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The waste fly ash obtained from coal-tired power plants was refined by physical ball milling, activated with a silane coupling agent, and then used as a tiller to prepare polypropylene (PP) matrix composites by melt blending. The results indicated that, compared to pure PP, the composites exhibited an increase in bending strength by 11.5 %, in tensile strength by 10.7 %, and in impact strength by 34.1 % when using the fly ash only treated by ball milling. Moreover, there was an improvement in the melt flow index and thermal stability of the composites. When the fly ash was treated with a silane coupling agent and then used for PP, the resulting composites showed a further improvement in mechanical properties and thermal stability. Based on our experimental results, there was a good toughening effect on PP when 20 wt% of surface-modified fly ash was incorporated, thus leading to optimal comprehensive performance for PP composites. [ABSTRACT FROM AUTHOR]

Energy is the basic source related to the people's livelihood. China has a population of 1.3 billion, second-largest economy in the world, is especially acute for energy demand and consumption. According to British Petroleum (BP) energy statistics, China's coal reserves ranked third in the world, primary energy consumption ratio of 75%, above the global average more than 1 time. China is a coal country, environmental pollution and energy security has always been a double-edged sword, as well as the use of existing technology to energy saving and emission reduction, and reasonable resource allocation through industrial adjustment in real time. We need continuous innovation, and make it become the core plate of perfecting the national strategy once again. Based on the production system, strategic management theory and actual situation, there uses the quantitative method of Analytic Hierarchy Process (AHP) to identify the advantage and disadvantage industries and clear the priority order of 8 industries for development. [ABSTRACT FROM AUTHOR]

Our study attempts to address the following questions: among numerous photosynthetic modules, which parameters notably influence the rapid chlorophyll fluorescence (ChlF) rise, the so-called O-J-I-P transient, in conjunction with the P515 signal, as these two records are easily obtained and widely used in photosynthesis research, and how are these parameters ranked in terms of their importance? These questions might be difficult to answer solely through experimental assays. Therefore, we employed an established photosynthesis model. Firstly, we utilized the model to simulate the measured rapid ChlF rise and P515 kinetics simultaneously. Secondly, we employed the sensitivity analysis (SA) tool by randomly altering model parameters to observe their effects on model output variables. Thirdly, we systematically identified significant parameters for both or one of the kinetics across various scenarios. A novel aspect of our study is the application of the Morris method, a global SA tool, to simultaneously assess the significance of model parameters in shaping both or one of the kinetics. The Morris SA technique enables the quantification of how much a specific parameter affects O-J-I-P transient during particular time intervals (e.g., J, I, and P steps). This allowed us to theoretically analyze which step is more significantly influenced by the parameter. In summary, our study contributes to the field by providing a comprehensive analysis of photosynthesis kinetics and emphasizing the importance of parameter selection in modelling this process. These findings can inform future research efforts aimed at improving photosynthesis models and advancing our understanding of photosynthetic processes., (© 2024 Scandinavian Plant Physiology Society.)

Purpose: Pain is one of the most common and harmful symptoms experienced by individuals with acute herpetic neuralgia (AHN). In this population, studies to determine the causes that affect patients taking medications compliance are rare. This study aimed to construct a predictive model for medication compliance of patients with AHN and to verify its performance., Design and Methods: In this prospective study of 398 patients with AHN who were discharged from a tertiary hospital with medications from July 2020 to October 2022, we used logistic regression analysis to explore the predictive factors of medication compliance of patients with AHN and to construct a nomogram. The area under the curve was used to evaluate the predictive effect of the model., Results: A predictive model of drug compliance of patients with AHN was constructed based on the following four factors: disease duration, pain severity before treatment, medication beliefs, and comorbidity of chronic diseases. The area under the curve of the model was 0.766 (95% confidence interval [0.713, 0.819]), with a maximum Youden's index of 0.431, sensitivity of 0.776, and specificity of 0.655. A linear calibration curve was found with a slope close to 1., Conclusions: The prediction model constructed in this study had good predictive performance and provided a reference for early clinical screening of independent factors that affected the medication compliance of patients with AHN., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Chlorophyll a fluorescence, a sensitive and cost-effective probe, is widely used in photosynthetic research. Its rapid phase, occurring within 1 second under intense illumination, displays complex O-J-I-P transients, providing valuable insights into various aspects of photosynthesis. In addition to employing experimental approaches to measure the rapid Fluorescence Induction (FI) kinetics, mathematical modeling serves as a crucial tool for understanding the underlying mechanisms that drive FI dynamics. However, the significant uncertainty and arbitrary nature of selecting model parameters amplify concerns about the effectiveness of modeling tools in aiding photosynthesis research. Therefore, there is a need to gain a deeper understanding of how these models operate and how arbitrary parameter choices may influence their outcomes. In this study, we employed the Morris method, a global Sensitivity Analysis (SA) tool, to assess the significance of rate constants employed in an existing fluorescence model, particularly those linked to the entire electron transport chain, in shaping the rapid FI dynamics. In summary, utilizing the insights gained from the Morris SA allows for targeted refinement of the photosynthesis model, thereby improving our understanding of the complex processes inherent in photosynthetic systems., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lyu, Lin and Liakopoulos.)

Background: Chinese Martial Arts (CMAs) have garnered a global following, with their rich historical and cultural heritage transcending geographical and cultural differences, sparking profound interest among an international community. As an increasing number of non-Chinese individuals persist in practicing CMAs, investigating the motivations behind their continued participation has emerged as a compelling question. This study aims to delve deeper into the factors driving international practitioners to sustain their practice of CMAs, thereby broadening our understanding of the global resonance of CMAs., Methods: Employing Self-Determination Theory, 226 international CMAs practitioners completed the Physical Activity and Leisure Motivation Scale, Perceived Belonging Scale, and Persistence in Practicing CMAs Scale. SPSS 20.0 was utilized for conducting descriptive statistics, common method bias tests, and correlation analyses. Structural equation modeling was performed using AMOS 26.0., Results: Motivation for Practicing CMAs, comprised of enjoyment, mastery, physical condition, psychological condition, and appearance, has a positive impact on Persistence in Practicing CMAs ( β  = 0.297, p  < 0.01). Sense of Belonging also positively affects Persistence in Practicing CMAs ( β  = 0.268, p  < 0.01). The aforementioned variables account for 22.1% of the variance in Persistence in Practicing CMAs. Furthermore, Affiliation, Competition/Ego, and Others' Expectations were found to have no significant correlation with Persistence in Practicing CMAs., Conclusion: The formation of persistence in the practice of CMAs among international practitioners is propelled by their ongoing desire for skill mastery, enjoyment, enhanced physical and mental health, body shape improvement, and a Sense of Belonging. The study reveals that a stronger motivation and Sense of Belonging significantly enhance their commitment to CMAs. Recommendations include that international instructors should center their teaching strategies around the practitioners, helping them to find joy in their practice, achieve skill mastery, and foster the development of physical, mental, and aesthetic qualities, alongside virtues and etiquette. Additionally, building a supportive CMAs community and cultivating a sense of ritual are essential. Such strategies are intended to reinforce practitioners' self-affirmation and group identity, thus boosting their Sense of Belonging and encouraging their continued engagement in CMAs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Cao and Lyu.)

Objective: To compare and analyze the clinical features of patients with severe coronavirus disease 2019 (sCOVID-19) and severe community acquired pneumonia (sCAP) who meet the diagnostic criteria for severe pneumonia of the Infectious Diseases Society of America/American Thoracic Society (IDSA/ATS)., Methods: A retrospective comparative analysis of the clinical records of 116 patients with sCOVID-19 admitted to the department of critical care medicine of Wuhan Third Hospital from January 1, 2020 to March 31, 2020 and 135 patients with sCAP admitted to the department of critical care medicine of Shanghai First People's Hospital from January 1, 2010 to December 31, 2017 was conducted. The basic information, diagnosis and comorbidities, laboratory data, etiology and imaging results, treatment, prognosis and outcome of the patients were collected. The differences in clinical data between sCOVID-19 and sCAP patients were compared, and the risk factors of death were analyzed., Results: The 28-day mortality of sCOVID-19 and sCAP patients were 50.9% (59/116) and 37.0% (50/135), respectively. The proportion of arterial partial pressure of oxygen/fraction of inspired oxygen (PaO 2 /FiO 2 ) ≤ 250 mmHg (1 mmHg ≈ 0.133 kPa) in sCOVID-19 patients was significantly higher than that of sCAP [62.1% (72/116) vs. 34.8% (47/135), P < 0.01]. The possible reason was that the proportion of multiple lung lobe infiltration in sCOVID-19 was significantly higher than that caused by sCAP [94.0% (109/116) vs. 40.0% (54/135), P < 0.01], but the proportion of sCOVID-19 patients requiring mechanical ventilation was significantly lower than that of sCAP [45.7% (53/116) vs. 60.0% (81/135), P < 0.05]. Further analysis of clinical indicators related to patient death found that for sCOVID-19 patients PaO 2 /FiO 2 , white blood cell count (WBC), neutrophils (NEU), neutrophil percentage (NEU%), neutrophil/lymphocyte ratio (NLR), total bilirubin (TBil), blood urea nitrogen (BUN), albumin (ALB), Ca 2+ , prothrombin time (PT), D-dimer, C-reactive protein (CRP) and other indicators were significantly different between the death group and the survival group, in addition, the proportion of receiving mechanical ventilation, gamma globulin, steroid hormones and fluid resuscitation in death group were higher than survival group. Logistic regression analysis showed that the need for mechanical ventilation, NLR > 10, TBil > 10 μmol/L, lactate dehydrogenase (LDH) > 250 U/L were risk factors for death at 28 days. For sCAP patients, there were significant differences in age, BUN, ALB, blood glucose (GLU), Ca 2+ and D-dimer between the death group and the survival group, but there was no significant difference in treatment. Logistic regression analysis showed that BUN > 7.14 mmol/L and ALB < 30 g/L were risk factors for 28-day death of sCAP patients., Conclusions: The sCOVID-19 patients in this cohort have worse oxygen condition and symptoms than sCAP patients, which may be due to the high proportion of lesions involving the lungs. The indicators of the difference between the death group and the survival group were similar in sCOVID-19 and sCAP patients. It is suggested that the two diseases have similar effects on renal function, nutritional status and coagulation function. But there were still differences in risk factors affecting survival. It may be that sCOVID-19 has a greater impact on lung oxygenation function, inflammatory cascade response, and liver function, while sCAP has a greater impact on renal function and nutritional status.

Aim: To explore the efficacy of the orthokeratology lens for anisometropic myopia progression., Methods: A retrospective study was performed. Cycloplegic refraction and axial length (AL) were collected from 50 children (10.52±1.72y) who visited Peking University Third Hospital from July 2015 to August 2020. These children's one eyes (Group A) received monocular orthokeratology lenses at first, after different durations (12.20±6.94mo), their contralateral eyes (Group B) developed myopia and receive orthokeratology as well. The data in 1-year of binocular period were recorded. AL growth rate (difference of follow-up and baseline per month) were compared between two groups by paired t test. Interocular differences of AL were compared by Wilcoxon test., Results: During monocular period, the AL growth rate of the Group A (0.008±0.022 mm/mo) was significantly slower than that of the Group B (0.038±0.018 mm/mo; P <0.0001). However, during binocular period, the AL growth rate of the Group A (0.026±0.014 mm/mo) was significantly faster than that of the Group B (0.016±0.015 mm/mo; P <0.0001). The AL difference between both eyes was 0.6 (0.46) mm, then significantly decreased to 0.22 (0.39) mm when started binocular treatment ( P <0.0001). However, it was significantly increased to 0.30 (0.32) mm after a year ( P <0.0001), but still significantly lower than baseline ( P <0.0001)., Conclusion: The orthokeratology lens is efficient for control the AL elongation of monocular myopia eyes and reduce anisometropia. For the condition that the contralateral eyes develop myopia and receive orthokeratology lens later, there is no efficiency observed on control interocular difference of AL during binocular treatment., (International Journal of Ophthalmology Press.)

Objective: To explore the risk factors of intensive care unit-acquired weakness (ICU-AW), and to establishment and verify its risk prediction model., Methods: A modeling group of 231 patients who met the inclusion criteria and were admitted to the intensive care unit (ICU) of the First Hospital of Jiaxing from July 2019 to June 2020 was collected by convenience sampling method. According to whether they developed ICU-AW, they were divided into ICU-AW group (55 cases) and non ICU-AW group (176 cases). The clinical data were collected concerning patients' individual information, disease-related factors, treatment-related factors and laboratory indicators, and the differences of the above indexes between two groups were compared. Logistic regression was used to analyze the ICU-AW risk factors and a risk prediction model was constructed. Calculate the area under ROC curve (AUC) to test the prediction effect of the model. At the same time, 60 patients who admitted to ICU from July to October 2020 and met the standards were collected to verify the model., Results: Compared with non ICU-AW group, there were more males in ICU-AW group [61.8% (34/55) vs. 44.3% (78/176), P < 0.05], with higher levels of systemic inflammatory response syndrome (SIRS), sepsis, immobilization and the use of neuromuscular blockers [SIRS: 30.9% (17/55) vs. 3.4% (6/176), sepsis: 12.7% (7/55) vs. 2.3% (4/176), immobilization: 72.7% (40/55) vs. 39.2% (69/176), the use of neuromuscular blockers: 50.9% (28/55) vs. 14.2% (25/176), all P < 0.05], and acute physiology and chronic health evaluation II (APACHE II) score, blood lactic acid level and duration of mechanical ventilation, length of hospital stay were all increased [APACHE II score: 18 (15, 24) vs. 12 (8, 17), blood lactic acid (mmol/L): 2 (1, 2) vs. 1 (1, 2), duration of mechanical ventilation (days): 7 (4, 12) vs. 2 (2, 5), length of hospital stay (days): 10 (6, 16) vs. 5 (3, 9), all P < 0.05]. SIRS, APACHE II score, duration of mechanical ventilation and blood lactic acid were included to construct a risk prediction model [odds ratio (OR) values were 4.835, 1.083, 1.210, 1.790, P values were 0.018, 0.013, 0.015, 0.013]. The model equation was P = exp [-5.207+(1.576×SIRS)+(0.079×APACHE II)+(0.191×duration of mechanical ventilation)+(0.582×blood lactic acid)]. Internal verification: Calibration diagram showed the calibration curve above the ideal curve, AUC = 0.888, 95% confidence interval (95%CI) was 0.839-0.938; when the cut-off value was 0.166, the sensitivity was 89.1%, the specificity was 75.6%, and the maximum index was 0.649. External verification: Calibration diagram showed that the calibration curve was above the ideal curve, and the plotted AUC = 0.853, 95%CI was 0.753-0.953. When the cut-off value of the corresponding predictive risk value was 0.367, the sensitivity was 68.8%, the specificity was 86.4%, and the maximum approximate index was 0.552., Conclusions: The risk prediction model of ICU-AW constructed in this study has good consistency and prediction efficiency, which can provide reference for medical personnel to identify high-risk groups of ICU-AW patients in the early stage and provide targeted interventions in advance.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows promising antitumor activity in preclinical studies. However, the efficacy of recombinant TRAIL in clinical trials is compromised by its short serum half-life and low in vivo stability. Induction of endogenous TRAIL may overcome the limitations and become a new strategy for cancer treatment. Here, we discovered that metformin increased TRAIL expression and induced apoptosis in triple-negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC) cells. Metformin did not alter the expression of TRAIL receptors (TRAIL-R1/DR4 and TRAIL-R2/DR5). Metformin-upregulated TRAIL was secreted into conditioned medium (CM) and found to be functional, since the CM promoted TNBC cells undergoing apoptosis, which was abrogated by a recombinant TRAIL-R2-Fc chimera. Moreover, blockade of TRAIL binding to DR4/DR5 or specific knockdown of TRAIL expression significantly attenuated metformin-induced apoptosis. Studies with a tumor xenograft model revealed that metformin not only significantly inhibited tumor growth but also elicited apoptosis and enhanced TRAIL expression in vivo . Collectively, we have demonstrated that upregulation of TRAIL and activation of death receptor signaling are pivotal for metformin-induced apoptosis in TNBC and NSCLC cells. Our studies identify a novel mechanism of action of metformin exhibiting potent antitumor activity via induction of endogenous TRAIL., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

Objective: To observe the effects of dihydromyricetin (DHM) on obesity induced by high-fat diet in mice, and to explore whether its mechanism of action is related to the promotion of WAT browning., Methods: Sixty c57bl/6j mice were randomly divided into 6 groups (n=10): ①normal control group (ND group): normal feed feeding; ②Normal control + low dose DHM group (ND+L-DHM group): normal feed feeding was treated with low dose DHM (125 mg/(kg·d)); ③Normal control + high dose DHM group (ND+H-DHM group): normal feed feeding was treated with high dose DHM (250 mg/(kg·d)); ④High-fat diet group (HFD): high-fat diet; ⑤high-fat diet + low-dose DHM group (HFD+L-DHM group): high-fat diet feeding with low-dose DHM; ⑥High-fat diet + high-dose DHM group (HFD+H-DHM group): High-fat diet was treated with high-dose DHM. After 16 weeks, the mice were fasted overnight, blood samples were collected for fasting blood glucose and blood lipids, then the animals were sacrificed, body length was measured, and Lee's index was calculated. After weighing the adipose tissue in the scapula, groin and epididymis, formaldehyde fixation and HE staining were used to observe the fat cells size, immunohistochemistry was used to detect the expression of uncoupling protein 1 (UCP1). The body weight was measured every 4 weeks during the experiment., Results: Compared with the ND group, the body weight of the mice in the HFD group was increased significantly, suggesting that the obese mouse model replicated successfully. In addition, the body fat weight, fat cell diameter, Lee's index and blood glucose of the HFD group were increased significantly, and the expression of UCP1 in the adipocytes was increased. Body weight, fat cell diameter, Lee's index and blood glucose of HFD mice treated with L-DHM and H-DHM were reversed significantly, while the expression of UCP1 in adipocytes was more significantly increased; however, L-DHM and H-DHM had no significant effects on the above indicators in normal mice., Conclusion: Dihydromyricetin inhibited high fat diet induced mouse obesity; the mechanism might be associated with promoting WAT browning.

The method of classifying the quality grade of traditional Chinese medicine slices with cross section model quality constant was applied to the grade evaluation of Ligusticum chuanxiong pieces,and a reasonable grade standard of L. chuanxiong pieces was established. The purpose is to classify the 15 batches of L. chuanxiong pieces by combining the advantages of traditional grading with modern quality control indicators. By measuring the natural morphological parameters,processing parameters and the intrinsic content of ferulic acid,an important active ingredient,of the 15 batches of L. chuanxiong pieces collected from different manufacturers and different batches of different medicinal materials markets,we can synthesize the results. The mass constants and percentage mass constants are calculated and analyzed based on the above data. The results showed that the quality constants of 15 batches of L. chuanxiong pieces collected ranged from 0.53-3.00; if the percentage mass constants were more than 80%,50%-80% was second-class pieces,and the rest were third-class pieces,the evaluation results were as follows: the quality constants of first-class L. chuanxiong pieces were more than 2.40,the quality constants of second-class L. chuanxiong pieces should be 1.70-2.40,and the quality constants of third-class L. chuanxiong pieces should be less than 1.70. In this paper,the method of dividing the quality constants of the top blade model into different grades is further applied and practiced,which proves that the method is scientific,reasonable and multi-adaptable. At the same time,it enriches the research data of the grade evaluation of L. chuanxiong pieces,provides a useful reference for the promotion of the grade evaluation of L. chuanxiong pieces,and lays an experimental foundation for the next research of the subject group.

As a rare endangered medical plant that newly cultivated,little experimental information is available for growth and metabolites of Tetrastigma hemsleyanum in response to nitrogen( N). The effects of different levels of N on growth of T. hemsleyanum and the content of phytochemicals( polysaccharide,total flavonoids and phenolics) and antioxidant activity( ABTS and FRAP) in stems and leaves were investigated in this study. A certain amount of N had positive effects on most of biological traits,and excessive dose of N went against growth of T. hemsleyanum. With N levels decreased,the polysaccharide content in stems and leaves had no significant change,while the total flavonoid and phenolic content,and antioxidant activities increased steadily. Antioxidant activities and total flavonoid and phenolic content had significant positive correlation. Excessive N fertilizer should be avoided by cultivation.

Objective: To explore genes potentially co-expressed with cyclin E in gastric cancer and discover possible targets for gastric cancer treatment., Methods: The Cancer Genome Atlas (TCGA) stomach adenocarcinoma sequencing data were used to predict genes co-expressed with cyclin E. Co-expression genes predicted by cBioPortal online analysis with Pearson correlation coefficient ≥0.4 were analyzed by gene ontology (GO) enrichment annotation using the PANTHER online platform (Ver. 7). Interactions between proteins encoded by these genes were analyzed using the STRING online platform (Ver. 10.5) and Cytoscape software (Ver. 3.5.1). Genes displaying a high degree of connection were analyzed by transcription factor enrichment prediction using FunRich software (Ver. 3). The significant transcription factor and cyclin E expression levels and their impact on gastric cancer progression were analyzed by Western blotting and Kaplan-Meier survival curve analysis., Results: After filtering the co-expression gene prediction results, 78 predicted genes that included 73 protein coding genes and 5 non-coding genes with Pearson correlation coefficient ≥0.4 were selected. The expressions of the genes were considered to be correlated with cyclin E expression. Among the 78 genes co-expressed with cyclin E, 19 genes at the central of the regulatory network associated with cyclin E were discovered. Nuclear transcription factor Y subunit alpha (NF-YA) was identified as a significant transcription factor associated with cyclin E co-expressing genes. Analysis of specimen donors' clinical records revealed that high expression of NF-YA tended to be associated with increased cyclin E expression. The expression of both was associated with progression of gastric cancer. Western blotting results showed that compared with normal tissues, NF-YA and cyclin E were highly expressed in tumor tissues ( P  < 0.001). Survival curve analysis clearly demonstrated relatively poor overall survival of gastric cancer patients with high cyclin E or high NF-YA expression level, compared to patients with low cyclin E or NF-YA expression ( P  < 0.05)., Conclusions: NF-YA may promote gastric cancer progression by increasing the transcription of cyclin E and other cell cycle regulatory genes. NF-YA might be a potential therapeutically useful prognostic factor for gastric cancer.

A model was constructed which includes electron transport (linear and cyclic and Mehler type reaction) coupled to proton translocation, counter ion movement, ATP synthesis, and Calvin-Benson cycle. The focus is on modeling of the light-induced total electric potential difference (ΔΨ) which in this model originates from the bulk phase electric potential difference (ΔΨ b ), the localized electric potential difference (ΔΨ c ), as well as the surface electric potential difference (ΔΨ s ). The measured dual wavelength transmittance signal (ΔA515-560nm, electrochromic shift) was used as a proxy for experimental ΔΨ. The predictions for theoretical ΔΨ vary with assumed contribution of ΔΨ s , which might imply that the measured ΔA515-560nm trace on a long time scale reflects the interplay of the ΔΨ components. Simulations also show that partitioning of proton motive force (pmf) to ΔΨ b and ΔpH components is sensitive to the stoichiometric ratio of H + /ATP, energy barrier for ATP synthesis, ionic strength, buffer capacity and light intensity. Our model shows that high buffer capacity promotes the establishment of ΔΨ b , while the formation of pH i minimum is not 'dissipated' but 'postponed' until it reaches the same level as that for low buffer capacity. Under physiologically optimal conditions, the output of the model shows that at steady state in light, the ΔpH component is the main contributor to pmf to drive ATP synthesis while a low ΔΨ b persists energizing the membrane. Our model predicts 11mV as the resting electric potential difference across the thylakoid membrane in dark. We suggest that the model presented in this work can be integrated as a module into a more comprehensive model of oxygenic photosynthesis., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Both erbB3 and IGF-1 receptor (IGF-1R) have been shown to play an important role in trastuzumab resistance. However, it remains unclear whether erbB3- and IGF-1R-initiated signaling pathways possess distinct effects on the sensitivity of lapatinib, a dual tyrosine kinase inhibitor against both EGFR and erbB2, in trastuzumab-resistant breast cancer. Here, we show that the trastuzumab-resistant SKBR3-pool2 and BT474-HR20 breast cancer sublines, as compared the parental SKBR3 and BT474 cells, respectively, exhibit refractoriness to lapatinib. Knockdown of erbB3 inhibited Akt in SKBR3-pool2 and BT474-HR20 cells, significantly increased lapatinib efficacy, and dramatically re-sensitized the cells to lapatinib-induced apoptosis. In contrast, specific knockdown of IGF-1R did not alter the cells' responsiveness to lapatinib. While the levels of phosphorylated Src (P-Src) were reduced upon IGF-1R downregulation, the P-Akt levels remained unchanged. Furthermore, a specific inhibitor of Akt, but not Src, significantly enhanced lapatinib-mediated anti-proliferative/anti-survival effects on SKBR3-pool2 and BT474-HR20 cells. These data indicate that erbB3 signaling is critical for both trastuzumab and lapatinib resistances mainly through the PI-3K/Akt pathway, whereas IGF-1R-initiated Src activation results in trastuzumab resistance without affecting lapatinib sensitivity. Our findings may facilitate the development of precision therapeutic regimens for erbB2-positive breast cancer patients who become resistant to erbB2-targeted therapy.

The kinase deficient erbB3 receptor frequently co-expresses and interacts with erbB2 in human breast cancer to activate the oncogenic signaling pathways, and thus promote breast cancer cell survival/proliferation. In the current study, we discovered that the expression of endogenous mouse erbB3 was increased in the mammary tumors-derived from wild type (wt) rat erbB2/neu-transgenic mice, and the co-expression of erbB2 and erbB3 significantly promoted mammary tumor proliferation in vivo. Co-immunoprecipitation assays detected a heterodimeric complex consisting of the transgene encoded protein rat erbB2 and the endogenous mouse erbB3 in the mammary tumors. Specific knockdown of mouse erbB3 dramatically inhibited proliferation of the mammary tumor cell lines-derived from the transgenic mice. Elevated expression of erbB3 protein, but not mRNA, was abserved in human breast cancer cells upon ectopic expression of erbB2. Additional studies revealed that overexpression of erbB2 downregulated three erbB3-targeting miRNAs, miR-125a, miR-125b, and miR-205, whereas the erbB2 kinase inhibitor (lapatinib) significantly enhanced expression of the three miRNAs in breast cancer cells, suggesting that erbB2 might regulate erbB3 expression through a miRNA-dependent mechanism. Furthermore, an anti-erbB3 monoclonal IgG1 antibody (Ab) in combination with Herceptin mainly inactivated Akt and significantly inhibited proliferation of erbB2-overexpressing breast cancer cells. Collectively, our data indicate that increased expression of erbB3 plays a pivotal role in activating downstream PI-3K/Akt pathway and promoting erbB2-driven mammary/breast tumorigenesis. Simultaneous targeting of erbB2 and erbB3 with two IgG1 Abs may be an effective strategy to treat breast cancer patients whose tumors overexpress both erbB2 and erbB3.

Survivin, the smallest member of IAP (inhibitor of apoptosis) family, is a dual functional protein acting as a critical apoptosis inhibitor and key cell cycle regulator. Survivin is usually expressed in embryonic tissues during development and undetectable in most terminally differentiated tissues. Numerous studies demonstrate that survivin is selectively upregulated in almost all types of human malignancies and its overexpression positively correlates with poor prognosis, tumor recurrence, and therapeutic resistance. This differential expression of survivin in tumors and normal tissues draws a great interest to develop survivin-targeted therapy for cancer treatment. Nonetheless, the molecular mechanisms controlling survivin expression in malignant tumor cells have not been fully understood. While aberrant activation of receptor tyrosine kinases (RTKs) and the downstream signaling, such as PI-3K/Akt, MEK/MAPK, mTOR, and STAT pathways, have frequently been shown to upregulate survivin, recent data suggest that a class of noncoding RNAs, microRNAs (miRNAs) also play an important role in survivin dysregulation in human cancers. Here, we focus on survivin expression-regulated by specific miRNAs binding to the 3'-UTR of survivin mRNA, and summarize the latest advances on survivin-targeted therapy in clinical trials and the therapeutic potential of survivin-targeting miRNAs in cancer.

Objective: To investigate the molecular epidemiological characteristics and antibiotic resistance profiles of Vibrio cholerae O139 in Shandong province., Methods: A total of 13 strains of V. cholerae O139 (9 clinical strains and 4 environmental strains) isolated from cholera epidemics in Shandong province since 1997 were recovered and confirmed with serum agglutination and biochemical reaction. Pulsed-field gel electrophoresis (PFGE) was carried out for molecular subtyping. Virulence genes and drug resistance related genes were detected by PCR. Antibiotic susceptibility tests were performed using micro-broth dilution method., Results: Thirteen strains of V. cholerae O139 were differentiated into seven pulsetypes. One clinical strain and two environmental strains isolated from Jining in 2013 were clustered into the pulsetype namely KZGN11O139. CN0077, and an identical PFGE pattern of KZGN11O139. CN0002 was found among three clinical strains from Jinan in 2005, Jining in 2005 and Heze in 2009. Other pulsotypes were unique in China and found only in Shandong province. Because of deletion of ctxAB and tcpI, the PFGE patterns of two strains isolated from Yantai in 2000 and 2004 were different from other 11 strains which harbored ctxAB, tcpA, tcpI, rtxA, hlyA and toxR. All strains contained one or more drug resistance related genes such as intI 1, intI 4 and sxt, and were resistant to two kinds of antibiotics at least. Among the 12 kinds of antibiotics, the resistant ratioes to kamamycin, trimethoprim-sulfamethoxazole, ampicillin and gentamicin were 11/13, 9/13, 7/13 and 7/13, respectively., Conclusion: Molecular subtyping indicates possible epidemiological links among V.cholerae O139 in Shandong province, and almost all strains were toxigenic and drug resistant.