OoD-Control: Generalizing Control in Unseen Environments.

Generalizing out-of-distribution (OoD) is critical but challenging in real applications such as unmanned aerial vehicle (UAV) flight control. Previous machine learning-based control has shown promise in dealing with complex real-world environments but suffers huge performance degradation facing OoD scenarios, posing risks to the stability and safety of UAVs. In this paper, we found that the introduced random noises during training surprisingly yield theoretically guaranteed performances via a proposed functional optimization framework. More encouragingly, this framework does not involve common Lyapunov assumptions used in this field, making it more widely applicable. With this framework, the upperbound for control error is induced. We also proved that the induced random noises can lead to lower OoD control errors. Based on our theoretical analysis, we further propose OoD-Control to generalize control in unseen environments. Numerical experiments demonstrate the superiority of the proposed algorithm, surpassing previous state-of-the-art by 65% under challenging unseen environments. We further extend to outdoor real-world experiments and found that the control error is reduced by 50% approximately.

DNA polymerase iota promotes EMT and metastasis of esophageal squamous cell carcinoma by interacting with USP7 to stabilize HIF-1α.

Esophageal squamous cell carcinoma (ESCC) is one of the most lethal cancer types, with a low 5-year survival rate of ~20%. Our prior research has suggested that DNA Polymerase iota (Pol ι), a member of Y-family DNA polymerase, plays a crucial role in the invasion and metastasis of ESCC. However, the underlying mechanism is not well understood. In this study, we utilized ChIP-PCR and luciferase reporter assays to investigate the binding of HIF-1α to the promoter of the Pol ι gene. Transwell, wound healing, and mouse models were employed to assess the impact of Pol ι and HIF-1α on the motility of ESCC cells. Co-immunoprecipitation and Western blot were carried out to explore the interaction between Pol ι and HIF-1α, while qRT-PCR and Western blot were conducted to confirm the regulation of Pol ι and HIF-1α on their downstream targets. Our results demonstrate that HIF-1α activates the transcription of the Pol ι gene in ESCC cells under hypoxic conditions. Furthermore, the knockdown of Pol ι impeded HIF-1α-induced invasion and metastasis. Additionally, we found that Pol ι regulates the expression of genes involved in epithelial-mesenchymal transition (EMT) and initiates EMT through the stabilization of HIF-1α. Mechanistically, Pol ι maintains the protein stability of HIF-1α by recruiting USP7 to mediate the deubiquitination of HIF-1α, with the residues 446-578 of Pol being crucial for the interaction between Pol ι and USP7. Collectively, our findings unveil a novel feedforward molecular axis of HIF-1α- Pol ι -USP7 in ESCC that contributes to ESCC metastasis. Hence, our results present an attractive target for intervention in ESCC.

HER3 functions as an effective therapeutic target in triple negative breast cancer to potentiate the antitumor activity of gefitinib and paclitaxel.

BACKGROUND: Triple negative breast cancer (TNBC) represents a significant clinical challenge. Chemotherapy remains the mainstay for a large part of TNBC patients, whereas drug resistance and tumor recurrence frequently occur. It is in urgent need to identify novel molecular targets for TNBC and develop effective therapy against the aggressive disease. METHODS: Immunohistochemistry was performed to examine the expression of HER3 in TNBC samples. Western blots were used to assess protein expression and activation. Cell proliferation and viability were determined by cell growth (MTS) assays. TCGA databases were analyzed to correlate HER3 mRNA expression with the clinical outcomes of TNBC patients. Specific shRNA was used to knockdown HER3 expression. IncuCyte system was utilized to monitor cell growth and migration. LIVE/DEAD Cell Imaging was to detect live and dead cells. HER3 recognition by our anti-HER3 monoclonal antibody (mAb) 4A7 was verified by ELISA, flow cytometry, and co-immunoprecipitation assays. Orthotopic tumor models were established in nude mice to determine the capability of TNBC cells forming tumors and to test if our mAb 4A7 could potentiate the antitumor activity of paclitaxel in vivo. RESULTS: Elevated expression of HER3 was observed in approximately half of the TNBC specimens and cell lines tested. Analyses of TCGA databases found that the TNBC patients with high HER3 mRNA expression in the tumors showed significantly worse overall survival (OS) and relapse-free survival (RFS) than those with low HER3 expression. Specific knockdown of HER3 markedly inhibited TNBC cell proliferation and mammosphere formation in vitro and tumor growth in vivo. Our mAb 4A7 abrogated heregulin (a ligand for HER3), but not SDF-1 (a ligand for CXCR4)-induced enhancement of TNBC cell migration. Combinations of 4A7 and the EGFR-tyrosine kinase inhibitor (TKI) gefitinib dramatically decreased the levels of phosphorylated HER3, EGFR, Akt, and ERK1/2 in TNBC cells and potently induced growth inhibition and cell death. Moreover, 4A7 in combination with paclitaxel exerted significant antitumor activity against TNBC in vitro and in vivo. CONCLUSIONS: Our data demonstrate that increased HER3 is an effective therapeutic target for TNBC and our anti-HER3 mAb (4A7) may enhance the efficacy of gefitinib or paclitaxel in TNBC.

Immune Activation Effects at Different Irradiated Sites and Optimal Timing of Radioimmunotherapy in Patients with Extensive-Stage Small Cell Lung Cancer: a Real-World Analysis.

BACKGROUND: In view of the limited data on radiotherapy (RT) combined with immunotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC), this study aimed to identify the immune activation effect on different sites and the survival outcomes of radioimmunotherapy at different treatment stages. METHODS: Forty-five patients diagnosed with ES-SCLC were included in this retrospective analysis. We collected the overall survival (OS) of the patients,, recorded the blood cell counts before, during, and after RT, and derived blood index ratios such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII). The datasets were analyzed using the Spearman rank correlation test, Kruskal-Wallis rank sum test and logistic regression. RESULTS: Among the selected blood indices, the delta-NLR/PLR/Sll correlated with different irradiated organs, and the mean ranks of these three indices were the lowest in the brain-irradiated group during immunotherapy. Additionally, adjunct first-line immunotherapy with RT demonstrated a significant improvement compared to second- or third-line therapy and subsequent therapies. CONCLUSION: Our findings suggest that compared to other organs, the strongest immune activation effect occurs with brain RT, and ES-SCLC patients who received radioimmunotherapy (RIT) earlier achieved higher OS rates.

Polymerase iota (POLI) confers radioresistance of esophageal squamous cell carcinoma by regulating RAD51 stability and facilitating homologous recombination.

Radiotherapy resistance is an important and urgent challenge in the clinical management of esophageal squamous carcinoma (ESCC). However, the factors mediating the ESCC resistance to radiotherapy and its underlying molecular mechanisms are not fully clarified. Our previous studies have demonstrated the critical role of DNA polymerase iota (POLI) in ESCC development and progression, here, we aimed to investigate the involvement of POLI in ESCC radiotherapy resistance and elucidate the underlying molecular mechanism. We found that highly expressed POLI was correlated with shorter overall survival of ESCC patients received radiotherapy. Down-regulation of POLI sensitized ESCC to IR, prolonged γH2AX foci in nuclei and comet tails after IR. HR but not NHEJ repair is inhibited in POLI-deficient ESCC cells. POLI stabilizes RAD51 protein via competitively binding with and blocking the interaction between RAD51 and E3 ligase XIAP and XIAP-mediated ubiquitination. Furthermore, loss of POLI leads to the activation of GAS signaling. Our findings provide novel insight into the role of POLI in the development of radioresistance mediated by stabilizing RAD51 protein in ESCC.

Efficacy and Safety of Anlotinib in Overall and Disease-Specific Advanced Gynecological Cancer: A Real-World Study.

Purpose: Anlotinib is a novel oral small-molecule multi-target tyrosine kinase inhibitor that has been approved for treating non-small cell lung cancer. However, its efficacy and safety among patients with advanced gynecological cancer have not been comprehensively evaluated. We conducted this study to address this issue in the real-world setting. Patients and Methods: Data from patients treated with Anlotinib for persistent, recurrent or metastatic gynecological cancer were collected from 17 centers from August 2018. The database lock-time was on March 2022. Anlotinib was administered orally on days 1-14 every 3 weeks until disease progression, severe toxicity occurred, or death. In this study, disease-specific advanced gynecological cancer was mainly referred to cervical, endometrial, and ovarian cancer. The outcomes included objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). Results: A total of 249 patients were analyzed, with a median follow-up of 14.5 months. The overall ORR and DCR were 28.1% [95% confidence interval (CI) 22.6% to 34.1%] and 80.7% (95% CI 75.3% to 85.4%), respectively. Specifically, the ORR varied from 19.7% to 34.4% and the DCR differed from 81.7% to 90.0% in disease-specific advanced gynecological cancer. The median PFS was 6.1 months and ranged from 5.6 to 10.0 months in the overall and disease-specific advanced gynecological cancer, respectively. Larger cumulative dosage of Anlotinib (>700 mg) was in general associated with longer PFS in the overall and disease-specific advanced gynecological cancer. The most common adverse event related to Anlotinib treatment was pain/arthralgia (18.3%). Conclusion: In conclusion, Anlotinib holds promise in treating patients with advanced gynecological cancer including its disease-specific types, with reasonable efficacy and tolerable safety.

Efficacy and Safety Analysis of Immune Checkpoint Inhibitors plus Angiogenesis Inhibitors for the Treatment of Advanced Driver-negative NSCLC in Elderly Patients: A Retrospective Study.

Background and Objective: Immune checkpoint inhibitors (ICIs) combined with angiogenesis inhibitors may have synergistic effects in elderly patients with advanced driver-negative NSCLC, but its true efficacy remains unclear. In addition, chemotherapy tolerance in elderly NSCLC patients is poor, and the precise identification of the population that may benefit from ICIs combined with angiogenesis inhibitors is also the focus of current research. Methods: We retrospectively compared the efficacy and safety of ICIs combined with or without antiangiogenic agents in elderly patients with advanced driver-gene negative NSCLC ≥65 years of age in the Cancer Center of Suzhou Hospital Affiliated to Nanjing Medical University. The primary endpoint was PFS. Secondary endpoints were OS, ORR, and immune-related adverse events (irAEs). Results: A total of 36 patients in the IA group (immune checkpoint inhibitors plus angiogenesis inhibitors group) and 43 patients in the NIA group (immune checkpoint inhibitors without angiogenesis inhibitors group) were enrolled in the study between January 1, 2019 and December 31, 2021. The median follow-up time for patients in the IA group and NIA group was 18.2 months (95%CI: 14 - 22.5 months) and 21.4 months (95%CI: 16.7 -26.1 months), respectively. The median PFS and median OS were longer in the IA group compared to the NIA group (8.1 months vs 5.3 months; HR for PFS: 0.778, 95%CI: 0.474-1.276, P=0.32; NA vs 30.9 months; HR for OS: 0.795, 95%CI: 0.396-1.595, P=0.519). There were no significant differences in median PFS and median OS between the two groups. Subgroup analysis showed that patients in the IA group had significantly longer PFS in the subgroup with PD-L1 expression ≥50% (P=0.017), and the association between different groups and disease progression was still different in the two subgroups (P for interaction = 0.002). There was no significant difference in ORR between the two groups (23.3% vs 30.5%, P=0.465). The incidence of irAEs in the IA group was lower than that in the NIA group (39.5% vs 19.4%, P=0.05), and the cumulative incidence of treatment interruptions due to irAEs was significantly reduced (P=0.045). Conclusion: In elderly patients with advanced driver-negative NSCLC, the addition of antiangiogenic agents to ICIs therapy did not provide significant clinical benefit, but the incidence of irAEs and treatment interruptions due to irAEs was significantly reduced. In the subgroup analysis, we found that the clinical benefit of this combination therapy was observed in patients with PD-L1 expression ≥50%, which warrants further exploration.

Improving the registration stability of cone-beam computed tomography with the Sphere-Mask Optical Positioning System: a feasibility study.

Background: Cone-beam computed tomography (CBCT) is an important tool for patient positioning in radiotherapy due to its outstanding advantages. However, the CBCT registration shows errors due to the limitations of the automatic registration algorithm and the nonuniqueness of manual verification results. The purpose of this study was to verify the feasibility of using the Sphere-Mask Optical Positioning System (S-M_OPS) to improve the registration stability of CBCT through clinical trials. Methods: From November 2021 to February 2022, 28 patients who received intensity-modulated radiotherapy and site verification with CBCT were included in this study. S-M_OPS was used as an independent third-party system to supervise the CBCT registration result in real time. The supervision error was calculated based on the CBCT registration result and using the S-M_OPS registration result as the standard. For the head and neck, patients with a supervision error ≥3 or ≤-3 mm in 1 direction were selected. For the thorax, abdomen, pelvis, or other body parts, patients with a supervision error ≥5 or ≤-5 mm in 1 direction were selected. Then, re-registration was performed for all patients (selected and unselected). The registration errors of CBCT and S-M_OPS were calculated based on the re-registration results as the standard. Results: For selected patients with large supervision errors, CBCT registration errors (mean ± standard deviation) in the latitudinal (LAT; left/right), vertical (VRT; superior/inferior), and longitudinal (LNG; anterior/posterior) directions were 0.90±3.20, -1.70±0.98, and 7.30±2.14 mm, respectively. The S-M_OPS registration errors were 0.40±0.14, 0.32±0.66, and 0.24±1.12 mm in the LAT, VRT, and LNG directions, respectively. For all patients, CBCT registration errors in the LAT, VRT, and LNG directions were 0.39±2.69, -0.82±1.47, and 2.39±2.93 mm, respectively. The S-M_OPS registration errors were -0.25±1.33, 0.55±1.27, and 0.36±1.34 mm for all patients in the LAT, VRT, and LNG directions, respectively. Conclusions: This study shows that S-M_OPS registration offers comparable accuracy to CBCT for daily registration. S-M_OPS, as an independent third-party tool, can prevent large errors in CBCT registration, thereby improving the accuracy and stability of CBCT registration.

Setup error assessment based on "Sphere-Mask" Optical Positioning System: Results from a multicenter study.

Background: The setup accuracy plays an extremely important role in the local control of tumors. The purpose of this study is to verify the feasibility of "Sphere-Mask" Optical Positioning System (S-M_OPS) for fast and accurate setup. Methods: From 2016 to 2021, we used S-M_OPS to supervise 15441 fractions in 1981patients (with the cancer in intracalvarium, nasopharynx, esophagus, lung, liver, abdomen or cervix) undergoing intensity-modulated radiation therapy (IMRT), and recorded the data such as registration time and mask deformation. Then, we used S-M_OPS, laser line and cone beam computed tomography (CBCT) for co-setup in 277 fractions, and recorded laser line-guided setup errors and S-M_OPS-guided setup errors with CBCT-guided setup result as the standard. Results: S-M_OPS supervision results: The average time for laser line-guided setup was 31.75s. 12.8% of the reference points had an average deviation of more than 2 mm and 5.2% of the reference points had an average deviation of more than 3 mm. Co-setup results: The average time for S-M_OPS-guided setup was 7.47s, and average time for CBCT-guided setup was 228.84s (including time for CBCT scan and manual verification). In the LAT (left/right), VRT (superior/inferior) and LNG (anterior/posterior) directions, laser line-guided setup errors (mean±SD) were -0.21±3.13mm, 1.02±2.76mm and 2.22±4.26mm respectively; the 95% confidence intervals (95% CIs) of laser line-guided setup errors were -6.35 to 5.93mm, -4.39 to 6.43mm and -6.14 to 10.58mm respectively; S-M_OPS-guided setup errors were 0.12±1.91mm, 1.02±1.81mm and -0.10±2.25mm respectively; the 95% CIs of S-M_OPS-guided setup errors were -3.86 to 3.62mm, -2.53 to 4.57mm and -4.51 to 4.31mm respectively. Conclusion: S-M_OPS can greatly improve setup accuracy and stability compared with laser line-guided setup. Furthermore, S-M_OPS can provide comparable setup accuracy to CBCT in less setup time.

TAB182 aggravates progression of esophageal squamous cell carcinoma by enhancing ß-catenin nuclear translocation through FHL2 dependent manner.

TAB182 (also named TNKS1BP1), a binding protein of tankyrase 1, has been found to participate in DNA repair. Our previous study has revealed the involvement of TAB182 in the radioresistance of esophageal squamous cell carcinoma (ESCC) cells. However, whether TAB182 contributes to the ESCC tumorigenesis and progression remains unclear. In this study, we found that highly expressed TAB182 is closely associated with a poor prognosis of patients with ESCC. TAB182 silencing reduced ESCC cell proliferation and invasion in vitro, tumorigenicity and metastasis in vivo. RNA-seq and IP-MS analysis revealed that TAB182 could affect the ß-catenin signaling pathway via interacting with ß-catenin. Furthermore, TAB182 prevented ß-catenin to be phosphorylated by GSK3ß and recruited four and a half of LIM-only protein 2 (FHL2), which thereby promoted ß-catenin nucleus translocation to result in activation of the downstream targets transcription in ESCC cells. Our findings demonstrate that TAB182 enhances tumorigenesis of esophageal cancer by promoting the activation of the ß-catenin signaling pathway, which provides new insights into the molecular mechanisms by which TAB182 accelerates progression of ESCC.

Reforming the Chimeric Antigen Receptor by Peptide Towards Optimized CAR T Cells With Enhanced Anti-Cancer Potency and Safety.

The emerging chimeric antigen receptor (CAR) T cell revolutionized the clinic treatment of hematological cancers, but meet its Waterloo in solid tumor therapy. Although there exist many reasons for this limitation, one of the largest challenges is the scarcity of recognition for tumor cells, resulting in the undesirable side effects and the subsequent ineffectiveness. To overcome it, a lung-cancer-cell-targeting peptide termed A1 was used in this work to reform the scFv domain of CAR by genetic manipulation. As a result, this modified A1CAR T exhibited the optimized cancer-cell targeting and cytotoxicity in vitro and in vivo. More importantly, by tuning the sensitivity of CAR to antigen, peptide-based A1CAR T cells could distinguish tumors from normal tissue, thereby eliminating the off-tumor toxicity in healthy organs. Collectively, we herein constructed a genetic peptide-engineered CAR T cells by inserting A1 peptide into the scFv domain. Profitted from the optimized recognition pattern and sensitivity, A1CAR T cells showed the ascendancy in solid tumor treatment. Our findings demonstrate that peptide-based CAR T holds great potential in solid tumor therapy due to an excellent targeting ability towards tumor cells.

RAD18 confers radioresistance of esophagus squamous cell carcinoma through regulating p-DNA-PKcs.

BACKGROUND: Radiotherapy has recently become more common for the treatment of esophageal squamous cell carcinoma (ESCC). Radioresistance, on the other hand, continues to be a major issue because it interferes with the effectiveness of ESCC radiation. It has been demonstrated that RAD18, an E3 ubiquitin-protein ligase that regulates translesion DNA synthesis (TLS), is implicated in the regulation of genomic integrity and DNA damage response. METHODS: In the present study, immunohistochemical staining and western blotting were utilized to determine RAD18 expression in ESCC tissues and cells. ESCC cell proliferation was determined using a colony formation assay. Immunofluorescence staining, comet assay, and homologous recombination (HR)/non-homologous end-joining (NHEJ) assays were conducted to examine the effect of RAD18 on the DNA damage response in ESCC cells. RESULTS: We found that high RAD18 expression was positively associated with a poorer prognosis in patients with ESCC who received radiotherapy. Downregulation of RAD18 expression significantly increased the sensitivity of ESCC cells to irradiation. Moreover, RAD18 knockdown prolonged the repair kinetics of γH2AX foci and resulted in longer comet tails. Furthermore, loss of RAD18 expression markedly decreased non-homologous end-joining (NHEJ) activity, but it did not affect homologous recombination (HR)-mediated double-strand break repair in ESCC cells. RAD18 upregulated p-DNA-dependent protein kinase complex (p-DNA-PKc) expression in vivo and in vitro. CONCLUSIONS: These data indicated that RAD18 may regulate radioresistance by facilitating NHEJ via phosphorylation of DNA-PKcs in ESCC cells, providing a novel radiotherapy target for ESCC.

Exploring the Pharmacological Mechanism of Radix Salvia Miltiorrhizae in the Treatment of Radiation Pneumonia by Using Network Pharmacology.

BACKGROUND: Radiation pneumonia (RP) is the most common complication of radiotherapy to the thorax and seriously affects the survival rate and quality of life of patients. Radix Salviae Miltiorrhizae (RSM) is an ancient Chinese medicine, whose main pharmacological effect is to promote blood circulation and remove stasis. A growing number of studies have proved that RSM has a good effect on RP. However, the underlying mechanism is still unclear and needs to be fully elucidated. METHODS: The effective components and predictive targets of RSM were analyzed by Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, and the related targets of RP were predicted by GeneCards database. The common targets of the two targets mentioned above were analyzed by protein-protein interaction on the STRING website, GO and KEGG analysis on the DAVID website, visualization by CytoScape3.7.0, and screening for Hubber gene by cytoHubber plug-in. RESULTS: A search of the TCMSP database revealed that RSM contains 65 chemical constituents and 165 potential protein targets. A total of 2,162 protein targets were found to be associated with RP. The top 10 hub genes were obtained by MCC algorithm for 70 common genes, including TP53, CASP3, MAPK1, JUN, VEGFA, STAT3, PTGS2, IL6, AKT1, and FOS. By analyzing the Gene Ontology, The anti-radiation pneumonia effect of RSM is that it performs molecular functions (protein homodimerization activity) in the nucleus through three biological processes (positive regulation of transcription from RNA polymerase II promoter,Extrinsic apoptotic signaling pathway in absence of ligand and lipopolysaccharide-mediated signaling pathway). Through KEGG analysis, the mechanism of RSM treatment of radiation pneumonia may be through PI3K-Akt, HIF-1, TNF signaling pathways. CONCLUSIONS: Through network pharmacology analysis, we found the possible target genes of RSM on RP and revealed the most likely signaling pathway, providing theoretical basis for further elucidating the potential mechanism of RSM on RP.

DNA Polymerase Iota Promotes Esophageal Squamous Cell Carcinoma Proliferation Through Erk-OGT-Induced G6PD Overactivation.

Esophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers with rapid progression and a high mortality rate. Our previous study demonstrated that DNA polymerase iota (Pol ι) is overexpressed in ESCC tumors and correlates with poor prognosis. However, its role in ESCC proliferation remains obscure. We report here that Pol ι promotes ESCC proliferation and progression through Erk- O-GlcNAc transferase (OGT) regulated Glucose-6-phosphate dehydrogenase (G6PD) overactivation. Cell clonogenic ability was assessed by colony formation assay. Cell proliferation was assessed by EdU incorporation assay. Our transcriptome data was reanalyzed by GSEA and validated by analysis of cellular metabolism, G6PD activity, and cellular NADPH concentration. The level of Pol ι, OGT, G6PD and O-GlcNAcylation in ESCC cells and patient samples were analyzed. The MEK inhibitor PD98059 was applied to confirm OGT expression regulation by the Erk signaling. The G6PD inhibitor polydatin was used to examine the role of G6PD activation in Pol ι promoted proliferation. We found that Pol ι promotes ESCC proliferation. It shunted the glucose flux towards the pentose phosphate pathway (PPP) by activating G6PD through OGT-promoted O-GlcNAcylation. The expression of OGT was positively correlated with Pol ι expression and O-GlcNAcylation. Notably, elevated O-GlcNAcylation was correlated with poor prognosis in ESCC patients. Pol ι was shown to stimulate Erk signaling to enhance OGT expression, and the G6PD inhibitor polydatin attenuated Pol ι induced tumor growth in vitro and in vivo. In conclusion, Pol ι activates G6PD through Erk-OGT-induced O-GlcNAcylation to promote the proliferation and progression of ESCC, supporting the notion that Pol ι is a potential biomarker and therapeutic target of ESCC.

Tumor cell membrane-based peptide delivery system targeting the tumor microenvironment for cancer immunotherapy and diagnosis.

The development of an effective delivery system for peptides targeting the tumor microenvironment has always been a hot topic of research in the field of cancer diagnosis and therapy. In this study, superparamagnetic iron oxide nanoparticles (SPIO NPs) were encapsulated with H460 lung cancer cell membranes (SPIO NP@M), and two peptides, namely PD-L1 inhibitory peptide (TPP1) and MMP2 substrate peptide (PLGLLG), were conjugated to the H460 membrane (SPIO NP@M-P). Homologous targeting, cytotoxicity, and pharmacokinetics of SPIO NP@M-P were evaluated. The TPP1 peptide was delivered and released to the tumor microenvironment through the homotypic effect of tumor cell membrane and specific digestion by the tumor-specific enzyme MMP2. The newly developed delivery system (SPIO NP@M-P) for the PD-L1 inhibitory peptide could effectively extend the half-life of the peptides (60 times longer than that for peptides alone) and could maintain the ability to reactivate T cells and inhibit the tumor growth both in vitro and in vivo. Furthermore, SPIO NPs in the system could be used as a tumor imaging agent and thus show the effect of peptide treatment. The SPIO NP@M might serve as a promising theranostic platform for therapeutic application of peptides in cancer therapy. STATEMENT OF SIGNIFICANCE: A multifunctional delivery system (SPIO NP@M) was constructed for effectively delivering therapeutic peptides into the tumor microenvironment for cancer diagnosis and therapy. In this paper, the TPP-1 peptide inhibiting the binding of PD-L1 and PD-1 was delivered and released into the tumor microenvironment by the homotypic targeting of H460 cell membrane and specific digestion by the MMP2 enzyme. SPIO NPs in this system were aggregated effectively at the tumor sites and were used for magnetic resonance imaging of tumors. The SPIO NP@M-P delivery system could effectively extend the half-life of the TPP-1 peptide (60 times longer than that of the free peptide) and could maintain the ability to re-activate T cells and inhibit tumor growth in vitro and in vivo. In conclusion, the SPIO NP@M system coated with lung cancer cell membrane and loaded with the PD-L1-blocking TPP-1 peptide could be a promising integrated platform for tumor diagnosis and treatment.

Elevated TAB182 enhances the radioresistance of esophageal squamous cell carcinoma through G2-M checkpoint modulation.

BACKGROUND: Radiotherapy is one of the main strategies for the treatment of esophageal squamous cell carcinoma (ESCC). However, treatment failure often occurs due to the emergence of radioresistance. In this study, we report a key regulator of radiation sensitivity, termed TAB182 that may become an ideal biomarker and therapeutic target to overcome radioresistance. MATERIALS AND METHODS: By applying qRT-PCR and immunohistochemical staining, the expression of TAB182 was detected in patient tissues. We next assessed the influence of TAB182 downregulation to radiosensitivity using clonogenic survival assay and γ-H2A.X foci analysis in TE-1, TE-10, and radioresistant TE-1R cell lines after ionizing radiation. To unveil the mechanism underlying, TAB182 interacting proteins were identified by mass spectrometry following co-immunoprecipitation. Furthermore, flow cytometry and western blot assay were applied to validate the identified proteins. RESULTS: Our results demonstrated that the expression of TAB182 is higher in cancer tissues than normal tissues and elevated expression of TAB182 correlates with poor outcomes of postoperative radiotherapy. Downregulation of TAB182 sensitized cancer cells to ionizing radiation, particularly in radioresistant TE-1R cells that spontaneously overexpress TAB182. Mechanically, TAB182 interacts with FHL2 to induce G2-M arrest through wiring the CHK2/CDC25C/CDC2 signaling pathway. Finally, overexpression of shRNA-resistant TAB182 restored the checkpoint and radioresistance. CONCLUSION: TAB182 potentiates the radioresistance of ESCC cells by modulating the G2-M checkpoint through its interaction with FHL2. Thus, TAB182 may become an ideal biomarker and therapeutic target of ESCC radiotherapy.

Blocking podoplanin inhibits platelet activation and decreases cancer-associated venous thrombosis.

BACKGROUND: Patients with cancer are at a high risk of venous thromboembolism (VTE), studies have shown that high expression of podoplanin (PDPN) in tumors is associated with increased risk of VTE. METHODS: Two human malignant cell lines (NCI-H226 and C8161) expressing high levels of PDPN were selected to explore the role of platelet in cancer-associated venous thrombosis in vitro and in vivo. Immunohistochemical staining using anti-PDPN antibody was performed in the pulmonary carcinoma patients. RESULTS: Both NCI-H226 and C8161 cells expressing high PDPN triggered platelet activation via CLEC-2 in vitro, which was abrogated by an anti-PDPN antibody SZ-168. Furthermore, the in vivo study revealed that injection of CHO-PDPN or C8161 in two mouse model of venous thrombosis activated platelets, increased platelet counts and enhanced thrombosis. More importantly, PDPN-enhanced thrombosis was reduced in mice treated with SZ168. A total of 63.3% tumor specimens stained positive for PDPN. High PDPN expression was associated with an increased risk of VTE and poor prognosis. CONCLUSIONS: PDPN expression in tumors induced platelet activation and was related to a high risk of VTE via platelet activation. SZ168 inhibited PDPN-induced platelet activation in vitro and decreased the incidence of VTE in mice.

Compensation of lens manufacturing errors and inhomogeneities by filtering view images in three-dimensional lenticular displays.

For a multiview autostereoscopic three-dimensional display based on the lenticular lens, the manufacturing errors and inhomogeneities of the lenticular sheet can deteriorate the view image quality. A calibration method is proposed by filtering the pixel mapping of all view images. Each view is first sequentially turned on to show a white test image, and the intensity distribution of every view will be analyzed. Then individual filter functions are derived and applied to the corresponding view images to correct the subpixel value. Experimental results show that the proposed method can solve view image loss and significantly improve the quality of stereoscopic images.

Prognostic significance of negative conversion of high-risk Human Papillomavirus DNA after treatment in Cervical Cancer patients.

Objective: To evaluate the prognostic value of conversion of high-risk human papillomavirus (HR-HPV) status after treatment for cervical cancer. Methods: A total of 112 cervical cancer patients with HR-HPV positivity without distant metastasis treated with surgery or radical concurrent radiochemotherapy were enrolled. HR-HPV status was analyzed before and after treatment and at the time point of recurrence or metastasis. Log-rank tests and Cox proportional hazard models were used to evaluate the association between conversion of HR-HPV status after treatment and survival. Results: Eighty-four (75%) patients had negative conversion HR-HPV (ncHR-HPV) after treatment and twenty-eight (25%) were persistent positive HR-HPV (ppHR-HPV). The negative conversion rate was 75.8% in patients who received surgical treatment and 71.4% in patients who received radical concurrent radiochemotherapy. There was no significant difference between the two groups (χ2=0.000, P=1.000). There was no significant correlation between HR-HPV conversion after treatment with age (χ2=0.616, P=0.252), FIGO stage (χ2=0.051, P=0.823) and pathological type (χ2=0.000, P=1.000). Univariate analysis showed that treatment regimen and ncHR-HPV was closely related to progression-free survival (PFS) and overall survival (OS) of cervical cancer patients. Multivariate COX regression model showed that treatment regimen (HR=3.57, 95% CI: 1.57-8.11, P=0.002) and ncHR-HPV (HR=5.14, 95% CI: 2.32-11.46, P<0.001) were independent prognostic factors for PFS, while only ncHR-HPV (HR=12.56, 95% CI: 3.54-44.65, P<0.001) was an independent prognostic factor for OS. The presence of ppHR-HPV after treatment (χ2=14.827, P<0.001) was associated with recurrence and metastasis. Eleven of the patients with ncHR-HPV after treatment had recurrence or metastasis, and HPV reinfection was not detected in any of them. Conclusion: ncHR-HPV after treatment in cervical cancer patients indicated better PFS and OS, while ppHR-HPV indicated worse prognosis and high risk of recurrence or metastasis. For patients with ncHR-HPV after treatment, continued HPV screening may not predict recurrence or metastasis. This study suggested that HR-HPV monitoring is necessary for ppHR-HPV patients after treatment but may not be for ncHR-HPV patients. However, further large and multi-center prospective studies should be performed to confirm these findings.