Design, synthesis, and mechanism of action of novel µ-conotoxin KIIIA analogues for inhibition of the voltage-gated sodium channel Nav1.7.

µ-Conotoxin KIIIA, a selective blocker of sodium channels, has strong inhibitory activity against several Nav isoforms, including Nav1.7, and has potent analgesic effects, but it contains three pairs of disulfide bonds, making structural modification difficult and synthesis complex. To circumvent these difficulties, we designed and synthesized three KIIIA analogues with one disulfide bond deleted. The most active analogue, KIIIA-1, was further analyzed, and its binding pattern to hNav1.7 was determined by molecular dynamics simulations. Guided by the molecular dynamics computational model, we designed and tested 32 second-generation and 6 third-generation analogues of KIIIA-1 on hNav1.7 expressed in HEK293 cells. Several analogues showed significantly improved inhibitory activity on hNav1.7, and the most potent peptide, 37, was approximately 4-fold more potent than the KIIIA Isomer I and 8-fold more potent than the wildtype (WT) KIIIA in inhibiting hNav1.7 current. Intraperitoneally injected 37 exhibited potent in vivo analgesic activity in a formalin-induced inflammatory pain model, with activity reaching ∼350-fold of the positive control drug morphine. Overall, peptide 37 has a simplified disulfide-bond framework and exhibits potent in vivo analgesic effects and has promising potential for development as a pain therapy in the future.

Synapses do not facilitate prion-like transfer of alpha-synuclein: a quantitative study in reconstructed unidirectional neural networks.

Alpha-synuclein (aSyn) aggregation spreads between cells and underlies the progression of neuronal lesions in the brain of patients with synucleinopathies such as Parkinson's diseases. The mechanisms of cell-to-cell propagation of aggregates, which dictate how aggregation progresses at the network level, remain poorly understood. Notably, while prion and prion-like spreading is often simplistically envisioned as a "domino-like" spreading scenario where connected neurons sequentially propagate protein aggregation to each other, the reality is likely to be more nuanced. Here, we demonstrate that the spreading of preformed aSyn aggregates is a limited process that occurs through molecular sieving of large aSyn seeds. We further show that this process is not facilitated by synaptic connections. This was achieved through the development and characterization of a new microfluidic platform that allows reconstruction of binary fully oriented neuronal networks in vitro with no unwanted backward connections, and through the careful quantification of fluorescent aSyn aggregates spreading between neurons. While this allowed us for the first time to extract quantitative data of protein seeds dissemination along neural pathways, our data suggest that prion-like dissemination of proteinopathic seeding aggregates occurs very progressively and leads to highly compartmentalized pattern of protein seeding in neural networks.

Exosomal transfer of miR-181b-5p confers senescence-mediated doxorubicin resistance via modulating BCLAF1 in breast cancer.

BACKGROUND: Doxorubicin resistance represents a major clinical challenge for treating patients with advanced breast cancer (BC). Exosomes, exchanging genetic cargo between heterogeneous populations of tumour cells, have been proposed to mediate drug resistance and cancer progression in other cancer types. However, their specific role in mediating doxorubicin resistance in BC remains unclear. Here, we demonstrate the important role of exosomal miR-181b-5p (exo-miR-181b-5p) in mediating doxorubicin resistance. METHODS: Small-RNA sequencing and bioinformatic analyses were used to screen miRNAs mediating doxorubicin resistance in BC, which were further verified by RT-qPCR. SA-ß-gal staining assays allowed us to measure cellular senescence. Exosomes from patients' serum before and after neoadjuvant chemotherapy were isolated for exo-miR-181b-5p quantification. RESULTS: Doxorubicin-resistant BC cell lines exhibited upregulated exosomal miR-181b-5p. Addition of exo-miR-181b-5p actively fused with recipient cells and transferred a drug-resistant phenotype. Overexpression of miR-181b-5p downregulated p53/p21 levels and inhibited doxorubicin-induced G1 arrest and senescence by suppressing BCLAF1 expression in vitro. Further, in vivo experiments showed treatment of exo-miR-181b-5p inhibitors exhibited superior tumour control and reversed the doxorubicin-resistance phenotype, accompanied with increased tumoral BCLAF1. CONCLUSION: Our data suggests exo-miR-181b-5p as a prognostic biomarker and a therapeutic potential for exo-miR-181b-5p inhibitors in the treatment of doxorubicin-resistant BC patients.

The role of TXNIP in cancer: a fine balance between redox, metabolic, and immunological tumor control.

Thioredoxin-interacting protein (TXNIP) is commonly considered a master regulator of cellular oxidation, regulating the expression and function of Thioredoxin (Trx). Recent work has identified that TXNIP has a far wider range of additional roles: from regulating glucose and lipid metabolism, to cell cycle arrest and inflammation. Its expression is increased by stressors commonly found in neoplastic cells and the wider tumor microenvironment (TME), and, as such, TXNIP has been extensively studied in cancers. In this review, we evaluate the current literature regarding the regulation and the function of TXNIP, highlighting its emerging role in modulating signaling between different cell types within the TME. We then assess current and future translational opportunities and the associated challenges in this area. An improved understanding of the functions and mechanisms of TXNIP in cancers may enhance its suitability as a therapeutic target.

HeapMS: An Automatic Peak-Picking Pipeline for Targeted Proteomic Data Powered by 2D Heatmap Transformation and Convolutional Neural Networks.

The process of peak picking and quality assessment for multiple reaction monitoring (MRM) data demands significant human effort, especially for signals with low abundance and high interference. Although multiple peak-picking software packages are available, they often fail to detect peaks with low quality and do not report cases with low confidence. Furthermore, visual examination of all chromatograms is still necessary to identify uncertain or erroneous cases. This study introduces HeapMS, a web service that uses artificial intelligence to assist with peak picking and the quality assessment of MRM chromatograms. HeapMS applies a rule-based filter to remove chromatograms with low interference and high-confidence peak boundaries detected by Skyline. Additionally, it transforms two histograms (representing light and heavy peptides) into a single encoded heatmap and performs a two-step evaluation (quality detection and peak picking) using image convolutional neural networks. HeapMS offers three categories of peak picking: uncertain peak picking that requires manual inspection, deletion peak picking that requires removal or manual re-examination, and automatic peak picking. HeapMS acquires the chromatogram and peak-picking boundaries directly from Skyline output. The output results are imported back into Skyline for further manual inspection, facilitating integration with Skyline. HeapMS offers the benefit of detecting chromatograms that should be deleted or require human inspection. Based on defined categories, it can significantly reduce human workload and provide consistent results. Furthermore, by using heatmaps instead of histograms, HeapMS can adapt to future updates in image recognition models. The HeapMS is available at: https://github.com/ccllabe/HeapMS.

GGNBP2 suppresses triple-negative breast cancer aggressiveness through inhibition of IL-6/STAT3 signaling activation.

BACKGROUND: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, lacking effective targeted therapies, and whose underlying mechanisms are still unclear. The gene coding for Gametogenetin-binding protein (GGNBP2), also known as Zinc Finger Protein 403 (ZNF403), is located on chromosome 17q12-q23, a region known as a breast cancer susceptibility locus. We have previously reported that GGNBP2 functions as a tumor suppressor in estrogen receptor-positive breast cancer. The aim of this study was to evaluate the role and mechanisms of GGNBP2 in TNBC. METHODS: The effect of GGNBP2 on TNBC aggressiveness was investigated both in vitro and in vivo. The protein and mRNA expression levels were analyzed by western blotting and reverse transcription quantitative polymerase chain reaction, respectively. Fluorescence-activated cell sorting analysis was used to evaluate the cell cycle distribution and cell apoptosis. Immunohistochemistry was used to determine the expression of GGNBP2 in breast cancer tissues. RESULTS: We find that GGNBP2 expression decreases in TNBC tissues and is associated with the outcome of breast cancer patients. Furthermore, experimental overexpression of GGNBP2 in MDA-MB-231 and Cal51 cells suppresses cell proliferation, migration and invasion, reduces the cancer stem cell subpopulation, and promotes cell apoptosis in vitro as well as inhibits tumor growth in vivo. In these cell models, overexpression of GGNBP2 decreases the activation of IL-6/STAT3 signaling. CONCLUSION: Our data demonstrate that GGNBP2 suppresses cancer aggressiveness by inhibition of IL-6/STAT3 activation in TNBC.

FBXL19-AS1 promotes cell proliferation and inhibits cell apoptosis via miR-876-5p/FOXM1 axis in breast cancer.

As the most common cancer and one of the leading causes of cancer-associated mortality, breast cancer continues to need more key molecules to regulate its progression. F-box and leucine-rich repeat protein 19 antisense RNA 1 (known as FBXL19-AS1) is a long non-coding RNA (lncRNA) which has been reported as an oncogene in several types of human cancers. However, the specific downstream targets of FBXL19-AS1 remain unknown. In this study, we set out to find more reliable downstream molecules of FBXL19-AS1 in breast cancer. FBXL19-AS1 was expressed at a high level in breast cancer cells. Loss-of-function experiments revealed that silencing FBXL19-AS1 could impair cell proliferation and induce cell apoptosis in breast cancer. In addition, the location of FBXL19-AS1 in the cytoplasm was detected by fluorescent in situ hybridization assay, while FBXL19-AS1 regulated the expression of Forkhead box M1 (FOXM1) by directly absorbing miR-876-5p. Through rescue assays, it was observed that FOXM1 overexpression recovered the inhibited tumor growth caused by FBXL19-AS1 downregulation. We affirmed the function of FBXL19-AS1 in breast cancer and described the mechanism of the FBXL19-AS1/miR-876-5p/FOXM1 axis. The current work presents the molecular mechanism which underlies FBXL19-AS1 in breast cancer and suggests a comprehensive, feasible FBXL19-AS1-mediated therapeutic approach for treating breast cancer.

Correlation of radiotherapy with prognosis of elderly patients with hormone receptor-positive breast cancer according to immunohistochemical subtyping.

OBJECTIVE: The present study examined the effect of radiotherapy on recurrence and survival in elderly patients with hormone receptor-positive early breast cancer. METHODS: A retrospective analysis of 327 patients aged ≥65 years, with stage I-II, hormone receptor-positive breast cancer who underwent breast-conserving surgery and received endocrine therapy (ET) or radiotherapy plus endocrine therapy (ET+RT) was performed. Both groups were divided into luminal A type and luminal B type subgroups. Evaluation criteria were 5-year disease-free survival (DFS), local relapse rate (LRR), overall survival (OS), and distant metastasis rate (DMR). RESULTS: There were significant differences in 5-year DFS [hazard ratio (HR)=1.59, 95% confidence interval (95% CI), 1.15-2.19; P=0.005] and LRR (HR=3.33, 95% CI, 1.51-7.34; P=0.003), whereas there were no significant differences in OS and DMR between ET group and ET+RT group. In luminal A type, there was no significant difference in 5-year DFS, LRR, OS and DMR between ET group and ET+RT group. In luminal B type, there were statistically significant differences in 5-year DFS (HR=2.19, 95% CI, 1.37-3.49; P=0.001), LRR (HR=5.45, 95% CI, 1.65-17.98; P=0.005), and OS (HR=1.75, 95% CI, 1.01-3.05; P=0.048) between ET group and ET+RT group. In the ET group, there were significant differences between luminal A type and luminal B type in 5-year DFS (HR=1.84, 95% CI, 1.23-2.75; P=0.003) and OS (HR=1.76, 95% CI, 1.07-2.91; P=0.026). CONCLUSIONS: After breast-conserving surgery, radiotherapy can reduce the LRR and improve the DFS and OS of luminal B type elderly patients, whereas luminal A type elderly patients do not benefit from radiotherapy. Without radiotherapy, luminal A type patients have better DFS and OS than luminal B type patients.

Silencing of TGIF attenuates the tumorigenicity of A549 cells in vitro and in vivo.

The aim of this study was to investigate the effects of the silencing of the TG-interacting factor (TGIF) on the tumorigenicity of A549 cells in vitro and in vivo. Stable TGIF-silenced A549 cells were established by infecting shRNA lentiviral particles. Western blotting analysis was used to detect the expression of proteins. Cell cycle was detected by flow cytometry. Soft agar assay and tumor formation assay in nude mice were applied. The silencing of TGIF inhibited A549 cell proliferation, colony formation in vitro, growth of tumor xenograft in vivo, and arrested the cell cycle in the G1 phase. The expression of CDK4, cyclin D1, and phospho-Rb was markedly decreased in the A549-shTGIF cells compared with the A549-shcon cells, and p21 was markedly increased in the A549-shTGIF cells compared with the A549-shcon cells. A lower level of ß-Catenin protein expression was observed in the A549-shTGIF cells than that in the A549-shcon cells. The silencing of TGIF attenuates the tumorigenicity of A549 cells in vitro and in vivo.

Isolation of CHS Gene from Brunfelsia acuminata Flowers and Its Regulation in Anthocyanin Biosysthesis.

Chalcone synthase gene (BaCHS) from Brunfelsia acuminata flowers was isolated using RT-PCR and RACE. The coding region of the gene is 1425-bp with an open reading frame of 1170-bp, 73-bp 5'UTR, and 172-bp 3'UTR. Its deduced protein does not have a signal peptide but does contain a cond_enzyme superfamily domain, and consists of 389 amino acids with a predicted molecular mass of 42,699 Da and a pI of 6.57. The deduced amino acid sequence of BaCHS shares 90%, 88%, 85%, 84% and 79% identity with CHS from Petunia hybrida, Nicotiana tabacum, Solanum lycopersicum, Capsicum annuum and Camellia sinensis, respectively. The striking color change from dark purple to light purple and ultimately lead to pure white resulted from a decline in anthocyanin content of the petals and was preceded by a decrease in the expression of BaCHS. Its gene expression was positively correlated with the contents of anthocyanin (p ≤ 0.01).

The improvement effect and mechanism of citrus fiber on the water-binding ability of low-fat frankfurters.

Water-binding ability is a major quality attribute of low-fat meat products. This study aimed to evaluate the effects of citrus fiber on the water-binding ability of low-fat frankfurters. Low-fat (10% fat) frankfurters with different contents (0, 1, 2, and 3%) of citrus fiber were prepared. Their cooking loss, water distribution, microstructure, and protein structure were assessed and compared to those of normal-fat (20% fat) frankfurters. Results demonstrated that citrus fiber could significantly reduce the cooking loss of low-fat frankfurters from 12.69 to 4.71%. Adding citrus fiber led to a faster relaxation time in low-fat frankfurters, and a significant increase in the proportion of immobilized water. Frankfurters with citrus fiber exhibited a more compact, continuous protein network structure. Furthermore, the intensity changes in the Raman bands near 760 and 2930 cm-1 showed that citrus fiber increased hydrophobic interactions around hydrocarbon chains and tryptophan residues in myofibrillar proteins. In conclusion, citrus fiber effectively improved the water-binding ability of low-fat frankfurters by increasing the hydrophobic interactions of myofibrillar proteins and changing the frankfurter microstructure.

Effect of shaddock albedo addition on the properties of frankfurters.

To explore the potential as a natural auxiliary emulsifier, shaddock albedo was added into frankfurters at six different levels: 0.0, 2.5, 5.0, 7.5, 10 and 12.5 %. The emulsion capacity (EC) of meat batters and cooking properties of frankfurters were evaluated. EC of meat batters was improved with the addition of shaddock albedo and the maximum value was reached at the 5 % albedo concentration. The addition of shaddock albedo resulted in lower cooking losses of frankfurters, with the lowest value obtained at the 7.5 % level. The presence of shaddock albedo decreased the total expressible fluid (TEF) and the proportion of fat in total expressible fluid (PF) which indicated the emulsion stability of frankfurters and the lowest values both occurred at the concentration of 7.5 %. Shaddock albedo inclusion increased the lightness and yellowness of frankfurters and decreased redness. Texture profile analysis showed increased hardness and decreased chewiness of frankfurters with the addition of shaddock albedo. Consequently, shaddock albedo could be a potential source of auxiliary emulsifier filler for emulsion-type meat products.

Three different surgical methods of the special tracheobronchial foreign body (pen cap) in children: Case series.

We present three novel cases of tracheobronchial foreign bodies (TFBs) in children caused by pen caps. One was removed by the rigid bronchoscopy successfully, the second was removed by rigid bronchoscopy combined with tracheotomy, and the last one was treated by bronchotomy from an external thoracic approach. Rigid bronchoscopy is the most widely used for treating TFBs in clinics, especially treating large and special foreign bodies, because rigid bronchoscopy can provide a good view for observation and operation. Successful removal of a foreign body under rigid bronchoscopy (an experienced doctor, suitable instruments, etc.) can obviate tracheotomy/tracheostomy or thoracotomy/bronchotomy.

Tumor-derived nanovesicles enhance cancer synergistic chemo-immunotherapy by promoting cGAS/STING pathway activation and immunogenetic cell death.

AIMS: Checkpoint blockade immunotherapy is a promising therapeutic modality that has revolutionized cancer treatment; however, the therapy is only effective on a fraction of patients due to the tumor environment. In tumor immunotherapy, the cGAS-STING pathway is a crucial intracellular immune response pathway. Therefore, this study aimed to develop an immunotherapy strategy based on the cGAS-STING pathway. MATERIALS AND METHODS: The physicochemical properties of the nanoparticles EM@REV@DOX were characterized by TEM, DLS, and WB. Subcutaneous LLC xenograft tumors were used to determine the biodistribution, antitumor efficacy, and immune response. Blood samples and tissues of interest were harvested for hematological analysis and H&E staining. SIGNIFICANCE: Overall, our designed nanovesicles provide a new perspective on tumor immunotherapy by ICD and cGAS-STING pathway, promoting DCs maturation, macrophage polarization, and activating T cells, offering a meaningful strategy for accelerating the clinical development of immunotherapy. KEY FINDINGS: EM@REV@DOX accumulated in the tumor site through EPR and homing targeting effect to release REV and DOX, resulting in DNA damage and finally activating the cGAS-STING pathway, thereby promoting DCs maturation, macrophage polarization, and activating T cells. Additionally, EM@REV@DOX increased the production of pro-inflammatory cytokines (e.g., TNF-α and IFN-ß). As a result, EM@REV@DOX was effective in treating tumor-bearing mice and prolonged their lifespans. When combined with αPD-L1, EM@REV@DOX significantly inhibited distant tumor growth, extended the survival of mice, and prevented long-term postoperative tumor metastasis, exhibiting great potential in antitumor immunotherapy.

Comprehensive pan-cancer analysis reveals prognostic implications of TMEM92 in the tumor immune microenvironment.

BACKGROUND: Transmembrane protein 92 (TMEM92) has been implicated in the facilitation of tumor progression. Nevertheless, comprehensive analyses concerning the prognostic significance of TMEM92, as well as its role in immunological responses across diverse cancer types, remain to be elucidated. METHODS: In this study, data was sourced from a range of publicly accessible online platforms and databases, including TCGA, GTEx, UCSC Xena, CCLE, cBioPortal, HPA, TIMER2.0, GEPIA, CancerSEA, GDSC, exoRBase, and ImmuCellAI. We systematically analyzed the expression patterns of TMEM92 at both mRNA and protein levels across diverse human organs, tissues, extracellular vesicles (EVs), and cell lines associated with multiple cancer types. Subsequently, analyses were conducted to determine the relationship between TMEM92 and various parameters such as prognosis, DNA methylation, copy number variation (CNV), the tumor microenvironment (TME), immune cell infiltration, genes with immunological relevance, tumor mutational burden (TMB), microsatellite instability (MSI), mismatch repair (MMR), and half-maximal inhibitory concentration (IC50) values. RESULTS: In the present study, we observed a pronounced overexpression of TMEM92 across a majority of cancer types, which was concomitantly associated with a less favorable prognosis. A notable association emerged between TMEM92 expression and both DNA methylation and CNV. Furthermore, a pronounced relationship was discerned between TMEM92 expression, the TME, and the degree of immune cell infiltration. Intriguingly, while TMEM92 expression displayed a positive correlation with macrophage presence, it inversely correlated with the infiltration level of CD8 + T cells. Concurrently, significant associations were identified between TMEM92 and the major histocompatibility complex, TMB, MSI, and MMR. Results derived from Gene Set Enrichment Analysis and Gene Set Variation Analysis further substantiated the nexus of TMEM92 with both immune and metabolic pathways within the oncogenic context. CONCLUSIONS: These findings expanded the understanding of the roles of TMEM92 in tumorigenesis and progression and suggest that TMEM92 may have an immunoregulatory role in several malignancies.

[Mammalian target of rapamycin regulates androgen receptor and Akt phosphorylation in prostate cancer 22RV1 cells].

OBJECTIVE: To investigate the roles of the mammalian target of rapamycin-1 and -2 (mTORC1 and TORC2) in the proliferation and apoptosis of prostate cancer 22RV1 cells. METHODS: After silencing mTORC1 and TORC2, we examined the proliferation and apoptosis of prostate cancer 22RV1 cells by methylthiazol tetrazolium (MTT) assay and flow cytometry, respectively, and detected the expressions of the androgen receptor (AR) and Akt phosphorylation in the prostate cancer 22RV1 cells by Western blot after transfecting Raptor-siRNA and Rictor-siRNA to the 22RV1 cells. RESULTS: MTT showed that the prostate cancer 22RV1 cells had no significant change in the growth rate after mTORC1 silence (P > 0.05), but their proliferation was markedly inhibited after mTORC2 silence (P < 0.01). Flow cytometry revealed a dramatic increase in the apoptosis of the 22RV1 cells after mTORC1 silence (P < 0.01), but no obvious change after mTORC2 silence (P > 0.05). Western blot exhibited that mTORC1 silence significantly increased the expression of AR and Akt phosphorylation (P < 0.05), while mTORC2 silence markedly decreased them (P < 0.05). CONCLUSION: mTORC2 is not only required for the survival of prostate cancer 22RV1 cells, but also a promising therapeutic target of prostate cancer.

An Integrated Analysis Identified TAGLN2 As an Oncogene Indicator Related to Prognosis and Immunity in Pan-Cancer.

Background: Transgelin-2 (TAGLN2) has long been regarded as an actin-binding protein that modulates actin gelation and controls actin cytoskeleton dynamics. However, recent studies have reported that TAGLN2 can directly or indirectly participate in multiple cancer-related processes, including cell migration, proliferation, differentiation, and apoptosis. To further investigate the role of TAGLN2 in carcinogenesis, a comprehensive analysis was launched to evaluate the expression status and prognostic value of TAGLN2 in pan-cancer. Methods: Herein, data was retrieved from publicly online websites and databases, including The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Cancer Cell Line Encyclopedia (CCLE), UCSC Xena, cBioPortal, Human Protein Atlas (HPA), TIMER2.0, CancerSEA, GDSC, and ImmuCellAI. Gene expression pattern and its correlation with prognosis were assessed across cancer types. Moreover, an analysis was conducted to explore the relationships between TAGLN2 and methylation, copy number values (CNVs), tumor microenvironment (TME), immune cell infiltration, immune-relevance genes, tumor mutation burden (TMB), microsatellite instability (MSI), and IC50. Additionally, R package "clusterProfiler" was utilized to perform enrichment analysis on TAGLN2. Finally, the ability of TAGLN2 as an oncogene was preliminarily verified in vitro in UCEC. Results: Our findings revealed that TAGLN2 was specifically overexpressed and related to an unfavorable prognosis in most cancers. There was a significant connection between TAGLN2 expression and methylation and CNVs. Besides, we identified TAGLN2 correlated to TME, immune cell infiltration, immune-relevant genes, TMB, and MSI, suggesting an immunoregulatory role in cancers. Notably, TAGLN2 expression showed a positive correlation with macrophages, and cancer-associated fibroblasts, whereas a negative correlation with the infiltration degree of B cells. Mechanically, the results obtained from Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) provided theory-supportive evidence that TAGLN2 interlinkages with immunity and programmed cell death. Overall, anti-tumor drugs were overtly associated with TAGLN2 dysregulation among diverse cancers. At last, UCEC cell lines with TAGLN2-depleting had an inhibition of the migration and invasion ability. Conclusions: These findings enriched the knowledge about the role of TAGLN2 in tumorigenesis and progression, revealing TAGLN2 may serve as a potential therapeutic strategy for various malignancies.

A robust lateral shift free (LSF) electrothermal micromirror with flexible multimorph beams.

Electrothermal bimorph-based scanning micromirrors typically employ standard silicon dioxide (SiO2) as the electrothermal isolation material. However, due to the brittle nature of SiO2, such micromirrors may be incapable to survive even slight collisions, which greatly limits their application range. To improve the robustness of electrothermal micromirrors, a polymer material is incorporated and partially replaces SiO2 as the electrothermal isolation and anchor material. In particular, photosensitive polyimide (PSPI) is used, which also simplifies the fabrication process. Here, PSPI-based electrothermal micromirrors have been designed, fabricated, and tested. The PSPI-type micromirrors achieved an optical scan angle of ±19.6° and a vertical displacement of 370 µm at only 4 Vdc. With a mirror aperture size of 1 mm × 1 mm, the PSPI-type micromirrors survived over 200 g accelerations from either vertical or lateral directions in impact experiments. In the drop test, the PSPI-type micromirrors survived falls to a hard floor from heights up to 21 cm. In the standard frequency sweeping vibration test, the PSPI-type micromirrors survived 21 g and 29 g acceleration in the vertical and lateral vibrations, respectively. In all these tests, the PSPI-type micromirrors demonstrated at least 4 times better robustness than SiO2-type micromirrors fabricated in the same batch.

Establishment of risk model for elderly CAP at different age stages: a single-center retrospective observational study.

Community-acquired pneumonia (CAP) is one of the main reasons of mortality and morbidity in elderly population, causing substantial clinical and economic impacts. However, clinically available score systems have been shown to demonstrate poor prediction of mortality for patients aged over 65. Especially, no existing clinical model can predict morbidity and mortality for CAP patients among different age stages. Here, we aimed to understand the impact of age variable on the establishment of assessment model and explored prognostic factors and new biomarkers in predicting mortality. We retrospectively analyzed elderly patients with CAP in Minhang Hospital, Fudan University. We used univariate and multiple logistic regression analyses to study the prognostic factors of mortality in each age-based subgroup. The prediction accuracy of the prognostic factors was determined by the Receiver Operating Characteristic curves and the area under the curves. Combination models were established using several logistic regressions to save the predicted probabilities. Four factors with independently prognostic significance were shared among all the groups, namely Albumin, BUN, NLR and Pulse, using univariate analysis and multiple logistic regression analysis. Then we built a model with these 4 variables (as ABNP model) to predict the in-hospital mortality in all three groups. The AUC value of the ABNP model were 0.888 (95% CI 0.854-0.917, p < 0.000), 0.912 (95% CI 0.880-0.938, p < 0.000) and 0.872 (95% CI 0.833-0.905, p < 0.000) in group 1, 2 and 3, respectively. We established a predictive model for mortality based on an age variable -specific study of elderly patients with CAP, with higher AUC value than PSI, CURB-65 and qSOFA in predicting mortality in different age groups (66-75/ 76-85/ over 85 years).

Exosomal transfer leads to chemoresistance through oxidative phosphorylation-mediated stemness phenotype in colorectal cancer.

Background: Recently years have seen the increasing evidence identifying that OXPHOS is involved in different processes of tumor progression and metastasis and has been proposed to be a potential therapeutical target for cancer treatment. However, the exploration in oxidative phosphorylation-mediated chemoresistance is still scarce. In our study, we identify exosomal transfer leads to chemoresistance by reprogramming metabolic phenotype in recipient cells. Methods: RNA sequencing analysis was used to screen altered targets mediating exosome transfer-induced chemoresistance. Seahorse assay allowed us to measure mitochondrial respiration. Stemness was measured by spheroids formation assay. Serum exosomes were isolated for circ_0001610 quantification. Results: The induced oxidative phosphorylation leads to more stem-like properties, which is dependent on the transfer of exosomal circ_0001610. Exosome transfer results in the removal of miR-30e-5p-mediated suppression of PGC-1a, a master of mitochondrial biogenesis and function. Consequently, increased PGC-1a reshapes cellular metabolism towards oxidative phosphorylation, leading to chemoresistance. Inhibition of OXPHOS or exosomal si-circ_0001610 increases the sensitivity of chemotherapy by decreasing cell stemness in vitro and in vivo. Conclusion: Our data suggests that exosomal circ_0001610-induced OXPHOS plays an important role in chemoresistance and supports a therapeutical potential of circ_0001610 inhibitors in the treatment of oxaliplatin-resistant colorectal cancer by manipulating cell stemness.