger than the control group under both stressing and resting, and the difference was statistically significant. CZT-SPECT can effectively assess LVMD in obese patients, and they are more likely to develop LVMD, which may be related to their left ventricular volume.
Abstract Background Astatine-211 is an α-emitter with high-energy α-ray and high cytotoxicity for cancer cells. However, the targeted alpha therapy (TAT) also suffers from insufficient systematic ...immune activation, resulting in tumor metastasis and relapse. Combined immune checkpoint blockade (ICB) with chemodynamic therapy (CDT) could boost antitumor immunity, which may magnify the immune responses of TAT. This study aims to discourage tumor metastasis and relapse by tri-model TAT-CDT-ICB strategy. Methods We successfully designed Mn-based radioimmunotherapy promoters ( 211 At-ATE-MnO 2 -BSA), which are consisting of 211 At, MnO 2 and bovine serum albumin (BSA). The efficacy of 211 At-ATE-MnO 2 -BSA was studied as monotherapy or in combination with anti-PD-L1 in both metastatic and relapse models. The immune effects of radioimmunotherapy promoters on cytotoxic T lymphocytes and dendritic cells (DCs) were analyzed by flow cytometry. Enzyme-linked immunosorbent assay and immunofluorescence were used to explore the underlying mechanism. Results Such radioimmunotherapy promoters could not only enhance the therapeutic outcomes of TAT and CDT, but also induce robust anti-cancer immune activity by activating dendritic cells. More intriguingly, 211 At-ATE-MnO 2 -BSA could effectively suppress the growths of primary tumors and distant tumors when combined with immune checkpoint inhibitors. Conclusions The tri-model TAT-CDT-ICB strategy provides a long-term immunological memory, which can protect against tumor rechallenge after eliminating original tumors. Therefore, this work presents a novel approach for TAT-CDT-ICB tri-modal cancer therapy with repressed metastasis and relapse in clinics.
Purpose:
To evaluate the value of texture analysis for the differential diagnosis of spinal metastases and to improve the diagnostic performance of 2-deoxy-2-fluorine-18fluoro-D-glucose positron ...emission tomography/computed tomography (
18
F-FDG PET/CT) for spinal metastases.
Methods:
This retrospective analysis of patients who underwent PET/CT between December 2015 and January 2020 at Shanghai Tenth People's Hospital due to high FDG uptake lesions in the spine included 45 cases of spinal metastases and 44 cases of benign high FDG uptake lesions in the spine. The patients were randomly divided into a training group of 65 and a test group of 24. Seventy-two PET texture features were extracted from each lesion, and the Mann-Whitney
U
-test was used to screen the training set for texture parameters that differed between the two groups in the presence or absence of spinal metastases. Then, the diagnostic performance of the texture parameters was screened out by receiver operating characteristic (ROC) curve analysis. Texture parameters with higher area under the curve (AUC) values than maximum standardized uptake values (SUVmax) were selected to construct classification models using logistic regression, support vector machines, and decision trees. The probability output of the model with high classification accuracy in the training set was used to compare the diagnostic performance of the classification model and SUVmax using the ROC curve. For all patients with spinal metastases, survival analysis was performed using the Kaplan-Meier method and Cox regression.
Results:
There were 51 texture parameters that differed meaningfully between benign and malignant lesions, of which four had higher AUC than SUVmax. The texture parameters were input to build a classification model using logistic regression, support vector machine, and decision tree. The accuracy of classification was 87.5, 83.34, and 75%, respectively. The accuracy of the manual diagnosis was 84.27%. Single-factor survival analysis using the Kaplan-Meier method showed that intensity was correlated with patient survival.
Conclusion:
Partial texture features showed higher diagnostic value for spinal metastases than SUVmax. The machine learning part of the model combined with the texture parameters was more accurate than manual diagnosis. Therefore, texture analysis may be useful to assist in the diagnosis of spinal metastases.
The cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) pathway is an essential component of the innate immune system and is central to the identification of abnormal DNA leakage ...caused by ionising radiation (IR) damage. Cell‐intrinsic cGAS–STING initiation has been revealed to have tremendous potential for facilitating interferon synthesis and T‐cell priming. Targeting the cGAS–STING axis has been proposed as a strategy to improve radiosensitivity or enhance immunosurveillance. However, due to the complex biology of the irradiated tumour microenvironment and the extensive involvement of the cGAS–STING pathway in various physiological and pathological processes, many defects in this strategy limit the therapeutic effect. Here, we outline the molecular mechanisms by which IR activates the cGAS–STING pathway and analyse the dichotomous roles of the cGAS–STING pathway in modulating cancer immunity after radiotherapy (RT). Then, based on the crosstalk between the cGAS–STING pathway and other signalling events induced by IR, such as necroptosis, autophagy and other cellular effects, we discuss the immunomodulatory actions of the broad cGAS–STING signalling network in RT and their potential therapeutic applications. Finally, recent advances in combination therapeutic strategies targeting cGAS–STING in RT are explored.
Ionising radiation (IR)‐induced activation of the cGAS–STING cytosolic nucleic acid sensing pathway has a dichotomous role in initiating cancer immunosurveillance and immunosuppression, which is critical for remodelling the tumour microenvironment. Other signalling events activated after IR, such as various cell death modalities, can further regulate cancer immunity indirectly by enhancing or inhibiting cGAS–STING signalling. Therefore, targeting the cGAS–STING pathway in radiotherapy (RT) to enhance antitumour immune activation without causing negative effects such as immunosuppression and RT resistance is a promising combination therapy approach.
ETHNOPHARMACOLOGICAL RELEVANCEPulmonary injury and fibrosis can be caused by various factors because of their inflammatory nature, both can lead to serious clinical consequences. Inula japonica ...Thunb. is used in traditional Chinese medicine for the treatment of lung diseases. However, the effect and mechanism of action of the essential oil of I. japonica (EOI) on pulmonary injury and fibrosis are not well understood.AIM OF THE STUDYTo investigate the therapeutic effects of EOI on mice with bleomycin (BLM)-induced acute pulmonary injury and chronic fibrosis formation, as well as its potential mechanism.MATERIALS AND METHODSA short-term mouse model of pulmonary injury was established by intratracheal injection of BLM to investigate the anti-inflammatory effect of EOI, and a long-term model of pulmonary fibrosis was used to explore the anti-fibrosis effect of EOI. High-dose EOI (200 mg/kg) was administered intragastrically, and low-dose (50 mg/kg) was administered by intratracheal injection. Gas chromatography-mass spectrometry (GC-MS) was used to identify the ingredients in EOI, and high-performance liquid chromatography (HPLC) was performed for the preparation of EOI compounds. Western blot and real-time qPCR were used to verify the effects of EOI and its active composition on inflammation, oxidative stress and fibrosis signaling pathway.RESULTSTreatment with EOI significantly reduced the inflammation and oxidative stress by reducing the levels of inflammatory and oxidative cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and malondialdehyde in BLM-treated mice with acute pulmonary injury. EOI treatment could also suppress the formation of fibrous tissue in mice with BLM-induced pulmonary fibrosis through inhibiting TGF-β/Smad and PI3K/Akt pathways. Chromatographic analysis and preparation suggested that fatty acid and phenol derivatives are present in EOI. Based on cellular inflammation and fibrosis models, the phenolic compounds in EOI can represent the anti-inflammatory and anti-fibrotic effects of EOI by regulating pro-inflammatory and pro-fibrotic cytokines such as NO, TNF-α, IL-6, TGF-β1, and α-SMA.CONCLUSIONEOI ameliorated BLM-induced pulmonary injury and fibrosis in mice by inhibiting the inflammatory response and regulating the redox equilibrium, as well as by mediating TGFβ/Smad and PI3K/Akt, which suggested that EOI has potential to treat pulmonary diseases.
Experiments have shown that metformin can inhibit cancer cell growth, but clinical observations have been inconsistent, so we pooled the currently available data to evaluate the impact of metformin ...on cancer survival and progression.
PubMed, web of science, Embase, and Cochrane databases were searched. Pooled hazard ratios (HRs) were identified using a random-effects model to estimate the strength of the association between metformin and survival and progression in cancer patients.
We incorporated 80 articles published from all databases which satisfied the inclusion criterion. It showed that metformin was associated with better overall survival (hazard ratio HR = 0. 81; 95% confidence interval CI: 0.77-0.85) and cancer-specific survival (HR = 0.79; 95% CI: 0.73-0.86), and metformin was associated with progression-free survival (HR = 0.76; 95% CI: 0.66-0.87). In patients with diabetes mellitus, the HR of overall survival was 0.79(95% CI: 0.75-0.83), progression-free survival was 0.72(95% CI: 0.60-0.85), and the cancer-specific survival was 0.76(95% CI: 0.68-0.86). It was proposed that metformin can improve the prognosis of cancer patients with diabetes mellitus.
Based on cohort studies, metformin therapy has potential survival benefits for patients with malignancy, especially with the greatest benefits seen in breast cancer on overall survival, progression-free survival, and cancer-specific survival. And metformin also showed potential benefits in cancer-specific survival in colorectal and prostate cancer.
Small cell lung cancer (SCLC) is a neuroendocrine tumor with a high degree of malignancy. Due to limited treatment options, patients with SCLC have a poor prognosis. We have found, however, that ...intravenously administered octreotide (Oct) armed with astatine-211 (211AtSAB-Oct) is effective against a somatostatin receptor 2 (SSTR2)-positive SCLC tumor in SCLC tumor-bearing BALB/c nude mice. In biodistribution analysis, 211AtSAB-Oct achieved the highest concentration in the SCLC tumors up to 3 h after injection as time proceeded. A single intravenous injection of 211AtSAB-Oct (370 kBq) was sufficient to suppress SSTR2-positive SCLC tumor growth in treated mice by inducing DNA double-strand breaks. Additionally, a multitreatment course (370 kBq followed by twice doses of 370 kBq for a total of 1110 kBq) inhibited the growth of the tumor compared to the untreated control group without significant off-target toxicity. Surprisingly, we found that 211AtSAB-Oct could up-regulate the expressions of calreticulin and major histocompatibility complex I (MHC-I) on the tumor cell membrane surface, suggesting that α-particle internal irradiation may activate an endogenous antitumor immune response through the regulation of immune cells in the tumor microenvironment, which could synergically enhance the efficacy of immunotherapy. We conclude that 211AtSAB-Oct is a potential new therapeutic option for SSTR2-positive SCLC.
PDF
