The effect of polylactic acid ordering on the long-term corrosion protection capacity of biodegradable magnesium alloys.

The polylactic acid (PLA) coatings of different crystallinity were prepared on biodegradable Mg-2.2Zn-0.3Ca alloy wires to improve the long-term anti-corrosion properties. The composition characteristics and microstructure of the samples were investigated by differential scanning calorimetry (DSC), Fourier transform infrared spectroscope (FTIR), wide angle X-ray diffraction (WAXD) and scanning electron microscope (SEM). The corrosion resistance of all samples was investigated by immersion tests and electrochemical techniques in vitro simulated body fluid (SBF). The results indicated heat treatment improved the crystallinity of PLA coating and heated-coating performed protective behaviors in the short and long-term immersion. The corrosion rate of heated samples was lower than that of unheated samples and exhibited superior long term protective effect for Mg alloy wires. The lifetime of heated sample (H2) increased significantly from 33 to 55 days. The initial electrochemical performance of unheated coating was better than heated coating, but it declined more rapidly during the long-term immersion. These results indicated that PLA coating could not ignore the effect of its crystallinity to anti-corrosion ability, and only the suit heat treatment makes PLA coating more ordering and achieves higher corrosion resistance in vitro immersion. Therefore, it has promising potential by controlling effectively the PLA ordering for surgical implant applications.

Functional poly(e-caprolactone)/SerMA hybrid dressings with dimethyloxalylglycine-releasing property improve cutaneous wound healing.

Medical dressings with multifunctional properties, including potent regeneration capability and good biocompatibility, are increasingly needed in clinical practice. In this study, we reported a novel hybrid wound dressing (PCL/SerMA/DMOG) that combines electrospun PCL membranes with DMOG-loaded methacrylated sericin (SerMA) hydrogel. In such a design, DMOG molecules are released from the hybrid dressing in a sustained mannerin vitro. A series ofin vitroassays demonstrated that DMOG-loaded hybrid dressing has multiple biological functions, including promotion of human umbilical vein endothelial cells proliferation and migration,in vitrovascularization, and the generation of intracellular NO. When applied to the cutaneous wound, the PCL/SerMA/DMOG dressing significantly accelerated wound closure and tissue regeneration by promoting angiogenesis in the wound area, collagen deposition, and cell proliferation within the wound bed. These results highlight the potential clinical application of PCL/SerMA/DMOG hybrid dressings as promising alternatives for accelerating wound healing via improved biocompatibility and angiogenesis amelioration.

The predictive value of delta-like3 and serum NSE in evaluating chemotherapy response and prognosis in patients with advanced small cell lung carcinoma: An observational study.

Lung cancer is one of the most malignant tumors with fastest morbidity and mortality. Small cell lung cancer (SCLC) is the most malignant pathological type of lung cancer with early metastasis and poor prognosis. At present, there is a lack of effective indicators to predict prognosis of SCLC patients. Delta-like 3 protein (DLL3) is selectively expressed on the surface of SCLC and is involved in proliferation and invasion. Neuron-specific enolase (NSE) is an enolase isoenzyme that is generally regarded as a biomarker for SCLC and may correlate with stage of SCLC, prognosis and chemotherapy response. NSE can be influenced by different types of factors. To explore the associations between expression levels of DLL3 in tumor tissues with platinum/etoposide chemotherapy response, and assess the prognostic values of DLL3, NSE and other potential prognostic factors in advanced SCLC patients were herein studied. Ninety-seven patients diagnosed with SCLC in Zhongda Hospital from 2014 to 2020 were enrolled in the study. Serum NSE levels were tested using ELISA methods before any treatment. The expression of DLL3 in tumor tissue was detected by Immunohistochemistry (IHC). We investigated the relationship of DLL3 expression with chemotherapy and survival. Progression free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Multivariate Cox-proportional hazard regression was used to identify predictors of PFS and OS. DLL3 was detected in 84.5% (82/97) of all patients' tumor samples by IHC, mainly located on the surface of SCLC cells. Lower DLL3 expression was associated with longer PFS and better chemotherapy response. OS had no significant differences. Multivariate analysis by Cox Hazard model showed that, high DLL3 expression and maximum tumor size >5 cm were independent risk factors for PFS, where NSE < 35 ng/mL and age < 70 were independent prognostic factors for OS. Early stage was independent prognostic factors for PFS and OS (P < .05 log-rank). DLL3 was expressed in the most of SCLCs. DLL3 expression level in the tumor and NSE level in the serum may be useful biomarkers to predict the prognosis of SCLC. DLL3 may be a potential therapeutic target for SCLC in the future.

A risk model based on 10 ferroptosis regulators and markers established by LASSO-regularized linear Cox regression has a good prognostic value for ovarian cancer patients.

Ovarian cancer is the deadliest gynecologic cancer due to its high rate of recurrence and limited early diagnosis. For certain patients, particularly those with recurring disorders, standard treatment alone is insufficient in the majority of cases. Ferroptosis, an iron- and ROS (reactive oxygen species)-reliant cell death, plays a vital role in the occurrence of ovarian cancer. Herein, subjects from TCGA-OV were calculated for immune scores using the ESTIMATE algorithm and assigned into high- (N = 185) or low-immune (N = 193) score groups; 259 ferroptosis regulators and markers were analyzed for expression, and 64 were significantly differentially expressed between two groups. These 64 differentially expressed genes were applied for LASSO-regularized linear Cox regression for establishing ferroptosis regulators and a markers-based risk model, and a 10-gene signature was established. The ROC curve indicated that the risk score-based curve showed satisfactory predictive efficiency. Univariate and multivariate Cox risk regression analyses showed that age and risk score were risk factors for ovarian cancer patients' overall survival; patients in the high-risk score group obtained lower immune scores. The Nomogram analysis indicated that the model has a good prognostic performance. GO functional enrichment annotation confirmed again the involvement of these 10 genes in ferroptosis and immune activities. TIMER online analysis showed that risk factors and immune cells were significantly correlated. In conclusion, the risk model based on 10 ferroptosis regulators and markers has a good prognostic value for ovarian cancer patients.

Deep learning enables stochastic optical reconstruction microscopy-like superresolution image reconstruction from conventional microscopy.

Despite its remarkable potential for transforming low-resolution images, deep learning faces significant challenges in achieving high-quality superresolution microscopy imaging from wide-field (conventional) microscopy. Here, we present X-Microscopy, a computational tool comprising two deep learning subnets, UR-Net-8 and X-Net, which enables STORM-like superresolution microscopy image reconstruction from wide-field images with input-size flexibility. X-Microscopy was trained using samples of various subcellular structures, including cytoskeletal filaments, dot-like, beehive-like, and nanocluster-like structures, to generate prediction models capable of producing images of comparable quality to STORM-like images. In addition to enabling multicolour superresolution image reconstructions, X-Microscopy also facilitates superresolution image reconstruction from different conventional microscopic systems. The capabilities of X-Microscopy offer promising prospects for making superresolution microscopy accessible to a broader range of users, going beyond the confines of well-equipped laboratories.

Clinical values of metagenomic next-generation sequencing in patients with severe pneumonia: a systematic review and meta-analysis.

Background: Clinical values of metagenomic next-generation sequencing (mNGS) in patients with severe pneumonia remain controversial. Therefore, we conduct this meta-analysis to evaluate the diagnostic performance of mNGS for pathogen detection and its role in the prognosis of severe pneumonia. Methods: We systematically searched the literature published in PubMed, Embase, Cochrane Library, Web of Science, Clinical Trials.gov, CNKI, Wanfang Data, and CBM from the inception to the 28th September 2022. Relevant trials comparing mNGS with conventional methods applied to patients with severe pneumonia were included. The primary outcomes of this study were the pathogen-positive rate, the 28-day mortality, and the 90-day mortality; secondary outcomes included the duration of mechanical ventilation, the length of hospital stay, and the length of stay in the ICU. Results: Totally, 24 publications with 3220 patients met the inclusion criteria and were enrolled in this study. Compared with conventional methods (45.78%, 705/1540), mNGS (80.48%, 1233/1532) significantly increased the positive rate of pathogen detection [OR = 6.81, 95% CI (4.59, 10.11, P < 0.001]. The pooled 28-day and 90-day mortality in mNGS group were 15.08% (38/252) and 22.36% (36/161), respectively, which were significantly lower than those in conventional methods group 33.05% (117/354) [OR = 0.35, 95% CI (0.23, 0.55), P < 0.001, I2 = 0%] and 43.43%(109/251) [OR = 0.34, 95% CI (0.21, 0.54), P < 0.001]. Meanwhile, adjusted treatment based on the results of mNGS shortened the length of hospital stay [MD = -2.76, 95% CI (- 3.56, - 1.96), P < 0.001] and the length of stay in ICU [MD = -4.11, 95% CI (- 5.35, - 2.87), P < 0.001]. Conclusion: The pathogen detection positive rate of mNGS was much higher than that of conventional methods. Adjusted treatment based on mNGS results can reduce the 28-day and 90-day mortality of patients with severe pneumonia, and shorten the length of hospital and ICU stay. Therefore, mNGS advised to be applied to severe pneumonia patients as early as possible in addition to conventional methods to improve the prognosis and reduce the length of hospital stay.

Associations between diet and incidence risk of lung cancer: A Mendelian randomization study.

Background: Observational studies have revealed associations between diet and lung cancer. However, it is unclear whether the association is disturbed by confounding factors. We used a two-sample Mendelian randomization (MR) method to characterize the associations between diet and the lung cancer risk (including 3 subtypes: lung adenocarcinoma (LA), squamous cell lung carcinoma (SqCLC), and small cell lung cancer (SCLC)). Materials and methods: Data on 20 diets were screened from the UK Biobank. Lung cancer data came from a large meta-analysis of 85,716 individuals. The inverse-variance weighted method was used as the main analysis. Sensitivity analysis was also used to explain the different multiplicity patterns of the final model. Results: Our results showed significant evidence that 3 diets were associated with lung cancer [odds ratio (OR): 0.271, 95% confidence interval (CI): 0.150-0.488, p = 1.46 × 10-4, dried fruit; OR: 3.010, 95% CI: 1.608-5.632, p = 5.70 × 10-4, beer] and SqCLC (OR: 0.135, 95% CI: 0.062-0.293, p = 2.33 × 10-5, dried fruit; OR: 0.485, 95% CI: 0.328-0.717, p = 2.9 × 10-4, cheese). There were also suggestive correlations between 5 dietary intakes and lung cancer (OR: 0.441, 95% CI: 0.250-0.778, p = 0.008, cereal; OR: 2.267, 95% CI: 1.126-4.564, p = 0.022, beef), LA (OR: 0.494, 95% CI: 0.285-0.858, p = 0.012, dried fruit; OR: 3.536, 95% CI: 1.546-8.085, p = 0.003, beer) and SCLC (OR: 0.006, 95% CI: 0.000-0.222, p = 0.039, non-oily fish; OR: 0.239, 95% CI: 0.086-0.664, p = 0.006, dried fruit). No other association between diet and lung cancer was observed. Conclusion: Our study preliminary found that cheese, dried fruit, and beer intake were significantly associated with the risk of lung cancer or its subtypes, while cereal, beef, and non-oily fish intake were suggestively associated with the risk of lung cancer or its subtypes. Well-designed prospective studies are still needed to confirm our findings in the future.

lncRNA AC005224.4/miR-140-3p/SNAI2 regulating axis facilitates the invasion and metastasis of ovarian cancer through epithelial-mesenchymal transition.

BACKGROUND: Ovarian cancer is one of the most widespread malignant diseases of the female reproductive system worldwide. The plurality of ovarian cancer is diagnosed with metastasis in the abdominal cavity. Epithelial-mesenchymal transition (EMT) exerts a vital role in tumor cell metastasis. However, it remains unclear whether long non-coding RNA (lncRNA) are implicated in EMT and influence ovarian cancer cell invasion and metastasis. This study was designed to investigate the impacts of lncRNA AC005224.4 on ovarian cancer. METHODS: LncRNA AC005224.4, miR-140-3p, and snail family transcriptional repressor 2 ( SNAI2 ) expression levels in ovarian cancer and normal ovarian tissues were determined using real-time quantitative polymerase chain reaction (qRT-PCR). Cell Counting Kit-8 (CCK-8) and Transwell (migration and invasion) assays were conducted to measure SKOV3 and CAOV-3 cell proliferation and metastasis. E-cadherin, N-cadherin, Snail, and Vimentin contents were detected using Western blot. Nude mouse xenograft assay was utilized to validate AC005224.4 effects in vivo . Dual-luciferase reporter gene assay confirmed the targeted relationship between miR-140-3p and AC005224.4 or SNAI2 . RESULTS: AC005224.4 and SNAI2 upregulation and miR-140-3p downregulation were observed in ovarian cancer tissues and cells. Silencing of AC005224.4 observably moderated SKOV3 and CAOV-3 cell proliferation, migration, invasion, and EMT process in vitro and impaired the tumorigenesis in vivo . miR-140-3p was a target of AC005224.4 and its reduced expression level was mediated by AC005224.4. miR-140-3p mimics decreased the proliferation, migration, and invasion of ovarian cancer cells. SNAI2 was identified as a novel target of miR-140-3p and its expression level was promoted by either AC005224.4 overexpression or miR-140-3p knockdown. Overexpression of SNAI2 also facilitated ovarian cancer cell viability and metastasis. CONCLUSION: AC005224.4 was confirmed as an oncogene via sponging miR-140-3p and promoted SNAI2 expression, contributing to better understanding of ovarian cancer pathogenesis and shedding light on exploiting the novel lncRNA-directed therapy against ovarian cancer.

Nucleus-Targeting Manganese Dioxide Nanoparticles Coated with the Human Umbilical Cord Mesenchymal Stem Cell Membrane for Cancer Cell Therapy.

Recently, development of drug delivery systems for accurate delivery of antitumor drugs to tumor sites to improve their antitumor efficacy has attracted great interest in the area of cancer immunotherapy. In this report, an intelligent biodegradable hollow manganese dioxide (HMnO2) nanoparticle (NP) with a human umbilical cord mesenchymal stem cell (hUC-MSC) membrane coating was designed to exert efficient chemo-immunotherapy for cancer treatment. A TAT peptide-modified membrane structure was constructed for nuclear targeting. Our findings showed that this new nanoreactor inherited the active targeting capability of MSCs and exhibited tumoritropic accumulation significantly at the cancerous parts. Compared with other formulations, intravenous injection of the NPs markedly inhibited tumor growth, relapse, and metastasis. Moreover, we found that the NPs effectively boosted dendritic cell maturation and recruited effector T cells into tumors. Overall, this work demonstrates the great potential of applying MSC membrane-coated manganese dioxide NPs as nucleus-targeting nanocarriers in cancer chemo-immunotherapy.

Investigating Causal Associations of Circulating Micronutrients Concentrations with the Risk of Lung Cancer: A Mendelian Randomization Study.

Previous observational studies have suggested that the effect of diet-derived circulating micronutrient concentrations on lung cancer (LC) risk is controversial. We conducted a two-sample Mendelian randomization (MR) analysis to investigate the causal relationship between circulating micronutrient concentrations and the overall risk of LC and three LC subtypes (namely lung adenocarcinoma (LA), squamous cell lung cancer (SqCLC), and small cell lung cancer (SCLC)). The instrumental variables (IVs) of 11 micronutrients (beta-carotene, calcium, copper, folate, lycopene, magnesium, phosphorus, retinol, selenium, zinc, and vitamin B6) were screened from the published genome-wide association studies (GWAS). Summary statistics related to LC and its subtypes came from the largest meta-analysis, including 29,266 cases and 56,450 controls. Inverse-variance weighted (IVW) method is used as the main MR analysis, and the sensitivity analysis is carried out to ensure the MR assumptions. This MR study found suggestive evidence that genetically predicted 6 circulating micronutrient concentrations was correlated with the risk of overall LC (odds ratio (OR): 1.394, 95% confidence interval (CI): 1.041-1.868, p = 0.026, phosphorus), LA (OR: 0.794, 95% CI: 0.634-0.995, p = 0.045, beta-carotene; OR: 0.687, 95%CI: 0.494-0.957, p = 0.026, calcium), SqCLC (OR: 0.354, 95% CI: 0.145-0.865, p = 0.023, retinol), and SCLC (OR: 1.267, 95% CI: 1.040-1.543, p = 0.019, copper; OR: 0.801, 95% CI: 0.679-0.944, p = 0.008, zinc). We found no evidence that other micronutrients are associated with the risk of overall LC or its subtypes. Our study suggested that the increase in circulating beta-carotene, calcium, retinol, and zinc concentration may reduce the risk of LC; the increase in circulating copper and phosphorus concentration may be related to the increased risk of LC. In the future, larger replication samples of LC genetic data and larger micronutrient-related GWAS will be needed to verify our findings.

Facile Synthesis, Characterization, and Photocatalytic Evaluation of In2O3/SnO2 Microsphere Photocatalyst for Efficient Degradation of Rhodamine B.

The tin dioxide (SnO2) photocatalyst has a broad application prospect in the degradation of toxic organic pollutants. In this study, micron-sized spherical SnO2 and flower indium oxide (In2O3) structures were prepared by a simple hydrothermal method, and the In2O3/SnO2 composite samples were prepared by a "two-step method". Using Rhodamine B (RhB) as a model organic pollutant, the photocatalytic performance of the In2O3/SnO2 composites was studied. The photocurrent density of 1.0 wt.% In2O3/SnO2 was twice that of pure SnO2 or In2O3, and the degradation rate was as high as 97% after 240 min irradiation (87% after 120 min irradiation). The reaction rate was five times that of SnO2 and nine times that of In2O3. Combined with the trapping experiment, the transient photocurrent response, and the corresponding characterization of active substances, the possible degradation mechanism was that the addition of In2O3 inhibited the efficiency of electron-hole pair recombination, accelerated the electron transfer and enhanced the photocatalytic activity.

Improving Suspected Pulmonary Infection Diagnosis by Bronchoalveolar Lavage Fluid Metagenomic Next-Generation Sequencing: a Multicenter Retrospective Study.

Metagenomic next-generation sequencing (mNGS) has been gradually applied to clinical practice due to its unbiased characteristics of pathogen detection. However, its diagnostic performance and clinical value in suspected pulmonary infection need to be evaluated. We systematically reviewed the clinical data of 246 patients with suspected pulmonary infection from 4 medical institutions between January 2019 and September 2021. The diagnostic performances of mNGS and conventional testing (CT) were systematically analyzed based on bronchoalveolar lavage fluid (BALF). The impacts of mNGS and CT on diagnosis modification and treatment adjustment were also assessed. The positive rates of mNGS and CT were 47.97% and 23.17%, respectively. The sensitivity of mNGS was significantly higher than that of CT (53.49% versus 23.26%, P < 0.01), especially for infections of Mycobacterium tuberculosis (67.86% versus 17.86%, P < 0.01), atypical pathogens (100.00% versus 7.14%, P < 0.01), viruses (92.31% versus 7.69%, P < 0.01), and fungi (78.57% versus 39.29%, P < 0.01). The specificity of mNGS was superior to that of CT, with no statistical difference (90.32% versus 77.42%, P = 0.167). The positive predictive value (PPV) and negative predictive value (NPV) of mNGS were 97.46% and 21.88%, respectively. Diagnosis modification and treatment adjustment were conducted in 32 (32/246, 13.01%) and 23 (23/246, 9.35%) cases, respectively, according to mNGS results only. mNGS significantly improved the diagnosis of suspected pulmonary infection, especially infections of M. tuberculosis, atypical pathogens, viruses, and fungi, and it demonstrated the pathogen distribution of pulmonary infections. It is expected to be a promising microbiological detection and diagnostic method in clinical practice. IMPORTANCE Pulmonary infection is a heterogeneous and complex infectious disease with high morbidity and mortality worldwide. In clinical practice, a considerable proportion of the etiology of pulmonary infection is unclear, microbiological diagnosis being challenging. Metagenomic next-generation sequencing detects all nucleic acids in a sample in an unbiased manner, revealing the microbial community environment and organisms and improving the microbiological detection and diagnosis of infectious diseases in clinical settings. This study is the first multicenter, large-scale retrospective study based entirely on BALF for pathogen detection by mNGS, and it demonstrated the superior performance of mNGS for microbiological detection and diagnosis of suspected pulmonary infection, especially in infections of Mycobacterium tuberculosis, atypical pathogens, viruses, and fungi. It also demonstrated the pathogen distribution of pulmonary infections in the real world, guiding targeted treatment and improving clinical management and prognoses.

Bloodstream infection and pneumonia caused by Chlamydia abortus infection in China: a case report.

BACKGROUND: Chlamydia abortus is generally considered to cause abortion, stillbirth, and gestational sepsis in pregnant women, but it's rare in bloodstream infection and pneumonia. CASE PRESENTATION: We present details of a patient with bloodstream infection and pneumonia caused by Chlamydia abortus. Both blood next-generation sequencing (NGS) and sputum NGS indicate Chlamydia abortus infection. The patient received intravenous infusion of piperacillin sodium and tazobactam sodium (4.5 g/8 h) and moxifloxacin (0.4 g/d) and oral oseltamivir (75 mg/day). Within one month of follow-up, the patient's clinical symptoms were significantly improved, and all laboratory parameters showed no marked abnormality. However, chest computer tomography (CT) showed the inflammation wasn't completely absorbed. And we are still following up. CONCLUSIONS: Chlamydia abortus can cause pneumonia in humans. NGS has the particular advantage of quickly and accurately identifying the infection of such rare pathogens. Pneumonia is generally not life-threatening, and has a good prognosis with appropriate treatment. However, Chlamydia infection can lead to serious visceral complications which clinicians should pay attention to.

Efficient photocatalytic degradation of volatile organic compounds over carbon quantum dots decorated Bi2WO6 under visible light.

A series of CQDs/Bi2WO6 (CBW) hybrid materials with different loading amounts of carbon quantum dots (CQDs) were prepared via a facile in situ hydrothermal method. As determined by multiple techniques including XRD, TEM, UV-vis, PL, TPR, and XPS, the CBW possessed expanded visible light response interval, decreased recombination rate of the photogenerated electron hole, and enhanced oxidation ability as compared with the pristine Bi2WO6. In addition, with different loading amounts of CQDs, the optical and electronic properties of the corresponding CBW were different. These CBW materials performed superior activities to the pristine Bi2WO6 in the photodegradation of VOCs under visible light, among which the CBW-2 demonstrated the best activity of almost complete degradation within only 120 min. Moreover, the CBW-2 exhibited high stability and reusability after five cycles.

Improved Cycle Stability of LiSn Alloy Anode for Different Electrolyte Systems in Lithium Battery.

Lithium metal anode still confronts a series of problems at the way to commercialization though it has advantages in high energy density. The formation of Li dendrite is the major limitation need to be conquered. Here, a facile and simple LiSn alloy anode prepared by a direct metallurgy method is fabricated and evaluated in both liquid electrolyte and solid electrolyte. Structural analysis and electrochemical measurements reveal the promoted ionic transference of interface and enhanced cycling stability in different electrolyte systems, without dendrite formation. Furthermore, the application of this simple and sustainable LiSn alloy can be extended to more alloy anode and might unlock the next-generation anode in the future.

Ribosomal Protein L15 is involved in Colon Carcinogenesis.

Ribosomal biogenesis is responsible for protein synthesis in all eukaryotic cells. Perturbation of ribosomal biogenesis processes can cause dysfunctions of protein synthesis and varieties of human diseases. In this study, we examine the role of RPL15, a large ribosomal subunit protein, in human colon carcinogenesis. Our results reveal that RPL15 is remarkably upregulated in human primary colon cancer tissues and cultured cell lines when compared with paired non-cancerous tissues and non-transformed epithelium cells. Elevated expression of RPL15 in colon cancer tissues is closely correlated with clinicopathological characteristics in patients. We determine the effects of RPL15 on nucleolar maintenance, ribosomal biogenesis and cell proliferation in human cells. We show that RPL15 is required for maintenance of nucleolar structure and formation of pre-60S subunits in the nucleoli. Depletion of RPL15 causes ribosomal stress, resulting in a G1-G1/S cell cycle arrest in non-transformed human epithelium cells, but apoptosis in colon cancer cells. Together, these results indicate that RPL15 is involved in human colon carcinogenesis and might be a potential clinical biomarker and/or target for colon cancer therapy.

A Novel Microtubule Inhibitor Overcomes Multidrug Resistance in Tumors.

Microtubule inhibitors as chemotherapeutic drugs are widely used for cancer treatment. However, the development of multidrug resistance (MDR) in cancer is a major challenge for microtubule inhibitors in their clinical implementation. From a high-throughput drug screen using cells transformed by oncogenic RAS, we identify a lead heteroaryl amide compound that blocks cell proliferation. Analysis of the structure-activity relationship indicated that this series of scaffolds (exemplified by MP-HJ-1b) represents a potent inhibitor of tumor cell growth. MP-HJ-1b showed activities against a panel of more than 1,000 human cancer cell lines with a wide variety of tissue origins. This compound depolymerized microtubules and affected spindle formation. It also induced the spike-like conformation of microtubules in vitro and in vivo, which is different from typical microtubule modulators. Structural analysis revealed that this series of compounds bound the colchicine pocket at the intra-dimer interface, although mostly not overlapping with colchicine binding. MP-HJ-1b displayed favorable pharmacological properties for overcoming tumor MDR, both in vitro and in vivo Taken together, our data reveal a novel scaffold represented by MP-HJ-1b that can be developed as a cancer therapeutic against tumors with MDR.Significance: Paclitaxel is a widely used chemotherapeutic drug in patients with multiple types of cancer. However, resistance to paclitaxel is a challenge. This study describes a novel class of microtubule inhibitors with the ability to circumvent multidrug resistance across multiple tumor cell lines. Cancer Res; 78(20); 5949-57. ©2018 AACR.

The peripheral blood neutrophil-to-lymphocyte ratio is a prognostic predictor for survival of EGFR-mutant nonsmall cell lung cancer patients treated with EGFR-TKIs.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are the standard first-line treatment for EGFR-mutant nonsmall cell lung cancer (NSCLC) patients. However, studies have reported that not all NSCLC patients harboring kinase domain mutations in epidermal growth factor receptor (EGFR) show significant clinical benefits from EGFR-targeted tyrosine kinase inhibitors (TKIs). Therefore, it is necessary to establish feasible biomarkers to predict the prognosis of EGFR-mutant NSCLC patients treated with EGFR-TKIs. This study aimed to determine biomarkers using inflammatory parameters from complete blood counts to predict the prognosis of EGFR-mutant NSCLC patients treated with EGFR-TKIs.We retrospectively investigated 127 stage IIIB/IV NSCLC patients with activating EGFR mutations who were treated with EGFR-TKIs. We used receiver operating characteristic (ROC) curves to determine the optimal cut-off for the inflammatory markers as prognostic factors. Additionally, univariate and multivariate analyses were used to identify prognostic factors for progression-free survival (PFS) and overall survival (OS) of EGFR-mutant NSCLC patients treated with EGFR-TKIs.The receiver operating characteristic analysis indicated that the lymphocyte-to-monocyte ratio (LMR) and neutrophil-to-lymphocyte ratio (NLR) cut-off values were 3.37 and 2.90, respectively. The univariate analysis showed that a high LMR (>3.37) and low NLR (≤2.90) were significantly correlated with long-term PFS and OS (LMR, P = .007; NLR, P < .001). The multivariate Cox regression analysis revealed that only low NLR was an independent prognostic factor for long-term PFS and OS (PFS, HR = 0.573, 95% CI: 0.340-0.964, P = .036; OS, HR = 0.491, 95% CI: 0.262-0.920, P = .026).The data show that a low NLR was a good prognostic factor in EGFR-mutant NSCLC patients receiving EGFR-TKIs treatment. Moreover, the NLR measurement has better prognostic value than LMR.

Cdk phosphorylation licenses Kif4A chromosome localization required for early mitotic progression.

The chromokinesin Kif4A controls proper chromosome condensation, congression/alignment, and cytokinesis to ensure faithful genetic inheritance. Here, we report that Cdk phosphorylation of human Kif4A at T1161 licenses Kif4A chromosomal localization, which, in turn, controls Kif4A early mitotic function. Phosphorylated Kif4A (Kif4AWT) or Cdk phospho-mimetic Kif4A mutant (Kif4ATE) associated with chromosomes and condensin I (non-SMC subunit CAP-G and core subunit SMC2) to regulate chromosome condensation, spindle morphology, and chromosome congression/alignment in early mitosis. In contrast, Cdk non-phosphorylatable Kif4A mutant (Kif4ATA) could neither localize on chromosomes nor associate with CAP-G and SMC2. Furthermore, Kif4ATA could not rescue defective chromosome condensation, spindle morphology, or chromosome congression/alignment in cells depleted of endogenous Kif4A, which activated a mitotic checkpoint and delayed early mitotic progression. However, targeting Kif4ATA to chromosomes by fusion of Kif4ATA with Histone H1 resulted in restoration of chromosome and spindle functions of Kif4A, similar to Kif4AWT and Kif4ATE, in cells depleted of endogenous Kif4A. Thus, our results demonstrate that Cdk phosphorylation-licensed chromosomal localization of Kif4A plays a critical role in regulating early mitotic functions of Kif4A that are important for early mitotic progression.

Kinesin KIF4A is associated with chemotherapeutic drug resistance by regulating intracellular trafficking of lung resistance-related protein.

Multidrug resistance (MDR) is the major impediment to cancer chemotherapy. The expression of lung resistance-related protein (LRP), a non-ATP-binding cassette (ABC) transporter, is high in tumor cells, resulting in their resistance to a variety of cytotoxic drugs. However, the function of LRP in tumor drug resistance is not yet explicit. Our previous studies had shown that Kinesin KIF4A was overexpressed in cisplatin (DDP)-resistant human lung adenocarcinoma cells (A549/DDP cells) compared with A549 cells. The expression of KIF4A in A549 or A549/DDP cells significantly affects cisplatin resistance but the detailed mechanisms remain unclear. Here, we performed co-immunoprecipitation experiments to show that the tail domain of KIF4A interacted with the N-terminal of LRP. Immunofluorescence images showed that both the ability of binding to LRP and the motility of KIF4A were essential for the dispersed cytoplasm distribution of LRP. Altogether, our results shed light on a potential mechanism in that motor protein KIF4A promotes drug resistance of lung adenocarcinoma cells through transporting LRP-based vaults along microtubules towards the cell membrane. Thus KIF4A might be a cisplatin resistance-associated protein and serves as a potential target for chemotherapeutic drug resistance in lung cancer.