mTOR signaling promotes rapid m6A mRNA methylation to regulate NK-cell activation and effector functions.

Natural killer (NK) cells can be rapidly activated in response to cytokines during host defense against malignant cells or viral infection. However, it remains unclear what mechanisms precisely and rapidly regulate the expression of the numerous genes involved in activating NK cells. In this study, we discovered that NK-cell N6-methyladenosine (m6A) methylation levels were rapidly upregulated upon short-term NK-cell activation and were repressed in the tumor microenvironment. Deficiency of methyltransferase-like 3 (METTL3) or METTL14 moderately influenced NK-cell homeostasis, while double knockout of METTL3/14 significantly impacted NK-cell homeostasis, maturation, and antitumor immunity. This suggests a cooperative role of METTL3 and METTL14 in regulating NK-cell development and effector functions. Using methylated RNA immunoprecipitation sequencing (MeRIP-seq), we demonstrated that genes involved in NK-cell effector functions, such as Prf1 and Gzmb, were directly modified by m6A methylation. Furthermore, inhibiting mTOR complex 1 (mTORC1) activation prevented m6A methylation levels from increasing when NK cells were activated, and this could be restored by S-adenosylmethionine (SAM) supplementation. Collectively, we have unraveled crucial roles for rapid m6A mRNA methylation downstream of the mTORC1-SAM signal axis in regulating NK-cell activation and effector functions.

The ω-3 Polyunsaturated Fatty Acid Docosahexaenoic Acid Enhances NK-Cell Antitumor Effector Functions.

ω-3 polyunsaturated fatty acids (PUFA) are known to directly repress tumor development and progression. In this study, we explored whether docosahexaenoic acid (DHA), a type of ω-3 PUFA, had an immunomodulatory role in inhibiting tumor growth in immunocompetent mice. The number of natural killer (NK) cells but not the number of T or B cells was decreased by DHA supplementation in various tissues under physiologic conditions. Although the frequency and number of NK cells were comparable, IFNγ production by NK cells in both the spleen and lung was increased in DHA-supplemented mice in the mouse B16F10 melanoma tumor model. Single-cell RNA sequencing revealed that DHA promoted effector function and oxidative phosphorylation in NK cells but had no obvious effects on other immune cells. Using Rag2-/- mice and NK-cell depletion by PK136 antibody injection, we demonstrated that the suppression of B16F10 melanoma tumor growth in the lung by DHA supplementation was dependent mainly on NK cells. In vitro experiments showed that DHA directly enhanced IFNγ production, CD107a expression, and mitochondrial oxidative phosphorylation (OXPHOS) activity and slightly increased proliferator-activated receptor gamma coactivator-1α (PGC-1α) protein expression in NK cells. The PGC-1α inhibitor SR-18292 in vitro and NK cell-specific knockout of PGC-1α in mice reversed the antitumor effects of DHA. In summary, our findings broaden the current knowledge on how DHA supplementation protects against cancer growth from the perspective of immunomodulation by upregulating PGC-1α signaling-mediated mitochondrial OXPHOS activity in NK cells.

Impact of left atrial appendage occlusion device position on potential determinants of device-related thrombus: a patient-specific in silico study.

BACKGROUND: Device-related thrombus (DRT) after left atrial appendage occlusion (LAAO) is potentially linked to adverse events. Although clinical reports suggest an effect of the device type and position on the DRT risk, in-depth studies of its mechanistic basis are needed. This in silico study aimed to assess the impact of the position of non-pacifier (Watchman) and pacifier (Amulet) LAAO devices on surrogate markers of DRT risk. METHODS: The LAAO devices were modeled with precise geometry and virtually implanted in different positions into a patient-specific left atrium. Using computational fluid dynamics, the following values were quantified: residual blood, wall shear stress (WSS) and endothelial cell activation potential (ECAP). RESULTS: In comparison to an ostium-fitted device position, deep implantation led to more residual blood, lower average WSS and higher ECAP surrounding the device, especially on the device's atrial surface and the surrounding tissue, suggesting increased risk for potential thrombus. For the non-pacifier device, an off-axis device orientation resulted in even more residual blood, higher ECAP and similar average WSS as compared to an ostium-fitted device position. Overall, the pacifier device showed less residual blood, higher average WSS and lower ECAP, compared to the non-pacifier device. CONCLUSIONS: In this in silico study, both LAAO device type and implant position showed an impact on potential markers of DRT in terms of blood stasis, platelet adhesion and endothelial dysfunction. Our results present a mechanistic basis for clinically observed risk factors of DRT and the proposed in silico model may aid in the optimization of device development and procedural aspects.

Genomic characteristics and prognosis of lung cancer patients with MSI-H: A cohort study.

BACKGROUND: Microsatellite instability (MSI) is the first pan-cancer biomarker approved to guide immune checkpoint inhibitor therapy for MSI-high (MSI-H) solid tumors. In lung cancer, the MSI-H frequency is very low, and the genetic characteristics and prognosis of lung cancer with MSI-H were rarely reported. METHODS: Next-generation sequencing and immunohistochemistry were used detect MSI status, tumor mutation burden (TMB) and PD-L1 expression. RESULTS: Among 12,484 lung cancer patients screened, 66 were found with MSI-H, the proportion was as low as 0.5%. Compared with Microsatellite stability (MSS), TMB was higher in MSI-H lung cancer patients, while PD-L1 expression showed no considerable difference between MSI-H and MSS. After propensity score matching, compared with MSS, the most common companion mutations in MSI-H were TP53, BRCA2, TGFBR2, PTEN and KMT2C. In MSI-H lung adenocarcinoma with EGFR mutation, TGFBR2 and ERBB2 had higher mutation frequency than in MSS. CONCLUSION: The current study reveals the genetic characteristics of MSI-H lung cancer, which advanced our understanding of MSI-H lung cancer.

Neoadjuvant Anlotinib and chemotherapy followed by minimally invasive esophagectomy in patients with locally advanced esophageal squamous cell carcinoma: Short-term results of an open-label, randomized, phase II trial.

Background: Clinical benefits of neoadjuvant Anlotinib for locally advanced esophageal squamous cell carcinoma (ESCC) remains unclear. This study evaluated the efficacy and safety of neoadjuvant Anlotinib plus chemotherapy followed by minimally invasive esophagectomy (MIE) for the treatment of patients with locally advanced ESCC. Methods: Patients with locally advanced ESCC were randomly assigned to neoadjuvant Anlotinib combined with chemotherapy (Anlotinib group) or neoadjuvant chemoradiotherapy alone (nCRT group) with an allocation ratio of 1:1. The primary endpoint was the R0 surgical resection rate. Secondary endpoints included postoperative pathologic stage, complete response (CR) rate, and safety. Safety was assessed by adverse events (AEs) and postoperative complications. Results: From August 2019 to August 2021, 93 patients were assigned to the nCRT or Anlotinib group. Of the 93 patients, 79 underwent MIE and were finally included in the per-protocol set (nCRT group: n=39; Anlotinib group: n=40). The R0 resection rate was 97.4% for nCRT versus 100.0% for Anlotinib group (p>0.05). Compared with the nCRT group, patients in the Anlotinib group had shorter total operation duration (262.2 ± 39.0 vs. 200.7 ± 25.5 min, p=0.010) and less blood loss (161.3 ± 126.7 vs. 52.4 ± 39.3 mL, p<0.001). No significant differences were found in the postoperative pathologic stage between the Anlotinib group and nCRT group (all p>0.05). Besides, the incidences of AEs (80.0% vs. 92.3%) and postoperative complications (22.5% vs. 30.8%) were similar between the two groups (all p>0.05). Conclusions: Neoadjuvant Anlotinib plus chemotherapy had a similar safety profile and pathologic response, but better surgical outcomes than nCRT for locally advanced ESCC.

Knockdown of NUSAP1 inhibits cell proliferation and invasion through downregulation of TOP2A in human glioblastoma.

Nucleolar and spindle associated protein 1 (NUSAP1), an indispensable mitotic regulator, has been reported to be involved in the development, progression, and metastasis of several types of cancer. Here, we investigated the expression and biological function of NUSAP1 in human glioblastoma (GBM), an aggressive brain tumor type with largely ineffective treatment options. Analysis of the molecular data in CGGA, TCGA and Rembrandt datasets demonstrated that NUSAP1 was significantly upregulated in GBM relative to low grade gliomas and non-neoplastic brain tissue samples. Kaplan-Meier analysis indicated that patients with tumors showing high NUSAP1 expression exhibited significantly poorer survival in both CGGA (P = 0.002) and Rembrandt cohorts (P = 0.017). Analysis of RNA sequencing data from P3-cells with stable knockdown of NUSAP1 revealed topoisomerase 2A (TOP2A) as a possible molecule downregulated by the loss of NUSAP1. Molecular analysis of the CGGA data revealed a strong correlation between NUSAP1 and TOP2A expression in primary gliomas and recurrent gliomas samples. SiRNA knockdown of either NUSAP1 or TOP2A in U251, T98 and GBM derived patient P3 cells inhibited GBM cell proliferation and invasion, and induced cell apoptosis. Finally, stable knockdown of NUSAP1 with shRNA led to decreased tumor growth in an orthotopic xenograft model of GBM in mice. Taken together, NUSAP1 gene silencing induced apoptosis possibly through the downregulation of the candidate downstream molecule TOP2A. Interference with the expression of NUSAP1 might therefore inhibit malignant progression in GBM, and NUSAP1 might thus serve as a promising molecular target for GBM treatment.

Docosahexaenoic acid supplementation represses the early immune response against murine cytomegalovirus but enhances NK cell effector function.

BACKGROUND: Docosahexaenoic acid (DHA) supplementation is beneficial for several chronic diseases; however, its effect on immune regulation is still debated. Given the prevalence of cytomegalovirus (CMV) infection and because natural killer (NK) cells are a component of innate immunity critical for controlling CMV infection, the current study explored the effect of a DHA-enriched diet on susceptibility to murine (M) CMV infection and the NK cell effector response to MCMV infection. RESULTS: Male C57BL/6 mice fed a control or DHA-enriched diet for 3 weeks were infected with MCMV and sacrificed at the indicated time points postinfection. Compared with control mice, DHA-fed mice had higher liver and spleen viral loads at day 7 postinfection, but final MCMV clearance was not affected. The total numbers of NK cells and their terminal mature cell subset (KLRG1+ and Ly49H+ NK cells) were reduced compared with those in control mice at day 7 postinfection but not day 21. DHA feeding resulted in higher IFN-γ and granzyme B expression in splenic NK cells at day 7 postinfection. A mechanistic analysis showed that the splenic NK cells of DHA-fed mice had enhanced glucose uptake, increased CD71 and CD98 expression, and higher mitochondrial mass than control mice. In addition, DHA-fed mice showed reductions in the total numbers and activation levels of CD4+ and CD8+ T cells. CONCLUSIONS: These results suggest that DHA supplementation represses the early response to CMV infection but preserves NK cell effector functions by improving mitochondrial activity, which may play critical roles in subsequent MCMV clearance.

Whole exome and transcriptome sequencing reveal clonal evolution and exhibit immune-related features in metastatic colorectal tumors.

Liver is the most common site where metastatic lesions of colorectal cancer (CRC) arise. Although researches have shown mutations in driver genes, copy number variations (CNV) and alterations in relevant signaling pathways promoted the tumor evolution and immune escape during colorectal liver metastasis (CLM), the underlying mechanism remains largely elusive. Tumor and matched metastatic tissues were collected from 16 patients diagnosed with colorectal cancer and subjected to whole-exome sequencing (WES) and RNA sequencing (RNA-seq) for studying colorectal cancer clonal evolution and immune escape during CLM. Shared somatic mutations between primary and metastatic tissues with a commonly observed subclonal-clonal (S-C) changing pattern indicated a common clonal origin between two lesions. The recurrent mutations with S-C changing pattern included those in KRAS, SYNE1, CACNA1H, PCLO, FBXL2, and DNAH11. The main CNV events underwent clonal-clonal evolution (20q amplification (amp), 17p deletion (del), 18q del and 8p del), subclonal-clonal evolution (8q amp, 13q amp, 8p del) and metastasis-specific evolution (8q amp) during the process of CLM. In addition, we revealed a potential mechanism of tumor cell immune escape by analyzing human leukocytes antigens (HLA) related clonal neoantigens and immune cell components in CLM. Our study proposed a novel liver metastasis-related evolutionary process in colorectal cancer and emphasized the theory of neo-immune escape in colorectal liver metastasis.

Mediating effects of general self-efficacy on the relationship between the source of meaning in life and prosocial behaviours in vocational college nursing students: A cross-sectional study.

OBJECTIVES: To examine the mediating effect of general self-efficacy on the relationship between the source of meaning in life (SML) and prosocial behaviours in vocational college nursing students. METHODS: Between March and June 2019, a cross-sectional descriptive study was conducted, and 799 nursing students from three vocational colleges completed the Source of Meaning in Life Scale, General Self-Efficacy Scale and Prosocial Behaviours Scale. Data were analyzed using structural equation modelling and statistical analysis by SPSS (version 23.0, IBM). RESULTS: The average SML, general self-efficacy and prosocial behaviours scores of the 799 nursing students were 6.43±0.83, 2.48±0.59 and 3.69±0.62, respectively. Correlation analysis showed that SML, general self-efficacy and prosocial behaviours were positively correlated (P<0.01). General self-efficacy partially mediated the relationship between SML and prosocial behaviours (P<0.01); this mediating effect contributed 22.97% of the total effect and explained 17.6% of the variance in the dependent variable. CONCLUSIONS: Educators should focus on cultivating nursing students' cognition and experience of meaning in life and their efficacy in life, study and work, which can improve students' "people-oriented" service and prosocial behaviour and the quality of nursing services.

Landscape of active enhancers developed de novo in cirrhosis and conserved in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) patients always have a background of cirrhosis. Aberrant epigenetic changes in cirrhosis provide a conductive environment for HCC tumorigenesis. Active enhancers (AEs) are essential for epigenetic regulation and play an important role in cell development and the progression of many diseases. However, the role of AEs in the progression from cirrhosis to HCC remains unclear. We systemically constructed a landscape of AEs that developed de novo in cirrhosis and were conserved in HCC, referred to as CL-HCC AEs. We observed significant upregulation of these CL-HCC AE-associated genes in cirrhosis and HCC, with no other epigenetic changes. Enrichment analysis of these CL-HCC AE-associated genes revealed enrichment in both hepatocyte-intrinsic tumorigenesis and tumor immune response, which might contribute to HCC tumorigenesis. Analysis of the diagnostic ability of these CL-HCC AE-associated genes provided a five-gene (THBS4, OLFML2B, CDKN3, GABRE, and HDAC11) diagnostic biomarker for HCC. Molecular subtype (MS) identification based on the CL-HCC AE-associated genes identified 3 MSs. Samples representing the 3 MSs showed differences in CL-HCC AE-associated gene expression levels, prognosis, copy number variation (CNV)/mutation frequencies, functional pathways, tumor microenvironment (TME) cell subtypes, immunotherapy responses and putative drug responses. We also found that the BET bromodomain inhibitor JQ1 downregulated the expression of CL-HCC AE-associated genes. Collectively, our results suggest that CL-HCC AEs and their associated genes contribute to HCC tumorigenesis and evolution, and could be used to distinguish the different landscapes of HCC and help explore the mechanism, classification, prediction, and precision therapy of HCC.

Mitochondrial APE1 promotes cisplatin resistance by downregulating ROS in osteosarcoma.

Apurinic/apyrimidinic endonuclease 1 (APE1) is a primary nuclear­localized multifunctional protein in osteosarcoma. However, the cytoplasmic localization of APE1 was found to be functional and to increase with cisplatin resistance, yet the molecular mechanism is unknown. In the present study, we explored the cisplatin resistance mechanism in osteosarcoma from the new perspective of APE1 extranuclear biological activity. Using cisplatin­resistant and cisplatin­sensitive osteosarcoma cell lines, we found that mitochondrial APE1 (mtAPE1) was overexpressed in cisplatin­resistant cells but not in sensitive cells. Overexpression of mtAPE1 reduced cisplatin­induced apoptosis, while knockdown of APE1 reversed this phenomenon and caused oxidative DNA damage via overproduction of reactive oxygen species (ROS). We further demonstrated that high mtAPE1 expression could downregulate ROS production by decreasing the phosphorylation of Rac1 (p­Rac1), further promoting cisplatin resistance in osteosarcoma. Our findings suggest that mitochondrial APE1 promotes cisplatin resistance by decreasing ROS generation, which may provide new ideas for researching the molecular mechanism of osteosarcoma chemoresistance and strategies to overcome cisplatin resistance in osteosarcoma.

ADAMTS12 acts as a cancer promoter in colorectal cancer via activating the Wnt/ß-catenin signaling pathway in vitro.

BACKGROUND: ADAMTS12, a member of the ADAMTS family, is reported to be associated with the clinic outcome of colorectal cancer (CRC) patients. However, the functions and precise mechanism in CRC progression have yet to be fully understood. METHODS: By analyzing The Cancer Genome Atlas (TCGA) database, we examined the mRNA level of ADAMTS12 and assessed the prognostic value of ADAMTS12 in CRC patients using a tissue microarray containing 41 CRC patient samples. Cell Counting Kit-8 (CCK-8), colony formation, and transwell assays were used to quantify the impact of ADAMTS12 on cell proliferation and migration in ADAMTS12-overexpressing and ADAMTS12-deficient cell lines. The signaling pathways that ADAMTS12 mediated were identified by dual-luciferase reporter assays, and confirmed by western blotting and quantitative teal-time polymerase chain reaction (qRT-PCR). RESULTS: The ADAMTS12 mRNA level was upregulated in CRC tissues, and CRC patients with a high level of ADAMTS12 showed worse prognosis when compared with the patients with a low level of ADAMTS12. In vitro functional assays demonstrated that overexpression of ADAMTS12 significantly boosted cell proliferation and migration while ADAMTS12 deficiency remarkably impaired both tumor cell behaviors. Mechanical studies further verified that ADAMTS12 overexpression enhanced the transcriptional activity of ß-catenin in the Wnt/ß-catenin signaling pathway. In the ADAMTS12-deficient context, the downstream gene expression of myc and cyclin D1 was significantly reduced compared with that in wild-type cancer cells. CONCLUSIONS: ADAMTS12 fulfills the tumor-promotor role by activating Wnt/ß-catenin signaling pathway in colon cells and may represent a new option in CRC target treatment.

Challenge of parents caring for children or adolescents with early-stage schizophrenia in China: A qualitative study.

PURPOSE: To explore the challenges of parents caring for early-stage schizophrenia (ESS) children/adolescents in China. DESIGN AND METHODS: Thirteen parents of ESS subjects completed semi-structured interviews. Thematic analysis was used to analyze data. FINDINGS: Seven themes emerged from the data: psychological shock and emotional burden; lack of disease knowledge and care skill; poor treatment compliance of the patient; difficulty getting along with the patient; conflict within the family or in the workplace; financial burden; and need sufficient social support. Each challenge was produced and influenced under the Chinese special social context. PRACTICE IMPLICATIONS: Professional support was needed to help patients with schizophrenia to cope with their situation promptly. Education initiatives should focus on mental health to prevent discrimination from society and enable people to recognize the early symptoms of schizophrenia in children. Telemedicine should be explored for application in the treatment of mental illness. Also, a broader nationwide healthcare policy would be needed to help to reduce the individual and societal financial burdens associated with schizophrenia.

Control of thermal deformation with photonic sintering of ultrathin nanowire transparent electrodes.

Development of electronic devices on ultrathin flexible plastic substrates is of great value in terms of portability, cost reduction, and mechanical flexibility. However, because thin plastic substrates with low heat capacity can be more easily damaged by thermal energy, their use is limited. Highly flexible nanowire (NW) transparent conductive electrodes on ultrathin (∼10 µm) low cost polyethylene terephthalate (PET) substrates are fabricated. The control of intense pulsed light (IPL) irradiation process parameters to induce NW welding for maximum conductivity and minimal thermal damage of the PET substrate is explored. For this purpose, trends in temperature variation of NW thin films irradiated by IPL under various operating conditions are numerically analyzed using commercial software. Simulations indicate that irradiating light operated at a higher voltage and for a shorter time, and use of multiple pulses of low frequency can reduce thermal deformation of the PET substrate. Furthermore, we experimentally confirm that NW transparent electrodes can be successfully fabricated with less thermal deformation of the ultrathin plastic substrate when light is irradiated under well-controlled conditions derived from the simulation. The highly flexible NW transparent conducting electrode exhibits excellent mechanical flexibility to withstand severe deformation and can be successfully implemented in flexible organic light-emitting diodes (OLEDs).

Cytoplasmic APE1 promotes resistance response in osteosarcoma patients with cisplatin treatment.

Chemotherapy resistance has become a hold back and major clinical challenge in osteosarcoma cancer. The alteration and subcellular distribution of apurinic/apyrimidinic endonuclease 1 (APE1) has been reported to be involved in chemotherapy resistance in many cancers. Here, we report that the cytoplasmic distribution of APE1 plays a key role in the sensitivity of combination platinum chemotherapy in osteosarcoma. Interestingly, the prevalence of cisplatin-induced DNA damage and apoptosis in low cytoplasmic APE1 osteosarcoma cell lines was higher than in high expression of cytoplasmic APE1 cell lines. Overexpression of cytoplasmic APE1 protected the osteosarcoma cells from CDDP-induced apoptosis. In addition, clinical data also show that the level of cytoplasmic APE1 was negatively associated with sensitivity to combination chemotherapy of cisplatin in osteosarcoma patients. Our findings suggest that cytoplasmic APE1 plays a significant role in chemotherapy resistance. This role is a supplement to the extranuclear function of APE1, and cytoplasmic APE1 expression level could be a promising predictor of platinum treatment prognosis for osteosarcoma patients.

Identification of a Five-Autophagy-Related-lncRNA Signature as a Novel Prognostic Biomarker for Hepatocellular Carcinoma.

Although great progresses have been made in the diagnosis and treatment of hepatocellular carcinoma (HCC), its prognostic marker remains controversial. In this current study, weighted correlation network analysis and Cox regression analysis showed significant prognostic value of five autophagy-related long non-coding RNAs (AR-lncRNAs) (including TMCC1-AS1, PLBD1-AS1, MKLN1-AS, LINC01063, and CYTOR) for HCC patients from data in The Cancer Genome Atlas. By using them, we constructed a five-AR-lncRNA prognostic signature, which accurately distinguished the high- and low-risk groups of HCC patients. All of the five AR lncRNAs were highly expressed in the high-risk group of HCC patients. This five-AR-lncRNA prognostic signature showed good area under the curve (AUC) value (AUC = 0.751) for the overall survival (OS) prediction in either all HCC patients or HCC patients stratified according to several clinical traits. A prognostic nomogram with this five-AR-lncRNA signature predicted the 3- and 5-year OS outcomes of HCC patients intuitively and accurately (concordance index = 0.745). By parallel comparison, this five-AR-lncRNA signature has better prognosis accuracy than the other three recently published signatures. Furthermore, we discovered the prediction ability of the signature on therapeutic outcomes of HCC patients, including chemotherapy and immunotherapeutic responses. Gene set enrichment analysis and gene mutation analysis revealed that dysregulated cell cycle pathway, purine metabolism, and TP53 mutation may play an important role in determining the OS outcomes of HCC patients in the high-risk group. Collectively, our study suggests a new five-AR-lncRNA prognostic signature for HCC patients.

Satisfactory short-term outcome after anlotinib and docetaxel chemotherapy in tongue cancer with N3 cervical lymph node metastasis: A case report.

Patients with tongue squamous cell carcinoma (TSCC) and cervical lymph node metastasis are particularly difficult to treat. This is the first report of about anlotinib combined with docetaxel chemotherapy for chemotherapy-refractory TSCC with cervical lymph node metastasis, may provide a new, suitable therapeutic option for these patients.

MicroRNA-765 sensitizes osteosarcoma cells to cisplatin via downregulating APE1 expression.

OBJECTIVES: Osteosarcoma (OS) is the most common bone cancer diagnosed in children and adolescents. Expression of APE1 is commonly increased in OS, and this is negatively correlated with a sensitivity to platinum and a favorable prognosis. However, the mechanism underlying high APE1 expression in OS is not fully understood. METHODS: A bioinformatics analysis of the APE1 3'-UTR combined with previous microarray data was used to identify miRNAs that regulate APE1 expression. The effects of miR-765 on cisplatin (cDDP) sensitivity were estimated in OS cell lines (9901 and HOS) and BALB/c mice (n=4 per group). The relative expression and association between miR-765 and APE1 were assessed in a cohort of OS patients (n=43 in total) with Kaplan-Meier and Cox proportional hazards regression. All statistical tests were two-sided and p<0.05 was considered significant. RESULTS: Bioinformatics analysis implied that miR-765 may target APE1. Luciferase assay and WB showed that miR-765 bound directly to the 3'-UTR of APE1 and downregulated APE1 expression in OS cells. Further experiments revealed that miR-765 sensitized OS cells to cisplatin and was associated with decreased DNA repair activity. In vivo analyses suggested the sensitivity of cisplatin in xenograft OS tissues was increased after injection with miR-765 agomir. The clinical data showed a negative correlation between miR-765 and APE1 expression (r=0.307, p=0.045). Log-rank test revealed that OS patients with positive expression of miR-765 obtained a significantly longer survival than those with negative expression (22.0 vs. 9.0 months, p=0.001), which is just the opposite with respect to APE1 expression (12.00 vs. 22.00 months, p=0.039). The Cox regression analysis found miR-765 may be an independent prognostic factor for OS survival (p=0.007, HR=0.389, 95% CI: 0.196-0.772). CONCLUSION: miR-765 sensitizes OS cells to cisplatin and impedes DNA damage repair through the downregulation of APE1. High expression of miR-765 may benefit OS patient survival, making it a viable target for reversing cisplatin-induced resistance in OS patients.

Three-Dimensionally Printed Stretchable Conductors from Surfactant-Mediated Composite Pastes.

A stretchable conductor is a critical prerequisite to achieve various forms of stretchable electronics. In particular, directly printable stretchable conductors have gathered considerable attention with recent growing interest in a variety of large-area, deformable electronics. In this study, we have developed a chemical pathway of incorporating a surfactant with a moderate hydrophilic-lipophilic balance in formulating composite pastes for printed stretchable conductors, with a possibility of a vertically stackable, three-dimensional printing process. We demonstrate that the addition of a nonionic surfactant, sorbitane monooleate (commonly called SPAN 80) in Ag flake-based composite pastes, allows a critical reduction in resistance variation under an external strain. The four-layer stacked, surfactant-added composite conductors show a resistance variation of merely 1.6 at a strain of 0.6 and excellent cycling durability over 1000 cycles. The effectiveness of the methods suggested in this study is demonstrated with basic light-emitting diode circuits and the thermal heating characteristics of stretchable conductors.

Erlotinib versus gemcitabine/cisplatin in Chinese patients with EGFR mutation-positive advanced non-small-cell lung cancer: Crossover extension and post-hoc analysis of the ENSURE study.

OBJECTIVES: Sequential combination of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) and chemotherapy has shown greater benefits than either treatment alone in non-small-cell lung cancer (NSCLC). In this follow-up of the ENSURE study, we evaluated progression-free survival (PFS) with first-line erlotinib followed by chemotherapy at progression versus the inverse treatment sequence in 175 Chinese patients with EGFR mutation-positive NSCLC. MATERIALS AND METHODS: Forty-five of the 175 patients included in the follow-up analysis experienced progressive disease (PD). Those with PD on first-line erlotinib (n = 24) received gemcitabine/cisplatin while those who failed first-line chemotherapy (n = 21) received erlotinib until second-line PD. The primary endpoint was PFS in the crossover subpopulation. Post-hoc analysis of survival outcomes was also measured for the overall population of 175 Chinese patients. RESULTS: Among patients who crossed over at progression, PFS was comparable between those who received second-line erlotinib and those who received second-line chemotherapy (median, 26.3 months and 23.4 months, respectively; P = 0.529). Regardless of the sequence in which the therapies were administered, patients in the crossover treatment subgroup benefited from either second-line therapy after progression with a median overall survival of 51.6 months versus 23.0 months achieved among patients in the non-crossover treatment subgroup. Post-hoc biomarker analyses of Kaplan-Meier survival curves and Cox regression showed that survival benefits with either treatment sequence were similar between patients with circulating free DNA EGFR mutations in exons 19 and 21; however, those with undetectable mutations achieved significantly greater survival benefits. CONCLUSION: In advanced EGFR mutation-positive NSCLC, first-line erlotinib followed by chemotherapy at progression demonstrated comparable PFS benefit with the inverse treatment sequence, irrespective of mutation subtype. Utilizing both EGFR-TKIs and chemotherapy, irrespective of the sequence, maximizes survival benefits for patients.