Chaperone- and PTM-mediated activation of IRF1 tames radiation-induced cell death and the inflammatory response.

The key role of structural cells in immune modulation has been revealed with the advent of single-cell multiomics, but the underlying mechanism remains poorly understood. Here, we revealed that the transcriptional activation of interferon regulatory factor 1 (IRF1) in response to ionizing radiation, cytotoxic chemicals and SARS-CoV-2 viral infection determines the fate of structural cells and regulates communication between structural and immune cells. Radiation-induced leakage of mtDNA initiates the nuclear translocation of IRF1, enabling it to regulate the transcription of inflammation- and cell death-related genes. Novel posttranslational modification (PTM) sites in the nuclear localization sequence (NLS) of IRF1 were identified. Functional analysis revealed that mutation of the acetylation site and the phosphorylation sites in the NLS blocked the transcriptional activation of IRF1 and reduced cell death in response to ionizing radiation. Mechanistically, reciprocal regulation between the single-stranded DNA sensors SSBP1 and IRF1, which restrains radiation-induced and STING/p300-mediated PTMs of IRF1, was revealed. In addition, genetic deletion or pharmacological inhibition of IRF1 tempered radiation-induced inflammatory cell death, and radiation mitigators also suppressed SARS-CoV-2 NSP-10-mediated activation of IRF1. Thus, we revealed a novel cytoplasm-oriented mechanism of IRF1 activation in structural cells that promotes inflammation and highlighted the potential effectiveness of IRF1 inhibitors against immune disorders.

Causal effects of hypertensive disorders of pregnancy on future gynecologic tumors: A two-sample Mendelian randomization study.

BACKGROUND: Numerous observational studies have investigated the potential link between hypertensive disorders of pregnancy (HDPs) and the subsequent risks of gynecologic tumors, yet the findings have been inconsistent. In this study, we utilized Mendelian randomization (MR) approach to assess the influence of HDPs on the future risks of ovarian, cervical, endometrial, and breast cancer and uterine fibroids, controlling for confounding factors. METHODS: The genome-wide association studies (GWAS) summary data relevant to HDPs was obtained from the FinnGen databases (10,736 cases and 136,325 controls). Gynecologic tumor outcomes were extracted from the IEU Open GWAS project and UK Biobank (47,690 cases and 1, 092,073 controls). The inverse variance weighted (IVW) approach was selected as the principal method for MR analysis, supplemented by MR-Egger, weighted median, weighted model, simple model methods, MR pleiotropy residual sum and outlier (MR-PRESSO) test, and leave-one-out method. Multivariate MR (MVMR) analysis was conducted after adjusting systolic blood pressure (SBP), body mass index (BMI) and type 2 diabetes mellitus (T2DM). RESULTS: Our univariate MR analysis (UVMR) results revealed no significant relationship between HDPs and the risks of ovarian cancer (odds ratio [OR] = 0.924, p = 0.360), cervical cancer (OR = 1.230, p = 0.738), endometrial cancer (OR = 1.006, p = 0.949), uterine fibroids (OR = 1.155, p = 0.158), and breast cancer (OR = 0.792, p = 0.241) by IVW test. Similar results were observed in gestational hypertension and preeclampsia/eclampsia. Additionally, our study detected neither heterogeneity nor pleiotropy. MVMR analysis also provided no evidence of a causal association between HDPs and common gynecologic tumors after adjusting SBP, BMI, and T2DM. CONCLUSION: We discovered no causal relationship between HDPs and ovarian, cervical, endometrial, breast cancer, and uterine fibroids in European populations. However, present analysis did not explore the effect of HDPs on the subtypes of gynecologic tumors across varied ethnic populations, which may require additional research.

Long-term effects of prenatal magnesium sulfate exposure on nervous system development in preterm-born children.

This study used structural magnetic resonance imaging to analyze changes in the gray matter volume (GMV) of preterm-born (PTB) and term-born (TB) children to help elucidate the influence of magnesium sulfate treatment on the nervous system development. A total of 51 subjects were recruited, including 28 PTB and 23 TB children. The intelligence scale and MRI scan were completed at the corrected age of 10 to 16 years. A whole-brain voxel-wise analysis tested the main effect of the status (PTB without magnesium, PTB with magnesium, and TB) using a factorial design in SPM8. The mean volumes of the regions that showed significant group effects on the GMV after the FDR correction were extracted in the common space for each subject. Verbal and full-scale intelligence quotient scores were significantly lower for PTB children without magnesium than for TB children; however, the scores of PTB children with magnesium and TB children were almost identical. Compared with TB children, PTB children had significantly reduced left straight gyrus and left inferior frontal gyrus GMVs; however, the volumes of PTB children with magnesium were closer to those of TB children. Changes in the GMV of the left inferior frontal gyrus were significantly correlated with full-scale and verbal intelligence quotient scores, whereas the lower gestational age at the time of mgsou4 treatment led to a larger GMV of the left inferior frontal gyrus. Brain structural abnormalities could exist in PTB children. The GMVs of the left straight gyrus and left inferior frontal gyrus were significantly reduced in these children. The influence of magnesium sulfate treatment was not significant, but the cognitive levels of these children were significantly increased and almost identical to those of TB children. Initiation of magnesium sulfate treatment during gestation is negatively correlated with the left inferior frontal gyrus GMV.

Ubiquitin-specific peptidase 47 (USP47) regulates cutaneous oxidative injury through nicotinamide nucleotide transhydrogenase (NNT).

Human skin is daily exposed to oxidative stresses in the environment such as physical stimulation, chemical pollutants and pathogenic microorganisms, which are likely to cause skin diseases. As important post-translational modifications, protein ubiquitination and deubiquitination play crucial roles in maintaining cellular homeostasis by the proteolytic removal of oxidized proteins. We have previously reported that the expression of ubiquitin-specific protease 47 (USP47), a kind of deubiquitinating enzymes (DUBs), was significantly elevated in response to oxidative stress. However, the role of USP47 in cutaneous oxidative injury remains unclear. Usp47 wild-type (Usp47+/+) mice and Usp47 knockout (Usp47-/-) mice were used to establish two animal models of oxidative skin damage: (1) radiation- and (2) imiquimod (IMQ)-induced skin injury. Loss of Usp47 consistently aggravated mouse skin damage in vivo. Subsequently, we screened 63 upregulated and 170 downregulated proteins between the skin tissues of wild-type and Usp47-/- mice after 35 Gy electron beam radiation using proteomic analysis. Among the dysregulated proteins, nicotinamide nucleotide transhydrogenase (NNT), which has been reported as a significant regulator of oxidative stress and redox homeostasis, was further investigated in detail. Results showed that NNT was regulated by USP47 through direct ubiquitination mediated degradation and involved in the pathogenesis of cutaneous oxidative injury. Knockdown of NNT expression dramatically limited the energy production ability, with elevated mitochondrial reactive oxygen species (ROS) accumulation and increased mitochondrial membrane potential in irradiated HaCaT cells. Taken together, our present findings illustrate the critical role of USP47 in oxidative skin damage by modulating NNT degradation and mitochondrial homeostasis.

Lymph drainage and cervical fascia anatomy-oriented differential nodal CTV delineation at the supraclavicular region for esophageal cancer and nasopharyngeal cancer.

PURPOSE: To determine the differences in supraclavicular lymph node metastasis between esophageal cancer (EC) and nasopharyngeal cancer (NPC) and explore the feasibility of differential supraclavicular clinical target volume (CTV) contouring between these two diseases based on the involvement of different fascial spaces. MATERIALS AND METHODS: One hundred patients with supraclavicular nodes positive for EC or NPC were enrolled, and their pre-treatment images were reviewed. The distribution patterns of nodes between the two diseases were compared in the context of node levels defined by the 2017 Japanese Esophageal Society and 2013 International Consensus on Cervical Lymph Node Level Classification. Grouping supraclavicular nodes based on sub-compartments formed by the cervical fascia was discussed, and the feasibility of differential CTV contouring based on the differences in the involvement of these sub-compartments between EC and NPC was explored. RESULTS: The 2013 Consensus on cervical node levels and 2017 Japanese Esophageal Society node station could not practically guide supraclavicular CTV contouring. We divided the supraclavicular space into six sub-compartments: the para-esophageal space (PES), carotid sheath space (CSS), sub-thyroid pre-trachea space (STPTS), pre-vascular space (PVS), and vascular lateral space (VLS) I and II. EC mainly spread to the PES, STPTS, CSS, and VLS I, whereas NPC tended to spread to the CSS, VLS I, and VLS II. These combinations of sub-compartments may help constitute the supraclavicular CTVs for EC and NPC. CONCLUSIONS: The fascia anatomy-based sub-compartments sufficiently distinguished metastasis to the supraclavicular space between EC and NPC, thus facilitating differential CTV contouring between these two diseases.

Fenofibrate Attenuates Radiation-Induced Oxidative Damage to the Skin through Fatty Acid Binding Protein 4 (FABP4).

BACKGROUND: Radiation facilities and radioactive materials have been widely used in military, industry, medicine, science and nuclear facilities, which has significantly increased the potential of large-scale, uncontrolled exposure to radiation. The skin is one of the radiosensitive organ systems and radiation-induced skin injury remains a serious concern after ionizing radiation exposure. Our previous report indicates the involvement of the peroxisome proliferator-activated receptor pathway in the response of skin tissues to ionizing radiation. PPARα is a member of the PPAR nuclear hormone receptor superfamily, which can be activated by fibrate ligands. However, the protection of fenofibrate against ionizing radiation in skin keratinocytes and fibroblasts has not been described. METHODS: The PPARα mRNA levels in irradiated and nonirradiated skin tissues of rats were determined by real-time assay. The expression of PPARα, and FABP4 were evaluated by western blot and IHC assay. The cell proliferation was detected by colony formation. The γH2AX foci and ROS levels in irradiated WS1 cells with FABP4 overexpression than in control cells were performed by Immunofluorescence assay. RESULTS: We found that PPARα expression was lower in the irradiated skin tissues of mouse, rat, monkey, and human patients than in their nonirradiated counterparts. PPARα fenofibrate significantly decreased radiation-induced ROS and apoptosis in a dose-dependent manner in human keratinocyte HaCaT and skin fibroblast WS1 cells. Moreover, fenofibrate significantly decreased radiation-induced ROS and malondialdehyde (MDA) levels in electron beam irradiated skin tissues of rats. Mechanistically, the proximal promoter of fatty acid binding protein 4 (FABP4) harbored three binding sites of PPARα and fenofibrate stimulated the transcription of FABP4 in skin cells. FABP4 overexpression decreased radiation-induced ROS and γH2AX foci. FABP4 inhibitor BMS309403 abrogated the ROS-eliminating activity as well as the lipid-accumulating role of fenofibrate, indicating that FABP4 mediates the radioprotective role of fenofibrate. In addition, FABP4 overexpression significantly decreased radiation-induced oxidative damage in vivo. CONCLUSIONS: These results confirm that fenofibrate attenuated radiation-induced oxidative damage to the skin by stimulating FABP4.

The Dynamic Alternation of Local and Systemic Tumor Immune Microenvironment During Concurrent Chemoradiotherapy of Cervical Cancer: A Prospective Clinical Trial.

PURPOSE: This work assessed local and systemic alternations of the tumor immune microenvironment during concurrent chemoradiation therapy (CCRT) of local advanced cervical cancer to estimate the optimal timing for immune therapy in relation to CCRT. METHODS AND MATERIALS: In this single-center prospective clinical trial, 55 patients with stage IIA through IVA cervical cancer were enrolled between December 2016 and November 2017. The median follow-up was 32.1 months. All patients received cisplatin concurrently with external beam radiation therapy combined with high-dose-rate brachytherapy. Tumor tissues and peripheral blood mononuclear cells (PBMCs) were collected before, during and after CCRT. We analyzed the changes in lymphocyte subpopulations, programmed death-1 (PD-1) and programmed cell death ligand 1 (PD-L1) expression, and the T cell receptor (TCR) repertoire that occurred throughout CCRT. RESULTS: The frequencies of CD4+ and PD-1+ T cells in PBMCs decreased after the start of CCRT, whereas that of inhibitory regulatory T cells increased. In the tumor tissues, CCRT decreased the numbers of CD4+ and CD8+ T cells and reduced the median percentage of positive cells expressing PD-L1 from 78.1% to 49.8%. As indicated by the numbers of unique clones, the TCRs of PBMCs exhibited greater diversity before CCRT than after CCRT. Greater TCR diversity in PBMCs before CCRT was associated with superior 30-month progression-free survival (hazard ratio [HR], 0.12; 95% confidence interval [CI], 0.04-0.39; P = .001) and overall survival (HR, 0.17; 95% CI, 0.04-0.68; P = .004). CONCLUSIONS: CCRT for cervical cancer altered the tumor immune microenvironment by reducing CD4+ and CD8+ T lymphocyte populations, PD-1/PD-L1 expression, and TCR diversity. Higher TCR diversity in PBMCs before CCRT resulted in better survival and prognosis, indicating that CCRT might inhibit immune activation. Our results suggest that it might be more effective to administer immune checkpoint inhibitors before CCRT of cervical cancer rather than during or after CCRT.

Independent risk factors for ovarian metastases in stage IA-IIB cervical carcinoma.

INTRODUCTION: Cervical cancer is a common malignant tumor in women; most cervical cancer patients are premenopausal. Ovarian resection or preservation remains controversial. The purpose of this study was to discover the risk factors for ovarian metastasis in women with stage I-II cervical cancer. MATERIAL AND METHODS: A total of 3292 women with cervical carcinoma who had undergone radical hysterectomy, with pelvic lymphadenectomy and bilateral oophorectomy or wedge resection of ovaries, were included in this multicenter retrospective study. We analyzed patients' demographics, International Federation of Obstetrics and Gynecology stage, and histopathologic records to determine clinicopathologic risk factors of ovarian metastasis. RESULTS: Of the patients, 115 (3.49%) were confirmed to have ovarian metastasis. The ovarian metastasis rate was 2% (56/2794) for squamous cell carcinoma and 11.8% (59/498) for nonsquamous cell carcinoma. The risk factors independently associated with ovarian metastasis were histologic type (odds ratio [OR] 8.76, 95% CI 2.09-19.24), lymph node metastasis (OR 2.57, 95% CI 1.76-4.89), lymphovascular space invasion (OR 2.82, 95% CI 1.98-4.24), and corpus invasion (OR 6.34, 95% CI 2.37-11.42). CONCLUSIONS: The histologic type, lymph node metastasis, lymphovascular space invasion, and corpus invasion were independently associated with ovarian metastasis. Histologic type and corpus invasion were the most important risk factors. Therefore, we suggest that corpus invasion might be a strong contraindication for preservation of the ovaries.

Pulmonary sclerosing hemangioma with a rare symptom: A case report and review of the literature.

Pulmonary sclerosing hemangioma (PSH) is a relatively rare benign tumor. However, as it occurs only rarely, the natural course of the tumor is not well understood. In the present study, a case is presented of a 35-year-old woman who underwent intermittent fevers for more than one year. This case highlighted fever as a rare symptom of PSH. Fever is possibly one of the symptoms of PSH, although it is less likely to occur. Another symptom of the patient was that the tumor grew quickly in two months. The lesion was diagnosed as multiple sclerosing hemangioma of the lung (i.e., PSH), in which papillary, solid and sclerotic patterns appeared. Immunohistochemical evaluation of the lesion revealed positive staining for thyroid transcription factor 1 (TTF1), epithelial membrane antigen (EMA), pancytokeratin (PCK) and cytoskeleton 7 (CK7). In the present case study, the biological activity of PSH was identified to be aggressive. A review of the literature was performed in order to comment further on the clinical and pathological features of this rare disease.

Improved antitumor activity and reduced myocardial toxicity of doxorubicin encapsulated in MPEG-PCL nanoparticles.

Doxorubicin (Dox) is a broad-spectrum antitumor drug used for the treatment of many types of malignant tumors. Although it possesses powerful antitumor activity, its clinical application is seriously encumbered by its unselective distribution and systemic toxicities, particularly myocardial toxicity. Thus, it is imperative to modify Dox to decrease its systemic toxicities and improve its therapeutic index. In the present study, we adopted a novel type of monomethoxy poly(ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) micelles to encapsulate Dox to prepare Dox-loaded MPEG-PCL (Dox/MPEG-PCL) nanoparticles by a controllable self-assembly process. The cellular uptake efficiency and cell proliferation inhibition of the Dox/MPEG-PCL nanoparticles were examined. The antitumor activity of the Dox/MPEG-PCL nanoparticles was tested on a multiple pulmonary metastasis model of melanoma on C57BL/6 mice. Systemic toxicities and survival time were compared between the mice treated with the Dox/MPEG-PCL nanoparticles and free Dox. The potential myocardial toxicity of the Dox/MPEG-PCL nanoparticles was investigated using a prolonged observation period. Encapsulation of Dox in MPEG-PCL nanoparticles significantly improved the cellular uptake and cell proliferation inhibition of Dox in vivo. Intravenous injection of Dox/MPEG-PCL nanoparticles obtained significant inhibition of the growth and metastasis of melanoma in the lung and prolonged survival time compared with free Dox (P<0.05). The Dox/MPEG-PCL nanoparticles did not show obvious additional systemic toxicities compared with free Dox during the treatment time. During the prolonged observation period, obvious decreased cardiac toxicity was observed in the Dox/MPEG-PCL nanoparticle-treated mice compared with that observed in the free Dox-treated mice. These results indicated that encapsulating Dox with MPEG-PCL micelles could significantly promote its antitumor activity and reduce its toxicity to the myocardium.

GSTP1 Ile105Val polymorphism and colorectal cancer risk: an updated analysis.

BACKGROUND: Many studies have investigated the association between the Glutathione S transferase-P1 (GSTP1) Ile105Val polymorphism and colorectal cancer (CRC) susceptibility, but the results were conflicting. The aim of this study is to quantitatively summarize the relationship between this polymorphism and CRC risk. METHODS: Two investigators independently searched the Medline, Embase, China National Knowledge Infrastructure (CNKI) and Chinese Biomedicine databases for studies published before December 2012. Summary odds ratios (ORs) and 95% confidence intervals (95% CIs) for GSTP1 polymorphism and CRC were calculated in a fixed-effects model (the Mantel-Haenszel method) and a random-effects model (the DerSimonian and Laird method) when appropriate. RESULTS: This meta-analysis included 29 case-control studies, which included 8160 CRC cases and 10,450 controls. Overall, the variant genotypes (ValVal and IleVal) of the Ile105Val were not associated with CRC risk when compared with the wild-type IleIle homozygote. Similarly, no associations were found in the dominant and recessive models. When stratifying for ethnicity, source of controls, study sample size and genotyping methods, no evidence of significant association was observed in any subgroup, except among those studies taking others as genotyping methods (recessive model, OR=0.71, 95%CI=0.52-0.96). Limiting the analysis to the studies within Hardy-Weinberg equilibrium, the results were persistent and robust. No publication bias was found in the present study. CONCLUSION: This updated meta-analysis suggests that the GSTP1 Ile105Val polymorphism may not be associated with CRC risk, while the observed decrease in risk of CRC may be due to small-study bias.

Antitumor effects of PLGA nanoparticles encapsulating the human PNAS-4 gene combined with cisplatin in ovarian cancer.

Human PNAS-4 (hPNAS-4), as a pro-apoptotic gene, can inhibit tumor growth when overexpressed in some malignant cells. Poly (lactic-co-glycolic acid) (PLGA) was used as a gene transfer vector due to the advantage of sustained release, nontoxicity and biodegradability. In this study, we aimed to investigate the effect of PLGA nanoparticles encapsulating hPNAS-4 combined with cisplatin (DDP) on ovarian carcinoma. Expression of hPNAS-4 was determined by RT-PCR. Mice bearing intraperitoneal ovarian carcinomas were treated with PBS, pVAX-PLGA nanoparticles (P-P), pVAX-hPNAS-4-PLGA nanoparticles (PhP-P), DDP and PhP-P plus DDP, respectively. Intraperitoneal tumors were weighed to assess the antitumor efficacy. The percentage of proliferative cells and apoptotic cells was evaluated by Ki-67 staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. The anti-angiogenic effects were detected by CD31 staining and the alginate-encapsulate assay. Overexpression of hPNAS-4 was detected by RT-PCR in the PhP-P and PhP-P plus DDP groups. PhP-P exerted significant antitumor activity through induction of apoptosis, inhibition of cell proliferation and suppression of angiogenesis, compared with treatment with P-P or PBS alone. The combination of PhP-P with DDP showed enhanced antitumor activity compared with therapy of PhP-P or DDP alone. PLGA encapsulating hPNAS-4 combined with DDP may have promising applications in the therapy of ovarian cancer.

Efficient inhibition of ovarian cancer by short hairpin RNA targeting claudin-3.

Ovarian cancer is one of the most lethal gynecologic neoplasms. Even though various new chemotherapeutics have been developed for the treatment of ovarian cancer, drug resistance and undesired serious side effects remain unavoidable obstacles for chemotherapeutic approaches. New strategies to overcome the therapeutic dilemma are needed. Claudin-3 (CLDN3) is a recently discovered gene generally overexpressed in human ovarian cancers but not in normal ovarian tissue. Its high expression has been identified to associate with the invasion, proliferation and survival of cancer cells, making it a promising target for gene therapy of ovarian cancer. However, in gene therapy, traditional gene carriers such as virus or cationic liposomes suffer from distressing shortcomings of potential carcinogenicity, obvious cytotoxicity and immunogenicity. Nanoparticles (NPs) based on PLGA are a novel gene delivery system with good biodegradability, excellent biocompatibility and low toxcity for in vivo gene delivery compared with traditional gene carriers. We constructed a plasmid expressing shRNA targeted CLDN3 (pshCLDN3) encapsulated with PLGA-NPs, and administered it by i.p. injection to nude mice bearing intraperitoneal SKOV3 ovarian cancer, to investigate the antitumor potential of knocking down CLDN3. After 12 times of administration, the tumors of each group were compared. The underlying antitumor mechanisms were revealed by immunostaining of CD31, Ki-67 and TUNEL assay, to exhibit possible alterations in microvessel density, cell proliferation and cell apoptosis. Our study demonstrated that i.p. administration of pshCLDN3 effectively suppressed the expression of CLDN3 and, thus, inhibited the growth of ovarian tumors, significantly reducing tumor weight by 67.4% compared with blank controls (p<0.05). Immunostaining of CD31, Ki-67 and TUNEL assay demonstrated decreased angiogenesis (p<0.05), reduced proliferation (p<0.05) and increased apoptosis (p<0.05) in the pshCLDN3 treated group compared with controls. No obvious toxicity of PLGA-NPs was observed either in vitro or in vivo. Our results indicated that knockdown of CLDN3 by pshCLDN3 encapsulated in PLGA NPs may provide a promising approach for the treatment of ovarian cancer.