Norcantharidin Enhances the Antitumor Effect of 5-Fluorouracil by Inducing Apoptosis of Cervical Cancer Cells: Network Pharmacology, Molecular Docking, and Experimental Validation.

The high recurrence rate of cervical cancer is a leading cause of cancer deaths in women. 5-Fluorouracil (5-FU) is an antitumor drug used to treat many types of cancer, but its diminishing effectiveness and side effects limit its use. Norcantharidin (NCTD), a demethylated derivative of cantharidin, exhibits various biological activities. Here, we investigated whether NCTD could potentiate 5-FU to induce cervical cancer cell death. To assess the cell viability and synergistic effects of the drugs, cell counting kit-8 and colony formation assays were performed using HR-HPV-positive cervical cancer cell lines. Annexin V-FITC/PI staining and TUNEL assays were performed to confirm the induction of apoptosis. The synergistic effect of NCTD on the antitumor activity of 5-FU was analyzed using network pharmacology, molecular docking, and molecular dynamics simulations. Apoptosis-related proteins were examined using immunoblotting. The combination of NCTD and 5-FU was synergistic in cervical cancer cell lines. Network pharmacological analysis identified 10 common targets of NCTD and 5-FU for cervical cancer treatment. Molecular docking showed the strong binding affinity of both compounds with CA12, CASP9, and PTGS1. Molecular dynamics simulations showed that the complex system of both drugs with caspase-9 could be in a stable state. NCTD enhanced 5-FU-mediated cytotoxicity by activating apoptosis-related proteins. NCTD acts synergistically with 5-FU to inhibit cervical cancer cell proliferation. NCTD enhances 5-FU-induced apoptosis in cervical cancer cell lines via the caspase-dependent pathway.

Predictive factors of exclusive breastfeeding attrition at Week 6 post-partum among mothers of preterm infants based on the theory of planned behaviour.

Breastfeeding plays an important role in the growth and development of preterm infants, and exclusive breastfeeding (EBF) in the first 6 weeks post-partum is the key to continuous breastfeeding. This study was designed to explore the influencing factors that contribute to breastfeeding attrition among mothers of preterm infants at Week 6 post-partum based on the theory of planned behaviour (TPB). We herein adopted a prospective observational study design in which 97 mothers who exclusively breastfed at Week 6 post-partum at a tertiary specialised hospital in Shanghai from June 2021 to February 2022 were taken as the EBF group, and 179 mothers without EBF were assigned to the EBF attrition group. Through an extensive literature review and expert consultation, we determined the possible factors influencing EBF attrition, analysed those factors that showed statistical significance in our univariate analysis by applying binary logistic regression, and constructed a nomogram model for predicting EBF attrition. The results revealed that negative breastfeeding sentiment (odds ratio [OR] = 1.006; 95% confidence interval [CI], 1.000-1.011) generated a greater risk of breastfeeding attrition. However, positive breastfeeding sentiment (OR = 0.991; 95% CI, 0.983-0.999), social and professional support (OR = 0.993; 95% CI, 0.987-0.999), breastfeeding control (OR = 0.945; 95% CI, 0.896-0.996), knowledge (OR = 0.893; 95% CI, 0.799-0.998), and intention to EBF at Week 6 post-partum (OR = 0.522; 95% CI, 0.276-0.988) were the protective factors and facilitated the development of our nomogram model. The Hosmer-Lemeshow goodness-of-fit test generated a χ2 value of 11.344 (p = 0.183) and an area under the curve of 0.822 (95% CI, 0.771-0.873). The C-index was 0.800 in the internal bootstrap validation, indicating that the nomogram model possessed favourable predictive accuracy and discrimination.

EGFR mutation mediates resistance to EGFR tyrosine kinase inhibitors in NSCLC: From molecular mechanisms to clinical research.

With the development of precision medicine, molecular targeted therapy has been widely used in the field of cancer, especially in non-small-cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) is a well-recognized and effective target for NSCLC therapies, targeted EGFR therapy with EGFR-tyrosine kinase inhibitors (EGFR-TKIs) has achieved ideal clinical efficacy in recent years. Unfortunately, resistance to EGFR-TKIs inevitably occurs due to various mechanisms after a period of therapy. EGFR mutations, such as T790M and C797S, are the most common mechanism of EGFR-TKI resistance. Here, we discuss the mechanisms of EGFR-TKIs resistance induced by secondary EGFR mutations, highlight the development of targeted drugs to overcome EGFR mutation-mediated resistance, and predict the promising directions for development of novel candidates.

Void-free bonding for a large slab laser crystal.

A void-free bonding technique was demonstrated for a large slab Nd: YAG crystal with a bonding surface dimension of ∼160mm×70mm. By using the novel fluxless oxide layer removal technology, the indium-oxide barrier problem was resolved. With the help of electrochemical-polished indium solder and a plasma-cleaned heat sink, the solderability of the indium was enhanced; in particular, the contact angle of the solder was improved from 51° to 31°. With the largest-bonding-size slab, a single-slab laser created a maximum output power of 7.3 kW under an absorbed pump power of 12.8 kW, corresponding to an optical to optical efficiency of 57% and a slope conversion of 67.8%. By detecting the wavefront of the interferometer before and after bonding, the RMS of wavefront was 0.192λ and 0.434λ (λ=633nm), respectively. To the best of our knowledge, this is the largest void-free bonding size for a laser slab and the highest output power achieved from a single-slab crystal laser oscillator.

Low serum osteocalcin levels are correlated with left ventricular systolic dysfunction and cardiac death in Chinese men.

Osteocalcin is a newly identified type of cytokine secreted by osteoblasts, which has an endocrine function, mediates energy and glycol-lipid metabolism, and is closely related to cardiovascular diseases. In this study, we investigated the value of serum osteocalcin levels in predicting left ventricular systolic dysfunction and cardiac death. A total of 258 patients in the Department of Cardiology were included. Two-dimensional echocardiography was performed in all the subjects. The cardiac death of subjects occurring with a median follow-up of 4.6 years was informed via phone calls or the electronic medical records. The serum osteocalcin levels were measured using electrochemiluminescent immunoassay. We found that the median left ventricular ejection fractions (LVEFs) were 62% in men and 63% in women. In the men with a LVEF > 62%, the serum osteocalcin levels were significantly higher than in those with LVEF ≤ 62% (P = 0.042), whereas this difference was absent in the women. Both the serum osteocalcin (ß = 0.095, P = 0.028) and serum N-terminal pro-brain natriuretic peptide (NT-pro-BNP; ß = -0.003, P < 0.01) levels remained independently significantly correlated with LVEF in the men but not in the women. Receiver operating characteristic (ROC) analyses of the men revealed that the serum osteocalcin (P = 0.007), serum NT-pro-BNP (P = 0.018) and serum osteocalcin + NT-pro-BNP (P < 0.01) levels were all significant in identifying left ventricular systolic dysfunction at baseline, but the pairwise comparisons of the three areas under the curves (AUCs) were all non-significant. The men in the lower osteocalcin level group at baseline suffered a greater risk of future cardiac death than those in the higher osteocalcin level group, whereas the result for NT-pro-BNP exhibited the opposite pattern. In conclusion, lower serum osteocalcin levels in the men could identify left ventricular systolic dysfunction and cardiac death in a manner that was not inferior to high serum NT-pro-BNP levels.

Modulating the Morphology of Gold Graphitic Nanocapsules for Plasmon Resonance-Enhanced Multimodal Imaging.

With their unique optical properties and distinct Raman signatures, graphitic nanomaterials can serve as substrates for surface-enhanced Raman spectroscopy (SERS) or provide signal amplification for bioanalysis and detection. However, a relatively weak Raman signal has limited further biomedical applications. This has been addressed by encapsulating gold nanorods (AuNRs) in a thin graphitic shell to form gold graphitic nanocapsules. This step improves plasmon resonance, which enhances Raman intensity, and has the potential for integrating two-photon luminescence (TPL) imaging capability. However, changing the morphology of gold graphitic nanocapsules such that high quality and stability are achieved remains a challenge. To address this task, we herein report a confinement chemical vapor deposition (CVD) method to prepare the construction of AuNR-encapsulated graphitic nanocapsules with these properties. Specifically, through morphological modulation, we (1) achieved higher plasmon resonance with near-IR incident light, thus achieving greater Raman intensity, and (2) successfully integrated two-photon luminescence dual-modal (Raman/TPL) bioimaging capabilities. Cancer-cell-specific aptamers were further modified on the AuNR@G graphitic surface through simple, but strong, π-π interactions to achieve imaging selectivity through differential cancer cell recognition.

Inverse relationship between serum osteocalcin levels and nonalcoholic fatty liver disease in postmenopausal Chinese women with normal blood glucose levels.

AIM: Osteocalcin is involved in the progression of nonalcoholic fatty liver disease (NAFLD) in animal models and humans. In this study we investigated the relationship between serum osteocalcin levels and NAFLD in postmenopausal Chinese women. METHODS: A total of 733 postmenopausal women (age range: 41-78 years) with normal blood glucose levels were enrolled in this cross-sectional study. Women taking lipid-lowering or anti-hypertensive drugs were excluded. Serum osteocalcin levels were assessed using an electrochemiluminescence immunoassay. The degree of NAFLD progression for each subject was assessed through ultrasonography. The fatty liver index (FLI) of each subject was calculated to quantify the degree of liver steatosis. RESULTS: The median level of serum osteocalcin for all subjects enrolled was 21.99 ng/mL (interquartile range: 17.84-26.55 ng/mL). Subjects with NAFLD had significantly lower serum osteocalcin levels (18.39 ng/mL; range: 16.03-23.64 ng/mL) compared with those without NAFLD (22.31 ng/mL; range: 18.55-27.06 ng/mL; P<0.01). Serum osteocalcin levels decreased with incremental changes in the FLI value divided by the quartile (P-value for trend<0.01). The serum osteocalcin levels showed a negative correlation with the FLI values, even after adjusting for confounding factors (standardized ß=-0.124; P<0.01). Binary logistic regression analysis identified an individual's serum osteocalcin level as an independent risk factor for NAFLD (odds ratio: 0.951; 95% confidence interval: 0.911-0.992; P=0.02). CONCLUSION: Serum osteocalcin levels are inversely correlated with NAFLD in postmenopausal Chinese women with normal blood glucose levels.

8.2 kW high beam quality quasi-continuous-wave face-pumped Nd:YAG slab amplifier.

An 8 kW level quasi-continuous-wave (QCW) face-pumped 1064 nm slab laser with high beam quality was developed by a master oscillator power amplifier (MOPA) system. A single-mode fiber seed laser was amplified by two-stage single-pass Nd:YAG rod preamplifiers and four face-pumped Nd:YAG slab amplifiers. The slab amplifiers were well designed with uniform pumping and uniform cooling for well-distributed thermal and stress. A dynamically feedbacked optical aberration compensation device was employed to correct low-order optical aberration, and the residue high-order optical aberration was corrected by an adaptive optics system. The QCW MOPA delivered up to an average power of 8.2 kW with a pulse duration of 200 µs at a repetition rate of 400 Hz. The beam quality factor was measured to be ß=3.5.

An anoikis-related gene signature predicts prognosis and reveals immune infiltration in hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is a global health burden with poor prognosis. Anoikis, a novel programmed cell death, has a close interaction with metastasis and progression of cancer. In this study, we aimed to construct a novel bioinformatics model for evaluating the prognosis of HCC based on anoikis-related gene signatures as well as exploring the potential mechanisms. Materials and methods: We downloaded the RNA expression profiles and clinical data of liver hepatocellular carcinoma from TCGA database, ICGC database and GEO database. DEG analysis was performed using TCGA and verified in the GEO database. The anoikis-related risk score was developed via univariate Cox regression, LASSO Cox regression and multivariate Cox regression, which was then used to categorize patients into high- and low-risk groups. Then GO and KEGG enrichment analyses were performed to investigate the function between the two groups. CIBERSORT was used for determining the fractions of 22 immune cell types, while the ssGSEA analyses was used to estimate the differential immune cell infiltrations and related pathways. The "pRRophetic" R package was applied to predict the sensitivity of administering chemotherapeutic and targeted drugs. Results: A total of 49 anoikis-related DEGs in HCC were detected and 3 genes (EZH2, KIF18A and NQO1) were selected out to build a prognostic model. Furthermore, GO and KEGG functional enrichment analyses indicated that the difference in overall survival between risk groups was closely related to cell cycle pathway. Notably, further analyses found the frequency of tumor mutations, immune infiltration level and expression of immune checkpoints were significantly different between the two risk groups, and the results of the immunotherapy cohort showed that patients in the high-risk group have a better immune response. Additionally, the high-risk group was found to have higher sensitivity to 5-fluorouracil, doxorubicin and gemcitabine. Conclusion: The novel signature of 3 anoikis-related genes (EZH2, KIF18A and NQO1) can predict the prognosis of patients with HCC, and provide a revealing insight into personalized treatments in HCC.

High-power narrow-linewidth quasi-CW diode-pumped TEM00 1064 nm Nd:YAG ring laser.

We demonstrated a high average power, narrow-linewidth, quasi-CW diode-pumped Nd:YAG 1064 nm laser with near-diffraction-limited beam quality. A symmetrical three-mirror ring cavity with unidirectional operation elements and an etalon was employed to realize the narrow-linewidth laser output. Two highly efficient laser modules and a 90° quartz rotator for birefringence compensation were used for the high output power. The maximum average output power of 62.5 W with the beam quality factor M(2) of 1.15 was achieved under a pump power of 216 W at a repetition rate of 500 Hz, corresponding to the optical-to-optical conversion efficiency of 28.9%. The linewidth of the laser at the maximum output power was measured to be less than 0.2 GHz.

Single-cell sequencing reveals the landscape of the tumor microenvironment in a skeletal undifferentiated pleomorphic sarcoma patient.

Skeletal undifferentiated pleomorphic sarcoma (SUPS) is an invasive pleomorphic soft tissue sarcoma with a high degree of malignancy and poor prognosis. It is prone to recur and metastasize. The tumor microenvironment (TME) and the pathophysiology of SUPS are barely described. Single-cell RNA sequencing (scRNA-seq) provides an opportunity to dissect the landscape of human diseases at an unprecedented resolution, particularly in diseases lacking animal models, such as SUPS. We performed scRNA-seq to analyze tumor tissues and paracancer tissues from a SUPS patient. We identified the cell types and the corresponding marker genes in this SUPS case. We further showed that CD8+ exhausted T cells and Tregs highly expressed PDCD1, CTLA4 and TIGIT. Thus, PDCD1, CTLA4 and TIGIT were identified as potential targets in this case. We applied copy number karyotyping of aneuploid tumors (CopyKAT) to distinguish malignant cells from normal cells in fibroblasts. Our study identified eight malignant fibroblast subsets in SUPS with distinct gene expression profiles. C1-malignant Fibroblast and C6-malignant Fibroblast in the TME play crucial roles in tumor growth, angiogenesis, metastasis and immune response. Hence, targeting malignant fibroblasts could represent a potential strategy for this SUPS therapy. Intervention via tirelizumab enabled disease control, and immune checkpoint inhibitors (ICIs) of PD-1 may be considered as the first-line option in patients with SUPS. Taken together, scRNA-seq analyses provided a powerful basis for this SUPS treatment, improved our understanding of complex human diseases, and may afforded an alternative approach for personalized medicine in the future.

Compact high-efficiency 100-W-level diode-side-pumped Nd:YAG laser with linearly polarized TEM00 mode output.

We present a compact high-efficiency and high-average-power diode-side-pumped Nd:YAG rod laser oscillator operated with a linearly polarized fundamental mode. The oscillator resonator is based on an L-shaped convex-convex cavity with an improved module and a dual-rod configuration for birefringence compensation. Under a pump power of 344 W, a linearly polarized average output power of 101.4 W at 1064 nm is obtained, which corresponds to an optical-to-optical conversion efficiency of 29.4%. The laser is operated at a repetition rate of 400 Hz with a beam quality factor of M(2)=1.14. To the best of our knowledge, this is the highest optical-to-optical efficiency for a side-pumped TEM(00) Nd:YAG rod laser oscillator with a 100-W-level output ever reported.

MicroRNA and long noncoding RNA involvement in gout and prospects for treatment.

MicroRNAs (miRNAs) and long noncoding RNAs (lncRNAs) are both types of noncoding RNA. They have been demonstrated to be involved in the regulation of various human inflammatory diseases and can be used as biomarkers for disease diagnosis and prognosis, and even be developed into new drugs. Gout is an arthritic disease caused by the deposition of monosodium urate crystal (MSU) in the joints, which can lead to acute inflammation and damage adjacent tissue. Recent studies have shown that miRNAs and lncRNAs mediate the progress of gout. Based on the pathogenesis of gout, including hyperuricemia, MSU deposition, acute gouty arthritis and gouty bone erosion, this paper reviewed the role of miRNAs and lncRNAs in the processes and the possible therapeutic targets of miRNAs and lncRNAs in gout.

Interleukin-17A and -17F single nucleotide polymorphisms associate with susceptibility of asthma in Chinese Han population.

Interleukin 17 (IL-17) plays important roles in the progression of asthma. Genetic variants in the Il-17 may influence the immunopathogenesis of many diseases. Many studies have investigated the relevance of IL-17 polymorphism with cancers or immune diseases, including asthma. In this study, single nucleotide polymorphisms (SNPs) of IL-17 were explored by PCR-RFLP and verified by sequencing method. The frequencies of genotypes and alleles were analyzed. Haplotypes were analyzed with the SHEsis online program. The relationship between the genotypes of SNPs and IgE level was also investigated. The False Discovery Rate (FDR) correction was performed (P-adjusted < 0.05). The frequencies of A allele, GA and (GA + AA) genotype of rs3748067 were significantly higher in asthma patients. As for rs763780, the C allele in patients was more frequent than healthy controls. In addition, we found C carriers (CT + CC) were significantly higher in asthma patients. We further found that the haplotype CT for IL-17F (rs763780/rs2397084) was associated with an increased susceptibility of asthma, but this association did not survive after FDR correction. The level of serum total IgE in mutant group (GA + AA) of rs3748067 was significantly higher than the wild genotype (GG) group and control group. These results suggested that IL-17 SNPs, but not haplotypes may be associated with the susceptibility of asthma in Chinese Han population from central China.

Magnetic-graphitic-nanocapsule templated diacetylene assembly and photopolymerization for sensing and multicoded anti-counterfeiting.

Molecular self-assembly, a process to design molecular entities to aggregate into desired structures, represents a promising bottom-up route towards precise construction of functional systems. Here we report a multifunctional, self-assembled system based on magnetic-graphitic-nanocapsule (MGN) templated diacetylene assembly and photopolymerization. The as-prepared assembly system maintains the unique color and fluorescence change properties of the polydiacetylene (PDA) polymers, while also pursues the superior Raman, NIR, magnetic and superconducting properties from the MGN template. Based on both fluorescence and magnetic resonance imaging (MRI) T2 relaxivity, the MGN@PDA system could efficiently monitor the pH variations which could be used as a pH sensor. The MGN@PDA system further demonstrates potential as unique ink for anti-counterfeiting applications. Reversible color change, strong and unique Raman scattering and fluorescence emission, sensitive NIR thermal response, and distinctive magnetic properties afford this assembly system with multicoded anti-counterfeiting capabilities.

Understanding the different types of social support offered by audience to A-list diary-like and informative bloggers.

Blogs offer audiences a forum through which they can exchange ideas and provide feedback about the everyday lives and experiences of the bloggers. Such interactions and communication between audiences and bloggers could be regarded as a kind of social support. The present study aims to identify and compare the types of social support offered by audiences to continuous popular diary-like and informative bloggers, and to explore the possible benefits that bloggers may obtain from such social support. Content analysis was used to analyze the 485 and 390 comments provided by the audiences to the A-list diary-like and informative blog posts, respectively. Results reveal that validation, compliment, and encouragement are the most common types of social support given by audiences to A-list bloggers. Chi-square test results show that the audiences offer more encouragement-type of social support to diary-like bloggers and more complimentary and informational social support to informative bloggers. Such types of social support may enhance A-list bloggers' self-esteem, boost their confidence, promote their self-understanding, and help them obtain the benefits of social validation, which in turn encourage bloggers to commit continuous self-disclosure.

Age-related maculopathy susceptibility 2 participates in the phagocytosis functions of the retinal pigment epithelium.

AIM: Age-related macular degeneration (AMD) is a multifactorial disease and a prevalent cause of visual impairment in developed countries. Many studies suggest that age-related maculopathy susceptibility 2 (ARMS2) is a second major susceptibility gene for AMD. At present, there is no functional information on this gene. Therefore, the purpose of the present study was to detect the expression of ARMS2 in retinal pigment epithelium (RPE) cells and to investigate the effect of ARMS2 on the phagocytosis function of RPE cells. METHODS: Immunofluorescence and reverse transcriptase PCR were used to demonstrate the presence and location of ARMS2 in ARPE-19 (human retinal pigment epithelial cell line, ATCC, catalog No.CRL-2302) cells. siRNA was used to knock down ARMS2 mRNA, and the effects of the knockdown on the phagocytosis function of the ARPE-19 cells were evaluated via Fluorescence Activated Cell Sorting (FACS). RESULTS: ARMS2 was present in ARPE-19 cells, localized in the cytosol of the perinuclear region. The expression of ARMS2 mRNA (messenger RNA) in ARPE-19 cells transfected with ARMS2-siRNA (small interfering RNA, 0.73±0.08) was decreased compared with normal cells (1.00±0.00) or with cells transfected with scrambled siRNA (0.95±0.13) (P<0.05). After incubation of RPE cells with a latex beads medium for 12, 18, or 24 hours, the fluorescence intensities were 38.04±1.02, 68.92±0.92, and 78.00±0.12 in the ARMS2-siRNA-transfected groups, respectively, and 77.98±5.43, 94.87±0.60, and 98.30±0.11 in the scrambled siRNA-transfected groups, respectively. The fluorescent intensities of the same time points in the two groups were compared using Student's t-test, and the p values were all less than 0.001 at the three different time points. CONCLUSION: There is endogenous expression of ARMS2 in ARPE-19 cells. ARMS2 plays a role in the phagocytosis function of RPE cells, and this role may be one of the mechanisms that participates in the development of AMD.