Prognostic factors in patients with thymoma who underwent surgery.

PURPOSE: Thymoma is the most common primary tumor in the anterior mediastinum. The prognostic factors of patients with thymoma still need to be clarified. In this study, we aimed to investigate the prognostic factors of patients with thymoma who received radical resection and establish the nomogram to predict the prognosis of these patients. MATERIALS AND METHODS: Patients who underwent radical resection for thymoma with complete follow-up data between 2005 and 2021 were enrolled. Their clinicopathological characteristics and treatment methods were retrospectively analyzed. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared by the log-rank test. Univariate and multivariate Cox proportional hazards regression analyses were performed to identify the independent prognostic factors. According to the results of the univariate analysis in the Cox regression model, the predictive nomograms were created. RESULTS: A total of 137 patients with thymoma were enrolled. With a median follow-up of 52 months, the 5-year and 10-year PFS rates were 79.5% and 68.1%, respectively. The 5-year and 10-year OS rates were 88.4% and 73.1%, respectively. Smoking status (P = 0.022) and tumor size (P = 0.039) were identified as independent prognostic factors for PFS. Multivariate analysis showed that a high level of neutrophils (P = 0.040) was independently associated with OS. The nomogram showed that the World Health Organization (WHO) histological classification contributed more to the risk of recurrence than other factors. Neutrophil count was the most important predictor of OS in patients with thymoma. CONCLUSION: Smoking status and tumor size are risk factors for PFS in patients with thymoma. A high level of neutrophils is an independent prognostic factor for OS. The nomograms developed in this study accurately predict PFS and OS rates at 5 and 10 years in patients with thymoma based on individual characteristics.

Application of two glycosylated Lactobacillus surface layer proteins in coating cationic liposomes.

The ability of isolated surface layer proteins (SLPs) to reassemble on suitable surfaces enables the application of SLPs in various fields of nanotechnology. In this work, SLPs from Lactobacillus buchneri BNCC 187,964 and L. kefir BNCC 190,565 were extracted and verified as glycosylated proteins. They were applied to coat on the surface of cationic liposomes. The absorption of the two SLPs on liposomes induced the zeta potential reduction and particle size increase. The two kinds of SLP-coated liposomes demonstrated better thermal, light and pH stability than the control liposomes. And the L. kefir SLP showed better protective effects than the L. buchneri SLP. Moreover, both of the SLPs could endow liposomes with the function of binding ferritin as observed by transmission electron microscope. Fourier transform infrared spectroscopy illustrated that the interaction between the two SLPs and liposomes was similar. The recrystallization of the two SLPs on the liposomes might drive the lipid into a higher order state and hydrogen bonds were formed between the two SLPs and the liposomes. All the findings demonstrated that L. kefir SLP and L. buchneri SLP had great potential to be explored as effective coating agents to improve the stability and function of cationic liposomes.Please check and confirm that the authors and their respective affiliations have been correctly identified and amend if necessary.Yes, all have been checked.

Clinical characteristics and patient outcomes of molecular subtypes of small cell lung cancer (SCLC).

BACKGROUND: Recent studies have shown that according to the expression levels of achaete-scute homolog 1 (ASCL1), neurogenic differentiation factor 1 (NEUROD1), and POU class 2 homeobox 3 (POU2F3), small cell lung cancer (SCLC) can be divided into four subtypes: SCLC-A (ASCL1-dominant), SCLC-N (NEUROD1-dominant), SCLC-P (POU2F3-dominant), and SCLC-I (triple negative or SCLC-inflamed). However, there are limited data on the clinical characteristics and prognosis of molecular subtypes of SCLC. METHODS: Immunohistochemistry (IHC) was used to detect the expression levels of ASCL1, NEUROD1, and POU2F3 in 53 patient samples of resectable SCLC. The subtype was defined by the differential expression of the transcription factors for ASCL1, NEUROD1, and POU2F3 or the low expression of all three factors with an inflamed gene signature (SCLC-A, SCLC-N, SCLC-P, and SCLC-I, respectively). The clinicopathological characteristics, immunological features (programmed death ligand 1 [PD-L1] expression and CD8+ tumor infiltrating lymphocyte [TIL] density), and patient outcomes of the four subtypes of SCLC were analyzed. RESULTS: Positive ASCL1, NEUROD1, and POU2F3 staining was detected in 43 (79.2%), 27 (51.0%), and 17 (32.1%) SCLC specimens by IHC. According to the results of IHC analysis, SCLC was divided into four subtypes: SCLC-A (39.6%), SCLC-N (28.3%), SCLC-P (17.0%), and SCLC-I (15.1%). The 5-year overall survival (OS) rates of these four subtypes were 61.9%, 69.3%, 41.7%, and 85.7%, respectively (P=0.251). There were significant differences in smoking status among different subtypes of SCLC (P= 0.031). However, we did not confirm the correlation between subtypes of SCLC and other clinicopathological factors or immune profiles. Cox multivariate analysis showed that N stage (P=0.025), CD8+ TILs (P=0.024), Ki-67 level (P=0.040), and SCLC-P (P=0.023) were independent prognostic factors for resectable SCLC. CONCLUSIONS: Our IHC-based study validated the proposed classification of SCLC using the expression patterns of key transcriptional regulatory factors. We found that SCLC-P was associated with smokers and was one of the poor prognostic factors of limited-stage SCLC. In addition, no correlation was found between PD-L1 expression or CD8+ TIL density and SCLC subtypes.

Protective function of surface layer protein from Lactobacillus casei fb05 against intestinal pathogens in vitro.

Escherichia coli and Salmonella are common pathogenic bacteria in human intestine, which can infect epithelial cells and cause diseases. Adhesion to intestinal tissue is the first step of pathogen infection. This work was to investigate the protective function of surface layer protein (SLP) from Lactobacillus casei fb05 against the harmful effects of E. coli and Salmonella on intestinal tissue (collagen and HT-29 cells). The SLP of L. casei fb05 was identified by transmission electron microscopy and SDS-PAGE. The purified SLP could reduce the adhesion of E. coli and Salmonella to collagen and HT-29 cells as observed by light microscope. The flow cytometry results showed that the L. casei fb05 SLP decreased the two pathogens-induced apoptosis of HT-29 cells by about 45%-49%. In addition, the activation of caspase-9 and caspase-3 caused by the two pathogens was significantly declined by the interference of the L. casei fb05 SLP. All the findings demonstrated that the L. casei fb05 SLP could decrease the deleterious effects of E. coli and Salmonella on intestinal tract in two ways: reducing pathogen adhesion and inhibiting pathogen-induced apoptosis. The potential of L. casei fb05 SLP in the treatment of intestinal diseases might be explored in this work.

The role of the deubiquitinating enzyme DUB3/USP17 in cancer: a narrative review.

The balance between ubiquitination and deubiquitination is critical for the degradation, transport, localization, and activity of proteins. Deubiquitinating enzymes (DUBs) greatly contribute to the balance of ubiquitination and deubiquitination, and they have been widely studied due to their fundamental role in cancer. DUB3/ubiquitin-specific protease 17 (USP17) is a type of DUB that has attracted much attention in cancer research. In this review, we summarize the biological functions and regulatory mechanisms of USP17 in central nervous system, head and neck, thoracic, breast, gastrointestinal, genitourinary, and gynecologic cancers as well as bone and soft tissue sarcomas, and we provide new insights into how USP17 can be used in the management of cancer.

FTO regulates the chemo-radiotherapy resistance of cervical squamous cell carcinoma (CSCC) by targeting ß-catenin through mRNA demethylation.

The role of N6 -methyladenosine (m6 A) demethylase fat mass and obesity-associated protein (FTO) in the regulation of chemo-radiotherapy resistance remains largely unknown. Here, we show that the mRNA level of FTO is elevated in cervical squamous cell carcinoma (CSCC) tissues when compared with respective adjacent normal tissues. FTO enhances the chemo-radiotherapy resistance both in vitro and in vivo through regulating expression of ß-catenin by reducing m6 A levels in its mRNA transcripts and in turn increases excision repair cross-complementation group 1 (ERCC1) activity. Clinically, the prognostic value of FTO for overall survival is found to be dependent on ß-catenin expression in human CSCC samples. Taken together, these findings uncover a critical function for FTO and its substrate m6 A in the regulation of chemo-radiotherapy resistance, which may bear potential clinical implications for CSCC treatment.

AT-101 enhances gefitinib sensitivity in non-small cell lung cancer with EGFR T790M mutations.

BACKGROUND: Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) have become the standard care of patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC), development of acquired resistance is inevitable. A secondary mutation of threonine 790 (T790M) is associated with approximately half of the cases of acquired resistance. Strategies or agents to overcome this type of resistance are still limited. In this study, enhanced antitumor effect of AT-101, a-pan-Bcl-2 inhibitor, on gefitinib was explored in NSCLC with T790M mutation. METHODS: The effect of cotreatment with AT-101 and gefitinib on the viability of NSCLC cell lines harboring acquired T790M mutation was investigated using the MTT assay. The cellular apoptosis of NSCLC cells after cotreatment with AT-101 and gefitinib was assessed by FITC-annexin V/PI assay and Western blots analysis. The potential underlying mechanisms of the enhanced therapeutic effect for AT-101 was also studied using Western blots analysis. The in vivo anti-cancer efficacy of the combination with AT-101 and gefitinib was examined in a mouse xenograft model. RESULTS: In this study, we found that treatment with AT-101 in combination with gefitinib significantly inhibited cell proliferation, as well as promoted apoptosis of EGFR TKIs resistant lung cancer cells. The apoptotic effects of the use of AT-101 was related to the blocking of antiapoptotic protein: Bcl-2, Bcl-xl, and Mcl-1 and downregrulation of the molecules in EGFR pathway. The observed enhancements of tumor growth suppression in xenografts supported the reverse effect of AT-101 in NSCLC with T790M mutation, which has been found in in vitro studies before. CONCLUSIONS: AT-101 enhances gefitinib sensitivity in NSCLC with EGFR T790M mutations. The addition of AT-101 to gefitinib is a promising strategy to overcome EGFR TKIs resistance in NSCLC with EGFR T790M mutations.

Preclinical evidences toward the use of triterpenoid CDDO-Me for solid cancer prevention and treatment.

Solid cancer remains a major cause of death in the world. As limited treatment options are currently available to patients with solid cancer, novel preventive control and effective therapeutic approaches are considered to be reasonable and decisive measures to combat this disease. The plant-derived triterpenoids, commonly used for medicinal purposes in many Asian countries, poses various pharmacological properties. A large number of triterpenoids exhibit cytotoxicity against a variety of cancer cells, and cancer preventive, as well as anticancer efficacy in preclinical animal models. To improve antitumor activity, some synthetic triterpenoid derivatives have been synthesized, including cyano-3,12-dioxooleana-1,9(11)- dien-28-oic (CDDO), its methyl ester (CDDO-Me), and imidazolide (CDDO-Im) derivatives. In this review, we will critically examine the current preclinical evidences of cancer preventive and therapeutic activity about one of the synthetic triterpenoids, CDDO-Me. Both in vitro and in vivo effects of this agent and related molecular mechanisms are presented.

The role of transforming growth factor-ß (TGF-ß) in the formation of exhausted CD8 + T cells.

CD8 + T cells exert a critical role in eliminating cancers and chronic infections, and can provide long-term protective immunity. However, under the exposure of persistent antigen, CD8 + T cells can differentiate into terminally exhausted CD8 + T cells and lose the ability of immune surveillance and disease clearance. New insights into the molecular mechanisms of T-cell exhaustion suggest that it is a potential way to improve the efficacy of immunotherapy by restoring the function of exhausted CD8 + T cells. Transforming growth factor-ß (TGF-ß) is an important executor of immune homeostasis and tolerance, inhibiting the expansion and function of many components of the immune system. Recent studies have shown that TGF-ß is one of the drivers for the development of exhausted CD8 + T cells. In this review, we summarized the role and mechanisms of TGF-ß in the formation of exhausted CD8 + T cells and discussed ways to target those to ultimately enhance the efficacy of immunotherapy.

Silencing UBQLN2 Enhances the Radiosensitivity of Esophageal Squamous Cell Carcinoma (ESCC) via Activating p38 MAPK.

Background: Ubiquilin 2 (UBQLN2) is an adaptor of ubiquitinated proteins and the proteasome. The potential role of UBQLN2 in carcinogenesis has been demonstrated. However, its role in modulating the radiosensitivity of cancer is not clear. Here, we explored the radiosensitizing effect of silencing UBQLN2 on esophageal squamous cell carcinoma (ESCC) and its mechanisms. Methods: We analyzed the prognostic role of UBQLN2 in the ESCC patient cohort from the Cancer Genomic Atlas (TCGA) database and our hospital. We also conducted a series of experiments in vivo and in vitro to investigate the effect of silencing UBQLN2 on ESCC radiosensitivity and its mechanisms. Results: UBQLN2 is highly expressed in ESCC tissues and positively correlated with poor overall survival (OS). The knockdown of UBQLN2 dramatically increased the radiosensitivity of ESCC cells. Mechanically, UBQLN2 suppression substantially upregulated p38 mitogen-activated protein kinases (MAPK). The p38 MAPK inhibitor SB203580 could reverse the radiation-enhancing effect induced by UBQLN2 knockdown. The direct interaction between UBQLN2 and p38 MAPK was confirmed by co-immunoprecipitation (CO-IP) assay. Furthermore, silencing UBQLN2 also inhibited the expression of phosphorylated DNA-dependent protein kinase catalytic subunit (p-DNA-PKcs) after irradiation. Finally, the xenografted tumor experiment confirmed the radiosensitizing effect of silencing UBQLN2 on ESCC in vivo. Conclusion: Our results suggest that silencing UBQLN2 enhances the radiosensitivity of ESCC by activating p38 MAPK, and UBQLN2 may be a potential target to enhance the radiosensitivity of ESCC.

[Spatial-temporal Variation and Driving Factors of Ozone in China from 2019 to 2021 Based on EOF Technique and KZ Filter].

Based on the hourly O3 concentration data of 337 prefectural-level divisions and simultaneous surface meteorological data in China, we applied empirical orthogonal function (EOF) analysis to analyze the main spatial patterns, variation trends, and main meteorological driving factors of O3 concentration in China from March to August in 2019-2021. In this study, a KZ (Kolmogorov-Zurbenko) filter was used to decompose the time series of O3 concentration and simultaneous meteorological factors into corresponding short-term, seasonal, and long-term components in 31 provincial capitals.Then, the stepwise regression was used to establish the relationship between O3 and meteorological factors. Ultimately, the long-term component of O3 concentration after "meteorological adjustment" was reconstructed. The results indicated that the first spatial patterns of O3 concentration showed a convergent change, that is, the volatility of O3 concentration was weakened in the high-value region of variability and enhanced in the low-value region.Before and after the meteorological adjustment, the variation trend of O3 concentration in different cities was different to some extent. The adjusted curve was "flatter" in most cities. Among them, Fuzhou, Haikou, Changsha, Taiyuan, Harbin, and Urumqi were greatly affected by emissions. Shijiazhuang, Jinan, and Guangzhou were greatly affected by meteorological conditions. Beijing, Tianjin, Changchun, and Kunming were greatly affected by emissions and meteorological conditions.

Recall of reactive cutaneous capillary endothelial proliferation (RCCEP) induced by stereotactic body radiation therapy (SBRT) in a patient with lung squamous cell carcinoma.

Camrelizumab (SHR-1210) is a humanized IgG4 monoclonal anti-programmed cell death protein 1 (PD-1) antibody that has been shown to inhibit the binding of PD-1 to PD-L1, thereby blocking the immune escape of various types of cancer, including lung squamous cell carcinoma (LSCC). Reactive cutaneous capillary endothelial proliferation (RCCEP) is the most common adverse event in camrelizumab-treated patients. Here, we introduce a case of LSCC with recall RCCEP induced by stereotactic body radiation therapy (SBRT). A 76-year-old LSCC patient developed RCCEP when he received camrelizumab and chemotherapy. After discontinuing camrelizumab treatment, the RCCEP lesions spontaneously regressed and fell off. However, when the patient received subsequent SBRT, the RCCEP occurred again at the same sites. This case may provide clues for additional study of the immune reactivation effect of SBRT or the underlying mechanism of RCCEP.

Integrated 18F-FDG PET/CT parameter defines metabolic oligometastatic non-small cell lung cancer.

AIMS: The purpose of this study was to define metabolic oligometastatic non-small cell lung cancer (NSCLC) by using the number of metastatic lesions and 18F-FDG PET/CT parameters. METHODS: One hundred twenty-four newly diagnosed stage IV NSCLC patients who received pretreatment 18F-FDG PET/CT examination were retrospectively analyzed. The maximum standardized uptake value (SUVmax) of primary and metastatic lesions and the collected clinical parameters were fed into the univariate and multivariate Cox proportional hazard model. Survival analysis was performed using Kaplan-Meier and log-rank test. RESULTS: In univariate analysis, the results revealed that histology, metastatic organ numbers, adrenal gland metastasis, SUVmax of both primary and metastatic lesions, lactate dehydrogenase, systemic treatment, and local treatment were significantly correlated with overall survival of stage IV NSCLC patients. Multivariate analysis demonstrated that SUVmax of primary lesions and systemic treatment were independent risk factors of stage IV NSCLC patients. The addition of primary lung cancer SUVmax to traditional method (only count the numbers of metastasis lesions) enhanced the identification of oligometastatic NSCLC and the C-index increased from 0.601 to 0.693. CONCLUSION: We developed a method for the definition of metabolic oligometastatic NSCLC, which combined the number of organs involved, the number of metastatic lesions, and the SUVmax of primary lung cancer.

Changes in Patellar Morphology Following Soft Tissue Surgical Correction of Recurrent Patellar Dislocation in Children with Low-Grade Trochlear Dysplasia.

OBJECTIVE: To investigate the changes in patellar morphology following soft tissue surgical correction of recurrent patellar dislocation in children with low-grade trochlear dysplasia. METHODS: The prospective cohort study was performed between November 2007 and December 2012. Finally, 25 cases, with the mean age of 8.4 years (range from 7 to 10 years), were admitted to the study. All patients were diagnosed as bilateral recurrent patellar dislocation associated with femoral trochlear dysplasia. The knee that suffered injury or was dislocated was treated with medial patellar retinacular plasty (surgery group). The contralateral knee, which served as a control, was treated conservatively (conservative group). Axial CT scans were undertaken in all patients to assess the patellar morphological characteristics. RESULTS: The mean follow-up time was 60.8 months (range 48 to 75 months). Preoperatively, there were no statistically significant differences between the patellar morphology in the two groups (P > 0.05). Many radiological parameters of patellar morphology were significantly different between the two groups at the final follow-up, including well-known parameters, such as the mean patellar width (surgery group, 40.58 mm [SD 1.26]; conservative group, 36.41 mm [SD 1.17]; P < 0.05), the mean patellar thickness (surgery group, 11.59 mm [SD 0.74]; conservative group, 9.38 mm [SD 0.56]; P < 0.05) and the mean Wiberg index (surgery group, 0.54 [SD 0.06]; conservative group, 0.72 [SD 0.08]; P < 0.05). There are also little-known parameters, such as the ratio of length of lateral patella to medial patella (surgery group, 1.26 [SD 0.17]; conservative group, 1.69 [SD 0.21]; P < 0.05), which was a measurement of facet asymmetry. However, the Wiberg angle was not significantly different between the two groups (surgery group, 128.63° [SD 9.05]; conservative group, 125.47° [SD 13.96°]; P > 0.05) at the final follow-up. No complications were found. CONCLUSIONS: The patellar morphology can be significantly improved by early soft tissue surgical correction in children with patellar instability associated with low-grade femoral trochlear dysplasia.

CDK4/6 inhibitor enhances the radiosensitization of esophageal squamous cell carcinoma (ESCC) by activating autophagy signaling via the suppression of mTOR.

OBJECTIVE: To investigate the radiosensitizing effect of cyclin D-cyclin dependent kinase (CDK) 4/6 inhibitor palbociclib on esophageal squamous cell carcinoma (ESCC) and its underlying mechanisms. METHODS: The effect of palbociclib on ESCC cell radiosensitivity was detected by cell counting kit-8 (CCK-8) and clonogenic assay. γH2AX immunofluorescent staining was used to assess the repair of DNA damage induced by radiation. The expression of DNA repair proteins were examined by western blotting. Subsequently, immunoblotting and autophagy inhibitors were used to evaluate the underlying mechanisms of palbociclib triggered radiosensitization. Finally, the xenografts of ESCC were established to study the radiosensitizing effect of palbociclib in vivo. RESULTS: Palbociclib combined with irradiation significantly inhibited the cell viability of ESCC in vitro. The expression level of γH2AX showed that radiation induced DNA damage repair was inhibited by palbociclib treatment. Palbociclib also suppressed the expression of RAD51 and phosphorylated DNA-dependent protein kinase catalytic subunit (p-DNA-PKcs) after irradiation. Mechanically, palbociclib enhanced the radiosensitization of ESCC by activating autophagy via suppression of mammalian target of rapamycin (mTOR). Inhibition of autophagy using chloroquine could partially reverse the radiation enhancing effect of palbociclib. Lastly, the xenografted tumor experiment confirmed the radiosensitizing effect of palbociclib in ESCC in vivo. CONCLUSION: Our results showed that palbociclib improved the radiosensitivity of ESCC in vivo and in vitro, and thus it may be a promising radiosensitization agent for the treatment of ESCC.

Lymphopenia in Esophageal Cancer: What Have We Learned?

Lymphopenia caused by disease or treatment is frequent in patients with cancer, which seriously affects the prognosis of these patients. Immune checkpoint inhibitors (ICIs) have garnered attention as one of the most promising strategies for the treatment of esophageal cancer (EC). The status of the immune system, such as, the lymphocyte count, is now considered to be an important biomarker for ICI treatments. Recognition of the significant impact of the lymphocyte count on the survival of patients with EC in the era of immunotherapy has revived interest in understanding the causes of lymphopenia and in developing strategies to predict, prevent and eliminate the adverse effect of lymphopenia. Here, we review what we have learned about lymphopenia in EC, including the prognostic and predictive value of lymphopenia in patients with EC, the predictors of lymphopenia, and the strategies to ameliorate the effect of lymphopenia in patients with EC.

Coating function and stabilizing effects of surface layer protein from Lactobacillus acidophilus ATCC 4356 on liposomes.

Surface layer proteins (SLPs) are crystalline arrays in the outermost layer of cell envelope in many archaea and bacteria. SLPs subunits have the ability to reassemble on the surface of lipid layers. In this work, the SLP from Lactobacillus acidophilus ATCC 4356 was extracted and reassembled on the surface of positively charged liposomes composed of dipalmitoyl phosphatidylcholine, cholesterol and octadecylamine. Zeta potentials and particle size were determined to describe the adsorption process of SLP on liposomes. The liposomes completely coated with SLP were observed by transmission electron microscope. To investigate the stabilizing effects of SLP on liposomes, carboxyfluorescein (CF) was encapsulated and its leakage was determined as an evaluation index. The results showed that the L. acidophilus ATCC 4356 SLP significantly (P < 0.05) increased the stability of the liposomes in the course of thermal challenge. Furthermore, SLP was able to reduce the aggregation of liposomes in serum. Storage stability of liposomes was performed at 25 °C, 4 °C and -20 °C for 90 days. And the SLP-coated liposomes released less CF than the control liposomes during storage at the three evaluated temperatures. Our findings extended the application field of Lactobacillus SLPs and introduced a novel nanocarrier system with good chemical stability.

Nrf2 promotes esophageal squamous cell carcinoma (ESCC) resistance to radiotherapy through the CaMKIIα-associated activation of autophagy.

BACKGROUND: NF-E2-related factor 2 (Nrf2) is involved in the radiation resistance of esophageal squamous cell carcinoma (ESCC), but the underlying molecular mechanism is unclear. The purpose of our study was to explore the role of Nrf2 in the radiation resistance of ESCC and the potential molecular mechanism. RESULTS: Nrf2 expression was introduced into Ec109 and KYSE-30 ESCC cells with lentivirus. CCK-8 and colony formation assays were used to evaluate the effect of Nrf2 on radioresistance in culture. The autophagy level was assessed by western blotting, flow cytometry, and confocal fluorescence microscopy. The effect of Nrf2 on the transcription of Ca2 +/calmodulin-dependent protein kinase II α (CaMKIIα) was studied by chromatin immunoprecipitation. We found that the overexpression of Nrf2 increased the radiation resistance of ESCC cells. Mechanistically, Nrf2 triggered the radiation resistance of ESCC cells by targeting CaMKIIα and subsequently activating autophagy. In addition, we found that Nrf2 directly regulated the transcription of CaMKIIα by binding to its promoter region. The effect of Nrf2 on radiation resistance was also explored in both a xenograft mouse model and ESCC patient samples. Consistent with the results of the in vitro study, high Nrf2 expression level resulted in in vivo radioresistance in an Ec109-derived xenograft mouse model. Furthermore, we also demonstrated that upregulations of both Nrf2 and CaMKIIα was closely related to lower survival rates of ESCC patients. CONCLUSIONS: Our study reveals that Nrf2 promotes the radiation resistance of ESCC by targeting CaMKIIα and subsequently activating autophagy, which is characterized by the suppression of phosphorylated mTOR and p62, activation of Beclin 1, and transformation of LC3-I to LC3-II.

The role of Nrf2/PIWIL2/purine metabolism axis in controlling radiation-induced lung fibrosis.

NF-E2-related factor 2 (Nrf2) is a key transcription factor recently implicated in the control of radiation-induced lung fibrosis (RILF). However, the molecular mechanism of Nrf2 in the pathogenesis of RILF is still unclear. The purpose of this study was to evaluate the regulatory effect and mechanism of Nrf2 in the pathogenesis of RILF. The effects of different Nrf2 expression levels on RILF were explored in vitro and in vivo. The RILF model of Nrf2 knockout mice was established for in vivo study. In the study of the mechanism of action, ChIP-seq assay and metabolomics analysis were performed. The discovered mechanism of Nrf2-mediated RILF alleviation was further validated in vitro and in vivo. We found that overexpression of Nrf2 significantly alleviated the fibrosis caused by irradiation in vivo and in vitro. Conversely, Nrf2 silencing strongly aggravated the development of RILF. Mechanistically, Nrf2 signaling increased the expression of piwi-like RNA-mediated gene silencing 2 (PIWIL2), leading to the alteration of purine metabolism and contributing to the relief of RILF. These results suggest that Nrf2 promotes the attenuation of RILF in vivo and in vitro by directly targeting PIWIL2 and activating purine metabolism.

Induction of Pyroptosis and Its Implications in Cancer Management.

Pyroptosis is a gasdermins mediated programmed cell death, which has been widely studied in inflammatory disease models. Recently, there are growing evidences that pyroptosis can be chemically induced in cancer cells without any bacterial or viral infection. Pyroptosis may affect all stages of carcinogenesis and has become a new topic in cancer research. In this review, we first briefly introduced pyroptosis. In the subsequent section, we discussed the induction of pyroptosis in cancer and its potential role as a promising target for cancer therapy. In addition, the biological characteristics of gasdermin D (GSDMD) and gasdermin E (GSDME), two important pyroptosis substrates, and their prognostic role in cancer management were reviewed. These results help us to understand the pathogenesis of cancer and develop new drugs, which based on pyroptosis modulation, for cancer patients.