Different functions of DEPTOR in modulating sensitivity to chemotherapy for esophageal squamous cell carcinoma.

There have been paradoxical findings regarding the expression of DEP domain-containing mTOR-interacting protein (DEPTOR) and its role in predicting prognosis in esophageal squamous cell carcinoma (ESCC). Here we show that DEPTOR expression was significantly increased in tumor tissues and predicted good survival in early stage ESCC patients but not in advanced stage patients. In vitro，our studies showed that ESCC cell lines could be classified into relatively high and low DEPTOR-expressing subgroups according to esophageal squamous epithelial cell line Het-1A.In our study, different levels of DEPTOR expression absolutely determined the response to chemotherapy. In relatively low-expressing cell lines, DEPTOR increased chemotherapy sensitivity via deactivation of the AKT pathway. In relatively high-expressing cell lines, DEPTOR increased cell survival and chemoresistance by strong feedback activation of the IRS1-PI3K-AKT-survivin pathway that occurred after downregulation of ribosomal protein S6 kinase (S6K). Collectively, our findings highlight the dichotomous nature of DEPTOR functions in modulating chemotherapy sensitivity in different ESCC cells.

Development and Validation of Lactate Metabolism-Related lncRNA Signature as a Prognostic Model for Lung Adenocarcinoma.

Background: Lung cancer has been a prominent research focus in recent years due to its role in cancer-related fatalities globally, with lung adenocarcinoma (LUAD) being the most prevalent histological form. Nonetheless, no signature of lactate metabolism-related long non-coding RNAs (LMR-lncRNAs) has been developed for patients with LUAD. Accordingly, we aimed to develop a unique LMR-lncRNA signature to determine the prognosis of patients with LUAD. Method: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were utilized to derive the lncRNA expression patterns. Identification of LMR-lncRNAs was accomplished by analyzing the co-expression patterns between lncRNAs and LMR genes. Subsequently, the association between lncRNA levels and survival outcomes was determined to develop an effective signature. In the TCGA cohort, Cox regression was enlisted to build an innovative signature consisting of three LMR-lncRNAs, which was validated in the GEO validation cohort. GSEA and immune infiltration analysis were conducted to investigate the functional annotation of the signature and the function of each type of immune cell. Results: Fourteen differentially expressed LMR-lncRNAs were strongly correlated with the prognosis of patients with LUAD and collectively formed a new LMR-lncRNA signature. The patients could be categorized into two cohorts based on their LMR-lncRNA signatures: a low-risk and high-risk group. The overall survival of patients with LUAD in the high-risk group was considerably lower than those in the low-risk group. Using Cox regression, this signature was shown to have substantial potential as an independent prognostic factor, which was further confirmed in the GEO cohort. Moreover, the signature could anticipate survival across different groups based on stage, age, and gender, among other variables. This signature also correlated with immune cell infiltration (including B cells, neutrophils, CD4+ T cells, CD8+ T cells, etc.) as well as the immune checkpoint blockade target CTLA-4. Conclusion: We developed and verified a new LMR-lncRNA signature useful for anticipating the survival of patients with LUAD. This signature could give potentially critical insight for immunotherapy interventions in patients with LUAD.

LncRNA miR205HG hinders HNRNPA0 translation: anti-oncogenic effects in esophageal carcinoma.

Esophageal carcinoma (ESCA) affects 4 450 000 people and causes approximately 400 000 deaths annually worldwide, making it the sixth most lethal and eighth most common cancer. Patients with ESCA are often diagnosed at the later stages in which cancer cell metastasis is the main factor contributing to the low 5-year survival rate (< 20%) of this disease. Long noncoding RNAs (lncRNAs) are a group of regulatory RNAs with a length of > 200 nucleotides but which fail to encode proteins. In this study, by using real-time quantitative PCR, we found that the expression of the miR205 host gene (miR205HG; a lncRNA) was downregulated in ESCA tumors when compared with normal esophageal tissues or adjacent normal tissues of tumors. Furthermore, we demonstrated that miR205HG modulates the expression of extracellular matrix-related genes in ESCA cells. In the transwell assay, downregulation of miR205HG contributes to migration and invasion of ESCA cells. In relation to the mechanism, our data show that miR205HG interacts with heterogeneous nuclear ribonucleoprotein A0 (HNRNPA0) mRNA and then hamper its translation by interacting with lin-28 homolog A (LIN28A). Altogether, we highlight that the miR205HG-HNRNPA0 axis is implicated in the migration and invasion of ESCA cells and that these members of this pathway may serve as therapeutic targets to inhibit metastasis of ESCA.

Oesophageal squamous cell carcinoma-associated IL-33 rewires macrophage polarization towards M2 via activating ornithine decarboxylase.

BACKGROUND: The tumour microenvironment primarily constitutes macrophages in the form of an immunosuppressive M2 phenotype, which promotes tumour growth. Thus, the development of methodologies to rewire M2-like tumour-associated macrophages (TAMs) into the M1 phenotype, which inhibits tumour growth, might be a critical advancement in cancer immunotherapy research. METHODS: The expressions of IL-33 and indicators related to macrophage polarization in oesophageal squamous cell carcinoma (ESCC) tissues and peripheral blood mononuclear cell (PBMC)-derived macrophages were determined. Inhibition of ornithine decarboxylase (ODC) with small interfering RNA was used to analyse the phenotype of macrophage polarization and polyamine secretory signals. CCK-8, wound-healing and Transwell assays were used to detect the proliferation and migration of ECA109 cells in vitro. The tumour xenograft assay in nude mice was used to examine the role of IL-33 in ESCC development in vivo. RESULTS: This study showed the substantially elevated IL-33 expression in ESCC tissues compared with the normal tissues. Additionally, enhanced infiltration of M2-like macrophages into the ESCC tumour tissue was also observed. We observed a strong correlation between the IL-33 levels and the infiltration of M2-like macrophages in ESCC tumours locally. Mechanistically, IL-33 induces M2-like macrophage polarization by activating ODC, a key enzyme that catalyses the synthesis of polyamines. Inhibition of ODC suppressed M2-like macrophage polarization. Finally, in vivo, we confirmed that IL-33 promotes tumour progression. CONCLUSIONS: This study revealed an oncogenic role of IL-33 by actively inducing M2-like macrophage differentiation; thus, contributing to the formation of an immunosuppressive ESCC tumour microenvironment. Thus, IL-33 could act as a novel target for cancer immunotherapies.

Tumor size-dependent abscopal effect of polydopamine-coated all-in-one nanoparticles for immunochemo-photothermal therapy of early- and late-stage metastatic cancer.

Metastatic cancer is a persistent clinical enigma, which requires combination of several treatment modules. Here, we developed an all-in-one nanomedicine strategy to systemically co-deliver photosensitive, chemotherapeutic, and immunomodulating agents for effective immunochemo-photothermal therapy (PTT) to inhibit both primary tumor and distal metastatic tumor. Two types of polydopamine (dp)-coated nanoparticles (NPs) (N/PGEM/dp-5 and N/PGEM/dp-16) co-loaded with gemcitabine (GEM) and NLG919, a potent indoleamine-2, 3-dioxygenase (IDO) inhibitor, were prepared. N/PGEM/dp-16 NPs with a thicker dp coating layer showed higher photothermal conversion ability, more favorable biodistribution profile and better tumor inhibition effect compared to N/PGEM/dp-5 NPs with a thinner coating layer. Combination with laser irradiation further enhanced the tumor inhibition effect of N/PGEM/dp-16 NPs. In an "early metastatic" pancreatic cancer PANC02 model with small distal tumors, introduction of NLG and dp coating improved the inhibition effect on both primary and distal tumors. Compared to N/PGEM/dp-16, N/PGEM/dp-16 plus laser irradiation further enhanced the inhibition effect on primary tumor, but didn't improve the abscopal antitumor effect. When the initial volume of distal tumor was sufficiently large in a "late metastasis" model, a more dramatic abscopal antitumor effect was achieved, resulting in a significant growth inhibition of both primary tumor and the unirradiated distal tumor. Furthermore, laser irradiation can amplify the immunochemo-NPs-mediated innate and adaptive immune responses in both tumors. This work demonstrated a distal tumor-size dependent abscopal effect, and provided a perspective for future design of more effective immunochemo-PTT nano-formulations for early- and late-stage metastatic tumors.

Delivery of gefitinib with an immunostimulatory nanocarrier improves therapeutic efficacy in lung cancer.

BACKGROUND: Combining different cancer treatments represents a promising strategy to improve the therapeutic outcome for lung cancer patients with or without druggable gene alterations. METHODS: We previously developed a polyethylene glycol-based (PEG-based) immunostimulatory nanocarrier (PEG2k-Fmoc-NLG919) which can efficiently co-deliver an indoleamine 2,3-dioxygenase-1 (IDO1) inhibitor and the chemotherapeutic agent, paclitaxel. This method was found to improve cancer therapy by simultaneously performing immuno- and chemo-therapy. However, whether this nanocarrier could deliver targeted drugs to implement targeted therapy together with immunotherapy remains unclear. RESULTS: Here, we report that the delivery of the classical tyrosine kinase inhibitor (TKI), gefitinib, with the optimized PEG5k-Fmoc-NLG919 nanocarrier, increased the sensitivity of lung cancer cells to gefitinib in vitro. Gefitinib was gradually but sufficiently released from the nanocarrier with comparable capacity to inhibit epidermal growth factor receptor (EGFR) activity as using free gefitinib directly. More importantly, treatment with gefitinib-loaded PEG5k-Fmoc-NLG919 could suppress lung tumor development more efficiently than gefitinib alone in vivo by inducing an immune active microenvironment with more functional CD8+ T cells and less regulatory T cell infiltration. CONCLUSIONS: Our study therefore demonstrates that delivery of small molecular targeted drugs with the immunostimulatory nanocarrier is a straightforward strategy for improving antitumor response for lung cancer therapy.

The first comprehensive database of germline pathogenic variants in East Asian cancer patients.

Pathogenic germline variants in cancer-associated genes are risk factors for cancer predisposition. However, systematic mining and summarizing of cancer pathogenic or likely pathogenic variants has not been performed for people of East Asian descent. This study aimed to investigate publicly available data to identify germline variants in East Asian cancer cohorts and compare them to variants in Caucasian cancer cohorts. Based on the data we retrieved, we built a comprehensive database, named COGVIC (Catalog of Germline Variants in Cancer). A total of 233 variants in the East Asian population were identified. The majority (87%) of genes with cancer-associated variants were not shared between the East Asian and Caucasian cohorts. This included pathogenic variants in BRCA2. Our study summarized the prevalence of germline variants in East Asian cancer cohorts and provides an easy-to-use online tool to explore germline mutations related to cancer susceptibility. DATABASE URL: http://www.cogvic.vip/.

Circular RNA circNELL2 Acts as the Sponge of miR-127-5p to Promote Esophageal Squamous Cell Carcinoma Progression.

INTRODUCTION: Owing to its involvement in both the initiation and progression of various cancers, aberrant circular RNA (circRNA) expression has been researched extensively in the recent times. In the present study, we aim to investigate the effect of a novel circRNA has_circ_0025933 (circNELL2) in the progression of esophageal squamous cell carcinoma (ESCC). MATERIALS AND METHODS: Sanger sequencing and the detection of circNELL2 level after RNase R or actinomycin D treatment were performed to identify the existence of cirNELL2 in ESCC cells. WST, EDU staining and colony-formation assay were used to assess the proliferation while transwell assay was used to evaluate the migration of ESCC cells. Luciferase assay, RNA pull down and the FISH assay were performed to verify the interaction between circNELL2 and miR-127-5p as well as miR-127-5p and CDC6. Xenograft model was carried out to evaluate the effect of circNELL2 in vivo. RESULTS: circNELL2 was proved to exist in ESCC cells. The up-regulated expression of circNELL2 in the clinical ESCC specimens was also verified. Next, function studies suggested that circNELL2 knockdown inhibited the proliferation of ESCC cells in vitro and in vivo, while circNELL2 overexpression promotes that of ESCC cells. Besides, this study mechanically predicted and verified the target miR of circNELL2, which is miR-127-5p. It was found that miR-127-5p was capable of reversing the effect of circNELL2 on ESCC cells. Moreover, miR-127-5p was also found to target CDC6 to participate in the regulation of cell phenotype. DISCUSSION: circNELL2 promoted the progression of ESCC cells via sponging miR-127-5p, and it has the potential to serve as a novel prognostic and therapeutic target for ESCC.

Sensitizing Triple Negative Breast Cancer to Tamoxifen Chemotherapy via a Redox-Responsive Vorinostat-containing Polymeric Prodrug Nanocarrier.

There is an urgent and unmet need to develop effective therapies for triple negative breast cancers (TNBCs) which are much more aggressive and have poor prognosis due to lack of receptor targets for Her2-targeted and endocrine therapy. In this study we systematically evaluated the effect of Vorinostat (SAHA, a pan-HDAC inhibitor) in reactivating the expression of functional estrogen receptor α (ERα) and synergizing with tamoxifen (TAM, a selective estrogen-receptor modulator) in antitumor activity. In addition, a SAHA prodrug-based dual functional nanocarrier was developed for codelivery of SAHA and TAM for effective combination therapy. Methods: A SAHA-containing polymeric nanocarrier, POEG-co-PVDSAHA was developed via reversible addition-fragmentation transfer (RAFT) polymerization with SAHA incorporated into the polymer through a redox-responsive disulfide linkage. The effect of both free SAHA and POEG-co-PVDSAHA on reactivating the expression of functional ERα was investigated in several human and murine TNBC cell lines via examining the mRNA and protein expression of ERα target genes. The cytotoxicity of free SAHA and TAM combination and TAM-loaded POEG-co-PVDSAHA micelles was examined via MTT assay. The in vivo antitumor activity of TAM-loaded POEG-co-PVDSAHA was investigated in a murine breast cancer model (4T1.2). Results: Both free SAHA and POEG-co-PVDSAHA were effective in inducing the reexpression of functional estrogen receptor α (ERα), which may have helped to sensitize TNBCs to TAM. More importantly, POEG-co-PVDSAHA self-assembled to form small-sized micellar carrier that is effective in formulating and codelivery of TAM. TAM-loaded POEG-co-PVDSAHA micelles exhibited enhanced and synergistic cytotoxicity against TNBC cell lines compared with free SAHA, free TAM and TAM loaded into a pharmacologically inert control carrier (POEG-co-PVMA). In addition, codelivery of TAM via POEG-co-PVDSAHA micelles led to significantly improved antitumor efficacy in 4T1.2 tumor model compared with other groups such as combination of free SAHA and TAM and TAM-loaded POEG-co-PVMA micelles. Conclusion: Our prodrug-based co-delivery system may provide an effective and simple strategy to re-sensitize TNBCs to TAM-based hormone therapy.

Triple drugs co-delivered by a small gemcitabine-based carrier for pancreatic cancer immunochemotherapy.

Poor tumor penetration and highly immunosuppressive tumor microenvironment are two major factors that limit the therapeutic efficacy for the treatment of pancreatic ductal adenocarcinoma (PDA). In this work, a redox-responsive gemcitabine (GEM)-conjugated polymer, PGEM, was employed as a tumor penetrating nanocarrier to co-load an immunomodulating agent (NLG919, an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1) and a chemotherapeutic drug (paclitaxel (PTX)) for immunochemo combination therapy. The NLG919/PTX co-loaded micelles showed very small size of ~15 nm. In vivo tumor imaging study indicated that PGEM was much more effective than the relatively large-sized POEG-co-PVD nanoparticles (~160 nm) in deep tumor penetration and could reach the core of the pancreatic tumor. PTX formulated in the PGEM carrier showed improved tumor inhibition effect compared with PGEM alone. Incorporation of NLG919 in the formulation led to a more immunoactive tumor microenvironment with significantly decreased percentage of Treg cells, and increased percentages of CD4+ IFNγ+ T and CD8+ IFNγ+ T cells. PGEM micelles co-loaded with PTX and NLG919 showed the best anti-tumor activity in pancreatic (PANC02) as well as two other tumor models compared to PGEM micelles loaded with PTX or NLG919 alone, suggesting that codelivery of NLG919 and PTX via PGEM may represent an effective strategy for immunochemotherapy of PDA as well as other types of cancers. STATEMENT OF SIGNIFICANCE: In order to effectively accumulate and penetrate the PDA that is poorly vascularized and enriched with dense fibrotic stroma, the size of nanomedicine has to be well controlled. Here, we reported an immunochemotherapy regimen based on co-delivery of GEM, PTX and IDO1 inhibitor NLG919 through an ultra-small sized GEM-based nanocarrier (PGEM). We demonstrated that the PGEM carrier was effective in accumulating and penetrating into PDA tumors. Besides, PGEM co-loaded with PTX and NLG9 induced an improved anti-tumor immune response and was highly efficacious in inhibiting tumor growth as well as in prolonging the survival rate in PANC02 xenograft model. Our work represents a potential strategy for enhancing PDA tumor penetration and immunochemotherapy.

Case report: Crizotinib is effective in a patient with ROS1-rearranged pulmonary inflammatory myofibroblastic tumor.

OBJECTIVES: Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal tumor and is prevalent among children and adolescents. In recent years, following the emergence of high-throughput sequencing techniques, rearrangements in genes, such as ALK, ROS1, NTRK, RET, and PDGFRß, have been detected in a considerable proportion of IMT patients. However, the practice of targeted therapy for those patients remains extremely limited. In this study, we report about a 14-year-old boy diagnosed with pulmonary IMT with a mass measuring 12 × 8 cm in the right lower lobe. MATERIALS AND METHODS: Immunohistochemistry (IHC) assay and comprehensive next-generation sequencing (NGS) were performed on the biopsied tumor tissue. RESULTS: The IHC assay revealed an ALK-negative tumor, while NGS detected aTFG-ROS1 rearrangement. The patient achieved continuous remission after treatment with crizotinib (250 mg, bid). CONCLUSION: This case broadens the experience regarding targeted therapy forROS1-rearranged IMT and supports the use of broad molecular profiling testing for optimizing therapeutic options.

The Current Situation of Esophageal Cancer Staging and Perioperative Strategies Determination in Central and Southern China: A Cross Sectional Survey.

Purpose: We aim to investigate the current esophageal cancer staging according to the 7th edition TNM classification for esophageal carcinoma proposed by American Joint Committee on Cancer (AJCC) among oncology-related physicians in China. Methods: A specifically-designed 14-item questionnaire was distributed to 366 doctors who were working with esophageal cancer patients. We collected and analyzed the feedbacks and explored the possible associations within different departments, including thoracic surgery, the internal medicine of gastroenterology, oncology, and/ radiotherapy in eight different hospitals from central and southern China. Results: Among all the responses, 31.42% of them were from thoracic surgery department, 40.44% were from oncology and/or radiation therapy and 28.14% were from the internal medicine of gastroenterology, respectively. Surprisingly, in total 66.12% of all the physicians were unaware that the 7th edition of esophageal carcinoma TNM classification was released in 2009; only 21.86 and 16.67% of physicians recognized cervical nodes and celiac nodes as regional lymph nodes. Furthermore, 67.21% physicians didn't know that tumor location, histologic grade, and histopathology were accepted as new prognostic factors in the latest TNM system; and 51.37% physicians could not determine the correct TNM classification of esophagogastric junction cancers. Intriguingly, over 50% of them could still design appropriate perioperative strategies. Conclusions: The 7th edition of the TNM classification for esophageal carcinoma is poorly recognized and understood in central and southern China, which might contribute to the relatively low rates of appropriate perioperative procedures applied for esophageal cancer patients.

3D-printing aided resection of intratracheal adenoid cystic carcinoma and mediastinal mature cystic teratoma in a 26-year-old female: a case report.

Complete resection remains the ideal treatment for most patients with primary intratracheal tumors. Due to the limit in the resection length, the localization of the tumor during the surgery could be rather difficult if it hasn't invaded out of the trachea, which might be more difficult when there's another tumor in the anterior mediastinum. A 26-year-old woman with intratracheal adenoid cystic carcinoma (ACC) presented with dyspnea. CT scan revealed not only an ACC without extension out of trachea, but also a mediastinal teratoma (MT) near aorta, making the operation much more complicated than usual. To solve this problem, 3D-printing was applied for facilitating surgery plan making and intraoperative locating of ACC. And as we expected, the operation went successfully and the patient achieved full recovery without complications. To the best of our knowledge, the case of both intratracheal ACC and MT in one patient has not been previously reported.

[Laryngeal mask anesthesia in video-assisted thoracoscopic surgery for pulmonary bulla: comparison with intubation anesthesia].

OBJECTIVE: To assess the feasibility and safety of thoracoscopic bulla resection under laryngeal mask anesthesia with low tidal volume high-frequency lung ventilation. METHODS: Sixty patients with pulmonary bulla were randomized into two groups (n=30) to undergo video-assisted thoracoscopic surgery (VATS) for bulla resection with laryngeal mask anesthesia and high-frequency low tidal volume lung ventilation general anesthesia and or with intubation anesthesia and one-lung ventilation through double-lumen endotracheal intubation. RESULTS: No significant differences were found in anesthesia time, surgery time, intraoperative lowest SpO2, intraoperative highest PetCO2, operative field, anesthetic effects, or blood loss between the two groups. The post-operative WBC and NEU% showed significantly smaller increments in the mask anesthesia group than in the intubation group, and the postoperative awake time, initial eating time, ambulation time, in-hospital stay, and drainage time were significantly shortened in the former group with also lower incidences of gastrointestinal reactions, throat discomfort and hoarseness. CONCLUSION: Thoracoscopic bulla resection under laryngeal mask anesthesia with low tidal volume high-frequency lung ventilation is safe and feasible and results in better patient satisfaction and shorter in-hospital stay than procedures performed under intubation anesthesia with one-lung ventilation.