A Single-Cell Metabolic Profiling Characterizes Human Aging via SlipChip-SERS.

Metabolic dysregulation is a key driver of cellular senescence, contributing to the progression of systemic aging. The heterogeneity of senescent cells and their metabolic shifts are complex and unexplored. A microfluidic SlipChip integrated with surface-enhanced Raman spectroscopy (SERS), termed SlipChip-SERS, is developed for single-cell metabolism analysis. This SlipChip-SERS enables compartmentalization of single cells, parallel delivery of saponin and nanoparticles to release intracellular metabolites and to realize SERS detection with simple slipping operations. Analysis of different cancer cell lines using SlipChip-SERS demonstrated its capability for sensitive and multiplexed metabolic profiling of individual cells. When applied to human primary fibroblasts of different ages, it identified 12 differential metabolites, with spermine validated as a potent inducer of cellular senescence. Prolonged exposure to spermine can induce a classic senescence phenotype, such as increased senescence-associated ß-glactosidase activity, elevated expression of senescence-related genes and reduced LMNB1 levels. Additionally, the senescence-inducing capacity of spermine in HUVECs and WRL-68 cells is confirmed, and exogenous spermine treatment increased the accumulation and release of H2O2. Overall, a novel SlipChip-SERS system is developed for single-cell metabolic analysis, revealing spermine as a potential inducer of senescence across multiple cell types, which may offer new strategies for addressing ageing and ageing-related diseases.

Identification and validation of ferroptosis-related prognostic gene signature in patients with cervical cancer.

Background: Ferroptosis is an iron-dependent cell death, which is distinct from the other types of regulated cell death. Considerable studies have demonstrated that ferroptosis is involved in the biological process of various cancers. However, the role of ferroptosis in cervical cancer (CC) remains unclear. This study aims to explore the ferroptosis-related prognostic genes (FRPGs) expression profiles and their prognostic values in CC. Methods: The ferroptosis-related genes (FRGs) were obtained from The Cancer Genome Atlas (TCGA) and FerrDb databases. Core FRGs were determined by the Search Tool for the Retrieval of Interacting Genes (STRING) website. FRPGs were identified using univariate and multivariate Cox regressions, and the ferroptosis-related prognostic model was constructed. FRPGs were verified in clinical specimens. The relationship between FRPGs and tumor infiltrating immune cells were assessed through the CIBERSORT algorithm and the LM22 signature matrix. Bioinformatics functions of FRPGs were explored with the Database for Annotation, Visualization, and Integrated Discovery (DAVID). Results: Thirty-three significantly up-regulated and 28 down-regulated FRGs were screened from databases [P<0.05; false discovery rate (FDR) <0.05; and |log2 fold change (FC)| ≥2]. Twenty-four genes were found closely interacting with each other and regarded as hub genes (degree ≥3). Solute carrier family 2 member 1 (SLC2A1), carbonic anhydrases IX (CA9), and dual oxidase 1 (DUOX1) were identified as independent prognostic signatures for overall survival (OS) in a Cox regression. Time-dependent receiver operating characteristic (ROC) curves showed the predictive ability of the ferroptosis-related prognostic model, especially for 1-year OS [area under the curve (AUC) =0.76]. Consistent with the public data, our experiments demonstrated that the mRNA levels of SLC2A1 and DUOX1, and the protein levels of SLC2A1, DUOX1, and CA9 were significantly higher in the tumor tissues. Further analysis showed that there was a significant difference in the proportion of tumor infiltrating immune cells between the low- and high-risk group based on our prognostic model. The function enrichment of FRPGs was explored by applying Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Conclusions: In this study, the features of FRPGs in CC were pictured. The results implicated that targeting ferroptosis may be a new reliable biomarker and an alternative therapy for CC.

The Protective Effect and Mechanism of Mild Hypothermia on Lung Injury after Cardiopulmonary Resuscitation in Pigs.

To explore the protective effect and mechanism of mild hypothermia on lung tissue damage after cardiopulmonary resuscitation in pigs. In this experiment, we electrically stimulated 16 pigs (30 ± 2 kg) for 10 min to cause ventricular fibrillation. The successfully resuscitated animals were randomly divided into two groups, a mild hypothermia group and a control group. We took arterial blood 0.5, 1, 3, and 6 h after ROSC recovery in the two groups of animals for blood gas analysis. We observed the structural changes of lung tissue under an electron microscope and calculate the wet weight/dry weight (W/D) ratio. We quantitatively analyzed the expression differences of representative inflammatory factors [interleukin-6 (IL-6) and tumor necrosis factor-alpha TNF-α)] through the ELISA test. We detected the expression levels of Bax, Bcl-2, and Caspase-3 proteins in lung tissues by Western blot. After 3 h and 6 h of spontaneous circulation was restored, compared with the control group, PaO2/FiO2 decreased significantly (P < 0.05). In addition, the pathological changes, lung W/D and lung MDA of the mild hypothermia group were better than those of the control group. The levels of IL-6 and TNF-α in the lung tissue of the mild hypothermia group were significantly lower than those of the control group (P < 0.05). The content of Caspase-3 and Bax in the mild hypothermia group was significantly lower than that of the control group. Our experiments have shown that mild hypothermia can reduce lung tissue damage after cardiopulmonary resuscitation.

Protein Kinase N1 Level Predicts Acute Kidney Injury in Patients Undergoing Cardiac Surgery: A Prospective Cohort Study.

INTRODUCTION: The objective of this study was to examine the utility of protein kinase N1 (PKN1) as a biomarker of cardiac surgery-associated AKI (CSA-AKI). METHODS: A prospective cohort study of 110 adults undergoing on-pump cardiac surgery was conducted. The associations between post-operative PKN1 and CSA-AKI, AKI severity, need for renal replacement therapy (RRT), duration of AKI, length of ICU stay, and post-operative hospital stay were evaluated. RESULTS: Patients were categorized into three groups according to PKN1 tertiles. The incidence of CSA-AKI in the third tertile was 3.4-fold higher than that in the first. PKN1 was an independent risk factor for CSA-AKI. The discrimination of PKN1 to CSA-AKI assessed by ROC curve indicated that the AUC was 0.70, and the best cutoff was 5.025 ng/mL. This group (>5.025 ng/mL) was more likely to develop CSA-AKI (p < 0.001). The combined AUC of EuroSCORE, aortic cross-clamp time, and PKN1 was 0.82 (p < 0.001). A higher level of PKN1 was related to increased need for RRT, longer duration of AKI, and length of ICU and post-operative hospital stays. CONCLUSIONS: PKN1 could be a potential biomarker for the prediction of CSA-AKI. The combination of PKN1, EuroSCORE, and aortic cross-clamp time was likely to predict the occurrence of CSA-AKI.

Enrichment of microbial consortia for MEOR in crude oil phase of reservoir-produced liquid and their response to environmental disturbance.

Developing microbial consortiums is necessary for microbial enhanced oil recovery (MEOR) in heavy crude oil production. The aqueous phase of produced fluid has long been considered an ideal source of microorganisms for MEOR. However, it is recently found that rich microorganisms (including hydrocarbon-degrading bacteria) are present in the crude oil phase, which is completely different from the aqueous phase of produced fluid. So, in this study, the microbial consortia from the crude oil phase of produced fluids derived from four wells were enriched, respectively. The microbial community structure during passage was dynamically tracked, and the response of enriched consortia to successive disturbance of environmental factors was investigated. The results showed the crude oil phase had high microbial diversity, and the original microbial community structure from four wells was significantly different. After ten generations of consecutive enrichment, different genera were observed in the four enriched microbial consortia, namely, Geobacillus, Bacillus, Brevibacillus, Chelativorans, Ureibacillus, and Ornithinicoccus. In addition, two enriched consortia (eG1614 and eP30) exhibited robustness to temperature and oxygen perturbations. These results further suggested that the crude oil phase of produced fluids can serve as a potential microbial source for MEOR.

Targeted delivery of pexidartinib to tumor-associated macrophages via legumain-sensitive dual-coating nanoparticles for cancer immunotherapy.

Tumor-associated macrophage (TAM) is regarded as an appealing cell target for cancer immunotherapy. However, it remains challenging to selectively eliminate M2-like TAM in tumor microenvironment. In this work, we employed a legumain-sensitive dual-coating nanosystem (s-Tpep-NPs) to deliver CSF-1R inhibitor pexidartinib (PLX3397) for targeting TAM therapy. The PLX3397-loaded NPs exhibited uniform size of ∼240 nm in diameter, good drug loading capacity and efficiency, as well as sustained drug release profile. Compared to non-sensitive counterpart ns-Tpep-NPs, s-Tpep-NPs showed distinguished selectivity upon M1 and M2 macrophage uptake with relation to incubation time and dose. Besides, the selectivity of anti-proliferation effect was also identified for s-Tpep-NPs against M1 and M2 macrophage. In vivo imaging demonstrated that s-Tpep-NPs exhibited much higher tumoral accumulation and TAM recognition specificity as compared to non-sensitive ns-Tpep-NPs. In vivo efficacy verified that s-Tpep-NPs formulation was much more effective than ns-Tpep-NPs and other PLX3397 formulations to treat B16F10 melanoma via targeting TAM depletion and modulating tumor immune microenvironment. Overall, this study provides a robust and promising nanomedicine strategy for TAM-targeted cancer immunotherapy.

Effects of acupuncture on obstructive sleep apnea-hypopnea syndrome: A meta-analysis.

Our study aimed to systematically evaluate the effect of acupuncture in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS). Literature search of four Chinese databases and six English databases for studies published from the inception of each database to March 1, 2022 and identify relevant studies published in Chinese or English. Related randomized controlled trials of acupuncture for the treatment of OSAHS were included to analyze the efficacy of acupuncture. Two researchers independently reviewed all of the retrieved studies to screen for eligible studies and extract the required relevant data. Included studies were subjected to a methodological quality assessment using the Cochrane Manual 5.1.0, and to a meta-analysis using Cochrane Review Manager version 5.4. A total of 19 studies with 1365 participants were examined. Compared with the control group, the apnea-hypopnea index, lowest oxygen saturation, Epworth Sleepiness Scale, interleukin-6, tumor necrosis factor α, and nuclear factor κ-B indicators all exhibited statistically significant changes. Thus, acupuncture was effective in alleviating the state of hypoxia and sleepiness and reduced the inflammatory response and disease severity among reported patients with OSAHS. Therefore, acupuncture could be widely used in the clinical treatment of OSAHS patients as a complementary strategy and warrants further study.

Hyperoside protects against cyclophosphamide induced ovarian damage and reduced fertility by suppressing HIF-1α/BNIP3-mediated autophagy.

Ovarian damage and infertility are the main side effects of chemotherapy for women of childbearing age with cancer. The main objective of this study was to investigate the protective effects and mechanisms of hyperoside against cyclophosphamide (Cy) -induced ovarian damage and reduced fertility. This study consists of two parts: in vivo experiments using Cy intraperitoneal injections to simulate clinical chemotherapy sessions and in vitro experiments using 4-HC, a precursor of an activated form of Cy, to intervene in human granulosa-like cell line (KGN). We found that Cy disrupted the estrous cycle in mice, resulting in decreased serum Anti-Mullerian hormone (AMH) levels, loss of primordial follicles, primary follicle and secondary follicle, increased atretic follicles, and diminished ovarian reserve function. Cy prolonged the time between mating and pregnancy in mice and increased the number of absorbed embryos. Western Blot analysis demonstrate that Cy activated key proteins of HIF-1α/BNIP3-associated autophagy both in vivo and in vitro, while in vivo experiments we also found that 4-HC increased KGN cell apoptosis, damaged mitochondrial membrane potential, and activated autophagic flow. Co-treatment with hyperoside diminished follicular depletion of the primordial follicles, decreased follicular atresia, prevented Cy-induced excessive hypoxia and autophagy activation, increased mitochondrial membrane potential, thereby increasing follicular reserve and rescuing fertility in Cy-treated mice. It suggests that HIF-1α/BNIP3-mediated autophagy is an essential mechanism by which Cy impairs ovarian function and fertility in mice, by blocking this activation, hyperoside shows potential as an ovarian protectant that may be capable of preserving fertility in women undergoing chemotherapy.

Anti-tumor effect of Yanggan Huayu granule by inducing AKT-mediated apoptosis in hepatocellular carcinoma.

ETHNOPHARMACOLOGICAL RELEVANCE: Yanggan Huayu granule (YGHY) is a formula of traditional Chinese medicine that has been widely used to treat patients with liver cancer. But its working mechanism is still poorly understood. AIM OF THE STUDY: To investigate the anti-tumor effect of YGHY and its working mechanisms in hepatocellular carcinoma (HCC). MATERIALS AND METHODS: H22 mouse xenograft model was used to detect the effect of YGHY on hepatocellular carcinoma (HCC). MTT and CCK8 assays were performed to assess the effect of YGHY on HCC cell growth. Transwell assay was performed to detect the invasion and migration activities of HCC cells. Effect of YGHY drug-contained serum on apoptosis was detected by flow cytometry. Western blot was performed to detect the protein expressions. RESULTS: Results showed that YGHY inhibited tumor volume and weight, induced the apoptosis of HepG2 and SMMC-7721 cells and increased the protein expressions of Cleaved-Caspase3 and Cleaved-PARP. Furthermore, YGHY significantly down-regulated the protein expression of p-AKT. SC79, as an activator of AKT signaling, was able to increase the expression of p-AKT, and regulate the protein expressions of Cleaved-Caspase3, Cleaved-PARP, BCL-2 and BAX. YGHY drug-contained serum negated the protein expression change provided by SC79. CONCLUSIONS: Taken together, this data indicates that YGHY could inhibit HCC growth by inducing apoptosis, operating through AKT signaling.

Legumain protease-sheddable PEGylated, tuftsin-modified nanoparticles for selective targeting to tumour-associated macrophages.

Tumour-associated macrophages (TAMs) represent an attractive cell target for anticancer therapy. However, selective and efficient targeting of TAMs remains difficult. Here, we constructed a novel dually functionalised nanoparticle platform (s-Tpep-NPs) by surface co-modification of nanoparticles (NPs) with tuftsin (Tpep) and legumain protease-sheddable polyethylene glycol 5k (PEG5k) to achieve selective targeted delivery to TAMs. The fluorescence resonance energy transfer experiment and in vitro cellular uptake assay confirmed that s-Tpep-NPs can responsively shed PEG5k and transform into active Tpep-NPs upon the cleavage of legumain that is overexpressed on TAM surfaces, which then promotes TAM phagocytosis through Fc receptor-mediated pathways. Owing to the shielding effect by legumain-sheddable PEG5k, s-Tpep-NPs can effectively decrease the Tpep-induced non-specific accumulation in mononuclear phagocyte system (MPS) organs during systemic circulation. Moreover, s-Tpep-NPs can significantly enhance the tumoural accumulation and improve the specificity and efficiency of targeting to TAMs, as compared with both controls of Tpep-NPs and non-sheddable ns-Tpep-NPs. Overall, this study provides a robust nanoplatform with a novel avenue for improved selectivity of targeted delivery to TAMs.

Network-based cancer genomic data integration for pattern discovery.

BACKGROUND: Since genes involved in the same biological modules usually present correlated expression profiles, lots of computational methods have been proposed to identify gene functional modules based on the expression profiles data. Recently, Sparse Singular Value Decomposition (SSVD) method has been proposed to bicluster gene expression data to identify gene modules. However, this model can only handle the gene expression data where no gene interaction information is integrated. Ignoring the prior gene interaction information may produce the identified gene modules hard to be biologically interpreted. RESULTS: In this paper, we develop a Sparse Network-regularized SVD (SNSVD) method that integrates a prior gene interaction network from a protein protein interaction network and gene expression data to identify underlying gene functional modules. The results on a set of simulated data show that SNSVD is more effective than the traditional SVD-based methods. The further experiment results on real cancer genomic data show that most co-expressed modules are not only significantly enriched on GO/KEGG pathways, but also correspond to dense sub-networks in the prior gene interaction network. Besides, we also use our method to identify ten differentially co-expressed miRNA-gene modules by integrating matched miRNA and mRNA expression data of breast cancer from The Cancer Genome Atlas (TCGA). Several important breast cancer related miRNA-gene modules are discovered. CONCLUSIONS: All the results demonstrate that SNSVD can overcome the drawbacks of SSVD and capture more biologically relevant functional modules by incorporating a prior gene interaction network. These identified functional modules may provide a new perspective to understand the diagnostics, occurrence and progression of cancer.

Circulating tumor cells: biology and clinical significance.

Circulating tumor cells (CTCs) are tumor cells that have sloughed off the primary tumor and extravasate into and circulate in the blood. Understanding of the metastatic cascade of CTCs has tremendous potential for the identification of targets against cancer metastasis. Detecting these very rare CTCs among the massive blood cells is challenging. However, emerging technologies for CTCs detection have profoundly contributed to deepening investigation into the biology of CTCs and have facilitated their clinical application. Current technologies for the detection of CTCs are summarized herein, together with their advantages and disadvantages. The detection of CTCs is usually dependent on molecular markers, with the epithelial cell adhesion molecule being the most widely used, although molecular markers vary between different types of cancer. Properties associated with epithelial-to-mesenchymal transition and stemness have been identified in CTCs, indicating their increased metastatic capacity. Only a small proportion of CTCs can survive and eventually initiate metastases, suggesting that an interaction and modulation between CTCs and the hostile blood microenvironment is essential for CTC metastasis. Single-cell sequencing of CTCs has been extensively investigated, and has enabled researchers to reveal the genome and transcriptome of CTCs. Herein, we also review the clinical applications of CTCs, especially for monitoring response to cancer treatment and in evaluating prognosis. Hence, CTCs have and will continue to contribute to providing significant insights into metastatic processes and will open new avenues for useful clinical applications.

In vitro Generation of Megakaryocytes and Platelets.

Platelets, the tiny anucleate cells responsible for stopping bleeding through thrombosis, are derived from hematopoietic stem cells through a series of differentiation steps. Thrombocytopenia, characterized by abnormally low blood platelet counts, may arise from cancer therapies, trauma, sepsis, as well as blood disorders, and could become a life-threatening problem. Platelet transfusion is the most effective strategy to treat thrombocytopenia, however, the source of platelets is in great shortage. Therefore, in vitro generation of platelets has become an important topic and numerous attempts have been made toward generating platelets from different types of cells, including hematopoietic stem cells, pluripotent stem cells, fibroblast cells, and adipose-derived cells. In this review, we will detail the efforts made to produce, in the in vitro culture, platelets from these different cell types. Importantly, as transfusion medicine requires a huge number of platelets, we will highlight some studies on producing platelets on a large scale. Although new methods of gene manipulation, new culture conditions, new cytokines and chemical compounds have been introduced in platelet generation research since the first study of hematopoietic stem cell-derived platelets nearly 30 years ago, limited success has been achieved in obtaining truly mature and functional platelets in vitro, indicating the studies of platelets fall behind those of other blood cell types. This is possibly because megakaryocytes, which produce platelets, are very rare in blood and marrow. We have previously developed a platform to identify new extrinsic and intronic regulators for megakaryocytic lineage development, and in this review, we will also cover our effort on that. In summary, stem cell-based differentiation is a promising way of generating large-scale platelets to meet clinical needs, and continuous study of the cellular development of platelets will greatly facilitate this.

A Systematic Review of Anogenital Distance and Gynecological Disorders: Endometriosis and Polycystic Ovary Syndrome.

Background and Aim: Anogenital distance (AGD) can serve as a life-long indicator of androgen action in gestational weeks 8-14. AGD has been used as an important tool to investigate the exposure to endocrine-disrupting compounds in newborns and in individuals with male reproductive disorder. Endometriosis and polycystic ovary syndrome (PCOS) are two common gynecological disorders and both are related to prenatal androgen levels. Therefore, we performed a systematic review to evaluate the relationships of AGD with these gynecological disorders. Methods: PubMed, Web of Science, and Embase were searched for published studies up to January 25, 2021. No language restriction was implemented. Results: Ten studies were included in this review. Five focused on women with endometriosis, and six investigated women with PCOS. According to these studies, PCOS patients had longer AGD than controls, while endometriosis patients had shorter AGD than controls. In conclusion, this study provides a detailed and accurate review of the associations of AGD with endometriosis and PCOS. Conclusion: The current findings indicate the longer AGD was related to PCOS and shorter AGD was related to endometriosis. However, further well-designed studies are needed to corroborate the current findings.

Dietary Fiber and Human Papillomavirus Infection among US Women: The National Health and Nutrition Examination Survey, 2003-2016.

The impact of dietary fiber on human papillomavirus (HPV) infection is still underway. The aim of our study was to investigate the association between intake of dietary fiber and HPV infection. Overall, 14,151 eligible women, aged 18-59 years old, who submitted an adequate sample for HPV test, were collected from an ongoing, large scale population-based survey for seven cycles. The association of dietary fiber intake and HPV infection was assessed in multivariate logistic models. For sensitivity analysis, generalized additive model (GAM) and smooth curve fitting were employed to verify the robustness of the results. Among 14,151 eligible participants, intake of dietary fiber was negatively associated with HPV infection. Each additional increase in log10 dietary fiber consumption was associated with a 57% lower risk of HPV infection (OR, 0.43; 95% CI 0.38-0.48). The result is stable in minimally and fully adjusted model. The possibility of nonlinear association of dietary fiber and HPV infection has been excluded by GAM and smooth curve fitting. There was an inverse linear correlation between intake of dietary fiber and HPV infection. Our findings obtained from NHANES dataset suggested that increasing dietary fiber consumption may be associated with the prevalence of HPV infection.

Matrix Metalloproteinase-3 induces proteoglycan degradation in gouty arthritis model.

BACKGROUND: Gout is an inflammatory arthritis resulting from precipitation of monosodium urate (MSU) crystals in joints and surrounding tissues. However, the mechanism underlying high levels of uric acid inducing gouty arthritis has not been clarified. OBJECTIVE: The purpose was to investigate the role of Matrix Metalloproteinase-3 (MMP-3) in the development of gouty arthritis from hyperuricemia. METHOD: MSU crystal-induced gouty arthritis model and chondrocytes were used to evaluate changes of MMP-3 levels. Western blot, qPCR and ELISA were performed to detect MMP-3, Tissue Inhibitors of Metalloproteinase-1 (TIMP-1) and A Disintegrin and Metalloproteinase with Thrombospondin Motifs-4 (ADAMTS-4) expressions in rabbit chondrocytes. Expression of proteoglycan was determined through toluidine blue staining. Concentrations of glycosaminoglycan, Interleukin-6 (IL-6), Interleukin-1ß (IL-1ß) and Tumor Necrosis Factor-α (TNF-α) in chondrocytes were assessed via ELISA kits. Concentration of uric acid in supernate was tested by Automatic Analyzer. RESULTS: MMP-3 was significantly increased in rat serum, synovial fluid, cartilages and chondrocytes treated with high-level uric acid. Increased concentration of glycosaminoglycancould be observed in chondrocytes incubated with MMP-3, as well as the remarkable downregulation of proteoglycan expression. Furthermore, high-level uric acid contributed to the degradation of proteoglycan via the activation of MMP-3. IL-6, IL-1ß and TNF-α concentrations were increased significantly in 35 °C compared to 37 °C with MMP-3 and high-level uric acid. CONCLUSION: Our study showed that MMP-3 was enhanced by high levels of uric acid, which promoted proteoglycan degradation, and induced MSU crystallization in turn. A low temperature environment is an important factor in the development of gout.

Legumain protease-activated tuftsin-functionalized nanoparticles for dual-targeting TAMs and cancer chemotherapy.

M2 tumor-associated macrophages (TAMs) play a pivotal role in cancer progression and therapy resistance. Inhibition of TAMs is of great significance to reshape the protumor environment to benefit therapeutic outcomes. In this work, we developed a novel TAMs and tumor cells dual-targeting nanoparticle (ATpep-NPs) system for cancer chemotherapy by integrating a docetaxel (DTX)-loaded nanocarrier and a multi-function peptide ATpep, which is composed of a phagocytosis-stimulating peptide-tuftsin (Tpep) fused with a substrate peptide-alanine-alanine-asparagine (AAN) of endoprotease legumain. In vitro protelytic and cellular uptake assays confirmed ATpep-NPs can be responsively activated into Tpep-NPs by cleavage of legumain that is overexpressed in both tumor cells and TAMs, which then promoted tumor cells internalization and TAMs phagocytosis through neuropilin-1/Fc receptor pathways. Due to AAN deactivation effect, ATpep-NPs can effectively decrease the Tpep-induced non-specific uptake by M1-polarized and normal macrophage during systemic circulation. Our results of in vivo experiments demonstrated ATpep-NPs outperformed Tpep-NPs in tumor and TAMs dual-targeting delivery efficiency with markedly enhanced efficacy against both tumor growth inhibition and TAMs depletion. Overall, this study offers a novel approach for development of multitargeted delivery vehicle for improved cancer chemotherapy.

Association of Thiamine Intake with Human Papillomavirus (HPV) Infection in American Women: A Secondary Data Analysis Based on the National Health and Nutrition Examination Survey from 2003 to 2016.

BACKGROUND Studies have shown that thiamine intake is associated with cervical cancer, but the relationship between thiamine and HPV infection remains unclear. In the present study, we used the National Health and Nutrition Examination Survey (NHANES) database to investigate whether HPV infection was associated with thiamine intake. MATERIAL AND METHODS A total of 13 471 women ages 18-59 years were selected from the NHANES database from 2003 to 2016. Using thiamine intake as the independent variable, HPV infection as the dependent variable, and sociodemographic data and other data as the covariates, we analyzed the relationship between thiamine and HPV infection by conducting a weighted logistic regression model in a cross-sectional research design. RESULTS The two-piecewise linear model indicated the inflection point of thiamine intake was 2.07 mg. On the left side of the inflection point, the difference in the thiamine intake of log2 conversion was related to the difference of 0.82 in HPV infection, which means that the increase of every 1 unit increase in thiamine intake is associated with the decrease of the HPV infection by 18%. On the right side of the inflection point, we did not observe a correlation between HPV infection and thiamine intake. CONCLUSIONS Thiamine intake is negatively correlated with HPV infection. Intake of an appropriate amount of thiamine can prevent HPV infection. The best preventive effect can be achieved when the intake is about 2 mg, and excessive intake will not increase the preventive effect.

Caprin-1 promotes HepG2 cell proliferation, invasion and migration and is associated with poor prognosis in patients with liver cancer.

The present study aimed to investigate the role of caprin-1 in liver cancer and its association with the clinicopathological features and prognosis of liver cancer, as well as the underlying mechanism of caprin-1 function. Caprin-1 expression levels in a tissue microarray containing 40 liver cancer tissues, 10 peritumoral tissues and 20 normal liver tissues were analyzed using immunohistochemistry. The clinical data of 154 patients with liver cancer were also collected from The Cancer Genome Atlas database. Kaplan-Meier analysis and a Cox proportional hazards regression model were used to assess the association between caprin-1 expression levels and survival in patients with liver cancer. The effects of caprin-1 knockdown on the mRNA levels of cyclin D1 and cyclin D2 as well as the proliferation, invasion and migration of HepG2 cells were also investigated. The expression level of caprin-1 in liver cancer tissues was significantly higher compared with normal liver tissues or cells (P<0.01). High caprin-1 expression levels were associated with advanced clinical stage (P<0.001) and enhanced tumor invasion (P<0.001). Kaplan-Meier analysis showed that the overall survival time and disease-free survival time in patients with liver cancer with high caprin-1 expression were significantly shorter compared with patients with low caprin-1 expression levels (P=0.002 and P=0.033, respectively). The Cox proportional hazards regression model showed that high caprin-1 expression levels were an independent prognostic factor for liver cancer (P<0.001). Knockdown of caprin-1 in HepG2 cells significantly downregulated mRNA expression levels of cyclin D1 and cyclin D2, inhibited cell proliferation and invasion and the cells were arrested at G0/G1 phase. In conclusion, caprin-1 may be a novel prognostic indicator for patients with liver cancer.

A Model to Predict Treatment Failure of Single­Dose Methotrexate in Patients with Tubal Pregnancy.

BACKGROUND In China, approximately 15% of tubal pregnancy patients treated with MTX eventually required surgery because the ectopic mass was ruptured; therefore, it is essential to develop a model to predict the risk of failure with methotrexate treatment in tubal pregnancy. MATERIAL AND METHODS In this research, 168 patients met the eligibility criteria, and 29 candidate risk factors for treatment failure were collected. Multivariable logistic regression analysis was used to analyze the factors, and a full model was developed. We used a multiple fractional polynomial model and a stepwise model to increase the reliability. Bootstrap resampling for 500 times was used to internally test the prediction model. The integral performance of the model depends on the evaluation of the nomogram, the discriminative performance by receiver operating characteristic (ROC) curve analysis, and calibration. RESULTS The model showed excellent discrimination and calibration. The area under the ROC curve for the prediction model, mfp model, and stepwise model were 0.879 (95% CI: 0.812-0.942), 0.872 (95% CI: 0.805-0.931), and 0.880 (95% CI: 0.817-0.949), respectively. At a cutoff value of ≥0.40, sensitivity was 60%, specificity was 91%, positive predictive value (PPV) was 81%, and negative predictive value (NPV) was 77%. The model provides a net benefit when clinical decision thresholds are between 0% and 40% of predicted risk. CONCLUSIONS This model indicated good accuracy in predicting methotrexate treatment failure for tubal pregnancy patients.