Exosomes in esophageal cancer: Promising nanocarriers in cancer progression, diagnosis, prognosis, and therapy.

Esophageal cancer (EC) is one of the most fatal cancers all over the world. Sensitive detection modalities for early-stage EC and efficient treatment methods are urgently needed for the improvement of the prognosis of EC. Exosomes are small vesicles for intercellular communication, mediating many biological responses including cancer progression, which are not only promising biomarkers for diagnosis and prognosis but also therapeutic tools for EC. This review provides an overview of the relationships between exosomes and EC progression, as well as the application of exosomes in the diagnosis, prognosis, and treatment of EC. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Clinical efficacy of different therapeutic strategies in patients with spontaneous rupture of the esophagus: a multicenter retrospective cohort study.

BACKGROUND: The therapeutic strategy for patients with spontaneous rupture of the esophagus includes surgical repair, endoscopic therapy, supportive care, and others. However, no evidence exists to direct clinical decision-making regarding the choice of operative and nonoperative management. The aim of this study was to determine the clinical efficacy of different therapeutic strategies in both general and stratified patients. METHODS: This study retrospectively analyzed a consecutive cohort of 101 patients at nine tertiary referral hospital centers in China. Patients were divided into operative and nonoperative groups based on the initial treatment. Short-term outcomes, including 90-day mortality, length of hospital stay, and postoperative leakage were compared. Subgroup analysis was performed based on treatment timing and Pittsburgh perforation severity score (PSS). RESULTS: Of 101 patients, 60 (58.4%) underwent operative management. A significant difference of 90-day mortality between operative and nonoperative groups was observed (15.0% vs. 34.1%, P=0.031). Operative management tend to yield similar therapeutic benefits in timely (OR, 0.250; 95% CI, 0.05-1.14, P=0.073) and delayed (OR, 0.42; 95% CI, 0.12-1.47, P=0.175) treatment groups. Based on PSS stratification, operative management significantly decreased the risk of 90-day mortality (OR, 0.211; 95% CI, 0.064-0.701; P=0.011) for patients in low- and moderate-risk groups but may be detrimental for patients in high-risk group (OR, 1.333; 95% CI, 0.233-7.626; P=0.746). CONCLUSIONS: Operative management might be superior to nonoperative management for low- and moderate-risk patients with spontaneous rupture of the esophagus. However, for patients at high risks, operative management might not provide additional benefits compared with nonoperative management. Further research involving larger sample sizes is required for accurate patient stratification and conclusive evidence-based guideline.

Identification of the continuum field structure at multiple scale levels.

For continuum fields such as turbulence, analyses of the field structure offer insights into their kinematic and dynamic properties. To ensure the analyses are quantitative rather than merely illustrative, two conditions are essential: space-filling and structure quantification. A pertinent example is the dissipation element (DE) structure, which is however susceptible to noisy interference, rendering it inefficient for extracting the large-scale features of the field. In this study, the multi-level DE structure is proposed based on the multi-level extremal point concept. At a given scale level, the entire field can be decomposed into the corresponding space-filling and non-overlapping DEs, each characterized by its length scale l and the scalar difference Δϕ between its two extremal points. We will first elaborate on the fundamental principles of this method. Results from an artificially constructed two-scale field indicate that the decomposed units adequately represent the geometry of the original field. In examining the fractal Brownian motion, a structure function equivalent ⟨Δϕ|l⟩ and an energy spectrum equivalent are introduced. The scaling relation derived from ⟨Δϕ|l⟩ corresponds with the Hurst number. Furthermore, the multi-level DE structure distinctly reveals the two different inertial ranges in two-dimensional turbulence. Overall, this novel structure identification approach holds significant potential for complex analyses concerning the field geometry.

DHCR7 promotes lymph node metastasis in cervical cancer through cholesterol reprogramming-mediated activation of the KANK4/PI3K/AKT axis and VEGF-C secretion.

Cervical cancer (CC) patients with lymph node metastasis (LNM) have a poor prognosis. However, the molecular mechanism of LNM in CC is unclear, and there is no effective clinical treatment. Here, we found that 7-dehydrocholesterol reductase (DHCR7), an enzyme that catalyzes the last step of cholesterol synthesis, was upregulated in CC and closely related to LNM. Gain-of-function and loss-of-function experiments proved that DHCR7 promoted the invasion ability of CC cells and lymphangiogenesis in vitro and induced LNM in vivo. The LNM-promoting effect of DHCR7 was partly mediated by upregulating KN motif and ankyrin repeat domains 4 (KANK4) expression and subsequently activating the PI3K/AKT signaling pathway. Alternatively, DHCR7 promoted the secretion of vascular endothelial growth factor-C (VEGF-C), and thereby lymphangiogenesis. Interestingly, cholesterol reprogramming was needed for the DHCR7-mediated promotion of activation of the KANK4/PI3K/AKT axis, VEGF-C secretion, and subsequent LNM. Importantly, treatment with the DHCR7 inhibitors AY9944 and tamoxifen (TAM) significantly inhibited LNM of CC, suggesting the clinical application potential of DHCR7 inhibitors in CC. Collectively, our results uncover a novel molecular mechanism of LNM in CC and identify DHCR7 as a new potential therapeutic target.

Programmed cell death 11 modulates but not entirely relies on p53-HDM2 loop to facilitate G2/M transition in colorectal cancer cells.

We previously described a nucleolar protein RSL1D1 but distributed throughout the nucleus in HCT116 colorectal cancer (CRC) cells to facilitate G1/S transition by inhibiting p53 signaling. Here, we found another nucleolar protein, programmed cell death 11 (PDCD11), also with an "Extra-nucleolar" localization in CRC cells but to regulate G2/M checkpoint. This protein directly interacts with p53 and HDM2 in the nucleoplasm, thereby recruiting p53 to HDM2 for ubiquitination and degradation. The ensuing downregulation of p53 increases the CDK1 level to help the cells pass G2/M checkpoint. Upon DNA damage stress, PDCD11 gains the power to upregulate CDK1 independently of p53. Beyond these, PDCD11 also upregulates CDC25C in a p53-independent manner to dephosphorylate CDK1 to facilitate G2/M transition. Downregulation of PDCD11 greatly reduced cancer cell growth in vitro and in vivo, additionally sensitized cells to DNA damage signals, highlighting that PDCD11 is a crucial driving factor of CRC and a potential target for cancer treatment.

Sequential pulmonary resections by uniportal video-assisted thoracic surgery for bilateral multiple pulmonary nodules.

Objective: The aim of this study was to evaluate the effect of sequential pulmonary resections by uniportal video-assisted thoracoscopic surgery (VATS) for bilateral multiple pulmonary nodules (BMPNs). Methods: A single-center, prospective, nonrandomized study was performed on patients who underwent one-stage or two-stage operations by uniportal VATS. The clinical, pathological and perioperative data were summarized and analyzed from January 2021 to December 2021. Results: A total of 80 patients were included during the study period. Sequential pulmonary resection by uniportal VATS was underwent in 40 patients. There were no perioperative deaths and serious complications, 2 patients had postoperative pneumonia, 3 patients had transient atrial fibrillation, 1 patient had persistent severe air leakage, 1 patient occurred hemoptysis. The one-stage group had less operative time, surgical blood loss, pleural drainage, chest tube duration and postoperative admission duration(P<0.05). The results of pathological examination of pulmonary nodules revealed adenocarcinoma in situ (n=12), minimally invasive adenocarcinoma (n=24), invasive adenocarcinoma (n=42), squamous carcinoma (n=1),and benign nodules (n=10). The pathological diagnosis included multiple primary lung cancers (30/40, 75%), single primary lung cancer (6/40, 15%). The most advanced pathologic stage of the primary lung cancer was classified as IA (n=19), IB (n=5), II (n=3), and IIIA (n=2). Conclusion: For patients with excellent pulmonary function, sequential pulmonary resection by uniportal VATS is a safe and feasible for BMPNs. Strict control of surgical indications, reasonable preoperative planning, accurate intraoperative operation, and standardized perioperative management can effectively reduce complications and maximize benefits for suitable patients.

Co-Delivery of p53 Restored and E7 Targeted Nucleic Acids by Poly (Beta-Amino Ester) Complex Nanoparticles for the Treatment of HPV Related Cervical Lesions.

The p53 gene has the highest mutation frequency in tumors, and its inactivation can lead to malignant transformation, such as cell cycle arrest and apoptotic inhibition. Persistent high-risk human papillomavirus (HR-HPV) infection is the leading cause of cervical cancer. P53 was inactivated by HPV oncoprotein E6, promoting abnormal cell proliferation and carcinogenesis. To study the treatment of cervical intraepithelial neoplasia (CIN) and cervical cancer by restoring p53 expression and inactivating HPV oncoprotein, and to verify the effectiveness of nano drugs based on nucleic acid delivery in cancer treatment, we developed poly (beta-amino ester)537, to form biocompatible and degradable nanoparticles with plasmids (expressing p53 and targeting E7). In vitro and in vivo experiments show that nanoparticles have low toxicity and high transfection efficiency. Nanoparticles inhibited the growth of xenograft tumors and successfully reversed HPV transgenic mice's cervical intraepithelial neoplasia. Our work suggests that the restoration of p53 expression and the inactivation of HPV16 E7 are essential for blocking the development of cervical cancer. This study provides new insights into the precise treatment of HPV-related cervical lesions.

Reciprocal modulation of long noncoding RNA EMS and p53 regulates tumorigenesis.

p53 plays a central role in tumor suppression. Emerging evidence suggests long noncoding RNA (lncRNA) as an important class of regulatory molecules that control the p53 signaling. Here, we report that the oncogenic lncRNA E2F1 messenger RNA (mRNA) stabilizing factor (EMS) and p53 mutually repress each other's expression. EMS is negatively regulated by p53. As a direct transcriptional repression target of p53, EMS is surprisingly shown to inhibit p53 expression. EMS associates with cytoplasmic polyadenylation element-binding protein 2 (CPEB2) and thus, disrupts the CPEB2-p53 mRNA interaction. This disassociation attenuates CPEB2-mediated p53 mRNA polyadenylation and suppresses p53 translation. Functionally, EMS is able to exert its oncogenic activities, at least partially, via the CPEB2-p53 axis. Together, these findings reveal a double-negative feedback loop between p53 and EMS, through which p53 is finely controlled. Our study also demonstrates a critical role for EMS in promoting tumorigenesis via the negative regulation of p53.

A Nutrition and Inflammation-Related Nomogram to Predict Overall Survival in Surgically Resected Esophageal Squamous Cell Carcinoma (ESCC) Patients.

Pretreatment inflammation-based biomarkers and the prognostic nutrition index (PNI) have been used to evaluate prognosis in cancer patients. However, few studies have focused on the prognostic value of post-treatment inflammation-based biomarkers and PNI in ESCC patients. We aimed to investigate the values of pre/post-treatment inflammatory parameters and PNI for establishing a nomogram to predict overall survival (OS) in ESCC patients. A retrospective review was performed on 268 ESCC patients with esophagectomy. The prognostic values of inflammatory and nutrition indexes were evaluated. Based on the results of multivariable Cox analysis, a nomogram was developed. The predictive accuracy and discriminative ability of the nomogram were determined using the concordance-index (C-index) and a calibration curve and subsequently compared to tumor-node-metastasis (TNM) staging by C-index, receiver operating characteristic (ROC) and decision curve analysis (DCA). PreSII, PostSII, PrePNI, N stage, and TNM classification were assembled into a nomogram. The C-index of the nomogram was 0.774, and the area under curve (AUC) of the nomogram was 0.862. DCA demonstrated that the established nomogram was a better predictive model compared to the TNM system. The developed nomogram with superior predictive ability provides more valuable prognostic information for patients and clinicians than TNM classification.

Covering the gastric tube with the mediastinal pleura during minimally invasive McKeown esophagectomy can reduce the incidence of anastomotic fistulae.

INTRODUCTION: The rate of anastomotic leakage from intrathoracic esophagogastric anastomoses can be reduced by covering them with the mediastinal pleura. Whether anastomotic leakage can be reduced by covering the portion of the gastric tube in the upper mediastinum with the mediastinal pleura during minimally invasive McKeown esophagectomy (MIE McKeown) is unknown. AIM: To evaluate the consequence of covering the mediastinal pleural during minimally invasive McKeown esophagectomy. MATERIAL AND METHODS: Consecutive patients who underwent MIE McKeown between January 2015 and December 2019 were retrospectively analyzed. Participants for whom the portion of the gastric tube in the upper mediastinum was not covered with the mediastinal pleura were assigned to group A; otherwise, they were assigned to group B. Chi-square analysis and univariable and multivariable logistic analyses were used to compare the differences between the two groups and explore the risk factors for anastomotic fistulae. RESULTS: A total of 267 patients with middle and lower esophageal cancer were included in this study (131 in group A and 136 in group B). Anastomotic leakage occurred in 5 patients (5/136) in group B compared with 13 patients (13/131) in group A (p = 0.042). Univariable and multivariable logistic analyses identified a gastric tube not covered with the mediastinal pleura as a risk factor for significantly greater anastomotic leakage (p = 0.042), but it was not an independent prognostic factor for anastomotic leakage (odds ratio = 0.585, 95% confidence interval: lower bound: 0.069, upper bound, 1.122). CONCLUSIONS: This study provides preliminary evidence that covering the gastric tube with the mediastinal pleura during MIE McKeown can decrease the incidence of anastomotic leakage.

RIPK1 regulates starvation resistance by modulating aspartate catabolism.

RIPK1 is a crucial regulator of cell death and survival. Ripk1 deficiency promotes mouse survival in the prenatal period while inhibits survival in the early postnatal period without a clear mechanism. Metabolism regulation and autophagy are critical to neonatal survival from severe starvation at birth. However, the mechanism by which RIPK1 regulates starvation resistance and survival remains unclear. Here, we address this question by discovering the metabolic regulatory role of RIPK1. First, metabolomics analysis reveals that Ripk1 deficiency specifically increases aspartate levels in both mouse neonates and mammalian cells under starvation conditions. Increased aspartate in Ripk1-/- cells enhances the TCA  flux and ATP production. The energy imbalance causes defective autophagy induction by inhibiting the AMPK/ULK1 pathway. Transcriptional analyses demonstrate that Ripk1-/- deficiency downregulates gene expression in aspartate catabolism by inactivating SP1. To summarize, this study reveals that RIPK1 serves as a metabolic regulator responsible for starvation resistance.

The Positive Role and Mechanism of Herbal Medicine in Parkinson's Disease.

Parkinson's disease (PD) is a complex neurodegenerative disease, manifested by the progressive functional impairment of the midbrain nigral dopaminergic neurons. Due to the unclear underlying pathogenesis, disease-modifying drugs for PD remain elusive. In Asia, such as in China and India, herbal medicines have been used in the treatment of neurodegenerative disease for thousands of years, which recently attracted considerable attention because of the development of curative drugs for PD. In this review, we first summarized the pathogenic factors of PD including protein aggregation, mitochondrial dysfunction, ion accumulation, neuroinflammation, and oxidative stress, and the related recent advances. Secondly, we summarized 32 Chinese herbal medicines (belonging to 24 genera, such as Acanthopanax, Alpinia, and Astragalus), 22 Chinese traditional herbal formulations, and 3 Indian herbal medicines, of which the ethanol/water extraction or main bioactive compounds have been extensively investigated on PD models both in vitro and in vivo. We elaborately provided pictures of the representative herbs and the structural formula of the bioactive components (such as leutheroside B and astragaloside IV) of the herbal medicines. Also, we specified the potential targets of the bioactive compounds or extractions of herbs in view of the signaling pathways such as PI3K, NF-κB, and AMPK which are implicated in oxidative and inflammatory stress in neurons. We consider that this knowledge of herbal medicines or their bioactive components can be favorable for the development of disease-modifying drugs for PD.

Increased interleukin-17A-producing γδT cells predict favorable survival in elderly patients with LUAD and LUSC.

PURPOSE: Aging is closely related to the occurrence of many diseases, including cancer, and involves changes in the immune microenvironment. γδT cells are important components of resident lymphocytes in mucosal tissues. However, little is known about the effects that the aged lung has on γδT cells and their prognostic significance in non-small cell lung cancer. METHODS: In the current study, the expression of γδTCR and IL-17A was measured by immunohistochemistry in paraffin-embedded lung tissues from 168 patients with adenocarcinoma (LUAD) and 144 patients with squamous cell carcinoma (LUSC). Furthermore, gene transcription patterns in LUAD and LUSC tumors and normal controls were extracted from TCGA and GTEx databases and were analyzed. RESULTS: High frequency of γδT cells was observed in patients with LUAD and LUSC, whereas the levels of CD4 + T cells, CD8 + T cells and CD56 + cells were decreased. Elevated γδT cells in tumors were mainly IL-17A-releasing γδT17 cells, which were found to be enriched in aged patients. High γδT cell levels positively corelated with the overall survival (OS) of patients, especially the 5-year OS in the elderly. Further analysis of gene transcription patterns indicated that increased expression of LTBR, HES1, RORC, CCR6, IL1, and IL23A may contribute to the transformation of the tumor microenvironment in a manner conducive to γδT17 cell development and differentiation. Finally, gene analysis between different age groups revealed that the expression of CCR6 and IL7 in LUAD, as well as Hes1, IL7, and IL23A in LUSC, were remarkably higher in elderly (age ≥ 60 years) than in younger individuals (age < 60 years). CONCLUSION: Our findings suggest that intrinsic alterations in the aging lung lead to γδT17 cell enrichment, which subsequently may exert anti-tumor effects in the elderly.

Corrigendum: Innate Immune Cells in the Esophageal Tumor Microenvironment.

[This corrects the article DOI: 10.3389/fimmu.2021.654731.].

Innate Immune Cells in the Esophageal Tumor Microenvironment.

Esophageal cancer (EC) is one of the most common mucosa-associated tumors, and is characterized by aggressiveness, poor prognosis, and unfavorable patient survival rates. As an organ directly exposed to the risk of foodborne infection, the esophageal mucosa harbors distinct populations of innate immune cells, which play vital roles in both maintenance of esophageal homeostasis and immune defense and surveillance during mucosal anti-infection and anti-tumor responses. In this review, we highlight recent progress in research into innate immune cells in the microenvironment of EC, including lymphatic lineages, such as natural killer and γδT cells, and myeloid lineages, including macrophages, dendritic cells, neutrophils, myeloid-derived suppressor cells, mast cells and eosinophils. Further, putative innate immune cellular and molecular mechanisms involved in tumor occurrence and progression are discussed, to highlight potential directions for the development of new biomarkers and effective intervention targets, which can hopefully be applied in long-term multilevel clinical EC treatment. Fully understanding the innate immunological mechanisms involved in esophageal mucosa carcinogenesis is of great significance for clinical immunotherapy and prognosis prediction for patients with EC.

The Emerging Role of Tissue-Resident Memory CD8+ T Lymphocytes in Human Digestive Tract Cancers.

Malignant digestive tract tumors are a great threat to human public health. In addition to surgery, immunotherapy brings hope for the treatment of these tumors. Tissue-resident memory CD8+ T (Trm) cells are a focus of tumor immunology research and treatment due to their powerful cytotoxic effects, ability to directly kill epithelial-derived tumor cells, and overall impact on maintaining mucosal homeostasis and antitumor function in the digestive tract. They are a group of noncirculating immune cells expressing adhesion and migration molecules such as CD69, CD103, and CD49a that primarily reside on the barrier epithelium of nonlymphoid organs and respond rapidly to both viral and bacterial infection and tumorigenesis. This review highlights new research exploring the role of CD8+ Trm cells in a variety of digestive tract malignant tumors, including esophageal cancer, gastric cancer, colorectal cancer, and hepatocellular carcinoma. A summary of CD8+ Trm cell phenotypes and characteristics, tissue distribution, and antitumor functions in different tumor environments is provided, illustrating how these cells may be used in immunotherapies against digestive tract tumors.

Effectiveness of jejunostomy for enteral nutrition during complete thoracoscopic and laparoscopic Ivor-Lewis esophagectomy in thoracic segment esophageal carcinoma.

BACKGROUND: Although jejunostomy is widely used in complete thoracoscopic and laparoscopic minimally invasive Ivor-Lewis esophagectomy, its clinical effectiveness remains undefined. This study aimed to assess the therapeutic and side effects of jejunostomy in patients undergoing Ivor-Lewis esophagectomy for thoracic segment esophageal carcinoma. METHODS: A total of 1400 patients with esophageal carcinoma who underwent minimally invasive esophagectomy in the Thoracic Surgery of our hospital from 2015 to 2018 were retrospectively evaluated. Of these, 356 and 1044 were treated with nasojejunal feeding tubes (Nasojejunal group) and by jejunostomy (Jejunostomy group), respectively. Clinicopathologic factors, postoperative complications and tubule-related complications between the two groups were compared. RESULTS: Both groups were well-balanced for clinicopathological data, except tumor location, which was significantly different (P < 0.001). Operation time (208.8 ± 53.5 min vs. 218.1 ± 43.2 min) was shorter in the Jejunostomy group compared with the Nasojejunal group, while intraoperative (26.6 ± 10.4 min vs 18.4 ± 9.1 min) and postoperative (38.6 ± 6.9 min vs 18.5 ± 7.6 min) indwelling times of nutrition tubes were prolonged (all P < 0.05). Postoperative pulmonary infection (17.0% vs 22.2%), incision infection (0.2% vs 1.1%), nutrient tube slippage (0.2% vs 5.1%) and nutrient reflux 1 (0.1% vs 5.6%) rates were reduced in the Jejunostomy group compared with the Nasojejunal group (P < 0.05). Meanwhile, ileus rates perioperatively (1.7% vs 0.3%) and at 3 postoperative months (1.7% vs 0.3%) were both higher in the Jejunostomy group compared with the Nasojejunal group. CONCLUSIONS: Jejunostomy is a reliable enteral nutrition method in Ivor-Lewis esophagectomy for thoracic segment esophageal carcinoma.

Inhibiting MARSs reduces hyperhomocysteinemia-associated neural tube and congenital heart defects.

Hyperhomocysteinemia is a common metabolic disorder that imposes major adverse health consequences. Reducing homocysteine levels, however, is not always effective against hyperhomocysteinemia-associated pathologies. Herein, we report the potential roles of methionyl-tRNA synthetase (MARS)-generated homocysteine signals in neural tube defects (NTDs) and congenital heart defects (CHDs). Increased copy numbers of MARS and/or MARS2 were detected in NTD and CHD patients. MARSs sense homocysteine and transmit its signal by inducing protein lysine (N)-homocysteinylation. Here, we identified hundreds of novel N-homocysteinylated proteins. N-homocysteinylation of superoxide dismutases (SOD1/2) provided new mechanistic insights for homocysteine-induced oxidative stress, apoptosis and Wnt signalling deregulation. Elevated MARS expression in developing and proliferating cells sensitizes them to the effects of homocysteine. Targeting MARSs using the homocysteine analogue acetyl homocysteine thioether (AHT) reversed MARS efficacy. AHT lowered NTD and CHD onsets in retinoic acid-induced and hyperhomocysteinemia-induced animal models without affecting homocysteine levels. We provide genetic and biochemical evidence to show that MARSs are previously overlooked genetic determinants and key pathological factors of hyperhomocysteinemia, and suggest that MARS inhibition represents an important medicinal approach for controlling hyperhomocysteinemia-associated diseases.

Predictive significance of CYFRA21-1, squamous cell carcinoma antigen and carcinoembryonic antigen for lymph node metastasis in patients with esophageal squamous cancer.

From January 2018 to May 2018, 108 patients with thoracic esophageal cancer underwent esophagectomy with two- to three-field lymph node dissection. Serum cytokeratin 19 fragment antigen 21-1 (CYFRA21-1), squamous cell carcinoma antigen, and carcinoembryonic antigen levels were detected before surgery. Preoperative serum levels of CYFRA21-1 and squamous cell carcinoma antigen were correlated closely with pN stage (P = 0.000 and P = 0.045). CYFRA21-1 and pathological T status were independent predictors of lymph node metastasis (P = 0.000). The area under the curve values of CYFRA21-1 and squamous cell carcinoma antigen for predicting lymph node metastasis were 0.731 (P =0.000) and 0.650 (P =0.007), respectively. Our study demonstrated that serum CYFRA21-1 and squamous cell carcinoma antigen levels were associated with lymph node metastasis in esophageal squamous cell carcinoma, especially in patients at the early T stage. The preoperative serum CYFRA21-1 level was an independent predictor of lymph node metastasis.