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Abstract Hepatocellular carcinoma is one of the most common malignant tumors, and radiotherapy plays a pivotal role in its therapeutic regimen. However, radiotherapy resistance is the main cause of therapeutic failure in patients. Our previous study revealed that Adiponectin Receptor 1 (AdipoR1) is involved in regulating radiation resistance in liver cancer patients treated with stereotactic body radiotherapy. To explore the mechanism, we performed high-throughput transcriptome sequencing of hepatocellular carcinoma cells with stable knockdown of AdipoR1. KEGG enrichment analysis indicated that the cell cycle and ubiquitination degradation pathways may be involved in the regulation of radiation resistance by AdipoR1.The knockdown of AdipoR1 can attenuate the radiation-induced G2/M phase arrest through cyclin B1.By the ubiquitination IP assay and a rescue experiment, we confirmed that CCNB1IP1 regulated the ubiquitination and degradation of cyclin B1. Combined with information from transcription factor database and AdipoR1 transcriptome sequencing, these results showed that estrogen receptor 1 (ESR1) may be a transcription factor of CCNB1IP1. We found that AdipoR1 promoted the translocation of ESR1 from the cytoplasm to the nucleus, and ESR1 inhibited the transcription of CCNB1IP1.Therefore, we propose that AdipoR1 regulates the ubiquitination level, cell cycle progression, and radiation resistance of HCC cells through the “AdipoR1 /ESR1/CCNB1IP1/cyclin B1” axis. This study will promote the development of novel targeted radiosensitizing drugs.

Abstract Radiotherapy is one of the main treatment modalities for advanced hepatocellular carcinoma (HCC). Ferroptosis has been shown to promote the radiosensitivity of HCC cells, but it remains unclear whether epigenetic regulations function in this process. In this study, we found that the overexpression of METTL3 was associated with poor prognosis. Knockdown of METTL3 promoted radiosensitivity of HCC by inducing ferroptosis. Mechanistically, METTL3 targeted adenine (+1795) on the SLC7A11 mRNA, and the m6A reader IGF2BP2 promoted SLC7A11 mRNA stability by recognizing and binding to the m6A site. Additionally, METTL3 decreased the ubiquitination of SLC7A11 protein through the m6A/YTHDF2/SOCS2 axis. Furthermore, in vivo studies showed that HCC models with low METTL3/IGF2BP2 expression have higher radiosensitivity. In conclusion, our study suggests that METTL3 regulates the stability of SLC7A11 mRNA in an m6A/IGF2BP2-dependent manner and the ubiquitination of SLC7A11 protein through the m6A/YTHDF2/SOCS2 pathway, both of which require the m6A methyltransferase activity of METTL3. METTL3 or IGF2BP2 may be promising targets for radiotherapy of HCC.

Abstract This study aimed to assess the efficacy and safety of a combination therapy of Allisartan Isoproxil 240 mg and Amlodipine 5 mg (ALI/AML) compared to AML 5 mg monotherapy in patients with mild‐to‐moderate essential hypertension. In this phase III, multicenter, double‐blind, parallel‐group, randomized controlled trial, patients aged 18–70 years with mean sitting systolic blood pressure (msSBP) between 140 and

Summary: Background: Existing studies have not provided robust evidence about the CVD risk of non-smoking patients with restrictive spirometric pattern (RSP) or airflow obstruction (AFO), and how the risk is modified by body shape. We aimed to bridge the gap. Methods: We used never-smokers' data from the China Kadoorie Biobank (CKB) and performed Cox models by sex (278,953 females and 50,845 males). Spirometry was used to assess the baseline spirometric pattern. CVD outcomes were captured through multiple sources. Findings: Females’ results were presented primarily, though males' results were similar. During a median 12-year (maximum 14.5 years) follow-up, both RSP and AFO patients had increased risks of acute myocardial infarction (AMI), other ischaemic heart disease (other IHD), heart failure, pulmonary heart disease, arrhythmia, and intracerebral haemorrhage (ICH). RSP was also associated with ischaemic stroke (IS). The HRs (95% CIs) for AFO in females ranged from 1.29 (1.15–1.45) for ICH to 8.84 (7.79–10.03) for pulmonary heart disease, while those for RSP ranged from 1.11 (1.08–1.15) for IS to 3.17 (2.80–3.59) for pulmonary heart disease. These risks increased with the severity of AFO and reduced FVC. RSP/AFO was more strongly associated with other IHD, heart failure, and pulmonary heart disease in underweight females than in normal and obese counterparts, respectively. Interpretation: With the confounding of smoking fully controlled, both RSP and AFO were associated with higher risks of various CVD outcomes, which further increased with the severity of AFO and reduced FVC. These associations were even stronger in underweight individuals. Funding: National Natural Science Foundation of China, National Key Research and Development Program of China, Ministry of Science and Technology of the People's Republic of China, Kadoorie Charitable Foundation, UK Wellcome Trust, UK Medical Research Council, Cancer Research UK, and British Heart Foundation.

Excessive agricultural investment brought about by increased multiple-cropping index may compromise environmental sustainability. There are few studies on the sustainability of diversified multi-cropping systems in the Yangtze River Basin (YRB). Therefore, this study selected five representative locations in the YRB. According to the local climate characteristics and food demand, diversified multi-cropping systems were designed, and the main local winter crops were selected as the previous crops of the corn–soybean strip compound cropping system, with the local traditional double-cropping model as the control (CK). The emergy evaluation method was introduced to quantitatively compare the efficiency and sustainability of diversified multi-cropping systems in the YRB. The results showed that by incorporating soybean by intercropping with corn, compared with the CK, the total energy input, annual energy output, and annual economic output increased by 15.80%, 9.78%, and 33.12% on average, respectively. The unit emergy value (UEV) and unit non-renewable value (UNV) increased by 6.03% and 5.98%, respectively; the emergy yield ratio (EYR) and environmental loading ratio (ELR) decreased by 0.91% and 0.44%, respectively; the emergy sustainability index (ESI) was the same. In the third mature crop selection, compared with that of corn, the ELR of soybean decreased by 14.32%, and the ESI increased by 18.55%. In addition, the choice of winter crops plays a vital role in the system’s efficiency and sustainability. Compared with those of other winter crops, the annual economic outputs of potato (upper reaches of the YRB), potato or forage rape (middle reaches of the YRB), and wheat (lower reaches of the YRB) increased by 51.02%, 32.27%, and 0.94%, respectively; their ESI increased by 71.21%, 47.72%, and 12.07%, respectively. Potato–corn/soybean or potato/corn/soybean (upper reaches of the YRB), forage rape–corn/soybean or potato/corn/soybean (middle reaches of the YRB), and wheat–corn/soybean (lower reaches of the YRB) were chosen to facilitate the coexistence of high economic benefits and environmental sustainability. Additionally, promoting mechanization and reducing labor input were essential to improve the efficiency and sustainability of multi-cropping systems. This study would provide a scientific basis and theoretical support for the development of efficient and sustainable multiple-cropping systems in the dryland of the YRB.

Summary: Background: Ultrasonography is the most widely used technique to diagnose echinococcosis; however, challenges in using this technique and the demand on medical resources, especially in low-income or remote areas, can delay diagnosis. We aimed to develop a deep convolutional neural network (DCNN) model based on ultrasonography to identify echinococcosis and its types, especially alveolar echinococcosis. Methods: This retrospective, large-scale, multicentre study used ultrasound images from patients assessed at 84 hospitals in China, obtained between Jan 1, 2002, and Dec 31, 2021. Patients with a diagnosis of cystic echinococcosis, alveolar echinococcosis, or seven other types of focal liver lesions were included. We tested ResNet-50, ResNext-50, and VGG-16 as the backbone network architecture for a classification DCNN model and input the perinodular information from the ultrasound images. We trained and validated the DCNN model to diagnose and classify echinococcosis using still greyscale ultrasound images of focal liver lesions in four stages: differentiating between echinococcosis and other focal liver lesions (stage one); differentiating cystic echinococcosis, alveolar echinococcosis, and other focal liver lesions (stage two); differentiating cystic echinococcosis, alveolar echinococcosis, benign other focal liver lesions, and malignant focal liver lesions (stage three); and differentiating between active and transitional cystic echinococcosis and inactive cystic echinococcosis (stage four). We then tested the algorithm on internal, external, and prospective test datasets. The performance of DCNN was also compared with that of 12 radiologists recruited between Jan 15, 2022, and Jan 28, 2022, from Qinghai, Xinjiang, Anhui, Henan, Xizang, and Beijing, China, with different levels of diagnostic experience for echinococcosis and other focal liver lesions in a subset of ultrasound data that were randomly chosen from the prospective test dataset. The study is registered at ClinicalTrials.gov (NCT03871140). Findings: The study took place between Jan 1, 2002, and Dec 31, 2021. In total, to train and test the DCNN model, we used 9631 liver ultrasound images from 6784 patients (2819 [41·7%] female patients and 3943 [58·3%] male patients) from 87 Chinese hospitals. The DCNN model was trained with 6328 images, internally validated with 984 images, and tested with 2319 images. The ResNet-50 network architecture outperformed VGG-16 and ResNext-50 and was generalisable, with areas under the receiver operating characteristic curve (AUCs) of 0·982 (95% CI 0·960–0·994), 0·984 (0·972–0·992), and 0·913 (0·886–0·935) in distinguishing echinococcosis from other focal liver lesions; 0·986 (0·966–0·996), 0·962 (0·946–0·975), and 0·900 (0·872–0·924) in distinguishing alveolar echinococcosis from cystic echinococcosis and other focal liver lesions; and 0·974 (0·818–1·000), 0·956 (0·875–0·991), and 0·944 (0·844–0·988) in distinguishing active and transitional cystic echinococcosis from inactive echinococcosis in the three test datasets. Specifically, in patients with the hepatitis B or hepatitis C virus, the model could distinguish alveolar echinococcosis from hepatocellular carcinoma with an AUC of 0·892 (0·812–0·946). In identifying echinococcosis, the model showed significantly better performance compared with senior radiologists from a high-endemicity area (AUC 0·942 [0·904–0·967] vs 0·844 [0·820–0·866]; p=0·027) and improved the diagnostic ability of junior, attending, and senior radiologists before and after assistance with AI with comparison of AUCs of 0·743 (0·714–0·770) versus 0·850 (0·826–0·871); p

Abstract Given the rapid developments in RNA-seq technologies and bioinformatic analyses, circular RNAs (circRNAs) have gradually become recognized as a novel class of endogenous RNAs, characterized by covalent loop structures lacking free terminals, which perform multiple biological functions in cancer genesis, progression and metastasis. Hypoxia, a common feature of the tumor microenvironments, profoundly affects several fundamental adaptive responses of tumor cells by regulating the coding and non-coding transcriptomes and renders cancer’s phenotypes more aggressive. Recently, hypoxia-responsive circRNAs have been recognized as a novel player in hypoxia-induced non-coding RNA transcriptomics to modulate the hypoxic responses and promote the progression and metastasis of hypoxic tumors. Moreover, via extracellular vesicles-exosomes, these hypoxia-responsive circRNAs could transmit hypoxia responses from cancer cells to the cells of surrounding matrices, even more distant cells of other organs. Here, we have summarized what is known about hypoxia-responsive circRNAs, with a focus on their interaction with hypoxia-inducible factors (HIFs), regulation of hypoxic responses and relevance with malignant carcinoma’s clinical features, which will offer novel insights on the non-coding RNAs’ regulation of cancer cells under hypoxic stress and might aid the identification of new theranostic targets and define new therapeutic strategies for those cancer patients with resistance to radiochemotherapy, because of the ubiquity of tumoral hypoxia.

Objective: Effects of phycobiliprotein and phycocyanin from artifically raised Nostoc sphaeroides Kützing on the growth of tumor in S180 tumor-bearing mice and its mechanism. Methods: The in vivo antitumor activity of phycobiliprotein and phycocyanin from Nostoc sphaeroides Kützing was evaluated by examining the tumor volume of S180 tumor-bearing mice, mouse organ indices and tumor tissue section observation, and its mechanism of action was initially studied. Results: The results of in vivo antitumor effect showed that the tumor inhibition rates of phycobiliprotein 12.5, 25 and 50 mg/kg dose groups were 11.19%, 20.14% and 37.65%, respectively, against mouse sarcoma S180. The tumor inhibition rates of phycocyanin 12.5, 25 and 50 mg/kg dose groups were 19.74%, 35.00% and 52.06%, respectively, against mouse sarcoma S180. Phycocyanin significantly promoted the expression of oncoprotein P53 and pro-apoptotic protein Bax, and inhibited the expression of apoptosis suppressor protein Bcl2. Conclusion: Phycocyanin high dose group significantly reduced the proliferation of S180 sarcoma cells. Phycocyanin low and medium doses and phycocyanin high doses also had some inhibitory effects. Phycobiliprotein and phycocyanin from artifically raised Nostoc sphaeroides Kützing have better in vivo antitumor activity.

Systemic lupus erythematosus (SLE) is a latent, insidious autoimmune disease, and with the development of gene sequencing in recent years, our study aims to develop a gene-based predictive model to explore the identification of SLE at the genetic level. First, gene expression datasets of SLE whole blood samples were collected from the Gene Expression Omnibus (GEO) database. After the datasets were merged, they were divided into training and validation datasets in the ratio of 7:3, where the SLE samples and healthy samples of the training dataset were 334 and 71, respectively, and the SLE samples and healthy samples of the validation dataset were 143 and 30, respectively. The training dataset was used to build the disease risk prediction model, and the validation dataset was used to verify the model identification ability. We first analyzed differentially expressed genes (DEGs) and then used Lasso and random forest (RF) to screen out six key genes (OAS3, USP18, RTP4, SPATS2L, IFI27 and OAS1), which are essential to distinguish SLE from healthy samples. With six key genes incorporated and five iterations of 10-fold cross-validation performed into the RF model, we finally determined the RF model with optimal mtry. The mean values of area under the curve (AUC) and accuracy of the models were over 0.95. The validation dataset was then used to evaluate the AUC performance and our model had an AUC of 0.948. An external validation dataset (GSE99967) with an AUC of 0.810, an accuracy of 0.836, and a sensitivity of 0.921 was used to assess the model’s performance. The external validation dataset (GSE185047) of all SLE patients yielded an SLE sensitivity of up to 0.954. The final high-throughput RF model had a mean value of AUC over 0.9, again showing good results. In conclusion, we identified key genetic biomarkers and successfully developed a novel disease risk prediction model for SLE that can be used as a new SLE disease risk prediction aid and contribute to the identification of SLE.

AimsEvaluating the prognostic validity of new R2-CHA2DS2-VASc score for no-reflow phenomena and long-term prognosis in patients following primary percutaneous coronary intervention (PCI) with ST-elevation myocardial infarction (STEMI).Materials and methodsFrom January 2017 to December 2018, a total of 401 patients with STEMI were continuously enrolled. According to the cut-off value, the patients were separated into two groups: R2-CHA2DS2-VASc < 3 group (n = 275) and R2-CHA2DS2-VASc ≥ 3 group (n = 126).ResultsWith a sensitivity of 52.6% and a specificity of 73.1%, the optimal cut-off value for predicting no-reflow is R2-CHA2DS2-VASc ≥ 3. R2-CHA2DS2-VASc ≥ 3 as the ideal cut-off value for predicting major adverse cardiovascular events (MACE) with an area under the curve (AUC) of 0.781 [95% Confidence interval (CI): 0.738–0.801, P 0.001], a sensitivity of 50%, and a specificity of 91.1%. The incidence of MACE, death from all causes, and worsening heart failure was greater in the R2-CHA2DS2-VASc ≥ 3 group, although there was no significant difference in the incidence of repeated revascularisation procedures following PCI between the two groups. R2-CHA2DS2-VASc ≥ 3 was also an independent predictor of MACE (hazard ratio = 2.48, 95% confidence interval CI: 1.33–4.62, P = 0.04). Moreover, this score has a greater sensitivity (66.7%) and specificity (88.7%) for predicting the progression of heart failure.ConclusionR2-CHA2DS2-VASc ≥ 3 was independently associated with no-reflow phenomenon and poor clinical outcomes for patients in STEMI after primary PCI.

Radiation-induced lung injuries (RILI) is one of the serious complications of radiotherapy posed by the damage of alveolar cells and inflammation over-reaction. We aimed to investigate the potential protective effects of doxepin on RILI (20 Gy total dose at 3 Gy/min of X-ray irradiation), as well as its underlying mechanism. For animal experiments, such parameters as Immunohistochemistry and hematoxylin and eosin (H&E) staining, WBC (white blood cell), CRP (C-reactive protein), Western blot, and q-PCR were detected. The results indicated that both survival status and weight increase of irradiated rats treated by doxepin (3 mg/kg/day, rat) were higher than those of treated with irradiation alone (Dosing started the day before irradiation). Further, histological examinations showed doxepin could tenuate the radiation injury, as indicated as alveolar inflammatory exudation and there was only mild interstitial inflammation infiltration. Western blotting and q-PCR showed that expression of NF-κβ in X group were higher than that in XMD group. For the first time, we reported doxepin functioned as a radioprotectant candidate, which provide a promising application of doxepin for protecting radiotherapy injuries.

Objective So far there are still no effective immediate-early markers for assessing the efficacy of Stereotactic Body Radiation Therapy (SBRT). To find effective biomarkers for accurate assessment of the efficacy of SBRT in patients with primary liver cancer, we conducted this study including retrospective part and prospective part. Material and Methods 589 patients with primary liver cancer were included at Ruikang Hospital affiliated to Guangxi Medical University from January 2012 to December 2018. Follow-up was conducted, clinical information and a total of 17 patients with 51 blood samples (before SBRT, before discharge and 2 months after SBRT) were collected. mRNAs profiles on 2 patients with 6 blood samples were detected by high-throughput sequencing, followed by qPCR verification on 15 patients with 45 blood samples. Results The commonly used serum biomarkers such as AFP, CEA, and CA125 shown low prognostic value in distinguishing survival group and death group, indicated by low AUC (less than .7) and Youden indexes (less than .5). Based on high-throughput sequencing of test group and qPCR detection of another verification group, we found 16 up-regulated and 12 downregulated genes after SBRT. Among them, ADIPOR1 and EPB42 showed significantly different between effective and ineffective group after SBRT, ROC suggested that based on the optimal threshold of .5838, ADIPOR1 shown a sensitivity of 100% and a specificity of 83.33% to distinguish effective from ineffective group. And EPB42 had a sensitivity of 75% and a specificity of 100% at the optimal threshold of 1.3817. In addition, GSEA showed that high expression of ADIPOR1 was mainly related to Mismatch repair, Circadian rhythm, Protein processing in endoplasmic reticulum, DNA replication, and Fanconi anemia pathways. Conclusion ADIPOR1 in whole blood is a promising candidate to act as prognostic biomarker for predication of SBRT outcomes in primary liver cancer patients.

Radiotherapy is one of the most important treatments for breast cancer. Ferroptosis is a recently recognized form of regulated cell death that is characterized by lipid peroxidation. However, whether ionizing radiation (IR) could induce ferroptosis in breast cancer and how it works remain unknown. Bioinformatics analysis were performed to screen ferroptosis-related genes differentially expressed in breast tumor tissue and normal tissue. Then, breast cancer cell lines with different estrogen receptor (ER) phenotypes were used for studies in vitro, including ER-positive (MCF-7 and ZR-75-1) and ER-negative (MDA-MB-231) cells. The dynamic changes of mRNA and protein levels were examined after x-ray of 8 Gy by qRT-PCR and Western blotting, respectively. Immunoprecipitation (IP) was used to explore the interaction between proteins. Luciferase assay was used to analyze the transcriptional regulation effect of ESR1 on SLC7A11. BODIPY C11 and trypan blue dyes were used to determine lipid peroxidation and cell death, respectively. The result showed that the ferroptosis-related gene SLC7A11 was higher in breast cancer tissues compared with normal tissues and associated with poor survival. A positive correlation exists between ESR1 and SLC7A11 expression. ESR1 promoted SLC7A11 expression at the early stage after IR. ESR1/SLC7A11 knockdown significantly enhanced IR-induced ferroptosis in ER-positive cells. At 12 h after IR, the IP data showed the interaction between E3 ubiquitin ligase NEDD4L and SLC7A11 increased, followed by the ubiquitylation and degradation of SLC7A11. Thus, SLC7A11 expression was regulated by both ESR1 and NEDD4L, in opposite ways. For the first time, we elucidated that ESR1 and NEDD4L functioned together after radiation treatment and finally induced ferroptosis in breast cancer cells, which provides novel insight into the guidance of clinical treatment of breast cancer.

Light presents an important exogenous factor for poultry. This study examined effects of LED lights with different defined spectrums on growth and reproduction of indigenous Beijing-You chickens. A total of 576 one-day old female chicks were divided into 16 rooms, and each were exposed to four different lights: LED A (21% green light, 30% blue light, 24% yellow light, and 25% red light), B (35%, 35%, 18%, and 12%), C (27%, 30%, 22%, and 21%), or compact fluorescent lamps (CFL, 15%, 28%, 41%, and 16%). Results showed that feed intake and feed conversion ratio were comparable among treatments throughout the 17 week rearing period (p > 0.05). LED C showed similar body weight gain with CFL, but higher than LED A and B. The CFL birds start to lay on 132.25 d, while LED B did not lay until 148.25 d. The age at 50% egg production did not vary among groups (p = 0.12). Total egg number until 43 week of LED B was higher than others (p < 0.05). Therefore, LED lights with defined spectral proportion have different effects on chickens’ growth and reproduction. The LED C promotes the prepubertal growth, and the LED B provides proper sexual maturation age and better egg-laying persistence.

Purpose Since protein arginine methyltransferase 5 (PRMT5) is abnormally expressed in various tumors, in this study we aim to assess the association between PRMT5 and clinicopathological and prognostic features. Methods Electronic databases including PubMed, Web of Science, Scopus, ScienceDirect, and the Cochrane Library were searched until July 25, 2021. The critical appraisal of the eligible studies was performed using the Newcastle–Ottawa Quality Assessment Scale. Pooled hazard ratios (HR) and pooled odds ratios (OR) were calculated to assess the effect. Engauge Digitizer version 12.1, STATA version 15.1, and R version 4.0.5 were used to obtain and analysis the data. Results A total of 32 original studies covering 15,583 patients were included. In our data, it indicated that high level of PRMT5 was significantly correlated with advanced tumor stage (OR = 2.12, 95% CI: 1.22-3.70, P =.008; I 2 = 80.7%) and positively correlated with poor overall survival (HR = 1.59, 95% CI: 1.46-1.73, P < .001; I 2 = 50%) and progression-free survival (HR = 1.53, 95% CI: 1.24-1.88, P < .001; I 2 = 0%). In addition, sub-group analysis showed that high level of PRMT5 was associated with poor overall survival for such 5 kinds of cancers as hepatocellular carcinoma, pancreatic cancer, breast cancer, gastric cancer, and lung cancer. Conclusion For the first time we found PRMT5 was pan-cancerous as a prognostic biomarker and high level of PRMT5 was associated with poor prognosis for certain cancers.

Background Multidrug resistance (MDR), a major problem in oncology therapy, limits the effectiveness of anticancer drugs. Although p53 functions as a tumor suppressor, the associations between p53 status, autophagy, and MDR are complicated and conditional. Method In this report, p53-null human ovarian cancer cell line SKOV3 and its MDR phenotype SKVCR and human leukemia cell line CEM and its MDR phenotype CEM-VLB) (p53 mutant cell line) were used. Results Compared to parental SKOV3, the mRNA and protein levels of MAPLC3-II and Beclin1 were higher in SKVCR cells. The inhibition of autophagy by 3-MA significantly sensitized SKVCR to VCR. Conversely, in drug-resistant leukemic cells CEM-VLB, the expressions of Beclin1 and MAPLC3-II were lower than CEM. CEM and CEM-VLB cells were treated with VLB .01 or 0.5 μg/mL, respectively, and the expression of p53 and autophagy up-regulated after VLB (.01 μg/mL) treatment in CEM cells. The percentage of S-phase and G2/M phase cells up-regulated significantly by .01 μg/mL VLB in CEM, which may relate to the status of p53 of CEM cells. A combination of radiation with 3-MA significantly increased apoptosis in CEM-VLB cells. Conclusion Our discovery found that p53 is an important regulator controlling the balance between autophagy and MDR, as a potential drug target for ovarian cancer and leukemia.

In radiation oncology, ionizing radiation is used to kill cancer cells, in other words, the induction of different types of cell death. To investigate this cellular death and the associated iron accumulation, the transfer, release, and participation of iron after radiation treatment was analyzed. We found that radiation-induced cell death varied in different breast cancer cells and autophagy was induced in MDA-MB-231 and BT549 cells (triple negative breast cancer cell line) rather than in MCF-7 and zr-75 cells. Iron chelator deferoxamine (DFO), the autophagy inhibitor 3MA, silencing of the autophagy-related genes ATG5, and Beclin 1 could decrease radiation induced cell death in MDA-MB-231 cells, while inhibitors of apoptosis such as Z-VAD-FMK, ferroptosis inhibitor ferrostatin-1 (Fer-1), and necroptosis inhibitor Necrostatin-1 showed no change. This suggests the occurrence of autophagic cell death. Furthermore, we found that iron accumulation and iron regulatory proteins, including transferrin (Tf), transferrin receptor (CD71), and Ferritin (FTH), increased after radiation treatment, and the silencing of transferrin decreased radiation-induced cell death. In addition, radiation increased lysosomal membrane permeabilization (LMP) and the release of lysosomal iron and cathepsins, while cathepsins silencing failed to change cell viability. Radiation-induced iron accumulation increased Reactive oxygen species (ROS) generation via the Fenton reaction and increased autophagy in a time-dependent manner. DFO, N-acetylcysteine (NAC), and overexpression of superoxide dismutase 2 (SOD2) decreased ROS generation, autophagy, and cell death. To summarize, for the first time, we found that radiation-induced autophagic cell death was iron-dependent in breast cancer MDA-MB-231 cells. These results provide new insights into the cell death process of cancers and might conduce to the development and application of novel therapeutic strategies for patients with apoptosis-resistant breast cancer.

The protein arginine methyltransferases (PRMTs) are involved in such biological processes as transcription regulation, DNA repair, RNA splicing, and signal transduction, etc. In this study, we mainly focused on PRMT5, a member of the type II PRMTs, which functions mainly alongside other interacting proteins. PRMT5 has been shown to be overexpressed in a wide variety of cancers and other diseases, and is involved in the regulation of Epstein-Barr virus infection, viral carcinogenesis, spliceosome, hepatitis B, cell cycles, and various signaling pathways. We analyzed the regulatory roles of PRMT5 and interacting proteins in various biological processes above-mentioned, to elucidate for the first time the interaction between PRMT5 and its interacting proteins. This systemic analysis will enrich the biological theory and contribute to the development of novel therapies.

Radiotherapy (RT) shows advantages as one of the most important precise therapy strategies for cancer treatment, especially high-dose hypofractionated RT which is widely used in clinical applications due to the protection of local anatomical structure and relatively mild impairment. With the increase of single dose, ranging from 2~20 Gy, and the decrease of fractionation, the question that if there is any uniform standard of dose limits for different therapeutic regimens attracts more and more attention, and the potential adverse effects of higher dose radiation have not been elucidated. In this study, the immunological adverse responses induced by radiation, especially the cytokine storm and the underlying mechanisms such as DAMPs release, pro-inflammatory cytokine secretion and cGAS-STING pathway activation, will be elucidated, which contributes to achieving optimal hypofractionated RT regimen, improving the killing of cancer cells and avoiding the severe side effects.

Ferroptosis is a cell death pathway characterized by iron-dependent accumulation of reactive oxygen species (ROS) within the cell. The combination of siramesine, a lysosome disruptor, and lapatinib, a dual tyrosine kinase inhibitor, has been shown to synergistically induce cell death in breast cancer cells mediated by ferroptosis. These treatments also induce autophagy but its role in this synergistic cell death is unclear. In this study, we determined that siramesine and lapatinib initially induced ferroptosis but changes to an autophagy induced cell death after 24 hours. Furthermore, we found that intracellular iron level increased in a time dependent manner following treatment accompanied by an increase in ROS. Using the iron chelator deferoxamine (DFO) or the ROS scavenger alpha-tocopherol decreased both autophagy flux and cell death. We further discovered that decreased expression of the iron storage protein, ferritin was partially dependent upon autophagy degradation. In contrast, the expression of transferrin, which is responsible for the transport of iron into cells, is increased following treatment with lapatinib alone or in combination with siramesine. This indicates that ferroptosis and autophagy induced cell death occur independently but both are mediated by iron dependent ROS generation in breast cancer cells.

To observe the adaptive response (AR) induced by ionizing radiation in human fibroblasts under monolayer and 3-dimensional (3-D) condition. Three kinds of fibroblasts were cultured under both monolayer and 3-D condition. Immunofluorescent staining was used to detect the γ-H2AX foci and the morphological texture. Trypan blue staining was used to detect the cell death. Western blot was used to detect the expressions of γ-H2AX, p53 and CDKN1A/p21 (p21). We found that DNA damage increased in a dose-dependent and time-dependent manner after high doses of radiation. When cells were pretreated with a priming low dose of radiation followed by high dose radiation, DNA damage was attenuated under both monolayer and 3-D condition, and the adaptive response (AR) was induced. Additionally, the morphology of cells under monolayer and 3-D conditions were different, and radiation also induced AR according to morphological texture analysis. Priming low dose radiation induced AR both under monolayer and 3-D condition. Interestingly, 3-D microenvironment made cells more sensitive to radiation. The expression of p53 and p21 was changed and indicated that they might participate in the regulation of AR.

Abstract Background The impact of simultaneous conversion of dialysate calcium (DCa) concentration from 3.0 to 2.6 mEq/L and dialysate magnesium (DMg) concentration from 1.0 to 1.2 mEq/L on mineral and bone metabolism in patients undergoing hemodialysis remains unknown. Methods We retrospectively recruited 52 patients undergoing hemodialysis who experienced a conversion of dialysates from dialysate A (DCa 3.0 mEq/L and DMg 1.0 mEq/L) to dialysate B (DCa 2.6 mEq/L and DMg 1.2 mEq/L) at a hemodialysis center. The effects of changing the DCa and DMg concentrations on serum bone and mineral parameters were examined over 7 months. Results A total of 48 patients were finally analyzed. After changing the dialysate, serum magnesium (Mg) levels increased significantly from 2.31 ± 0.38 at 0 months to 2.54 ± 0.43 mg/L at 7 months, and serum calcium (Ca) levels decreased significantly from 9.51 ± 0.80 at 0 months to 9.14 ± 0.57 mg/dL at 7 months, with no change in serum intact parathyroid hormone levels. Notably, the serum Ca-to-serum-Mg ratio and serum Ca × inorganic phosphate-to-serum-Mg ratio decreased significantly after dialysate conversion. Around 10% of patients started or increased the dose of vitamin D receptor activators, and 18% of patients started or increased the dose of Ca-based phosphate binders. Notably, the serum Mg levels in three patients exceeded 3.5 mg/dL during the observation period. Conclusions Conversion of DCa from 3.0 to 2.6 mEq/L and DMg from 1.0 to 1.2 mEq/L lowers serum Ca levels and increases serum Mg levels, possibly leading to decreased Ca loading and increased Mg storage among patients undergoing hemodialysis.

Excessive local movement and inflammation are common problems in the process of wound repair, which lead to failure of later repair. In order to solve this problem, inspired by the octopus sucker structure, we successfully developed a photocrosslinked hydrogel that can adsorb skin surface fascia. In addition, extracellular vesicles from human bone marrow mesenchymal stem cells are encapsulated in the octopus like sucker structure. The morphology and structure of extracellular vesicles in bone marrow mesenchymal stem cells were detected by scanning electron microscopy and particle size analysis. Through iTRAQ, we tested the expression of angiogenesis related proteins contained in extracellular vesicles. Design small interfering RNA to verify its impact on angiogenic related genes and proteins. Macrophage polarization was detected by immunofluorescence. The expression of new blood vessels was detected by constructing a skin defect model and injecting microfil contrast agent into the heart. When the sucker is firmly adsorbed on the damaged wound, the sucker will slowly degrade. Using its delivery system, it is observed that the extracellular vesicles are released in the wound. Through iTRAQ, it was found that the angiogenesis regulator (angiopoietin-like 4, angiopoietin-like 3 and aminopeptidase N) released in the extracellular vesicles regulates collagen deposition, angiogenesis, and inhibits macrophage aggregation. In addition, the slowly released extracellular vesicles will further inhibit the polarization of proinflammatory macrophages. This biological behavior can provide an adaptive microenvironment for skin regeneration at an early stage. This new bionic octopus sucker structure gel creates a good microenvironment for wound repair and shortens the wound healing time. Therefore, this hydrogel inspired by the octopus sucker structure may provide a good strategy and commercial value for promoting wound repair treatment in clinical practice.

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